Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed Umpolung 1,4-Addition of Aryl Iodides to Enals

Article abstract of DOI:10.1002/anie.201912584

An umpolung 1,4-addition of aryl iodides to enals promoted by cooperative (terpy)Pd/NHC catalysis was developed that generates various bioactive β,β-diaryl propanoate derivatives. This system is not only the first reported palladium-catalyzed arylation of NHC-bound homoenolates but also expands the scope of NHC-induced umpolung transformations. A diverse array of functional groups such as esters, nitriles, alcohols, and heterocycles are tolerated under the mild conditions. This method also circumvents the use of moisture-sensitive organometallic reagents.

Full text of DOI:10.1002/anie.201912584

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed
Umpolung 1,4-Addition of Aryl Iodides to Enals
Authors: Wenjun Yang, Bo Ling, Bowen Hu, Haolin Yin, Jianyou Mao,
and Patrick Walsh
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912584
Angew. Chem. 10.1002/ange.201912584
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http://dx.doi.org/10.1002/ange.201912584

10.1002/anie.201912584
Angewandte Chemie International Edition
RESEARCH ARTICLE
Synergistic N-Heterocyclic Carbene/Palladium-Catalyzed Um-
polung 1,4-Addition of Aryl Iodides to Enals
Wenjun Yang, Bo Ling, Bowen Hu, Haolin Yin, Jianyou Mao,* and Patrick J. Walsh*
Abstract: A (terpy)Pd/NHC cooperative catalyzed umpolung 1,4-
addition of aryl iodides to enals to generate various bioactive β,β-
diaryl propanoate derivatives is described. The system developed
herein not only represents the first palladium-catalyzed arylation of
NHC-bound homoenolates but also expands the scope of NHC-
induced umpolung transformations. A diverse array of functional
groups such as esters, nitriles, alcohols and heterocycles are
tolerated under the mild conditions. This protocol also circumvents
use of moisture-sensitive organometallic reagents.
introduced by the Liu group using Pd/NHC dual catalysis (Scheme
1b).[12a][12b] Glorius and co-workers developed
highly
a
enantioselective umpolung annulation of enals (Scheme 1c).[13]
More recently, Ohmiya and co-workers reported NHC/Pd-
catalyzed allylation/benzylation of alkyl aldehydes (Scheme
1d).[14] These impressive applications highlight the utility of Pd(π-
allyl) and related intermediates in combination with NHCs in
synergistic catalysis. To broaden the synthetic utility of NHC-
bound nucleophilic intermediates in C–C bond-forming reactions,
we set out to develop their union with less reactive electrophiles
promoted by transition metal catalysts.
Introduction
a) Scheidt and co-workers
O
A powerful synthetic strategy is synergistic or cooperative
catalysis, wherein one catalyst activates the nucleophile and a
second catalyst activates the electrophile.[1] The two catalytic
CHO
NHC
Pd
NHC
O
O
O
O
LnPd
cycles intersect at the bond-forming event. The marriage of
organocatalysts with transition metals in synergistic catalysis
enables exploitation of the unique reactivity of these two catalyst
classes, making possible novel bond-forming processes.[2]
Recent progress employing amine[3] or phosphoric acid[4]
catalysts with transition metal catalysts have met with significant
success.[2], [5] N-Heterocyclic carbenes (NHCs) also rank among
the most useful organocatalysts, promoting a host of unique
transformations.[6] The partnering of NHCs with transition-metals
in synergistic catalysis, however, remains less developed,
presumably due to catalyst quenching via strong binding of the
NHC to transition metals.[7]
We were attracted to NHCs because of their exceptional
nucleophilicity and ability to invert the reactivity of aldehydes from
electrophilic to nucleophilic, generating NHC-bound intermediates,
including acyl anions,[8] homoenolate equivalents,[9] or
enolates.[10] These species are best partnered with very reactive
electrophiles, diminishing their applications. Activation of the
electrophile with a transition metal catalyst, however, could
dramatically increase the pool of electrophiles potentially suitable
for reactions with NHC-activated intermediates. As shown by
Scheidt[11] and co-workers (Scheme 1a), the NHC-activated
species could react with allylic electrophiles upon interception of
a palladium intermediate in the Tsuji-Trost reaction. Subsequently,
an efficient allylation of (O-azaaryl)-carboxaldehydes was
O
O
b) Liu and co-workers
O
PdLn
O
OH
NHC
H
NHC
R1
R1
R1
N
N
N
c) Glorius and co-workers
O
O
O
O
O
R2
O
R2
Pd
NHC*
O
R1
PdLn
R1
R1
OH
NHC*
PdLn
R
Pd
R
O
N
N
N
O
Ts
O
Ts
Ts
d) Ohmiya and co-workers
LG
OH
NHC
R2
R1
O
PdLn
R2
Pd
R1
R1
LG = OBoc, OH
Scheme 1. The merger of NHC organocatalysis with palladium catalysis.
Herein, we disclose the first palladium-catalyzed 1,4-aryl addition
to NHC-bound homoenolates with aryl iodides (Scheme 2). This
work represents a valuable complement to traditional 1,4-addition
of aryl organometallics to α,β-unsaturated esters with the
advantage of avoiding moisture sensitive aryl zinc, lithium,
magnesium, and boron reagents. These organometallic reagents
are usually prepared from the aryl halides,[15] although in some
cases they may be generated in situ (cross-electrophile
coupling).[16] Our work also complements reductive Heck
reactions, which require an external reducing agent.[17]
Furthermore, the products generated herein are important
[*]
W. Yang, B. Ling, Prof. Dr. J. Mao
Institute of Advanced Synthesis, School of Chemistry and Molecular
Engineering, Nanjing Tech University, 30 South Puzhu Road,
Nanjing 211816 (P.R. China)
E-mail: ias_jymao@njtech.edu.cn
B. Hu, H. Yin, Prof. Dr. P. J. Walsh
Roy and Diana Vagelos Laboratories, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, PA
19104, USA
E-mail: pwalsh@sas.upenn.edu
This article is protected by copyright. All rights reserved.

10.1002/anie.201912584
Angewandte Chemie International Edition
RESEARCH ARTICLE
scaffolds in pharmaceutical chemistry and natural product
synthesis.[18]
mixture against an internal standard). Other NHCs either gave
little or no product 3aa (0–14% AY, entries 2–4). Since palladium
sources affect reactivity, we tested Pd(OAc)2, and Pd(PPh3)4
under the conditions of entry 1, but these complexes did not
promote this transformation (entry 1 vs. 5 and 6). Thus, Pd2(dba)3
was used in further optimizations. We next screened a series of
mono- and bidentate phosphines and pyridine derivatives under
the conditions of entry 1 (entries 7–10). Terpyridine (L5) afforded
the desired product in 59% AY, while bipy provided the product in
50% yield (see Supporting Information for details). Continuing
with terpy, decreasing the reaction concentration from 0.1 molar
to 0.05 molar improved the AY to 75% (entry 11). Control
experiments indicated that in the absence of NHC or Pd and L5,
no reaction was observed (entries 12 and 13). The combination
of Pd2(dba)3 and NHC, but without a phosphine or pyridine-based
ligand for Pd, the product 3aa was obtained in 14% AY. Therefore,
O
OH
NHC
Ar'
O
Pd, L
NHC
Ar
H
Ar
Ar'I
MeOH
Ar
OMe
Scheme 2. NHC/Pd co-catalyzed 1,4-addition of aryl iodides to enals.
Our mechanism-based design was motivated by the
nucleophilicity of NHC-bound homoenolates and the idea that
they might undergo nucleophilic substitution with LnPd(Ar)I
(Figure 1), in analogy to a transmetallation. In the organocatalytic
cycle, addition of the NHC to an enal leads to formation of the
NHC-bound homoenolate intermediate (A).[9i] In the Pd cycle,
oxidative addition of the aryl iodide generates the activated
electrophile (B).[19] The two catalytic cycles intersect when the
homoenolate attacks the palladium to form a Pd–C bond in C,
envisioned to proceed by displacement of the iodide. Reductive
elimination from C forms the C–C bond. The NHC-bound
intermediate (D) reacts with basic MeOH affording the β,β-diaryl
propanoate (3), liberating the NHC catalyst. Despite the simplicity
of the proposed mechanism, several challenges must be
overcome: 1) NHCs are well known to exhibit strong coordination
to palladium, resulting in catalyst quenching. 2) The addition of
NHCs to enals can also generate enolates and acyl anions. These
two species could be envisioned to react with aryl palladium
intermediates, leading to byproducts. 3) The palladium-catalyzed
Mizoroki-Heck reaction of aryl halides with α,β-unsaturated
carbonyl compounds is known,[20] and would lead to undesired
β,β-diaryl enals.
our optimized conditions are
1 equiv enal (1a), 2 equiv
iodobenzene (2a), 1.5 equiv KOtBu, 5 mol % Pd2(dba)3, 10 mol %
terpy (L5) and 15 mol % N1 in THF/MeOH at room temperature
for 12 h.
Table 1. Reaction Optimization[a]
F
Pd (10 mol%)
Ligand (10 mol%)
NHC-precat. (15 mol%)
CHO
I
+
KOtBu (1.5 equiv)
F
*
CO2Me
THF/MeOH (20:1)
rt, 12 h
Ph
1a
2a
3aa
entry
Pd source
NHC
Ligands
AY (%)[b]
1
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
--
N1
N2
N3
N4
N1
N1
N1
N1
N1
N1
N1
N1
--
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L5
--
22
2
14
OH
R
O
Ar'
N
PdLn
3
trace
trace
trace
trace
trace
48
Ar
I
H
Ar
N
A
B
4
1
R
5
R
Ar’–I
(2)
Organocat.
cycle
OH Ar
Pd
cycle
R
I
6
N
N
KI
+
PdLn
N
7
R
N
Ar'
O
Ar
R
8
C
MeO
Ar'
OH Ar
R
9
50
3
N
MeOH
MeOK
Ar'
10
11[c]
12
13
14[c]
59
PdLn
N
D
R
75
I
0
Figure 1. Strategy for the umpolung arylation.
Pd2(dba)3
Pd2(dba)3
L5
--
0
N1
14
With these formidable challenges in mind, our optimization was
initiated with trans-cinnamaldehyde (1a) and iodobenzene (2a).
Our hypothesis was that multidentate ligands on palladium would
be needed to prevent coordination of the NHC. Thus, we
examined 4 different NHC precursors (N1 – N4, 15 mol %, Table
1, bottom), using Pd2(dba)3 (5 mol %)/BINAP (10 mol %) as the
metal catalyst, KOtBu (to deprotonate the NHC-precatalyst in
Figure 1) in THF : MeOH (20 : 1) at room temperature for 12 h
(Table 1, entries 1–4). To our delight, more sterically hindered
NHC precursor N1 furnished the 1,4-addition product methyl β,β-
diphenyl propanoate (3aa) in 22% AY (entry 1, AY = assay yield,
determined by 1H NMR integration of the unpurified reaction
[a] Reactions were conducted with 1a (0.1 mmol), 2a (0.2 mmol), THF (1 mL),
MeOH (50 μL), 25 oC, 12 h. [b] Assay yields determined by 1H NMR using
CH2Br2 as internal standard. [c] 2 mL THF and 100 μL MeOH were used.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912584
Angewandte Chemie International Edition
RESEARCH ARTICLE
With the optimized conditions in hand, we next explored the
substrate scope of aryl iodides with trans-cinnamaldehyde (1a).
In general, a broad range of substitution patterns were tolerated
in this umpolung transformation (Scheme 3). The parent
iodobenzene underwent reaction affording the desired product in
We next turned our attention to the scope of the enals in this
umpolung process. As shown in Scheme 4, enals containing
electron-donating groups on the arene ring, such as 4-methoxy
(1b), 4-methyl (1c), and 4-N,N-dimethylamino (1d) afforded the
71% isolated yield. Aryl iodides bearing electron-donating groups, corresponding products in 80, 70, and 64% yields, respectively.
such as 4-iodoanisole 2b, 4-tert-butyl iodobenzene 2c, and 4-
N,N-dimethylamino iodobenzene 2d, exhibited good reactivity,
furnishing 3ab–3ad in 65–68% yield. Aryl iodides containing
electronegative or electron-withdrawing groups are also good
partners. 4-Fluoroiodobenzene (2e), 4-chloroiodobenzene (2f)
and 4-trifluoromethyl iodobenzene (2g) produced the
corresponding products in 72, 70 and 62% yields, respectively.
Meta-substituted 3-chloroiodobenzene (2h) gave 3ah in 74%
yield. Sterically hindered 2-iodotoluene and 1-iodonaphthalene
reacted with 1a and afforded the products in 61 and 50% yields,
respectively. Aryl iodides bearing reactive functional groups,
such as cyano, ester and alcohol, also reacted with 1a to generate
the corresponding products 3ak–3am in 48–67% yield. β,β’-
Diaryl propanoates containing thiophene, benzothiophene,
benzofuran and quinoline groups could be prepared with our
method, as exemplified by the generation of 3an–3aq in 51–67%
yield.
Enals bearing electronegative groups, such as 4-fluoro (1e) and
4-chloro (1f), generated 3ec and 3fe in 61 and 55% yield,
respectively. Substituents at the meta and ortho positions were
both tolerated, generating the products in 52–71% yields (3ge and
3he). A heteroaryl containing enal was also compatible with our
approach, furnishing 3ib in 51% yield. However, the aliphatic enal
was not compatible with this reaction, and no desired product was
observed when crotonaldehyde (1j) was treated with
iodobenzene under standard condition for 24 h.
Scheme 4. Substrate scope of aryl enals.[a], [b]
R
Pd2(dba)3 (5 mol %)
R'
N1 (15 mol %)
L5 (10 mol %)
I
CHO
+
KOtBu (1.5 equiv)
R
R'
THF : MeOH (20:1)
rt, 12 h
CO2Me
R = OMe (2b)
or F (2e)
1
3
Scheme 3. Substrate scope of aryl iodides.[a], [b]
OMe
F
OMe
Pd2(dba)3 (5 mol %)
N1 (15 mol %)
L5 (10 mol %)
CHO
Ar
Ar
I
+
CO2Me
CO2Me
Me
KOtBu (1.5 equiv)
CO2Me
CO2Me
Ph
2
3
1a
THF:MeOH (20:1)
rt, 12 h
MeO
Me2N
3db, 64%
3ce, 70%
3bb, 80%
tBu
NMe2
OMe
F
F
OMe
O
O
O
O
F C
CO2Me
CO2Me
3
CO2Me
Cl
Ph
OMe
OMe Ph
OMe
OMe
OMe
Ph
OMe Ph
3aa 71%
3ab 65%
3ac 68%
3ad 68%
F
Cl
F
CF3
3ge, 52%
3eb, 61%
3fe, 55%
Cl
O
F
OMe
O
O
O
Ph
OMe
Ph
Ph
OMe
OMe Ph
CO2Me
CO2Me
O
3ah 74%
3af 70%
3ag 62%
3ae 72%
CN
CO2Me
OMe
3he, 71%
3ib, 51%
[a] Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Pd2(dba)3 (5 mol%),
precatalyst N1 (15 mol%), ligand L5 (10 mol%), KOtBu (0.15 mmol), MeOH (100
uL), and THF (2 mL) at rt for 12 h. [b] Yields of isolated and purified products.
O
O
O
Me
O
Ph
OMe Ph
OMe
Ph
3ak 67%
Ph
OMe
OMe
3aj 50%
3ai 61%
3al 65%
As indicated in Figure 2a, the 1 mmol scale 1,4-addition of 3-
iodothiophene (2n) proceeded smoothly to produce the
corresponding product 3an in 56% yield. To further study the
application of this reaction, a pharmaceutically active compound
fendiline was synthesized (Figure 2b). trans-Cinnamaldehyde (2
mmol) was coupled with iodobenzene under the standard reaction
conditions to form the corresponding methyl β,β-diphenyl
propanoate (3aa), which was then hydrolyzed to propanoic acid
in 99% yield. Conversion of carbonic acid to acyl chloride and
further amidation with benzyl amine afforded amide 5 in 98% yield.
Finally, compound 6 (fendiline) was obtained in 77% yield by
reduction with LiAlH4.
CH2OH
O
S
S
O
O
O
O
Ph
Ph
OMe
Ph
Ph
OMe
OMe
3ap 67%
3an, 60%
3am 48%
3ao 51%
N
O
Ph
3aq 66%
OMe
[a] Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol), Pd2(dba)3 (5 mol%),
precatalyst N1 (15 mol%), ligand L5 (10 mol%), KOtBu (0.15 mmol), MeOH (100
uL), and THF (2 mL) at rt for 12 h. [b] Yields of isolated and purified products.
This article is protected by copyright. All rights reserved.

10.1002/anie.201912584
Angewandte Chemie International Edition
RESEARCH ARTICLE
S
Pd2(dba)3 (5 mol %)
N1 (15 mol %)
L5 (10 mol %)
enables the tolerance of a diverse array of functional groups.
Studies toward the asymmetric version of this umpolung 1,4-
addition reaction are ongoing in our laboratories.
a)
I
CHO
+
CO2Me
KOtBu (1.5 equiv)
Ph
S
THF-MeOH (20:1)
2n, 2 equiv
rt, 12 h
3an, 137.8 mg
56% yield
1a, 1 mmol
Acknowledgements
b)
Iodobenzene
(2 equiv)
Ph
Ph
Ph
CHO
NaOH (2 M)
The authors acknowledge National Natural Science Foundation
of China (21801128 to J.M.), Natural Science Foundation of
Jiangsu Province, China (BK20170965 to J.M.) and Nanjing Tech
University (3980001601 and 39837112) for financial support.
PJW thanks the US National Science Foundation (CHE-1464744).
The authors are grateful for financial support from SICAM
Fellowship by Jiangsu National Synergetic Innovation Center for
Advanced Materials.
CO2H
CO2Me
MeOH, 60oC
Ph
standard
condition
4, 99% yield
Ph
3aa, 71% yield
1a, 1 mmol
Ph
Ó
LiAlH4
(4equiv.)
Ph
NH2
(1.1 equiv.)
Oxalyl chloride
(2 equiv.)
N
H
N
H
THF, reflux
Ph
Ph
DMF
Et3N(1.2 equiv.)
DCM, rt
Ph
Ph
DCM, 0oC-rt
5, 98% yield
6, Fendiline
77% yield
Keywords: Cooperative catalysis • Umpolung 1,4-Addition • N-
Figure 2. a. 1 mmol scale reaction. b. Synthesis of Fendiline.
Heterocyclic Carbene • Palladium catalysis
To obtain insight into possible reaction pathways and discount
others, additional experiments were conducted. When the
reaction of trans-cinnamaldehyde (1a) and iodobenzene (2a) was
performed without NHC precursor, but with Pd2(dba)3 and terpy,
no Heck reaction product (7) was observed and no 3a was
detected (Figure 3a). Treating compound 7 with N1, KOtBu and
methanol in THF did not afford product 3aa (Figure 3b). These
results disfavor a possible Heck arylation pathway followed by
redox esterification.21 Next, we independently synthesized the
(bipy)Pd(Ar)I complex 8 to probe the cooperative catalytic cycle
(bipyridine and terpyridine showed similar activities in Table 1).
The reaction of 8 with 1a was performed in the presence of
stoichiometric N1 and KOtBu in THF/MeOH, providing 1,4-
addition product in 55% yield. Moreover, only trace amounts of
free bipy was found in the crude reaction mixture (1H NMR), which
suggests that bipy was not displaced by NHC N1. Given that
NHC’s are well known to activate enals and palladium catalysts
renowned for their ability to promote oxidative addition of aryl
halides and perform reductive elimination to form C–C bonds, a
mechanism akin to that outlined in Scheme 1 seems quite likely.
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Ph
Pd2(dba)3 (5 mol %)
L5 (10 mol %)
CHO
CHO
no 3aa
PhI
Ph
not observed
+
KOtBu (1.5 equiv)
THF:MeOH (20:1)
rt, 12 h
[4]
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7
2a
1a
b)
Ph
N1 (15 mol %)
no 3aa
CHO
KOtBu (0.5 equiv)
Ph
THF:MeOH (20:1)
rt, 12 h
7
c)
Ph
O
N1(1 equiv)
N
I
N
CHO
+
Ph
Ph
OMe
KOtBu (2 equiv)
Pd
Ph
THF:MeOH (20:1)
rt, 12 h
3aa, 55% yield
1a, 2.5 equiv
8
[5]
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In conclusion, we have developed the first umpolung 1,4-addition
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additions to α,β-unsaturated esters with organometallic reagents,
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Title
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RESEARCH ARTICLE
Wenjun Yang, Bo Ling, Bowen Hu,
Haolin Yin, Jianyou Mao,* and Patrick J.
Walsh*
OH Ar
Ar
C
H
O
N
H
C
R
O
H
A
r
I
Ar
'
+
Ar'
Pd
N
N
R
Ar'
d
Ln
Ar
CO2Me
I
CHO
R
I
Ar'
NHC
Pd
Ar
N
CO2Me
Page No. – Page No.
PdLn
Ar'
+
Ar'
Ar
N
I
R
Synergistic N-Heterocyclic
Carbene/Palladium-Catalyzed Um-
polung 1,4-Addition of Aryl Iodides to
Enals
Text for Table of Contents:
The power of two: Synergistic catalysis between NHC and palladium catalysts enables conjugate addition of aryl iodides to enals
under redox neutral conditions.
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