Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol: Stereoselective Synthesis of Chlorinated Methylene Oxindoles and Quinolinones

Article abstract of DOI:10.1002/anie.202103323

Hexafluoroisopropanol (HFIP) was employed as an additive for the generation of 3-(chloromethylene)oxindoles via the chloroacylation of alkyne-tethered carbamoyl chlorides. This reaction avoids the use of a metal catalyst and accesses products in high yields and stereoselectivities. Additionally, this reaction is scalable and proved amenable to a series of product derivatizations, including the synthesis of nintedanib. The reactivity of alkene-tethered carbamoyl chlorides with hexafluoroisopropanol (HFIP) was harnessed towards the synthesis of 2-quinolinones.

Full text of DOI:10.1002/anie.202103323

Angewandte
Communications
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How to cite: Angew. Chem. Int. Ed. 2021, 60, 18478–18483
International Edition:
German Edition:
doi.org/10.1002/anie.202103323
doi.org/10.1002/ange.202103323
Synthetic Methods
Cycloisomerization of Carbamoyl Chlorides in Hexafluoroisopropanol:
Stereoselective Synthesis of Chlorinated Methylene Oxindoles and
Quinolinones
Josꢀ F. Rodrꢁguez, Anji Zhang, Jonathan Bajohr, Andrew Whyte, Bijan Mirabi, and
Mark Lautens*
Abstract: Hexafluoroisopropanol (HFIP) was employed as an
additive for the generation of 3-(chloromethylene)oxindoles
via the chloroacylation of alkyne-tethered carbamoyl chlorides.
This reaction avoids the use of a metal catalyst and accesses
products in high yields and stereoselectivities. Additionally, this
reaction is scalable and proved amenable to a series of product
derivatizations, including the synthesis of nintedanib. The
reactivity of alkene-tethered carbamoyl chlorides with hexa-
fluoroisopropanol (HFIP) was harnessed towards the syn-
thesis of 2-quinolinones.
M
ethylene oxindoles display a broad range of biological
activities and have become key targets in medicinal chemis-
try.[1] As a result, several strategies have been developed for
their preparation.[2,3] Further solidifying the importance of
these compounds is their synthetic versatility, which has been
exploited in the total synthesis of spirocyclic oxindole natural
products;[4,5] scaffolds such as 3-(halomethylene)oxindoles
are useful intermediates for accessing these medicinally active
motifs.[6] Nevertheless, highly stereoselective methods for
their preparation are scarce in the literature and commonly
require precious transition-metal-based catalysts. Conse-
quently, the development of metal-free methodologies for
the stereoselective synthesis of 3-(halomethylene)oxindoles is
of considerable interest.
Scheme 1. Strategies for the synthesis of 3-(chloromethylene)oxin-
doles.
synthesis of the corresponding Z-isomers in good yields and
excellent stereoselectivities.[11]
In 2007, a PdII-catalyzed carbonylative annulation of 2-
alkynylanilines was reported by Li and co-workers
(Scheme 1).[7] This report employs CuCl2 as a stoichiometric
oxidant and generates (E)-3-(chloromethylene)oxindoles in
moderate yields, displaying stereoselectivities ranging from
2.7:1 to > 99:1. In 2015, our group reported a complementary
synthesis of these scaffolds via a Pd0-catalyzed chloroacyla-
tion of alkyne-tethered carbamoyl chlorides;[8a] however,
sterically bulky alkynyl substituents were required to promote
a challenging C(sp2)–Cl reductive elimination.[8–10] Address-
ing this limitation, our group reported a PdII-catalyzed
While cycloisomerizations from readily available organo-
halides are a powerful method to introduce molecular
complexity and retain the halide functionality, these reactions
typically require transition-metal catalysts which can impose
substrate limitations.[8–10] When searching for new method-
ologies for the synthesis of (E)-3-(chloromethylene)oxin-
doles, we found that fluorinated alcohol additives promote
the intramolecular carbochlorination of alkynes without
metal catalysts. We describe herein a metal-free, simple, and
effective cycloisomerization of alkyne-tethered carbamoyl
chlorides for the synthesis of these scaffolds.
We envisioned using alkyne-tethered carbamoyl chloride
1a as a substrate for an alkyne chloroacylation process similar
to previous reports from our group.[8a,11a] We discovered the
propensity of alkyne-tethered carbamoyl chlorides to cyclo-
isomerize in the presence of TFE at high temperatures.
Product 2a was generated in 52% yield and high E-selectivity
by heating 1a in TFE (Table 1, entry 1). Notably, the olefin
stereochemistry was complementary to our previous PdII-
catalyzed chloroacylation report.[11] Alcoholic solvents lack-
ing fluorine atoms were ineffective in this reaction, which is
[*] J. F. Rodrꢀguez, A. Zhang, J. Bajohr, A. Whyte, B. Mirabi,
Prof. Dr. M. Lautens
Davenport Research Laboratories, Department of Chemistry,
University of Toronto
80 St. George Street, Toronto, Ontario M5S 3H6 (Canada)
E-mail: mark.lautens@utoronto.ca
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.202103323.
18478
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Table 1: Synthesis of methylene oxindoles: Optimization of reaction conditions. Reactions were
performed on a 0.2 mmol scale. NMR yields and isomeric ratios determined using CH2Br2 as internal
standard. Isolated yield given in parenthesis.
aniline core was also investigated
(2i–2o), and the corresponding
products were obtained in yields
ranging from 86% to 97% yield.
Products containing a variety
of alkyne substitutions were syn-
thesized (2p–2w). The acidity of
HFIP may also be responsible for
O-TBS cleavage in product 2s,
resulting in diminished yields.
Complementary to known meth-
ods for the synthesis of (E)-3-
(chloromethylene)oxindoles,[6c,7]
products containing aryl substitu-
ents at the alkene were obtained in
excellent yields and good selectiv-
ities. Product 2u, encompassing an
unsubstituted phenyl group, was
formed in 80% yield, and 7:1 E/Z
ratio. Excellent yield and stereose-
lectivity was obtained when 1v was
employed, containing an electron-
rich -OMe substituent. Product 2w,
containing a p-fluoride on the aryl
Entry
Solvent (0.2 m)
Temp. (8C)
Additive
Yield 2a (%)
E/Z ratio
1
2
3
4
5
6
7
8
TFE
100
100
80
None
None
None
HFIP (8 equiv)
HFIP (3 equiv)
iPrOH (8 equiv)
None
None
None
TFA (8 equiv)
AcOH (8 equiv)
BzOH (8 equiv)
TfOH (8 equiv)
52
71
27
96 (94)
34
11
N. D.
10
N. D.
61
N. D.
N. D.
N. D.
20:1
>20:1
2.2:1
HFIP
HFIP
PhMe
PhMe
PhMe
PhMe
MeCN
NMP
PhMe
PhMe
PhMe
PhMe
100
100
100
100
100
150
100
100
100
100
>20:1
>20:1
N. D.
N. D.
>20:1
N. D.
>20:1
N. D.
N. D.
N. D.
9[a]
10
11
12
13[a]
N. D.=Not detected. [a] Complete decomposition of starting material.
attributed to the distinct physical properties of their fluori-
nated counterparts. These include increased acidity and
hydrogen bond-donating ability, reduced nucleophilicity,
and the ability to stabilize cationic species.[12] With this
observation, an improved yield of 71% and > 20:1 E/Z
selectivity was observed when HFIP was employed as the
solvent (entry 2).
Decreased yield and stereoselectivity was obtained at
a lower temperature (entry 3). The loss in stereoselectivity
suggests that higher temperatures lead to preferential for-
mation of the more stable isomer (vide infra). Ultimately,
8 equivalents of HFIP in toluene solvent gave the product in
96% yield and > 20:1 E/Z (entry 4). The product was formed
in lower yield when 3 equivalents of HFIP were used
(entry 5). Interestingly, we observed product formation in
11% yield using a PhMe/iPrOH solvent system (entry 6).
Complete recovery of starting material was observed in the
absence of HFIP (entry 7). The product was formed in low
yields by heating 1a in acetonitrile (entry 8), while heating the
substrate in NMP at 1508C resulted in decomposition of the
starting material (entry 9). TFA was an effective reagent,
generating the product in 61% yield and > 20:1 E/Z
(entry 10). However, other protic acids were inefficient in
this process (entries 11–13).
The generality of this process was evaluated (Scheme 2).
Apart from products 2u and 2w, which displayed decreased
E/Z ratios, all products were furnished with complete E-
selectivity. Initially, we examined the effect of substitutions at
the nitrogen atom (entries 2a–2h). The corresponding prod-
ucts were obtained in good to excellent yields. The acidic
nature of HFIP is responsible for the decreased yields in 2d,
resulting from PMB-group cleavage. Increased HFIP loadings
and longer reaction times were required for complete
conversion in the presence of electron-withdrawing function-
alities (2e and 2 f). The effect of various substituents on the
moiety, was formed in 84% yield and 11:1 E/Z. X-ray
crystallographic analysis of 2w[26] served to confirm the E-
1
stereochemistry of the products, while H NMR analysis was
applied for all other examples using characteristic chemical
shifts. Chlorinated methylene pyrrolidone 2x was isolated in
84% yield. In contrast to the oxindole products, the 2-
pyrrolidone scaffold was obtained with complete Z-selectivity
as determined by X-ray crystallographic analysis.[26] The
synthesis of this class of compounds has not been achieved
by previous metal-catalyzed alkyne chloroacylation
reports.[6c,7,8,11a]
We sought to determine the substrate limitations of this
reaction. Unreacted starting material was observed when
substrate 1b-TIPS was subjected to the reaction conditions.
The bulky TIPS substituent likely hinders addition of the
chloride to the alkyne moiety. Similarly, no reaction took
place with substrate 1y, containing a bromide substituent
ortho to the carbamoyl functionality which may impact its
conformation. In addition, substrate 1z, containing an acid-
sensitive alkyl carbonate on the alkyne, led to complete
decomposition of the starting material.
The chloroacylation of 1a was successfully performed on
a 2 mmol scale, forming product 2a in 90% yield and
complete E-selectivity (Scheme 3). The synthetic utility of
the chlorinated methylene oxindole products was determined
by carrying out various transformations. Nucleophilic sub-
stitution with p-anisidine resulted in generation of Z-3 in 96%
yield and complete Z-selectivity. When benzyl mercaptan was
used as a nucleophile, product E-4 was furnished in 87%
yield.[11a] Employing dimethyl malonate as the nucleophile
generated product Z-5 in 83% yield and > 20:1 Z/E ratio. The
stereoselective formation of products Z-3, E-4, and Z-5 is
likely resulting from a stereoselective addition/elimination
mechanism to form the more stable isomer. This phenomenon
has been reported by Meyer and Cossy, who observed a shift
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Scheme 3. Scale-up and derivatization studies of 2a. Values represent
isolated yields. Isomeric ratios determined by 1H NMR analysis of the
crude reaction mixture. Stereochemistry determined via 1D and 2D-
NOESY experiments.
in alkene stereochemistry when E-chlorinated methylene
oxindoles were reacted with amines.[6c] Finally, concomitant
À
reduction of both the olefin and C Cl s-bond was performed
via palladium-hydride catalysis, accessing oxindole 6 in 82%
yield. The alkene stereochemistry of all derivatization prod-
ucts was elucidated by 1D and 2D NOESY experiments.
Following stereochemical confirmation of derivatization
product Z-3, we sought to use the developed chloroacylation
methodology alongside stereoinvertive C–N coupling for the
synthesis of the medicinal agent, nintedanib (Scheme 4).[13] By
subjecting alkyne-tethered carbamoyl chloride 7 to the
reaction conditions, followed by PMB deprotection and
condensation with aniline 10, nintedanib was isolated in
21% yield (unoptimized). Developed by Boehringer Ingel-
heim, nintedanib is used in the treatment of idiopathic
pulmonary fibrosis and non-small-cell lung cancer under the
brand names Ofevꢀ and Vargatefꢀ.[14,15] Furthermore it has
demonstrated potential as a treatment of pulmonary fibrosis
associated with COVID-19 infection.[16] The developed syn-
thetic route represents a unique disconnection of the oxindole
moiety for the formation of this pharmaceutically relevant
scaffold.[13,17]
Although HFIP has been employed in various processes
such as substitutions, Friedel–Crafts alkylations and acyla-
Scheme 2. Scope for the HFIP-assisted chloroacylation of alkynes.
Reactions run on a 0.2 mmol scale. Values represent isolated yields of
2. Isomeric ratios determined by 1H NMR analysis of the crude
reaction mixture. a Reaction performed using 8 equivalents of HFIP,
PhMe (0.2 m), and heated at 1008C for 12 h. b Reaction performed
using 16 equivalents of HFIP, PhMe (0.2 m), and heated at 1008C for
24 h.
Scheme 4. Synthesis of nintedanib. Reagents and conditions: a) HFIP,
PhMe, 1008C; b) TFA, PhOMe, 808C; c) 10, DMF, 808C.
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tions, and others,[12,18] its application in haloacylation reac-
tions has not been described in the literature.[19] We per-
formed DFT calculations (see supporting information for
computational details) to obtain further insight on the
stereoselective formation of methylene oxindole product 2a
(> 20:1 E/Z) and methylene pyrrolidone 2x (> 20:1 Z/E).
Ground-state analysis reveals that the products arising from
these two substrate classes are each the thermodynamically
favoured ones (Scheme 5). Additionally, we performed iso-
merization studies by independently reacting both E- and Z-
isomers of substrate 2bu with excess potassium chloride and
HFIP.[11a] No isomerization was observed in either experi-
ment, resulting in complete recovery of the starting material
(See supporting information for additional isomerization and
halide exchange experiments). These results indicate that
methylene oxindole products are formed stereoselectively
and irreversibly under the reaction conditions.[20]
Scheme 6. Scope for the HFIP-assisted synthesis of 2-quinolinones.
Reactions run on a 0.2 mmol scale. Values represent isolated yields of
12. a Reaction performed using 8 equivalents of HFIP, PhMe (0.2 m),
and heated for 16 h. b Reaction performed using 16 equivalents of
HFIP, PhMe (0.2 m), and heated for 24 h.
applied in the synthesis of biologically active compounds
and in materials science.[23] Various methods for their
preparation have been previously described,[12,24] including
a related report from the Takemoto group, who synthesized 2-
quinolinones by heating alkene-tethered carbamoyl chlorides
in NMP with catalytic HBr at 1508C under microwave
conditions.[25] We investigated the generality of the HFIP-
promoted process, and soon discovered the need for a higher
proportion of additive to obtain complete conversions. Using
this method, 12b–12k were obtained in yields ranging from
74% to 99%.
Scheme 5. Computational and experimental mechanistic investiga-
We have developed a metal-free, high yielding, and
stereoselective synthesis of chlorinated methylene oxindoles
and pyrrolidones using HFIP. This methodology was demon-
strated in the synthesis of various derivatives including
nintedanib. The application of alkene-tethered carbamoyl
chlorides in an HFIP-assisted synthesis of 2-quinolinones was
investigated. Additional experimental investigations to gain
further mechanistic insight are currently underway in our
laboratory.
tions.
A possible pathway for the formation of 2a involves
HFIP-assisted ionization of 1a via a hydrogen bonding
interaction to form an isocyanate cation intermediate, with
concomitant release of chloride.[21,22] Addition of the latter
across the alkyne in a trans-chloroacylation stereoselectively
forms 2e as its E-isomer. Methylene pyrrolidone product 2x
can be generated with complete Z-selectivity following
formation of an isocyanate cation via two pathways: 1) cis-
chloroacylation across the alkyne, or 2) trans-chloroacylation
and subsequent isomerization. Additional studies are needed
on this latter class of substrates for a more concrete
mechanistic proposal.
We were intrigued to investigate the reactivity of carba-
moyl chlorides bearing a tethered alkene. Reaction of
substrate 11a with HFIP furnished 2-quinolinone product
12a in 98% yield through a vinylogous Friedel–Crafts
reaction (Scheme 6). The 2-quinolinone motif has been
Acknowledgements
We are grateful for financial support from the University of
Toronto (U of T), the Natural Science and Engineering
Research Council (NSERC), Alphora/Eurofins, and Kennar-
shore, Inc., for financial support. J.F.R thanks NSERC for
graduate funding (PGS-D). A.Z. thanks NSERC for USRA
funding. A.W. thanks the Walter C. Summer Memorial
Fellowship and the Province of Ontario (QEII) for funding.
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[8] a) C. M. Le, X. Hou, T. Sperger, F. Schoenebeck, M. Lautens,
Angew. Chem. Int. Ed. 2015, 54, 15897 – 15900; Angew. Chem.
2015, 127, 16127 – 16131; b) R. K. Shukla, K. Pal, C. M. R. Volla,
Chem. Asian J. 2018, 13, 2435 – 2439; c) D. He, L. Huang, J. Li,
W. Wu, H. Jiang, Org. Lett. 2019, 21, 8308 – 8311.
[9] For reviews on palladium-catalyzed C-X bond-forming reductive
elimination: a) D. A. Petrone, C. M. Le, S. G. Newman, M.
Lautens in New Trends in Cross-Coupling: Theory and Appli-
cation, Vol. 1 (Ed.: T. Colacot), RSC, Cambridge, 2015, pp. 276 –
321; b) D. A. Petrone, J. Ye, M. Lautens, Chem. Rev. 2016, 116,
8003 – 8104; c) D. J. Jones, M. Lautens, G. P. McGlacken, Nat.
Catal. 2019, 2, 843 – 851.
B.M. thanks NSERC for graduate funding (CGS-D). We
thank A. D. Marchese (U of T) for substrates 11c and 11e. We
thank I. Franzoni and J. Chen (U of T) for fruitful discussions.
Computational studies were enabled in part through support
provided by Compute Ontario (www.computeontario.ca) and
Compute Canada (www.computecanada.ca). We thank Dr.
Alan Lough (U of T) for X-ray crystallographic analysis. We
thank Dr. Darcy Burns and Dr. Jack Sheng (U of T) for their
assistance in NMR experiments.
[10] Selected examples: a) A. H. Roy, J. F. Hartwig, J. Am. Chem.
Soc. 2001, 123, 1232 – 1233; b) S. G. Newman, M. Lautens, J. Am.
Chem. Soc. 2011, 133, 1778 – 1780; c) C. M. Le, P. J. C. Menzies,
D. A. Petrone, M. Lautens, Angew. Chem. Int. Ed. 2015, 54, 254 –
257; Angew. Chem. 2015, 127, 256 – 259; d) D. A. Petrone, I.
Franzoni, J. Ye, J. F. Rodrꢄguez, A. I. Poblador-Bahamonde, M.
Lautens, J. Am. Chem. Soc. 2017, 139, 3546 – 3557; e) Y. H. Lee,
B. Morandi, Angew. Chem. Int. Ed. 2019, 58, 6444 – 6448; Angew.
Chem. 2019, 131, 6510 – 6515; f) Y.-L. Sun, X.-B. Wang, F.-N.
Sun, Q.-Q. Chen, J. Cao, Z. Xu, L.-W. Xu, Angew. Chem. Int. Ed.
2019, 58, 6747 – 6751; Angew. Chem. 2019, 131, 6819 – 6823;
g) Z.-M. Zhang, B. Xu, L. Wu, L. Zhou, D. Ji, Y. Liu, Z. Li, J.
Zhang, J. Am. Chem. Soc. 2019, 141, 8110 – 8115.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: chloroacylation · cycloisomerization · HFIP ·
methylene oxindoles · stereoselectivity
[1] a) L. Sun, N. Tran, F. Tang, H. App, P. Hirth, G. McMahon, C.
Tang, J. Med. Chem. 1998, 41, 2588 – 2603; b) S. Hauf, R. W.
Cole, S. LaTerra, C. Zimmer, G. Schnapp, R. Walter, A. Heckel,
J. van Meel, C. L. Rieder, J.-M. Peters, J. Cell Biol. 2003, 161,
281 – 294; c) F. Hilberg, G. J. Roth, M. Krssak, S. Kautschitsch,
W. Sommergruber, U. Tontsch-Grunt, P. Garin-Chesa, G. Bader,
A. Zoephel, J. Quant, A. Heckel, W. J. Rettig, Cancer Res. 2008,
68, 4774 – 4782.
[2] Selected examples: a) S. Lin, S. J. Danishefsky, Angew. Chem.
Int. Ed. 2001, 40, 1967 – 1970; Angew. Chem. 2001, 113, 2021 –
2024; b) R. Yanada, S. Obika, T. Inokuma, K. Yanada, M.
Yamashita, S. Ohta, Y. Takemoto, J. Org. Chem. 2005, 70, 6972 –
6975; c) R. Shintani, T. Yamagami, T. Hayashi, Org. Lett. 2006, 8,
4799 – 4801.
[3] Selected examples: a) A. Pinto, L. Neuville, P. Retailleau, J. Zhu,
Org. Lett. 2006, 8, 4927 – 4930; b) B. M. Trost, N. Cramer, H.
Bernsmann, J. Am. Chem. Soc. 2007, 129, 3086 – 3087; c) T.
Miura, Y. Takahashi, M. Murakami, Org. Lett. 2008, 10, 1743 –
1745; d) H.-L. Wang, Z. Li, G.-W. Wang, S.-D. Yang, Chem.
Commun. 2011, 47, 11336 – 11338; e) M. S. L. Kumar, S. K.
Manna, S. Maji, G. Panda, Org. Biomol. Chem. 2017, 15,
1762 – 1766.
[4] a) M. R. Fielding, R. Grigg, C. J. Urch, Chem. Commun. 2000,
2239 – 2240; b) P. R. Sebahar, R. M. Williams, J. Am. Chem. Soc.
2000, 122, 5666 – 5667; c) S. Kamijo, Y. Sasaki, C. Kanazawa, T.
Schꢁßeler, Y. Yamamoto, Angew. Chem. Int. Ed. 2005, 44, 7718 –
7721; Angew. Chem. 2005, 117, 7896 – 7899.
[5] a) A. Pinto, L. Neuville, J. Zhu, Angew. Chem. Int. Ed. 2007, 46,
3291 – 3295; Angew. Chem. 2007, 119, 3355 – 3359; b) T. Miura,
T. Toyoshima, Y. Takahashi, M. Murakami, Org. Lett. 2009, 11,
2141 – 2143; c) S. Ueda, T. Okada, H. Nagasawa, Chem.
Commun. 2010, 46, 2462 – 2464; d) R. Dalpozzo, G. Bartoli, G.
Bencivenni, Chem. Soc. Rev. 2012, 41, 7247 – 7290.
[6] a) E. M. Beccalli, A. Marchesini, T. Pilati, Tetrahedron 1994, 50,
12697 – 12712; b) M. S. C. Pedras, J. L. Sorensen, F. I. Okanga,
I. L. Zaharia, Bioorg. Med. Chem. Lett. 1999, 9, 3015 – 3020;
c) G. Cantagrel, B. de Carnꢂ-Carnavalet, C. Meyer, J. Cossy,
Org. Lett. 2009, 11, 4262 – 4265; d) M. Sassatelli, ꢃ. Debiton, B.
Aboab, M. Prudhomme, P. Moreau, Eur. J. Med. Chem. 2006, 41,
709 – 716; e) F.-M. Liao, Z.-Y. Cao, J.-S. Yu, J. Zhou, Angew.
Chem. Int. Ed. 2017, 56, 2459 – 2463; Angew. Chem. 2017, 129,
2499 – 2503; f) A. D. Marchese, E. M. Larin, B. Mirabi, M.
Lautens, Acc. Chem. Res. 2020, 53, 1605 – 1619.
[11] a) C. M. Le, T. Sperger, R. Fu, X. Hou, Y. H. Lim, F.
Schoenebeck, M. Lautens, J. Am. Chem. Soc. 2016, 138,
14441 – 14448; b) T. Sperger, C. M. Le, M. Lautens, F. Schoene-
beck, Chem. Sci. 2017, 8, 2914 – 2922.
[12] For selected reviews on fluorinated alcohols as solvents and
promoters in synthesis: a) J.-P. Bꢂguꢂ, D. Bonnet-Delpon, B.
Crousse, Synlett 2004, 18 – 29; b) I. A. Shuklov, N. V. Dubrovina,
A. Bçrner, Synthesis 2007, 2925 – 2943; c) T. Sugiishi, M.
Matsugi, H. Hamamoto, H. Amii, RSC Adv. 2015, 5, 17269 –
17282; d) S. Khaksar, J. Fluorine Chem. 2015, 172, 51 – 61; e) J.
Wencel-Delord, F. Colobert, Org. Chem. Front. 2016, 3, 394 –
400; f) I. Colomer, A. E. R. Chamberlain, M. B. Haughey, T. J.
Donohoe, Nat. Rev. Chem. 2017, 1, 0088; g) X.-D. An, J. Xiao,
Chem. Rec. 2020, 20, 142 – 161.
[13] a) A. Heckel, G. J. Roth, R. Walter, J. Van Meel, N. Redemann,
U. Tontsch-Grunt, W. Spevak, F. Hilberg, WO2001027081A1,
2001; b) G. J. Roth, A. Heckel, R. Walter, J. Van Meel, N.
Redemann, U. Tontsch-Grunt, W. Spevak, F. Hilberg,
US6762180B1, 2004; c) G. J. Roth, A. Heckel, F. Colbatzky, S.
Handschuh, J. Kley, T. Lehmann-Lintz, R. Lotz, U. Tontsch-
Grunt, R. Walter, F. Hilberg, J. Med. Chem. 2009, 52, 4466; d) M.
Lautens, J. F. Rodrꢄguez, J. Bajohr (University of Toronto)
Disclosure 10004072, 2021.
[14] I. A. Dimitroulis, Resp. Care 2014, 59, 1450 – 1455.
[15] C. Rolfo, L. E. Raez, G. Bronte, E. S. Santos, K. Papadimitriou,
L. Buffoni, J. P. van Meerbeeck, A. Russo, Expert Opin. Invest.
Drugs 2013, 22, 1081 – 1088.
[16] a) E. Weisberg, A. Parent, P. L. Yang, M. Sattler, Q. Liu, Q. Liu,
J. Wang, C. Meng, S. J. Buhrlage, N. Gray, J. D. Griffin, Pharm.
Res. 2020, 37, 167; b) K. Lechowicz, S. Droz˙dz˙al, F. Machaj, J.
´
Rosik, B. Szostak, M. Zegan-Baranska, J. Biernawska, W.
Dabrowski, I. Rotter, K. Kotfis, J. Clin. Med. 2020, 9, 1917.
[17] a) J. Merten, G. Linz, J. Schnaubelt, R. Schmid, W. Rall, S.
Renner, C. Reichel, R. Schiffers, WO2009071523A1, 2009; b) L.
Meca, WO2017016530A1, 2017; c) V. Arava, S. Gogireddy,
Synth. Commun. 2017, 47, 975 – 981.
[18] Selected examples: a) C. S. Jeffrey, K. L. Barnes, J. A. Eickhoff,
C. R. Carson, J. Am. Chem. Soc. 2011, 133, 7688 – 7691; b) L.
Dumitrescu, K. Azzouzi-Zriba, D. Bonnet-Delpon, B. Crousse,
Org. Lett. 2011, 13, 692 – 695; c) P. A. Champagne, Y. Benhas-
sine, J. Desroches, J.-F. Paquin, Angew. Chem. Int. Ed. 2014, 53,
13835 – 13839; Angew. Chem. 2014, 126, 14055 – 14059; d) R.-J.
[7] S. Tang, Q.-F. Yu, P. Peng, J.-H. Li, P. Zhong, R.-Y. Tang, Org.
Lett. 2007, 9, 3413 – 3416.
18482 www.angewandte.org
ꢁ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 18478 –18483

Angewandte
Communications
Chemie
Tang, T. Milcent, B. Crousse, RSC Adv. 2018, 8, 10314 – 10317;
[23] a) P. R. Angibaud, M. G. Venet, W. Filliers, R. Broeckx, Y. A.
e) Y. Zhu, I. Colomer, T. J. Donohoe, J. Am. Chem. Soc. 2019,
141, 6489 – 6493; f) C. Qi, G. Force, V. Gandon, D. Leboeuf,
Angew. Chem. Int. Ed. 2021, 60, 946 – 953; Angew. Chem. 2021,
133, 959 – 966.
Ligny, P. Muller, V. S. Poncelet, D. W. End, Eur. J. Org. Chem.
2004, 479 – 486; b) P. Cheng, Q. Zhang, Y.-B. Ma, Z.-Y. Jiang, X.-
M. Zhang, F.-X. Zhang, J.-J. Chen, Bioorg. Med. Chem. Lett.
2008, 18, 3787 – 3789; c) S. Helmstetter, T. Badur, N. Hampp, J.
Polym. Res. 2016, 23, 249.
[19] Selected examples of chloroacylation of p-bonds: a) M. Suda,
Tetrahedron Lett. 1980, 21, 2555 – 2556; b) Y. Li, H. Matsumura,
M. Yamanaka, T. Takahashi, Tetrahedron 2004, 60, 1393 – 1400;
c) R. Hua, S.-Y. Onozawa, M. Tanaka, Chem. Eur. J. 2005, 11,
3621 – 3630; d) R. Cano, M. Yus, D. J. Ramꢅn, Tetrahedron 2013,
69, 7056 – 7065; e) C. Chen, J.-C. Kang, C. Mao, J.-W. Dong, Y.-Y.
Xie, T.-M. Ding, Y.-Q. Tu, Z.-M. Chen, S.-Y. Zhang, Green
Chem. 2019, 21, 4014 – 4019; f) Z. Lei, A. Banerjee, E. Kusevska,
E. Rizzo, P. Liu, M.-Y. Ngai, Angew. Chem. Int. Ed. 2019, 58,
7318 – 7323; Angew. Chem. 2019, 131, 7396 – 7401; g) Q.-S. Zhao,
G.-Q. Xu, H. Liang, Z.-Y. Wang, P.-F. Xu, Org. Lett. 2019, 21,
8615 – 8619; h) D. V. Patil, H. Y. Kim, K. Oh, Org. Lett. 2020, 22,
3018 – 3022.
[20] Isomerization experiments using substrates 2v and 2w indicate
some isomerization can occur under the reaction conditions. This
result likely arises due to the presence of electron-donating or
electron-withdrawing substituents in the aryl moiety, and thus it
is substrate dependent (see supporting information).
[21] a) H. K. Hall, C. H. Lueck, J. Org. Chem. 1963, 28, 2818 – 2825;
b) C. Jouitteau, P. L. Perchec, A. Forestiꢆre, B. Silicon, Tetrahe-
dron Lett. 1980, 21, 1719 – 1722; c) E. K. Raja, S. O. Nilsson Lill,
D. A. Klumpp, Chem. Commun. 2012, 48, 8141 – 8143; d) A.
Sumita, H. Kurouchi, Y. Otani, T. Ohwada, Chem. Asian J. 2014,
9, 2995 – 3004.
[24] Selected examples: a) J. Ferguson, F. Zeng, N. Alwis, H. Alper,
Org. Lett. 2013, 15, 1998 – 2001; b) D. Liang, Z. Hu, J. Peng, J.
Huang, Q. Zhu, Chem. Commun. 2013, 49, 173 – 175; c) V.
Rajeshkumar, T.-H. Lee, S.-C. Chuang, Org. Lett. 2013, 15,
1468 – 1471; d) Z. Zhang, L.-L. Liao, S.-S. Yan, L. Wang, Y.-Q.
He, J.-H. Ye, J. Li, Y.-G. Zhi, D.-G. Yu, Angew. Chem. Int. Ed.
2016, 55, 7068 – 7072; Angew. Chem. 2016, 128, 7184 – 7188;
e) A. K. Kabi, R. Gujjarappa, N. Vodnala, D. Kaldhi, T. Ujjawal,
K. Mukherjee, C. C. Malakar, Tetrahedron Lett. 2020, 61, 152535.
[25] Y. Yasui, I. Kakinokihara, H. Takeda, Y. Takemoto, Synthesis
2009, 3989 – 3993.
[26] Deposition Numbers 2062479 (for 2x) and 2062480 (for 2w)
contains the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum
Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
Manuscript received: March 7, 2021
[22] a) H. F. Motiwala, R. H. Vekariya, J. Aubꢂ, Org. Lett. 2015, 17,
5484 – 5487; b) R. H. Vekariya, J. Aubꢂ, Org. Lett. 2016, 18,
3534 – 3537.
Revised manuscript received: May 24, 2021
Accepted manuscript online: June 22, 2021
Version of record online: July 16, 2021
Angew. Chem. Int. Ed. 2021, 60, 18478 –18483
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