Ruthenium catalyzed β-selective alkylation of vinylpyridines with aldehydes/ketonesviaN2H4mediated deoxygenative couplings

Article abstract of DOI:10.1039/d0sc06586b

Umpolung (polarity reversal) tactics of aldehydes/ketones have greatly broadened carbonyl chemistry by enabling transformations with electrophilic reagents and deoxygenative functionalizations. Herein, we report the first ruthenium-catalyzed β-selective alkylation of vinylpyridines with both naturally abundant aromatic and aliphatic aldehyde/ketonesviaN₂H₄mediated deoxygenative couplings. Compared with one-electron umpolung of carbonyls to alcohols, this two-electron umpolung strategy realized reductive deoxygenation targets, which were not only applicable to the regioselective alkylation of a broad range of 2/4-alkene substituted pyridines, but also amenable to challenging 3-vinyl and steric-embedded internal pyridines as well as their analogous heterocyclic structures.

Full text of DOI:10.1039/d0sc06586b

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Ruthenium catalyzed b-selective alkylation of
vinylpyridines with aldehydes/ketones via N2H4
mediated deoxygenative couplings†
Cite this: Chem. Sci., 2021, 12, 2870
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
b
*
*
Leiyang Lv
and Chao-Jun Li
Umpolung (polarity reversal) tactics of aldehydes/ketones have greatly broadened carbonyl chemistry by
enabling transformations with electrophilic reagents and deoxygenative functionalizations. Herein, we
report the first ruthenium-catalyzed b-selective alkylation of vinylpyridines with both naturally abundant
aromatic and aliphatic aldehyde/ketones via N2H4 mediated deoxygenative couplings. Compared with
one-electron umpolung of carbonyls to alcohols, this two-electron umpolung strategy realized
reductive deoxygenation targets, which were not only applicable to the regioselective alkylation of
a broad range of 2/4-alkene substituted pyridines, but also amenable to challenging 3-vinyl and steric-
embedded internal pyridines as well as their analogous heterocyclic structures.
Received 1st December 2020
Accepted 30th December 2020
DOI: 10.1039/d0sc06586b
rsc.li/chemical-science
chemistry. In 2012, Lam et al.9 realized an elegant copper-
catalyzed a-selective reductive coupling of vinyl pyridines with
Introduction
ketones. The presence of copper-hydride species upon which a-
organocopper species was exclusively generated, was respon-
sible for the a-selectivity of the C–C coupling products (Scheme
1a). Later, Ngai,10 and Wang et al.11 independently reported the
b-selective reductive coupling of vinyl pyridines with aldehydes
via tactfully synergistic Lewis or Brønsted acid/photoredox
catalysis (Scheme 1b). The nucleophilic ketyl radical, gener-
ated by one electron reduction of electrophilic carbonyl with
Hantzsch ester (one electron umpolung), was crucial to warrant
C–C bond formation at the b-position of the alkene moiety in
a radical process.12 Notably, these seminal reports offered
a useful tool to deliver partially reductive (i.e. carbonyl reduced
The pyridine ring is one of the most signicant structural subunits
that are ubiquitous in a variety of natural products, bioactive
compounds, pharmaceuticals and ligands in catalysis.1 The post-
elaboration of this privileged scaffold continues to play a vital
role to rapidly assemble related functionalized N-containing
heterocycles and new molecular architectures.2 To this end, vinyl
pyridines have been well adopted as versatile synthons3 in terms of
their electrophilic nature, especially in analogous Michael-type
additions with external nucleophiles, such as Grignard reagents4
or boronic acids.5 In contrast, the reductive couplings6 of vinyl
pyridines with another electrophile have been less explored and
remained a challenging study.7 The scarcity of this approach is
attributed to three aspects: (1) substantially attenuated activation
from the N-heteroaryl group compared with carbonyl or nitrile in
Michael acceptors; (2) catalyst poisoning due to the strong coor-
dination of basic nitrogen with a transition-metal catalyst; and (3)
the competitive direct reduction of an alkene moiety to ethyl pyri-
dine under reductive conditions. To ll this gap, Krische and co-
workers in 2008, made a pioneering contribution in this eld,
which disclosed the rst Rh-catalyzed a-selective reductive C–C
coupling of vinyl pyridines with imines under a H2 atmosphere.8
As is well-known, carbonyl compounds are versatile, readily-
available and naturally abundant feedstocks in synthetic
aDepartment of Chemistry, Renmin University of China, Beijing 100872, China. E-mail:
lvleiyang2008@ruc.edu.cn
bDepartment of Chemistry, FRQNT Center for Green Chemistry and Catalysis, McGill
University, 801 Sherbrooke Street West, Montreal, Quebec, H3A 0B8, Canada. E-mail:
cj.li@mcgill.ca
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0sc06586b
Scheme
vinylpyridines.
1 Strategies of reductive couplings of carbonyls with
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Table 1 Optimization of reaction conditionsa
to hydroxyl) products. However, a selective method for the
completely reductive couplings (i.e. carbonyl reduced to meth-
ylene) of vinyl pyridines with carbonyls is yet to be explored. In
addition, only pyridines assembled with 2- and/or 4-alkene
substitution (positive charge delocalization at the vinyl group
owing to the electron-withdrawing properties of the pyridine
ring) were viable substrates. However analogous 3-vinyl pyridine
that lacks the conjugate activation effect, even with an acid co-
catalyst to lower the olenic b-carbon LUMO energy, was totally
unreactive in the related reactions.13 Moreover, compared with
aromatic aldehydes/ketones, the one electron umpolung of
aliphatic ones is less accessible due to its higher reduction
potential (typically lower than ꢀ2 V versus SCE)14 or lacking
stabilization from vicinal aromatic rings. Last but not least,
examples of reductive coupling of carbonyls with bulky internal
vinyl pyridines were rarely reported because of intrinsic steric
hindrance. Therefore, the development of a general deoxy-
genative reductive transformation,15 especially involving chal-
lenging 3-vinyl pyridines, and internal pyridines as well as
aliphatic aldehydes and ketones to overcome these limitations,
would provide novel and complimentary access to synthetically
useful products.
Inspired by the one electron carbonyl umpolung strategy,16
we wondered whether two electron carbonyl umpolung tactics
could be used as a solution to realize reductive couplings with
vinyl pyridines that were previously unattainable. Based on our
previous work regarding N2H4 as the reductant in aryl–aryl/alkyl
cross-couplings17 and pinacol couplings,18 as well as N2H4
mediated carbonyl umpolung,19 herein, we wish to report
a ruthenium-catalyzed b-selective reductive coupling of vinyl
pyridines with aldehydes/ketones using N2H4 as the reducing
agent (Scheme 1c). This deoxygenative alkylation methodology
exempts the pre-activation of weakly electrophilic vinylpyridines
with a Brønsted/Lewis acid, wherein not only 2- or 4 vinyl
pyridines but also previously inert 3-vinyl substituted and
internal ones as well as other N-containing hetero-aromatic
variants were all proved to be eligible electrophiles to couple
with umpolung carbonyl compounds including both aromatic
and aliphatic aldehydes/ketones.
Entry
Variation from “standard conditions”
4aab (%)
1
No change
97 (95)
Trace
Trace
96
96
71
24
14
N.D.
N.D.
96
84
66
92
66
12
10
2
3
No [Ru(p-cymene)Cl2]2
No base
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ru(PPh3)3Cl2 used instead
Ru(PPh3)3Cl2 used instead
[RuCl(p-cymene)(dppe)]Cl used instead
Cp*Ru(cod)Cl used instead
Ru(Cp)(PPh3)2Cl used instead
Ni(cod)2 used instead
[Pd(allyl)Cl]2 used instead
Dppe instead of dmpe
Dppb instead of dmpe
Dppf instead of dmpe
t
KOH instead of BuOLi
K3PO4 instead of tBuOLi
K2CO3 instead of tBuOLi
t
DBU instead of BuOLi
a
Reaction conditions: benzaldehyde 1a (0.4 mmol), hydrazine (0.48
mmol), para-vinyl pyridine 3a (0.2 mmol), [Ru(p-cymene)Cl2]2
(2.5 mol%), ligand (5 mol%) and base (0.1 mmol) in THF (0.5 mL) at
80 ꢁC for 12 h under N2 unless otherwise noted. Note that phenyl
hydrazone 2a was generated in situ from benzaldehyde and hydrazine
without isolation. b The yield of 4aa was determined by H NMR using
1
mesitylene as an internal standard and based on 3a (isolated yield of
4aa in parentheses). N.D. ¼ not detected.
6), but the yield of 4aa was reduced dramatically with Cp*Ru(-
cod)Cl or Ru(Cp)(PPh3)2Cl (entries 7 and 8). The catalysts
frequently applied in coupling reactions, such as Ni(cod)2 and
[Pd(allyl)Cl]2, displayed no catalytic activity in this trans-
formation, probably due to the coordinative complexation of
the basic nitrogen of the pyridine (entries 9 and 10). The
examination of the ligand revealed that bidentate phosphine
dppe [1,2-bis(diphenylphosphino)ethane] gave a comparable
result (entry 11), while further increasing the bite angle of the
phosphine ligand resulted in diminished efficiency (entries 12
and 13). A base was presumably used to deprotonate the in situ
formed hydrazone and its effect was also assessed. KOH showed
good reactivity to generate 4aa in 92% yield (enter 14). Relatively
weak K3PO4 gave 4aa in moderate yield (entry 15), while K2CO3
or organic base DBU [1,8-diazabicyclo(5.4.0)undec-7-ene] led to
poor results (entries 16–17).
With the optimal reaction conditions obtained, we examined
the scope of the reductive couplings with respect to carbonyls.
As depicted in Table 2, the reaction provided the deoxygenated
products with complete b-selectivity in good to excellent yields.
For example, aromatic aldehydes bearing either electron-
donating or electron-withdrawing substituents at the para-
position of aryl rings, smoothly afforded the desired products
4ab–4ae in 92–97% yields. The halogen substituents such as F,
Results and discussion
To test the feasibility of our hypothesis, we initially chose
benzaldehyde (1a) and para-vinyl pyridine (3a) as the model
substrates in combination with N2H4 as the reductant (Table 1).
Aer preliminary investigations, we were glad to nd that the
desired deoxygenative linear product 4aa was attained in 97%
yield in the presence of [Ru(p-cymene)Cl2]2 (2.5 mol%), dmpe
[1,2-bis(dimethylphosphino)ethane] (5.0 mol%) and 0.5 equiv-
t
ꢁ
alent of LiO Bu in THF at 80 C for 12 h (entry 1). Based upon
this encouraging result, we then evaluated the parameters that
may affect the reaction efficiency. Only trace product 4aa was
detected in the absence of the ruthenium catalyst or base
(entries 2–3). We observed that the reaction proceeded equally
well when [Ru(p-cymene)Cl2]2 was substituted with [Ru(C6Me6)
Cl2]2 or Ru(PPh3)3Cl2 (entries 4 and 5) and a slightly decreased
efficiency was observed with [RuCl(p-cymene)(dppe)]Cl20 (entry
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Table 2 Evaluation of aldehydes/ketonesa,b
a
Reaction conditions: aldehyde/ketone 1 (0.4 mmol), hydrazine (0.48 mmol), vinyl heteroarene 3a (0.2 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol%),
ligand (5 mol%) and base (0.1 mmol) in THF (0.5 mL) at 80 ꢁC for 12 h under N2. Note that hydrazone 2 was generated in situ from an
aldehyde/ketone with hydrazine without isolation; however, the one-pot reaction gave no product. Yields of isolated products based on 3a.
b
Cl and Br, regardless of the substitution patterns, were well yields. 4ap was also generated efficiently when the aldehyde
tolerated (4af–4aj) without detection of dehalogenative by- with extended conjugation (e.g., 1-naphthaldehyde) was tested.
products. Electron-rich 3,4,5-trimethoxybenzaldehyde could be As documented in the literature, engagement of ketyl radicals
readily coupled with 4-vinylpyridines 4ak. The reaction yield from alkyl aldehydes in reductive couplings via one electron
was decreased to 54% when sterically hindered mesitaldehyde umpolung is largely inhibited unless under harsh conditions,
was tested under the optimal conditions. When hetero-aromatic due to its highly negative reduction potential or transient
aldehydes such as furan, thiophene and N-methylpyrrole alde- stability. To overcome this limitation as well as to expand the
hydes were subjected to the standard conditions, the desired reaction scope, we next evaluated the feasibility of aliphatic
reductive coupling products 4am–4ao were obtained in 69–91% aldehydes in the reductive coupling with the two electron
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Table 3 Evaluation of vinyl heteroarenesa,b
a
Reaction conditions: benzaldehyde (1a, 0.4 mmol), hydrazine (0.48 mmol), vinyl heteroarene 3 (0.2 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol%), ligand
(5 mol%) and base (0.1 mmol) in THF (0.5 mL) at 80 ꢁC for 12 h under N2. b Yields of isolated products based on 3. c 0.1 mmol of 2,6-divinylpyridine
was used.
umpolung strategy. Gratifyingly, an array of aliphatic aldehydes alkylation reaction, alkenes bearing other N-heterocyclic
including primary (1q–1v), secondary (1w–1y) and even bulky aromatic rings such as quinolone, pyrimidine, N-tosyl-pyrrole
tertiary (1z) ones all reacted efficiently and furnished the alky- and benzothiazole were examined accordingly, all affording
lated pyridine derivatives 4aq–4az in good to excellent yields.
Encouraged by these promising results, we attempted to apply
more challenging ketones as potential partners in deoxy-
genative couplings. To our delight, under the standard reaction
conditions, acetophenone, 1-indanone and simple cyclohexa-
none could react smoothly with vinylpyridine, delivering the
corresponding products 4ba–4bc in 78–96% yields under the
optimal conditions. These results clearly demonstrated the
powerful generality and enhanced exibility of our designed
two-electron carbonyl umpolung strategy.
Next, we directed our attention to explore the scope of
vinylpyridine coupling partners (Table 3). 2-Vinyl pyridine (3b),
2-methyl-6-vinylpyridine (3c), 2-bromo-6-vinylpyridine (3d) and
2-uoro-4-vinylpyridine (3e) were converted into the corre-
sponding products 5a–5d in good to excellent yields with
complete b-regio-selectivity. Nevertheless, electron-rich 2-
methoxy-4-(3-phenylpropyl)pyridine failed to undergo this
transformation. Based upon the generality of this deoxygenative
Scheme 2 Gram-scale and control experiments.
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the desired products 5f–5i in synthetically useful yields. Firstly, the catalytically active species A is generated from pre-
Notably, the deoxygenative coupling method was not limited to catalyst [Ru(p-cymene)Cl2]2 upon ligand dissociation/
activated 2/4-vinyl N-hetero-aromatics; 3-vinylpyridine (3j), 2- association with dmpe or dppe. Secondly, hydrazone 2 and
(triuoromethyl)-5-vinylpyridine (3k), and 3-vinylquinoline (3l) vinylpyridine 3 coordinate to the ruthenium center and form
as well as 4-vinylisoquinoline (3m), which were challenging in a chair-like transition state C, which undergoes intramolecular
previous Michael additions or coupling reactions due to the rearrangement to form a new carbon–carbon bond and the six-
lack of conjugation or metal–nitrogen atom coordination acti- membered ring intermediate
D
simultaneously. Lastly,
vation, were also effective substrates to undergo the deoxy- decomposition of this species via N2 extrusion and proto-
genative coupling reactions. Notably, previous synthesis of demetalation releases the nal product 4 or 5, and completes
these kinds of products mainly relied on transition-metal cat- the catalytic cycle. An alternative mechanism involving the
alysed cross-coupling reactions involving 3-halopyridines with ruthenium mediated oxidative cyclization of the C]C bond of
organometallic reagents.21 Moreover, our preliminary study vinyl pyridine and the C]N bond of hydrazone, followed by b-H
showed that internal vinylpyridines, such as 4-(prop-1-en-1-yl) elimination and reductive elimination cannot be ruled out.8
pyridine (3n), 4-(hex-1-en-1-yl)pyridine (3o) and 4-(5-
phenylpent-1-en-1-yl)pyridine (3p), regardless of cis–trans-
isomers, all reacted efficiently and selectively to deliver the b-
Conclusions
coupling products 5n–5p. The vinylpyridine with an alkene
moiety bearing an a-substituent was totally unreactive (5q).
Gratifyingly, the attempt to apply 2,6-divinylpyridine as a reac-
tion partner also proved viable, affording the corresponding bis-
We have demonstrated an unprecedented ruthenium-catalyzed
b-selective alkylation of vinylpyridines with both aromatic and
aliphatic aldehydes/ketones via deoxygenative coupling. A
broad range of valuable alkyl pyridine and related N-hetero-
aromatic structures were obtained in a highly efficient and
selective manner. This N2H4 mediated two-electron carbonyl
alkylation product 5r in 92% yield.
To explore the practicality of this protocol, a gram-scale
deoxygenative alkylation of vinylpyridine was performed with
umpolung process not only solved the challenges of the inval-
a reduced ruthenium catalyst loading (1.0 mol%) and air-stable
dppe ligand, and the desired product 4aa was obtained in 89%
substrates in C–C bond formations via the one-electron umpo-
yield (1.40 g) (Scheme 2a). When N-Ts hydrazone 6 was utilized
instead of simple hydrazone 2a to react with vinylpyridine 3a,
the corresponding product 4aa was not detected. This result
idity of naturally abundant ketones and aliphatic aldehydes as
lung pathway, but also realized selective reductive alkylation of
2/4-alkene substituted pyridines, especially previously chal-
lenging 3-vinyl and steric-embedded internal pyridines as well
as their analogous heteroarenes.
excluded the possibility that hydrazone 2a acted as the benzyl
carbene precursor in this deoxygenative coupling reaction
(Scheme 2b).22 When deuterated hydrazone 7-d1 was tested with
Conflicts of interest
3a under the standard conditions, no H/D loss or scrambling
among the benzylic moiety and other positions was observed
(Scheme 2c). This outcome revealed the absence of C–H bond
There are no conicts to declare.
activation of hydrazone or [Ru]–H species generation during the
reaction process.23
Acknowledgements
Based on these results and our previous studies,19,23
We are grateful to the Canada Research Chair Foundation (to C.-
a possible reaction mechanism was proposed (Scheme 3).
J. L.), the Canadian Foundation for Innovation, the FRQNT
Centre in Green Chemistry and Catalysis, the Natural Science
and Engineering Research Council of Canada and the Killam
Research Fellow of the Canadian Council of Arts. The research
was also supported by the Fundamental Research Funds
(to L. L.) for the Central Universities, and the Research Funds of
Renmin University of China.
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