Polarity-Reversed Addition of Enol Ethers to Imines under Visible Light: Redox-Neutral Access to Azide-Containing Amino Acids

Article abstract of DOI:10.1021/acs.orglett.9b03238

A three-component and polarity-reversed addition cascade with a glyoxylate-based imine, an enol ether, and TMSN₃ was established for the construction of γ-azido amino acids under visible light. This transformation features mild and redox-neutra

Full text of DOI:10.1021/acs.orglett.9b03238

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Polarity-Reversed Addition of Enol Ethers to Imines under Visible
Light: Redox-Neutral Access to Azide-Containing Amino Acids
Sen Yang, Shuangyu Zhu, Dengfu Lu,* and Yuefa Gong
School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan,
Hubei 430074, China
S
* Supporting Information
ABSTRACT: A three-component and polarity-reversed
addition cascade with a glyoxylate-based imine, an enol
ether, and TMSN3 was established for the construction of γ-
azido amino acids under visible light. This transformation
features mild and redox-neutral conditions, affording a series
of amino esters with excellent chemoselectivity. Preliminary
mechanistic studies revealed that the addition of an oxyalkyl radical to imine is likely the rate-determining step. The obtained
azido-containing amino esters could be successfully converted to various valuable building blocks.
Scheme 1. Redox-Neutral Oxyalkylation of Imines
onproteinogenic amino acids play important roles in
1
Nmolecular biology and medicinal chemistry, not only
serving as neurotransmitters2 and toxins3 but also acting as
essential building units in protein engineering.4 The synthesis
of highly functionalized α-amino acids has drawn vast attention
due to their increasing applications in recent years.5 Especially,
the incorporation of azide group into amino acids is a
fascinating but challenging endeavor6 because azide is by far
the most useful linker in bioorthogonal chemistry.7 Also, such
structural motifs also widely occur in natural products and
pharmaceuticals, such as mugineic acid,8 caprazol,9 and
Nikkomycin Z (Figure 1).
participation of the product. Bode et al. have established an
intramolecular strategy based on saturated N-heterocycle
building blocks. The oxyalkyl radicals generated through either
the homolysis of C−Sn13 and C−Si14 bonds or the hydride
radical addition to enol ethers15 rapidly cyclized with imine to
afford corresponding cyclic amino ethers (Scheme 1b).
Figure 1. γ-Azidothreonine and its natural analogs.
Owing to the versatile applications of organic azides,16 the
past few years have witnessed the renascence of olefin
azidation via new approaches,17 including single-electron
redox metals,18 electrochemistry,19 and photoredox catalysis.20
Based on these discoveries, we envisaged assembling azide-
containing threonine derivatives via a polarity-reversed
addition cascade among an enol ether, an anionic azide
The addition of oxyalkyl radicals to glyoxylate-based imines
has been proven an efficient approach to threonine analogs.10
For example, several α C−H functionalization methods of
ethers/alcohols have been established by using H atom
abstracting radicals,11 including our own work (Scheme
1a).12 However, this strategy faces inevitable downsides, such
as the requirement of a large excess amount of substrate and
limited scope. These drawbacks may be ascribed to the high
barrier of the C−H abstraction, as well as the competitive
Received: September 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03238
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
source, and a glyoxylate imine as illustrated in Scheme 1c.
Although similar sequences have been reported by Liu,21
Chu,20a and Nagib22 with heteroarenes as the final radical
acceptors, intermolecular multicomponent radical additions to
imines remained a challenge due to their complicate reactivity.
On one hand, imines are easily attacked by enol ethers via
ionic pathways, leading to Mannich, Povarov,23 or Imino-ene24
reactions. On the other hand, enol ethers are also sensitive to
strong oxidants, generating radical cation species. Therefore,
developing a non-Lewis acidic and mild catalytic system for the
oxidative azide radical formation is pivotal to materialize our
working hypothesis.
the final product may come from moisture. Next, diluting the
reaction to 0.1 M led to a noticeably decreased yield (entry 8).
Importantly, no product was detected when the reaction was
performed in darkness (entry 9). To our surprise, the reaction
proceeded smoothly in the absence of a photosensitizer to
afford 4aa in moderate yield (entry 10). This result will be
discussed later in the mechanistic section.
Although the reaction proceeded to a certain extent without
a photosensitizer, in order to achieve good reproducibility and
faster conversions, we decided to employ fluorenone as the
catalyst to explore the substrate scope of this radical addition
cascade (Table 2). First, a series of imines prepared from ethyl
As a safe and easy to operate azide source,25 TMSN3 exhibits
certain Lewis acidity that promotes polar reactions. For-
tunately, N-aryl imine 1a showed decent stability toward a
cyclic enol ether 2a in the presence of TMSN3, while a Povarov
product 3 was afforded in 72% yield with a stronger Lewis acid
TMSOTf in 10 min.26 1a and 2a were therefore used as model
substrates to commence our reaction discovery, and the
conversion and yield were determined by quantitative 19F
NMR analysis. After extensive condition screening, fluorenone
(FLN) was found to be the optimal photosensitizer and the
polarity-reversed adduct 4aa was selectively obtained in
acetone (Table 1, entry 1, 89% yield, dr = 1.2:1). A few
a
Table 2. Scope of Imines
b
c
entry
product
Ar
yield (%)
dr
1
2
3
4
5
6
7
8
9
10
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
4-F-Ph
Ph
86
81
86
86
84
63
84
79
81
84
1.2
1.2
1.3
1.2
1.1
1.3
1.2
1.1
1.1
1.2
4-Cl-Ph
4-Br-Ph
4-CH3-Ph
4-OMe-Ph
3-F-Ph
3-Cl-Ph
3-Br-Ph
3-CH3-Ph
a
Table 1. Optimization of Reaction Conditions
4ja
a
Unless otherwise stated, the reaction was performed under N2 with
an imine 1 (0.2 mmol), dihydrofuran 2a (0.6 mmol), and TMSN3
(0.24 mmol) in the presence of a fluorenone (0.02 mmol) in acetone
b
under light irradiation (3 W blue LEDs) for 24 h. Isolated yield.
c
1
Determined by H NMR.
glyoxalate and substituted anilines were applied with
dihydrofuran 2a and TMSN3 under the optimized conditions,
and the results are listed in Table 2. Product 4aa was obtained
in 86% yield after purification through a silica gel flash column.
Imine 1b with a simple N-phenyl ring exhibited comparable
reactivity to produce 4ba in 81% yield (entry 2). Several para-
substituted imines are perfectly tolerated under the same
conditions to provide the azide-containing amino esters 4ca−
4ea in satisfactory yields (entries 3−5). Notably, imine 1f with
a removable para-methoxyphenyl group (PMP) was also
reactive under the standard conditions, furnishing 4fa in a
moderate yield (entry 6). In addition, an array of substrates
with meta-substituents were also proved to be suitable for this
transformation (entries 7−10).
b
c
entry
catalysts and conditions
conv. (%)
yield (%)
1
2
3
FLN, standard cond.
BD, standard cond.
benzophenone, standard cond.
Eosin Y, standard cond.
FLN, in CH3CN
FLN, in CH2Cl2
FLN, DMF
c = 0.1 M
FLN, in the dark
>95
>95
>95
>95
>95
>95
>95
93
89
70
65
69
87
78
75
80
<5
70
d
4
5
6
7
8
9
10
<5
90
no catalyst, standard cond.
a
Unless otherwise stated, the reaction was performed under N2 with
imine 1a (0.2 mmol), dihydrofuran (0.6 mmol), and TMSN3 (0.24
Next, the scope of enol ethers was examined (Figure 2).
Simple vinyl alkyl ethers are equally active under the standard
conditions, providing γ-azido-threonine derivatives 4db and
4dc with good selectivity. Compound 4dd bearing a silyl
protected hydroxyl group was obtained with trimethylsilyl vinyl
ether as a substrate. The tolerance of functionalities on the
vinyl ethers was then assessed. Hydroxyl, ester, and tosylate
groups all survived the transformation, affording product 4de,
4df, and 4dg, respectively. In addition, with a common
protecting group, benzyl vinyl ether displayed good compat-
ibility with this method, giving compounds 4bh, 4ch, and 4dh.
It is noteworthy that a di-TBS protected glycal 2l that is easily
obtained from thymidine was successfully ligated with imine
mmol) in the presence of a photosensitizer (0.02 mmol) with light
b
irradiation (3 W blue LEDs). Determined by quantitative 19F NMR
c
analysis with 4-fluoroiodobenzene as an internal standard. Deter-
d
mined by NMR; 4aa consists of a pair of diastereomers, dr ≈ 1.2:1. 2
mol % of Eosin Y was used.
other organic photosensitizers were then tested, and inferior
yields were generally observed (entries 2−4). This cascade
showed good compatibility in various solvents such as CH2Cl2,
acetonitrile, or DMF, giving 4aa in slightly diminished yields
(entries 5−7). It is noteworthy that all the reactions were
performed in regular solvents without drying, so the proton on
B
DOI: 10.1021/acs.orglett.9b03238
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Preliminary Studies on the Reaction Mechanism
Figure 2. Scope of enol ethers. Unless otherwise stated, the reaction
was performed under N2 with imine 1d (0.2 mmol), an enol ether
(0.6 mmol), and TMSN3 (0.24 mmol) in the presence of fluorenone
(0.02 mmol) in acetone under light irradiation (3 W blue LEDs) for
1
24 h; dr was determined through H NMR analysis.
1d to yield 4di as a pair of diastereomers. This example
promises a potential way that integrates an amino acid as an
aglycon into a furanose. Furthermore, a propanal-derived silyl
enol ether 5 with an acyclic internal double bond showed
moderate reactivity in CH2Cl2, affording product 6 as a
mixture of diastereomers (eq 2).27
In order to gain mechanistic insights into this cascade, we
performed a series of experiments with 1a and 2a to study the
reaction kinetic profile (Scheme 2). First, the reactions’
progress were compared side by side in the presence/absence
of a fluorenone, and the formation of product 4aa was found to
be much faster when fluorenone was used, especially in the
initial stage (Scheme 2a). Then, the impact of the
concentration of each reagent on the reaction rate was
investigated. When the amount of imine was cut by half, the
formation of 4aa slowed down accordingly within the first 3 h
(Scheme 2b). In comparison, no distinct rate difference was
observed during the early stage when the reaction was
performed with a halved amount of dihydrofuran (DHF)
(Scheme 2c). These data indicated that imine 1a was involved
in the rate-determining step, while DHF was likely not. Next,
the addition of an azide radical to double bonds is reported to
be a reversible process, which could cause the isomerization of
cis-alkenes (Scheme 2d).28 Therefore, we envisioned probing
the efficiency of azide radical generation by monitoring the
ratio change of trans/cis-enol ether 5. When a mixture of 5
(trans/cis = 1.2:1) was submitted under the standard reaction
conditions, the ratio was increased to 5.3:1 after 3 h. When this
experiment was performed in the absence of fluorenone, the
ratio was also enhanced after the same amount of time, but to a
lesser extent (trans/cis = 1.7:1, Scheme 2e). This observation
verified the fact that product 4aa was also obtained without a
photosensitizer (Table 1, entry 10), and suggested that the
azide radical might be gradually generated from TMSN3 under
visible light, while this process could be expedited by a proper
photosensitizer.
Based on these collected data, we proposed a plausible
mechanism for this sequential radical addition (Scheme 2f).
First, the azide radical is generated with TMSN3 under visible
light with the assistance of fluorenone. Then, the azide radical
reversibly adds to an enol ether, rendering an oxyalkyl radical A
in an equilibrium. Since the concentration of enol ether does
not show distinct influence on the reaction rate, the oxyalkyl
radical intermediate A is probably the thermodynamically
favored species in this equilibrium ([A] ≈ [·N3]). Con-
sequently, radical A adds to an imine, resulting in an N-
centered radical B, which is then reduced and protonated to
afford the final product 4. Notably, as in the TMSOTf
promoted Povarov reaction,26 a Lewis acidic trimethylsilyl
cation29 might also play a role activating the imine toward the
oxyalkyl radical. Within the whole process, the addition of A to
imine is probably the rate-limiting step, so that the overall
reaction rate depends on the concentration of imine and
intermediate A, which, in turn, is influenced by the efficiency of
azide radical formation.
Last, the synthetic applications of these azide-containing
amino esters obtained with this method were evaluated
(Scheme 3). First, the ester group could be readily converted
to corresponding alcohol 7 or carboxylic acid 8 via simple
reduction or hydrolysis. Then, the azide could be either
reduced to amine (9) or linked up with an alkyne to give 10
through copper-catalyzed cycloaddition. Next, product 4dg
with a distal tosylate was cyclized to afford morphrine
C
DOI: 10.1021/acs.orglett.9b03238
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Notes
Scheme 3. Product Derivatizations and Synthetic
Applications
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Huazhong University of Science &
Technology is gratefully acknowledged as well as from the
National Natural Science Foundation of China (21801083)
and Hubei Provincial Natural Science Foundation of China
(0216013067). We also thank Huazhong University of Science
& Technology Analytical & Testing Center for characterizing
new compounds.
REFERENCES
■
(1) (a) Non-Proteinogenic α-Amino Acids, Natural Origin,
Biological Functions. Asymmetric Synthesis of Non-Proteinogenic
Amino Acids; p 1. (b) Bell, E. A. Nonprotein Amino Acids of
Plants: Significance in Medicine, Nutrition, and Agriculture. J. Agric.
Food Chem. 2003, 51, 2854.
(2) Rodgers, K. J. Non-protein amino acids and neurodegeneration:
The enemy within. Exp. Neurol. 2014, 253, 192.
(3) (a) Nunn, P. B.; Bell, E. A.; Watson, A. A.; Nash, R. J. Toxicity of
Non-protein Amino Acids to Humans and Domestic Animals. Nat.
Prod. Commun. 2010, 5, 485. (b) Rodgers, K. J.; Samardzic, K.; Main,
B. J. Toxic Nonprotein Amino Acids. In Plant Toxins;
Gopalakrishnakone, P., Carlini, C. R., Ligabue-Braun, R., Eds.;
Springer Netherlands: Dordrecht, 2015; p 1.
(4) (a) Walsh, C. T.; O’Brien, R. V.; Khosla, C. Nonproteinogenic
Amino Acid Building Blocks for Nonribosomal Peptide and Hybrid
Polyketide Scaffolds. Angew. Chem., Int. Ed. 2013, 52, 7098.
(b) Neumann-Staubitz, P.; Neumann, H. The use of unnatural
amino acids to study and engineer protein function. Curr. Opin. Struct.
derivatives 11. Notably, the trans-isomer was generated
spontaneously, while the formation of cis-11 was much slower
and required hasher conditions. Further, the PMP group on
compound 4fa was easily removed with ceric ammonium
nitrate (CAN) to give a free amino ester 12. Moreover, a γ-
lactam 13 was obtained through the reduction and
lactamization of 4db.
In summary, we have developed a polarity-reversed, metal-
free, and redox-neutral radical addition cascade with a
glyoxylate imine, an enol ether, and TMSN3 promoted by
visible light. This method implements an efficient approach to
γ-azido unnatural amino acids with readily accessible and
inexpensive materials. The obtained multifunctional amino
esters have showcased versatile applications for the synthesis of
amino alcohols, amino acids, and heterocycles. Preliminary
mechanistic studies revealed that the azide radical addition to
an enol ether is a favorable and quick process to afford an
oxyalkyl radical intermediate, while the addition process to an
imine presumably limits the overall reaction rate. Further
efforts are currently focused on the synthetic applications and
the improvement of the stereoselectivity with this method.
̈
Biol. 2016, 38, 119. (c) Nodling, A. R.; Spear, L. A.; Williams, T. L.;
Luk, L. Y. P.; Tsai, Y.-H. Using genetically incorporated unnatural
amino acids to control protein functions in mammalian cells. Essays
Biochem. 2019, 63, 237.
(5) Kumar, V.; Mudgal, M. M.; Rani, N.; Jha, A.; Jaggi, M.; Singh, A.
T.; Sanna, V. K.; Singh, P.; Sharma, P. K.; Irchhaiya, R.; Burman, A. C.
Synthesis of functionalized amino acid derivatives as new
pharmacophores for designing anticancer agents. J. Enzyme Inhib.
Med. Chem. 2009, 24, 763.
(6) (a) VanBrunt, M. P.; Shanebeck, K.; Caldwell, Z.; Johnson, J.;
Thompson, P.; Martin, T.; Dong, H.; Li, G.; Xu, H.; D’Hooge, F.;
Masterson, L.; Bariola, P.; Tiberghien, A.; Ezeadi, E.; Williams, D. G.;
Hartley, J. A.; Howard, P. W.; Grabstein, K. H.; Bowen, M. A.;
Marelli, M. Genetically Encoded Azide Containing Amino Acid in
Mammalian Cells Enables Site-Specific Antibody−Drug Conjugates
Using Click Cycloaddition Chemistry. Bioconjugate Chem. 2015, 26,
2249. (b) Tookmanian, E. M.; Fenlon, E. E.; Brewer, S. H. Synthesis
and protein incorporation of azido-modified unnatural amino acids.
RSC Adv. 2015, 5, 1274. (c) Baskin, J. M.; Prescher, J. A.; Laughlin, S.
T.; Agard, N. J.; Chang, P. V.; Miller, I. A.; Lo, A.; Codelli, J. A.;
Bertozzi, C. R. Copper-free click chemistry for dynamic in vivo
imaging. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 16793.
(7) (a) Devaraj, N. K. The Future of Bioorthogonal Chemistry. ACS
Cent. Sci. 2018, 4, 952. (b) Li, L.; Zhang, Z. Development and
Applications of the Copper-Catalyzed Azide-Alkyne Cycloaddition
(CuAAC) as a Bioorthogonal Reaction. Molecules 2016, 21, 1393.
(c) Kiick, K. L.; Saxon, E.; Tirrell, D. A.; Bertozzi, C. R. Incorporation
of azides into recombinant proteins for chemoselective modification
by the Staudinger ligation. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 19.
(8) Takagi, S.; Nomoto, K.; Takemoto, T. Physiological aspect of
mugineic acid, a possible phytosiderophore of graminaceous plants. J.
Plant Nutr. 1984, 7, 469.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03238.
General procedures, experimental details, character-
ization data of all new compounds as well as NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: dlu@hust.edu.cn.
ORCID
(9) Hirano, S.; Ichikawa, S.; Matsuda, A. Total Synthesis of
Caprazol, a Core Structure of the Caprazamycin Antituberculosis
Antibiotics. Angew. Chem., Int. Ed. 2005, 44, 1854.
Dengfu Lu: 0000-0003-1931-9559
Yuefa Gong: 0000-0001-9944-4055
D
DOI: 10.1021/acs.orglett.9b03238
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(10) For selected examples: (a) Halland, N.; Jørgensen, K. A.
Intermolecular addition of alkyl radicals to imines in the absence and
in the presence of a Lewis acid. J. Chem. Soc., Perkin Trans. 1 2001,
1290. (b) Ji, P.; Zhang, Y.; Wei, Y.; Huang, H.; Hu, W.; Mariano, P.
A.; Wang, W. Visible-Light-Mediated, Chemo- and Stereoselective
Radical Process for the Synthesis of C-Glycoamino Acids. Org. Lett.
2019, 21, 3086. (c) Kamimura, D.; Nagatomo, M.; Urabe, D.; Inoue,
M. Expanding the scope of Et3B/O2-mediated coupling reactions of
O,Te-acetal. Tetrahedron 2016, 72, 7839. (d) Matos, J. L. M.;
nation of Alkenes Mediated by a TEMPO−N3 Charge-Transfer
Complex. J. Am. Chem. Soc. 2018, 140, 12511.
(20) (a) Chen, J.; Zhu, S.; Qin, J.; Chu, L. Intermolecular, redox-
neutral azidoarylation of alkenes via photoredox catalysis. Chem.
Commun. 2019, 55, 2336. (b) Wang, J.-J.; Yu, W. Anti-Markovnikov
Hydroazidation of Alkenes by Visible-Light Photoredox Catalysis.
Chem. - Eur. J. 2019, 25, 3510. (c) Wei, W.; Cui, H.; Yue, H.; Yang, D.
Visible-light-enabled oxyazidation of alkenes leading to α-azidoke-
tones in air. Green Chem. 2018, 20, 3197. (d) Yang, B.; Lu, Z. Visible-
Light-Promoted Metal-Free Aerobic Hydroxyazidation of Alkenes.
ACS Catal. 2017, 7, 8362.
(21) Liu, Z.; Liu, Z.-Q. An Intermolecular Azidoheteroarylation of
Simple Alkenes via Free-Radical Multicomponent Cascade Reactions.
Org. Lett. 2017, 19, 5649.
(22) Lear, J. M.; Buquoi, J. Q.; Gu, X.; Pan, K.; Mustafa, D. N.;
Nagib, D. A. Multi-component heteroarene couplings via polarity-
reversed radical cascades. Chem. Commun. 2019, 55, 8820.
(23) (a) Huo, C.; Chen, F.; Yuan, Y.; Xie, H.; Wang, Y. Iron
Catalyzed Dual-Oxidative Dehydrogenative (DOD) Tandem Annu-
lation of Glycine Derivatives with Tetrahydrofurans. Org. Lett. 2015,
́
́
Vasquez-Cespedes, S.; Gu, J.; Oguma, T.; Shenvi, R. A. Branch-
Selective Addition of Unactivated Olefins into Imines and Aldehydes.
J. Am. Chem. Soc. 2018, 140, 16976.
́
(11) (a) Fernandez, M.; Alonso, R. Diastereoselective Intermolec-
ular Addition of the 1,3-Dioxolanyl Radical to N-Acyl Aldohydra-
zones. Asymmetric Synthesis of α-Amino Acid Derivatives. Org. Lett.
2003, 5, 2461. (b) Hashizume, S.; Oisaki, K.; Kanai, M. Catalytic
Migratory Oxidative Coupling of Nitrones. Org. Lett. 2011, 13, 4288.
(12) (a) Zeng, H.; Yang, S.; Li, H.; Lu, D.; Gong, Y.; Zhu, J.-T. Site-
Specific Functionalization of 1,3-Dioxolane with Imines: A Radical
Chain Approach to Masked α-Amino Aldehydes. J. Org. Chem. 2018,
83, 5256. (b) Yang, S.; Zhu, S.; Lu, D.; Gong, Y. Formylation of
Fluoroalkyl Imines through Visible-Light-Enabled H-Atom Transfer
Catalysis: Access to Fluorinated α-Amino Aldehydes. Org. Lett. 2019,
21, 2019.
̀
17, 5028. (b) Boglio, C.; Lemiere, G.; Hasenknopf, B.; Thorimbert,
̂
S.; Lacote, E.; Malacria, M. Lanthanide Complexes of the Monovacant
Dawson Polyoxotungstate [α1-P2W17O61]10− as Selective and
Recoverable Lewis Acid Catalysts. Angew. Chem., Int. Ed. 2006, 45,
3324. (c) He, Y.; Yan, B.; Tao, H.; Zhang, Y.; Li, Y. Metal-free
photocatalyzed aerobic oxidative Csp3−H functionalization of glycine
derivatives: one-step generation of quinoline-fused lactones. Org.
Biomol. Chem. 2018, 16, 3816. (d) Ghashghaei, O.; Masdeu, C.;
Alonso, C.; Palacios, F.; Lavilla, R. Recent advances of the Povarov
reaction in medicinal chemistry. Drug Discovery Today: Technol. 2018,
29, 71.
(13) (a) Vo, C.-V. T.; Luescher, M. U.; Bode, J. W. SnAP reagents
for the one-step synthesis of medium-ring saturated N-heterocycles
from aldehydes. Nat. Chem. 2014, 6, 310. (b) Luescher, M. U.; Vo,
C.-V. T.; Bode, J. W. SnAP Reagents for the Synthesis of Piperazines
and Morpholines. Org. Lett. 2014, 16, 1236. (c) Luescher, M. U.;
Bode, J. W. Catalytic Synthesis of N-Unprotected Piperazines,
Morpholines, and Thiomorpholines from Aldehydes and SnAP
Reagents. Angew. Chem., Int. Ed. 2015, 54, 10884.
(14) (a) Jackl, M. K.; Legnani, L.; Morandi, B.; Bode, J. W.
Continuous Flow Synthesis of Morpholines and Oxazepanes with
Silicon Amine Protocol (SLAP) Reagents and Lewis Acid Facilitated
Photoredox Catalysis. Org. Lett. 2017, 19, 4696. (b) Hsieh, S.-Y.;
Bode, J. W. Silicon Amine Reagents for the Photocatalytic Synthesis
of Piperazines from Aldehydes and Ketones. Org. Lett. 2016, 18, 2098.
(15) Wang, Y.-Y.; Bode, J. W. Olefin Amine (OLA) Reagents for the
Synthesis of Bridged Bicyclic and Spirocyclic Saturated N-Hetero-
cycles by Catalytic Hydrogen Atom Transfer (HAT) Reactions. J. Am.
Chem. Soc. 2019, 141, 9739.
(16) (a) Huang, D.; Yan, G. Recent Advances in Reactions of
Azides. Adv. Synth. Catal. 2017, 359, 1600. (b) Intrieri, D.; Zardi, P.;
Caselli, A.; Gallo, E. Organic azides: “energetic reagents” for the
intermolecular amination of C−H bonds. Chem. Commun. 2014, 50,
11440. (c) Minozzi, M.; Nanni, D.; Spagnolo, P. From Azides to
Nitrogen-Centered Radicals: Applications of Azide Radical Chemistry
to Organic Synthesis. Chem. - Eur. J. 2009, 15, 7830. (d) Scriven, E. F.
V.; Turnbull, K. Azides: their preparation and synthetic uses. Chem.
Rev. 1988, 88, 297.
(24) (a) Yamanaka, M.; Nishida, A.; Nakagawa, M. Imino Ene
Reaction Catalyzed by Ytterbium(III) Triflate and TMSCl or
TMSOTf. J. Org. Chem. 2003, 68, 3112. (b) Oliver, L. H.; Puls, L.
A.; Tobey, S. L. Brønsted acid promoted imino-ene reactions.
Tetrahedron Lett. 2008, 49, 4636.
(25) Zhu, H.-T.; Arosio, L.; Villa, R.; Nebuloni, M.; Xu, H. Process
Safety Assessment of the Iron-Catalyzed Direct Olefin Diazidation for
the Expedient Synthesis of Vicinal Primary Diamines. Org. Process Res.
Dev. 2017, 21, 2068.
(26) For experimental details, see Supporting Information.
(27) Note: butanedione (BD) was used as the catalyst for the
reaction of 5. Fluorenone is also able to promote this reaction;
however, it is similar in polarity and thus inseperable with product 6.
(28) Li, H.; Shen, S.-J.; Zhu, C.-L.; Xu, H. Direct Intermolecular
Anti-Markovnikov Hydroazidation of Unactivated Olefins. J. Am.
Chem. Soc. 2019, 141, 9415.
(29) For examples on trimethylsilyl-cation-activated imines:
(a) Kaboudin, B.; Moradi, K. TMSCl-Promoted Addition of Diethyl
Phosphite to an Imine for the Synthesis of Bis[1-
diethoxyphosphorylalkyl]amines. Synthesis 2006, 2006, 2339−2342.
(b) Downey, C. W.; Ingersoll, J. A.; Glist, H. M.; Dombrowski, C. M.;
Barnett, A. T. One-Pot Silyl Ketene Acetal-Formation Mukaiyama−
Mannich Additions to Imines Mediated by Trimethylsilyl Trifluor-
omethanesulfonate. Eur. J. Org. Chem. 2015, 2015, 7287−7291.
(17) Wu, K.; Liang, Y.; Jiao, N. Azidation in the Difunctionalization
of Olefins. Molecules 2016, 21, 352.
(18) (a) Chen, Y.; Tian, T.; Li, Z. Mn-Catalyzed azidation−
peroxidation of alkenes. Org. Chem. Front. 2019, 6, 632. (b) Hossain,
A.; Vidyasagar, A.; Eichinger, C.; Lankes, C.; Phan, J.; Rehbein, J.;
Reiser, O. Visible-Light-Accelerated Copper(II)-Catalyzed Regio- and
Chemoselective Oxo-Azidation of Vinyl Arenes. Angew. Chem., Int. Ed.
2018, 57, 8288. (c) Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y.-F.;
Jiao, N. Mn-Catalyzed Highly Efficient Aerobic Oxidative Hydrox-
yazidation of Olefins: A Direct Approach to β-Azido Alcohols. J. Am.
Chem. Soc. 2015, 137, 6059. (d) Yuan, Y.-A.; Lu, D.-F.; Chen, Y.-R.;
Xu, H. Iron-Catalyzed Direct Diazidation for a Broad Range of
Olefins. Angew. Chem., Int. Ed. 2016, 55, 534.
(19) (a) Fu, N.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S. Metal-
catalyzed electrochemical diazidation of alkenes. Science 2017, 357,
575. (b) Siu, J. C.; Sauer, G. S.; Saha, A.; Macey, R. L.; Fu, N.;
́
Chauvire, T.; Lancaster, K. M.; Lin, S. Electrochemical Azidooxyge-
E
DOI: 10.1021/acs.orglett.9b03238
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