Cooperative N-Heterocyclic Carbene/Palladium-Catalyzed Enantioselective Umpolung Annulations

Article abstract of DOI:10.1021/jacs.6b04364

A combination of NHC organocatalysis and transition-metal catalysis gives rise to fundamentally new cooperative reactivity and enables the regio- and enantioselective annulation reaction between enals and vinyl benzoxazinanones. The cooperative umpolung annulation eliminates mutual deactivation and leads to a diverse set of benzazepine derivatives in good yields with excellent enantioselectivities (up to 99% ee). The development of such a cooperative catalytic system dramatically expands the scope of NHC organocatalysis by opening up new metal-catalyzed reaction pathways for homoenolate intermediates.

Full text of DOI:10.1021/jacs.6b04364

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Communication
Cooperative N-Heterocyclic Carbene/Palladium-
Catalyzed Enantioselective Umpolung Annulations
Chang Guo, Mirco Fleige, Daniel Janssen-Müller, Constantin G. Daniliuc, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04364 • Publication Date (Web): 08 Jun 2016
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Cooperative N-Heterocyclic Carbene/Palladium-Catalyzed En-
antioselective Umpolung Annulations
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Chang Guo, Mirco Fleige, Daniel Janssen-Müller, Constantin G. Daniliuc and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster,
Germany
Supporting Information Placeholder
give rise to fundamentally new cooperative umpolung reac-
tivity capable of expanding the fields of both strategies and
ABSTRACT: A combination of NHC organocatalysis
and transition metal catalysis gives rise to fundamen-
providing access to currently inaccessible reaction pathways,
tally new cooperative reactivity and enables the regio-
especially via the umpolung of “natural” reactivity.8 However,
and enantioselective annulation reaction between
enals and vinyl benzoxazinanones. The cooperative
to date, an asymmetric cooperative system for the intermo-
lecular reaction that combines transition metal/NHC or-
umpolung annulation eliminates mutual deactivation
and leads to a diverse set of benzazepine derivatives in
good yields with excellent enantioselectivities (up to
99% ee). The development of such a cooperative cata-
lytic system dramatically expands the scope of NHC
organocatalysis by opening up new metal-catalyzed
reaction pathways for homoenolate intermediates.
ganocatalysis has not been realized. Limited research has
been reported in this field, presumably due to the assump-
tion that NHCs would act as ligands for the late transition
metal involved,9 thus diminishing or even preventing the
individual reactivity of each component. The major unsolved
challenge in the design of cooperative transition metal/NHC
organocatalysis has been the difficulty of controlling compat-
ibility problems.
Scheme 1. Design of enantioselective catalytic um-
polung annulation
N-Heterocyclic carbenes (NHCs)1 are recognized as the
most powerful organocatalysts for accessing umpolung reac-
tivity,2 as a platform for the discovery of novel asymmetric
synthetic transformations, allowing access to a wide array of
heterocycles and bioactive compounds. The use of NHCs as
umpolung catalysts has introduced a set of elementary steps
that operate via discrete reactive species, wherein the natural
polarity based reactivity is inverted from electrophilic to
nucleophilic through catalysis. One particularly versatile and
reactive species is the NHC-homoenolate generated upon
addition of the carbene to an enal substrate.3 This species is
nucleophilic at the β-position and thus provides an um-
polung approach for accessing β-anionic carbonyl equivalent.
However, despite the potential progress of this NHC-
homoenolate intermediate, highly activated electrophilic
substrates are required while less activated partners fail to
engage the NHC-homoenolate efficiently.
In recent years, cooperative catalysis by combining transi-
tion metal and organocatalysis has enabled a series of new
enantioselective transformations.4 Importantly, the com-
bined use of transition metal catalyst with organocatalytic
activation modes, such as chiral phase transfer catalyst,5
chiral amine6 or phosphoric acid catalyst,7 has emerged as a
new and powerful strategy. In addition, cooperative activa-
tion of both substrates could allow using less reactive start-
ing materials and consequently enable milder reaction condi-
tions. We envisaged that the cooperative combination of
transition metal catalysis and NHC organocatalysis could
Indeed, several research groups have demonstrated that
NHCs can be combined with a second mode of activation,
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such as Lewis acid catalysis10 or Brønsted acid,11 to enable
1a and enal 2a (Table 1). However, the precatalyst 4a did not
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8
new transformations. Furthermore, racemic intramolecular
transformations were also achieved recently in the combina-
tion of transition metal catalysis and NHC organocatalysis
(Scheme 1A).12 We speculated, however, that a successful
system could be developed, if careful consideration is taken
to avoid mutual deactivation.13
catalyze this transformation (entry 1). Gratifyingly, the use of
chiral triazolium 4b as an NHC precatalyst could lead to the
desired product 3aa in moderate yield with 63% ee (entry 2).
Encouraged by this result, we next evaluated chiral triazoli-
um NHC precatalysts, which displayed remarkable effects on
the outcome of the reaction (entries 2-6). To great delight,
using the newly designed cooperative NHC/Pd system, we
found that the desired annulation product could be forged in
excellent yield and excellent enantioselectivity (99% ee) at
room temperature using 15 mol% of NHC (4c) as an organo-
catalyst along with 5 mol% of Pd(PPh3)4 as allylation catalyst.
However, no improvement in yield was observed for the
reaction by screening different bases and solvents (entries 7-
9, see Supporting Information (SI)). A series of control exper-
iments verified the necessity of each reaction component
(entries 10-12). In the absence of any one of the reaction
components (palladium, NHC precatalyst or base) no prod-
uct was formed.
Our reaction design involves an allylic alkylation process
where an electrophilic allyl-palladium intermediate (I,
Scheme 1B) is generated upon Pd-mediated decarboxylation
of an electrophilic allylic substrate (1a).14 Meanwhile, the
combination of an α,β-unsaturated aldehyde 2 and an NHC
would lead to the nucleophilic homoenolate equivalent (II).
Subsequent nucleophilic addition of the NHC-coordinated
homoenolate (II) in an umpolung process onto the allyl-
palladium species15 followed by cyclization would provide a
powerful route to access enantioenriched benzazepines.
Herein, we describe the development of such a cooperative
catalytic system which combines NHC-mediated umpolung
of an enal substrate with palladium-catalyzed allylic substitu-
tion onto benzoxazinanones. This asymmetric process
demonstrates the compatibility of these two important cata-
lytic modes for the first time and efficiently delivers annulat-
ed 1-benzazepine products with excellent regio- and enanti-
oselectivities. These compounds are key structural motifs in
a range of biologically active natural products and pharma-
ceuticals, such as Tolvaptan, Zilpaterol and Benazepril.16 The
asymmetric synthesis of 1-benzazepine derivatives is also
relatively unexplored despite their importance.17
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Table 2. Functionalization of substituents on the
enalsa
Table 1. Optimization of the reaction conditionsa
entry precat. solvent yield (%)b dr of 3aac ee (%)d
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9
THF
THF
THF
THF
THF
nr
38
86
58
nr
28
56
29
85
nr
-
5:1
12:1
14:1
-
7:1
12:1
15:1
12:1
-
-
4a
4b
4c
4d
4e
4f
4c
4c
4c
-
63
99
98
-
90
96
94
98
-
THF
Toluene
CHCl3
DME
THF
THF
THF
10
11e
12f
aReaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(PPh3)4 (5
mol%), precatalyst 4c (15 mol%), Cs2CO3 (0.2 mmol) and THF (3 mL)
in a sealed Schlenk tube at r.t. for 24 h. benal (4 equiv.).
nr
nr
-
-
-
-
4c
4c
aReactions were conducted with 1.0 equiv of 1a and 2.0 equiv of 2a,
b
c
With the optimal conditions in hand, we next sought to
explore the scope of the enal component in this new
NHC/Pd-catalyzed asymmetric annulation reaction. As
shown in Table 2, a diverse array of electron-donating and
electron-withdrawing enals with a variety of functional
groups (methyl, chloro, nitro, furanyl) performed well in this
synergistic reaction. The corresponding products were isolat-
ed in good yields with excellent ee’s (3aa-3ak). The absolute
configuration of the resulting molecule 3aa was assigned by
single-crystal X-ray diffraction analysis. To test the synthetic
utility of this method, the enantioselective annulation was
conducted on a gram scale and 3aa was produced in compa-
rable yield and selectivity (0.93 g of product, 74% yield, 12:1
24h. Isolated yields after chromatography are shown. Determined
by H NMR spectroscopy. dDetermined by HPLC analysis. eIn the
1
absence of Pd(PPh3)4.fIn the absence of Cs2CO3. nr = no reaction. rt =
room temperature.
On the basis of this synergistic catalysis design plan, we
began our investigations into the proposed NHC/Pd-
catalyzed umpolung annulation using vinyl benzoxazinanone
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dr, 98% ee). Moreover, 4-hydroxycinnamaldehyde was found
strategy,18 giving the corresponding products 3aa in moder-
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5
6
7
to be a competent substrate in this transformation, demon-
strating the diversity of substituents that are tolerated in this
transformation (3aj, 69% yield, 15:1 dr, 98% ee). Notably, this
method was compatible with β-alkyl enals, giving the desired
products in moderate yields and good enantioselectivities
(3al and 3am).
ate yields and excellent enantioselectivity (eq 1, 99% ee). In
contrast, the reaction failed in the absence of Pd(PPh3)4, also
suggesting that a cooperative activation mode in the annula-
tion is operative. Next, the importance of the olefin on the
benzoxazinanone was demonstrated by the inability of ethyl
benzoxazinaone 1n to form π-allyl-palladium species (eq 2).
Table 3. Scope of vinyl benzoxazinanonesa
Scheme 2. Derivatization of benzazepine 3aa
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The optically active benzazepine 3aa could be easily elabo-
rated in different ways, as shown in Scheme 2, highlighting
the synthetic potential of the present method. Hydrogena-
tion of 3aa in the presence of a catalytic amount of Pd/C led
to the reduction of the olefin, providing compound 5 in good
yield with no loss of enantiopurity. In addition, the vinyl
moiety of 3aa underwent cross-metathesis with amylene in
the presence of the Grubbs-Hoveyda II catalyst to generate 6
in 82% yield.
aReaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(PPh3)4 (5
mol%), precatalyst 4c (15 mol%), Cs2CO3 (0.2 mmol) and THF (3 mL)
b
in a sealed Schlenk tube at r.t. for 24 h. enal (4 equiv.).cPhosphine
ligand dppf (10 mol%) and Pd(dba)2 (5 mol%) were used.
The generality of the reaction with respect to the substitu-
ents on the benzoxazinanone coupling partners was also
investigated (Table 3). Both electron-donating and electron-
withdrawing substituents were accommodated on the ben-
zoxazinanone ring with excellent levels of enantioselectivity
(3ba–3ka). A variety of vinyl benzoxazinanones proved to be
excellent electrophiles with 2-furanacrolein (2k) or 4-
methoxycinnamaldehyde(2c) as umpolung coupling partners
in this annulation, and afforded the desired 1-benzazepines
in high yields and excellent enantioselectivities (3bk-3jc).
Figure 1. Proposed cooperative catalytic cycle
A plausible mechanistic cycle, in which palladium catalysis
intertwines with asymmetric NHC organocatalysis, is out-
lined in Figure 1. This challenging “cooperative activation”
concept was successfully realized through concomitant cata-
lytic generation of two reactive species: a nucleophilic NHC-
homonenolate (B) and a highly electrophilic allyl-palladium
cation (A). Herein, the catalysis is initiated by the coordina-
tion of vinyl benzoxazinanone 1a to the palladium catalyst,
followed by the formation of an electrophilic allyl-
To further demonstrate the utility of this cooperative ca-
talysis strategy, we investigated the direct annulation of
acyclic substrates with enals. 3-(2-aminophenyl)allyl acetate
1m was also accommodated in this cooperative umpolung
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
glorius@uni-muenster.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors acknowledge financial support from the Alexan-
der von Humboldt Foundation (C. G.), Deutsche For-
schungsgemeinschaft (IRTG 2027, Leibniz award). The au-
thors also thank Dr. Mattew N. Hopkinson and Dr. Kathryn
M. Chepiga for discussions and corrections during the prepa-
ration of the manuscript.
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