On the importance of an acid additive in the synthesis of pyrido[1,2-a]benzimidazoles by direct copper-catalyzed amination

Article abstract of DOI:10.1002/chem.201100574

Not just an acid! An expedient and highly modular synthesis of 6-, 7-, and 8-substituted pyrido[1,2-a]benzimidazoles (4) has been developed by a direct intramolecular C-H amination of N-phenylpyridin-2-amines (3). Efficient C-H amination of 3 could only be achieved in the presence of catalytic copper and an acid additive. The type of acid (pK_a) proved to be crucial for the catalysis. C-Cl aminations in N-(2-chloroaryl)pyridin-2-amines allow access to 9-substituted pyrido[1,2-a]benzimidazoles. Copyright

Full text of DOI:10.1002/chem.201100574

COMMUNICATION
DOI: 10.1002/chem.201100574
On the Importance of an Acid Additive in the Synthesis of PyridoACTHNUTRGNE[NUG 1,2-
a]benzimidazoles by Direct Copper-Catalyzed Amination
Kye-Simeon Masters,[a] Tom R. M. Rauws,[a] Ashok K. Yadav,[a] Wouter A. Herrebout,[b]
Benjamin Van der Veken,[b] and Bert U. W. Maes*[a]
Pyrido
G
thetic procedure that eliminated the need for preactivation
of the 2-position of the 2-chloroarylamino entity could be
developed, this would be even more powerful, as anilines
are more readily commercially available than 2-chloroani-
pounds both from the viewpoint of medicinal chemistry[2–7]
(solubility,[7] DNA intercalation[3]) and materials chemistry[8]
(fluorescence). Of note among the former is the antibiotic
drug Rifaximin,[5] which contains this heteroaromatic core.
The classical synthetic approach for the assembly of pyrido-
lines. Therefore the synthesis of pyridoACTHNUTRGNE[UNG 1,2-a]benzimidazoles
À
(4) by a transition-metal-catalyzed intramolecular C H ami-
nation approach from N-arylpyridin-2-amines (3) was ex-
plored (Scheme 1).
ACHTUNGTRENNUNG[1,2-a]benzimidazoles is by [3+3] cyclocondensation of ben-
zimidazoles containing a methylene group at C2 with appro-
priate bielectrophiles.[2a] However, these procedures are
often low-yielding, involve indirect/lengthy sequences, and/
or provide access to a limited range of products, primarily
providing derivatives with substituents located on the pyri-
dine ring (A ring, Scheme 1).[2–4] Theoretically, a good alter-
[12a]
À
Reports on C N bond formation,
in comparison with
[12b–p]
À
À
C C bond formation,
by transition-metal-catalyzed C
H functionalization are still relatively rare despite the unde-
À
niably important role of C N bond formation in organic
synthesis. In comparison with existing methodology, direct
À
transition-metal-catalyzed C H amination has an advantage
À
over nitrene C H insertion, since the latter requires preacti-
vation of amine.[12a,13]
À
There are hitherto two approaches used to attain C N
[14]
À
bond formation by direct C H bond functionalization.
À
The difference lies in the C N bond-forming step from the
M+n intermediate, which can either be achieved by using an
+(n+2)
À
À
À
oxidant that delivers a C M
N species allowing C N
bond formation by reductive elimination to reform M+n, or
alternatively, the M+n intermediate can directly undergo re-
ductive elimination forming M0, and an oxidant is required
to bring the transition metal back to the M+n oxidation
state. The majority of the examples published involve the
II
À
Scheme 1. Cu -catalyzed intramolecular C H amination.
native synthetic method for the synthesis of pyrido
a]benzimidazoles with substituents in the benzene ring (C
ring) should be accessible by intramolecular transition-
[1,2-
use of a PdII catalyst in combination with CuII
ACTHNGUTERN(NUG OAc)2 as re-
oxidant of Pd0, in either an equimolar amount or catalytic
amount when used in combination with O2. Only two proce-
dures are based on CuII catalysis, one in the presence and
one in the absence of acetic acid.[14g,i] We decided to focus
on CuII catalysis to achieve ring closure of N-arylpyridin-2-
amine (3) as only one transition metal is required and O2
can be used for the reoxidation. The use of O2 is beneficial
as it is the greenest oxidant available to chemists, and an ox-
idation of an M+n intermediate would require stronger and
less sustainable oxidants.
À
metal-catalyzed C N bond formation in N-(2-chloroaryl)-
pyridin-2-amines, based on chemistry recently developed in
our research group.[9] These substrates themselves are easily
available through SNAr or selective Pd-catalyzed amina-
tion[10] of 2-chloropyridine with 2-chloroanilines.[11] If a syn-
[a] Dr. K.-S. Masters, T. R. M. Rauws, Dr. A. K. Yadav,
Prof. Dr. B. U. W. Maes
N-Phenylpyridin-2-amine (3a) was chosen as the test sub-
Organic Synthesis, University of Antwerp
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
Fax : (+32)32653233
strate for this transformation, using CuII
ACHTUNGTRENNUNG
E-mail: bert.maes@ua.ac.be
A
[b] Prof. Dr. W. A. Herrebout, Prof. Dr. B. Van der Veken
Cryospectroscopy, University of Antwerp
(Table 1, entry 1). The addition of acid proved beneficial as
one equivalent of acetic acid gave a higher consumption of
substrate (53%, Table 1, entry 3). When a catalytic amount
of acid (15 mol%) was used, a similar conversion was ob-
Groenenborgerlaan 171, 2020 Antwerp (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100574.
Chem. Eur. J. 2011, 17, 6315 – 6320
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6315

À
Table 1. Optimization of the intramolecular C H amination of N-phenyl-
pyridin-2-amine (3a).
(Table 1, entries 12 and 13) promoted the reaction to a sig-
nificantly lesser extent. Other copper salts (Table 1, en-
tries 14 and 15) failed to effect the conversion.
Subsequently, the influence of the structure of the acid
additive was investigated (Table 1).[17] Other carboxylic acids
such as butyric, pivalic, and benzoic acid gave essentially the
same conversion of 3a to 4a after a reaction time of 18 h
(Table 1, entries 16–18). Stronger acids such as trifluoroace-
tic acid can also be used but only in a catalytic amount
(Table 1, entries 19 and 20). Also non-carboxylic acid con-
taining acids are allowed (Table 1, entries 21 and 22), but
again when the acid is strong the use of a stoichiometric
amount is detrimental (Table 1, entry 23). As the conversion
data in Table 1 do not take into account side reactions of
the substrate 3a, we looked at isolated yields in the pres-
ence of acetic acid and several substituted benzoic acids pos-
sessing different pKa values.
Interestingly, a significant difference in the isolated yields
and amount of recovered substrate was found for the stud-
ied acids (acetic acid: 60% 4a, 10% 3a; 4-methoxybenzoic
acid (pKa: 4.47): 52% 4a, 30% 3a; benzoic acid (pKa: 4.17):
75% 4a, 16% 3a; 3,4,5-trifluorobenzoic acid (TFBA) (pKa:
3.46): 92% 4a, no 3a).[18] These results indicate that the se-
lectivity of the reaction is dependent on the type of acid ad-
ditive used. In the case of acetic acid and 4-methoxybenzoic
acid, the missing mass balance is 22% and 10%, respective-
ly, in comparison with the experiment involving 3,4,5-tri-
fluorobenzoic acid (Table 2, entry 2). 3,4,5-Trifluorobenzoic
acid is clearly a superior additive, additionally providing a
faster reaction and full conversion of 3a. In the case of less
acidic additives (acetic, 4-methoxybenzoic, and benzoic
acid), starting material was recovered. A similar selectivity
trend was observed for N-(4-fluorophenyl)pyridin-2-amine
(3b) with the yield of the desired compound increased with
decreasing pKa value (4-methoxybenzoic acid: 38% 4b;
benzoic acid: 68% 4b; 3,4,5-trifluorobenzoic acid: 75%
4b). In this case, however, no starting material remained.
Ultra performance liquid chromatography (UPLC) analysis
of the crude reaction mixtures showed various amounts of
substrate dimers depending on the acid used. We therefore
currently believe that the pKa related selectivity of the acid
can be rationalized by the control of competing intra- and
Entry Solvent
Catalyst
Additive mol%
T
Conv.
[8C] [%][a,b]
1
2
3
4
5
6
7
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO/1%
H2O v/v
Cu
Cu(OAc)2·H2O AcOH
Cu(OAc)2·H2O AcOH
Cu(OAc)2·H2O
Cu(OAc)2·H2O AcOH
Cu(OAc)2 AcOH
Cu(OAc)2·H2O AcOH
(OAc)2·H2O
–
–
15
100
–
100 43
100 47
100 53
120 82
120 92
120 65
120 90
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
T
–
T
15
15
15
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
8
DMSO/10% Cu
(OAc)2·H2O AcOH
15
120 19
120 17
H2O v/v
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
Cu
Cu
Cu(O2CCF3)2
Cu(OTf)2
A
100
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
A
120
0
N
AcOH
AcOH
AcOH
AcOH
AcOH
15
15
15
15
15
120 84
120 28
120 29
120
120
120 91
120 92
120 90
120 95
120 17
120 92
120 89
AHCTUNGTRENNUNG
CuSO4
CuCl2
Cu(OH)2
5
0
Cu
Cu(OAc)2·H2O PivOH
Cu(OAc)2·H2O BzOH
Cu(OAc)2·H2O TFA
Cu(OAc)2·H2O TFA
Cu(OAc)2·H2O NH4Cl
Cu(OAc)2·H2O HCl
Cu(OAc)2·H2O HCl
Cu(OAc)2·H2O TFBA
A
T
15
15
15
100
15
15
AHCTUNGTRENNUNG
N
G
AHCTUNGTRENNUNG
N
E
100
15
120
2
AHCTUNGTRENNUNG
120 15[c,d,e]
[a] Reactions were performed under an atmosphere of O2 (ca. 1 atm) at a
concentration of 0.5m in standard (undried) DMSO, unless otherwise in-
dicated with 15 mol% CuII salt. [b] Conversion of 3a to 4a determined
by HPLC after 18 h. [c] Under an Ar atmosphere, after 24 h. [d] Con-
firmed by 1H NMR spectroscopy of the crude reaction mixture. [e] With
AcOH (15 mol%) in either DMSO or DMF under an Ar atmosphere,
similar results were obtained.
served as with one equivalent (Table 1, entry 2). At higher
temperature (1208C) a better conversion was achieved
(Table 1, entries 4 and 5). Because the addition of 15 mol%
acid was optimal, we decided to perform further optimiza-
tions with a catalytic amount of acid. Interestingly, anhy-
drous CuII
ACHTUNGTRENNUNG(OAc)2 proved less effective than the monohy-
À
drate (Table 1, entry 6), and the reaction proved not to be
sensitive to the presence of 1% v/v water (Table 1, entry 7),
but a higher amount was detrimental (Table 1, entry 8). The
use of dimethoxyethane, dioxane, acetonitrile, 1-propanol,
or toluene as solvent failed to effect the cyclization. Only
solvents in which a S=O or C=O moiety was present al-
lowed the reaction (DMSO, sulfolane, NMP, DMA, and
DMF).[15] Among these DMSO and DMF gave the highest
conversions, and the former was arbitrarily chosen for fur-
ther studies.[15] Interestingly, the use of base instead of acid
(acetate and carbonate) had an inhibitory effect on the con-
version (Table 1, entries 9 and 10), and bidentate amine li-
gands[16] completely shut the reaction down. CuII catalysts
with carboxylate counterions performed well (Table 1, en-
tries 5 and 11), whilst those with a sulfonate or sulfate group
intermolecular C N bond formation. This will be studied in
future research.
The results obtained for substrates 3a and 3b clearly indi-
cated that the use of a catalytic amount of 3,4,5-trifluoro-
benzoic acid is superior and therefore the scope was as-
sessed for these optimized reaction conditions [CuII-
.
(OAc)2 H2O
(15 mol%),
3,4,5-trifluorobenzoic
acid
(15 mol%), DMSO, 1208C] for a set of substituted N-phe-
nylpyridin-2-amines (Table 2). Both electron-donating
(OMe, entry 8) and electron-withdrawing groups (Cl,
entry 11; COOEt, entry 12; CF3, entry 16) in the para posi-
tion of the benzene ring were tolerated, although the ethox-
ycarbonyl and trifluoromethyl group required a 20% load-
ing of catalyst (Table 2, entries 13 and 17). With 15 mol%
CuII
ACHTNUTRGNE(UNG OAc)2 at least 15% of substrate 3 could be recovered.
6316
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6315 – 6320

PyridoACHTUNGTRENNUNG[1,2-a]benzimidazoles
COMMUNICATION
À
Table 2. Intramolecular C H amination of N-arylpyridin-2-amines (3).
Cl substitution process exclusively, and only traces
À
of product due to the C H amination pathway
were detectable. Cs2CO3 proved more effective
than CsOAc, and the use of a CuII-stabilizing ligand
(trans-1,2-diaminocyclohexane (DACH))[21] provid-
ed a means by which the catalyst loading could be
reduced to 5%.[15] Application of these optimal
conditions to 2,6-dichloro substrate 5c gave 6-
Entry
Catalyst
and acid
loading
Acid
R
Product
R
Yield [%][a,b]
1
2
3
4
5
6
7
8
15
15
15
15
20
15
20
15
15
15
15
15
20
15
20
15
20
AcOH
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
TFBA
H
H
4-F
3-F
3-F
2-F
2-F
4-OMe
3-OMe
2-OMe
4-Cl
4-CO2Et
4-CO2Et
3-CO2Et
3-CO2Et
4-CF3
4-CF3
4a
4a
4b
4c + 4c’
4c + 4c’
4d
4d
4e
4 f + 4 f’
4g
4h
4i
4i
4j + 4j’
4j + 4j’
4k
H
H
8-F
7- + 9-F
7- + 9-F
6-F
60
92
chloropyridoACTHNUTRGNEUNG[1,2-a]benzimidazole (4m), in good
75
yield (entry 3, Scheme 2), and without observable
hydrodechlorination of 5c and 4m. The latter con-
ditions also provided the 9-fluoro derivative 4c’
from 5d (entry 4, Scheme 2) in 83% isolated yield.
This compound could only be obtained as a minor
compound by the direct amination of 3c (Table 2,
58[d]
79 (12:1)[c,e]
62[d]
6-F
98
60
8-OMe
7- + 9-OMe
6-OMe
8-Cl
8-CO2Et
8-CO2Et
7- + 9-CO2Et
7- + 9-CO2Et
8-CF3
9
70 (13:1)[c,e]
10
11
12
13
14
15
16
17
59
À
À
entry 5). The C Cl and the C H functionalization
process are thus complementary, in conjunction
providing selective access to 6-, 7-, 8-, and 9-substi-
78
46[d]
57
31[d]
55 (26:1)[c]
71[d]
80
tuted benzo
We next sought to apply our methodology to the
synthesis of the benzimidazo[1,2-a]quinoline core 7
ACHTUNGTREN[NUNG 1,2-a]imidazoles.
AHCTUNGTRENNUNG
4k
8-CF3
(Scheme 3), which has antitumor properties. N-Phe-
nylquinoline-2-amine (6) was accessed in 99% iso-
lated yield by heating 2-chloroquinoline neat with
[a] Yields refer to isolated products with a purity of >95% by 1H NMR analysis.
[b] Cu
(7:9). [d] At least 15% substrate could be recovered. [e] The regioisomers were ob-
tained as separate compounds.
.
(OAc)2 H2O (n mol%), acid (n mol%), DMSO, O2, 24 h. [c] Regioisomer ratio
À
1.5 equivalents of aniline. The C H amination of 6
was performed by using the optimized reaction con-
All substituents in meta or ortho positions (Table 2, en-
tries 5, 7, and 15), except the methoxy group (Table 2, en-
tries 9 and 10), also required this higher loading. The meta-
substituted substrates proved interesting, as in all cases a
high regioselectivity for the 7- over the 9-substituted pyrido-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
able to access the minor component from the cyclization of
À
meta-substituted substrates (3) by blocking one C H func-
tionalization position with a chloro substituent, which could
later be removed by hydrodechlorination (Scheme 2). N-(2-
Chloro-5-methoxyphenyl)pyridin-2-amine (5a) was chosen
À
as the model substrate. A C Cl amination pathway was
À
found to be competitive under the intramolecular C H ami-
nation reaction conditions (entry 1, Scheme 2). Such cycliza-
tions mediated by copper have been reported, however
these are always promoted by basic rather than acidic condi-
tions.[19–20]
Scheme 2. Cyclization of N-(2-chloroaryl)pyridin-2-amines (5). [a] Incom-
plete conversion.
With the simplified 2-chloro substrate 5b (entry 2,
Scheme 2) a similar behavior was observed. A substrate
À
with a C Cl moiety located remotely from the site of the
CuII coordination, as in substrate 3h, was not effected by
À
the C H amination reaction conditions (Table 2, entry 11).
À
The intramolecular C2 Cl activation is therefore directed,
requiring less energy than an intermolecular process. This
À
rationalizes why a deactivated C Cl can react so easily with-
out requiring electron-rich ligands. A change of conditions
À
from catalytic acid to stoichiometric base promoted the C2
Scheme 3. Synthesis of anti-cancer core 7.
Chem. Eur. J. 2011, 17, 6315 – 6320
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6317

B. U. W. Maes et al.
ditions, smoothly delivering 7[22,3a] in 80% yield. This cycli-
zation is notable as it takes place at an o,o-disubstituted ni-
trogen.
To gain an insight into the mechanism, both intra- and in-
termolecular kinetic isotope effects (KIEs) were determined
(Scheme 4). The intramolecular KIE, determined through
the reaction is executed under oxygen-free conditions
(Table 1, entry 24). This excludes a mechanism via dispro-
portionation of two CuII complexes, yielding a CuI and CuIII
species of which only one will act as the catalyst. Occur-
rence of a disproportionation process therefore would deliv-
er a conversion to product of a maximum of half the copper
loading, which is clearly not in accordance with our experi-
mental finding. The observation that reaction product can
be formed under an oxygen-free atmosphere shows that
oxygen acts as the final electron acceptor (a two electron
oxidant) and regenerates the CuII species.[28] A syn b-hydride
elimination as ꢁHꢂ-removal process is consistent with the ki-
netic isotope effect experimentally observed (Scheme 4).[29]
A concerted metallation–deprotonation /CMD) mechanism
is unlikely as substrate 3c containing a meta fluoro substitu-
ent preferentially cyclizes in C6 of the aniline moiety.
Taking into account that a fluorine atom is small, a CMD
mechanism would be consistent with a preferential C2 direct
functionalization process.[23] A C H activation process via B
À
is in agreement with the higher kobsd value measured for sub-
strate 3b (0.37) versus 3a (0.19),[30a] since DFT calculations
performed on the respective intermediates B clearly point
to a lower activation energy for R1 =4-F (75.6 kJmolÀ1) than
for R1 =H (87.0 kJmolÀ1).[15,30] The observation that more
acidic benzoic acids give faster reactions can be rationalized
by taking into account that these give more electrophilic
(RCO2)2CuII species, and consequently a higher concentra-
tion of B, which is involved in the rate-limiting step of the
reaction.
Scheme 4. Determination of intra- and intermolecular KIE.
competitive H/D cyclization from 2,4-dideutero-N-phenyl-
À
pyridin-2-amine (8a), was 3.5, showing that the C H bond
rupture is a kinetically relevant process.[23] The intermolecu-
lar KIE was determined to be 3.1 through comparison of a
reaction of substrate 3a and the 2,3,4,5,6-pentadeuterated
À
analogue 8b, revealing that the C H bond breakage is in-
volved in the rate-determining step of the catalytic cycle.[24]
A possible rationalization of the mechanism is presented
in Scheme 5. Coordination of (RCO2)2CuII with substrate 3
(A), followed by intramolecular nucleophilic attack of the
amidine on the activated arene (h2 p complex) delivers the
s-alkyl CuII species B.[25] Subsequent b-hydride elimination
While this work was nearing completion Zhu and Zhang
reported another catalytic system for the direct intramolecu-
lar C H amination of N-arylpyridin-2-amines.[31] They
À
showed the use of a combination of a Cu
A
.
AHCTNUGTER(GNNNU NO3)3 9H2O catalyst to be essential to achieve high yields
of the target compounds. The unique role of the FeIII is be-
lieved to lie in its ability to form an electrophilic CuIII spe-
cies, beneficial for the SEAr mechanism. The catalytic
system we disclose here results from a fundamental study of
the role of the acid additive on the reaction (rate and selec-
tivity). By using a catalytic amount of 3,4,5-trifluorobenzoic
gives
4
and RCO2CuIIH.[26] Reductive elimination of
RCO2H from RCO2CuIIH yields Cu0, which can be reoxi-
dized to (RCO2)2CuII with O2 and RCO2H.[27] This mecha-
nism proceeding via a CuII/Cu0 catalytic cycle is in agree-
ment with the 1:1 CuII/product stoichiometry obtained when
acid, high yields of target compound can be achieved with-
.
out the requirement of co-catalytic Fe
N
trast to the CuII/FeIII system, our methodology allows
smooth cyclization of electron-deficient substrates, as exem-
plified by a fluoro group in the ortho (3d) and meta (3c) po-
sition of the phenyl ring. Substrates with a sterically hin-
dered pyridine nitrogen atom, as in N-phenylquinoline-2-
amine (6), were also viable substrates using 3,4,5-trifluoro-
benzoic acid additive. The Zhu and Zhang procedure re-
quired a stoichiometric amount of CuACTHNUTRGENUN(G OAc)2 to achieve sim-
ilar yields for products common to both studies, namely 3c,
3d, and 6. Moreover, for substrates 3c and 6 a reaction time
of more than 65 h was necessary. For other substrates our
method requires generally a lower loading of copper catalyst
and shorter reaction times to achieve similar yields.
In summary, we have developed new and efficient syn-
thetic protocols for pyridoACTHNGUTERNNU[G 1,2-a]benzimidazoles based on
À
Scheme 5. Proposed mechanism for the intramolecular C H amination of
3.
6318
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 6315 – 6320

PyridoACHTUNGTRENNUNG[1,2-a]benzimidazoles
COMMUNICATION
À
À
[5] Rifaximin, containing the pyridoACHNUTGRTNEUNG[1,2-a]benzimidazole core, is a
C H and C Cl functionalization. Together, the two methods
represent a ꢁsynthetic kitꢂ for expedient access to 6-, 7-, 8-,
unique gastrointestinal-selective antibiotic for enteric diseases: H. L.
Koo, H. L. Dupont, Curr. Opin. Gastroenterol. 2010, 26, 17–25.
[6] Alteration of the lifespan of eukaryotic organisms: D. F. Goldfarb
(University of Rochester, Rochester), US 2009163545, 2009.
[7] Solubility: 94 mg of 4a dissolves in 100 mL of distilled H2O at 208C;
592 mg at 1008C.
and 9-substituted pyridoACTHUNRGTNE[NUG 1,2-a]benzimidazoles in good to ex-
cellent yields. In the C H amination reaction an unprece-
dented influence of the type of acid on the catalysis has
been identified.
À
[8] Fluorescence: a) E. N. Smirnova, T. V. Onschenskaya, V. P. Zvolin-
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Experimental Section
À
General procedure for the C H amination (conditions a, b, and c): Sub-
strate 3 (0.50 mmol), Cu
A
15 mol%; conditions c: 0.1 mmol, 20 mol%), additive (conditions a:
acetic acid, 0.075 mmol; conditions b: 3,4,5-trifluorobenzoic acid (3,4,5-
TFBA), 0.075 mmol; conditions c: 3,4,5-TFBA, 0.1 mmol), and solvent
(DMSO, 1.00 mL) were added to a 10 mL microwave vial. The resulting
reaction mixture was stirred under a flow of oxygen for 5 min prior to
sealing under oxygen with a pressure cap, then supplied with additional
oxygen by a balloon and being heated by a temperature-calibrated alumi-
num hotplate[15] at 1208C. Depending on the reaction, samples were
taken at the designated times by using a syringe/needle (HPLC/UPLC
conversions), or the reaction was run to the stated time and worked up
with isolation of reaction product(s) 4 (and recovered substrate 3).
Workup: The vial was unsealed and the reaction mixture taken up in
CH2Cl2 (50 mL per mmol 3), then washed with concentrated
NH4OH(aq)/saturated brine (3:2, 50 mL per mmol 3). The wash was re-
peated, then the organic phase was dried over MgSO4 and the volatiles
removed under reduced pressure. The resulting residue was purified by
column chromatography on silica gel by eluting with CH2Cl2, then gradi-
ent CH2Cl2/ammonia in MeOH (7m) (199:1, 124:1, 99:1, 66:1, 49:1) to
deliver the isolated product (and remaining substrate, if applicable).
À
[12] For selected reviews dealing with C H functionalization, see: a) F.
Collet, R. H. Dodd, P. Dauban, Chem. Commun. 2009, 5061–5074;
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Chem. 2009, 121, 5196–5217; Angew. Chem. Int. Ed. 2009, 48, 5094–
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5883; e) L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem.
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Acknowledgements
This work was financially supported by the University of Antwerp
(BOF), the Fund for Scientific Research-Flanders (FWO-Flanders), the
Institute for the promotion of Innovation by Science and Technology in
Flanders (IWT-Flanders) (PhD scholarship for T.R.M. Rauws), and the
Hercules Foundation.
À
À
À
Keywords: catalysis · C H activation · C H amination · C
H functionalization · copper
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Received: November 21, 2010
Revised: February 27, 2011
Published online: April 20, 2011
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6320
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