Carbene-Catalyzed Enantioselective Aromatic N-Nucleophilic Addition of Heteroarenes to Ketones

Article abstract of DOI:10.1002/anie.201912160

The aromatic nitrogen atoms of heteroarylaldehydes are activated by carbene catalysts to react with ketone electrophiles. Multi-functionalized cyclic N,O-acetal products are afforded in good to excellent yields and optical purities. Our reaction involves the formation of an unprecedented aza-fulvene-type acylazolium intermediate. A broad range of N-heteroaromatic aldehydes and electron-deficient ketone substrates works effectively in this transformation. Several of the chiral N,O-acetal products afforded through this protocol exhibit excellent antibacterial activities against Ralstonia solanacearum (Rs) and are valuable in the development of novel agrichemicals for plant protection.

Full text of DOI:10.1002/anie.201912160

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Accepted Article
Title: Carbene-Catalyzed Enantioselective Aromatic N-Nucleophilic
Addition of Heteroarenes to Ketones
Authors: Yonggui Liu, Guoyong Luo, Xing Yang, Shichun Jiang, Wei
Xue, Yonggui Robin Chi, and ZHICHAO JIN
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10.1002/anie.201912160
Angewandte Chemie International Edition
RESEARCH ARTICLE
Carbene-Catalyzed Enantioselective Aromatic N-Nucleophilic
Addition of Heteroarenes to Ketones
Yonggui Liu,[a]† Guoyong Luo,[b]† Xing Yang,[c]† Shichun Jiang,[a] Wei Xue,[a] Yonggui Robin Chi,[a,c] and
Zhichao Jin*[a]
Dedication ((optional))
Abstract: The aromatic nitrogen atoms of heteroarylaldehydes are
activated by carbene catalysts to react with ketone electrophiles.
Multi-functionalized cyclic N,O-acetal products are afforded in
generally good to excellent yields and optical purities. Our reaction
involves the formation of an unprecedented aza-fulvene typed
reactive carbons (Scheme 1a).[14-26] In 2017, Chi and co-workers
found that through the addition of carbene to the aldehyde
moiety of
a 2-hydroxyl benzaldehyde under an oxidative
condition, the phenol oxygen atom could be activated for
enantioselective reactions.[27] This activation converted the
acylazolium to an o-QMs intermediate with the oxygen as the
reactive center (Scheme 1b, left part). Very recently, Scheidt
and co-workers disclosed that N-methylisatoic anhydrides could
serve as N-centered nucleophile precursors under the catalysis
of NHCs and gave the aza-o-QMs intermediates to react with
electrophilic ketone substrates (Scheme 1b, right part).[28]
acylazolium intermediate.
A broad range of N-heteroaromatic
aldehydes and electron-deficient ketone substrates work effectively
in this transformation. Several of the chiral N,O-acetal products
afforded through this protocol exhibit excellent anti-bacterial
activities against Rs and are valuable in the development of novel
agrichemicals for plant protection.
In both Chi’s and Scheidt’s studies, the heteroatoms are not
part of the -system of the aryl rings. To the best of our
knowledge, carbene-catalyzed activation of the heteroatoms that
are part of the aromatic -rings for asymmetric reactions is not
developed. In a broader picture, it remains difficult to push the
power of carbene catalysts crossing aromatic molecules.[29-33]
Introduction
Heteroarenes are privileged structures with enormous
presence in medicines, pesticides, ligands, natural products, and
other functional molecules. The heteroatoms in some of these
aryl molecules, such as indoles and pyrroles, can serve as
convenient handles for structural modifications and function
alternations. For example, the nitrogen atoms of indole
molecules can undergo addition reactions with reactive ketones
to form N,O-acetals.[1,2] Acetals are versatile structural motifs
with proven applications in organic synthesis[3,4] and
pharmaceutical research.[5-9] Most of such acetal forming
reactions themselves can be made very efficient. The main
challenges, on the other hand, lies on controlling the
enantioselectivities of these transformations. In the field of
transition metal-free catalysis, chiral phosphoric acid catalysts
have found impressive success to mediate asymmetric acetal
formations, as pioneered by Antilla,[10] List[11] and others.[12,13]
We are interested in exploring N-heterocyclic carbenes
(NHCs) as key organic catalysts for new activations and
enantioselective reactions. In the past, NHCs are mostly used to
activate carbon atoms as either nucleophilic or electrophilic
[a]
Y. Liu, S. Jiang, Prof. Dr. W. Xue, Prof. Dr. Y. R. Chi, Prof. Dr. Z. Jin
Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Huaxi
District, Guiyang 550025, China
E-mail: zcjin@gzu.edu.cn
[b]
[c]
Dr. G. Luo
School of Pharmacy, Guizhou University of Traditional Chinese
Medicine, Huaxi District, Guiyang 550025, China
Dr. X. Yang, Prof. Dr. Y. R. Chi
Scheme 1. NHC-Promoted Carbon and Heteroatom Activations.
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore.
Here we disclose that the NH units of indoles and pyrroles
can be activated via carbene catalysis for enantioselective
additions to reactive ketones (Scheme 1c). The reaction starts
[†]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201912160
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RESEARCH ARTICLE
with addition of carbene catalyst to the aldehyde moiety
attached to indoles or pyrroles. Under an oxidative condition,
this carbene addition reaction forms acyl azolium intermediate I.
This oxidative process shall remove electron-densities from the
indole (or pyrrole) and make the overall -system (of I) less
nucleophilic (when compared to the arylaldehyde substrate). For
instance, as a potential nucleophilic center, the carbon at the 2-
or 3-position[34-36] is deactivated through the formation of I. On
the other hand, the nitrogen atom[37,38] is selectively activated as
a reactive center through deprotonation of I to form the aza-
fulvene intermediate II.[39-43] An enantioselective aza-nucleophilic
addition of II to a ketone substrate followed by intramolecular
ester formation furnishes the final acetal products with excellent
yields and er values. Both indole and pyrrole aldehydes are
effective substrates, and multiple types of ketones can serve as
the electrophiles.[44] It is worth noting that Jørgensen and co-
workers have recently disclosed the enantioselective N-
functionalization of heteroaromatic aldehydes with chiral
secondary amines used as the key organic catalysts.[45]
We first chose indole aldehyde 1a and isatin 2a as the model
substrates in the presence of DQ oxidant[46] to search for
suitable conditions, with seleted results illustrated in Table 1.
NHC catalysts derived from aminoindanol skeletons were
evaluated for this transformation (Table 1, entries 1 to 5). NHC
pre-catalyst A[47,48] bearing an N-Mes substituent could promote
the formation of the desired product 3a in a moderate yield and
excellent enantioselectivity (entry 1). No desired product could
be observed when using NHC pre-catalyst B[49] (entry 2).
Although the use of NHC pre-catalyst C[49] bearing an N-C6F5
substituent could give the product 3a in nearly quantitative yield,
the enantioselectivity was poor (entry 3). Both the product yield
and er value could be increased with the use of pre-catalyst D[50]
(entry 4). The yield of 3a could be further improved by switching
-
the anion of pre-catalyst D from BF4 to Cl- (to form pre-catalyst
E) without erosion of the reaction enantioselectivity (entry 5).
Both organic and inorganic bases with mild basicities could be
used in this reaction, with the desired product 3a formed in good
to excellent yields and er values (e.g., entries 6 to 7). The use of
strong bases (such as DBU) resulted in decomposition of the
N,O-acetal product 3a, thus leading to poor yields (e.g., entry 8).
Mulitple solvents were studied (e.g., entries 9-11). In general,
solvents other than THF did not perform well (see SI): either
yields or er values were significantly decreased likely due to
partial decomposition and reversible reaction of the acetal
products (e.g., entry 11). To our delight, the enantioselectivity
could be further improved when carrying out the reaction with 5
Results and Discussion
Table 1. Optimization of Reaction Conditions.[a]
o
mol% of the NHC catalyst E at 10 C, with excellent yield of 3a
remained (entry 12). As a technical note, the N,O-acetal product
3a exhibited good stability under this condition and the reaction
also showed tolerance to slight condition variations.[51,52]
Having identified an acceptable condition for this
enantioselective aza-[3 + 2] cycloaddition reaction, we then
examined the scope of both indole aldehydes (1) and isatins (2)
(Figure 1). Substituents possessing both electron-donating and
electron-withdrawing properties could be installed on each
position of the benzene rings of the indole aldehydes (1), with
the corresponding products (3) afforded in good to excellent
yields and enantioselectivities (Figure 1, 3b to 3l). Various
substituents were also well tolerated on the isatin substrates (2),
regardless of their electronic properties or the substitution
patterns (4a to 4v). The reaction also proceeded smoothly with
the isatin bearing an N-methyl group without much erosion on
the product er value (4w). A more steric hindered N-Trt
protecting group led to product 4x with excellent optical purity,
albeit with a droped yield under the current standard condition.
Entry
NHC
A
base
solvent
yield [%][b]
er[c]
1
Et3N
THF
58
94:6
-
2
B
Et3N
THF
0
3
C
Et3N
THF
99
59:41
94:6
94:6
95:5
95:5
54:46
95:5
96:4
60:40
96:4
4
D
Et3N
THF
74
5
E
Et3N
THF
99
6
E
DIEA
NaOAc
DBU
DIEA
DIEA
DIEA
DIEA
THF
99
7
E
THF
84
8
E
THF
28
9
E
Toluene
MTBE
CH3CN
THF
79
10
11
12[d]
E
49
E
59
E
99 (88)
[a] General conditions: 1a (0.15 mmol), 2a (0.10 mmol), NHC (0.02 mmol),
base (0.17 mmol), DQ (0.17 mmol), solvent (1.0 mL), rt, 24 h. [b] The yields of
3a were determined via 1H NMR with sym-trimethoxybenzene used as the
inner standard. The data in the parenthesis indicated isolated yield of 3a after
purification by column chromagraphy. [c] Er was determined via HPLC on
chiral stationary phase. [d] 1a (0.15 mmol), 2a (0.10 mmol), E (0.005 mmol),
DIEA (0.15 mmol), DQ (0.17 mmol), THF (1.0 mL), 10 oC, 24 h.
This aza-[3 + 2] cycloaddition reaction of indole aldehydes (1)
could be developed as a general approach for the asymmetric
synthesis of various N,O-acetal indoline products (Figure 2).
Electron-deficient ketoesters (5) are another class of suitable
electrophiles for this NHC-catalyzed process. After a quick re-
evaluation of the reaction conditions, the cyclic N,O-acetal
products 6 could be afforded in good to excellent yields and
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10.1002/anie.201912160
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RESEARCH ARTICLE
enantioselectivities. One acceptable condition involves the use
of pre-catalyst C (20 mol%) as the reaction catalyst, DIEA (250
mol%) as the base, MTBE as the reaction solvent in the
presence of DQ oxidant (250 mol%). Specifically, indole
aldehydes (1) bearing various substituents or substitution
patterns could react effectively (6a to 6g). Both electron-
withdrawing and electron-donating substituents could be
installed on the 3- or 4-positions of the benzene rings of the
ketoester substrates (6h to 6k). Interestingly, although the 2-
FC6H4 substituted ketoester substrate worked well in this
transformation (6l), the 2-Cl and 2-Br substituents on the
benzene rings of the ketoester substrates gave the desired
products 6m and 6n in lower enantioselectivities. This is
probably due to the higher steric hindrance existed during the
catalytic process between the two reaction substrates. A variety
of ester groups were also tolerated on the ketoester substrates
(6o to 6r), albeit only poor er values were obtained with
benzhydrol (6q) and phenol (6r) esters. Replacement of the
ester group on the ketoester substrate with either an amide
group or a phosphoric ester group resulted in no or trace
formation of the desired N,O-acetal products (6s or 6t).
Figure 1. Scope of Indole Aldehydes 1 and Isatins 2. General conditions: 1 (0.15 mmol), 2 (0.10 mmol), E (0.005 mmol), DIEA (0.15 mmol), DQ (0.17 mmol),
THF (1.0 mL), 10 oC, 24 h. [a] The reaction was carried out at 1.0 mmol scale based on 2a.
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Figure 2. Scope of Indole Aldehydes 1 and Ketones 5. General conditions: 1 (0.25 mmol), 5 (0.10 mmol), E (0.02 mmol), DIEA (0.25 mmol), DQ (0.25 mmol),
MTBE (1.0 mL), 45 oC, 24 h. [a] The reaction was carried out at 1.0 mmol scale based on 5a.
To further demonstrate the generality and utility of this NHC-
catalyzed nitrogen atom activation approach, we next
investigated pyrrole aldehyde 7a (Table 2) as the heteroarene
substrate. The earlier conditions used for indole aldehydes
(Figures 1 & 2) did not work well here, so we searched for a new
set of conditions for the activation and reaction of pyrrole
aldehydes. To our great delight, the aza-[3 + 2] reaction between
pyrrole aldehyde 7a and N-Bn isatin 2a could go smoothly with
the catalysis of NHC pre-catalyst A or C, although the products
9a′ could only be afforded with very poor enantioselectivities
(Table 2, entries 1 & 3). NHC pre-catalyst B bearing an N-Ph
substituent was not effective for this process (entry 2). The
enantioselectivity of the aza-[3 + 2] cycloaddition reaction could
be dramatically improved by using N-Trt isatin 8a as the reaction
substrate, with the corresponding product 9a afforded in 86:14
er (entry 4). Lewis acids have been proven to be promising co-
catalysts that can enhance the stereo-selectivity controls in
multiple NHC catalytic reactions.[24,53] We therefore examined
Lewis acids as co-catalysts (entries 5 to 7) and found that the
addition of urea molecule G[27] could succefully enhance the
reaction er from 86:14 (etnry 4) to 90:10 (entry 7). Organic or
inorganic bases with strong basicities resulted in docomposions
of the N,O-acetal products (e.g., entry 8). KOAc performed
better than K2CO3 (entries 9 vs 7). A survey of solvents revealed
that CHCl3 was a most suitable choice (entry 10). An acceptable
condition was eventualy found as using 10 mol% of NHC pre-
catalyst C with 130 mol% of KOAc, 10 mol% of urea G in CHCl3
at 0 oC in the presence of 130 mol% of the DQ oxidant (entry 11).
Table 2. Optimization of Reaction Conditions.[a]
Entry
ketone
NHC
additive
base
solvent
yield
[%][b]
36
er[c]
1
2
3
4
5
6
7
8
2a
2a
2a
8a
8a
8a
8a
8a
A
B
C
C
C
C
C
C
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
58:42
-
0
42
30
31
40
34
60:40
86:14
85:15
87:13
90:10
-
Sc(OTf)3
F
G
G
Cs2CO3 /
DBU
0
9
8a
8a
8a
C
C
C
G
G
G
KOAc
CH2Cl2
CHCl3
CHCl3
47
88
75
90:10
93:7
96:4
10
11[d]
KOAc
KOAc
[a] General conditions: 7a (0.12 mmol), 2a or 8a (0.10 mmol), NHC (0.02
mmol), base (0.14 mmol), additive (0.02 mmol), DQ (0.12 mmol), solvent (1.0
mL), rt, 24 h. [b] Isolated yield of 9 after purification by column chromagraphy.
[c] Er was determined via HPLC on chiral stationary phase. [d] 7a (0.12 mmol),
8a (0.10 mmol), C (0.01 mmol), KOAc (0.13 mmol), G (0.01 mmol), DQ (0.13
mmol), CHCl3 (1.0 mL), 0 oC, 48 h.
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10.1002/anie.201912160
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RESEARCH ARTICLE
pyrrole aldehyde resulted in drops on
the product enantioselectivities, with
reaction
yield
unaffected
(9d).
Substitution on the 5-position of the
pyrrole aldehyde could deactivate the
nucleophilicity of its N-heteroaromatic
ring, with the product afforded in only
moderate yield (9e). Trt-protected isatin
substrates
bearing
different
substituents or substitution patterns on
the benzene rings all worked well (9f to
9u).
The indole protecting groups on the
chiral molecules 3a and 9a could be
effectively removed to give the free
oxindole products 10 and 11 in good
yields, although the optical purities
were slightly dropped (Scheme 2). We
also examined the anti-bacterial
activities of the afforded chiral N,O-
acetal products using Ralstonia
solanacearum (abbrieviated as Rs) as
the target bacterium. Rs can cause
blight on plant leafs and resulted in
death of
a
variety of crops.[54,55]
Thiodiazole-copper and bismerthiazol
are two of the most frequently used
commercial agrichemicals to control
these deseases. Several of the
afforded chiral N,O-acetal products
from our approach exhibit superior anti-
baterial activities against Rs over the
commercially available agrichemicals.
These results encourage us to further
Figure 3. Scope of Pyrrole Aldehydes 7 and Isatins 8. General conditions: 7 (0.12 mmol), 8 (0.10 mmol), C
(0.01 mmol), KOAc (0.13 mmol), G (0.01 mmol), DQ (0.12 mmol), CHCl3 (1.0 mL), 0 oC, 48 h. [a] The
reaction was carried out at 1.0 mmol scale based on 8a. [b] Toluene (1.0 mL) was used as the reaction
solvent and the reaction was stirred at 40 oC for 48 h.
After a suitable condition was established, the scope of
investigate the bio-activities of our chiral N,O-acetal products in
order to get novel agrichemicals with better efficiencies and less
polutions for effective plant protection.
pyrrole aldehydes (7) and isatins (8) were examined (Figure 3).
Substituents on the 4-position of the pyrrole aldehyde were well
tolerated (Figure 3, 9b to 9c). Substition on the 3-position of the
Ralstonia solanacearum (Rs) inhibition rate (%)
compound
100 μg/mL
86.67 ± 1.76
83.91 ± 5.05
71.55 ± 9.02
89.49 ± 8.26
89.08 ± 5.15
76.61 ± 6.38
88.22 ± 0.98
82.03 ± 9.22
64.06 ± 4.71
63.00 ± 8.85
46.82 ± 3.46
62.42 ± 1.63
50 μg/mL
3a
3c
3h
3i
81.88 ± 0.55
80.74 ± 4.22
59.53 ± 5.24
85.88 ± 3.70
88.17 ± 1.01
68.72 ± 0.68
83.01 ± 8.89
77.04 ± 8.64
55.74 ± 4.78
55.82 ± 2.99
28.58 ± 4.42
53.25 ± 3.10
3j
4a
4b
9a
9e
9g
thiodiazole-copper
bismerthiazol
Scheme 2. Synthetic Transformations and Anti-bacterial Activities of the N,O-Acetal Products.
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10.1002/anie.201912160
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RESEARCH ARTICLE
Removal of the Trt group of 9a. To a stirred solution of 9a (0.1 mmol) in
PhOCH3 (0.5 mL) was added AcOH (3.0 mL). Then the reaction mixture
was stirred at 120 oC for 24 hours. After concentration under reduced
pressure, the reaction mixture was directly subjected to column
chromatography to give the pure product 11 in 84% yield.
Conclusion
In summary, we have developed a new approach for the
activation of nitrogen atoms in heteroarenes for enantioselective
reactions. Through the addition of a carbene catalyst to the
aldehyde moiety of indole and pyrrole aldehydes under oxidative
conditions, the nitrogen atom in the aromaric -system is
activated. This carbene-catalyzed activation generates
unpresendented aza-fulvene typed acylazolium intermediates
that enantioselectively react with ketones to form N,O-acetals
with excelent yields and er values. The reactions are found to be
general, with a broad range of N-heteroaroamtic aldehydes and
electron-deficient ketones reacted effectively. The chiral N,O-
acetal products obtained from our strategy exihibit encouraging
anti-bacterial activities against Rs and are valuable in the
development of novel chiral agrichemicals for plant protection.
Our study constitutes the first NHC-catalyzed activation of
nitrogen atoms that are part of aromtic -rings. It shall expand
the power of carbene catalysis in achieving asymmetric
reactions invovling aromatic skeletons.
Data and materials availability: X-ray crystallographic data for
compound 4u, 6a and 9a are available free of charge from the
Cambridge Crystallographic Data Centre under CCDC 1935291,
1935292 and 1935293. Full experimental details for the preparation of all
new compounds, and their spectroscopic and chromatographic data, can
be found in the supplementary materials.
Acknowledgements ((optional))
We acknowledge financial support from the National Natural
Science Foundation of China (No. 21772029, 21801051,
21961006), National Key Technologies R&D Program (No.
2014BAD23B01), The 10 Talent Plan (Shicengci) of Guizhou
Province [2016]5649, Guizhou Province Returned Oversea
Student Science and Technology Activity Program, Science and
Technology Department of Guizhou Province [2018]2802,
Guizhou University, the Guizhou Province First-Class Disciplines
Project (Yiliu Xueke Jianshe Xiangmu)-GNYL(2017)008,
Guizhou University of Traditional Chinese Medicine (China).
Singapore National Research Foundation (NRF-NRFI2016-06),
the Ministry of Education of Singapore (MOE2013-T2-2-003;
MOE2016-T2-1-032; RG108/16), A*STAR Individual Research
Grant (A1783c0008), Nanyang Research Award Grant, and
Nanyang Technological University.
Experimental Section
General procedure for the enantioselective synthesis of 3 (4). To a 4
mL vial was subsequently added indole aldehyde 1 (0.15 mmol), isatin 2
(0.1 mmol), pre-catalyst E (5 mol%) and THF (1.0 mL). After DIEA (150
mol%) was added, the reaction mixture was stirred at 10 oC for 24 hours.
Then the reaction was quenched by 1 M HCl (1.0 mL) and extracted with
EtOAc (3 × 3 mL). The combined organic phase was concentrated under
reduced pressure and the residue was purified by column
chromatography to give the pure products 3 or 4 in 44% to 98% isolated
yields.
Keywords: N-heterocyclic carbene • aromatic nitrogen
activation • aza-fulvene • acylazolium • N,O-acetal
General procedure for the enantioselective synthesis of 6. To a 4 mL
vial was subsequently added indole aldehyde 1 (0.25 mmol), ketoester 5
(0.1 mmol), pre-catalyst C (20 mol%) and MTBE (1.0 mL). After DIEA
(250 mol%) was added, the reaction mixture was stirred at 45 oC for 24
hours. Then the reaction was quenched by 1 M HCl (1.0 mL) and
extracted with EtOAc (3 × 3 mL). The combined organic phase was
concentrated under reduced pressure and the residue was purified by
column chromatography to give the pure products 6 in 55% to 99%
isolated yields.
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General procedure for the enantioselective synthesis of 9. To a 4 mL
vial was subsequently added pyrrole aldehyde 7 (0.12 mmol), isatin 8
(0.1 mmol), pre-catalyst C (10 mol%), urea G (10 mol%), KOAc (130
mol%) and CHCl3 (1.0 mL). Then the reaction mixture was stirred at 0 oC
for 48 hours. The reaction was quenched by 1 M HCl (1.0 mL) and
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Removal of the Bn group of 3a. To a stirred solution of 3a (0.2 mmol) in
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concentration under reduced pressure, the reaction mixture was directly
subjected to column chromatography to give the pure product 10 in 70%
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Entry for the Table of Contents (Please choose one layout)
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Yonggui Liu, Guoyong Luo, Xing Yang,
Shichun Jiang, Wei Xue, Yonggui Robin
Chi, and Zhichao Jin*
Page No. – Page No.
Carbene-Catalyzed Enantioselective
Aromatic N-Nucleophilic Addition of
Heteroarenes to Ketones
The aromatic nitrogen atoms of heteroarylaldehydes are activated by carbene
catalysts to react with ketone electrophiles. A broad scope of cyclic N,O-acetal
products are afforded in good to excellent yields and optical purities. Our reaction
involves the formation of an unprecedented aza-fulvene acylazolium intermediate.
Several of the chiral N,O-acetal products exhibit excellent anti-bacterial activities
and are valuable in the development of novel agrichemicals.
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