Carboxylation of C-H bonds using N -heterocyclic carbene gold(I) complexes

Article abstract of DOI:10.1021/ja103429q

A highly efficient [(NHC)Au^I]-based (NHC = N-heterocyclic carbene) catalytic system for the carboxylation of aromatic and heteroaromatic C-H bonds was developed. The significant base strength of the Au-OH species is at the origin of the activation process and permits the facile functionalization of C-H bonds without the use of other organometallic reagents.

Full text of DOI:10.1021/ja103429q

Published on Web 06/11/2010
Carboxylation of C-H Bonds Using N-Heterocyclic Carbene Gold(I)
Complexes
Ine I. F. Boogaerts and Steven P. Nolan*
EaStCHEM School of Chemistry, UniVersity of St Andrews, St. Andrews KY16 9ST, U.K.
Received April 22, 2010; E-mail: snolan@st-andrews.ac.uk
Carbon dioxide (CO2) is considered an abundant and renewable
C1 source; thus transition-metal mediated activation of this
thermodynamically and kinetically stable molecule has received
much attention over the past decade.1 In this context, C-C bond
formation reactions simply involving CO2 and a unique metal center
with allyl halides, alkenes, alkynes, and allenes have been achieved,
although with limited functional group compatibility.2-5 Recently,
Hou and co-workers reported the catalytic carboxylation of orga-
noboronic esters6 using N-heterocyclic carbene (NHC) copper
complexes as a route to functionalized carboxylic acid derivatives.7
One fundamental drawback of this coupling reaction is the required
use of a stoichiometric amount of an expensive organometallic
reagent, which requires prior preparation or is generated in situ.
We and others have recently reported that gold(I) complexes
bearing strong donor ligands can perform the activation of C-H
bonds of electron-deficient arenes.8,9 The strongly basic [(IPr)-
AuOH] (1) (IPr ) 1,3-bis(diisopropyl)phenylimidazol-2-ylidene)
species which has a pKaDMSO of 30.3(2) as determined by potentio-
metric titrimetry (see Supporting Information (SI)) is of particular
interest as it effects bond activation by a simple protonolysis
mechanism which could possibly be extrapolated to a methodology
for C-H bond functionalization. Furthermore, these protonolysis
reactions occur under remarkably mild conditions with H2O formed
as the waste product.
aliquot of the catalyst solution could be recycled six times with
98% activity retention per cycle, giving a cumulative turnover
number of 78.1 mol per mol of catalyst (see SI).
Table 1. Carboxylation of Oxazole with NHC-Gold(I) Catalystsa
Loading
(mol %)
T
(°C)
TOFb
(h-1
Yieldc
(%)
Entry
[Au]
)
1
2
3
4
5
6
7
8
[(IPr)AuOH] (1)
1
1
1
[(IPr)AuCl]
[(IPr)AuCl]
[(IMes)AuCl]
[(ItBu)AuCl]
3.0
1.5
1.5
1.5
3.0
3.0
3.0
3.0
45
45
20
8
45
25
45
45
14.1
13.8
16.5
16.9
8.7
0.4
n.d.
n.d.
94
93
96
94
88
86
76
68
a Conditions: 1 mmol of 2a, 1.05 mmol of KOH, pCO2 ) 1.5 bar, 5
mL of THF, t ) 12 h. b Turnover frequency determined after 2 h,
defined as mol of acid per mol of Au per hour. c Yield of isolated
product.
We hypothesized that [(IPr)AuOH] (1) could act as an effective
catalyst for the carboxylation of aromatic C-H bonds featuring
protons with a pKa
below 30.3,10 furnishing important structural
DMSO
motifs found in numerous biologically active compounds and natural
To ascertain a scope for this methodology, a number of other
aromatic heterocycles were subjected to carboxylation catalysis
under optimized catalytic conditions. Gratifyingly, gold(I) mediated
C-H activation showed high regioselectivity for the most acidic
C-H bond. The oxazoles were converted cleanly to the corre-
sponding C2 carboxylic acids (Table 2, entries 3a-3c). Carboxy-
lation of the related thiazoles afforded comparable selectivities;
parent thiazole gave a 2.3/1 mixture of C2/C5 regioisomers,
attributed to the presence of similarly acidic protons in these
positions (Table 2, entries 3d-3f). The azoles and pyrimidine were
products.11 We initially examined the reaction of oxazole (2a)
(pKa ) 27.1)10 with CO2 using isolated [(NHC)AuOH] com-
DMSO
plexes. In the presence of 3 mol % 1 and 1.05 mmol of KOH in
THF at 45 °C, treatment of 2a (1 mmol) with CO2 (1.5 bar) and
subsequent acid hydrolysis afforded oxazole 2-carboxylic acid (3a)
in a quantitative yield (Table 1, entry 1). Under otherwise identical
conditions, carboxylation took place neither in the absence of either
[(IPr)AuOH] or KOH nor in the presence of only free NHC ligand.
Screening revealed that catalyst loading could be reduced to 1.5
mol %, with higher turnover frequencies at lower temperatures, an
observation that correlates with the increased solubility of CO2
(Table 1, entries 2-4). The [(IPr)Au] species generated in situ from
[(IPr)AuCl] and KOH also demonstrated activity for the carboxy-
lation of 2a,12 but profiles of CO2 consumption versus time clearly
show the existence of a significant induction period at lower
temperatures (Table 1, entries 5 and 6). Interestingly, the presence
of alternative NHC ligands13 led to lower yields of 3a (Table 1,
entries 7 and 8). We suspected that the efficacy of this catalyst
system was grounded in the solution stability of the active species.
We felt that this resilience could be best showcased in catalyst
recycling experiments. Aqueous extraction of the catalyst solution
at 45 °C allowed recovery of potassium oxazole 2-carboxylate and
efficient recycling of [(IPr)AuOH] in the organic phase. A single
not activated by [(IPr)AuOH] as all C-H bonds have a pKa
DMSO
exceeding 30.3; however the more basic [(ItBu)AuOH] (ItBu)1,3-
di-tert-butylimidazol-2-ylidene) species (pKa ) 32.4(2); see SI)
could catalyze their carboxylation (Table 2, entries 3g-3i). It is
interesting to note that 2a, 2b, 2d, 2e, and 2g react selectively at
the C4 position when traditional acylation methodologies are
employed.14 Substrates containing three or four heteroatoms were
also converted to their corresponding carboxylic acids with high
regioselectivity (Table 2, entries 3j-3l).
Synthetic methodology often necessitates the conversion of
carboxylic acid to ester, which encouraged us to explore the
possibility for their direct formation using the present methodology.
Following this carboxylation protocol, the potassium carboxylate
salts of 3a-3c and 3e-3f were quenched with iodomethane to
9
8858 J. AM. CHEM. SOC. 2010, 132, 8858–8859
10.1021/ja103429q  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Carboxylation of arenes with [(IPr)AuOH]a
Table 2. Carboxylation of Aromatic Heterocycles with [(IPr)AuOH]
a Yields are isolated and average of two runs. b Reaction performed
using 2 equivalents of KOH.
a Yields are isolated and average of two runs. b Reaction performed
using [(ItBu)AuOH].
isolated, characterized, and shown to be active in the carboxylation
reaction. Further work is underway to integrate this methodology
into tandem sequences and to test the limits of this seemingly very
straightforward Coinage Metal C-H bond functionalization reaction.
afford the corresponding methyl esters 4a-4c and 4e-4f in good
isolated yields (>80%). The mechanism postulated for copper(I)
catalyzed carboxylation of organoboronic esters was validated for
the current methodology by stoichiometric reactions (Scheme 1).7,15
Thus, protonolysis of [(IPr)AuOH] by 1 equiv of 2a gave the gold(I)
oxazole species 5, isolated in 93% yield. A solution of 5 was
saturated with CO2 at -100 °C; nucleophilic addition of the oxazole
ligand to the electron-deficient carbon atom of CO2 thus afforded
carboxylate complex 6, isolated in 86% yield. [(IPr)AuOH] was
regenerated upon metathesis of 6 with 1 equiv of KOH, with
precipitation of potassium oxazole-2-carboxylate. Isolated species
5 and 6 demonstrated high activity for the carboxylation of 2a,
both affording 3a in 88% yield.
Acknowledgment. Financial support for this work was provided
by the EPSRC and the ERC (FUNCAT).
Supporting Information Available: Detailed experimental proce-
dures and characterization data; pKa and titrimetry data. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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Scheme 1. Intermediates Involved in the Carboxylation of 2a
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(12) Using [(IPr)CuCl] in this in situ carboxylation leads to the formation of 3a
in 89% yield. This chemistry is presently being explored.
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As activated heterocyclic C-H bonds showed a propensity for
activation/functionalization, the previously examined activated
arenes8 and congeners were subjected to similar carboxylation
catalysis. To our delight, the transformations examined cleanly
converted to the corresponding carboxylic acid (Table 3).
In summary, we have shown that NHC gold(I) hydroxide
complexes can catalyze the carboxylation of carbo- and heterocycles
with high regioselectivity at the most acidic C-H bond position.
The selective carboxylation can be rationalized in terms of simple
acid/base theory. The proposed catalytic intermediates have been
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