Iron-Catalyzed Direct Olefin Diazidation via Peroxyester Activation Promoted by Nitrogen-Based Ligands

Article abstract of DOI:10.1021/acscatal.8b00821

We herein report an iron-catalyzed direct diazidation method via activation of bench-stable peroxyesters promoted by nitrogen-based ligands. This method is effective for a broad range of olefins and N-heterocycles, including those that are difficult substrates for the existing olefin diamination and diazidation methods. Notably, nearly a stoichiometric amount of oxidant and TMSN₃ are sufficient for high-yielding diazidation for most substrates. Preliminary mechanistic studies elucidated the similarities and differences between this method and the benziodoxole-based olefin diazidation method previously developed by us. This method effectively addresses the limitations of the existing olefin diazidation methods. Most notably, previously problematic nonproductive oxidant decomposition can be minimized. Furthermore, X-ray crystallographic studies suggest that an iron-azide-ligand complex can be generated in situ from an iron acetate precatalyst and that it may facilitate peroxyester activation and the rate-determining C-N₃ bond formation during diazidation of unstrained olefins.

Full text of DOI:10.1021/acscatal.8b00821

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Iron-Catalyzed Direct Olefin Diazidation via Peroxyester
Activation Promoted by Nitrogen-Based Ligands
Shou-Jie Shen, Cheng-Liang Zhu, Dengfu Lu, and Hao Xu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00821 • Publication Date (Web): 06 Apr 2018
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IronꢀCatalyzed Direct Olefin Diazidation via
Peroxyester Activation Promoted by NitrogenꢀBased
Ligands
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Shou-Jie Shen, Cheng-Liang Zhu, Deng-Fu Lu, and Hao Xu*
Department of Chemistry, Georgia State University, 100 Piedmont Avenue SE, Atlanta Georgia,
30303, United States
ABSTRACT: We herein report an ironꢀcatalyzed direct diazidation method via activation of
benchꢀstable peroxyesters promoted by nitrogenꢀbased ligands. This method is effective for a
broad range of olefins and Nꢀheterocycles, including those that are difficult substrates for the
existing olefin diamination and diazidation methods. Notably, nearly a stoichiometric amount of
oxidant and TMSN3 are sufficient for highꢀyielding diazidation for most substrates. Preliminary
mechanistic studies elucidated the similarities and differences between this method and the
benziodoxoleꢀbased olefin diazidation method previously developed by us. This method
effectively addresses the limitations of the existing olefin diazidation methods. Most notably,
previously problematic nonꢀproductive oxidant decomposition can be minimized. Furthermore,
Xꢀray crystallographic studies suggest that an ironꢀazide–ligand complex can be generated in situ
from an iron acetate precatalyst and that it may facilitate peroxyester activation and the rateꢀ
determining C–N3 bond formation during diazidation of unstrained olefins.
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Keywords: iron catalyst, peroxyesters, olefins, Nꢀheterocycles, diazidation, diamination.
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INTRODUCTION
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Vicinal primary diamines are incorporated in a large number of smallꢀmolecule
pharmaceuticals and biological probes; therefore, extensive efforts have been devoted to the
development of selective and general olefin diamination methods, and a variety of powerful
methods have been invented.1 However, there are still significant synthetic challenges that
cannot be fully addressed by these methods. These challenges include: a) it is still difficult to
directly convert aliphatic isolated olefins, especially internal olefins, to vicinal primary diamines;
b) methods for selective diamination of highly functionalized olefins have remained underꢀ
developed; and c) direct diamination of Nꢀheterocycles to afford vicinal primary diamines for
complexꢀalkaloid synthesis has been underꢀexplored.2
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Alternatively, both stoichiometric3 and catalytic4–5 olefin diazidation methods have emerged
with unique value. These methods complement the olefin diamination methods and provide a
convenient approach to producing synthetically important vicinal primary diamines that are
otherwise difficult to obtain. Although an array of olefin diazidation methods have been reported
to date,3–5 the vast majority of them are predominantly restricted to certain limited types of
olefins.3,4cꢀd Furthermore, many of them involve the usage of superꢀstoichiometric amount of
NaN3 in acidic media. Additionally, selective diazidation methods for functionalized Nꢀ
heterocycles have been underꢀdeveloped.6
In 2015, we reported an ironꢀcatalyzed direct diazidation method for a broad range of olefins,
in which an iron catalyst activates TMSN3 in the presence of benchꢀstable benziodoxole 1a to
achieve direct olefin diazidation (Scheme 1).4a This reaction occurs at room temperature with
low catalyst loading and it is effective for a wide variety of olefins, including those that are
incompatible with the existing methods.3 Notably, the anti-selectivity for cyclic olefins can be
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modulated by iron catalysts (dr up to >20:1). Coupled with facile reduction, this method readily
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provides an array of valuable vicinal primary diamines.
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FeII catalyst
R1
O
R1
tridentate ligand
H3N
R3
N3
reduction
TsOH
R2
+
R1
R3
R2
R2
room temperature
O
+ TMSN3
R3
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dr up to >20:1
yield up to 91%
I
(TsO)2 NH3
N3
1a
OH
R2
R1
O
O
R1
N3
TMSN3
TMSN3
R2
R3
Fe(X)2Ln
OTMS
N3
O
1a
R3
I
I
N3
1b
1c
N3
N3
Scheme 1. Ironꢀcatalyzed olefin diazidation with benziodoxole 1a and the proposed mechanistic
working hypothesis
The preliminary mechanistic analysis has revealed that TMSN3 may reversibly convert the
insoluble benziodoxole 1a to azidoiodinane 1b, and then to a transient iodine(III)–diazide
species 1c, with which an iron catalyst may be oxidized to a highꢀvalent ironꢀazide species that
promotes the stepwise olefin diazidation (Scheme 1).4a–b A variety of control experiments
corroborate that the iron–ligand complexes are involved in the rateꢀ, and diastereoselectivityꢀ
determining C–N3 bond forming step in diazidation of unstrained olefins.4a
Identification of the highꢀvalent ironꢀazide species as a possible reactive intermediate has
inspired us to develop a new method that significantly improves upon the reported method.
There are two outstanding challenges in this benziodoxoleꢀbased diazidation method.
First, in the absence of an olefin, an iron catalyst completely decomposes benziodoxole 1a
together with TMSN3 in 3 h (eq 1a), presumably through the ironꢀpromoted decomposition of
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iodine(III)–diazide species 1c.7 In contrast, 1a is stable towards TMSN3 in the absence of an iron
catalyst in CH2Cl2 (eq 1b).7 This competing pathway can be particularly problematic for
substrates with low reactivity since an excess amount of oxidant 1a would be necessary to
achieve a synthetically useful yield. Some of these problematic substrates include electronically
deactivated allylic esters and carbamates. Therefore, a new catalytic method has yet to be
developed such that this nonꢀproductive oxidantꢀdecomposition pathway may be suppressed or
even eliminated.
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Next, an excess amount of TMSN3 (3.6–4.0 equiv) is often applied to achieve high yields in
the aforementioned ironꢀcatalyzed olefin diazidation, in order to effectively activate
benziodoxole 1a.4a A stoichiometric amount of TMSN3 (2.0–2.5 equiv) often led to incomplete
conversion for certain substrates in the aforementioned method, especially aliphatic isolated
olefins. Ideally, nearly a stoichiometric amount of TMSN3 should be sufficient for a more
sustainable and efficient olefin diazidation method.
Herein, we report a new ironꢀcatalyzed direct diazidation method via nitrogenꢀbased ligandꢀ
promoted activation of benchꢀstable peroxyesters that effectively address the limitations of the
previously developed method (Scheme 2). In this method, nearly a stoichiometric amount of
oxidant and TMSN3 are sufficient for effective diazidation of a broad range of olefins and N-
heterocycles at room temperature. Notably, a variety of previously difficult substrates are
compatible with this new method, some of which include allylic esters and carbamates, βꢀpinene,
highly functionalized indoles, pyrroles that are prone to rapid reꢀaromatization, as well as β,γꢀ
unsaturated ketones.
FeII catalyst/ligand
iPrOH (1.2 equiv)
N3 R1
R2
R1
R3
O
R2
room temperature
TMSN3
+
+
R3
O
tBu
O
R4
dr up to >20:1
yield up to 92%
N3
1.2 1.4 equiv
2.4 equiv
R1, R2, R3, R4: alkyl or aryl
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Scheme 2. Ironꢀcatalyzed olefin diazidation via nitrogenꢀbased ligandꢀpromoted peroxyester
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activation
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Compared with the benziodoxoleꢀbased method, preliminary mechanistic studies revealed that
the previously problematic nonꢀproductive oxidantꢀdecomposition pathway can be effectively
suppressed with this new method. Xꢀray crystallographic studies further suggest that an ironꢀ
azide–ligand complex can be generated in situ from an iron acetate precatalyst and it may
facilitate peroxyester activation and the rateꢀdetermining C–N3 bond formation during
diazidation of unstrained olefins.
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RESULTS AND DISCUSSION
Table 1. Catalyst discovery for indene diazidation via nitrogenꢀbased ligandꢀpromoted
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peroxyester activation
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aReactions were carried out under N2 and subsequently quenched with saturated Na2CO3
solution. Conversion was measured by H NMR analysis. Isolated yield. Standard safety
precautions about handling TMSN3 should be taken; see SI for details.
b
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c
Benchꢀstable tertꢀbutyl peroxyesters have been extensively applied in a variety of oxygenꢀ
atom transfer reactions;8 however, roomꢀtemperature olefin diazidation via ligandꢀpromoted
peroxyester activation using nearly a stoichiometric amount of azide source has not been
developed.9 To explore the possible new reactivity through iron catalysis, we select indene (2) as
a model substrate in catalyst discovery for both synthetic and mechanistic considerations (Table
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1). Extensive exploration of a range of iron catalysts and ligands revealed that the Fe(OAc)2–
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bidentate ligand L1 complex effectively activates benchꢀstable tertꢀbutyl peroxybenzoate 3a in
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the presence of TMSN3 (2.4 equiv) and PrOH (1.2 equiv), and that it catalyzes efficient indene
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diazidation with excellent dr at room temperature (Table 1).
There are several key observations that are mechanistically important (Table 1). First, the ironꢀ
catalyzed peroxyester activation and olefin diazidation are enabled by nitrogenꢀbased ligands: in
the absence of a ligand, essentially no reaction was observed and both 2 and 3a were fully
recovered (entry 1). Next, mild proton donors are critical for catalyst turnover and iPrOH leads to
a more efficient reaction than H2O (entries 2–3). Furthermore, the iron catalyst can activate a
range of peroxyesters (entries 4–5): a more electronꢀdeficient peroxyester 3c leads to a faster
reaction and distinct dr values were observed with different peroxyesters (3b vs 3c). These
observations suggest that the corresponding carboxylate ligand, presumably generated through
the ironꢀmediated O–O bond cleavage, may be involved in the drꢀdetermining transition state.
To our surprise, the Fe(OAc)2–tridentate ligand L2 complex, an effective catalyst in our
previously reported, benziodoxoleꢀbased olefin diazidation method,4a is almost inactive in this
reaction: only a small amount of product was observed (entry 6, 6% yield, dr: 16:1).
Furthermore, another Fe(OAc)2–tridentate ligand L3 complex also suffers from low reactivity
(entry 7). Interestingly, both the Fe(NTf2)2–L1 and Fe(NTf2)2–L2 complexes catalyze a rapid
reaction; however, the desired indene diazide 4 was isolated in only moderate yields (entries 8–
9). These results suggest that there may be mechanistic nuances between the Fe(OAc)2ꢀ and
Fe(NTf2)2ꢀcatalyzed reactions.
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Most notably, in the absence of an olefin, the vast majority of 3a is recovered under the
reaction condition (eq 2),7 which suggests that the non-productive oxidant decomposition has
been minimized with this new method.
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Upon the discovery of active iron catalysts, we explored this method with a range of
unfunctionalized olefins (Table 2). First, we evaluated olefins with electron-rich allylic C–H
bonds which tend to undergo C–H azidation.10 We observed that both the Fe(OAc)2–L1 and
Fe(NTf2)2–L2 complexes are effective for allylsilane diazidation; however, the Fe(NTf2)2–L2
catalyst promotes a more rapid reaction with low catalyst loading (entry 1). It is noteworthy that
a slight excess of peroxyester 3a (1.4 equiv) is used to ensure reaction reproducibility since a
strong Lewisꢀacidic Fe(NTf2)2 catalyst is applied. Allylbenzene, a substrate prone to undergo
direct C–H azidation, is selectively converted to the corresponding diazide (entry 2). We also
observed that this method is effective for isolated olefins, including monoꢀsubstituted, 1,1ꢀ
disubstituted, and transꢀdiꢀsubstituted olefins (entries 3–5). Notably, the ironꢀcatalyzed
diazidation of (+)ꢀcamphene diastereoselectively affords the camphene diazide with excellent dr
(entry 6, dr >20:1).11
Since norbornane diamines are valuable synthetic building blocks and their previous syntheses
are lessꢀstraightforward,12 we evaluated norbornene in this ironꢀcatalyzed diazidation and
discovered that the Fe(OAc)2–L1 complex catalyzes norbornene diazidation with a good overall
yield, albeit in moderate dr (entry 7). Gratifyingly, a facile reduction–NꢀBoc protection
procedure furnishes the readily separable NꢀBoc norbornane diamines 6a and 6b in an excellent
overall yield (eq 3).
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Table 2. Ironꢀcatalyzed peroxyester activation for diazidation of unfunctionalized olefins
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aReactions were carried out under N2 unless stated otherwise. bIsolated yield. cFe(NTf2)2 (5 mol
%), L2 (5 mol %), BuOOBz (1.4 equiv), TMSN3 (2.5 equiv), PrOH (1.2 equiv). Fe(OAc)2 (10
t
i
d
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mol %), L1 (10 mol %), tBuOOBz (1.2 equiv), TMSN3 (2.4 equiv), iPrOH (1.2 equiv). eCatalyst
loading (5 mol %).
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This method also proves compatible with styrenyl olefins. We observed that the Fe(OAc)2–L1
complex catalyzes highꢀyielding diazidation of styrene, α, and βꢀmethyl styrenes, as well as
transꢀstilbene (entries 8–11). Furthermore, the same catalyst also promotes diazidation of indene
and dihydronaphthalene with excellent diastereoselectivity (entries 12–13).
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Both 1,2ꢀ and 1,4ꢀallylic primary diamines are important building blocks in synthesis;
however, expedient synthesis of 1,4ꢀallylic primary diamines through direct 1,4ꢀdiene
diamination has been difficult.13 Likewise, methods for vicinal diamination of the terminal olefin
in a 1,4ꢀdiene for primary diamine synthesis have also been underꢀdeveloped.14 To achieve
expedient synthesis of these allylic primary diamines, we explored the ironꢀcatalyzed diazidation
with 1,3ꢀdienes (entries 14–15). We observed that the Fe(OAc)2–L1 complex catalyzes vicinal
diazidation of a phenylꢀsubstituted 1,3ꢀdiene and that the Fe(NTf2)2–L2 complex rapidly
catalyzes alkylꢀsubstituted 1,3ꢀdiene diazidation to afford a 1:1 mixture of 1,2ꢀ and 1,4ꢀdiazides
that are in equilibrium, presumably through a facile allylic azide rearrangement.15 A standard
reduction–NꢀBoc protection procedure can convert the diazide mixture 7a/b to readily separable
1,2ꢀ and 1,4ꢀNꢀBocꢀdiamines 8a and 8b (eq 4).15
With the success of this new method for selective diazidation of unfunctionalized olefins, we
subsequently evaluated a wide variety of Nꢀheterocycles as well as highly functionalized olefins
(Table 3).
Table 3. Ironꢀcatalyzed peroxyester activation for diazidation of Nꢀheterocycles and highly
functionalized olefins
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aReactions were carried out under N2 unless stated otherwise. bIsolated yield. cFe(NTf2)2 (5 mol
t
i
d
%), L2 (5 mol %), BuOOBz (1.4 equiv), TMSN3 (2.5 equiv), PrOH (1.2 equiv). 10 mol %
e
i
f
Catalyst was applied. Neither PrOH nor other proton donor was applied. MeI (5.0 equiv),
g
t
K2CO3 (3.0 equiv). Fe(OAc)2 (10 mol %), L1 (10 mol %), BuOOBz (1.2 equiv), TMSN3 (2.4
equiv), iPrOH (1.2 equiv). hFe(NTf2)2 (10 mol %), L2 (10 mol %), tBuOOBz (3.0 equiv), TMSN3
(4.0 equiv), iPrOH (0.5 equiv).
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We discovered that both NꢀTroc indole and 3ꢀmethyl NꢀTroc indole are excellent substrates
and the corresponding transꢀdiazides were isolated as a single diastereomer (entries 1–2).9 We
further observed that the iron catalyst is sufficiently functional groupꢀtolerant such that
tryptamine carbamate, indole propionic acid, and NꢀTroc dihydroquinoline are all readily
converted to the corresponding transꢀdiazides with excellent dr (entries 3–5). Interestingly, the
Fe(NTf2)2–L2 complex also catalyzes a previously difficult 1,4ꢀselective NꢀBoc pyrrole
diazidation, affording a transꢀpyrrol diazide with excellent dr (entry 6, dr >20:1).16
Highly functionalized terpenes are important building blocks for organic synthesis; however,
selective terpene diazidation has been difficult since redoxꢀlabile functional groups are lessꢀ
compatible with the vast majority of the existing diazidation methods. Therefore, we further
explored this ironꢀcatalyzed method with a range of complex terpenes. We observed that a more
electronꢀrich olefin at the distal position in geranyl acetate can be preferentially functionalized,
affording a geranyl diazide (entry 7). Likewise, two olefinic moieties within (–)ꢀcarvone can be
differentiated and the azidoꢀgroup is selectively transferred to the less electronꢀdeficient olefin
(entry 8). Notably, the labile aliphatic aldehyde group in (±)ꢀcitronellal is compatible with the
method without detrimental aldehyde oxidation (entry 9). Furthermore, a β,γꢀunsaturated ketone
can readily undergo diazidation without olefin isomerization (entry 10). Moreover, this method is
effective for both electronꢀdeficient methyl cinnamate and an electronꢀrich enamide (entries 11–
12). It is also compatible with a carboxylic acid functional group without lactone formation
(entry 13).
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Multiꢀfunctional vicinal diamino alcohols and triꢀamines are valuable building blocks for
organic synthesis; however, diamination methods for allylic esters and carbamates have not been
developed.17,18 Additionally, electronically deactivated allylic esters and carbamates present low
reactivity under the standard reaction condition in our previously reported method. As a result,
we explored the new method with these challenging substrates and discovered that the
Fe(NTf2)2–L2 complex catalyzes highꢀyielding diazidation of these electronically deactivated
substrates (entries 14–15). A straightforward reduction–protection sequence can thereby afford
the functionalized vicinal diamino alcohol 10 and triꢀamine 12 (eqs 5 and 6).
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The unique synthetic strength of this ironꢀcatalyzed method has inspired us to probe for its
mechanistic details with a series of control experiments and to elucidate the similarities and
differences between this olefin diazidation method and the previously reported, benziodoxoleꢀ
based method.4a
Scheme 3. Mechanistic experiments to probe for the intermediacy of a carboꢀradical species
aFe(NTf2)2 (10 mol %), L2 (10 mol %), 3a (1.4 equiv), TMSN3 (2.5 equiv), iPrOH (1.2 equiv),
TEMPO (1.0 equiv); bFe(OAc)2 (10 mol %), L1 (10 mol %), 3a (1.2 equiv), TMSN3 (2.4 equiv),
iPrOH (1.2 equiv), TEMPO (1.0 equiv); cFe(NTf2)2 (5 mol %), L2 (5 mol %), 3a (1.4 equiv),
i
TMSN3 (2.5 equiv), PrOH (1.2 equiv); dFe(OAc)2 (10 mol %), L1 (10 mol %), 3a (1.2 equiv),
TMSN3 (2.4 equiv), iPrOH (1.2 equiv).
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First, TEMPO radical was introduced in the ironꢀcatalyzed dodecene (13) diazidation and a
TEMPOꢀaddition product 14 was observed when either Fe(NTf2)2 or Fe(OAc)2 was used as a
catalyst (Scheme 3). Next, we evaluated a substituted vinylcyclopropane 15 with this ironꢀ
catalyzed method and isolated the ringꢀopening product 1,5ꢀdiazide 16 in excellent yields with
either iron catalyst (Scheme 3). These results suggest that azido radical is likely involved in the
first C–N3 bond forming step, which may initiate radical addition to an olefin and afford a
carbo-radical species.
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After the first C–N3 bond formation, the second C–N3 bond forming step can proceed through
azido group transfer to either a carboꢀradical or a carbocation species. In order to differentiate
these two mechanistic possibilities, we explored diazidation of (ꢀ)ꢀβꢀpinene 17 (Scheme 4).
Notably, the exocyclic olefin of (ꢀ)ꢀβꢀpinene can be selectively 1,2ꢀdifunctionalized using both
iron catalysts, which exclusively affords a vicinal diazide 18 with excellent dr (Scheme 4, dr
>20:1). Facile reduction and protonation of 18 furnishes diaminium salt 19.
Scheme 4. Ironꢀcatalyzed regioꢀ and diastereoꢀselective diazidation of (ꢀ)ꢀβꢀpinene
i
aFe(NTf2)2 (5 mol %), L2 (5 mol %), 3a (1.4 equiv), TMSN3 (2.5 equiv), PrOH (1.2 equiv);
i
bFe(OAc)2 (10 mol %), L1 (10 mol %), 3a (1.2 equiv), TMSN3 (2.4 equiv), PrOH (1.2 equiv);
d
cPd/C (10 wt. %) in MeOH, 12 h, then pꢀTsOH·H2O; Fe(OAc)2 (20 mol %), L1 (20 mol %), 3a
(1.2 equiv), TMSN3 (2.4 equiv), iPrOH (1.2 equiv), TEMPO (0.5 equiv).
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To our surprise, neither a ringꢀcontraction nor a ringꢀfragmentation product (20a or 20b) was
detected. Since ringꢀcontraction from the (ꢀ)ꢀβꢀpinene scaffold has been wellꢀprecedented in
carbocationꢀmediated reactions,19 the absence of 20a suggests that the second C–N3 bond
formation likely proceeds through a carbo-radical instead of a carbocation species.
Additionally, the lack of the ringꢀfragmentation product 20b suggests that the rate of the second
C–N3 bond formation is faster than the one of carboꢀradical fragmentation.
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Unlike dodecene (Scheme 3), the diazidation of highly strained (ꢀ)ꢀβꢀpinene in the presence of
TEMPO radical affords both the TEMPOꢀaddition product 21 and the diazidation product 18,
which suggests that the second C–N3 bond forming step is not rate-limiting for this highly
strained substrate.
Scheme 5. Control experiments to determine the rateꢀlimiting step for diazidation of unstrained
olefins
aFe(NTf2)2 (5 mol %), L2 (5 mol %), 3a (1.4 equiv), TMSN3 (2.5 equiv); b1 M aq. H2SO4, 15
c
min; Fe(OAc)2 (10 mol %), L1 (10 mol %), 3a (1.2 equiv), TMSN3 (2.4 equiv); dFe(OAc)2 (10
mol %), L1 (10 mol %), 3c (1.2 equiv), TMSN3 (2.4 equiv).
In order to determine which C–N3 bond forming step is rateꢀlimiting for unstrained olefins, we
carried out a few control experiments (Scheme 5). First, we evaluated (Z)-hexꢀ3ꢀenꢀ1ꢀol 22a in
the Fe(NTf2)2ꢀcatalyzed diazidation with 3a and identified a significant amount of the
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isomerization product (E)-hexꢀ3ꢀenꢀ1ꢀol 22b along with the diazide 23 within 5 min. Notably,
both 22a and 22b were converted to diazide 23 in a stereoꢀconvergent manner in 2 h.
Interestingly, when the Fe(OAc)2–L1 complex was used as the catalyst, only the isomerization
product 22b was observed. Notably, the Fe(OAc)2 catalyst promotes a faster reaction with a
more electronꢀdeficient oxidant 3c: both 22b and 23 were observed within 2 h. These results
suggest that the second C–N3 bond forming step is rate-limiting in the iron-catalyzed diazidation
of unstrained olefins.
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Scheme 6. Control experiments to probe for mechanistic insights of azidoꢀradical generation
b
i
a1a (1.2 equiv), TMSN3 (4.0 equiv), 2 h; 3a (1.2 equiv), TMSN3 (2.4 equiv), PrOH (1.2
equiv).
Since azidoꢀradical is likely involved in the first C–N3 bond forming step, we further
investigated the mechanistic details of the ligandꢀpromoted peroxyester activation for azidoꢀ
radical generation (Scheme 6). We observed that benziodoxole 1a and TMSN3 promote
isomerization of cisꢀstilbene 24a to transꢀstilbene 24b in the absence of an iron catalyst.4a
However, without an iron catalyst, cisꢀstilbene 24a is completely unreactive towards peroxyester
3a with TMSN3, and no isomerization is observed. These results suggest that, unlike the
benziodoxole-based method, azido-radical generation is iron catalyst-dependent in this new
method.
Likewise, in the absence of an olefin, an iron catalyst completely decomposes benziodoxole 1a
with TMSN3, furnishing oꢀiodobenzoic acid 25 (eq 1a in introduction).7 However, we observed
that the vast majority of peroxyester 3a is recovered with either iron catalyst in the absence of an
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olefin using this new method (eq 2 on page 8).7 These observations suggest that the non-
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Scheme 7. Control experiments to corroborate the involvement of a carboxylate ligand in the
rateꢀdetermining C–N3 bond forming step for unstrained olefins
aFe(NTf2)2 (10 mol %), L2 (10 mol %), 3a (3.0 equiv), TMSN3 (4.0 equiv), iPrOH (0.5 equiv);
bFe(NTf2)2 (10 mol %), L2 (10 mol %), 3c (3.0 equiv), TMSN3 (4.0 equiv), iPrOH (0.5 equiv).
The observed electronic effect of a peroxyester over the reaction rate in an Fe(OAc)2ꢀcatalyzed
diazidation (Scheme 5) has inspired us to reꢀevaluate the Fe(NTf2)2ꢀcatalyzed diazidation of
challenging substrates, such as allyl benzoate 26. As a result, we observed an evidently faster
reaction using a more electronꢀdeficient peroxyester 3c compared with the standard oxidant 3a
(Scheme 7). Since the O–O bond cleavage of electronically distinct 3a/3c is less-likely to be rate-
limiting (Scheme 5), this result suggests that the carboxylate ligand, presumably generated
through the O–O bond cleavage, is likely involved in the rate-determining transition state in both
Fe(NTf2)2- and Fe(OAc)2-catalyzed reactions.
Not only can an oxidant affect the diazidation rate, a ligand can also evidently modulate the
reactivity. In particular, the observed ligand effect in the Fe(OAc)2ꢀcatalyzed olefin diazidation is
mechanistically intriguing: while the Fe(OAc)2–bidentate ligand L1 complex is effective for
indene diazidation, the Fe(OAc)2–tridentate ligand L2 complex is almost inactive (Table 1, entry
6). Since the first C–N3 bond formation is reversible for diazidation of unstrained olefins, the
observed rate retardation with the Fe(OAc)2–L2 complex may be attributed to either ineffective
peroxyester O–O bond cleavage or inefficient carbo-radical oxidation.
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Scheme 8. Control experiments to probe for ligand effect
aFe(OAc)2 (10 mol %), L2 (10 mol %), 1a (1.2 equiv), TMSN3 (4.0 equiv); bFe(OAc)2 (10 mol
%), L2 (10 mol %), 3d (1.2 equiv), TMSN3 (2.4 equiv), iPrOH (1.2 equiv).
To differentiate these two possibilities, we carried out a few control experiments (Scheme 8).
First, we observed that the Fe(OAc)2–tridentate L2 complex rapidly catalyzes dodecene
diazidation using benziodoxole 1a; however, it is completely inactive when tert-butyl peroxy 2-
iodobenzoate 3d is used as the oxidant. These results suggest that the inefficient O–O bond
cleavage by the Fe(OAc)2–L2 complex is likely the reason for the observed low reactivity.
Since the Fe(OAc)2ꢀ and Fe(NTf2)2ꢀcatalyzed reactions present distinct reactivity profiles
(Table 1), we suspect that different active catalytic species may be involved. Therefore, we
further studied the coordination chemistry of the Fe(OAc)2ꢀ and Fe(NTf2)2–ligand complexes in
the presence of TMSN3 (Scheme 9).
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viscous oil
no characteristic
Fe−N3 IR stretches
O
O
TMSN3 (1.0 equiv)
N
Fe(NTf2)2
10 mol %
+
N
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L2
10 mol %
CH2Cl2/MeCN (10:1)
22 °C
Me
Me
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Me
Scheme 9. Structure–reactivity relationship studies of the Fe(OAc)2 and Fe(NTf2)2 catalysts in
the presence of TMSN3
a28 (10 mol %), 3a (1.2 equiv), TMSN3 (2.4 equiv), iPrOH (1.2 equiv); b28 (10 mol %), 3a (1.2
equiv), iPrOH (1.2 equiv); c28 (25 mol %), 3c (1.2 equiv).
We observed that the grey solution of the Fe(OAc)2–L1 complex turned dark when an excess
amount of TMSN3 was introduced. Subsequent ether trituration readily afforded solid 28 and IR
analysis revealed strong azido group absorptions (2041 and 2073 cmꢀ1) shifted to lower energy in
comparison to free azide, characteristic of ironꢀazide complexes (Scheme 9).20 We discovered
that 28 is catalytic active for indene diazidation. Interestingly, in the absence of TMSN3, 28 also
promotes the diazidation with essentially the same dr, albeit in a low yield (Scheme 9).21
Additionally, 28 promotes diazidation of (Z)-hexꢀ3ꢀenꢀ1ꢀol 22a in the absence of TMSN3, which
readily affords both the diazidation product 23 and olefin isomerization product 22b (Scheme 9).
Extensive exploration of crystallization conditions of 28 afforded solid 29 that is suitable for
Xꢀray crystallographic analysis, which revealed the bridged dimeric structure of solid 29 as
FeIII (L1)2(N3)6 (Scheme 9). We suspect that 28 may be oxidized to afford 29 during crystal
2
growth.22 These experiments suggest that the Fe(OAc)2 catalysts are converted to iron-azide
complexes in their resting state by TMSN3, and that the iron–azide bond may be involved in the
rate-limiting azido-group transfer during diazidation of unstrained olefins.
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Interestingly, we did not observe the solid formation of the Fe(NTf2)2–L2 complex under the
analogous condition and IR analysis of the resulting viscous oil revealed lack of characteristic
azidoꢀgroup absorptions (Scheme 9). This experiment suggests that the Fe(NTf2)2 catalysts may
not be converted to the corresponding iron-azide complexes by TMSN3 in their resting state.
Based upon a variety of collected mechanistic insights, we propose the mechanistic working
hypotheses for the Fe(NTf2)2ꢀ and Fe(OAc)2ꢀcatalyzed olefin diazidation respectively (Scheme
10).
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Fe(OAc)2Ln
N3 Si(Me)3
N3 R1
O
b)
Fe(N3)2Ln
TMSO2CR4
+
R2
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tBu
O
R4
R3
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3
N3
N3 Si(Me)3
O2CR4
tBuO
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N3 Si(Me)3
+ iPrOH
R3
N3 FeLn
N3
R2
R1
N3
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R3
tBuOH + TMSOiPr
Scheme 10. Mechanistic working hypotheses of the Fe(NTf2)2ꢀ and Fe(OAc)2ꢀcatalyzed olefin
diazidation via ligandꢀpromoted activation of peroxyesters
In an Fe(NTf2)2ꢀcatalyzed reaction (Scheme 10a), an Fe(NTf2)2–ligand complex may
reductively cleave the O–O bond in a peroxyester 3 to generate a tertꢀbutoxyl radical which is
i
associated with a highꢀvalent iron complex 30 with a carboxylate ligand. PrOH presumably
facilitates gradual release of HN3 from TMSN3, and tertꢀbutoxyl radical may thereby be rapidly
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sequestered by HN3 to liberate azido radical. The azido radical may readily add to an olefin to
afford carboꢀradical species 31. Since the carboxylate ligand is involved in the rateꢀdetermining
transition state in the Fe(NTf2)2ꢀcatalyzed diazidation, we propose that TMSN3 may reversibly
convert the iron(III) species 30 to a highꢀvalent ironꢀazide species 32, which presumably
mediates the rateꢀdetermining azidoꢀgroup transfer to the carboꢀradical species 31 and afford the
diazidation product.23 Notably, the Fe(NTf2)2–ligand complex can be readily regenerated by the
transiently generated TMSNTf2.
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In an Fe(OAc)2ꢀcatalyzed reaction (Scheme 10b), an ironꢀazide–ligand complex 33 can be
generated in situ, which may facilitate the O–O bond cleavage and azidoꢀradical generation in an
analogous way. However, the highꢀvalent ironꢀazide species 34 may directly mediate the rateꢀ
limiting azidoꢀgroup transfer to the carboꢀradical species 31 and furnish the diazidation product.
Subsequently, TMSN3 may readily convert the iron(II)ꢀcarboxylate complex back to the
catalytically active ironꢀazide complex 33 via anion metathesis.
CONCLUSIONS
In conclusion, we have reported an ironꢀcatalyzed direct diazidation method via nitrogenꢀbased
ligandꢀpromoted activation of benchꢀstable peroxyesters. This method significantly improves
upon our previously reported, benziodoxoleꢀbased method and it is effective for a broad range of
olefins and Nꢀheterocycles, including those that are difficult substrates for the existing olefin
diamination and diazidation methods. Most notably, nearly a stoichiometric amount of oxidant
and TMSN3 are sufficient for highꢀyielding diazidation for most substrates. Furthermore,
preliminary mechanistic studies were carried out to elucidate the similarities and differences
between this new method and the benziodoxoleꢀbased diazidation method. It was revealed that,
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unlike the benziodoxoleꢀbasedꢀmethod, azidoꢀradical generation is ironꢀcatalystꢀdependent and
the nonꢀproductive oxidantꢀdecomposition pathway can be effectively suppressed using this new
method. Xꢀray crystallographic studies further suggest that an ironꢀazide–ligand complex can be
generated in situ from an iron acetate precatalyst and it may facilitate peroxyester activation and
the rateꢀdetermining C–N3 bond formation for diazidation of unstrained olefins. Our current
efforts focus on synthetic applications of this new method for complexꢀmolecule synthesis.
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ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
* hxu@gsu.edu (Hao Xu) ORCID: 0000ꢀ0001ꢀ5029ꢀ8392
Funding Sources
This research was supported by the National Institutes of Health (GM110382) and Alfred P.
Sloan Foundation (FGꢀ2015ꢀ65240).
Supporting Information.
Experimental procedure, characterization data for all new compounds, and selected NMR
spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
H. X. is an Alfred P. Sloan Research Fellow. We thank Prof. Caleb D. Martin and Ms. Sam
Yruegas for Xꢀray crystallographic analysis of an ironꢀazide complex 29. We also thank a referee
for the insightful critiques.
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REFERENCES
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(1) For selected references of olefin diamination methods, see: a) Chong, A. O.; Oshima, K.;
Sharpless, K. B. Synthesis of Dioxobis(tertꢀalkylimido)osmium(VIII) and Oxotris(tertꢀ
alkylimido)osmium(VIII) Complexes. Stereospecific Vicinal Diamination of Olefins. J. Am.
Chem. Soc. 1977, 99, 3420−3426; b) Bäckvall, J.ꢀE. Stereospecific PalladiumꢀPromoted Vicinal
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Diamination of Olefins. Tetrahedron Lett. 1978, 19, 163−166; c) Becker, P. N.; White, M. A.;
Bergman, R. G.
A
New Method for 1,2ꢀDiamination of Alkenes Using
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Bar, G. L. J.; LloydꢀJones, G. C.; BookerꢀMilburn, K. I. Pd(II)ꢀCatalyzed Intermolecular 1,2ꢀ
Diamination of Conjugated Dienes. J. Am. Chem. Soc. 2005, 127, 7308−7309; e) Streuff, J.;
Hövelmann, C. H.; Nieger, M.; Muñiz, K. Palladium(II)ꢀCatalyzed Intramolecular Diamination
of Unfunctionalized Alkenes. J. Am. Chem. Soc. 2005, 127, 14586−14587; f) Zabawa, T. P.;
Kasi, D.; Chemler, S. R. Copper(II) Acetate Promoted Intramolecular Diamination of
Unactivated Olefins. J. Am. Chem. Soc. 2005, 127, 11250−11251; g) Du, H.; Yuan, W.; Zhao,
B.; Shi, Y. Catalytic Asymmetric Diamination of Conjugated Dienes and Triene. J. Am. Chem.
Soc. 2007, 129, 11688−11689; h) Zhao, B. G.; Peng, X. G.; Cui, S. L.; Shi, Y. Cu(I)ꢀCatalyzed
Regioselective Diamination of Conjugated Dienes via Dual Mechanistic Pathways. J. Am. Chem.
Soc. 2010, 132, 11009−11011; i) Sibbald, P. A.; Rosewall, C. F.; Swartz, R. D.; Michael, F. E.
Mechanism of NꢀFluorobenzenesulfonimide Promoted Diamination and Carboamination
Reactions: Divergent Reactivity of a Pd(IV) Species. J. Am. Chem. Soc. 2009, 131,
15945−15951; j) Iglesias, Á.; Pérez, E. G.; Muñiz, K. An Intermolecular PalladiumꢀCatalyzed
Diamination of Unactivated Alkenes. Angew. Chem., Int. Ed. 2010, 49, 8109−8111; k) Olson, D.
E.; Su, J. Y.; Roberts, D. A.; Du Bois, J. Vicinal Diamination of Alkenes under RhꢀCatalysis. J.
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