Palladium-catalyzed benzylic C(sp3)-H carbonylative arylation of azaarylmethyl amines with aryl bromides

Article abstract of DOI:10.1039/d1sc02078a

A highly selective palladium-catalyzed carbonylative arylation of weakly acidic benzylic C(sp3)-H bonds of azaarylmethylamines with aryl bromides under 1 atm of CO gas has been achieved. This work represents the first examples of use of such weakly acidic pronucleophiles in this class of transformations. In the presence of a NIXANTPHOS-based palladium catalyst, this one-pot cascade process allows a range of azaarylmethylamines containing pyridyl, quinolinyl and pyrimidyl moieties and acyclic and cyclic amines to undergo efficient reactions with aryl bromides and CO to provide α-amino aryl-azaarylmethyl ketones in moderate to high yields with a broad substrate scope and good tolerance of functional groups. This reaction proceeds via in situ reversible deprotonation of the benzylic C-H bonds to give the active carbanions, thereby avoiding prefunctionalized organometallic reagents and generation of additional waste. Importantly, the operational simplicity, scalability and diversity of the products highlight the potential applicability of this protocol.

Full text of DOI:10.1039/d1sc02078a

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Palladium-catalyzed benzylic C(sp3)–H
carbonylative arylation of azaarylmethyl amines
Cite this: DOI: 10.1039/d1sc02078a
with aryl bromides†
Haoqiang Zhao,‡ab Bowen Hu,‡a Lijin Xu
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
b
a
*
*
and Patrick J. Walsh
A highly selective palladium-catalyzed carbonylative arylation of weakly acidic benzylic C(sp3)–H bonds of
azaarylmethylamines with aryl bromides under 1 atm of CO gas has been achieved. This work represents the
first examples of use of such weakly acidic pronucleophiles in this class of transformations. In the presence
of
a NIXANTPHOS-based palladium catalyst, this one-pot cascade process allows a range of
azaarylmethylamines containing pyridyl, quinolinyl and pyrimidyl moieties and acyclic and cyclic amines
to undergo efficient reactions with aryl bromides and CO to provide a-amino aryl-azaarylmethyl ketones
in moderate to high yields with a broad substrate scope and good tolerance of functional groups. This
reaction proceeds via in situ reversible deprotonation of the benzylic C–H bonds to give the active
carbanions, thereby avoiding prefunctionalized organometallic reagents and generation of additional
waste. Importantly, the operational simplicity, scalability and diversity of the products highlight the
potential applicability of this protocol.
Received 14th April 2021
Accepted 6th July 2021
DOI: 10.1039/d1sc02078a
rsc.li/chemical-science
preparation of a-amino ketones starting from alkenes,12
alkynes13 and sulfonium ylides.14 Despite these promising
Introduction
advances, exploration of straightforward methods that enable
formation of multiple C–C bonds remain appealing.
a-Amino ketones are key components of numerous biologically
active natural products and synthetic compounds. They display
a wide range of medicinal and biological activities, such as anti-
depressant, appetite suppressant, and anti-platelet properties
(Fig. 1).1 a-Amino ketones also serve as effective synthetic
intermediates for the preparation of various heterocycles and
1,2-amino alcohols.1b,2 As a result of their widespread utility,
there has been substantial and long-standing interest in the
efficient construction of a-amino ketones in the synthetic
community.3 General approaches to construct a-amino ketones
from ketones or their derivatives involve nucleophilic amina-
tion,4 electrophilic amination5 or oxidative amination.6
Considerable efforts have also been made to synthesize a-amino
ketones via acylation of imines with aldehydes, acylsilanes or
carboxylic acids,7 Stille reaction of sulfonamides with benzoyl
chlorides,8 cross-coupling of thiol esters with boronic acids or
organostannanes,9 hydrogenation of a-dehydroamino ketones
or a-ketoketimines,10 and rearrangement of a-hydroxyl imines
or enamines.11 Moreover, recent years have witnessed the
Due to its low cost, high reactivity and abundance, CO has
been extensively explored as a versatile C1 building block for the
production of carbonyl-containing compounds and heterocy-
cles.15 Impressive achievements have been recorded in
transition-metal catalyzed reactions of CO in multicomponent
carbonylation reactions to construct carbonyl-containing
molecules from simple starting materials.15d,16 Little attention,
however, has been paid to the application of this strategy for the
preparation of synthetically valuable a-amino ketones. There is
only one such report in the literature. In 2018, Wang, Zhang and
co-workers described an elegant synthesis of a-amino ketones
via a Pd(0)-catalyzed four-component carbonylation reaction of
aryl iodides, N-tosylhydrazones and amines under 1 atm of CO
(Scheme 1).17 Despite the synthetic potential of this 4 compo-
nent coupling, this protocol is only applicable to aryl iodides
and no examples with heteroaryl groups were reported.
Recent progress has established the viability of palladium-
catalyzed carbonylative cross-coupling reactions of acidic
C(sp3)–H bonds for the concurrent formation of two new C–C
bonds with the introduction of a carbonyl group.18,19 Early
reports focused on the arylation of activated C(sp3)–H bonds of
malonate derivatives.18 In 2012, Skrydstrup and co-workers rst
realized carbonylative a-arylation of ketones with aryl iodides
using CO in the presence of a catalytic amount of [Pd(dba)2] and
a bidentate phosphine ligand to afford 1,3-diketones (Scheme
2a).19a Subsequently, the same group accomplished
aRoy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput
Experimentation, Department of Chemistry, University of Pennsylvania, 231 South
34th Street, Philadelphia, Pennsylvania 19104-6323, USA. E-mail: pwalsh@sas.
upenn.edu
bDepartment of Chemistry, Renmin University of China, Beijing 100872, China. E-mail:
20050062@ruc.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1sc02078a
‡ These authors contribute equally.
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Fig. 1 Selected pharmacologically active compounds containing a-amino aryl ketones.
iodides and aryl bromides under palladium catalysis. Mean-
while, Beller and co-workers described the Pd-catalyzed car-
bonylative a-arylation of ketones and nitriles with aryl iodides
and pressurized CO gas (Scheme 2a).19c,f These studies take
advantage of strongly activated C(sp3)–H bonds to facilitate
deprotonation. The carbonylative a-arylation of weakly acidic
C(sp3)–H bonds remains underdeveloped, despite the potential
utility of such a method with a wide variety of pronucleophiles.
In recent years, our team has built a program around direct
arylation of weakly acidic C(sp3)–H bonds (pKa 25–43 in
DMSO)20 with aryl halides by employing palladium catalysts and
suitable bases (Scheme 2b). We called these reactions depro-
tonative cross-coupling processes (DCCP).21 Based on these
Scheme 1 Carbene-based approach of Wang and co-workers.
carbonylative a-arylation of monoester potassium malonate,19b
acetylacetones,19d ketones,19e 2-oxindoles,19g nitromethanes,19h
substituted 1,3-dioxin-4-ones,19i and cyanoacetates19j with aryl
Scheme 2 Deprotonative carbonylative cross-coupling reactions (a) Prior art with more acidic pro-nucleophiles, (b) Our prior work on the direct
coupling reaction in the absence of CO, (c) The current study using weakly acidic Azaarylmethylamine pro-nucleophiles.
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studies from our lab, we envisioned that merging DCCP with carbonylative coupling product (also called the direct coupling
carbonylation reactions would enable preparation of a host of product) 3aa0 in 8% AY (Table 1, entry 1 and ESI, Table S2†).
new ketones. Herein we describe such a new and efficient
With an aim to improve the reaction efficiency, the perfor-
process that allows highly selective carbonylative arylation of mance of the coupling in other solvents, such as THF, CPME
weakly acidic benzylic C(sp3)–H bonds of azaarylmethylamines (cyclopentyl methyl ether) and DME were examined (Table 1,
with aryl bromides. These reactions are conveniently conducted entries 2–4), but none outperform 1,4-dioxane. Replacement of
with 1 atm of CO and a palladium catalyst to deliver a-amino LiN(SiMe3)2 with NaN(SiMe3)2, or KN(SiMe3)2 failed to give
aryl-azaarylmethyl-ketone products in good to excellent yields. better results, and the reaction was not promoted with LiOtBu,
The reaction has a broad substrate scope and good tolerance of NaOtBu, or KOtBu as the base (ESI, Table S2†). The subsequent
functional groups (Scheme 2c).
screening of palladium salts revealed the superiority of Pd(dba)2
in this reaction, allowing the generation of product 3aa in 43%
yield (Table 1, entry 8). Unexpectedly, increasing the loading of
LiN(SiMe3)2 to 3 equiv. improved the yield of 3aa to 89% with
only a small amount of direct coupling byproduct 3aa0 (7%)
(Table 1, entry 9 and ESI, Table S2†). The yield of 3aa could be
further enhanced to 93% with an increase of reaction temper-
ature to 80 ꢀC (Table 1, entry 10), but a higher reaction
temperature of 100 ꢀC was found to be detrimental (Table 1,
entry 11). Further examination of the stoichiometry indicated
that increasing the amount of 2a from 1.2 to 1.5 equiv. resulted
in almost exclusive formation of 3aa in an excellent assay yield
of 97% with 92% isolated yield (Table 1, entry 12). The phos-
phine ligand bound to palladium also proved to be critical.
Variation of the bidentate phosphine ligand to dppe, dppb,
dppp, dppf and xantphos all led to substantial decreases in the
reaction conversion (ESI, Table S2†). Control experiments
Results and discussion
We started our studies by exploring the reaction conditions of
benzylic C–H carbonylative arylation of 4-(pyridin-2-ylmethyl)
morpholine (1a) with 1-bromo-4-(tert-butyl)benzene (2a) under
1 atm of CO gas (Table 1). Considering that we have recently
achieved the coupling of azaarylmethyl amines with aryl halides
to generate aryl(azaaryl)methyl amines in 1,4-dioxane using
a
Pd(OAc)2/NIXANTPHOS-based catalyst together with
LiN(SiMe3)2 as the base,21c we rst assessed the feasibility of the
proposed reaction of 1a, 2a and CO (1 atm) at 65 ꢀC for 16 h by
employing the same catalytic system. To our delight, the car-
bonylative arylation reaction indeed occurred, delivering the
expected product 3aa in 27% AY (AY ¼ assay yield, determined
by 1H NMR spectroscopy) with the formation of the non-
Table 1 Optimization of reaction conditions for benzylic C–H carbonylative arylation of 1a with 2aa
Entry
Pd source
Solvent
Temp (ꢀC)
3aa Assay yieldb (%)
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd G4 dimer
[PdCl(allyl)]2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
—
1,4-Dioxane
THF
CPME
65
65
65
65
65
65
65
65
65
80
100
80
80
80
80
27
22
21
10
31
37
7
43
89
93
89
97 (92)e
0
DME
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
8
9c
10c
11c
12c,d
13c,d,f
14c,d
15c,d,g
0
4
Pd(dba)2
a
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), LiN(SiMe3)2 (2 equiv.), [Pd] (5 mol%), NIXANTPHOS (6 mol%), solvent (1 mL). b Yields were
determined by 1H NMR analysis of unpuried reaction mixtures with internal standard CH2Br2. LiN(SiMe3)2 (3 equiv.) was employed. 2a (1.5
equiv.) was employed. Isolated yield. In the absence of NIXANTPHOS. CO (8.6 atm) was applied. Pd G4 dimer: Buchwald G4 precatalysts;
dba: dibenzylideneacetone.
c
d
e
f
g
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conrmed the dependency on both the phosphine ligand and crucial dependency on the main group metal in such multistep
the palladium source in this transformation (Table 1, entries 13 reactions. To further extend the scope of this carbonylative
and 14). Increasing the CO pressure to 8.6 atm resulted in only arylation, other azaarylmethylamines were tested. Notably,
4% AY (Table 1, entry 15), which suggested a higher CO pressure when
4-(benzo[d]thiazol-2-ylmethyl)morpholine
1l
was
could potentially saturate the metal catalyst and deactivate it. employed, the product (3la) was obtained in 50% yield as
With the optimized reaction conditions in hand, we then a mixture of the ketone and enol isomers (the ratio was keto-
evaluated the substrate scope of azaarylmethylamines and the ne : enol ¼ 3 : 1). However, for other kinds of azaarylmethyl-
results are summarized in Table 2. 2-Pyridylmethylamines (1b– amines like 2-(morpholinomethyl)benzo[d]oxazole, 4-((1-
1f) bearing thiomorpholine, methylpiperazine, dimethylamine, methyl-1H-imidazol-2-yl)methyl)morpholine, 4-benzylmorpho-
pyrrolidine and piperidine underwent smooth C–H carbon- line or even 2-(ethoxymethyl)pyridine, the reaction failed to
ylative arylation to afford the expected a-amino ketone products yield the desired products (See ESI, Table S3† for substrates that
(3ba–3fa) in 64–87% yield. Substrate 1g bearing a sterically were unsuccessful with this catalyst system). When 2-quinoli-
hindered ortho-substituent on the pyridine ring was also reac- nylmethyl amines 1m and 1n were employed, the correspond-
tive, delivering the desired product 3ga in 52% yield. The more ing products 3ma and 3na were obtained in 74% and 72%
acidic 4-pyridylmethylamines (1h–1k) containing different yields, respectively. Moreover, 2-pyrimidylmethylamine 1o also
amino groups reacted efficiently to give the desired products reacted smoothly, affording product 3oa in 93% yield.
(3ah–3ak) in 61–88% yield. In the case of 3-pyridylmethylamine,
We next investigated the reaction of various aryl bromides
however, the reaction failed to yield any desired product, with with 1a under 1 atm CO (Table 3). A variety of para-substituted
recovery of most of the starting materials. It is interesting to aryl bromides bearing electron-donating groups (2b–2f, 2j and
note that in the that direct coupling with the 3-pyridylmethyl- 2k) and electron-withdrawing groups (2g–2i) were all effective
amine (in the absence of CO), the reaction was successful with reaction partners, providing the corresponding products (3ab–
KN(SiMe3)2 as base.21c Use of KN(SiMe3)2 instead of LiN(SiMe3)2 3ak) in moderate to high yields (57–90%). Moreover, the reac-
under CO at 110 ꢀC, however, did not lead to ketone product.21c tion could be successfully extended to meta-substituted aryl
It is likely that the higher pKa of this pronucleophile, in bromides (2l–2n), delivering the desired products (3al–3an) in
combination with the less reactive base LiN(SiMe3)2 disfavors 61–84% yields. Lower yields were generally observed with
formation of sufficient quantities of the nucleophile and electron-poor aryl bromides, possibly due to the partial
prevents the reaction from proceeding.20 This result shows the decomposition of these aryl bromides in the presence of the
Table 2 Pd-catalyzed benzylic C–H carbonylative arylation of azaarylmethylamines 1 with 2aa,b
a
Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Pd(dba)2 (5 mol%), NIXANTPHOS (6 mol%), LiN(SiMe3)2 (3.0 equiv.), 1,4-dioxane (2.0 mL),
80 ꢀC, 16 h, under CO atmosphere (1 atm). b Isolated yields. c A mixture of ketone and enol forms were obtained (ketone : enol ¼ 3 : 1).
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Table 3 Pd-catalyzed benzylic C–H carbonylative arylation of 1a with aryl bromidesa,b
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), Pd(dba)2 (5 mol%), NIXANTPHOS (6 mol%), LiN(SiMe3)2 (3.0 equiv.), 1,4-dioxane (2.0 mL),
80 ꢀC, 16 h, under CO atmosphere (1 atm). b Isolated yields.
base. Notably, 1-bromo-4-chlorobenzene (2h) and 1-bromo-3- heteroaryl bromides 2s and 2t to generate 3as and 3at in 50%
chlorobenzene (2m) led to the formation of products 3ah and and 55% yields, respectively. It is noteworthy that the products
3am in 77% and 71% yields, respectively, with the chloro group of these reactions are rich in heterocycles.
remaining intact during the reaction process. The
Preliminary studies were conducted to gain insight into the
Pd(NIXANTPHOS)-based catalysts is known to oxidatively add reaction product. We hypothesized that the product generated
aryl chlorides at room temperature (see ESI, Table S2†).21 In the under the reaction conditions before workup was not the
presence of CO, however, aryl chlorides were not reactive. These ketone, but the enolate that is protonated upon aqueous
observations suggest to us that the palladium catalyst bears workup. Thus, we rst prepared the enolate 3aA by deprotona-
a CO ligand that tempers its ability to oxidatively add the tion of ketone 3aa with LiN(SiMe3)2 (Scheme 3a). Next, the
stronger C–Cl bond of aryl chlorides.
carbonylative a-arylation reaction of 1a, 2a and CO was con-
Multi-substituted aryl bromides (2o–2r) also readily engaged ducted and the product characterized by NMR spectroscopy
in the transformation to afford the corresponding products before quenching with water (Scheme 3b). This product was
(3ao–3ar) in 65–87% yields. The generality of the current cata- found to be identical to the independently synthesized enolate
lytic system was further demonstrated by the success of 3aA, conrming our hypothesis that the enolate is the product
Scheme 3 Detection of product precursor (a) Independent synthesis of enolate 3aA, (b) Determination of the reaction product before workup.
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of the reaction (Scheme 3). This result also helps to explain why
Based on the aforementioned results in DCCP chemistry (no
3 equiv. of LiN(SiMe3)2 are optimal. An equivalent is needed to CO)21 and previous reports on carbonylative arylation,19,23
consume the starting material 1 and a second to deprotonate a plausible mechanism is proposed in Scheme 5. The catalytic
the ketone. The role of the third is to deprotonate the catalyst cycle starts with complexation of NIXANTPHOS (see Scheme 2b
backbone N–H and to react with any advantageous water.
for structure) and Pd(dba)2 to yield the (NIXANTPHOS)Pd(0)
To showcase the synthetic utility of our method, we rst species A.21a We previously demonstrated that the
conducted a gram-scale reaction of 1a, 2a and CO under the NIXANTPHOS N–H (pKa 21 in DMSO) will be deprotonated by
standard reaction conditions. The desired product 3aa was silyl amide bases to afford bimetallic adducts that have
obtained in 71% yield (1.2 g) (Scheme 4a). Next, we attempted exhibited cooperativity between the Pd and main group cati-
the transformation of the product ketones into other useful on.21m In the absence of CO, the resulting heterobimetallic
derivatives. Although Baeyer–Villiger oxidation of 3aa with m- complex will oxidatively add aryl chlorides at room temperature
CPBA in CH2Cl2 failed to give the desired ester, an unexpected through a mechanism involving cooperativity between the main
oxidative cleavage reaction occurred to give product 4 in 91% group metal and the palladium.21m In the presence of CO we also
yield (Scheme 4b). Notably, further study revealed that this expect the ligand N–H to be deprotonated by LiN(SiMe3)2. The
oxidative cleavage reaction could take place under air oxidation oxidative addition does not appear to be accelerated and the
to give a high yield of 4 (83%). Moreover, reduction of 3aa with carbonylation reaction does not work with aryl chlorides. Under
NaBH4 in MeOH at room temperature for 16 h resulted in the CO atmosphere, the Pd(0) species is proposed to undergo CO
formation of amino alcohol product 5 in 68% yield (Scheme 4c). coordination to generate Pd(0) carbonyl (B) and dicarbonyl C
Finally, treatment of 3aa with LiN(SiMe3)2 and Me2NEt followed complexes.23b This proposal is consistent with inhibition at high
by addition of allyl chloroformate gave the allyl enol carbonate CO pressures. Upon dissociation of CO from C to generate the
product 6 in 87% isolated yield as a single diastereomer 16 electron mono-carbonyl adduct B, oxidative addition of the
(Scheme 4d). As reported by the Stoltz group,22 this enol aryl bromide
2 takes place to produce (NIXANTPHOS)
carbonate product can undergo palladium-catalyzed enantio- Pd(CO)(Ar)Br-complex D. Intermediate D likely undergoes CO
selective decarboxylative allylic alkylation to afford a chiral a- insertion into the Pd–Ar bond to furnish the acyl–Pd(II) complex
quaternary ketone.
E. Intermediate E reacts with the deprotonated pronucleophile
Scheme 4 Synthetic applications (a) scale-up of reaction, (b) product oxidation, (c and d) further transformations of the product.
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Scheme 5 Plausible mechanism.
10 in a transmetallation step to deliver the reductive elimination
precursor F. Reductive elimination of F gives the ketone product
3 and Pd(0) species A to close the catalytic cycle. In the presence
of LiN(SiMe3)2 the ketone 3 is rapidly deprotonated, furnishing
the enolate 30. Quenching the reaction with H2O results in the
formation of the observed ketone product 3. The direct coupling
product likely forms when transmetallation takes place before
CO insertion or if CO insertion is reversible. At this stage, we
cannot rule out the possibility of an adduct between Pd(0) and
the enolate, as described by Skrydstrup and coworkers.19e
Further investigations into the reaction mechanism will be
presented in due course.
Author contributions
HZ performed the optimization of the reaction with help from
BH. The substrate scope and product characterization was
performed by HZ and BH. The rst dra was written by HZ and
all authors contributed to revising the dra. The project was
conceived by PJW and the research directed by PJW and LX.
Conflicts of interest
The authors declare no competing nancial interest.
Acknowledgements
Conclusion
P. J. W. thanks the U.S. National Science Foundation (CHE-
1902509). We acknowledge the Program for China Scholarship
Council (No. 201806360122), National Natural Science Foun-
dation of China (21372258) for nancial support. Yue Fu is
acknowledged for preliminary experiments.
In conclusion, we have developed the carbonylative arylation of
weakly acidic benzylic C(sp3)–H bonds of azaarylmethylamines
with aryl bromides and CO using a Pd catalyst. This work is
unique in that it employs pronucleophiles with high pKa values,
suggesting a wide variety of previously overlooked substrates
may be viable coupling partners in carbonylation reactions. The
reaction is operative under 1 atm of CO and does not require
high pressure equipment. This one-pot cascade process is
applicable to the coupling of a wide range of azaarylmethyl-
amines and aryl bromides, enabling facile access to useful a-
amino aryl-azaarylmethyl-ketones in moderate to high yields
with good functional group tolerance. This work provides an
attractive and complementary approach to prepare heteroatom-
rich a-amino ketones.
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