Photochemical Approach to the Cyclohepta[b]indole Scaffold by Annulative Two-Carbon Ring-Expansion

Article abstract of DOI:10.1002/chem.202002581

We report on the implementation of the concept of a photochemically elicited two-carbon homologation of a π-donor–π-acceptor substituted chromophore by triple-bond insertion. Implementing a phenyl connector between the slide-in module and the chromophore enabled the synthesis of cylohepta[b]indole-type building blocks by a metal-free annulative one-pot two-carbon ring expansion of the five-membered chromophore. Post-irradiative structural elaboration provided founding members of the indolo[2,3-d]tropone family of compounds. Control experiments in combination with computational chemistry on this multibond reorganization process founded the basis for a mechanistic hypothesis.

Full text of DOI:10.1002/chem.202002581

Accepted Article
Accepted Article
Title: Photochemical Approach to the Cyclohepta[b]indole Scaffold by
Annulative Two-Carbon Ring-Expansion
Authors: Martin Hiersemann, David Tymann, Dina Christina Tymann,
Lars Benedix, Ljuba Iovkova, Roman Pallach, and Sebastian
Henke
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002581
Link to VoR: https://doi.org/10.1002/chem.202002581
01/2020

10.1002/chem.202002581
Chemistry - A European Journal
COMMUNICATION
Photochemical Approach to the Cyclohepta[b]indole Scaffold by
Annulative Two-Carbon Ring-Expansion
Dina Christina Tymann,[a] Lars Benedix,[a] Lyuba Iovkova,[a] Roman Pallach,[a] Sebastian Henke,[a]
David Tymann,[a] and Martin Hiersemann*[a]
[a]
Dr. D. C. Tymann, M.Sc. L. Benedix, Dr. L. Iovkova, M.Sc. R. Pallach, Prof. Dr. S. Henke, Dr. D. Tymann, Prof. Dr. M. Hiersemann
Fakultät für Chemie und Chemische Biologie
TU Dortmund
44227 Dortmund (Germany)
E-mail: martin.hiersemann@tu-dortmund.de
Supporting information for this article is given via a link at the end of the document.
1
This article is protected by copyright. All rights reserved.

10.1002/chem.202002581
Chemistry - A European Journal
COMMUNICATION
Abstract: We report on the implementation of the concept of a
photochemically elicited two-carbon homologation of a π-donor–π-
acceptor substituted chromophore by triple bond insertion.
Implementing a phenyl connector between the slide-in module and
the chromophore enabled the synthesis of cylohepta[b]indole-type
building blocks by a metal-free annulative one-pot two-carbon ring
expansion of the five-membered chromophore. Post-irradiative
structural elaboration provided founding members of the indolo[2,3-
d]tropone family of compounds. Control experiments in combination
with computational chemistry on this multibond reorganization
process founded the basis for a mechanistic hypothesis.
The N-heteroacene cyclohepta[b]indol[1] (1) features the basic
scaffold of a variety of man-made pharmaceutically active
compounds[2] and natural products[3], e.g. alstonlarsine A (2)[4]
(Figure 1). To address the challenges associated with the
synthesis of cyclohepta[b]indol-type building blocks, a well-
diversified portfolio of enabling synthetic methods is already
available.[ 5 ] Variations of annulation reactions[ 6 ], of (m+n)-
cycloadditions[7], and of the Cope rearrangement[8] have proven
particularly valuable. Notably, however, organic photochemistry
Figure 2. Fuse–Compress–Expand Strategy to 6,7-Dihydrocyclohepta[b]indol-
8(5H)-ones.
The experimental procedures and characterization data for the
products 8 of the fuse-phase are provided in full detail in the
Supporting Information (29 examples). The results of our study
on the photochemically triggered two-carbon ring-expansion of 8
are summarized in Schemes 1–3. We adopted our previously
optimized conditions for the alkyne de Mayo reaction without the
necessity of optimization. Hence, solutions of the N-protected
vinylogous amides 8a‒ab (0.16 mmol) in degassed 2,2,2-
trifluoroethanol (TFE, c = 0.03 M) were irradiated in sealable
quartz tubes using the low-pressure mercury vapor lamps (Emax
= 254 nm) of a commercially available photoreactor. Reaction
times refer to reactor running times. The appearance of yellow
colored reaction mixtures served as an indicator for product
formation and progression of conversion was detected by TLC.
Representative examples for aliphatic and aromatic substituents
at C-10 were initially screened (Table 1). Ring expansion
proceeded for R1 = octyl- (8a), 4-hydroxylbutyl- (8b) and 4-
siloxybutyl (8c) to deliver 4a–c in useful yields (85–92%).
Somewhat unexpectedly, hydroxylmethyl-substitution (8d)
triggered decomposition under irradiation. No defined
degradation product could be isolated. The nature of the
decomposition pathway(s) remains speculative. Fortunately,
irradiation of the corresponding silyl ether 8e delivered the ring-
expansion product 4e in 86% yield. 2-Aminotolane-derived 8f
was susceptible to ring-expansion at prolonged reaction times
and delivered the R1 = phenyl substituted 4f in moderate yield
(52%).
has
not
yet
been
exploited
to
access
perhydrocyclohepta[b]indole-type building blocks (3).
Figure 1. Motif (1), Variation (2), and Building Block (3).
To complement the existing methodology, we aimed for a fuse–
compress–expand sequence to 6,7-dihydro-cyclohepta[b]indol-
8(5H)-ones 4 that exploits an unprecedented photochemically
triggered two-carbon ring-expansion (Figure 2).[ 9 ] Fusing is
accomplished by Sonogashira cross-coupling between o-iodo
anilines (5) and terminal alkynes (6), followed by condensation
with five-membered cyclic 1,3-dicarbonyl compounds (7) and
finalized by N-acylation to deliver photochemistry-competent
vinylogous amides 8. The subsequent compress-and-expand
phase consists of a photochemically triggered formation of a
transient (2+2)-cycloadduct that subsequently collapses to
deliver the 6,7-dihydro-cyclohepta[b]indol-8(5H)-one 4; hence,
the actual ring-expansion merges excited-state with ground state
chemistry to an unprecedented one-pot process.
Table 1. Two-Carbon Ring Expansion: Varying R1
2
This article is protected by copyright. All rights reserved.

10.1002/chem.202002581
Chemistry - A European Journal
COMMUNICATION
We proceeded to study substituent effects at C-3 or C-4 for R2 =
H at C-2 and R1 = CH3 at C-10. (Table 3). Subjecting vinylogous
amides featuring methyl (8q), fluoro (8r), or chloro (8s)
substitution at C-3 to the ring-expansion protocol afforded 4q
(90%), 4r (83%), and 4s (86%) in valuable yields. Ring-
expansion of m-aminobenzoic acid-derived 8t (R1 = CH3, R3 =
CO2Me) required strikingly prolonged irradiation (60 h, 4o: 7 h)
and delivered 4t (66%, 4o: 86%) in moderate yield. Degradation
was observed for R4 = CH3 (8u); in the event, we speculate that
“steric hindrance” interferes with the photochemical compress-
phase of the ring-expansion process. 2-Aminonaphthalene-
based 8w resisted irradiation (96 h) and was re-isolated (96%),
whereas
aminonaphthalene-based 8v proceeded reluctantly to afford
tetracyclic 4v (50%) in moderate yield. 5-
irradiation
of
the
5,6,7,8-tetrahydro-2-
Aminobenzo[d][1,3]dioxole-derived 8x successfully underwent
the ring-expansion to yield tetracyclic 4x (52%) in reasonable
yield. Finally, we turned to chromophore diversification.
Irradiation of N-acetyl derivative 8y yielded the ring-expanded
product 4y in 86% yield after only 2.75 h of reactor running time.
When irradiating tetronic acid-originated 8z (R1 = CH3, Z = O), no
conversion was detected by TLC. Tetramic acid-derived 8aa (R1
= CH3) and 8ab (R1 = Si(CH3)3), however, could be converted
into the desired ring-expansion products 4aa (51%) and 4ab
(41%) with moderate success.
For phamaceutically relevant cyclohepta[b]indoloids, substituent
diversification at C-2 is frequently found.[2] Consequently, we
moved on to study substituent effects for R2 ≠ H at C-2 and
using R1 = CH3 at C-10 as a prototype for alkyl substitution
(Table 2). Methyl- (8g), trifluoromethyl- (8h) and t-butyl-
substitution (8i) at C-2 were tolerated and 4g–i were isolated in
valuable yields (75–91%). 4-Aminobiphenyl-based 8j underwent
the ring-expansion slowly and sluggishly to provide 4j (26%) in
low yield. Bromo or fluoro substitution enabled access to 4k
(83%) or 4l (83%). Suzuki–Miyaura cross-coupling of 4k with
phenylboronic acid under carefully optimized conditions
delivered 4j (92%); thus 4k may serve as a relay compound for
post-ring expansion structural diversification (vide infra).[10] π-
Donor (R2 = OCH3) and π-acceptor (R2 = CO2Me or CN)
substitution allowed the formation of 4m (57%), 4n (86%), and
4o (86%). However, no conversion was observed for R2 = NO2
(8p, not depicted).
Table 3. Two-Carbon Ring Expansion: Varying R2
4
–
Table 2. Two-Carbon Ring Expansion: Varying R2
We
are
interested
in
utilizing
indole‒tropone-fused
cyclohepta[b]indol-8-ones (indolo[2,3-d]tropones, 10) as scaffold
elements for the synthesis of extended N-heteroacenes, N-
heterohelicenes, and as building blocks in natural product total
synthesis (Table 4). Thus, we explored the dehydrogenation of
[a] PhB(OH)2 (1.5 equiv), Pd(PPh3)2Cl2 (0.05 equiv), PCy3 (0.1 equiv), Cs2CO3
(1.5 equiv), 1,4-dioxane (297 equiv), 80 °C, 5.5 h, 92% (226 mg).
3
This article is protected by copyright. All rights reserved.

10.1002/chem.202002581
Chemistry - A European Journal
COMMUNICATION
selected 6,7-dihydro-cyclohepta[b]indol-8(5H)-ones 4. The
corresponding lithium enolates were treated with N-tert-
butylbenzenesulfinimidoyl chloride[ 11 ] to deliver Boc-protected
indolo[2,3-d]tropones 9.[12],[13] Purification of the thus prepared
cyclohepta[b]indol-8-ones 9 was complicated by intractable
kcal/mol) 5-exo-dig cyclization to T1-13 via 12 is predicted to be
highly exoenergetic (‒21.1 kcal/mol). T1-13 was calculated to be
almost isoenergetic to the double bond isomeric T1-14 (‒0.5
kcal/mol); T1-13 is interconnected with T1-14 via a low-barrier
transition state (+1.8 kcal/mol, not depicted). Rapid ISC of T1-14
to S0-14 is followed by an almost barrier-less (+1.1 kcal/mol) and
highly exoenergetic (‒42.1 kcal/mol) cyclization via 15 to the
(2+2) photocycloadduct 16. According to gas-phase DFT
calculations, the π-donor‒π-acceptor substituted cyclobutene
segment of 16 is susceptible to a slightly endoenergetic (+2.8
kcal/mol) concerted bond reorganization via the transition-state
17 (+24.1 kcal/mol) to afford 18 featuring a trans-α,β-enone
moiety.[21] The stereochemical result of the modeled conversion
of 16 to 18 is in accordance with a bond reorganization
impurities
of
N-(tert-butyl)-S-phenylthiohydroxylamine.
Alternatively, the enolate of 4k was treated with I2 to deliver Boc
protected 9d (79%); aryl bromide 9d is anticipated to serve as a
relay compound for scaffold extension as exemplified by Suzuki
cross-coupling with potassium vinyltrifluoroborate to afford 9e
(70%). Removal of the Boc protecting group delivered 10a
(68%) and 10b[12] (91%) representing founding members of the
indolo[2,3-d]tropone (10) family of compounds.[14],[15],[16]
proceeding by
a conrotatory 4π-electrocyclic ring-opening.
Table 4. Two-Carbon Ring Expansion: Varying R2
Although predicted to be highly exoenergetic, attempts to
localize a pathway leading from 18 (or 16) to the model
compound 19 for the experimentally observed ring expansion-
products by gas-phase computations were futile. The scale of
the predicted barrier height (+24.1 kcal) for the conversion of 16
to 18 encouraged experimental studies to identify the (2+2)-
cycloadduct. However, efforts to detect the elusive (2+2)-
cycloadduct from 8k by (preparative) TLC or by NMR
experiments in deuterated solvents failed. The ring-opening was
then re-modeled by considering explicit hydrogen-bonding
interactions between two molecules of 2,2,2-trifluoroethanol
(TFE) and the carbonyl oxygen atom of 16 (Scheme 5). Our DFT
calculations predict a slightly lower barrier for the weakly
endoenergetic electrocyclic ring-opening of 16•2TFE via
17•2TFE (+22.7 kcal/mol, not depicted; corresponds to a
calculated t1/2 = 81 min) to 18•2TFE (+3.4 kcal/mol). Notably,
however, consideration of explicit hydrogen bonding interactions
opens a low-barrier (+11.2 kcal/mol) pathway for the double
bond isomerization of 18•2TFE to 19•2TFE (‒35.5 kcal/mol, not
depicted) via 20•2TFE. The transition-state structure 20•2TFE
may be best explained as a tightly hydrogen-bonded non-π-
resonating α,β-eniminium‒enolate zwitterion that we could not
locate computationally without considering the transition-state
stabilizing interaction with TFE. Experimentally, attempts to
perform the two-carbon ring-expansion of 8k in CH3CN or
CH3OH led to considerably lower isolated yields of 4k (CH3CN:
61%; CH3OH: 33%). In both cases 4k was contaminated with
unidentified inseparable impurities. To further study the apparent
solvent effect, control experiments were run in 1,1,1,3,3,3-
hexafluoroisopropanol (HFIP). Much to our initial surprise, the
resulting isolated yields were considerably lower (HFIP: 66%,
TFE: 83%) 4k but free of detectable impurities. We later realized
that the comparatively lower yields in HFIP can be attributed to
the cleavage of the Boc protecting group in HFIP [22] which slowly
proceeds even at ambient temperature without irradiation.
[a] LDA, THF, ‒78 °C, then t-BuNS(Cl)Ph, ‒78 °C; [b] LDA (1.5 equiv), THF,
‒78 °C to ‒50 °C, 1 h, then I2 (1.6 equiv), ‒50 °C to rt, 0.5 h, 79% (207 mg); [c]
TFA (28 equiv), CH2Cl2, 40 °C; [d] CH2CHBF3K (2 equiv), Pd2(dba)3 (0.1
equiv), P(t-Bu)3•HBF4 (0.1 equiv), Cs2CO3 (3 equiv), 1,4-dioxane–H2O (10:1),
60 °C, 30 min, 70% (108 mg)
We used experimental and computational studies to gain
mechanistic insights into the ring-expansive multibond
reorganization process. Experimentally, irradiation (350 nm) of
8k in the presence of a triplet sensitizer (xanthone) triggered
formation of 4k; on the other hand, formation of 4k was
suppressed at 254 nm in the presence of a triplet quencher (2,5-
dimethylhexa-2,4-diene).[17] On this basis, we assumed a (2+2)
cycloaddition on the triplet surface. To gain further mechanistic
insights, we performed (TD)DFT studies using the model
compound 11 (Figure 2).[ 18 ],[ 19 ] Our calculations on the
B3LYP/def2-TZVP level of theory predict a vertical excitation of
S0-11 to an upper Sn-state (+112.6 kcal/mol) that is followed by
internal conversion (IC) to the S1-11 state (n,π* character with
respect to the α,β-enone segment) and intersystem crossing
(ISC) to the T1-11 state.[ 20 ] Our computations suggest π,π*
character for T1-11 with spin-density being located above and
below the α,β-enone segment. Subsequent low-barrier (+4.8
In summary, we reveal a conceptually novel approach to the
cyclohepta[b]indole scaffold. Irradiation (254 nm) of modularly
assembled vinylogous amides from 2-alkynyl anilines in 2,2,2-
trifluoroethanol at ambient temperature triggered an
intramolecular one-pot annulative two-carbon ring expansion to
deliver 6,7-dihydro-cyclohepta[b]indol-8(5H)-ones. The process
merges exited-state (2+2)-cycloaddition with ground-state 4π
electrocyclic ring-opening. Computational chemistry suggests
that solvent cooperativity is fundamental to the success of the
overall multibond reorganization process. We also report the
post-irradiative synthesis and characterization of founding
members of the indolo[2,3-d]tropone family of compounds.
4
This article is protected by copyright. All rights reserved.

10.1002/chem.202002581
Chemistry - A European Journal
COMMUNICATION
By enabling cooperativity of substituent and solvent effects, the
concept of
a photochemically triggered two-carbon ring
expansion was implemented to open a modular synthetic access
to cyclohepta[b]indole-type buildings blocks.
[1] a) W. Treibs, Justus Liebigs Ann. Chem. 1952, 576, 110–115. b) J. H.
Boyer, J. De Jong, J. Am. Chem. Soc. 1969, 91, 5929–5930.
[2] a) C. Kuehm-Caubère, P. Caubère, B. Jamart-Grégoire, B. Pfeiffer, B.
Guardiola-Lemaître, D. Manechez, P. Renard, Eur. J. Med. Chem.
1999, 34, 51–61. b) A. D. Napper, J. Hixon, T. McDonagh, K. Keavey,
J.-F. Pons, J. Barker, W. T. Yau, P. Amouzegh, A. Flegg, E. Hamelin, R.
J. Thomas, M. Kates, S. Jones, M. A. Navia, J. O. Saunders, P. S.
DiStefano, R. Curtis, J. Med. Chem. 2005, 48, 8045–8054. c) T. Barf, F.
Lehmann, K. Hammer, S. Haile, E. Axen, C. Medina, J. Uppenberg, S.
Svensson, L. Rondahl, T. Lundbäck, Bioorg. Med. Chem. Lett. 2009, 19,
1745–1748. d) E. Yamuna, R. A. Kumar, M. Zeller, R. P. K.
Jayarampillai, Eur. J. Med. Chem. 2012, 47, 228–238.
[3] For a recent example, see: P. Krishnan, F.-K. Lee, K.-W. Chong, C.-W. Mai,
A. Muhamad, S.-H. Lim, Y.-Y. Low, K.-N. Ting, K.-H. Lim, Org. Lett.
2018, 20, 8014–8018.
[4] X.-X. Zhu, Y.-Y. Fan, L. Xu, Q.-F. Liu, J.-P. Wu, J.-Y. Li, J. Li, K. Gao, J.-M.
Yue, Org. Lett. 2019, 21, 1471–1474.
[5] E. Stempel, T. Gaich, Acc. Chem. Res. 2016, 49, 2390–2402.
[6] For selected recent examples, see: a) J. Kaufmann, E. Jäckel, E. Haak,
Angew. Chem. Int. Ed. 2018, 57, 5908–5911. b) M. A. Kroc, A.
Prajapati, D. J. Wink, L. L. Anderson, J. Org. Chem. 2018, 83, 1085–
1094. c) A. S. Jadhav, Y. A. Pankhade, R. Vijaya Anand, J. Org. Chem.
2018, 83, 8615–8626. d) Q. Zeng, K. Dong, J. Huang, L. Qiu, X. Xu,
Org. Biomol. Chem. 2019, 17, 2326–2330. e) L. Zhang, Y. Zhang, W. Li,
X. Qi, Angew. Chem. Int. Ed. 2019, 58, 4988–4991.
[7] For selected recent examples, see: a) T. Takeda, S. Harada, A. Okabe, A.
Nishida, J. Org. Chem. 2018, 83, 11541–11551. b) C. Gelis, G. Levitre,
J. Merad, P. Retailleau, L. Neuville, G. Masson, Angew. Chem. Int. Ed.
2018, 57, 12121–12125. c) Z. Wang, Y. Addepalli, Y. He, Org. Lett.
2018, 20, 644–647. d) A. N. Parker, M. C. Martin, R. Shenje, S. France,
Org. Lett. 2019, 21, 7268–7273. e) J. Xu, V. H. Rawal, J. Am. Chem.
Soc. 2019, 141, 4820–4823.
Figure 2. (TD)DTF (u)B3LYP/def2-TZVP calculated (relative) electronic plus
zero-point energies (ΔE) at 298.15 K in kcal/mol.
[8] For selected recent examples, see: a) G. Xu, L. Chen, J. Sun, Org. Lett.
2018, 20, 3408–3412. b) M. Häfner, Y. M. Sokolenko, P. Gamerdinger,
E. Stempel, T. Gaich, Org. Lett. 2019, 21, 7370–7374.
[9] For the initial example, see: D. Tymann, D. C. Tymann, U. Bednarzick, L.
Iovkova-Berends, J. Rehbein, M. Hiersemann, Angew. Chem. Int. Ed.
2018, 130, 15779–15783.
Acknowledgements
Financial support by the TU Dortmund is gratefully
acknowledged.
[10] Conditions adapted from: E. N. Agbo, T. J. Makhafola, Y. S. Choong, J. M.
Mphatele, P. Ramasami, Molecules 2016, 21, 28.
[11] T. Mukaiyama, J.-i. Matsuo, H. Kitagawa, Chem. Lett. 2000, 29, 1250–
1251.
Keywords: cascade reaction • cyclohepta[b]indole • indole[2,3-
d]tropone • photochemistry • ring expansion
[12] CCDC 1991297 and 1985305 (9a and 10b) contain the supplementary
crystallographic data. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
[13] Structural assignment in solid state and in solution is in accordance with
the notion of 9 as cyclohepta[b]indol-8(5H)-one and not as tautomeric
cyclohepta[b]indol-8-ol.
Entry for the Table of Contents
[14] To the best of our knowledge, parent indolo[2,3-d]tropone has been
mentioned only once, see: T. Nozoe, H. Horino, T. Toda, Tetrahedron
Lett. 1967, 8, 5349–5353.
5
This article is protected by copyright. All rights reserved.

10.1002/chem.202002581
Chemistry - A European Journal
COMMUNICATION
[15] For the synthesis of indolo[2,3-b]tropones, see: a) K. Yamane, K. Fujimori,
Bull. Chem. Soc. Jpn. 1976, 49, 1101–1104. b) J. Jiye, I. Kunihiro, T.
Fumiki, O. Mitsunori, Chem. Lett. 2010, 39, 861–863. c) J. De Jong, J.
H. Boyer, J. Org. Chem. 1972, 37, 3571–3577.
[16] For the synthesis of indolo[3,2-b]tropones, see: a) U. K. Mishra, S. Yadav,
S. S. V. Ramasastry, J. Org. Chem. 2017, 82, 6729–6737. b) see also
reference 15 a).
[17] For experimental details, see the Supporting Information.
[18] For computational details, see the Supporting Information.
[19] For related computational studies, see: a) E. García-Expósito, M. J.
Bearpark, R. M. Ortuño, M. A. Robb, V. Branchadell, J. Org. Chem.
2002, 67, 6070–6077. b) J. R. Cucarull-González, J. Hernando, R.
Alibés, M. Figueredo, J. Font, L. Rodríguez-Santiago, M. Sodupe, J.
Org. Chem. 2010, 75, 4392–4401.
[20] O. Schalk, M. S. Schuurman, G. Wu, P. Lang, M. Mucke, R. Feifel, A.
Stolow, J. Phys. Chem. A 2014, 118, 2279–2287.
[21] For mechanistic studies concerning the electrocyclic ring opening of fused
cyclobutenes, see: a) C. S. López, O. N. Faza, Á. R. de Lera, Chem.
Eur. J. 2007, 13, 5009–5017. b) X.-N. Wang, E. H. Krenske, R. C.
Johnston, K. N. Houk, R. P. Hsung, J. Am. Chem. Soc. 2014, 136,
9802–9805. c) M. J. Ralph, D. C. Harrowven, S. Gaulier, S. Ng, K. I.
Booker-Milburn, Angew. Chem. Int. Ed. 2015, 54, 1527–1531.
[22] For N-Boc cleavage in fluorinated alcohols at elevated temperatures, see:
J. Choy, S. Jaime-Figueroa, L. Jiang, P. Wagner, Synth. Commun.
2008, 38, 3840–3853.
6
This article is protected by copyright. All rights reserved.