Phosphoric Acid Catalyzed 1,2-Rearrangements of 3-Hydroxyindolenines to Indoxyls and 2-Oxindoles: Reagent-Controlled Regioselectivity Enabled by Dual Activation

Article abstract of DOI:10.1002/ejoc.201700085

A common synthetic route to indoxyl and 2-oxindole alkaloids utilizes the oxidation of indoles to 3-hydroxyindolenines, followed by acid-mediated 1,2-rearrangement. However, controlling the regioselectivity is often challenging and there is an ongoing need for new reaction conditions allowing to steer product selectivity. We report herein that phosphoric acids are ideal organocatalysts for the highly regioselective 1,2-rearrangement of 3-hydroxyindolenines to 2-oxindoles, with predictable product selectivity arising from an efficient dual activation mode.

Full text of DOI:10.1002/ejoc.201700085

A Journal of
Accepted Article
Title: Phosphoric acid-catalyzed 1,2-rearrangements of 3-
hydroxyindolenines to indoxyls and 2-oxindoles: reagent-
controlled regioselectivity enabled by dual activation
Authors: Eva Schendera, Stephanie Lerch, Thorsten von Drathen,
Lisa-Natascha Unkel, and Malte Brasholz
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700085
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10.1002/ejoc.201700085
European Journal of Organic Chemistry
COMMUNICATION
Phosphoric acid-catalyzed 1,2-rearrangements of 3-hydroxy-
indolenines to indoxyls and 2-oxindoles: reagent-controlled
regioselectivity enabled by dual activation
Eva Schendera,[a] Stephanie Lerch,[a] Thorsten von Drathen,[a] Lisa-Natascha Unkel[a]
and Malte Brasholz[a]*
Abstract: A common synthetic route to indoxyl- and 2-oxindole
alkaloids utilizes the oxidation of indoles to 3-hydroxyindolenines,
followed by acid-mediated 1,2-rearrangement. However, controlling
the regioselectivity is often challenging and there is an ongoing need
for new reaction conditions allowing to steer product selectivity. We
report here that phosphoric acids are ideal organocatalysts for the
highly regioselective 1,2-rearrangement of 3-hydroxyindolenines to
2-oxindoles, with a predictable product selectivity arising from an
efficient dual activation mode.
reagents,6 DMDO7 and H2O2 in combination with aspartyl
peptides,8 or alternatively, by catalytic photooxygenation.6a,9 The
subsequent semipinacol rearrangement to indoxyls 3 proceeds
at elevated temperatures and typically, sodium methoxide in
methanol4b,7a,10 is used, or Brønsted acids like HCl, formic and
acetic acid,5a,11 as well as stoichiometric amounts of Lewis acids
12
like BF3·OEt2 or lanthanide triflates.5a,7b,8,12a,13 However, the
semipinacol rearrangement is in competition with an alternate
1,2-rearrangement pathway leading to 2-oxindoles 4, and as a
result, controlling the regioselectivity of the protocol is often
challenging, particularly when the substrate 2 shows little or no
bias for one of the competing reaction pathways. Moreover, a
possible equilibration between indoxyls 3 and 2-oxindoles 4
under the reaction conditions may complicate matters, which
has been demonstrated to occur in at least one example of a
boron trifluoride-mediated rearrangement.12b
Spirocyclic indoxyls and 2-oxindoles constitute fascinating
classes of oxygenated indole alkaloids, and many of these
natural products possess highly attractive medicinal properties
such as analgesic, antihypertensive, antitumor or antiviral
activity (Figure 1).1
R1
R2
R1
R1
R2
R2
R1
R2
Scheme 1. Oxidation of 1H-indoles 1 to 3-hydroxyindolenines 2 and 1,2-
rearrangements to 2,2-disubstituted indoxyls
3 and 3,3-disubstituted 2-
oxindoles 4.
Figure 1. Natural spiroindoxyl and spirooxindol alkaloids.
A recent example from natural product synthesis illustrated
the difficulty of steering the regioselectivity of the competing 1,2-
rearrangement pathways. A 2,3-diaryl-substituted hydroxyindole-
nine 2 served as a key intermediate in the formal total synthesis
of the marine natural product diazonamide A, however, it
underwent a moderately selective scandium triflate-mediated
rearrangement to generate a 2:1 mixture of regioisomers, in
favor of the undesired indoxyl product.14
Clearly, there is a need for reaction conditions that lead to
predictable results in the 1,2-rearrangements of compounds 2,
and herein we report that phosphoric acid derivatives as simple
as diphenyl phosphate (DPP) selectively and reliably promote
the formation of 2-oxindoles 4 in many cases and under catalytic
conditions. Secondly, we report that 3-alkyl-2-aryl-substituted
substrates 2 are in fact switchable systems, for which product
selectivity can be controlled by choosing between either
phosphoric acid organocatalysis, or acetic acid as a stoichio-
metric promoter.
Numerous structurally complex spiroindoxyls and -oxindoles
have been targets of total synthesis,2 and a well-known synthetic
route to these compounds utilizes the oxidation of 1H-indoles 1
to 3-hydroxyindolenines 2, followed by acid- or base-mediated
1,2-rearrangement (Scheme 1).3 The oxidation of indoles 1 to
intermediates 2 can be performed employing stoichiometric
oxidants like peracids,4 oxaziridines,5 hypervalent iodine(III)
[a]
E. Schendera, S. Lerch, T. von Drathen, L.-N. Unkel,
Prof. Dr. M. Brasholz
University of Hamburg
Department of Chemistry – Institute of Organic Chemistry
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
E-mail: malte.brasholz@chemie.uni-hamburg.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700085
European Journal of Organic Chemistry
COMMUNICATION
Our interest in the 1,2-rearrangements of hydroxyindolenines
was stimulated by our recently reported photooxygenation of
2,3-disubstituted indoles 1a, efficiently catalyzed by visible light-
absorbing aminoanthraquinones (Scheme 2a).9a Intermediates
2a, bearing a migration-prone C3-arylmethyl substituent, could
not be isolated, but in acetic acid solution they underwent an
instantaneous semipinacol rearrangement at room temperature,
to furnish 2,2-disubstituted indoxyls 3a as single products. As we
extended our photooxygenation method to 2-phenyltryptamine
derivative 1b,7b we could however readily isolate the stable
hydroxyindolenine 2b, as its acid-mediated rearrangement re-
quires elevated temperatures. When 2b was generated and the
reaction mixture in acetic acid was subsequently heated to
130°C for 5 h, the indoxyl 3b was obtained in 31% yield, but
notably, the 2-oxindole regioisomer 4b was also formed, in
amounts up to 5% (Scheme 2b).
a similarly attractive selectivity for oxindole 4b, with a slightly
reduced conversion of 83% after 24 h. L-Proline (J) on the other
hand exclusively promoted the formation of the indoxyl product
3b, however, no catalytic turn-over was observed, resulting in
only 12% conversion after 24 h. Finally, we compared the
phosphoric acid catalysts K-N, which all gave full conversion of
2b and which all offered high regioselectivity in favour of the
oxindole 4b. Imidodiphosphoric acid N produced product 4b with
96% selectivity, however, using more readily available diphenyl
phosphate (DPP, K) also gave an attractive product ratio of 91:9
in favour of 4b. For comparison with the organic acid catalysts
A-N, we also performed the rearrangement of 2b using 10 mol-
% of methanolic HCl in toluene (130 °C, 24 h) and this reaction
gave 63% conversion and a ratio of 3b/4b of 56:44. Further, we
carried out the reaction in neat acetic acid (A, 130 °C, 24 h) and
we made the very useful observation that under these conditions,
not only conversion of 2b was complete after 24 h, but also, the
regioselectivity improved, to reproducibly generate indoxyl 3b
with a good selectivity of 75% (see below for a possible
explanation). Hence, with this last result and the phosphoric
acid-catalyzed procedure, we effectively established a set of
metal-free reaction conditions which allowed us to switch the
regioselectivity in the acid-induced rearrangement of 3-hydroxy-
indolenine 2b, and consequently we set out to investigate the
applicability to differently substituted substrates.
A
B
C
D
E
Scheme 2. Aminoanthraquinone-catalyzed photooxygenation/1,2-rearrange-
ments of a) indoles 1a to 2,2-disubstituted indoxyls 3a and b) of tryptamine
derivative 1b to the regioisomeric products 3b and 4b. AAQ = 1,5-diamino-
anthraquinone derivative.
3b/4b 48:52
(conv. 79%)
3b/4b 14:86
(conv. 83%)
3b/4b 29:71
(conv. 33%)
3b/4b 33:66
(conv. 29%)
3b/4b 45:55
(conv. 37%)
While the 1,2-rearrangement of hydroxyindolenine 2b has
previously been studied in the presence of various stoichiometric
transition metal Lewis acids,7b we were intrigued by investigating
the same reaction but using Brønsted acids, and under catalytic
conditions. Consequently, we compared a range of Brønsted
acid organocatalysts A-N in the rearrangement of 2b, and as
shown in Scheme 3, carboxylic, sulfonic, phenolic and phos-
phoric acids were employed. All reactions were performed in
toluene solution, using 10 mol-% of catalyst, and heated to
130 °C for 24 h (sealed reaction vials). The catalyst screening
showed that the relatively weak carboxylic acids like acetic acid
(A), benzoic acid derivatives (D,E,I) as well as perfluorophenol
(F) led to incomplete conversions between 29-79% after 24 h,
and hardly any regioselectivity between products 3b and 4b was
observed. Employing stronger sulfonic acids (G,H) allowed for
full conversion of substrate 2b and the oxindole product 4b was
formed with good selectivities of up to 81% in the case of
camphor sulfonic acid (CSA, H). Trifluoroacetic acid (B) showed
F
G
H
I
J
3b/4b 44:56
(conv. 47%)
3b/4b 29:71
3b/4b 19:81
3b/4b 41:59
(conv. 39%)
3b/4b 100:0
(conv. 12%)
K
L
M
N
3b/4b 9:91
3b/4b 16:84
3b/4b 18:82
3b/4b 4:96
Scheme 3. Catalyst screening for the 1,2-rearrangement of substrate 2b. All
reactions were performed at c = 50 μM of 2b in PhCH3, and in sealed vials.
Regioisomer ratios were determined by analysis of crude 1H-NMR spectra.
Table 1 shows a set of fourteen 3-hydroxyindolenines 2b-2o
which were reacted either in neat acetic acid (A) or using
10 mol-% of DPP (K), with temperatures ranging from 80-130 °C
and within 24 h reaction time. We found that the 3-alkyl-2-aryl-
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10.1002/ejoc.201700085
European Journal of Organic Chemistry
COMMUNICATION
substituted substrates 2b-2e are indeed switchable, leading
either to indoxyl products 3 when using HOAc, or to 2-oxindoles
4 when using catalytic DPP (10 mol-%) in toluene, with good to
excellent regioselectivities and isolated yields. The examples 2f
and 2g however show that substrates bearing C3-substituents
with a very high migrational aptitude like isopropyl and allyl,
almost exclusively undergo the ‘simple’ semipinacol rearrange-
ment leading to the indoxyl products 4f and 4g (compound 2a of
Scheme 2a also belongs into this category). We next examined
2,3-diarylated substrates 2h-2l. Generally, these compounds all
underwent very clean and perfectly selective rearrangement with
catalytic DPP, exclusively generating the oxindole products 4h-
4l. In contrast with a previous report, the selectivity in the HOAc-
mediated reaction is poor for substrate 2h11c and 2j (which form
1:1 mixtures of products) and only in case of the 3-(4-cyano-
phenyl)-2-phenyl-substituted indolenine 2i, a slight preference in
favor of indoxyl 3i could be observed. Yet again, substrates 2k
and 2l with electron-rich C3-heteroaryl groups undergo exclusive
rearrangement to oxindoles 4k and 4l with catalytic DPP, and
surprisingly also in HOAc. Finally, the examples 2m-2o illustrate
the behavior of 2,3-dialkyl-substituted hydroxyl-indolenines and
compounds 2m and 2n undergo highly selective rearrangement
to their oxindole congeners 4m and 4n, irrespective of the
conditions used. In case of the tryptophane-derived substrate 2n,
the spirocyclic oxindole product 4n was obtained with formally
inverted configuration at the spirocyclic center (stereochemical
assignments based on NOESY experiments), which is consis-
tent with previous observations.7b,8
Compound 2o in turn was found highly unstable to our
conditions and generated a complex mixture of undefined
products.
Table 1. Scope and regioselectivity of the Brønsted acid-mediated 1,2-rearrangement of substrates 2 to products 3 and 4.
T
[°C]
r.r. 3/4
T
[°C]
r.r. 3/4
substrate
conditions
3 [%]b
4 [%]b
substrate
conditions
3 [%]b
4 [%]b
[%]a
[%]a
(A) HOAc
(B) DPP
130
130
75:25
9:91
3b 52
4b 14
4b 67
(A) HOAc
(B) DPP
130
130
64:36
0:100
3i 37
-/-
4i 36
4i 40
2b
2i
3b
6
(A) HOAc
(B) DPP
130
130
83:17
29:71
3c 82
3c 16
4c
4c 55
3
(A) HOAc
(B) DPP
130
130
50:50
0:100
3j 47
-/-
4j 47
4j 76
2c
2d
2j
(A) HOAc
(B) DPP
130
130
81:19
8:92
3d 76
4d 10
4d 58
(A) HOAc
(B) DPP
130
130
0:100
0:100
-/-
-/-
4k 97
4k 95
2k
3d
6
(A) HOAc
(B) DPP
130
130
85:15
17:83
3e 65
3e 16
4e 10
4e 53
(A) HOAc
(B) DPP
130
130
0:100
0:100
-/-
-/-
4l 98
4l 97
2e
2f
2l
(A) HOAc
(B) DPP
130
80
95:5
92:8
3f 85
3f 86
4f
4f
0
7
(A) HOAc
(B) DPP
80
130
8:92
0:100
3m
-/-
6
4m 71
4m 89
2m
(A) HOAc
(B) DPP
130
130
100:0
100:0
3g 78
3g 70
-/-
-/-
(A) HOAc
(B) DPP
130
80
0:100
0:100
-/-
-/-
4n 68
4n 89
2g
2h
2n
2o
(A) HOAc
(B) DPP
130
130
50:50
3:97
3h 46
3h 0
4h 43
4h 95
(B) DPP
(B) DPP
80
25
-/-
-/-
-/-
3o <5
-/-
-/-
Reaction time 24 h in all cases, in neat HOAc A (conditions A) or in PhCH3 and using 10 mol-% DPP K (conditions B). All reactions were performed in selead vials.
[a] Determined by 1H-NMR of crude products. [b] Isolated yields after chromatography.
In order to gain mechanistic insight, we first investigated the
effect of the reaction temperature. Temperature-conversion
profiles were recorded for the reaction of substrate 2b, at
temperatures ranging from 25-150 °C, and using neat HOAc as
well as phosphoric acid catalysts K and M (see Figures S3a-S3c,
supporting information). These data clearly showed that the
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10.1002/ejoc.201700085
European Journal of Organic Chemistry
COMMUNICATION
required temperature for the induction of the rearrangement of
2b is at least 100 °C irrespective of the acid used, and thus it is
mostly dependent on substrate structure, and only marginally
influenced by the acid pKa. Further, no interconversion between
products 3b and 4b occured under the Brønsted-acidic
conditions. For the 2,3-diarylated substrates 2h-2j, the minimum
reaction temperature was similarly determined to be 100 °C.
In terms of the catalytic activity and regioselectivity, a close
inspection of the data in Scheme 3 shows that there is no clear
correlation between acid pKa, conversion of substrate 2b or
product ratio (Figure S1). Consequently, we studied the catalyst-
substrate binding by 1H-NMR spectroscopy in solution. Job-
plots15 were acquired for the 2,3-diphenyl-substituted
hydroxyindolenine 2h, in [D6]-benzene or [D8]-toluene solution
and using acid catalysts A, B and K-N (Figure 2a), and the
chemical shifts of the ortho-protons of the peripheral phenyl
rings of 2h (δ = 7.46 and 8.38 ppm in [D6]-benzene in the
uncomplexed form) were used for binding quantification (see
Figures S2a-S2g). HOAc (A) shows only very weak and
unspecific binding to substrate 2h, and a saturation could not
even be achieved using 10 molar equivalents of the acid. This
might explain why the regioselectivity of the 1,2-rearrangement
using catalytic HOAc differs markedly from the reaction in HOAc
as solvent. By contrast, TFA (B) shows strong binding and the
curve has a maximum at χi (molar fraction) of 0.33, indicating a
2:1 binding stoichiometry between the acid and substrate 2h.
The same is observed with diphenyl phosphate (DPP, K).
Triflimide catalyst M and (4-Nitrophenyl)phosphate catalyst L,
both with much decreased pKa compared to DPP, even more
strongly bind substrate 2h, and each in a well-defined 1:1
complex (saturation is observed at χi = 0.50) for which we
propose the structure shown in Scheme 2b. Imidodiphosphoric
acid N in turn is a weak 1:1 binder.
We can presently only speculate about the structure of the DPP-
complex 2h·(K)2, but we think it is probably identical to the
complexes 2h·L and 2h·M, with one additional weak hydrogen
bond-contact between the indoline nitrogen and a second
phosphate molecule (Figure 2b).
A proposed mechanism for the phosphoric acid-catalyzed
rearrangement is shown in Scheme 4. Substrate 2 equilibrates
with indolyl cation 5, but complexation with the catalyst shifts the
equilibrium to the 1:1-complex 2’, from which a suprafacial [1,2]-
shift leads to product 3 (the indoxyl is a free, unbound species in
solution according to 1H-NMR analysis, see Figure S2h).
However, the dual activation16 in complex 2’ strongly promotes
the formation of epoxide 6, and this pathway generally
outcompetes the ‘simple’ semipinacol rearrangement 2’→3.
Ring-opening of 6 to the benzylic cation 7 is again facilitated by
dual activation, and even more when substituent R1 is electron-
donating, which is particularly well-illustrated by the examples 2k
and 2l with electron-rich C3-heteroaryl groups. Finally, an
irreversible [1,2]-shift of the substituent R2 in 7 generates the
complex-bound oxindole 4’ (Figure S2h), with a formally inverted
configuration at C3.7b,8 Reaction of complex 4’ with substrate 2
releases the oxindole product 4 and closes the catalytic cycle.
cat.
H+
cat.
4
2
~[1,2]
2’
5
3
2
4’
6
a)
Δδ (ppm)
0.10
L
~[1,2]
M
K
0.08
0.06
0.04
0.02
7
Scheme 4. Proposed mechanism.
N
A
B
The equilibrium between hydroxyinolenine 2 and the planar
indolyl cation 5 shown in Scheme 4 suggests that a dynamic
kinetic resolution may be feasible using chiral phosphoric acid
catalysis. In preliminary experiments, we have screened a
number of BINOL-phosphate derived catalysts in the
rearrangement of reference substrate 2b (again using 10 mol-%
of catalyst at 130 °C in PhCH3, Table S1),17 however, with only
limited success so far. The bis-silylated catalyst (R)-O for
instance offers excellent regiocontrol in favour of oxindole 4b
(3b/4b = 3:97) but both rearrangement products are fully
racemic. Conversely, catalyst (S)-P induces no regioselectivity
(3b/4b 46:54), but generates at least the indoxyl product (+)-3b
with promising enantioselectivity (e.r. 13:87; the oxindole 4b has
e.r. 35:65).
0
0.25
0.50
0.75
1
χ
i (molar fraction) of 2h
b)
7.46 ppm
shifted upfield
L,M,K
K
shifted
downfield
2h
8.38 ppm
2h·L, 2h·M,
2h·K
2h·(K)2
Figure 2. a) Job-plot analysis of the binding between substrate 2h and
catalysts A, B and K-N in [D6]-benzene or [D8]-toluene solution. Lines serve as
guide to the eye. b) Complexation leading to the proposed 1:1 complexes 2h·L,
2h·M and 2h·K, and the 2:1 complex 2h·(K)2.
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10.1002/ejoc.201700085
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COMMUNICATION
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a large variety of substrates. NMR studies suggest that the high
level of regioselectivity observed in the phosphoric-acid
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Acknowledgements
The authors thank the Deutsche Forschungsgemeinschaft
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Keywords: • organocatalysis • phosphoric acids • rearrange-
ments • oxindoles • alkaloids
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700085
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Rearrangements
Eva Schendera, Stephanie Lerch,
R1
R2
Thorsten von Drathen, Lisa-Natascha
Unkel, Malte Brasholz*
Acid-induced 1,2-rear-rangements of
hydroxyindolenines lead to indoxyls
and 2-oxindoles, but controlling
product selectivity is often challenging.
Phosphoric acids were found to be
ideal organocatalysts for inducing the
highly regioselective rearrangement to
2-oxindoles in many examples.
R1
R2
Page No. – Page No.
Phosphoric acid-catalyzed 1,2-rear-
rangements of 3-hydroxyindolenines
to indoxyls and 2-oxindoles: reagent-
controlled regioselectivity enabled by
dual activation
R1
R2
phosphoric acid
catalysis
This article is protected by copyright. All rights reserved.