Cu(II)-catalyzed direct and site-selective arylation of indoles under mild conditions

Article abstract of DOI:10.1021/ja801767s

We have developed a new site-selective Cu(II)-catalyzed C-H bond functionalization process that can selectively arylate indoles at either the C3 or C2 position under mild conditions. The scope of the arylation process is broad and tolerates broad functionality on both the indole and aryl unit, which makes it amenable to further elaboration. The mechanism of the arylation reaction is proposed to proceed via a Cu(III)-aryl species that undergoes initial electrophilic addition at the C3 position of the indole motif. We speculate that site of indole arylation arises through a migration of the Cu(III)-aryl group from C3 to C2, and this can be controlled by the nature of the group on the nitrogen atom; free (NH)- and N-alkylindoles deliver the C3-arylated product, whereas N-acetylindoles afford the C2 isomer, both with excellent yield and selectivity. Copyright

Full text of DOI:10.1021/ja801767s

Published on Web 06/11/2008
Cu(II)-Catalyzed Direct and Site-Selective Arylation of Indoles Under Mild
Conditions
Robert J. Phipps, Neil P. Grimster, and Matthew J. Gaunt*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road, Cambridge, U.K. CB2 1EW
Received March 10, 2008; E-mail: mjg32@cam.ac.uk
Transition-metal-catalyzed functionalization of hydrocarbons is
emerging as a versatile strategy for chemical synthesis.1 In particular,
direct catalytic C-C bond formation events on arene motifs have led
to many pioneering advances.2 However, before the potential of C-H
bond functionalization can be realized, these transformations will have
to become more compatible with the delicate functionality that exists
within more complex molecular architectures.3 With this in mind, the
development of direct metal-catalyzed transformations that operate
under ambient and selective reaction parameters2f,g is an attractive goal
for the advancement of chemical synthesis.
We have been engaged in the development of oxidative C-H bond
functionalization programs that utilize electrophilic metal catalysts to
induce C-H bond cleavage via a Friedel-Crafts-type process (1).4,5
Herein, we describe a Cu(II)-catalyzed C-H bond arylation strategy
that enables direct and site-selective indole functionalization. Indoles
that display aryl groups at C2 and/or C3 have demonstrated importance
in a range of therapeutics in addition to a prevalence in natural
products.6 This Cu(II)-catalyzed arylation process does not require
prefunctionalization of the indole, operates under ambient conditions,
uses equimolar amounts of the coupling partners, and is selective for
either the C2 or the C3 position (2).
selective processes seemingly exploit a migratory mechanism to afford
2-arylindoles.7a–c These outcomes present a paradox to the conventional
C3 reactivity of indole, and it has been surprising that few methods
for C3-arylation7h–j under ambient conditions have emerged.
In considering a C-H arylation of indoles, we questioned whether
this might be effected by utilizing highly electrophilic metal catalysts
other than those based on Pd(II) salts.7e By analogy with other d8
species, such as Pd(II) and Rh(I), we reasoned that other d8-configured
metals may enable C-H bond arylation (3). The realization that Cu(III)
would also possess a d8 configuration and carry a +3 charge should
render it more reactive, in line with our electrophilic metalation
hypothesis. Surprisingly, Cu-catalyzed C-H bond functionalization
processes are rare,8 but their use would offer an economic advantage
compared to the more frequently used, but expensive, Pd complexes.
Initially, we were encouraged by reports from Barton and co-workers
who had described how Cu metal, in combination with aryl-Bi(V)
reagents could affect C- and N-arylation reactions.9 We reasoned that
a Cu(I) catalyst could be oxidized in the presence of diaryl-iodine(III)
reagents10 to form a highly electrophilic aryl-Cu(III) intermediate that
would enable a mild arylation process.11
Table 1. Optimization Studies for Cu-Catalyzed C-H Arylation
equiv
of 1a
equiv
of 2, (X)
temp,
°C
yield
3a %
entry
catalyst
base
C3:C2b
1
2
3
4
5
6
1 mol % Cu(OAc)
1 mol % Cu(OAc)2
1 mol % Cu(OAc)2
10 mol % Cu(OAc)2
10 mol % Cu(OTf)2
10 mol % Cu(OTf)2
2
2
1
1
1
1
1.0 (BF4)
1.0 (BF4)
-
rt
rt
10:1 57
11:1 56
-
1.1 (BF4) dtbpy 35 4.5:1 14a
1.1 (BF4) dtbpy 35
1.1 (BF4) dtbpy 35
1.1 (OTf) dtbpy rt
3:1 57a
12:1 69
14:1 72
a Reaction conversion. b Determined by 1H NMR.
At the outset of our studies, we were pleased to find that treatment
of N-methyl indole 1a with [Ph-I-Ph]BF4 (2a) in the presence of 1
mol % of Cu(OAc) gave the arylated indole 3a in moderate yield but
good C3 selectivity under the mild conditions we were targeting (Table
1, entry 1). Interestingly, using Cu(OAc)2 as catalyst also afforded
the C3 product in almost identical yield and selectivity, and due to
ease of handling, we chose to continue our studies with Cu(II) catalysts
(entry 2). The moderate yields of 3a arose from a competitive acid-
catalyzed dimerization of the indole 1a. A range of bases were screened
in order to prevent this deleterious side reaction, and we found the
use of 2,6-di-tert-butylpyridine (dtbpy) prevented indole dimerization,
but at the expense of conversion (entry 3). In order to improve the
conversion, 10 mol % of the Cu catalyst was required, presumably
because the pyridine base binds to the Cu center and reduces its activity.
Interestingly, on addition of dtbpy, the C3 selectivity for the arylation
was greatly diminished (entries 3 and 4). However, we subsequently
In line with an electrophilic metalation strategy, we have previously
reported an oxidative and site-selective Pd(II)-catalyzed C-H bond
alkenylation of the indole5a and pyrrole nuclei.5b Since these reports,
a number of elegant examples of metal-catalyzed indole arylations have
emerged.7 However, it is notable that there are few examples where
indole arylation proceeds under mild conditions. In these cases, the
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8172 J. AM. CHEM. SOC. 2008, 130, 8172–8174
10.1021/ja801767s CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Scope of Cu(II)-Catalyzed Aryl Group Transfer
Table 2. Scope of Cu(II)-Catalyzed C3-Indole C-H Phenylation
entry
R1
R2
X
temp, °C
isolated yield 3 %
1
2
3
4
5
6
7
8
Me
H
H
H
H
H
H
H
H
H
5-OMe
2-Me
6-CO2Me
5-CHO,
5-NO2
5-Br
OTf
OTf
BF4
BF4
OTf
BF4
OTf
OTf
rt
rt
rt
60
60
60
60
35
72 (3a)
74 (3b)
64 (3c)
63 (3d)
85 (3e)
70 (3f)
73 (3g)
75 (3h)
found that the use of Cu(OTf)2 restored the C3:C2 selectivity (to
12-14:1) with either the triflate or the tetrafluoroborate salt of 2 (entries
5 and 6). Therefore, our optimization identified that treatment of indole
1a with 10 mol % of Cu(OTf)2 as catalyst, 1.1 equiv of [Ph-I-Ph]OTf
(2b), and 1.1 equiv of dtbpy in anhydrous dichloromethane at room
temperature afforded the 3-arylindole 3a in 72% isolated yield.
With a set of optimized conditions in hand, we next examined the
scope of the indole motif in the C-H arylation process.12 We found
that both free (NH)-indoles and N-alkyl indoles were smoothly
converted to the 3-phenylindoles (C3:C2, 12-14:1) at room temper-
ature (Table 2, entries 1 and 2). Indoles bearing electron-donating
substituents underwent facile arylation (entries 3 and 4), and the
corresponding indoles with electron-withdrawing groups also delivered
the arylated products, albeit at a higher reaction temperature (entries
5-7). This difference in reactivity between electron-rich and electron-
deficient indoles supports an electrophilic metalation mechanism for
the arylation process.
a BF4 salt at 60 °C. b With 25 mol % of Cu(OTf)2. c Determined by
1H NMR.
Scheme 1. Proposed Catalytic Cycle
In this reaction, only one of the two aryl groups of the symmetrical
diaryl-iodine(III) reagent is utilized in the indole arylation. This would
be problematic when complex aryl groups are required in the process.
To minimize this problem, we designed an unsymmetrical diaryl-I(III)
reagent containing the desired aryl group and a second aryl unit that
would not transfer in the catalytic process. Selective aryl transfer has
been observed in other metal-catalyzed processes as a the result of
poor aryl transfer of a large group (such as mesityl) compared to a
less substituted aryl unit.7a,10 In our Cu(II)-catalyzed arylation we found
that [mesityl-I-Ph]OTf resulted in a 16:1 selectivity for the desired
aryl transfer (Ph over mesityl). However, using a larger “spectator”
group, 2,4,6-tri-isopropylphenyl (TRIP) (2d), resulted in exclusive
transfer of the desired aryl group to give a good yield of 3a (4). It is
notable that most [TRIP-I-Ar]OTf salts can be generated in a one-
step process from commercially available starting materials (4).13
The mechanism of the Cu(II)-catalyzed C-H bond arylation is
proposed to begin with reduction of the Cu(II) catalyst to Cu(I) by
the indole (Scheme 1a). Oxidative addition of the diaryl-iodine(III)
reagent 2b to the Cu(I) salt would generate the electrophilic Cu(III)-aryl
intermediate I that can undergo attack at the C3 position of indole to
II.14 Rearomatization via C-H bond cleavage to III would be followed
by reductive elimination, delivering the product 3 and re-forming the
Cu(I) catalyst.9c,15
Having established C3 reactivity in the Cu(II)-catalyzed C-H
arylation, our attention turned to investigating how we might steer the
reaction to produce the C2 isomer. We speculated that the Cu(III)-aryl
intermediate I would react initially through the C3 position before
migration to C2 and rearomatization to afford the C2-metalated
indole.5a In assessing how to effect this migration, we tested the effect
of acid additives on the reaction. Despite a clear influence, it was not
possible to reverse the selectivity of the arylation.16 Therefore, in order
to further promote a migration mechanism, we reasoned that the use
The scope of the arylation was tested with a range of unsymmetrical
[TRIP-I-Ar]OTf salts, and we were pleased to find that the Cu(II)-
catalyzed process was able to transfer a range of substituted aryl groups
to the indole nucleus to form the C3-regioisomer with excellent
selectivity and in good yield. Electron-rich (entries 1-4), electron-
deficient (entries 5-9), sterically hindered (entries 10 and 11), and
heteroarene aryl motifs (entries 12 and 13) were all readily transferred
via this reaction. Notably, aryl substrates bearing C-Br and eVen C-I
bonds (entries 5-7, Table 3 and entry 8 in Table 2) are unaffected by
the Cu(II)-catalyzed arylation, providing a complementary platform
for further elaboration via conventional Pd(0)-catalyzed cross-coupling.
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C O M M U N I C A T I O N S
Table 4. Cu(II)-Catalyzed C2 Phenylation on N-Acetylindoles
particular, the C3 to C2 migration, and application of Cu(II)-catalyzed
arylation to other systems. This work will be reported in due course.
Acknowledgment. We gratefully acknowledge BBSRC and
GlaxoSmithKline for Industrial Case Award (R.J.P.), the Royal Society
(for University Research Fellowship to M.J.G.), Philip & Patricia
Brown (for Next Generation Fellowship to M.J.G.), and EPSRC Mass
Spectrometry Service (Swansea). We also thank Dr Simon Peace (GSK
Medicines Research Center, Gunnels Wood Road, Stevenage, SG1
2NY, UK) for useful discussion.
entry
R
temp, °C
C2:C3a
isolated yield 5 %
1
2
3
4
H
60
70
60
70
70
70
9:1
8:1
7:1
7:1
6:1
9:1
83 (5a)
76 (5b)
72 (5c)
81 (5d)
61 (5e)
37 (5f)
5-Br
5-OMe
6-CO2Me
5-CHO
5-NO2
5
6b
Supporting Information Available: Experimental data and proce-
dures for all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a Determined by 1H NMR. b Isolated yield at 63% conversion of
indole using 20 mol % of Cu(OTf)2.
References
Table 5. Cu(II)-Catalyzed C2 Arylation of N-Acetylindole
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entry
Ar
C2:C3 (total yield)a
isolated yield 5 %
1
2
3
4
5
6
7
8
9
4-(Me)C6H4
4-(OMe)C6H4
4-(F)C6H4
4-(Cl)C6H4
4-(Br)C6H4
4-(I)C6H4
3-(Br)C6H4
3-(CF3)C6H4
4-(CO2Et)C6H4
4-(NO2)C6H4
6.5:1 (79)
2.6:1 (68)
6:1 (84)
5:1 (83)
6:1 (95)
5.5:1 (66)
7:1 (91)
6.5:1 (90)
4:1 (92)
3:1 (72)
69 (5g)
49 (5h)
72 (5i)
83 (5j)
82 (5k)
56 (5l)
80 (5m)
78 (5n)
73 (5o)
54 (5p)
10
a Ratio determined by 1H NMR.
of an N-acetyl group might render the intermediate iminium ion IV
more likely to accept the migrating C-Cu bond at the C2 position
(IV to V to VI). Moreover, the carbonyl oxygen of the amide may
steer the Cu(III) species to C2 (Scheme 1b).
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We were delighted to find that when N-acetylindole (4a) was treated
with [Ph-I-Ph]OTf (2b) the 2-arylindole 5a was obtained as a 9:1
ratio (91% overall yield) in favor of the C2 isomer (Table 4, entry 1).
In this case, the lower reactivity of the N-acetylindole means that the
temperature of the reaction needs to be increased to 60 °C. Encouraged
by these results, we explored the scope of this C2-arylation process.
A range of electronically diverse indoles worked well in this process,
delivering the C2-arylated products in excellent yield (Table 4).
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The transferring aryl group could also be varied, using a range of
[TRIP-I-Ar]OTf salts, enabling a selection of 2-arylindoles to be
delivered in high yields (Table 5). In particular, the halogen-containing
motifs (F, Cl, Br, and I, entries 3-7) work well in the C2 selective
arylation, again highlighting the potential of this process in combination
with further conventional cross-coupling transformations.
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In summary, we have developed a new site-selective Cu(II)-
catalyzed C-H bond functionalization process that can selectively
arylate indoles at either the C3 or C2 position under mild conditions.
The scope of the arylation process is broad and tolerates many
functionalities on both the indole and the aryl unit. The mechanism of
the arylation reaction is proposed to proceed via a Cu(III)-aryl species
that undergoes initial electrophilic addition at the C3 position of the
indole motif. We speculate that site of indole arylation arises through
a migration of the Cu(III)-aryl group from C3 to C2, and this can be
controlled by the nature of the group on the nitrogen atom. Free (NH)-
and N-alkylindoles deliver the C3-arylated product, whereas N-
acetylindoles afford the C2 isomer, with high yield and selectivity.
We are currently exploring aspects of the reaction mechanism, in
(10) Deprez, N. R.; Sanford, M. S. Inorg. Chem. 2007, 46, 1924.
(11) For a Cu-mediated enolate-indole coupling reaction, see: Richter, J. M.;
Whitefield, B. W.; Maimone, T. J.; Lin, D. W.; Castroviejo, M. P.; Baran,
P. S. J. Am. Chem. Soc. 2007, 129, 12857.
(12) See Supporting Information for details.
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(14) (a) Lockhart, T. P. J. Am. Chem. Soc. 1983, 105, 1940. (b) Balogh-
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(15) Although we cannot rule out a radical mechanism for this process, we
observed that, in the presence of a radical inhibitor, 1,1-diphenylethylene,
the reaction was not affected.
(16) Acid additives and other counterions (in 2) reduce the C3 to C2 selectivity.
See Supporting Information for details.
JA801767S
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8174 J. AM. CHEM. SOC. VOL. 130, NO. 26, 2008