Rhodium-catalyzed oxygenative addition to terminal alkynes for the synthesis of esters, amides, and carboxylic acids

Article abstract of DOI:10.1002/anie.201303669

A gem of a couple: The title reaction of terminal alkynes with O and Nnucleophiles proceeds in the presence of [Rh(cod)Cl}₂], P(4-FC ₆H₄)₃, and 4-picoline N-oxide. Alcohols, amines, and water add to the terminal alkynes to give esters, amides, and carboxylic acids, respectively. The reaction involves formation of a rhodium vinylidene, oxidation to a ketene by oxygen transfer, and nucleophilic addition.

Full text of DOI:10.1002/anie.201303669

Angewandte
Chemie
DOI: 10.1002/anie.201303669
Synthetic Methods
Rhodium-Catalyzed Oxygenative Addition to Terminal Alkynes for the
Synthesis of Esters, Amides, and Carboxylic Acids**
Insu Kim and Chulbom Lee*
Transition-metal-catalyzed transfer oxygenation of alkynes is
a useful means for the synthesis of carbonyl compounds.
While an oxirene generated by the direct alkyne oxidation
under metal-oxo-mediated catalysis has traditionally been
used as an intermediate,[1] recent approaches exploiting
alkynes as metallocarbene precursors have led to an array
of reactions which can be performed under mild reaction
conditions. Mechanistically, these reactions involve oxygen
transfer to an h2-alkyne metal complex to produce a metal
carbene, which undergoes a variety of reactions as exempli-
fied by the a-oxo gold carbene catalysis (Scheme 1, path a).[2]
has indeed been practiced, but only in intramolecular settings
for the cycloisomerization of aromatic substrates.[4] Despite
the potential utility for catalytic alkyne functionalization, the
general approach taking advantage of the oxidative pathway
from metal vinylidenes to ketenes has remained largely
unexplored. Herein, we describe the rhodium-catalyzed oxy-
genative addition to terminal alkynes, a reaction which can be
carried out with a broad range of alcohol and amine
nucleophiles, and water to furnish carboxylic acid derivatives.
Our study began with evaluating the feasibility of the
reaction inducing methanol addition to sulfoxyalkyne 1 with
concomitant intramolecular oxygen transfer (Table 1). Thus,
Table 1: Catalyst screening experiments for intramolecular transfer
oxygenative addition of methanol to sulfoxyalkyne 1.[a]
Entry
Catalyst
Yield [%][b]
1
2
3
4
[CpRu(PPh3)2Cl]
5
4
3
Scheme 1. Transition-metal-catalyzed oxygenative addition to terminal
alkynes.
[{Ru(p-cymene)3Cl}2]/PPh3
[CpRu(CH3CN)3]PF6/PPh3
[TpRu(PPh3)2Cl]
4
Additionally, it has also been shown that a metallocarbene
resulting from a metal-mediated process involving an alkyne
can be oxidatively demetalated to install a carbonyl group.[3]
These examples collectively illustrate the viability of effecting
catalysis by making use of alkyne-derived metal alkylidenes
for catalyst turnover. A distinct opportunity exists for
catalytic oxygenative alkyne functionalization, wherein the
unsaturated carbene (vinylidene) metal intermediate, an h1-
isomer of the p-alkyne metal complex, is oxidized (path b). In
this scenario, a ketene arising from oxygenation of a vinyli-
dene complex may be exploited in the subsequent addition
process. Conceivably, this mechanistic modality offers a ver-
satile platform for alkyne functionalization since the metal
vinylidene species resulting from alkynes by mild catalysis can
be readily channeled to the synthetic utility of ketenes. The
strategy based on oxygenation of a metal vinylidene complex
5
6
7
8
[Rh(PPh3)3Cl]
51
56
54
59
40
76
[Rh(C2H4)2Cl]2/PPh3
[{Rh(cod)OH}2]/PPh3
[{Rh(cod)Cl}2]/PPh3
[{Rh(cod)Cl}2]/P(4-MeOC6H4)3
[{Rh(cod)Cl]2]/P(4-FC6H4)3
9
10[c]
[a] Reaction conditions: alkyne 1 (0.1 mmol), methanol (0.3 mmol),
catalyst (5 mol% entries 1–5; 3 mol%, entries 6–10), CH3CN (0.25 mL),
[Ru] or [Rh]/phosphine=1:2 except for entry 5. [b] Determined by GC.
[c] The reaction was completed in 12 h. Yield of isolated product.
cod=cyclo-1,5-octadiene, Cp=cyclopentadienyl.
a series of screening experiments were conducted by employ-
ing a set of metal complexes known to mediate catalysis by
vinylidene formation. The reactions using various ruthenium
catalysts did produce the desired methyl ester 2a but in very
low yield (ꢀ 5%), while mostly returning unreacted
1 (Table 1, entries 1–4). In contrast, when the mixture of
1 and methanol in acetonitrile was heated at 508C in the
presence of Wilkinsonꢀs catalyst, complete conversion took
place to give 2a in 51% yield (entry 5). A brief survey of the
phosphine ligand revealed that the rhodium-catalyzed reac-
tion could be most efficiently carried out by using tri(4-
fluorophenyl)phosphine, which afforded 2a in 76% yield
within 12 hours (entry 10).
[*] I. Kim, Prof. C. Lee
Department of Chemistry, Seoul National University
Seoul 151-747 (Republic of Korea)
E-mail: chulbom@snu.ac.kr
Homepage: http://cbleegroup.snu.ac.kr/
[**] This work was supported by the Basic Research Laboratory (BRL)
program of the National Research Foundation (NRF) of Korea. We
thank Suhong Kim for performing preliminary experiments.
With an effective catalyst identified, we examined exten-
sion of the addition process to include other nucleophiles
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303669.
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(Table 2). Under the reaction conditions using [{Rh(cod)Cl}2]
and P(4-FC6H4)3 as the catalyst, a variety of alcohols and
amines reacted with 1 to provide the corresponding esters and
amides as products. The scope of the nucleophile was
considerable in that the reaction was tolerant of primary as
an intermolecular process. Thus, an assortment of sulfoxides
and N-oxides were screened for their ability to serve as
oxygen donors in the oxygenative coupling of alkyne 5 with
methanol (Table 4). Initial results from the use of sulfoxides
Table 4: Screening of various oxidants for intermolecular transfer oxy-
genative addition of methanol to the alkyne 5.[a]
Table 2: Rhodium-catalyzed addition to alkyne 1.[a]
Entry
NuH
Yield [%][b]
Entry
Oxidant
Yield [%][b]
1
2
3
4
5
6
ethanol
isopropyl alcohol
phenol
aniline
butylamine
morpholine
2b (74)
2c (50)
2d (45)
2e (94)
2 f (61)
2g (69)
1
2
3
4
5
6
7
8
dimethylsulfoxide
diphenylsulfoxide
0
0
0
methylphenylsulfoxide
N-methylmorpholine N-oxide
pyridine N-oxide
3,5-dichloropyridine N-oxide
3,5-dibromopyridine N-oxide
2-picoline N-oxide
3-picoline N-oxide
4-picoline N-oxide
2,6-lutidine N-oxide
8-methylquinoline N-oxide
0
87
54
44
81
92
95
13
54
[a] Reaction conditions: alkyne 1 (0.5 mmol), alcohol (2.5 mmol) or
amine (0.6 mmol) in CH3CN (1.25 mL). [b] Yield of isolated product.
9
10[c]
11
12
well as secondary substitutions and fared well with both
aliphatic and aromatic substrates.
Encouraged by these initial results obtained with the
sulfoxide 1, we investigated the applicability of the protocol to
an N-oxide substrate (Table 3). When the alkyne-tethered
[a] Reaction conditions: alkyne 5 (0.2 mmol), oxidant (0.4 mmol),
methanol (0.8 mmol) in CH3CN (0.4 mL). [b] Yields determined by GC.
[c] Yield of isolated product.
were not too promising, as no reaction took place in these
cases (entries 1–3). Similarly, N-methylmorpholine N-oxide
(NMO) was ineffective (entry 4). In sharp contrast, when
pyridine N-oxide was employed as an oxidant, methyl ester 6a
was produced in 87% yield (entry 5). Further examination
showed that the intermolecular transfer oxygenative addition
could be accomplished with a variety of pyridine N-oxide
derivatives (entries 5–12), among which 4-picoline N-oxide
proved most effective (entry 10). It was intriguing to note that
8-methylquinoline N-oxide, an oxidant most commonly
employed in gold catalysis,[2h] displayed only modest perfor-
mance in this rhodium catalysis to give a 54% yield of 6a
(entry 12).
With the optimized reaction conditions in hand, we tested
various alkynes and nucleophiles to probe the scope and
limitations of the intermolecular oxygenative coupling reac-
tion. As summarized in Table 5, the diversity of alkynes and
nucleophiles suitable for this reaction proved quite extensive.
Furthermore, a variety of functional groups did not interfere,
thus highlighting the highly chemoselective feature of the
process. In the reactions of the alkyne 5, both aliphatic and
aromatic alcohols and anilines were found to be competent
nucleophiles to give esters and amides (6b–6e). Notably, the
reaction proceeded well in wet acetonitrile to furnish the
carboxylic acid 6 f as the product. From the perspective of the
alkyne structure, the reaction tolerated aryl (6–9 and 16),
heteroaryl (10), alkenyl (11), branched alkyl (12), and linear
alkyl (13–15) substituents. Various amines also participated
well in the reaction to give rise to primary (15b), secondary
(15c), and tertiary (15d) amides, including a Weinrebꢀs amide
(15e).[6] When serine methyl ester was employed as the
Table 3: Rhodium-catalyzed addition to the alkyne 3.[a]
Entry
NuH
Yield [%][b]
1
2
3
4
5
6
7
methanol
ethanol
isopropyl alcohol
phenol
aniline
butylamine
morpholine
4a (51)
4b (70)
4c (37)
4d (41)
4e (46)
4 f (77)
4g (88)
[a] Reaction conditions: alkyne 3 (0.2 mmol), alcohol (1.0 mmol) or
amine (0.24 mmol) in CH3CN (0.5 mL). [b] Yield of isolated product.
TBS=tert-butyldimethylsilyl.
pyridine N-oxide 3 was subjected to the rhodium-catalyzed
conditions with a collection of alcohols and amines, the
oxygenative addition reaction took place smoothly to yield
the ester and amide products 4. Interestingly, however, the
use of [{Rh(cod)OH}2] instead of [{Rh(cod)Cl}2] gave higher
yields in these reactions.[5] As in the case of 1, the reaction of
N-oxide 3 was also compatible with a wide range of
nucleophiles possessing varying steric and electronic proper-
ties.
Having established the feasibility of oxygenative alkyne
addition through an intramolecular S-to-C or N-to-C oxygen
transfer, we next turned our attention to the development of
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Table 5: Rhodium-catalyzed intermolecular oxygenative addition to
product 15 f. These amide-forming reactions benefited from
terminal alkynes.[a]
the use of ammonium salts rather than free amines as
nucleophiles, as higher yields were consistently obtained from
the reactions of amine salts compared to those of the free
amines.[7] It should also be noted that only 1.2 equivalents of
the nucleophile were required in these reactions. Similarly,
although the reactions forming methyl esters were carried out
employing 3 equivalents of methanol and 3.0 mol% of the
rhodium catalyst, the amounts of the alcohol and the rhodium
catalyst could be reduced without a decrease in the yield. For
example, the reaction of a 1:1.2 mixture of l-menthol and
phenyl acetylene could be performed on a multigram scale
with only 1.0 mol% of the catalyst to produce menthyl
phenylacetate (16) in 90% yield.
6b (89%, 2 h)
6c (71%, 2 h)
6d (78%, 2 h)
6 f (82%, 8 h)[b]
6e (85%, 4 h)
7 (89%, 2 h)
The mechanism of the rhodium-catalyzed oxygenative
alkyne addition is proposed in Scheme 2. In this catalytic
cycle, the oxygen transfer from an N-oxide to the h1-Rh
vinylidene complex A delivers h2-Rh ketene species B, which
8 (83%, 2 h)
10 (79%, 2 h)
9 (86%, 2 h)
11 (63%, 2 h)[c]
12 (53%, 24 h)[c]
14 (75%, 19 h)[c]
13 (73%, 24 h)[c]
15a (82%, 4 h)[c]
Scheme 2. Proposed mechanism of the rhodium-catalyzed oxygenative
addition to terminal alkynes.
may exist in equilibrium with C.[8] Subsequent to demetala-
tion, the free ketene D undergoes a nucleophilic addition to
provide the carbonyl product.[9,10] Alternatively, the nucleo-
phile may add to a rhodium-coordinated ketene (B or C), in
which case the catalyst turnover would involve protonation of
a rhodium enolate. The intermediacy of a ketene species is
supported by the result of a control experiment, where
subjection of the alkyne 5 to the reaction without a nucleo-
phile generates p-anisaldehyde (42%) presumably by the
oxidation of the alkylidene E derived from CO deinsertion of
rhodium ketene complex C/C’.[11]
The findings from this study are significant in several
respects. They demonstrate that terminal alkynes can be
directly transformed into carboxylic acid derivatives under
mild rhodium catalysis by a distinct mechanism. The oxygen-
ative coupling process occurring in an anti-Markovnikov
fashion represents a novel method for alkyne 1,1-difunction-
alization,[12] thus providing a selectivity complementary to
that of the process mediated by a-oxo metallocarbene
catalysis. The facile transfer oxygenation of metal vinylidene
species established in both intra- and intermolecular settings
by this study also offers a new mechanistic manifold through
15b (83%, 12 h)[d,e]
15d (75%, 12 h)[d]
15c (87%, 12 h)[d]
15e (75%, 12 h)[d]
15 f (91%, 12 h)[d]
16 (90%, 48 h)[f]
[a] Reaction conditions: alkyne (1.0 mmol), alcohol (3.0 mmol) or amine
(1.2 mmol), 4-picoline N-oxide (1.2 mmol) in CH3CN (2 mL). The yield is
of the isolated product. [b] H2O (10 mmol). [c] MeOH (5.0 mmol).
[d] Alkyne (0.5 mmol), amine·HCl (0.6 mmol), NaPF6 (0.6 mmol), K2CO3
(0.1 mmol). [e] NH4NO3 (0.6 mmol). [f] Phenylacetylene (2.45 g,
24 mmol), l-menthol (3.13 g, 20 mmol), 4-picoline N-oxide (2.62 g,
24 mmol), [{Rh(cod)Cl}2] (1 mol%), P(4-F-C6H4)3 (4 mol%).
nucleophile, the reaction occurred exclusively at the amino
group in preference to the alcohol, thus providing the N-acyl
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[7] In general, the reactions using free amines gave the amide
products in yield decreased by 10%. See the Supporting
Information.
which the rich chemistry of ketenes might be harnessed in the
context of catalytic alkyne functionalization.[13] Further
investigations in this direction are currently underway in
our laboratory, and the results will be reported in due course.
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[9] The intermediacy of rhodium vinylidene A was supported by
a deuterium-labeling experiment, where a reaction of deuterio-5
(98% alkynyl D) with methanol led to the formation of 6a in
78% yield (92% deuterium incorporation). See the Supporting
Information.
Received: April 30, 2013
Revised: June 25, 2013
Published online: && &&, &&&&
Keywords: alkynes · homogeneous catalysis · oxygenation ·
.
rhodium · vinylidene ligands
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Synthetic Methods
I. Kim, C. Lee*
&&&& — &&&&
Rhodium-Catalyzed Oxygenative Addition
to Terminal Alkynes for the Synthesis of
Esters, Amides, and Carboxylic Acids
A gem of a couple: The title reaction of
terminal alkynes with O and N nucleo-
philes proceeds in the presence of
[{Rh(cod)Cl}2], P(4-FC6H4)3, and 4-pico-
line N-oxide. Alcohols, amines, and water
add to the terminal alkynes to give esters,
amides, and carboxylic acids, respec-
tively. The reaction involves formation of
a rhodium vinylidene, oxidation to
a ketene by oxygen transfer, and nucleo-
philic addition.
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