Visible-Light-Induced Photoaddition of N-Nitrosoalkylamines to Alkenes: One-Pot Tandem Approach to 1,2-Diamination of Alkenes from Secondary Amines

Article abstract of DOI:10.1021/acs.orglett.1c00786

The generation of aminium radical cation species from N-nitrosoamines is disclosed for the first time through visible-light excitation at 453 nm. The developed visible-light-promoted photoaddition reaction of N-nitrosoamines to alkenes was combined with the o-NQ-catalyzed aerobic oxidation protocol of amines to telescope the direct handling of harmful N-nitroso compounds, where the desired α-amino oxime derivatives were obtained in a one-pot tandem N-nitrosation and photoaddition sequence.

Full text of DOI:10.1021/acs.orglett.1c00786

pubs.acs.org/OrgLett
Letter
Visible-Light-Induced Photoaddition of N‑Nitrosoalkylamines to
Alkenes: One-Pot Tandem Approach to 1,2-Diamination of Alkenes
from Secondary Amines
Dilip V. Patil,§ Tengda Si,§ Hun Young Kim,* and Kyungsoo Oh*
Cite This: Org. Lett. 2021, 23, 3105−3109
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The generation of aminium radical cation species from
N-nitrosoamines is disclosed for the first time through visible-light
excitation at 453 nm. The developed visible-light-promoted photo-
addition reaction of N-nitrosoamines to alkenes was combined with the
o-NQ-catalyzed aerobic oxidation protocol of amines to telescope the
direct handling of harmful N-nitroso compounds, where the desired α-
amino oxime derivatives were obtained in a one-pot tandem N-
nitrosation and photoaddition sequence.
vapor pressure lamps in immersion-well reactors are not readily
he synthetic utility of nitrogen-centered radicals has been
Twidely recognized in the functionalization of amine accessible for the majority of synthetic laboratories. In
derivatives through new C−N bond formations.1 In particular,
addition, the hazard associated with the use of strong UV
lights often calls for special safety measures in conducting the
photochemical reactions.5 Among the photoinduced N−X
cleavage reaction pathways, the N-nitrosoamines have received
a great deal of attention from the scientific community after
the initial reports of their biological function as potent nitric
oxide donors, but with significant carcinogenic properties.6
Because nitrosoamines are omnipresent in food, tobacco
smoke, and drinking water, the removal of such contaminants
under photolytic conditions has been the focus of intense
investigation.7 Nevertheless, no unified photochemical decom-
position pathway of N-nitrosoamines has been established to
date, and the growing concerns about N-nitrosoamine-
contaminated pharmaceuticals still pose grave health risks to
patients.8
the single-electron oxidation of amines to their corresponding
aminium radical cations allows the facile addition to alkenes
and alkynes,2 and the recent development of photoredox
catalysis amply demonstrates the synthetic powers of photo-
addition of amines to C−C π bonds.3 While N−X homolytic
cleavage (X = Cl, NO, NO2, or NHNNH) in the presence
of acids has been known as the best strategy for generating
aminium radical cations upon UV irradiation (Scheme 1a),2,4
the traditional photochemical experiment setups using mercury
Scheme 1. Photochemical Generation of Aminium Radical
Cations from N-Nitrosoamines
The photochemistry of N-nitrosoamines was pioneered by
the laboratory of Chow in 1965, where the N−NO bond was
homoloytically cleaved by UV-light and added to alkenes
(Scheme 1b).9 The key to the successful generation of
aminium radical cation species exclusively relied on the
protonated form of the N-nitrosoamines using 1 equiv of
HCl. Thus, under the typical photochemical reaction setup in
an external cooling immersion-well reactor with a Hanovia UV
lamp, a mixture of N-nitrosoamines and alkenes was irradiated
at 254 nm (with a Vycor filter) to induce the photoaddition of
Received: March 6, 2021
Published: April 1, 2021
https://doi.org/10.1021/acs.orglett.1c00786
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3105−3109
3105

Organic Letters
pubs.acs.org/OrgLett
Letter
the aminium radical cation to alkenes to give the α-amino
oxime derivatives. The photochemical behaviors of N-nitroso-
amines have been studied in detail,10 and the triplet and singlet
excited-state energy transitions of N-nitrosoamines were
identified as S0 → S2 (πN → π*NO), S0 → S1 (nN → π*NO),
and S0 → T1 (πO → π*NO).11 The burning question of whether
visible-light excitation of S0 → T1 (πO → π*NO) at 453 nm
could induce the homolytic cleavage of N-nitrosoamines to
generate the aminium radical cations arises, given that the S0
→ S2 (πN → π*NO) and S0 → S1 (nN → π*NO) transitions are
related to the homolytic N−NO bond cleavage at 230 and 360
nm, respectively.11a The implication of such visible-light-
induced aminium radical cation formation will be significant in
understanding of photochemical pathways of N-nitrosoamines
as well as the synthetic application of in situ-generated
aminium radical cations. Herein, we disclose the generation of
aminium radical cations from N-nitrosoamines under visible-
light irradiation for the first time, and the subsequent reaction
with alkenes to give the α-amino oxime derivatives (Scheme
1c).
The photochemical N−NO bond cleavage of N-nitroso-
amines was investigated in the presence of indene 2a (Table
1). Thus, the irradiation of N-nitrosopiperidine 1a and 2a
using blue LED light did not promote the formation of the
aminium radical cation (entry 1). The protonated form of 1a
with HCl failed to undergo the desired N−NO bond cleavage
in the absence of a light source (entry 2). The use of visible
light with blue LED light at 470 nm drastically changed the
outcome of the reaction, where protonated 1a smoothly
underwent the photoinduced N−NO bond cleavage, and
subsequently reacted with alkene 2a to give the corresponding
α-amino oxime 3a as respective (Z) and (E) isomers in a
combined yield of 93% (entry 3). The acidity−reactivity
relationship of protonated 1a was further examined using
different acids (entries 4−10), and the employment of acids
with pKa values of no less than −0.44 was beneficial to the
current visible-light-promoted photoaddition of N-nitrosopi-
peridine 1a to alkene 2a (TfOH pKa = −14, Tf2NH pKa =
−11.9, HCl pKa = −8.0, MsOH pKa = −2.6, TsOH pKa =
−0.51, HBF4 pKa = −0.44, HCOOH pKa = 3.77, and PhCO2H
pKa = 4.2). Solvent screening also revealed that the current
photoaddition reaction was not sensitive to the nature of
solvents, providing good to excellent yields of 3a in various
organic solvents (entries 11−17). The wavelength of the
applied light source significantly influenced the reaction rates
(entries 18−21). Thus, the reaction under the green LEDs
gave only 24% conversion within 48 h (entry 18), whereas the
reactions under purple light and UV light significantly
decreased the reaction time to 6 and 2 h, respectively (entries
19 and 20, respectively). The reaction could be also performed
under white light without much change in the reaction time or
chemical yield (entry 21). The use of 1 equiv of TsOH·H2O or
1a was tested, and the slightly reduced yields of 3a were
observed to be 77−78% (entries 22 and 23). As a result of the
optimization process, the use of TsOH·H2O was chosen to
broaden the substrate scope due to the easy handling of the
solid acid. Also, the current photoaddition reaction could be
equally performed in laboratory grade EtOH, implying the
beneficial effect of a nontoxic solvent.12 The reaction of N-
nitrosodiethylamine 1b resulted in the formation of 3b in 62%
yield under purple LED light in 48 h (entry 24). The use of N-
nitrosopyrrolidine 1c and N-nitroso 4-phenylpiperidine 1d also
provided the desired α-amino oximes 3c and 3d, respectively,
Table 1. Optimization of Photoaddition of N-Nitrosoamines
to Indene
a
b
entry
1/acid
1a/−
1a/HCl
1a/HCl
hυ
solvent
yield (%)
1
2
3
4
5
6
7
8
Blue LED’s
−
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
i-PrOH
MeCN
acetone
EtOAc
DMF
DMSO
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
0
0
93
95
84
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
green LEDs
purple LEDs
UV-A LEDs
white LEDs
white LEDs
white LEDs
purple LEDs
purple LEDs
purple LEDs
1a/TfOH
1a/HNTf2
1a/MsOH
1a/TsOH
1a/HBF4
1a/HCOOH
1a/PhCO2H
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1a/TsOH
1b/TsOH
1c/TsOH
1d/TsOH
96
93 (92)
82
9
7
0
88
80
39
80
49
77
89
24
89
79
93
77
78
62
10
11
12
13
14
15
16
17
18
19
20
21
c
d
e
f
g
22
g
c
c
c
,h
23
24
25
26
EtOH
EtOH
66
72
a
Reaction conditions: 1 (0.6 mmol), 2a (0.3 mmol), and acid (0.6
mmol) in degassed solvent (0.1 M) under LED light at 23 °C for 16
b
h. Yield determined by 1H NMR using an internal standard (isolated
c
d
e
yield in parentheses). Reaction for 48 h. Reaction for 6 h. Reaction
f
g
for 2 h. Reaction for 15 h. Reaction with 1 equiv of TsOH.
Reaction with 1 equiv of 1a.
h
in 66−72% yields (entries 25 and 26, respectively). Thus, the
conformation of N-nitrosoamines greatly influenced the
photoaddition reactions of N-nitrosoamines.13 It is noteworthy
that the addition of aminium radical cations to 2a was highly
selective, resulting in the regioselective formation of α-amino
oximes from the more stable benzylic radical intermediate
species. This observation concurred with Chow’s results.9
While the visible-light-promoted photoaddition of N-nitro-
soamines to alkenes possesses high synthetic potential in the
preparation of 1,2-diamine derivatives,14 the toxicity associated
with the N-nitrosoamines prompted the in situ generation of
N-nitrosoamines through the aerobic oxidation of amines
(Scheme 2). Thus, piperidine was aerobically oxidized to N-
nitrosopiperidine 1a in the presence of an o-naphthoquinone
(o-NQ) catalyst.15 The subsequent one-pot photoaddition
reaction did not occur under white LED light (400−700 nm),
although the use of UV-A LED light (365 nm) provided
desired product 3a in 60% yield (Scheme 2a). Because the
3106
https://doi.org/10.1021/acs.orglett.1c00786
Org. Lett. 2021, 23, 3105−3109

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. One-Pot Tandem Functionalization
Scheme 3. Alkene Substrate Scope for the One-Pot Tandem
N-Nitrosation and Photoaddition Sequence
“NO” source, i-PrNO2, was visible-light transparent, the o-NQ
catalyst with a dark color was suspected for inefficient light
transmission. Indeed, the control experiments with added i-
PrNO2 and o-NQ catalyst confirmed the significant interfer-
ence of visible-light transmission by the o-NQ catalyst
(Scheme 2b). Thus, to better transmit the visible light into
the colored reaction solution, purple LED light (395 nm) was
utilized. In addition, the amount of o-NQ catalyst in the
aerobic N-nitrosation was decreased to 1 mol %, while
employing 5 equiv of i-PrNO2 (Scheme 2c).
With the optimized one-pot tandem N-nitrosation and
visible-light-promoted photoaddition reaction sequence, the
alkene substrate scope on a 1 mmol scale was examined with in
situ-generated N-nitrosopiperidine 1a (Scheme 3). While the
dark colored reaction mixture from the aerobic N-nitrosation
required a more penetrating light source, the use of indene 2a
and 1,2-dihydronaphthalene 2b in the one-pot tandem reaction
sequence provided desired products 3a and 3e in 83−87%
yields. The electronically diverse styrenes were also suitable
under the current one-pot photoaddition reaction conditions,
providing products 3f−3o in 55−95% yields, with the
exception of 3g in a rather low yield of 41%. The reaction
could also be applied to 2-vinylnaphthalene and cyclohexene,
where desired products 3p and 3q were obtained in 77% and
37% yields, respectively. The subjection of trans-β-methylstyr-
ene provided the corresponding α-amino oxime 3r in 53%
yield along with (E)-benzaldehyde oxime 3r′ in 15% yield
through the carbon−carbon bond cleavage pathway instead of
the tautomerization pathway to the oxime moiety.9b Likewise,
the use of α-methylstyrene exclusively promoted the carbon−
carbon bond cleavage pathway to give (E)-acetophenone
oxime 3s in 68% yield.
Scheme 4. Amine Substrate Scope for the One-Pot Tandem
N-Nitrosation and Photoaddition Sequence
The one-pot tandem N-nitrosation and photoaddition
sequence was further examined using various secondary amines
(Scheme 4). In situ-generated N-nitrosodiethylamine 1b from
the aerobic N-nitrosation reaction was dark-colored and thus
required the more penetrating light source, UV-A LED lights,
to promote the photoaddition to furnish product 3b in 79%
yield. The tandem reaction sequence could be applied to N-
nitrosopyrrolidine 1c as well as N-nitrosopiperidine derivatives,
where good functional group tolerance was demonstrated
(3c−3d and 3t−3y). In addition, the use of morpholine,
thiomorpholine, and piperazine derivatives led to the
corresponding α-amino oximes in 29−57% yields.
The current visible-light-promoted aminium radical cation
formation from the direct excitation of the protonated N-
nitrosoamine via the S0 → T1 (πO → π*NO) transition greatly
improved the practicality of photoaddition of N-nitrosoamines
to alkenes. Thus, what appears to be a negligible absorption
peak of the S0 → T1 (πO → π*NO) transition at 450 nm was
sufficient to induce homolytic N−NO bond cleavage under the
3107
https://doi.org/10.1021/acs.orglett.1c00786
Org. Lett. 2021, 23, 3105−3109

Organic Letters
pubs.acs.org/OrgLett
Letter
visible-light condition. The absorption peaks of N-nitroso-
amines at 450 nm in various organic solvents were weak, and
the intensity of the corresponding peaks did not change after
the protonation (see the Supporting Information for UV−vis
spectra). Previously, Chow and co-workers suggested that the
triplet excited-state (T1) of N-nitrosoamines do not lead to an
irreversible chemical change because (1) when the S0 → T1
transition band at 450 nm was excited at 77 K, the
phosphorescence centered at 550 nm was observed and (2)
no chemical reaction was observed in the presence of triplet
sensitizers.11a However, a recent theoretical calculation contra-
dicted the reactivity of the triplet excited state (T1), estimating
the homolytic and adiabatic N−NO bond dissociation of T1
with 3.1 kcal/mol after excitation from S0.16 Thus, a plausible
reaction mechanism for the visible-light-promoted photo-
addition of N-nitrosoamines to alkenes is proposed on the
basis of the photochemical decomposition of their triplet
excited state of the N−NO bond (Scheme 5a). In this
unprecedented excitation of the triplet state (T1) at 453 nm.
Thus, the current method boasts the immersion photochemical
apparatus-free visible-light-promoted photochemical reaction.
In addition, the developed reaction sequence does not
necessitate the handling of harmful N-nitroso compounds
and also utilizes a nontoxic solvent, EtOH. Given that the
decomposition pathways of N-nitroso compounds are of great
interest to the scientific community, the current one-pot
tandem N-nitrosation and photoaddition reaction sequence
should stimulate considerable interest in the photochemical
functionalization of N-nitrosoamines.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00786.
Experimental procedures, characterization data for all
compounds, and NMR spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds (Z)-3a−3z, (E)-3a′−3z′, and 4−6 (ZIP)
Scheme 5. A Plausible Photoaddition Mechanism and
Functionalization of α-Amino Oximes
AUTHOR INFORMATION
Corresponding Authors
■
Kyungsoo Oh − Center for Metareceptome Research,
Graduate School of Pharmaceutical Sciences, Chung-Ang
University, Seoul 06974, Republic of Korea; orcid.org/
0000-0002-4566-6573; Email: kyungsoooh@cau.ac.kr
Hun Young Kim − Department of Global Innovative Drugs,
Chung-Ang University, Seoul 06974, Republic of Korea;
orcid.org/0000-0002-8461-8910; Email: hunykim@
cau.ac.kr
Authors
Dilip V. Patil − Center for Metareceptome Research, Graduate
School of Pharmaceutical Sciences, Chung-Ang University,
Seoul 06974, Republic of Korea; orcid.org/0000-0003-
2103-3840
Tengda Si − Center for Metareceptome Research, Graduate
School of Pharmaceutical Sciences, Chung-Ang University,
Seoul 06974, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00786
Author Contributions
§D.V.P. and T.S. contributed equally to this work.
Notes
scenario, protonated N-nitrosoamine A is photolytically
transformed to N-nitrosoammonium ion B that is readily
homolytically cleaved to give aminium radical cation C and
nitric oxide D. Because aminium radical cation C is known to
add to alkenes faster than it abstracts hydrogen from MeOH by
a factor of 5000,17 resulting carbon radical E is recombined
with nitric oxide D. The tautomerization of F finally leads to α-
amino oximes 3. The involvement of carbon radical E was
supported by the TEMPO adduct when the reaction was
performed with a radical inhibitor. α-Amino oxime products 3
could be selectively transformed to trans-diamine 5 or
hydrolyzed to the corresponding ketone 6 in good yields
(Scheme 5b).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) funded by the Korean govern-
ment (MSICT) (NRF-2015R1A5A1008958 and NRF-
2019R1A2C2089953).
REFERENCES
■
(1) (a) Stella, L. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 407−
426. (b) Zard, S. Z. Recent Progress in the Generation and Use of
Nitrogen-centered Radicals. Chem. Soc. Rev. 2008, 37, 1603−1618.
(c) Xiong, T.; Zhang, Q. New Amination Strategies Based on
Nitrogen-Centered Radical Chemistry. Chem. Soc. Rev. 2016, 45,
In summary, we have developed the one-pot tandem N-
nitrosation of amines and photoaddition reaction to alkenes.
The use of visible-light-promoted photoaddition of N-nitroso-
amines to alkenes was disclosed for the first time through the
3108
https://doi.org/10.1021/acs.orglett.1c00786
Org. Lett. 2021, 23, 3105−3109

Organic Letters
pubs.acs.org/OrgLett
Letter
3069−3087. (d) Kärkäs, M. D. Photochemical Generation of
Nitrogen-Centered Amidyl, Hydrazonyl, and Imidyl Radicals:
Methodology Developments and Catalytic Applications. ACS Catal.
2017, 7, 4999−5022.
(2) (a) Danen, W. C.; Neugebauer, F. A. Aminyl Free Radicals.
Angew. Chem., Int. Ed. Engl. 1975, 14, 783−789. (b) Chow, Y. J.;
Danen, W. C.; Nelsen, S. F.; Rosenblatt, D. H. Nonaromatic Aminium
Radicals. Chem. Rev. 1978, 78, 243−274.
Photoreactions of Nitroso Compounds in Solution. XXIII. A Novel
Oxidative Photoreaction of Nitrosamines and Nitrosamides. Can. J.
Chem. 1973, 51, 2469−2476. (c) Mojelsky, T.; Chow, Y. L.
Photoreactions of Nitroso Compounds in Solution. XXVII. Polar
Effects of the Aminium Radical Addition to Styrenes. J. Am. Chem.
Soc. 1974, 96, 4549−4554. (d) Cessna, A. J.; Sugamori, S. E.; Yip, R.
W.; Lau, M. P.; Snyder, R. S.; Chow, Y. L. Flash Photolysis Studies of
N-Chloro- and N-Nitrosopiperidine in Aqueous Solution. Assignment
and Reactivity of the Piperidium Radical. J. Am. Chem. Soc. 1977, 99,
4044−4048. (e) Keefer, L. K.; Hrabie, J. A.; Hilton, B. D.; Wilbur, D.
Nitrogen Protonation of N-Nitrosodimethylamine. J. Am. Chem. Soc.
1988, 110, 7459−7462. (f) Wagner, B. D.; Ruel, G.; Lusztyk, J.
Absolute Kinetics of Aminium Radical Reactions with Olefins in
Acetonitrile Solution. J. Am. Chem. Soc. 1996, 118, 13−19.
(3) (a) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Visible Light
Photoredox-Controlled Reactions of N-Radicals and Radical Ions.
Chem. Soc. Rev. 2016, 45, 2044−2056. (b) Jiang, H.; Studer, A.
Chemistry with N-Centered Radicals Generated by Single-Electron
Transfer-Oxidation Using Photoredox Catalysis. CCS Chem. 2019, 1,
38−49. (c) Yu, X.-Y.; Zhao, Q.-Q.; Chen, J.; Xiao, W.-J.; Chen, J.-R.
When Light Meets Nitrogen-Centered Radicals: From Reagents to
Catalysts. Acc. Chem. Res. 2020, 53, 1066−1083. (d) Ganley, J. M.;
Murray, P. R. D.; Knowles, R. R. Photocatalytic Generation of
Aminium Radical Cations for C-N Bond Formation. ACS Catal. 2020,
10, 11712−11738.
(11) (a) Chow, Y. L.; Wu, Z.-Z.; Lau, M.-P.; Yip, R. W. On the
Singlet and Triplet Excited States of Nitrosamines. J. Am. Chem. Soc.
1985, 107, 8196−8201. (b) Piech, K.; Bally, T.; Sikora, A.; Marcinek,
A. Mechanistic Aspects of the Oxidative and Reductive Fragmentation
of N-Nitrosoamines: A New Method for Generating Nitrenium
Cations, Amide Anions, and Aminyl Radicals. J. Am. Chem. Soc. 2007,
129, 3211−3217. (c) Oliveira, M. S.; Ghogare, A.; Abramova, I.;
Greer, E. M.; Prado, F. M.; Di Mascio, P.; Greer, A. Mechanism of
Photochemical O-Atom Exchange in Nitrosamines with Molecular
Oxygen. J. Org. Chem. 2015, 80, 6119−6127. (d) Ghogare, A. A.;
Debaz, C. J.; Silva Oliveira, M.; Abramova, I.; Mohapatra, P. P.;
Kwon, K.; Greer, E. M.; Prado, F. M.; Valerio, H. P.; Di Mascio, P.;
Greer, A. Experimental and DFT Computational Insight into
Nitrosamine Photochemistry-Oxygen Matters. J. Phys. Chem. A
2017, 121, 5954−5966.
(4) (a) Wawzonek, S.; Thelen, P. J. Preparation of N-
Methylgranatanine. J. Am. Chem. Soc. 1950, 72, 2118−2120.
(b) Wolff, M. E. Cyclization of N-Halogenated Amines (The
̈
Hofmann-Loffler Reaction). Chem. Rev. 1963, 63, 55−64.
(c) Beard, J. C.; Swager, T. M. An Organic Chemist’s Guide to N-
Nitrosoamines: Their Structure, Reactivity, and Role as Contami-
nants. J. Org. Chem. 2021, 86, 2037−2057.
(5) (a) Mattay, J.; Griesbeck, A. Photochemical Key Steps in Organic
Synthesis: An Experimental Course Book; VCH: Weinheim, Germany,
1994. (b) Ninomiya, I.; Naito, T. Photochemical Synthesis; Academic
Press: London, 1989.
(12) Q3C-Tables and List Guidance for Industry. U.S. Department
of Health and Human Services, Food and Drug Administration, 2017
ICH, rev. 3.
(6) (a) Magee, P. N.; Barnes, J. M. The Production of Malignant
Primary Hepatic Tumors in the Rat by Feeding Dimethylnitroso-
amine. Br. J. Cancer 1956, 10, 114−122. (b) DeRubertis, F. R.;
Craven, P. A. Calcium-Independent Modulation of Cyclic GMP and
Activation of Guanylate Cyclase by Nitrosamines. Science 1976, 193,
897−899.
(7) (a) Shank, R. C. Toxicology of N-Nitroso Compounds. Toxicol.
Appl. Pharmacol. 1975, 31, 361−368. (b) Hecht, S. S. Biochemistry,
Biology, and Carcinogenecity of Tobacco-Specific N-Nitrosoamines.
Chem. Res. Toxicol. 1998, 11, 559−603. (c) N-Nitrosoamines: 15
Listings; National Toxicology Program, U.S. Department of Health
and Human Services, November 2016, 14th Report on Carcinogens
(https://ntp.niehs.nih.gov/ntp/roc/content/profiles//nitrosamines.
pdf) (accessed 2021-03-06).
(8) (a) Lee, C.; Choi, W.; Kim, Y. G.; Yoon, J. UV Photolytic
Mechanism of N-Nitrosodimethylamine in Water: Dual Pathways to
Methylamine versus Dimethylamine. Environ. Sci. Technol. 2005, 39,
2101−2106. (b) Lee, C.; Choi, W.; Yoon, J. UV Photolytic
Mechanism of N-Nitrosodimethylamine in Water: Roles of Dissolved
Oxygen and Solution pH. Environ. Sci. Technol. 2005, 39, 9702−9709.
(c) FDA Update and Press Announcements on Angiotensin II
Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesar-
tan). 2019 (https://www.fda.gov/drugs/drug-safety-and-availability/
fda-updates-and-press-announcements-angiotensin-ii-receptor-
blocker-arb-recalls-valsartan-losartan) (accessed 2021-03-06). (d) Gil-
lette, M.; Taylor, A.; Butulija, D.; Kadiyala, H.; Jneid, H. Reflections
of the Angiotensin Receptor Blocker Recall by the FDA and
Repercussions on Healthcare. Cardiovasc. Drugs Ther. 2020, 34,
579−584.
(13) (a) Chow, Y. L.; Colon, C. J. Photochemistry of Nitroso
Compounds in Solution. IX. Steric Effects in the Photoaddition of N-
Nitrosodialkylamines to Olefins. Magnetic Non-Equivalence of
Methylene Protons Caused by a Distant Asymmetry. Can. J. Chem.
1967, 45, 2559−2568. (b) Ohwada, T.; Miura, M.; Tanaka, H.;
Sakamoto, S.; Yamaguchi, K.; Ikeda, H.; Inagaki, S. Structural
Features of Aliphatic N-Nitrosamines of 7-Azabicyclo[2.2.1]heptanes
That Facilitate N-NO Bond Cleavage. J. Am. Chem. Soc. 2001, 123,
10164−10172.
(14) For recent alkene diamination examples, see: (a) Govaerts, S.;
Angelini, L.; Hampton, C.; Malet-Sanz, L.; Ruffoni, A.; Leonori, D.
Photoinduced Olefin Diamination with Alkylamines. Angew. Chem.,
Int. Ed. 2020, 59, 15021−15028. (b) Makai, S.; Falk, E.; Morandi, B.
Direct Synthesis of Unprotected 2-Azidoamines from Alkenes via an
Iron-Catalyzed Difunctionalization Reaction. J. Am. Chem. Soc. 2020,
142, 21548−21555. For a recent review, see: (c) De Jong, S.; Nosal,
D. G.; Wardrop, D. J. Methods for Direct Alkene Diamination, New
& Old. Tetrahedron 2012, 68, 4067−4105.
(15) (a) Si, T.; Kim, H. Y.; Oh, K. Substrate Promiscuity of ortho-
Naphthoquinone Catalyst: Catalytic Aerobic Amine Oxidation
Protocols to Deaminative Cross-Coupling and N-Nitrosation. ACS
Catal. 2019, 9, 9216−9221. (b) Si, T.; Kim, H. Y.; Oh, K. One-Pot
Tandem ortho-Naphthoquinone-Catalyzed Aerobic Nitrosation of N-
Alkylanilines and Rh(III)-Catalyzed C-H Functionalization Sequence
to Indole and Aniline Derivatives. J. Org. Chem. 2021, 86, 1152−1163.
(16) Peláez, D.; Arenas, J. F.; Otero, J. C.; Soto, J. Dependence of N-
Nitrosodimethylamine Photodecomposition on the Irradiation Wave-
length: Excitation to the S2 State as a Doorway to the Dimethylamine
Radical Ground-State Chemistry. J. Org. Chem. 2007, 72, 4741−4749.
(17) Lau, M. P.; Cessna, A. J.; Chow, Y. L.; Yip, R. W. Flash
Photolysis of N-Nitrosopiperidine. The Reactive Transient. J. Am.
Chem. Soc. 1971, 93, 3808−3809.
(9) (a) Chow, Y. L. Photo-addition of N-Nitrosodialkylamines to
Cyclohexene. Can. J. Chem. 1965, 43, 2711−2716. (b) Chow, Y. L.
Carbon-Carbon Double Bond Cleavage by Photoaddition of N-
Nitrosoalkylamines to Olefins. J. Am. Chem. Soc. 1965, 87, 4642−
4643. (c) Chow, Y.-L.; Colon, C. J.; Chen, S. C. Photochemistry of
Nitroso Compounds in Solution. VII. Photoaddition of Nitrosamines
to Various Olefins. J. Org. Chem. 1967, 32, 2109−2115.
(10) (a) Axenrod, T.; Milne, G. W. A. Photochemistry of
Nitrosamines Mechanism Studies. Tetrahedron 1968, 24, 5775−
5783. (b) Chow, Y. L.; Tam, J. N. S.; Colon, C. J.; Pillay, K. S.
3109
https://doi.org/10.1021/acs.orglett.1c00786
Org. Lett. 2021, 23, 3105−3109