Addition of indoles to oxyallyl cations for facile access to α-indole carbonyl compounds

Article abstract of DOI:10.1021/ol300591z

A direct coupling of unprotected indoles and α-halo ketones via in situ generated oxyallyl cation intermediates is described. The reactions efficiently afford α-indole carbonyl compounds with good to quantitative yields.

Full text of DOI:10.1021/ol300591z

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1922–1925
Addition of Indoles to Oxyallyl Cations
for Facile Access to r-Indole Carbonyl
Compounds
Qiang Tang, Xingkuan Chen, Bhoopendra Tiwari, and Yonggui Robin Chi*
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
robinchi@ntu.edu.sg
Received March 7, 2012
ABSTRACT
A direct coupling of unprotected indoles and R-halo ketones via in situ generated oxyallyl cation intermediates is described. The reactions
efficiently afford R-indole carbonyl compounds with good to quantitative yields.
R-Indole carbonyl compounds are important building
blocks for the concise preparation of synthetic or naturally
occurring bioactive molecules, such as β-carbolines, car-
bazoles, serotonins, tryptophols, hapalindole Q, and
Fishcherindole U (Figure 1).1 The synthesis of R-indole
carbonyl compounds can be realized via multistep pro-
tocols,2 such as epoxide opening by indole magnesium chlo-
rides followed by oxidation,3 reactions of Weinreb amides
with Grignard reagents,4base-promoted condensation between
protected indoles and ketones followed by hydroxylation
and oxidation,5 and other cross-coupling methods,6 in
which substrate protection and prefunctionalization are
typically required. Baran and co-workers recently devel-
oped the direct coupling of unprotected indoles with in situ
(6) Richter, J. M.; Whitefield, B. W.; Maimone, T. J.; Lin, D. W.;
Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857.
(7) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450.
(8) (a) Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.;
Llamas, T. S.; Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
17938. (b) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446,
404. (c) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394.
(d) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed. 2005,
44, 609.
(9) For reviews, see: (a) Lohse, A. G.; Hsung, R. P. Chem.;Eur. J.
2011, 17, 3812. (b) Harmata, M. Chem. Commun. 2010, 46, 8886. (c)
Harmata, M. Chem. Commun. 2010, 46, 8904. (d) Foley, D. A.; Maguire,
A. R. Tetrahedron 2010, 66, 1131. (e) Grant, T. N.; Rieder, C. J.; West,
F. G. Chem. Commun. 2009, 5676. (f) Harmata, M. Adv. Synth. Catal.
2006, 348, 2297. (g) Battiste, M. A.; Pelphrey, P. M.; Wright, D. L.
Chem.;Eur. J. 2006, 12, 3438. (h) Huang, J.; Hsung, R. P. Chemtracts
2005, 18, 207. (i) Tamaru, Y. Eur. J. Org. Chem. 2005, 2647. (j) Niess, B.;
Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2005, 44, 26. (k) Hartung,
I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2004, 43, 1934. (l)
Harmata, M.; Rashatasakhon, P. Tetrahedron 2003, 59, 2371. (m)
Harmata, M. Acc. Chem. Res. 2001, 34, 595. (n) Rigby, J. H.; Pigge,
F. C. Org. React. 1997, 51, 351. (o) Harmata, M. Tetrahedron 1997, 53,
6235. (p) Mann, J. Tetrahedron 1986, 42, 4611. (q) Tidwell, T. T. Angew.
Chem., Int. Ed. 1984, 23, 20. (r) Hoffmann, H. M. R. Angew. Chem., Int.
Ed. 1984, 23, 1. (s) Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163.
(t) Noyori, R. Acc. Chem. Res. 1979, 12, 61. (u) Takaya, H.; Makino, S.;
Hayakawa, Y.; Noyori, R. J. Am. Chem. Soc. 1978, 100, 1765.
(v) Hoffmann, H. M. R. Angew. Chem., Int. Ed. 1973, 12, 819.
(1) (a) Cao, R.; Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007,
€
14, 479. (b) Knolker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303. (c)
Berger, M.; Gray, J. A.; Roth, B. L. Annu. Rev. Med. 2009, 60, 355. (d)
Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110,
4489. (e) Moore, R. E.; Cheuk, C.; Yang, X. Q. G.; Patterson, G. M. L.;
Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.; Jones,
N. D. J. Org. Chem. 1987, 52, 1036. (f) Stratmann, K.; Moore, R. E.;
Bonjouklian, R.; Deeter, J. B.; Patterson, G. M. L.; Shaffer, S.; Smith,
C. D.; Smitka, T. A. J. Am. Chem. Soc. 1994, 116, 9935.
(2) Bartels, B.; Weinbrenner, S.; Marx, D.; Diefenbach, J.; Dunkern,
T.; Menge, W. M. P. B.; Christiaans, J. A. M. WO 2010/015587 A1,
2010, Nycomed GmbH, Germany, and references therein.
(3) Ghosh,A.;Wang,W.;Freeman,J.P.;Althaust,J.S.;VonVoigtlander,
P. F.; Scahill, T. A.; Mizsak, S. A.; Szmuszkovicz, J. Tetrahedron 1991, 47,
8653.
(4) Duval, E.; Cuny, G. D. Tetrahedron Lett. 2004, 45, 5411.
(5) (a) Deskus, J. A.; Epperson, J. R.; Sloan, C. P.; Cipollina, J. A.;
Dextraze, P.; Qian-Cutrone, J.; Gao, Q.; Ma, B.; Beno, B. R.; Mattson,
G. K.; Molski, T. F.; Krause, R. G.; Taber, M. T.; Lodge, N. J.;
Mattson, R. J. Bioorg. Med. Chem. Lett. 2007, 17, 3099. (b) Bignan,
G. C.; Battista, K.; Connolly, P. J.; Orsini, M. J.; Liu, J.; Middleton,
S. A.; Reitz, A. B. Bioorg. Med. Chem. Lett. 2006, 16, 3524.
r
10.1021/ol300591z
Published on Web 03/28/2012
2012 American Chemical Society

derived from R-chloroketones caught our attention in part
due to synthetic simplicity and potential to develop en-
antioselective catalysis. These oxyallyl cations have been
extensively explored in the context of (4 þ 3) cycloaddi-
tions with dienes.9 The interrupted processes (i.e., simple
nucleophilic addition to the oxyallyl cations), however,
often give poor yields and thus show limited utilities.10
Here we report a direct nucleophilic addition of unpro-
tected indoles to in situ generated oxyallyl cations for an
efficient access to R-indole carbonyl compounds (Table 1).
The oxyallyl cations are formed from R-chloroketones
under mild conditions, and some of the products can be
obtained in pure form after a simple filtration, further
highlighting the practical utilities of this method. It is
worth noting that oxyallyl cations could also be generated
during Nazarov cycloadditions to be trapped by indole
nucleophiles, as disclosed by the groups of Burnell11 and
Tius.12
We first studied the reaction between 2-chlorocyclopen-
tanone (1a) and indole (2a). Little product (3a) was
obtained using common organic solvents such as DMSO,
THF, and toluene in the presence of Na2CO3 (Table 1,
entry 1). The use of water or methanol as solvent led to 3a
with low to moderate yields, in part due to side reactions
between these nucleophilic solvents and the oxyallyl cation
intermediates (Table 1, entries 2 and 3).13 Fluorinated
alcohols (such as trifluoromethanol, TFE) were then
evaluated (Table 1, entries 4ꢀ9). With TFE as the solvent,
the choice of bases showed a significant effect on the
reaction cleanliness and yields. The starting materials
(1a and 2a) remained largely unconsumed when relatively
weak bases such as NaHCO3 were used. On the other
hand, when strong bases such as NaOH were used, the
reaction became a little complex with the formation of
Favorskii rearrangement14 adducts, among other side
Figure 1. Natural products synthesized from R-indole carbonyls.
generated enolates to prepare R-indole carbonyl com-
pounds.7 By using a slight excess amount of the indole to
avoid homocouplings of the enolates, the Baran group has
applied this strategy to rapidly construct a diverse set of
indole-containing natural products, such as hapalindoles,
Fischerindoles, ketorolac, and acremoauxin A.8
Table 1. Model Reaction Optimizationa
time
[h]
yield
[%]b
entry
base
solvent
1
2
3
4
5
6
7
8
9
Na2CO3
Na2CO3
Na2CO3
NaHCO3
NaOH
solventsc
H2O
48
4
<5
22
50
<5
60
79
83
>95
91
(11) (a) Marx, V. M.; LeFort, F. M.; Burnell, D. J. Adv. Synth. Catal.
2011, 353, 64. (b) Marx, V. M.; Burnell, D. J. J. Am. Chem. Soc. 2010,
132, 1685. (c) Marx, V. M.; Cameron, T. S.; Burnell, D. J. Tetrahedron
Lett. 2009, 50, 7213. (d) Marx, V. M.; Burnell, D. J. Org. Lett. 2009, 11,
1229.
(12) (a) Basak, A. K.; Tius, M. A. Org. Lett. 2008, 10, 4073. (b)
Dhoro, F.; Kristensen, T. E.; Stockmann, V.; Yap, G. P. A; Tius, M. A.
J. Am. Chem. Soc. 2007, 129, 7256. (c) Santos, D. B. D.; Banaag, A. R.;
Tius, M. A. Org. Lett. 2006, 8, 2579.
MeOH
TFE
12
48
4
TFE
pyrrolidine
Et3N
TFE
48
48
12
16
TFE
Na2CO3
Na2CO3
TFE
HFIP
€
(13) Fohlisch, B.; Gehrlach, E.; Stezowski, J. J.; Kollat, P.; Martin,
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), base (0.6 mmol)
in solvent (1 mL) at rt. b Isolated yield of 3a. c DMF, DMSO, THF, Et2O,
toluene, CH2Cl2, EtOAc, CH3CN. TFE = 2,2,2-trifluoroethanol;
HFIP = hexafluoro-2-propanol.
E.; Gottstein, W. Chem. Ber. 1986, 119, 1661.
(14) (a) Fohlisch, B.; Franz, T.; Kreiselmeier, G. Eur. J. Org. Chem.
2005, 4687. (b) Fort, A. W. J. Am. Chem. Soc. 1962, 84, 4979.
(15) (a) Berkessel, A.; Adrio, J. A.; Huttenhain, D.; Neudorfl, J. M.
€
€
€
ꢀ
ꢀ
J. Am. Chem. Soc. 2006, 128, 8421. (b) Begue, J.-P.; Bonnet-Delpon, D.;
Crousse, B. Synlett 2004, 18. (c) Schaal, H.; Haber, T.; Suhm, M. A.
J. Phys. Chem. A 1999, 104, 265. (d) Middleton, W. J.; Lindsey, R. V.
J. Am. Chem. Soc. 1964, 86, 4948.
We are interested in developing alternative methods for
efficient access to R-indole carbonyls. Oxyallyl cations
(16) Another possible pathway involving the addition of indole to the
ketone carbonyl group followed by a cyclopropane formation and
cleavage is ruled out, as this will lead to a different regioisomer of 4b
from 1d, contrary to our observation. For relevant studies, see: (a)
Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc. 2002,
124, 7440. (b) Yasuda, M.; Tsuji, S.; Shibata, I.; Baba, A. J. Org. Chem.
1997, 62, 8282. (c) Kelin, A. V.; Kulinkovich, O. G. Synthesis 1996, 330.
(d) Yasuda, M.; Katoh, Y.; Shibata, I.; Baba, A.; Matsuda, H.; Sonoda,
N. J. Org. Chem. 1994, 59, 4386. (e) Yasuda, M.; Oh-Hata, T.; Shibata,
I.; Baba, A.; Matsuda, H. J. Chem. Soc., Perkin Trans. 1 1993, 859. (f)
Baba, A.; Yasuda, M.; Yano, K.; Shibata, I.; Matsuda, H. J. Chem. Soc.,
Perkin Trans. 1 1990, 3207. (g) Kosugi, M.; Takano, I.; Sakurai, M.;
Sano, H.; Migita, T. Chem. Lett. 1984, 13, 1221.
(10) (a) The Harmata group recently reported a successful ene-type 1
reaction between an oxyallyl cation bearing a good leaving group
(Me2PhSi group) and enol ethers. Without the Me2PhSi group, an
inseparable mixture of both ene-type 1 product and (4 þ 3) cycloadduct
was produced. See: Harmata, M.; Huang, C.; Rooshenas, P.; Schreiner,
P. R. Angew. Chem., Int. Ed. 2008, 47, 8696. (b) Harsh conditions (e.g.,
high temperature, strong acid) have also been used to generate oxyallyl
cations from other functionalized ketones for nucleophilic reactions
with low to moderate yields; see: Leitich, J.; Heise, I. Eur. J. Org. Chem.
2001, 2707. (c) Freter, K. Liebigs Ann. 1978, 1357.
Org. Lett., Vol. 14, No. 7, 2012
1923

products (Table 1, entry 5). Finally we found that organic
bases such as pyrrolidine and Et3N, and inorganic bases
such as Na2CO3 could effectively promote the reaction
(Table 1, entries 6ꢀ9). Using Na2CO3 in TFE, a very clean
reaction was realized with quantitative formation of 3a,
obtained in essentially pure form after a simple filtration
and solvent evaporization (Table 1, entry 8). The high
ionizing power and low nucleophilicity of the fluorinated
solvents are believed to contribute to the cleanliness and
high yield of the reactions.15
Table 2. Addition of Indole to Different R-Halo Ketonesa
Scheme 1. Addition of Different Indoles to 1aa,b
a 1a (0.5 mmol), 2 (0.5 mol), Na2CO3 (0.6 mmol) in TFE (1 mL).
bIsolated yield. c1a (0.60 mmol) and Na2CO3 (0.75 mmol) were used.
Scheme 2. Mechanistic Studies
a 1 (0.5 mmol), 2a (0.5 mmol), Na2CO3 (0.6 mmol) in TFE (1 mL); no
column chromatography required. b 1 (0.6 mmol), Na2CO3 (0.7 mmol).
c TFE/HFIP (0.9 mL þ 0.3 mL) as solvent. d 1 (2.5 mmol), TFE/HFIP
(0.9 mL þ 0.3 mL) as solvent. e 2a (2.5 mmol).
Next, we examined different indoles in the reaction with
1a. Both electron-rich and -deficient indoles reacted well to
give 3 in good to excellent yields (Scheme 1, 3bꢀ3j). One
notable variation was that indoles substituted with very
strong electron-withdrawing functionalities (ꢀNO2) re-
quired a slight excess of 1a (1.2 equiv) and base (1.5 equiv)
to drive the reaction to its completion (3d and 3e).
The reaction outcome remained unaffected with different
substitution patterns on the indoles (3hꢀ3j). We also
examined N-protected indoles: N-methyl indole gave the
product in excellent yield (Scheme 1, 3k), and N-phenyl-
sulfonyl indole remained unreacted.
We then evaluated the addition of indole to different
R-haloketones (1), as summarized in Table 2. The same
product (4b) was obtained starting with two different
isomers of chloro-2-methyl-cyclohexanone (1c and 1d),
suggesting an SN1 reaction pathway via the same oxyallyl
1924
Org. Lett., Vol. 14, No. 7, 2012

cation intermediate (Scheme 2).16 Similarly, the two iso-
mers of dichloroacetone (1m and 1n) gave the identical
product (4k). A significant difference in the reaction time
was observed for 1,3-dichloroacetone 1m (8 h) and 1,1-
dichloroacetone 1n (4 days). This difference can be ex-
plained by the relative ease of oxyallyl cation formations
from the two chloro ketone isomers (1m and 1n), as
illustrated in Scheme 2. 1,3-Dichloroacetone 1m contains
a more acidic proton (R-CH-Cl; compared to R-CH-H of
1,1-dichloroacetone 1n) which can undergo faster depro-
tonation to eventually give oxyallyl cation intermediate II.
These results also suggest that the oxyallyl cation forma-
tion is likely the rate-determine step for the indole addition
reactions. The same hypothesis explains the longer reac-
tion time and requirement for a higher ionizing solvent
(HFIP, instead of TFE) for 1i, compared to 1j (Table 2).
As for the scope of the reaction regarding the haloketone
substrates, dichloro or dibromo ketones (1jꢀl) in reaction
with an equimolar amount or excess of indole gave the
monosubstitution products in excellent yields (Table 2,
4gꢀ4i). With an extended reaction time in TFE/HFIP, 1l
(and 1k) could undergo a second (intramolecular) nucleo-
philic addition via 4i to give an indole-fused multicyclic
ketone product 4j in 68% yield and essentially as a single
diastereomer. It is interesting to note that such intramolec-
ular reactions were not observed while using other dihalo-
ketones 1j and 1mꢀp. In the cases using 1mꢀp, two mole-
cules of indole reacted with one molecule of ketone to give
4kꢀm. No product was observed with 1i, 1m, and 1n using
TFE as the solvent, even at reflux temperature. We also
tested R-haloketones such as 2-bromo-1-phenyl ethanone
and 1-bromo-3,3-dimethyl butan-2-one under the above
reaction conditions. As expected these substrates remained
unreacted as they could not form oxyallyl cations.
diastereomer was isolatedin 11% yield, Scheme 3). Adduct
5 is the key intermediate in Baran’s total syntheses of
several natural products including hapalindole Q.7,8b,8c
Scheme 3. Synthesis of the Key Intermediate 5 of Hapalindole
In conclusion, we have developed a highly efficient and
practical method for the direct coupling of indoles and
R-halo ketones. The R-indole carbonyl compounds were
obtained in good to quantitative yields, and in many cases
analytically pure products were obtained after simple
filtrations followed by solvent removal. No protection or
prefunctionalization of the indole substrates is required in
our protocol. Compared to the cycloaddition reactions,
direct nucleophilic additions to oxyallyl cations (and their
analogs or equivalents) have remained underdeveloped.
Further development of these SN1-type direct coupling
reactions, including their asymmetric catalytic versions, is
being pursued in our laboratory.
Acknowledgment. We thank the generous financial sup-
ports from Singapore National Research Foundation
(NRF), Singapore Economic Development Board (EDB),
GlaxoSmithKline (GSK), and Nanyang Technological Uni-
versity (NTU). We also appreciate the scientific and editorial
suggestions from the referees.
Supporting Information Available. Experimental pro-
cedures, compound characterization, NMR spectra, and
HRMS. This material is available free of charge via the
Internet at http://pubs.acs.org.
The utility of our method is further illustrated with the
synthesis of a key intermediate in the total synthesis of
hapalindole Q. Dibromoketone 1q and indole 2a were
subjected to a base-promoted coupling reaction in
TFE/HFIP to give 5 with 57% isolated yield (the minor
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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