Dehydrogenative β-Arylation of Saturated Aldehydes Using Transient Directing Groups

Article abstract of DOI:10.1021/acs.orglett.9b00695

An unprecedented cross-dehydrogenative-coupling (CDC) reaction of saturated aldehyde β-C-H with arenes to form cinnamaldehydes via the cleavages of four C-H bonds has been developed. The reaction possesses complete E-stereoselectivity for the C=C double bond. The protocol is featured by atom and step economy, mild reaction conditions, and convenient operation.

Full text of DOI:10.1021/acs.orglett.9b00695

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dehydrogenative β‑Arylation of Saturated Aldehydes Using
Transient Directing Groups
Xing-Long Zhang,§ Gao-Fei Pan,§ Xue-Qing Zhu, Rui-Li Guo, Ya-Ru Gao, and Yong-Qiang Wang*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, People’s Republic of China
S
* Supporting Information
ABSTRACT: An unprecedented cross-dehydrogenative-cou-
pling (CDC) reaction of saturated aldehyde β-C−H with
arenes to form cinnamaldehydes via the cleavages of four C−
H bonds has been developed. The reaction possesses complete
E-stereoselectivity for the CC double bond. The protocol is
featured by atom and step economy, mild reaction conditions, and convenient operation.
imple aldehydes, such as propionaldehyde, are very
important bulk chemical materials.1 Insofar as reactivity
Scheme 1. CDC Reaction of Propionaldehydes with Arenes
To Synthesize Cinnamaldehydes
S
is concerned, these aldehydes rely very heavily on their
carbonyl moieties (e.g., Grignard reactions, Wittig olefinations,
and Aldol condensation) or acidic α-hydrogens (e.g., α-CO
oxidations, alkylations, and halogenations).2 Although the
equal importance of β-position, the direct β-C−H functional-
ization of the saturated aldehydes remains difficult, because of
the inertness of the β-C−H bonds.3 One potential solution
would be a metal-catalyzed redox cascade strategy,4 namely, a
metal-mediated oxidative α,β-desaturation, followed by the
functionalization on the β-position. However, such a trans-
formation is a challenge, because of the aldehyde’s
susceptibility toward oxidation under oxidative conditions,5
and undesired metal insertion into an acyl C−H bond.6
Cross-dehydrogenative-coupling (CDC) reactions, which
combine two C−H bonds to form new C−C bonds, represent
one of the most ideal synthetic procedures, because it avoids
the requirement of prefunctionalized starting materials (i.e.,
organohalides and/or organometallic species) to make
synthetic schemes shorter and more efficient, as well as
lower cost and less waste.7 β-Arylation of propionaldehydes is a
very appealing transformation, because of the broad
application of β-arylated products, particularly cinnamalde-
hydes,8 which are used as flavoring in ice cream and candy,9 as
safe, effective fungicides and insecticides,10 and as corrosion
inhibitors for steel and other ferrousalloys.11 Moreover,
cinnamaldehydes are versatile building blocks in organic
synthesis.12 However, to the best our knowledge, the CDC
reaction of saturated aldehyde β-C−H with arene has not been
reported to date. Apparently, the realization of such CDC
reactions to form cinnamaldehyde must cleave four inert C−H
bonds (Scheme 1); therefore, the method is very challenging.
To make the process possible, we thought that two aspects
should be implemented: (1) for the cleavage of four inert C−H
bonds in one step, a more efficient catalytic system should be
developed; and (2) to realize regioselective arylation of the β-
C−H bond of saturated aldehyde, a directing group should be
introduced. The directing group could facilitate the carbon−
metalation of β-C−H bond of aldehyde, thereby allowing
subsequent coupling readily, and simultaneously prevent
susceptible aldehyde groups from being oxidized. In the field
of the directing group, undoubtedly, the transient directing
group (TDG) is more attractive, because it can be easily
removed or detached after the reaction.13 Inspired by elegant
and pioneering works of Yu13a and Ge3f,13b et al. on TDG, we
started this research.
The study commenced with 2-methyl propionaldehyde (1a)
and anisol (2a) as model substrates. We initially chose
Pd(OAc)2 (10 mol %) as a catalyst, glycine (50 mol %) as a
transient directing group, and K2S2O8 (2.0 equiv) as an
oxidant, and the reaction was performed in CH3CN at 60 °C
for 24 h. Nevertheless, the reaction did not afford any desired
product but propionaldehyde drained gradually (Table 1, entry
1). The experiment not only indicated the difficulty of the
transformation, but also reminded us that susceptible aldehyde
groups were compatible with palladium-catalyzed oxidative
systems to an extent, which encouraged us to modify the
current palladium catalytic system. Considering that trifluoro-
acetic acid (TFA) and Pd(OAc)2 can facilitate the generation
of more active [Pd(II)O2CCF3]+ species in situ,14 the same
reaction was set up again just with TFA (2.0 equiv) introduced
in the reaction system. To our delight, the reaction gave the
desired product 3a in 10% yield (Table 1, entry 2). Despite a
low yield, the result verified the feasibility of our conception.
Encouraged by this result, the amount of TFA was
investigated, and the best result was gotten when 9.0 equiv
Received: February 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00695
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Letter
(10 mol %), amino acid A6 (50 mol %), TFA (9 equiv) at 60
°C.
Table 1. Optimization of Dehydrogenative Arylation of 2-
Methyl Propionaldehyde with Anisol
a
With the optimal reaction conditions in hand, the direct
oxidative dehydrogenative arylation was applied to various
arenes with 2-methyl propionaldehyde (1a) as the coupling
partner (Scheme 2). Benzenes substituted by monoalkoxyl
Scheme 2. Reactions of Various Arenes with 2-Methyl
a b
,
Propionaldehyde
b
amino
acid
temperature
TFA
(equiv)
yield
(%)
entry
Pd source
(°C)
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(dba)2
PdCl2
A1
A1
A1
A1
A1
A1
A1
A1
A2
A3
A4
A5
A6
A7
A8
A6
A6
A6
A6
A6
A6
A6
A6
A6
A6
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
rt
40
80
100
120
60
60
60
60
60
0
0
10
23
34
52
45
<5
<18
31
35
33
16
69
42
34
<5
17
19
0
2.0
5.0
7.0
9.0
15.0
30.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
9.0
c
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
0
35
34
37
23
<40
a
Reaction conditions: 1a (0.2 mmol), 2 (1.0 mmol), Pd(OAc)2 (10
mol %), A6 (50 mol %), K2S2O8 (0.4 mmol), TFA (1.8 mmol),
b
c
Pd(PPh3)4
Pd(OAc)2
CH3CN (1.0 mL) for 24 h. Isolated yield. Arene (1.0 mL), no
CH3CN.
d
25
a
Reaction conditions: 1a (0.2 mmol), 2a (1.0 mmol), [Pd] (10
mol %), amino acid (50 mol %), oxidant (0.4 mmol), for 24 h.
Isolated yield. Other solvent (1.0 mL): for DMSO, THF and DMA,
b
c
(e.g., MeO, EtO) only afforded para-substituted products in
good yields (3a, 3b), and no ortho- or meta-substituted
products observed, which could be attributed to steric and
electronic effects. Benzenes substituted by monoalkyl, except
toluene, also presented complete para-position selectivity (3c−
3i). Interestingly, fluorobenzene and chlorobenzene mainly
provided ortho-substituted products (3j, 3k), which were
possibly attributed to weak interactions of halogens (F, Cl)
with palladium, thereby the halogens somewhat acted as
directing groups in the reactions. Notably, simple benzene was
suitable for the reaction to give the desired product in
moderate yield (3l). For 1,2-, 1,3-, and 1,4-disubstituted
benzenes, the reactions proceeded smoothly affording the
corresponding products (3m−3s) in good yields. Note that all
reactions preferred to occur at electronic-rich and less-
hindered positions. Particularly noticeable is the performance
of 2,3-dihydrobenzofuran (2t) in the reaction. Based on the
literatures,15 2,3-dihydrobenzofuran can undergo the dehydro-
genation to produce benzofuran under oxidative dehydrogen-
ative conditions. Surprisingly, it only provided the cross-
dehydrogenative coupling product (3t) in good yield. The
structure of 3t was confirmed by single-crystal X-ray diffraction
(see the Supporting Information (SI)). This result indicated
that the current oxidative dehydrogenative reaction conditions
are mild. It is noteworthy that, in all cases, only E-isomers were
no product; MeOH, trace product; ClCH2CH2Cl, 17% yield.
d
(NH4)2S2O8 (35%), O2 (39%), Cu(OAc)2 (<5%), Cu2O (<5%),
PhI(OAc)2 (19%), Ag2CO3 (24%), AgOAc (26%).
of TFA was used (Table 1, entries 3−7). Then the effect of
solvent was investigated. Other solvents proved to be either
less effective or totally ineffective (Table 1, entry 8). Next
other possible TDG were tested. Substituted α-amino acids
A2−A5 gave inferior results (Table 1, entries 9−12).
Pleasingly, simple β-amino acid, β-alanine (A6 in Table 1)
provided a better result (Table 1, entry 13), while other
substituted β-amino acids did not show superior results (Table
1, entries 14 and 15). Temperature had a noticeable effect on
the reaction, and 60 °C was preferred (Table 1, entries 16−
20). By using other palladium sources (Table 1, entries 21−
24), oxidants (Table 1, entry 25), and amounts of K2S2O8, the
same reaction proceeded but less efficiently. A series of control
experiments were also conducted. The reaction did not
proceed in the absence of the Pd(OAc)2, A6 or TFA.
Significantly, instead of TFA, acetic acid, benzoic acid, and
pivalic acid did not give any product, respectively. Accordingly,
the reaction conditions were optimized as follows: Pd(OAc)2
B
DOI: 10.1021/acs.orglett.9b00695
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Letter
obtained, and no Z-isomers can be detected by analyzing the
reaction mixtures.
Next, the simplest propionaldehyde was tested. Gratifyingly,
propionaldehyde was a suitable substrate for this process, and
the reactivity of propionaldehyde was similar to 2-methyl
propionaldehyde (Scheme 3). Propionaldehyde reacted with
Scheme 3. Reactions of Various Arenes with Other
a b
,
Propionaldehydes
two reactions provided corresponding cinnamaldehydes in
75% and 64% yields, respectively (eqs 3 and 4). Notably, in the
absence of A6, the coupling reactions were somewhat slowed,
but the yields were similar if more time was permitted. These
outcomes suggest that dehydrogenation followed by the Heck
reaction is also possible.
To further understand the reaction, a mechanistic analysis of
the dehydrogenative arylation was performed by monitoring
the conversion of 2-methyl propionaldehyde 1a into
cinnamaldehyde 3q under standard reaction conditions
(Figure 1). Within 3 h, the 2-methyl propenal 5a was formed
a
Reaction conditions: 1b (0.2 mmol), 2 (1.0 mmol), Pd(OAc)2 (10
mol %), A6 (50 mol %), K2S2O8 (0.4 mmol), TFA (1.8 mmol),
b
c
CH3CN (1.0 mL) for 24 h. Isolated yield. Arene (1.0 mL), no
CH3CN. Pd(TFA)2 (10 mol %) as catalyst.
d
1,2-, 1,3-, or 1,4-disubstituted benzenes to generate the
corresponding cinnamaldehydes in good yields (4a−4c), and
the reaction also occurred selectively at electronic-rich and
less-hindered sites. Simple benzene coupled with propionalde-
hyde to produce common cinnamaldehyde in moderate yield
(4d). Monosubstituted benzenes underwent the reaction to
mainly give para-substituted products (4e−4g). 2,3-Dihydro-
benzofuran also reacted with propionaldehyde successfully,
providing the desired product in a good yield (4h). Then, α-
aryl propionaldehydes were checked. The substrates possessing
either an electron-withdrawing group or an electron-donating
group on benzene rings all reacted successfully to afford the
desired products in moderate yields (4i−4k). Again, all
reactions show complete E-stereoselectivity for the CC
double bond. Note that 2-methyl butanal only gave
dehydrogenative 2-methyl crotonaldehyde, and no coupling
product with benzene was detected.
Figure 1. Reaction profile of the palladium(II)-catalyzed dehydrogen-
ation/arylation of 2-methyl propionaldehyde with m-xylene.
(∼65%), and the cinnamaldehyde 3q was subsequently
produced with concomitant disappearance of 5a, thus
indicating the intermediacy of 5a in the course of the arylation.
On the basis of these results and the related literatures,16
two tentative mechanisms for the dehydrogenative arylation of
propionaldehydes with arenes are proposed, as shown in
Scheme 4. First, 2-methyl propionaldehyde is condensed
reversibly with A6 to form imine intermediate I and its
enamine isomer II.3 Simultaneously, the active Pd(O2CCF3)+
is generated in situ by the treatment of Pd(OAc)2 with TFA.14
Enamine II then undergoes Saegusa oxidation,16a namely, α-
To test the practicality of the developed oxidative
dehydrogenative arylation, we conducted the reaction on 10
mmol of 2-methyl propionaldehyde to couple with m-xylene,
and 976 mg (61% yield) of product 3q was isolated (eq 1).
Scheme 4. Plausible Mechanism
In the reaction system, 2-propenals were always observed.
We reasoned that 2-propenals might be intermediates, and the
transformations probably commenced by the dehydrogenation
to generate 2-propenals, then underwent dehydrogenative
coupling with arenes to yield cinnamaldehydes. To verify the
speculation, we checked the behavior of 2-methyl propional-
dehyde in the absence of arene, and observed that 2-methyl
propionaldehyde indeed underwent dehydrogenation to
produce 2-methyl propenal in 82% yield after 6 h (eq 2).
We also performed the couplings of 2-methyl propenal and 2-
propenal with m-xylene under our standard conditions. The
C
DOI: 10.1021/acs.orglett.9b00695
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palladation of enamine, followed by β-H elimination to afford
intermediate IV that can be hydrated to propenal observed in a
reaction system. Next, there are two pathways: path a and path
b.
In path a, coordination of an α-imino acid moiety to a
palladium species generates palladium complex V. An intra-
molecular C−H palladation of intermediate V gives rise to the
five-membered ring intermediate VI, probably via a concerted
metalation−deprotonation (CMD) process.17 The oxidation of
intermediate VI by K2S2O8 gives Pd(IV) species VII,18 which
is arylated by arene to afford intermediate VIII, and then the
following reductive elimination resulted in product formation
and the catalysts (Pd and A6) regeneration.
In path b, Pd(II)-catalyzed nondirected C−H activation of
arene gives rise to aryl-Pd(II) species (II′), which can react
with propenal via the Heck reaction to give the final product
and Pd(0). K2S2O8 oxidizes Pd(0) under TFA to regenerate
Pd(II) species. Detailed studies on the mechanism are
underway.
In summary, we developed unprecedented CDC reactions of
simple saturated aldehydes β-C−H with arenes to synthesize
important cinnamaldehydes via the cleavages of four C−H
bonds. The reaction used very simple and common reagents as
the starting materials, and it showed complete E-stereo-
selectivity for the CC double bond. The reaction conditions
were mild and the operation was convenient. Detailed
mechanism and application studies are currently ongoing in
our laboratory.
Key Science and Technology Innovation Team of Shaanxi
Province (No. 2017KCT-37).
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00695.
Experimental procedures and spectral data (PDF)
Accession Codes
CCDC 1889340 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridgeCrystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
(12) Yoshioka, E.; Inoue, M.; Nagoshi, Y.; Kobayashi, A.;
Mizobuchi, R.; Kawashima, A.; Kohtani, S.; Miyabe, H. J. Org.
Chem. 2018, 83, 8962.
Corresponding Author
*E-mail: wangyq@nwu.edu.cn.
ORCID
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Yong-Qiang Wang: 0000-0002-2774-3248
Author Contributions
§These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We are grateful for financial support from National Natural
Science Foundation of China (Nos. NSFC-21572178 and
NSFC-21702162), Natural Science Basic Research Plan in
Shaanxi Province of China (Program No. 2017JM2006), the
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