Polycyclic Indoline Derivatives by Dearomatizing Anionic Cyclization of Indole and Tryptamine-Derived Ureas

Article abstract of DOI:10.1021/acs.orglett.8b02468

The base-promoted dearomatizing cyclization of anionic indole-containing urea derivatives provided tri- or tetracyclic indoline-containing scaffolds from lithiated urea intermediates. 3-Substituted indoles, including tryptamine derivatives, generally underwent the reaction in high yield and with excellent diastereoselectivity. In situ IR spectroscopy suggests a deprotonation-carbolithiation-reprotonation mechanism.

Full text of DOI:10.1021/acs.orglett.8b02468

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Polycyclic Indoline Derivatives by Dearomatizing Anionic
Cyclization of Indole and Tryptamine-Derived Ureas
Jessica E. Hill,‡ Quentin Lefebvre,‡ Laura A. Fraser, and Jonathan Clayden*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
S
* Supporting Information
ABSTRACT: The base-promoted dearomatizing cyclization
of anionic indole-containing urea derivatives provided tri- or
tetracyclic indoline-containing scaffolds from lithiated urea
intermediates. 3-Substituted indoles, including tryptamine
derivatives, generally underwent the reaction in high yield
and with excellent diastereoselectivity. In situ IR spectroscopy
suggests a deprotonation−carbolithiation−reprotonation
mechanism.
he amino acid tryptophan provides the starting material
for the biosynthesis of a broad array of indole-derived
Scheme 1. Nucleophilic Dearomatization of Indoles
T
secondary metabolites, many of them with valuable biological
activity.1 Not all contain the aromatic indole structure: a
significant proportion of indole-derived alkaloids retain the
indole connectivity, but are saturated in the five-membered
ring.2 Synthetic approaches to these indoline-containing
products commonly entail dearomatization of an indole
precursor by electrophilic attack at the C-3 position, followed
by nucleophilic addition into C-2 of the resulting iminum
intermediate. Dearomatization is a powerful strategy for the
synthesis of partially saturated heterocycles,3 and recent work
building upon this reactivity showed that the combination of a
strong Lewis acid and a proton source could generate the
iminum intermediate without C3-functionalization, resulting in
dearomatizing C2-functionalization upon addition of an aryl
nucleophile.4
By contrast, dearomatization reactions initiated by nucleo-
philic attack on the electron-rich indole ring are virtually
unknown.3a Both Studer5 and ourselves6 have shown that
attack on the C-2 position by a silyllithium or organolithium
reagent results in ring opening to give products that no longer
contain the indoline scaffold (Scheme 1). Indoles, pyrroles,6
thiophenes, and benzothiophenes7 undergo comparable
reactions, but for indoles the structural requirements for
successful reactions are rather stringent: the bulky DEB
protecting group was essential, for example. Likewise, Studer’s
silylation is limited to N-aryl indoles, and carbolithiation was
unsuccessful with n-BuLi or t-BuLi. A general method for the
nucleophilic dearomatization of N-protected indoles to provide
polycyclic indoline-containing alkaloid-like structures is still
lacking.
Recent work has shown that the carbonyl-directed lithiation
of heterocyclic ureas provides fertile ground for the generation
of new reactivity.8 As part of this work, we explored the
metalation of indole-derived N-benzyl ureas. Treating N-
benzyl-N-methyl-1H-indole-1-carboxamide 1a with 2 equiv of
LDA in THF at −78 °C led to rapid decomposition to indole
and other unidentified side products. However, in the presence
of 5 equiv of the lithium-coordinating cosolvent DMPU, full
conversion was attained after 2 h and the tricyclic indoline 2a
was obtained in 20% yield as a single diastereomer (Scheme 2).
A similar reaction with the 6-methoxy indole 1b provided a
39% yield of 2b. Substitution of the 3-position of the indole
starting material had an even more beneficial effect on the
reaction. 3-Methylindole derivative 1c reacted cleanly under
the same conditions to give 2c as a single diastereomer in 66%
yield. Repeating the reaction on a 1 g scale further increased
this yield to 79%, and treatment of the product with LiAlH4
Received: August 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02468
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Dearomatizing Cyclization of Indoles: Initial
Results
Scheme 3. Cyclizations of 3-Methylindole Derivatives
a
Yield on 1 g scale.
transformed it to the imidazolidine 3c, indicating possible
applications of this dearomatizing cyclization to the synthesis
of polycyclic amines with alkaloid-like structures.
The success of these cyclizations suggested that the
increased basicity of the organolithium intermediate 2Li
presumably generated by anionic cyclization may promote a
cleaner reaction by favoring proton transfer from i-Pr2NH (see
mechanistic discussion below). We thus proceeded to develop
further reactions of 3-substituted indoles.
A further range of starting materials 1d−j were made from
their parent indoles by a Vilsmeier−Haack reaction followed
by reduction with LiAlH4 and N-acylation9 (see Supporting
Information). These new starting materials were subjected to
the conditions (LDA, DMPU) used for 1a−c (Scheme 3). 5-
Fluoro- and 5-chloro-substituted indoles cyclized successfully
to give products 2d and 2e.10 Similarly, substrates with methyl
or methoxy groups at the 5- or 6-position gave the
dearomatized products in good yields (2g−j). In contrast,
substitution at the 7-position was detrimental to the reaction,
and the product 2f (from 3,7-dimethylindole) was obtained in
only 18% yield. All the products were obtained as essentially
single diastereomers11 with the X-ray crystal structure of 2g
(CCDC 1859678), supported by NOESY of 2c, confirming
relative stereochemistry in which the phenyl and methyl
substituents occupy the exo face of the 5,5-fused bicyclic
system.
A reaction performed on the related substrate 4 bearing an
enantioenriched α-methylbenzyl substituent (98:2 er) also led
to cyclization of the intermediate organolithium to a product 5
in 59% yield as a separable 4:1 mixture of diastereomers. The
major diastereoisomer was formed without erosion of
enantiomeric ratio, and presumably with retention of
configuration,12 indicating that the cyclization is faster than
the racemization of the intermediate organolithium under the
conditions of the reaction.8f
a
b
c
>20:1 dr unless otherwise stated. 10:1 dr. Minor diastereoisomer
has the opposite configuration at the two centers of the indoline ring.
yield of 2k as a single diastereoisomer. The particular success
of these dearomatizing cyclizations of 3-alkylindoles suggested
that tryptophan-derived ureas might also be suitable substrates,
allowing the formation of alternatively connected tricyclic
products.13 Pleasingly, tryptamine derivatives 1l and 1m
reacted cleanly to give the products 2l and 2m with dibenzyl
and 2,6-dimethylpyrrole protecting groups.
Similar cyclizations of 1n and 1o bearing electron-with-
drawing groups at the 3-position also gave the products 2n and
2o in good yield. However, these reactions were much less
diastereoselective, perhaps because the delocalized, planar
product anion is protonated less diastereoselectively (see
Scheme 6).
A final set of starting materials was made in which the 2-
position of the indole was substituted. The first of these, the 2-
methylindole derivative 6a, cyclized in good yield under the
standard conditions, although a mixture of diastereoisomers
was obtained (Scheme 5; X-ray crystallography revealed the
relative stereochemistry of the major diastereoisomer (7a,
CCDC 1541914)).14 The fact that cyclization onto a
substituted position was successful made possible the synthesis
of a series of more elaborate tetracyclic products from ring-
fused starting materials. Thus, tetrahydrocarbazole 6b gave the
Alternative substituents at the 3-position were tolerated well
(Scheme 4). The 3-benzyl-substituted indole 1k gave a good
B
DOI: 10.1021/acs.orglett.8b02468
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Cyclizations of Other 3-Substituted Indoles
Scheme 6. In Situ IR Investigation and Postulated
Mechanism
a
Scheme 5. 2-Substituted and Tricyclic Indole Derivatives
a
Solvation or aggregation of the organolithium species is not shown
but may be assumed.
three new absorptions at 1596, 1715, and 1720 cm−1 whose
relative intensities changed over the remaining 70 min of the
reaction, with the 1596 cm−1 signal decreasing while the other
two increased. Quenching with aqueous ammonium chloride
led to the disappearance of signals at 1596 and 1715 cm−1 and
simultaneously intensified the signal at 1720 cm−1. This signal
was assigned to the product 2c by comparison with the
spectrum of the authentic sample, obtained in 52% yield after
workup and purification. We tentatively assign the structures
2cLi and 2cLi′ to the absorptions at 1715 and 1596 cm−1,
respectively.8b These results point toward a mechanism that
entails rapid benzylic lithiation followed by syn-carbolithiation
of the indole ring. Slower equilibration then occurs by proton
transfer between the diisopropylamine generated in the
deprotonation step and the two alternative weakly acidic
sites of the product.16 Control over this equilibrium may be the
reason why 3-substituents enhance the dearomatization
reaction.
tetracycle 7b in 46% yield with a 3:1 diastereomeric ratio,
while its 5-ring congener 6c gave cis-7c in moderate yield with
small amounts of the other diastereoisomer. The stereo-
chemistry of the major isomers of 7b and 7c was confirmed by
NOESY NMR analysis.
Some details of the mechanism of the cyclization of 1c were
revealed by in situ infrared spectroscopy (Scheme 6).15 To
eliminate the obscuring effect of its urea carbonyl absorption,
we performed the reaction in the absence of DMPU. A
solution of 1c in THF showed a strong carbonyl absorption at
1682 cm−1. Upon addition of 2 equiv of LDA at −78 °C, this
absorption was rapidly replaced by another carbonyl
absorption at 1633 cm−1 corresponding to a transient species
that we assume to be the lithiated starting material 1cLi,
possibly in a more complex solvated/aggregated state.15b Over
a period of a few minutes this transient signal was replaced by
In summary, this intramolecular hydroalkylation reaction of
lithiated indole-containing urea derivatives leads to hetero-
cyclic indoline-containing polycyclic ring systems in a rare
nucleophilic indole dearomatization reaction. The reactions
proceed with high yields and excellent selectivity for 3-
alkylated indole substrates, while other substitution patterns
C
DOI: 10.1021/acs.orglett.8b02468
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Morioku, K.; Suzuki, H.; Takeuchi, Y.; Nishina, Y. Org. Lett. 2016, 18,
2020.
̈
(5) Xu, P.; Wurthwein, E.-U.; Daniliuc, C. G.; Studer, A. Angew.
Chem., Int. Ed. 2017, 95, 1527.
(6) Clayden, J.; Turnbull, R.; Pinto, I. Org. Lett. 2004, 6, 609.
(7) Clayden, J.; Turnbull, R.; Helliwell, M.; Pinto, I. Chem. Commun.
2004, 21, 2430.
(8) (a) Hill, J. E.; Matlock, J. V.; Lefebvre, Q.; Cooper, K. G.;
Clayden, J. Angew. Chem., Int. Ed. 2018, 57, 5788. (b) Hall, J. E.;
Matlock, J. V.; Ward, J. W.; Gray, K. V.; Clayden, J. Angew. Chem., Int.
led to less predictable yields and selectivities. Substrates
derived from tryptamine, as well as other biorelevant structures
such as tricyclic indoles 6, underwent the reaction. The
reaction proved to be diastereoselective and (with enantioen-
riched α-chiral organolithiums) enantiospecific, and the
method has potential for the modular synthesis of modified
indole alkaloid derivatives.
ASSOCIATED CONTENT
* Supporting Information
■
́
Ed. 2016, 55, 11153. (c) Corbet, B. P.; Matlock, J. V.; Mas Rosello, J.;
S
Clayden, J. C. R. Chim. 2017, 20, 634. (d) Tait, M. B.; Butterworth,
S.; Clayden, J. Org. Lett. 2015, 17, 1236. (e) Maury, J.; Clayden, J. J.
Org. Chem. 2015, 80, 10757. (f) Clayden, J.; Dufour, J.; Grainger, D.
M.; Helliwell, M. J. Am. Chem. Soc. 2007, 129, 7488. (g) Tetlow, D. J.;
Hennecke, U.; Raftery, J.; Waring, M. J.; Clarke, D. S.; Clayden, J.
Org. Lett. 2010, 12, 5442. (h) Clayden, J.; Donnard, M.; Lefranc, J.;
Minassi, A.; Tetlow, D. J. J. Am. Chem. Soc. 2010, 132, 6624.
(i) Clayden, J.; Farnaby, W.; Grainger, D. M.; Hennecke, U.;
Mancinelli, M.; Tetlow, D. J.; Hillier, I. H.; Vincent, M. A. J. Am.
Chem. Soc. 2009, 131, 3410.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02468.
Full experimental data and NMR spectra of all new
compounds (PDF)
Accession Codes
CCDC 1541914 and 1859678 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(9) Cheng, H.-G.; Lu, L.-Q.; Wang, T.; Yang, Q.-Q.; Liu, X.-P.; Li,
Y.; Deng, Q.-H.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2013,
52, 3250.
(10) A similar substrate containing a bromine atom completely
decomposed under the reaction conditions, presumably due to
competitive aryne generation.
(11) For 2d and 2e, 10% of a minor diastereoisomer was obtained.
(12) Vincent, M. A.; Maury, J.; Hillier, I. H.; Clayden, J. Eur. J. Org.
Chem. 2015, 2015, 953.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.clayden@bristol.ac.uk.
ORCID
(13) This method provides an unusual 6−5−5 tricyclic system,
comparable to the ubiquitous 6−5−6 tricyclic system of tryptolines.
For examples and relevance of such tricycles in medicinal chemistry,
see: (a) Alagille, D.; Pfeiffer, B.; Scalbert, E.; Ferry, G.; Boutin, J. A.;
Renard, P.; Viaud-Massuard, M.-C. J. Enzyme Inhib. Med. Chem. 2004,
19, 137. (b) Chaulet, C.; Croix, C.; Alagille, D.; Normand, S.; Delwail,
A.; Favot, L.; Lecron, J.-C.; Viaud-Massuard, M.-C. Bioorg. Med.
Chem. Lett. 2011, 21, 1019. (c) Kong, W.-J.; Chen, X.; Wang, M.; Dai,
H.-X.; Yu, J.-Q. Org. Lett. 2018, 20, 284.
(14) Replacing the methyl by a phenyl group almost completely
diverted the reaction to decomposition, giving the product in less than
10% yield.
(15) (a) Atkinson, R. C.; Leonard, D. J.; Maury, J.; Castagnolo, D.;
Volz, N.; Clayden, J. Chem. Commun. 2013, 49, 9734. (b) Fournier, A.
M.; Nichols, C. J.; Vincent, M. A.; Hillier, I. H.; Clayden, J. Chem. -
Eur. J. 2012, 18, 16478.
Jonathan Clayden: 0000-0001-5080-9535
Author Contributions
‡J.E.H. and Q.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the EPSRC, the Bristol Centre for
Doctoral Training in Chemical Synthesis, AstraZeneca through
a CASE award and the Deutsche Forschungsgemeinschaft
(research fellowship LE 3853/1-1). We thank Dr. Hazel
Sparkes and Dr. Natalie Pridmore (School of Chemistry,
University of Bristol) for determining the X-ray crystal
structures of 2g and 7a.
(16) Deuterolysis of the reaction mixture did not give deuterated
products, maybe because of rapid H/D exchange with i-Pr2NH.
REFERENCES
■
(1) (a) Seigler, D. S. Plant secondary metabolism; Springer: Boston,
MA, 1998; p 628. (b) Xu, W.; Gavia, D. J.; Tang, Y. Nat. Prod. Rep.
2014, 31, 1474. (c) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat.
Prod. Rep. 2015, 32, 1389.
(2) Examples of such alkaloids are found in Aspidosperma and
Strychnos spp., as well as among pyrroloindoles, cyclotryptamines,
communesines, and spiroindolines.
̀
(3) (a) Dearomatizing reactions using organolithiums: Lemiere, G.;
Clayden, J. Sci. Synth., 2011, 4, 139. (b) Clayden, J.; Kenworthy, M.
N.; Helliwell, M. Org. Lett. 2003, 5, 831. (c) Clayden, J.; Purewal, S.;
Helliwell, M.; Mantell, S. Angew. Chem., Int. Ed. 2002, 41, 1049.
(d) Bragg, R. A.; Clayden, J.; Bladon, M.; Ichihara, I. Tetrahedron Lett.
2001, 42, 3411. (e) Clayden, J.; Menet, C. J. Tetrahedron Lett. 2003,
44, 3059. (f) Clayden, J.; Hamilton, S. D.; Mohammed, R. T. Org.
Lett. 2005, 7, 3673.
(4) (a) Nandi, R. K.; Ratsch, F.; Beaud, R.; Guillot, R.; Kouklovsky,
C.; Vincent, G. Chem. Commun. 2016, 52, 5328. (b) Morimoto, N.;
D
DOI: 10.1021/acs.orglett.8b02468
Org. Lett. XXXX, XXX, XXX−XXX