Ruthenium-Catalyzed Oxidative Amidation of Alkynes to Amides

Article abstract of DOI:10.1021/acs.orglett.9b01993

Complex CpRuCl(PPh₃)₂ catalyzes reactions of terminal alkynes with 4-picoline N-oxide and primary and secondary amines to afford the corresponding amides. The reactions occur in chlorinated solvent and aqueous medium, showing applications in peptide chemistry. Stoichiometric studies reveal that the true catalysts of the processes are the vinylidene cations [CpRu(=C=CHR)(PPh₃)₂]⁺ which are oxidized to the Ru(η²-CO)-ketenes by the N-oxide. Finally, nucleophilic additions of primary and secondary amines to the free ketenes yield the corresponding amides.

Full text of DOI:10.1021/acs.orglett.9b01993

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ruthenium-Catalyzed Oxidative Amidation of Alkynes to Amides
†
,§
§
†
́
́
́
Andrea Alvarez-Perez, Miguel A. Esteruelas,* Susana Izquierdo, Jesus A. Varela,
,†
́
and Carlos Saa*
†
́
́
́
Centro Singular de Investigacion en Química Bioloxica e Materiais Moleculares (CiQUS), Departamento de Química Organica,
Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
§
́
́
́
́
Departamento de Química Inorganica-Instituto de Síntesis Química y Catalisis Homogenea (ISQCH)−Centro de Innovacion en
Química Avanzada (ORFEO−CINQA), Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
S
* Supporting Information
ABSTRACT: Complex CpRuCl(PPh3)2 catalyzes reactions of
terminal alkynes with 4-picoline N-oxide and primary and
secondary amines to afford the corresponding amides. The
reactions occur in chlorinated solvent and aqueous medium,
showing applications in peptide chemistry. Stoichiometric
studies reveal that the true catalysts of the processes are the vinylidene cations [CpRu(CCHR)(PPh3)2]+ which are
oxidized to the Ru(η2-CO)-ketenes by the N-oxide. Finally, nucleophilic additions of primary and secondary amines to the free
ketenes yield the corresponding amides.
Scheme 1. Ruthenium-Catalyzed Oxidative Amidations of
Terminal Alkynes Using an N-Oxide as External Oxidant
mide bonds play a crucial role in living organisms and are
Apresent in a great number of pharmacologically active
compounds. Furthermore, they are widely used as synthetic
materials, including nylon, hydrogels, supported catalysts, etc.1
The conventional approach to amide formation is the
condensation of an amine with a carboxylic acid via an active
ester. In recent years, new catalytic methods, which offer
alternatives for selective amide bond formation, have emerged
to overcome some of the limitations of these standard
protocols.2 In this context, the use of surrogates for the
reaction partners is currently being intensively assayed.1
Although terminal alkynes are promising surrogates of acyls
in reactions with amines, through catalytic oxidative
amidations, their use remains largely underused.3
We initially tested the oxidative amidation of phenyl-
acetylenes 1a and 1b with secondary amines 2a and 2b
using Rh catalysts (Lee’s conditions, Table 1). To our initial
surprise, while 1a and 1b reacted smoothly with aniline 2a to
give the secondary amides 3aa and 3ba in fairly good yields
(entry 1), 1a and 1b were recovered when reacted with N-Me-
phenethylamine 2b either in CH3CN or DCE or in the
presence of catalyst RhCl(PPh3)3 (entry 2).8,2a It was
mandatory to use the ammonium salt of 2b in order to obtain
the corresponding amides 3ab and 3bb in fairly good yields
(entry 3).3b After this singular behavior of secondary amines
under Rh catalysts (aniline 2a vs alkylamine 2b), we decided to
compare these results against ruthenium catalysts. To our
delight, we found that the use of electron-rich CpRu catalysts11
in noncoordinating DCE9e,12 as solvent13 gives good to
excellent yields of amides 3aa, 3ab, 3ba, and 3bb in two sets
of conditions using the free amines (entries 1 and 2). Both N-
oxide (entry 4) or Ru catalyst (entry 5) are required for the
reaction to take place (see the SI for other conditions tried).
The substrate scope varying the nature of the alkyne was
then examined under optimized conditions A (Scheme 2).
Either electron-poor or electron-rich heteroaryl alkynes also
participated as active substrates, giving rather good yields of
tertiary amides 3cb and 3db. In addition, aliphatic and
functionalized aliphatic alkynes (Cl, OBn) as well as enynes
Formation of ketenes4 from alkynes is essential for successful
amidations. These electrophilic species can be readily formed
via rearrangement of oxirene intermediates5 or by oxidation of
metal vinylidenes,6 which are also electrophilic at the carbene
center.7 Lee recently reported Rh-catalyzed oxidations of
terminal alkynes to ketenes, with internal and external
oxidants, along with subsequent [2 + 2] cycloaddition
reactions8 or intermolecular trapping with heteronucleophiles
to give lactams or linear amides. Ruthenium-promoted
oxidative transformations of terminal alkynes into ketenes,
with substrates bearing internal oxidants,9 have been also
performed to finally afford efficient intramolecular electrocyclic
reactions and intermolecular [2 + 2] cycloadditions. Following
our interest in the chemistry of M−vinylidenes,10 we herein
report a new and efficient Ru-catalyzed oxidative amidation of
alkynes to primary and secondary amides using 4-picoline N-
oxide as external oxidant (Scheme 1). Mechanistic studies
indicate that the catalysis involves the oxidation of metal−
vinylidene intermediates to free ketenes, which are trapped by
the nucleophile.
Received: June 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01993
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Comparative Results of Rh- and Ru-Catalyzed Oxidative Amidations of Arylacetylenes 1a,b with Secondary Amines
2a,b
b
[Ru] cat.
a
entry
alkyne
amine
2a
2a
2b
2b
amide
[Rh] cat. (%)
method A (amine 2 equiv) (%)
method B (amine 1 equiv/KPF6 1 equiv) (%)
1
2
3
4
5
1a
1b
1a
1b
1a
3aa
3ba
3ab
3bb
3ab
79
85
99
92
96
88
95
90
91
89
d
c,
ad
,
traces
e
f
2b·HCl
92
96
a
Reaction conditions Rh: alkyne 1 (0.4 mmol), amine 2 (1.2 equiv), [Rh(cod)Cl]2 (3 mol %), P(4-FC6H4)3 (12 mol %), 4-picoline N-oxide (1.2
b
equiv), CH3CN (0.8 mL), 60 °C. Reaction conditions Ru: alkyne 1 (0.4 mmol), CpRuCl(PPh3)2 (5 mol %), 4-picoline N-oxide (2 equiv), DCE
(3 mL), 100 °C, amine 2 (2equiv) (method A) or amine 2 (1 equiv) + KPF6 (1 equiv) (method B). Starting material recovered either with
CH3CN or DCE as solvents. CpRhCl(PPh3)3 (6 mol %) was used as catalyst. K2CO3 (0.3 equiv) and KPF6 (1 equiv) were added. K2CO3 (0.3
equiv) was added.
c
d
e
f
Scheme 2. Ru-Catalyzed Oxidative Amidations of Alkynes
1c−h with Secondary Amines 2c−h
we tested and compared the oxidative amidations of phenyl-
acetylene 1a with three different primary amines 2i−k under
Rh and Ru catalytic conditions (Table 2). While the
Table 2. Comparative Results of Rh- and Ru-Catalyzed
Oxidative Amidations of Phenylacetylene 1a with Primary
Amines 2i,j,k
a
entry
R
amine
2i
2j
2j·HCl
2k
2k·HCl
amide
[Rh] (%)
[Ru] (%)
b
1
2
Ph
Bn
4ai
4aj
72
23
99
98
96
c
d
3
(CH2)2Ph
4ak
traces
98 (94)
c
98
a
b
Method B. A mixture of H2O/DCE 95:5 was used as solvent.
K2CO3 (0.3 equiv) and KPF6 (1 equiv) were added. Isolated yield
c
d
using 1 mmol of 1a.
employment of Rh catalyst (Lee’s conditions)5,15,2a proved
relatively efficient for the preparation of anilide 4ai from
aniline 2i (entry 1, 72%), it gave lower to negligible yields in
the case of phenethyl and benzyl amides 4aj and 4ak from the
free amines 2j and 2k (entries 2 and 3). Once again, it was
mandatory to use the ammonium salts of 2j,k in order to
obtain the corresponding amides 4aj and 4ak in excellent
yields (entries 2 and 3). In contrast, amides 4ai−ak were
always obtained in excellent yields from the free amines 2i−k
using Ru catalysts (entries 1−3). Scaling was also possible
since amide 4ak could be obtained in 94% isolated yield using
1 mmol of alkyne 1a.
The substrate scope varying the nature of the alkyne was first
examined (Scheme 3). The (trimethylsilyl)acetylene 1i was
found to be a good substrate for this amidation reaction to
deliver the desilylated N-acetyl amide 4ik in excellent yield.
Gratifyingly, functionalized aliphatic alkynes bearing CN,
NHAc, OBn, and Cl groups as well as enynes and aromatic
diynes were all well tolerated to afford moderate to excellent
yields of the corresponding amides 4jk−pk′. Then variation of
a
b
c
Reaction conditions ARu. Reaction conditions BRu. Reaction
conditions BRu with 2g·HCl (1 equiv) + K2CO3 (0.3 equiv).
were also tolerated to give tertiary amides 3eb, 3fb, 3gb, and
3hb, respectively, in fairly good yields. Second, other secondary
amines were also tested. Thus, five- and six-membered cyclic
amines reacted smoothly to give good to excellent yields of
cyclic tertiary amides 3ac, 3ad, 3ae, and 3af, respectively. In
addition, the linear N,O-dimethylhydroxylamine and dibenzyl-
amine gave the interesting Weinreb amide14 3ag and dibenzyl-
protected amide 3ah in rather good yields.
We also evaluated whether this oxidative amidation is
suitable for the preparation of the interesting secondary amides
(peptide bonds). As we already did with the secondary amines,
B
DOI: 10.1021/acs.orglett.9b01993
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Organic Letters
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Scheme 3. Ru-Catalyzed Oxidative Amidations of Alkynes
1i−p with Primary Amines 2l−s
Scheme 4. Ru-Catalyzed Oxidative Amidations of Alkynes 1
with Aminoesters 8 in Aqueous Media at 37 °C
a
Reaction conditions: alkyne 1 (0.4 mmol), aminoester·HCl 8 (1
equiv), CpRuCl(PPh3)2 (5 mol %), 4-picoline N-oxide (1.1 equiv),
KPF6 (1 equiv), K2CO3 (0.3 equiv), H2O/DCE (3 mL), 37 °C, 24 h.
b
4-Picoline N-oxide (2 equiv), 100 °C, 24 h.
acyl derivatives 9aa−ad in excellent yields. Interestingly, the
oxidative amidation is completely chemoselective since
reaction only by the more nucleophilic amino group of serine
8b was observed. On the other hand, oxidative amidations of
N-nosyl-N-propargyl γ-aminoester 1q16 occurred uneventfully
to give the amidoester derivatives 9qd and 9qe in quite good
yields.17
To gather information about the mechanism of the
amination, we reproduced the elemental steps of the catalysis
through stoichiometric reactions performed at room temper-
ature. In DCE, the ruthenium complex CpRuCl(PPh3)2 reacts
with phenylacetylene (1a) in the presence of KPF6 to give the
previously reported vinylidene salt [CpRu(CCHPh)-
a
b
Reaction conditions BRu. (Trimethylsilyl)acetylene 1i was used.
c
d
1o, 1,3-diethynylbenzene; 1p, 1,4-diethynylbenzene. Reaction
e
conditions BRu with 2l·HCl + K2CO3 (0.3 equiv). 1a (2 equiv)
was used.
18
(PPh3)2]PF6 (5) as a result of the extraction of the chloride
the amine partner was analyzed. Either simple methylamine 2l
or functionalized allyl- and propargylamines 2m and 2n gave
moderate to good yields of the corresponding amides 4al−an.
Pleasingly, 2-(aminomethyl)aniline 2o, a difunctional aniline,
and benzyl amine could be conveniently diacylated to give the
diamide 4ao in fairly good yield. Natural alkaloids bearing
primary amines like (−)-leelamine 2p and tryptamine 2q were
also acylated to the corresponding amides 4ap and 4aq with
very good yields. Interestingly, oxidative amidations with the
more challenging chiral secondary (R)-1-phenylethylamine 2r
and tertiary tert-butylamine 2s smoothly occurred to give the
chiral secondary amide 4ar and N-tert-butylphenylacetamide
4as with excellent yields.
The oxidative amidation not only occurred in boiling
chlorinated solvents but also in aqueous media at 37 °C, which
suggests interesting applications in peptide chemistry (Scheme
4). Thus, excellent yields of the secondary amide 4ai (98%)
were obtained when the reaction was run either in pure DCE
or in a mixture DCE/H2O 5:95 (Table 2). Oxidative
amidations of phenylacetylene 1a with methyl ester derivatives
of L-amino acids bearing primary amines such as phenylglycine
8a, serine 8b, and MeS-cysteine 8c and secondary amines such
as proline 8d smoothly occurred to give the corresponding N-
anion and the alkyne−vinylidene tautomerization of the
hydrocarbon. Phosphine dissociation is not observed. The
addition of a stoichiometric amount of 4-picoline N-oxide to
an NMR tube containing a dichloromethane-d2 solution of 5
smoothly affords a mixture of 5 (10%), the picoline derivative
19
[CpRu(4-Me-py)(PPh3)2]PF6 (6; 59%), and a Ru−C(
O)CH2Ph acyl species (31%). Noticeable spectroscopic
features of the latter are a singlet at 3.34 ppm due to the
CH2 group in the 1H NMR spectrum, two singlets at 194.5 and
48.1 ppm corresponding to the CO and CH2 acyl-carbon
atoms in the 13C{1H} NMR spectrum, and a singlet at 39.0
ppm in the 31P{1H} NMR spectrum. Its formation is a strong
indirect evidence of the oxidation of the RuC bond of 5 to
give a Ru(η2-CO)-ketene intermediate20 that is trapped by
traces of water present in the medium (Scheme 5). The
dissociation of the ketene and the subsequent coordination of
the generated 4-picoline leads to 6. In addition, it should be
pointed out that traces of phosphine oxide are not observed.
The formation of the acyl species does not appear to take place
under catalytic conditions, i.e., in the presence of an excess of
amine. When 4-picoline N-oxide and benzylamine (2j) were
added to the dichloromethane-d2 solution of 5, N-benzyl-2-
phenylacetamide (4aj) and 6 were formed. Complex 6 reacts
C
DOI: 10.1021/acs.orglett.9b01993
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
released and trapped by the nucleophilic primary and
secondary amines to yield the corresponding amides.
Scheme 5. Formation of the Acyl Species
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01993.
Detailed experimental procedures and compound
characterization data (PDF)
with phenylacetylene to regenerate the vinylidene 5 and release
4-picoline.21
The previously mentioned stoichiometric results reveal that
(i) complex CpRuCl(PPh3)2 is the catalytic precursor, whereas
the vinylidene derivative 5 is the true catalyst of the amidation;
(ii) the catalysis takes place via Ru(η2-CO)-ketene inter-
mediates, which are formed by oxygen transfer from 4-picoline
N-oxide; (iii) 4-picoline, which is generated from the oxidation
of the vinylidene, displaces the ketene from the ruthenium
coordination sphere; and (iv) the formation of the amide is an
outer-sphere process involving the capture of the released
ketene by the amine. The cycle shown in Scheme 6
summarizes these features.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: maester@unizar.es.
*E-mail: carlos.saa@usc.es.
ORCID
Miguel A. Esteruelas: 0000-0002-4829-7590
́
Jesus A. Varela: 0000-0001-8499-4257
́
Carlos Saa: 0000-0003-3213-4604
Notes
The authors declare no competing financial interest.
Scheme 6. Mechanism Proposed for the Ru-Catalyzed
Oxidative Amidation of Terminal Alkynes with Amines
ACKNOWLEDGMENTS
■
This work has received financial support from MINECO
(projects CTQ2014-59015R, CTQ2017-87939R, and
CTQ2017-82935-P and the ORFEO−CINQA network
CTQ2016-81797-REDC), the Xunta de Galicia (project
GRC2014/032, ED431C 2018/04, Centro singular de
́
investigacion de Galicia accreditation 2016−2019, ED431G/
09), DGA (No.E06_17R), and the European Union (Euro-
́
pean Regional Development Fund - ERDF). A.A.-P. thanks the
Spanish MICINN for a predoctoral FPI fellowship. We thank
Prof. J. Granja (CiQUS) for a generous gift of aminoester
derivatives.
REFERENCES
■
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E
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Org. Lett. XXXX, XXX, XXX−XXX