Umpolung coupling of pyridine-2-carboxaldehydes and propargylic carbonatesviaN-heterocyclic carbene/palladium synergetic catalysis

Article abstract of DOI:10.1039/d1cc01311d

The umpolung cross-coupling reaction of pyridine-2-carboxaldehydes and propargylic carbonates has been developed for the first time through N-heterocyclic carbene/palladium cooperative catalysis with the judicious selection of the palladium catalyst, ligand and N-heterocyclic carbene, giving the propargylic ketones regioselectively.

Full text of DOI:10.1039/d1cc01311d

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Umpolung coupling of pyridine-2-
carboxaldehydes and propargylic carbonates via
N-heterocyclic carbene/palladium synergetic
catalysis†
Cite this: Chem. Commun., 2021,
57, 4452
Received 10th March 2021,
Accepted 26th March 2021
ab
abc
Weiyang Bi,ab Yunhui Yang,abc Song Ye
and Congyang Wang
*
DOI: 10.1039/d1cc01311d
rsc.li/chemcomm
The umpolung cross-coupling reaction of pyridine-2-carboxaldehydes cross-coupling reactions through NHC catalysis.10 In 2018, Zhao and
and propargylic carbonates has been developed for the first time co-workers disclosed a transition-metal-free NHC-catalyzed asym-
through N-heterocyclic carbene/palladium cooperative catalysis metric decarboxylative propargylic substitution/cyclization of alde-
with the judicious selection of the palladium catalyst, ligand and hydes (Scheme 1a).11 A series of skeletally diverse polycyclic products
N-heterocyclic carbene, giving the propargylic ketones regioselectively. were approached selectively depending upon the categories of
aldehydes and reaction conditions. In 2019, Gong et al. demon-
Synergetic catalysis is a powerful synthetic strategy wherein strated an NHC/Cu cooperative catalysis enabling [3+3] and [3+4]
diverse catalysts activate different substrates simultaneously in cyclizations of isatin-derived aldehydes with propargylic electro-
a single chemical transformation.1 Recent progress on combin- philes to access spirooxindoles selectively (Scheme 1b).6b
ing transition metal catalysis and organocatalysis has attracted
On the other hand, palladium-catalyzed cross-coupling reac-
considerable attention as it could enable unprecedented trans- tions of propargylic electrophiles with varied nucleophiles are
formations not achieved by the use of transition metal catalysis among the most successful tools for chemical bond formation
or organocatalysis alone.2 Nevertheless, the combination of in organic synthesis.12 To the best of our knowledge, the
N-heterocyclic carbene (NHC) catalysis with transition metal combinative catalysis of palladium and NHC for the reaction
catalysis remains continuously challenging, possibly due to the
reactivity mismatch of key organic and metallic intermediates,
incompatibility of reaction conditions, and the fact that NHC is
an important type of ligand that can bind to transition metals
thus causing difficulties for their individual catalytic cycles,
among others.3 A number of groups have recently addressed
these problems by judicious choices of transition metals,
reaction conditions, competitive ligands and so on to achieve
the synergetic catalysis of NHC and transition metal catalysts
such as palladium,4 ruthenium,5 copper,6 gold,7 silver8 and
iridium.9
In comparison with the widely studied allylic electrophiles,4,6,9
the propargylic electrophiles have been less explored in the
a Beijing National Laboratory for Molecular Sciences,
CAS Key Laboratory of Molecular Recognition and Function,
CAS Research/Education Center for Excellence in Molecular Sciences,
Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
E-mail: wangcy@iccas.ac.cn
b University of Chinese Academy of Sciences, Beijing 100049, China
c Physical Science Laboratory, Huairou National Comprehensive Science Center,
Beijing 101400, China
† Electronic supplementary information (ESI) available. CCDC 2068444. For ESI
Scheme 1 NHC-catalyzed reactions of aldehydes with propargylic
electrophiles.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
d1cc01311d
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of propargylic electrophiles with aldehydes remains surprisingly 6% NMR yield in the presence of catalytic Pd(OAc)2 with
unknown so far. We surmised that the reactivity match between bidentate dppe L1 as the ligand and a thiazolium precatalyst
organopalladium catalytic intermediates derived from the pro- preNHC1 (Table 1, entry 1). Encouraged by this result, the
pargylic electrophile and Breslow intermediate from the aldehyde influence of the critical reaction parameters was investigated.
would be the key issue in view of the tetrasubstituted olefin First, commonly used palladium catalysts were examined and it
characteristics of the Breslow intermediate, which will be challen- was shown that Pd(dba)2 was the most effective one (entries
ging to react with the palladium species via inner- or outer-sphere 2–4). Next, a series of ligands for palladium were tested. It
mechanisms. The judicious tuning of the ligands for palladium revealed that monodentate triphenylphosphine (PPh3, L2)
and NHC for the Breslow intermediate and, importantly, rendering failed to give the expected product (entry 5). In contrast,
these two species close via coordination assistance4f might be bisphosphorus ligands (L3–L6) mostly worked better for this
essential to meet the above challenge. Herein, we report our efforts reaction (entries 6–9) and xantphos (L3) could provide the
on the umpolung cross coupling of o-azaaryl aldehydes and product 3aa in a 47% yield (entry 6). Finally, a survey of NHC
propargylic carbonates by resorting to NHC/palladium synergetic precatalysts (preNHC2–6) indicated that only the thiazolium
catalysis, which represents the first example of the Breslow inter- NHC precatalysts were compatible with the palladium catalysts
mediate reacting with organopalladium derived from propargylic affording the corresponding product 3aa successfully (entries
electrophiles.
10–14) and the combination of preNHC2, Pd(dba)2 and xant-
We commenced our study from the model reaction of phos L3 was the optimal catalyst system (entry 10). After further
pyridine-2-carboxaldehyde 1a with propargylic carbonate 2a evaluation of the reaction temperature, solvents, bases and
under the co-catalysis of NHC and palladium (Table 1). After reaction times, a 74% isolated yield of product 3aa could be
the initial screening of the reaction conditions, it was found obtained when the reaction was performed at 65 1C for 24 h
that the reaction gave the propargylic ketone product 3aa in a with NaHCO3 as the base (entry 15). It should be noted that
Pd-catalyzed reactions of propargylic electrophiles with hard
nucleophiles typically afford allene products via the allenyl
palladium intermediate (Scheme 1c), while reactions with soft
Table 1 Optimization of key reaction parametersa
nucleophiles may deliver alkene products through nucleo-
philic attack twice.12 Meanwhile, regioselective formation of
a-propargylic products has been reported in rare cases.13
Remarkably, no g-attack allene product 4aa or b,g-attack alkene
product 5aa was detected during the whole optimization
process of the current NHC/Pd-catalyzed cross coupling of
propargylic carbonate with the umpolung Brewslow inter-
mediate, which demonstrated excellent regioselectivity in the
reaction.
With the optimized conditions in hand, we first examined
the reactivity of various substituted pyridine-2-carboxaldehydes
using propargylic carbonate 2a as a model reaction partner
(Scheme 2). Aldehydes 1 bearing different substituents at the 2-,
3-, 4- or 5-positions of the pyridine ring all gave the desired
Entry
[Pd]
Ligand
preNHC
Yieldb (%)
products 3aa–ga in good yields with sole regioselectivity. In
addition, quinoline-2-carbaldehyde (1h) was also suitable for
the reaction to afford the corresponding product 3ha in a
synthetically useful yield. Then, the scope of propargylic carbo-
nates 2 to react with pyridine-2-carboxaldehyde 1a was exam-
ined. Substrates bearing either electron-deficient or electron-
rich groups on the benzene ring could participate in the
umpolung coupling, affording the corresponding ketones
smoothly (3ab–aj). Functional groups such as fluoro, chloro,
trifluoromethyl, alkyl, methoxy and ester were all tolerated at
the para-, meta- or ortho-positions of aryl propargylic carbo-
nates. Moreover, propargylic carbonates with naphthyl, thienyl
or n-butyl groups also reacted with 1a successfully to give the
desired products in decent yields (3ak–am). Unfortunately,
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
L1
L1
L1
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
preNHC1
preNHC1
preNHC1
preNHC1
preNHC1
preNHC1
preNHC1
preNHC1
preNHC1
preNHC2
preNHC3
preNHC4
preNHC5
preNHC6
preNHC2
6
21
34
29
n.d.
47
4
42
32
56
28
39
n.d.
n.d.
74d
Pd(dba)2
Pd(PPh3)4
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
9
10
11
12
13
14
15c
a
Reaction conditions unless otherwise noted: 1a (0.4 mmol), 2a
(0.2 mmol), [Pd] catalyst (10 mol%), ligand (10 mol%), preNHC variations in the dimethyl groups of the propargylic carbonates
(20 mol%), K2CO3 (0.4 mmol), THF (3.0 mL) and under a nitrogen
have been unsuccessful so far, which reflects the steric impor-
b
atmosphere. Yields determined by 1H NMR analysis using 1,3,
c
tance at this position for the reaction (see Scheme S1 in ESI†).
5-trimethoxybenzene as an internal standard. NaHCO3 was used
d
instead of K2CO3 at 65 1C for 24 h. Isolated yield on 0.5 mmol scale. In addition, the structure of product 3hk was confirmed
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Scheme 4 Proposed reaction mechanism.
(Scheme 3b). Finally, in order to verify the importance of ortho-
pyridine coordination assistance, pyridinecarboxaldehydes 1i and
1j with N-atoms at other positions, benzaldehyde 1k, 2-furaldehyde
1l and 2-thiophenecarboxaldehyde 1m were tested in the reactions
(Scheme 3c) and only benzoin by-products were found after the
reactions, which indicated the indispensible role of the ortho
N-coordination of pyridine towards the palladium center for the
reaction.
Scheme 2 Scope of o-azaaryl aldehydes and propargylic carbonates.a
a Reaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), Pd(dba)2 (10 mol%), L3
(10 mol%), preNHC2 (20 mol%), NaHCO3 (1.0 mmol), and THF (6.0 mL)
under a nitrogen atmosphere. Isolated yields are shown.
A plausible reaction mechanism comprising two fused catalytic
cycles, namely NHC and palladium catalysis, is depicted in
Scheme 4. The Breslow intermediate A is first formed by the
reaction of preNHC2 and the aldehyde 1a in the NHC catalytic
cycle. Meanwhile, the reaction of the palladium catalyst with
propargylic carbonate 2a generates the Z1-, Z3-propargylic palla-
dium or allenyl palladium complexes B in the Pd catalytic cycle.
Then, the above two intermediates approach each other through
coordination assistance of the N-atom in the pyridine towards Pd
and form the key palladium complex C. Thereafter, intermediate
D is generated via an intramolecular nucleophilic attack of the
Breslow intermediate at the a-position of Z3-propargylic palla-
dium. Finally, the intermediate D releases the desired product 3aa
and regenerates free NHC2 and the palladium catalyst for the next
catalytic cycles. Currently, the reaction pathways through the
allenyl palladium complex cannot be ruled out in the reaction.
In summary, the umpolung cross-coupling reaction of
o-azaaryl carboxaldehydes and propargylic carbonates has been
developed for the first time through NHC/palladium synergetic
catalysis. Thus, the propargylic ketones were accessed directly
and regioselectively without the formation of allenyl or alkenyl
ketone by-products. The judicious choices of the palladium
catalyst bearing a xantphos ligand and the thiazolium-derived
NHC catalyst are crucial for the successful merging of the two
NHC and palladium catalytic cycles. Further studies on NHC/
palladium synergetic catalysis are ongoing in our laboratories.
Financial support from the National Natural Science Founda-
tion of China (21772202, 21831008, and 22025109), Beijing Muni-
cipal Science & Technology Commission (No. Z191100007219009),
Beijing National Laboratory for Molecular Sciences (BNLMS-
CXXM-201901) and the K. C. Wong Education Foundation are
gratefully acknowledged.
unambiguously by single-crystal X-ray diffraction analysis
(CCDC†: 2068444).
To gain insights into the possible reaction pathways operating
in the NHC/Pd synergetic catalysis, control experiments were first
conducted. It was shown that no product 3aa was detected in the
absence of either Pd(dba)2, the ligand of L3 or preNHC2 under
otherwise identical conditions (Scheme 3a), which highlights
the essential roles of these key components for the umpolung
coupling. Next, the preformed palladium/xantphos complex,
[Pd(xantphos)Cl2], was subjected to the reaction and the pro-
pargylic ketone product 3aa could be obtained in 42% yield
Scheme 3 Mechanistic experiments.
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B. Hu, H. Yin, J. Mao and P. J. Walsh, Angew. Chem., Int. Ed., 2020,
59, 161; (l) B. Ling, W. Yang, Y. E. Wang and J. Mao, Org. Lett., 2020,
22, 9603.
5 (a) D. A. DiRocco and T. Rovis, J. Am. Chem. Soc., 2012, 134, 8094;
(b) J. Zhao, C. Mu¨ck-Lichtenfeld and A. Studer, Adv. Synth. Catal.,
2013, 355, 1098; (c) Q. Wang, J. Chen and Y. Huang, Chem. – Eur. J.,
2018, 24, 12806; (d) L. Dai, Z. H. Xia, Y. Y. Gao, Z. H. Gao and S. Ye,
Angew. Chem., Int. Ed., 2019, 58, 18124; (e) L. Dai and S. Ye, Org. Lett.,
2020, 22, 986; ( f ) L. Dai, Y. Y. Xu, Z. H. Xia and S. Ye, Org. Lett., 2020,
22, 8173.
6 (a) K. Namitharan, T. Zhu, J. Cheng, P. Zheng, X. Li, S. Yang,
B. A. Song and Y. R. Chi, Nat. Commun., 2014, 5, 3982;
(b) Z. J. Zhang, L. Zhang, R. L. Geng, J. Song, X. H. Chen and
L. Z. Gong, Angew. Chem., Int. Ed., 2019, 58, 12190; (c) Z. J. Zhang,
Y. H. Wen, J. Song and L. Z. Gong, Angew. Chem., Int. Ed., 2020, 59, 2;
(d) Y.-F. Han, Z.-H. Gao, C.-L. Zhang and S. Ye, Org. Lett., 2020,
22, 8396.
7 (a) M. F. A. Adamo, G. Bellini and S. Suresh, Tetrahedron, 2011,
67, 5784; (b) L. Zhou, X. Wu, X. Yang, C. Mou, R. Song, S. Yu,
H. Chai, L. Pan, Z. Jin and Y. R. Chi, Angew. Chem., Int. Ed., 2020,
59, 1557.
8 Z. Chen, X. Yu and J. Wu, Chem. Commun., 2010, 46, 6356.
9 (a) A. V. Davies, K. P. Fitzpatrick, R. C. Betori and K. A. Scheidt,
Angew. Chem., Int. Ed., 2020, 59, 9143; (b) S. Singha, E. Serrano,
S. Mondal, C. G. Daniliuc and F. Glorius, Nat. Catal., 2020, 3, 48.
10 H. Ohmiya, ACS Catal., 2020, 10, 6862.
11 S. Lu, J.-Y. Ong, S. B. Poh, T. Tsang and Y. Zhao, Angew. Chem., Int.
Ed., 2018, 57, 5714.
12 (a) L. Guo, X. Duan and Y. Liang, Acc. Chem. Res., 2011, 44, 111;
(b) M. Yoshida, Chem. Pharm. Bull., 2012, 60, 285; (c) J. Tsuji and
T. Mandai, Angew. Chem., Int. Ed. Engl., 1995, 34, 2589;
(d) C. Q. O’Broin and P. J. Guiry, J. Org. Chem., 2020, 85, 10321.
13 For selected rare examples of palladium-catalyzed propargylation of
carbon nucleophiles: (a) X. Huang, S. Wu, W. Wu, P. Li, C. Fu and
S. Ma, Nat. Commun., 2016, 7, 12382; (b) I. Ambrogio, S. Cacchi,
G. Fabrizi, A. Goggiamani and A. Iazzetti, Eur. J. Org. Chem., 2015,
3147; (c) Z. S. Chen, X. H. Duan, L. Y. Wu, S. Ali, K. G. Ji, P. X. Zhou,
X. Y. Liu and Y. M. Liang, Chem. – Eur. J., 2011, 17, 6918.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 For selected reviews: (a) A. E. Allen and D. W. Macmillan, Chem. Sci.,
2012, 3, 633; (b) M. N. Hopkinson, A. Tlahuext-Aca and F. Glorius,
Acc. Chem. Res., 2016, 49, 2261; (c) U. B. Kim, D. J. Jung, H. J. Jeon,
K. Rathwell and S. G. Lee, Chem. Rev., 2020, 120, 13382; (d) X. Xiao,
B. X. Shao, Y. J. Lu, Q. Q. Cao, C. N. Xia and F. E. Chen, Adv. Synth.
Catal., 2021, 363, 352; (e) L. Guillemard and J. Wencel-Delord,
Beilstein J. Org. Chem., 2020, 16, 1754; ( f ) F. Romiti, J. Del Pozo,
P. H. S. Paioti, S. A. Gonsales, X. Li, F. W. W. Hartrampf and
A. H. Hoveyda, J. Am. Chem. Soc., 2019, 141, 17952; (g) Y. Hu and
C. Wang, Acta Phys.-Chim. Sin., 2019, 35, 913.
2 For selected reviews: (a) D. S. Kim, W. J. Park and C. H. Jun, Chem.
Rev., 2017, 117, 8977; (b) S. Afewerki and A. Cordova, Chem. Rev.,
2016, 116, 13512; (c) Z. Shao and H. Zhang, Chem. Soc. Rev., 2009,
38, 2745; (d) Z. Du and Z. Shao, Chem. Soc. Rev., 2013, 42, 1337;
(e) L. Dai and S. Ye, Chin. Chem. Lett., 2021, 32, 660.
3 (a) K. Nagao and H. Ohmiya, Top. Curr. Chem., 2019, 377, 35;
(b) D. Janssen-Muller, C. Schlepphorst and F. Glorius, Chem. Soc.
Rev., 2017, 46, 4845.
4 (a) R. Lebeuf, K. Hirano and F. Glorius, Org. Lett., 2008, 10, 4243;
(b) C. Guo, M. Fleige, D. Janssen-Muller, C. G. Daniliuc and
F. Glorius, J. Am. Chem. Soc., 2016, 138, 7840; (c) C. Guo,
D. Janssen-Muller, M. Fleige, A. Lerchen, C. G. Daniliuc and
F. Glorius, J. Am. Chem. Soc., 2017, 139, 4443; (d) S. Singha,
T. Patra, C. G. Daniliuc and F. Glorius, J. Am. Chem. Soc., 2018,
140, 3551; (e) K. Liu, M. T. Hovey and K. A. Scheidt, Chem. Sci., 2014,
5, 4026; ( f ) Y. Bai, S. Xiang, M. L. Leow and X. W. Liu, Chem.
Commun., 2014, 50, 6168; (g) Y. Bai, W. L. Leng, Y. Li and X. W. Liu,
Chem. Commun., 2014, 50, 13391; (h) S. Yasuda, T. Ishii,
S. Takemoto, H. Haruki and H. Ohmiya, Angew. Chem., Int. Ed.,
2018, 57, 2938; (i) H. Haruki, S. Yasuda, K. Nagao and H. Ohmiya,
Chem. – Eur. J., 2019, 25, 724; ( j) J. Gao, J. Zhang, S. Fang, J. Feng,
T. Lu and D. Du, Org. Lett., 2020, 22, 7725; (k) W. Yang, B. Ling,
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