Copper-mediated multiple C-H functionalization of aromatic N-heterocycles: Bromoamination of indoles and pyrroles

Article abstract of DOI:10.1021/om300553b

A copper-mediated bromoamination of aromatic N-heterocycles has been achieved using oxime esters as the N-reagents under mild conditions (ca. 70 °C). The reaction with N-alkyl indoles proceeds regioselectively to produce the 2-amino-3-bromo indole derivatives as confirmed by X-ray crystallographic analysis of the bromoaminated product, 3aa-Br. With N-methylpyrrole both the monobromoaminated and dibromoaminated products were produced by this method.

Full text of DOI:10.1021/om300553b

Article
pubs.acs.org/Organometallics
Copper-Mediated Multiple C−H Functionalization of Aromatic
N‑Heterocycles: Bromoamination of Indoles and Pyrroles
Alex John and Kenneth M. Nicholas*
Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, 101 Stephenson
Parkway, Norman, Oklahoma 73019, United States
S
* Supporting Information
ABSTRACT: A copper-mediated bromoamination of aro-
matic N-heterocycles has been achieved using oxime esters as
the N-reagents under mild conditions (ca. 70 °C). The
reaction with N-alkyl indoles proceeds regioselectively to
produce the 2-amino-3-bromo indole derivatives as confirmed
by X-ray crystallographic analysis of the bromoaminated
product, 3aa-Br. With N-methylpyrrole both the monobromoaminated and dibromoaminated products were produced by
this method.
tion of azoles and other acidic arenes has been achieved in the
presence of a base under transition metal catalysis.20
INTRODUCTION
■
Transition metal promoted aromatic C−H bond functionaliza-
tion that involves electrophilic metal catalysis to induce C−H
bond cleavage has emerged as a promising alternative to
classical methods of preparing functionalized arenes.1 This new
methodology of installing functional groups on the aryl
skeleton is greener,2 as it obviates the need for prefunction-
alized substrates and, hence, the resulting waste during
synthesis, yet presently suffers from several limitations. The
more often encountered ones are the need for a directing
group, which dictates the regiochemistry of the functionaliza-
tion,3 and the use of catalysts derived from expensive second-
or third-row late transition metals such as Pd,4 Pt,5 Ru,6 Rh,7
Ir,8 and Au.9 While new reports of C−H functionalization using
late metals continue to emerge, growing concerns regarding
their toxicity and cost-effectiveness have prompted interest in
the use of cheap, benign, and readily available first-row metals
such as Fe and Cu.10 Although copper-promoted reactions are
mostly proposed to proceed via a single-electron transfer
process11 or a Cu(II)/Cu(0) pathway,12 of late the
intermediacy of highly electrophilic d8 Cu(III) intermediates
has also been suggested.13
The C−H amination reaction, which allows direct access to
aromatic/heteroaromatic amines from the corresponding
arenes/heteroarenes, is particularly significant owing to the
ubiquitous presence of the amine functionality in pharmaceut-
icals, specialty chemicals, and biologically important mole-
cules.14 Analogous to other C−H functionalizations, the C−H
amination reactions developed to date also rely heavily on the
use of precious metal catalysts and prefunctionalized,
coordinating substrates.15 As the C−H amination reaction
falls into the broad category of oxidative coupling, successful
catalysis requires the use of either a stoichiometric oxidant16 or
more oxidized N-reagents such as hydroxylamine derivatives,17
chloramines,18 or oxycarbamates.19 Additionally, C−H amina-
Our continuing interest in the discovery of new, more
practical catalyst and N-reagent combinations for effecting
selective C−H amination reactions21 led us to consider
developing new methods for the amination22 of indoles,
which are widely represented in therapeutic drugs and natural
products.23 We were particularly fascinated by recent reports of
C−H arylation of indole24 and other arenes25 putatively
involving highly electrophilic (aryl)2Cu(III)X intermediates.
Additionally, Liebeskind et al.26 have reported on the amination
of boronic acids and organostannanes presumed to involve an
(imino)Cu(III)(OAc)X intermediate, produced by the oxida-
tive addition of O-acyl ketoximes to Cu(I)(2-thiophene
carboxylate). Also relevant to our objective is the recent report
by Li and co-workers of a Cu-catalyzed C-2 selective oxidative
amidation of indoles.27 The potential of oxime acetates as
aminating agents has been realized in Hartwig’s Pd-catalyzed
intramolecular amination of arenes to produce indoles.28 On
the basis of these precedents, we reasoned that with a suitable
Cu(I) precursor it would be possible to generate an
electrophilic (imino)Cu(III)(OAc)X species, capable of effect-
ing C−H amination of indole (Scheme 1).
Herein we disclose the discovery of an unprecedented
copper-mediated C−H difunctionalization, namely, haloamina-
tion, of the N-heterocycles indole and pyrrole, using
benzophenone O-acetyloxime, a cheap and readily available
N-reagent.
RESULTS AND DISCUSSION
With the intent of developing a new methodology for
synthesizing aminoindoles by C−H amination we chose to
■
Special Issue: Copper Organometallic Chemistry
Received: June 18, 2012
© XXXX American Chemical Society
A
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Scheme 1
Scheme 2
focus on Cu(I) catalysts and use oxime esters as the N-reagents,
which could operate via a Cu(III)-imino intermediate. We
began our investigation by attempting the amination of N-
methylindole (1a) with benzophenone O-acetyloxime (2a)
using {Cu(I)OTf}2·toluene (20 mol %) as the copper source in
CH3CN at 70 °C. However, to our disappointment we did not
observe any conversion of 1a, while the N-reagent was fully
consumed; benzophenone azine (5a) was identified in the
reaction mixture. With various other Cu(I) salts, e.g.,
Cu(CH3CN)4PF6, Cu2O, and Cu(2-thiophene carboxylate),29
similar results were obtained. Interestingly, when Me2S·CuBr
(20 mol %) was used as the copper source, we isolated the
azine 5a, N-methyl-3-bromoindole 4a (∼10%), and the
yellowish-orange compound 3aa-Br (Scheme 2). Analysis of
3aa-Br by ESI-MS suggested that the compound included both
a bromo (−Br) and a benzophenone imine (−NCPh2)
moiety on the indole skeleton (m/z = 389). Surprisingly, the
1H NMR spectrum of 3aa-Br was devoid of C-2 or C-3 proton
resonances of an indole skeleton. The identity and
regiochemistry of the bromoaminated indole product, 3aa-Br,
was confirmed as 3-bromo-2-diphenylimino-N-methylindole by
X-ray crystallography (Figure 1 and Supporting Information).
We note that Liu et al. recently reported a related
chloroamination of indole by N-alkyl chlorosulfonamides with
palladium and copper cocatalysts and stoichiometric quantities
of Ag2CO3.30
Excited by the discovery of the bromoaminated product 3aa-
Br, we reasoned that since its formation requires a
stoichiometric amount of bromide, we could potentially render
the reaction catalytic by supplying bromide from an external
source. Toward this end we conducted reactions that included
equivalent amounts of bromide salts, including NaBr, LiBr,
KBr, and Bu4NBr. However, no significant improvement in the
yield of 3aa-Br resulted. Interestingly, we observed that 1a was
fully consumed during these reactions, and we could trace its
fate to 3-bromo-N-methylindole, 4a. Recent reports31 on
Cu(II)-catalyzed 3-bromination of indole led us to reason
that we could be generating Cu(II) in our reaction, which
impedes the desired bromoamination reaction.32
Being unable to achieve catalytic turnover in the bromoami-
nation reaction, we focused on optimizing the stoichiometric
reaction. Accordingly, the stoichiometric reaction was improved
with a batchwise addition of a 2:1 ratio of N-reagent/[CuX] to
obtain a 58% yield of 3aa-Br along with 42% of 4a.33 Several
attempts were made to improve the selectivity of the reaction in
favor of bromoamination. A screening of reaction solvents
showed that the indole conversion and the bromoaminoindole/
bromoindole selectivity decreased in the order acetonitrile >
THF > toluene > t-BuOH ≫ DMSO. Inorganic base additives
such as Cs2CO3 and KOAc, which were found to be crucial for
the related palladium−copper-catalyzed chloroamination re-
action,30 completely suppressed the bromoamination reaction
(Table 2). Similarly, the inclusion of various N-donor ligands,
including bipyridine and electron-poor pyridine ligands (entries
4−6), provided lower conversions and yields of 3aa-Br.
From our knowledge that 4a is produced only by CuBr2, we
reasoned that if we could sequester the Cu(II) generated during
the reaction or reduce it in situ to Cu(I), we might be able to
promote the formation of 3aa-Br. In this respect, we explored
the effect of established Cu(II) complexing agents and reducing
agents in the bromoamination reaction. Among the additives
screened, sodium citrate showed comparable yields, but others
resulted in lowered selectivity (Table 1, entries 7−10).
Similarly, of the reductants studied, Cu powder and NaHSO3
furnished comparable yields but no significant improvement.
To determine the effect of varying the N-reagent on the
bromoamination/bromination selectivity and the reaction
scope with respect to the N-reagent, we employed several
electronically modified oxime esters (Table 2). Most of the
modifications to the compounds resulted in reduced yields and
selectivity. The only N-reagents that produced appreciable
quantities of the bromoaminated product were the benzophe-
Figure 1. X-ray ORTEP structure of 3aa-Br.
B
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a
Table 1. Additive Effects on the Bromoamination of N-Methylindole (1a)
a
Reaction conditions: N-methylindole (0.013 mmol), oxime ester (0.026 mmol), and MeS·CuBr (0.013 mmol) in 2 mL of CH3CN, 70 °C, 16 h.
b
1
Conversions and selectivity determined by H NMR spectroscopy. Produced iodoaminated product 3aa-I.
none O-benzoyloxime (2c) and the 4,4′-dimethoxybenzophe-
none O-acetyloxime (2e). No bromoamination product was
observed using the dinitrobenzophenone O-acetyloxime (2f),
while the fluoren-9-one oxime (2g), which is electronically
similar to 2a, produced only trace amounts (ca. 5%) of the
corresponding bromoaminated product.
proton doublets (J = 6 Hz) at 4.6 and 5.9 ppm for 6aa-Br is
indicative of a 2,3- or a 2,5-substitution pattern. On the basis of
NMR correlation studies (gHMBC, C−H 2-3 bond correlation;
see Supporting Information) and considering the typical C-2
attack by electrophiles on pyrroles34 and the proven indole
bromoamination regioselectivity, we assign the structure of 6aa-
Br as the 2-bromo-3-amino derivative and, analogously, the
dibromoaminated compound as the 2,5-dibromo-3-amino
derivative (6aa-Br2).
With respect to the scope of the bromoamination reaction,
we found that N-benzylindole and other electronically diverse
indoles could be bromoaminated as well, e.g., to produce the
products 3ba, 3ca, and 3da in moderate yields (Chart 1, yields
in parentheses), along with the corresponding bromoindoles.
The CuX-promoted reaction can also be extended to effect
chloroamination as well as iodoamination, using CuCl and CuI,
producing indole derivatives 3aa-Cl and 3aa-I, respectively.
We also established the viability of the Cu-promoted
bromoamination reaction on a representative pyrrole substrate,
N-methylpyrrole (6a). Operating under typical reaction
conditions, (pyrrole:oxime ester:Me2S·CuBr = 1:2:1, CH3CN,
70 °C), a mixture of a single bromoaminated pyrrole (6aa-Br,
14%) and a single dibromoaminated derivative (6aa-Br2, 39%)
was produced judging by their NMR and mass spectral features
(Scheme 3). Changing the pyrrole:oxime ester:Me2S·CuBr
ratio to 1:1.25:1 allowed us to isolate a 69% yield of 6aa-Br (6%
of 6aa-Br2 was detected by NMR). The presence of two pyrrole
Since the bromoindole 4a was consistently produced in the
copper bromide-mediated indole reactions, we wondered if it is
a precursor to the bromoaminated product 3aa-Br. To further
understand the reaction pathway, we monitored the time-
1
dependent production of both 3aa-Br and 4a by H NMR
analysis. A plot of the NMR-determined conversions for the
consumption of 1a and the evolution of 3aa-Br and 4a (Figure
2) suggests that these two products are generated by
independent pathways. Further evidence of 4a not being a
precursor to 3aa-Br was obtained by subjecting 4a to the
bromoamination reaction, which failed to produce any 3aa-Br.
This observation is in contrast to that made by Liu et al.,30
where the presence of the chlorine atom at the 3-position was
seen to improve the amination efficiency.
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a
Table 2. Screening of Oxime Esters for Bromoamination of N-Methylindole (1a)
a
Reaction conditions: N-methylindole (0.013 mmol), oxime ester (0.026 mmol), and Me2S·CuBr (0.013 mmol) in 2 mL of CH3CN, 70 °C, 16 h.
1
Conversions and selectivity determined by H NMR spectroscopy.
Chart 1. Scope of the Bromoamination Reaction Mediated
by CuX (X = Cl, Br, I)
Scheme 3
have no direct mechanistic evidence on the reaction pathways.
The previously cited precedents and the general features of Cu-
redox chemistry prompt us to speculate that a Cu(III)-imino
species, e.g., Cu(NCAr2)X(OAc), could be involved in the
formation of the haloaminated products, while Cu(II)X2 is
responsible for the halogenation.31 These copper species could
be generated as outlined in Scheme 4A. The novel
haloamination process could proceed via addition of the
electrophilic Cu(III)-imino species to the unsaturated hetero-
Aside from the apparent independence of the processes
leading to the brominated and bromaminated products, we
D
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EXPERIMENTAL SECTION
■
General Procedures. All manipulations were carried out using
Schlenk tube techniques under an inert atmosphere. Cu salts,
acetonitrile, and indole(s) were purchased from commercial sources.
Acetonitrile was freshly distilled over CaH2 and degassed by repeated
freeze−pump−thaw cycles. 1H and 13C{1H} NMR spectra were
recorded on a 300 MHz NMR spectrometer. 2D NMR data were
1
acquired on a 500 MHz spectrometer. H NMR peaks are labeled as
singlet (s), doublet (d), triplet (t), and multiplet (m). Mass spectra
were acquired in the ESI (+) mode. Benzophenone O-acetyloxime
(2a),26 acetophenone O-acetyloxime (2b),40 benzophenone O-
benzoyloxime (2c),26 benzophenone O-tosyloxime (2d),41 4,4′-
dimethoxybenzophenone O-acetyloxime (2e),26 3,4′-dinitrobenzophe-
none O-acetyloxime (2f),26 fluoren-9-one O-acetyloxime (2g),26 N-
benzylindole (1b),42 N-benzyl-5-methoxyindole,43 and N-benzyl-5-
bromoindole43 were synthesized by adapting literature procedures. X-
ray quality crystals of 3aa-Br were grown by slow evaporation from a
1:1 diethyl ether/hexanes solution.
General Procedure for Bromoamination Reactions. To a
stirred solution of N-methylindole (1a) (0.017 g, 0.013 mmol) in dry
and degassed solvent (ca. 2 mL) were added the oxime ester (0.026
mmol), Me2S·CuBr (0.013 mmol), and additive (0.026 mmol), and
the reaction mixture was stirred at 70 °C for 16 h. The reaction
mixture was cooled to room temperature and filtered through a plug of
silica using CH2Cl2 (ca. 5 mL). The filtrate was concentrated under
vacuum, and the residue analyzed by NMR. The crude reaction
mixture was purified by silica gel column chromatography to obtain
the pure products using 20−40% CH2Cl2 in hexane as the elutant. The
Figure 2. Time-dependent reactant/product evolution during the
bromination−bromoamination of N-methylindole (1a).
cycle (Scheme 4B). A similar addition has been supported
computationally35 in the Cu-promoted amidation of indoles27
and accounts for the observed regioselectivity in directing the
Cu-electrophile to the more nucleophilic C-3 of indole,34a,36
delivering the nucleophilic imino unit to C-2. Sequential
elimination of acetic acid and copper hydride would produce
the 3-halo-2-imino products. Alternative pathways such as the
initial addition of an iminyl radical (Ph2CN•) to the indole
skeleton followed by oxidation with Cu(II) and subsequent
electrophilic bromination of the resulting 2-amino indole
product37 can be envisioned, but their distinction must await
future investigations of this novel reaction.
In conclusion, we have discovered a novel and regioselective
heterodifunctionalization method for the aromatic N-hetero-
cycles indole and pyrrole. The bromoimino products will allow
easy access to the respective halo-2-aminoindoles via acidic
hydrolysis.38 Furthermore, the halogen functionality could
enable further synthetic manipulations through cross-coupling
and other substitution reactions.39
1
N-alkyl-3-bromoindoles were identified in the reaction mixture by H
NMR spectroscopy based on literature data.
1
3aa-Br: orange solid (0.028 g, 55%). H NMR (CDCl3, 300 MHz,
3
3
25 °C): δ 7.83 (d, JHH = 8.7 Hz, 2H), 7.55 (t, JHH = 7.5 Hz, 1H),
3
7.45 (t, JHH = 8.4 Hz, 2H), 7.32−7.29 (m, 2H), 7.25−7.21 (m, 5H),
7.14 (t, 3JHH = 6.9 Hz, 1H), 7.08 (t, 3JHH = 7.2 Hz, 1H), 3.69 (s, 3H).
13C{1H} NMR (CDCl3, 75 MHz, 25 °C): δ 172.7, 143.1, 137.9, 135.7,
133.8, 130.5, 129.1, 128.7, 128.3, 127.2, 127.0, 126.1, 119.8, 118.9,
117.3, 107.5, 28.7. HRMS (ESI): calcd for C22H18BrN2 (M + H)+
requires m/z = 389.0653, found m/z = 389.0669.
1
3aa-Cl: orange solid (0.016 g, 36%). H NMR (CDCl3, 300 MHz,
25 °C): δ 7.86−7.80 (m, 3H), 7.57 (t,, 3JHH = 7.2 Hz, 1H), 7.52−7.45
(m, 3H), 7.33−7.30 (m, 1H), 7.26−7.06 (m, 6H), 3.70 (s, 3H).
13C{1H} NMR (CDCl3, 75 MHz, 25 °C): δ 173.5, 142.6, 139.1, 137.1,
134.3, 131.7, 130.3, 129.8, 129.3, 128.4, 128.3, 125.7, 121.1, 119.9,
Scheme 4. Proposed Mechanism for the Bromoamination Reaction
E
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117.7, 108.7, 29.7. HRMS (ESI): calcd for C22H18ClN2 (M + H)+
requires m/z = 345.1159, found m/z = 345.1159.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: knicholas@ou.edu. Tel: +1-(405)-325-3696. Fax: +1-
(405)-325-6111.
3aa-I: red-orange solid (0.029 g, 51%). 1H NMR (CDCl3, 300
3
MHz, 25 °C): δ 7.86−7.80 (m, 3H), 7.57 (t,, JHH = 7.2 Hz, 1H),
7.52−7.45 (m, 3H), 7.33−7.30 (m, 1H), 7.26−7.06 (m, 6H), 3.70 (s,
3H). 13C{1H} NMR (CDCl3, 75 MHz, 25 °C): δ 174.2, 147.8, 139.1,
137.7, 136.7, 136.0, 132.6, 131.8, 130.4, 130.2, 130.0, 129.8, 128.5,
128.4, 128.2, 121.0, 120.2, 108.8, 30.3. HRMS (ESI): calcd for
C22H18IN2 (M + H)+ requires m/z = 437.0515, found m/z = 437.0508.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
■
3ae: orange solid (0.017 g, 29%). H NMR (CDCl3, 300 MHz, 25
°C): δ 7.79 (d, 3JHH = 9.3 Hz, 2H), 7.32 (d, 3JHH = 8.7 Hz, 1H), 7.23−
We are grateful for financial support provided by the National
Science Foundation. A.J. would like to thank Dr. Steven Foster
and Mr. Kieth J. Thomas III for help with ESI-mass spectral
acquisition. We also thank Dr. Douglas Powell for determining
the X-ray structure of 3aa-Br and Dr. Susan L. Nimmo for help
with 2D NMR experiments for determining the structure of
6aa-Br.
3
3
7.05 (m, 5H), 6.96 (d, JHH = 8.7 Hz, 2H), 6.75 (d, JHH = 9.0 Hz,
2H), 3.89 (s, 3H), 3.76 (s, 3H), 3.67 (s, 3H). 13C{1H} NMR (CDCl3,
75 MHz, 25 °C): δ 173.0, 162.6, 160.6, 145.0, 134.8, 132.3, 132.1,
131.3, 129.3, 127.4, 120.7, 119.9, 118.2, 113.7, 113.6, 108.6, 55.7, 55.3,
29.9. HRMS (ESI): calcd for C24H22BrN2O2 (M + H)+ requires m/z =
449.0865, found m/z = 449.0860.
1
3ba: orange solid (0.027 g, 46%). H NMR (CDCl3, 300 MHz, 25
3
3
°C): δ 7.76 (d, JHH = 9.0 Hz, 2H), 7.54 (t, JHH = 7.5 Hz, 1H), 7.43
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3
(t, JHH = 7.5 Hz, 2H), 7.32−7.11 (m, 9H), 6.98 (d, JHH = 7.2 Hz,
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1
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6aa-Br: yellow-orange solid (0.030 g, 69%). 1H NMR (CDCl3, 300
MHz, 25 °C): δ 7.77−7.74 (m, 2H), 7.52−7.49 (m, 3H), 7.38−7.35
(m, 3H), 7.24−7.21 (m, 2H), 5.92 (d, JHH = 4.8 Hz, 1H), 4.65 (d, JHH
= 4.2 Hz, 1H), 3.81 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz, 25 °C):
δ 158.4, 140.3, 138.9, 129.9, 129.6, 128.8, 128.3, 128.2, 127.6, 110.2,
103.1, 102.1, 31.5. HRMS (ESI): calcd for C18H16BrN2 (M + H)+
requires m/z = 339.0497, found m/z = 339.0490.
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6aa-Br2. orange solid (0.019 g, 36%). 1H NMR (CDCl3, 300 MHz,
3
3
25 °C): δ 7.74 (d, JHH = 6.9 Hz, 2H), 7.51 (t, JHH = 6.9 Hz, 1H),
7.44−7.33 (m, 5H), 7.21 (d, 3JHH = 6.0 Hz, 2H), 5.98 (s, 1H), 3.51 (s,
3H). 13C{1H} NMR (CDCl3, 75 MHz, 25 °C): δ 171.4, 139.5, 139.4,
137.3, 131.3, 130.1, 129.8, 129.7, 128.3, 128.2, 111.7, 99.2, 32.6.
HRMS (ESI): calcd for C18H15Br2N2 (M + H)+ requires m/z =
418.9582, found m/z = 418.9576.
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ASSOCIATED CONTENT
■
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̈
S
* Supporting Information
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Spectral data for all new compounds reported and X-ray
collection data for 3aa-Br are available free of charge via the
Internet at http://pubs.acs.org.
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dx.doi.org/10.1021/om300553b | Organometallics XXXX, XXX, XXX−XXX

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dx.doi.org/10.1021/om300553b | Organometallics XXXX, XXX, XXX−XXX