Carboxylation of N-H/C-H bonds using n-heterocyclic carbene copper(I) complexes

Article abstract of DOI:10.1002/anie.201004153

Greenhouse gas makes good: A simple copper-mediated protocol has been developed where N-H or C-H bonds can be directly functionalized using an easily prepared catalyst. The novel [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene] copper(I) hydroxide, [Cu(IPr)(OH)], permits the facile activation and carboxylation of N-H and C-H bonds with pK_avalues of less than 27.7 (see scheme).

Full text of DOI:10.1002/anie.201004153

Communications
DOI: 10.1002/anie.201004153
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C H/N H Bond Functionalization
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À
Carboxylation of N H/C H Bonds Using N-Heterocyclic Carbene
Copper(I) Complexes**
Ine I. F. Boogaerts, George C. Fortman, Marc R. L. Furst, Catherine S. J. Cazin,* and
Steven P. Nolan*
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À
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Transition-metal-mediated carboxylation of N H and C H feasibility and site selectivity of such a C H bond function-
bonds represents a nascent area in organic chemistry, because alization. In this earlier report, an alternative to the use of the
these reactions enable the efficient construction of valuable well-defined [Au(IPr)(OH)] was devised, which made use of
synthons.[1] Palladium-catalyzed N-carbonylation–oxidation its synthetic precursor, namely [Au(IPr)Cl], in the presence of
sequences are well-documented, but they often require high KOH to generate [Au(IPr)(OH)] in situ. The possibility to
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catalyst loadings and the use of either gaseous carbon perform this exact C H bond functionalization with
monoxide or Group VI metal–carbonyl complexes.[2] An [Cu(IPr)Cl][13] was also demonstrated.[11]
analogous transformation sequence is also promoted by
We have recently developed the synthetically versatile
molybdenum and tungsten carbonyl amine species under analogue [Cu(IPr)(OH)] (1),[14] for which a pKaDMSO value of
forcing temperatures.[3] Important advances in C-carboxyla- 27.7(2) was determined by potentiometric titrimetry.[15] As the
tion reactions have been made using ruthenium[1a] and nickel pKa value for 1 was found to be inferior to that of
complexes;[4] however, examples under mild conditions are [Au(IPr)(OH)], we suspected on the basis of this simple
elusive. The carboxylation of allylstannanes,[5] organozincs,[6] acid/base reactivity prediction method that the scope of the
and organoboronic esters[7,8] have been described as a new C H bond carboxylation might be more limited. However, in
À
method to improve functional group tolerance, but the view of the straightforward synthetic access to the precursor
stoichiometric consumption of an organometallic reagent to 1, we deemed the exploration of such a powerful and
remains a disadvantage. The reactivity of allylstannanes and simple functionalization protocol worthy of exploration.
organozinc compounds necessitates handling under an inert Herein, we show that 1 is a highly regioselective catalyst for
À
À
atmosphere, while organoboronic esters are expensive. A the carboxylation of N H and C H bonds that possess a
protocol has recently been developed for the C-carboxylation pKaDMSO value of less than 27.7.[16]
of simple aromatic groups under very mild reaction con-
ditions. In this case the strongly basic [Au(IPr)(OH)][9] important motif in natural product chemistry,[17] 2-methyl-
(IPr=1,3-bis(diisopropyl)phenylimidazol-2-ylidene[10]
com- 1H-imidazole (2a) was selected as the model substrate
plex (pKaDMSO = 30.3(2)) was used,[11] which contains an (pKaDMSO = 19.2). A rudimentary screening of the reaction
As 2-substituted N-carbamoylimidazoles represent an
)
N-heterocyclic carbene (NHC) ligand [Eq. (1)].
parameters defined the optimized catalyst system as 3 mol%
of [Cu(IPr)(OH)] and 1.1 equivalents of CsOH in THF
(Table 1, entry 1). This solution was heated to 408C under
1.5 bar of CO2 for 12 hours, then quenched with iodomethane
Table 1: N-carboxylation of 2-methyl-1H-imidazole with NHC–copper(I)
À
As the initial C H activation proceeds through a simple
catalysts.[a]
protonolysis mechanism,[12] simple Brønsted/Lowry acid/base
theory was used as an effective method to predict the
[*] Dr. I. I. F. Boogaerts, Dr. G. C. Fortman, M. R. L. Furst,
Dr. C. S. J. Cazin, Prof. Dr. S. P. Nolan
EaStCHEM School of Chemistry
Entry [Cu]
Loading (mol%) Base
CsOH
Yield [%][b]
1
[Cu(IPr)(OH)] (1) 3.0
94
0
0
University of St. Andrews
St. Andrews KY16 9ST (United Kingdom)
Fax: (+44)1334-463808
2
–
–
CsOH
–
3
4
[Cu(IPr)(OH)] (1) 3.0
[Cu(IPr)(OH)] (1) 1.5
CsOH
88
E-mail: cc111@st-andrews.ac.uk
5
6
7
8
9
10
11
[Cu(IPr)Cl]
[Cu(IPr)Cl]
[Cu(IPr)Cl]
[Cu(IPr)Cl]
[Cu(SIPr)Cl]
[Cu(IMes)Cl]
[Cu(SIMes)Cl]
3.0
3.0
3.0
1.5
1.5
1.5
1.5
NaOH 72
snolan@st-andrews.ac.uk
Homepage: http://chemistry.st-andrews.ac.uk/staff/cc/group
http://chemistry.st-andrews.ac.uk/staff/spn/group
KOH
84
91
69
28
16
23
CsOH
CsOH
CsOH
CsOH
CsOH
[**] The EPSRC and the ERC (FUNCAT- Advanced Investigator Award to
S.P.N.) are gratefully acknowledged for support of this work.
Chemetall are thanked for their generous gift of materials. S.P.N. is
a Royal Society Wolfson Research Merit Award holder.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004153.
[a] Conditions: 1 mmol 2a, 1.1 mmol base, p(CO2)=1.5 bar, 408C,
20 Hz, 2 mL THF, t=8 h. [b] Yield of isolated product.
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to afford the stable N-methyl-2-methylimidazole carboxylate
(3a) in quantitative yield.
The parent acid was isolated as a white solid in 88% yield
after acid hydrolysis of the solution containing the catalyst,
but underwent spontaneous decarboxylation (28% in 3 h at
228C). Under otherwise analogous reaction conditions, no
conversion of 2a was observed in the absence of
[Cu(IPr)(OH)], and no catalyst turnover was observed in
the absence of CsOH. Traces of oxygen led to the decom-
position of 1 within one hour and must therefore be strin-
gently excluded during loading. Catalyst loading could be
decreased to 1.5 mol% with a slight erosion of the yield
(Table 1, entry 4). Treatment of [Cu(IPr)Cl] in situ with
alternative alkali metal hydroxide reagents could also medi-
ate the N-carboxylation of 2a (Table 1, entries 5–7). The
effect of the base was evaluated and reaction plots indicate
that although NaOH and KOH are effective bases, CsOH is
most effective in generating the active species when carbox-
ylation reactions are conducted at 408C.[15] In reactions where
the active species is generated in situ, catalyst turnover was
only observed after approximately three hours and the
profiles of CO2 consumption in time suggest that the kinetics
of the carboxylation reaction are relatively independent of
the IPr–copper(I) source beyond the induction time
(Figure 1).
Figure 2. NHC ligands used in this study. IMes=1,3-bis(2,4,6-trime-
thylphenyl)imidazol-2-ylidene, SIMes=1,3-bis(2,4,6-trimethylphenyl)
imidazolin-2-ylidene.
bonds (Table 3). Gas chromatography analysis showed that
the conversion of heteroaromatic compounds 4a–4c under
the aforementioned reaction conditions was lethargic (16–
29%). However, simply increasing the temperature to 658C
significantly improved the catalyst turnover to afford 5a–5c
in quantitative yields (Table 3, entries 1–3). It is worth noting
that the C2-selective carboxylation of 4c is distinct from the
Friedel–Crafts mechanism, which promotes C3 selectivity,[20]
thus highlighting the complementarily of this method to the
classical transformation. Polyfluorinated arenes 4d–4e were
also found to undergo clean conversion into the correspond-
ing carboxylic acids under these reaction conditions (Table 3,
entries 4 and 5). Moreover, the presence of two activated
À
C H bonds in 4e allowed facile synthesis of the symmetrical
terephthalic acid 5f when 2.2 equivalents of CsOH were
employed (Table 3, entry 6).
Preliminary mechanistic studies suggest that the catalytic
cycle is very similar to the one proposed for the gold-
catalyzed carboxylation reaction[11] (Scheme 1), where proto-
nolysis of 2-methyl-1H-imidazole (2a) by
Figure 1. Reaction profiles for the N-carboxylation of 2-methyl-1H-
imidazole with 1 at 408C: well-defined complex (bottom, c),
complex generated in situ (top, a).
The use of other NHC ligands (Figure 2) gave significantly
lower yields of 3a under analogous reaction conditions
(Table 1, entries 9–11). The IPr ligand appears optimum at
this stage.
The scope of N-carboxylation under the optimized
reaction conditions is outlined in Table 2. The imidazole,
indole, and pyrazole derivatives were transformed cleanly and
quantitatively to the corresponding methyl esters (Table 2,
entries 1–3). No further purification step had to be used after
the simple work-up (extraction, separation, and conversion
into ester).[15] Competitive O and C reactivity has been
reported to render regioselective carbamoylation of indoli-
nones and pyrrolones problematic.[18] It was, therefore,
gratifying to observe 3e as the only product (Table 2,
À
entry 4). Substrates possessing N H bonds with pKa values
above 27.7 fail to undergo carboxylation, thereby supporting
the usefulness of the prediction based on the pKa value. This
Scheme 1. Proposed catalytic cycle for the N-carboxylation of 2-methyl-
1H-imidazole with [Cu(IPr)(OH)] (1).
À
method was then extrapolated to the carboxylation of C H
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Communications
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Table 2: N H-carboxylation of N-heterocycles with [(Cu(IPr)(OH)].
[Cu(IPr)(OH)] (1) generates the copper(I)-imida-
zole species A. Nucleophilic addition of the
imidazole ligand to the electron-deficient carbon
atom of CO2 effects insertion to give the corre-
sponding carboxylate complex B. The cycle pro-
ceeds with a salt metathesis involving KOH to
regenerate 1, with concurrent precipitation of
potassium 2-methyl-1H-imidaxole-1-carboxylate
(K-3a).
[b]
Entry
1
Substrate
pKa[a] (N H) Product (Yield [%])
TOF [hÀ1 [c]
]
À
2b 18.6
3b (88) 17.5
In summary, we have demonstrated the ability
of NHC copper(I) hydroxide complexes to enable
2
3
4
5
2c 16.4
2d 19.8
2e 15.0
2 f 37.0
3c (93) 19.1
3d (85) 16.6
3e (90) 20.3
À
À
the regioselective carboxylation of N H and C H
bonds that are predicted to be suitably acidic by
Brønsted/Lowry theory. The copper-based system
À
À
permits a significant range of N H and C H
carboxylation reactions. Current efforts are
focused on understanding how variation in the
composition of the catalyst can influence this
potentially quite powerful transformation.
3 f (0)
3g (0)
–
–
Experimental Section
6
2g 30.6
Representative general procedure for the catalytic car-
boxylation with NHC-CuI complexes: A reaction tube
was charged with a solution of [Cu(IPr)(OH)] (14.0 mg,
0.03 mmol), CsOH (164.9 mg, 1.1 mmol), and tetrade-
cane (0.1 mL, 0.19 mmol) in THF (1.7 mL) under 1.5 bar
of CO2. The mixture was incubated for about 15 min at
408C with vigorous stirring (1450 rpm). A solution of the
aromatic substrate (1 mmol) in THF (0.3 mL) was
introduced through a CO2-flushed syringe. The reaction
was run at 408C for 12 h, then quenched with iodo-
[a] pKa values taken from Ref. [16]. [b] Yields of the isolated product are the average of
three runs. [c] Turnover frequency determined after 1 h, defined as mol of ester per mol
of Cu per hour.
methane (62 mL, 1 mmol; or 1 mmol HCl in the case of carboxylic acid
formation). The product mixture was concentrated under reduced
pressure. The residue was dissolved in EtOAc (6 mL), washed with
15% aqueous NaCl (3 ꢀ 4 mL), and dried over Na2SO4. Volatiles were
removed under reduced pressure to afford the methyl carboxylate.
À
Table 3: C H-carboxylation of aromatic substrates with [Cu(IPr)(OH)].
Received: July 7, 2010
Revised: August 24, 2010
Published online: September 30, 2010
Entry
1
Substrate
pKa[a](C H) Product (Yield [%])[b]
À
Keywords: carbene ligands · carboxylation ·
4a 24.8
5a (90)
5b (82)
5c (77)
.
À
C H activation · copper catalysts · N heterocycles
2[c]
3
4b 27.3
4c 27.7
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6
4d 26.1
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