Complex Carbocyclic Skeletons from Aryl Ketones through a Three-Photon Cascade Reaction

Article abstract of DOI:10.1002/anie.201915731

Starting from readily available 7-substituted 1-indanones, products with a tetracyclo[5.3.1.0^1,70^4,11]undec-2-ene skeleton were obtained upon irradiation at λ=350 nm (eight examples, 49–67 % yield). The assembly of the structurally complex carbon framework proceeds in a three-photon process comprising an ortho photocycloaddition, a disrotatory [4π] photocyclization, and a di-π-methane rearrangement. The flat aromatic core of the starting material is converted into a functionalized polycyclic hydrocarbon with exit vectors in three dimensions. Ring opening reactions at the central cyclopropane ring were explored, which enable the preparation of tricyclo[5.3.1.0^4,11]undec-2-enes and of tricyclo[6.2.1.0^1,5]undecanes.

Full text of DOI:10.1002/anie.201915731

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Accepted Article
Title: Complex Carbocyclic Skeletons from Aryl Ketones by a Three-
Photon Cascade Reaction
Authors: Line Næsborg, Christian Jandl, Andreas Zech, and Thorsten
Bach
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915731
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DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Photochemistry
Complex Carbocyclic Skeletons from Aryl Ketones by a Three-Photon
Cascade Reaction
Line Næsborg, Christian Jandl, Andreas Zech, and Thorsten Bach*
Abstract. Starting from readily available 7-substituted 1-indanones,
The transformation 1 → 2[7] represents an intramolecular reaction
products with a tetracyclo[5.3.1.01,704,11]undec-2-ene skeleton were
of this type which proceeded with a high degree of regioselectivity.
obtained upon irradiation at  = 350 nm (eight examples, 49-67%
Cascade reactions in which an initial photochemical step is
yield). The assembly of the structurally complex carbon framework
followed by a second photochemical transformation can be
proceeds in
a three-photon process comprising an ortho
similarly efficient in creating molecular complexity. A notable two-
photon process reported by Booker-Milburn and co-workers[8]
concerned the formation of strained aziridines from pyrroles (e.g. 3
→ 4) in a sequence of [2+2] photocycloaddition and photochemical
rearrangement.
photocycloaddition, a disrotatory [4] photocyclization, and a di-
-methane rearrangement. The flat aromatic core of the starting
material is converted into a functionalized polycyclic hydrocarbon
with exit vectors in three dimensions. Ring opening reactions at the
central cyclopropane ring were explored which allow for the
preparation of tricyclo[5.3.1.04,11]undec-2-enes and of tricyclo-
[6.2.1.01,5]undecanes.
In an ongoing project[9] on photochemical cascade reactions[10]
initiated by an ortho photocycloaddition[6,11] we have now found a
facile entry into a yet unexplored class of hydrocarbons with a
tetracyclo[5.3.1.01,704,11]undec-2-ene core (I, Figure 1). Ring
opening of the cyclopropane ring at positions a or b provides
access to tricyclo[5.3.1.04,11]undec-2-enes (II) or tricyclo-
[6.2.1.01,5]undecanes (III). Both skeletons have high relevance to
the synthesis of natural products.[12] It was found that the cascade
reaction which starts form simple aromatic ketones as precursors is
a three-photon process[13] and we disclose in this communication
our preliminary results on this topic.
There is an increasing demand in pharmaceutical research for
molecules with spatially distinct functional groups (exit vectors) at
defined locations.[1] While flat – often heterocyclic – skeletons
have previously been dominant structural features of synthetic
drugs[2] it has been recognized in more recent years that chemical
space needs to be explored in three dimensions in order to find
molecules which match biological receptors.[3] This need can be
nicely met by organic photochemistry which provides a toolbox of
reactions for the creation of molecular complexity in a few steps.[4]
The most appealing transformations in this context allow the
conversion of readily accessible molecules with a planar structure
into complex alicyclic or heterocyclic scaffolds. The high energy
content of the excited state paves the way for the construction of
strained molecules frequently by concomitant cleavage of strong
bonds. Single-photon processes of this type include the celebrated
meta photocycloaddition[5,6] in which an arene core is converted
into a polycyclic hydrocarbon (Scheme 1).
Figure 1. The tetracyclo[5.3.1.01,704,11]undec-2-ene skeleton (I) as
precursor for tricyclo[5.3.1.04,11]undec-2-enes (II) by cleavage of
bond a and for tricyclo[6.2.1.01,5]undecanes (III) by cleavage of bond
b.
Cyclic aryl ketones in which the carbonyl group is embedded in a
five-membered ring (1-indanones) can be prepared from phenol
and -chlorobutyryl chlorides in
a
two-step procedure.[14]
Subsequent alkylation of the free phenolic hydroxy group with -
alkenyl halides delivered potential starting materials 5 (Scheme 2)
for an intramolecular ortho photocycloaddition (see the Supporting
Information for more details). Although reactions of this type have
been explored for acyclic aromatic ketones[15] we are not aware of
any studies with 1-indanones prior to our own work. Initial
experiments were performed with ketone 5a at an irradiation
wavelength of  = 350 nm (fluorescent lamps) in methanol as the
solvent. Unexpectedly, the product of the reaction (irradiation time
17 h) did not exhibit the structure of previously reported ortho
photocycloaddition cascade products[9] but turned out to be the
pentacyclic ketone 6a. The initial structure assignment for
compound 6a was based on one- and two-dimensional NMR
experiments and was later confirmed by X-ray crystallographic
data (vide infra). In subsequent reactions we probed the influence
of methyl substituents at various positions (R-R4) of the substrate.
In all cases we were able to isolate a defined product with a
Scheme 1. Examples for previously reported[7,8] photochemical
transformations of arene substrates into complex polycyclic products.
[]
Dr. L. Næsborg, Dr. C. Jandl, Dr. A. Zech, Prof. Dr. T. Bach
Department Chemie and Catalysis Research Center (CRC)
Technische Universität München
Lichtenbergstr. 4, D-85747 Garching
Fax: +49 (0)89 289 13315
E-mail: thorsten.bach@ch.tum.de
Homepage: http://www.oc1.ch.tum.de/home_en/
Supporting information and the ORCID identification
number(s) for the author(s) of this article can be found
under: http://dx.doi.org./10.1002/....
tetracyclo[5.3.1.01,704,11]undec-2-ene core.
A heterocyclic six-
membered ring is attached to positions C4 and C5 by a four atom
1
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10.1002/anie.201915731
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bridge that has originally linked the arene and the olefin in the
substrate. This linker can contain two oxygen atoms (product 6c)
making it amenable to easy ring opening or it can contain a
stereogenic center which induces – as seen for product 6g – a high
facial diastereoselctivity. The facial diastereoselectivity achieved
with a chiral ketone that exhibits a stereogenic center in -position
to the carbonyl group was less pronounced (product 6e).
Product 7i was isolated as a single diastereoisomer giving
testimony to the high facial diastereoselectivity of the cascade
reaction. The same observation was made for product 7k derived
from substrate 5k which displayed a stereogenic center at the
central carbon atom of the propyloxy linker. The constitution and
relative configuration of product 7k was established by single
crystal X-ray analysis. Product 7j was obtained as a mixture of
products from the respective E-configured hex-5-enyloxy
substituted ketone 5j. The relative configuration of the olefin is not
retained in the product and the reaction is not stereospecific.
The more challenging ring opening of the tetracyclo-
[5.3.1.01,704,11]undec-2-ene at bond b was accidentally discovered
when we attempted to prove the constitution of parent product 6a.
The oily compound was converted into the crystalline dibromide 9
by treatment with bromine in dichloromethane. Stereospecific anti
addition to the double bond occurred at 78 °C leaving the carbon
skeleton of the molecule untouched. Upon treatment with an excess
of bromine at higher temperature (0 °C) the cyclopropane was
opened selectively and tetrabromide 10 with an alicyclic tricyclo-
[6.2.1.01,5]undecane core was isolated. The ring opening occurs
with retention at carbon atom C7 and with inversion at carbon atom
C11 of the tetracyclo[5.3.1.01,704,11]undecane core. The result is in
line with initial formation of a tetracyclic bromonium intermediate
followed by nucleophilic attack by a bromide ion.[17]
Scheme 2. Synthesis of pentacyclic ketones 6 from aryl ketones 5
by a photochemical reaction cascade.
The central cyclopropane ring of products 6 lends itself to
subsequent ring opening reactions. Given the potential of the
ketone to act as an enol leaving group in acidic medium,[16] ring
opening of bond a (see Figure 1) at the allylic position by a
nucleophile is facile. Compound 6a produced readily the
corresponding methyl ether 7a upon treatment with catalytic
quantities of para-toluenesulfonic acid (TsOH) but formation of
ketal 8 was also observed. Addition of trimethylorthoformate
enabled isolated of the latter product as a single isomer in 66%
yield (Scheme 3). For other photoproducts the ring opening
occurred already during irradiation presumably due to the increased
ring strain exerted by substituents R2 and R3.
Scheme 4. Structure proof for compound 6a by bromination and
cleavage of cyclopropane bond b (Figure 1) to product 10.
Although the central tricyclo[3.3.0.02,8]oct-3-ene skeleton of
products 6 is reminiscent of reaction products obtained from a meta
photocycloaddition (cf. product 2 in Scheme 1), neither the
stereoelectronic properties of the substrates nor the exact
constitution of the products fit to this transformation. Rather it
seems likely that the 1-indanones undergo a three-photon process
(Scheme 5) which initially follows a known reaction pathway.[9]
For substrate 5a, ortho photocycloaddition is suggested to lead to
cyclobutane 11a which undergoes a thermally allowed pericyclic
ring opening to cyclooctatriene 12a. A second photon induces a
disrotatory [4] cyclization to cyclobutene 13a. Unlike the ketone
that bears an -disubstitution[9b] and unlike the respective ester
derivatives,[9a] this compound appears to undergo a successive di--
methane rearrangement.[18,19] Rearrangements of this type are
known to occur mostly on the triplet hypersurface and are
conceived as a 1,2-migration followed by cyclopropane ring
closure. Accordingly, 1,3-diradical 14a is postulated as an
intermediate which upon ISC and ring closure delivers product 6a.
The relative configuration of product 6a (see Scheme 4) is in line
with the suggested 1,2-shift which is directed by the stereogenic
center in -position to the ether oxygen atom and by
Scheme 3. Cleavage of cycloproane bond
a (Figure 1) in
intermediates 6 by MeOH: Direct formation of products 7 from
aromatic ketones 5.
2
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10.1002/anie.201915731
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conformational restrictions within the tetracyclic skeleton. Support
for the intermediacy of cyclobutenes 13 stems from the fact that it
was possible to isolate the respective compound 13b from the
reaction mixture of the reaction 5b → 6b in 27% yield if the
irradiation was stopped after 2.5 hours. Continued irradiation of
cyclobutene 13b at  = 350 nm in MeOH for another five hours
gave product 6b in 72% yield.
products and two consecutive reactions have already been found
which illustrate its potential use.
Acknowledgement
This project was supported by the Deutsche Forschungs-
gemeinschaft (Ba 1372/22-1), by the Carlsberg foundation
(Postdoctoral Scholarship to L.N.), and by the TUM Graduate
School. We thank N. Rauscher for synthetic assistance.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: carbocycles · diastereoselectivity · domino reactions ·
pericyclic reactions · photochemistry · rearrangement
[1] C. Boss, J. Hazemann, T. Kimmerlin, M. von Korff, U. Lüthi, O.
Peter, T. Sander, R. Siegrist, Chimia 2017, 71, 667-677.
[2] a) A. P. Taylor, R. P. Robinson, Y. M. Fobian, D. C. Blakemore, L.
H. Jones, O. Fadeyi, Org. Biomol. Chem. 2016, 14, 6611-6637; b) J.
J. Li (Ed.), Heterocyclic Chemistry in Drug Discovery, Wiley,
Hoboken, 2013.
[3] a) C. M. Marson, Chem. Soc. Rev. 2011, 40, 5514-5533; b) F.
Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752-6756.
[4] Reviews: a) M. D. Kärkäs, J. A. Porco Jr., C. R. J. Stephenson, Chem.
Rev. 2016, 116, 9683−9747; b) T. Bach, J. P. Hehn, Angew. Chem.
Int. Ed. 2011, 50, 1000-1045; Angew. Chem. 2011, 123, 1032-1077;
c) N. Hoffmann, Chem. Rev. 2008, 108, 1052-1103.
[5] For reviews exclusively on meta photocycloaddition reactions, see: a)
D. Chappell, D.; A. Russell, Org. Biomol. Chem. 2006, 4, 4409-4430;
b) J. Cornelisse, Chem. Rev. 1993, 93, 615-669; c) P. A. Wender, L.
Siggel, J. M. Nuss, Org. Photochem. 1989, 10, 357-473.
[6] For reviews covering both the meta and the ortho photocycloaddition,
see: a) R. Remy, C. G. Bochet, Chem. Rev. 2016, 116, 9816-9849; b)
N. Hoffmann, Photochem. Photobiol. Sci. 2012, 11, 1613-1641; c) U.
Streit, C. G. Bochet, Beilstein J. Org. Chem. 2011, 7, 525-542; d) U.
Streit, C. G. Bochet, Chimia 2008, 62, 962-966; e) J. Mattay, Angew.
Chem. Int. Ed. 2007, 46, 663-665; Angew. Chem. 2007, 119, 674-
677; f) N. Hoffmann, Synthesis 2004, 481-495.
Scheme 5. Suggested mechanism of the three-photon cascade
illustrated for the reaction 5a → 6a.
Given the high ISC rate of aromatic ketones[20] it is likely that the
initial formation of cyclobutanes 11 occurs via the indanone
triplet.[21] The addition step is indeed not stereospecific (product 7j)
but it is decisive for the configuration of the stereogenic center
within the tetrahydropyran ring which is retained throughout the
sequence (products 6g, 7i, 7k). If a 5-heptenyloxy substituent was
linked to the 7-position of the 1-indanone but not a 4-pentenyloxy
group, product 15 was observed in which the alkenyl chain was
dehydrogenated and the ketone group was reduced. The formation
of this product can be explained by an intramolecular hydrogen
abstraction at the -position to the oxygen atom by the indanone
n* triplet.[22] Subsequent hydrogen atom transfer within radical 16
(R = CH2CH2CH2CH=CH2) to product 15 is preferred over the
Norrish-Yang cyclization.[23]
[7] G. C. R. Ellis-Davies, J. Cornellisse, Tetrahedron Lett. 1985, 26,
1893-1896.
[8] K. G. Maskill, J. P. Knowles, L. D. Elliott, R. W. Alder, K. I.
Booker-Milburn, Angew. Chem. Int. Ed. 2013, 52, 1499-1502;
Angew. Chem. 2013, 125, 1539-1542.
[9] a) A. Zech, T. Bach, J. Org. Chem. 2018, 83, 3069-3077; b) A. Zech,
C. Jandl, T. Bach, Angew. Chem. Int. Ed. 2019, 58, 14629-14632;
Angew. Chem. 2019, 131, 14771-14774.
[10] For selected recent examples of photochemical reaction cascades: a)
S. Pusch, D. Schollmeyer, T. Opatz, Org. Lett. 2016, 18, 3043-3045;
b) P. J. Koovits, J. P. Knowles, K. I. Booker-Milburn, Org. Lett.
2016, 18, 5608-5611; c) Ł. Woźniak, G. Magagnano, P. Melchiorre,
Angew. Chem. Int. Ed. 2018, 57, 1068-1072; Angew. Chem. 2018,
130, 1080-1084; d) 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; Angew. Chem. 2018, 130, 6702-
6706; e) M. J. James, J. L. Schwarz, F. Strieth-Kalthoff, B.
Wibbeling, F. Glorius, J. Am. Chem. Soc. 2018, 140, 8624-8628.
[11] For reviews exclusively on ortho photocycloaddition reactions, see:
a) J. Cornelisse, R. de Haan in Molecular and Supramolecular
Photochemistry, Vol. 8 (Eds: V. Ramamurthy, K. Schanze), Dekker,
New York, 2001, pp. 1-126; b) P. J. Wagner, Acc. Chem. Res. 2001,
34, 1-8.
Figure 2. Intramolecular redox reaction of substrate 5l to product 15
and proposed intermediates 16 and 17 formed by intramolecular
hydrogen abstraction.
If the reaction 5a → 6a was performed in MeOD but not in
MeOH we observed deuterium incorporation in -position to the
oxygen atom in the product. After a shorter reaction time (30 min)
recovered starting material 5a showed the same degree (ca. 20%)
of deuteration. Irradiation of product 6a in MeOD did not lead to
any deuterium incorporation. Likewise, no deuterium incorporation
was found to occur in CD3OH. A potential explanation for the
observations could be a deuteration of putative intermediate 17 (R
= CH2CH=CH2) derived from intramolecular hydrogen abstraction.
[12] a) R. M. Coates, Z. Ho, M. Klobus, S. R. Wilson, J. Am. Chem. Soc.
1996, 118, 9249-9254; b) M. K. Sharma, M. G. Banwell, A. C. Willis,
Asian J. Org. Chem. 2014, 3, 632-637; c) A. Y. Hong, B. Stoltz,
Angew. Chem. Int. Ed. 2014, 53, 5248-5260; Angew. Chem. 2014,
126, 5350-5362; d) F. L. Bideau, M. Kousara, L. Chen, L. Wei, F.
Dumas, Chem. Rev. 2017, 117, 6110-6159; e) N. S. Radulović, M.
In conclusion, we have discovered an unprecedented cascade
reaction that converts a readily available starting material in a
pentacyclic molecule with a complex carbon skeleton. The reaction
holds promise for applications in the concise synthesis of natural
3
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Mladenović, N. M. Stojanović, P. D. Blagojević, J. Nat. Prod. 2019,
82, 1874-1885.
[18] Reviews: a) M. G. Banwell, D. J.-Y. D. Bon in Molecular
Rearrangements in Organic Synthesis (Ed. C. M. Rojas), Wiley,
Hoboken, 2015, pp. 261-288; b) E. Riguet, N. Hoffmann in
Comprehensive Organic Synthesis (Eds. P. Knochel, G. A.
Molander), Elsevier, Amsterdam, 2nd ed., 2014, 5, pp. 200-221; c) T.
Tsuno in Handbook of Synthetic Photochemistry (Eds. A. Albini, M.
Fagnoni), Wiley-VCH, Weinheim, 2010, pp. 95-135; d) H. E.
Zimmerman, D. Armesto, Chem. Rev. 1996, 96, 3065-3112.
[19] For related examples, see: a) R. H. van der Veen, C. Kruk, H.
Cerfontain, J. Am. Chem. Soc. 1983, 105, 4367-4374; b) J. Oren, L.
Schleifer, S. Weinman, B. Fuchs, Chem. Comm. 1988, 315-317; c) H.
E. Zimmerman, W. Chen, Org. Lett. 2002, 4, 1155-1158; d) A.
Tröster, A. Bauer, C. Jandl, T. Bach, Angew. Chem. Int. Ed. 2019, 58,
3538-3541; Angew. Chem. 2019, 131, 3576-3579.
[20] P. F. McGarry, C. E. Doubleday, Jr., C.-H. Wu, H. A. Staab, N. J.
Turro, J. Photochem. Photobiol. A: Chem. 1994, 77, 109-117.
[21] a) N. C. Yang, S. Murov, J. Chem. Phys. 1966, 45, 4358; b) T.
Nakayama, A. Otani, K. Hamanoue, J. Chem. Soc., Faraday Trans.
1995, 91, 855-861.
[22] For a related example: E. M. Sharshira, M. Okamura, E. Hasegawa,
T. Horaguchi, J. Heterocycl. Chem. 1997, 34, 861-869.
[23] Norrish-Yang cyclization of tetralones: E. M. Sharshira, H. Iwanami,
M. Okamura, E. Hasegawa, T. Horaguchi, J. Heterocycl. Chem. 1996,
33, 17-25.
[13] In contrast to multi-photon absorption which refers to theabsorption
of multiple photons by a structurally unchanged molecule (e.g. two-
photon absorption: M. Pawlicki, H. A. Collins, R. G. Denning, H. L.
Anderson, Angew. Chem. Int. Ed. 2009, 48, 3244-3266; Angew.
Chem. 2009, 121, 3292-3316) we use the term two- or three-photon
process for the sequential absorption of multiple photons by
structurally different compounds in a reaction cascade.
[14] W. D. Crow, U. Engkaninan-Low, Y. T. Pang, Aust. J. Chem. 1984,
37, 1915-1924.
[15] For pioneering studies on ortho photocycloaddition reactions of
aromatic ketones, see: a) H. Gotthardt, G. S. Hammond, Chem. Ber.
1975, 108, 657-663; b) P. J. Wagner, K. Nahm, J. Am. Chem. Soc.
1987, 109, 6528-6530; c) P. J. Wagner, M. Sakamoto, J. Am. Chem.
Soc. 1989, 111, 9256-9258; d) D. Döpp, H. R. Memarian, Liebigs
Ann. Chem. Ber. 1990, 123, 315-319; e) P. J. Wagner, K. McMahon,
J. Am. Chem. Soc. 1994, 116, 10827-10828; f) S. Al-Qaradawi, A.
Gilbert, D. T. Jones, Recl. Trav. Chim. Pays-Bas 1995, 114, 485-491;
g) H. R. Memarian, M. Nasr-Esfahani, R. Boese, D. Döpp, Liebigs
Ann. 1997, 1023-1027; h) H. R. Memarian, M. Nasr-Esfahani, D.
Döpp, New J. Chem. 2001, 25, 1605-1609; i) P. J. Wagner, J.-I. Lee,
Tetrahedron Lett. 2002, 43, 3569-3571.
[16] Examples: a) J. F. Ruppert, J. D. White, J. Am. Chem. Soc. 1981, 103,
1808-1813; b) M. E. Meyer, J. H. Phillips, E. M. Ferreira, B, M.
Stoltz, Tetrahedron, 2013, 69, 7627-7635.
[17] a) J. B. Lambert, E. C. Chelius, W. J. Schulz, Jr., N. E. Carpenter, J.
Am. Chem. Soc. 1990, 112, 3156-3162; b) C. Rösner, U. Hennecke,
Org. Lett. 2015, 17, 3226-3229 and refs. cited therein.
4
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Angewandte Chemie International Edition
Entry of the Table of Contents
Photochemistry
L. Næsborg, C. Jandl, A. Zech, T. Bach*
Page – Page
Complex Carbocyclic Skeletons from
Aryl Ketones by a Three-Photon
Cascade Reaction
Up the hill: A major bond reorganization takes the marked arene carbon atom from
flatland to the summit of three-dimensional hydrocarbon hills. Three photons create
in a cascade reaction (11 examples, 37-67%) products with a pentacyclic skeleton
which are prone to further ring opening reactions in situ or in a two-step process.
5
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