Iron-Catalyzed Enantioselective Radical Carboazidation and Diazidation of α,β-Unsaturated Carbonyl Compounds

Article abstract of DOI:10.1021/jacs.1c05881

Azidation of alkenes is an efficient protocol to synthesize organic azides which are important structural motifs in organic synthesis. Enantioselective radical azidation, as a useful strategy to install a C-N3 bond, remains challenging due to the inherently instability and unique structure of radicals. Here, we disclose an efficient enantioselective radical carboazidation and diazidation of α,β-unsaturated ketones and amides catalyzed by chiral N,N′-dioxide/Fe(OTf)2 complexes. An array of substituted alkenes was transformed to the corresponding α-azido carbonyl derivatives in good to excellent enantioselectivities, benefiting the preparation of chiral α-amino ketones, vicinal amino alcohols, and vicinal diamines. Control experiments and mechanistic studies proved the radical pathway in the reaction process. The DFT calculations showed that the azido transferred to the radical intermediate via an intramolecular five-membered transition state with the internal nitrogen of the Fe-N3 species.

Full text of DOI:10.1021/jacs.1c05881

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Iron-Catalyzed Enantioselective Radical Carboazidation and
Diazidation of α,β-Unsaturated Carbonyl Compounds
Wen Liu,# Maoping Pu,# Jun He, Tinghui Zhang, Shunxi Dong, Xiaohua Liu,* Yun-Dong Wu,*
and Xiaoming Feng*
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ABSTRACT: Azidation of alkenes is an efficient protocol to
synthesize organic azides which are important structural motifs in
organic synthesis. Enantioselective radical azidation, as a useful
strategy to install a C−N3 bond, remains challenging due to the
inherently instability and unique structure of radicals. Here, we
disclose an efficient enantioselective radical carboazidation and
diazidation of α,β-unsaturated ketones and amides catalyzed by
chiral N,N′-dioxide/Fe(OTf)2 complexes. An array of substituted alkenes was transformed to the corresponding α-azido carbonyl
derivatives in good to excellent enantioselectivities, benefiting the preparation of chiral α-amino ketones, vicinal amino alcohols, and
vicinal diamines. Control experiments and mechanistic studies proved the radical pathway in the reaction process. The DFT
calculations showed that the azido transferred to the radical intermediate via an intramolecular five-membered transition state with
the internal nitrogen of the Fe−N3 species.
bisoxazoline−Cu(II)−N3 from Liu’s work,25 have proven to
1. INTRODUCTION
be efficient for the creation of azido-containing stereocenters.
Organic azides enable a number of important transformations,
The strategy included either an intramolecular addition of a
such as the Huisgen “click” reaction, the aza-Wittig reaction,
M−N3 nucleophile (M = Ti) to the metal-bonded
Staudinger ligation, and C−H bond amination, making them
intermediate, or an intermolecular mode through which M−
highly versatile intermediates for organic synthesis, materials,
N3 species (M = Fe, Cu) transferred the azido group into the
and biological applications.1−3 Moreover, the azido group
untethered prochiral radicals.
exists in natural products and bioactive compounds, for
Previously, our group successfully achieved asymmetric
instance, the anti-HIV azidonucleoside drug Zidovudine
haloazidation of α,β-unsaturated carbonyl compounds
AZT.4 Among diverse synthetic protocols,5−7 azido-function-
(Scheme 1A, top) in the presence of chiral N,N′-dioxide
alization of alkenes represents one of the most efficient routes
complexes36−39 of ferrous or ferric salts, yielding β-azido
to synthesize organic azides (Scheme 1). The introduction of
carbonyl derivatives.12,13 The formation of an Fe−N3 species
an azido group could employ ionic addition of N3− species, like
was detected for ionic addition in these cases. Chiral α-azido
hydroazidation8−11 and haloazidation12,13 of electron-deficient
carbonyl derivatives could be easily transformed to optically
alkenes (Scheme 1A, top), or haloazidation of allylic alcohols14
active α-amino ketones40,41 and vicinal amino alcohols,42,43
and azidothiolation of allylic sulfonamides15 (Scheme 1A,
which are important building blocks and versatile precursors to
bottom). Constructing organic azides through radical
physiologically active compounds. We attempted to install an
difunctionalization of alkenes16−18 has recently enjoyed
azido unit into α-position of carbonyl group via a radical
considerable interest, and two reaction pathways are generally
azidation pathway (Scheme 1D), where the reaction performs
involved: the addition of an azido radical to alkene followed by
more likely through an alternative intramolecular fashion due
the introduction of another functional group (Scheme 1B,
to the intrinsic strong coordination ability of ketone. The
top)19−22 or the addition of a radical precursor to alkene
control of enantioselectivity could be expected because the
followed by azido group transfer (Scheme 1B, bottom).23−25
chiral catalyst is well able to discriminate the benzylic radical
Although many radical azidation of alkenes were explored,
almost all of them led to the racemic targets,26−35 and the
Received: June 7, 2021
Published: July 23, 2021
asymmetric process remains elusive. To synthesize the
optically pure azides, several chiral organocatalysts10,11,15 and
metal complex catalysts8,9,12−14 have been discovered. Chiral
metal−N3 species (M−N3) (Scheme 1C), including Schiff
base−Ti(IV)−N3 from Burn’s study,14 tridentate NON-pincer
ligand−Fe(III)−N3 from Bao’s work,23,24 and anionic
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Scheme 1. Asymmetric Catalytic Azido-Functionalization of Alkenes
after coordination to the ferric ion centered platform.
Nevertheless, different from previous untethered radical
transfer mode, the high coordination number of the ferric
complex and Lewis acid bonded benzylic radical will have a
dramatic influence on the efficiency of the redox step, posing
new challenges. Herein, we report the enantioselective radical
carboazidation and diazidation of enones and acrylamides
through azido group transfer process. Some mechanistic
features of the reaction are also discussed in the last section.
2. RESULTS AND DISCUSSION
2.1. Reaction Optimization of Enantioselective
Carboazidation. Initially, we chose α,β-unsaturated ketone
A1 as the substrate, Togni’s reagent II B1 as the radical
precursor, TMSN3 as the azide source to optimize the reaction
conditions (Figure 1). In the presence of 10 mol % of L3-
PrPr2/Fe(OTf)2, the desired carboazidation product D1 was
obtained in 57% yield and 63:37 enantiomeric ratio at 70 °C
after 3 h. The subsequent investigation of subunits of chiral
Figure 1. Optimization conditions for enantioselective carboazidation
of enones. All reactions were performed with ligand/Fe(OTf)2 (1:1,
10 mol %), A1 (0.1 mmol), B (2.0 equiv), and C1 (TMSN3, 2.0
equiv) in DME (1,2-dimethoxyethane, 1.0 mL) at 70 °C for 3 h under
Ar. Yield was determined by 1H NMR experiments using
CHBr2CHBr2 as an internal standard. The er was determined by
HPLC analysis on a chiral stationary phase.
N,N′-dioxide ligands indicated amide groups and amino acid
backbone displayed a significant effect on the outcomes of the
reaction.
Switching 2,6-diisopropylaniline-based L3-RaPr2 to 1-ada-
mantylamine-based L3-Ra1Ad led to a dramatic improvement
of the enantiomeric ratio (91:9). L-Pipecolic acid derived L3-
Pi1Ad (50% yield with 96:4 er) was superior to L3-Ra1Ad
(derived from L-ramipril) and L3-Pr1Ad (derived from L-
proline, 50:50 er) in terms of enantioselectivity. When Togni’s
reagent I B2 was used instead of B1, both the yield and
enantioselectivity were enhanced (84% yield, 98:2 er).
Optimization of other reaction parameters, such as metal
counterion, solvent, temperature, and catalyst loading, finally
concluded that the best results could be obtained when the
reaction was run at 70 °C with 10 mol % of L3-Pi1Ad/
Fe(OTf)2 in DME (see Tables S1−S8 for more details).
2.2. Substrate Scope of Enantioselective Carboazida-
tion. With the optimized reaction conditions established, we
investigated the substrate scope of enones in the asymmetric
trifluoromethylazidation reaction (Table 1). With the use of
Togni’s reagent I and TMSN3 as the reaction partners, a wide
range of α-aryl α,β-unsaturated ketones smoothly delivered the
corresponding β-trifluoromethyl-α-azido ketones (D1−D28)
with good enantioselectivity. Generally, the enones with
substituted benzoyl groups or a thiophene-2-carbonyl group
were tolerated well, affording the desired products (D1−D8)
in good yields (68%−88%) with high enantioselectivity
(96.5:3.5−98:2 er). For α-aryl substitutions, the position and
electronic nature had limited effect on the enantioselectivity
(D9−D23, 95:5−98:2 er). A β-naphthyl, 2,3-dihydrobenzo-
furyl, or piperonyl group could also be introduced into the α-
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a
Table 1. Substrates Scope of α,β-Unsaturated Carbonyl Compounds and Carbon Sources for Carboazidation
a
The reactions were performed with L3-Pi1Ad/Fe(OTf)2 (1:1, 10 mol %), A (0.1 mmol), B (2.0 equiv), and TMSN3 (2.0 equiv) in DME (1.0 mL)
at 70 °C for 3 h under Ar. Yield was determined by 1H NMR experiments using CHBr2CHBr2 as an internal standard. Isolated yield was given in
parentheses. The er was determined by HPLC or UPC2 analysis on a chiral stationary phase. The products D29, D30, and D34 were reduced to
1
determine the er, and the dr was determined by H NMR experiments. LPO: lauroyl peroxide.
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a
Table 2. Substrates Scope of α,β-Unsaturated Carbonyl Compounds for Diazidation
a
Unless otherwise noted, all reactions were performed with A (0.1 mmol), B13 (2.0 equiv), TMSN3 (4.0 equiv), L3-Pi1Ad/Fe(OTf)2 (1:1, 10 mol
1
%), and DME (1.0 mL) at 70 °C for 3 h under Ar. Yield was determined by H NMR experiments using CHBr2CHBr2 as an internal standard.
b
Isolated yield is in parentheses. The er was determined by HPLC or UPC2 analysis on a chiral stationary phase. Reaction was performed with A1
(0.1 mmol), B14 (2.0 equiv), TMSN3 (4.0 equiv), L3-Pi1Ad/Fe(OTf)2 (1:1, 10 mol %), and DME (1.0 mL) at 70 °C for 3 h under Ar.
Figure 2. Synthetic applications and control experiments. (a) Gram-scale synthesis and reduction of D1. (b) Reduction of E1. (c) Synthesis of
triazoles. (d) Radical trap experiment. (e) Radical clock experiment. (f) Radical clock experiment.
position of enones, resulting in equally good results (D24, D26
and D27, 96.5:3.5−97.5:2.5 er). In contrast, a decreased
enantioselectivity was given for 1-naphthyl-substituted enone
(D25, 70.5:29.5 er). In addition, α,β-unsaturated amide was
compatible in the current system, and the expected product
(D28) was generated in 90% yield with 88:12 er. However, the
chalcone, α-alkyl- or α-benzyl-substituted enones, acrylamides
with N-alkyl groups, and others were proven to be unsuitable
for the current asymmetric carboazidation (see the Supporting
Information unsuccessful substrate scope). It implied that the
structures of the substrates had a dramatic effect on the
process.
Notably, other commercially available carbon sources, for
instance, fluoroalkyl iodides, were suitable carbon partners
under the assistance of lauroyl peroxide, delivering the desired
adducts (D29 and D30) in 94:6 er and 93.5:6.5 er,
respectively. Furthermore, the alkyl peroxides could also
serve as ideal carbon sources for alkylazidation. The methyl
and ethyl radicals generated from the corresponding peroxides
took part in the reaction as well, furnishing the product D31 in
93.5:6.5 er and D32 in 87:13 er separately. A series of primary
alkyl radicals, bearing various functional substitutions such as
chlorine and ester, could be generated from the corresponding
alkyl peroxides and afforded the related products (D33−D38)
with good yields in moderate to good enantiomeric ratio.
2.3. Substrate Scope of Enantioselective Diazidation.
The successful employment of chiral catalyst L3-Pi1Ad/
Fe(OTf)2 for carboazidation of alkenes encouraged us to
tackle the challenging enantioselective diazidation reaction of
α,β-unsaturated ketones, which enabled straightforward syn-
thesis of various chiral vicinal primary diamines through direct
reduction of the products (Table 2). Gratifyingly, the reaction
of enone A1 proceeded nicely with respect to benziodoxole
B14 as the oxidant under the slightly modified conditions,
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yielding the desired product E1 in 78% yield, 91:9 er. In
consideration of the fact that B14 is prepared from bench-
stable benziodoxole (B13) with an excess amount of TMSN3
and is more easily to be handled, we explored the use of B13 as
the terminal oxidant under these reaction conditions. To our
delight, E1 was obtained with higher yield albeit a slight
decrease of enantioselectivity (90% yield, 89:11 er). Next, the
scope of this iron-catalyzed diazidation was examined. As
indicated in Table 2, an array of α,β-unsaturated ketones with
various substituents on the α-phenyl ring were all amenable in
diazidation (E2−E10, 75:25−91.5:8.5 er). Different hetero-
aromatic rings, such as 2,3-dihydrobenzofuryl-, piperonyl-, and
2-naphthyl-substituted enones were further tested, delivering
the desired products with good enantioselectivity (E11−E13,
83:17−91.5:8.5 er). Moreover, the acrylamides also performed
smoothly to furnish the target vicinal diazide E14 in 68% yield
with 71:29 er.
2.4. Synthetic Applications. To illustrate the potential
synthetic utility of this reaction, a gram-scale synthesis of chiral
azide D1 was performed. By treatment of 5 mmol of A1 in the
presence of L3-Pi1Ad/Fe(OTf)2 for 3 h, 1.06 g of the isolated
D1 was obtained with maintained enantioselectivity (Figure
2a). Chiral α-amino ketones,40,41 1,2-amino alcohols,42,43 and
vicinal diamines44,45 are important compounds and frequently
found in pharmaceuticals and medicinally relevant natural
products. Direct reduction of the product D1 by Pd/C with H2
provided the chiral amino ketone F1 (Figure 2a); reduction of
D29 and D30 afforded vicinal amino alcohols G1 and G2
(Table 1); and reduction E1 resulted in vicinal diamines H1
efficiently (Figure 2b). The absolute configuration of the
optically pure F1 was unambiguously determined to be S
according to X-ray crystallography. Furthermore, the copper-
catalyzed Huisgen cycloaddition was employed to transform
the chiral azides into the corresponding triazoles I1−I4 in
good yield without any erosion of the enantioselectivity
(Figure 2c).
We carried out the control experiments to probe into the
different reactivities of styrene,23,24 enone A1, and α,β-
unsaturated amide A2825 (see the Supporting Information
for more details). It was found that in the presence of
Fe(OTf)2 styrene showed the highest reactivity, followed by
A28 and A1. Nevertheless, the corresponding product of
styrene dropped dramatically when chiral L3-Pi1Ad/Fe(OTf)2
was used. It implied that the catalytic species might be changed
upon the addition of chiral ligands. The styrene performed the
reaction principally via an intermolecular azidation pathway.
However, the introduction of tetradentate ligand with steric
hindrance generated a new octahedra species, which acted as a
strong Lewis acid to bond the α,β-unsaturated carbonyl
compounds. As a result, the gap between the SOMO of the
alkyl radical and LUMO of the electron deficient alkene might
be reduced,46 and the reactivity of enone or amide surpassed
the uncoordinated styrene.
Based on the above experimental evidence, we rationalized
the possible catalytic process for this iron-catalyzed asymmetric
carboazidation. As illustrated in Figure 3, the Lewis acid
2.5. Mechanistic Studies. To gain more insight of the
mechanism, some control experiments were conducted. First, a
radical-trapping experiment was performed with 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) under standard con-
ditions with B8, and the desired product D34 was not
observed, while the alkyl-TEMPO adduct was isolated in 56%
yield based on B8 (Figure 2d). Then, the radical clock study
was run with either A29 or B15, and it was found that the ring-
opened product D39 and D40 were isolated in 65% and 24.5%
yield, separately (Figure 2e,f). These results strongly supported
that a radical addition process and benzylic radical were
involved in this reaction. EPR experiments using DMPO (5,5-
dimethyl-1-pyrroline-N-oxide) indicated the formation of
radicals via single-electron transfer, especially with the aid of
a chiral N,N’-dioxide−Fe(II) complex (see Figures S18−S20
for more details).
Figure 3. Proposed catalytic cycle.
catalyst I, in situ generated from the tetradentate L3-Pi1Ad and
Fe(OTf)2, undergoes ligand exchange with TMSN3 to afford
L−Fe(II)−N3 species II. Togni’s reagent B2 oxidizes II via a
single-electron transfer (SET) process to generate the chiral
Fe(III)−N3 species III and CF3 radical. During this step, the
SET process may proceed prior or posterior to the
coordination of enone A1 to iron. Next, CF3 radical adds to
catalyst-bonded enone species III to form the trisubstituted
radical species, which coordinates to the metal center (IV).
Finally, the intermediate IV under goes the critical azido group
transfer, giving the product D1 and regenerating the catalyst.
2.6. DFT Calculations. To gain insights into the
mechanisms of azido transfer and the origin of the
enantioselectivity induced by the N,N′-dioxide ligand, we
carried out DFT calculations using L3-Pi1Ad as the ligand. The
discussion here is based on the data calculated on CPCM
(tetrahydrofuran), M06L/Def2-TZVP//M06L/6-31G(d,p),
SDD(Fe) level of theory. DFT calculations were performed
using Gaussian software (for more details, see the Supporting
Information). A benzylic radical bonded Fe(III) intermediate
IV was considered as a reactive species for the following
investigations (Figure 4). The six coordination sites of IV are
saturated by a tetradentate ligand, a carbonyl group of one
It was clear that the orange mixture of the L3-Pi1Ad/
Fe(OTf)2 complex in CH2Cl2 changed to a red solution upon
addition of TMSN3. IR analysis of the aforementioned mixture
showed that azido group absorption appeared at 2049 cm−1,
indicating a red shift in comparison to TMSN3 (2132 cm−1).
ESI-MS analysis of the mixture showed a clear peak at m/z
843.3279, which corresponded to [Fe3+ + L3-Pi1Ad + OTf− +
− +
N3 ] (see Figure S11 for more details). Those observation
confirmed the formation of Fe−N3 species and implied that
the ferrous species was readily oxidated into the ferric
intermediate.
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Figure 4. DFT calculations of the azido-transfer step and the enantioselective control mode.
enone, and one N3 anion. We examined four pathways by
which the azido transferred from Fe(III)−N3 to the benzylic
radical: approach of the Re or Si face of the benzylic radical
with either the Fe(III)-bound internal N1 via five-member
transition state or terminal N3 via seven-member transition
state. Moreover, potential energy surfaces with variant spin
states were investigated as well, and the quintet energy surface
is the lowest (see Supporting Information for details).
3. CONCLUSION
We have developed an iron-catalyzed enantioselective
carboazidation and diazidation of alkenes via radical azido
transfer of chiral Fe(III)−N3 species. This efficient protocol
provided a facile access to a wide array of chiral α-azido
carbonyl derivatives, which could be further transformed into
highly valuable chiral amino ketones, amino alcohols, and
vicinal diamines. The radical pathway and the chiral Fe(III)−
N3 species of this reaction was proved by the control
experiments and mechanistic studies. The DFT calculations
clarified the process of the azido group transferred from
Fe(III)−N3 to the radical intermediate and the enantiose-
lective control mode. Further studies on other related radical
reactions enabled by chiral N,N′-dioxide/metal complex are
ongoing in our lab.
Unlike the reported results which radical interacted with the
25,48
Mn(IV)−N3,47 Fe(III)−N3,23 or Cu(II)−N3
by approach
to the terminal N3, the lowest energy transition state was
obtained for azido transfer through Fe(III)-bound internal N1,
which had an energy barrier of only 6.0 kcal/mol with respect
to the intermediate IV. Azido transfer at N3 via seven-
membered transition state, for the energy was up to 17.9 kcal/
mol, was less favored. Interestingly, the dispersion interaction
between the azido group and the equatorial adamantyl group
(right) on the ligand afforded extra stability to the transition
state TS-N1-(S). The interaction is qualitatively shown by
color code using NCI plot developed by Yang group.49 The
less stable transition state TS-N1-(R) gave D1 with R
conformer as the minor product due to the steric repulsion
between the phenyl of the benzylic radical and the axial
adamantyl group (left) of the ligand (see the Supporting
Information for details).
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05881.
Experimental procedures, full spectroscopic data for all
new compounds, and copies of 1H, 13C{1H} NMR,
19F{1H} NMR, and HPLC spectra (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
Xiaohua Liu − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0001-9555-0555; Email: liuxh@scu.edu.cn
Yun-Dong Wu − Shenzhen Bay Laboratory, Shenzhen
518055, China; Lab of Computational Chemistry and Drug
Design, State Key Laboratory of Chemical Oncogenomics,
Peking University Shenzhen Graduate School, Shenzhen
518055, China; orcid.org/0000-0003-4477-7332;
Email: wuyd@pkusz.edu.cn
Xiaoming Feng − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-4507-0478; Email: xmfeng@scu.edu.cn
Authors
Wen Liu − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, China
Maoping Pu − Shenzhen Bay Laboratory, Shenzhen 518055,
China; orcid.org/0000-0002-0745-9549
Jun He − Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, China
Tinghui Zhang − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Shunxi Dong − Key Laboratory of Green Chemistry &
Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0002-3018-3085
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05881
Author Contributions
#W.L. and M.P. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Natural
Science Foundation of China (21625205 and 21890723) and
Sichuan University (2020SCUNL204).
(22) Cheng, Y.-F.; Liu, J.-R.; Gu, Q.-S.; Yu, Z.-L.; Wang, J.; Li, Z.-L.;
Bian, J.-Q.; Wen, H.-T.; Wang, X.-J.; Hong, X.; Liu, X.-Y. Catalytic
Enantioselective Desymmetrizing Functionalization of Alkyl Radicals
via Cu(I)/CPA Cooperative Catalysis. Nat. Catal. 2020, 3, 401−410.
(23) Ge, L.; Zhou, H.; Chiou, M.-F.; Jiang, H.; Jian, W.; Ye, C.; Li,
X.; Zhu, X.; Xiong, H.; Li, Y.; Song, L.; Zhang, X.; Bao, H. Iron-
Catalysed Asymmetric Carboazidation of Styrenes. Nat. Catal. 2021,
4, 28−35.
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