Regioselective Formation of Substituted Indoles: Formal Synthesis of Lysergic Acid

Article abstract of DOI:10.1002/chem.202004107

A Diels–Alder reaction-based strategy for the synthesis of indoles and related heterocycles is reported. An intramolecular cycloaddition of alkyne-tethered 3-aminopyrones gives 4-substituted indolines in good yield and with complete regioselectivity. Additional substitution is readily tolerated in the transformation, allowing synthesis of complex and non-canonical substitution patterns. Oxidative conditions give the corresponding indoles. The strategy also allows the synthesis of carbazoles. The method was showcased in a formal synthesis of lysergic acid.

Full text of DOI:10.1002/chem.202004107

Accepted Article
Accepted Article
Title: Regioselective Formation of Substituted Indoles: Formal
Synthesis of Lysergic Acid
Authors: Gary L. Points, Kenneth T. Stout, and Christopher Beaudry
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To be cited as: Chem. Eur. J. 10.1002/chem.202004107
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10.1002/chem.202004107
Chemistry - A European Journal
COMMUNICATION
Regioselective Formation of Substituted Indoles: Formal
Synthesis of Lysergic Acid
Gary L. Points III, Kenneth T. Stout and Christopher M. Beaudry*
required.
Creative and elegant Diels–Alder reactions are known to
Abstract: A Diels–Alder reaction-based strategy for the synthesis of
indoles and related heterocycles is reported. An intramolecular
cycloaddition of alkyne-tethered 3-aminopyrones gives 4-substituted
indolines in good yield and with complete regioselectivity. Additional
substitution is readily tolerated in the transformation, allowing
synthesis of complex and non-canonical substitution patterns.
Oxidative conditions give the corresponding indoles. The strategy
also allows the synthesis of carbazoles. The method was showcased
in a formal synthesis of lysergic acid.
prepare indoles, with substitution at C4 and the other benzenoid
carbons.4 For example, Wipf has demonstrated that aminofurans
tethered with alkene dienophiles undergo Diels–Alder-
elimination cascades to form indoles.5 Boger has used alkyne-
and allene-tethered diazines in Diels–Alder reaction-based
sequences to prepare substituted indolines and indoles,
respectively.6 Other strategies featuring alkyne-tethered pyrones
are also known, which use 6-aminopyrone architectures. 7
Snyder reported the cyclization of alkyne-tethered 4-chloro-6-
amidopyrones to give N-acyl-6-chloroindolines.8 Recently, Cui
Aromatic heterocycles represent core architectures of natural
products, pharmaceuticals, and biological polymers. The
substitution pattern featured on the aromatic ring is directly
related to molecular function and biological activity.1 As a result,
the preparation of heteroaromatics with control of substituent
regiochemistry has been, and continues to be, an important
longstanding theme in synthetic chemistry.
disclosed
a
reaction
forming
indolines
from
6-
sulfonamidopyrones bearing tethered alkynes.9
A flexible synthesis of indoles was sought that could not only
deliver substitution at C4, but also create indoles with
programmable substitution at other positions and avoid the use
of activating or protecting groups on nitrogen. Our laboratory has
been interested in using pericyclic reactions for the synthesis of
substituted aromatic rings,10 and we hypothesized that a Diels–
Alder reaction-based strategy using 3-aminopyrones tethered
with an alkyne dienophile (1) would deliver the 4-substituted
indoles (2); however, this transformation is unknown in the
literature.
The substituted indole represents a common motif among
molecules with potent activities toward
receptors.2 As a result, substituted indoles are widely used
pharmaceuticals (Figure 1). Ergometrine features C4-
G protein-coupled
a
substituted indole, and it is used in obstetrics for postpartum
bleeding. Sumatriptan is a migraine medicine that contains a C5-
We anticipated that the advantages of using 3-aminopyrones
rather than either 6-aminopyrones or other heterodienes would
be several fold. First, the key substrates 1 could be prepared
using simple alkylations of 3-aminopyrones. Second, unlike with
6-aminopyrones, there would be no requirement that the
nitrogen atom bears an electron withdrawing or protecting group
(i.e., acyl or sulfonyl) for the synthesis or cyclization of 2. Finally,
all positions of the indoline product (i.e., R1–R4) could, at least in
principle, be substituted with alkyl, heteroatom, or aromatic
groups.
substituted indole (or tryptamine). Finally, vindoline is
a
precursor to the chemotherapeutic vinblastine, and it displays an
indoline bearing a C6-methoxy group.
With these expectations in mind, our attempts to realize the 3-
aminopyrone to indoline transformation began with the synthesis
of alkyne-tethered 3-aminopyrones such as 1. We surveyed
several methods known for the synthesis of 3-
aminopyrones;8,9,11 however, we did not find a convenient and
general synthesis of these compounds. Interestingly, the parent
compound, 3-aminopyrone, was an unknown molecule.
Scheme 1. Substituted Indole Derivatives: Structure and Synthetic Strategy.
The importance of such indole derivatives has inspired
synthetic chemists over several decades to create methods for
the synthesis of substituted indoles.3 The synthesis of indoles
with C4-substitution is notoriously challenging; however,
substitution at the other benzenoid positions (C5, C6, and C7) is
also far from trivial, particularly when multiple substituents are
Scheme 2. Synthesis of Alkyne-Tethered 3-Aminopyrones.
[a]
G. L. Points, III, K. T. Stout, and Prof. C. M. Beaudry
Department of Chemistry
Oregon State University
153 Gilbert Hall
Corvallis, OR 97333, USA
E-mail: christopher.beaudry@oregonstate.edu
Eventually, we considered preparing 3-aminopyrones from the
corresponding 3-hydroxypyrones. 3-Hydroxypyrone (3a) can be
obtained commercially, or it can be prepared from inexpensive
mucic acid.12 , 13 3-Hydroxypyrone (3a) was activated as the
corresponding triflate, which was envisioned to undergo C–N
Supporting information for this article is given via a link at the end of
the document.
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bond formation to give 3-aminopyrone (4a).14 However, this
ostensibly benign C–N bond formation was complicated by the
discovery that 3-triflato-2-pyrone immediately decomposed in
the presence of bases commonly used for such couplings (e.g.
NaOtBu).15 Additionally, the triflate was not stable to primary
amines, precluding a direct coupling with butynylamines to give
1. As a result, we investigated couplings with an ammonia-
equivalent carbamate.
The reaction was also successful under microwave heating,
and reaction times were significantly shorter (entry 10). A brief
survey of bases revealed that K2CO3 gave higher yields than
DBU with microwave heating (entry 11). Using these optimized
conditions (entries 7 and 11) the yield of the pericyclic cascade
was nearly quantitative.
The indoline synthesis was further evaluated with an
expanded set of substrates (1 à 2, Scheme 3). A wide variety of
substitution was possible on the alkyne. Substituted phenyl rings
were tolerated giving 2b and 2c, which display branching
adjacent to the biaryl bond. Indolines bearing phenyl rings with
electron donating substitutents (2d) and electron withdrawing
substituents (2e) were formed in good yield. The rate of the
reaction was not significantly different in these cases.
Heteroaromatic rings were well tolerated; 4-(2-thiophenyl)-
indoline (2f) and 4-(3-pyridinyl)-indoline (2g) were prepared. The
alkyne substituent need not be aromatic, and cyclohexenyl-
substituted indoline (2h) was prepared in high chemical yield.
Enamine-containing product 2i was also produced in good yield.
Products bearing sp3-hybridized carbon were also conveniently
prepared, and indolines bearing a methyl (2j), tertiary carbinol
(2k), and allyl groups (2l) at C4 were all formed in high yield.
Finally, we found that bromoalkyne-tethered aminopyrone 1m
(R1 = Br; R2–R4 = H) smoothly reacted to give 2m.
We found that Buchwald–Hartwig coupling of the triflate
derived from 3a with BocNH2 followed by TFA removal gave 3-
aminopyrone (4a).16 Alkylation of 4a with triflate 5a gave our
initial substrate (1a) to evaluate the pericyclic cascade. A benefit
of this strategy for the synthesis of 3-aminopyrones is that the
many known substituted 3-hydroxypyrones (3; Scheme 2,
bottom) can be easily converted in to their substituted 3-amino
congeners (4), and the corresponding alkynylated compounds
(1, see SI for details).
Simple heating of 1a did induce conversion to the
corresponding indoline 2a in low yield (Table 1, entry 1);
however, 2a was accompanied by several decomposition
products. Pyrones bearing acidic functional groups at C3 can be
activated for cycloaddition by treatment of base.17 We found that
addition of DBU gave cycloaddition with fewer by products (entry
2); however, the reaction was still quite sluggish. We believe the
base activates the amino pyrone through deprotonation to give a
more electron-rich diene. Additionally, the added base may also
eliminate adventitious acids that lead to decomposition of the
starting material. Control experiments indicated that protic acids
gave relatively fast decomposition of the starting material with no
observable indoline (entry 3).18
More forcing conditions were also evaluated in order to
increase the product yield. Increasing the temperature gave 2a
in 60%, albeit after a 7 d reaction time (entry 4). Increasing the
equivalents of base did not noticeably improve the reaction yield
or shorten the reaction time (entry 5).
The reaction rate did increase in more polar solvents, and we
found butyronitrile (BuCN) to be an operationally convenient
solvent with suitably high boiling point (entry 6). Increasing the
amount of base, and the temperature (entry 7) gave 2a in high
chemical yield and with a tolerable reaction time. The reaction
was sensitive to the choice of base, and use of potassium
carbonate (entry 8) or other inorganic bases led to slightly
decreased yields.
Scheme 3. Synthesis of Substituted Indolines.
Synthesis of indolines with substitution at C4 is a classic
challenge in organic chemistry; however, preparing indolines
with additional substitution (i.e., 4,x-disubstituted or 4,x,y-
trisubstituted indolines) is also non-trivial. Gratifyingly,
substitution was well tolerated on the pyrone ring. Substituted
Table 1. Optimization of Reaction Conditions.
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aminopyrones (1, R2, R3, or R4 ≠ H) were prepared from the
corresponding substituted 3-hydroxypyrones following the
conditions shown in Scheme 2 (see Supporting Information).
4,5,6-Trisubstitited indoline 2n was prepared in high yield.
Heteroatom (2o) and halogen (2p) substituents were also
tolerated in the reaction.
pharmaceuticals (e.g. ergometrine), as well as notorious
psychedelic drugs.20 A common precursor to these ergot-derived
molecules is lysergic acid. Many syntheses of lysergic acid are
known,21 and a central concern in the synthesis of this molecule
is the method by which the C4-substituted indole is constructed.
Our approach to substituted indoles was applied in a formal
The reaction also produced indolines without substitution at
C4 through use of terminal alkynes (1, R1 = H). Indoline itself
(2q) was produced in high yield. Additionally, 7-methoxy-5-
methylindoline (2r) and 6-ethyl-5-phenylindoline (2s) were
prepared. Finally, carbazole 2t was prepared in high yield from
the corresponding alkynyl-substituted diphenylaniline starting
material.
synthesis of lysergic acid. Chloropyridine 7 was prepared
following the method of Hendrickson, 22 and it was converted to
8a. 3-Aminopyrone (3a) was alkylated with the triflate derived
from 8a to give pericyclic cascade substrate 1u. Oxidative
cyclization following our conditions gave indole 6u in good
chemical yield. Intermediate 6u is a known precursor to lysergic
acid.22
Our method was also extended to a one-pot indole synthesis
(1 à 6, Scheme 4). Oxidations of indolines to indoles occurs
under a variety of mild conditions.3 We subjected standard
substrate 1 to our optimized conditions for the pericyclic cascade
(Method B). When the starting material was consumed (TLC
check), we added an oxidant and observed formation of the
corresponding indole. After a brief survey of oxidants, we found
that the inexpensive 4-hydroxy-TEMPO gave clean conversion
of the indoline to the corresponding indole.19 The chemical yield
on the one-pot indole formation was essentially identical to the
yield of the indoline synthesis, and control experiments further
confirmed that the oxidation of the indolines to indoles with 4-
hydroxy-TEMPO was quantitative.
The one-step indole synthesis was evaluated using additional
substrates (Scheme 4). Our standard substrate 1a gave indole
6a in high yield. 4-Arylindoles with substitution proximal to the
biaryl bond were formed with no loss in yield compared with the
indoline. Products bearing alkyl groups (6b), halogen
substitution (6c), electron donating groups (6d), and electron
withdrawing groups (6e) were all prepared in high yields.
Pyridine (6g) substituents were also well tolerated in the reaction.
Indoles bearing alkenyl groups (6h), a methyl group (6j), a
Scheme 5. Formal synthesis of lysergic acid and ergometrine.
Many previous synthetic approaches toward lysergic acid
cannot be extended to analogs with increased substitution.
However, our method was extended using 3-aminopyrone 3c,
which gave pyrone 1v. Pericyclic cascade reaction under our
conditions gave 6v, which contains additional substitution on the
ergot alkaloid A-ring. Such substitution may be used to probe
the structure activity relationship between the A-ring and activity
in dopamine and serotonin receptors. Efforts to advance this
material to ergometrine derivatives are underway in our
laboratory.
tertiary carbinol (6k), and
a C4-bromide (6m) were also
prepared in high yield.
In summary, we have discovered a new pericyclic cascade
approach to substituted indolines and indoles that allows for
programmed substitution on the benzenoid ring of the
heterocycle. Chemical yields are high, even when multiple
substituents are present. Substituents at the indoline C4 position
can be aryl, heteroaryl, alkenyl, alkyl, or halogen groups.
Conducting the key transformation in the presence of 4-hydroxy-
TEMPO results in the formation of the corresponding indole with
very little decrease in chemical yield. Synthesis of indolines and
indoles with substitution at the other benzenoid positions is
possible, and 4,x-disubstituted or 4,x,y-trisubstituted indolines
are readily prepared. We have showcased this reaction in a
formal synthesis of lysergic acid. Finally, congeners such as 6v,
with additional substitution on the A-ring are also available using
this transformation.
Scheme 4. Synthesis of Substituted Indoles.
Acknowledgements
We gratefully acknowledge funding from the NSF (CHE-
1956401) and Oregon State University.
Among indole natural products that feature substitution at C4,
the ergot alkaloids are perhaps the most well known. This family
of alkaloids is represented by several clinically-used
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Keywords: indoles • indolines • lysergic acid • pericyclic
Suzuki, M. Ozako, I. Mizota, M. Shimizu Asian J. Org. Chem., 2018, 7,
910–913. (g) M. Parameshwar, M. Rajesh, S. Balasubramanian, M. S.
Reddy ACS Omega 2019 4, 18846–18854.
reactions • total synthesis
12 Pyrolytic distillation of mucic acid gives 3-hydroxypyrone, see: J. A. Profitt,
T. Jones, D. S. Watt Synth. Commun. 1975, 5, 457–460.
1 Y. Izawa, D. Pun, S. S. Stahl, Science 2011, 333, 209–213.
2 Y. Lee, S. Basith, S. Choi J. Med. Chem. 2018, 61, 1–46.
13 We found the conversion of mucic acid to 3-hydroxypyrone more convenient
and reproducible in solution, see Supporting Information for details.
14 (a) P. Ruiz–Castillo, S. L. Buchwald Chem. Rev. 2016, 116, 12564–12649.
(b) P. A. Forero–Cortés, A. M. Haydl Org. Process Res. Dev. 2019, 23,
1478–1483.
15 J. Louie, M. S. Driver, B. C. Hamann, J. F. Hartwig J. Org. Chem. 1997, 62,
1268–1273.
16 J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy, L. M. Alcazar–
Roman J. Org. Chem. 1999, 64, 5575–5580.
3
G. W. Gribble, Indole Ring Synthesis: From Natural Products to Drug
Discovery, John Wiley & Sons: Chichester, West Sussex, 2016.
4 For review, see: D. F. Taber, P. K. Tirunahari Tetrahedron 2011, 67, 7195–
7210.
5 (a) F. Petronijevic, C. Timmons, A. Cuzzupe, P. Wipf Chem. Commun. 2009,
104–109. (b) J. Xu, P. Wipf Org. Biomol. Chem. 2017, 15, 7093–7096;
(c) S. R. McCabe, P. Wipf Angew. Chem. Int. Ed. 2017, 56, 324–327.
6 J. Zhang, V. Shukla, D. L. Boger J. Org. Chem. 2019, 84, 9397–9445.
7 D. Perez, E. Guitlan, L. Castedo Tetrahedron Lett. 1992, 33, 2407–2408.
8 P. Gan, M. W. Smith, N. R. Braffman, S. A. Snyder Angew. Chem. Int. Ed.
17 (a) Y. Wang, H. Li, Y.-Q. Wang, Y. Liu, B. M. Foxman, L. Deng J. Am. Chem.
Soc. 2007, 129, 6364–6365. (b) R. P. Singh, K. Bartelson, Y. Wang, H.
Su, X. Liu, L. Deng J. Am. Chem. Soc. 2008, 130, 2422–2423.
2016, 55, 3625–3630.
9 Y. Shen, C. Wang, W. Chen, S. Cui Org. Chem. Front. 2018, 5, 3574–3578.
10 (a) P. Zhao, C. M. Beaudry Angew. Chem. Int. Ed. 2014, 53, 10500–10503.
(b) X. Zhang, C. M. Beaudry Org. Lett. 2020, 22, 6086–6090. (c) J.
Chen, A. J. Ferreira, C. M. Beaudry Angew. Chem. Int. Ed. 2014, 53,
11931–19934.
18
N-alkyl-N-butynyl-3-aminopyrones also underwent the transformations to
give N-alkylindolines, and the rate of the reaction was not affected by
presence or absence of base.
19 B. Huang, H. Tian, S. Lin, M. Xie, X. Yu, Q. Xu Tetrahedron Lett. 2013, 54,
2861–2864.
11 (a) J. Lee, C. Cho Tetrahedron Lett. 2003, 44, 65–67. (b) F. Požgan; K.
Kranjc, V. Kepe, S. Polanc, M. Kočevar ARKIVOC 2007, 8, 97–111. (c)
A. M. Prior, M. J. Gunaratna, D. Kikuchi, J. Desper, Y. Kim, K. Chang, I.
Maezawa, L. Jin, D. H. Hua Synthesis 2014, 46, 2179–2190. (d) W.
Fan, S. Ma Angew. Chem., Int. Ed. 2014, 53, 14542–14545. (e) H. Y.
Kim, E. Song, K. Oh Org. Lett. 2017, 19, 312–315. (f) K. Nakahama, M.
20 H. D. Abraham, A. M. Aldridge Addiction 1993, 88, 1327–1334.
21 For reviews of ergot alkaloid syntheses, see: (a) J.-J. Chen, M.-Y. Han, T.
Gong, J.-L. Yang, P. Zhu RSC Adv. 2017, 7, 27384–27396. (b) H. C.
Liu, Y. X. Jia Nat. Prod. Rep. 2017, 34, 411–432.
22 J. B. Hendrickson, J. Wang Org. Lett. 2004, 6, 3–5.
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Entry for the Table of Contents (Please choose one layout)
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Gary L. Points III, Kenneth T. Stout and
Prof. Dr. Christopher M. Beaudry*
Page No. – Page No.
Regioselective Formation of
Substituted Indoles: Formal
Synthesis of Lysergic Acid
Pericyclic cascade of alkyne-tethered 3-aminopyrones gives indolines or indoles
with substitution at C4. Additional substitution is readily tolerated to give 4,x-
disubstituted or 4,x,y-trisubstituted indolines. The reaction was showcased in a
formal synthesis of lysergic acid.
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