Palladium-catalyzed β-allylation of 2,3-disubstituted indoles

Article abstract of DOI:10.1021/ol8006277

(Chemical Equation Presented) Given the prevalence of the indole nucleus in biologically active compounds, the direct C3-functionalization of 2,3-disubstituted indoles represents an important problem. Described is a general, high-yielding method for the palladium-catalyzed β-allylation of carba- and heterocycle fused indoles, including complex natural product substrates.

Full text of DOI:10.1021/ol8006277

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2381-2384
Palladium-Catalyzed ꢀ-Allylation of
2,3-Disubstituted Indoles
Natsuko Kagawa, Jeremiah P. Malerich, and Viresh H. Rawal*
Department of Chemistry, UniVersity of Chicago, 5735 South Ellis AVenue,
Chicago, Illinois 60637
Vrawal@uchicago.edu
Received March 18, 2008
ABSTRACT
Given the prevalence of the indole nucleus in biologically active compounds, the direct C3-functionalization of 2,3-disubstituted indoles represents
an important problem. Described is a general, high-yielding method for the palladium-catalyzed ꢀ-allylation of carba- and heterocycle fused
indoles, including complex natural product substrates.
Indoles and indole-derived heterocycles are prevalent struc-
tural motifs in natural products, medicinal compounds, and
organic materials.1 Given their importance, much effort has
been directed toward the development of methods for the
selective functionalization of the indole nucleus at the N1,
C2, and C3 sites.2 A particularly difficult transformation is
the electrophilic attack at C3 on 3-substituted indoles to
produce indolenines containing a new carbon-carbon bond
and a quaternary stereocenter. Indolenine units are found as
the core of many natural products, as biogenetic precursors
to indole alkaloids, and as pivotal intermediates in total
synthesis.3,4 Traditional methods for ꢀ-functionalization of
indoles, which take advantage of the ambident character of
indoles or indole anions, have limitations.5 Not only is
alkylation of C3-substituted indoles difficult, but the strong,
nucleophilic bases (e.g., Grignard reagents, NaNH2) typically
used for such transformations restrict their scope due to
functional group incompatibility. In the course of our studies
toward the total synthesis of complex alkaloids, we required
a mild, functional group tolerant method for the introduction
of an allyl group regioselectively on a ꢀ-carboline substrate
(e.g., 1, Scheme 1). While the literature records methods for
the palladium-catalyzed ꢀ-allylation of simple indoles,6 the
direct allylation of hindered, 2,3-disubstituted indoles, such
as 1, remains an unsolved problem.7 We report here a
general, high-yielding method for the palladium-catalyzed
(4) For examples of indolenines used in total synthesis, see: (a) Li, C.;
Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007,
46, 1444–1447. (b) Bosch, J.; Bennasar, M.-L.; Amat, M. Pure Appl. Chem.
1996, 68, 557–560. (c) Sapi, J.; Dridi, S.; Laronze, J.; Sigaut, F.; Patigny,
D.; Laronze, J. Y.; Levy, J.; Toupet, L. Tetrahedron 1996, 52, 8209–8222.
(d) Rey, A. W.; Szarek, W. A.; MacLean, D. B. Can. J. Chem. 1992, 70,
2922–2928. (e) Vercauteren, J.; Massiot, G.; Levy, J. J. Org. Chem. 1984,
49, 3230–3231. (f) Wenkert, E.; Sliwa, H. Bioorganic Chem. 1977, 6, 443–
452. (g) Bramely, R. K.; Caldwell, J.; Grigg, R. J. Chem. Soc., Perkin Trans.
1 1973, 1913–1921. (h) Barton, J. E. D.; Harley-Mason, J. Chem. Commun.
(London) 1965, 298–299. (i) Robinson, R.; Suginome, H. J. Chem. Soc.
1932, 298–304.
(1) (a) Sundberg, R. J. Indoles; Academic Press: London, 1996. (b)
Saxton, J. E. E. Indoles; John Wiley & Sons: New York, 1983; Vol. 25,
Part 4.
(2) (a) Remers, W. E. In Indoles, Part 1; Houlihan, W. J., Ed.; John
Wiley & Sons: New York, 1983; pp 1-226. (b) Nunomoto, S.; Kawakami,
Y.; Yamashita, Y.; Takeuchi, H.; Eguchi, S. J. Chem. Soc., Perkin Trans.
1 1990, 111–114. For reviews, see: (c) Cacchi, S.; Fabrizi, G. Chem. ReV.
2005, 105, 2873–2920. (d) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-
Ronchi, A. Synlett 2005, 1199–1222.
(3) Julian, J. L.; Meyer, E. W.; Printy, H. C. In Heterocyclic Compounds;
Elderfield, R. C., Ed.; John Wiley & Sons: New York, 1952; Vol. 3, pp
(5) (a) Hoshino, T. Ann. 1933, 500, 35–42. (b) Nakazaki, M. Bull. Chem.
Soc. Jpn. 1961, 34, 334–337.
74-114
.
10.1021/ol8006277 CCC: $40.75
Published on Web 05/21/2008
2008 American Chemical Society

trifurylphosphine than with triphenylphosphine.11 Addition-
ally, under these conditions, none of the N-allylated product
was observed. Reduction in the amount of P(2-furyl)3 used
to a 1:1 ratio with palladium did not appreciably affect the
yield or rate of the reaction (entry 12). Given the faster rate,
lower catalyst loadings were examined. When the reaction
was carried out using 1 mol % of Pd2(dba)3 (entry 13), the
product was obtained in high yield, but required longer for
the reaction to go to completion. Further reduction of
Pd2(dba)3 to 0.5 mol % proved less satisfactory, giving 5 in
66% yield, even after 2 days (entry 14). Allyl acetate (entry
15) was found to be an ineffective allylation precursor, giving
the desired product in a reduced yield and accompanied with
the N-allylation product (19%). This survey defined conve-
nient and mild conditions for the ꢀ-allylation of hindered
indoles in high yield (entry 12).
Scheme 1
allylation of carba- and heterocycle fused indoles, including
highly functionalized complex natural product substrates.8
In initial studies, we examined the effectiveness of
published methods for the palladium-catalyzed indole ally-
lation using 1,2,3,4-tetrahydrocarbazole (3) as a challenging
substrate and allyl methyl carbonate (4) as the allyl source
(Table 1, entries 1-4).6,7,9 The modest yields obtained using
The reaction conditions developed above were found to
be broadly applicable to a wide variety of carba- and
heterocycle fused indoles (Table 2). Substitution the 6-posi-
tion of tetrahydrocarbazole is well tolerated (entries 1-3),
although chloride 6c required 20 h for complete conversion.
Cycloheptane- and cyclooctane-fused indoles 6d and 6e
participate in the reaction and give high yields of the
corresponding allyl indolenine products (entries 4-5). Tet-
rahydro-γ-carbolines are competent substrates as well but
generally require longer reaction times than their all carbon
counterparts. Electron-rich γ-carbolines (6f-h) were allylated
in greater than 90% yield, whereas the more electron-
deficient chlorocarboline 6i reacted more sluggishly, generat-
ing the allylation product 7i in 76% yield after 48 h.
Tetrahydro-ꢀ-carbolines were evaluated also. Boc-protected
ꢀ-carbolines 6j and 6k provided the allylated products in
high yield and exhibited similar rates of reaction as the
γ-carbolines. Even the more electron-deficient dihydro-ꢀ-
carboline 6l was allylated at room temperature, albeit more
slowly and in lower yield (63%). Allylation of simpler,
monosubstituted indoles gave the expected allyl-indolenines
in good yields (entries 13 and 14). Finally, substituted
tetrahydro-ꢀ-carboline 6o gave the corresponding allylation
product in 73% yield as a 1.2:1 ratio of diastereomers.
Table 1. Optimization of Allylation Reaction
time yield
[Pd] (mol %)
PR3 (mol %)
PPh3 (2.0)
(h)
(%)
1a Pd(acac)2 (2.0)
2b Pd(PPh3)4 (5.0)
20
20
20
20
20
20
20
20
20
20
2
17
20
52
90
91
trace
85
3c
Pd2(dba)3 (2.5)
Trost’s ligand (7.5)
4d [PdCl(π-allyl)]2 (5.0) dppe (11)
5
6
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.5)
Pd2(dba)3 (2.0)
Pd2(dba)3 (2.5)
PPh3 (15)
t-Bu3P (15)
P(tBu)2(biphenyl) (15)
rac-BINAP (6.0)
dppp (2.5)
7e
8e
9
45
NR
trace
99
10 Pd2(dba)3 (2.5)
11 Pd2(dba)3 (2.5)
12 Pd2(dba)3 (2.5)
13 Pd2(dba)3 (1.0)
14 Pd2(dba)3 (0.05)
15f Pd2(dba)3 (2.5)
P(OMe)3 (5.0)
P(2-furyl)3 (15)
P(2-furyl)3 (5.0)
P(2-furyl)3 (2.0)
P(2-furyl)3 (1.0)
P(2-furyl)3 (15)
2
99
20
48
20
92
66
20
(6) For examples of the 3-allylation of 3-unsubstituted indoles, see: (a)
Billups, W. E.; Erkes, R. S.; Reed, L. E. Synth. Commun. 1980, 10, 147–
154. (b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Org. Lett. 2004, 6,
3199–3202. (c) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi,
S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424–1425. (d) Liu,
Z.; Liu, L.; Shafiq, Z.; Wu, Y. C.; Wang, D.; Chen, Y. J. Tetrahedron Lett.
2007, 48, 3963–3967. (e) Zaitsev, A. B.; Gruber, S.; Pregosin, P. S. Chem.
Commun. 2007, 4692–4693. (f) Yadav, J. S.; Reddy, B. V. S.; Aravind, S.;
Kumar, G.; Reddy, A. S. Tetrahedron Lett. 2007, 48, 6117–6120.
(7) For examples of the 3-allylation of 3-substituted indoles, see: (a)
Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005,
127, 4592–4593. (b) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006,
128, 6314–6315.
a Run in AcOH at 70 °C with allyl acetate in place of 4. b Allyl alcohol
and Et3B were used in place of 4. c Allyl alcohol and n-hexyl-9-BBN were
used in place of 4; Trost’s phosphine ligand is described in ref 7. d Run at
40 °C in the presence of Li2CO3. e Run in PhMe. f Allyl acetate was used
in place of 4.
these protocols prompted us to explore other catalyst systems
for this transformation.10 Some of the many conditions
examined during this optimization process are shown in
Table 1. Pd2(dba)3 was quickly determined to be a suitable
source of the catalytically active palladium species (entries
5-11). With regard to phosphine ligands, hindered alkyl-
phosphines gave the allylated product in fair to good yields,
whereas triphenylphosphine (entry 5) and trifurylphosphine
(entry 11) gave the best yields of 5. Significantly, the rate
of the reaction was found to considerably faster with
(8) For reviews of π-allyl palladium chemistry, see: (a) Trost, B. M.;
Crawley, M. L. Chem. ReV. 2003, 103, 2921–2943. (b) Trost, B. M.; Van
Vranken, D. L. Chem. ReV. 1996, 96, 395–422. (c) Tsuji, J.; Minami, I.
Acc. Chem. Res. 1987, 20, 140–145.
(9) When 3 was subjected to MeMgBr and allyl iodide, 5 was obtained
in 94% yield. However, significantly lower yields were observed for
carboline substrates.
(10) Although the conditions in entry 4 were successful for 3, signifi-
cantly lower yields (<30%) were observed for carboline substrates.
(11) For a review of the applications of tri(2-furyl)phosphine, see:
Andersen, N. G.; Keay, B. A. Chem. ReV. 2001, 101, 997–1030.
2382
Org. Lett., Vol. 10, No. 12, 2008

The high efficiency of the allylation reactions described
above prompted us to extend the reaction to substituted allyl
carbonates. The results of these studies are summarized in
Table 3. Methallyl carbonate 8a reacted with carbazole 3 to
give 9a in 98% yield (entry 1). The corresponding reaction
with crotyl carbonate 8bproceeded cleanly to afford indo-
Table 2. Scope of Pd-Catalyzed ꢀ-Allylation of Indolesa
Table 3. Allylation with Substituted Allyl Carbonatesa
a Reactions were carried out on 0.250 mmol of 3 with 2.5 mol % of
Pd2(dba)3, 5.0 mol % of P(2-furyl)3, and 2.0 equiv of 8 in 2.5 mL of CH2Cl2
at rt. b Reaction was carried out in dichloroethane heated to reflux with 5.0
mol % of Pd2(dba)3 and 10 mol % of P(2-furyl)3.
lenine 9b in high yield (entry 2). Notably, the regio- and
geometric alkene isomer products were observed in only trace
amounts. The prenylation of 3 with prenyl carbonate 8c was
much slower than analogous allylation reactions but did
provide the prenylated indolenine 9c in 45% yield (entry 3).
Lastly, the reaction of carbazole 3 with cinnamyl carbonate
8d afforded 9d in 92% yield as the sole observed isomer
(entry 4).
The capability of a method is assessed best when it is
utilized for complex molecules containing multiple functional
groups. With that consideration in mind, we examined the
allylation of three different indole alkaloids of varying
functional group complexity (Scheme 2). Subjection of
synthetic, unprotected (()-geissoschizol (10)12 to the ally-
lation protocol afforded the corresponding allyl-indolenine
(11) in high diastereoselectivity in 45% yield (Scheme 2, eq
1).13,14 The allylation of yohimbine (12) was also highly
a Reactions were carried out on 0.250 mmol of indole substrate with
0.025 equiv of Pd2(dba)3, 0.050 equiv of P(2-furyl)3, and 2.0 equiv of allyl
methyl carbonate (4) in 2.5 mL of CH2Cl2 at rt. b 0.300 equiv of P(2-furyl)3
was used.
Org. Lett., Vol. 10, No. 12, 2008
2383

The allyl derivatives represent novel analogues of these
bioactive indole alkaloids.
Scheme 2. Allylation of Complex Natural Products
In summary, we have described a convenient, high-
yielding method for the regioselective allylation of carbazole
and carboline substrates, which can be extended to substituted
allyl analogs as well as to complex indole alkaloids.16 Studies
directed toward the implementation of an asymmetric variant
of the above reaction are underway, and the results will be
detailed in due course.
Acknowledgment. Financial support from the National
Cancer Institute of the National Institutes of Health, USA
(R01 CA101438) is gratefully acknowledged. We thank
Merck & Co. for additional support.
Supporting Information Available: Characterization data
and NMR spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8006277
(12) (a) Birman, V. B.; Rawal, V. H. Tetrahedron Lett. 1998, 39, 7219–
7222. (b) Birman, V. B.; Rawal, V. H. J. Org. Chem. 1998, 63, 9146–
9147.
(13) The low isolated yield of 11 is attributed to difficulties in isolation
and purification. The conversion of this reaction is estimated to be >60%.
(14) For a study on the diastereoselectivity of chlorination of compounds
related to geissoschizol, see: Ito, M.; Clark, C. W.; Mortimore, M.; Goh,
J. B.; Martin, S. F. J. Am. Chem. Soc. 2001, 123, 8003–8010.
(15) For a review of the oxidation and chlorination of yohimbine, see:
Borschberg, H.-J. Curr. Org. Chem. 2005, 9, 1465–1491. Reaction of
yohimbane with NaNH2 and BnBr gave the N-benzyl and both epimeric
C-benzyl products: von Strandtmann, M.; Eilertse, R.; Shavel, J. J. Org.
Chem. 1966, 31, 4202–4204.
diastereoselective, providing a single allylation product (13)
in 79% yield (Scheme 2, eq 2).15 An even more intricate
molecule, reserpine (14), underwent allylation under the
standard conditions and provided roughly equal amounts of
the two diastereomeric allylated products 15 (Scheme 2, eq
3). The relative stereochemistries of the allylation products
have been tentatively assigned based on their NMR spectral
properties. The dramatic differences in levels of diastereo-
selection for the three alkaloids are not immediately apparent.
(16) Typical Procedure for Allylation of Indoles. To a solution of
Pd2(dba)3 (5.7 mg, 0.0063 mmol) and P(2-furyl)3 (2.9 mg, 0.013 mmol) in
CH2Cl2 (1.3 mL) at rt was added allyl methyl carbonate (57 µL, 0.50 mmol).
After 10 min, a solution of the appropriate indole (0.250 mmol) in CH2Cl2
(1.3 mL) was added. When indole starting material had disappeared
(monitored by TLC), the reaction mixture was concentrated. The residue
was purified by flash chromatography to afford the desired 3-allylated
products.
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Org. Lett., Vol. 10, No. 12, 2008