Alkyl Radical Addition to Aliphatic and Aromatic N-Acylhydrazones Using an Organic Photoredox Catalyst

Article abstract of DOI:10.1021/acs.orglett.9b03053

Increased versatility of intermolecular radical addition to imino acceptors via photoredox catalysis is reported. Primary and secondary radicals, generated via visible-light photocatalysis from alkyl biscatecholatosilicates with organocatalyst 4CzIPN, add

Full text of DOI:10.1021/acs.orglett.9b03053

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Alkyl Radical Addition to Aliphatic and Aromatic N‑Acylhydrazones
Using an Organic Photoredox Catalyst
Stephen T. J. Cullen and Gregory K. Friestad*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States
*
S Supporting Information
ABSTRACT: Increased versatility of intermolecular radical
addition to imino acceptors via photoredox catalysis is
reported. Primary and secondary radicals, generated via
visible-light photocatalysis from alkyl biscatecholatosilicates
with organocatalyst 4CzIPN, add successfully to both aromatic
and aliphatic N-acylhydrazones in the presence of MgCl . With N-benzoylhydrazones, a simple reductive cleavage of the N−N
2
bond of the hydrazine adduct furnishes the free amine. Synthetic utility is exemplified in a synthetic application toward
repaglinide, a clinically important hypoglycemic agent.
mines are prevalent in natural products, drugs, and other
Scheme 1. Bridging a Gap in Radical Addition to CN
A
biologically significant molecules, underlining the im-
1
portance of developing efficient methods for their synthesis.
Expanding upon classical imine reduction and addition
2
methods, recent developments in this area include transition
metal-catalyzed hydroamination of alkenes and other C−N
3
bond constructions. However, imines remain attractive amine
precursors because of their ready availability from a wide range
of commercial materials and also the versatility for either C−C
or C−H bond constructions at the imine carbon to form chiral
1
α-branched amines. Often, such reactions have limited
applicability to imines from aliphatic aldehydes, as these
substrates are subject to competing aza-enolization by
4
deprotonation of the α-carbon. We have addressed this
issue through the use of radical additions to CN bonds of
5
−7
hydrazones.
In support of that objective, our group
developed a versatile Mn-mediated radical addition to chiral
N-acylhydrazones, which enabled the asymmetric synthesis of
chiral amines using both primary and secondary radicals
8
(
Scheme 1a). These reactions are compatible with additional
functionality in both radicals and acceptors, facilitating
9
,10
applications in complex molecule synthesis.
While very
effective for aliphatic imino acceptors, the Mn-mediated
additions were unsuccessful with hydrazones derived from
aromatic aldehydes. Conversely, Molander recently reported
radical additions to N-sulfonylimines and N-phenylimines that
are effective for aromatic acceptors, but incompatible with
catalytic conditions for radical generation, and (c) expands the
versatility of photoredox-catalyzed radical additions to include
both aliphatic and aromatic imino acceptors (Scheme 1c).
Recent developments in photoredox catalysis have impacted
1
1
imines from aliphatic aldehydes. These reactions use
organosilicate salts as radical precursors in the presence of
13
12
a wide variety of radical transformations, including radical
the organic photoredox catalyst 4CzIPN (Scheme 1b).
14
additions to imino acceptors. We planned to exploit N-
acylhydrazones such as 1a (Table 1) as radical acceptors, using
the known reductive quenching of photoexcited 4CzIPN by
alkyl biscatecholatosilicates to generate alkyl radicals. We
envisioned that the proven Lewis acid promoted radical
Informed by our prior successes with radical additions to
aliphatic N-acylhydrazones, we hypothesized that a combina-
tion of N-acylhydrazone radical acceptors with photoredox-
catalyzed radical generation would lead to improved versatility
in radical additions to CN bonds. Here, we report a
carbon−carbon bond constructive amine synthesis method
that (a) takes advantage of the excellent radical acceptor
behavior of the N-acylhydrazone functional group, (b) adopts
Received: August 27, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03053
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Radical Addition Reaction
were selected as a starting point to test substrate scope (entry
17).
As noted above, one of our main goals for this project was a
versatile method tolerant of both aliphatic and aromatic
substituents at the CN bond. Complementing the result
with benzaldehyde N-acylhydrazone 1a (Table 2, entry 1),
Table 2. N-Acylhydrazone Compatibility Study with
Secondary and Primary Radical Addition
Lewis acid
(2 equiv)
silicate
(equiv)
time
(h)
a
entry
solvent
% conv
1
2
3
4
5
6
7
8
9
none
none
ZnBr2
Zn(OTf)2
ZnBr2
2
2
1
1
2
4
2
2
2
2
2
2
1.2
2.6
3
3
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
24
49
18
18
18
18
18
18
18
18
16
16
23
48
48
48
47
24
40
48
27
27
63
64
49
59
54
31
28
44
10
86
ZnBr2
ZnBr (3 equiv)
R1
Ph (1a)
PhCH CH (1b)
product
R2
yield (%)
a
2
entry
MgCl2
MgBr2
Mg(OTf)2
ZnBr2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
MgCl2
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
3
Cy
Cy
Cy
Cy
Cy
n-Pr
60
28
22
19
0
45
21
14
2
2
10
11
12
13
14
15
16
17
18
n-C H (1c)
5
11
i-Pr (1d)
t-Bu (1e)
Ph (1a)
DMF
EtOH
DMSO
DMSO
DMSO
DMSO
DMSO
Ph (1a)
4
5
PhCH CH2
2
b
22
68
PhCH CH (1b)
i-Bu
2
2
c
a
Used 3 equiv of silicate and 15 mol % of 4CzIPN.
d
e
88 (60 )
73
MgCl2
2
cyclohexyl addition to aliphatic N-acylhydrazones 1b and 1c
occurred in modest isolated yields in the presence of
unbranched alkyl groups (entries 2 and 3); branching at the
α-position of the hydrazone was detrimental to yield (entries 4
and 5). Additions of more reactive primary radicals furnished
expected adducts in low yield (entries 6−8), presumably
impacted by premature quenching through H-abstraction.
While Table 2 demonstrated some potential for improved
versatility, yields were not consistently at a practical level.
Fortunately, further scope studies revealed that N-benzoylhy-
drazones were superior to the hydrazones of Tables 1 and 2.
Cyclohexyl addition to N-benzoylhydrazones 6a−6c gave
significant improvement to 79−94% isolated yield (Table 3,
a
1
b
c
Determined by H NMR integration. 1 mol % of catalyst loading. 5
d
mol % of catalyst loading. Conversions in control experiments using
conditions of entry 17: Absence of blue LED (0%), absence of
4
CzIPN (0%), open to air (67%), replacing silicate with CyBF K
3
e
(
59%). Isolated yield.
acceptor properties of N-acylhydrazones could expand the
versatility of such reactions; hydrazones have not yet been
exploited in reductive additions to CN bonds via photo-
1
1b
redox catalysis.
After radical addition, SET reduction and
proton transfer to the intermediate aminyl radical would
furnish the desired adduct and also regenerate 4CzIPN.
Toward this end, our initial experiments sought to test
whether this photoredox catalysis cycle could be completed
with CN acceptors lacking an anion-stabilizing N-
substituent such as sulfonyl; the efficiency of aminyl radical
reduction and catalyst turnover was in question. Indeed, N-
acylhydrazones are compatible with this redox cycle: In an
initial trial at 15 mol % loading of photocatalyst 4CzIPN,
cyclohexyl silicate addition to 1a proceeded in DMSO solution
with 40% conversion to 2a over 24 h (Table 1, entry 1).
Although this result demonstrated successful photocatalyst
turnover, the modest conversion did not increase via longer
reaction time (entry 2). Next, a variety of Lewis acids (2 equiv)
were tested in order to assess the potential for enhanced
Table 3. Addition of Alkyl Radicals to Aliphatic and
Aromatic N-Benzoylhydrazones, Including Gram-Scale
Reaction
entry
R
product
yield (%)
a
b
1
2
3
4
5
6
7
8
Ph (6a)
p-tolyl (6b)
7a
7b
7c
7d
7e
7f
79 (75 )
a
94
8
,10a
reactivity via chelation of the N-acylhydrazone
(entries 3−
a
p-ClC H (6c)
84
6
4
1
0), with ZnBr and MgCl offering the most improved results
b
c
2
2
PhCH CH (6d)
63 (60 )
2
2
(
see the Supporting Information for results with various Lewis
b
i-Pr (6e)
o-tolyl (6f)
25
acids). Increased Lewis acid loading did not improve reactivity
a
94
(
compare Table 1, entries 5 and 7).
a
o-ClC H (6g)
7g
7h
84
6
4
Aside from DMSO, other solvents were screened and found
a
4-(Me N)C H (6h)
32
2
6
4
to be inferior; we attribute this to alkyl silicate insolubility
problems (entries 11−13). Reaction time, catalyst loading, and
silicate stoichiometry were also examined and gratifyingly led
to greatly improved conversion (entry 17); these conditions
a
0
.1−0.3 mmol of 6, 3 equiv of silicate, and 15 mol % of 4CzIPN.
b
c
1.5 equiv of silicate and 5 mol % of 4CzIPN. Gram-scale reaction (4
mmol).
B
DOI: 10.1021/acs.orglett.9b03053
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
6
entries 1−3). When silicate loading was reduced from 3 to 1.5
equiv and catalyst loading was lowered from 15 to 5 mol %, the
yield of 7a was only slightly diminished from 79% to 75%
combat diabetic hyperglycemia. Nucleophilic aromatic
substitution of commercially available 2-fluorobenzaldehyde
with piperidine, followed by condensation with benzoic
(
6
entry 1). Additions to aliphatic N-benzoylhydrazones 6d and
e also afforded improved yield versus their analogues in Table
hydrazide (BzNHNH ) afforded hydrazone 16 in excellent
2
yield. Photoredox-catalyzed isobutyl addition then provided
17, the chiral amine portion of repaglinide (Scheme 4). It is
noteworthy that the bulky o-piperidinyl substituent is tolerated
in this radical addition.
2
. Importantly, a 15-fold scaleup to 1 g of 6d afforded 60%
yield of 7d (entry 4). Cyclohexyl additions to a series of
substituted benzaldehyde hydrazones showed tolerance for the
presence of electron-donating or -withdrawing effects, and
identical yields were obtained when ortho versus para
substituents were compared (entries 2, 3, 6, and 7). As before,
the effect of branching on the α-carbon for N-benzoylhy-
drazones was detrimental to radical addition (entry 5).
Scheme 4. Progress toward Formal Synthesis of Racemic
Repaglinide
The diversity of alkyl radicals suitable for this transformation
was next examined (Scheme 2). Primary alkyl silicates were
Scheme 2. Addition of 1° Radicals to N-Benzoylhydrazones
Amine synthesis has always been a critical undertaking in
organic chemistry, given that amines are commonly found in a
broad spectrum of compounds of biological importance. The
N-acylhydrazone radical acceptors herein allow both aromatic
and aliphatic aldehydes to undergo carbon−carbon bond
constructive synthesis of amines, facilitating access to a broad
range of valuable building blocks for drug discovery.
Considering the asymmetric induction strategies we have
17
previously developed for hydrazone radical acceptors, further
advances in this direction may be anticipated.
a
1
.5 eq silicate and 5 mol % 4CzIPN used.
ASSOCIATED CONTENT
Supporting Information
■
added to N-benzoylhydrazones using the conditions described
previously (Table 3) to afford adducts 8−13. Tolerance of
heteroatoms either on the alkyl radical (10 and 11) or on the
hydrazone acceptor (7c, 7g, 7h, 12, and 13) suggests that
various functional group manipulations (including transition
metal-catalyzed cross coupling) can be sequenced with these
radical additions.
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03053.
Experimental procedures, spectral data for new com-
pounds, and determination of percent conversion for
Table 1 (PDF)
Previously, we have observed that hydrazines bearing N-
benzoyl functionality readily undergo N−N bond reduction
15
with SmI to liberate the free amine. Treatment of adduct 7a
AUTHOR INFORMATION
Corresponding Author
2
■
*
with SmI yielded free amine 14 in 66% yield (Scheme 3). In
2
combination with the functional group compatibilities of the
radical addition, the ease of N−N bond cleavage enhances the
potential for applications in syntheses of more complex targets.
As a demonstration of synthetic utility, we targeted
repaglinide, a drug that stimulates insulin production to
E-mail: gregory-friestad@uiowa.edu.
ORCID
Gregory K. Friestad: 0000-0001-5374-2620
Notes
The authors declare no competing financial interest.
Scheme 3. Accessing a Primary Amine by N−N Cleavage
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1362111) for support of our
research, University of Iowa training program in Pharmaco-
logical Sciences for a predoctoral trainee award to S.C. (T32
GM067795), Ms. Vivian Mitchell and Ms. Mikayla Wymore
for their preparation of alkyl silicates, and Mr. Reid Hein for
C
DOI: 10.1021/acs.orglett.9b03053
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
his preparation of compound 1. We also thank Dr. George
Crull and Mr. Mike Estenson for assistance with NMR data
acquisition and photoreactor construction, respectively.
Gruyter, J. N.; Schmitt, D. C.; Mousseau, J. J.; Gallego, G. M.; Yang,
S.; Collins, M. R.; Qiao, J. X.; Yeung, K.-S.; Langley, D. R.; Poss, M.
A.; Scola, P. M.; Qin, T.; Baran, P. S. A General Amino Acid Synthesis
Enabled by Innate Radical Cross-Coupling. Angew. Chem., Int. Ed.
2
018, 57, 14560−14565. (e) Matos, J. L. M.; Vasquez-Cespedes, S.;
́ ́
REFERENCES
Gu, J.; Oguma, T.; Shenvi, R. A. Branch-Selective Addition of
■
Unactivated Olefins into Imines and Aldehydes. J. Am. Chem. Soc.
(
1) (a) Kobayashi, S.; Ishitani, H. Catalytic Enantioselective
2
018, 140, 16976−−16981. (f) Wang, Y.-Y.; Bode, J. W. Olefin
Addition to Imines. Chem. Rev. 1999, 99, 1069−1094. (b) Friestad,
G. K.; Mathies, A. K. Recent developments in asymmetric catalytic
addition to CN bonds. Tetrahedron 2007, 63, 2541−2569. (c) Nugent,
T. C.; El-Shazly, M. Chiral Amine Synthesis − Recent Developments
and Trends for Enamide Reduction, Reductive Amination, and Imine
Reduction. Adv. Synth. Catal. 2010, 352, 753−819. (d) Topics In
Current Chemistry: Stereoselective Formation of Amines; Li, W., Zhang,
X., Eds.; Springer-Verlag: Berlin, 2014; Vol. 343.
Amine (OLA) Reagents for the Synthesis of Bridged Bicyclic and
Spirocyclic Saturated N-Heterocycles by Catalytic Hydrogen Atom
Transfer (HAT) Reactions. J. Am. Chem. Soc. 2019, 141, 9739−9745.
(
8) Friestad, G. K.; Qin, J.; Suh, Y.; Marie, J.-C. Mn-Mediated
Coupling of Alkyl Iodides and Chiral N-Acylhydrazones: Optimiza-
tion, Scope, and Evidence for a Radical Mechanism. J. Org. Chem.
2
(
006, 71, 7016−7027.
9) Romero, K. J.; Galliher, M. S.; Pratt, D. A.; Stephenson, C. R. J.
Radicals in natural product synthesis. Chem. Soc. Rev. 2018, 47, 7851−
866.
10) (a) Friestad, G. K.; Deveau, A. M.; Marie, J.-C. Stereoselective
(
2) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. N-tert-
Butanesulfinyl Imines: Versatile Intermediates for the Asymmetric
7
(
Synthesis of Amines. Acc. Chem. Res. 2002, 35, 984−995.
(
b) Hoffmann, S.; Nicoletti, M.; List, B. Catalytic Asymmetric
Mn-Mediated Coupling of Functionalized Iodides and Hydrazones: A
Synthetic Entry to the Tubulysin gamma-Amino Acids. Org. Lett.
Reductive Amination of Aldehydes via Dynamic Kinetic Resolution. J.
Am. Chem. Soc. 2006, 128, 13074−13075. (c) Storer, R. I.; Carrera, D.
E.; Ni, Y.; MacMillan, D. W. C. Enantioselective Organocatalytic
Reductive Amination. J. Am. Chem. Soc. 2006, 128, 84−86.
2
004, 6, 3249−3252. (b) Friestad, G. K.; Jiang, T.; Mathies, A. K.
Aldehyde-Selective Wacker Oxidation in a Thiyl-Mediated Vinyl
Group Transfer Route to Daunosamine. Org. Lett. 2007, 9, 777−780.
(
d) Louillat, M.-L.; Patureau, F. W. Oxidative C−H amination
reactions. Chem. Soc. Rev. 2014, 43, 901−910.
3) (a) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada,
(c) Friestad, G. K.; Jiang, T.; Fioroni, G. M. Stereocontrol in Radical
(
̈
Mannich Equivalents for Aminosugar Synthesis: Haloacetal and 2-
(Phenylthio)vinyl Tethered Radical Additions to alpha-Hydroxyhy-
drazones. Tetrahedron 2008, 64, 11549−11557. (d) Friestad, G. K.; Ji,
A.; Baltrusaitis, J.; Korapala, C. S.; Qin, J. Scope of Stereoselective
Mn-Mediated Radical Addition to Chiral Hydrazones and Application
in a Formal Synthesis of Quinine. J. Org. Chem. 2012, 77, 3159−3180.
M. Hydroamination: Direct Addition of Amines to Alkenes and
Alkynes. Chem. Rev. 2008, 108, 3795−3892. (b) Ruiz-Castillo, P.;
Buchwald, S. L. Applications of Palladium-Catalyzed C−N Cross-
Coupling Reactions. Chem. Rev. 2016, 116, 12564−12649. (c) Huang,
L.; Arndt, M.; Gooßen, K.; Heydt, H.; Gooßen, L. J. Late Transition
Metal-Catalyzed Hydroamination and Hydroamidation. Chem. Rev.
(e) Friestad, G. K.; Banerjee, K.; Marie, J.-C.; Mali, U.; Yao, L.
́
2
(
015, 115, 2596−2697.
Stereoselective Access to Tubuphenylalanine and Tubuvaline:
Improved Mn-Mediated Radical Additions and Assembly of A
Tubulysin Tetrapeptide Analog. J. Antibiot. 2016, 69, 294−298.
(11) (a) Patel, N. R.; Kelly, C. B.; Siegenfeld, A. P.; Molander, G. A.
Mild, Redox-Neutral Alkylation of Imines Enabled by an Organic
Photocatalyst. ACS Catal. 2017, 7, 1766−1770. For nonreductive
photoredox radical processes involving hydrazones, see: (b) Xu, P.; Li,
W.; Xie, J.; Zhu, C. Exploration of C−H Transformations of Aldehyde
Hydrazones: Radical Strategies and Beyond. Acc. Chem. Res. 2018, 51,
484−495.
4) Friestad, G. K. Addition of Carbanions to Azomethines. In
Science of Synthesis, Vol. 40a: Compounds with One Saturated Carbon-
Heteroatom Bond: Amines and Ammonium Salts; Enders, D.,
Shaumann, E., Eds.; Thieme: Stuttgart, 2009; pp 305−342.
(
5) Reviews: (a) Friestad, G. K. Addition of Carbon-Centered
Radicals to Imines and Related Compounds. Tetrahedron 2001, 57,
461−5496. (b) Friestad, G. K. Control of Asymmetry in the Radical
5
Addition Approach to Chiral Amine Synthesis In Topics In Current
Chemistry: Stereoselective Formation of Amines; Li, W., Zhang, X., Eds.;
Springer-Verlag: Berlin, 2014; Vol. 343, pp 1−32. (c) Friestad, G. K.
Asymmetric Radical Addition to Chiral Hydrazones. In Topics In
Current Chemistry: Radicals in Synthesis III; Gansauer, A., Heinrich,
M., Eds.; Springer-Verlag: Berlin, 2012; Vol. 320, pp 61−92.
(12) (a) Corce, V.; Chamoreau, L.-M.; Derat, E.; Goddard, J.-P.;
́
Ollivier, C.; Fensterbank, L. Silicates as Latent Alkyl Radical
Precursors: Visible-Light Photocatalytic Oxidation of Hypervalent
Bis-Catecholato Silicon Compounds. Angew. Chem., Int. Ed. 2015, 54,
11414−11418. (b) Luo, J.; Zhang, J. Donor-Acceptor Fluorophores
for Visible-Light Promoted Organic Synthesis: Photoredox/Ni Dual
Catalytic C(sp3)-C(sp2) Cross-Coupling. ACS Catal. 2016, 6, 873−
877. 4CzIPN is inexpensively prepared in one step from carbazole
and isophthalonitrile. (c) Uoyama, H.; Goushi, K.; Shizu, K.; Nomura,
H.; Adachi, C. Highly efficient organic light-emitting diodes from
delayed fluorescence. Nature 2012, 492, 234−238.
(13) Reviews: (a) Narayanam, J. M. R.; Stephenson, C. R. J. Visible
light photoredox catalysis: applications in organic synthesis. Chem.
Soc. Rev. 2011, 40, 102−113. (b) Goddard, J.-P.; Ollivier, C.;
Fensterbank, L. Photoredox Catalysis for the Generation of Carbon
Centered Radicals. Acc. Chem. Res. 2016, 49, 1924−1936. (c) Romero,
N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev.
2016, 116, 10075−10166. (d) Shaw, M. H.; Twilton, J.; MacMillan,
D. W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem.
2016, 81, 6898−6926. (e) Sideri, I. K.; Voutyritsa, E.; Kokotos, C. G.
Photoorganocatalysis, small organic molecules and light in the service
of organic synthesis: the awakening of a sleeping giant. Org. Biomol.
Chem. 2018, 16, 4596−4614.
(
6) (a) Friestad, G. K.; Qin, J. Intermolecular Alkyl Radical Addition
to Chiral N-Acylhydrazones Mediated by Manganese Carbonyl. J. Am.
Chem. Soc. 2001, 123, 9922−9923. (b) Friestad, G. K.; Shen, Y.;
Ruggles, E. L. Enantioselective Radical Addition to N-Acylhydrazones
Mediated by Chiral Lewis Acids. Angew. Chem., Int. Ed. 2003, 42,
5
061−5063. (c) Friestad, G. K.; Massari, S. E. A Silicon Tether
Approach for Addition of Functionalized Radicals to Chiral alpha-
Hydroxyhydrazones: Diastereoselective Additions of Hydroxymethyl
and Vinyl Synthons. J. Org. Chem. 2004, 69, 863−875. (d) Slater, K.
A.; Friestad, G. K. Mn-Mediated Radical-Ionic Annulations of Chiral
N-Acylhydrazones. J. Org. Chem. 2015, 80, 6432−6440.
(
7) Selected recent developments in radical addition to imino
acceptors: (a) Fernandez-Salas, J. A.; Rodríguez-Fernandez, M. M.;
́
́
Maestro, M. C.; García-Ruano, J. L. Synthesis of Enantiomerically
Pure (α-Phenylalkyl)amines with Substituents at the ortho Position
through Diastereoselective Radical Alkylation Reaction of Sulfini-
mines. Eur. J. Org. Chem. 2014, 2014, 5265−5272. (b) Fujii, S.;
Konishi, T.; Matsumoto, Y.; Yamaoka, Y.; Takasu, K.; Yamada, K.
Radical Aminomethylation of Imines. J. Org. Chem. 2014, 79, 8128−
8
133. (c) Prieto, A.; Melot, R.; Bouyssi, D.; Monteiro, N. C−H
(14) (a) Zhang, H.-H.; Yu, S. Radical Alkylation of Imines with 4-
Alkyl-1,4-dihydropyridines Enabled by Photoredox/Brønsted Acid
Cocatalysis. J. Org. Chem. 2017, 82, 9995−10006. (b) Li, Y.; Zhou,
K.; Wen, Z.; Cao, S.; Shen, X.; Lei, M.; Gong, L. Copper(II)-
Difluoroalkylation of Aldehyde Hydrazones with Functionalized
Difluoromethyl Bromides under Copper Catalysis. ACS Catal. 2016,
6, 1093−1096. (d) Ni, S.; Garrido-Castro, A. F.; Merchant, R. R.; de
D
DOI: 10.1021/acs.orglett.9b03053
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Letter
Catalyzed Asymmetric Photoredox Reactions: Enantioselective
Alkylation of Imines Driven by Visible Light. J. Am. Chem. Soc.
2
018, 140, 15850−15858. (c) Zheng, D.; Studer, A. Photoinitiated
Three-Component α-Perfluoroalkyl-β-heteroarylation of Unactivated
Alkenes via Electron Catalysis. Org. Lett. 2019, 21, 325−329.
(
d) Pantaine, L. R. E.; Milligan, J. A.; Matsui, J. K.; Kelly, C. B.;
Molander, G. A. Photoredox Radical/Polar Crossover Enables
Construction of Saturated Nitrogen Heterocycles. Org. Lett. 2019,
2
1, 2317−2321. (e) 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, 3086−3092. (f) Wang, T.; Wang, D.-H.
Potassium Alkylpentafluorosilicates, Primary Alkyl Radical Precursors
in the C-1 Alkylation of Tetrahydroisoquinolines. Org. Lett. 2019, 21,
3
981−3985. (g) Supranovich, V. I.; Levin, V. V.; Dilman, A. D.
Radical Addition to N-Tosylimines via C−H Activation Induced by
Decatungstate Photocatalyst. Org. Lett. 2019, 21, 4271−4274.
(
15) Ding, H.; Friestad, G. K. Trifluoroacetyl-Activated Nitrogen−
Nitrogen Bond Cleavage of Hydrazines by Samarium(II) Iodide. Org.
Lett. 2004, 6, 637−640.
(
16) (a) Wolffenbuttel, B. H. R.; Nijst, L.; Sels, J. P. J. E.; Menheere,
P. P. C. A.; Muller, P. G.; Nieuwenhuijzen Kruseman, A. C. Effects of
̈
a new oral hypoglycaemic agent, repaglinide, on metabolic control in
sulphonylurea-treated patients with NIDDM. Eur. J. Clin. Pharmacol.
1993, 45, 113−116. (b) Nagarajan, P.; Rajendiran, C.; Naidu, A.;
Dubey, P. K. Studies on Diastereofacial Selectivity of a Chiral tert-
Butanesulfinimines for the Preparation of (S)-3-Methyl-1-(2-piper-
idin-1-yl-phenyl)butylamine for the Synthesis of Repaglinide. Asian J.
Chem. 2013, 25, 9345−9350. (c) Sundaram, D. T. S. S.; Mitra, J.;
Rajesh, C.; Islam, A.; Prabahar, K. J.; Rao, B. V.; Douglas, S. P.
Synthesis of Repaglinide Congeners. Synth. Commun. 2015, 45,
2
(
092−2098.
17) (a) Friestad, G. K. Chiral N-Acylhydrazones: Versatile Imino
Acceptors for Asymmetric Amine Synthesis. Eur. J. Org. Chem. 2005,
005, 3157−3172. (b) See refs 5 and 6.
2
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DOI: 10.1021/acs.orglett.9b03053
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