Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed Reactions of Aldehyde Acyl Anions with either Diarylmethyl or Allylic Carbonates

Article abstract of DOI:10.1002/anie.201712811

Benzylation and allylation of aldehyde acyl anions were enabled by the merger of a thiazolium N-heterocyclic carbene (NHC) catalyst and a palladium/bisphosphine catalyst in a synergistic manner. Owing to the mildness of the reaction conditions, various functional groups were tolerated in the substrates.

Full text of DOI:10.1002/anie.201712811

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
International Edition Chemie
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Accepted Article
Title: Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed
Reactions of Aldehyde Acyl Anions with Diarylmethyl or Allylic
Carbonates
Authors: Shigeo Yasuda, Takuya Ishii, Shunsuke Takemoto, Hiroki
Haruki, and Hirohisa Ohmiya
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712811
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Angewandte Chemie International Edition
10.1002/anie.201712811
COMMUNICATION
Synergistic
N-Heterocyclic
Carbene/Palladium-Catalyzed
Reactions of Aldehyde Acyl Anions with Diarylmethyl or Allylic
Carbonates
Shigeo Yasuda, Takuya Ishii, Shunsuke Takemoto, Hiroki Haruki, and Hirohisa Ohmiya*
Abstract: Benzylation and allylation of aldehyde acyl anions were
enabled by the merger of a thiazolium N-heterocyclic carbene catalyst
and a palladium–bisphosphine catalyst in a synergistic manner.
Owing to the mildness of the reaction conditions, various functional
groups were tolerated in the substrates.
examples, some of which require the use of specific or highly
functionalized substrates. Accordingly, the development of a
general and simple reaction by synergistic NHC/transition metal
catalysis is highly desirable, given the importance of umpolung
[
11]
approaches for organic synthesis.
Herein, we report a
2
synergistic NHC/palladium catalyst system that enables C(sp )–
H benzylation and allylation of widely available aldehydes (Figure
Synergistic (cooperative) catalysis is a synthetic strategy
wherein multiple distinct catalysts activate two different substrates
1
E). To our knowledge, this protocol is the first catalytic
benzylation and allylation using aldehydes as umpolung acyl
simultaneously, thereby facilitating
a
single chemical
The development of new reactions by the
synergistic merger of organocatalysis and metal catalysis has
[12–14]
anion equivalents.
Thus, this protocol provides a new
[
1,2]
transformation.
[15]
synthetic route to a-arylated ketones or b,g-unsaturated
which are prominent motifs in bioactive natural
[16]
ketones,
[
2]
made remarkable progress over the last decades. Nevertheless,
the merger of nucleophilic organocatalysis, which exhibits a
characteristic ability to access umpolung reactivity, with late
transition metal catalysis still remains a challenge due to the
difficulty attributed to the strong propensity of the organocatalysts
compounds, pharmaceuticals and various synthetic intermediates.
A. Enone cycloallylation (Krische, ref 6)
OCO Me
2
O
cat. Bu3P
cat. Pd
O
R
R
[
3–5]
to bind to transition metals with high affinity.
Several groups
B. Synthesis of 1,4-dicarbonyl compounds (Liu, ref 7a)
have overcome such problems. Specifically, Krische and co-
workers developed an enone cycloallylation by the merger of
O
cat. NHC
cat. Pd
O
N
AcO
+
H
N
[
6]
N
phosphine organocatalyst/palladium catalyst (Figure 1A).
O
Recently, successful examples of synergistic NHC/late transition
metal-catalyzed umpolung reactions involving the catalytic
generation of acyl anion, enolate or homoenolate equivalents
C. Synthesis of 3-allyl dihydrocoumarin derivatives (Scheidt, ref 8)
O
[
7–10]
from aldehydes have been reported (Figures 1B–D).
co-workers reported the synthesis of 1,4-dicarbonyl compounds
by thiazolium N-heterocyclic carbene (NHC)/palladium-
Liu and
H
cat. NHC
cat. Pd
O
O
O
a
O
O
catalyzed reaction of (o-azaaryl)carboxaldehydes and simple allyl
D. Annulation of enals and vinyl benzoxazinanones (Glorius, ref 9)
acetate, which involves allylation followed by an uncontrollable
[
7a]
alkene isomerization–conjugate addition pathway (Figure 1B).
cat. NHC
cat. Pd
R
O
O
Scheidt and co-workers reported the synthesis of 3-allyl
+
O
R
H
dihydrocoumarin derivatives from a,b-unsaturated aldehydes
N
O
N
Ts
bearing an allyloxycarbonyl moiety through
NHC/palladium-catalyzed allylation and
a
imidazolium
subsequent
Ts
E. Aldehyde benzylation and allylation (this work)
[
8]
intramolecular acylation (Figure 1C). Glorius and co-workers
reported the enantioselective umpolung annulation between a,b-
unsaturated aldehydes and vinyl benzoxazinanones with a chiral
triazolium NHC/palladium catalyst, yielding chiral azepine
cat. NHC
cat. Pd
O
O
BocO
+
R1
R1
H
R2
R2
1
2 or 4
3 or 5
[
9]
Figure 1. The merger of nucleophilic organocatalysis with late transition metal
derivatives (Figure 1D). However, these are only limited
catalysis.
The mechanistic details of our working hypothesis of the
synergistic NHC/palladium-catalyzed benzylation and allylation,
in which two distinct catalytic cycles should operate
simultaneously with an ideal balance between the reactivity of
both catalysts, are outlined in Figure 2. One cycle involves the
formation of a nucleophilic Breslow intermediate A by the reaction
[a]
Dr. S. Yasuda, T. Ishii, S. Takemoto, H. Haruki, Prof. Dr. H. Ohmiya
Division of Pharmaceutical Sciences, Graduate School of Medical
Sciences
Kanazawa University
Kakuma-machi, Kanazawa 920-1192, Japan
E-mail: ohmiya@p.kanazawa-u.ac.jp
Homepage: http://seimitsu.w3.kanazawa-u.ac.jp/eng/index
[17]
between NHC and aldehyde (1). Another cycle comprises the
Supporting information for this article is given via a link at the end of
the document.
reaction of the palladium catalyst with benzylic/allylic carbonate
(
2 or 4) to generate π-benzyl/π-allyl palladium(II) intermediate
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Angewandte Chemie International Edition
10.1002/anie.201712811
COMMUNICATION
[
18, 19]
B.
These two independently generated species would couple
Effects of bidentate and monodentate phosphine ligands on
palladium are shown in Table 1, entries 15–20. The use of BINAP
instead of DPPF decreased the product yield (48%) (entry 15).
The use of Xantphos having a larger bite-angle resulted in a
moderate yield (57%) (entry 16). The DPPE ligand promoted no
to form a new carbon–carbon bond (in C) and regenerate the
palladium species. Finally, elimination of the NHC from C would
afford the desired ketone product (3 or 5) and allow the NHC to
re-enter the catalytic cycle.
–
t
O Bu
reaction (entry 17), nor did monophosphines such as PPh, PCy
3
PdLn+
X
N
O
and Xphos (entries 18–20). These results imply that the bidentate
coordination of a bulky bisphosphine to palladium might suppress
the formation of undesired NHC–palladium complexes. No
reaction occurred without the DPPF ligand (entry 21).
Y
R2
H
1
R1
A
B
CO2
NHC catalytic
cycle
Pd catalytic
cycle
X
N
Y
[a]
Table 1. Screening of conditions for reaction of 1a with 2a
2
or 4
3
or 5
X
N
O
N1 (20 mol %)
Pd(TFA)2 (10 mol %)
DPPF (10 mol %) Ph
O
Y
H
–
O
+
BocO
t
R1
+
H
O Bu
PdLn
Ph
H
K2CO3
THF, 60 ˚C, 3 h
t
R2
O Bu
1a
2a
3aa
C
[
b]
Figure 2. Working hypothesis.
entry
change from standard conditions
none
yield (%) of 3aa
1
2
3
4
5
6
7
8
9
1
1
1
1
78
85 (81)
0
After careful screening of the reaction conditions based on our
hypothesis, we found that the reaction between 3-
phenylpropionaldehyde (1a) (0.3 mmol) and tert-butyl (2-
naphthyl)(phenyl)methyl carbonate (2a) (0.2 mmol) as the
substrate couple occurred in the presence of catalytic amounts of
the N-mesityl-substituted seven-membered ring thiazolium salt
3 equivalent of 1a
without N1
without Pd(TFA)
2
/DPPF
0
N2 instead of N1
77
73
13
17
6
[c]
N2 (10 mol %) instead of N1
N3 instead of N1
[
20]
N1 (20 mol %) as the NHC precursor,
trifluoroacetate [Pd(TFA) ] (10 mol %), DPPF (10 mol %), and a
stoichiometric amount of K CO as the base (0.2 mmol) in THF at
0 °C to produce the ketone product 3aa in high yield (Table 1,
palladium(II)
N4 instead of N1
2
N5 instead of N1
2
3
0
1
2
3
N6 instead of N1
15
39
62
10
16
48
57
0
6
N7 instead of N1
entry 1). A small amount of the expected side product, a-
hydroxyketone derived from NHC-catalyzed homobenzoin
condensation of 1a, was observed (See Supporting
Pd(OAc)
Pd(acac)
Pd (dba)
2 2
instead of Pd(TFA)
2
instead of Pd(TFA)
2
2
[
21]
14
2
3
instead of Pd(TFA)
Information).
increased amount of aldehyde 1a (entry 2). Importantly, reactions
without the NHC precatalyst N1 or Pd(TFA) –DPPF did not give
the ketone product at all, leaving the diarylmethyl substrate nearly
untouched (entries and 4). These results indicated the
A higher yield (81%) was obtained with an
1
1
1
1
1
2
2
5
6
7
8
9
0
1
BINAP instead of DPPF
Xantphos instead of DPPF
DPPE instead of DPPF
2
PPh
PCy
3
3
instead of DPPF
instead of DPPF
0
3
0
synergistic cooperation of the NHC and palladium catalysts in this
transformation.
Xphos instead of DPPF
without DPPF
0
0
The nature of the NHC showed marked influences on the
product yield (Table 1, entries 5–10). 2-tert-Butylphenyl-
substituted seven-membered ring thiazolium salt N2 was as
effective as N1 (entry 5). The catalyst loading of N2 could be
reduced to 10 mol % with the high level of product yield (72%)
retained (entry 6). Introducing bulky aryl substituents, such as 2,6-
diisopropylphenyl (N3), 1-naphthyl (N4), and 3,5-di-tert-butyl-4-
methoxyphenyl (N5) groups, instead of the mesityl group in N1
resulted in low product yields (entries 7–9). A cycloheptane
backbone was essential for the efficient reaction. Thus, replacing
the seven-membered ring of N1 with a six-membered ring
significantly decreased the product yield (entry 10). The dimethyl
backbone was not effective (entry 11). Imidazolium and triazolium
NHCs with different steric and electronic natures were also
screened, but they did not promote the reaction at all (data not
shown).
[
a] Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), NHC (20 mol %), Pd (10
2 3
mol %), bisphosphine (10 mol %) or monophosphine (20 mol %), K CO (0.2
1
mmol), THF (0.2 mL), 60 °C, 3 h. [b] H NMR yield. Yield of the isolated product
is in parentheses. [c] N2 (10 mol %) was used.
Me
Me
+
+
Me
+
+
Me
Me
S
N
S
N
S
N
S
N
Ar
Me
Me
Me
ClO –
ClO –
N2 (Ar = 2-tBu-C
N3 (Ar = 2,6-iPr -C
N4 (Ar = 1-naphthyl)
ClO –
4
ClO –
4
Me
4
Me
4
Me
6 4
H )
N1
N6
N7
2
6 3
H )
N5 (Ar = 3,5-tBu
2
6 2
-4-MeO-C H )
PPh
2
PPh2
PPh
DPPF
PPh
2
2
PPh
PPh
2
Me
Me
PCy2
iPr
Fe
O
iPr
2
2
PPh
PPh2
Xantphos
DPPE
iPr
Xphos
BINAP
Results of the reaction conducted with other palladium sources
We next explored the scope of the aldehydes in the synergistic
NHC/palladium-catalyzed reaction with (2-
naphthyl)(phenyl)methyl carbonate 2a (Table 2). An aliphatic
are shown in Table 1, entries 12–14. Pd(OAc)
the product yield (entry 12), whereas the use of Pd(acac)
Pd (dba) significantly decreased the product yield (entries 13 and
4).
2
slightly decreased
2
or
[
22]
2
3
aldehyde, having a methyl group at the b-position, exhibited better
reactivity than unbranched aldehyde 1a to afford 3ba in 86% yield.
1
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Angewandte Chemie International Edition
10.1002/anie.201712811
COMMUNICATION
3
-Methylbutanal also served as a suitable substrate (3ca). The
(phenyl)(4-trifluoromethylphenyl)methyl
carbonate
was
sterically more demanding a-branched aldehydes such as
cyclohexanecarboxaldehyde and cyclopropanecarboxaldehyde
participated in the reaction (3da, 3ea). Functional groups such as
alkene and thiomethyl substituents at the terminus of the aliphatic
compatible with the reaction (3ap). The diphenylmethyl carbonate
or (4-methoxyphenyl)(phenyl)methyl carbonate did not participate
in the reaction (data not shown). The heteroaromatic substituted
substrates such as phenyl(pyridin-3-yl)methyl carbonate,
phenyl(thiophen-3-yl)methyl carbonate or phenyl(furan-3-
yl)methyl carbonate underwent the reaction (3aq, 3ar, 3as).
[
23]
chain aldehyde substrates were tolerated (3fa, 3ga).
Interestingly, even an aldehyde with an unprotected hydroxyl
group underwent the reaction (3ha). Carbamate groups were
compatible with this reaction (3ia, 3ja). A steroidal aldehyde,
which was prepared from lithocholic acid, resulted in the formation
of a diarylmethylated steroid with the enolizable ketone moiety
remaining untouched (3ka). An a,b-unsaturated aldehyde
underwent the direct functionalization to give the corresponding
a,b-unsaturated ketone (3la). Thus, a,b-unsaturated aldehyde
acted not as enolate or homoenolate equivalents but as acyl anion
The synergistic NHC/palladium catalysis was also possible with
2
allylic carbonates, allowing the aldehyde C(sp )–H allylation
[25]
(
Table 4).
For instance, the reaction between cinnamyl
carbonates and 1a occurred to afford the b,g-unsaturated ketone
[24]
derivatives (5aa, 5ab, 5ac) with a useful product yield.
The
chloro and 1,2-methylenedioxy moieties in the benzene ring of
the cinnamyl carbonate decreased the product yield (5ad, 5ae).
Alkene and hydroxyl groups at the terminus of the aliphatic chain
aldehyde substrates were tolerated (5fc, 5hc).
[
8, 9]
equivalent.
Aromatic aldehydes did not participate in the
[
24]
reaction (data not shown).
[
a]
Table 3. Scope of benzylic carbonates
[
a]
Table 2. Scope of aldehydes
N1 or N2 (20 mol %)
Pd(TFA) (10 mol %)
DPPF (10 mol %)
2
R
1
O
N1 or N2 (20 mol %)
Pd(TFA)2 (10 mol %)
DPPF (10 mol %)
O
R1
O
O
Ar
Ar
BocO
+
BocO
+
R1
Ph
R1
Ph
H
2 3
K CO
THF, 60 ˚C, 12 h
H
R2
R2
K2CO3
THF, 60 ˚C, 12 h
a (R1 = H)
b (R = Me)
3
1
1
2b–r
1
b–j
2a
3
1
O
O
O
O
O
O
2-Nap
2-Nap
2-Nap
2-Nap
2-Nap
2-Nap
Ph
Ph
R = OMe (3ab), 68%
Ph
R = CF3 (3ac), 78%[
R = F (3ad), 76%
R = Cl (3ae), 78%
b]
Ph
ba, 86%[b]
Ph
Ph
Ph
3da, 61%[c]
3ea, 98%[c]
3
3ca, 77%[c]
MeO
R
3bf, 85%[c]
O
O
O
2-Nap
2-Nap
HO
2-Nap
O
O
O
O
MeS
2-Nap
2-Nap
Ph
2-Nap
2-Nap
N
Ph
Ph
Ph
Ph
Ph
Ph
fa, 86%[b,d]
3ga, 55%
3ha, 78%[b,c]
Me
3
O
F
F
O
O
O
O
3ah, 39%[b]
3bi, 66%[c]
3bj, 86%[c]
3
bg, 83%[c]
2
-Nap
2-Nap
BnO
N
H
2-Nap
BocN
Ph
ia, 63%[c]
Ph
H
OMe
Ph
Ph
O
O
O
3ja, 51%[c]
-Nap
3
H
H
O
ka, 72%[b,d]
Ph
Ph
X
3
O
Ph
2
H
Ph
Ph
bk, 82%[c,d]
3al, 65%[d]
X = O (3bm), 87%[c]
X = S (3bn), 68%[
3
Ph
la, 52%[c]
c]
3
CF3
Ph
N
O
O
O
O
X
[
a] Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), N1 (20 mol %), Pd(TFA)
2
2-Nap
(
10 mol %), DPPF (10 mol %), K
2
CO
3
(0.2 mmol), THF (0.2 mL), 60 °C, 12 h.
Ph
Ph
Ph
Me
ao, 39%[e,f]
Ph
Ph
3aq, 57%[b,g]
Ph
[
b] Diastereomeric ratio (1:1). [c] 1 (0.6 mmol) was used. [d] N2 was used. 2-
3
3ap, 58%[b,g]
X = S (3ar), 86%[b,g,h]
X = O (3as), 79%
Nap = 2-naphthyl.
[b,g,h]
[
a] Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), N1 (20 mol %), Pd(TFA)
2
Various secondary benzylic carbonates were examined (Table
(
10 mol %), DPPF (10 mol %), K CO (0.2 mmol), THF (0.2 mL), 60 °C, 12 h.
2
3
[
22]
3
).
Methoxy, trifluoromethyl, fluoro and chloro groups were
[
b] 1 (0.6 mmol) was used. [c] Diastereomeric ratio (1:1). [d] N2 was used. [e]
tolerated at the para- or meta positions of the benzene ring of the
1
DMSO was used as solvent. [f] H NMR yield. [g] Reaction time was 72 h. [h]
Reaction was carried out at 40 ˚C. 2-Nap = 2-naphthyl.
[
23]
(
2-naphthyl)(phenyl)methyl carbonate (3ab–3ae, 3bf).
difluorophenyl-substitituted carbonate was a suitable substrate
3bg). A carbonate bearing a sterically demanding o-tolyl group
A
[
a]
Table 4. Aldehyde allylation
(
N1 (20 mol %)
Pd(TFA)2 (10 mol %)
DPPF (10 mol %)
gave a moderate yield of the product (3ah). The replacement of
the benzene ring in 3aa with a heteroaromatic ring such as a furyl
or pyridyl group was possible (3bi, 3bj). The diarylmethyl
carbonates with 6-methoxy-2-naphthyl or 1-naphthyl substituents
at the a position served as substrates (3bk, 3al). Heteroaromatic
rings such as benzofuran or benzothiophene could be introduced
at the benzylic position of the substrate (3bm, 3bn). The (2-
naphthyl)ethyl carbonate could be employed in the aldehyde
benzylation, although the yield was moderate (3ao). tert-Butyl
O
O
R2
+
BocO
R2
R1
R1
H
K2CO3
THF, 60 ˚C, 3 h
1
4
5
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Angewandte Chemie International Edition
10.1002/anie.201712811
COMMUNICATION
O
[
1]
R. Peters, Ed. Cooperative Catalysis: Designing Efficient Catalysis for
Synthesis; Wiley-VCH: Weinheim, Germany, 2015.
R2
Me
Me
O
Ph
R2 = Ph (5aa), 54%
[2]
For reviews on synergistic catalysis, see: a) A. E. Allen, D. W. C.
MacMillan, Chem. Sci. 2012, 3, 633; b) Z. Du, Z. Shao, Chem. Soc. Rev.
R2 = 2-Me-C
H
(5ab), 54%
(5ac), 64%
6 4
H
(5ad), 25%[b]
6
4
Me
Me
R2 = 2,6-Me
5fc, 71%
2
-C
6
H
3
2
013, 42, 1337; c) D.-F. Chen, Z.-Y. Han, X.-L. Zhou, L.-Z. Gong, Acc.
R2 = 4-Cl-C
Chem. Res. 2014, 47, 2365; d) S. Afewerki, A. Córdova, Chem. Rev.
2016, 116, 13512; e) D.-S. Kim, W.-J. Park, C.-H. Jun, Chem. Rev. 2017,
117, 8977.
O
O
O
O
HO
Ph
5
hc, 46%[b]
[3]
For reviews on nucleophilic organocatalysis, see: a) A. Grossmann, D.
Enders, Angew. Chem. 2012, 124, 320; Angew. Chem. Int. Ed. 2012, 51,
5
ae, 46%
a] Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), N1 (20 mol %), Pd(TFA)
10 mol %), DPPF (10 mol %), K CO (0.2 mmol), THF (0.2 mL), 60 °C, 3 h. [b]
[
2
3
2
2
14; b) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature
014, 510, 485; c) R. S. Menon, A. T. Biju, V. Nair, Chem. Soc. Rev.
015, 44, 5040; d) D. M. Flanigan, F. Romanov-Michailidis, N. A. White,
(
2
3
The isolated products were contaminated with traces amount of unidentified
materials.
T. Rovis, Chem. Rev. 2015, 115, 9307; e) S. E. Denmark, G. L. Beutner,
Angew. Chem. 2008, 120, 1584; Angew. Chem., Int. Ed. 2008, 47, 1560.
For reviews on synergistic NHC/metal catalysis, see: a) D. T. Cohen, K.
A. Scheidt, Chem. Sci. 2012, 3, 53; b) M. H. Wang, K. A. Scheidt, Angew.
Chem. 2016, 128, 15134; Angew. Chem. Int. Ed. 2016, 55, 14912.
For cascade reactions utilizing NHC and palladium catalysts, see: a) T.
Nemoto, T. Fukuda, Y. Hamada, Tetrahedron Lett. 2006, 47, 4365; b) R.
Lebeuf, K. Hirano, F. Glorius, Org. Lett. 2008, 10, 4243; c) J. He, S. Tang,
S. Tang, J. Liu, Y. Sun, X. Pan, X. She, Tetrahedron Lett. 2009, 50, 430.
B. G. Jellerichs, J.-R. Kong, M. J. Krische. J. Am. Chem. Soc. 2003, 125,
The proposed catalytic cycle illustrated in Figure 2 was
[
[
4]
5]
supported by the reaction using
a
bisphosphine-ligated
cinnamylpalladium(II) complex that was considered to be relevant
to the catalysis (Scheme 1A). The reaction of the
cinnamylpalladium 6, which was prepared in situ from
[
(cinnamyl)PdCl]
2
and DPPF, with 3-phenylpropionaldehyde (1a)
CO in THF at 60 °C.
was performed in the presence of N1 and K
2
3
[
[
6]
7]
The reaction gave the allylation product 5aa in 48% yield (based
on 6). Additionally, the reaction without DPPF under otherwise
identical conditions did not afford 5aa (Scheme 1B). Thus, the
possibility of the NHC–palladium complex participating in the
reaction was ruled out (See also Table 1, entry 21).
7
758.
a) Y. Bai, S. Xiang, M. L. Leow, X.-W. Liu, Chem. Commun. 2014, 50,
168. For a related work, see: b) Y. Bai, W. L. Leng, Y. Li, X.-W. Liu,
6
Chem. Commun. 2014, 50, 13391.
[
8]
K. Liu, M. T. Hovey, K. A. Scheidt, Chem. Sci. 2014, 5, 4026.
a) G. Guo, M. Fleige, D. Janssen-Müller, C. G. Daniliuc, F. Glorius, J.
Am. Chem. Soc. 2016, 138, 7840; b) G. Guo, D. Janssen-Müller, M.
Fleige, A. Lerchen, C. G. Daniliuc, F. Glorius, J. Am. Chem. Soc. 2017,
139, 4443.
Ph
A.
[9]
Ph
Ph
O
O
P
+
N1 (2.5 equiv)
+
Ph
Fe
Pd
K CO (7.5 equiv) Ph
Ph
H
2
3
–Cl
P
THF, 60 ˚C, 3 h
5
aa
1
a
Ph
Ph
48% yield
(
5 equiv)
[10] For
asymmetric
acylation
at
the
a-position
of
N-
6
(1 equiv)
aryltetrahydroisoquinolines with aldehydes by
a
chiral triazolium
Ph
B.
NHC/ruthenium-based photoredox catalysis, see: D. A. DiRocco, T.
Rovis, J. Am. Chem. Soc. 2012, 134, 8094.
Cl
N1 (2.5 equiv)
1
a
+
Pd
Pd
5aa
Cl
0.5 equiv)
Scheme 1. Reactions with cinnamylpalladium(II) complexes.
K
2
CO (7.5 equiv)
3
(
5 equiv)
not detected
[11] T. A. Hase, Ed. Umpoled Synthons: a Survey of Sources and Uses in
THF, 60 ˚C, 3 h
Ph
(
Synthesis; Wiley: New York, 1987.
2
[
12] For aldehyde C(sp )–H arylation, alkylation or alkynylation by
photoredox-based catalysis, see: a) X. Zhang, D. W. C. MacMillan, J. Am.
Chem. Soc. 2017, 139, 11353; b) S. Mukherjee, R. A. Garza-Sanchez,
A. Tlahuext-Aca, F. Glorius, Angew. Chem. 2017, 129, 14915; Angew.
Chem. Int. Ed. 2017, 56, 14723.
In summary, the synergistic merger of a thiazolium NHC
organocatalyst and a palladium–bisphosphine catalyst enabled
2
the C(sp )–H benzylation of aldehydes. The reaction with
aldehydes and diarylmethyl carbonates as the substrate couple
proceeded under mild conditions to produce a-arylated ketone
derivatives. This protocol was also applicable to allylic carbonates.
[13] For the synthesis of a-arylketones by the reaction between aldehydes
and primary benzyl halides in the presence of a stoichiometric amount of
NHC, see: L. Lin, Y. Li, W. Du, W.-P. Deng, Tetrahedron Lett. 2010, 51,
3
571.
The synergistic NHC/palladium catalysis provides
a new,
[
14] For palladium-catalyzed benzylation and allylation of acylmetal
nucleophiles, see: a) Y. Hanzawa, N. Tabuchi, T. Taguchi, Tetrahedron
Lett. 1998, 39, 6249; b) H. Sakurai, K. Tanabe, K. Narasaka, Chem. Lett.
previously inaccessible, synthetic strategy using readily available
aldehydes as umpolung acyl anion equivalents. Studies on
expanding this strategy to include the use of different coupling
partners as well as the asymmetric variants will be carried out in
our laboratory.
1
999, 309; c) Y. Obora, Y. Ogawa, Y. Imai, T. Kawamura, Y. Tsuji, J. Am.
Chem. Soc. 2001, 123, 10489; d) Y. Obora, M. Nakanishi, M. Tokunaga,
Y. Tsuji, J. Org. Chem. 2002, 67, 5835.
[
[
15] For reviews, see: a) D. A. Culkin, J. F. Hartwig, Acc. Chem. Res. 2003,
3
6, 234; b) C. C. C. Johansson, T. J. Colacot, Angew. Chem. 2010, 122,
86; Angew. Chem. Int. Ed. 2010, 49, 676; c) F. Bellina, R. Rossi, Chem.
Acknowledgements
6
Rev. 2010, 110, 1082; d) R. Noväk, R. Martin, Curr. Org. Chem. 2011,
5, 3233.
This work was supported by JSPS KAKENHI Grant Number
JP15H03803 to Scientific Research (B) and JSPS KAKENHI
Grant Number JP17H06449 in Hybrid Catalysis for Enabling
Molecular Synthesis on Demand.
1
16] a) B. M. Trost, H. Yang, O. R. Thiel, A. J. Frontier, C. S. Brindle, J. Am.
Chem. Soc. 2007, 129, 2206; b) B. A. Trofimov, E. Y. Schmidt, N. V.
Zorina, E. V. Ivanova, I. A. Ushakov, J. Org. Chem. 2012, 77, 6880 and
references cited therein.
[
[
17] R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719.
Keywords: carbene · palladium · benzylation · allylation ·
18] For a review on benzylic alkylations via p-benzylpalladium intermediates,
see: B. M. Trost, L. C. Czabaniuk, Angew. Chem. 2014, 126, 2868;
Angew. Chem. Int. Ed. 2014, 53, 2826.
aldehyde
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Angewandte Chemie International Edition
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[
19] For reviews on allylic alkylations via p-allylpalladium intermediates (Tsuji-
Trost reaction), see: a) J. Tsuji, Acc. Chem. Res. 1969, 2, 144; b) B. M.
Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921; c) B. M. Trost,
Tetrahedron 2015, 71, 5708; d) J. Tsuji, Tetrahedron 2015, 71, 6330.
20] a) J. Pesch, K. Harms, T. Bach, Eur. J. Org. Chem. 2004, 2025; b) I. Piel,
M. D. Pawelczyk, K. Hirano, R. Fröhlich, F. Glorius, Eur. J. Org. Chem.
homobenzoin/retro-benzoin reaction process does not play an important
role in the catalyst system. See ref 20b.
[22] For Tables 2 and 3, a small amount of a-hydroxyketone derived from
NHC-catalyzed homobenzoin condensation of aldehyde (1) was
observed in the crude material.
[
[
[23] Functional groups such as nitro, nitrile, acetoxy, acryloyl or phenol group
in the substrates inhibited the reactions.
2
011, 5475.
21] The reaction of a-hydroxyketone (0.15 mmol) derived from homobenzoin
condensation of 1a, with 2a (0.2 mmol) under the conditions described
for Table 1, entry 1 gave a trace amount of 3aa (4%). Thus, the reversible
[24] The benzylation or allylation of aromatic aldehydes did not proceed. The
unreacted carbonate and a-hydroxyketone were observed in the crude
materials. The oxidative esterification product was not detected. See 4b.
[
25] S. W. Kim, W. Zhang, M. J. Krische, Acc. Chem. Res. 2017, 50, 2371.
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Shigeo Yasuda, Takuya Ishii, Shunsuke
Takemoto, Hiroki Haruki, and Hirohisa
Ohmiya*
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Synergistic N-Heterocyclic
Carbene/Palladium-Catalyzed
Reactions of Aldehyde Acyl Anions
with Diarylmethyl or Allylic
Carbonates
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