Versatile access to chiral indolines by catalytic asymmetric fischer indolization

Article abstract of DOI:10.1002/anie.201301618

"Fisching" for complexity: The chiral Bronsted acid (R)-STRIP catalyzes the asymmetric Fischer indolization of a range of monosubstituted cyclopentanones and cyclohexanones to give chiral fused indolines bearing a quaternary stereogenic center at the 3-position. The method has been extended to include substrates bearing a tethered nucleophile, thus allowing for enantioselective indolization/ring-closing cascades to complex propellanes featuring two vicinal quaternary stereocenters. Copyright

Full text of DOI:10.1002/anie.201301618

Angewandte
Chemie
DOI: 10.1002/anie.201301618
Brønsted Acid Catalysis
Versatile Access to Chiral Indolines by Catalytic Asymmetric Fischer
Indolization**
Alberto Martꢀnez, Matthew J. Webber, Steffen Mꢁller, and Benjamin List*
Dedicated to the Bayer company on the occasion of its 150th anniversary
3,3-Disubstituted fused indolines are privileged substructures
of diverse natural products, and their synthesis has attracted
intense attention (Scheme 1).[1,2] While a number of enantio-
Scheme 2. Potential formation of enantioenriched 3,3-disubstituted
fused indolines. HX*=chiral Brønsted acid.
carbazoles, could potentially have further-reaching applica-
tions in organic synthesis, just as the non-asymmetric version
has had throughout its long history.[8] For example, we
envisaged that upon condensation of an a-substituted cyclic
ketone with a phenylhydrazine, a chiral Brønsted acid
Scheme 1. Examples of natural products containing 3,3-disubstituted
fused indoline cores.
catalyzed [3,3]-sigmatropic rearrangement of the higher
substituted ene–hydrazine would lead to an enantioenriched
selective approaches to monosubstituted indolines have been
reported,[3] the asymmetric synthesis of challenging 3,3-
fused indoline [Scheme 2, Equation (2)].[9,10]
With this plan in mind, we began our studies with
commercially available N-benzyl-N-phenylhydrazine (1a)
and 2-phenylcyclohexanone (2a). In the presence of a range
of chiral phosphoric acids and the weakly acidic cation
exchange polymer Amberlite CG50, indoline–enamine 3a
could indeed be obtained in promising yields and enantiose-
lectivities (Table 1).[11]
disubstituted indoline targets has been less developed.[4]
A
recent achievement in this field of research has been the work
of MacMillan et al., who employed a Diels–Alder-Michael
addition cascade to enantioselectively generate precursors for
a number of indole alkaloid total syntheses,[5] illustrating the
potential of organocatalysis for natural product synthesis.[6]
Herein we report a complementary strategy to 3,3-disubsti-
tuted fused-indolines based on the Fischer indolization, in
which the formation of the indole scaffold itself serves as the
basis for asymmetric induction.
Recently, our group developed an organocatalytic asym-
metric variant of the Fischer indole synthesis [Scheme 2,
Equation (1)].[7] We speculated that this procedure, originally
designed for the synthesis of chiral 3-substituted tetrahydro-
Both BINOL-[12] and SPINOL-derived[13] phosphoric
acids were employed, and it was noticeable that the highest
yields were obtained with SPINOL-derived catalysts (Table 1,
entries 5–7). Moreover, the hindered SPINOL phosphoric
acid STRIP (5e), previously introduced by our group,[13b] was
seen to comfortably outperform its BINOL analogue TRIP
(4e)[14] in terms of enantioselectivity (Table 1, entries 4 and
7). Thus (R)-STRIP became the catalyst of choice for further
studies.[15] The importance of the weakly acidic CG50 polymer
was then underlined by running the reaction in its absence
(Table 1, entry 8). A poor yield (15%) was obtained, which is
thought to be due to the build-up of ammonia, inhibiting
protonation of the key ene–hydrazine intermediate and
drastically hindering turnover of the acid catalyst (e.r.
93.5:6.5 with or without polymer).[7]
[*] Dr. A. Martꢀnez,[+] Dr. M. J. Webber,[+] Dr. S. Mꢁller, Prof. Dr. B. List
Max-Planck-Institut fꢁr Kohlenforschung
Kaiser Wilhelm-Platz 1, 45470 Mꢁlheim an der Ruhr (Germany)
E-mail: list@mpi-muelheim.mpg.de
[+] These authors contributed equally to this work.
[**] Generous support by the Max Planck Society is acknowledged. We
also thank our HPLC and crystallography departments for their
support.
We next turned our attention to assessing the substrate
scope of the reaction (Scheme 3). It was found that indoline
3a could be quantitatively furnished in 24 h at 458C and with
an enantiomeric ratio (e.r.) of 94.5:5.5.[16] Varying the aryl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301618.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Catalyst optimization.[a]
ers (d.r. 8.5:1) after in situ reduction of the corresponding
unstable enamine with NaBH3CN. NOE-NMR studies
showed that the major diastereoisomer was the cis-fused
system with an e.r. of 93:7.
The presence of a benzyl group on the nitrogen atom was
found to be essential for the enantioselectivity of the reaction.
This is illustrated by the synthesis of product 3h bearing an N-
methyl group, with a poor e.r. of 55:45. It should be noted that
all of the reactions were regioselective, with rearrangement
taking place at the most substituted a-position of the starting
ketone. The possible 1-substituted tetrahydrocarbazoles were
not observed in any case.[9]
Entry
Catalyst
Yield [%][b]
e.r.[c]
Encouraged by these results with cyclohexanones, we
were compelled to pursue opportunities with 2-substituted
cyclopentanone substrates (Scheme 4). Such substrates have
1
2
3
4
5
6
4a
4c
4d
4e
5b
5c
5e
5e
81
84
81
82
99
97
99
15
60:40
68:32
71.5:28.5
59:41
87:13
64:36
93.5:6.5
93.5:6.5
7
8[d]
[a] Reactions were run on a 0.05 mmol scale with 50 mg of Amberli-
te CG50. Bn=benzyl. [b] Determined by 1H NMR spectroscopy with
1,3,5-trimethoxybenzene as an internal standard. [c] Determined by
HPLC analysis on a chiral stationary phase. [d] Amberlite CG50 omitted
from the reaction mixture.
Scheme 4. Synthesis of a) 2-hydroxyindolines 6 and b) indolines 7 after
in situ reduction with NaBH3CN post-indolization.
previously been put forward as challenging for the Fischer
indolization, with the products apparently showing instability
to the usual rather harsh conditions of the reaction.[17] We
hoped that under our mild conditions, synthetically useful
yields would be obtained. Interestingly, we were able to
isolate 2-hydroxyindolines of type 6, rather than the corre-
sponding indoline–enamines. Alkyl and benzyl substituents
were well-tolerated (6a,b), and incorporation of a naphthyl
substituent led to indoline product 6c with remarkably high
enantioselectivity of 99.5:0.5.
The moderate yield obtained for methyl-substituted indo-
line 6a (54%) is due to its instability to chromatographic
purification methods. We supposed that the yield of the
process could be improved by incorporating a reductive step
to the reaction sequence. Indeed, adding NaBH3CN to the
reaction mixture once indolization was judged to be complete
resulted in an improved yield of 84% of reduced indoline 7a.
Methyl-substituted products 6a and 7a were obtained with
identical e.r. of 96.5:3.5. In a similar fashion, reduced indoline
products 7b,c could also be obtained in good yields and high
Scheme 3. Substrate scope for the synthesis of indoline derivatives.
[a] After in situ reduction of the unstable enamine with NaBH3CN.
substituent R3 had little effect on either yield or e.r. (3a–d),
while more marked effects were revealed when varying the
starting hydrazine. First, the introduction of a methyl group in
the 3-position of the hydrazine gave a single regioisomeric
product 3e with improved enantioselectivity compared to the
unsubstituted analogue. A bromo substituent was well
tolerated (3 f, e.r. 95:5). 2-Alkylcyclohexanones proved to
be less reactive (the reaction was carried out at 508C for 36 h).
One example was the isolation of the n-propylindoline
derivative 3g in moderate yield as a mixture of diastereisom-
2
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
enantioselectivity. Once again, the presence of an aryl group
in the substrate led to the indoline product with outstanding
enantioselectivity (e.r. 99.5:0.5 for 7d with R2 = Ph).
yields and enantioselectivities. Protection of the hydroxy
group with a silyl group is crucial to achieve a high e.r.[20] In
the case of amide-containing ketones, the temperature had to
be increased upon completion of the indolization to accel-
erate the ring closure by nucleophilic attack of the amide
nitrogen atom. Thus indoline 12a was obtained in moderate
yield and good enantioselectivity. Finally, to study ketones
bearing a carbon nucleophile, we incorporated an electron-
rich N-methylindole into its side chain. To the best of our
knowledge, there had been no prior examples of an inter-
rupted Fischer indolization featuring a carbon-based nucle-
ophile. The investigated ketone substrates reacted efficiently
with hydrazines 1a and 1c to give the polycyclic indolines
13a–d bearing two vicinal quaternary stereocenters in good
yields and enantioselectivities.[21] In both cases yields
obtained for the hydrazine 1c, bearing bromine in the
aromatic ring, were lower owing to the slower reaction rate
relative to the unsubstituted hydrazine 1a. The absolute
configuration of the indolo–indoline 13d was unambiguously
assigned by X-ray structural analysis (see the Supporting
Information).
After confirming that our catalytic system could success-
fully form enantioenriched 3,3-disubstituted fused indolines,
we intended to apply this method for the synthesis of more
complex molecules. We envisaged that by appropriate design
of the starting ketone, the Fischer indolization pathway could
be interrupted by the attack of an appropriate tethered
nucleophile on the iminium functionality, which is formed
upon the loss of ammonia (Scheme 5). This could give rapid
Scheme 6 shows the proposed catalytic cycle, which is in
agreement with the accepted mechanism of the Fischer
indolization.[22] We suggest that chiral phosphoric acid 5e
Scheme 5. Catalytic asymmetric interrupted Fischer indolization fur-
nishing enantioenriched (hetero)propellanes. [a] TBAF addition;
[b] 708C for 3 h after indolization. Nu=nucleophile, TIPS=triisopro-
pylsilyl.
access to polycyclic cores, which are present in a number of
natural products. The so-called interrupted Fischer indoliza-
tion has been widely studied, most recently by the group of
Garg.[18,19] However, approaches to render the process
asymmetric have so far been limited to a single example,
employing an excess of a chiral phosphoric acid and inducing
moderate enantioselectivity.[18b] We wished to harness the
power of our Fischer indolization process to deliver a catalytic
asymmetric variant of this complexity-generating reaction.
With this idea in mind, we prepared a range of 5- and 6-
membered cyclic ketones bearing oxygen, nitrogen, and
carbon nucleophiles at the appropriate positions, which
were then subjected to our optimized catalytic system in the
presence of different phenyl hydrazines (Scheme 5).
Scheme 6. Plausible catalytic cycle of formation of 3a.
catalyzes the formation of protonated hydrazone A, followed
by tautomerization to the thermodynamically more stable
cationic enehydrazine isomer B. The enantioselectivity-deter-
mining key step would then be the irreversible [3,3]-sigma-
tropic rearrangement of intermediate B, directed by the chiral
phosphate counteranion, affording ion pair C. Upon ring
closure, aminal D eliminates one equivalent of ammonia to
give the final product 3a. Ammonia is trapped by the cation-
exchange polymer Amberlite CG50, allowing the turnover of
the catalytic system.
In summary, we wish to emphasize the potential power of
the catalytic asymmetric Fischer indole synthesis to rapidly
access highly diverse indoline scaffolds, often displaying
considerable structural complexity, in a single step from
simple starting materials. The process has been developed to
Ketones containing a g-silyl ether on the side chain
reacted smoothly with hydrazine 1a and, after in situ treat-
ment with TBAF, the corresponding [3.3.3]- and [3.3.4]-
oxapropellane furoindolines 11a,b were obtained in good
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[5] S. B. Jones, B. Simmons, A. Mastacchio, D. W. C. MacMillan,
Nature 2011, 475, 183 – 188.
the extent that it may now offer an attractive approach
towards the asymmetric synthesis of a wide variety of indole-
containing targets under mild reaction conditions. Research
along these lines is currently underway within our group.
[6] For examples of organocatalytic reactions towards natural
product syntheses, see: a) R. Marcia de Figueiredo, M. Christ-
mann, Eur. J. Org. Chem. 2007, 2575 – 2600; b) C. Grondal, M.
Jeanty, D. Enders, Nat. Chem. 2010, 2, 167 – 178; c) M. Wasser,
Asymmetric Organocatalysis in Natural Product Syntheses,
Springer, Wien, 2012; d) M. Christmann, Science of Synthesis
Asymmetric Organocatalysis 1, Lewis Base and Acid Catalysts,
Thieme, Stuttgart, 2012, pp. 439 – 454.
Experimental Section
Representative procedure: A reaction vial was charged with (R)-
STRIP (5e, 3.60 mg, 0.005 mmol), Amberlite CG50 (100 mg), 1-
benzyl-1-phenylhydrazine (1a, 19.8 mg, 0.100 mmol), and 2-phenyl-
cyclohexanone (2a, 17.4 mg, 0.100 mmol). Toluene (1.0 mL) was
added and the resulting mixture was stirred in the sealed vial at 458C
for 24 h. The crude reaction mixture was directly submitted to column
chromatography on SiO2, eluting with hexanes/EtOAc (97:3). Prod-
uct 3a was obtained as a colorless solid (32.9 mg, 98%, e.r. 94.5:4.5).
[7] S. Mꢀller, M. J. Webber, B. List, J. Am. Chem. Soc. 2011, 133,
18534 – 18537.
[8] For reviews on the applications of the Fischer indole synthesis,
see: a) B. Robinson, Chem. Rev. 1963, 63, 373 – 401; b) B.
Robinson, Chem. Rev. 1969, 69, 227 – 250; c) B. Robinson, The
Fischer Indole Synthesis, Wiley-Interscience: New York, 1982.
[9] For a study on the regioselectivity of Fischer indolizations of 2-
substituted cyclohexanones, see: K. H. Pausacker, J. Chem. Soc.
1950, 621 – 624.
Received: February 25, 2013
Published online: && &&, &&&&
[10] For reviews on asymmetric counteranion-directed catalysis, see:
a) R. J. Phipps, G. L. Hamilton, F. D. Toste, Nat. Chem. 2012, 4,
603 – 614; b) M. Mahlau, B. List, Isr. J. Chem. 2012, 52, 630 – 638;
c) J. Lacour, V. Hebbe-Viton, Chem. Soc. Rev. 2003, 32, 373 –
382; d) M. Mahlau, B. List, Angew. Chem. 2013, 125, 540 – 556;
Angew. Chem. Int. Ed. 2013, 52, 518 – 533.
[11] For a rare previous example of a related racemic reaction, see: B.
Cox, B. Robinson, J. Heterocycl. Chem. 1988, 25, 271 – 272.
[12] For reviews on chiral phosphoric acid catalysis, see: a) M.
Terada, Synthesis 2010, 1929 – 1982; b) D. Kampen, C. M. Rei-
singer, B. List, Top. Curr. Chem. 2010, 291, 395 – 456; c) T.
Akiyama, Chem. Rev. 2007, 107, 5744 – 5758.
Keywords: Brønsted acid catalysis · Fischer indole synthesis ·
heterocycles · indoline · organocatalysis
.
[1] a) D. Zhang, H. Song, Y. Qin, Acc. Chem. Res. 2011, 44, 447 –
457; b) E. Attorusso, O. Taglialatela-Scafati, Modern Alkaloids:
Structure, Isolation, Synthesis and Biology, Wiley-VCH, Wein-
heim, 2008; c) N. H. Greig, X.-F. Pei, T. T. Soncrant, D. K.
Ingram, A. Brossi, Med. Res. Rev. 1995, 15, 3 – 31.
[2] Total synthesis of (À)-vindoline: a) D. Kato, Y. Sasaki, D. L.
Boger, J. Am. Chem. Soc. 2010, 132, 3685 – 3687; (À)-strychnine:
b) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem.
Soc. 1993, 115, 9293 – 9294; (Æ)-aspidophylline A: c) L. Zu,
B. W. Boal, N. K. Garg, J. Am. Chem. Soc. 2011, 133, 8877 – 8879;
(+)-minfiensine: d) A. B. Dounay, L. E. Overman, A. D. Wro-
bleski, J. Am. Chem. Soc. 2005, 127, 10186 – 10187; e) S. B. Jones,
B. Simmons, D. W. C. MacMillan, J. Am. Chem. Soc. 2009, 131,
13606 – 13607; (Æ)-vincorine: f) M. Zhang, X. Huang, L. Shen, Y.
Qin, J. Am. Chem. Soc. 2009, 131, 6013 – 6020.
[3] For selected examples, see: a) W. F. Bailey, M. J. Mealy, J. Am.
Chem. Soc. 2000, 122, 6787 – 6788; b) G. S. Gil, U. M. Groth, J.
Am. Chem. Soc. 2000, 122, 6789 – 6790; c) R. Kuwano, K.
Kaneda, T. Ito, K. Sato, T. Kurokawa, Y. Ito, Org. Lett. 2004,
6, 2213 – 2215; d) R. Kuwano, M. Kashiwabara, Org. Lett. 2006,
8, 2653 – 2655; e) D.-S. Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G.
Zhou, X. Zhang, J. Am. Chem. Soc. 2010, 132, 8909 – 8911; f) D.-
S. Wang, J. Tang, Y.-G. Zhou, M.-W. Chen, C.-B. Yu, Y. Duan, G.-
F. Jiang, Chem. Sci. 2011, 2, 803 – 806; g) M. Nakanishi, D.
Katayev, C. Besnard, E. P. Kꢀndig, Angew. Chem. 2011, 123,
7576 – 7579; Angew. Chem. Int. Ed. 2011, 50, 7438 – 7441; h) T.
Saget, S. J. Lemouzy, N. Cramer, Angew. Chem. 2012, 124, 2281 –
2285; Angew. Chem. Int. Ed. 2012, 51, 2238 – 2242.
[13] SPINOL-derived phosphoric acids were independently intro-
duced by three research groups: a) F. Xu, D. Huang, C. Han, W.
Shen, X. Lin, Y. Wang, J. Org. Chem. 2010, 75, 8677 – 8680; b) I.
ˇ
´
Coric, S. Mꢀller, B. List, J. Am. Chem. Soc. 2010, 132, 17370 –
17373; c) C.-H. Xing, Y.-X. Liao, J. Ng, Q.-S. Hu, J. Org. Chem.
2011, 76, 4125 – 4131.
[14] G. Adair, S. Mukherjee, B. List, Aldrichimica Acta 2008, 41, 31 –
39.
[15] Reaction conditions were screened in parallel with 2-butylcy-
clopentanone. See the Supporting Information for details.
[16] At the lower temperature of 258C, a higher e.r. could be
obtained at the expense of slow conversion (74%, e.r. 95.5:4.5,
5 days).
[17] a) N. P. Buu-Hoꢁ, P. Jacquignon, T. B. Loc, J. Chem. Soc. 1958,
738 – 740; b) A. H. Kelly, D. H. McLeod, J. Parrick, Can. J.
Chem. 1965, 43, 296 – 301; c) J. Shimizu, S. Murakami, T. Oishi,
Y. Ban, Chem. Pharm. Bull. 1971, 19, 2561 – 2566.
[18] For recent studies for the interrupted Fischer indolization using
latent aldehydes in acid media, see: a) B. W. Boal, A. W.
Schammel, N. K. Garg, Org. Lett. 2009, 11, 3458 – 3461;
b) A. W. Schammel, B. W. Boal, L. Zu, T. Mesganaw, N. K.
Garg, Tetrahedron 2010, 66, 4687 – 4695.
[4] For selected recent examples, see: a) B. M. Trost, J. Quancard, J.
Am. Chem. Soc. 2006, 128, 6314 – 6315; b) A. Pinto, Y. Jia, L.
Neuville, J. Zhu, Chem. Eur. J. 2007, 13, 961 – 967; c) U. Groth, P.
Kçttgen, P. Langenbach, A. Lindenmaier, T. Schꢀtz, M. Wie-
gand, Synlett 2008, 1301 – 1304; d) J.-C. Hsieh, S. Ebata, Y.
Nakao, T. Hiyama, Synlett 2010, 1709 – 1711; e) Q. Cai, C. Zheng,
J.-W. Zhang, S.-L. You, Angew. Chem. 2011, 123, 8824 – 8828;
Angew. Chem. Int. Ed. 2011, 50, 8665 – 8669; f) Q.-F. Wu, C.
Zheng, S.-L. You, Angew. Chem. 2012, 124, 1712 – 1715; Angew.
Chem. Int. Ed. 2012, 51, 1680 – 1683; g) Z. Zhang, J. C. Antilla,
Angew. Chem. 2012, 124, 11948 – 11952; Angew. Chem. Int. Ed.
2012, 51, 11778 – 11782; h) Q. Cai, S.-L. You, Org. Lett. 2012, 14,
3040 – 3043; i) Q. Cai, C. Liu, X.-W. Liang, S.-L. You, Org. Lett.
2012, 14, 4588 – 4590.
[19] For first examples of interrupted Fischer indolization reactions,
see: a) S. Takano, M. Moriya, Y. Iwabuchi, K. Ogasawara, Chem.
Lett. 1990, 109 – 112; b) A. Z. Britten, W. G. Bardsley, C. M. Hill,
Tetrahedron 1971, 27, 5631 – 5639; c) P. Rosenmund, E. Sadri,
Liebigs Ann. Chem. 1979, 927 – 943; d) P. Rosenmund, S.
Gektidis, H. Brill, R. Kalbe, Tetrahedron Lett. 1989, 30, 61 – 62.
[20] 2-(2-hydroxyethyl)cyclopentanone gives low enantioselectivity
under the optimal conditions (e.r. 62:38 at 258C).
[21] Low enantioselectivity was achieved using N-H-indole deriva-
tive as a starting material (e.r. 82:18 at 258C).
[22] For the original proposal of this mechanism, see: G. M.
Robinson, R. Robinson, J. Chem. Soc. Trans. 1924, 125, 827 – 840.
4
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Brønsted Acid Catalysis
A. Martꢁnez, M. J. Webber, S. Mꢂller,
B. List*
&&&& — &&&&
Versatile Access to Chiral Indolines by
Catalytic Asymmetric Fischer Indolization
“Fisching” for complexity: The chiral
Brønsted acid (R)-STRIP catalyzes the
asymmetric Fischer indolization of
a range of monosubstituted cyclopenta-
nones and cyclohexanones to give chiral
fused indolines bearing a quaternary ste-
reogenic center at the 3-position. The
method has been extended to include
substrates bearing a tethered nucleo-
phile, thus allowing for enantioselective
indolization/ring-closing cascades to
complex propellanes featuring two vicinal
quaternary stereocenters.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!