Iron-Catalyzed Direct Diazidation for a Broad Range of Olefins

Article abstract of DOI:10.1002/anie.201507550

Reported herein is a new iron-catalyzed diastereoselective olefin diazidation reaction which occurs at room temperature (1-5 mol % of catalysts and d.r. values of up to >20:1). This method tolerates a broad range of both unfunctionalized and highly functionalized olefins, including those that are incompatible with existing methods. It also provides a convenient approach to vicinal primary diamines as well as other synthetically valuable nitrogen-containing building blocks which are difficult to obtain with alternative methods. Preliminary mechanistic studies suggest that the reaction may proceed through a new mechanistic pathway in which both Lewis acid activation and iron-enabled redox-catalysis are crucial for selective azido-group transfer. With iron hand: The title reaction proceeds at room temperature and tolerates a broad range of both unfunctionalized and highly functionalized olefins. It also provides a convenient synthetic approach to a variety of nitrogen-containing building blocks. Preliminary mechanistic studies suggest both Lewis acid activation and iron-enabled redox catalysis are crucial for the selective azido-group transfer.

Full text of DOI:10.1002/anie.201507550

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International Edition: DOI: 10.1002/anie.201507550
German Edition: DOI: 10.1002/ange.201507550
Homogeneous Catalysis
Iron-Catalyzed Direct Diazidation for a Broad Range of Olefins
Yong-An Yuan+, Deng-Fu Lu+, Yun-Rong Chen, and Hao Xu*
Abstract: Reported herein is a new iron-catalyzed diastereo-
selective olefin diazidation reaction which occurs at room
temperature (1–5 mol% of catalysts and d.r. values of up to
> 20:1). This method tolerates a broad range of both
unfunctionalized and highly functionalized olefins, including
those that are incompatible with existing methods. It also
provides a convenient approach to vicinal primary diamines as
well as other synthetically valuable nitrogen-containing build-
ing blocks which are difficult to obtain with alternative
methods. Preliminary mechanistic studies suggest that the
reaction may proceed through a new mechanistic pathway in
which both Lewis acid activation and iron-enabled redox-
catalysis are crucial for selective azido-group transfer.
transformation. First, a general and selective catalytic method
that is compatible with a broad range of both unfunctional-
ized and highly functionalized olefins has yet to be developed.
Second, a diastereoselective method for internal olefins has
not yet been reported. Furthermore, a new diazidation
reaction which proceeds through a new selective pathway
under mild reaction conditions (thus avoiding both heating
and cryogenic cooling) has yet to be discovered.
Herein, we describe an iron-catalyzed diastereoselective
olefin diazidation at room temperature with low catalyst
loading (Scheme 1).[4] This new method tolerates a broad
S
elective nitrogen-atom-transfer for olefin functionalization
is a powerful transformation which generates high-value
chemicals from hydrocarbons. Among a range of olefin
functionalization processes by azido-group transfer, catalytic
olefin diazidation has emerged with unique value for a few
reasons.[1] First, this reaction provides a convenient approach
to producing synthetically important vicinal primary diamines
which are difficult to obtain with the existing olefin diamina-
tion methods.[2] Next, it can also rapidly convert olefins into
a variety of probes for the robust azide–alkyne click
chemistry, which becomes increasingly important for biolog-
ical and material sciences.[1h] Therefore, searching for a gen-
eral, yet selective olefin diazidation method has been an
important research topic and a range of methods for certain
limited types of olefins have been developed.[3]
Scheme 1. Iron-catalyzed diastereoselective olefin diazidation.
TMS=trimethylsilyl, Ts =4-toluenesulfonyl.
range of olefins, including those that are incompatible with
existing methods. Notably, the anti-selectivity can be modu-
lated by iron catalysts (d.r. up to > 20:1). This method also
provides a convenient approach to a variety of nitrogen-
containing molecules, including vicinal primary diamines and
2-azido glycosyl azides, which are valuable for N-linked
glycoprotein synthesis. Furthermore, preliminary mechanistic
studies suggest that this reaction may proceed through a new
selective pathway, which has a promise to become a general
strategy for selective olefin difunctionalization.
Indene (1) was selected as a model substrate for catalyst
discovery since it is incompatible with existing diastereose-
lective olefin diazidation methods. Azidoiodinane (2a) and
Fe(OTf)2 were initially selected as the azido-transfer reagent
and the catalyst, respectively. We observed that Fe(OTf)2 was
ineffective for the azido-group transfer in the absence of
TMSN3 and both 1 and 2a were fully recovered (Table 1,
entry 1). However, in the presence of TMSN3, a catalytic
amount of Fe(OTf)2 was sufficient to turn over the catalytic
cycle, thus affording the indene diazide 3 in high yields
(entries 2, 4, and 5). Notably, in the absence of iron catalysts,
no desired product was observed and 1 was fully recovered
(entry 3). These observations suggest that TMSN3 is necessary
to activate 2a for the azido-group transfer and that iron
catalysts are also necessary for the olefin diazidation.
Although the Fe(OTf)2/L1 complex catalyzed a moderately
diastereoselective reaction (entry 2), the d.r. value was sig-
nificantly improved when the ligand L2 was used (entry 4).
Notably, a bulkier ligand (L3) induced a higher d.r. value
(entry 5). Since 2a is prepared from bench-stable benziodox-
Among these methods, Minisci developed an FeII–FeIII-
mediated stoichiometric approach, with peroxydisulfate and
NaN3, specifically for styrenyl olefins. However, this method
is incompatible with nonstyrenyl olefins.[3a] Fristad and co-
workers reported a MnIII-mediated stoichiometric method
only for nonfunctionalized aliphatic olefins with a large excess
of NaN3 in acetic acid at 1108C. Snider later reported a key
improvement using TFA at À208C.[3b,c] This modified proce-
dure is effective for glycal diazidation, however, it is
unsuitable for acyclic aliphatic olefins. The groups of Armi-
moto and Magnus independently reported (PhIO)n/TMSN3-
mediated methods specifically for electron-rich allyl silanes
and cyclic silyl enol ethers, respectively, at À788C.[3e,f]
These methods have been valuable for synthetic chemis-
try, however, significant gaps still exist for this important
[*] Y.-A. Yuan,[+] D.-F. Lu,[+] Y.-R. Chen, Prof. H. Xu
Department of Chemistry, Georgia State University
100 Piedmont Avenue SE, Atlanta, GA 30303 (USA)
E-mail: hxu@gsu.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507550.
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Table 1: Catalyst discovery for the diastereoselective indene diazida-
Table 2: Substrate scope for the iron-catalyzed olefin diazidation.[a]
tion.[a]
Entry Fe(X)2
Ligand
2
TMSN3
[equiv]
t
[h]
Yield[b] d.r.[b]
[%]
1[c]
2
3
4
5
6
7
8
Fe(OTf)2
Fe(OTf)2
none
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(NTf2)2 L3
Fe(OAc)2 L3
L1
L1
none
L2
L3
2a
0
24.0
1.0
1.0
1.0
1.0
1.0
1.0
3.5
<5
81
<5
82
85
82
–
3.7:1
–
7.1:1
8.5:1
8.6:1
8.0:1
>20:1
2a 1.5
2a 1.5
2a 1.5
2a 1.5
2b 3.6
2b 3.6
2b 3.6
L3
78
87
[a] Reactions were carried out under N2 and then quenched with
saturated NaHCO3 solution. Reduction conditions: PPh3, H2O, THF,
508C, 2 h, then TsOH. Reactions in the absence of ligands [FeCl2 or
Fe(NTf2)2 only] afford the product with a low d.r. value. [b] Yield of
1
isolated product. The d.r. value was measured by H NMR analysis.
[c] Conversion is <5% in the absence of TMSN3. Tf=trifluorometha-
nesulfonyl.
ole (2b) with an excess amount of TMSN3, and 2b is barely
soluble under the olefin diazidation conditions,[5] we explored
using 2b as the terminal oxidant under heterogeneous
conditions (entry 6). To our pleasure, 3 was obtained with
essentially the same yield and d.r. value under these new
reaction conditions. This observation suggests that 2a may be
rapidly derived from 2b in situ. Note that precautions with
regard to handling TMSN3 should be taken during the
reaction workup.[6]
We thereby evaluated the counterion effect and discov-
ered that Fe(NTf2)2 was equally effective (Table 1, entry 7).
Surprisingly, the Fe(OAc)2/L3 complex catalyzed highly
diastereoselective anti-diazidation of 1 with an excellent
yield (entry 8).[7] Since 3 is a convenient precursor for the
indene diamine, it is further converted into the anti-indene
diaminium salt 4 in a high yield by a mild reduction/
protonation sequence. Furthermore, standard resolution
with tartaric acid readily provided the indene diamine
essentially in its enantiopure form (97% ee).[8]
To examine the scope of this new iron-catalyzed olefin
diazidation, we explored the reactivity with a broad range of
olefins (Table 2). Since the C/N ratios for these diazides
generally vary from 1 to 3, careful isolation were executed
strictly under small-scale (< 100 mg) conditions.[6] Addition-
ally, direct diazide reduction without solvent concentration
conveniently affords a variety of vicinal primary diamines.
[a] TMSN3 (3.6–4.0 equiv)[9] was used. [b] Yield of isolated product is
given. [c] Fe(OTf)2/L2 (1 mol%), 2 h. [d] PPh3, H2O, 508C, then TsOH.
[e] Pd/C, H2 228C, then TsOH. [f] Fe(OAc)2/L3 (5 mol%), 4 h. [g] Fe-
(NTf2)2/L3 (10 mol%), 4 h. [h] Fe(OTf)2/L3 (5 mol%). [i] PMe3, H2O,
508C, then TsOH. [j] 08C, 10 h. [k] 92% yield for reduction. HRMS
analysis was performed on diamimium salts. TIPS=triisopropylsilyl,
Troc=2,2,2-trichlorethoxycarbonyl.
À
First, olefins with labile C H bonds, including allyl benzene
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and an allyl silane, were evaluated because they have been
challenging substrates for the existing diazidation methods.[10]
For synthetic convenience, L2, with a lower molecular weight,
was selected as the ligand for terminal olefins, and we
discovered that the Fe(OTf)2/L2 complex catalyzed the
The observed catalyst-modulated diastereoselectivity is
mechanistically important because it suggests that iron
catalysts are involved in the d.r.-determining step. Therefore,
we selected cis-stilbene [(Z)-10] as a probe for several control
experiments (Scheme 3). First, when TMSN3 is absent, no
À
efficient diazidation: the amount of competing direct C H
azidation product is less than 5% (entries 1 and 2).[10] Mild
derivatization converted the diazides into functionalized
diaminium salts with excellent yields. Styrenyl and aliphatic
terminal olefins are also excellent substrates: the correspond-
ing diazides were isolated with good yields (entries 3–6).
Next, we evaluated a range of cyclic olefins and discovered
that the Fe(OAc)2/L3 complex is effective for highly diaste-
reoselective diazidation of indene, dihydronaphthalene, dihy-
droquinoline, and indole (entries 7–10).[11] Standard derivati-
zation afforded a range of valuable anti-vicinal diamines,
which are challenging to synthesize with existing diazidation
or diamination methods.[11] Further evaluation of acyclic
internal olefins revealed that trans-2-octene is an excellent
substrate for the diazidation yet with a low d.r. value
(entry 11).[12] Fortunately, the diastereomers were separable
and the straightforward derivatization converted them into
vicinal primary diamines, which are difficult to obtain with the
existing olefin diamination methods. We also observed that an
electron-deficient cinnamate ester is an excellent substrate,
and an electron-rich enamide is also compatible with this
method (entries 12 and 13). We further evaluated geranyl
acetate and observed that the diazidation occurred regiose-
lectively at the distal position with a more electron-rich olefin
(entry 14).
Furthermore, we explored this new method with densely
functionalized olefins (Scheme 2). The acetyl quinine 5
smoothly participates in the diazidation to afford the diazide
6, which provides a new structural motif for organocatalysis.
Additionally, the glycal 7 is also a reasonable substrate, which
affords the 2-azido glycosyl azides 8.[13] Interestingly, both
diastereomers were elaborated into the 2-azido N-linked
glycopeptide 9 as a single diastereomer by a reduction/
ligation procedure.[13] Notably, 9 is also a valuable building
block for N-linked glycoprotein synthesis.[13]
Scheme 3. Control experiments for mechanistic insights of the iron-
catalyzed olefin diazidation. a) Fe(OTf)2/L3 (5 mol%). b) TMSN3.
c) Fe(OTf)2/L3 (5 mol%), TMSN3. d) Fe(OTf)2/L3 (5 mol%), TMSN3,
TEMPO. e) TMSN3, TEMPO. f) Fe(OTf)2/L3 (5 mol%), nBu4NN3, 2a,
À15–228C. g) Fe(OTf)2/L3 (5 mol%), nBu4NN3, TMSN3, 2a,
À15–228C. Other reactions were carried out at 228C.
reaction was observed and both (Z)-10 and 2a were fully
recovered. Next, under iron-free conditions, but in the
presence of TMSN3, (Z)-10 was isomerized into trans-stilbene
[(E)-10] and no diazidation product was observed. We further
observed that (Z)-10, as well as (E)-10, were converted into
11 with essentially the same d.r. value.[14] Furthermore, 12 was
obtained in the presence of TEMPO. These experiments
provide several mechanistic insights. First, TMSN3 is crucial
to activate 2a. Next, an azido radical species is possibly
involved in the olefin diazidation and a reversible radical
addition may convert (Z)-10 into a carbo radical species
under both standard and iron-free conditions. Additionally,
this radical can be captured by TEMPO. Moreover, stereo-
convergent diazidation of cis/trans stilbenes suggest that the
second azido-group transfer may be rate-limiting.
To probe the role of TMSN3, it was further replaced by
nBu4NN3 (Scheme 3). Surprisingly, no diazidation was
observed and (Z)-10 was fully recovered. However, in the
presence of both TMSN3 and nBu4NN3, (Z)-10 was isomer-
ized to (E)-10 and no diazidation was observed. These
observations suggest that the Lewis-acidic TMS group is
crucial for the activation of 2a and that an excess amount of
azide anion may deactivate iron catalysts.
Based on the collective evidence from the aforemen-
tioned control experiments and key observations in catalyst
discovery (Table 1), we propose a mechanism which is
supported by the experimental data (Scheme 4). First,
TMSN3 reacts with 2b and possibly converts 2b into 2a
in situ. Next, 2a may be further activated by TMSN3 to
reversibly generate the intermediate A. In the absence of iron
catalysts, A may react with (Z)-10, presumably through
Scheme 2. Iron-catalyzed diazidation of acetyl quinine and glycals for
N-linked glycopeptide synthesis. a) Fe(OTf)2/L2 (10 mol%), 2b,
TMSN3, 228C; 82% yield, d.r.: 3:1. b) Fe(OTf)2/L2 (5 mol%), 2b,
TMSN3, 08C; 52% yield, d.r.: 1.5:1. c) PMe3 in THF, À60–228C; then
H2O in THF, 408C; 76% yield, d.r. >20:1; then HATU, DIPEA, the
corresponding peptide acid, DMF, 228C, 86% yield for the ligation
step. DIPEA=diisopropylethylamine, DMF=N,N-dimethylformamide,
HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridi-
nium 3-oxid hexafluorophosphate.
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16, 1790; e) X. Sun, X. Li, S. Song, Y. Zhu, Y.-F. Liang, N. Jiao, J.
Am. Chem. Soc. 2015, 137, 6059; f) R. Zhu, S. L. Buchwald, J.
À
Am. Chem. Soc. 2015, 137, 8069; For recent references of C H
azidation, see: g) A. Sharma, J. F. Hartwig, Nature 2015, 517,
600; h) X. Huang, T. M. Bergsten, J. T. Groves, J. Am. Chem.
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Scheme 4. Proposed mechanism for the iron-catalyzed olefin diazida-
tion using benziodoxole and TMSN3.
[2] For selected recent references of catalytic olefin diamination,
see: a) G. L. J. Bar, G. C. Lloyd-Jones, K. I. Booker-Milburn, J.
Am. Chem. Soc. 2005, 127, 7308; b) J. Streuff, C. H. Hçvelmann,
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reversible azido radical addition, thus affording the carbo
radical species B and azidoiodobenzene C. Nevertheless, B
may not be further oxidized in the absence of iron and the
elimination from B will afford more stable (E)-10 and
regenerate A. However, in the presence of an iron catalyst,
À
it may reductively cleave the I N3 bond of A, and presumably
generates a high-valent iron species and an azido radical. The
azido radical may thereby react with (Z)-10 to afford another
carbo radical species (E), which is associated with the iron
catalyst. Since the d.r. value of olefin diazidation can be
modulated both by the ligand and counterion of the catalyst,
it is likely that the high-valent iron species may further
oxidize E through inner-sphere azido ligand transfer to afford
the diazide 11.[15]
[3] For selected references of olefin diazidation, see: a) F. Minisci,
R. Galli, M. Cecere, Gazz. Chim. Ital. 1964, 94, 67; b) W. E.
Fristad, T. A. Brandvold, J. R. Peterson, S. R. Thompson, J. Org.
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3881; h) D. A. Kamble, P. U. Karabal, P. V. Chouthaiwale, A.
Sudalai, Tetrahedron Lett. 2012, 53, 4195; i) X. Zong, Q.-Z.
Zheng, N. Jiao, Org. Biomol. Chem. 2014, 12, 1198; For IN3-
mediated diazidation for olefins which lack an allylic hydrogen,
see: j) T. Sasaki, K. Kanematsu, Y. Yukimoto, J. Org. Chem.
1972, 37, 890; For diazidation of styrenyl enamides, see: k) S.
Nocquet-Thibault, A. Rayar, P. Retailleau, K. Cariou, R. H.
Dodd, Chem. Eur. J. 2015, asap; For selected example of
germinal diazidation of 1,3-dicarbonyls, see: l) T. Harschneck, S.
Hummel, S. F. Kirsch, P. Klahn, Chem. Eur. J. 2012, 18, 1187;
m) P. Klahn, H. Erhardt, A. Kotthaus, S. F. Kirsch, Angew.
Chem. Int. Ed. 2014, 53, 7913; Angew. Chem. 2014, 126, 8047; For
a recent example of catalytic styrene diazidation, see n) G.
Fumagalli, P. T. G. Rabet, S. Boyd, M. F. Greaney, Angew. Chem.
Int. Ed. 2015, 54, 11481; Angew. Chem. 2015, 127, 11643.
[4] For selected references of olefin difunctionalization via iron
nitrenoid intermediates, see: a) G.-S. Liu, Y.-Q. Zhang, Y.-A.
Yuan, H. Xu, J. Am. Chem. Soc. 2013, 135, 3343; b) D.-F. Lu, C.-
L. Zhu, Z.-X. Jia, H. Xu, J. Am. Chem. Soc. 2014, 136, 13186;
c) Y.-Q. Zhang, Y.-A. Yuan, G.-S. Liu, H. Xu, Org. Lett. 2013, 15,
3910; d) D.-F. Lu, G.-S. Liu, C.-L. Zhu, B. Yuan, H. Xu, Org. Lett.
2014, 16, 2912.
In conclusion, we have discovered a new iron-catalyzed
diastereoselective olefin diazidation method which tolerates
a broad range of olefins, including those which are incompat-
ible with the existing methods. It can also afford a variety of
synthetically valuable building blocks which are difficult to
prepare with alternative methods. Our mechanistic studies
suggest that the reaction may proceed through a new selective
pathway in which Lewis-acid activation is indispensable for
the first azido-group transfer and that iron catalysts are
crucially involved with the second azido-group transfer. Our
current efforts focus on mechanistic understanding of this new
reaction and achieving effective asymmetric induction
through new catalyst discovery.
Acknowledgements
This work was supported by the NIH (GM110382) and
Georgia State University. H. X. is an Alfred P. Sloan Fellow.
We thank N. Thrimurtulu for preparation of the dipeptide
during the synthesis of 9.
Keywords: alkenes · amination · homogeneous catalysis · iron ·
synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 534–538
Angew. Chem. 2016, 128, 544–548
[5] For preparation of 2a from 2b, see: V. V. Zhdankin, A. P.
Krasutsky, C. J. Kuehl, A. J. Simonsen, J. K. Woodward, B.
Mismash, J. T. Bolz, J. Am. Chem. Soc. 1996, 118, 5192. Both 2a
and 2b have limited solubility in the reaction mixture (ca. 10 mm
in CH2Cl2/MeCN (20:1). They can be removed through filtration
during the workup.
[1] For selected references of azido-group transfer to olefins, see:
a) J. Waser, H. Nambu, E. M. Carreira, J. Am. Chem. Soc. 2005,
127, 8294; b) E. K. Leggans, T. J. Barker, K. K. Duncan, D. L.
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[6] For safely handling TMSN3 and organic azides, see the Support-
ing Information.
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[7] Exploration with a variety of ligands suggests that the observed
counter ion effect is consistent across a range of ligands. See the
Supporting Information.
[8] For the detailed procedure of indene diamine optical resolution,
see the Supporting Information.
[9] 3.6 equiv of TMSN3 is sufficient to obtain high yields with
anhydrous 2b which is stored in a glove-box. 4.0 equiv of TMSN3
is used to achieve the same yield with 2b stored outside of
a glove-box.
[12] The Fe(OAc)2/L3 complex catalyzed a slower diazidation with
a modest improvement of the d.r. value.
[13] The aza-ylides generated from 8 rapidly epimerize under the
reduction conditions. See the Supporting Information. For
selected references of N-linked glycoprotein synthesis, see:
a) P. Wang, S. Dong, J.-H. Shieh, E. Peguero, R. Hendrickson,
M. A. S. Moore, S. J. Danishefsky, Science 2013, 342, 1357;
b) K. J. Doores, Y. Mimura, R. A. Dwek, P. M. Rudd, T. Elliott,
B. G. Davis, Chem. Commun. 2006, 1401.
[10] Allyl benzene is incompatible with the existing olefin diazidation
methods. A small amount (14%) of triazidation product was
isolated, presumably through the azido radical addition followed
by elimination and the further addition reaction. See the
Supporting Information.
[11] Fe(NTf2)2/L3 and Fe(OTf)2/L3 complexes catalyzed rapid indole
and dihydroquinoline diazidation with excellent d.r. values.
Indene, dihydronaphthalene, dihydroquinoline, and indoles are
incompatible with the existing olefin diamination reactions.
Dihydroquinoline is incompatible with existing diazidation
methods. The d.r. values for existing indene and indole diazida-
tion (via an iodo azide) are 1:1 and 3.5:1, respectively.
[14] For stereoconvergent stilbene diazidation, see the Supporting
Information.
[15] For the oxidation of a radical species by a high-valent metal
through ligand transfer, see: a) M. S. Kharasch, G. Sosnovsky, J.
Am. Chem. Soc. 1958, 80, 756; b) J. K. Kochi, Science 1967, 155,
415.
Received: August 20, 2015
Revised: September 26, 2015
Published online: November 23, 2015
538
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Angew. Chem. Int. Ed. 2016, 55, 534 –538