Nitroxyl Catalysts for Six-Membered Ring Bromolactonization and Intermolecular Bromoesterification of Alkenes with Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.0c03546

We developed a nitroxyl-catalyzed bromoesterification of alkenes with bromo reagents, which includes a six-membered ring bromolactonization of alkenyl carboxylic acids catalyzed by AZADO as the nitroxyl radical catalyst, and an intermolecular bromoesterification of alkenes with carboxylic acids using NMO as the N-oxide catalyst. We also accomplished a remote diastereoselective bromohydroxylation via an AZADO-catalyzed six-membered ring bromolactonization and a subsequent ring cleavage reaction with alkylamines to furnish ?-bromo-δ-hydroxy amides with high diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.0c03546

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Letter
Nitroxyl Catalysts for Six-Membered Ring Bromolactonization and
Intermolecular Bromoesterification of Alkenes with Carboxylic Acids
Katsuhiko Moriyama,* Masako Kuramochi, Seiji Tsuzuki, Kozo Fujii, and Takeshi Morita
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ABSTRACT: We developed a nitroxyl-catalyzed bromoesterification of alkenes with bromo reagents, which includes a six-
membered ring bromolactonization of alkenyl carboxylic acids catalyzed by AZADO as the nitroxyl radical catalyst, and an
intermolecular bromoesterification of alkenes with carboxylic acids using NMO as the N-oxide catalyst. We also accomplished a
remote diastereoselective bromohydroxylation via an AZADO-catalyzed six-membered ring bromolactonization and a subsequent
ring cleavage reaction with alkylamines to furnish ε-bromo-δ-hydroxy amides with high diastereoselectivity.
and a a halogen reagent is often used for its generation (Anelli
method).10 N-Oxide catalysts also play a key role as a Lewis base
functional group, such as a ligand in a metal complex catalyst11
or for the activation of silylated nucleophiles.12 In addition, it
was confirmed by single-crystal X-ray analysis and physico-
chemical characterization that N-oxides undergo halogen
bonding interaction with halogen atoms on halogen com-
pounds.13 In this context, we envisaged that these nitroxyl
catalysts bearing a N−O single bond induce the high
electrophilicity of halogen atoms on halogen reagents in a
redox system of the nitroxyl radical, which functions as a Lewis
acid catalyst via formation of an oxoammonium salt, or the
presence of an oxide, which is predisposed to interact with a
bromine atom as the Lewis base,14 on the zwitterion in N-oxide
to promote the electrophilic addition of weak electron-donor
alkenes (Scheme 1c). Herein, we report a haloesterification
using nitroxyl catalysts, that is, a nitroxyl radical-catalyzed six-
membered ring bromolactonization of alkenyl carboxylic acids
and an N-oxide-catalyzed intermolecular bromoesterification of
he design of organocatalysts for the halo-functionalization
Tof alkenes is imperative for the construction of versatile
halogenated compounds in organic synthesis. However, it is
difficult to control the halogenation chemoselectively because
the halonium ion intermediate generated by the electrophilic
addition of olefin on alkenes and halogen reagents is highly
reactive and induces some side reactions.1 Recently, some
catalytic halo-functionalizations have been achieved by design-
ing elaborately organocatalysts.2−8 Among them, Lewis base
catalysts containing heteroatoms having an electron-donating
nature, such as nitrogen,3 oxygen,4 sulfur,5 selenium,6 and
phosphorus,7 are efficient at inducing the desired halo-
functionalization (Scheme 1a). These Lewis base catalysts
activate the halogen atom on the halogen reagent via
noncovalent interaction to promote a chemoselective reaction.
In particular, Lewis base−acid cooperative catalysts have been
designed as a bifunctional organocatalyst to activate both the
halogen atom and the counteranion on the halogen reagent for
bromocyclizations (Scheme 1b).8 On the other hand, nitroxyl
catalysts, including a nitroxyl radical catalyst bearing an unpaired
electron and N-oxide catalyst bearing a zwitterion, have often
been cited for their unique performance as an organocatalyst for
fine catalytic transformations. Such nitroxyl radicals as 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO) and 2-azaadamantane
N-oxyl (AZADO) have been widely used as redox organo-
catalysts for the oxidation of alcohols.9 The active species is an
oxoammonium salt generated by the oxidation with an oxidant,
Received: October 24, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03546
© XXXX American Chemical Society
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radical catalysts were much less effective than AZADO (entries
5−8).
To explore the substrate scope for the six-membered ring
bromolactonization, δ-alkenyl carboxylic acids (1) were
examined under the optimum conditions (Scheme 2). In
Scheme 1. Organocatalyst for Bromo-functionalization
Scheme 2. AZADO-Catalyzed Six-Membered Ring
Bromolactonization of 1
alkenes with carboxylic acids, both of which are novel catalytic
systems in halo-functionalization chemistry.
First, we attempted to perform the nitroxyl-radical-catalyzed
six-membered ring bromolactonization of alkenyl carboxylic
acids (1) and screened for the optimum catalysts and solvents in
the reaction of 1a and NBS as the bromo reagent (Table 1). The
a
Number in brackets indicates yield of 4-bromo-tetrahydropyrano-
[2,3-b]indol-2(3H)-one derivative.
Table 1. Screening for Catalysts and Solvents for the Six-
Membered Ring Bromolactonization of 1a
particular, heteroatom-containing δ-lactones are very important
frameworks as biologically active compounds and functional
organic compounds.15 The reactions of α-substituted hexenoic
acids (1b and 1c) and hexenoic acids bearing disubstituted
alkenes (1d and 1e) proceeded smoothly, and corresponding
bromo-lactones (2b−2e) were obtained in high yields (91−
>99%). α-Alkenyloxy carboxylic acids (1f and 1g) and α-amino
carboxylic acids (1h−1p) derived from α-amino acids also
provided corresponding products (2f−2p) in high yields with
good diastereoselectivity, respectively.
In addition, the remote bromohydroxylation of 1 was carried
out via an AZADO-catalyzed bromolactonization, followed by a
ring cleavage reaction with alkylamines to obtain ε-bromo-δ-
hydroxy amides (3) (Scheme 3). When benzylamine and p-
methoxybenzylamine (PMBNH2) were used as the nucleophile
for the remote bromohydroxylation of 1a, corresponding
products (3a and 3b) were generated in good yields. Use of
α-amino alkenyl acids (1h and 1j) and various amines, including
allylamine and n-propylamine, also furnished corresponding
products (3c−3g) in good yields, respectively. This strategy
offers the advantage of controlling the diastereoselectivity of the
hydroxyl group and the α-substituted groups at remote
positions. The diastereomeric transformation of α-substituted
alkenyl acids yielded products (3h, 3i, and 3l−3o) with excellent
diastereoselectivity (dr = 93:7−>99:<1). The relative config-
uration of 3h was identified to be anti-isomer by single-crystal X-
Entry
Catalyst (mol %)
Solvent
Yield (%)
a
1
2
3
4
5
6
7
8
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
NHPI (20)
Nor-AZADO (20)
AZADO (20)
AZADO (5)
CH2Cl2
AcOEt
THF
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
86 (2)
a
68 (13)
a
43 (47)
a
28 (0)
17
85
97
b
98 (95)
a
Numbers in parentheses indicate the yield of 2a without catalyst.
Number in parentheses indicates the yield of 2a in 1 mmol scale.
b
use of the TEMPO catalyst in CH2Cl2 in the bromolactonization
furnished the desired product in 86% yield, whereas the reaction
hardly proceeded in the absence of the catalyst (entry 1). Other
solvents used in the catalytic reaction did not improve the yield
of 2a; nevertheless, catalytic activity was noted in most cases
(entries 2−4). Decreasing the amount of the AZADO catalyst to
5 mol % improved the yield of 2a to 98%, and other nitroxyl
B
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ylphthalimide, and pyridinium N-oxide as the oxygen Lewis base
catalyst increased the reactivity of the bromoesterification (48−
56%). When N-methylmorpholine N-oxide (NMO) (10 mol %)
was used in the presence of Na2SO4 as desiccant, bromoester-
ification product (6a) was obtained in 99% yield. We suggest
that the oxygen atom on the NMO catalyst accelerated the
bromoesterification, not the amine-base catalyst3 or the
hydrogen-bond donor catalyst,16 because N-methylmorpholine
and N,N-dimethylmorpholinium tosylate catalysts have lower
reactivity than the NMO catalyst.
Scheme 3. Remote Bromohydroxylation via Six-Membered
Ring Bromolactonization of 1
Then, we investigated the catalytic intermolecular bromoes-
terification of various alkenes (4) with carboxylic acids (5) and
NBP using an N-oxide catalyst (Scheme 5).
Scheme 5. N-Oxide-Catalyzed Intermolecular
Bromoesterification of Alkenes (4)
a
b
The second reaction was carried out in MeCN (0.5 M). The first
reaction was carried out for 5 h.
ray structure analysis. Unfortunately, the diastereoselectivity of
lactic acid derivatives (3j and 3k) was unsatisfactory (dr =
65:35−68:32).
We focused on the intermolecular bromoesterification of
alkenes, which is a challenging chemoselective transformation
because it has higher entropy than the halolactonization and
uses weakly nucleophilic carboxylic acids (Scheme 4). To clarify
the optimum reaction conditions, the reaction of cyclohexene
(4a) and benzoic acid (5a) with N-bromophthalimide (NBP) in
the presence of nitroxyl catalyst was carried out. Whereas the
reaction almost did not proceed in the absence of a catalyst, a
nitroxyl radical catalyst (TEMPO and AZADO), N-hydrox-
a
Abbreviation of diastereo- and regioselectivity indicates perfect
b
chemoselectivity (>99:<1). NMO (20 mol %) was used in the
absence of Na2SO4. Carboxylic acid (5) (1.5 equiv) and NBP (2.0
equiv) were used with NMO (20 mol %).
c
Scheme 4. Screening for Organocatalyst for Intermolecular
Bromoesterification of 4a
With regard to the reaction of cyclohexene (4a), the use of
substituted benzoic acids containing electron-donating and
electron-withdrawing groups, and aliphatic acetic acid contain-
ing a quaternary carbon at the α-position and a chiral carbon
center ((+)-ketopinic acid) gave the corresponding bromoesters
(6b−6n) in high yields (77−96%), respectively. Other
symmetric alkenes were also valuable as an esterification partner
(6o−6q; 90−>99% yield). The bromoesterification of terminal
alkenes gave corresponding products (6r−6t) in good yields
(58−>99% yield) but with unsatisfactory regioselectivity (rr =
55:45−81:19). The reaction using dihydropyran proceeded
smoothly to obtain 3-bromo-2-acetoxyfuran (6u) with high
regio- and diastereoselectivity.
To clarify the role of the nitroxyl radical catalyst in the
activation of bromo reagents in these bromoesterifications, we
determined the respective variation of nitroxyl catalysts and
bromo reagents by Raman spectroscopic analysis17 (Figures S2
and S3, Supporting Information). When NBS and AZADO were
mixed in CH2Cl2 at room temperature, peaks assignable to 2-
a
b
NBS was used instead of NBP. Na2SO4 (2.0 equiv) was added.
C
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oxo-2-azoniatricyclo[3,3,1,13,7]decane bromide (oxoammo-
nium bromide) were observed (spectrum d vs spectrum e,
Figures S2 and S3). In addition, the 2-oxo-2-azoniatricyclo-
[3,3,1,13,7]decane salt (X = Br, BF4) catalyzed bromolactoniza-
tion of 1a with NBS provided desired product 2a in high yields
(97% and 99% yield), respectively (Scheme 6, eq 1). Use of a
and NBP were mixed in corresponding solvent. These results
indicate that the NMO−NBP complex (B) is formed from
NMO and NBP.
From DFT calculations for the NMO−NBP complex (B)
(ΔE = −12.3 kcal/mol), we found that the N−Br bond in the
NMO−NBP complex (1.96 Å) is longer than that in NBP (1.86
Å). The bond length between the oxygen atom on the N-oxide
moiety and the bromine atom (2.34 Å) is significantly smaller
than the sum of the corresponding van der Waals radii (Figure
2). The positive charge on the bromine atom in the NMO−NBP
Scheme 6. Mechanistic Study of AZADO-Catalyzed Six-
Membered Ring Bromolactonization
stoichiometric amount of 2-oxo-2-azoniatricyclo[3,3,1,13,7]-
decane bromide in the reaction of 1a did not furnish 2a, and
some nitroxyl adducts were obtained (Scheme 6, eq 2).
Figure 2. Plausible intermediate from NMO and NBP. ΔE is energy
change associated with NMO−NBP complex (B) formation.
To explain the activation of the oxoammonium-catalyzed
bromolactonization, DFT calculations were carried out using
the Gaussian 09 program. The B3LYP functional18 and 6-
311+G(d,p) basis set were used for all calculations including
geometry optimizations and vibrational analysis with solvent
effects in CH2Cl2 considered using the polarizable continuum
model.19 The atomic charges were calculated using Mulliken
population analysis. The calculated atomic charges show that the
positive charge on the bromine atom of the oxoammonium−
NBS complex (A) (+0.181) is larger than that of isolated NBS
(+0.170) (Figure 1). These results suggest that the oxoammo-
complex (B) (+0.199) is larger than that in isolated NBP
(+0.184). From these results, we suggest that the halogen
bonding interaction13,14 between axial N-oxide in NMO and the
bromine atom in NBP increases the electrophilicity of the
bromine atom in NBP by cleaving off the bromine atom from the
phthalimide moiety to promote the bromoesterification of
alkenes.
Furthermore, we demonstrated the six-membered ring
bromo-lactonization of 1a with the NMO catalyst under the
optimum conditions and obtained the corresponding δ-lactone
(2a) in quantitative yield (Scheme 7).
Scheme 7. Six-Membered Ring Bromolactonization of 1a
Using NMO Catalyst
Figure 1. Plausible intermediate from AZADO and NBS. ΔE is energy
change associated with oxoammonium−NBS complex (A) formation.
In conclusion, we have developed a nitroxyl-catalyzed
bromoesterification of alkenes with bromo reagents, which
includes a six-membered ring bromolactonization of alkenyl
carboxylic acids catalyzed by AZADO as the nitroxyl radical
catalyst, and an intermolecular bromoesterification of alkenes
with carboxylic acids using the NMO catalyst as the N-oxide
catalyst, furnishing products in high yields. We also accom-
plished a remote diastereoselective bromohydroxylation via an
AZADO-catalyzed six-membered ring bromolactonization and a
subsequent ring cleavage reaction with alkylamines to furnish ε-
bromo-δ-hydroxy amides with high diastereoselectivity. We
believe that nitroxyl catalysts could be used in various
transformations through the activation of halogen compounds.
The development of novel nitroxyl-catalyzed reactions is
underway in our laboratory.
nium bromide catalyst obtained by the oxidation of the nitroxyl
radical activates NBS as a Lewis acid catalyst through the
formation of the oxoammonium−NBS complex (A) and not
reaction by formation of Br2 to promote the six-membered
bromolactonization. This reaction is the first example of an
oxoammonium-catalyzed transformation.
1
We also conducted H NMR studies and Raman spectro-
scopic analysis of NMO with NBP to gather evidence of the
generation of an active species for the intermolecular bromo
esterification (Supporting Information). Noticeably low mag-
netic field chemical shifts of the NMO group signals for the 1H
NMR measurement (Figure S5−S7) and an expression of three
characteristic peaks (228 cm−1, 788 cm−1, and 1764 cm−1) in the
Raman spectra (Figure S8−S19) were observed when NMO
D
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Halogenation and Dehalogenation Reactions: Pervasive and Mecha-
ASSOCIATED CONTENT
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Additional information, experimental procedures, char-
1
acterization of new compounds, and H NMR and 13C
NMR spectra of all new compounds (PDF)
Accession Codes
CCDC 2023320 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, or by emailing data_
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AUTHOR INFORMATION
Corresponding Author
■
Katsuhiko Moriyama − Department of Chemistry, Graduate
School of Science and Soft Molecular Activation Research
Center, Chiba University, Chiba 263-8522, Japan;
orcid.org/0000-0001-8443-3599; Email: moriyama@
faculty.chiba-u.jp
Authors
Masako Kuramochi − Department of Chemistry, Graduate
School of Science and Soft Molecular Activation Research
Center, Chiba University, Chiba 263-8522, Japan
Seiji Tsuzuki − Research Initiative of Computational Sciences
(RICS), Nanosystem Research Institute (NRI), National
Institute of Advanced Industrial Science and Technology
(AIST), Ibaraki 305-8568, Japan
Kozo Fujii − Department of Chemistry, Graduate School of
Science and Soft Molecular Activation Research Center, Chiba
University, Chiba 263-8522, Japan
Takeshi Morita − Department of Chemistry, Graduate School
of Science and Soft Molecular Activation Research Center,
Chiba University, Chiba 263-8522, Japan; orcid.org/
0000-0002-9721-1298
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support in the form of a Grant-in-Aid for Scientific
Research (No. G19K05469) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan (K.M.) and
from the Sumitomo Foundation (K.M.) is gratefully acknowl-
edged.
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