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

Link to VoR: https://doi.org/10.1002/chem.202004107

01/2020
Chemistry - A European Journal 10.1002/chem.202004107

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Regioselective Formation of Substituted Indoles: Formal
Synthesis of Lysergic Acid
Gary L. Points III, Kenneth T. Stout and Christopher M. Beaudry*
Abstract: A Diels–Alder reaction-based strategy for the synthesis of required.
indoles and related heterocycles is reported. An intramolecular Creative and elegant Diels–Alder reactions are known to
cycloaddition of alkyne-tethered 3-aminopyrones gives 4-substituted prepare indoles, with substitution at C4 and the other benzenoid
indolines in good yield and with complete regioselectivity. Additional carbons.4 For example, Wipf has demonstrated that aminofurans
substitution is readily tolerated in the transformation, allowing
tethered with alkene dienophiles undergo Diels–Alder-
elimination cascades to form indoles.5 Boger has used alkyne-
synthesis of complex and non-canonical substitution patterns.
and allene-tethered diazines in Diels–Alder reaction-based
Oxidative conditions give the corresponding indoles. The strategy sequences to prepare substituted indolines and indoles,

Accepted Manuscript
also allows the synthesis of carbazoles. The method was showcased respectively.6 Other strategies featuring alkyne-tethered pyrones
in a formal synthesis of lysergic acid. 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 disclosed a reaction forming indolines from 6-
products, pharmaceuticals, and biological polymers. The sulfonamidopyrones bearing tethered alkynes.9
substitution pattern featured on the aromatic ring is directly A flexible synthesis of indoles was sought that could not only
related to molecular function and biological activity.1 As a result, deliver substitution at C4, but also create indoles with
the preparation of heteroaromatics with control of substituent programmable substitution at other positions and avoid the use
regiochemistry has been, and continues to be, an important of activating or protecting groups on nitrogen. Our laboratory has
longstanding theme in synthetic chemistry. been interested in using pericyclic reactions for the synthesis of
The substituted indole represents a common motif among substituted aromatic rings,10 and we hypothesized that a Diels–
molecules with potent activities toward G protein-coupled Alder reaction-based strategy using 3-aminopyrones tethered
receptors. 2 As a result, substituted indoles are widely used with an alkyne dienophile (1) would deliver the 4-substituted
pharmaceuticals (Figure 1). Ergometrine features a C4- indoles (2); however, this transformation is unknown in the
substituted indole, and it is used in obstetrics for postpartum literature.
bleeding. Sumatriptan is a migraine medicine that contains a C5- We anticipated that the advantages of using 3-aminopyrones
substituted indole (or tryptamine). Finally, vindoline is a rather than either 6-aminopyrones or other heterodienes would
precursor to the chemotherapeutic vinblastine, and it displays an be several fold. First, the key substrates 1 could be prepared
indoline bearing a C6-methoxy group. 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.
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 Eventually, we considered preparing 3-aminopyrones from the
Corvallis, OR 97333, USA corresponding 3-hydroxypyrones. 3-Hydroxypyrone (3a) can be
E-mail: christopher.beaudry@oregonstate.edu obtained commercially, or it can be prepared from inexpensive
mucic acid. 12 , 13 3-Hydroxypyrone (3a) was activated as the
Supporting information for this article is given via a link at the end of
corresponding triflate, which was envisioned to undergo C–N
the document.

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Chemistry - A European Journal 10.1002/chem.202004107

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bond formation to give 3-aminopyrone (4a). 14 However, this

ostensibly benign C–N bond formation was complicated by the The reaction was also successful under microwave heating,
discovery that 3-triflato-2-pyrone immediately decomposed in and reaction times were significantly shorter (entry 10). A brief
the presence of bases commonly used for such couplings (e.g. survey of bases revealed that K2CO3 gave higher yields than
NaOtBu). 15 Additionally, the triflate was not stable to primary DBU with microwave heating (entry 11). Using these optimized
amines, precluding a direct coupling with butynylamines to give conditions (entries 7 and 11) the yield of the pericyclic cascade
1. As a result, we investigated couplings with an ammonia- was nearly quantitative.
equivalent carbamate.
The indoline synthesis was further evaluated with an
We found that Buchwald–Hartwig coupling of the triflate expanded set of substrates (1 à 2, Scheme 3). A wide variety of
derived from 3a with BocNH2 followed by TFA removal gave 3- substitution was possible on the alkyne. Substituted phenyl rings
aminopyrone (4a). 16 Alkylation of 4a with triflate 5a gave our were tolerated giving 2b and 2c, which display branching
initial substrate (1a) to evaluate the pericyclic cascade. A benefit adjacent to the biaryl bond. Indolines bearing phenyl rings with
of this strategy for the synthesis of 3-aminopyrones is that the electron donating substitutents (2d) and electron withdrawing
many known substituted 3-hydroxypyrones (3; Scheme 2, substituents (2e) were formed in good yield. The rate of the
bottom) can be easily converted in to their substituted 3-amino reaction was not significantly different in these cases.

Accepted Manuscript
congeners (4), and the corresponding alkynylated compounds Heteroaromatic rings were well tolerated; 4-(2-thiophenyl)-
(1, see SI for details). indoline (2f) and 4-(3-pyridinyl)-indoline (2g) were prepared. The
Simple heating of 1a did induce conversion to the alkyne substituent need not be aromatic, and cyclohexenyl-
corresponding indoline 2a in low yield (Table 1, entry 1); substituted indoline (2h) was prepared in high chemical yield.
however, 2a was accompanied by several decomposition Enamine-containing product 2i was also produced in good yield.
products. Pyrones bearing acidic functional groups at C3 can be Products bearing sp3-hybridized carbon were also conveniently
activated for cycloaddition by treatment of base.17 We found that prepared, and indolines bearing a methyl (2j), tertiary carbinol
addition of DBU gave cycloaddition with fewer by products (entry (2k), and allyl groups (2l) at C4 were all formed in high yield.
2); however, the reaction was still quite sluggish. We believe the Finally, we found that bromoalkyne-tethered aminopyrone 1m
base activates the amino pyrone through deprotonation to give a (R1 = Br; R2–R4 = H) smoothly reacted to give 2m.
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-
Table 1. Optimization of Reaction Conditions. trisubstituted indolines) is also non-trivial. Gratifyingly,
substitution was well tolerated on the pyrone ring. Substituted

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aminopyrones (1, R2, R3, or R4 ≠ H) were prepared from the pharmaceuticals (e.g. ergometrine), as well as notorious
corresponding substituted 3-hydroxypyrones following the psychedelic drugs.20 A common precursor to these ergot-derived
conditions shown in Scheme 2 (see Supporting Information). molecules is lysergic acid. Many syntheses of lysergic acid are
4,5,6-Trisubstitited indoline 2n was prepared in high yield. known,21 and a central concern in the synthesis of this molecule
Heteroatom (2o) and halogen (2p) substituents were also is the method by which the C4-substituted indole is constructed.
tolerated in the reaction. Our approach to substituted indoles was applied in a formal
The reaction also produced indolines without substitution at synthesis of lysergic acid. Chloropyridine 7 was prepared
C4 through use of terminal alkynes (1, R1 = H). Indoline itself following the method of Hendrickson, 22 and it was converted to
(2q) was produced in high yield. Additionally, 7-methoxy-5- 8a. 3-Aminopyrone (3a) was alkylated with the triflate derived
methylindoline (2r) and 6-ethyl-5-phenylindoline (2s) were from 8a to give pericyclic cascade substrate 1u. Oxidative
prepared. Finally, carbazole 2t was prepared in high yield from cyclization following our conditions gave indole 6u in good
the corresponding alkynyl-substituted diphenylaniline starting chemical yield. Intermediate 6u is a known precursor to lysergic
material. acid.22
Our method was also extended to a one-pot indole synthesis
(1 à 6, Scheme 4). Oxidations of indolines to indoles occurs

Accepted Manuscript
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 Scheme 5. Formal synthesis of lysergic acid and ergometrine.
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. Many previous synthetic approaches toward lysergic acid
Indoles bearing alkenyl groups (6h), a methyl group (6j), a cannot be extended to analogs with increased substitution.
tertiary carbinol (6k), and a C4-bromide (6m) were also However, our method was extended using 3-aminopyrone 3c,
prepared in high yield. 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.
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

Among indole natural products that feature substitution at C4, We gratefully acknowledge funding from the NSF (CHE-
the ergot alkaloids are perhaps the most well known. This family 1956401) and Oregon State University.
of alkaloids is represented by several clinically-used

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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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