Palladium-catalyzed intermolecular alkenylation of indoles by solvent-controlled regioselective C-H functionalization

Article abstract of DOI:10.1002/anie.200500468

(Chemical Equation Presented) Either the C2- or the C3-substituted product can be obtained with the same palladium(II) catalyst in an oxidative intermolecular alkenylation of indoles. A variety of conditions can be used for derivatization at the 3-positio

Full text of DOI:10.1002/anie.200500468

Angewandte
Chemie
has had a huge impact on organic synthesis despite the
disadvantage that the overall coupling of the two fragments
requires two discrete activation steps: 1) the formation of an
aryl or vinyl halide and 2) the palladium(0)-catalyzed union of
the reaction partners [Eq. (1)]. A direct oxidative Heck
reaction would bypass the need for preactivated reaction
partners and lead to a more efficient process. To this end,
Fujiwara, Moritani et al. developed an efficient coupling of
arenes and activated alkenes through an oxidative palladium-
(ii)-catalyzed process, and this transformation has found
widespread use in synthesis [Eq. (2)].[2]
We are interested in the development of catalytic
À
processes that exploit selective and controllable C H func-
tionalization[3] to elaborate simple aromatic compounds to
useful products. The catalytic functionalization of aromatic
heterocycles is an important transformation, and methods for
the synthesis and elaboration of indoles in particular have
received significant attention.[4] The indole motif is a ubiq-
uitous feature of alkaloid and peptide natural products and
represents an important structural element for the pharma-
ceutical industry. As a result, many useful and practical
processes exist for the modification of the indole structure,
and, as previously mentioned, metal-catalyzed coupling
reactions are of particular utility, although these methods
often require a prefunctionalized indole unit for each elab-
oration.[4,5] Surprisingly, the development of an oxidative C3
alkenylation of free (NH) indoles has received little atten-
tion,[6] and to the best of our knowledge there is no example of
an intermolecular oxidative C2 alkenylation of a free (NH)
indole.[7] Nor is there a method to select between the two
positions of the important fundamental motif. Herein we
describe a general direct oxidative Heck reaction that exploits
Oxidative Heck Reaction
Palladium-Catalyzed Intermolecular
Alkenylation of Indoles by Solvent-Controlled
À
Regioselective C H Functionalization**
Neil P. Grimster, Carolyn Gauntlett,
Christopher R. A. Godfrey, and Matthew J. Gaunt*
Over the past three decades the Heck reaction has become
À
one of the most fundamental metal-catalyzed C C bond-
forming processes for the synthesis of complex molecules.[1] It
À
a novel, selective, solvent-controlled, palladium-catalyzed C
[*] N. P. Grimster, C. Gauntlett, Dr. M. J. Gaunt
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB21EW (UK)
Fax: (+44)1223-336-362
H functionalization of free (NH) indoles and leads to the
elaboration of the heteroaromatic core at either the 2- or the
3-position [Eq. (3)].
E-mail: mjg32@cam.ac.uk
The natural reactivity of indole suggested that palladation
and Heck coupling would take place preferentially at the 3-
Dr. C. R. A. Godfrey
Syngenta Crop Protection Research AG, WRO 1060.2.06
Schwazaldallee 215, 4002 Basel (Switzerland)
[**] We gratefully acknowledge Syngenta and the EPSRC for an Industrial
Case Award (to N.P.G.), the Royal Society for a University Research
Fellowship (to M.J.G.), and Professor Steven Ley for support and
useful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200500468
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Table 1: Optimization studies for indole functionalization.[a]
position.[6] However, we speculated
that it might be possible to control
the selectivity of the reaction by
the use of different solvents and
additives. Fundamental to this
hypothesis was the knowledge
that the migration of groups from
the 3- to the 2-position of indole
has been observed in the alkylation
Entry Catalyst
loading [%]
Oxidant (equiv) Solvent (v/v)
Yield of
3a/2a
2+3 [%][b]
1
2
3
4
5
6
7
8
9
10
Cu(OAc)2 (1.8)
Cu(OAc)2 (1.8)
Cu(OAc)2 (1.8)
tBuOOBz (0.9)
Cu(OAc)2 (1.8)
tBuOOBz (0.9)
Cu(OAc)2 (1.8)
tBuOOBz (0.9)
tBuOOBz (0.9)
DMF
DMSO
1,4-dioxane
1,4-dioxane
DMF/AcOH (3:1)
1,4-dioxane/AcOH (3:1)
DMF/DMSO (10:1)
MeCN/AcOH (3:1)
54
66
n.r.
48
54
58
79
65
>95:5
>95:5
–
10
10
10
10
20
10
10
10
of
3-substituted
indoles
1:2
1:1
1:7
(Scheme 1).[8] By analogy, we
anticipated that a migration of the
À
C3 PdX bond to the 2-position
>95:5
>95:5
>95:5
would enable a complementary
À
1,4-dioxane/AcOH/DMSO (3:1:0.4) 66
C H functionalization process.
We began by screening the
reaction between indole (1a, R1 =
H) and n-butyl acrylate (4a) in the
[a] For all reactions the mixture (0.4m) was stirred for 18 h. [b] Yields after isolation and purification by
flash silica-gel chromatography. n.r. =no reaction. Bz=benzoyl, DMF=N,N-dimethylformamide,
DMSO=dimethyl sulfoxide.
may prevent the precipitation of Pd0 in the reaction mixture
prior to reoxidation.[10a] Although no further improvements to
the C2 functionalization reaction were made,[11] we found that
the use of MeCN/AcOH switched the selectivity back in favor
of the 3-position (Table 1, entry 8), as did the addition of
DMSO to the reaction in 1,4-dioxane/AcOH (Table 1,
entry 9).[10b] It is remarkable that the addition of a polar
coordinating cosolvent seems to promote a total switch in the
selectivity of the reaction, and investigations into the nature
of this selectivity are ongoing.
Scheme 1. Electrophilic attack on indoles.
Although at this stage we can not be certain of the
presence of Pd(OAc)2 as a catalyst with a variety of solvents
and Cu(OAc)2 as the oxidant.[9] Reactions in polar solvents
gave exclusively the C3-functionalized indoles 3a (Table 1,
entries 1–2), except when 1,4-dioxane was used (Table 1,
entry 3), in which case no reaction was observed, perhaps
because of the insolubility of Cu(OAc)2 in this solvent. The
use of tert-butyl benzoyl peroxide (tBuOOBz) as the soluble
reoxidizing agent, however, led to a reaction in 1,4-dioxane,
but with a surprising reversal of selectivity to produce a 2:1
mixture of the C2- and C3-substituted indoles 2a and 3a,
respectively (Table 1, entry 4). Careful monitoring of the
reaction showed that 3a predominated at the beginning of the
reaction with 2a only starting to form as the reaction
proceeded. Benzoic acid is produced as a result of the
reoxidation of Pd0 by tBuOOBz, and it was believed
that the increasing concentration of acid may be
responsible for the switch in selectivity as the reaction
progresses. This hypothesis was supported by the
result of the reaction in DMF/AcOH, which led to a
1:1 mixture of isomers (Table 1, entry 5), whereas only
3a was formed in DMF alone. To our delight, the use
of AcOH as a cosolvent with 1,4-dioxane led to a 7:1
ratio of 2a:3a (Table 1, entry 6) and demonstrated
that the regioselectivity of palladium-catalyzed indole
alkenylation could be controlled.
mechanism of this process, we propose plausible pathways for
the two reactions in Scheme 2. Palladation at C3 is thought to
occur via intermediate I, and following rearomatization to II a
Heck-type reaction forms the C3-functionalized indole 3.
Under neutral conditions, the acetate ion formed from the
attack of indole on Pd(OAc)2 will readily remove a proton
from I to form the C3-palladated species II. In contrast, under
acidic reaction conditions we propose that this deprotonation
À
would be slowed, which could allow a migration of the C3
PdX bond in I to the highly activated 2-position of the
iminium intermediate to give intermediate III and ultimately
IV.[12] The effect of the cosolvent, as well as the presence of
Further optimization showed that the use of
DMSO as a cosolvent with DMF improved the yield
À
of 3a (Table 1, entry 7), thus suggesting that DMSO Scheme 2. Proposed mechanism of C H functionalization.
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Table 2: Regioselective C3 functionalization of indoles.
AcOH, is also important since the
results in Table 1 suggest that strongly
coordinating solvents (DMSO, MeCN)
override any effect that the presence of
acid may have, thus leading to C3
selectivity. However, with weakly coor-
dinating 1,4-dioxane as a solvent the
proposed migration still appears to be
facile, even without the addition of acid,
thus leading to the C2-functionalized
indole 2 as the major isomer. It is also
possible that the C3 palladation is rever-
sible, and that the intermediate derived
from C2 palladation is ultimately
formed prior to coupling. In this case
the C2-palladated species must be ther-
modynamically more stable and the rate
of insertion into the alkene slow. Mech-
anistic investigations are currently
underway, and these results will be
reported in due course.
Entry
1
Alkene
Indole
Product[a]
Yield [%][b]
91
X, R1 =H
1a
4b
3b
3c
3d
3e
X, R1 =H
1a
2
3
4
4c
70
68
70
X, R1 =H
1a
4d
X, R1 =H
1a
4e[d]
Table 2 shows that a range of indoles
and alkenes participate in the regiose-
lective oxidative coupling reaction.
Importantly, free (NH) indoles are suit-
able substrates for this process. The C3-
functionalization process worked well
for electron-deficient alkenes, such as
4a–d, which reacted with 1a to form
indoles 3a–d in good yield. Indole
phosphonate 3e could also be generated
from vinyl phosphonate 4e in good
yield. The reaction of 1a with lactone
4 f produced a mixture of alkenyl indole
regioisomers 3 f (1:1) in 66% combined
yield. The non-activated alkenes styrene
(4g) and cyclohexene (4h) reacted with
1a to form the corresponding indoles 3g
and 3h (after hydrogenation) in good
yield. The N-methyl indole derivative
1b reacted with 4a to form 3i in 75%
yield, and 5-nitroindole 1c was smoothly
converted into 3j in 76% yield. Of
particular note was the use of 5-bro-
moindole (1d); the highly versatile
product 3k was isolated in 75% yield
with the aryl bromide moiety intact.
Thus, this first general method for the
direct oxidative Heck coupling at C3 of
X, R1 =H
1a
5
6
4 f
3 f
66[c]
62
X, R1 =H
1a
4g[e]
3g
X, R1 =H
1a
7
8
4h[f]
3h
3i
62
75
X=H,
R1 =Me
1b
4a
X=NO2,
R1 =H
1c
9
4a
4a
3j
76
75
X=Br,
R1 =H
1d
10
3k
[a] Only the C3-functionalized isomer was produced. [b] Yields of products after purification. [c] A 1:1
mixture of isomers was produced. [d] 4e: 5 equivalents. [e] 1a: 2 equivalents, 4g: 1 equivalent. [f] 4h:
10 equivalents used because of its volatility; yield after hydrogenation.
free (NH) indoles can be applied to a range of indoles and
alkenes.
conditions. Nevertheless, indole alkenylation occurred selec-
tively at the C2 position with all substrates tested, in generally
good yields for this type of transformation. Interestingly, the
use of N-methylindole (1b) resulted in no alkenylation at
either C2 or C3 under these conditions, thus highlighting a
potentially crucial role of the free NH moiety in these
reactions.
We next turned our attention to the development of the
corresponding catalytic C2 alkenylation. When the reactions
were performed with dioxane/AcOH as the solvent (Table 1,
entry 6) the regioselectivity of the oxidative process was
switched in favor of reaction at the 2-position (Table 3).
However, the yields were generally lower in these cases,
presumably as a result of competitive oxidative decomposi-
tion of indole 1a and the product 2 under these reaction
It was also possible to further derivatize the indole
À
products through C H functionalization (Scheme 3). Indole
3b reacted with 4a to form 5 in a moderate 41% yield as the
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Table 3: Regioselective C2 functionalization of indoles.
Experimental Section
General procedure for C3 alkenylation: Palla-
dium acetate (0.1 equiv) was added to a mixture
of the alkene (2 equiv), copper(ii) acetate
(1.8 equiv), and the indole (1 equiv) in DMF/
DMSO (9:1, 0.4m), and the reaction mixture
was stirred at 708C. After 18 h the reaction
mixture was cooled to room temperature and
partitioned between water and ethyl acetate,
then filtered through a plug of celite. The layers
were separated, and the organic layer was
washed with aqueous saturated brine solution,
dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by flash
chromatography afforded the C3-alkenylated
indole.
General procedure for C2-alkenylation:
Palladium acetate (0.2 equiv) was added to a
mixture of the alkene (2 equiv), tBuOOBz
(0.9 equiv), and the indole (1 equiv) in 1,4-
dioxane/AcOH (3:1, 0.4m), and the reaction
mixture was stirred at 708C. After 18 h the
reaction mixture was cooled to room temper-
ature and neutralized with aqueous sodium
hydrogen carbonate solution, diluted with
ethyl acetate, and filtered through a plug of
celite. The layers were separated, and the
organic layer was washed with aqueous
sodium hydrogen carbonate solution and aque-
ous saturated brine solution, dried over MgSO4,
filtered, and concentrated under reduced pres-
sure. Purification by flash chromatography
afforded the C2-alkenylated indole.
Entry
1
Alkene
Indole
Product[a]
Yield [%][b]
51[c]
R1 =H
1a
4a
4b
4c
4e
4a
2a
2b
2c
2e
2i
R1 =H
1a
2
3
4
5
57
34
51
n.r.
R1 =H
1a
R1 =H
1a
R1 =Me
1b
[a] Only the C2-functionalized isomer was produced. [b] Yields of products after purification. [c] A 7:1
mixture of 2/3 was produced; 51% is the yield of isolated 2a.
Received: February 7, 2005
Published online: April 12, 2005
À
Keywords: C C coupling · Heck reaction · indoles · palladium ·
regioselectivity
.
[1] For recent reviews, see: a) A. B. Dounay, L. E. Overman, Chem.
Rev. 2003, 103, 2945; b) I. P. Beletskaya, A. V. Cheprakov, Chem.
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Scheme 3. Formation of bis(alkenyl)indoles.
[2] a) I. Moritani, Y. Fujiwara, Tetrahedron Lett. 1967, 1119; b) Y.
Fujiwara, I. Moritani, S. Danno, R. Asano, S. Teranishi, J. Am.
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sole product, whereas indole 2b was converted into diene 6 in
71% yield through reaction with 4a in 1,4-dioxane/DMSO.
This strategy thus allows the selective installation of sub-
stituents at either position in any order and provides access to
highly functionalized indoles by catalytic methods.
À
[3] The term C H functionalization is used in a general sense to
À
describe the activation and transformation of a C H bond. This
In summary, we have developed a general method for the
selective intermolecular alkenylation of indoles through a
term was described by Sames and co-workers; see: a) B. Sezen,
D. Sames, J. Am. Chem. Soc. 2003, 125, 10580; see also: b) A. E.
Shilov, G. B. Shulꢀpin, Chem. Rev. 1997, 97, 2879; c) V. Ritleng,
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Angew. Chem. 1999, 111, 1808; Angew. Chem. Int. Ed. 1999, 38,
1698.
À
palladium-catalyzed C H functionalization reaction. The
nature of the solvent determines the regioselectivity of the
reaction, so that the alkenylation can be directed to either the
2- or the 3-position of free (NH) indoles. This discovery could
have important consequences for the selective elaboration of
other heteroaromatic core structures. Current efforts are
directed towards the improvement of the efficiency and scope
of the reaction, a more detailed mechanistic investigation, and
application to other types of heteroaromatic compounds.
[4] a) R. J. Sundberg, Indoles, Academic Press, New York, 1996;
b) L. S. Hegedus, Angew. Chem. 1988, 100, 1147; Angew. Chem.
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indoles, see: d) M. C. Willis, G. N. Brace, I. P. Holmes, Angew.
Chem. 2005, 117, 407; Angew. Chem. Int. Ed. 2005, 44, 403.
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À
[5] For examples of the palladium-catalyzed intramolecular C H
functionalization of indoles, see: a) E. M. Ferreira, B. M. Stoltz,
J. Am. Chem. Soc. 2003, 125, 9578; b) C. Liu, X. Han, X. Wang,
R. A. Widenhoefer, J. Am. Chem. Soc. 2004, 126, 3700; c) G.
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68, 7625; for direct palladium-catalyzed arylation reactions, see:
d) B. Sezen, D. Sames, J. Am. Chem. Soc. 2003, 125, 5274; e) B. S.
Lane, D. Sames, Org. Lett. 2004, 6, 2897; for a gold-catalyzed
coupling reaction, see: f) A. Arcadi, G. Bianchi, M. Chiarini, G.
DꢀAnniballe, F. Marinelli, Synlett 2004, 944; for a stoichiometric
palladium-catalyzed alkenylation, see: g) T. Itahara, M. Ikeda, T.
Sakakibara, J. Chem. Soc. Perkin Trans. 1 1983, 1361.
[6] J. Chengguo, W. Lu, T. Kitamura, Y. Fujiwara, Org. Lett. 1999, 1,
2097.
[7] During the preparation of this manuscript we became aware of a
report relating to a C2 alkenylation of an indole that contains a
metal-directing group on the indole nitrogen atom: E. Capito,
J. M. Brown, A. Ricci, Chem. Commun. 2005, in press.
[8] a) R. J. Sundberg, The Chemistry of Indoles, Academic Press,
New York, 1970, pp. 78 – 83; b) A. H. Jackson, B. Naidoo, P.
Smith, Tetrahedron 1968, 24, 6119.
[9] For an overview of oxidative palladium-catalyzed transforma-
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2, 2551.
[10] a) B. A. Steinhoff, S. R. Fix, S. S. Stahl, J. Am. Chem. Soc. 2002,
124, 766; b) for an effect of DMSO, see: M. S. Chen, C. M.
White, J. Am. Chem. Soc. 2004, 126, 1346.
[11] Conditions reported by Ferreira and Stoltz (reference [5a]) for
an intramolecular process gave 2a in 34% yield.
[12] For a recent example of Pd migrations, see: M. A. Campo, Q.
Huang, T. Yoa, Q. Tian, R. C. Larock, J. Am. Chem. Soc. 2003,
125, 11507.
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