Catalytic Generation of C1 Ammonium Enolates from Halides and CO for Asymmetric Cascade Reactions

Article abstract of DOI:10.1002/anie.201901501

A general strategy for the design of asymmetric cascade reactions using readily available halides and carbon monoxide (CO) as substrates is developed. The key is the catalytic generation of C1-ammonium enolates for the subsequent asymmetric cascade reactions through the combination of palladium-catalyzed carbonylation and chiral Lewis base catalysis. Utilizing this strategy, we have established asymmetric formal [1+1+4] and [1+1+2] reactions to afford chiral dihydropyridones and β-lactams with high yields and high enantio- and diastereoselectivities.

Full text of DOI:10.1002/anie.201901501

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Accepted Article
Title: Catalytic generation of C1 ammonium enolates from halides and
CO for asymmetric cascade reactions
Authors: Liuzhu Gong, Lu-Lu Li, Du Ding, Jin Song, and Zhi-Yong Han
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10.1002/anie.201901501
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Catalytic generation of C1 ammonium enolates from halides and
CO for asymmetric cascade reactions
Lu-Lu Li, Du Ding, Jin Song, Zhi-Yong Han*, Liu-Zhu Gong*
Abstract: A general strategy for the design of asymmetric cascade
reactions using readily available halides and carbon monoxide (CO)
as substrates is developed. The key is the catalytic generation of C1-
ammonium enolates for the subsequent asymmetric cascade
reactions through the combination of palladium-catalyzed
carbonylation and chiral Lewis base catalysis. Utilizing this strategy,
we have established asymmetric formal [1+1+4] and [1+1+2]
reactions to afford chiral dihydropyridones and β-lactams with high
yields, enantio- and diastereoselectivities.
the catalytic activity are common sense to address this issue. On
the other hand, transition metal catalysts have provided abundant
activation modes, including those that are widely used to activate
inert chemical bonds.[6] As such, incorporating transition metal
catalysis into organocatalytic asymmetric cascade reactions in a
one-pot relay manner could make full use of their advantages and
complement each other, allowing for the direct transformation of
available feedstock chemicals to high-value chiral products
(Figure 1).[7]
Lewis base catalysis,[8] as an important member of
organocatalysis, has found widespread applications in
asymmetric cascade reactions. In particular, tertiary amines or N-
heterocyclic carbenes, two representative types of Lewis base
catalysts, are able to form C1-ammonium (or azolium) enolates[9a,
The everlasting pursuit of maximum efficiency and sustainability
in the synthesis of complex organic molecules continues to
stimulate new catalytic transformations. In this connection,
catalytic asymmetric cascade reactions, being able to build up
molecular complexity with high efficiency, are greatly desirable.[1]
These reactions not only essentially avoid additional time-
consuming, costly workup, and isolation processes associated
with the step-wise synthesis, but also provide a thermodynamic
leveraging mechanism by chemically integrating multiple catalytic
cycles.[2] Among them, organo-catalyzed asymmetric cascade
reactions have achieved a great deal of success,[3] especially after
the milestone work describing a triple cascade organocatalytic
reaction.[4] These transformations enable facile and efficient
access to densely functionalized chiral architectures often with
excellent stereocontrol. Nevertheless, the substrate scope is
restricted to relatively functionalized molecules, such as
aldehydes, ketones, imines, nitro olefins, and so on, and more
available feedstock chemicals are not applicable due to the
limitation of available activation mode of asymmetric
organocatalysis.[5] Seeking new activation mode beyond the
traditional wisdom and modulation of organocatalysts to enhance
9c]
capable of undergoing various types of cascade reactions to
access a wide scope of structurally diverse chiral products such
as β-lactones, β-lactams and so on, which are highly significant in
the synthesis of bioacitive substances.[9] This type of chemistry
started with the generation of the C1 ammonium enolate from a
chiral Lewis base (LB*) and a pre-formed or in situ generated
ketene (Scheme 1a).[9c, 10] As early as 1982, Wynberg and co-
workers reported the seminal work of chiral β-lactones synthesis
via a cinchona alkaloid catalyzed aldol lactonization strategy,
leading to a rapid development of this organocatalysis field.[11]
Since most of ketenes are unstable and ready to undergo
dimerization and other side reactions, their synthesis and the
Figure 1. Integrating metal- and organocatalysis for the creation of
asymmetric cascade reactions.
Scheme 1. The evolution of catalytic asymmetric C1-ammonium enolate
chemistry: a) Formation of C1 ammonium enolates from pre-synthesized or in
situ generated ketene at low temperature and a nucleophilic tertiary amine
catalyst; b) Generation of C1 ammonium enolates from activated carboxylate
functionality and nucleophilic catalyst; c) Catalytic generation of C1 ammonium
enolates from halides and CO through the combination of Pd-catalyzed
carbonylation and organocatalysis.
[a]
L.-L. Li, D. Ding, J. Song, Prof. Dr. Z.-Y. Han, Prof. Dr. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at Microscale and
Department of Chemistry, University of Science and Technology of
China, Hefei, 230026 (China)
E-mail: hanzy2014@ustc.edu.cn; gonglz@ustc.edu.cn
Prof. Dr. L.-Z. Gong
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin (China)
following reactions have to be performed at low temperature.[10b,
12] To avoid the use of unstable ketenes, searching for alternative
routes to C1-ammonium enolates has become an active research
field. Recently, activated carboxylates, including esters and
anhydrides, are found to be able to form acylammonium
Supporting information for this article is given via a link at the end of
the document.
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Table 1: Reaction optimization.[a]
Initial investigations probed the viability of the asymmetric
cascade reaction using benzyl bromide 1a and ketimine 2a under
2 bar of CO at 50 oC in the presence of catalytic amounts of
Pd(Ph3P)4 and benzotetramisole (BTM) 4a.[17] The reaction
provided 3a in 21% yield with 8:1 dr and 78% ee of the trans-
product as the major isomer (entry 1). Notably, Smith group
reported the asymmetric annulation of α,β-unsaturated ketimine
and in situ generated anhydride using catalyst 4a.[14b] Screening
of ligands for the palladium metal (See supporting information for
details) identified Xantphos to be competent for the cascade
reaction (entry 2). Lowering the reaction temperature greatly
enhanced the enantioselectivity, but resulted in lower yield
(entries 3 and 4). At this stage, the examination of the CO
pressure revealed that lower pressure is beneficial for the reaction
(entries 6-8). Although high pressure of CO favors the CO
insertion process, it might also suppress the oxidative addition
and ketene formation processes due to coordination effect, thus
Entry
X/Y
BTM
CO
T
(oC)
50
50
40
30
30
30
30
30
30
30
30
30
Yield
(%)[b]
21
d.r.[c]
ee
(%)[d]
78
76
89
94
94
94
82
83
96
96
--
(bar)
2
1[e]
2
--
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
--
8:1
5:1
5:1
6:1
6:1
6:1
7:1
9:1
6:1
10:1
--
5/10
5/10
5/10
5/5.5
5/5.5
5/5.5
5/5.5
10/11
10/11
10/11
5/5.5
2
95
3
2
94
4
2
43
5
2
64
led to more sluggish reaction. Evaluation of
a set of
6
1
84
benzotetramisole catalysts (Table S1 in Supporting Information)
revealed that BTM 4b[18] could enhance the diastereoselectivity
with excellent enantioselectivity and quantitative yield (entry 10).
The absence of BTM catalyst rendered the reaction unproductive
(entry 11). At this stage, lowering the loading of metal catalyst and
ligand only led to slight erosion of the ee (entry 12 vs 6).
7
3
47
8
4
31
9[f]
10[f]
11[f]
12
1
>99
>99
trace
>99
1
1
4b
1
10:1
94
Next, with the optimized reaction conditions in hand, we
studied the generality of the asymmetric formal [1+1+4]
annulation reaction of bromides 1, CO and ketimine 2, with initial
work focusing upon the variation of benzyl bromides (Table 2).
Notably, electron-rich benzyl bromides seem to provide the
corresponding products with higher enantioselectivities in
comparison with those bearing electron-withdrawing groups (3b-
d vs 3g-j). The reactions of benzyl bromide 1a with a number of
N-tosyl-α,β-unsaturated ketimines 2 were also examined (3o-3s).
Variation of the aryl group of the ketimine, including heterocycles
(3q), was readily tolerated, giving anti-dihydropyridones with high
dr (up to >20:1) and ee (up to 99%). Sultam-derived cyclic imine
could also be well tolerated, providing polycyclic compound 3t in
a high yield and stereoselectivity. The reaction of oxindole-
derived α,β-unsaturated imine also proceeded smoothly to
a] Unless indicated otherwise, the reaction was carried out under CO (1-4
bar) in the scale of 1a (0.2 mmol), 2a (0.1 mmol), Pd(dba)2 (5-10 mol%),
Xantphos (5.5-11 mol%), BTM (0.02 mmol) and i-Pr2NEt (0.4 mmol) in THF
(0.5 mL) for 12 h. [b] NMR yield. [c] Determined by 1H NMR analysis of the
crude reaction product. [d] Determined by chiral HPLC. [e] Pd(Ph3P)4
(0.005 mol%) was used. [f] THF (1 mL) was used.
intermediates that can subsequently undergo deprotonation to
generate C1-ammonium enolate in the presence of a tertiary
amine catalyst (Scheme 1b).[9a, 13] In the case of NHC catalysis,
C1-azolium enolates with similar properties could be generated
from α-functionalized aldehydes, enals or aliphatic aldehydes in
the presence of stoichiometric amounts of oxidant.[9b] Encouraged
by these achievements,[13b, 14] aiming to establish a general route
to the catalytic generation of chiral C1-ammonium enolates from
readily available feedstock chemicals and to maximize the
simplicity of the procedure, we tend to introduce a transition-
metal-catalyzed carbonylation into this organocatalysis field.
Palladium-catalyzed carbonylation reaction has been a versatile
tool both in academic and industry for the manufacture of
carbonyl-containing chemicals from simple starting materials,
which also increase the carbon number at the same time using
inexpensive CO as the C1 source.[15] An acylpalladium bearing an
α-proton, usually generated via oxidative addition of halides and
CO insertion, could be transformed to a ketene intermediate that
is able to undergo a wide scope of transformations.[16] We
envisioned that in the presence of a chiral tertiary amine catalyst
the ketene intermediate could form C1-ammonium enolate and
then undergo subsequent asymmetric cascade reactions
generate
a
spirocyclic compound 3u with high ee.
Cinnamaldehyde and crotonophenone-derived N-tosyl imines
were both suitable for the reaction, delivering the desired products
in good yields with high enantioselectivities (3v and 3w).
To demonstrate that the current method could be a general
approach to C1-ammonium enolates for a diverse scope of
cascade reactions, we turned our attention to the development of
the asymmetric formal [1+1+2] reaction to give chiral β-lactams,
one of the most important motifs of antibiotics prescribed for
antibacterial treatment today.[19] Under otherwise almost identical
reaction conditions, the reaction of benzyl bromide, CO and N-
tosylimine 5a provided β-lactam 6a in 78% yield, 94% ee and 20:1
dr., with the anti-isomer as the major product (Table 3, 6a).[20]
A
brief examination of the substrate scope revealed that the reaction
conditions could be applied to other N-tosylimines (e.g. 6b and
6c) to give the corresponding products with high enantio- and
diastereoselectivities and good yields. As for the benzyl bromides,
different aryl rings, such as alkyl or chloro substituted phenyl, 2-
(Scheme 1c). Taking advantage of the rich chemistry of C1-
9c]
ammonium enolates,[9a,
this strategy could be a general
approach for the concise transformation of halides, CO and
another counterpart reactants into various high-value chiral
products.
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Table 3: Formal [1+1+2] reaction for the synthesis of chiral β-lactams.[a]
Table 2: Scope of the asymmetric formal [1+1+4] reaction for the synthesis
of chiral dihydropyridones.[a]
[a] Unless indicated otherwise, the reaction was carried out under CO (1
bar) atmosphere in the scale of 1 (0.2 mmol), 5 (0.1 mmol), Pd(dba)2 (0.01
mmol), Xantphos (0.011 mmol), 4b (0.02 mmol) and i-Pr2NEt (0.4 mmol)
in THF (1mL) at 30 oC for 12 h. [b] The reaction was carried out under CO
(1 bar) in the scale of 1o (0.3 mmol), 5a (0.1 mmol), Pd(dba)2 (0.01mmol),
Xantphos (0.011 mmol), 4b (0.02 mmol) and i-Pr2NEt (0.4 mmol) in THF
(1 mL) at 10 oC for 12 h.
[a] Unless indicated otherwise, the reaction was carried out under CO (1 bar)
atmosphere in the scale of 1 (0.2 mmol), 2 (0.1 mmol), Pd(dba)2 (0.01 mmol),
Xantphos (0.011 mmol), 4b (0.02 mmol) and i-Pr2NEt (0.4 mmol) in THF (1mL)
at 30 oC for 12 h. [b] The ee of the minor isomer is shown in the brackets.
Scheme 2. Derivatization and functionalization of the products: a)
Derivatization of 3a; b) Synthesis of bioactive chiral β-lactam 10 using the
formal [1+1+2] reaction.
naphthyl and 3-furanyl, could also undergo the reaction smoothly
to give 6d-6g with 49-82% yields, 82-96% ee and excellent
diastereoselectivities.
hydrogen might be transformed to the ketene V through β-hydride
elimination (possibly the turnover-limiting step, path a),[16a] which
then reacts with the BTM catalyst 4b to form the key C1-
ammonium enolate intermediate VI. Due to the slow generation
and in situ capture of the unstable ketene intermediate, side
reactions and racemic background reaction could be avoided. As
such, the three-component reaction of 1f, CO and 2a showed a
The obtained chiral heterocycles could undergo a variety of
classical transformations to afford synthetically useful building
blocks and bioactive compounds. The treatment of 3a with SmI2
readily removed the N-tosyl group to give compound 7 in high
yield without notable erosion of the optical purity. Compound 7
could be allylated to afford N-allyl compound 8 under basic
conditions, which led to slight decrease in the ee (Scheme 2a).
Performing the formal [1+1+2] annulation provided chiral β-lactam
6h with 68% yield, 95% ee and excellent diastereoselectivity
(Scheme 2b). A sequential deprotection of the N-tosyl group and
Buchwald-Hartwig amination reaction[21] led to an antiproliferative
agent 10 with high yield and excellent ee.[22]
Scheme 3. Proposed mechanism for the formal [1+1+4] annulation.
A
series of kinetic studies were performed to gain
mechanistic insights into the transformation (Figure S1-S4 in
Supporting Information). The observed kinetic isotope effect
indicates that C–H cleavage is likely involved in the rate-limiting
step of the reaction. On the basis of these experimental results
and previous work,[16d-f] a plausible reaction pathway is outlined in
Scheme 3. Initially, an intermediate II is generated from the
oxidative addition of the Pd(0) catalyst I to benzyl bromide 1a and
then undergoes an insertion reaction with CO to generate
acylpalladium III. The acylpalladium intermediate III bearing a β-
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Information). An alternative pathway to generate VI from
acylpalladium III is also possible: the nucleophilic Lewis base
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β-lactam 6.[16f, 20]
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Acknowledgements
We are grateful for the financial support from NSFC (Grants
21831007, 21772184), 973 Program (No. 2015CB856602) and
Chinese Academy of Science (Grant No. XDB20000000).
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Keywords: asymmetric relay catalysis • carbonylation • C1-
ammonium enolate
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10.1002/anie.201901501
Angewandte Chemie International Edition
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Lu-Lu Li, Du Ding, Jin Song, Zhi-Yong
Han*, and Liu-Zhu Gong*
Page No. – Page No.
Catalytic generation of C1 ammonium
enolates from halides and CO for
asymmetric cascade reactions
Asymmetric annulations of benzyl bromides, CO and N-tosylimines for the
synthesis of chiral β-lactams and dihydropyridones have been developed by
integrating the palladium-catalyzed carbonylation and chiral Lewis base
catalysis.
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