Synthesis and Reactions of 3,3-Difluoro-2- exo-methylidene Indolines

Article abstract of DOI:10.1021/acs.orglett.0c01175

A dearomative electrophilic fluorination of 2-methylindoles is reported, delivering 3,3-difluoroindolines bearing an exomethylidene. The model substrate was synthesized on up to a 20 mmol scale and was purified by a practical recrystallization as a crystalline bench-stable, yet reactive solid. The olefin is amphoteric and can react both as a nucleophile and as an electrophile. A wide range of metal-free, palladium, rhodium, and copper reactions was explored, forming new C-H, C-B, C-C (alkyl and aryl), C-N, C-O, C-P, and C-S bonds.

Full text of DOI:10.1021/acs.orglett.0c01175

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Letter
Synthesis and Reactions of 3,3-Difluoro-2-exo-methylidene
Indolines
Nicolas Zeidan, Matthew Zambri, Sven Unger, Christian Dank, Alexa Torelli, Bijan Mirabi,
and Mark Lautens*
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sı Supporting Information
ABSTRACT: A dearomative electrophilic fluorination of 2-methyl-
indoles is reported, delivering 3,3-difluoroindolines bearing an
exomethylidene. The model substrate was synthesized on up to a
2
0 mmol scale and was purified by a practical recrystallization as a
crystalline bench-stable, yet reactive solid. The olefin is amphoteric
and can react both as a nucleophile and as an electrophile. A wide
range of metal-free, palladium, rhodium, and copper reactions was
explored, forming new C−H, C−B, C−C (alkyl and aryl), C−N, C−
O, C−P, and C−S bonds.
luorine-containing molecules continue to account for a
disproportionate number of pharmaceuticals and agro-
chemicals due to an increase in solubility, lipophilicity, and
Scheme 1. Use of NFSI for Electrophilic Fluorination of
Indoles and Allylic Fluoride Substitutions
F
biological stability against oxidation as compared to the C−H
1
counterparts. Additionally, the benefits of fluorine incorpo-
ration are extended to other stages of API development. For
example, the nuclei can be used to track compounds in vitro or
2
18
in vivo by NMR or MRI, respectively. Finally, F is the most
commonly used radioisotope in positron emitting tomography
due to its convenient half-life (110 min) and its low positron
3
energy (635 keV).
Diverse strategies have been employed for fluorine
incorporation, including the use of catalysts, nucleophilic
4
reagents, electrophilic reagents, and radical additions. One of
the most commonly used electrophilic sources of fluorine is N-
fluorobenzenesulfonimide (NFSI) due to its shelf-stability,
controlled reactivity, modest cost, ability to vary its electronic
18
5
properties, and the availability of a F variant. NFSI has been
shown to be a versatile reagent capable of fluorine or
sulfonamide transfer to heterocycles, typically by modifying
6
the solvent (Scheme 1a). The incorporation of fluorine
proved to be a useful method to rapidly access functionalized
6
e,7
isatin analogues.
1
c). Herein, we report a scalable synthesis of these scaffolds
Functionalization of allylic and propargylic fluorides has
and their modular functionalization. They behave as
nucleophiles, electrophiles, and as substrates for metal-
catalyzed transformations of the allyl fluoride moiety, allowing
been studied with various nucleophiles, metal catalysts, and
8
organocatalysts. Reactions catalyzed by palladium and
platinum have been investigated in detail, and in some cases,
the reactivity is found to be superior compared to many
8i,j
Received: April 1, 2020
commonly used oxygen-based leaving groups. Recently, the
Trost group developed an asymmetric palladium-catalyzed
trifluoromethylation of allylic fluorides using chiral Trost
9
ligands (Scheme 1b). In our attempts at a dearomative
fluorination of 2-alkylindoles with NFSI, we isolated 3,3-gem-
difluoroindoline bearing an exocyclic double bond (Scheme
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c01175
A
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access of highly substituted indoles and indolines. We were
able to successfully form new C−C (aryl/alkyl), C−H, C−N,
C−B, C−O, C−P, and C−S bonds.
An optimization of solvent, temperature, and concentration
found that the reaction improved in polar solvents such as
THF as well as with increased concentration and milder
temperatures (see Supporting Information, section 3.1).
indole; MeO- functionalized indole (2e) provided the product
in slightly diminished yield, and F-containing indole (2f) was
accessed in good yield. Dimethoxy containing indoline 2g was
isolated in low yield; however, an interesting restrictive
rotation around the C−N bond was elucidated by NMR,
suggesting meta-functionalized benzoyl groups are too steri-
cally bulky for the reaction. Azaindole derivative produced 2h
in modest yield, which proved to be unstable and decomposed
during storage. A carbonyl moiety on the nitrogen was
necessary as only acetyl (2i) and Boc (2j) protected indoles
gave the desired product ( H NMR and F NMR),
accompanied by inseparable byproducts. Benzyl (2k) and
tosyl (2l) protected indoles decomposed upon reaction with
NFSI. Extending the carbon chain at the 2-position led to no
desired product.
With an efficient medium-scale synthesis of indoline 2a in
hand, we sought to evaluate the reactivity of these interesting
exomethylidene-containing fluorinated scaffolds. First, we
aimed to study the electronic properties of the olefin as it
appears there is potential for amphoteric reactivity as there are
σ-bond withdrawing fluorine atoms as well as weak π-donation
from the nitrogen atom (Scheme 4).
Additionally, NH Cl (1 equiv) was found to benefit the
4
reaction, presumably by either activating NFSI or quenching
byproducts of the reaction. The fluorination of 2-methylindole
1
19
(
1a, 0.2−20 mmol) with NFSI (2.2 equiv) delivered
exomethylidene containing indoline 2a as a crystalline, bench
10
stable product (Scheme 2). The reaction could be scaled to
0 mmol and purified without the need for column
2
chromatography, as the product could be crystallized from
pentanes.
Scheme 2. Dearomative Fluorination of 2-Methylindole on
Various Scales
Scheme 4. Nucleophilic and Electrophilic Reactivity of
Product 2a
a
b
Using column chromatography purification. Using one round of
recrystallization
Next, we investigated the impact of the protecting group on
nitrogen as well as a few substituents on the indole backbone
(
Scheme 3).
The substrate bearing an electron-rich benzoyl group
delivered product 2b in comparable yield. However,
electron-withdrawing groups had a negative effect on yield,
with the strong π-withdrawing nitro group having the greatest
impact (2c and 2d). The opposite trend was found when
introducing electronic perturbations at the 5-position of the
We found that the olefin could participate in an S 2′
N
11
reaction with morpholine acting as the nucleophile. The
reaction required DMA as no product was isolated in toluene,
in contrast to the outcome using palladium (vide infra). Rapid
and quantitative epoxidation with DMDO was also achieved
with preservation of the fluorine moiety.
Scheme 3. Nitrogen-Protecting Group and Electronic
Perturbation Screening
a
We aimed to further elucidate the electrophilic nature of
these indolines as potential substrates in palladium-allylation
8k,12
chemistry with various nucleophiles (Scheme 5).
Phenylsilane, a mild hydride source, delivered 3-fluoroindole
13
5
in quantitative yield. When reactions were run with 1.5
equiv of morpholine at 60 °C, we obtained a 4:1 mixture
14
favoring 3 over 6. However, using a larger excess of
morpholine (5 equiv) and running the reaction at 100 °C
led to an 80% yield of 6. In a similar manner, sulfonylation of
2
a led to the product of double addition (7), which upon
treatment with LiOH led to cleavage of the labile benzoyl
moiety. A clean phosphorylation reaction was observed using
15
dialkylphosphite as a nucleophile, producing product 8 in good
16
yield. Finally, using sodium dimethylmalonate, according to
the literature procedure, the difunctionalized product 9 was
8j,17
isolated in excellent yield.
We sought to investigate the order of events in the double
addition reaction and in particular the site of the first
amination under palladium catalysis (Scheme 6).
With this goal in mind, we subjected 3 to the higher
temperature reaction conditions (see Scheme 5) and observed
no reaction, which implies that 3 is not the species that leads to
a
b
Reactions run on a 0.2 mmol scale. Reaction run on a 1 mmol scale.
c
Separation difficult, NMR yield using trifluorotoluene as an internal
standard.
B
https://dx.doi.org/10.1021/acs.orglett.0c01175
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a
Scheme 5. Palladium-Catalyzed Allylic Functionalizations
Scheme 7. Cu and Rh Addition/β-Fluoride Elimination
catalyzed borylation/β-fluoride elimination provided product
1
3, which possesses two handles for future transformations.
In conclusion, we developed an efficient and scalable
protocol for the synthesis of a gem-difluoroindoline bearing
an exocyclic and allylic olefin without the need for column
chromatography. These scaffolds are versatile building blocks
capable of acting in an amphoteric sense as well as with various
Pd/Cu/Rh reactions forming new C−H, C−B, C−C, C−N,
C−O, C−P, and C−S bonds.
a
Unless otherwise stated, reactions were run on a 0.1 mmol scale
using [(C H )PdCl] (2.5−5 mol %) and xantphos (5−10 mol %).
Reaction conditions: (a) XPhos (5 mol %) instead of xantphos,
PhSiH (2 equiv), Et N (1 equiv), EtOH, 50 °C, 6 h. (b) Morpholine
3
5
2
3
3
(
5 equiv), PhMe, 100 °C, 6 h. (c) Sodium phenylsulfinate (5 equiv),
ASSOCIATED CONTENT
sı Supporting Information
■
PhMe, 100 °C, 18 h, then LiOH (2 M), 2 h. (d) HP(O)(OEt) (2
2
*
equiv), CsF (1 equiv), PhMe, 70 °C, 18 h. (e) Sodium
dimethylmalonate (5 equiv), 15-crown-5 (5 equiv), DCM, r.t., 2 h.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01175.
Scheme 6. Investigation of the Mechanism for the Double
Addition Reaction of Morpholine
Experimental procedures, optimization, mechanistic
studies, characterization data, X-ray data, and
1
13
19 31
H/ C/ F/ P NMR spectra (PDF)
Accession Codes
CCDC 1956222 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Mark Lautens − Davenport Research Laboratories, Department
of Chemistry, University of Toronto, Toronto, Ontario M5S
3H6, Canada; orcid.org/0000-0002-0179-2914;
Email: mark.lautens@utoronto.ca
6
. Instead it appears that reaction occurs via the π-allyl
intermediate to give 10 which undergoes an amine-assisted
ionization and amination or a second palladium-mediated
ionization and amination. All attempts to observe 10 have
met with failure, so for the moment, this is a proposal that
requires confirmation.
We also explored the viability of metal-catalyzed addition to
the olefin through a sterically congested metal complex 11
14
Authors
Nicolas Zeidan − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada; orcid.org/0000-0002-7959-
5005
18
which could undergo a β-fluoride elimination (Scheme 7).
The rhodium-catalyzed arylation/β-fluoride elimination of
a provided monoarylated product 12 in good yield and
maintained a fluoride within the product. Similarly, the copper-
Matthew Zambri − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada
2
C
https://dx.doi.org/10.1021/acs.orglett.0c01175
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Letter
Sven Unger − Davenport Research Laboratories, Department of
Chemistry, University of Toronto, Toronto, Ontario M5S 3H6,
Canada
Christian Dank − Davenport Research Laboratories,
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada
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Alexa Torelli − Davenport Research Laboratories, Department
of Chemistry, University of Toronto, Toronto, Ontario M5S
3
H6, Canada
Bijan Mirabi − Davenport Research Laboratories, Department of
Chemistry, University of Toronto, Toronto, Ontario M5S 3H6,
Canada
(
10) CCDC deposition number 1956222.
(11) Bergeron, M.; Guyader, D.; Paquin, J. F. Org. Lett. 2012, 14,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01175
5
(
888.
12) Trost, B. M. Tetrahedron 1977, 33, 2615.
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The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
(
We thank the Natural Science and Engineering Research
Council (NSERC), the University of Toronto (UofT),
Alphora Inc, and Kennarshore Inc. for financial support.
N.Z., A.T., and B.M. thank the province of Ontario for a
graduate scholarship (OGS). C.D. was supported by an Erwin
1981, 1981, 56. (b) Hong, Y.; Liu, W.; Dong, M.; Chen, X.; Xu, T.;
Tian, P.; Tong, X. Org. Lett. 2019, 21, 5742.
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17) Drouin, M.; Tremblay, S.; Paquin, J. F. Org. Biomol. Chem.
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016, 138, 12340. (c) Gao, P.; Yuan, C.; Zhao, Y.; Shi, Z. Chem.
2018, 4, 2201.
2
(
Schrodinger postdoctoral fellowship (J 4348-N28) awarded by
̈
the Austrian Science Fund (FWF). Thanks to Dr. Darcy Burns
and the NMR team at UofT, as well as Dr. Alan Lough for
single-crystal X-ray results.
2
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