Palladium-catalyzed synthesis of N-tert-prenylindoles

Article abstract of DOI:10.1021/ol4011344

Palladium-catalyzed N-tert-prenylations of indoles, tricarbonylchromium- activated indoles, and indolines that occur in high yields (up to 94%) with high tert-prenyl-to-n-prenyl selectivity (up to 12:1) are reported.

Full text of DOI:10.1021/ol4011344

ORGANIC
LETTERS
2013
Vol. 15, No. 11
2798–2801
Palladium-Catalyzed Synthesis
of N-tert-Prenylindoles
Kirsten F. Johnson, Ryan Van Zeeland, and Levi M. Stanley*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
lstanley@iastate.edu
Received April 23, 2013
ABSTRACT
Palladium-catalyzed N-tert-prenylations of indoles, tricarbonylchromium-activated indoles, and indolines that occur in high yields (up to 94%) with
high tert-prenyl-to-n-prenyl selectivity (up to 12:1) are reported.
Prenylated indoles are found in structurally diverse
fungal, plant, and bacterial natural products1 and have
been the focus of many recent synthetic2 and biosynthetic
studies.3 The diversity of these natural products stems
from nature’s ability to incorporate the prenyl group
throughout the indole core as either an n-prenyl (prenyl)
or tert-prenyl (reverse prenyl) moiety. Synthetic chemists
have developed a variety of methods to prepare both
prenylated and tert-prenylated indoles that exhibit promis-
ing medicinal properties.1ꢀ3 Despite these efforts, the
synthetic methodology necessary to access certain classes
of tert-prenylated indoles remains underdeveloped.
N-tert-Prenylated indoles (Figure 1) are a unique class of
prenylated indoles in which the prenyl group is linked to
the indole core through a CꢀN bond. N-tert-Prenylated
indoles and analogs containing oxidized prenyl moieties
exhibit an array of medicinal properties including activa-
tion of insulin receptors and cytotoxicitiy toward cancer
cell lines, as well as antiinflammatory, antimycobacterial,
and antifungal activities.4
(1) For recent reviews, see: (a) Li, S.-M. Nat. Prod. Rep. 2010, 27, 57.
(b) Lindel, T.; Marsch, N.; Adla, S. K. Top. Curr. Chem. 2012, 309, 67.
(2) For a recent review, see: (a) Miller, K.; Williams, R. M. Chem.
Soc. Rev. 2009, 38, 3160. For selected recent examples, see: (b) Scheerer,
J. R.; Laws, S. W. J. Org. Chem. 2013, 78, 2422. (c) Trost, B. M.;
Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2001, 133, 7328.
(d) Finefield, J. M.; Sherman, D. H.; Tsukamoto, S.; Williams, R. M.
J. Org. Chem. 2011, 76, 5954. (e) Ignatenko, V. A.; Zhang, P.; Viswanathan,
R. Tetrahedron Lett. 2011, 52, 1269. (f) Finefield, J. M.; Williams, R. M.
J. Org. Chem. 2010, 75, 2785. (g) Grant, C. D.; Krische, M. J. Org. Lett.
2009, 11, 4485. (h) Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat.
Chem. 2009, 1, 63. (i) Baran, P. S.; Guerrero, C. S.; Corey, E. J. J. Am.
Chem. Soc. 2003, 125, 5628.
(3) For selected recent examples, see: (a) Haynes, S. W.; Gao, X.;
Tang, Y.; Walsh, C. T. ACS Chem. Biol. 2013, 8, 741. (b) Rudolf, J. D.;
Wang, H.; Poulter, C. D. J. Am. Chem. Soc. 2013, 135, 1895. (c) Chen, J.;
Morita, H.; Wakimoto, T.; Mori, T.; Noguchi, H.; Abe, I. Org. Lett.
2012, 14, 3080. (d) Yin, S.; Yu, X.; Wang, Q.; Liu, X.-Q.; Li, S.-M. Appl.
Microbiol. Biotechnol. 2013, 97, 1649. (e) Li, S.; Finefield, J. M.;
Sunderhaus, J. D.; McAfoos, T. J.; Williams, R. M.; Sherman, D. H.
J. Am. Chem. Soc. 2012, 134, 788. (f) Yin, W.-B.; Xie, X.-L.; Matuschek,
M.; Li, S.-M. Org. Biomol. Chem. 2010, 8, 1133.
Current synthetic routes to N-tert-prenylated indoles
involve (1) multiple nonstrategic redox steps, (2) the use
(4) For activity as insulin receptor modulators, see: (a) Webster,
N. J. G.; Park, K.; Pirrung, M. C. ChemBioChem 2003, 4, 379. For a
report of activity against cancer cell lines: (b) Yamamoto, Y.; Nishimura,
K. I.; Kiriyama, N. Chem. Pharm. Bull. 1976, 24, 1853. For anti-
inflammatory activity, see: (c) Renner, M. K.; Shen, Y.-C.; Cheng, X.-C.;
Jensen, P. R.;Frankmoelle, W.;Kauffman, C. A.;Fenical, W.;Lobkovsky,
E.; Clardy, J. J. Am. Chem. Soc. 1999, 121, 11273. For antimycobacterial
activity, see: (d) Schmitt, E. K.; Riwanto, M.; Sambandamurthy, V.;
Roggo, S.; Miault, C.; Zwingelstein, C.; Krastel, P.; Noble, C.; Beer, D.;
Rao, S. P. S.; Au, M.; Niyomrattanakit, P.; Lim, V.; Zheng, J.; Jeffery, D.;
Pethe, K.; Camacho, L. R. Angew. Chem., Int. Ed. 2011, 50, 5889. For
antifungal activity, see: (e) Levy, L. M.; Cabrera, G. M.; Wright, J. E.;
Seldes, A. M. Phytochemistry 2000, 54, 941.
r
10.1021/ol4011344
Published on Web 05/28/2013
2013 American Chemical Society

Scheme 1. Strategies To Form N-tert-Prenylated Indoles
Figure 1. Examples of N-tert-prenylindole natural products.
ofprefunctionalizedstarting materials, or (3) highloadings
of a precious metal catalyst and metal co-oxidants (Scheme 1).
The traditional, four-step synthetic sequence to generate
N-tert-prenylated indoles includes reduction of the indole
to an indoline, Cu(I)-catalyzed propargylic substitution,
partial reduction of the alkyne to an alkene, and oxidation
of the N-tert-prenylated indoline to the corresponding
indole (Route A).5 In 2007, Willis et al. reported a tandem
Pd-catalyzed synthesis of N-tert-prenylated indoles from
2-methyl-3-butene-2-amine and 2-bromo-β-chlorostyrenes
by a sequence of aryl amination and alkenyl amination
(Route B).6 In 2011, Nishikawa et al. reported the N-tert-
prenylation of methyl indole-3-acetate by alkylation with
the dicobalthexacarbonyl complex of 2-methyl-3-butyn-2-
ol in the presence of TMSOTf, followed by reduction and
decomplexation with n-Bu3SnH (Route C).7
To date, only one direct N-tert-prenylation of indoles
has been reported. In 2009, Baran et al. reported a direct
synthesis of N-tert-prenylated indoles by Pd-mediated
CꢀH functionalization of 2-methyl-2-butene with indoles
(Route D).8 The direct CꢀH functionalization 2-methyl-2-
butene enables the synthesis of N-tert-prenylated indoles
from a broad array of readily accessible indoles, but the
synthetic utility and practicality of this strategy remain limited
because high loadings of the Pd catalyst (20ꢀ40 mol %) and a
Ag co-oxidant (2.0ꢀ2.5 equiv) are required.
To establish the viability of our allylic substitution
approach, we conducted reactions of tert-butyl (2-methyl-
but-3-en-2-yl) carbonate with indole-3-carboxaldehyde in
the presence of Cs2CO3 and catalysts generated from a
variety of Pd precursors and bisphosphine ligands (Sup-
porting Information (SI)). We found that Pd complexes of
bisphosphine ligands with wide natural bite angles catalyze
theN-prenylation of indole-3-carboxaldehyde1awithhigh
tert-prenyl/n-prenyl selectivity (9:1 to 13:1). The reaction
of 1awith tert-butyl(2-methylbut-3-en-2-yl) carbonate2 in
the presence of a catalyst generated from [Pd(η3-prenyl)-
Cl]2 and Xantphos occurred with the best combination of
yield (76% isolated yield of 3a) and tert-prenyl/n-prenyl
selectivity (12:1) (eq 2).
At the outset of this project, we sought to develop
strategies toformN-tert-prenylindoleswitha rangeof elec-
tronic properties that minimize the number of nonstrategic
redox steps and employ practical loadings of catalyst
precursors. Here, we report syntheses of N-tert-prenylated
indoles by a Pd-catalyzed allylic alkylation approach
(eq 1).9 Three distinct protocols for the synthesis of N-tert-
prenylindoles are described, using indole, (η6-indole)-
Cr(CO)3, and indoline nucleophiles in the presence of
the same Pd catalyst prepared in situfrom readily available
precursors. These reactions require loadings of the Pd
catalyst that are up to 10 times less than that required for
previously reported direct N-tert-prenylations of indoles.
We then evaluated these conditions for palladium-
catalyzed N-tert-prenylation in reactions of a series of
indoles containing electron-withdrawing groups at either
the 3- or 5-position with carbonate 2. The data from these
experiments are summarized in Table 1. As shown in
entries 1ꢀ4, 3-substituted indoles 1aꢀ1d (R1 = CHO,
Org. Lett., Vol. 15, No. 11, 2013
2799

C(O)Me, CO2Me, orCN) reacted withcarbonate2 toform
N-tert-prenylindoles 3aꢀ3d in good-to-excellent yield with
10:1 or greater regioselectivity (3:4). N-tert-Prenylindoles
3a and 3b were isolated in 76% and 65% yield as single
constitutional isomers. Incontrast, N-tert-prenylindoles3c
and 3d were not readily separable from the N-n-prenyl
isomers 4c and 4d. These products were isolated as 12:1
mixtures of the N-tert- and N-n-prenylindole isomers.
The presence of electron-withdrawing substitution atthe
3-position of the indole core is not a strict requirement
under our reaction conditions. Reactions of 5-cyanoindole
1e and 5-nitroindole 1f with carbonate 2 occurred to form
mixtures of N-prenylindole products 3eꢀf and 4eꢀf in
40%and 62% yield with 7:1tert-prenyl/n-prenylselectivity
(entries 5 and 6). However, reactions of indoles lacking
electron-withdrawing substitutents and reactions of
2-substituted indoles did not form N-prenylindole products.
intermediate. Thus, the difference in the relative acidity
of the indole NꢀH is likely responsible for the difference
in reactivity between more acidic, electron-deficient
indoles and less acidic, electron-rich indoles.10 Since
η6-coordination of metal carbonyl complexes to arenes is
known to increase the acidity of benzylic CꢀH bonds,11 we
hypothesized that η6-coordination of a metal carbonyl
complex to the indole core would similarly increase the
acidity of the indole NꢀH bond by reducing the electron
density in the indole π-system.
We prepared a series of (η6-indole)Cr(CO)3 complexes
of electron-rich indoles and evaluated their reactivity as
nucleophiles in Pd-catalyzed prenylation reactions. Reac-
tions of (η6-indole)Cr(CO)3 complexes of indoles 5aꢀg
with carbonate 2 are summarized in Table 2. As shown in
entries 1ꢀ3, (η6-indole)Cr(CO)3 complexes prepared from
indole, 3-methylindole, and methyl indole-3-acetate (5aꢀc)
reacted with carbonate 2 to form N-tert-prenylindoles
3gꢀ3i after oxidative decomplexation with DDQ. These
one-pot, two-step transformations gave the N-tert-prenyl-
indoles 3gꢀi and N-n-prenylindoles 4gꢀi in 62ꢀ86% yield
with 6:1 to 9:1 tert-prenyl/n-prenyl selectivity. Reactions of
(η6-indole)Cr(CO)3 complexes prepared from 4-MeO-,
5-MeO-, and 6-MeO-indole also occurred in moderate to
good yields with high tert-prenyl/n-prenyl selectivities
(entries 4ꢀ6). The reactions of (η6-indole)Cr(CO)3 com-
plexes 5dꢀf with 2 and subsequent decomplexation formed
N-tert-prenylindoles 3jꢀl and N-n-prenylindoles 4jꢀl in
51ꢀ78% yield and 7ꢀ8:1 tert-prenyl/n-prenyl selectivity.
In contrast, the prenylation of (η6-7-MeO-indole)Cr(CO)3
5g with 2 occurred with >20:1 selectivity favoring the
N-n-prenylindole isomer 4m (entry 7).
Table 1. Scope of Pd-Catalyzed N-tert-Prenylation of Indolesa
yield
3 þ 4 (%)b
entry
1
R1
R2
3
3:4c
1
1a
1b
1c
1d
1e
1f
CHO
C(O)Me
CO2Me
CN
H
3a
3b
3c
3d
3e
3f
76d
65d
90
12:1
10:1
12:1
12:1
7:1
2
H
3
H
4
H
94
Table 2. Scope of Pd-Catalyzed N-tert-Prenylation of
(η6-Indole)Cr(CO)3 Complexesa
5e
6e
H
CN
NO2
40
H
62
7:1
a For detailed reaction conditions, see SI. b Isolated yield of 3 þ 4.
c Determined by 1H NMR spectroscopy. d Isolated yield of 3. e Reactions
run at rt.
The disparate reactivity of indoles with and without
electron-withdrawing substituents suggested that indolate
anions of the electron-deficient indoles were primarily
responsible for nucleophilic attack on a prenylpalladium(II)
yield
entry
5
R1
R2
3
3 þ 4 (%)b
3:4c
8:1
(5) (a) Sugiyama, H.; Yokokawa, F.; Aoyama, T.; Shioiri, T. Tetra-
hedron Lett. 2001, 42, 7277. (b) Sugiyama, H.; Shioiri, T.; Yokokawa, F.
Tetrahedron Lett. 2002, 43, 3489. (c) Della Salla, G.; Capozzo, D.; Izzo,
I.; Giordano, A.; Iommazzo, A.; Spinella, A. Tetrahedron Lett. 2002, 43,
8839. (d) Yokokawa, F.; Sugiyama, H.; Aoyama, T.; Shioiri, T. Synthe-
sis 2004, 9, 1476.
(6) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem. Commun. 2007,
4764.
(7) Isaji, H.; Nakazaki, A.; Isobe, M.; Nishikawa, T. Chem. Lett.
2011, 40, 1079.
(8) Luzung, M. R.; Lewis, C. A.; Baran, P. S. Angew. Chem., Int. Ed.
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
H
H
H
H
3g
3h
3i
86
75
78
78
51
72
46
Me
8:1
CH2CO2Me
9:1
H
H
H
H
4-MeO
5-MeO
6-MeO
7-MeO
3j
7:1
3k
3l
8:1
7:1
5g
3m
<1:20
a For detailed reaction conditions, see SI. b Isolated yield of 3 þ 4.
c Determined by 1H NMR spectroscopy.
2009, 48, 7025.
(9) For a related synthesis of N-tert-prenylindole by Rh-catalyzed
amination of tertiary allylic trichloroacetimidates, see: (a) Arnold, J. S.;
Cizio, G. T.; Nguyen, H. M. Org. Lett. 2011, 13, 5576–5579. For related
Pd-catalyzed tert-prenylations of nitrogen nucleophiles, see: (b) Johns,
A. M.; Liu, Z.; Hartwig, J. F. Angew. Chem., Int. Ed. 2007, 46, 7259.
(10) For similar trends in reactivity of indoles, see: Stanley, L. M.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2009, 48, 7841.
2800
Org. Lett., Vol. 15, No. 11, 2013

The synthesis of N-tert-prenylindoles from electron-rich
indole precursors is enabled by the markedly different
electronic properties of the corresponding (η6-indole)Cr-
(CO)3 complexes. The utility of these complexes is, however,
inherently limited by the need for stoichiometric quantities
of chromium. In addition, the synthesis of (η6-indole)Cr-
(CO)3 complexes from indoles containing even weakly
deactivating groups is challenging. For example, standard
procedures for the synthesis of (η6-indole)Cr(CO)3 complexes
formed (η6-5-bromoindole)Cr(CO)3 in <5% yield.
Table 3. Scope of Pd-Catalyzed N-tert-Prenylation of Indolinesa
We conducted the reactions of indolines with carbonate
2 under the assumption that the increased nucleophilicity
of the indoline nitrogen would enable us to synthesize
N-tert-prenylindoleswith a greater rangeofelectronicchar-
acter after oxidation (Table 3).12 Indoline, 3-methylindo-
line, methyl indoline-3-acetate, and 3-phenylindoline react
with carbonate 2 to form 3gꢀi and 3n after oxidation of
the intermediate N-tert-prenylindolines with MnO2 (entries
1ꢀ4). The reactions occur with 5ꢀ6:1 tert-prenyl/n-prenyl
selectivity, and the N-tert-prenylindolines are readily
separated. N-tert-Prenylindoles 3gꢀi and 3n were isolated
in 43ꢀ80% yield over two steps as single constitutional
isomers. Reactions of 4-MeO-, 5-MeO-, and 6-MeO-
indolines with 2 occurred with 2ꢀ4:1 selectivity, and
subsequent oxidation gave N-tert-prenylindoles 3jꢀl in
25ꢀ60% yield (entries 6ꢀ8) as single constitutional isomers.
The sequence of N-prenylation of indolines followed by
oxidation to the corresponding indoles allowed us to form
N-tert-prenylindoles that were not accessible via the ap-
proaches shown in Tables 1 and 2. Reactions of protected
tryptamine derivatives, 3-phenylindole, and 5-bromoin-
dole with carbonate 2 either did not occur in high yields
or the corresponding (η6-indole)Cr(CO)3 complexes were
difficult to isolate. However, reactions of 3-phenylindoline
6d, indoline 6e (R1 = (CH2)2NPhth), and 5-bromoindo-
line 6i with 2 occurred with 4ꢀ5.5:1 tert-prenyl/n-prenyl
selectivity (entries 4, 5, and 9). After oxidation of the inter-
mediate N-tert-prenylindolines, the N-tert-prenylindoles
3nꢀp were isolated in 47ꢀ64% yield over two steps.
In summary, we have developed three strategies based
on Pd-catalyzed allylic alkylation reactions to generate
yield
tert-/
entry
6
R1
R2
3
3 (%)b n-prenylc
1
2
3
4
5
6
7
8
9
6a
6b
6c
H
H
H
H
H
H
3g
3h
3i
80
57
43
47
47
54
26
60
64
6:1
5:1
5:1
5:1
4:1
4:1
2:1
5:1
5.5:1
Me
CH2CO2Me
6d Ph
3n
3o
6e
6f
(CH2)2NPhth
H
H
H
H
4-MeO 3j
5-MeO 3k
6-MeO 3l
6g
6h
6i
5-Br
3p
a For detailed reaction conditions, see SI. b Isolated yield of 3 over
two steps. c Ratio of N-tert-prenylindoline/N-n-prenylindoline deter-
mined by 1H NMR spectroscopy.
N-tert-prenylindoles. In the presence of the same Pd catalyst,
good yields and high regioselectivity are observed for three
distinct classes of nucleophiles. Direct N-tert-prenylations of
electron-deficient indoles and indolines occur readily,
while N-tert-prenylations of electron-rich indoles are fa-
cilitatedbycomplexation withchromium. Straightforward
procedures for oxidative decomplexation of the chromium
carbonyl fragment from the (η6-N-tert-prenylindole)Cr-
(CO)3 intermediates and oxidation of the N-tert-prenylin-
dolines provide access to electron-rich N-tert-prenylindoles
in moderate to good yields. Thus, N-tert-prenylindoles with
a broad range of substitution and electronic character can
be accessed through these complementary approaches.
Efforts to extend these tert-prenylation methods to addi-
tional heterocyclic nucleophiles are ongoing.
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Acknowledgment. We thank Iowa State University and
the ISU Institute for Physical Research for financial sup-
port of this work. We thank Professor Emeritus Richard
Larock (Iowa State University) for instrumentation and
chemicals. L.S. thanks the NIH for a Pathways to Inde-
pendence Award (GM95697).
Supporting Information Available. Experimental pro-
cedures, supporting tables, and characterization for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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