Iridium-catalyzed direct C-H amidation with weakly coordinating carbonyl directing groups under mild conditions

Article abstract of DOI:10.1002/anie.201310544

An iridium-catalyzed direct C-H amidation of weakly coordinating substrates, in particular of those bearing ester and ketone groups, under very mild conditions has been developed. The observed high reaction efficiency was achieved by the combined use of acetic acid and lithium carbonate as additives. Copyright

Full text of DOI:10.1002/anie.201310544

Angewandte
Chemie
DOI: 10.1002/anie.201310544
À
C H Amidation
Hot Paper
À
Iridium-Catalyzed Direct C H Amidation with Weakly Coordinating
Carbonyl Directing Groups under Mild Conditions**
Jinwoo Kim and Sukbok Chang*
À
À
Abstract: An iridium-catalyzed direct C H amidation of
C N bond formation. Herein, we describe the Ir(III)-
2
À
weakly coordinating substrates, in particular of those bearing
ester and ketone groups, under very mild conditions has been
developed. The observed high reaction efficiency was achieved
by the combined use of acetic acid and lithium carbonate as
additives.
catalyzed direct amidation of aryl and alkenyl C(sp ) H
bonds using esters and ketones as viable chelating groups
under very mild conditions (Scheme 1b). The results of this
work are significant considering that the ester unit may be
used as a readily manageable protecting group in organic
synthesis,[5] as it can be converted into various functional
groups under ambient conditions.[6]
S
ince the pioneering work of Murai and co-workers,[1]
À
transition-metal-catalyzed direct C H functionalizations
with various directing groups have provided a straightforward
tool for the regioselective formation of carbon–carbon and
carbon–heteroatom bonds.[2] Whereas strongly coordinating
units, including thio, pyridyl, amino, or amide groups, have
Cyclometalation can be accelerated by the addition of
external bases, such as acetates or carbonates.[7] Whereas
these species may assist the formation of metallacycles in
a concerted manner, they often detain the generation of
catalytically reactive species as they compete with the
substrates for coordination sites. On the other hand, the
dissociation of anionic ligands from a metal center can be
facilitated by acidic additives to lead to unsaturated cationic
metal species.[8] For instance, Dixneuf and co-workers
reported a RuII-mediated autocatalytic process, revealing
that carboxylic acid additives can enhance the catalytic
activity of ruthenium by promoting the dissociation of an
acetate ligand from the metal acetate resting species.[8b] In this
context, we envisaged that the coordinating efficiency of
weakly binding substrates such as esters and ketones towards
a metal center could be increased by suppressing the binding
affinity of basic ligands with the aid of suitable acid additives.
To examine the above hypothesis, we screened various
reaction conditions for the amidation of ethyl benzoate (1a)
with an equimolar amount of para-toluenesulfonyl azide (2a)
À
been widely employed for chelation-assisted C H bond
activation, the use of substrates that bear only weakly
coordinating moieties has been much less successful, which
is mainly due to the less efficient formation of the key
metallacyclic intermediate.[3] In particular, the utilization of
esters as directing groups is still rare, even though this
functional group is omnipresent in numerous natural products
and synthetic compounds. In spite of a few elegant examples
(Scheme 1a),[4] to the best of our knowledge, esters have not
been utilized as directing groups for intermolecular direct
À
that are based on our recently developed procedures for C H
amidation[9,10] using a {Cp*IrIII} catalyst system (Table 1;
Cp* = pentamethylcyclopentadienyl).[11] When a silver salt,
which is required for the generation of a cationic iridium
species, was used as the sole additive (entry 1), no reaction
occurred. However, the use of certain additional additives
was found to initiate the amidation to some extent. Among
various bases screened (entries 2–6), the use of LiOAc
(7.5 mol%) resulted in a notable increase in product yield
at 508C (entry 5). Interestingly, the lithium countercation
exerts a significantly stronger effect on the transformation
than other cations, such as ammonium, sodium, or potassium
ions (entries 2–5). Whereas the use of lithium carbonate on its
own led to no conversion (entry 6), we were pleased to
observe that the combined use of this salt with acetic acid
gave an almost quantitative yield (entry 7). Surprisingly, the
amidation proceeded even at room temperature, albeit with
slightly lower efficiency (entry 8). The use of CF3COOH
instead of AcOH significantly reduced the reaction efficiency
(entry 9). A combination of AcOH and LiOAc gave rise to an
inferior result (entry 10) compared to AcOH/Li2CO3
À
Scheme 1. Direct C H functionalizations with an ester directing group.
Pin=pinacolato.
[*] J. Kim, Prof. Dr. S. Chang
Center for Catalytic Hydrocarbon Functionalization
Institute of Basic Science (IBS)
Daejeon 305-701 (Republic of Korea)
and
Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 305-701 (Republic of Korea)
E-mail: sbchang@kaist.ac.kr
[**] This research was supported financially by the Institute of Basic
Science (IBS).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310544.
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Table 1: Additive screening for the Ir-catalyzed amidation of esters.[a]
species. A combination of AcOH and Li2CO3 will generate
lithium acetate and lithium bicarbonate in situ.[12] Consider-
ing the weak coordinating ability of an ester group, an acetate
ion is expected to coordinate more favorably to the cationic
iridium center to form the iridium acetate resting species A.
Indeed, we could isolate an analogue of complex A, namely
trifluoroacetato iridium complex A’, which bears one mole-
cule of water; its solid state structure was analyzed by X-ray
crystallography (Figure 1). Complex A’ has a piano stool
structure with an almost equivalent distance (ca. 2.13 ꢀ)
between the iridium center and the five carbon atoms of the
Cp* ring. Two CF3COOÀ ligands are coordinated to the
iridium center in an h1 fashion with similar bond lengths (ca.
2.11 ꢀ).
Entry
Additive
T [8C]
Yield [%]
1
2
3
4
5
6
7
8
–
50
50
50
50
50
50
50
25
50
50
50
0
0
7
15
45
0
98
75
9
NBu4OAc
NaOAc
KOAc
LiOAc
Li2CO3
AcOH/Li2CO3
AcOH/Li2CO3
CF3COOH/Li2CO3
AcOH/LiOAc
B(C6F5)3/Li2CO3
Dissociation of an acetate ligand from A leaves one
vacant site (B) that will subsequently be occupied by an ester
group (C). The lithium ion is believed to drive the equilibrium
forward by abstracting an acetate species as the correspond-
9
10
11
44
0
[a] Conditions: 1a (0.1 mmol), 2a (1.0 equiv), [{IrCp*Cl2}2] (2 mol%),
AgNTf2 (8 mol%), additives (7.5 mol% in each case), DCE (0.2m), 12 h
(for detailed screening data, see the Supporting Information). DCE=1,2-
dichloroethane, Tf=trifluoromethanesulfonyl, Ts=4-toluenesulfonyl.
À
ing salt. C H bond activation should then occur with the
assistance of a bound acetate to afford iridacycle F (via E),
presumably passing through a transition state D. In fact, we
isolated an analogous iridacycle species, which is derived from
an acetophenone derivative (see below). In another crucial
À
(entry 7). On the other hand, the use of a Lewis acid additive
instead of acetic acid was ineffective (entry 11).
As the above optimization results were consistent with
our working hypothesis, we could propose a plausible cata-
step, C N bond formation will occur upon reversible
coordination of the azide to the iridium metal center (G),
which is followed by an amido insertion process to deliver the
desired amidated product with concomitant release of N2.[13]
We investigated the scope of the amidation with ester-
substituted substrates and sulfonyl azides under the optimized
conditions at 508C (Scheme 2). It should be emphasized that
the two reactants, namely ester and azide, were used in an
equimolar ratio. Furthermore, for
À
lytic cycle for the Ir-catalyzed direct C H amidation of ethyl
benzoate (Figure 1). As suggested in our previous studies,[9e,f]
upon treatment with a silver salt, a neutral dimeric iridium
precursor will first be converted into its cationic monomeric
many substrates, satisfactory prod-
uct yields were obtained even at
room temperature. In addition, the
reaction was highly selective, and
monoamidated products were
obtained exclusively without for-
mation of bisamidated by-prod-
ucts.[14]
A broad range of ester-con-
taining substrates was successfully
amidated to afford the desired
products in good to excellent
yields. An electron-rich substrate
was amidated with high efficiency
even at room temperature (3b).
Amidation of ethyl 2-naphthoate
took place exclusively at the
3-position (3c). Functional group
tolerance was excellent, as demon-
strated by the amidation of bromo-
or hydroxy-substituted substrates
(3d and 3e). Methoxy and cyclo-
propyloxy esters were also ami-
dated without difficulty at 508C
(3 f and 3g). Furthermore, lactones
with six- or seven-membered rings
Figure 1. Proposed mechanistic cycle.
(3h and 3i) were effective direct-
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Scheme 3. Synthesis of benzodiazepine derivative 5. a) 1a
(6.67 mmol), 2a (1.0 equiv), [{IrCp*Cl2}2] (2 mol%), AgNTf2 (8 mol%),
AcOH (7.5 mol%), Li2CO3 (7.5 mol%), DCE, 508C; b) DEAD, PPh3,
THF, 258C; c) HCl (1.5m), MeOH, 258C; d) TsCl, Et3N, CH2Cl2, 258C;
e) LAH, THF, 258C; f) DEAD, PPh3, THF, 258C. Bn=benzyl, Boc=
tert-butoxycarbonyl, DEAD=diethyl azodicarboxylate, LAH=lithium
aluminium hydride.
delighted to find that the reaction conditions that had been
optimized for ester derivatives were also suitable for the
2
À
amidation of aryl and olefinic C(sp ) H bonds of ketones
(Scheme 4). Significantly, most of the examined substrates
were amidated smoothly at room temperature in excellent
Scheme 2. Scope of the Ir-catalyzed amidation with an ester directing
group. Reaction conditions: 1 (0.1 mmol), 2 (1.0 equiv), [{IrCp*Cl2}2]
(4 mol%), AgNTf2 (16 mol%), AcOH (15 mol%), Li2CO3 (15 mol%),
DCE (0.2m). Yields of isolated products are given (yields obtained for
reactions at room temperature are shown in parentheses). [a] 1
(1.5 equiv). [b] 808C.
À
ing groups to facilitate the desired C H amidation. Signifi-
À
cantly, olefinic C H bonds could be readily amidated (3j and
3k), which greatly extends the applicability of the present
method. 2-Phenylacrylate was selectively amidated at the
À
olefinic C H bond, while no reaction occurred at the arene
moiety (3l).
As expected, a wide range of sulfonyl azides were
successfully employed as efficient sources for the amide
group. Methyl and benzyl variants reacted efficiently even at
room temperature (3m and 3n). The amidation of ethyl
benzoate with 10-camphorsulfonyl azide was also facile (3o).
An aryl sulfonyl azide with a bromo group at the ortho po-
sition was readily utilized in the current amidation, thus
allowing for subsequent modifications of the obtained
product (3p).
The present method was successfully applied to the
synthesis of a benzodiazepine derivative (Scheme 3). The
À
iridium-catalyzed direct C H amidation of ethyl benzoate
(1a) could be carried out on a gram scale without difficulty.
The secondary amine 3a was alkylated under Mitsunobu
conditions to give 4, which was then cyclized through four
conventional steps, all at ambient temperature, to obtain
tetrahydrobenzodiazepine derivative 5. This molecular skel-
eton is present in a series of biologically important com-
pounds (Scheme 3).[15]
We next turned our attention to ketone substrates, as this
functional group may be employed as another weakly
coordinating group with high synthetic utility. We were
Scheme 4. Scope of the Ir-catalyzed amidation with a ketone directing
group. Reaction conditions: 6 (0.1 mmol), 2 (1.0 equiv), [{IrCp*Cl2}2]
(4 mol%), AgNTf2 (16 mol%), AcOH (15 mol%), Li2CO3 (15 mol%),
DCE (0.2m). Yields of isolated products are given. [a] 508C. [b] 6
(1.5 equiv). [c] 30 h.
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yields. Again, the two reactants, namely ketone derivative and
sulfonyl azide, were employed in an equimolar ratio. Aceto-
phenone was amidated in quantitative yield (7a). Both
electron-withdrawing and -donating substituents hardly influ-
enced the reaction efficiency (7b and 7c). Functional group
compatibility was excellent as was demonstrated with
hydroxy- (7d) and bromo-substituted (7e) derivatives. Ami-
dation selectively occurred at the ortho position relative to
the ketone in the presence of an ester group (7 f), thus
indicating that the former is a more effective chelating group
than the latter substituent. The introduction of alkyl sub-
stituents on the acetophenone substrate was not detrimental
to this transformation (7g). Cyclic ketone derivatives were
À
also suitable substrates for arene C H amidation. Biorelevant
molecular skeletons, such as a-tetralone (7h), chromone (7i),
flavone (7j), and anthrone (7k) derivatives, were all amidated
in excellent yields at room temperature.[16] Aryl vinyl ketones
were exclusively amidated at the arene ring (7l and 7m). On
Figure 2. Crystal structure of complex 8. Ellipsoids set at 50% proba-
bility.
À
the other hand, olefinic C H amidation was viable for alkenyl
ketones to give enamides in high yields (7n–7p). Further-
more, an acyclic olefinic ketone was readily amidated to
afford Z enamide 7p, although a longer reaction time was
required. All of the examined sulfonyl azides were found to
be suitable substrates for the iridium-catalyzed amidation of
acetophenone at room temperature (7q–7t).
À
Ir C bonds (2.24 ꢀ) to the Cp* ring are slightly longer than
the remaining three (2.14, 2.14, and 2.16 ꢀ), presumably
owing to a different trans influence of the three other ligands,
as reported previously.[18] The catalytic activity of 8 was
subsequently investigated for the amidation of acetophenone
(Scheme 5b) and ethyl benzoate (Scheme 5c). Whereas the
amidated acetophenone derivative was obtained in high yield
at room temperature, the reaction of ethyl benzoate pro-
ceeded with lower efficiency. This result strongly suggests that
an iridacyclic intermediate is involved in the catalytic cycle of
the current amidation reaction.
To shed light on the mechanistic aspects of the present
À
C H amidation reaction, we first tried to obtain iridacyclic
intermediates that are derived from weakly coordinating
substrates. We were delighted to be able to isolate metalla-
cycle 8 of 4-methoxyacetophenone (6b) when AgOTFA and
Li2CO3 were used as additives (Scheme 5a; TFA = trifluor-
oacetyl). To the best of our knowledge, its single-crystal
The initial amidation rates of normal substrates and their
deuterated analogues were also examined. A primary kinetic
isotope effect (KIE; kH/kD = 4.0) was observed for the
amidation of ethyl benzoate and its deuterated derivative
À
(Scheme 6a), implying that C H bond cleavage is likely to be
a rate-limiting step. Interestingly, a significant KIE value (kH/
kD = 2.9) was also measured for acetophenone derivatives, in
this case by using iridacyclic species 8 as the catalyst
(Scheme 6b).
In summary, we have described the iridium-catalyzed
À
direct intermolecular C H amidation of weakly coordinating
substrates, particularly of ester and ketone derivatives. The
reaction exhibits a broad substrate scope and proceeds under
Scheme 5. Formation of iridacycle complex 8 and its catalytic reactivity.
structure is the first one that has been obtained for a discrete
iridacycle generated from a ketone compound, although there
are some examples of the corresponding Pd complexes
(Figure 2).[4k,17] The distance between the iridium center and
the carbonyl oxygen atom is 2.14 ꢀ, which is similar to that
between the iridium and trifluoroacetato oxygen atoms
(2.12 ꢀ). The distance between iridium and aryl carbon
atom is 2.04 ꢀ, and the chelate bite angle is 78.08. Two of the
Scheme 6. KIE measurements for the amidation of ester and ketone
substrates.
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very mild conditions with excellent functional group toler-
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be achieved by the combined use of acetic acid and lithium
carbonate, and the role of these additives was proposed with
respect to mechanistic aspects. Another attractive feature of
this present study is the facile conversion of ester and ketone
directing groups, which offers new opportunities in diverse
areas, including organic synthesis, medicinal chemistry, and
materials science.
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Experimental Section
Representative procedure: Ethyl benzoate (1a, 0.1 mmol), para-
toluenesulfonyl azide (2a, 0.1 mmol), [{IrCp*Cl2}2] (3.2 mg, 4 mol%),
AgNTf2 (6.2 mg, 16 mol%), Li2CO3 (1.1 mg, 15 mol%), AcOH
(0.90 mg, 15 mol%) and 1,2-dichloroethane (0.5 mL) were placed in
a screw-capped vial equipped with a Spinvane triangular stir bar
under argon atmosphere. The reaction mixture was stirred at 508C in
a pre-heated oil bath for 12 hours, cooled to room temperature,
filtered through a pad of celite and silica gel, and washed with CH2Cl2
(3 ꢁ 10 mL). The solvents were removed in vacuo, and the residue was
purified by column chromatography on silica gel (n-hexane/EtOAc =
5:1, v/v) to give 3a (31.6 mg, 99%).
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Received: December 5, 2013
Published online: January 27, 2014
[12] Fagnou and co-workers reasoned that a carbonate base makes
À
a C H cleavage step irreversible by segregating an abstracted
À
Keywords: azides · C H amidation · esters · iridium ·
weakly coordinating groups
.
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À
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[16] When
4-methoxy-4’-trifluoromethylbenzophenone
was
À
employed, C H amidation took place selectively at the elec-
tron-rich aryl ring with a ratio of 4.6:1 (see the Supporting
Information for details).
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