The ubiquity of nitrogenous functional groups in industrially and medicinally important
organic molecules cannot be overstated. Given their known importance, the development
of reactions that can introduce nitrogen-based functionality to a molecular scaffold
has been a well-traversed area of research. Organic azides serve as versatile precursors
to primary amines following a simple hydrogenation or Staudinger reduction. Outside
of their utility as amine surrogates, the biological stability and diverse reactivity
of azides has led to the development of a variety of bioconjugation methods that hinge
on so-called azide ‘click chemistry’ – typically in the form of copper-catalyzed [3+2]
Huisgen type cycloadditions or Staudinger ligation processes.[1]
[2]
[3]
[4]
[5]
Organic azides are typically prepared via SN2 type substitution reactions, utilizing an inorganic azide source (often sodium azide)
and a primary or secondary alkyl halide. However, this limits the scope of possible
azide products to those that can be tracked to commercially available or synthetically
viable alkyl halide precursors. The direct reaction of a hydrazoic acid (HN3) across olefins is known, but often limited to substrates that produce stabilized
carbocations following protonation and requires the use of excess HN3.[6] Compounded with the well-documented hazards associated with the use of HN3, including its explosive and toxic nature, the direct reaction of alkenes with hydrazoic
acid is not a realistic solution to the preparation of organic azides in a small-scale
laboratory setting.
Several transition-metal-mediated and radical hydroazidation reactions have been reported
in recent years (Scheme [1]). In 2005, Carreira and co-workers reported a hydroazidation reaction of simple
unactivated olefins by using a cobalt Schiff base complex that was prepared in situ
in the presence of a substoichiometric quantity of hydroperoxide oxidant, silane,
and tosyl azide.[7] While this method is mild and tolerant of a variety of functional groups, examples
utilizing styrenes or other types of electron-rich olefin substrates are limited.
Electrophilic nitrogen-centered azide radicals engage in anti-Markovnikov addition
reactions with unactivated olefins.[8]
[9]
[10]
[11] Azide radicals may be generated using hypervalent azido-iodine compounds in combination
with a copper catalyst or photoredox catalyst, affecting the hydroazidation of simple
olefins.[12,13] Earlier this year, Xu and co-workers reported the generation of azide radicals using
a benziodoxole organocatalyst in the presence of water and trimethylsilylazide (TMSN3).[14] This reaction proceeds smoothly with a variety of mono-, di- and tri-substituted
olefins bearing a number of potentially sensitive functional groups. However, more
electron-rich olefins, including substituted and unsubstituted styrenes, enol ethers
and enamines proved unreactive under the optimized conditions.
Scheme 1 Recent work in alkene hydroazidation
To our knowledge, methods for the direct anti-Markovnikov hydroazidation of activated
alkenes are nonexistent. As such, we sought to develop a hydroazidation reaction that
would operate smoothly on these more electron-rich substrates. A methodology that
would enable the hydroazidation of styrenyl substrates is particularly interesting
given the known biological activity of phenylethylamine derivatives.[15]
Based on previous work from our group focused on alkene hydrofunctionalization reactions,
we envisioned that photoredox catalysis may be a useful tool to develop a methodology
enabling the anti-Markovnikov hydroazidation of this class of substrates.
By using a strongly oxidizing acridinium salt photoredox catalyst, alkene cation radicals
may be generated in catalytic quantities via photoinduced electron transfer (PET)
upon irradiation with blue light. The removal of an electron from the alkene π-system
renders the resulting cation radical electrophilic and able to react with a suitably
paired nucleophilic partner. Following interception of the cation radical by a nucleophile,
a hydrogen atom transfer event facilitated by a hydrogen atom donor co-catalyst can
trap the resulting benzylic radical, affording formal hydrofunctionalization products.[16]
[17] Since the regioselectivity of nucleophile addition is dictated by the formation
of the more stable radical species, this process proceeds with anti-Markovnikov selectivity
in nearly all cases (Scheme [2]).
Scheme 2 Regioselectivity in nucleophilic addition to alkene radical cations
The generation of reactive cation radical and neutral radical species in catalytic
qualities renders this chemistry tolerant of a variety of synthetically useful functional
handles. Our group has leveraged the reactivity of PET-generated alkene cation radicals
to develop formal anti-Markovnikov hydroacetoxylation, hydroamination, and hydroetherification
reactions, among others.[17]
[18]
[19]
[20]
[21] Based on this body of work, we envisioned that a formal hydroazidation reaction
could be conceived through a similar reaction manifold.
Scheme 3 Reaction optimization
Reaction development began with the use of indene as a substrate in the presence of
5 mol% of acridinium photooxidant tBu-Acr-BF4, 20 mol% of diphenyl disulfide, and 2.0 equivalents of sodium azide in trifluoroethanol
(TFE, 0.1 M), a solvent commonly employed in our past reactions that was also thought
to act as a proton source (Scheme [3]). Tetrabutylammonium tetrafluoroborate (TBA BF4; 2.0 equiv) was added under the assumption that the tetrabutylammonium cation would
serve as a phase-transfer agent, helping to solubilize azide ions. Following irradiation
for 18 hours, the desired hydroazidation product was formed in 30% yield (based on
1H NMR analysis using HMDSO as an internal standard). Along with the desired product,
a nearly equal amount of the corresponding thiol-ene product, resulting from addition
of a thiyl radical formed via homolysis of diphenyl disulfide to the olefin, was observed.
When acetonitrile (MeCN) was used as the solvent under otherwise identical conditions,
only alkene starting material was observed following irradiation. By exchanging the
hydrogen atom transfer catalyst from diphenyl disulfide to the bulkier 2,4,6-triisopropylthiophenol
(TRIP-SH), the desired product was formed in 75% yield with no formation of thiol-ene
byproducts. Further optimization showed that the loadings of acridinium photocatalyst
and TMSN3 could be lowered to 1 mol% and 1.25 equivalents, respectively, with no adverse effect
on the yield of the hydroazidation product.
Interestingly, in a series of experiments utilizing various TFE/MeCN solvent mixtures
and isosafrole as the substrate, the yield of the desired hydroazidation product decreased
from 91% to 75% as the percentage of acetonitrile in the solvent mixture was increased
from 10% to 25% (Scheme [3], entries 5–8).
Early spectroscopic investigations of the reaction between alkene cation radicals
and various nucleophiles have demonstrated that hydrogen bonding and solvent polarity
have profound effects on the rates of nucleophilic addition to these reactive species.[22]
[23] More specifically, previous work from the Schepp group has demonstrated that the
addition of azide anion to alkene radical cations is strongly affected by hydrogen-bond
attenuation of redox potentials. The kinetics of the reaction between styrene cation
radicals and azide anion has been previously studied via flash photolysis transient
absorption spectroscopy. In non-hydrogen-bonding solvents, such as acetonitrile, the
azide ion (N3
–) is oxidized by the alkene cation radical to yield azide radical (N3
•) and the corresponding neutral alkene. The azide radical then quickly equilibrates
with a second equivalent of azide ion to generate an inactive, non-nucleophilic N6
•– radical anion dimer with an estimated equilibrium constant of ca. 200 M–1 (in MeCN), which is identifiable by an absorption centered at 700 nm.[24] However, when trifluoroethanol is used as the solvent, no absorption attributed
to the formation of N6
•– is identifiable. Following flash photolysis of TFE solutions of styrene derivatives
in the presence of azide ion, an absorption maxima between 350 and 380 nm is observed,
indicating the formation of a benzylic radical resulting from nucleophilic addition
of azide ion to the alkene cation radical.[25] Furthermore, the peak potential observed via cyclic voltammetry for oxidation of
azide ion is shifted +0.5 V in TFE versus MeCN, indicating that hydrogen bonding is
capable of dramatically attenuating the redox potential of this anionic species (E
°
peak (MeCN) = 0.275 V vs. Fc, E
°
peak (TFE) = 0.802 V vs. Fc). When reacted in TFE solution, the alkene cation radical
is no longer able to oxidize the azide ion, and productive nucleophilic addition takes
place. This previous work is in good accordance with our observations during reaction
optimization.
With optimized conditions in hand, the scope of this transformation with respect to
alkene partners was explored (Scheme [4]). β-Substituted styrene derivatives were found to be excellent substrates for this
transformation, with β-methylstyrene affording the desired hydroazidation product
9 in 98% yield (based on NMR analysis, using HMDSO as an internal standard). Simple
alkyl-, aryl-, and chloro-styrene derivatives were all smoothly converted into the
corresponding secondary azide products 11–14 in good yield. A variety of phenolic substrates were well-tolerated under the optimized
reaction conditions, including those bearing benzoyl (22), benzyl (24), and silyl (25) protecting groups. Aromatic ester product 27 was isolated in 70% yield with no transesterification observed. A more oxidizable
naphthalene-derived substrate also afforded the hydroazidation product 26 in good yield. Substrates containing potentially labile benzylic C–H bonds were converted
into the desired products 10, 17, and 28 in excellent yield and no functionalization was detected at these reactive C–H sites.
Notably, a substrate containing a terminal alkene was converted into the anti-Markovnikov
hydroazidation product 30 in 71% isolated yield with no functionalization of the unactivated alkene detected,
highlighting the complementarity of this method to other known radical hydroazidation
reactions. Heterocyclic quinoline and thiophene substrates were functionalized to
give the corresponding azide products 31 and 32, in 55% and 65% yield, respectively. Terminal styrene derivatives underwent the desired
transformation in poor to moderate yields. Notably, diphenyl disulfide was identified
as a more efficient hydrogen atom transfer catalyst than TRIP-SH for these substrates.
Due to the lack of substituents in the β-position, these styrenes are prone to oligomerization
via radical mechanisms. To combat this, a less sterically hindered HAT catalyst must
be employed to accelerate the rate of HAT versus oligomerization. Oxidizable vinyl
ethers were also competent reactants, with products 6 and 7 isolated in 58% and 79% yield. Product 7 is formed following elimination of the tertiary alcohol in hydroazidation product
of substrate 8 during chromatography.
Scheme 4 Substrate scope and proposed mechanism for photoredox alkene hydroazidation
Based on previous mechanistic investigations, the following mechanism is proposed.
Following excitation by 465 nm light, the excited state of the acridinium catalyst
engages in photoinduced electron transfer with the alkene substrate, yielding the
corresponding alkene cation radical and the reduced form of the catalyst. Nucleophilic
addition of azide ion generates a neutral radical species. Based on our observations,
it is not clear whether free azide ion is generated prior to addition to the alkene
cation radical. It is possible that a termolecular transition state involving a solvent
molecule-assisted desilylation/nucleophilic addition is operative or that an azide
silicate species could be the nucleophile. However, it is likely that some free azide
ion is in solution due to hydrolysis of TMSN3 by advantageous water in the reaction mixture, as strict exclusion of water was not
maintained. The benzylic radical engages in hydrogen atom transfer with TRIP-SH, generating
the desired anti-Markovnikov hydroazidation product and a thiyl radical. This thiyl
radical then oxidizes the reduced form of the catalyst, regenerating the ground state
tBu-Acr-BF4 as well as a thiolate anion. This anion is then protonated by solvent to yield the
starting co-catalyst and close the catalytic cycle.
In conclusion, we have developed an organic photoredox anti-Markovnikov hydroazidation
reaction of electron-rich olefin substrates. By utilizing electrophilic cation radical
intermediates, previously problematic hydroazidation reactions involving activated
olefins now proceed efficiently and in high yields with low loadings of both photocatalyst
and TMSN3. Furthermore, the transformation proceeds in the absence of any transition metals
using TMS-N3 as the only stoichiometric reagent.[26] This method fills the gap in the literature with regard to alkene hydroazidation
chemistry.
