Cooperative N-Heterocyclic Carbene/Palladium-Catalyzed Umpolung 1,4-Addition of Vinyl Bromides to Enals

Article abstract of DOI:10.1021/acs.orglett.0c03654

A highly stereoselective umpolung 1,4-addition of vinyl bromides to enals is enabled by NHC/palladium cooperative catalysis, generating various valuable γ,δ-unsaturated carbonyl derivatives in excellent yields (up to 90%). A detailed mechanism investigation indicates the NHC act as both organocatalyst and ligand for palladium during this system.

Full text of DOI:10.1021/acs.orglett.0c03654

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Letter
Cooperative N‑Heterocyclic Carbene/Palladium-Catalyzed
Umpolung 1,4-Addition of Vinyl Bromides to Enals
Bo Ling,∥ Wenjun Yang,∥ Yan-En Wang, and Jianyou Mao*
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ABSTRACT: A highly stereoselective umpolung 1,4-addition of
vinyl bromides to enals is enabled by NHC/palladium cooperative
catalysis, generating various valuable γ,δ-unsaturated carbonyl
derivatives in excellent yields (up to 90%). A detailed mechanism
investigation indicates the NHC act as both organocatalyst and
ligand for palladium during this system.
Scheme 1. Cooperative NHC/Palladium Catalysis
n the past two decades, N-heterocyclic carbene (NHC)
organocatalysts have been demonstrated to be a powerful
I
and versatile synthesis tool1 for the exceptional umpolung
reactivity via acyl anions,2 homoenolate equivalents,3 or
enolate intermediates.4 However, the reaction partner is
typically limited to strong electrophiles such as active ketones,
imines, Michael acceptors, and many others.5 The synergistic
merger of NHC catalysis with transition-metal (TM) catalysis
could relieve this limitation by enabling broader electrophiles
to be employed and thus to streamline previously inaccessible
transformations.6 NHCs are conventionally important ligands
and can irreversibly bind to TM with high propensity and
strong affinity,7 making their individual catalytic reactivity
disrupted. Recently, several groups have overcome such
problems and achieved the dual catalysis of NHC with
palladium,8 ruthenium,9 copper,10 and iridium11 catalysts.
Among them, the cooperative NHC/Pd catalysis, where the
two catalytic cycles intersect at the bond-forming step, have
drawn a lot interest. Specifically, Scheidt and co-workers
reported the intramolecular allylation of NHC-bound enolate
to Pd-activated allylic electrophiles, achieving allylated
dihydrocoumarin derivatives by a new strategy (Scheme
1a).8b Liu and co-workers described the intermolecular
allylation of active (O-azaaryl)carboxaldehydes to simple allyl
acetates, followed by an alkene isomerization/conjugate
addition process (Scheme 1a).8c,d Remarkably, cyclic allylic
substrates were introduced to the dual NHC/Pd catalysis by
Glorius’ group for the construction of chiral seven membered
ring compounds (Scheme 1a).8e,g More recently, Ohmiya and
co-workers reported the benzylation or allylation of widely
available alkyl aldehydes (Scheme 1a).8h,j
(Scheme 1b). Motivated by exploring new electrophiles for
reactions with NHC-activated intermediates, we herein
disclose an efficient and highly stereoselective umpolung 1,4-
addition of enals with vinyl bromides enabled by NHC/
palladium cooperative catalysis (Scheme 1c), leading to γ,δ-
unsaturated carbonyl derivatives, which serve as valuable
intermediates in the synthesis of natural products,12 hetero-
cycles,13 cyclic alkanes,14 and therapeutics.15 Noteworthy, extra
phosphine8a,j ligand or pyridine derivatives8k are not necessary
during this transformation to keep NHC from being fully
coordinated by palladium, further demonstrating the compat-
ibility between NHC and palladium catalysis. Compared to
Received: November 3, 2020
However, these examples only uncover Pd(π-allyl) and
related intermediates as feasible partners with NHC in
cooperative catalysis (Scheme 1a). Very recently, our group
reported an umpolung 1,4-addition reaction,8k showing that
less reactive electrophile aryl iodide is also a candidate
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© XXXX American Chemical Society
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A

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traditional conjugate addition for building homoallylic carbon-
yl compounds, this strategy applies vinyl halides directly
instead of their organometallic derivatives, such as magnesium
and boron regents, which require extra processes and are
moisture sensitive.
We began our studies by the reaction of trans-cinnamalde-
hyde (1a), β-bromostyrene (2a) with NHC precatalyst N1,
tridentate ligand terpy, and Pd2(dba)3. Gratifyingly, the dual
catalysis worked well, and the desired γ,δ-unsaturated ester 3aa
with a trans configuration was obtained in 45% assay yield (AY,
determined by 1H NMR integration of the unpurified reaction
mixture against an internal standard, Table 1, entry 1).
necessary.8k These changes highlight the different reactivity
between aryl iodides and vinyl bromides. The optimized
conditions are 3 equiv of enal, 1 equiv of β-bromostyrene, 1.5
equiv of KOtBu, 5 mol % of [(cinnamyl)PdCl]2, and 15 mol %
of N1 in THF/MeOH (20:1) at room temperature for 12 h.
Under the optimized reaction conditions, the scope with
respect to bromoalkyene was examined (Scheme 2). It was
a,b
Scheme 2. Substrate Scope of Bromoalkyenes
a
Table 1. Reaction Optimization
b
entry
Pd source
Pd2(dba)3
Pd(PPh3)4
NHC
solvent
THF
THF
THF
THF
THF
THF
THF
2-MeTHF
1,4-dioxane
toluene
DCE
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
AY
1
2
3
4
5
6
7
8
N1
N1
N1
N1
N2
N3
N4
N1
N1
N1
N1
N1
N1
N1
−
45
trace
35
Pd(OAc)2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
−
55
8
trace
trace
59
9
33
24
5
76
10
11
a
Reaction conditions: 1a (0.3 mmol), 2 (0.1 mmol), [(cinnamyl)-
c
12
d
PdCl]2 (5 mol %), precatalyst N1 (15 mol %), KOtBu (0.15 mmol),
MeOH (100 μL), and THF (2 mL) at rt for 12 h. Yields of isolated
b
13
88
14
15
16
trace
trace
91
and purified products.
[(cinnamyl)PdCl]2
[(cinnamyl)PdCl]2
d,e
N1
a
found that a broad range of β-bromostyrenes bearing electron-
withdrawing (Br, F, Cl, CF3) and electron-donating groups
(OMe, Me) on the arene rings were all tolerated to give the
desired β-vinylation products 3ab−3ag in good yields ranging
from 54% to 80% and with excellent stereoselectivity (>20:1
Z/E). So was the parent β-bromostyrene (1a), of which the
reaction afforded 3aa in 88% isolated yield. Methoxy, methyl,
and chloro at the ortho, meta positions were all accommodated,
generating the corresponding products 3ah−3aj in 68−78%
yields. γ,δ-Unsaturated esters containing thiophene, 1,3-
benzodioxole, and naphthalene groups (3ak−3am) could be
prepared in moderate to excellent yields. It is noteworthy that
bromobuta-1,3-diene16 reacted with enal and afforded product
3an in 74% yield. However, a cis-vinyl bromide gave low yield
of 3ao with high stereoselectivity. Also, β-alkyl-substituted
vinyl bromide such as 1-bromopropene reacted inefficiently
with trans cinnamaldehyde (1a), producing trace desired
product (see the Supporting Information for unsuccessful
examples).
We next sought to explore the scope of enals in this β-
vinylation reaction. As shown in Scheme 3, enals containing
electron-donating groups, such as 4-N,N-dimethylamino (1b),
4-methoxy (1c), 4-phenoxy (1d), 4-methyl (1e), afforded
corresponding products in 65−90% yields. In contrast, the
yields of 4-fluoro, 4-chloro, and 4-bromo substituted γ,δ-
unsaturated esters (3ha−3fa) through this method decreased
from 73% to 20%. The decreased yield of 3fa probably arise
Reactions were conducted with 1a (0.1 mmol), 2a (0.15 mmol),
b
THF (2 mL), MeOH (100 μL), 25 °C, 12 h. Assay yields
c
determined by 1H NMR using CH2Br2 as internal standard. 1a (0.15
d
mmol), 2a (0.1 mmol) were used. 1a (0.3 mmol), 2a (0.1 mmol)
were used. No terpy was used.
e
Moreover, this reaction was highly stereoselective without the
observation of cis isomer. An evaluation of Pd catalysts (entries
1−4) showed that the use of [(cinnamyl)PdCl]2 could
improve the yield of product to 55% (entry 4). We next
screened four different NHC precursors with [(cinnamyl)-
PdCl]2 (entries 4−7). Less sterically hindered NHC precursor
N2−N4 gave few or no product 3aa (entries 5−7). The tuning
of reaction parameters, including solvent (entries 8−11) and
ratio of substrates (entries 12 and 13), indicated that 2-
MeTHF and excessive cinnamaldehyde could promote the
reaction in higher AY (88%, entry 13). A series of control
experiments was carried to verify the necessity of each catalytic
components (entries 14−16). In the absence of palladium or
NHC precatalyst, no target product was formed (entries 14
and 15). Unexpectedly, remove of nitrogen ligands (terpy)
improved the AY to 91% (entry 16). It is noteworthy that in
such umpolung reactions with aryl iodides terpy was
B
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a,b
variation of substrate concentration and temperature caused
Scheme 3. Substrate Scope of Enals
negligible effects.
Figure 2. Assessment of reaction-condition-based sensitivity.
To gain insight into the reaction mechanism, we
independently synthesized a stable homoenolate 7 with a
slightly modified NHC (Figure 3a).19 When we carried out the
a
Reaction conditions: 1 (0.3 mmol), 2a (0.1 mmol), [(cinnamyl)-
PdCl]2 (5 mol %), precatalyst N1 (15 mol %), KOtBu (0.15 mmol),
MeOH (100 μL), and THF (2 mL) at rt for 12 h. Yields of isolated
b
and purified products.
from the coupling-reactions at the Ar−Br. Enals with
substituents at meta, ortho positions as well as dioxolane
fused phenyl ring (1i, 1j, 1m) were well tolerated.
Polyaromatic and heteroaryl-substituted enals (1k, 1n, 1l)
were also compatible. α-Methyl-substituted enal was tolerated
to give γ,δ-unsaturated ester 3oa in 72% yield with excellent
diastereoselectivity. However, β-alkyl-substituted enal such as
2-butenaldehyde exhibited low reactivity, generating trace
desired products (see the Supporting Information for
unsuccessful enals).
Figure 3. Mechanism studies.
reaction of 7 with 2a in the presence of stoichiometric
[(cinnamyl)PdCl]2 and KOtBu in THF/MeOH, no 1,4-
addition product was observed. In contrast, applying (IDipp)-
PdCl(phenylallyl) gave 3aa in 30% yield. The results
supported the postulated cooperative catalysis. Moreover, the
NHC was shown to perform a dual role of acting as
organocatalyst and forming a Pd/NHC complex.8e This
proposal was further supported by a study on the influence
of Pd/NHC ratio (Figure 3b). An excessive amount of
palladium to NHC led to a significant decrease in the yield of
3aa. These findings also demonstrated that when [(cinnamyl)-
PdCl]2 was used in such a transformation extra phosphine
ligand or pyridine derivative was not needed. A possible
mechanism is proposed in Figure 4 based on the above
experiments and our previous findings.8k Oxidative addition of
vinyl bromide to NHC-activated Pd generated electrophile B.
Subsequently, the NHC-bound homoenolate A interacted with
This umpolung 1,4-addition of vinyl bromide 1b to enal 1a
could be easily scaled up to 1 mmol scale with a slight decrease
in yield (73%, Figure 1). A route to enylamine was provided to
Figure 1. Synthetic application.
support the application of this reaction. Reduction of obtained
γ,δ-unsaturated ester gave alcohol 4, which was then oxidized
to aldehyde in 87% yield. Reductive amination of 5 with
benzylamine afforded 4-enylamine 6 (88% yield), which was a
potential precursor to biologically active pyrrolidine deriva-
tive.17 An assessment of reaction-condition-based sensitivity
was also performed to further show the practicality of this
approach (Figure 2).18 The graph revealed a negative
dependence on oxygen and moisture level, whereas the
Figure 4. Proposed mechanism for the cooperative catalysis.
C
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intermediate C. Reductive elimination from C formed C−C
bond and then produced 3 with the aid of basic methanol.
In conclusion, the NHC and palladium are highly
compatible and able to cooperatively catalyze umpolung 1,4-
addition of vinyl bromides to enals, leading to various γ,δ-
unsaturated carbonyl derivatives in good yields and high
stereoselectivities. Further studies on the asymmetric version
of this umpolung 1,4-addition reaction are ongoing in our
laboratories.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03654.
Experimental procedure, characterization data, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Jianyou Mao − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211816, P.R. China; orcid.org/0000-0003-0581-3978;
Email: ias_jymao@njtech.edu.cn
Authors
Bo Ling − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211816, P.R. China
Wenjun Yang − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211816, P.R. China; orcid.org/0000-0002-4410-6398
Yan-En Wang − College of Science, Hebei Agricultural
University, Baoding 071000, P.R. China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03654
Author Contributions
∥B.L. and W.Y. contributed equally
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the National Natural Science
Foundation of China (21801128 and 22071107), Natural
Science Foundation of Jiangsu Province, China
(BK20170965), and Nanjing Tech University (39837112)
for financial support.
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