Indium-Catalysed Transfer Hydrogenation for the Reductive Cyclisation of 2-Alkynyl Enones towards Trisubstituted Furans

Article abstract of DOI:10.1002/anie.202109266

Indium tribromide catalysed the transfer hydrogenation from dihydroaromatic compounds, such as the commercially available γ-terpinene, to enones, which resulted in the cyclisation to trisubstituted furan derivatives. The reaction was initiated by a Michae

Full text of DOI:10.1002/anie.202109266

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Indium-Catalysed Transfer-Hydrogenation for the Reductive
Cyclisation of 2-Alkynyl Enones towards Trisubstituted Furans
Authors: Luomo Li, Sascha Kail, Sebastian M. Weber, and Gerhard Hilt
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: Angew. Chem. Int. Ed. 10.1002/anie.202109266
Link to VoR: https://doi.org/10.1002/anie.202109266

10.1002/anie.202109266
Angewandte Chemie International Edition
COMMUNICATION
Indium-Catalysed Transfer-Hydrogenation for the Reductive
Cyclisation of 2-Alkynyl Enones towards Trisubstituted Furans
Luomo Li, Sascha Kail, Sebastian M. Weber, Gerhard Hilt*[a]
[a]
L. Li, S. Kail, S. M. Weber and Prof. Dr. G. Hilt
Institut für Chemie, Carl von Ossietzky Universität Oldenburg
Carl-von-Ossietzky-Straße 9–11, 26111 Oldenburg, Germany
E-mail: Gerhard.Hilt@uni-oldenburg.de
Abstract: Indium tribromide catalysed the transfer-hydrogenation
from dihydroaromatic compounds, such as the commercially available
-terpinene, to enones which resulted in the cyclisation to
trisubstituted furan derivatives. The reaction was initiated by a Michael
addition of a hydride nucleophile to the enone subunit followed by a
Lewis-acid assisted cyclisation and the formation of a furan-indium
catalysts are incompatible with hydride donors. Nevertheless,
these applications utilised transition metal catalysts for the
synthesis of highly substituted/functionalised furans via a -Lewis
acid activation of the alkyne moiety. In an outstanding report by
Selander,[5] InBr3 catalysed the synthesis of furan derivatives
starting from 1 in an annulation process with in situ generated
enamines (Scheme 1).
intermediate and
a Wheland intermediate derived from the
dihydroaromatic starting material. The product was formed by
protonation from the Wheland complex and replaced the indium
tribromide substituent. In addition, a site specific deuterium labelling
of the dihydroaromatic HD surrogates resulted in site specific labelling
of the products and gave useful insights into the reaction mechanism
by H-D scrambling.
Multiple substituted furans play an important role in organic
chemistry, not only as key structural motives in natural products
(e.g. crassifogenin A[1a] and plakorsin D,[1b] Figure 1) but also in
materials and pharmaceuticals. The synthesis of furans has a
long tradition in organic synthesis, and recent developments have
been highlighted in several recent reviews.[2]
Figure 1. Highly functionalised furan derivative pharmaceuticals and natural
products.
Among the numerous synthetic approaches towards furans,
the cyclisation of 2-alkynyl substituted 1,3-conjugated enones 1
with alcohols was first reported by Larock[3] in 2004 (Scheme 1)
utilising catalytic amounts of gold(III) and various nucleophiles for
the synthesis of trisubstituted furans. Further developments by
Zhang, Liu and several other groups (Scheme 1) utilising
transition metal catalysts, such as gold,[4a-n] palladium,[4o-r]
rhodium,[4s] copper[4t,u] and silver,[4v-x] were reported over the last
two decades. In these transition metal-catalysed cyclisation
reactions of alkynyl enones of type 1, a large number of different
types of nucleophiles were reported for the synthesis of highly
substituted and functionalised furans and annulated bicyclic
systems. However, the use of a hydride source as nucleophile
seems to be missing, probably because the transition metal
Scheme 1. Previous work concerning the cyclisation of 2-alkynyl-substituted
enones with nucleophiles.
The Oestreich group pioneered in the transfer-
hydrogenation of alkenes and imines by using dihydroaromatic
compounds as the H2 surrogate catalysed by B(C6F5)3 or strong
Brønsted acids.[6] and applied regiospecific deuterated
dihydroaromatic cyclohexadiene as a HD surrogate.[6g] In 2020
our group reported the regiodivergent hydrodeuterogenation and
the deuterohydrogenation utilising two specific deuterium-labelled
dihydroaromatic compounds.[7] Therefore, we became interested
in expanding the cyclisation of enone 1 with a hydride nucleophile
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202109266
Angewandte Chemie International Edition
COMMUNICATION
from a dihydroaromatic compound. Herein, an InBr3-catalysed
cyclisation of alkynyl enones 1 with the cost efficient and
commercially available dihydroaromatic compound -terpinene
(<100 €/kg) as H2 surrogate towards furans under C-O bond
formation is described.
the substrate and a low reaction temperature improved the yield
and 1.5 equiv. of reductant were sufficient for the reaction.
According to the calculated model, the optimal reaction conditions
(Scheme 3) were applied for the synthesis of 3a which was
isolated in 98% yield (predicted yield around 100%), and a variety
of alkynyl enones of type 1 were transformed in the InBr3-
catalysed cyclisation towards the furans of type 3 (Scheme 3).
The results of the InBr3-catalysed transfer-hydrogenation induced
cyclisation reactions are summarised in Table 1.
For the optimisation of the cyclisation reaction, we focused
on the following parameters: a) the catalyst loading (3-10 mol%,
continuous); b) the reaction temperature (0-50 °C, continuous); c)
the reaction time (1-15 h, continuous); d) the substrate
concentration (0.2-2 M, continuous); e) the reducing agent
loading (0.95-1.5 equiv., continuous) and f) the type of the
reductant (1,4-cyclohexadiene or -terpinene, categorical). For
the optimisation of all these variables efficiently and to reduce the
number of needed experiments, the Design of Experiments (DoE)
approach,[8] with 2-benzylidene-1,4-diphenylbut-3-yn-1-one 1a as
test substrate (Scheme 2), was applied. All of the parameters
were optimised in only 16 experiments (for further information see
Supporting Information).
Scheme 3. InBr3-catalysed cyclisation of 2-alkynyl-substituted enones 1.
Fortunately, the indium catalyst system tolerated a broad
range of functional groups. Enones comprising electron-rich as
well as electron-deficient aromatic substituents on the acyl moiety
(R1) led to products 3a-3d in good to excellent yields. Moreover,
the substituent on the acyl part (R1) can be an aliphatic group as
well (3n-3s) which had little impact on the yield. The alkenyl
moiety (R2) with both electron-rich and electron-deficient aryl
groups were compatible (3e-3h), including the 2-thiophenyl group.
Aryl substituents on the alkynyl moiety (R3) (3i-3m) were also
tolerated while electron-deficient aryl groups, such as 4-
trifluoromethyl-substituted substrate 1i and the 4-bromo-
substituted aryl substrate 1j led to lower reactivities at ambient
temperature, but the corresponding products (3i and 3j) were
formed with good and almost quantitative yields at 50 °C. Also,
the benzo[d][1,3]dioxole derivative 1r led to the formation of
product 3r in a good yield (83%), while the reaction required a
long time (more than 3 d) to reach completion, probably by
lowering the catalysts activity upon weak coordination. Also,
moderate to good yields were obtained for the products (3t-3w)
comprising alkyl groups on the alkynyl moiety R3, including a
cyclopropyl group (3u) and a -chloroalkyl substituent in product
3v. Unfortunately, the investigation of substrates with an aliphatic
side-chain as substituent R2 could not be realised. The route for
the synthesis for this type of starting material with aliphatic
substituents as R2 led either to decomposition, side-reactions
towards unidentified products or only trace amounts of the desired
enone derivatives. However, one exception is the cyclohexanone
derivative 1x which could be reacted successfully to afford 3x in
a moderate yield thus indicating that also alkyl chains are
tolerated as R2, but other synthetic routes must be used to access
such starting materials. On the basis of the results described by
Oestreich and us, substrates bearing strongly Lewis-basic groups,
such as a 4-nitrophenyl or a pyridyl substituent, are poor
substrates for the transfer-hydrogenation from diaromatic
compounds.6g In our previous work (unpublished), the CN group
decreased the reactivity of indium catalyst for the transfer-
hydrogenation and lead to low or no conversion. Notably, this
indium-catalysed cyclisation of alkynyl enones can be easily
scaled up. A gram-scale reaction of alkynyl enone 1a was
examined at 50 °C, providing 1.05 g (3.39 mol) of 3a in 98% yield.
Scheme 2. Test reaction for the optimisation for the reaction parameters by DoE.
Figure 2. Reaction optimisation for the cyclisation of alkenyl enone 1a with H2
surrogates. The predicted yields are plotted vs. the measured yields. Total
number of reactions: 19; 16 for the model, and three duplicates for the lack of
fit. The yields were determined by GC/FID analysis using mesitylene as internal
standard.
The resulting model identified eight relevant factors with an
R2 = 0.93 (see Supporting Information). The most relevant factors
were the substrate concentration and the reaction time (p-values
< 0.01). The quadratic temperature and the cross-interaction
between time and temperature and (p-values = 0.3) also affected
the design.
Surprisingly, the model showed that the catalyst loading (p-
values = 0.8) had a marginal impact while a low concentration of
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202109266
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Scope of the InBr3-catalysed transfer-hydrogenation and cyclisation of 2-alkynyl-substituted enones 1.
To gain a better understanding of the mechanism of this
alkynyl enone cyclisation, we conducted regiodiverse
The same reaction with the surrogate 5 providing a
deuterium cation (D+) a hydride (H-) afforded the furan 7 with 83%
yield and 65% deuterium incorporation was detected into the 3-
position of the furan ring. The significant loss of deuterium
labelling for the HD surrogate 5 was surprising. Neither
deuterium-labelling at other positions of product 7 nor additional
deuterium incorporation in the oxidised HD surrogate (4-deutero-
[1,1'-biphenyl]-3-yl)trimethylsilane) were detectable by GCMS
analysis.
a
deuterium-labelling experiments utilising the two regioselectively
substituted dihydroaromatic compounds 4 (99% D incorporation)
and 5 (96% D incorporation) developed by our group in 2020 as
HD surrogates.[7,9] The reaction of 1f with surrogate 4 providing a
deuteride (D-) and a proton (H+) in the presence of InBr3 at 50 °C
afforded the furan
6 in 85% yield and 99% deuterium
incorporation into the methylene group (Scheme 4).
Nevertheless, for the mechanistic considerations of this
InBr3-catalysed reaction the considerable loss of deuterium-
labelling might be informative. For the gold-catalysed cyclisation
of alkynyl enones (see Scheme 1), a plausible mechanisms was
proposed by Larock.[3] The cyclisation was initiated by a AuCl3-
catalysed -activation of the alkyne. However, compared to the
gold catalyst, InBr3 is believed to be more oxophilic. This led to a
mechanistic proposal shown in Scheme 5.
Scheme 4. Hydrodeuterogenation and deuterohydrogenation of enone 1f.
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202109266
Angewandte Chemie International Edition
COMMUNICATION
considerable
amounts
of
deuterium-labelling
via
dedeuteration/redeuteration when going from intermediate E via
C to the desired product 7. Even small amounts of a proton source
(e.g. H2O) could result in a considerable loss of deuterium
incorporation in product 7.
Based on these considerations outlined in Scheme 6, the
reaction of 1f with the HD surrogate 4 (Scheme 4) should not
show a loss of deuterium-labelling in product 6 when small
amounts of H2O are present. In an attempt to verify the
hydrogen/deuterium scrambling from intermediate E via C to the
furan product 7, the control experiment as outlined in Scheme 7
was conducted.
Scheme 5. Possible mechanism for the InBr3-catalysed cyclisation of enone 1f
with HD surrogate 5.
Scheme 7. InBr3-catalysed hydrodeuterogenation of 1f utilising -terpinene and
D2O as deuterium source.
The InBr3 catalyst could first coordinate to the alkynyl enone
1f, forming the intermediate complex A with indium interacting
with the carbonyl oxygen atom and the alkynyl moiety. Then a
hydride, originated from the HD surrogate 5, is transferred in
terms of a Michael addition to the activated alkenone moiety
resulting in the formation of the Wheland intermediate B. This
hydride transfer is either catalysed by InBr3, via a [H-InBr3]-
reactive intermediate, similar to the indium hydride published by
Baba[10], or by direct hydride transfer from 5 to the activated enone
A. The cyclisation of the carbonyl oxygen onto the alkynyl moiety,
led to the formation of the furan ring with covalently bonded
indium at the 3-position in the intermediate complex C. The
Wheland complex B, which is a strong proton donor, then
replaced the InBr3 moiety by a proton to afford product 7.
Compared to other transfer-hydrogenations of dihydroaromatic
surrogates catalysed by Lewis acids, this proposed mechanism
would be unprecedented.
When the transfer-hydrogenation of alkenes was discussed
in the literature,[6,7] the addition of hydride and proton was
reversed; the first steps in these reaction mechanisms were the
protonation of the alkene starting materials by the Wheland
complex to afford stabilised carbenium ions followed by hydride
transfers from the surrogate to the carbenium ions. Accordingly,
an alternative reaction mechanism would start with the
protonation of the starting material 1f by the Wheland complex B
towards intermediate D (Scheme 6).
Fortunately, InBr3-catalysed transfer-hydrogenation are not
highly sensitive to traces of H2O (or D2O)[5b-g] although the
reactivity of the catalyst was significantly diminished so that a
prolonged reaction time was needed. As expected, the proton
from the Wheland complex derived from -terpinene
(corresponding to B) protonated the starting material 1f and the
transfer-hydrogenation from -terpinene to the enone moiety in D
generated the intermediate E without any incorporation of
deuterium next to the tolyl substituent. In the experiment shown
in Scheme 7 the hydrogen/deuterium scrambling took place and
the product 7 was isolated in 82% with 55% deuterium
incorporation in the 3-position. In a control experiment, the H-
labelled product 3f was reacted with D2O in the presence of InBr3
but no deuterated product 7 was detected, indicating that the loss
of the deuterium labelling in the original reaction (1f → 7,
Scheme 4) might be associated to traces of H2O.
In conclusion, we developed an InBr3-catalysed cyclisation
of alkynyl enones utilising -terpinene as H2 surrogate. The
optimisation of the reaction with the Design of Experiments (DoE)
approach identified the crucial reaction parameters. This
transition metal free reaction tolerated a wide range of aromatic
and aliphatic functional groups and provided the substituted
furans in high yields under mild reaction conditions and low
catalyst loading. Moreover, deuterium-labelling studies utilising
regioselectively substituted dihydroaromatic compounds as HD
surrogates were conducted to gain insights into the reaction
mechanism.
Acknowledgements
The financial support by the German Science Foundation GRK
2226 is gratefully acknowledged.
Scheme 6. Alternative mechanism based on the deuterium-labelling
experiments for the InBr3-catalysed cyclisation of enone 1f with HD surrogate 5.
An InBr3-assisted cyclisation via a coordinative indium-
bonded intermediate E towards C would result in the formation of
the furan backbone in 7 but also could account for the loss of
Keywords: indium • furans • cyclisation • 1,4-cyclohexadienes •
deuterium labelling
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202109266
Angewandte Chemie International Edition
COMMUNICATION
[1]
a) N. Li, J.-J. Chen, J. Zhou, Helv. Chim. Acta 2004, 87, 845−850; b) J.
Zhang, X. Tang, J. Li, P. Li, N. J. de Voogd, X. Ni, X. Jin, X. Yao, P. Li,
G. Li, J. Nat. Prod. 2013, 76, 600−606.
129, 52−59; Angew. Chem. Int. Ed. 2017, 56, 52−59; g) S. Keess, M.
Oestreich, Org. Lett. 2017, 19, 1898−1901; i) S. Keess, M. Oestreich,
Chem. Eur. J. 2017, 23, 5925−5928; i) W. Yuan, P. Orecchia, M.
Oestreich, Chem. Commun. 2017, 53, 10390−10393; j) S. Keess, M.
Oestreich, Chem. Sci. 2017, 8, 4688−4695; k) A. Lefranc, Z.-W. Qu, S.
Grimme, M. Oestreich, Chem. Eur. J. 2016, 22, 10009−10016; l) M.
Oestreich, Angew. Chem. Int. Ed. 2016, 128, 504−509; Angew. Chem.
Int. Ed. 2016, 55, 494−499; m) I. Chatterjee, M. Oestreich, Org. Lett.
2016, 18, 2463−2466; n) I. Chatterjee, M. Oestreich, Org. Lett. 2016, 18,
2463−2466; o) I. Chatterjee, M. Oestreich, Angew. Chem. 2015, 127,
1988–1991; Angew. Chem. Int. Ed. 2015, 54, 1965−1968; p) I.
Chatterjee, Z.-W. Qu, S. Grimme, M. Oestreich, Angew. Chem. 2015,
127, 12326−12330; Angew. Chem. Int. Ed. 2015, 54, 12158−12162; q)
A. Simonneau, M. Oestreich, Nat. Chem. 2015, 7, 816−822; r) B.
Michelet, C. Bour, V. Gandon, Chem. Eur. J. 2014, 20, 14488−14492; s)
J. D. Webb, V. S. Laberge, S. J. Geier, D. W Stephan, C. M. Crudden,
Chem. Eur. J. 2010, 16, 4895−4902. For a review, see: t) J. C. L. Walker,
M. Oestreich, Synlett 2019, 30, 2216−2332. For recent alternative HD
surrogates, see: u) T. G. Linford-Wood, N. T. Coles, R. L. Webster,
Green Chem. 2021, 23, 2703−2709; v) Z. P. Vang, A. Reyes, R. E.
Sonstrom, M. S. Holdren, S. E. Sloane, I. Y. Alansari, J. L. Neill, B. H.
Pate, J. R. Clark, J. Am. Chem. Soc. 2021, 143, 7707–7718; w) Y. Wang,
X. Cao, L. Zhao, C. Pi, J. Ji, X. Cui, Y. Wu, Adv. Synth. Catal. 2020, 362,
4119−4129; x) S. E. Sloane, A. Reyes, Z. P. Vang, L. Li, K. T Behlow, J.
R. Clark, Org. Lett. 2020, 22, 9139−9144; y) M. Espinal-Viguri, S. E.
Neale, N. T. Coles, S. A. Macgregor, R. L. Webster, J. Am. Chem. Soc.
2019, 141, 572−582; z) P. Yang, H. Xu, J. Zhou, Angew. Chem. 2014,
126, 12406−12409; Angew. Chem. Int. Ed. 2014, 53, 12210−12213; aa)
Z. P. Vang, S. J. Hintzsche, J. R. Clark, Chem Eur. J. 2021, 27, 9988-
10000.
[2]
For selected reviews, see: a) V. Y. Chen, O. Kwon, Angew. Chem. 2021,
133, 8956–8963; Angew. Chem. Int. Ed. 2021, 60, 8874–8881; b) S.
Nejrotti, C. Prandi, Synthesis 2021, 53, 1046–1060; c) X. Bao, J. Ren, Y.
Yang, X. Ye, B. Wang, H. Wang, Org. Biomol. Chem. 2020, 18, 7977–
7986; d) D. Qian, J. Zhang, Acc. Chem. Res. 2020, 53, 2358−2371; e) A.
Deepthi, B. P. Babu, A. L. Balachandran, Org. Prep. Proced. Int. 2019,
51, 409–442; f) A. V. Gulevich, A. S. Dudnik, N. Chernyak, V. Gevorgyan,
Chem. Rev. 2013, 113, 3084−3213; g) W. Jia-Jie, Y. Zhu, Z.-P. Zhan,
Asian J. Org. Chem. 2012, 1, 108−129; h) B. A. Keay, J. M. Hopkins, P.
W. Dibble, In Comprehensive Heterocyclic Chemistry III; C. A. Ramsden,
E. F. V. Scriven, R. J. K. Taylor, Eds.; Elsevier: Oxford, 2008, 571−623;
i) S. F. Kirsch, Org. Biomol. Chem. 2006, 4, 2076−2080.
[3]
[4]
a) T. Yao, X. Zhang, R. C. Larock, J. Org. Chem. 2005, 70, 7679–7685;
b) T. Yao, X. Zhang, R. C. Larock, J. Am. Chem. Soc. 2004, 126, 11164–
11165.
For gold-catalysed cyclisations, see: a) Y. Xu, J. Sun, Org. Lett. 2021,
23, 853−857; b) R. D. Kardile, R.-S. Liu, Org. Lett. 2020, 22, 8229–8233;
c) S. Ge, Y. Zhang, Z. Tan, D. Li, S. Dong, X. Liu, X. Feng, Org. Lett.
2020, 22, 3551–3556; d) L. Zhou, B. Xu, D. Ji, Z.-M. Zhang, J. Zhang,
Chin. J. Chem. 2020, 38, 577–582; e) R. D. Kardile, T.-H Chao, M.-J.
Cheng, R.-S. Liu, Angew. Chem. 2020, 132, 10482–10486; Angew.
Chem. Int. Ed. 2020, 59, 10396–10400; f) J. Qi, Q. Teng, N. Thirupathi,
C.-H. Tung, Z. Xu, Org. Lett. 2019, 21, 692–695; g) Q. Du, J.-M. Neudörfl,
H.-G. Schmalz, Chem. Eur. J. 2018, 24, 2379–2383; h) S. Liu, P. Yang,
S. Peng, C. Zhu, S. Cao, J. Li, J. Sun, Chem. Commun. 2017, 53, 1152–
1155; i) L. Zhou, M. Zhang, W. Li, J. Zhang, Angew. Chem. 2014, 126,
6660–6663; Angew. Chem. Int. Ed. 2014, 53, 6542–6545; j) H. Gao, X.
Wu, J. Zhang, Chem. Eur. J. 2011, 17, 2838–2841; k) F. Liu, Y. Yu, J.
Zhang, Angew. Chem. 2010, 122, 6819–6822; Angew. Chem. Int. Ed.
2010, 49, 6669–6672; l) H. Gao, X. Zhao, Y. Yu, J. Zhang, Chem. Eur. J.
2010, 16, 456–459; m) H. Gao, X. Wu, J. Zhang, Chem. Commun. 2010,
46, 8764–8766; n) F. Liu, Y. Yu, J. Zhang, Angew. Chem. 2009, 121,
5613–5616; Angew. Chem. Int. Ed. 2009, 48, 5505–5508. For palladium-
catalysed cyclisations, see: o) C. Arroniz, G. Chaubet, E. A. Anderson,
ACS Catal. 2018, 8, 8290−8295; p) R. Liu, J. Zhang, Chem. Eur. J. 2009,
15, 9303–9306; q) Y. Xiao, J. Zhang, Adv. Synth. Catal. 2009, 351, 617–
629; r) Y. Xiao, J. Zhang, Angew. Chem. 2008, 120, 1929–1932; Angew.
Chem. Int. Ed. 2008, 47, 1903–1906. For a rhodium-catalysed cyclisation,
see: s) H. Gao, J. Zhang, Chem. Eur. J. 2012, 18, 2777–2782. For
copper-catalysed cyclisations, see: t) L. Wang, X. Liu, M. Wang,J. Liu,
Org. Lett. 2016, 18, 2162–2165; u) N. T. Patil, H. Wu, Y. Yamamoto, J.
Org. Chem. 2005, 70, 4531–4534. For silver-catalysed cyclisations, see:
v) L.-L. Qian, R. Yi, X.-T. Min, Y.-C. Hu, B Wan, Q. A. Chen, Tetrahedron,
2020, 76, 131327–131334; w) Z. Li, J. Peng, C. He, J. Xu, H. Ren, Org.
Lett. 2020, 22, 5768–5772. For a platinum-catalysed cyclisation, see: x)
C. H. Oh, V. R. Reddy, A. Kim, C.Y. Rhim, Tetrahedron Lett. 2006, 47,
5307–5310.
[7]
[8]
a) L. Li, G. Hilt, Org. Lett. 2020, 22, 1628−1632; b) L. Li, G. Hilt, Chem.
Eur. J. 2021, 22, doi.org/10.1002/chem.202101259.
For recent applications of DoE in organic electrochemistry, see: a) M. M.
Hielscher, B. Gleede, S. R. Waldvogel, Electrochim. Acta 2021, 368,
137555; b) M Dörr, M. M. Hielscher, J. Proppe, S. R. Waldvogel,
ChemElectroChem 2021, doi.org/10.1002/celc.202100318; c) E.
Babaoglu, G. Hilt, Chem. Eur. J. 2020, 26, 8879–8884; d) R. Möckel, J.
Hille, E. Winterling, S. Weidemüller, T. M. Faber, G. Hilt, Angew. Chem.
2018, 130, 450–454; Angew. Chem. Int. Ed. 2018, 57, 442–445; For
reviews/tutorials for the use of DoE in chemistry, see: e) B. Benedettia,
V. Caponigrob, F. Ardini, Critical Rev. Anal. Chem. 2020,
doi.org/10.1080/10408347.2020.1848517, f) P. M. Murray, F. Bellany, L.
Benhamou, D.-K. Buꢀar, A. B. Tabor, T. D. Sheppard, Org. Biomol.
Chem. 2016,14, 2373−2384; g) R. Leardi, Anal. Chim. Acta 2009, 652,
161–172.
[9]
For the synthesis of dihydroaromatic compounds, see: a) P. Rꢁse, G. Hilt,
Synthesis 2016, 48, 463−492; b) G. Hilt, Chem. Rec. 2014, 14, 386−395;
c) J. R. Kuttner, G. Hilt, Synthesis 2015, 47, 1170−1180; d) F. Erver, J.
R. Kuttner, G. Hilt, J. Org. Chem. 2012, 77, 8375−8385; e) A.-L. Auvinet,
J. P. A. Harrity, G. Hilt, J. Org. Chem. 2010, 75, 3893–3896; f) Hilt, C.
Hengst, J. Org. Chem. 2007, 72, 7337–7342; g) G. Hilt, J. Janikowski, W.
Hess, Angew. Chem. 2006, 118, 5328–5331; Angew. Chem. Int. Ed.
2006, 45, 5204–5206; h) G. Hilt, K. I. Smolko, Angew. Chem. 2003, 115,
2901–2903; Angew. Chem. Int. Ed. 2003, 42, 2795–2797; i) T. V.
RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116, 986−997; j) T.
V. RajanBabu, W. A. Nugent, M. S. Beattie, J. Am. Chem. Soc. 1990,
112, 6408−6409.
[5]
a) S. R. Pathipati, A. van der Werf, L. Eriksson, N. Selander, Angew.
Chem. 2016, 128, 12042–12045; Angew. Chem. Int. Ed. 2016, 55,
11863-11866. For reviews, see: b) M. Datta, ChemistrySelect 2021, 6,
187–216; c) S. K. Mahato, C. Acharya, K. W. Wellington, P.
Bhattacharjee, P. Jaisankar, ACS Omega 2020, 5, 2503–2519; d) Z.-L.
Shen, S.-Y. Wang, Y.-K. Chok, Y.-H. Xu, T.-P. Loh, Chem. Rev. 2013,
113, 271–401; e) J. S. Yadav, A. Antony, J. George, B. V. Subba Reddy,
Eur. J. Org. Chem. 2010, 591–605; f) J. Podlech, T. C. Meier, Synthesis
2003, 633–655; g) B. C. Ranu, Eur. J. Org. Chem. 2000, 2347–2356.
a) W. Chen, H. Fang, K. Xie, M. Oestreich, Chem. Eur. J. 2020, 26,
15126−15129; b) W. Chen, M. Oestreich, Org. Lett. 2019, 21,
4531−4534; c) P. Orecchia, W. Yuan, M. Oestreich, Angew. Chem. 2019,
131, 3617−3621; Angew. Chem. Int. Ed. 2019, 58, 3579−3583; d) A.
Djurovic, M. Vayer, Z. Li, R. Guillot, J.-P. Baltaze, V. Gandon, C. Bour,
Org. Lett. 2019, 21, 8132−8137; e) J. C. L. Walker, M. Oestreich, Angew.
Chem. 2019, 131, 15530−15534; Angew. Chem. Int. Ed. 2019, 58,
15386−15389; f) A. Bhunia, K. Bergander, A. Studer, J. Am. Chem. Soc.
2018, 140, 16353−16359; g) J. C. L. Walker, M. Oestreich, Org. Lett.
2018, 20, 6411−6414; h) S. Bähr, M. Oestreich, Angew. Chem. 2017,
[10] For indium hydride compounds and their applications, see: a) T. Miyai,
K. Inoue, M. Jasuda, I. Shibata, A. Baba, Tetrahedron Lett. 1998, 39,
1929−1932; b) K. Inoue, A. Sawada, I. Shibata, A. Baba, J. Am. Chem.
Soc. 2002, 124, 906−907.
[6]
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202109266
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Cheap but not Bad – InBr3 is used as functional group tolerant catalysts for the transfer-hydrogenation from -terpinene as H2 surrogate
to initiate the cyclisation of 2-alkynyl-substituted enones to tri-substituted furans in good yields. Design of Experiments was used to
optimise the reaction conditions with a few experiments to almost quantitative yields and deuterium-labelling experiments gave valuable
mechanistic insights.
6
This article is protected by copyright. All rights reserved.