Palladium(ii)-catalyzed regioselective direct c2 alkenylation of indoles and pyrroles assisted by the n-(2-pyridyl)sulfonyl protecting group

Full text of DOI:10.1002/anie.200902802

Angewandte
Chemie
DOI: 10.1002/anie.200902802
À
C H Alkenylation
Palladium(II)-Catalyzed Regioselective Direct C2 Alkenylation of
Indoles and Pyrroles Assisted by the N-(2-Pyridyl)sulfonyl Protecting
Group**
Alfonso Garcꢀa-Rubia, Ramꢁn Gꢁmez Arrayꢂs,* and Juan C. Carretero*
Driven by its synthetic power and environmental friendliness,
both the alkene component and directing group. To date, only
monosubstituted electrophilic alkenes (mainly acrylates)
have been applied in the C2 alkenylation of indoles, except
for one isolated example of coupling with styrene.[7c] We
disclose herein a highly efficient and structurally versatile
palladium(II)-catalyzed C2 alkenylation of indoles and pyr-
roles employing the easily installed and removed N-(2-
pyridyl)sulfonyl directing group.[11]
À
C C bond-forming reactions through catalytic activation of
[1]
À
Csp2 H bonds constitutes a hot area of research. Since the
pioneering work by Murai et al.[2] and Fujiwara and co-
workers,[3] remarkable progress has been made in this field,
with palladium occupying a prevalent position.[4] Most of
these procedures rely on the use of a coordinating function-
ality that aids in the transition metal mediated functionaliza-
À
tion of a proximal C H bond. However, from a synthetic
Given the electrophilic nature of the palladium(II) center,
our first challenge was to find an N-protecting group for the
C2 functionalization of indole instead of the more nucleo-
philic C3-position. A set of potential directing groups were
examined in the reaction of derivatives 2–7 with methyl
acrylate under [Pd(CH3CN)2Cl2] catalysis (10 mol%) using
Cu(OAc)2·H2O (1 equiv) as an oxidant in DMA at 1108C
(Table 1).[12] Not unexpectedly, under such conditions the
indole 1 cleanly underwent C3 alkenylation with complete
regiocontrol (Table 1, entry 1).[7b,c,9] In contrast, the Boc-
protected derivative 2 led to a 68:32 mixture of C2/C3
alkenylation products, in very low conversion (Table 1,
entry 2). Both C2 regioselectivity and conversion were
enhanced by switching to a Ts group (Table 1, entry 3) or a
p-Ns group (Table 1, entry 4), albeit at an unpractical level. N-
Heteroarylsulfonyl groups strongly influenced the reactivity
and regiocontrol. For example, the N-(2-thienyl)sulfonyl
group in 5 led to low conversion and no regiocontrol
viewpoint, the practicality of the directing groups can be
compromised when the target molecule does not contain such
functionality. Therefore, the discovery of efficient and remov-
able directing groups is in high demand.[5]
Owing to the prevalence of the indole unit in pharma-
ceuticals and bioactive natural products, its regioselective C
H functionalization represents an important challenge in this
area. In contrast to the much more developed C H arylation
À
À
reactions,[6] direct alkenylations have received much less
attention.[7–10] A particularly challenging transformation is the
intermolecular direct alkenylation at the C2-position, for
which only three protocols have been reported.[7] Ricci and
co-workers reported the palladium(II)-catalyzed regiocon-
trolled C2 alkenylation of indole directed by a nonremovable
N-2-pyridylmethyl group.[7a] Gaunt and co-workers described
a practical method for the palladium(II)-catalyzed alkenyla-
tion of indoles (without an N-protecting group) in which the
regioselectivity can be switched from C3 to C2 by varying the
nature of the solvent and additives.[7b] However, decreased
reaction yield was found in C2 alkenylation. Miura, Satoh
Table 1: Effect of N-substitution in the C2 alkenylation of indole with
methyl acrylate.
À
et al. disclosed the palladium(II)-catalyzed C H alkenyla-
tion/decarboxylation of indole-3-carboxylic acids to afford
exclusively 2-alkenyl indoles, where the carboxyl group
blocks the C3-position and acts as a removable directing
group.[7c] Despite these important advances there is room for
innovation, both in increasing the efficiency of the reaction
and in improving the current limited scope with regard to
Entry Indole
Product C2/C3[a]
Yield [%][b]
1
2
3
4
5
6
7
8
1: R=H
2: R=Boc
3: R=Ts
4: R=p-Ns
5: R=(2-thienyl)SO2-
6: R=(8-quinolyl)SO2- 14
7: R=(2-pyridyl)SO2-
8: R=(3-pyridyl)SO2-
9
<2:>98[c] 75 (66)[c]
10
11
12
13
68:32
87:13
85:15
10
45 (30)
28
[*] A. Garcꢀa-Rubia, Dr. R. G. Arrayꢁs, Prof. Dr. J. C. Carretero
Departamento de Quꢀmica Orgꢁnica, Facultad de Ciencias
Universidad Autꢂnoma de Madrid (UAM)
Cantoblanco 28049 Madrid (Spain)
50:50
18
79:21
70 (50)
100 (75)
27
15
16
>98:<2
76:24
E-mail: ramon.gomez@uam.es
juancarlos.carretero@uam.es
[a] Determined by 1H NMR methods from the reaction mixture. [b] Con-
version yield (1H NMR) of C2-alkenylation product. In parenthesis, yield
of product isolated after chromatography (regioisomeric mixtures could
[**] This work was supported by the Ministerio de Ciencia e Innovaciꢂn
(MICINN, project CTQ2006-01121). A.G.-R. thanks the MICINN for
a predoctoral fellowship.
À
not be separated). [c] In the C3 H alkenylation product. Boc=tert-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902802.
butoxycarbonyl, Ts=para-toluenesulfonyl, p-Ns=para-nitrobenzenesul-
fonyl.
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Table 2: Olefin scope in the C2 alkenylation of indole 7.[a]
(Table 1, entry 5), whereas the 8-
quinolylsulfonylindole (6) showed
improved reactivity, yet modest
regioselectivity (Table 1, entry 6).
Pleasingly, N-(2-pyridyl)sulfonylin-
dole (7) provided complete conver-
sion and C2 regiocontrol affording
15 in 75% yield upon isolation
(Table 1, entry 7). The low conver-
Entry
Alkene
Product
Yield [%][b]
1
2
17: R=nBu
18: R=tBu
72
78
sion
(Table 1, entry 8) displayed by 3-
pyridylsulfonylindole (8), an
isomer of 7, highlights the key role
of the 2-pyridylsulfonyl group as
directing group in the C2 alkenyla-
tion, which likely occurs through
stabilization of a cyclopalladated
intermediate.[13,14]
and
poor
regiocontrol
3
4
5
19
20
21
45 (83)[C]
57
85
We next studied the effect of
electronic and structural variations
on the alkene (Table 2). A variety
of monosubstituted alkenes, not
only electrophilic alkenes (Table 2,
entries 1–3) but also the more chal-
lenging non-activated tert-butyl-
ethylene (Table 2, entry 4) and sty-
rene derivatives (Table 2, entries 5–
9), coupled efficiently with the
indole 7 to give the corresponding
alkenylation products with excel-
lent regiocontrol and E stereose-
lectivity in synthetically useful
yields (typically 70–85%). The
electronic nature of the substitu-
ents on the phenyl ring of the
styrene-type substrates has no sig-
nificant effect on the reactivity.
This protocol can be also
applied to 1,3-dienes, a type of
olefin which is rarely employed in
6
7
22: X=F
23: X=Br
68
74
8
9
24: R=Ac
25: R=Me
75
80
10
11
12
13
14
15
16
17
26
68
65
72
70
71
60
68
60
27
28[e]
29[d,e]
30[e]
31[d]
[5i,15]
À
C H alkenylations.
pling of 7 with methyl-2,4-penta-
The cou-
dienoate (Table 2, entry 10) and 1-
phenyl-1,3-butadiene
(Table 2,
entry 11) proceeded at the terminal
double bond to give the 2-dienyl
indoles 26 and 27, respectively, in
good yields. Alkenes with higher
substitution are also suitable. Good
results were obtained with 1,1-dis-
ubstituted alkenes, such as methyl
methacrylate, a-ethylacrolein, or a-
methylstyrene, providing the corre-
sponding double bond isomerized
alkenylation products 28, 29, and
32 + 33[e]
(40:60)
34[d]
30,
respectively,
(Table 2,
[a] Reaction conditions: 7 (0.1 mmol), alkene (2–5 equiv), [Pd(CH3CN)2Cl2] (10 mol%), Cu(OAc)2·H2O
(1–2 equiv), DMA, 1108C, 8–24 h. [b] Yield of product isolated after chromatography. [c] Yield in
entries 12–14). Particularly remark-
parentheses based on recovered indole 7. [d] Obtained as a single diastereomer (see the Supporting able is the participation of 1,2-
Information for structure determination). [e] Compounds are the double bond isomers of the
alkenylation product. DMA=dimethylacetamide.
disubstituted alkenes, given the
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À
Table 4: Direct C H alkenylation of N-(2-pyridyl)sulfonyl pyrrole (47).
few precedents and lower reactivity of this kind of olefins in
oxidative alkenylation (Fujiwara–Moritani) reactions.[10a,16]
Under the standard reaction conditions, (E)-methyl crotonate
and (E)-propenylbenzene underwent smooth reaction with
indole 7 to provide the corresponding trisubstituted alkene
products 31 (60% yield, Table 2, entry 15) and 32 + 33 (68%
yield), respectively; in the latter case a 40:60 mixture of
double bond isomerization products was present (Table 2,
entry 16). The more challenging methyl-(E,E)-hexa-2,4-dien-
oate reacted at the distal double bond to give in acceptable
yield the dienyl indole 34 with complete stereocontrol
(Table 2, entry 17).
Entry
R1
R2
Product
Yield [%][a]
1
2
3
4
5
6
CO2nBu
CO2tBu
CHO
Ph
4-FC6H4
tBu
H
H
Et
H
H
H
48
49
50[c]
51
52
53
80
79
65
55 (82)[b]
69
62
Scope at the indole counterpart was explored with methyl
acrylate and styrene as model olefins (Table 3). Electron-
withdrawing or electron-donating groups at C5, C6, or C7 of
[a] Yield of product isolated after chromatography. [b] Yield in paren-
theses based on recovered pyrrole 47. [c] See structure below.
Table 3: Structural variations on the indole counterpart.[a]
the optimized conditions, pyrrole 47 cleanly produced the
corresponding products of double alkenylation at C2 and C5
(48–53) in acceptable to good yields. In all cases the C3
alkenylation product was not detected. Electronically varied
olefins including acrylates (Table 4, entries 1 and 2) and a-
ethylacrolein (Table 4, entry 3), styrenes (Table 4, entries 4
and 5) and a non-activated olefin such as 3,3-dimethyl-1-
butene (Table 4, entry 6) are suitable olefin substrates. The
selective C2 monoalkenylation of 47 with methyl acrylate was
efficiently achieved under milder reaction conditions[20]
(CH3CN, 808C, 8 h), affording pyrrole 54 in 81% yield
(Scheme 1). This provides access to unsymmetrical 2,5-
35: R=CO2Me, 73% 37: R=CO2Me, 85%
39: R=CO2Me, 76%
40: R=Ph, 81%
36: R=Ph, 97%
38: R=Ph, 95%
41: R=CO2Me, 70%
42: R=Ph, 85%
43: R=CO2Me, 81% 45: R=CO2Me, 47%
44: R=Ph, 68% 46: R=Ph, 35%
[a] Reaction conditions: N-SO2Py-indole (0.1 mmol), [Pd(CH3CN)2Cl2]
(10 mol%), Cu(OAc)2·H2O (1–2 equiv), alkene (2–5 equiv), DMA,
1108C, 8–24 h.
the indole ring did not have a significant impact in the
reactivity (products 35–42). The reaction even tolerates
substitution at C3, as demonstrated in the case of 3-
methylindole (products 43 and 44). This is remarkable, as
the C2 functionalization of 3-substituted indoles to give 2,3-
disubstituted products still remains an important challenge.[17]
Blocking the reactive C2-position with a methyl group
resulted in the formation of the C3-alkenylation products,
albeit in much lower yields (products 45 and 46). In all cases
studied, no C7-substituted products were detected.
Scheme 1. Regioselective sequential C2/C5 double alkenylation.
Encouraged by these results, we decided to test the
versatility of the 2-pyridylsulfonyl group in the alkenylation
of other nitrogen heterocycles. We focused our efforts on
extending this methodology to pyrrole derivatives, which rival
indoles in biological significance and as valuable synthetic
intermediates.[18] This skeleton has received much less atten-
disubstituted pyrroles by subsequent C5 alkenylation with a
different olefin, such as tert-butyl acrylate or styrene
(Scheme 1; products 55 and 56, respectively).
The easy reductive removal of the 2-pyridylsulfonyl group
to generate the unprotected indoles led us to realize the full
synthetic utility of this method, and it served as a chemical
correlation to confirm the structure of the C2-alkenylation
products[21] (Scheme 2). Interestingly, the sulfonyl removal
can be directed to the selective formation of either the C2-
alkenyl or the C2-alkyl indoles 57–59 and 60–62, depending
on the reducing agent used (Zn or Mg, respectively). This
deprotection can also be applied to the pyrrole derivatives
with comparable efficiency, as exemplified in the transforma-
tion of 54 into the known derivatives 63 and 64.[21]
À
tion that indoles in direct C H functionalization reactions,
possibly because of its lower stability under harsh oxidative
conditions. Gaunt and co-workers have reported a mild and
efficient protocol for the direct alkenylation of pyrroles with
electron-deficient alkenes in which the regioselectivity at C2
or C3 can be controlled by tuning the steric or electronic
properties of the N-protecting group.[10a]
Table 4 shows the feasibility of the C2 alkenylation of
pyrroles aided by the N-(2-pyridyl)sulfonyl group.[19] Under
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Communications
8872; i) D. Zhao, W. Wang, F. Yang, J. Lan, L. Yang, G. Gao, J.
You, Angew. Chem. 2009, 121, 3346; Angew. Chem. Int. Ed. 2009,
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[6] Recent review on direct arylation of indoles: L. Joucla, L.
Djakovitch, Adv. Synth. Catal. 2009, 351, 673.
[7] Intermolecular C2 alkenylation of indoles: a) E. Capito, J. M.
Brown, A. Ricci, Chem. Commun. 2005, 1854; b) N. P. Grimster,
C. Gauntlett, C. R. A. Godfrey, M. J. Gaunt, Angew. Chem.
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1159.
Scheme 2. Deprotection of 2-alkenyl-N-(2-pyridyl)sulfonyl indoles and
pyrroles.
À
[8] Intramolecular palladium(II)-catalyzed C H alkenylation of
indoles: a) E. M. Ferreira, B. M. Stoltz, J. Am. Chem. Soc. 2003,
125, 9578; b) G. Abbiati, E. M. Beccalli, G. Broggini, C. Zoni, J.
Org. Chem. 2003, 68, 7625; c) A. Kong, X. Han, X. Lu, Org. Lett.
2006, 8, 1339; d) J. A. Schiffner, A. B. Machotta, M. Oestreich,
Synlett 2008, 2271.
In summary, an efficient palladium(II)-catalyzed regiose-
lective C2 alkenylation of indoles and pyrroles displaying high
structural versatility with regard to the substitution at the
alkene is described. This protocol strongly relies on the use of
the N-(2-pyridyl)sulfonyl group as both an activating group
and a readily removable protecting group. Mechanistic
À
[9] Selected examples on C3 H alkenylation of indoles: a) T. Itara,
K. Kawasaki, F. Ouseto, Synthesis 1984, 236; b) Y. Yokoyama, T.
Matsumoto, Y. Murakami, J. Org. Chem. 1995, 60, 1486; c) Y.
Nakao, K. S. Kanyiva, S. Oda, T. Hiyama, J. Am. Chem. Soc.
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À
investigations and extension of this concept to other C H
functionalizations are underway.
À
[10] Selected recent examples on palladium(II)-catalyzed C H
Received: May 25, 2009
Revised: June 29, 2009
Published online: July 23, 2009
alkenylation of other aromatic ring systems: a) E. M. Beck,
N. P. Grimster, R. Hatley, M. J. Gaunt, J. Am. Chem. Soc. 2006,
128, 2528; b) J.-J. Li, T.-S. Mei, J.-Q. Yu, Angew. Chem. 2008, 120,
6552; Angew. Chem. Int. Ed. 2008, 47, 6452; c) S. H. Cho, S. J.
Hwang, S. Chang, J. Am. Chem. Soc. 2008, 130, 9254.
À
Keywords: alkenylation · C H activation · heterocycles ·
.
[11] Recent applications on the use of the 2-pyridylsulfonyl group in
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R. Gꢂmez Arrayꢃs, J. C. Carretero, Angew. Chem. 2007, 119,
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[12] See the Supporting Information for catalyst system optimization
studies.
[13] In an attempt to isolate a possible palladacycle intermediate,
indole 7 was heated (608C) with Pd(OAc)2 (1.2 equiv) in AcOH
for 18 hours. Instead of the palladacycle, the 2,2’-bis(indolyl) 65
was cleanly formed (71% yield, see scheme below). Product 65
was structurally characterized by X-ray diffraction analysis (see
the Supporting Information). We speculate that a C2-palladated
bis(indolyl) intermediate is formed, but it rapidly evolves
through reductive elimination to afford 65. For stoichiometric
Pd(OAc)2-promoted intramolecular 2,2’-oxidative coupling of
N,N’-carbonylindole, see: J. Bergman, N. Eklund, Tetrahedron
1980, 36, 1439.
À
[4] Recent review on palladium-catalyzed C H activation: a) E. M.
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À
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Chem. Soc. 2007, 129, 6880.
À
À
[5] Newly developed removable directing groups for C H and C C
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[14] CCDC 736591 (65) [Unit cell parameters:
a
8.4276(2)
b
[19] The reaction of N-tosyl pyrrole with methyl acrylate led to less
11.8616(2) c 12.3533(3) alpha 105.9180(10) beta 106.289(2)
gamma 91.296(2) space group P-1] contains the supplementary
crystallographic data 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.
than 10% conversion of monoalkenylation product at C2 under
the conditions shown in Table 4, highlighting the directing role of
the 2-pyridylsulfonyl group.
[20] A 1,2-disubstituted alkene such as the (E)-methyl crotonate also
afforded the monoalkenylation product 66 with 50% conversion
[45% yield (isolated)]:
[15] For an example, see: Y. Nakao, N. Nashihara, K. S. Kanyiva, T.
Hiyama, J. Am. Chem. Soc. 2008, 130, 16170.
[16] Y.-H. Zhang, B.-F. Shi, J.-Q. Yu, J. Am. Chem. Soc. 2009, 131,
5072.
[17] Examples on C2 arylation of 3-substituted indoles: B. B. Tourꢁ,
B. S. Lane, D. Sames, Org. Lett. 2006, 8, 1979.
[18] See, for instance: a) P. S. Baran, J. M. Richter, D. W. Lin, Angew.
Chem. 2005, 117, 615; Angew. Chem. Int. Ed. 2005, 44, 609;
b) N. K. Garg, D. D. Caspii, B. M. Stoltz, J. Am. Chem. Soc. 2005,
127, 5970; c) O. V. Larionov, A. de Meijere, Angew. Chem. 2005,
117, 5809; Angew. Chem. Int. Ed. 2005, 44, 5664.
[21] Compounds 57–59, and 60–64 were known. See the Supporting
Information for details.
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