Photoswitchable Regiodivergent Azidation of Olefins with Sulfonium Iodate(I) Reagent

Article abstract of DOI:10.1021/acs.orglett.9b03910

Photoswitchable strategy for selective azidation of structurally diverse olefins under transition-metal-free conditions is reported. The unprecedented reactivity of trimethylsulfonium [bis(azido)iodate(I)] species under visible light allows radical azidooxygenation of the C═C πbond with distinctive selectivity. In the absence of visible light, the reaction proceeds through an ionic intermediate which led to complementary regioselectivity to provide α-alkyl azides. Mechanistic studies reveal that light-controlled regiodivergent azidation involving radical or an ionic pathway can be accomplished with exclusive regioselectivity.

Full text of DOI:10.1021/acs.orglett.9b03910

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoswitchable Regiodivergent Azidation of Olefins with
Sulfonium Iodate(I) Reagent
Dodla S. Rao, Thurpu R. Reddy, Aakanksha Gurawa, Manoj Kumar, and Sudhir Kashyap*
Carbohydrate Chemistry Research Laboratory (CCRL), Department of Chemistry, Malaviya National Institute of Technology
(MNIT), Jaipur 302017, India
S
* Supporting Information
ABSTRACT: Photoswitchable strategy for selective azidation of structurally diverse olefins under transition-metal-free
conditions is reported. The unprecedented reactivity of trimethylsulfonium [bis(azido)iodate(I)] species under visible light
allows radical azidooxygenation of the CC π bond with distinctive selectivity. In the absence of visible light, the reaction
proceeds through an ionic intermediate which led to complementary regioselectivity to provide α-alkyl azides. Mechanistic
studies reveal that light-controlled regiodivergent azidation involving radical or an ionic pathway can be accomplished with
exclusive regioselectivity.
Scheme 1. Azidooxygenation of Alkenes with TEMPO and
Our Approach for Regiodivergent Azidation under
Photoswitchable Conditions
zido-functionalized molecules represent a potential
Aprecursor to vital nitrogen-based scaffolds of therapeutic
value and biologically active componds.1 In addition, the azido
group serves as powerful chemical tool involving several
fascinating chemical transformations;2 Aza-Wittig reaction, C−
H bond amination, “Click” reaction, and Staudinger ligation to
investigate biochemical actions in living organisms.3 In recent
years, the selective azidation process has gained significant
advances owing to the exceptional versatility of the azido
moiety in synthetic chemistry,4 material sciences,5 as well in
pharmaceutical inventions.6 In particular, azidooxygenation of
alkene has been recognized as asynthetically useful trans-
formation7 attributed to the readily transferable as well late-
stage utility of azido and oxy moieties.8 Notably, the vicinal oxy
azides serve as key intermediates for 1,2-amino alcohols,9
which constitutes an important subclass of medicinally
important molecules and several drugs.10
In this context, Studer et al. have first achieved the
azidooxygenation by employing highly reducing TEMPONa
as a single-electron aminoxyl radical precursor and azidoben-
ziodoxolone (IBA-N3 or Zhdankin reagent) as an azidyl radical
source7a (Scheme 1A). More recently, other pioneering works
advancing the synthetic versatility of persistent TEMPO
species have been reported by Lin and co-workers and imply
electrochemical oxygenation.7b Meanwhile, Loh et al. inves-
tigated Cu(II)-mediated oxyazidation of vinylarenes with IBA-
N3, illustrating the dual-role of hypervalent iodine(III) species
as an electrophilic azide source as well as O-nucleophile.7c On
the other hand, Greaney and co-workers outlined an elegant
approach for photoswitchable azidation of styrenyl substrates
employing IBA-N3 in the presence of photoredox catalyst.7d
Despite significant advances, the intrinsic shortcomings
associated with transition metals and utilization of expensive
photocatalysts/ligands/oxidants are some important issues and
reasons for developing the improved methods. The resurgence
of visible light as a milder and greener technique led to rapid
development in sustainable chemistry, emanating as promising
Received: November 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03910
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Organic Letters
Letter
alternative strategies.11 However, the selective radical transfer
of oxygen and nitrogen functional groups on an alkene under
visible-light irradiation without any precious photocatalyst/
additives is still an elusive process.
Table 1. Optimization of Selective Azidation Using
Sulfonium Iodate Reagent
a
Inspired by our recent interest in developing a protocol for
the selective functionalization of C−C multiple bonds by
employing sulfonium iodate salts,12 herein we present a
photoswitchable approach for regiodivergent azidation of
olefins under metal-free conditions. This light-controlled
modular aimed for regioselective azidation will be highly
advantageous in extensively studied C-heteroatom bond-
forming reactions. We previously developed a method for
the photochemical diazidation of the CC π bond, high-
lighting the distinctive outcome of sulfonium iodate species
under visible-light conditions12a (Scheme 1B). The protocol
involves radical diazidation of diverse functionalized alkenes in
a single step from sulfonium bis(acetoxy)iodate(I) and sodium
azide as radical precursor. In this paper, we envisioned that the
benzylic radical (A), initiated by the addition of azidyl radical,
could readily combine with the aminoxyl radical to accomplish
an azidooxygenation (Scheme 1B).
We further realized that the orthogonal reactivity of
sulfonium iodate species toward olefinic moiety in the presence
or absence of visible light and a radical scavenger aid in the
diverge regioselectivity for azidation reaction. The preliminary
mechanistic insights into this seminal method have ensured the
scope of fundamental radical and ionic pathways by standard-
izing light−dark conditions.
To commence our studies on the proposed hypothesis, we
first examined the radical azidation of styrene 1a (1.0 mmol)
with trimethylsulfonium [bis(azido)iodate(I)] species,12b
generated in situ by employing Me3SI(OAc)2 (1.1 mmol)
and NaN3 (2.5 mmol) in MeCN under visible-light irradiation
(CFL 27 W). The preliminary observations revealed the
formation of a mixture of anti-Markovnikov and Markovnikov
azidation products, 2:3 (1:4 ratios), in 66% yields (Table 1,
entry 1).13 Subsequently, the reaction of 1a with the
aforementioned reagent system in DCE or MeOH as the
solvent resulted in no improvement in the selectivity and
efficiency (entries 2 and 3). The use of acetic acid provided a
mixture of 2 and 3 with considerable amount of acetoxy
product (entry 4). Indeed, the reaction was working in water
without any significantly changes in regioselectivity, albeit with
a lower yields (entry 5).
To our delight, switching the solvent to toluene facilitated
the radical azidation, furnishing exclusively the β-azide 2 in
88% yields (Table 1, entry 6). Apparently, the azidation with
complementary regioselectivity could be accomplished while
performing the reaction in the dark or without light irradiation,
affording the α-azide 3 in 94% yield (entry 7). Consequently,
we attempted to investigate a direct oxyazidation of styrene
using an oxygen-radical scavenger. Gratifying, the reaction
proceeded well by employing TEMPO (2.5 mmol), furnishing
the desired vicinal oxyazide 4 in 65% yields (entry 8). We
further observed a modest enhancement in the efficiency when
the reaction was irradiated with white or green LEDs (entries 9
and 10). Finally, blue LEDs (λmax ∼ 460 nm) were found to be
an optimal tool to probe the radical azidation, providing the 4
in higher yields (entry 11). Additional experiments performed
instead with TMSN3 as azide source or DCM as the solvent
resulted a noticeable improvement in yields (entries 12 and
13). Further changing the solvents was found to be
b
solvent/azide/radical
source
product(s); yields %
c
entry
visible light
(ratio)
1
2
3
MeCN/NaN3
DCE/NaN3
MeOH/NaN3
AcOH/NaN3
H2O/NaN3
toluene/NaN3
toluene/NaN3
toluene/NaN3/
TEMPO
toluene/NaN3/
TEMPO
toluene/NaN3/
TEMPO
toluene/NaN3/
TEMPO
toluene/TMSN3/
TEMPO
CFL (27 W)
CFL (27 W)
CFL (27 W)
CFL (27 W)
CFL (27 W)
CFL (27 W)
dark
2:3; 66 (1:4)
2:3; 54 (1:2.5)
2:3; 58 (1:2)
2:3; 59 (1:2)
2:3; 43 (1:2)
2; 88
d
4
5
6
7
8
3; 94
4; 65
CFL (27 W)
9
white LEDs
(7 W)
green LEDs
(7 W)
blue LEDs
(7 W)
blue LEDs
(7 W)
blue LEDs (7
W)
blue LEDs
(7 W)
blue LEDs
(7 W)
4; 72
4; 78
4; 82
4; 85
4; 92
4; 63
4; 58
10
11
12
13
14
15
DCM/TMSN3/
TEMPO
MeCN/TMSN3/
TEMPO
THF/TMSN3/
TEMPO
a
Reaction conditions: 1a (1.0 mmol, 1.0 equiv), Me3SI(OAc)2 (1.1
equiv), TMSN3 or NaN3 (2.5 equiv), TEMPO (2.5 equiv), solvent (2
mL), stirred at 35 °C for 12 h, irradiated with a CFL (27 W) or LEDs
b
c
1
(7 W), unless otherwise noted. Isolated yields. Determined by H
d
NMR spectroscopy. Mixture of iodoacetoxy compound, observed by
1H NMR.
unsuccessful and led to diminished reactivity albeit with the
formation of undesirable products (entries 14 and 15).
Having identified the light-controlled azidation procedures,
we first explored the scope of azidooxygenation reaction with
structurally diverse olefins. All of the evaluated substrates
generally performed well, giving desired products (5−28) in
moderate-to-good yields (60−84%); results are illustrated in
Scheme 2. A series of styrenes including electron-donating
moieties (Me, tBu, OEt) with ortho, meta, or para substitutions
reacted smoothly to afford the desired products 5−10 in good
yields. Notably, the sterically hindered aryl alkenes with a di- or
trisubstituent at the arene ring performed well under present
system (7−8). The substrates bearing halogens (F, Cl, Br) at
different positions on the phenyl ring participated successfully
delivering the corresponding products 11−15 with decent
yields. Likewise, an electron-rich 4-vinylbiphenyl, 2-vinyl-
naphthalene, and vinylarene with an ester group were well
tolerated to give the corresponding oxyazides 16−18. We
further observed that α-methyl styrenes with different
electronic environments can be applied under standard
azidooxygenation to obtain the oxyazides 19 and 20 in
acceptable yields. Noteworthy, the azidooxygenation of a
synthetically useful 9-vinylanthracene can be achieved to
generate the desired product 21 albeit with slightly lower
efficiency.
B
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Letter
is amply demonstrated by late-stage transformations into
relevant structures.
Scheme 2. Substrate Scope for the Visible-Light-Induced
Azidooxygenation
Accordingly, reduction of 27 employing a Staudinger
condition following N-Boc protection and sulfonylation of
intermediate free amine readily afforded the functionalized
amine 29 (83%) and sulfonamide 30 (82%) respectively. A
“Click” coupling of azidyl group with alkyne or an iodoalkyne
under standard CuAAC provide rapid access to 5-H/
iodotriazoles 31 and 32 represents potential candidates to
probe the several biological activities.15
Having successfully established the photoinduced azidation,
we next focused on investigating the feasibility of ionic
azidation using sulfonium iodate species. As summarized in
Scheme 3, a wide range of substrates including terminal,
Scheme 3. Substrate Scope for the Azidoiodination
a
Reaction conditions: olefins (1.0 equiv), Me3SI(OAc)2 (1.1 equiv),
TMSN3 (2.5 equiv), TEMPO (2.5 equiv), DCM (2 mL), stirred at 35
b
°C for 12 h, irradiated with blue LEDs (7 W). The isolated and
c
unoptimized yields after chromatography. PPh3 (2.2 equiv), H2O/
d
THF, reflux, then Boc2O (3.0 equiv). Reduction using PPh3/H2O,
e
then 2-thiophenesulfonyl chloride (1.2 equiv), DCM (2 mL). CuSO4
(cat.), arylacetylenes (1.2 equiv), sodium ascorbate (cat.),tBuOH/
H2O (2 mL:1 mL).
It is pertinent to mention that trans-β-methyl styrene
including an internal olefin reacted in a completely regio-
and diastereoselective manner to afford the exclusive syn-
oxyazide 22 in 72% yields. In contrast, indene and 1,2-
dihydronaphthalene bearing a cyclic double bond underwent
anti-addition of azidyl and aminoxyl radical favoring the
formation of trans-oxyazides 23 and 24. The syn- vs trans-
addition may be attributed to the stereoelectronic and steric
contribution of conjugating substituent on the relative
configuration (A-strain model) of benzylic radical (A).14 We
next examined a bicyclic norbornene under the standardized
conditions, producing the desired endo/exo-25 in 69% yields
with a dr of 1:0.75. Nevertheless, a photochemically sensitive
sulfide linkage in phenylvinylsulfide was sustained to afford the
desired product 26 in complete regioselectivity. Subsequently,
a heterocycle such as thaizole and an estrone derivative were
conveniently functionalized into their corresponding oxyazides
27 and 28, constituting a masked 1,2-amino alcohol moiety.
The synthetic versatility of prefunctionalized oxy-azido groups
a
Reaction conditions: olefins (1.0 equiv), Me3SI(OAc)2 (1.1 equiv),
NaN3 (2.5 equiv), toluene (2 mL), stirred at 25 °C for 12 h in the
dark. The isolated and unoptimized yields after purification. The
reaction was irradiated with a 27 W CFL for 12 h at 35 °C. tert-
BuOK (1.2 equiv), THF (2 mL).
b
c
d
internal, cyclic, vinyl, and allylic olefins reacted smoothly to
obtain the desired α-azides 33−59 in good to excellent yields
(70−93%). Arylarenes substituted with both electron-donating
and -withdrawing groups (Me, tBu, OMe, OEt, F, Cl, Ph) were
well tolerated to afford the corresponding azides 33−41.
Vinylarenes with a labile NH-Boc and a naphthyl substrate
were transformed into their respective products 42 and 43
efficiently. Styrenes with α-substitutions (Me or Ph) were also
found to be compatible, affording the corresponding azides
44−46 in good yields. In particular, (E)-β-methylstyrene can
C
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Letter
exclusively undergo Markovnikov addition to give 47 with
complete trans-selectivity, attributed to the anti-opening of
putative iodonium intermediate.12 Likewise, indene and 1,2-
dihydronaphthalene followed stereoselective azidation furnish-
ing the trans-48 and -49 with high dr. Subsequently, a
disubstituted thaizole and eugenyl-derivative proved to be
favorable substrate accomplishing the desired products 50 and
51 with no discrepancy in Markovnikov selectivity. Indeed,
vinyl acetate, 1,2-dihydropyran, and cyclohexene reacted with
exclusive trans-diastereoselectivity to produce the correspond-
ing products 52−54 in good yields.
Notably, enamines such as N-vinyl carbazole and N-
vinylpyrrolidone were competent substrates in applied
protocol affording the desired azides 55−56 in high yields.
Moreover, alkenes with a long chain or a keto group performed
well to provide secondary organic azides 57−59, further
highlighting the synthetic advantage of our method. Specifi-
cally, the representative substrates were subjected to optimal
photoazidation (Table 1, entry 6) producing the terminal
azides 60 and 61 with complementary regioselectivity.
Noteworthy, the vicinal azido iodides resulting from photo-
switchable system are useful synthetic intermediate to enrich
the heterocyclic structures of high pharmaceutical value.16
Though, a sequential transformation of 4-tert-butylstyrene
under light-dark azidoiodination following dehydrohalogena-
tion afforded the corresponding α- and β-vinylazides 62 and 63
in good yields. The variant stereochemical outcomes in
photoswitchable operation are plausibly attributed to the
diverse radical and ionic pathways.
radical pathway involving a nonstereospecific addition of N/
O radical species on the CC bond. The spin-trapping
experiment with a competitive radical scavenger, for instance,
2,6-di-tert-butyl-4-methylphenol (BHT), completely inhibits
the azidooxgenation. However, the azidyl radical originating
from homolysis of weak I−N3 bond from Me3SI(N3)2 species
was trapped by BHT to give an unexpected azide adduct 65
(48%), which presumably arises from radical azidation of
benzylic carbon-H.17 Another spin adduct 4-azido-cyclo-
hexanedienone 66 was also observed occasionally in trace
amounts. The experiment employing 1,2-disubstituted alkenes
(1b, 1d) under photoazidoiodination provided diastereomeric
syn/anti 67 (dr; 2:1) and 68 (dr; 1:1), respectively.18 The
regioselective anti-Markovnikov addition further evidenced the
intermediacy of transient β-azido benzylic carbon radical (A).
Unlike TEMPO trapping step in the azidooxygenation, the
iodine radical generated from iodoazide species may approach
the radical (A) more readily in the absence of aminoxyl radical
to provide syn/anti β-azido products.14 Furthermore, the ionic
azidation of allyl ether under the standard dark reaction
conditions led to a 1:1 mixture of vicinal azidoiodo 69 and
rearranged cyclized adduct 70 (dr; 2:1) in 72% overall yields.
In conclusion, we have successfully developed metal-free
regioselective azidooxygenation and azidoiodination of alkene
under photoswitchable conditions. Generality and functional
group compatibility is amply demonstrated, employing opera-
tionally safer and economical visible-light source. The notable
advantage of this protocol includes the orthogonal reactivity of
sulfonium iodate(I) reagent under light-controlled conditions
resulting regiodivergent azidation. This method enables rapid
access to highly versatile synthetic intermediates en route to
nitrogen-functionalized biologically active natural products.
Light-induced selective radical processes render it a powerful
tool to investigate the specific and hitherto unknown chemical
transformations.
Several control experiments were conducted to further
validate the mechanistic rationalization (Scheme 4). Photo-
irradiation of (E)- or (Z)-stilbene under standard conditions
resulted an identical pair of isomeric-oxyazide 64 albeit with a
different dr. These findings are consistent with our previous
observations12a and unambiguously confirm the two-step
Scheme 4. Control Experiments To Probe the Mechanistic
Hypothesis for Photoswitchable Azidation Promoted by
Sulfonium Iodate Species
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03910.
Experimental details and copies of 1H, 13C NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: skashyap.chy@mnit.ac.in.
ORCID
Sudhir Kashyap: 0000-0001-7722-8554
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
S.K. gratefully acknowledges the Department of Science and
Technology, India, for the Early Career Research Award and
Research Grant for Young Scientists (SERB-ECR/2017/
001477). The authors are also grateful to the Director
MNIT for providing necessary infrastructure. A.G. acknowl-
edges a UGC Fellowship.
D
DOI: 10.1021/acs.orglett.9b03910
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DOI: 10.1021/acs.orglett.9b03910
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