Direct transformation of simple enals to 3,4-disubstituted benzaldehydes under mild reaction conditions via an organocatalytic regio- and chemoselective dimerization cascade

Article abstract of DOI:10.1002/chem.201201709

Straight to the point: An organocatalyzed, direct preparation of 3,4-disubstituted benzaldehydes from simple enals under mild conditions without the need for an additional oxidant has been developed. Notably, self-dimerization of an enal precursor and cro

Full text of DOI:10.1002/chem.201201709

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DOI: 10.1002/chem.201201709
Direct Transformation of Simple Enals to 3,4-Disubstituted Benzaldehydes
under Mild Reaction Conditions via an Organocatalytic Regio- and
Chemoselective Dimerization Cascade
Xixi Song,[a] Xinshuai Zhang,[a] Shilei Zhang,[a] Hao Li,*[b] and Wei Wang*[a, b]
The privileged status of functionalized benzaldehydes is
underscored by their broad applications in organic synthesis.
They serve as key constituents of pharmaceuticals, perfumes,
cosmetics, agrochemicals, and materials.[1,2] The utility of the
specific molecular architecture is directly reflected in the
substituents on the aromatic ring. However, the introduction
of functionalities with specific patterns on the aromatic ring
presents a significant challenge in their preparation. Classic
synthetic methods include electrophilic aromatic substitu-
tion, such as the Friedel–Crafts reaction, and directed ortho
metalation in the construction of substituted arenes.[3,4]
Since they introduce specific substituents to pre-existed
arenes, the scope of these reactions is restricted by the elec-
tronic characteristics of the substrates. This is particularly
problematic for arenes containing an electron-withdrawing
and highly sensitive aldehyde group. Recently, transition-
partners can participate in the cascade to afford, chemose-
lectively, structurally diverse benzaldehyde products.
Recently, we developed an organocatalytic stereoselective
cross-coupling-like a-arylation reaction of aromatic a,b-un-
saturated aldehydes with 4-bromophenols and 3-bromoin-
doles (Scheme 1a).[7] However, when an aliphatic crotonal-
dehyde was subjected to the reaction conditions, an unex-
pected 4-methyl benzaldehyde was obtained (Scheme 1b).
This serendipitous discovery prompted us to investigate this
interesting “side reaction”.
À
metal catalyzed direct C H functionalization of arenes has
open new doors for the synthesis of functionalized arenes.[5]
Nonetheless, directing groups and relatively harsh reaction
conditions are typically needed to achieve regioselectivity
and reactivity, respectively.[6]
Herein, we disclose a new organocatalytic “one-pot” ap-
proach to the synthesis of 3,4-disubstituted benzaldehydes
from simple enals through dimerization under very mild
conditions. Notably, an unprecedented organocatalytic Mi-
chael–aldol aromatization cascade involving a dienamine–
iminium has been successfully implemented for the “one-
pot” assembly of polysubstituted aromatic aldehydes. The
process proceeds in a highly regioselective manner at room
temperature in aerobic environment, without requiring an
additional oxidant, to give 3,4-disubstituted benzaldehydes
in high yields. Furthermore, both homo- and hetero-coupling
Scheme 1. The unexpected formation of 4-methylbenzaldehyde from the
study of cross-coupling-like a-arylation process. a) Previously reported
work on the organocatalytic a-arylation of enals.[7] b) This work, where 4-
methylbenzaldehyde is unexpectedly formed.
Initial studies were carried out by examining a simple
self-dimerization (homo-coupling) of hexenal as the sole re-
actant at room temperature in chloroform in the presence of
a secondary amine (Table 1). Hexenal was chosen as the
model starting material since it allows the determination of
the product(s) formed in terms of regioselectivity. Moreover,
instead of p-bromophenol, unsubstituted phenol was used as
a mediator to investigate the influence of the electronic
effect. Reaction in the presence of McMillanꢀs catalysts I
and II[8] did not generate any product, and the starting mate-
rials were left intact (entries 1 and 2, Table 1). With l-pro-
line (III), the starting material was completely consumed
after three days, but desired aromatic product 3a was ob-
tained in only 6% yield, and several byproducts were ob-
served (entry 3, Table 1). Diphenyl prolinol (IV)[9] also dis-
played low catalytic activity. Only starting material was re-
[a] Dr. X. Song, Dr. X. Zhang, Dr. S. Zhang, Prof. Dr. W. Wang
Department of Chemistry and Chemical Biology
University of New Mexico
MSC03 2060, Albuquerque, NM 87131-0001 (USA)
Fax : (+1)505-277-2609
E-mail: wwang@unm.edu
[b] Prof. Dr. H. Li, Prof. Dr. W. Wang
Shanghai Key Laboratory of New Drug Design
School of Pharmacy, East University of Science and Technology
130 Meilong Road, Shanghai 200237 (P. R. China)
E-mail: hli77@ecust.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201709.
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Table 1. Optimization of reaction conditions.[a]
form was identified as the reaction medium of choice after
screening various solvents.
With the optimized reaction conditions in hand, we
turned our attention to the scope of the “one-pot” synthesis
of substituted benzaldehydes 2 using catalyst V. As shown in
Scheme 2, the self-dimerized homo-coupling processes with
Entry
Catalyst
Additive (equiv)
t [d]
Yield[b] [%]
1
2
3
4
5
6
7
8
I
II
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
PhOH
Et3N
PhCO2H
4-MeO-PhOH
4-Me-PhOH
4-Br-PhOH
4-NO2-PhOH
4-NO2-PhOH
N
5
5
3
5
3
3
5
3
5
3
3
2
2
2
0
0
6
III
IV
V
VI
VII
V
V
V
V
V
0
35
10
<5
0
11
54
56
70
99
47
9
Scheme 2. Substrate scope of self-dimerization using catalyst V under the
given reaction conditions, with reaction times (days) and isolated yields
(%) given in parentheses.
10
11
12
13
14
V
V
single aliphatic enals proceed efficiently and regioselectively
to give 3,4-substitued benzaldehydes 2 under mild reaction
conditions. The majority of products were obtained in
almost quantitative yields (2a and 2c–g). Notably, reaction
of a crotonaldehyde bearing a terminal benzyloxy function-
ality (compound 1 where R=OBn) provides 3-benzyloxy-
substituted product 2g in 92% yield.
[a] A solution of enal 1a (0.4 mmol) in CHCl3 (2.0 mL) was treated with
catalyst (0.02 mmol) and additive (0.5–1 equiv). The reaction mixture was
stirred at RT for 2–5 days in a loosely capped vial. [b] Isolated yields.
covered after leaving the reaction for five days (entry 4,
Table 1). An encouraging result came from reaction in the
presence of diphenyl prolinol trimethylsilyl (TMS) ether
(V),[10] where compound 2a was formed in 35% (entry 5,
Table 1). Notably, the reaction proceeded with high regiose-
lectivity, and only 3,4-disubstituted product 2a was obtained.
Furthermore, no additional oxidant was needed. Other
amines, such as pyrrolidine (VI) or piperidine (VII) could
also be used to drive the reaction to completion, but much
lower yields of the desired product were achieved due to
complex side reactions (entries 6 and 7, Table 1).
Accordingly, catalyst V was selected for further studies.
We first examined the effect of additives on the reaction. It
was found that acids are crucial for the process since a basic
additive, such as triethylamine, produced no transformation
(entry 8, Table 1). Interestingly, benzoic acid with stronger
acidity displayed relatively low efficiency (entry 9, Table 1).
A survey of substituted phenols revealed a correlation be-
tween the electronic property of substituents and the reac-
tion efficiency (i.e., product yield; entries 4 and 10–13,
Table 1). The electronic deficiency on the phenol ring was
proportional to the yield. Notably, the use of p-nitrophenol
as an additive gave an almost quantitative yield (entry 13,
Table 1). However, decreasing the amount of p-nitrophenol
used resulted in decreased yields (entry 14, Table 1). Chloro-
It has been demonstrated that single aliphatic enals can
efficiently participate in arene formation with high regiose-
lectivity. However, use of two different enals in the reaction
presents a significant challenge because, in addition to regio-
selectivity, chemoselectivity could be an issue and multiple
products could be formed. We envisioned that the use of an
aliphatic enal as a donor with an aromatic coupling partner
(acceptor) would minimize this problem. With this in mind,
we probed the reaction between less hindered crotonalde-
hyde (1, where R=H) and highly activated p-nitro cinna-
maldehyde (3 where Ar=p-NO2-Ph) under the same reac-
tion conditions used for homo-coupling (Scheme 3). To our
delight, the process proceeded smoothly and both chemo-
and regioselectively to give a single product, bis-aryl deriva-
tive 2h, in high yield (87%). Encouraged by this outcome,
we attempted to extend the reaction to more hindered ali-
phatic substrates with longer chains (1 where R=Me, Et,
nPr and nBu) to give substituted arenes 2i–k. The steric
effect appeared to be limited. Remarkably, even higher
yields of the desired products were achieved (93–99%). Fur-
thermore, the substrate scope extended to include aromatic
acceptors enals that are more sterically demanding (3l, 3q,
3s, and 3t) and less reactive (3n–s). In addition to aromatic
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Transformation of Enals to 3,4-Disubstituted Benzaldehydes
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nicely also. We were particularly pleased to find that fused
aromatic (3t), heteroaryl (3v) and ester (3u) enals are toler-
ated to give valuable substituent-diversified bis-arylalde-
hydes 2t–u.
The unprecedented direct transformation of enals to 3,4-
disubstituted benzaldehydes triggered us to explore the re-
action pathway. A survey of the literature revealed that
Hong and co-workers had reported interesting [3+3] and
[4+2] reactions of enals.[11] In their studies, a mixture of two
nonarene products resulting from competing [3+3] and
[4+2] cycloadditions is observed. Therefore, an additional
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or man-
ganese dioxide-mediated oxidation is required to obtain the
desired arenes. However, in our case, under aerobic condi-
tions, 3,4-disubstituted benzaldehydes are obtained exclu-
sively and in high yields. A possible reaction mechanism is
proposed in Scheme 4.
A dienamine species, derived from a corresponding enal
through catalyst V-promoted formation, serves as a Michael
donor for conjugate addition to an iminium ion derived
from an enal acceptor. Critically, the resulting Michael
adduct transforms into a new dienamine with assistance
from p-nitrophenoxide; meanwhile, the enamine is hydro-
lyzed to give an aldehyde and release of the catalyst
(step 3). However, our experimental results indicate that hy-
drolysis of the iminiun ion derived from the enal to form 12
through an intramolecular aldol reaction, ultimately leading
to 3,4-disubstituted benzaldehydes 2, does occur. The possi-
ble reason is that for the aldol reaction to occur, trans-imini-
um ion 6 has to be transformed into more sterically hin-
dered cis-11. In the presence of p-nitrophenol as an activa-
tor, an intramolecular aldol reaction takes place (step 4).[12]
Aldol adduct 8 is then converted to enamine 9 (step 5).
Transformation of dienamine 9 to diene iminium ion 10
leads to electorn-rich trienamine 11, which can be oxidized
to arene 12. Finally, release of the catalyst furnishes target
compound 2.
In order to verify the proposed reaction mechanism, we
conducted a preliminary mechanistic investigation. In the
proposed reaction pathway, two key intermediates 6 and 8
are involved (Scheme 4). Therefore compounds 16 and 17,
derived from
6 and 8, respectively, were synthesized
(Scheme 5). When compound 16 was submitted to the same
reaction conditions in the presence of catalyst V and p-nitro-
phenol, the expected benzaldehyde was obtained in quanti-
tative yield (Scheme 5a). However, in the absence of p-ni-
trophenol, no aromatic product was formed, and reactant 16
was recovered (Scheme 5b). We concluded that p-nitrophe-
nol plays an important role in the intramolecular aldol pro-
cess. Reaction of compound 17 in the presence of catalyst V
with or without p-nitrophenol gave the anticipated product
with full conversion (Scheme 5c). Moreover, in the absence
of catalyst V, no reaction occurred. These studies imply that
catalyst V is essential for aromatization through iminium
ion and enamine transformations, while p-nitrophenol is not.
When the transformation was carried out in an argon atmos-
phere instead of in air, less than 15% conversion was ob-
Scheme 3. Substrate scope of cross-dimerization using catalyst V under
the given reaction conditions, with reaction times (days) and isolated
yields (%) given in parentheses.
enals carrying electron-withdrawing substitutes (3n–q),
those carrying electron-donating groups (3r–s) worked
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H. Li, W. Wang et al.
Scheme 5. Transformation of two key intermediates 16 and 17 to benzal-
dehydes. In the proposed reaction mechanism, this involves Michael–
aldol aromatization (see Scheme 4).
efficient, organocatalyzed Michael–aldol aromatization pro-
cess was proposed and verified by preliminary mechanistic
studies. The further exploration of interesting chemistry to
identify new organic transformations and understanding of
the reaction mechanism are currently being pursued in our
laboratory.
Experimental Section
Scheme 4. A proposed reaction mechanism for the formation of benzal-
dehydes 2.
General procedure: A solution of enal donor (0.2 mmol) and enal accept-
or (0.2 mmol) in CHCl3 (2.0 mL) was treated with p-nitrophenol
(0.2 mmol) and catalyst V (0.08 mmol, 40% mol relative to enal donor/
acceptor). When donor and acceptor enals were the same, 0.4 mmol of
enal was used, and the amount of catalyst V used was 20% mol relative
to the enal. The reaction mixture was stirred in a loosely capped vial at
RT for a given length of time. After all enal starting material was con-
sumed (determined by TLC analysis), the solvent was evaporated in
vacuo, and the crude residue was purified by column chromatography
(EtOAc/hexane). For full experimental details and product characteriza-
tion, see the Supporting Information.
served (Scheme 5d). Consequently, oxygen (air) is believed
to be acting as the oxidant in the aromatization process.
In conclusion, we have successfully transformed a “side
reaction” discovered in our earlier studies on a cross-cou-
pling-like a-arylation process into a new valuable method
for the direct construction of 3,4-disubstituted benzalde-
hydes from easily accessible enals. Notably, the cascade pro-
cess can proceed via two different routes: self-dimerization
of two equivalents of the same aliphatic enals and hetero-di-
merization of two distinct enals in a regio- and chemoselec-
tive manner. Polysubstituted arenes bearing a broad spec-
trum of functionalities including biologically and synthetical-
ly valuable bis-arylaldehydes have been generated in
a “one-pot” process in high yields under mild aerobic reac-
tion conditions.[13] Furthermore, an unprecedented, highly
Acknowledgements
Financial support from the Chinese National Science Foundation (CHE-
1057569 to W.W.), the Chinese Ministry of Education through the “Pro-
gram of Introducing Talents of Discipline to Universities” (111 Project)
(grant no. B07023), the East China University of Science and Technology
through the Shanghai Pujiang Program (11 J1411900 to H.L.), and the
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Shanghai Committee of Science and Technology (grant no.
11DZ2260600) is gratefully acknowledged.
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Keywords: arenes · aromatization · cascade reactions ·
dimerization · organocatalysis
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Received: May 15, 2012
Published online: && &&, 0000
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H. Li, W. Wang et al.
Arene Synthesis
X. Song, X. Zhang, S. Zhang, H. Li,*
W. Wang* ...................... &&&& — &&&&
Direct Transformation of Simple Enals
to 3,4-Disubstituted Benzaldehydes
under Mild Reaction Conditions via an
Organocatalytic Regio- and Chemose-
lective Dimerization Cascade
Straight to the point: An organocata-
lyzed, direct preparation of 3,4-disub-
stituted benzaldehydes from simple
enals under mild conditions without
the need for an additional oxidant has
been developed. Notably, self-dimeri-
zation of an enal precursor and cross-
dimerization of two distinct enals have
been realized with high regio- and che-
moselectivity to give structurally
diverse 3,4-substituted benzaldehydes
in good yields (76–99%).
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!