Gold-catalyzed intramolecular indole/alkyne cyclization cascades through a heterolytic fragmentation: 1,5-indole migration and allenylation

Article abstract of DOI:10.1021/jo1005125

Gold-catalyzed intramolecular reactions of 3-alkynyl-bearing indoles with diol groups lead to the formation of highly functionalized 3-allenylindoles with high efficiency. The reaction likely proceeds by a new gold-catalyzed cascade cyclization/heterolytic fragmentation/elimination reactions, which results in 1,5-indole migration and C-3 allenylation of indole moiety.

Full text of DOI:10.1021/jo1005125

pubs.acs.org/joc
SCHEME 1
Gold-Catalyzed Intramolecular Indole/Alkyne
Cyclization Cascades through a Heterolytic
Fragmentation: 1,5-Indole Migration
and Allenylation
Guijie Li and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032,
People’s Republic of China
yhliu@mail.sioc.ac.cn
[2 þ 2] cycloadditions of propargylic esters,4 1,2-indole migra-
tions,5 N-acyliminium cyclizations,6 etc. Particularly interest-
ing are the intramolecular indole/alkyne cyclizations due to the
versatile reaction modes occurring in the system.7-9 For
example, Echavarren et al. have reported that intramolecular
cyclization of indoles with alkynes proceeded either by an
endo- or exo-dig process which is highly dependent on the
oxidation state of the gold catalyst.7a-c Moreover, an unusual
allenylation of the indole nucleus at C-2 derived by fragmenta-
tion reaction has been disclosed in certain cases.7a,b Recently,
we have also developed a domino process for the efficient
construction of indole-fused carbocycles10a through a Frie-
del-Crafts/hydroarylation sequence. These annulation reac-
tions are suggested to proceed by first formation of a C-C
bond at C-3 leading to a spirocyclic iminium cation B followed
by 1,2-migration to generate fused indoles as depicted in path a
of Scheme 1 (exemplified by endo-cyclization).7a,b,10a We en-
visioned that a special R2 group such as a hydroxyl group R to
the indole ring might induce the C-C bond cleavage of bond b
in a similar manner of heterolytic fragmentation11 fiollowed by
the new transformations (Scheme 1, path b). In this paper, we
report a new cyclization of 3-alkynyl-bearing indoles with
Received March 20, 2010
Gold-catalyzed intramolecular reactions of 3-alkynyl-bearing
indoles with diol groups lead to the formation of highly
functionalized 3-allenylindoles with high efficiency. The
reaction likely proceeds by a new gold-catalyzed cascade
cyclization/heterolytic fragmentation/elimination reactions,
which results in 1,5-indole migration and C-3 allenylation of
indole moiety.
Transition-metal-catalyzed cascade reactions that enable
multiple bond-forming and -cleaving events in one sequence
occupy an important place in organic synthesis.1 In this regard,
gold complexes and its salts are emerging as powerful catalysts
due to their unique ability to activate alkynes, allenes, and
alkenes toward nucleophilic attack.2 Indoles can be viewed as
excellent nucleophiles to induce cascade reactions since both of
its C-2 and C-3 positions may react with activated intermedi-
ates. These include [4 þ 2] annulations,3 3,3-rearrangement/
(4) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804.
(5) Sanz, R.; Miguel, D.; Rodrıguez, F. Angew. Chem., Int. Ed. 2008, 47,
7354.
(6) (a) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. L.;
Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796. (b) Yang, T.;
Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2007, 129, 12070.
(7) (a) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45,
1105. (b) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.;Eur. J.
2007, 13, 1358. (c) Ferrer, C.; Escribano-Cuesta, A.; Echavarren, A. M.
Tetrahedron 2009, 65, 9015. (d) England, D. B.; Padwa, A. Org. Lett. 2008,
10, 3631.
(8) For gold-catalyzed intramolecular indole/allene cyclizations, see: (a)
Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9, 1935. (b) Zhang, Z.; Liu, C.;
Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc.
2006, 128, 9066.
(1) (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(2) Forrecentreviewson gold-catalyzedreactions, see: (a)Hashmi,A. S. K.;
Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896. (b) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395. (c) Hashmi, A. S. K. Chem. Rev. 2007,
(9) For related annulations of indoles catalyzed by other transition
metals, see: (a) Donets, P. A.; Hecke, K. V.; Meervelt, L. V.; Van der
Eycken, E. V. Org. Lett. 2009, 11, 3618. (b) Beccalli, E. M.; Broggini, C.
Tetrahedron Lett. 2003, 44, 1919. (c) Liu, C.; Han, X.; Wang, X.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 3700. (d) Liu, C.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250. (e) Bressy, C.;
Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. (f) Prasad,
B. A. B.; Yoshimoto, F. K.; Sarpong, R. J. Am. Chem. Soc. 2005, 127, 12468.
(10) (a) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351, 1517.
For related papers, see: (b) Lu, Y.; Fu, X.; Chen, H.; Du, X.; Jia, X.; Liu, Y.
Adv. Synth. Catal. 2009, 351, 129. (c) Chen, Y.; Lu, Y.; Li, G.; Liu, Y. Org.
Lett. 2009, 11, 3838.
€
107, 3180. (d) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
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ꢀ
ꢀ~
ꢀ
(f) Lipshutz, B. H.; Yamamoto, Y. Chem. Rev. 2008, 108, 2793. (g) Jimenez-
Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (h) Gorin, D. J.;
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A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37, 1766. (m) Shen, H. C.
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(11) For hydroxy-group-induced fragmentation, see: (a) Grob, C. A.;
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Long, Y. O. J. Am. Chem. Soc. 2002, 124, 6542.
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3526 J. Org. Chem. 2010, 75, 3526–3528
Published on Web 04/21/2010
DOI: 10.1021/jo1005125
r
2010 American Chemical Society

Li and Liu
JOCNote
TABLE 1. Optimzation of the Reaction Conditions
TABLE 2. Gold-Catalyzed 1,5-Migration of Indoles from the Indolyl
Alkynes 1
entry
1b
catalyst
time (h)
yielda (%)
5% Ph3PAuNTf2
2% [(Ph3PAu)3O]BF4
5% AuCl3
5% Ph3PAuCl
5% AgBF4
5% AgSbF6
7.5% Ph3PAuCl/5% AgBF4
7.5% Ph3PAuCl/5% AgSbF6
5% Ph3PAuCl/5% AgSbF6
5% PtCl2
2
2
5
3
2
4
1
1
1
75
73
20
2b
3b
4b
NRc
5b
d
6e
f
7b
73
79
68
8e
9e
10e,g
11e
15
4.5
58
h
10% TfOH
c
aIsolated yield. bOne of the diastereomers was used. No reaction.
dThere were three products, but no 2a. eAnother diastereomer was used.
fStarting material remained as a major component, and several products
were observed. gThe reaction was carried out at 60 °C. hComplicated
reaction mixture.
hydroxyl groups through a heterolytic fragmentation, which
resulted in a 1,5-indole migration and allenylation at C-3 of
indole nucleus. As far as we know, the 1,5-indole migration has
not been reported and herein we present the first example in
this context.
aIsolated yield. b10% Ph3PAuNTf2 was used. c30% Ph3PAuNTf2 was
used.
To test the hypothesis, the newly designed indoles 1 with diol
groups were synthesized in two or three steps from the readily
available indole-3-carbaldehydes. It was found that the reaction
of diol 1a with Ph3PAuNTf2 as catalyst in DCE at room
temperature gave the allenic aldehyde 2a cleanly in 75% yield
(Table 1, entry 1). A competitive cyclization derived by addition
of an oxygen nucleophile to the alkyne moiety was not observed.
The gold-oxo complex [(Ph3PAu)3O]BF4 also afforded 2a in
73% yield (entry 2). In contrast, AuCl3 only led to low yield
(entry 3). The best catalyst was proven to be PPh3AuCl/AgSbF6
with a slight excess of gold catalyst, which allowed the formation
of 2a in 79% yield (entry 8). It is interesting to note that in this
new transformation, allene 2a was obtained as a result of an
overall intramolecular allenylation at C-3 of the indole nucleus,
and most strikingly, a 1,5-indole migration occurred in the
catalytic process.
With this result in hand, we next examined the substrate
scope with a range of 3-alkynyl-bearing indoles 112,13 (Table 2).
The substrates containing electron-rich or electron-deficient
aryl groups afforded good yields of the desired 3-allenyl indoles
(entries 2-4). A thienyl group was also compatible under the
reaction conditions (entry 5). However, an alkyl group as R1 led
to only 37% yield of 2f by using 10 mol % of Ph3PAuNTf2
(entry 6). This result indicated that the nature of the substituent
on the alkyne terminus played an important role in this
reaction. Regarding the indole moiety, N-methyl- or N-allyl-
protected indoles were all suitable for this reaction (entries
7-13). The functionality of 5-MeO, 5-Br, or 6-Me on indole
SCHEME 2
ring can be incorporated well into the reaction (entries 10-12).
Interestingly, the C-2 methyl-substituted 1m on indole ring
underwent the similar indole-migration reaction to yield the
allene 2m in 63% yield, although with higher catalyst loading
(entry 13). These results indicated that the initial C-C bond
formation likely takes place at C-3 of the indole ring rather than
at C-2. The structures of 2a and 2b were unambiguously
confirmed by X-ray crystallographic analysis.14
To further highlight the synthetic potential of the allenyl-
indoles, treatment of 2g with 20% TsOH H2O at 80 °C in
CH3CN was carried out, and dihydrocyclopenta[b]indole 3
was efficiently synthesized in 90% yield (Scheme 2).
3
A possible reaction mechanism based on a cyclization-
induced rearrangement is outlined in Scheme 3. The reaction
is initiated through activation of the C-C triple bond in
3-alkynylindole 1 by cationic Ph3PAuþ generated through
(12) The indoles 1 used in this study were a mixture of two diastereomers
or single diastereomers. We noted that, in some cases, an isomerization
between the two diastereomers occurred during the reaction.
(13) The cyclopropane moiety in the substrates may not be necessary for
this reaction. However, we failed to synthesize substrates without the
cyclopropane ring so far.
(14) See the Supporting Information.
J. Org. Chem. Vol. 75, No. 10, 2010 3527

Li and Liu
JOCNote
SCHEME 3
Et3N = 100:10:1) to afford the desired product 2. (It should be
noted that these allenic aldehydes usually were not stable upon
separation by normal silica gel; however, we found that the
pure products could be obtained smoothly using the silica gel
pretreated with the eluent containing 1% Et3N.)
1-(3-(1-Benzyl-1H-indol-3-yl)-1,3-diphenylpropa-1,2-dienyl)-
cyclopropanecarbaldehyde (2a). The title product was synthe-
sized from 1a (the more polar isomer was used). It was isolated in
1
79% yield as a light yellow solid: mp 147-148 °C; H NMR
(CDCl3, Me4Si, 400 MHz) δ 1.31-1.34 (m, 1H), 1.37-1.40 (m,
1H), 1.61-1.67 (m, 2H), 5.26 (s, 2H), 7.02-7.11 (m, 4H), 7.17 (t,
J = 8.4 Hz, 1H), 7.20-7.34 (m, 10H), 7.51 (d, J = 8.0 Hz, 2H),
7.57 (d, J = 8.4 Hz, 2H) 7.64 (d, J = 8.0 Hz, 1H), 9.50 (s, 1H); 13
C
NMR (CDCl3, Me4Si, 100 MHz) δ 17.7, 18.1, 33.7, 50.2, 107.1,
107.7, 110.0, 120.2, 120.4, 122.4, 126.6, 126.7, 126.8, 127.3, 127.6,
128.2, 128.3, 128.5, 128.7, 128.8, 135.6, 136.8, 137.0, 137.1, 201.3,
208.3; IR (KBr) 3058, 3028, 2926, 2821, 2723, 2245, 1709, 1596,
1537, 1492, 1466, 1453, 1445, 1391, 1354, 1335, 1239, 1179, 1075,
1030, 1003, 908, 762, 737, 696 cm-1; HRMS (EI) for C34H27NO
calcd 465.2093, found 465.2096.
chloride abstraction by silver salts. A 6-endo-dig addition of
the indole C-3 position onto gold(I)-alkyne complex 4 results
in the formation of a spirocyclic intermediate 5. Then a
heterolytic fragmentation of 5 rather than normal 1,2-migra-
tion takes place, which results in a 1,5-indole migration to
afford the alkenyl gold species 6.15 This is followed by elimina-
tion to yield the allenyl aldehyde 2 and regenerate the cationic
Au(I) catalyst. The final step may also occur through a cationic
intermediate formed by elimination of H2O.
In conclusion, we have demonstrated that gold-catalyzed
intramolecular reactions of 3-alkynyl-bearing indoles with diol
groups lead to the formation of highly functionalized 3-allenyl-
indoles with high efficiency. The reaction likely proceeds by a
new gold-catalyzed cascade cyclization/heterolytic fragmenta-
tion/elimination reactions, which results in 1,5-indole migration
and C-3 allenylation of indole moiety.
Typical Procedure for the Synthesis of Dihydrocyclopenta-
[b]indole 3. To a solution of 2g (60 mg, 0.143 mmol) in CH3CN
(2.8 mL) was added TsOH H2O (5.4 mg, 0.0286 mmol), and the
3
reaction mixture was stirred at 80 °C for 5 min. The mixture was
cooled to room temperature. The solvent was evaporated, and
the residue was purified by flash column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 5:1. The silica
gel in the column must be pretreated first by a solution of
petroleum ether/Et3N = 100:1) to afford the product 1-(3-(4-
methoxyphenyl)-4-methyl-1-phenyl-3,4-dihydrocyclopenta[b]indol-
3-yl)cyclopropanecarbaldehyde (3) as a light yellow sticky liquid
in 90% yield: 1H NMR (CDCl3, Me4Si, 300 MHz) δ 0.84-0.91
(m, 1H), 1.05-1.12 (m, 1H), 1.23-1.30 (m, 1H), 1.53-1.59 (m,
1H), 3.56 (s, 3H), 3.76 (s, 3H), 6.50 (s, 1H), 6.81 (d, J = 9.0 Hz,
2H), 7.12-7.31 (m, 5H), 7.36-7.40 (m, 1H), 7.48 (t, J = 7.5 Hz,
2H), 7.76 (d, J = 7.2 Hz, 1H), 7.80-7.83 (m, 2H), 9.44 (s, 1H);
13C NMR (CDCl3, Me4Si, 75 MHz) δ 13.6, 14.7, 31.8, 34.0, 55.2,
56.2, 110.1, 114.1, 119.9, 120.1, 120.7, 121.0, 121.2, 127.3, 127.9,
128.5, 128.6, 129.0, 132.4, 135.9, 141.6, 141.9, 152.5, 158.6,
201.9; IR (KBr) 3055, 3033, 3004, 2953, 2932, 2836, 2749,
1709, 1608, 1580, 1510, 1462, 1413, 1333, 1295, 1250, 1179,
1116, 1036, 984, 951, 909, 833, 744, 699 cm-1; HRMS (EI) for
C29H25NO2 calcd 419.1885, found 419.1884.
Experimental Section
Typical Procedure for Au(I)-Catalyzed Intramolecular Cascade
Reactions of 3-Alkynyl-Bearing Indoles 1. To a solution of
Ph3PAuCl (0.015 mmol, 7.4 mg) in ClCH2CH2Cl (2 mL) was
added AgSbF6 (0.010 mmol, 200 μL, used as a 0.05 M solution in
CH3CN), and the reaction mixture was allowed to stir at room
temperature for 10 min. 1,3-Diol 1 (0.20 mmol) and ClCH2CH2-
Cl (2 mL) were added, and the resulting solution continued to
stir at room temperature until the reaction was complete as
monitored by thin-layer chromatography. Four drops of Et3N
were added to quench the reaction. The solvent was evaporated,
and the residue was purified by flash column chromatography
on silica gel (the silica gel in the column must be pretreated
first by a solution of petroleum ether/Et3N = 100:1; eluent:
petroleum ether/Et3N = 100:1, petroleum ether/ethyl acetate/
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant Nos. 20872163, 20732008,
20821002), Chinese Academy of Science, Science and Techno-
logy Commission of Shanghai (Grant No. 08QH14030), and the
Major State Basic Research Development Program (Grant No.
2006CB806105) for financial support.
Supporting Information Available: Experimental details,
spectroscopic characterization of all new compounds, and
crystallographic data of compounds 2a and 2b (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(15) This step also can be described as a retro-aldol-type fragmentation as
suggested by one reviewer.
3528 J. Org. Chem. Vol. 75, No. 10, 2010