Synthesis, Characterization, and Reactivity of a Hypervalent-Iodine-Based Nitrooxylating Reagent

Article abstract of DOI:10.1002/anie.202005720

Herein, the synthesis and characterization of a hypervalent-iodine-based reagent that enables a direct and selective nitrooxylation of enolizable C?H bonds to access a broad array of organic nitrate esters is reported. This compound is bench stable, easy-

Full text of DOI:10.1002/anie.202005720

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Accepted Article
Title: Synthesis, Characterization and Diverse Reactivity of a
Hypervalent Iodine-Based Nitrooxylating Reagent
Authors: Roxan Calvo, Antoine Le Tellier, Thomas Nauser, David
Rombach, Darryl Nater, and Dmitry Katayev
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10.1002/anie.202005720
Angewandte Chemie International Edition
RESEARCH ARTICLE
Synthesis, Characterization and Diverse Reactivity of a
Hypervalent Iodine-Based Nitrooxylating Reagent
Roxan Calvo,[a] Antoine Le Tellier,[b] Thomas Nauser, [a] David Rombach, [a] Darryl Nater, [a] Dmitry
Katayev*[a]
Dedicated to Professor Antonio Togni on the occasion of his 65th birthday.
[a]
[b]
R. Calvo, Dr. T. Nauser, Dr. D. Rombach, D. Nater, Dr. D. Katayev
Department of Chemistry and Applied Biosciences
Swiss Federal Institute of Technology ETH Zürich
Vladimir-Prelog-Weg 2, 8093 Zürich (Switzerland)
E-mail: katayev@inorg.chem.ethz.ch
A. Le Tellier
Department of Organic Chemistry
University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, the synthesis and characterization of a
hypervalent iodine-based reagent that enables a direct and
selective nitrooxylation of enolizable C-H bonds to access a broad
array of organic nitrate esters is reported. This compound is
bench stable, easy-to-handle, and delivers the nitrooxy (-ONO2)
group under mild reaction conditions. Activation of the reagent by
Brønsted and Lewis acids was demonstrated in the synthesis of
nitrooxylated β-keto esters, 1,3-diketones and malonates, while
its activity under photoredox catalysis was shown in the synthesis
of nitrooxylated oxindoles. Detailed mechanistic studies including
pulse radiolysis, Stern-Volmer quenching studies, and UV-Vis
spectroelectrochemistry reveal a unique single electron transfer
(SET)-induced concerted mechanistic pathway, not reliant upon
generation of the nitrate radical.
Despite the sustained interest in the development of new organic
nitrates, synthetic methods to access these compounds remain
remarkably underdeveloped. Classical approaches include
esterification of alcohols using either mixed acid (HNO3/H2SO4),
acetyl nitrate, nitronium tetrafluoroborate[9] or thionyl nitrate,[10]
nucleophilic displacement of alkyl (pseudo)halides with various
nitrate salts,[8,11] and ring opening of epoxides using mixed acid,[8]
Bi(III)nitrate salts,[12] tetranitromethane,[13] ceric ammonium nitrate
(CAN),[14] NO gas[15] or dinitrogen pentoxide[16] (Scheme 1a-b).
The requirement for prefunctionalized starting materials presents
a synthetic limitation in all cases, while further drawbacks include
the moisture sensitivity and thermal instability of reagents, the use
of strong oxidants, as well as harsh reaction conditions and poor
functional group tolerance. Alternative strategies include the
oxidative nitration of alkenes using tert-butyl nitrite/O2,[17] CAN in
the presence and absence of nucleophilic partners,[18] or Hg(II)
salts with halogens,[19] but a drawback to these examples remains
the need for hazardous reagents, as well as the formation of
product mixtures or dinitrooxylated products. Further
methodologies include a CAN-mediated radical alkylation, which
although interesting from a mechanistic stand point, presents
limited synthetic applicability and scope.[20] More recently, a CAN-
mediated benzylic nitrooxylation,[21] and the formal insertion of
HNO3 into aryldiazoacetates[22] have been described.
Evidently, a bench stable reagent that behaves as a convenient
source of the NO3 group and is amenable to direct C-H
nitrooxylation of a broad range of substrates under mild
conditions, while avoiding the use of prefunctionalized starting
materials or strong oxidants, remains synthetically desirable, and
essential to facilitate the development of new classes of organic
nitrates with unexplored properties. In view of our group’s interest
in C-H nitration[23] and hypervalent iodine chemistry,[24] we
envisaged that the merger of the nitrooxy functional group with a
hypervalent iodine scaffold would provide a platform for the
development of such a reagent. Hypervalent iodine benziodoxole
and benziodoxolone reagents have emerged as powerful tools for
oxidative functional group installation, and are generally
considered as environmentally benign and widely available
Organic nitrates are among the oldest class of compounds
employed in the treatment of general coronary heart disease, with
the earliest accounts on the use of glyceryl trinitrate as treatment
for angina pectoris dating back to 1879.[1] Since then, the activity
of organic nitrates as nitric oxide (NO) donors has been well
established, and over the past century the diverse biological role
of NO as a key signaling molecule involved in a variety of
physiological and pathological processes, including vasodilation,
platelet aggregation, neurotransmission and immune regulation,
has been elucidated.[1] Consequently, a manifold of novel classes
of organic nitrates have been developed in recent decades,
generally through coupling of known pharmacophores with the
nitrooxy (-ONO2) group. These “hybrid drugs” demonstrate
enhanced activity and a reduced number of side effects as non-
steroidal anti-inflammatory,[2] anti-diabetic,[3] anti-malarial,[4] anti–
glaucoma[5] and anti-Alzheimer’s agents,[6] while their application
as COX-2 inhibitors in cancer treatments has also been implicated
with a reduced risk of drug resistance in tumor cells.[7] In addition,
the nitrooxy group can behave as a versatile handle in organic
synthesis for the introduction of functionality by nucleophilic
displacement, or cleavage of the weak O-NO2 bond.[8]
1
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10.1002/anie.202005720
Angewandte Chemie International Edition
RESEARCH ARTICLE
Existing methodologies for nitrooxylation
a)
g) General reactivity of hypervalent iodine-based reagents
HNO3/H2SO4,[9] NO2BF4,[9]
R
Nu
I
H+/A
acetyl nitrate,[9] thionyl nitrate[10]
OH
reductive
elimination
H+/A
X
I
O
Nu-
R
X
O
R'
R
ONO2
Nu-X
R
R
R
R'
[8,11]
R
M(NO3)x
X
X
I
O
R'
A=non-reducing Lewis acid
X= Br, I, OMs, OTs
R
R
SET-induced
radical
fragmentation
HNO3/H2SO4,[8] Bi(NO3)3•5H2O,[12]
b)
ONO2
OH
I
OH
C(NO2)4,[13] CAN,[14]
O
R=Me,
2R=O
X
I
O
R
R
Nu-X
R
R
Nu-X
[16]
-e-
R
R
R
R'
R'
NO/O2,[15] N2O5
R'
Nu-H
R
tBuONO/H2O/O2,[17a] Hg(NO3)2/ X2,[19]
c)
[17b]
tBuONO/R2NOH/O2
ONO2
FG
h) This work
R'/H
R
O2NO
I
O
Lewis and Brønsted acid
CAN/NaN3,[18b] CAN/P(O)Ph2H,[18c]
O
O
FG = NO2, ONR2, X,
N3, P(O)Ph2, ONO2
activation
CAN/hv[18a]
ONO2
Photoredox catalysis
d)
e)
1
CAN/N-hydroxyphthalimide (cat.)[21]
ONO2
FG
Ar
FG
n
Ar
i) Synthesis of hypervalent iodine-based reagent 1
n
[20]
O
O
CAN/amine cat./
Ph
Ph
ONO2
CO2R
Cl
I
O
H
AgNO3 (1.6 equiv)
DCM, rt, 16 h
H
R
R
f)
Fe(NO3)3•9H2O[22]
Ar
CO2R
Ar
1, 96%
N2
ONO2
strong oxidants
harsh reaction conditions
stable in protic and aprotic solvents
crystalline solid bench stable can be handled under air
safety evaluated by DSC/TGA synthesis of new classes of nitrate esters
moisture sensitive/thermally unstable reagents
prefunctionalized starting materials
Scheme 1. Existing methods for synthesis of organic nitrates through: [a] esterification of alcohols and nucleophilic displacement of
(pseudo)halides; [b] ring opening of epoxides; [c] difunctionalization of alkenes; [d] oxidation at benzylic positions; [e] radical alkylation;
[f] formal insertion of HNO3 into aryldiazoacetates. [g] Generally accepted mechanisms of functional group transfer from benziodoxole
and benziodoxolone reagents to nucleophilic substrates. [h] This work; synthesis of new classes of nitrate esters. [i] Synthesis of
reagent 1.
alternatives to traditional transition metal-based reagents.[25] The
reactivity of these reagents is dependent upon suitable activation,
which has been shown to occur by two distinct pathways;
coordination of a Brønsted or Lewis acid to the O atom results in
elongation of the I-O bond, facilitating a 2-electron reductive
elimination from iodine (Scheme 1g).[26] Alternatively, a SET-
induced radical fragmentation involves reduction of the reagent,
followed by homolytic cleavage of the I-ligand bond. This latter
pathway has been proposed in the presence of single-electron
reductants, particular organic substrates, and under photoredox
catalysis.[26a] Herein, we demonstrate the reactivity of hypervalent
iodine-based reagent 1 towards the synthesis of new classes of
organic nitrate esters through both reductive elimination and outer
sphere photoredox mechanistic pathways.
We commenced by preparing 1 through a ligand exchange of the
readily available chloroiodane with AgNO3, affording the reagent
as a crystalline yellow solid in excellent yield (Scheme 1i).
Although the synthesis of 1 has been noted in the literature by
Kita and co-workers in 1996,[27] it has, to the best of our
knowledge, never been exploited in organic synthesis to date.
Optimization of the reagent synthesis revealed that chloroiodane
reacts smoothly with 1.6 equivalents of AgNO3 to yield 1 in 96%
yield, however further attempts to identify suitable cheaper nitrate
sources were unsuccessful (see SI). Studies toward the synthesis
of the corresponding benziodoxolone reagent unfortunately were
also unsuccessful. Single crystal X-ray structure analysis
confirmed the “closed-form” benziodoxole structure, which
displays a typical distorted T-shaped geometry. Further
characterization by differential scanning calorimetry and thermal
gravimetric analysis revealed 1 to be stable until 155 °C, whereby
exothermal decomposition was observed. In our hands 1 was
found to be shock insensitive, and could be stored under ambient
conditions for up to one year with no observed decomposition. A
reduction potential of –1.03 V versus Fc0/+ in MeCN was
determined by cyclic voltammetry (see SI). To gain some
preliminary insights into suitable activators, 1H NMR analyses of
1:1 mixtures of 1 with various additives were performed. Indeed,
a clear downfield shift was observed in the presence of select
Brønsted and Lewis acids including TfOH, Zn(NTf2)2 and AgOTf
(see SI). Motivated by these preliminary indications of reactivity,
we explored the nitrooxylation of carbonyl compounds and
commenced with β-keto esters, which are valuable building
blocks in the synthesis of natural products and bioactive
compounds.[28] We chose the easily enolizable indanone
carboxylate 2f as a model substrate, and after screening reaction
conditions (see SI) were pleased to observe that the reaction with
1 proceeds readily at room temperature in the absence of catalyst
or exogenous base, delivering the desired product in excellent
yield (Scheme 2). Incorporation of the nitrooxy group at the α-
position was unambiguously confirmed through single crystal X-
ray structure analysis of 3f. Under these conditions, a broad range
of previously unreported indanone-derived β-keto esters could be
nitrooxylated under exceedingly mild conditions and in good to
excellent yields. In addition to the t-butyl ester (3a), the reaction
2
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RESEARCH ARTICLE
Scheme 2. Substrate scope for nitrooxylation of carbonyl compounds using 1. [i] 3 equivalents of substrate employed. [ii] Treatment
of crude reaction mixture with TFA, 0 °C, 1 h. Isolated yields reported.
proceeded smoothly in the presence of methyl (3b), benzyl (3c)
and methyl adamantyl esters (3d), with no decrease in yield.
Various deactivating and activating substituents were tolerated at
the C4 (3l-o), C5 (3h-k), C6 (3g) and C7 (3e) positions, and we
were pleased to observe that the reaction also proceeded in good
yield in the presence of thiophene (3r) and phenylacetylene (3s)
substituents. Interestingly, the reaction with a 6-membered
tetralone-derived β-keto ester resulted in formation of the 1-
hydroxy-3-nitro-napthoate derivative, presumably following
reduction of the reagent by the substrate (see SI). Fortunately, the
reaction with a 7-membered fused ring system provided the
desired product 3t in acceptable yield. However, upon attempting
3
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RESEARCH ARTICLE
Scheme 3. Mechanistic proposal for synthesis of nitrooxylated oxindoles 5.
the nitrooxylation of acyclic β-keto ester 2w of lower acidity, no
reaction was observed. After screening various Lewis acids (see
SI), it was found that the reaction proceeds in acceptable yield in
the presence of 10 mol% CuOAc in DCM. Under these conditions,
β-keto esters 2w-y were successfully nitrooxylated, as well as
ester derivatives of cyclopentenone (2u) and cyclohexanone (2v).
In addition, these reaction conditions also proved amenable to the
mono-nitrooxylation of unsubstituted -keto ester 2z. We were
pleased to observe that the protocol could further be extended to
the nitrooxylation of 1,3-diketones (3aa), as well as malonates
(3ab), whereby the mono-substituted products were obtained in
acceptable yields.
dinitrobenzene, p-benzoquinone and allyl benzyl ether was
observed, while the complete suppression of reactivity after
addition of various bases including K2CO3, DIPEA and DBU
suggests that protonation of 1 may be critical to its activity. The
reaction was furthermore found to exhibit a first order dependence
on substrate 2f and reagent 1 under pseudo-order conditions (see
SI). From these findings, a preliminary mechanistic proposal
involving protonation of the reagent by a substrate molecule,
followed by reductive elimination from the iodine center is
plausible (Scheme 1g). However, an SN2 pathway cannot
completely be excluded at this stage, nor can a “metathesis” type
reaction occurring through concomitant protonation of 1 and IC
bond formation through a 4-membered TS.[26d, 29] While in the
Lewis acid catalyzed nitrooxylation of acylic β-keto esters,
chelation of Cu to the dicarbonyl moiety could facilitate
In order to elucidate mechanistic details, nitrooxylation of 2f in the
presence of various additives was conducted (see SI). A lack of
inhibition in the presence of radical scavengers styrene, 1,4-
4
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10.1002/anie.202005720
Angewandte Chemie International Edition
RESEARCH ARTICLE
protonation of 1, a dual activation by Cu involving coordination to
both substrate and reagent is also plausible.
radicals. Following the irradiation of a 1 mM solution of 1 with a
60 Gy dose, the build-up of a transient species with an
absorbance maximum at 420 nm was observed, which
subsequently decayed by a second-order process (Scheme 3b).
These findings indicate that homolytic fragmentation of 1’ is highly
improbable, and the observed decay of 1’ is likely due to oxidation
by t-BuOH radicals present in a comparable concentration. To
validate the identity of the reducing radical 1’ as the absorbing
species at 420 nm,[38] the measurement was repeated in the
presence of 40 μM methyl viologen (MV2+), which is a probe for
single electron reductants. MV2+ should be readily reduced by 1’
to produce the radical cation MV+• with a known λmax of 600 nm
(Scheme 3c).[39] Indeed, a strong absorption at 600 nm was
observed, and the gradual build-up in absorption over 6 μs after
Encouraged by our results with β-keto esters, we turned towards
the nitrooxylation of oxindoles which form the core of a large
number of natural products and bioactive compounds, many of
which have been studied as potential therapeutic agents.[30] Using
N-boc-protected 4b as a model substrate, various reaction
conditions and Lewis and Brønsted acids were screened, but did
not lead to formation of the desired product. Motivated by
voltammetric measurements, we speculated that in the presence
of
a
photocatalyst operating under oxidative quenching
conditions, 1 should undergo a reductive single electron transfer
to afford the radical anion 1’ (Scheme 3a), which in turn should
fragment to the NO3 radical. Indeed, we were pleased to observe
formation of the desired product upon irradiation of a solution of
1, 4b and a catalytic amount of [Ru(bpy)3](PF6)2 in DCM with high
intensity blue LEDs (see SI for optimization of reaction
conditions). To our surprise, no exogenous base was required.
While almost complete conversion to the N-Boc protected
nitrooxylated product was observed by NMR spectroscopy, partial
N-deprotection occurred during purification on silica gel. The free
amine 5b was instead isolated following treatment of the
intermediate with TFA (Scheme 2). Substitution of the methyl
group at the C3 position for a more sterically demanding isopropyl
group was well tolerated (5d), and the reaction also proved
amenable to the dimethyl ether (5e) N-protecting group. Upon
introduction of a benzyl group at the C3 position the N-protected
products could be isolated in most cases, with 5f isolated in
excellent yield. The acetoxy (5g) and Cbz (5h) N-protecting
groups were well tolerated, while introduction of a N-methyl group
(5i) resulted in a slightly lower yield. The reaction tolerated
activating and deactivating substituents at various positions on
both the oxindole core (5b-c, j) and the benzyl group (5k-n). To
demonstrate the synthetic utility of the nitrooxy group as a
tentative protecting group, 3f and 5b were reduced to the
corresponding alcohols using zinc in acetic acid (Scheme 2,
bottom).
initial irradiation confirms that MV+• is formed exclusively through
- [40]
a reaction with 1’ and not through direct reaction with eaq
.
Nevertheless, we remained curious about the deprotonation of
oxindole substrates, as their relatively high pKa values[41] make
deprotonation by 1 improbable in the absence of additional, non-
specific interactions. We turned to UV-Vis absorption
spectroscopy to determine whether such interactions between 4b
and 1 exist in solution, however, a titration of 4b with 1 did not
result in observation of a new species, and a mixture of both
species matched the linear combination of their individual
signatures (see SI). We speculated that the pKa of radical anion
1’ may be sufficiently high to deprotonate the oxindole substrates,
and we sought to observe this deprotonation using UV-Vis
spectroelectrochemistry (Scheme 3d). As the enolate of 4b was
not expected to exhibit a characteristic UV-Vis signature, phenyl
fluorene 11 was instead used as an indicator (pKa of 17.9 in
DMSO).[42] Indeed, subjecting a mixture of 11 and reagent 1 to an
applied voltage of -1.5 V vs. Ag0/+ resulted in irreversible reduction
of 1, and observation of the UV-Vis absorption signature
corresponding to anion 12 (Scheme 3d). In correspondence with
pulse radiolysis, the UV-Vis signature of the reduced 1’ species
was found to have an absorption maximum at 420 nm. A
preliminary mechanism for the synthesis of nitrooxylated
oxindoles 5 is proposed in Scheme 3e; oxidative quenching of
[Ru(bpy)3]2+* by 1 results in formation of radical anion 1’, which
deprotonates the oxindole substrate to form [1+H]’. This in turn
reacts with enolate 8 in a concerted fashion. Subsequent
oxidation of 9 completes the catalytic cycle. Although the reactive
intermediates involved in the transformation have been probed,
the intimate mechanism of addition of the nitrooxy group to 8
remains speculative. At this stage, a reaction sequence involving
radical addition of [1+H]’ to enolate 8, followed by single-electron
oxidation and reductive elimination from iodine, as proposed in
Zhu’s decarboxylative trifluoromethylation of α- β-unsaturated
carboxylic acids, cannot totally be excluded.[43] Nevertheless, this
work not only constitutes the first examples of a nitrooxylation
under photoredox catalysis, but is one of the exceedingly rare
examples whereby reduction of such hypervalent iodine-based
reagents does not result in fragmentation and liberation of a free
radical.
To acquire a preliminary mechanistic understanding, control
experiments were performed which validated the requirement of
both photocatalyst and light, and Stern-Volmer analysis confirmed
quenching of the excited state [Ru(bpy)3]2+* by 1 (see SI). Curious
about the identity of the radical intermediates involved in the
transformation, we turned to pulse radiolysis, which is a powerful
tool for probing the nature and studying the kinetics of highly
oxidizing and reducing species and radicals.[31] This technique
involves exposure of water to a single pulse of ionizing radiation,
-
resulting in formation of OH•, H•, H+ and the solvated electron eaq
in linear dose dependent concentrations. These species in turn
react with a sample of interest to generate transient reactive
intermediates, which can be observed by fast time-resolved
spectroscopic measurements. As such, pulse radiolysis provides
a means of characterizing reactive intermediates, and can further
be used to predict reactivity.[32] Motivated by a recent study
determining the rate of single electron reduction of the analogous
hypervalent iodine-based CF3 reagent by pulse radiolysis,[33] we
were interested in using this technique to observe the
fragmentation products following single electron reduction of 1.
Alternative fragmentation pathways and the corresponding
absorption maxima are presented in Scheme 3a. Argon saturated
sample solutions were prepared in MilliQ water containing
10 vol% t-BuOH, which was used to scavenge oxidizing OH•
In conclusion we have described the development of
a
hypervalent iodine-based reagent 1 and its application as a mild
and convenient source of the nitrooxy functional group through
the synthesis of new classes of organic nitrate esters with
unexplored properties. The reagent was furthermore revealed to
act as an internal base during the reactions, while transfer of the
nitrooxy group through two distinct pathways, namely reductive
5
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10.1002/anie.202005720
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RESEARCH ARTICLE
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demonstrated. We anticipate that the mechanistic insights in
combination with physical properties of 1 elucidated herein will
guide future reaction development towards a more facile
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thereby facilitating further investigations into the biological effects
imparted by this unique functional group.
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Acknowledgements
D.K and R.C gratefully acknowledge the financial support from the
ETH Zürich, the Holcim Stiftung and the Swiss National Science
Foundation (SNSF grant number PZ00P2 168043). The authors
thank Dr. Erich Meister for valuable assistance with spectroscopic
measurements, Diego Lorenzo Del Rio for synthetic contributions,
and Prof. Hans-Achim Wagenknecht as well as Prof. Frank
Breher for sharing parts of their infrastructure.
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Keywords: nitrate esters • photoredox catalysis • hypervalent
iodine • pulse radiolysis • spectroelectrochemistry
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Angewandte Chemie International Edition
RESEARCH ARTICLE
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7
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10.1002/anie.202005720
Angewandte Chemie International Edition
RESEARCH ARTICLE
A hypervalent iodine-based nitrooxylating reagent behaves as a convenient source of the ONO2 group for the synthesis of new classes
of organic nitrate esters. Its versatile reactivity under various forms of catalysis is demonstrated in the selective and direct
functionalization of enolizable C-H bonds via polar electrophilic and open shell pathways, enabling the synthesis of nitrooxylated -keto
esters, 1,3-diketones, malonates and oxindoles under mild conditions.
8
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