Photocatalytic Denitrative Alkenylation of Nitroalkanes

Ayumi Osawa, Kento Uemura†, Shuji Murakami†, and Yoshiaki Nakao*

Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan
ABSTRACT: Reductive radical generation has become a cornerstone of modern photoredox chemistry. However, the synthesis of
functionalized radical precursors remains a tedious multi-step process. In this study, we focus on the potential of the nitro group as a
redox-active functional group and present denitrative alkenylation of nitroalkanes, facilitated by photoreductive generation of alkyl
radicals from nitroalkanes. By taking advantage of the facile α-functionalization of nitroalkanes, we successfully generate various
functionalized alkyl radicals, which are subsequently used in the alkenylation reactions.

Radical chemistry has undergone significant advancements Scheme 1. Photoredox radical generation for C–C
facilitated by the emergence of photoredox chemistry, which bond formations.
has expanded the toolkit for chemists by enabling a diverse ar- A. Carboxylic acids as radical precursors
ray of compounds to serve as radical precursors.1–4 Among them,
carboxylic acids are the most widely employed via a single elec- α-functionalization
O O
tron oxidation of the carboxylate ions, owing to their relatively −e “C ”
H C
low redox potential and thermodynamic advantage via facile OH O
H H
decarboxylation (Scheme 1A). In addition, their abundance in −CO2
both natural and industrial feedstocks, and amenability to func-
tionalize their carbon frameworks by classical carbonyl chemis- B. Redox-active esters as radical precursors
try emphasizes the synthetic utility to access a wide range of or-
ganic compounds through decarboxylative C–C bond for- α-functionalization
mations.5–7 In contrast, redox-active esters such as N-hydroxy- hydrolysis
activation
phthalimide ester serve as radical precursors capable of gener- O O +e
ating alkyl radicals via a single electron reduction, followed by H RAG
OR O
eliminating CO2 and redox-active groups (RAG), thereby offer- H H −CO2
ing a complementary approach for radical generation in syn- pKa ~30 −
RAG : redox-active group − RAG
thetic chemistry (Scheme 1B).8–10 However, redox-active esters
are in common labile under the reaction conditions requisite for
C. Nitroalkanes as radical precursors
the pre-functionalization of their carbon frameworks. Conse-
quently, alternative carboxylic acid derivatives, such as alkyl es- α-functionalization
ters, are usually employed.11 Additionally, a multi-step sequence O O +e
including condensation of a carboxylic acid with a redox-active H N
O
N
O This Work
group is required to obtain the desired redox-active esters. Sim- H H
−NO2−
ilarly, other radical precursors including alcohol and amine de- pKa ~17

rivatives necessitate extra activation processes, which are not

necessary for the strategic construction of carbon frameworks. D. Competitive over-reduction via radical anions of nitroalkanes

To improve the overall efficiency in synthetic schemes utiliz-

!

C N +H• H
ing reductive radical generation, we focused on nitroalkanes, O
−
−NO2−
O
which have isoelectronic structures with carboxylic acids, re- N
+e
N
O
garding them as redox-active building blocks (Scheme 1C). Ni- O
!

N O OH
troalkanes can generate nitronate ions under mild reaction con- N
ditions due to the 1013-times higher acidity of the α-protons in +H•, +H+
−H2O
comparison to that of carboxylic acid derivatives.12,13 Their =H
amenability to facile C–C bond formation at the α-position transition metal catalysis. The iterative application of these re-
through straightforward reactions with various electrophiles actions has been routinely harnessed in multistep synthesis, no-
renders them valuable building blocks in organic synthesis. In tably in natural product synthesis, facilitating the construction
addition to the classical reactions with carbonyl compounds,14 of a myriad of diverse carbon frameworks.25–27 In addition to the
imines,15 and electron-deficient alkenes,16 recent advancements synthetic utility, the potent electron-withdrawing character of
have enabled arylations17–20 and alkylations21–24 facilitated by the nitro group enables it to accept one electron from electron
donors to generate the radical anions, followed by the alkyl rad-
icals through the C–N bond cleavage. However, in most cases,

https://doi.org/10.26434/chemrxiv-2024-qdxdv ORCID: https://orcid.org/0000-0002-5459-3660 Content not peer-reviewed by ChemRxiv. License: CC BY-NC-ND 4.0
 the alkyl radicals capture a hydrogen atom, resulting in denitra- 6 PC6 instead of PC1 <5
tion products.28 7 MeCN instead of DMSO 13
Denitrative C–C bond formation via radical intermediates 8 NMP instead of DMSO 11
was first described over half a century ago. The pioneering
works by Kornblum elucidated the denitrative substitution of 9 No PC1 <5
tertiary nitroalkanes with carbon nucleophiles through the SRN1 10 No light <5
mechanism.29,30 Additionally, Ono and co-workers have 11 32 °C, two blue LEDs 62c
achieved the Giese addition reaction of alkyl radicals generated
aReaction was carried out with 1a (0.10 mmol), 2 (0.30 mmol), and
through the abstraction of the nitro groups by tin radicals.31,32
In these instances, the utilization of a stoichiometric strong base PC1 (5.0 mol%) in DMSO (0.75 mL) under blue LED irradiation
at 60 °C for 40 h. bNMR yield using 1,4-pyrazine as the internal
or a toxic reducing agent was required. In our recent study, we
standard. cReaction at 32 °C for 88 h on a 0.50 mmol scale using
reported the denitrative C–C bond-forming reactions employ-
two Kessil blue LEDs.
ing 9-fluorenol as a single-electron reducing catalyst.33 However,
the application of basic conditions at high temperature hindered To examine the denitrative alkenylation with 1,1-diphe-
the utilization of nitroalkanes bearing base-sensitive functional nylethylene (2), we selected nitroalkane 1a, which was found to
groups, thereby limiting their synthetic potential. decompose under basic conditions used in our previous study,35
In the precedent literature, photocatalytic reduction of ni- possibly through the retro-Michael reaction. Our initial screen-
troalkanes employing terminal reductants mainly yields oximes ing of the reaction conditions revealed that 5.0 mol% of Ir(ppy)3,
via the N–O bond cleavage although denitration occurs in the PC1 as a photoredox catalyst in DMSO at 60 °C under blue-
case of a highly reactive α-acylnitroalkane through the C–N LED irradiation facilitated the conversion of 1a to the expected
bond cleavage.34 These phenomena imply the over-reduction of product 3a in 49% yield (entry 1, Table 1). Other iridium- and
radical anions generated through single-electron reduction ruthenium-based photocatalysts with lower reducing ability in
competes with the mesolytic cleavage of the nitro groups the excited state significantly decreased the reaction efficiency
(Scheme 1D). Therefore, we hypothesized that a redox-neutral (entries 2–4).36 Further investigation of organo-photocatalysts
system would lead to suppressing the side reactions. In this study, showed a similar trend, with stronger reductants in the excited
we present the first photocatalytic denitrative C–C bond-form- state resulting in better efficiency (entries 5 and 6).37 The choice
ing reaction of nitroalkanes. of solvent was crucial in this reaction; other polar solvents ex-
hibited lower conversion of 1a (entries 7 and 8). Both the pho-
tocatalyst and light irradiation were necessary for the reaction
Table 1. Optimization and Control Experimentsa (entries 9 and 10). After screening at 60 °C using one Kessil
PC1 (5.0 mol%)
LED, we found that increasing the light intensity by using two
Ph MeO2C Ph
MeO2C NO2
+ Kessil LEDs improved the reaction efficiency and allowed us to
Ph DMSO (0.75 mL)
blue LED, 60 °C, 40 h
Ph lower the reaction temperature, affording 3a in 62% yield, with
1a 2 3a
0.10 mmol 0.30 mmol
12% of 1a remaining unreacted (entry 11).
Having established the optimal conditions, we investigated the
F
scope of the denitrative alkenylation of various nitroalkanes (Ta-
CF3
PF6 PF6 ble 2). Τhe nitroalkanes possessing an electron-withdrawing
N N
tBu N
N
group at the γ-position were readily synthesized by Michael re-
N F
Ir Ir
F3C N
Ir
N action and were applicable to the denitrative alkenylation, af-
N N N N
tBu fording the expected products 3a, 3b, and 3c in moderate yields.
F
F
The reaction of a Henry-type nitroalkane containing a b-oxy-
PC1 PC2 PC3 gen-functional group, yielded b-aryloxy alkene 3d in 53% yield.
*Eox: −1.73 V *Eox: −0.96 V *Eox: −0.89 V
The doubly acyloxy- and siloxy-methylated nitroalkanes, which
are accessed through the iterative Henry reaction with formal-
dehyde, also participated in the denitrative C–C bond for-
2PF6 N mation, resulting in acyclic diester 3e and cyclic silyl ether 3f.
N
N
N
F F
NC CN Furthermore, the reaction of a nitroalkane with three different
N
N
Ru
N
functional groups at the a-position proceeded, yielding alkene
N N
N N N
N
3g well-functionalized at the allylic position. A nitroalkane
CN
bearing a simple alkyl chain with the terminal methoxy group
was also converted into alkene 3h. A phenyl group at the b-
PC4 PC5 PC6 position was tolerated to afford 3i in 66% yield. Substituents at
*Eox: −0.81 V *Eox: −1.60 V *Eox: −1.18 V the para-position including chlorine (3j), an electron-withdraw-
ing trifluoromethyl group (3k), or electron-donating alkoxy and
entry deviation from the initial conditions yield acyloxy groups (3l–3o) led to the formation of the correspond-
(%)b ing products. Although various tertiary nitroalkanes were suc-
1 none 49 cessfully employed, the reactions of secondary and primary ni-
troalkanes did not proceed under the standard conditions (3p
2 PC2 instead of PC1 13
and 3q).38 Most of these substrates decomposed, and other by-
3 PC3 instead of PC1 <5 products were not identified except for ketone 7 possibly de-
4 PC4 instead of PC1 <5 rived from the Nef-type reaction. In the case of Henry-type 1,2-
5 PC5 instead of PC1 47 nitroalcohol 1t, tandem cyclization occurred to form

https://doi.org/10.26434/chemrxiv-2024-qdxdv ORCID: https://orcid.org/0000-0002-5459-3660 Content not peer-reviewed by ChemRxiv. License: CC BY-NC-ND 4.0
 substituted tetrahydrofuran 5t (Scheme 2A). The reaction of To gain insights into the reaction mechanism, we conducted
MOM-protected nitroalcohol 1r resulted in a similar product. several control experiments (Scheme 3). First, we performed the
These findings suggest that the reactions proceed via carbo- reaction of 1a with 2 in the presence of commonly used single-
cation intermediates, which cyclized, with releasing proton or electron transfer (SET) inhibitors, 2,2,6,6-tetramethylpiperidine
the MOM group. In contrast, TIPS ether did not participate in 1-oxyl (TEMPO, Ered = −0.36 V)39 and 1,4-dinitrobenzene (Ered
the cyclization, but afforded the alkenylation product after the = −0.66 V),40 which have less negative redox potential com-
removal of the silyl group upon treatment with TBAF (3s). The pared to nitroalkanes (Ered = ca. −1.7 V, Scheme 3A)41,42. As a
alkylation of silyl enol ether 6 with a-nitroester 1u, the nitro result, no conversion of 1a was observed in either case. Stern–
group serving as a leaving group, provided b-quaternary ketone Volmer quenching studies were also conducted to probe SET
7u with a yield of 31% (Scheme 2B). Thus, a wide range of ni- from the excited state of PC1 (Scheme 3B).43,44 The linear plot
troalkanes accessible via various a-functionalization are appli- clearly showed the quenching of excited PC1 with 1a predom-
cable to the denitrative C–C bond formation. inantly occurred over that with 2. In addition, we performed a
light on/off experiment to determine if the reaction proceeded
through a radical chain mechanism (Scheme 3C). The conver-
Table 2. Scope for the Denitrative Alkenylationa sion of 1a into 3a was detected only under light irradiation, not
NO2 Ph PC1 (5.0 mol%) Ph under dark conditions, suggesting that a radical chain process
+
Ph DMSO Ph was not involved in this reaction. To demonstrate the genera-
1 2
blue LED
29–35 °C, 80 h 3a–3q
tion of alkyl radicals through the C–N bond cleavage, a radical-
clock experiment using cyclopropane-containing substrate 1v
NC was examined.45,46 The denitrative alkenylation product via
MeO2C Ar NC Ph
Ph ring-opening was obtained in 11% yield with a 58% recovery of
Ar Ph O
1v (Scheme 3D). Furthermore, as shown in Scheme 2A, the re-
Ph
Ar = Ph (3a): 57% (65% brsm)
3c, 45% 3d, 53% (60% brsm)
actions of 1r and 1t support the involvement of cationic inter-
4-tolyl (3b): 44% (59% brsm)
mediates, indicating a radical-polar crossover mechanism that
Me Me
Ph
involves the oxidation of alkyl radical intermediates.
Ph O MeO2C Ph
AcO tBu
Ph Si Ph MeO Et Ph
O
AcO tBu
Scheme 3. Mechanistic investigations
3e, 44% (51% brsm) 3f, 32% (45% brsm) 3g, 47% (71% brsm)b
A. SET inhibition experiments
R = H (3i): 66%c
Cl (3j): 55% PC1 (5.0 mol%)
Ph Ph CF3 (3k): 52% (56% brsm) additive (2.0 eq.) MeO2C Ph
MeO2C NO2
MeO OMe (3l): 67% (79% brsm) + 2
Ph Ph OCH2(4-tolyl) (3m): 52% DMSO Ph
R blue LED
OPiv (3n): 44% 1a 3a
3h, 36% (55% brsm)b 60 °C, 40 h
OBoc (3o): 46%
1,4-dinitrobenzne: < 5%
TEMPO: < 5%
Ph O Ph Ph B. Stern–Volmer quenching experiments
Ph Ph
Ph Ph

3p, <5% 4, 7%d 3q, <5%e

PC1 + 1a
aReaction was carried out with nitroalkane 1 (0.50 mmol), 2 (1.5 PC1 + 2
mmol), and PC1 (5.0 mol%) in DMSO (3.8 mL) in a range of 29–
35 °C for 80 h using two Kessil LEDs with a fan cooling. Isolated
yields are reported, with yields based on recovered starting material
shown in parentheses when >5% of 1 was recovered. b120 h. c1.0
mmol scale at 60 °C for 40 h. d1H NMR yield using 1,4-pyrazine as
the internal standard. e80 °C. C. On/Off experiments

ON OFF ON OFF ON OFF

Scheme 2. Related transformations
A. Tandem cylization via intramolecular cation-trapping
Ph
R1= MOM, H Ph
O
2 R2
R 1O standard R 1O H
conditions
NO2 Ph 5r, 24% (from 1r)
R2 R2 5t, 54% (from 1t)
Ph
HO
R 1, R 2 = R1= TIPS
MOM, H (1r) Ph
TIPS, H (1s) then TBAF D. Radical clock experiments
H, Bn (1t) Ph
3s, 42% (from 1s)
Ph Ph
PC1 (5.0 mol%)
B. The alkylation of silyl enol ether with a nitroalkane Ph NO2 + 2 Ph
DMSO
standard blue LED
EtO2C NO2 Ph conditions EtO2C Ph MeO2C CO2Me 60 °C, 40 h
+ MeO2C CO2Me
OTBS O 1v 3v, 11%

1u 6 7u, 31%
Based on these results, the proposed reaction mechanism is
depicted in Scheme 3. The photoexcited PC1 reduces the

https://doi.org/10.26434/chemrxiv-2024-qdxdv ORCID: https://orcid.org/0000-0002-5459-3660 Content not peer-reviewed by ChemRxiv. License: CC BY-NC-ND 4.0
 nitroalkane via a SET, generating radical anion I. A nitrite ion Ayumi Osawa − Department of Material Chemistry, Graduate
is then eliminated, producing alkyl radical II, which subse- School of Engineering, Kyoto University, Kyoto 615-8510, Japan;
quently adds across the alkene to form alkyl radical III. The orcid.org/ 0000-0002-5459-3660
alkyl radical is then oxidized by PC1 to form a carbocation in- Kento Uemura − Department of Material Chemistry, Graduate
termediate IV, which undergoes deprotonation to yield the de- School of Engineering, Kyoto University, Kyoto 615-8510, Japan
nitrative alkenylation product. In contrast to the alkyl radical Shuji Murakami − Department of Material Chemistry, Graduate
generation through C–N bond cleavage in the redox-neutral School of Engineering, Kyoto University, Kyoto 615-8510, Japan
system described above, N–O bond cleavage preferentially oc-
curred under photo-reductive conditions using terminal reduct- Author Contributions
†
ants, yielding the deoxygenative N-alkylation product with an A.O. and Y.N. directed this study and wrote the manuscript.
electron-deficient alkene (Scheme 5). These results support the A.O., K.U. and S.M. conducted the experiments. K.U. and S.M.
concept presented in Scheme 1D. contributed equally.
Scheme 4. Proposed mechanism

R NO2 R NO2
−
R
Notes
−NO2− The authors declare no competing financial interest.
I II
Ph
E = −1.7 V

E = −1.7 V
Ph
ACKNOWLEDGMENT
Ph This work was partially supported by FUJIFILM Wako Pure
*IrIII IrIV R Chemical Corporation Award in Synthetic Organic Chemistry, Ja-
Ph
E = +0.77 V E = +0.23 V III pan. We thank Prof. H. Ohmiya, Prof. K. Tanaka and Prof. S. Ito
Ph Ph for useful discussions and some experimental supports.
hv R R
IrIII Ph −H+ Ph
IV

Scheme 5. Deoxygenative N-alkylation of nitroalkanea REFERENCES

(1) Crespi, S.; Fagnoni, M. Generation of Alkyl Radicals: From the
O PC4 (1.5 mol%)
iPr EtN, HE OH Tyranny of Tin to the Photon Democracy. Chem. Rev. 2020, 120
N 2
(17), 9790–9833.
BzO O + CO2Me N
BzO CO2Me
THF, CH2Cl2 (2) Cannalire, R.; Pelliccia, S.; Sancineto, L.; Novellino, E.; Tron, G.
blue LED
1w 8 rt, 40 h 9, 40% C.; Giustiniano, M. Visible Light Photocatalysis in the Late-Stage
Functionalization of Pharmaceutically Relevant Compounds.
aReaction was carried out with 1w (1.0 mmol), 8 (2.0 mmol), PC4 Chem. Soc. Rev. 2021, 50 (2), 766–897.
(15 μmol), iPr2EtN (1.0 mmol), Hantzsch ester (1.5 mmol) in THF (3) Quirós, I.; Martín, M.; Gomez-Mendoza, M.; Cabrera-Afonso, M.
(5 mL) and CH2Cl2 (5 mL) under blue-LED irradiation at rt for 40 J.; Liras, M.; Fernández, I.; Nóvoa, L.; Tortosa, M. Isonitriles as
h. Alkyl Radical Precursors in Visible Light Mediated Hydro- and
Deuterodeamination Reactions. Angew. Chem. Int. Ed. 2024, 63 (7),
In summary, we have developed the catalytic denitrative C– e202317683.
C bond-forming reactions of nitroalkanes utilizing the photore- (4) Martín, M.; Romero, R. M.; Portolani, C.; Tortosa, M. Csp3-
dox system. This reaction can be applied to a wide range of ni- Csp2 Coupling of Isonitriles and (Hetero)Arenes through a Pho-
troalkanes, which are conveniently synthesized by Michael and toredox-Catalyzed Double Decyanation Process. ChemRxiv 2024.
Henry reactions, as well as a-alkylation. The mechanistic stud- DOI:10.26434/chemrxiv-2024-70psv
ies indicate that nitroalkanes are reduced by the excited photo- (5) Li, L.; Yao, Y.; Fu, N. Free Carboxylic Acids: The Trend of Rad-
catalyst in a single electron manner to form alkyl radicals upon ical Decarboxylative Functionalization. Eur. J. Org. Chem. 2023,
26 (21), e202300166.
releasing a nitrite ion. This method is expected not only to en-
(6) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A.; Mac-
hance the synthetic utility of nitroalkanes but also to provide a Millan, D. Merging Photoredox with Nickel Catalysis: Coupling
new radical precursor in photoredox reactions. of α-Carboxyl Sp3-Carbons with Aryl Halides. Science 2014, 345,
437–440.
(7) Chu, L.; Ohta, C.; Zuo, Z.; MacMillan, D. W. C. Carboxylic Ac-
ids as a Traceless Activation Group for Conjugate Additions: A
ASSOCIATED CONTENT
Three-Step Synthesis of (±)-Pregabalin. J. Am. Chem. Soc. 2014,
Supporting Information 136 (31), 10886–10889.
(8) Okada, K.; Okamoto, K.; Oda, M. A New and Practical Method
The Supporting Information is available free of charge on the ACS of Decarboxylation: Photosensitized Decarboxylation of N-
Publications website. Acyloxyphthalimides via Electron-Transfer Mechanism. J. Am.
Detailed experimental procedures and analytical data (PDF) Chem. Soc. 1988, 110 (26), 8736–8738.
(9) Zhang, Y.; Ma, D.; Zhang, Z. Utilization of Photocatalysts in De-
AUTHOR INFORMATION carboxylative Coupling of Carboxylic N-Hydroxyphthalimide
(NHPI) Esters. Arab. J. Chem. 2022, 15 (7), 103922.
Corresponding Author (10) Murarka, S. N-(Acyloxy)Phthalimides as Redox-active Esters in
Cross-coupling Reactions. Adv. Synth. Catal. 2018, 360 (9), 1735–
Yoshiaki Nakao − Department of Material Chemistry, Graduate
1753.
School of Engineering, Kyoto University, Kyoto 615-8510, Japan; (11) Tao, D. J.; Slutskyy, Y.; Muuronen, M.; Le, A.; Kohler, P.; Over-
orcid.org/0000-0003-4864-3761; Email: nakao.yoshi- man, L. E. Total Synthesis of (-)-Chromodorolide B By a Compu-
[email protected] tationally-Guided Radical Addition/Cyclization/Fragmentation
Cascade. J. Am. Chem. Soc. 2018, 140 (8), 3091–3102.
Author

https://doi.org/10.26434/chemrxiv-2024-qdxdv ORCID: https://orcid.org/0000-0002-5459-3660 Content not peer-reviewed by ChemRxiv. License: CC BY-NC-ND 4.0
 (12) Bordwell, F. G.; Vanier, N. R.; Matthews, W. S.; Hendrickson, J. (33) Kashihara, M.; Kosaka, K.; Matsushita, N.; Notsu, S.; Osawa, A.;
B.; Skipper, P. L. Acidities of Carbon Acids. VII. Conjugation and Nakao, Y. Catalytic Generation of Radicals from Nitroalkanes.
Strain in Some Cyclopropyl Anions. J. Am. Chem. Soc. 1975, 97 Synlett 2023, 34 (12), 1482–1486.
(24), 7160–7162. (34) Cai, S.; Zhang, S.; Zhao, Y.; Wang, D. Z. New Approach to Ox-
(13) Zhang, X. M.; Bordwell, F. G.; Van Der Puy, M.; Fried, H. E. imes through Reduction of Nitro Compounds Enabled by Visible
Equilibrium Acidities and Homolytic Bond Dissociation Energies Light Photoredox Catalysis. Org. Lett. 2013, 15 (11), 2660–2663.
of the Acidic Carbon-Hydrogen Bonds in N-Substituted Trime- (35) Unpublished result. The reaction conditions are consistent with
thylammonium and Pyridinium Cations. J. Org. Chem. 1993, 58 those described in ref. 33.
(11), 3060–3066. (36) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light
(14) Palomo, C.; Oiarbide, M.; Laso, A. Recent Advances in the Cat- Photoredox Catalysis with Transition Metal Complexes: Applica-
alytic Asymmetric Nitroaldol (Henry) Reaction. Eur. J. Org. Chem. tions in Organic Synthesis. Chem. Rev. 2013, 113 (7), 5322–5363.
2007, 2007 (16), 2561–2574. (37) Speckmeier, E.; Fischer, T. G.; Zeitler, K. A Toolbox Approach
(15) Noble, A.; Anderson, J. C. Nitro-Mannich Reaction. Chem. Rev. to Construct Broadly Applicable Metal-Free Catalysts for Photo-
2013, 113 (5), 2887–2939. redox Chemistry: Deliberate Tuning of Redox Potentials and Im-
(16) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Con- portance of Halogens in Donor–Acceptor Cyanoarenes. J. Am.
jugate Additions of Nitroalkanes to Electron-Poor Alkenes: Recent Chem. Soc. 2018, 140 (45), 15353–15365.
Results. Chem. Rev. 2005, 105 (3), 933–971. (38) Other photoredox catalysts enabled the conversion of 1p to 3p,
(17) Muratake, H.; Nakai, H. Intramolecular Cyclization Using Palla- but the yield varied between 0–20%. Further investigations are
dium-Catalyzed Arylation toward Formyl and Nitro Groups. Tet- ongoing in our group.
rahedron Lett. 1999, 40 (12), 2355–2358. (39) Zhao, X.; Yang, J.-D.; Cheng, J.-P. Revisiting the Electrochemis-
(18) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. Highly Active try of TEMPOH Analogues in Acetonitrile. J. Org. Chem. 2023, 88
and Selective Catalysts for the Formation of α-Aryl Ketones. J. Am. (1), 540–547.
Chem. Soc. 2000, 122 (7), 1360–1370. (40) Atifi, A.; Ryan, M. D. Electrochemistry and Spectroelectrochem-
(19) Walvoord, R. R.; Berritt, S.; Kozlowski, M. C. Palladium-Cata- istry of 1,4-Dinitrobenzene in Acetonitrile and Room-Tempera-
lyzed Nitromethylation of Aryl Halides: An Orthogonal Formyla- ture Ionic Liquids: Ion-Pairing Effects in Mixed Solvents. Anal.
tion Equivalent. Org. Lett. 2012, 14 (16), 4086–4089. Chem. 2014, 86 (13), 6617–6625.
(20) Huang, J.; Li, T.; Lu, X.; Ma, D. Copper-Catalyzed α-Arylation (41) Evans, D. H.; Gilicinski, A. G. Comparison of Heterogeneous and
of Nitroalkanes with (Hetero)Aryl Bromides/Iodides. Angew. Chem. Homogeneous Electron-Transfer Rates for Some Nitroalkanes
Int. Ed Engl. 2024, 63 (7), e202315994. and Diketones. J. Phys. Chem. 1992, 96 (6), 2528–2533.
(21) Gildner, P. G.; Gietter, A. A. S.; Cui, D.; Watson, D. A. Benzyla- (42) Pavlishchuk, V. V.; Addison, A. W. Conversion Constants for Re-
tion of Nitroalkanes Using Copper-Catalyzed Thermal Redox dox Potentials Measured versus Different Reference Electrodes in
Catalysis: Toward the Facile C-Alkylation of Nitroalkanes. J. Am. Acetonitrile Solutions at 25°C. Inorg. Chim. Acta 2000, 298 (1), 97–
Chem. Soc. 2012, 134 (24), 9942–9945. 102.
(22) Rezazadeh, S.; Devannah, V.; Watson, D. A. Nickel-Catalyzed C- (43) Arias-Rotondo, D. M.; McCusker, J. K. The Photophysics of Pho-
Alkylation of Nitroalkanes with Unactivated Alkyl Iodides. J. Am. toredox Catalysis: A Roadmap for Catalyst Design. Chem. Soc. Rev.
Chem. Soc. 2017, 139 (24), 8110–8113. 2016, 45 (21), 5803–5820.
(23) Rezazadeh, S.; Martin, M. I.; Kim, R. S.; Yap, G. P. A.; Rosen- (44) Speckmeier, E.; Fuchs, P. J. W.; Zeitler, K. A Synergistic LUMO
thal, J.; Watson, D. A. Photoredox-Nickel Dual-Catalyzed C-Al- Lowering Strategy Using Lewis Acid Catalysis in Water to Enable
kylation of Secondary Nitroalkanes: Access to Sterically Hindered Photoredox Catalytic, Functionalizing C-C Cross-Coupling of
α-Tertiary Amines. J. Am. Chem. Soc. 2023, 145 (8), 4707–4715. Styrenes. Chem. Sci. 2018, 9 (35), 7096–7103.
(24) Simlandy, A. K.; Rodphon, W.; Alturaifi, T. M.; Mai, B. K.; Ni, (45) Zytowski, T.; Fischer, H. Absolute Rate Constants for the Addi-
H.-Q.; Gurak, J. A., Jr; Liu, P.; Engle, K. M. Catalytic Addition tion of Methyl Radicals to Alkenes in Solution: New Evidence for
of Nitroalkanes to Unactivated Alkenes via Directed Carbopal- Polar Interactions. J. Am. Chem. Soc. 1996, 118 (2), 437–439.
ladation. ACS Catal. 2022, 12 (21), 13755–13762. (46) Griller, D.; Ingold, K. U. Free-Radical Clocks. Acc. Chem. Res.
(25) Ono, N. The Nitro Group in Organic Synthesis; John Wiley & Sons, 1980, 13 (9), 317–323.
2001.
(26) Faisca Phillips, A. M.; Guedes da Silva, M. F. C.; Pombeiro, A. J.
L. The Stereoselective Nitro-Mannich Reaction in the Synthesis
of Active Pharmaceutical Ingredients and Other Biologically Ac-
tive Compounds. Front Chem 2020, 8, 30.
(27) Sengupta, S.; Pabbaraja, S.; Mehta, G. Domino Reactions
through Recursive Anionic Cascades: The Advantageous Use of
Nitronates. Eur. J. Org. Chem. 2022, 2022 (42), e202200945.
(28) Valachová, D.; Marčeková, M.; Caletková, O.; Kolarovič, A.;
Jakubec, P. The Last Fortress of Tin’s Tyranny – Protodenitration
of Nitroalkanes. Eur. J. Org. Chem. 2023, 26 (13), e202201341.
(29) Kornblum, N.; Davies, T. M.; Earl, G. W.; Holy, N. L.; Kerber,
R. C.; Musser, M. T.; Snow, D. H. New and Facile Substitution
Reactions at Tertiary Carbon. J. Am. Chem. Soc. 1967, 89 (3), 725–
727.
(30) Kornblum, N.; Erickson, A. S. The Synthesis of Quaternary Car-
bon Compounds. J. Org. Chem. 1981, 46 (5), 1037–1039.
(31) Ono, N.; Miyake, H.; Kamimura, A.; Hamamoto, I.; Tamura, R.;
Kaji, A. Denitrohydrogenation of Aliphatic Nitro Compounds
and a New Use of Aliphatic Nitro Compounds as Radical Precur-
sors. Tetrahedron 1985, 41 (19), 4013–4023.
(32) Ono, N.; Kaji, A. Reductive Cleavage of Aliphatic Nitro Groups
in Organic Synthesis. Synthesis 1986, 1986 (9), 693–704.

https://doi.org/10.26434/chemrxiv-2024-qdxdv ORCID: https://orcid.org/0000-0002-5459-3660 Content not peer-reviewed by ChemRxiv. License: CC BY-NC-ND 4.0