Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion: Programming Conformation by [CH2CH2] → [CF2CHF] Isosterism

Article abstract of DOI:10.1002/anie.202102222

Saturated, fluorinated carbocycles are emerging as important modules for contemporary drug discovery. To expand the current portfolio, the synthesis of novel trifluorinated tetralins has been achieved. Fluorinated methyleneindanes serve as convenient precursors and undergo efficient difluorinative ring expansion with in situ generated p-TolIF₂ (>20 examples, up to >95 %). A range of diverse substituents are tolerated under standard catalysis conditions and this is interrogated by Hammett analysis. X-ray analysis indicates a preference for the CH?F bond to occupy a pseudo-axial orientation, consistent with stabilising σ_C?H→σ_C?F* interactions. The replacement of the symmetric [CH₂?CH₂] motif by [CF₂?CHF] removes the conformational degeneracy intrinsic to the parent tetralin scaffold leading to a predictable half-chair. The conformational behavior of this novel structural balance has been investigated by computational analysis and is consistent with stereoelectronic theory.

Full text of DOI:10.1002/anie.202102222

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How to cite:
International Edition: doi.org/10.1002/anie.202102222
German Edition: doi.org/10.1002/ange.202102222
Main-Group Catalysis
Trifluorinated Tetralins via I(I)/I(III)-Catalysed Ring Expansion:
Programming Conformation by [CH2CH2] ! [CF2CHF] Isosterism
Jessica Neufeld, Timo Stꢀnkel, Christian Mꢀck-Lichtenfeld, Constantin G. Daniliuc, and
Ryan Gilmour*
Dedicated to Professor Antonio Togni on the occasion of his retirement
Abstract: Saturated, fluorinated carbocycles are emerging as
important modules for contemporary drug discovery. To
expand the current portfolio, the synthesis of novel trifluori-
nated tetralins has been achieved. Fluorinated methylenein-
danes serve as convenient precursors and undergo efficient
difluorinative ring expansion with in situ generated p-TolIF2
(> 20 examples, up to > 95%). A range of diverse substituents
are tolerated under standard catalysis conditions and this is
interrogated by Hammett analysis. X-ray analysis indicates
ꢀ
a preference for the CH F bond to occupy a pseudo-axial
orientation, consistent with stabilising sCꢀ !sCꢀF* interac-
H ꢀ
tions. The replacement of the symmetric [CH2 CH2] motif by
[CF2 CHF] removes the conformational degeneracy intrinsic
to the parent tetralin scaffold leading to a predictable half-
chair. The conformational behavior of this novel structural
balance has been investigated by computational analysis and is
consistent with stereoelectronic theory.
ꢀ
C
arbocycles with tailored fluorination patterns are garner-
ing considerable attention in the design of functional materi-
als and therapeutics.[1] Fluorination at multiple sites provides
a molecular basis from which to modulate the physicochem-
ical characteristics of the molecule without causing excessive
alterations to the steric signature.[2] Striking examples include
the Janus ring systems developed by O’Hagan and co-
workers, which range from trifluorinated cyclopropanes
(1)[3] through to the venerable all-syn-hexafluorocyclohexane
motif (2) (Figure 1, top):[4] This latter example is noteworthy
as the fluorination pattern induces the highest calculated
dipole of an organic molecule to date (6.2 D). A more recent
comparison of the effects of selective tetrafluorination (3
versus 4)[5] in significantly lowering log P provides compelling
Figure 1. Top: Fluorinated carbocycles for contemporary drug discovery
(1, 2 and 4). Centre: Fluorination sites in common steroids (5 and 6),
and the b-blocker Nadolol (7). Bottom: An I(I)/I(III) paradigm to
access the novel trifluorotetralin scaffold (8 ! 9).
evidence for the efficiency of this approach to drug discovery.
These examples build upon the venerable history of mono-
fluorination in medicinal chemistry, as is exemplified by
Friedꢀs discovery that fluorinated cortisone exhibits enhanced
efficacy relative to the parent systems,[6] and the continued
success of fluorinated steroid derivatives, such as dexametha-
sone (5) and diflupredante (6).[7] Intriguingly, only three sites
of fluorination are commonly explored which, in turn, are
dictated by preparative considerations.[8] The two most
common are positions on the B-ring of the tetralin-derived
fragment. Interestingly, the dihydroxytetralin motif consti-
tutes the core of the b-blocker Nadolol (Cogardꢁ) (7), further
underscoring the importance of electronegative substituents
at the saturated periphery of the tetrahydronaphthalene core
(Figure 1, centre). Motivated by the pallet of opportunities
that multiply fluorinated carbocycles offer, the success of H/
OH ! F bioisosterism,[1,2] and the prevalence of tetralin-
derivatives in nature,[9,10] a route to generate fluorinated
tetralin motifs would expand the portfolio of novel motifs for
[*] M. Sc. J. Neufeld, B. Sc. T. Stꢀnkel, Dr. C. Mꢀck-Lichtenfeld,
Dr. C. G. Daniliuc, Prof. Dr. R. Gilmour
Organisch-Chemisches Institut
Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
Corrensstraße 36, 48149 Mꢀnster (Germany)
E-mail: ryan.gilmour@uni-muenster.de
Homepage: https://wwu.uni-muenster.de/Chemie.oc/gilmour
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102222.
ꢂ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
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molecular design.[11] Specifically, the trifluoro motif resulting
importance of Brønsted acidity in ArIX2 mediated proces-
ses,[15d,18] variation of the amine:HF ratio was explored using
mixtures of commercially available NEt3:HF 1:3 and pyr:HF
1:9.2 (Olahꢀs reagent). Initial attempts to induce difluorina-
tive ring expansion with an amine:HF ratio of 1:3 generated
the desired geminal fluorinated tetralin 9 in only 7% yield
(Table 1, entry 1). However, adjusting the ratio to 1:4.5 led to
a significant enhancement in efficiency (61%, entry 2).
Further increasing the amine:HF ratio to 1:6 proved to be
detrimental (47%, entry 3) and thus the remainder of the
study was conducted with amine:HF 1:4.5. A solvent screen
(entries 4–9) identified DCE as being the optimal reaction
medium for the title transformation (74% yield, entry 5).
Fluorinated solvents such as hexafluoroisopropanol (HFIP)
and ethyl trifluoroacetate (ETFA) led to moderate yields
(48% and 56%, respectively, entries 6–7). Furthermore, non-
halogenated solvents proved to be detrimental (entries 8–9).
Replacing Selectfluor with m-CPBA (entry 10) or oxone
(entry 11) did not lead to an improvement, nor did increasing
or decreasing temperature (entries 12 and 13). Lowering the
catalyst loading led to a slight decrease in yield, and the
control experiment without p-TolI supports the involvement
of an I(I)/I(III) catalysis paradigm (54% and < 5%, respec-
tively, entries 14–15).
Having established suitable reaction conditions for the
difluorinative ring expansion (Table 1, entry 5) the scope and
the limitations of the transformation were explored
(Scheme 1). Initially, the parent scaffold 9 was prepared
under the standard reaction conditions, and the process could
be scaled up to 1 mmol without loss of catalytic efficiency.
Halogens were found to be compatible with this protocol as is
exemplified by products 10–14 (up to > 95% yield), enabling
the regioisomeric bromides 12–14 to be prepared as syntheti-
cally-versatile coupling partners for downstream manipula-
tion. Although it was possible to generate the methyl-
derivative 15, the disparity in yield when compared with
electron deficient systems prompted a more detailed Ham-
mett analysis (vide infra). Electron-deficient substrates
proved to be highly competent precursors as exemplified by
the triflate (16), trifluoromethyl (17) and cyano (18) species
(up to 92% yield). Phthalimide 19 was smoothly generated to
provide access to masked aniline derivatives, and a substrate
with a pendant a,b-unsaturated ester (20) demonstrates the
chemoselectivity of the transformation. The addition of
substituents on the saturated ring system was tolerated (21
and 22), and catalysis enabled the formation of the tetra-
fluorinated compound 23 and mixed halogen system 24. In all
cases, reactions performed in the absence of p-TolI led to
< 5% yield for 9–24. To correlate the electronic signature of
the aryl fragment with catalysis efficiency, the Hammett
values sp and sm of several electronically diverse compounds
were plotted against the 19F NMR yields (Scheme 1, bottom).
The plot underscores the fact that strong electron-withdraw-
ing groups on the aryl fragment facilitate difluorinative ring
expansion.
ꢀ
from isosteric replacement of the symmetric [CH2 CH2]
ꢀ
motif distal to the aryl ring by [CF2 CHF] would circumvent
the conformational lability intrinsic to the parent tetralin
scaffold: the introduction of hyperconjugative interactions
(sCꢀH!sCꢀF*) would render the two half chairs non-degener-
ate. To access this novel class of fluorinated heterocycles,
fluorinated methyleneindanes (8) were selected as substrates.
[12]
It was envisaged that exposure to in situ generated p-TolIF2
under the auspices of I(I)/I(III) catalysis[13,14,15] would induce
a fluorinative ring expansion via an ephemeral, tricyclic
phenonium ion[16] to liberate the desired product (9)
(Figure 1, bottom).
Confidence in the feasibility of this catalysis-based
strategy stemmed from a plenum of stoichiometric ring
expansion processes. Pertinent examples include the gener-
ation of difluoro ethers from aryl-substituted ketones using
XeF2 by Zupan and co-workers.[17] Furthermore, the ability of
hypervalent iodine reagents to induce ring expansion with Pd
and Cu or BF3·OEt2, has been elegantly demonstrated by the
groups of Szabꢂ[14e] and Murphy,[14g,j] respectively. To devise
a catalysis-based platform to access novel, trifluorinated
tetralins, 2-fluoro-methyleneindane (8) was selected as
a model substrate for reaction optimisation (Table 1). It was
envisaged that this allyl fluoride would engage with p-TolIF2,
generated by in situ oxidation from inexpensive p-TolI, to
forge the desired carbocycle 9, where the CHF unit would
function as a conformational control unit.
Initially, the transformation was investigated using Select-
fluor as the terminal oxidant in CHCl3 at ambient temper-
ature using HF as a convenient fluoride source. Given the
Table 1: Optimisation of the reaction conditions.
entry[a]
oxidant
amine:HF[b]
solvent
yield[c]
1
2
3
4
5
6
7
8
9
10
11
12[d]
13[e]
14[f]
15[g]
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
Selectfluor
m-CPBA
1:3.0
1:4.5
1:6.0
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
1:4.5
CHCl3
CHCl3
CHCl3
CH2Cl2
DCE
HFIP
ETFA
toluene
CH3CN
DCE
7%
61%
47%
71%
74%
48%
56%
54%
28%
63%
39%
65%
29%
54%
<5%
Oxone
DCE
DCE
DCE
DCE
Selectfluor
Selectfluor
Selectfluor
Selectfluor
DCE
[a] Standard reaction conditions: 8 (0.2 mmol), p-TolI (20 mol%),
oxidant (1.5 equiv.), solvent (0.5 mL), amine:HF (0.5 mL), ambient
temperature, 24 h. [b] See supporting information for the exact calcu-
lation of the amine:HF mixtures. [c] Determined by 19F NMR analysis of
the crude reaction mixture using ethyl fluoroacetate as internal standard.
[d] Reaction was performed at 508C. [e] Reaction was performed at 08C.
[f] Reaction was performed with 10 mol% catalyst. [g] Reaction was
performed without catalyst.
To confirm that electron-rich groups suppress catalysis
(see Scheme 1, lower), the difluorinative ring expansion to
generate 25 was attempted, but led to degradation of the
starting material (Scheme 2). Furthermore, the requirement
2
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Scheme 2. Control reactions. Standard reaction conditions: substrate
(0.2 mmol), p-TolI (20 mol%), Selectfluor (1.5 equiv.), DCE (0.5 mL),
amine:HF 1:4.5 (0.5 mL), ambient temperature, 24 h. Yields refer to
19F NMR yields (determined by 19F NMR analysis of the crude reaction
mixture using ethyl fluoroacetate as internal standard).
Scheme 3. Exploring the scope of the reaction. Standard reaction
conditions: substrate (0.2 mmol), p-TolI (20 mol%), Selectfluor
(1.5 equiv.), DCE (0.5 mL), amine:HF 1:4.5 (0.5 mL), ambient temper-
ature, 24 h. Yields refer to isolated products while 19F NMR yields are
given in parentheses (determined by 19F NMR analysis of the crude
reaction mixture using ethyl fluoroacetate as internal standard). N.B.
Care must be taken during isolation due to the volatility of the
products.
30 render it a convenient linchpin for bidirectional function-
alisation. Moreover, the optical purity of the products was not
compromised under the standard catalysis conditions (100%
es).
Scheme 1. Top: Exploring the scope of the reaction. Standard reaction
conditions: substrate (0.2 mmol), p-TolI (20 mol%), Selectfluor
(1.5 equiv.), DCE (0.5 mL), amine:HF 1:4.5 (0.5 mL), ambient temper-
ature, 24 h. Yields refer to isolated products while 19F NMR yields are
given in parentheses (determined by 19F NMR analysis of the crude
reaction mixture using ethyl fluoroacetate as internal standard).
Bottom: Effect of arene electron density on reaction efficiency. N.B.
Care must be taken during isolation due to the volatility of the
products.
To explore the conformational consequences of replacing
ꢀ
the symmetric [CH2 CH2] motif by an isosteric non-symmet-
ric [CF2 CHF] group in tetralins [VvdW 138 ꢃ3 versus 156 ꢃ3
ꢀ
for tetralin and 9, respectively],[21] X-ray analysis of a repre-
sentative example was conducted. It was envisaged that
ꢀ
ꢀ
isosteric replacement of [CH2 CH2] by [CF2 CHF] would
bias the conformation, thereby bypassing the degeneracy of
for fluorinated methyleneindanes is demonstrated through
the failed attempts to generate 26 and 27. The latter example,
in which the allyl fluoride is essential, distinguishes this
catalysis-based platform from stoichiometric examples using
the non-fluorinated methyleneindane.[14j,19]
Given the plenum of methods to enable the enantiose-
lective fluorination of b-ketoesters,[20] which can be processes
to optically active precursors, it was envisaged that ring
expansion would provide a route to access enantio-enriched
trifluorinated products (Scheme 3). Despite the addition of an
additional electron-withdrawing group, catalysis was
the two half chairs in the parent system (Figure 2). In the case
3
ꢀ
of compound 12, the conformer in which the C(sp ) F of the
CHF unit adopts a quasi-axial orientation is observed.[22] This
allows for stabilising hyperconjugative [sCꢀH!sCꢀF*] inter-
ꢀ
ꢀ
actions, as is evident from the difference in C Fax. and C Feq.
bond lengths (1.442 and 1.428 versus 1.326 ꢃ, respectively,
DdCꢀ
0.1 ꢃ).
F(ax.-eq.)
To quantify this interaction, a conformational analysis of
compound 12 was conducted at the DFT level of theory
(Please see the Supporting Information for full details). The
optimised molecular structures (TPSS-D3/def2-TZVP) of the
two half chair conformers 12-a and 12-b (Figure 3), confirm
observed under the standard conditions reported (28–32, up
2
ꢀ
to 57% yield). The ester and C(sp ) Br motifs in compound
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Angewandte
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generous financial support. We thank Dr. Klaus Bergander
(WWU) for support with NMR analysis. Open access funding
enabled and organized by Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
Keywords: fluorination · iodine(III) · organocatalysis ·
ring expansion · tetralin
[1] a) D. O’Hagan, Chem. Eur. J. 2020, 26, 7981 – 7997; b) Y.-H.
Lam, C. Bobbio, I. R. Cooper, V. Gouverneur, Angew. Chem.
Int. Ed. 2007, 46, 5106 – 5110; Angew. Chem. 2007, 119, 5198 –
5202; c) R. Mondal, M. Agbaria, Z. Nairoukh, Chem. Eur. J.
2021 https://doi.org/10.1002/chem.202005425.
Figure 2. X-ray crystal structure of tetralin 12.[22]
[2] a) K. Mꢄller, C. Faeh, F. Diederich, Science 2007, 317, 1881 –
1886; b) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320 – 330; c) D. O’Hagan, Chem. Soc.
Rev. 2008, 37, 308 – 319; d) L. E. Zimmer, C. Sparr, R. Gilmour,
Angew. Chem. Int. Ed. 2011, 50, 11860 – 11871; Angew. Chem.
2011, 123, 12062 – 12074; e) D. O’Hagan, H. Deng, Chem. Rev.
2015, 115, 634 – 649; f) M. El. Qacemi, S. Rendine, P. Mainfisch,
in Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diag-
nostics, and Agrochemicals, Elsevier Inc, Amsterdam, 2019,
pp. 607 – 623.
[3] Z. Fang, D. B. Cordes, A. M. Z. Slawin, D. O’Hagan, Chem.
Commun. 2019, 55, 10539 – 10542.
[4] a) N. S. Keddie, A. M. Z. Slawin, T. Lebl, D. Philp, D. O’Hagan,
Nat. Chem. 2015, 7, 483 – 488; b) N. Santschi, R. Gilmour, Nat.
Chem. 2015, 7, 467 – 468; c) B. E. Ziegler, M. Lecours, R. A.
Marta, J. Featherstone, E. Fillion, W. S. Hopkins, V. Steinmetz,
N. S. Keddie, D. O’Hagan, T. B. McMahon, J. Am. Chem. Soc.
2016, 138, 7460 – 7463; d) For a synthetic study, see M. P.
Wiesenfeldt, Z. Nairoukh, W. Li, F. Glorius, Science 2017, 357,
908 – 912.
[5] A. Rodil, S. Bosisio, M. S. Ayoup, L. Quinn, D. B. Cordes,
A. M. Z. Slawin, C. D. Murphy, J. Michel, D. O’Hagan, Chem.
Sci. 2018, 9, 3023 – 3028.
[6] For the discovery that fluorinated cortisone is more potent than
the non-fluorinated systems, see: J. Fried, A. Borman, W. B.
Kessler, P. Grabowich, E. F. Sabo, J. Am. Chem. Soc. 1958, 80,
2338 – 2339.
[7] For a report demonstrating that F-vitamin D3 is more potent
than the non-fluorinated analogue, see: J. L. Napoli, M. A.
Fivizzani, H. K. Schnoes, H. F. DeLuca, Biochemistry 1979, 18,
1641 – 1646.
[8] I. Herraiz, Methods in Molecular Biology 2017, https://doi.org/
10.1007/978-1-4939-7183-1 2.
[9] a) B. Holmbom, C. Eckerman, P. Eklund, J. Hemming, L. Nisula,
M. Reunanen, R. Sjçholm, A. Sundberg, K. Sundberg, S. Willfçr,
Phytochem. Rev. 2003, 2, 331 – 340; b) W. K. Brewster, D. E.
Nichols, R. M. Riggs, D. M. Mottola, T. W. Lovenberg, M. H.
Lewis, R. B. Mailman, J. Med. Chem. 1990, 33, 1756 – 1764; c) M.
Kvasnica, L. Rarova, J. Oklestkova, M. Budesinsky, L. Kohout,
Bioorg. Med. Chem. 2012, 20, 6969 – 6978; d) M. J. Hatfield,
L. G. Tsurkan, J. L. Hyatt, C. C. Edwards, A. Lemoff, C. Jeffries,
B. Yan, P. M. Potter, J. Nat. Prod. 2013, 76, 36 – 44.
Figure 3. Optimised molecular structure (TPSS-D3/def2-TZVP) of 12-
a (left) and alternative conformer 12-b (right). Internuclear distances
are given in ꢃ. In square brackets: relative free energies DG298
(PW6B95-D3//TPSS-D3/def2-TZVP) in kcalmolꢀ1
.
a preference for the pseudo-axial species (DDG298 + 1.0 kcal
molꢀ1), and the calculated bond lengths are in good agree-
ment with the experimental values. A NBO second order
perturbation analysis reveals that the largest contribution
arises from vicinal sCꢀH!sCꢀF* interactions, which is fully in
line with the working hypothesis.
In conclusion, a main group catalysis-based strategy has
been leveraged to access novel trifluorinated tetralins by
difluorinative ring expansion of fluorinated methylenein-
ꢀ
danes. Isosteric replacement of the symmetric [CH2 CH2]
ꢀ
motif by a non-symmetric [CF2 CHF] group [DVvdW = ca.
13%] at the distal edge of the saturated carbocycle removes
the conformational degeneracy inherent to the parent system.
The stabilising hyperconjugative interactions [sCꢀH!sCꢀF*]
that underpin this effect manifest themselves in the X-ray
crystal structure analysis (DdCꢀ
0.1 ꢃ) and have been
F(ax.-eq.)
interrogated by DFT analysis. It is envisaged that these novel
tetralins, and the stereoelectronic bias that governs pre-
organisation, will find application in focused medicinal
chemistry and molecular design in a broader sense.
[10] For selected studies on tetrahydronaphthalenes, see: a) T.-X.
Liu, F.-B. Li, G.-W. Wang, Org. Lett. 2011, 13, 6130 – 6133; b) D.
Naduthambi, S. Bhor, M. B. Elbaum, N. J. Zondlo, Org. Lett.
2013, 15, 4892 – 4895; c) S.-I. Nakano, K. Kakugawa, T. Nemoto,
Y. Hamada, Adv. Synth. Catal. 2014, 356, 2088 – 2096; d) N.
Ishida, N. Ishikawa, S. Sawano, Y. Masuda, M. Murakami, Chem.
Acknowledgements
The WWU Mꢄnster and the Deutsche Forschungsgemein-
schaft (SFB 858, fellowship to J.N.) are acknowledged for
4
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Angewandte
Communications
Chemie
Commun. 2015, 51, 1882 – 1885; e) J. C. T. Reddel, W. Wang, K.
Lennox, Angew. Chem. Int. Ed. 2020, 59, 1155 – 1160; Angew.
Koukounas, R. J. Thomson, Chem. Sci. 2017, 8, 2156 – 2160; f) L.
Wang, F. Wu, J. Chen, D. A. Nicewicz, Y. Huang, Angew. Chem.
Int. Ed. 2017, 56, 6896 – 6900; Angew. Chem. 2017, 129, 7000 –
7004.
Chem. 2020, 132, 1171 – 1176; f) S. Meyer, J. Hꢆfliger, M.
Schꢆfer, J. J. Molloy, C. G. Daniliuc, R. Gilmour, Angew.
Chem. Int. Ed. 2021, 60, 6430 – 6434; Angew. Chem. 2021, 133,
6501 – 6506.
[11] a) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529 – 2591; b) E. P.
Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly, N. A. Meanwell,
J. Med. Chem. 2015, 58, 8315 – 8359; c) I. G. Molnꢅr, C. Thiehoff,
M. C. Holland, R. Gilmour, ACS Catal. 2016, 6, 7167 – 7173.
[12] a) C. Ye, B. Twamley, J. M. Shreeve, Org. Lett. 2005, 7, 3961 –
3964; b) S. Suzuki, T. Kamo, K. Fukushi, T. Hiramatsu, E.
Tokunaga, T. Dohi, Y. Kita, N. Shibata, Chem. Sci. 2014, 5, 2754 –
2760; c) J. C. Sarie, C. Thiehoff, R. J. Mudd, C. G. Daniliuc, G.
Kehr, R. Gilmour, J. Org. Chem. 2017, 82, 11792 – 11798; d) J.
Hꢆfliger, C. R. Pitts, D. Bornemann, R. Kꢆser, N. Santschi, J.
Charpentier, E. Otth, N. Trapp, N. Verel, H. P. Lꢄthi, A. Togni,
Chem. Sci. 2019, 10, 7251.
[16] T. Bykova, N. Al-Maharik, A. M. Z. Slawin, D. O’Hagan, J.
Fluorine Chem. 2015, 179, 188 – 192.
[17] a) S. Stavber, B. Sket, B. Zajc, M. Zupan, Tetrahedron 1989, 45,
6003 – 6010; b) B. Zajc, M. Zupan, J. Org. Chem. 1990, 55, 1099 –
1102.
[18] J. L. Cotter, L. J. Andrews, R. M. Keefer, J. Am. Chem. Soc.
1962, 84, 793 – 797.
[19] Possible conformations of the reactive complex of olefin 8 with
[pTolIF]+ have been investigated computationally (see inset
structure).
[13] For selected reviews, see a) N. Yoneda, J. Fluorine Chem. 2004,
125, 7 – 17; b) S. V. Kohlhepp, T. Gulder, Chem. Soc. Rev. 2016,
45, 6270 – 6288; c) A. M. Arnold, A. Ulmer, T. Gulder, Chem.
Eur. J. 2016, 22, 8728 – 8739; d) J. Charpentier, N. Frꢄh, A. Togni,
Chem. Rev. 2015, 115, 650 – 682.
[14] For selected examples of 1,1-difluorination, see: a) S. Hara, J.
Nakahigashi, K. Ishi-I, T. Fukuhura, N. Yoneda, Tetrahedron
Lett. 1998, 39, 2589 – 2592; b) N. O. Ilchenko, B. O. A. Tasch,
K. J. Szabꢂ, Angew. Chem. Int. Ed. 2014, 53, 12897 – 12901;
Angew. Chem. 2014, 126, 13111 – 13115; c) T. Kitamura, K.
Muta, J. Oyamada, J. Org. Chem. 2015, 80, 10431 – 10436;
d) S. M. Banik, J. W. Medley, E. N. Jacobsen, Science 2016, 353,
51 – 54; e) N. O. Ilchenko, K. J. Szabꢂ, J. Fluorine Chem. 2017,
203, 104 – 109; f) F. Scheidt, J. Neufeld, M. Schꢆfer, C. Thiehoff,
R. Gilmour, Org. Lett. 2018, 20, 8073 – 8076; g) Z. Zhao, L.
Racicot, G. K. Murphy, Angew. Chem. Int. Ed. 2017, 56, 11620 –
11623; Angew. Chem. 2017, 129, 11778 – 11781; h) T. Kitamura,
K. Yoshida, S. Mizuno, A. Miyake, J. Oyamada, J. Org. Chem.
2018, 83, 14853 – 14860; i) W.-X. Lv, Q. Li, J.-L. Li, Z. Li, E. Lin,
D.-H. Tan, Y.-H. Cai, W.-X. Fan, H. Wang, Angew. Chem. Int.
Ed. 2018, 57, 16544 – 16548; Angew. Chem. 2018, 130, 16782 –
16786; j) Z. Zhao, A. J. To, G. K. Murphy, Chem. Commun. 2019,
55, 14821 – 14824.
[15] For selected examples of 1,2-difluorination, see a) S. M. Banik,
J. W. Medley, E. N. Jacobsen, J. Am. Chem. Soc. 2016, 138, 5000 –
5003; b) I. G. Molnꢅr, R. Gilmour, J. Am. Chem. Soc. 2016, 138,
5004 – 5007; c) M. K. Haj, S. M. Banik, E. N. Jacobsen, Org. Lett.
2019, 21, 4919 – 4923; d) F. Scheidt, M. Schꢆfer, J. C. Sarie, C. G.
Daniliuc, J. J. Molloy, R. Gilmour, Angew. Chem. Int. Ed. 2018,
57, 16431 – 16435; Angew. Chem. 2018, 130, 16669 – 16673; e) S.
Doobary, A. T. Sedikides, H. P. Caldora, D. L. Poole, A. J. J.
In the thermodynamically preferred complex Cpx B (see the
Supporting Information) the I-F distance is slighly shorter than
the sum of the Van der Waals radii (3.45 ꢃ). For studies on
halogen bonding in I(III) compounds, see: a) G. Cavallo, J. S.
Murray, P. Politzer, T. Pilati, M. Ursini, G. Resnatin, IUCrJ 2017,
4, 411 – 419; b) F. Heinen, E. Engelage, C. J. Cramer, S. M.
Huber, J. Am. Chem. Soc. 2020, 142, 8633 – 8640.
[20] a) A. Granados, A. Villribera, Molecules 2020, 25, 3264; b) For
an example from this laboratory, see E.-M. Tanzer, W. B.
Schweizer, M.-O. Ebert, R. Gilmour, Chem. Eur. J. 2012, 18,
2006 – 2013.
[21] The Van der Waals volumes were calculated according to: Y. H.
Zhao, M. H. Abraham, A. M. Zissimos, J. Org. Chem. 2003, 68,
7368; Please see A. Bondi, J. Phys. Chem. 1964, 68, 441 – 451.
[22] 2057761 contain(s) the supplementary crystallographic data for
this paper. These data are provided free of charge by the joint
Cambridge Crystallographic Data Centre and Fachinforma-
tionszentrum Karlsruhe Access Structures service www.ccdc.
cam.ac.uk/structures.
Manuscript received: February 12, 2021
Revised manuscript received: March 12, 2021
Accepted manuscript online: March 15, 2021
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Main-Group Catalysis
J. Neufeld, T. Stꢁnkel,
C. Mꢁck-Lichtenfeld, C. G. Daniliuc,
R. Gilmour*
&&&& — &&&&
Trifluorinated Tetralins via I(I)/I(III)-
Catalysed Ring Expansion: Programming
Conformation by [CH2CH2] ! [CF2CHF]
Isosterism
To expand the current portfolio of satu-
rated, fluorinated carbocycles for drug
discovery, a main-group catalysis-based
synthesis of novel, trifluorinated tetralins
is disclosed. Isosteric replacement of
conformational degeneracy intrinsic to
ꢀ
the parent tetralin, since the CH F bond
occupies a pseudo-axial orientation (s
ꢀ
C
!s *). This provides pre-organised
ꢀ
H
C
F
module for contemporary medicinal
chemistry.
ꢀ
ꢀ
[CH2 CH2] by [CF2 CHF] removes the
6
www.angewandte.org
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!