Development of an Alkyne Analogue of the de Mayo Reaction: Synthesis of Medium-Sized Carbacycles and Cyclohepta[b]indoles

Article abstract of DOI:10.1002/anie.201808578

Embedded medium-sized carbacycles and cyclohepta[b]indoles occur frequently as scaffold elements in natural products and bioactive compounds. Described herein is a conceptionally novel photochemically triggered cascade process to these scaffolds. Key to the cascading ring-expansion process is an unprecedented intramolecular alkyne analogue of the de Mayo reaction.

Full text of DOI:10.1002/anie.201808578

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Accepted Article
Title: Development of an Alkyne-de Mayo Reaction for the Synthesis of
Medium-Sized Carbacycles and Cyclohepta[b]indoles
Authors: Martin Hiersemann, David Tymann, Dina Christina Tymann,
Ulf Bednarzick, Ljuba Iovkova-Berends, and Julia Rehbein
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808578
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Development of an Alkyne-de Mayo Reaction for the Synthesis of
Medium-Sized Carbacycles and Cyclohepta[b]indoles
David Tymann[a], Dina Christina Tymann[a], Ulf Bednarzick[a], Ljuba Iovkova-Berends[a], Julia Rehbein[b],
and Martin Hiersemann*[a]
Dedicated to Prof. H.-J. Knölker on occasion of his 60th birthday.
Abstract:
cyclohepta[b]indoles occur frequently as scaffold elements in natural
products and bioactive compounds. Herein, we reveal
Embedded
medium-sized
carbacycles
and
a
conceptionally novel photochemically triggered cascade process to
these scaffolds. Key to the cascading ring expansion process is an
unprecedent intramolecular alkyne-de Mayo reaction.
The photochemically triggered (2+2) cycloaddition of α,β-
unsaturated carbonyl compounds and alkenes is a widespread
method for cyclobutane synthesis.[ 1 ] Deployment of cyclic
vinylogous carboxylic acid derivatives in photochemically
triggered (2+2) cycloadditions affords π-acceptor-π-donor-
substituted cyclobutanes.[2] Such annulated cyclobutanoids can
be susceptible to ring opening to provide medium-sized rings. In
the event the ring-opening of a (2+2) photoadduct proceeds via
a retro-aldol type bond reorganization, the ring-enlargement
process may be classified as (alkene-)de Mayo reaction.[ 3 ]
Analogously, vinylogous amides and imides can be amenable to
(2+2) photocycloaddition/retro-Mannich reaction cascades (aza-
de Mayo reaction).[4]
Alkynes are frequently utilized in (2+2) photocycloadditions.[5]
However, the de Mayo reaction deploying alkynes (alkyne-de
Mayo reaction) has only sparsely been studied. The few
published attempts afforded low yields and/or triggered
decomposition (Figure 1). Cavazza and Pietra revealed a single
low-yielding intermolecular example for the alkyne-de Mayo
reaction of 1 to afford 2;[6] Tedaldi and Baker later reported that
the irradiation of 3a only triggered degradation.[7] Despite these
few and discouraging literature precedents, we were intrigued by
the prospect of developing the intramolecular alkyne-de Mayo
reaction to a versatile synthetic tool for the construction of
annulated medium-sized carbacycles (5) starting from readily
available vinylogous carboxylic acid derivatives (3) (Figure 1).
Figure 1. Literature precedents and research outline.
The reports by Cavazza as well as Tedaldi served as starting
point for method development (Figure 1). We surmised that the
usage of broad-band emitting medium-pressure mercury vapor
lamps
were
responsible
for
degradative
secondary
photochemical processes.[8] Therefore, we started to investigate
the alkyne-de Mayo reaction of the vinylogous ester 3b
deploying narrow-band emitting light sources (Table 1). The
UV/vis spectrum[ 9 ] of 3b in acetonitrile indicates a strong
absorption maximum at 231 nm (ε = 23063 M–1cm–1; assignable
to the allowed π,π* transition) and a weak, broad absorption
maximum at 274 nm (ε = 499 M–1cm–1; assignable to the
forbidden n,π* transition). When irradiating a solution of 3b in
acetonitrile for 12 h using fluorescent lamps emitting at 300 nm,
the desired cycloheptadienone 5b was isolated in 49% yield
along with unconsumed 3b (Table 1, Entry 1). Subjecting 3b to
the identical conditions for 24 h resulted in the isolation of 5b in
61% yield and recovered 3b (Entry 2). Further prolonged
irradiation increased the yield of 5b to 65% but did not trigger
complete consumption of 3b, and promoted the formation of
unidentifiable degradation products (Entry 3). Notably in this
regard, the UV/vis spectrum[9] of 5b in acetonitrile displays a
strong and broad absorption maximum at 351 nm (ε = 3466 M–
1cm–1; assignable to the π,π* transition). Consequently, the
prolonged irradiation of the substrate(3b)/product(5b) mixture in
acetonitrile at 300 nm may have triggered the formation of
degradation products.[10] In order to avoid product degradation
and to support selective π,π* substrate excitation, we turned to
quasi-monochromatic low-pressure mercury vapor lamps
emitting at 254 nm. In the event, irradiation of 3b in acetonitrile
for only 6 h afforded 5b in 66% yield (Entry 4). Running the
reaction at 254 nm in Et2O or CH2Cl2 led to markedly decreased
yields (Entry 5–6). Switching to solvent systems capable of
hydrogen-bonding resulted in rate-acceleration and improved
yields (Entry 7–10). Perfluorinated alcohols turned out to be
particularly supportive enabling yields >90% after 3 h of
[a]
[b]
D. Tymann, D. C. Tymann, U. Bednarzick, Dr. L. Iovkova-Berends,
Prof. Dr. M. Hiersemann
Fakultät für Chemie und Chemische Biologie
Technische Universität Dortmund
44227 Dortmund, Germany
david.tymann@tu-dortmund.de
Prof. Dr. J. Rehbein
Fakultät für Chemie und Pharmazie
Universität Regensburg
93053 Regensburg, Germany
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201808578
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irradiation at 254 nm (Entry 11–12); compromising between cost
and selectivity, we selected CF3CH2OH (TFE) over (F3C)2CHOH
(HFIP) for further investigations. Surprisingly, irradiation of 3b
using fluorescent lamps (300 nm) in TFE for 12 h led to the
isolation of 5b in 51% yield along with unconsumed 3b (33%)
indicating no effect of the solvent on the rate of the
intramolecular alkyne-de Mayo reaction at 300 nm (Entry 13).
Finally, a control experiment demonstrated that solvents should
be degassed to avoid decomposition (Entry 14).
cyclobutene intermediate 4p.[12] Notably, stirring a solution of
purified 4p in TFE (c = 30 mM) at 80 °C for 20 min without
irradiation led to complete conversion of 4p to 5p. Apparently,
cyclobutene ring-opening is thermally induced and not
13
]
photochemically triggered.[
Complete conversion of the
vinylogous imide 3p to 5p under the conditions of the
photochemical experiment was achieved after 9.5 h and 5p was
isolated in 95% yield. Interestingly, rate-retardation of the ring-
opening was also notable for X = NBoc and R1 = R2 = CH3 as
irradiation of 3q for 13 h afforded a mixture consisting of 4q and
5q. Complete conversion to 5q was achieved by heating in TFE
(c = 30 mM, 80 °C, 70 min). Ring-expansion of the vinylogous
thioester 3r required 20 h of irradiation and afforded 5r in 21%
yield along with the photocycloadduct 4r (6%)[14] and byproducts
useful for mechanistic analysis (vide infra).
Table 1. Alkyne-de Mayo reaction: Optimization[a]
2
1,5
1
0,5
0
Table 2. Alkyne-de Mayo reaction: Scope [a]
200
250
300
350
400
450
500
Wavelenght λ [nm]
Entry
1
2
λ [nm] [b]
300
300
300
254
254
254
254
254
254
254
254
254
300
254
Solvent
CH3CN
CH3CN
t [h]
Yield [%] [c]
12
24
48
6
49
61
3
CH3CN
65
4
CH3CN
66
5
CH2Cl2
6
30
6
Et2O
6
14
7
CH3CN–H2O (1000:1)
CH3CN–H2O (10:1)
CH3CN–H2O (1:1)
CH3OH
6
68
8
4
83
9
4
84
10
11
12
13
14
4
88
CF3CH2OH
(F3C)2CHOH
CF3CH2OH
CF3CH2OH [d]
3
93
3
95
12
3
51
decomp.
[a] Performed in degassed solvent (5.2 mL) with 0.16 mmol of 3b using low-
pressure mercury vapor lamps. [b] See the Supporting Information for the
emission spectra of low-pressure mercury lamps. [c] Isolated yield after
purification by chromatography. [d] Saturated with oxygen.
Having established conditions for the alkyne-de Mayo reaction,
we studied scope and limitations by variation of scale,
substituents (R1–4), linker atoms (X; Y), and ring-size (m = 0–1; n
= 1–2) (Table 2). Performing the photoreaction of 3b on a 1.5
mmol scale required an increased time of irradiation (9 h) but did
not affect the yield (93%). Irradiation of 3a with R1 = H, initially
used without success by Tedaldi and Baker (Figure 1), triggered
formation of 5a in 66% yield. This result emphasizes the pivotal
importance of the setup of the photochemical experiment.
Further efforts aimed to unveil limiting substituent effects by
variation of R1. However, saturated and unsaturated aliphatic,
including the cyclopropyl (“radical clock”) substituent, and
aromatic substituents were well tolerated, and the corresponding
cycloheptadienones 5c‒5l could be isolated in yields ranging
from 80% to 94%. Further expanding the scope by incorporation
of heteroatom substituents afforded the ring-expansion products
5m (R1 = Cl, 64%) and 5n (R1 = SiMe3, 86%). Finally, for R1 =
SnBu3 we noticed a diminished chemoselectivity and 5o was
isolated in only 20% yield.[11] Aiming to establish an alkyne-aza-
de Mayo reaction, vinylogous imide 3p with X = NBoc and R2 =
H was subjected to the optimized conditions. In the event, we
isolated a product mixture consisting of the expected ring
expansion product 5p as well as the proposed yet elusive
[a] Reactions were performed in degassed CF3CH2OH (50 mL) with 1.5 mmol
of 3a–3z at 254 nm using low-pressure mercury vapor lamps. Isolated yields
after purification by chromatography. [b] Contaminated with the putative
cyclobutene 4q (approx. 15% w/w). [c] After being irradiated for 11.5 h, the
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10.1002/anie.201808578
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reaction mixture was placed into a pre-heated oil bath (80 °C) and stirred at
80 °C for 2 h.
spiro-1,4-biradicals is supported by the isolation of unexpected
byproducts from interfering hydrogen atom transfer reactions
(Scheme 1). The ring-opening of the intermediate tricyclic
In order to study ring-size effects for n = 2, 3s‒3x were
subjected to our optimized conditions and 5s‒5x were isolated
in yields ranging from 59% to 94%.[15] Finally, alternative tethers
were investigated. Irradiation of 3y with m = 1 and Y = CH2
delivered the dihydropyrane 5y in 63% yield. Intriguingly,
irradiation of the methylene acetal 3z with m = 1 and Y = O
triggered formation of a mixture consisting of the cyclobutene 4z
and the ring expanded product 5z. Complete conversion to the
desired cycloheptadienone 5z then required heating the mixture
in TFE (80 °C, 2 h). This second-generation linker (X = Y = O)
should be amenable to straightforward linker cleavage using
Brønsted or Lewis acidic conditions.[16]
Cyclohepta[b]indole and cyclohepta[b]benzofuran structural
motifs are eminent as scaffold elements in natural product and
medicinal chemistry.[ 17 ],[ 18 ] Aiming to establish a metal-free
single-step annulative access to these scaffolds, we studied the
photochemistry of 6a–6f (Table 3). To our delight, subjecting the
vinylogous imides 6a and 6c–6e to the previously optimized
conditions afforded the cyclohepta[b]indolones 7a and 7c–7e in
yields ranging from 78% to 91%.[15] In contrast, irradiation of 6b
resulted in the formation of 7b in only 53% yield along with some
decomposition. However, treating 7c with TBAF smoothly
provided the desired protodesilylated cyclohepta[b]indolone 7b
in 87% yield. Subjecting the corresponding vinylogous ester 6f
cyclobutene S0-4 may be considered as
a stereospecific
conrotatory electrocyclic ring-opening. However, the conrotatory
pericyclic bond reorganization would deliver the strained ring
expansion product (E,E)-5. A rapid double bond isomerization of
(E,E)-5 to (Z,E)-5 under irradiation and in the presence of a
nucleophilic solvent appears possible. Alternatively, the ring-
opening may procced by a retro-aldol (X = O) or retro-Mannich-
type (X = NBoc) mechanism to provide (Z,E)-5 directly and
without the intermediate formation of strained (E,E)-5.[20] The
assumption of a polar concerted but non-pericyclic ring opening
would nicely explain the beneficial effect of hydrogen-bonding
polar protic solvents on the rate and the yield of the ring-opening
reaction. The rate difference of the ring opening for X = O and X
= NBoc may be rationalized from the same point of view: the
restricted availability of the lone pair of the nitrogen atom of the
NBoc functionality may retard the retro-Mannich type ring
opening reaction thus leading to a slow conversion and the
experimental observation of tricyclic cyclobutene intermediates.
to
the
identical
conditions
afforded
the
cyclohepta[b]benzofuranone 7f in inconsistent yield (23–47%)
along with yet unidentified byproducts.
Table 3. Alkyne-de Mayo reaction: Cyclohepta[b]indoles [a]
[a] Reactions were performed in CF3CH2OH (5.2 mL) with 0.16 mmol of 6a–6f
at 254 nm using low-pressure mercury vapor lamps emitting. Isolated yields
after purification by chromatography. [b] TBAF (1.2 equiv), THF, 0 °C, 15 min.
Scheme 1. Mechanistic hypothesis and supportive experimental results.
In summary, the intramolecular de Mayo reaction is not
restricted to alkenes. Employment of alkynes empowers a one-
pot metal-free entry to annulated medium-sized rings and
cyclohepta[b]indoles. Key to success in developing an alkyne-de
Mayo reaction was the deployment of a quasi-monochromatic
light source and a polar protic solvent. Valuable applications of
Mechanistically, we propose that irradiation at 254 nm causes
population of the excited state S2(π,π*) followed by an internal
conversion to S1(n,π*) (Scheme 1). Rapid intersystem crossing
to T1-3 triggers 5-exo-dig cyclization to the 1,4-biradical T1-8.
Subsequent transition to S0-8 is followed by cyclobutene ring-
closure to afford cis-S0-4.[19] Our proposal of the intermediacy of
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10.1002/anie.201808578
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the alkyne-de Mayo reaction in target-oriented synthesis are
easily conceivable.[21]
Kolding, J. L. Alleva, B. M. Stoltz, Angew. Chem. Int. Ed. 2011, 50,
6814–6818; Angew. Chem. 2011, 123, 6946–6950.
M. Cavazza, F. Pietra, J. Chem. Soc., Chem. Commun. 1986, 1480–
1481.
[6]
Acknowledgements
[7]
[8]
L. M. Tedaldi, PhD thesis, University College London, UK, 2011.
As recently noted by Aitken and co-workers, a different outcome of a
Financial contributions by the Beilstein-Institut (graduate
research fellowship to D.T.), the DFG (HI628/13-1 to M.H.;
Emmy-Noether grant RE3630 to J.R.), as well as by the TU
Dortmund are gratefully acknowledged.
photochemical experiment can be observed when deploying
a
polychromatic light source compared to fluorescent lamps: J. Buendia,
Z. Chang, H. Eijsberg, R. Guillot, A. Frongia, F. Secci, J. Xie, S. Robin,
T. Boddaert, D. J. Aitken, Angew. Chem. Int. Ed. 2018, 57, 6592–6596;
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[9]
For the UV/vis spectra of 3b and 5b in acetonitrile, see the Supporting
Information.
Keywords: cascade reaction • cycloaddition •
cyclohepta[b]indole • photochemistry • ring expansion
[10] For the photochemistry of 2,4-cycloheptadienones, see: a) H. Hart, T.
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providing mixtures of 5o and 5a.
[12] Notably, the corresponding vinylogous amide (X = NH) was completely
resistant to the conditions of our photochemical experiment.
[13] For computational studies on the thermodynamics of the ring-expansion
of 3b, see the Supporting Information.
[14] Contaminated with the allene 12.
[15 ] CCDC 1855390, 1830101 and 1830100 (5v, 6a and 7a) contain the
supplementary crystallographic data for this paper. These data are
provided free of charge by The Cambridge Crystallographic Data
Centre.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Enlightened and expanded: The
de Mayo reaction is not restricted to
alkenes. Deployment of a quasi-
monochromatic light source and a
hydrogen bonding polar protic
solvent enabled the development of
an alkyne-de Mayo reaction. This
broadly applicable method provides
rapid access to medium-sized
David Tymann, Dina Christina
Tymann, Ulf Bednarzick, Ljuba
Iovkova-Berends, Julia Rehbein,
Martin Hiersemann*
Page No. – Page No.
Development of an Alkyne-de Mayo
Reaction for the Synthesis of
Medium-Sized Carbacycles and
Cyclohepta[b]indoles
carbacycles
and
cyclohepta[b]indoles starting from
straightforwardly accessibly viny-
logous carboxylic acid derivatives.
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