Highly Enantioselective [5 + 2] Annulations through Cooperative N-Heterocyclic Carbene (NHC) Organocatalysis and Palladium Catalysis

Article abstract of DOI:10.1021/jacs.8b00868

The highly enantioselective [5 + 2] annulation of enals with vinylethylene carbonates through a cooperative N-heterocyclic carbene (NHC)/Pd catalytic system is reported. The use of a bidentate phosphine ligand was crucial to prevent coordination of the NH

Full text of DOI:10.1021/jacs.8b00868

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Communication
Highly Enantioselective [5+2] Annulations through
Cooperative NHC Organocatalysis and Palladium Catalysis
Santanu Singha, Tuhin Patra, Constantin G. Daniliuc, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b00868 • Publication Date (Web): 22 Feb 2018
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Highly Enantioselective [5+2] Annulations through Coopera-
tive NHC Organocatalysis and Palladium Catalysis
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Santanu Singha, Tuhin Patra, Constantin G. Daniliuc and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraβe 40, 48149 Münster,
Germany
ABSTRACT: The highly enantioselective [5+2] annulation of enals with vinylethylene carbonates through a cooperative
NHC/Pd catalytic system is reported. The use of a bidentate phosphine ligand was crucial to prevent coordination of the
NHC organocatalyst to the active Pd catalyst. The complementary and matched combination of the chiral NHC catalyst
and
chiral
phosphine
ligand
promotes
high
levels
of
both
reactivity
and
enantioselectivity.
NHC organocatalysis is a powerful tool for the construc-
tion of complex chiral molecules from simple and readily
available starting materials.1 However, NHC organocataly-
sis is typically limited to established substrate classes and
reaction partners. The incorporation of a second coopera-
tive catalyst could alleviate this limitation by enabling a
diverse range of new reaction partners to be used and
thus to provide access to fundamentally new transfor-
mations. Although there have been reports using NHCs
with a second activation mode to promote elusive reactiv-
ity,2 most of these studies are limited to the incorporation
of a cooperative Lewis acid3 or Brønsted acid catalyst.4
The use of a transition metal (TM) with an NHC organo-
catalysis in a cooperative fashion is still very rare,5 primar-
ily because the organocatalyst carbene has a strong affini-
ty to bind with the TM,6 which typically results in the
destruction of their desired individual reactivity. Consid-
ering this, the design of a dual catalytic system where
both TM catalyst and NHC catalyst will work in synergy
remains a formidable challenge. Recent pioneering stud-
ies from the group of Scheidt7 to synthesize allylated di-
hydrocoumarins in an intramolecular and racemic fashion
(Scheme 1A), followed by the report from our group on
enantioselective and intermolecular [4+3] annulation
reactions8 (Scheme 1B), are among the very first examples
of dual catalytic systems involving a palladium catalyst
and an NHC organocatalyst. Detailed mechanistic studies
on the latter system revealed that the NHC, besides its
role as an organocatalyst, also fortuitously acts as a ligand
on the active metal catalyst (formation of a mixed ligand
metal complex, Scheme 1B).8b In this context, we ques-
tioned whether it was possible to develop a dual catalytic
system where the ligation of NHC to the TM is prevented
and the NHC is only operative in the organocatalytic
cycle. This would significantly aid the development of
new enantioselective transformations by allowing the
fine-tuning of both the catalytic systems. Based on this
strategy, we report herein the first example of such
NHC/TM cooperativity to generate challenging ε-
caprolactones in a highly enantioselective fashion.
To date, synthesis of seven membered rings or higher,
especially in an enantioselective fashion,9 is a considera-
bly challenge in organic synthesis due to both unfavorable
entropy effects and transannular interactions.10 Here, we
envisioned that an annulation between a transition metal
activated electrophile and a NHC bound nucleophile
would enable the synthesis of these challenging products
with high levels of enantioselectivity.
Scheme 1. NHC/Pd dual catalytic enantioselective
annulation strategy
To validate this idea, we sought to use a substituted vi-
nylethylene carbonate (VEC) for the formation of an elec-
trophilic π-allyl-palladium intermediate (I) upon Pd-
mediated decarboxylation.11,12 Meanwhile, an α,β-
unsaturated aldehyde in combination with NHC would
form a homoenolate (II) or enolate intermediate (III),13
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Table 1. Reaction optimizationa
using an achiral NHC in combination with a second chiral
catalyst.3a,4a
1
2
3
Table 2. Scope of [5+2] annulation reactiona
4
5
6
7
Phos
phine
Yield
Ratio
ee
Entry
Precat.
Base
3aa (%)b
3aa:5aac
(%)d
1e,f
2e
3e
4
4a
4a
4a
4a
4a
4a
4b
PPh3
L1
K2CO3
K2CO3
K2CO3
NMPi
NMPi
DBU
-
-
1:2
-
8
9
20
55
70
76
-
98
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11
12
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60
L2
6:1
>99
>99
>99
-
L2
14:1
22:1
-
5
L3
6
L3
7
L3
NMPi
18
>20:1
94
aConditions: 1a (0.1 mmol), 2a (0.15 mmol). bYields determined by 1H
c
1
NMR using CH2Br2 as internal standard. Determined by H NMR.
dDetermined by HPLC using
a chiral column. NMPi = N-
Methylpiperidine. rt = room temperature. eEt2O as solvent. 12 mol%
PPh3.
f
which could nucleophilically attack this π-allyl-palladium
species and subsequently cyclize to form either a 7- or 8-
membered lactone product.
Our studies began by the reaction of phenyl vinylethylene
carbonate (1a), trans-cinnamaldehyde (2a) with NHC
precatalyst 4a and monodentate PPh3, from which no
product was detected (Table 1, entry 1). Realizing that
NHC 4a could easily compete the weakly coordinating
PPh3 for ligation to Pd,7 we switched to a more strongly
chelating bidentate ligand L1, which resulted in the for-
mation of the desired [5+2] annulation product (3aa) in
20% yield and with excellent ee (entry 2). Interestingly, as
3aa also contains an allylic carboxylate linkage, the γ-
lactone 5aa (cis:trans = 1.4:1) was also formed under the
reaction condition via a Pd catalyzed allylic rearrange-
ment of 3aa. In order to suppress the formation of 5aa a
variety of other bidentate phosphine ligands were exam-
ined and (R)-BINAP (L2) was found to improve the ratio
of 3aa:5aa to 6:1, increasing the yield of 3aa to 55% (˃99%
ee). Furthermore, the use of the weak amine base N-
methylpiperidine and toluene as solvent improved the
yield of 3aa to 70% (entry 4). Finally, using more bulky
and electron-rich ligand (R)-Tol-BINAP (L3) afforded the
desired product 3aa in 76% yield (entry 5). The use of
stronger bases, such as DBU (known to favor homoeno-
late reactivity),13f completely inhibited the reaction (no
trace of 7- or 8-membered lactone) (entry 6). Interesting-
ly, when the reaction was carried out with achiral NHC 4b
and chiral phosphine L3, the product 3aa was formed in
18% yield but with very good enantioselectivity (94% ee,
entry 7). To the best of our knowledge, this is the first
example of a highly enantioselective reaction performed
aConditions: 1 (0.2 mmol), 2 (0.3 mmol), Toluene (0.1
(ratio of 3:5cis after isolation mentioned in parenthesis as cis isomer
of γ-lactone formed an inseparable mixture with 7-membered lac-
tone product). bAt 15 oC for 15 h. cEnal 2e (0.8 mmol).
M), rt, 10-12 h
With the optimized conditions in hand, the scope with
respect to the VEC was examined. A range of VECs con-
taining electron-donating as well as electron-withdrawing
groups at the para-position of the phenyl ring (R2) per-
formed well in this reaction to deliver the corresponding
annulated products (Table 2, 3aa-3ia) in good yield and
with excellent enantioselectivity (mostly ˃99% ee). The
absolute configuration of 3aa was unambiguously con-
firmed by single-crystal X-ray diffraction analysis. Substi-
tution at the meta-position as well as dioxolane fused
phenyl ring were well tolerated (3ja and 3ka). Polyaro-
matic and heteroaryl substituted VECs were also compat-
ible (3la-3oa). A styryl substituted VEC was used to afford
lactone (3pa) in 67% yield and with >99% ee. Notably,
secondary alkyl substituted vinyl carbonate was tolerated
to give lactone (3qa) in 62% yield and with excellent ee
(99%). Alkyl substituents on both enal and VEC were also
tolerated to afford the product (3qb) in good yield and
with high enantioselectivity (99% ee). Finally, primary
alkyl groups were also compatible, as demonstrated with
the synthesis of lactone product (3rb) in high ee (99%)
although in diminished yield (30%).
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Next, the generality of the enal in this annulation reaction
3aa was indeed increased to 68% (>99% ee). The above-
mentioned studies indicate that the [((R)-BINAP)Pd]
complex is likely to be the active metal catalyst in this
reaction. To further validate our hypothesis that the NHC
is not ligating Pd, we searched for non-linear effects8b
using NHC 4a and an achiral bidentate phosphine L1 and
as per our expectation, we did not observe any non-linear
effect in the reaction.14
Next, we demonstrated the importance of matching both
the chiral NHC (4a) with the chiral phosphine (L2) for
enantioinduction. First, we performed the reaction with
(S)-BINAP instead of (R)-BINAP, from which we observed
only slight conversion of 2a and the formation of product
3aa in just 5% yield (55% ee, eq 1). However, when rac-
BINAP was used, 3aa was obtained in an improved 50%
yield and with 98% ee, which strongly indicates that (R)-
BINAP is the matched and most active ligand in this reac-
tion. All these results suggest that there is a strong match-
mismatch scenario. Furthermore, we have already shown
during the optimization studies that both NHC and
phosphine contribute towards the enantioselectivity as it
can be controlled by using either a chiral NHC catalyst
with an achiral phosphine (Table 1, entry 2) or a chiral
phosphine with an achiral NHC (Table 1, entry 7).
1
2
3
4
5
6
7
8
was examined. Simple aliphatic enals with different alkyl
groups at the β-position were well tolerated, providing
the corresponding products (3mb-3md) in very high
yields and with high enantioselectivity. Gratifyingly acro-
lein was also a viable substrate, affording the product
(3me) in moderate yield (52%) with excellent enantiose-
lectivity (˃99%). For aryl enals, electron-donating (OMe)
as well as electron-withdrawing groups (F, Cl) on the
phenyl ring were well suited to deliver lactone products
(3mf-3mh) in good yields and in all cases with excellent
enantioselectivity.
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In order to gain insight about the active palladium species
involved in this reaction, we first independently synthe-
sized [((R)-BINAP)Pd(η3-allyl)]BF4 (6) and [(NHC
4a)Pd(η3-allyl)]Cl (8) complexes. When we carried out
ESI-MS analysis of the crude reaction solution obtained
by mixing VEC 1a with complex 6, we observed the corre-
sponding π-allyl-palladium intermediate 7 in the mass
spectrum (Scheme 2A). In contrast, by mixing complex 8
and carbonate 1a, no mass of the corresponding allyl-
palladium species 9 was observed, indicating the incom-
petency of complex 8 in decarboxylation of 1a.
Scheme 2. Mechanistic studies
Based on these preliminary mechanistic investigations, we
assume that the reaction begins with the formation of the
extended Breslow (or homoenolate) intermediate A (Fig-
ure 1), followed by facile β-protonation to form the (Z)-
enol intermediate B with the top face blocked by the
substituents on NHC. In another cycle, upon Pd-mediated
decarboxylation, VEC 1a forms the intermediate C whose
bottom face is shielded by the phosphine.12c Finally, nu-
cleophilic attack from enol B to the terminal position of
the Pd-π-allyl moiety of C (via hydrogen bonded transi-
tion state D)14 followed by cyclization, delivers 3aa and
regenerates the free NHC and Pd catalysts.
When complex 8, (R)-BINAP (L2) and VEC 1a were mixed,
again the mass of 7 was observed along with the mass of
complex 6 and free NHC but no mass peak corresponding
to the allyl-Pd intermediate (generated upon decarboxyla-
tion of 1a) with mixed ligands (both NHC and (R)-BINAP)
was observed.14 The reaction could also be performed with
a catalytic amount of complex 6 and NHC 4a to afford
lactone 3aa in 70% yield (>99% ee), thus proving the
catalytic competency of complex 6 (Scheme 2B). When
the experiment was repeated with complex 8 and L2, 3aa
was obtained in 22% yield (>99% ee); this diminished
yield is probably because of the lower levels of free NHC
generated by slow ligand exchange from complex 8 by L2.
In support of this, when 10 mol% of precatalyst 4a was
added under otherwise identical conditions, the yield of
Figure 1. Proposed dual catalytic cycle
The potential synthetic utility of this protocol was then
demonstrated through the facile diversification of optical-
ly active lactone 3aa (Scheme 3). In all cases, no loss of
enantioselectivity was observed.
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Scheme 3. Diversification of 3aa
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9
Conditions: (i) Pd2(dba)3 (2 mol%), L1 (5 mol%), Toluene, 50 oC, 12 h;
(ii) DIBAL-H (3.0 equiv.), CH2Cl2, rt, 2 h; (iii) mCPBA (1.8 equiv.),
CH2Cl2, rt, 24 h; (iv) 10% Pd-C, H2 (1 bar), EtOAc, rt, 30 min.
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In conclusion, we have developed the first highly enanti-
oselective [5+2] annulation of an NHC enolate and a π-
allyl-palladium intermediate via a dual catalytic process.
Mechanistic studies revealed that use of a bidentate
phosphine ligand was crucial to prevent the binding of
NHC to the transition metal and thereby the success of
this transformation. Overall, we hope that this study will
aid the development of dual catalytic systems based on
transition metal-/organo-catalysis and enable the discov-
ery of new asymmetric transformations.
ASSOCIATED CONTENT
Experimental procedures, spectroscopic data and crystallo-
graphic data (CCDC 1588167). This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
glorius@uni-muenster.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Generous financial support by the Deutsche Forschungsge-
meinschaft (Leibniz Award), the Alexander von Humbolt
Foundation (T.P.) are gratefully acknowledged. We thank
Tobias Knecht, Dr. Zackaria Nairoukh, Dr. Michael J. James,
Adrian Tlahuext-Aca and Dr. Mirco Fleige (University of
Münster) for helpful discussions.
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46
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50
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5
ACS Paragon Plus Environment