Photochemical Transformations with Iodine Azide after Release from an Ion-Exchange Resin

Article abstract of DOI:10.1002/anie.202003079

This report discloses the photochemical homolytic cleavage of iodine azide after its formation following release from polymer-bound bisazido iodate(I) anions. A series of radical reactions are reported including the 1,2-functionlization of alkenes and the unprecedented chemoselective oxidation of secondary alcohols in the presence of primary alcohols.

Full text of DOI:10.1002/anie.202003079

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Accepted Article
Title: Photochemical Transformations with Iodine Azide after Release
from an Ion Exchange Resin
Authors: Andreas Kirschning, Gerald Dräger, Teresa Kösel, and
Goeran Schulz
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003079
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10.1002/anie.202003079
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Photochemical Transformations with Iodine Azide after Release
from an Ion Exchange Resin
Teresa Kösel,[a]# Göran Schulz,[a]# Gerald Dräger,[a] and Andreas Kirschning*[a]
This work is dedicated to Prof. Dr. Rolf Huisgen on the occasion of his 100th birthday
Abstract: The report discloses the photochemical homolytic
cleavage of iodine azide after its formation accompanied with
release from polymer-bound bisazido iodate(I) anions. A series of
radical reactions are reported including the 1,2-functionlisation of
alkenes and the unprecedented chemoselective oxidation of
secondary alcohols in the presence of primary alcohols.
useful functionalised ion exchange resin 3d was our reagent of
choice. This orange-coloured polymer is a non-explosive source
for iodine azide (5) and can be for stored in the dark for several
months under an argon atmosphere at ‒15 °C without loss of
activity. Reactions are commonly terminated by filtration through
a piece of cotton that is positioned at the outlet of the vials. The
polymeric byproduct 4 generated during transformations with 3d
is removed by simple filtration (Scheme 2)[11] and its
regeneration is achieved by exchange of azide with iodide,
PhI(OAc)2 promoted oxidation to 3b and ligand exchange with
TMSN3. Principally, polymer‐bound iodine azide 3d resolves the
problems arising from the explosive character of iodine azide (5).
So far photocatalytic reactions with iodine azide (5) have not
been reported.[12] Being a source for Hal-X species, we assumed
that 3d is ideally suited to generate and study the chemical
versatility of the azide radical (6) (Scheme 2).[13]
The pioneering work of Hassner[1] introduced iodine azide (IN3)
to the reagent portfolio of preparative organic chemists.
However, its explosive character hampered broader synthetic
studies. Due to this property iodine azide is commonly prepared
in-situ from sodium azide and iodine chloride in polar
solvents.[1,2]
Scheme 1. Preparation of haloate(I) complexes (Ac= acetyl, Nu= nucleophile,
Tfa= trifluoroacetyl; R1= alkyl or polystyrene and the ammonium counterion
can be substituted by phosphonium PR4+[3]).
Scheme 2. Polymer-bound bisazidoiodate(I) 3d, release of iodine azide (5),
proposed photochemical generation of the azide radical
regeneration.
6 and resin
Many years ago we reported on a new class of electrophilic
halonium reagents, which are obtained by iodine(III)-mediated
oxidation of ammonium bromide or iodide, respectively 1.[3] The
resulting acylated haloate(I)-complexes 2[4] can be further
diversified by ligand exchange using silylated nucleophiles that
yields ate(I) anions 3a-d. These reagents have been employed
in various transformations with alkenes and alkynes[5] for the
activation of thioglycosides[6] as well as dithioacetals[7] and as
cooxidants for TEMPO-mediated oxidations.[8] Chemically, these
haloate(I) anions 3a-d behave like Br-OAc, I-OAc, I-OTfa and
I-N3. It can be assumed that these species are liberated from 3a-
d prior to the reaction with different nucleophiles.[9,10]
Huang and Groves determined the bond dissociation energy
(BDE) for H-N3 (12) as 92.7 kcal/mol[14] which indicates that the
azide radical (6) is a much stronger hydrogen atom abstractor
than iodine or bromine radicals (BDE(H−I) = 71.3 kcal/mol,
BDE(H−Br) = 86.5 kcal/mol).[15] Azidoiodinanes 8-10 show
similar I-N3 BDE-values to iodine azide (5) in the range of 29-
35 kcal/mol (Figure 1).[14]
With these experiences in mind we initiated a programme for
extending their scope to photochemical reactions and the highly
[a]
T. Kösel, G. Schulz, Dr. G. Dräger, Prof. Dr. A. Kirschning
Institute of Organic Chemistry and Center of Biomolecular Drug
Research (BMWZ)
Figure 1. X-N3 bond dissociation energies (BDE) of common organic halogen
azides (5, 8-11) and of HN3 (12).[14]
Leibniz Universität Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
Fax: (+49) 511-762-3011
E-mail: andreas.kirschning@oci.uni-hannover.de
To prove that polymer-bound reagent 3d can serve as a source
for the azide radical (6) we exposed it to blue LED light (445-
510 nm) in the presence of indene (13). Under these conditions
the syn-bisazido adduct 14 formed (Scheme 3). The anti-azido-
iodination product 15 is commonly formed under non-radical
Supporting information under http://www.angewandte.org or from the authors.
# The authors contributed equally to this work.
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10.1002/anie.202003079
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conditions and was only detected in trace amounts. The syn-
stereochemistry in 14 was determined by comparison with
literature values.[16]
TEMPO-azide adducts can form, serving as an azide radical in a
“resting state”.[19] A sample taken from a reaction mixture
consisting of polymer 3d and TEMPO in acetonitrile was
analysed by HPLC-MS after 2h and a signal at e/z= 199.2
(M++1) was detected which could be TEMPO-N3 16.
Scheme 3. Radical bisazidation of indene (13) by photochemical activation of
polymer-bound reagent 3d.
Scheme 5. Radical clock experiment with vinyl cyclopropane 25.
Next, the scope of this radical process was extended to several
other alkenes. These yielded the corresponding 1,2-addition
products 17-23. 1,2-Disubstituted alkenes commonly reacted
with complete diastereocontrol. Under these conditions, 3-
(acetoxy)-androst-5-en-17-one yielded anti-1,2-bisazido adduct
24 in 50% yield and not the azido oxygenation product. The
structure of 24 was determined by X-ray crystallographic
analysis (see SI).[20] This result is consistent with the
observations of Lin and co-workers who found that aminoxyl
radicals are able to catalyse the anti-diazidation of alkenes likely
with 16 serving as azide radical reservoir.[19] This alternative
outcome of the reaction is fostered by increasing steric
hindrance around the alkene moiety and the aminoxyl radical.
A radical clock experiment was conducted under the established
conditions using vinyl cyclopropane 25 as starting material
(Scheme 5). It yielded ring-opened allyl azide 26 besides the
iodoazidated product formed by ionic 1,2-addition to the terminal
alkene. The formation of 26 clearly demonstrated the presence
of the azide radical (6).
Noteworthy, thiosulfate ion exchange resin was added for
reductive work-up of all reactions and removal of byproducts
such as iodine and IN3. Thus, the need for hydrolytic work-up is
bypassed. Further evidence for the presence of a radical
process was collected using 2,2,6,6-tetramethylpiperidinyloxyl
(TEMPO) as a radical scavenging agent. Consequently, the anti
1,2-adduct 17 was formed (Scheme 4).
Scheme 4. Radical 1,2-addition of azide and TEMPO to alkenes and
formation of 17-24 by photochemical activation of polymer-bound reagent 3d;
structure of TEMPO azide 16 (16 was also described to be a salt).[19]
A brief solvent check demonstrated that besides acetonitrile also
DMF, CH2Cl2 and THF can be employed. However, in THF
oxidised furan 18 was also detected in trace amounts. In the
absence of indene (13) the radically formed THF-adduct 18 was
isolated in 91% yield.[17] There is precedence for radical
H abstractions of tetrahydrofurans and other heterocycles by
mixing iodide salts with t-butyl hydroperoxide.[18a] Alternatively,
the azide radical (6) can be generated from PhI(OAc)2 and
sodium azide which also leads to H radical abstraction from the
solvent THF.[18b] As suggested for bulky TEMPO derivatives,
Scheme 6. Oxidation of secondary alcohols with functionalised polymer 3d
and formation of ketones 27-33 (grey mark refers to site of oxidation).
It has to be noted that azidooxygenations of alkenes were
reported before by Studer et al. who employed azido
benziodoxolone (Zhdankin´s reagent[21]) in combination with
highly reactive TEMPONa as reducing agent and precursor for
TEMPO.[22] A second approach relied on the electrochemical
reduction of TEMPO to TEMPO+. The resulting metastable
–
charge-transfer complex with azide 16 (TEMPO+/N3 )
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10.1002/anie.202003079
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COMMUNICATION
decomposes to TEMPO and the azide radical (6).[23] Recently,
Kashya and co-workers published the first photocatalysed
We found that primary alcohols are also oxidised by the azide
radical (6). Compared to fenchol (44) which was quantitatively
oxidised to fenchone (32) within seven hours at rt, heptanol 40
reacted much more sluggishly. After 20 h hexylcarbamoyl
azide (41) formed under the typical photolytic conditions in the
presence of polymer 3d (Scheme 8, top). Mechanistically, one
can assume that heptanal (42) is formed first followed by
H abstraction and generation of an acyl radical. When this is
trapped by the azide radical (6) the acyl azide 43 would form.
Next a Curtius rearrangement would yield the corresponding
isocyanate that finally reacts with HN3. Evidence for this series
of events was collected, when heptanal (42) was exposed to
polymer 3d under the typical photolytic conditions in the
presence of polymer 3d. Acyl azide 43 was isolated in 90%
yield. Obviously the Curtius rearrangement did not take place.
The number of equivalents HX formed (X= I or N3) is larger
when starting from heptanol (40) compared to heptanal (42).
These promote carbamoylazide 41 formation from acyl azide 43.
This chemoselectivity was unequivocally proven in a competition
experiment between (+)-fenchol 44 and heptanol 40 in the
presence of different amounts of 3d (Scheme 8, bottom).
azidooxygenation
that
relied
on
trimethylsulfonium
[bis(azido)iodate(I)] species, that are generated in-situ from
trimethylsilyl azide and sulfonium bis(acetoxy)iodate(I).[24]
During our studies we also unravelled an unexpected property of
iodine azide (5) under photolytic conditions. We found that
secondary alcohols are smoothly oxidised to the corresponding
ketones while primary alcohols reacted very sluggishly
(Schemes 6-8).
Scheme 7. Chemoselective oxidation of diols 34-36 with functionalised
polymer 3d.
This unexpected difference of reactivity was substantiated for
the diols 34-36 (Scheme 7).[25] In all cases the secondary
hydroxyl group was oxidised with remarkable chemoselectivity
forming hydroxyketones 37-39. The selective oxidation of the
2,3-deoxyglycoside 36[26] to the corresponding uloside 39 is
particular noteworthy and synthetically useful as protecting
group chemistry, a typical feature in carbohydrate synthesis, is
circumvented.
Scheme 9. Three experiments (A-C) that provide evidence for C-H activation
and ketyl radical formation during alcohol oxidation.
C-H activation similar to those described here were encountered
for cyclic and acyclic ethers using strongly oxidising reagents or
transition metal catalysts.[27-29]
For collecting evidence that alcohol oxidations proceed via ketyl
radicals we carried out three experiments. First, we employed 1-
cyclopropylethan-1-ol (45) that was expected to undergo a rapid
ring opening after radical formation (Scheme 9, example A).
Treatment of 45 under the established conditions yielded
bisazide 46, a clear indication that a ketyl radical 47 must have
formed as intermediate and follow-up reactions via intermediates
48 and 49 furnished bisazide 46. Secondly, methyl ether 50 was
exposed to the established conditions and the corresponding
ketone 51 was isolated as main product (Scheme 9, example B).
Scheme 8. Oxidation of heptanol (40) and heptanal (42), competition
experiments between (+)-fenchol (44) and heptanol (40) (ratios determined by
1H-NMR spectroscopic analysis; work-up by addition of thiosulfate ion
exchange resin and filtration).
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Finally, we carried out detailed mass spectrometric studies (LC-
ESI-MS) on the crude mixture collected from the oxidation of
isopropanol 52 in the presence of TEMPO. These revealed a
signal at m/z = 216.2 (M++1) which is indicative for TEMPO-
adduct 53 that, however, could not be isolated (Scheme 9,
example C).
Keywords: azide radical • C-H activation • iodine azide •
polymer-bound reagents • photochemistry
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[2]
[3]
[4]
With reference to the BDE of IN3, and the H-abstraction
capability of both radicals a mechanistic scheme can be
summarized (Scheme 10). Polymer-bound iodate(I) complex 3d
provides iodine azide (5) and under photocatalytic conditions
homolytic cleavage yields the azide and iodine radical 6 and 7.
While the iodine atom radical (7) is able to recombine to I2 the
corresponding dimerisation of the azide radical (6) to N6 is not
reported. The azide radical (6) is able to add to alkenes and the
newly formed radical I can be trapped by the iodine or the azide
radicals 6 and 7 or by TEMPO. The azide radical (6) also
enforces C-H abstraction next to a C-O bond such as in
tetrahydrofuran or alcohols. In the former example this was
proven by isolation of the TEMPO adduct while in the second
case the corresponding ketones formed from secondary
alcohols via the ketyl radicals II. Primary alcohols also form
intermediate II but the resulting aldehyde undergoes a second
C-H abstraction to yield an acyl radical III. This is trapped by 6 to
yield acyl azides that may undergo the Curtius rearrangement
with final addition of HN3 to the intermediate isocyanate.
[5]
a) Md. A. Hashem, A. Jung, M. Ries, A. Kirschning, Synlett 1998, 195-
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[12] A. Hassner, L. Marinescu, M. Bols, Iodine azide, e-EROS, 2005.
[13] H. Monenschein, Ph. D. thesis TU Clausthal, Germany, 2001.
[14] X. Huang, J. T. Groves, ACS Catal. 2016, 6, 751-759.
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[20] CCDC 1985449 contains the supplementary crystallographic data for
this compound. These data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
http://www.ccdc.cam.ac.uk/data_request/cif.
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Bolz, Tetrahedron Lett. 1994, 35, 9677-9680; b) V. V. Zhdankin, A. P.
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Scheme 10. Proposed mechanistic considerations on radical processes
reported here.
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In essence, we showed that the polymer-bound bisazido(iodate
(I)) anion 3d is the most versatile source of the azide radical (6)
in photocatalytic reactions.[30] It performs azido oxygenations of
alkenes and C-H abstractions of ethers and alcohols.
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[31] It can infinitely be regenerated (Scheme 2). Chemical changes of the
polymer backbone initated by the radicals formed were not studied here.
Acknowledgements
The work was in part funded by the BMBF (project: SILVIR). Dr.
J. Fohrer (Leibniz University Hannover) is thanked for support in
NMR analyses. We thank Alexey Stepanyuk (Leibniz University
Hannover) for expert technical assistance.
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Entry for the Table of Contents
Give me azide radicals! Stable
T. Kösel, G. Schulz,
and
storable
polymer-bound
G. Dräger, A.
Kirschning
bisazido-iodate(I) anions are
a
source for azide radicals upon
photochemical activation. These
promote azidooxygenations of
alkenes and C-H abstraction of
alcohols. The latter reactivity
Page No. – Page No.
Photochemical
Transformations of
Iodine Azide after
Release from an Ion
Exchange Resin
initiates
the
chemoselective
oxidation of secondary alcohols
and C-H abstraction of aldehydes.
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