N-heterocyclic carbene-catalyzed δ-Carbon LUMO activation of unsaturated aldehydes

Article abstract of DOI:10.1021/jacs.5b02219

An N-heterocyclic carbene (NHC) catalyzed domino reaction triggered by a δ-LUMO activation of α,β-γ,δ-diunsaturated enal has been developed for the formal [4 + 2] construction of multisubstituted arenes and 3-ylidenephthalide. These two products, formed i

Full text of DOI:10.1021/jacs.5b02219

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Communication
N-Heterocyclic Carbene-Catalyzed #-Carbon
LUMO Activation of Unsaturated Aldehydes
Tingshun Zhu, Chengli Mou, Bao-Sheng Li, Marie Smetankova, Bao-An Song, and Yonggui Robin Chi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b02219 • Publication Date (Web): 24 Apr 2015
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NꢀHeterocyclic CarbeneꢀCatalyzed δꢀCarbon LUMO Activation
of Unsaturated Aldehydes
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Tingshun Zhu1,2, Chengli Mou1,2, Baosheng Li2, Marie Smetankova2, BaoꢀAn Song1*, Yonggui Robin
Chi 1,2*
1Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agꢀ
ricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China.2 Nanyang
Technological University, Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences,
Singapore 637371, Singapore.
Supporting Information Placeholder
selectivity issue between the βꢀ and δꢀcarbons is addressed by
introducing a substituent to block the reactivity of the βꢀcarbon
(Scheme1)
ABSTRACT:An Nꢀheterocyclic carbene (NHC) catalyzed domꢀ
ino reaction triggered by aδꢀLUMO activation of α,βꢀγ,δꢀ
diunsaturatedenal has been developed for theformal [4+2] conꢀ
struction of multiꢀsubstitutedarenesand3ꢀylidenephthalide. These
two products, formed in a highly chemoꢀ and regioꢀselective
manner, were obtained via different catalytic pathways due to a
simple change of the substrate. The activation of the remoteδꢀ
carbon of unsaturated aldehydes expands the synthetic potentials
of NHC organocatalysis.
Figure 1. NHC Catalyzed δꢀCarbon Activation
Nꢀheterocyclic carbene (NHC) organocatalysts enable unique
reaction modes which allow for the development of highly selecꢀ
tive and effective reactions.1 To date, the carbonyl,2α,3β,4 and γꢀ
carbons5 of (unsaturated) aldehydes and esters have been successꢀ
fully activated by NHC catalysts for a diverse set of reactions
(Figure 1).For example, addition of NHC catalyst to α,βꢀ
unsaturated ester6 or aldehyde7 under oxidative conditions affords
an α,βꢀunsaturated azolium ester intermediate that can undergo
formal 1,4ꢀaddition reactions. The three carbons (carbonyl, α, and
βꢀcarbons) of the α,βꢀunsaturated aldehydes/esters can participate
in the formation of new molecules. In principle, the synthetic
potential of NHCꢀcatalyzed reactions of aldehydes can be signifiꢀ
cantly expanded by introducing additional conjugated C=C bonds
to the aldehydes. However, in enals conjugated with an additional
C=C bond (e.g., α,βꢀγ,δꢀdiunsaturated aldehydes), the activation
of the δꢀcarbon to participate in new bond formation is challengꢀ
ing and remains undeveloped under NHC catalysis.8 Typically, the
βꢀcarbon (or carbonyl carbon) is more reactive, and the δꢀcarbon
remains untouched in NHCꢀcatalyzed reactions, as reported by
Glorius,4f Ma,7d and in our previous work.6c In addition, when
nucleophiles such as enols and enamides were used to react with
unsaturated azolium ester intermediates, 1,2ꢀaddition of the enol
(oxygen) or enamide (nitrogen) to the azolium ester carbonyl
carbon could occur. This 1,2ꢀaddition followed by [3,3]ꢀ
rearrangement, as proposed by Bode,7bꢀc would favor reaction on
the βꢀcarbon.
A postulated reaction pathway is illustrated in Scheme 1. Key
catalytic steps include oxidative7a conversion of unsaturated aldeꢀ
hyde to unsaturated acyl azolium intermediate I; 1,6ꢀaddition of
1,3ꢀdiketone substrate 2 (through its enol isomer) to I, followed
by aldol reaction and intramolecular βꢀlactone formation leading
to bicyclic adduct IV, with the regeneration of NHC catalyst.
Decarboxylation followed by spontaneous oxidative aromatization
finally affords the multiꢀsubstituted benzene product 3. When R is
a reactive aryl ester unit (Scheme 1, path b), intramolecular transꢀ
esterification forms 5ꢀmember lactone (II’ to VI). Isomerization
(VI to VII)9 followed by aldol reaction then produces VIII, which
undergoes further transformations to eventually form the 3ꢀ
ylidenephthalide product 4 via a process similar to the conversion
of III to 3. Notably, the synthesis of multiꢀsubstituted arenes typiꢀ
cally starts with a preꢀexisting benzene unit and the introduction
of substituents requires long steps with rather tedious functional
group manipulations. We previously reported an NHCꢀcatalyzed
formal [3+3] reaction for the synthesis of substituted benꢀ
zenes.5d,10 Our present reaction, built upon a newly developed δꢀ
carbon activation and formal [4+2] reaction, provides a highly
effective and scalable approach in constructing the benzene unit
and preparing multiꢀsubstituted arenes by using readily available
substrates. The direct construction of benzene should find unique
applications, for example, as recently demonstrated in Li’s elegant
synthesis11 of natural products daphniphyllum, rubriflordilactone
and xiamycin via a 6πꢀelectrocyclization/aromatization strategy.
Here we report the first NHCꢀcatalyzed activation of the δꢀ
carbon of α,βꢀγ,δꢀdiunsaturated aldehydes (Figure 1). The chemoꢀ
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Scheme 1. δꢀActivation and Selective Reactions: Proposed Pathway
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of 3a in 81% yield (entry 6). Although the combination of THF
and Cs2CO3 was optimal, other common organic solvents (such as
toluene, CH2Cl2, EtOAc, CH3CN and DMF) and organꢀ
ic/inorganic bases (such as DBU, Et3N, K2CO3, KOtBu) could
also be used (see Supporting Information, SI). It is also worth
noting that in all cases, no formal 1,4ꢀaddition (reaction of the
unsaturated aldehyde βꢀcarbon) byproducts were observed. The
main side reaction was oxidation of the aldehyde to carboxylic
acid followed by an intramolecular Michael reaction forming a
lactone byproduct in trace amounts (See SI).16 Decreased amount
of oxidant led to lower conversion of 1a (See SI) and intermediate
V was not observed, suggesting that the oxidative aromatization
(V to 3, Scheme 1) was a facile step that was likely faster than
oxidation of the Breslow intermediate converting aldehyde to acyl
azolium (1 to I, Scheme 1).
TABLE 1. Condition Optimizationa
entry
NHC preꢀcatalyst (mol%)
yieldb (%)
0
trace
trace
52%
82%
81%
1
2
3
no NHC
A (30)
B (30)
C (30)
D (30)
D (10)
With acceptable conditions in hand, the scope of the reaction
was evaluated (Chart 1). 1,3ꢀDiketone 2a was selected as a model
substrate to study the generality of the enal substrates. The R subꢀ
stituent at the δꢀcarbon of the aldehydes could be various alkyl
alcohol ester units (3aꢀd), various aryl substituents with different
electronic properties (3eꢀi),17 or a CN group (3j). The substituent
at the aldehyde βꢀcarbon (R’) could be different (hetero)aryl units
with various substituents or various substitution patterns (3kꢀt).
Placing a tertꢀbutyl substituent on the aldehyde βꢀcarbon was also
tolerated (3uꢀv). Replacing the βꢀphenyl unit of 1a with a proton,
Cl or Br led to no formation of the benzene products: in these
cases, the βꢀcarbon formal 1,4ꢀaddition adducts (6ꢀmembered
lactones) were obtained.7d Putting a methyl unit on the enal βꢀ
carbon led to complicated mixtures, with only trace amounts of
the desired benzene product formed. The scope of the 1,3ꢀ
dicarbonyl substrates was also examined by using 1a as a model
aldehyde. βꢀKetoesters with various ester groups (3wꢀy) worked
well. The methyl unit (R1) of the ketone substrate could be reꢀ
placed with other alkyl or aryl units (3a1ꢀb1). When unsymmetꢀ
ricdiketones were used, the reaction was highly regioꢀselective
and only one isomer was obtained (products 3d1ꢀf1). The stericalꢀ
ly less bulky ketone moiety preferentially participated in the aldol
reaction step (II to III, Scheme 1) of the catalytic reaction.
4
5
6c
aReaction conditions:1a (0.1 mmol), 2a (0.1 mmol) in the
presence of NHC precatalyst (0.03 mmol), oxidant 5 (0.2 mmol)
b
c
and Cs2CO3 (0.03 mmol) in THF at rt. isolated yield. with 10
mol% Cs2CO3.
The unsaturated aldehyde substrate (1a) was readily prepared
in multiꢀgram scale via a 2ꢀstep wellꢀdeveloped protocol in over
80% overall yields12(see SI). As a technical note, it’s not necesꢀ
sary to separate the E/Z isomers of 1a, as both isomers participate
in our catalytic reactions to give the same product with essentially
the same yields. With aldehyde 1a and 1,3ꢀdiketone 2a as the
model substrates, and quinone 5 pioneered by Studer13 as an oxiꢀ
dant, we first found that in the absence of NHC catalyst, the proꢀ
posed product 3a was not formed (Table 1, entry 1). Use of triaꢀ
zolium NHC preꢀcatalysts A13and B14 led to trace amounts of 3a
(entries 2ꢀ3). We then found that by replacing the Nꢀphenyl group
of preꢀcatalyst B with an Nꢀmesityl substituent (catalyst C)15, 3a
could be formed in 52% yield (entry 4). The reaction could be
further improved by using imidazolium NHC preꢀcatalyst D4aꢀb
(entry 5). At last we found that the use of 10 mol% of D and
10mol% of Cs2CO3 base was sufficient to promote the formation
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benzene core is unprecedented. Here we found that by using enal
1b bearing a phenol ester unit as the substrate (e.g., Chart 2), the
catalytic reaction under otherwise identical conditions afforded
the 3ꢀylidenephthalide product 4. Similar with the substrate scope
in benzene formation, the substituent at the aldehyde βꢀcarbon (R’)
could be aryl units with different electronic properties (4aꢀd), and
the methyl unit (R1) of the ketone substrate could be replaced with
other alkyl or aryl units (4eꢀg).
CHART1. Substrate Scopea
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SCHEME2. Regioꢀselective reactions and access to both
regioꢀisomers with unsymmetrical 1,3ꢀdiketone substrate
Mechanistically, the 3ꢀylidenephthalide product (4) was
formed through an alternative pathway (Scheme 1; from II’ to 4):
when an enal with R = CO2Ar was used, the 5ꢀmembered ring
lactone moiety was formed (II’ to VI) before the aldol reaction
(VI to VII to VIII) occurred. This mechanistic proposal was supꢀ
ported by the observed regioꢀselectivities (e.g., comparing 4f with
3d1). Specifically, in the formation of 4f, the aldol reaction ocꢀ
curred on the more sterically bulky ketone moiety while in the
formation of benzene product 3d1, the aldol reaction took place
on the less bulky ketone moiety. Such regioꢀselectivity (e.g., in
the formation of 3ꢀylidenephthalide) could also be applied to preꢀ
pare the other regioꢀisomers of the multiꢀsubstituted arenes that
were not directly accessible in the catalytic reaction. For example,
opening of the lactone ring of 4f afforded the other regioꢀisomer
of 3g1 (3h1, Scheme 2).
a Reaction conditions as in Table 1, entry 6. Yields are isolatꢀ
ed yields.
CHART2. Synthesis of 3ꢀylidenephthalidea
SCHEME3. Synthetic applicability.
a
Reaction conditions as in Table 1, entry 6. Yields are isolated
yields.
Lastly, we showed that the substituted benzene adduct 3a
could be readily transferred to other functional molecules. The
multisubstituted benzene adduct 3a could be transformed to inꢀ
daneꢀ1,3ꢀdione21 6, phthalazine22 7, isochromanone23 8, and isoꢀ
coumarin24 9 via straightforward processes, as shown in Scheme 3.
In summary, we have developed an NHC organocatalytic
strategy for the δꢀLUMO activation of enals. Our method employs
readily available starting materials and provides rapid access to
multiꢀsubstituted arenes via a [4+2] process to construct a benzene
Encouraged by the success of the [4+2] construction of multiꢀ
substituted benzenes, we next moved on to other arenes.3ꢀ
ylidenephthalides became one class of our target molecules beꢀ
cause these moieties are widely present in many bioactive comꢀ
pounds.18 The synthesis of these molecules mainly relied on the
formation of lactone ring via intramolecular cyclization of benzoꢀ
ic acid (bearing preꢀinstalled functional groups) with alkyne,19
ketone,20 or by CO insertion.18bTo the best of our knowledge, the
synthesis of 3ꢀylidenephthalide through the construction of a new
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(5) For selected examples of γꢀcarbon activation via NHC catalysis, see:
framework. A simple change of the substrate leads to alternative
catalytic pathways that allow for different products to be obtained
in a highly regioꢀselective manner. Our activation of the remote δꢀ
carbon of unsaturated aldehydes expands the synthetic potentials
of NHC organocatalysis. It is expected that previously unattainaꢀ
ble reactions involving the δꢀcarbon and likely multiple carbons
of unsaturated aldehydes will become feasible with our approach.
(a) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc.2012, 134, 8810−8813.
(b) Chen, X.; Yang, S.; Song, B.ꢀA.; Chi, Y. R. Angew. Chem.Int.Ed.2013,
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Bernardi, L.; LópezꢀCantarero, J.; Niess, B.; Jørgensen, K. A. J. Am.
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ASSOCIATED CONTENT
Supporting Information
Experimental details and NMR Spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Corresponding Author
robinchi@ntu.edu.sg;
songbaoan22@yahoo.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We acknowledge support from Singapore’s National Research
Foundation (NRF), Ministry of Education (MOE), Nanyang
Technological University (NTU); and China’s National Key Proꢀ
gram for Basic Research (No. 2010CB 126105), Thousand Talent
Plan, National Natural Science Foundation (No. 21132003; No.
21472028), Guizhou Province Returned Oversea Student Science
and Technology Activity Program, and Guizhou University.
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