Titanocene(III)-catalyzed formation of indolines and azaindolines

Article abstract of DOI:10.1021/ol801860s

(Chemical Equation Presented) Reductive cyclization of epoxides tethered to substituted anilines and aminopyridines in the presence of 3 mol % of titanocene dichloride and stoichiometric manganese metal promotes a radical annulation to form 3,3-disubstituted indolines and azaindolines.

Full text of DOI:10.1021/ol801860s

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4383-4386
Titanocene(III)-Catalyzed Formation of
Indolines and Azaindolines
Peter Wipf* and John P. Maciejewski
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf@pitt.edu
Received August 9, 2008
ABSTRACT
Reductive cyclization of epoxides tethered to substituted anilines and aminopyridines in the presence of 3 mol % of titanocene dichloride and
stoichiometric manganese metal promotes a radical annulation to form 3,3-disubstituted indolines and azaindolines.
The continued development of new methodology for the
construction of indolines1,2 and azaindolines3 is well justified
by the tremendous therapeutic potential associated with these
heterocyclic building blocks.4 Natural products containing
the 3,3-disubstituted indoline motif include the clinically used
antitumor agent vinblastine (1),5 the novel marine metabolite
diazonamide A (2),6 and the cagelike structures of kopsi-
darine (3),7 and scholarisine A (4)8 (Figure 1).
Alkyl radical cyclization onto pyridine rings to prepare
azaindolines is common;9 in contrast, methods to construct
indolines by alkyl radical cyclization onto the aromatic
(1) For a review on indoline synthesis, see: Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045
.
(2) (a) Clive, D. L. J.; Sunasee, R. Org. Lett. 2007, 9, 2677. For indoline
preparation using xanthate transfer, see: (b) Zard, S. Z. In Radical Reactions
in Organic Synthesis; Oxford University Press, Inc.: New York, 2003; pp
153-163. (c) Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z.
Figure 1. Representative natural products with 3,3-disubstituted
Tetrahedron. Lett. 1999, 40, 2533
.
(3) For a review on azaindoline synthesis, see: Song, J. J.; Reeves, J. T.;
Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc. ReV. 2007,
36, 1120.
indoline scaffolds (outlined in bold).
nucleus without using xanthate transfer are scarce.2b,c While
the majority of known protocols for indoline synthesis utilize
nucleophilic, Lewis acid, and transition-metal cross-coupling
techniques, we envisioned a radical process that installs a
quaternary carbon simultaneous with pyrrolidine formation
from readily available epoxidized allylic amines.10 The
reductive opening of epoxides using either stoichiometric11
or catalytic12 titanocene(III) chloride was particularly at-
tractive toward this goal. Nearly two decades after the first
reports of using in situ prepared titanocene(III) chloride to
(4) Sun, H.; Ehlhardt, W. J.; Kulanthaivel, P.; Lanza, D. L.; Reilly, C. A.;
Yost, G. S. J. Pharmacol. Exp. Ther. 2007, 322, 843.
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Curmi, P. A.; Sobel, A.; Knossow, M. Nature 2005, 435, 519.
(6) Lachia, M.; Moody, C. J. Nat. Prod. Rep. 2008, 25, 227.
(7) Subramaniam, G.; Kam, T.-S. HelV. Chim. Acta 2008, 91, 930.
(8) Cai, X.-H.; Tan, Q.-G.; Liu, Y.-P.; Feng, T.; Du, Z.-Z.; Li, W.-Q.;
Luo, X.-D. Org. Lett. 2008, 10, 577.
(9) (a) Bertini, F.; Galli, R.; Perchinunno, M.; Minisci, F. Tetrahedron
1971, 27, 3575. (b) Studer, A.; Bossart, M. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp
62-76. (c) Togo, H. In AdVanced Free Radical Reactions for Organic
Synthesis; Elsevier: New York, 2004; pp 57-121. (d) Storey, J. M. D.;
Ladwa, M. M. Tetrahedron Lett. 2006, 47, 381.
10.1021/ol801860s CCC: $40.75
Published on Web 09/10/2008
2008 American Chemical Society

Table 1. Optimization of the Titanocene(III) Catalyzed Reductive Cyclization of Anilinesa,b
entry
epoxide
Cp2TiCl2 (mol %)
Mn (equiv)
concentration [M]
R1
R2
product (s), yield (%)
1
2
3
4
5
6
7
8
9
4a
4b
4b
4c
4c
4b
4a
4c
4c
4c
10
10
10
10
3
3
3
3
3
0.80
0.65
0.65
1.5
1.5
1.5
1.5
1.5
0
0.03
0.03
0.03
0.1
0.1
0.1
0.1
0.1
0.1
0.1
Ph
Ph
Ph
Cbz
Cbz
Ph
H
5a:6a (3:1)c,d
5b, 82d
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
5b, 84e
5c:7c (2:1)f
8c, 63g
5b, 89
Ph
5a:6a (3.8:1), 87
Cbz
Cbz
Cbz
5c, 14h
5c, 0
5c, 0
10
0
1.5
a For epoxide preparation, see the Supporting Information. b All reactions were performed in degassed THF heated at reflux unless otherwise noted.
c Yield not determined; product ratio was determined by GC analysis of crude reaction mixtures. d Reaction was performed in degassed THF at room
temperature using sonication. e Reaction was performed in degassed THF at room temperature using magnetic stirring. f Yield not determined; product ratios
were determined by 1H NMR analysis of crude reaction mixtures. g Yield was determined over two steps. h Starting material 4c was recovered in 43% yield.
generate reactive radical intermediates from epoxides, novel
applications of this reagent continue to emerge.13
to the epoxide in substrate 4b (R2 ) CH3) improved the
efficiency of the titanocene(III) chloride catalyzed process
and afforded 5b as a single product in 82% yield (entry 2).
With 1,1-disubstituted epoxides, sonication was not essential
and conventional magnetic stirring also afforded the product
in good yield (entry 3).
To test the potential of this methodology in the synthesis
of 3,3-disubstituted indoline and azaindoline heterocycles,
epoxide 4a14 was subjected to 10 mol % of Cp2TiCl2 at room
temperature in degassed THF (0.1 M) in the presence of 2
equiv of zinc dust. However, these conditions gave only
traces of the desired indoline and mainly undesired side
products. Fortunately, upon lowering the concentration of
the substrate to 0.03 M and using 10 mol % of precatalyst
in the presence of 0.80 equiv of 20-50 mesh manganese
powder under sonication15 at room temperature, a 3:1 ratio
of indoline 5a and tetrahydroquinoline 6a was detected by
GC analysis of the crude reaction mixture (Table 1, entry
1). Substoichiometric amounts of manganese metal increased
the ratio in favor of indoline 5a; a possible indication of
reversible radical pathways.12c Addition of a methyl group
Model substrates 4a and 4b were designed to facilitate
the cyclization by the presence of two symmetrical N-phenyl
substituents. However, in order to broaden the scope of this
reaction, we intended to replace one of them with a suitable
nitrogen protective group. For reasons that are not completely
clear, the secondary amine (R1 ) H) mostly decomposed in
the reaction mixture, and only a minor amount of reduced
amino alcohol was formed. Alternatively, among protecting
groups at this position, including the p-toluenesulfonyl,
benzyl, trifluoroacetyl, and tert-butoxycarbonyl functions, the
benzylcarbamate (Cbz) group proved to be the most versatile
substituent after we reoptimized the reaction parameters. At
room temperature, anilide 4c afforded a ∼2:1 mixture of 5c:
7c at 0.1 M concentration in the presence of 10 mol % of
titanocene dichloride (Table 1, entry 4). The undesired
reduced epoxide 7c could be suppressed by lowering the
precatalyst loading to 3 mol % of Cp2TiCl2 while increasing
the reaction temperature to THF at reflux.16 Under these
conditions, indoline 8c was isolated in 63% yield over two
steps (entry 5). When these optimized conditions were
applied to the earlier model system 4b, indoline 5b was
formed in 89% yield (entry 6). High yields were also
obtained for epoxide 4a, which provided a 3.8:1 mixture of
5a and 6a in 87% yield. We also explored the sensitivity of
the reaction to air. When the epoxide-opening rearrangement
with substrate 4c was performed in a flask kept open to the
atmosphere in nondegassed THF, the reactivity was greatly
diminished (entry 8). Additional control experiments using
(10) For our previous studies on indoline and isoindolinone synthesis
using nucleophilic addition strategies, see: (a) Wipf, P.; Kim, Y. Tetrahedron
Lett. 1992, 33, 5477. (b) Pierce, J. G.; Waller, D. L.; Wipf, P. J. Organomet.
Chem. 2007, 692, 4618.
(11) (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988,
110, 8561. (b) Rajanbabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994,
116, 986.
(12) (a) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998,
120, 12849. (b) Gansa¨uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem.,
Int. Ed. 1998, 37, 101. (c) Gansa¨uer, A.; Barchuk, A.; Keller, F.; Schmitt,
M.; Grimme, S.; Gerenkamp, M.; Mu¨ck-Lichtenfeld, C.; Daasbjerg, K.;
Svith, H. J. Am. Chem. Soc. 2007, 129, 1359, and references cited
therein.
(13) For reviews, see: (a) Gansa¨uer, A.; Pierobon, M.; Bluhm, H.
Synthesis 2001, 16, 2500. (b) Barrero, A. F.; Quilez del Moral, J. F.;
Sanchez, E. M.; Arteaga, J. F. Eur. J. Org. Chem. 2006, 1627. For additional
applications, see: (c) Fernandez-Mateos, A.; Herrero Teijon, P.; Mateos
Buron, L.; Rabanedo Clemente, R.; Rubio Gonzalez, R. J. Org. Chem. 2007,
72, 9973. (d) Monleon, L. M.; Grande, M.; Anaya, J. Tetrahedron 2007,
63, 3017.
(14) Barvainiene, B.; Stanisauskaite, A.; Getautis, V. Chem. Heterocycl.
Cmpd. 2006, 42, 123.
(15) Sonication was used to increase reagent solubility.
4384
Org. Lett., Vol. 10, No. 19, 2008

Table 2. Indolines Prepared Using Titanocene(III) Catalysis
Scheme 1. Preparation of 5-Azaindoline 28
24 from epoxide 23 did not yield any of the cyclized product
(entry 8). Meta-substituted anilines generally led to 1:1
mixtures of regioisomeric indolines (data not shown).
Azaindoles are attractive bioisosteres of indoles in phar-
maceutical research.17 We therefore investigated the pos-
sibility of applying this methodology toward the formation
of azaindolines, using aminopyridines in place of anilines.
Chemoselective epoxidation of alkenes in the presence of a
pyridine ring is precedented; however, attempts to efficiently
prepare the epoxide on an unsubstituted aminopyridine
substrate were unsuccessful. This was primarily due to the
reactivity of the nucleophilic pyridine nitrogen toward either
m-CPBA or DMDO.18 In contrast, an o-chlorine substitu-
tion19 proved to be sufficient to attenuate the nucleophilic
character of the pyridine nitrogen. Curtius rearrangement of
the known carboxylic acid 2520 and trapping of the inter-
mediate isocyanate with benzyl alcohol afforded aminopy-
ridine 26 (Scheme 1). Subsequent methallylation of the Cbz-
protected amine and epoxidation with m-CPBA led to
epoxide 27. Under the optimized titanocene(III) chloride
conditions, cyclization provided an intermediate 4,6-dichloro-
5-azaindoline, which was concurrently deprotected and
dechlorinated with Pd/C under an atmosphere of H2 to give
azaindoline 28 in 52% yield over two steps.
As a mechanism for the titanocene(III) chloride catalyzed
epoxide-opening annulation, we propose that the formation
of the ꢀ-titanoxy radical 3011,12 is followed by a reversible
(16) Typical Procedure: To a flame-dried two-neck flask was added
129 mg (0.43 mmol) of 4c, 3.2 mg (0.01 mmol) of Cp2TiCl2, 102 mg (0.64
mmol) of collidine hydrochloride, and 35.6 mg (0.64 mmol) of Mn0. The
vessel was fitted with a reflux condenser and purged three times with Ar.
After addition of 4.3 mL of deoxygenated THF (0.1 M), the reaction mixture
was placed in a preheated oil bath and heated at reflux for 3 h. The color
of the solution gradually changed from light pink to a dark violet. The
mixture was cooled to room temperature, quenched with satd NH4Cl,
extracted with 3 × 10 mL of Et2O, washed with brine, dried (MgSO4), and
concentrated in vacuo. The residue was redissolved in 5 mL of MeOH and
treated with 30 mg (25% w/w, 0.01 mmol) of Pd/C. The mixture was stirred
at room tempearture under 1 atm of H2, and the disappearance of starting
material was monitored by TLC (hexanes/EtOAc, 1:1). The solution was
then quenched with Celite, filtered, and purified by chromatography on SiO2
(hexanes/EtOAc, 1:2) to afford 44 mg (0.26 mmol, 63%, two steps) of 8c
as a yellow oil.
a Yields determined over two steps.
either solely the precatalyst (entry 9) or the manganese metal
(entry 10) under otherwise identical reaction conditions failed
to afford indoline products.
The general scope of indoline formation was further
illustrated by the conversions summarized in Table 2. Alkyl-
substituted substrates, including tetrahydroquinoline 15 af-
forded the corresponding indolines in modest to good yields
(entries 2-4). The electron-rich 5-methoxyindoline 18 was
isolated in low yield (21% over two steps). Electron-deficient
substrates underwent the epoxide-opening rearrangement to
afford substituted indolines in good yields (entries 6 and 7).
However, an attempt to prepare the tricyclic pyrroloindole
(17) Popowycz, F.; Merour, J.-Y.; Joseph, B. Tetrahedron 2007, 63,
8689.
(18) Scott, M. E.; Schwarz, C. A.; Lautens, M. Org. Lett. 2006, 8
5521.
(19) Bacque, E.; Qacemi, M. E.; Zard, S. Z. Org. Lett. 2004, 6, 3671.
(20) Mello, J. V.; Finney, N. S. Org. Lett. 2001, 3, 4263.
Org. Lett., Vol. 10, No. 19, 2008
4385

The titanocene(III) chloride catalyst or the manganese
byproducts may also serve as a Lewis acid to promote an
epoxide-opening Friedel-Crafts alkylation. However, 5-mem-
bered ring benzene annulations by epoxide openings under
Friedel-Crafts conditions are quite inefficient,24 and a
stoichiometric amount of reducing agent is required to drive
the titanocene(III) chloride catalyzed process to completion.23
Furthermore, it has previously been shown that the MnCl2
produced in the reaction is not Lewis-acidic enough to
promote epoxide-opening reactions.12a
In summary, we have developed a novel titanocene(III)
chloride catalyzed epoxide-opening arene annulation that
affords 3,3-disubstituted indolines and tolerates a range of
substituents on the aromatic ring. This methodology can be
extended toward other five-membered heterocycles, as
demonstrated by the preparation of a 3,3-disubstituted
5-azaindoline.
Figure 2. Proposed catalytic cycle for the titanocene(III) chloride
catalyzed epoxide-opening annulation.
Acknowledgment. This work has been supported by the
NIH/NIGMS CMLD program (GM067082) and, in part, by
R01-GM55433.
cyclization onto the aromatic ring, forming the cyclohexa-
dienyl radical intermediate 31 (Figure 2).21 Oxidation of the
dienyl radical by trace amounts of dioxygen and proton loss
affords the indoline 32.22 Furthermore, protodemetalation by
collidinium hydrochloride leads to product 33, and presum-
ably regenerates the precatalyst Cp2TiCl2.23
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
copies of 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL801860S
(21) (a) Curran, D. P.; Liu, H.; Josien, H.; Ko, S.-B. Tetrahedron 1996,
52, 11385. (b) Clyne, M. A.; Aldabbagh, F. Org. Biomol. Chem. 2006, 4,
268. (c) Clive, D. L. J.; Peng, J.; Fletcher, S. P.; Ziffle, V. E.; Wingert, D.
J. Org. Chem. 2008, 73, 2330.
(23) Performing the reaction with epoxide 4c using 3 mol % of Cp2TiCl2
and 15 mol % of Mn0, the desired Cbz-protected indoline was isolated in
only 35% yield.
(24) For Friedel-Crafts cycloalkylation with arylalkyloxiranes, see: (a)
Taylor, S. K.; Hockerman, G. H.; Karrick, G. L.; Lyle, S. B.; Schramm,
S. B. J. Org. Chem. 1983, 48, 2449. (b) Taylor, S. K.; May, S. A.; Stansby,
E. S. J. Org. Chem. 1996, 61, 2075.
(22) (a) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron 1991,
47, 10119. (b) Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann,
E.; Parr, J.; Storey, J. M. D. Angew. Chem., Int. Ed. 2004, 43, 95. (c) Curran,
D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128, 13706.
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Org. Lett., Vol. 10, No. 19, 2008