A cooperative N-heterocyclic carbene/palladium catalysis system

Article abstract of DOI:10.1039/c4sc01536c

N-heterocyclic carbenes (NHC) have been extensively studied as organocatalysts and ligands for transition metals, but the successful integration of NHCs and late transition metals in cooperative catalysis remains an underexplored area. We have developed a cooperative palladium-catalyzed allylation of NHC-activated aldehydes to access a variety of 3-allyl dihydrocoumarin derivatives. Kinetic experiments support a cooperative pathway for this transformation.

Full text of DOI:10.1039/c4sc01536c

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A cooperative N-heterocyclic carbene/palladium
catalysis system†
Cite this: Chem. Sci., 2014, 5, 4026
*
Kun Liu, M. Todd Hovey and Karl A. Scheidt
N-heterocyclic carbenes (NHC) have been extensively studied as organocatalysts and ligands for transition
metals, but the successful integration of NHCs and late transition metals in cooperative catalysis remains an
underexplored area. We have developed a cooperative palladium-catalyzed allylation of NHC-activated
aldehydes to access a variety of 3-allyl dihydrocoumarin derivatives. Kinetic experiments support a
cooperative pathway for this transformation.
Received 24th May 2014
Accepted 20th June 2014
DOI: 10.1039/c4sc01536c
www.rsc.org/chemicalscience
Pd-catalyzed allylations5 with a,b-unsaturated aldehydes under
carbene catalysis conditions could facilitate rapid access to
Introduction
synthetically valuable products, specically dihydrocoumarin
derivatives. number of methods for accessing dihy-
The integration of two distinct catalytic pathways in a single
ask is a powerful strategy in chemical synthesis.1 Through
independent activation of separate nucleophilic and electro-
philic species, this synergistic approach makes possible previ-
ously inaccessible transformations and can improve existing
chemical reactions. In particular, the fusion of transition metal
and organocatalysis concepts has become a major research
endeavor over the last decade.1 Although there has been
remarkable progress in this area, the combination of
N-heterocyclic carbenes (NHCs)2 with late transition metals
remains underexplored, and more importantly, quite counter-
intuitive given the strong propensity for NHCs to bind to tran-
sition metals with high affinity. While cooperative catalysis with
NHCs and Lewis or Brønsted acids has been shown to increase
reactivity and afford products with unprecedented levels of
selectivity,3 the incorporation of NHCs with late transition
metals (TMs) presents a considerable challenge due to the
potential for the formation of stable NHC–TM complexes
(Fig. 1),4 which do not possess the desired catalytic activity.
A
drocoumarins have been developed6 as this structural motif is
prevalent in natural products and biologically relevant small
molecules.7 However, few methods exist to prepare 3-allylated
dihydrocoumarins,8 and surprisingly the direct allylation of
dihydrocoumarins is un-explored.9 It is clear that new catalytic
methods to directly access this important molecular scaffold are
necessary to facilitate structural diversication and efficient
assembly of bioactive compounds. Herein we report the devel-
opment of the novel cooperative NHC/TM strategy for the
synthesis of allylated dihydrocoumarin derivatives through
allylation and subsequent acylation of aldehyde 1a. The acti-
vation of the a,b-unsaturated aldehyde moiety within 1a
through NHC catalysis and capture of a cationic Pd[p-allyl]Ln
Plan
Given the background above, we were motivated by the oppor-
tunity to harness the unconventional reactivity of NHCs with
the assistance of transition metals to effect new chemical
transformations. A highly desired objective is the addition of
NHC-bound nucleophiles to TM-activated electrophiles. As
proof of a concept to this general approach, the combination of
Department of Chemistry, Center for Molecular Innovation and Drug Discovery,
Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road,
Evanston, IL 60208, USA. E-mail: scheidt@northwestern.edu; Fax: +1-847-467-2184
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data for all new compounds. CCDC 969294. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c4sc01536c
Fig. 1 NHC/transition metal cooperative catalysis.
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Table 1 Optimization of reaction conditionsa
complex in a cooperative fashion facilitates access to dihy-
drocoumarins 2a or 3a through an enolate or homoenolate
pathway, respectively.
Results and discussion
Initially, we investigated the intermolecular reaction of 4 with
allyl carbonate 6 using our proposed cooperative NHC–Pd
catalysis system (eqn (1)). Aer extensive optimization, allylated
dihydrocoumarin 2a could be obtained in 50% yield, but with
dihydrocoumarin 5 as a competing side product in 31% yield.
Further investigation showed that omitting 6 from the reaction
mixture yielded the undesired dihydrocoumarin 5 in 87% yield.
With the robustness of this competing pathway uncovered,6e an
alternative strategy was deemed necessary to move forward with
our reaction development.
Entry
Azolium
Ligand (mol %)
Base (mol %)
Yieldb (%)
1
2
3
4
5
6
7
8
A
A
A
B
C
D
A
A
A
A
PPh3 (16)
PPh3 (16)
PPh3 (16)
PPh3 (16)
PPh3 (16)
PPh3 (16)
JohnPhos (16)
BINAP (8)
dppf (8)
DBU (20)
14
24
31
5
i-Pr2NEt (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (20)
K2CO3 (10)
4
—
49
19
56
61
9
10c
dppf (8)
a
b
See ESI. Determined by 1H NMR integration (500 MHz, PhSiMe3 as
c
an internal standard). 20 mol % azolium A.
(1)
in the heightened reactivity of the allyl moiety towards the
enolate.12 There is a balance between angle and yield since
DPE-Phos (natural bite angle ¼ 131ꢀ) afford decreased yields
(see ESI† for details). Other Pd sources have been evaluated
(such as [Pd(allyl)Cl]2 or Pd(OAc)2) with dppf as ligand, however
reactions evaluated with these sources of Pd(0) afforded
decreased yields of the desired product. Further evaluation of
reaction solvents did not improve the yield of 2a, with polar
solvents observed to depress reaction efficiency signicantly
(see ESI† for details). Finally, upon modication of the stoi-
chiometry of the azolium and base, the yield could be further
improved to 61% (entry 10).
We hypothesized that the phenolic proton promotes the
tautomerization of the NHC-enolate to the NHC-acyl adduct,
which leads to the undesired dihydrocoumarin 5. To overcome
this limitation, we envisioned using O-alloc aldehyde 1a to
inhibit the formation of dihydrocoumarin 5. By masking the
phenol with the allyl source, allylation of NHC-enolate inter-
mediate would be the preferred pathway. With this hypothesis,
we turned our focus toward utilizing aldehyde 1a in our coop-
erative catalysis system. Initial investigation with A (IMesCl)
and DBU, followed by addition of a solution of Pd2(dba)3 and
1
PPh3, provided enolate product 2a (14% yield by H NMR inte-
gration, Table 1, entry 1). The homoenolate adduct 3a (7% yield
by 1H NMR integration, not shown) was also detected. In an
effort to suppress formation of the homoenolate product (3a), a
Table 2 Evaluation of the role of the reaction components
¨
variety of bases were screened. Both Hunig's base and potas-
sium carbonate gave solely the enolate product, with the latter
resulting in a slightly higher yield (entry 2 and 3). Different NHC
precatalysts were also evaluated, but only the NHC derived from
A was found to be competent in this transformation (entry 4–6).
Gratifyingly, the use of a large cone angle ligand, JohnPhos,
(246ꢀ) led to an improved yield of 49% (entry 7).10
We hypothesized that a bidentate ligand would coordinate
strongly with palladium, thus minimizing Pd–NHC ligation. We
initially explored the use of BINAP (natural bite angle (ref. 11) ¼
92ꢀ), but were disappointed to obtain dihydrocoumarin 2a in a
diminished 19% yield (entry 8). However, with dppf (natural
bite angle ¼ 99ꢀ) as the ligand, enolate product 2a was gener-
ated in 56% yield (entry 9). This result is consistent with
observations that support the role of a larger natural bite angle
Variation of the standard
conditions
Entry
Resultsa
1
2
3
4
5
None
61% yield 2a
76% yield 7
69% recovered 1a
62% recovered 1a
56% yield 2a
No IMes (A)
No Pd2(dba)3
No ligand (dppf)
No base (k2CO3)
a
1
Yield determined by H NMR integration of the unpuried reaction.
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discounts the serial pathway and fully supports a cooperative
catalysis mechanism (vide infra).
To support formation of the Pd[p-allyl]Ln complex, deuter-
ated aldehyde 8 was subjected to the optimized reaction
conditions. The resultant allylated products were obtained as a
1 : 1 mixture of regioisomers 9 and 10 (eqn (3)). Moreover, when
an equimolar amount of aldehyde 8 was mixed with 1b under
the standard reaction conditions, cross-over products were
observed (see ESI† for details).15 These results, together with the
information gained from the control experiments, support the
initial formation of a Pd[p-allyl]Ln complex. In an effort to
understand the kinetics of ion exchange within the reaction,
aldehyde 11 was prepared and combined with 1b in a 1 : 1 ratio
under the standard conditions (eqn (4)). Only two products were
obtained from this experiment: the non-cross-over product (2b)
derived from aldehyde 1b in 29% yield and the cross-over
product (2a) from starting aldehyde 11 in 19% yield. The results
from the cross-over experiment indicate that although ion
exchange is rapid, the interaction between the phenoxide ion
and Pd[p-allyl]Ln complex is important as the non-cross-over
product is favored in the reaction.
Fig. 2 Fate of aldehyde 7 during the reaction.
In control experiments, we observed that in the absence of
NHC (A), aldehyde 7 was formed exclusively (Table 2, entry 2),
while the omission of either dppf or Pd2(dba)3 from the reaction
resulted in the recovery of the aldehyde starting material (Table
2, entry 3 and 4). Surprisingly, when the reaction was conducted
without an exogenous base, only a slight decrease in the yield of
allylation product 2a was observed. Typically a base is required
in NHC-catalyzed transformations to generate the active car-
bene, however, we hypothesize that in this case, the in situ
generated phenoxide can serve this role competently (Table 2,
entry 5).13
The rapid production of aldehyde 7 under palladium catal-
ysis conditions prompted us to investigate if 7 is a competent
intermediate in the cooperative pathway. Thus, the exposure of
7 to the standard reaction conditions resulted in formation of
dihydrocoumarin 2a, but in a signicantly lower yield (31%). To
further clarify if aldehyde 7 is a productive intermediate, the
reaction was carried out under the standard conditions using
GC-MS to monitor the presence of 1a, 7 and allylated adduct 2a
(Fig. 2).14 This experiment indicated that the starting aldehyde
was almost completely consumed aer 1 hour, during which
time aldehyde 7 accumulated and then was consumed. At pro-
longed reaction times (>100 min), the disappearance of alde-
hyde 7 corresponds approximately with the formation of
desired product 2a, demonstrating that the allylation of the in
situ generated phenoxide is faster than allylation of NHC-bound
enolate.
During our study, the formation of the undesired parent
dihydrocoumarin 5 was detected in approximately 10% yield.
This product could also serve as an intermediate en route to the
desired product 2a through a serial process in which the NHC
catalyzed unsubstituted coumarin formed rst, followed by Pd-
catalyzed allylation. Thus, dihydrocoumarin 5 was combined
with aldehyde 1b under the standard reaction conditions (eqn
(2)). The exclusive formation of 2b and quantitative recovery of 5
Based on the mechanistic investigations, we hypothesized
that increasing the concentration of the allyl electrophile could
improve the yield of the desired product (Table 3). Starting from
carbonate 6, we systematically screened phenolic allyl carbon-
ates arriving at carbonate 14 as the best allyl source additive. We
hypothesize that the subtle electronic effect of the ortho-chloro
substituent on the acidity of the phenol moiety plays a
crucial role in this result, but all experiments to probe this
empirical observation have proven inconclusive to date. This
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Table 3 Substrate scopea
Scheme 1 Proposed reaction pathway.
a
aldehyde 1a is rapidly consumed, we hypothesize that rate of
palladium insertion is more facile than addition of the NHC to
aldehyde 1a, resulting in formation of intermediate I or alde-
hyde 7 (formed Pd-allyl formation/allylation). Fortuitously,
either aldehyde I or 7 can enter into the catalytic cycle. The NHC
undergoes addition to either aldehyde I or 7 to generate
extended Breslow intermediate IIA or IIB, respectively. At this
point, NHC-bound homoenolate IIA can undergo either b-
protonation to generate catalytic enol intermediate III, or ally-
lation to arrive at an alternate catalytic enol to ultimately yield
the undesired homoenolate product 3a. Alternatively, b-
protonation and palladium insertion of IIB can occur to afford
the common enol intermediate III. The ionic interaction
between the in situ generated phenoxide anion and cationic Pd
[p-allyl]Ln species allows for pseudo-intramolecular allylation17
of the NHC-enol to generate acyl azolium IV, with concomitant
regeneration of the Pd catalyst. Current data suggests that this
ionic interaction is critical to achieve C–C bond formation over
acylation of phenoxide V, which would instead furnish unde-
sired dihydrocoumarin 5. Finally, intramolecular acylation of
allylated acyl azolium IV affords the desired product 2a and
regenerates the NHC catalyst.
See ESI for details. Reactions were carried out on 0.4 mmol scale (0.2 M
in degassed CH2Cl2). b 0.1 M in degassed CH2Cl2. c 20 mol% 1,3-bis(2,6-
diethylphenyl)imidazolium chloride used instead of A.
modication, in combination with increasing the amount of
palladium, afforded enolate allylation product 2a in an
improved 71% isolated yield. With these optimized conditions,
we explored the scope of this cooperative NHC/transition metal-
catalyzed transformation. We found that the electronic char-
acter of the allylation precursor greatly affected the reaction
outcome. We discovered that aldehydes with electron-donating
groups provided the corresponding products in good yield (2a–
2m). In certain cases, the yield of the allylated dihydrocoumarin
could be increased by conducting the reaction at reduced
concentration (2j–2m). We observed that aldehydes with elec-
tron-withdrawing groups on the phenol moiety provided lower
yields with precatalyst A. One possible explanation is that
weaker binding of the electron-decient phenoxides to the Pd
[p-allyl]Ln species leads to lower reactivity. For substrate alde-
hyde 1n, replacing the N-mesityl moieties of the imidazolium
precatalyst with 2,6-diethylphenyl increased the yield of 2n
slightly. This effect was also observed for chloro-substituted
aldehyde 1o and was necessary to obtain 2o in moderate yield.
This precatalyst effect was not observed for electron neutral
aldehyde 1a. The substitution of the allyl moiety was also
explored and found to be detrimental to reactivity. This limi-
tation is similar to many reported transition metal-catalyzed
allylation methods16 and is likely a result of unfavorable steric
Conclusions
In conclusion, a new cooperative NHC/TM catalysis approach
has been developed. This proof of concept process involves the
combination of an NHC-generated nucleophile with a TM-acti-
interactions. Investigations to understand this current restric- vated electrophile. Successful realization of this strategy
tion with our NHC/Pd platform are ongoing.
required judicious choice of the reaction components to
Based on the mechanistic studies above, the current under- maintain the operability of the NHC and TM$ligand complex
standing of this allylation process is shown in Scheme 1. Since as separate, operative catalytic entities. Multiple control
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experiments provide strong evidence for the proposed cooper-
ative catalysis pathway. These investigations also provided
insight into the role of ion exchange in this transformation,
prompting an increase in the concentration of the allyl elec-
trophile and resulting in an improvement in efficiency. This
system documents the feasibility of using NHCs and late TMs in
a cooperative fashion and further exploration of this catalysis
strategy involving N-heterocyclic carbenes and transition metals
is underway.
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allylation due to the presence of proposed intermediate III,
which involves an ion pair. However, since ion exchange
can occur, this is not a classic intramolecular allylation
reaction. However, an alternative mechanism would be
more inner-sphere with coordination of the NHC enolate
to the pi-allyl Pd species. This assembly would provide a
more intramolecular pathway. For a relevant detailed study
of enolate/pi allyl Pd coordination, see: J. A. Keith,
D. C. Behenna, N. Sherden, J. T. Mohr, S. Ma,
S. C. Marinescu, R. J. Nielsen, J. Oxgaard, B. M. Stoltz and
W. A. Goddard, J. Am. Chem. Soc., 2012, 134, 19050–19060
and references cited therein.
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