PdII-catalysed C-H functionalisation of indoles and pyrroles assisted by the removable N-(2-pyridyl)sulfonyl group: C2-alkenylation and dehydrogenative homocoupling

Article abstract of DOI:10.1002/chem.201001126

The easily installed and removed N-(2-pyridyl)sulfonyl group exerts complete C2 regiocontrol over the Pd^II-catalysed C-H alkenylation of indoles and pyrroles, affording the corresponding products in good isolated yields (typically ≥ 70%). A remarkable feature of this catalyst system is that it tolerates a wide variety of substituted alkenes, including conjugated electrondeficient alkenes, styrenes and 1,3- dienes, as well as conjugated 1,1- and 1,2-disubstituted olefins. The final reductive desulfonylation affords the C2- substituted, free-NH indoles and pyrroles in good yield. This N-(2-pyridyl)- sulfonyl-directing strategy has also been extended to the development of a protocol for the intermolecular, dehydrogenative homocoupling of indoles, providing 2,2'-biindoles. Mechanistic work based upon reactions with isotopically labelled starting materials and competitive kinetic studies of electronically varied substrates suggests a chelation- assisted electrophilic aromatic substitution palladation mechanism.

Full text of DOI:10.1002/chem.201001126

DOI: 10.1002/chem.201001126
II
À
Pd -Catalysed C H Functionalisation of Indoles and Pyrroles Assisted by
the Removable N-(2-Pyridyl)sulfonyl Group: C2-Alkenylation and
Dehydrogenative Homocoupling
Alfonso Garcꢀa-Rubia, Beatriz Urones, Ramꢁn Gꢁmez Arrayꢂs,* and
Juan Carlos Carretero*[a]
Abstract: The easily installed and re-
moved N-(2-pyridyl)sulfonyl group
dienes, as well as conjugated 1,1- and
1,2-disubstituted olefins. The final re-
ductive desulfonylation affords the C2-
substituted, free-NH indoles and pyr-
roles in good yield. This N-(2-pyridyl)-
sulfonyl-directing strategy has also
been extended to the development of a
protocol for the intermolecular, dehy-
drogenative homocoupling of indoles,
providing 2,2’-biindoles. Mechanistic
work based upon reactions with isotop-
ically labelled starting materials and
competitive kinetic studies of electroni-
cally varied substrates suggests a chela-
tion-assisted electrophilic aromatic sub-
stitution palladation mechanism.
exerts complete C2 regiocontrol over
II
À
the Pd -catalysed C H alkenylation of
indoles and pyrroles, affording the cor-
responding products in good isolated
yields (typically ꢀ70%). A remarkable
feature of this catalyst system is that it
tolerates a wide variety of substituted
alkenes, including conjugated electron-
deficient alkenes, styrenes and 1,3-
À
Keywords: alkenylation
functionalization · nitrogen hetero-
·
C H
cycles
· palladium · protecting
groups
À
Introduction
that aids the interaction with a proximal C H bond. Howev-
er, the synthetic practicality of many of the common direct-
ing groups is compromised if the target molecule does not
contain such functionality. Therefore, an intensive search for
easily attachable and removable directing groups that com-
bine high reactivity and selectivity has motivated the devel-
opment of very efficient protocols based upon N-acyl,[4] O-
acyl,[5] N-carbamoyl,[6] O-carbamoyl,[7] carboxylic,[8] N-
oxide,[9] cyano[10] and hydrosilane[11] directing groups, among
others.[12]
The direct and selective transformation of an unactivated
À
À
C H bond into a C C bond is one of the most powerful
tools to introduce molecular complexity into organic mole-
cules, taking into consideration both chemical efficiency and
environmental impact.[1] Since the pioneering work by both
Murai[2] and Fujiwara and Moritani[3] on C C bond-forming
À
2
À
reactions through the catalytic cleavage of C
(sp ) H bonds,
this research area has undergone rapid development, be-
coming an increasingly viable alternative[1] to traditional
cross-coupling strategies based upon organometallic re-
agents. Because reactivity and regiocontrol are major chal-
lenges in C H functionalisation, most of the reported appli-
cations rely on the use of a metal-coordinating functionality
A very attractive platform for developing new selective
C H functionalisation strategies is the indole skeleton,
which is a key component of many pharmacophores, natural
products and synthetic building blocks.[13] Driven by the bio-
logical importance of 2- and 3-arylindoles, metal-catalysed
À
À
À
oxidative C H arylation reactions of indole derivatives have
attracted considerable attention,[14] of which some efficient
[a] A. Garcꢀa-Rubia, B. Urones, Dr. R. Gꢁmez Arrayꢂs,
Prof. Dr. J. C. Carretero
À
cross-dehydrogenative protocols by double C H functionali-
sation stand out.[15] The intermolecular, oxidative homocou-
pling[16] of indoles can be envisaged to be a useful tool for
the preparation of biindolyl systems, which are a frequently
found structural unit in pharmaceuticals and functional ma-
terials.[17] However, achieving high regiocontrol in the inter-
molecular, dehydrogenative homocoupling of 2,3-unsubsti-
tuted indoles is challenging and has only very recently been
Departamento de Quꢀmica Orgꢂnica
Universidad Autꢁnoma de Madrid (UAM)
Cantoblanco, 28049 Madrid (Spain)
Fax : (+34)914-973-966
E-mail: ramon.gomez@uam.es
juancarlos.carretero@uam.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001126.
9676
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Chem. Eur. J. 2010, 16, 9676 – 9685

FULL PAPER
achieved. In particular, Zhang and co-workers have devel-
oped an efficient method for the assembly of 2,3’-biindolyl
systems with excellent selectivity through the dimerisation
(2-pyridyl)sulfonyl[24] directing group proved to be crucial to
ensuring high reactivity and complete regiocontrol.[25]
of indoles under catalysis by Pd
ACHTUNGTRENNUNG
fluoroacetate) in combination with Cu
G
Results and Discussion
(1.5 equiv), under mild reaction conditions.[18] However, to
the best of our knowledge, the complementary catalytic syn-
thesis of symmetrical 2,2’-biindoles[19] by regiocontrolled, in-
termolecular, dehydrogenative homocoupling (Scheme 1,
right) remains undocumented.
As mentioned, the normal reactivity (non-directed pathway)
of 2,3-unsubstituted indoles in oxidative Heck reactions with
activated olefins (e.g., methyl acrylate) favours the forma-
tion of the 3-alkenylated product.[20,21b,26] Our first aim was
to find a removable N-protecting group that allows function-
À
alisation of the C2 H position of the indole unit over the
À
more nucleophilic C3 H position. A set of potential direct-
ing groups were examined for the reactions of indole (1)
and derivatives 2–10 with methyl acrylate under [Pd-
ACHUTNGRENNU(G CH3CN)2Cl2] catalysis (10 mol%) with CuCAHUTNGTREN(NUGN OAc)2·H2O
(1 equiv) as the reoxidant in dimethylacetamide (DMA) at
1108C (Table 1).[27] As expected under such conditions, the
À
Scheme 1. C2 H functionalisation reactions on C2/C3-unsubstituted
indole derivatives.
Table 1. Effect of N-substitution on the C2 alkenylation of indole with
methyl acrylate.
Metal-catalysed alkenylation is a very appealing strategy
for the direct functionalisation of indoles. Due to the higher
nucleophilic character of the C3 position in indole compared
with the C2 position, C3-alkenylated indoles are normally
formed selectively.[20] In contrast, to the best of our knowl-
edge, only three protocols have been reported so far for
R
Product
C2/C3[a]
Yield
[%][b]
À
direct C H alkenylation at the C2 position of C2/C3-unsub-
stituted indoles (Scheme 1, left).[21–23] Gaunt et al. have de-
scribed a practical method for the PdII-catalysed alkenyla-
tion of NH indoles in which the regioselectivity can be
switched from C3 to C2 by varying the nature of the solvent
and the additives.[21a] Ricci et al. reported PdII-catalysed, re-
giocontrolled C2 alkenylation of indole directed by a non-
1
2
3
4
5
6
7
8
9
H (1)
Boc (2)
Ts (3)
p-Ns (4)
(2-thienyl)SO2 (5)
(8-quinolyl)SO2 (6)
(2-pyridyl)SO2 (7)
(3-pyridyl)SO2 (8)
(2-pyrimidinyl)SO2 (9)
11[c]
12
13
14
15
16
17
18
–
<2:>98
68:32
87:13
85:15
50:50
75 (66)[d]
10
45 (30)[d]
28
À
18
70 (50)[d]
100 (75)[d]
27
À
79:21
À
>98:<2
76:24
removable N-2-pyridylmethyl group.[21b] Recently, Miura,
À
[e]
[e]
À
–
–
–
–
II
À
Satoh et al. disclosed the Pd -catalysed C H alkenylation–
[f]
[f]
À
10
(2-pyridyl)S (10)
–
decarboxylation of indole-3-carboxylic acids to afford selec-
tively 2-alkenyl indoles, in which the carboxyl group blocks
the C3 position and acts as a removable directing group.[21c]
Despite these outstanding advances, there is plenty of room
for improvement, both by increasing the efficiency of the re-
action and enlarging the currently limited scope with regard
to the alkene component and the directing group. For in-
stance, to date, only monosubstituted electrophilic alkenes
(mainly acrylates and acrylamides) have been utilised in the
[a] Determined by 1H NMR spectroscopy of the reaction mixture.
[b] Conversion yield (from the H NMR spectra) [c] C3 H alkenylation
product. [d] In parentheses, isolated yield after chromatography (regioi-
someric mixtures could not be separated). [e] The starting material was
recovered. [f] Complex mixture.
1
À
free indole (1) underwent clean C3 alkenylation with com-
plete regioselectivity (75% conversion, Table 1, entry 1). In
contrast, the N-tert-butoxycarbonyl derivative (N-Boc) 2 led
to a 68:32 mixture of C2/C3 alkenylation products, albeit in
very low conversion (Table 1, entry 2). Both C2 regioselec-
tivity and conversion were enhanced by switching to a N-
tosyl (N-Ts) or N-nosyl (N-Ns) group (Table 1, entries 3 and
4, respectively), albeit at an impractical yield. N-Heteroaryl-
sulfonyl groups had a strong influence both reactivity and
regioselectivity. For example, N-(2-thienyl)sulfonyl indole
(5) led to low conversion (18%) and no regioselectivity (C2/
C3=50:50, Table 1, entry 5), whereas N-(8-quinolyl)sulfonyl
indole (6) showed improved reactivity, yet modest regiose-
lectivity (Table 1, entry 6). Pleasingly, N-(2-pyridyl)sulfonyl
À
C2 H alkenylation of indoles, except for an isolated exam-
ple that involved coupling with styrene.[21c] Furthermore, this
limited alkene versatility is a common trend in many metal-
À
catalysed C H alkenylation reactions of other aromatic and
heteroaromatic compounds.[1,23]
Herein, we describe in detail an efficient and structurally
À
versatile Pd-catalysed C2 H alkenylation of indoles and pyr-
roles, as well as an efficient intermolecular, dehydrogenative
homocoupling of indoles to give 2,2’-biindoles. Some mecha-
nistic studies based upon intermolecular competition experi-
ments and kinetic isotope effects have also been undertak-
en. For both types of transformation, the presence of a N-
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9677

J. C. Carretero, R. G. Arrayꢂs et al.
[a]
À
Table 2. Olefin scope in the C2 H alkenylation of indole 7.
indole (7) provided complete conversion and C2 regiose-
lectivity, affording 17 in 75% isolated yield (Table 1,
entry 7). The low conversion (27%) and poor regioselec-
tivity (C2/C3=76:24, Table 1, entry 8) displayed by the
N-(3-pyridyl)sulfonyl indole 8, an isomer of 7, highlights
the key role of the (2-pyridyl)sulfonyl moiety as a direct-
À
Alkene
Product
Yield
[%][b]
ing group in C2 H activation. Surprisingly, N-(2-pyrimi-
dinyl)sulfonyl indole 9 proved to be totally unreactive
(Table 1, entry 9) and N-(2-pyridyl)sulfenyl indole (10)
led to a complex mixture of products, likely due to the in-
19,
R=nBu 72
1
2
20,
R=tBu
78
À
stability of the N S bond under the harsh reaction condi-
tions. These results provide evidence of the clear superi-
ority of the N-(2-pyridyl)sulfonyl group as both an acti-
vating and regiocontrolling auxiliary.
45
3
4
5
6
7
21
22
23
24
25
(83)[c]
À
With a regioselective C2 H alkenylation protocol in
hand, we studied the effect of electronic and structural
variations to the alkene (Table 2). A variety of monosub-
stituted alkenes, not only the typical electrophilic alkenes
(Table 2, entries 1–4), but also the more challenging
simple, non-conjugated alkenes, such as 1-octene and tert-
butylethylene, successfully participated in the reaction,
albeit with a lower reactivity. The former led to indole
product 23, in which the alkene is not conjugated with
the indole, as the single product with 55% conversion
(40% isolated yield, Table 2, entry 5), whereas the latter
afforded the conjugated product in 57% yield (Table 2,
entry 6). Gratifyingly, styrene derivatives (Table 2, en-
tries 7–11) coupled efficiently with indole 7 to give the
corresponding alkenylation products with excellent regio-
selectivity, E stereoselectivity and in synthetically useful
yields (typically 70–85%). The reaction reached full con-
version with both electron-rich and electron-poor sub-
stituents. Interestingly, this protocol can also be applied
62
40
(56)[c]
57
85
26, X=F
27,
X=Br
8
9
68
74
28,
À
to 1,3-dienes, a class of olefins scarcely employed in C H
10
11
R=Ac
29,
R=Me
75
80
alkenylations.[6a,c,28] The coupling reactions of 7 with
methyl 2,4-pentadienoate and 1-phenyl-1,3-butadiene
(Table 2, entries 12 and 13, respectively) proceeded at the
terminal double bond to give 2-dienyl indoles 30 and 31
in good yields (65–68%). Alkenes with more substituents
are also suitable; good results were obtained with 1,1-di-
12
13
14
15
16
17
30
68
65
72
69
70
71
ACHTUNGTRENNUNGsubstituted alkenes, such as methyl methacrylate, methyl
31
a-phenylacrylate, a-ethylacrolein and a-methylstyrene,
providing the corresponding double-bond-isomerised
products 32, 33,[29] 34 and 35 in 70–72% yield (Table 2,
entries 14–17).
Particularly remarkable is the participation of 1,2-di-
ACHTUNGTRENNUNGsubstituted alkenes in this reaction, given the small
number of precedents and lower reactivity of this kind of
olefin in oxidative alkenylation (Fujiwara–Moritani) reac-
tions.[23b,e,30] Under the standard reaction conditions, (E)-
methyl crotonate and (E)-propenylbenzene underwent a
smooth reaction with 7 to provide the corresponding tri-
substituted alkene products 36[29] (60% yield, Table 2,
entry 18) and 37+38 (68% yield), in the latter case as a
40:60 mixture of double-bond-isomerised products
(Table 2, entry 19). The more challenging methyl (E,E)-
hexa-2,4-dienoate reacted at the distal double bond to
32[d]
AHCTUNGTRENGN(UN E/Z)-
33[e]
34[d,f]
35[d]
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À
C H Functionalisation of Indoles and Pyrroles
FULL PAPER
AHCTUNGTRENNUNG
Table 2. (Continued)
Alkene
Product
Yield
[%][b]
18
19
20
36[f]
60
68
60
ficulty in obtaining 2,3-disubstituted indoles, either by inter-
[31]
À
molecular C2 H functionalisation of 3-substituted indoles
[31a,32]
À
or by C3 H functionalisation of 2-substituted indoles,
37+38[d]
(40:60)
due to the high sensitivity of the metal-catalysed reaction to
steric effects.
As shown in Scheme 3, blocking the reactive C2 position
with a methyl group results in the formation of the C3 alke-
nylation product, albeit in much lower yield (59 and 60, 35–
39[f]
À
47%). In all cases studied, no C7 H activation product was
identified.[33]
[a] Reaction conditions: (0.1 mmol), alkene (2–5 equiv), [Pd-
G
7
24 h. [b] Isolated yield. [c] Yield based upon recovered indole 7.
[d] Double bond isomer of the alkenylation product. [e] As a 2.7:1 mix-
ture of E/Z diastereomers that was efficiently separated by flash column
chromatography. [f] Obtained as a single diastereomer (see the Support-
ing Information for structure determination).
give, in an acceptable yield, dienyl indole 39[29] with com-
plete stereoselectivity (Table 2, entry 20).
Scheme 3. C3 alkenylation of 2-methyl-substituted indole 58.
The applicable range of indole counterparts (substrates
40–45) was explored with methyl acrylate and styrene as
model olefins (Scheme 2). Electron-withdrawing or elec-
tron-donating groups at C5, C6 or C7 of the indole core did
not have a significant impact upon the reactivity (products
46–53, 70–97% yield). The reaction even tolerated substitu-
tion at C3, as demonstrated for the case of 3-methyl indole
(54 and 55, 81 and 68% yield). Even the highly sterically de-
manding 3-tert-butyl-substituted indole proved to be a suit-
In view of these results, we decided to test the versatility
of the N-(2-pyridyl)sulfonyl moiety as a directing group in
the alkenylation of other important nitrogen heterocycles,
such as pyrroles, which rival indoles in biological signifi-
cance and as valuable synthetic intermediates.[34] However,
pyrroles have received much less attention than indoles in
À
direct C H alkenylation reactions. In this field, Gaunt et al.
have reported an elegant and efficient protocol for the
direct alkenylation of pyrroles with electron-deficient al-
kenes, in which the regioselectivity at C2 or C3 can be con-
trolled by tuning the steric or electronic properties of the N-
protecting group.[30]
Table 3 shows the feasibility of the C2 alkenylation of pyr-
roles assisted by the N-(2-pyridyl)sulfonyl group.[35] First, we
confirmed again the key role exerted by the 2-pyridylsulfon-
yl group: a very low reactivity (<10% conversion) was ob-
served in the reaction of the N-tosyl pyrrole with methyl ac-
rylate under the conditions used in Table 3. In sharp con-
trast, 2-pyridylsulfonyl pyrrole 61 produced the correspond-
ing products of double alkenylation cleanly at C2 and C5
(62–67) in acceptable to good yields. No C3 alkenylation
products were detected. Electronically varied olefins, includ-
ing acrylates (Table 3, entries 1 and 2), a-ethylacrolein
(Table 3, entry 3), styrenes (Table 3, entries 4 and 5) and a
non-activated
entry 6) were suitable olefin substrates.
It is interesting to note that the selective C2 monoalke-
olefin,
3,3-dimethyl-1-butene
(Table 3,
AHCTUNGTRENNUNG
Scheme 2. Structural variation of the indole. Conditions: indole 40–45
(0.1 mmol), [Pd
ACHTUNGTRENNUNG(CH3CN)2Cl2] (10 mol%), CuACHUTNTGREN(NUGN OAc)2·H2O (1–2 equiv). In
parentheses, yield based upon recovered starting material 45. Py=pyridyl
AHCTUNGTREGsNNNU ubstituted pyrroles through subsequent C5 alkenylation
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J. C. Carretero, R. G. Arrayꢂs et al.
À
Table 3. Direct C H alkenylation of N-(2-pyridyl)sulfonyl pyrrole (61).
Finally, we undertook a study of the influence of the sub-
stitution pattern of the pyrrole ring (substrates 72–76) by
using methyl acrylate and styrene as model olefins
(Scheme 6). For the a-substituted pyrroles 72 and 73, ac-
R1
R2
Product
Yield
[%][a]
1
2
CO2nBu
CO2tBu
H
H
62
63
80
79
3
CHO
Et
65
4
5
6
Ph
4-FC6H4
tBu
H
H
H
65
66
67
55 (82)[b]
69
62
[a] Isolated yield after chromatography. [b] In parentheses, yield based
upon recovered pyrrole 59.
Scheme 6. Structural variations at the pyrrole.
ceptable to good yields were obtained of the expected C2 al-
kenylated pyrroles 77–80 (53–87% yield), albeit the elec-
tronically poorer pyrrole 73 (products 79 and 80) proved to
be less reactive than the methyl-substituted pyrrole 72
(products 77 and 78). On the other hand, the procedure also
tolerated the presence of substitution at the b position.
Thus, pyrroles 81–84 were isolated in satisfactory yields (49–
83%) from the b-substituted pyrroles 74 and 75. In the case
of ester-substituted pyrrole 74, only C2 alkenylation at the
electronically more reactive, least hindered a position was
observed (formation of the 2,4-disubstitued pyrroles 81 and
82). As a last example of pyrrole substitution, 2,5-dimethyl
pyrrole 76, which has both “C2 positions” blocked, reacted
at C3, albeit with much lower reactivity (products 85 and
86). This behaviour parallels that previously observed for 2-
methyl-substituted indole 58 (see Scheme 3).
The simple reductive removal of the 2-pyridylsulfonyl
group to generate the free NH indoles allowed us to realise
the full synthetic utility of this method (Scheme 7). Interest-
ingly, the sulfonyl cleavage can be directed to the selective
formation of either C2-alkenyl or C2-alkyl indoles (products
87–89 and 90–92, respectively),[36] depending upon the re-
ducing agent used (Zn or Mg, respectively). This deprotec-
tion can also be applied to pyrrole derivatives with compa-
rable efficiency, as exemplified by the transformation of 68
into the known derivatives 93 and 94.[36]
Scheme 4. Regioselective sequential C2/C5 double alkenylation.
with a different olefin, such as tert-butyl acrylate (product
69, 71% yield), or styrene (70, 63% yield, Scheme 4). Dis-
appointingly, these conditions for selective monoalkenyla-
tion at C2 could not be extended to other olefins. For exam-
ple, the reaction of 61 with tert-butyl acrylate afforded a
38:10:52 mixture of the monoalkenylation product, dialke-
nylated 63 and starting material 61, whereas the reaction of
61 with styrene led to a 50:50 mixture of the corresponding
dialkenylation product 65 along with the pyrrole starting
material 61.
As a final example of the alkene counterpart, we studied
the reaction with a challenging 1,2-disubstituted alkene, (E)-
methyl crotonate (Scheme 5). Interestingly, although the re-
activity was much lower (50% conversion after 24 h), the
monoalkenylation product 71 could be isolated in moderate
yield with only the E stereoisomer formed (45% isolated
yield).
The significant activation brought about by the 2-pyridyl-
sulfonyl group suggests an auxiliary-controlled, direct cyclo-
palladation at the C2 of indole (or pyrrole), facilitated by
coordination of palladium(II) to the nitrogen in the 2-pyri-
Scheme 5. C2 alkenylation of pyrrole 61 with (E)-methyl crotonate.
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C H Functionalisation of Indoles and Pyrroles
FULL PAPER
ically varied substrates. Under the standard conditions, an
equimolar mixture of unsubstituted indole 7, the electron-
deficient indole 42 and methyl acrylate was subjected to the
Pd-catalysed reaction conditions for 4 h (Scheme 9). This ex-
Scheme 7. Deprotection of 2-alkenyl-N-(2-pyridyl)sulfonyl indoles and
pyrroles.
dylsulfonyl group to form a six-membered ring, producing
palladacycle I[37] (Scheme 8). Coordination of the olefin (in-
termediate II) followed by 1,2-migratory insertion would
Scheme 9. Kinetic competitive experiments.
periment revealed that the more nucleophilic substrate 7 re-
acted preferentially to give the major component (17) of the
mixture of products (17/50, kH/kCO Me =2.3). As expected
2
from this result, a more distinct trend was observed for the
pyrrole series in which the substituents are directly bonded
to the reactive aromatic ring; the reaction of an equimolar
mixture of 2-methyl-substituted pyrrole 72, 2-methoxycar-
bonyl derivative 73 and methyl acrylate provided the alke-
nylation product 77 with high selectivity, arising from the re-
action of the more electron-rich pyrrole 72 (77/79, kMe
/
k
CO Me =14.3).[38] The strong dependence of the reactivity on
2
the electronic character of the reactive aromatic substrate
suggests the participation of an electrophilic palladation
pathway in the formation of the apparently key palladacy-
cle I.
Scheme 8. Proposed simplified catalytic cycle for the selective C2 alkeny-
lation reaction.
Further evidence of an electrophilic palladation mecha-
nism was achieved by studying the kinetic isotope effect in
C2 monodeuterated pyrrole derivative 95.[39] As shown in
Scheme 10, a value of 1.4 was obtained for kH/kD from the
1H NMR spectrum of the reaction of monodeuterated pyr-
role 95 with methyl acrylate under the normal reaction con-
ditions (DMA, 1108C, 2 h, 20% conversion). A similar,
small kinetic isotopic effect has previously been described in
some C2 arylation reactions of indoles, which is in accord-
lead to alkyl–Pd intermediate III, which would rapidly
evolve through b-hydride elimination to afford the alkenyla-
tion product. Finally, CuACTHNUTRGNE(UNG OAc)2 is assumed to play the role
of oxidant, converting Pd0 into PdII in order to close the cat-
alytic cycle. In full agreement with the syn character of the
carbopalladation and b-hydrogen elimination steps, the alke-
nylation reactions with (E)-methyl crotonate afforded ste-
reoselectively the trisubstituted alkenes of E configuration
(indole 36 and pyrrole 71).
ance with an electrophilic palladation pathway, rather than a
[40]
À
direct C H activation process.
In general terms, the key carbopalladation step may pro-
ceed through different pathways: primarily either a s-bond
metathesis (concerted metallation–deprotonation) or elec-
trophilic aromatic-type substitution (SEAr). To gain insight
into the pathway involved in this case, some mechanistic ex-
periments were designed. Since indoles and pyrroles are
known to be very reactive in a variety of electrophilic aro-
matic-type substitution processes and, consequently, are
very sensitive to the electronic effect of the substituents, we
performed some competitive experiments between electron-
Scheme 10. Intramolecular kinetic isotope effect on monodeuterated pyr-
role 95.
Chem. Eur. J. 2010, 16, 9676 – 9685
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9681

J. C. Carretero, R. G. Arrayꢂs et al.
In an attempt to isolate a palladacycle intermediate
(type I or related species), indole 7 was heated (608C) with
PdACHTUNGTRENNUNG
(OAc)2 (1.2 equiv) in AcOH for 18 h.[41] Instead of a pal-
ladacycle, 2,2’-biindolyl 97 was formed cleanly and isolated
in 71% yield (Scheme 11). The molecular structure of com-
Scheme 12. Catalytic dehydrogenative intermolecular homocoupling to
form 2,2’-biindoles.
Scheme 12, the reaction tolerates electronically varied sub-
stitution patterns of the indole unit (products 98 and 99, 64–
66% yield).
Interestingly, 5-bromoindole 100 also proved to be amena-
ble to these conditions, although it showed decreased reac-
tivity and required higher catalyst loading (20 mol% of Pd-
Scheme 11. PdACHTUNGTRENNUNG(OAc)2-promoted oxidative homocoupling of indole 7 to
form 2,2’-biindolyl 97.
pound 97 was confirmed by X-ray crystallography[42]
(Figure 1). We speculate that due to the facile C2 pallada-
tion, in the absence of an alkene component, the initial pal-
ladacycle I evolves by forming a C2 palladated bisindolyl in-
termediate, which would afford 97 through reductive elimi-
nation.[43]
ACHTUNGRTEN(NGNU OAc)2) and a prolonged reaction time (51 h) for complete
conversion to product 101 (62% isolated yield, Scheme 13).
The bromine substitution in product 101 is synthetically val-
uable, offering new opportunities for selective functionalisa-
tion through standard cross-coupling strategies.
Scheme 13. Synthesis of 5,5’-dibromo-2,2’-biindolyl compound 101.
The feasibility of the cleavage of the two N-(2-pyridyl)sul-
fonyl groups of the 2,2’-biindolyl system was demonstrated
for compound 97, for which deprotection with excess Mg
turnings in MeOH led to free NH-2,2’-biindole 102 in 54%
yield (Scheme 14).
Figure 1. X-ray crystal structure of compound 97.
Scheme 14. Cleavage of the N-(2-pyridyl)sulfonyl groups in 2,2’-biindolyl
systems.
The efficient conversion of indole 7 into 2,2’-biindolyl 97
with complete regiocontrol led us to focus on developing a
catalytic variant of this dehydrogenative homocoupling of
indoles (Scheme 12). The oxidative homocoupling of indoles
to give 2,3’-biindoles has been reported recently,[18] but, to
the best of our knowledge, the complementary homocou-
pling to give 2,2’-biindoles is unknown. After extensive opti-
misation experiments with a variety of palladium salts, oxi-
Conclusion
We have demonstrated the excellent ability of the N-(2-pyri-
dyl)sulfonyl group to function as a directing group for the
À
dants and solvents, we found that the use of Pd
mol%) in the presence of Cu(OTf)2 (1.5 equiv; OTf=tri-
flate)/O2 (1 atm) in AcOH at 90–1008C for 8 h were the op-
G
direct C2 H functionalisation of indoles and pyrroles and
À
A
its facile elimination by N S reductive cleavage. An efficient
PdII-catalysed regioselective alkenylation of indoles and pyr-
roles affording the corresponding products in good isolated
yields (typically ꢀ70%) and with complete regiocontrol for
the C2 position is described. A remarkable feature of this
methodology is that it displays high structural versatility
with regard to both substitution of the heterocycle and the
timal conditions. In particular, the choice of CuACTHUNRGTNEUNG(OTf)2 as co-
oxidant[44] and AcOH as solvent[45] proved to be crucial for
achieving a clean process and high conversions (68% isolat-
ed yield of 97). These conditions were then applied to other
N-(2-pyridyl)sulfonyl indole derivatives. As shown in
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À
C H Functionalisation of Indoles and Pyrroles
FULL PAPER
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alkene (including conjugated electron-deficient alkenes, styr-
enes and 1,3-dienes, as well as conjugated 1,1- and 1,2-disub-
stituted olefins). Two reductive desulfonylation protocols
have been developed to afford either the C2-alkenylated or
C2-alkylated NH products in good yield. In addition, by
using the same sulfonyl directing group, we performed the
catalytic, dehydrogenative, intermolecular homocoupling of
indole derivatives to give 2,2’-biindolyl systems in good
yields and with complete regiocontrol. Mechanistic investi-
gations based upon reactions with isotopically labelled start-
ing materials and competitive kinetic studies suggest an
electrophilic aromatic pathway for the key palladation step.
We anticipate that this, and related metal-coordinating, het-
eroaryl sulfur-based groups, have great potential as activat-
ing and removable scaffolds to open up new perspectives in
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À
the area. Extension of this concept to other C H functional-
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Experimental Section
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À
Representative procedure for direct C H alkenylation:
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The conversion of N-(2-pyridyl)sulfonyl indole (7) into methyl 3-[N-(2-
pyridylsulfonyl)indol-2-yl]acrylate (17): A screw-capped test tube was
2ACHTUGNTRENN(GNU CH3CN)2] (2.6 mg, 10 mol%)
and Cu(OAc)2·H2O (20.0 mg, 0.1 mmol). The mixture was placed under a
nitrogen atmosphere, then DMA (1 mL) and methyl acrylate (16.8 mL,
0.2 mmol) were added. This mixture was heated to 1108C for 8 h, and
was then allowed to cool to room temperature, diluted with EtOAc
(10 mL) and washed with water (3ꢄ5 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo. The residue was purified
by flash column chromatography (n-hexane/EtAcO, 9:1) to afford 17 as a
yellow solid (25.6 mg; 75%; m.p. 197–1998C; see the Supporting Infor-
mation for spectroscopic data).
charged with 7 (25.8 mg, 0.1 mmol), [PdCl
ACHTUNGTRENNUNG
Representative procedure for the dehydrogenative homocoupling to
form 2,2’-biindoles:
The conversion of N-(2-pyridyl)sulfonyl indole (7) into N,N’-bis(2-pyri-
dylsulfonyl)-2,2’-biindole (97): A screw-capped test tube was charged
with 7 (51.6 mg, 0.2 mmol), PdACHTUNTRGENNUG(OAc)2 (4.5 mg, 0.02 mmol) and CuACHTUTGNREN(NGUN OTf)2
[10] M. Tobisu, R. Nakamura, Y. Kita, N. Chatani, J. Am. Chem. Soc.
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(108.5 mg, 0.3 mmol), followed by addtion of AcOH (2 mL). Then O2
was bubbled into the mixture for 5 min. The mixture was then heated to
90–1008C for 8 h, before it was allowed to cool to room temperature, di-
luted with CH2Cl2 (20 mL) and washed successively with NH4OH (2ꢄ
10 mL), sat. aq NH4Cl (10 mL) and sat. aq NaCl (10 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo. The resi-
due was diluted with CH2Cl2 (10 mL) and passed through a pad of Celite
with a thin layer of silica gel on top. The filtrate was concentrated to dry-
ness to afford 97 as a light brown solid (35.1 mg; 68%; m.p. 257–2598C;
see the Supporting Information for spectroscopic data).
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Acknowledgements
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This work was supported by the Ministerio de Ciencia e Innovaciꢁn
(MICINN; project CTQ2009-07791) and the Consejerꢀa de Educaciꢁn de
la Comunidad de Madrid (programme AVANCAT; S2009/PPQ-1634).
A. G.-R. and B. U. thank the MICINN for predoctoral fellowships. We
thank Johnson Matthey PLC for generous loans of PdCl2 and PdACTHNURTGNENG(U OAc)2.
À
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www.chemeurj.org
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J. C. Carretero, R. G. Arrayꢂs et al.
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mainly by NOE experiments, see the Supporting Information for de-
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II
À
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À
[33] For an example of the directed C7 H alkenylation of indoles, see:
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À
[21] For the intermolecular C2 H alkenylation of indoles, see: a) N. P.
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[35] No reaction was observed when we tried the alkenylation of the sul-
fonyl pyrazole and imidazole derivatives 103 and 104 (see image
below). The lack of reactivity shown by these substrates can be as-
cribed to their considerably more electron-poor nature compared
with indoles and pyrroles in an SEAr mechanism and/or the presence
of an additional basic N atom that could bind to Pd and inhibit cat-
alysis.
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II
À
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À
[23] For selected recent examples of C H alkenylation of other aromatic
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[36] Compounds 87–94 are known. See the Supporting Information for
details.
[37] Catalytic palladation at C2 in NH and NMe indoles has been pro-
posed (refs. [21a] and [40a]) to occur via initial palladation at C3 to
[24] For recent applications of the 2-pyridylsulfonyl group in metal-cata-
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Chem. Int. Ed. 2007, 46, 9257; b) J. Hernꢂndez-Toribio, R. Gꢁme-
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À
give intermediate IV, followed by migration of the C3 PdX bond in
IV to the highly activated 2 position of the iminium intermediate to
give V and ultimately VI by proton abstraction (see image below).
Although this type of migration mechanism cannot be discarded, it
seems unlikely in light of the participation of 3-tert-butyl indole de-
rivative 45 in the C2 alkenylation (products 56 and 57, Scheme 2),
which would involve the initial formation of a highly sterically con-
gested iminium intermediate of type IV with an electron-withdraw-
ing N substituent (R1 =SO2Py, R2 =tBu). On the other hand, C2 pal-
ladation of indoles containing a strongly directing group with stoi-
chiometric amounts of the palladium source have also been report-
ed, see: a) S. Tollari, F. Demartin, S Cenini, G. Palmisano, P. Rai-
mondi, J. Organomet. Chem. 1997, 527, 93; b) M. Nonoyama, K.
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[26] T. Itahara, M. Ikeda, T. Sakakibara, J. Chem. Soc. Perkin Trans. 1
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[27] The use of stoichiometric amounts of CuACTHNUTRGENUG(N OAc)2 was necessary for
achieving complete conversion. For instance, the model reaction of
indole 7 with methyl acrylate under the conditions shown in Table 1
with 50 mol% of CuACTHNUTRGNEUNG(OAc)2 as co-oxidant (instead of 1 equiv) in the
presence of O2 as the sacrificial oxidant led to product 17 in 70%
conversion. See the Supporting Information for catalyst system opti-
misation studies.
[38] Under the conditions previously developed for selective monoalke-
nylation (CH3CN, 808C), only the more electron-rich substrate 72
gave olefination product 77, while the electron-poor pyrrole 73 re-
mained unaltered.
[39] This compound was prepared in three steps from N-tert-butoxycar-
bonyl-2-bromopyrrole by halogen/lithium exchange with nBuLi and
[28] Y. Nakao, N. Nashihara, K. S. Kanyiva, T. Hiyama, J. Am. Chem.
Soc. 2008, 130, 16170.
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À
C H Functionalisation of Indoles and Pyrroles
FULL PAPER
subsequent deuteration with CD3OD (74%), then N-deprotection
with NaOMe followed by N-sulfonylation with 2-PySO2Cl/NaH
(55% over the last two steps). Attempts to effect direct bromo/lithi-
um exchange from 2-bromo-N-(2-pyridyl)sulfonyl pyrrole resulted
in competitive deprotonation at the pyridyl ring. See the Supporting
Information for experimental details.
[41] Attempts to access such palladacycles by oxidative addition to 2-
bromo-N-(2-pyridyl)sulfonyl indole resulted in the formation of
complex mixtures.
[42] CCDC-736591 [unit cell parameters: a=8.4276(2), b=11.8616(2),
c=12.3533(3) ꢆ, a=105.9180(10), b=106.289(2), g=91.296(2)8,
¯
space group P1] contains the supplementary crystallographic data
[40] A similar kinetic isotope effect has been observed in PdII-catalysed
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
À
C2 H arylation of indoles: a) B. S. Lane, M. A. Brown, D. Sames, J.
Am. Chem. Soc. 2005, 127, 8050. For related results in other aromat-
ic systems, see: b) J.-J. Li, R. Giri, J.-Q. Yu, Tetrahedron 2008, 64,
6979; c) S. Chuprakov, N. Chernyak, A. S. Dudnik, V. Gevorgyan,
Org. Lett. 2007, 9, 2333; for mechanistic studies supporting a con-
certed metallation/proton abstraction in Pd-catalysed arylations, see,
for instance: d) S. Pascual, P. de Mendoza, A. A. C. Braga, F. Mase-
ras, A. M. Echavarren, Tetrahedron 2008, 64, 6021; e) D. Garcꢀa-
Cuadrado, P. de Mendoza, A. A. C. Braga, F. Maseras, A. M. Echa-
varren, J. Am. Chem. Soc. 2007, 129, 6880; f) S. I. Gorelsky, D. La-
pointe, K. Fagnou, J. Am. Chem. Soc. 2008, 130, 10848; g) Z. Shi, B.
Li, X. Wan, J. Cheng, Z. Fang, C. Qin, Y. Wang, Angew. Chem.
2007, 119, 5650; Angew. Chem. Int. Ed. 2007, 46, 5554; see also ref-
erence [23i].
[43] For stoichiometric PdACHTNUTGRNEUNG(OAc)2-promoted intramolecular 2,2’-oxidative
coupling of N,N’-carbonyl indole, see: J. Bergman, N. Eklund, Tetra-
hedron 1980, 36, 1439.
[44] Other co-oxidants including Cu
(OAc)2, oxone and tBuOOH led to very low conversions (<10%),
whereas Ce(SO4)2 provided slightly lower reactivity than Cu(OTf)2.
ACHTUNGERTN(NUNG OAc)2, AgOAc, benzoquinone, PhI-
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
[45] The use of AcOH proved to be essential for achieving high conver-
sions, since other polar solvents, such as DMA, DMSO, DMF,
CH3CN or tBuOH, resulted in conversions lower than 20%. Pro-
pionic acid was similarly effective, but not TFA.
Received: April 28, 2010
Published online: July 22, 2010
Chem. Eur. J. 2010, 16, 9676 – 9685
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9685