Photoredox-Catalyzed α-C(sp3)-H Activation of Unprotected Secondary Amines: Facile Access to 1,4-Dicarbonyl Compounds

Article abstract of DOI:10.1021/acs.orglett.0c02571

A photoredox-catalyzed α-C(sp3)-H activation approach of unprotected secondary amines is reported. Such transformations provide facile access to various 1,4-dicarbonyl compounds using readily available amines and α,β-unsaturated compounds as feedstocks under air conditions. The substrate scope of this method is broad, and a wide array of functional groups are tolerated.

Full text of DOI:10.1021/acs.orglett.0c02571

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Letter
Photoredox-Catalyzed α‑C(sp3)−H Activation of Unprotected
Secondary Amines: Facile Access to 1,4-Dicarbonyl Compounds
Qian Zhang,† Yan Huang,† Le-Wu Zhan, Wan-Ying Tang, Jing Hou,* and Bin-Dong Li*
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ABSTRACT: A photoredox-catalyzed α-C(sp3)−H activation
approach of unprotected secondary amines is reported. Such
transformations provide facile access to various 1,4-dicarbonyl
compounds using readily available amines and α,β-unsaturated
compounds as feedstocks under air conditions. The substrate scope
of this method is broad, and a wide array of functional groups are tolerated.
hotoredox-catalyzed functionalization of the α-C(sp3)−H
addition of α-amino radicals from primary and secondary
Pbond of amines through highly reactive α-amino radical amines to α,β-unsaturated esters under irradiation of a 450 W
medium pressure mercury lamp. Nevertheless, only limited
substrates gave desired products in low conversions and yields.
To realize the α-C(sp3)−H alkylation of primary and
secondary amines, methods employing amines with prein-
stalled cleavable groups at the α-position6 and protected
groups7 were developed (Scheme 1c). Recently, Cresswell and
co-workers reported an elegant C−H alkylation of unmasked
α-tertiary primary amine through the combination of photo-
redox and hydrogen-atom-transfer catalysis.8 However, direct
radical addition of unprotected secondary amines to electron-
deficient akenes remains a challenge.
intermediates has received considerable attention as an
efficient and straightforward way to construct C−C bonds.1
One particularly intriguing transformation is the visible-light-
mediated addition of α-amino radicals to electron-deficient
alkenes to provide γ-aminocarbonyl or other useful skeletons.1d
However, the reported approaches are mainly limited to
tertiary amine derivates due to the easy formation of α-amino
radicals by the single electron oxidation (Scheme 1a).2
Competitive N-alkylation products were usually observed for
unprotected primary and secondary amines, due to the
generation of aminyl radicals3 or direct aza-Michael addition
(Scheme 1b).4 In 1994, Das and co-workers5 reported the
1,4-Dicarbonyl compounds are useful synthetic intermedi-
ates in organic synthesis.9 Although tremendous efforts have
been made to construct these skeletons, greener and efficient
methods are still desirable.10 Visible-light-induced oxidative
C−N bond cleavage of amines to produce carbonyl
compounds through iminium ion intermediates has been
disclosed.11 In this regard, we envisioned that γ-aminocarbonyl
compounds generated from the addition of α-amino radicals to
α,β-unsaturated esters could be oxidized to 1,4-dicarbonyl
compounds under photoredox conditions. Thus, the radical
addition process may be promoted by introducing external
oxidants to transfer γ-aminocarbonyl products to 1,4-
dicarbonyl compounds (Scheme 1d). To this end, the
oxidation of initial primary and secondary amines to iminium
ions ought to be avoided. Herein, we described here the
successful realization of tandem addition of α-amino radicals
derived from unprotected primary and secondary amines to
Scheme 1. α-C(sp3)−H Alkylation of Amines via α-Amino
Radical Intermediates
Received: August 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02571
© XXXX American Chemical Society
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A

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a
α,β-unsaturated esters and oxidation of γ-aminocarbonyl
intermediates providing 1,4-dicarbonyl compounds using
oxygen as the oxidant under photoredox conditions.
Scheme 3. Substrate Scope of Alkenes
We initially carried out the transformation using dibutyl-
amine (1a) and benzyl acrylate (2a) as substrates under blue
LED irradiation. After extensive investigation (Scheme 2), we
a
Scheme 2. Reaction Optimization
a
a
Reaction conditions: 1a (0.1 mmol), 2a (0.4 mmol), 4CzIPN (4 mol
The standard reaction condition, isolated yields.
%), toluene:H2O (3 mL/1 mL), blue LED, Air (Sealed), 80 °C, 12 h.
b
1
Yields determined by H NMR spectroscopy using trimethoxyben-
c
zene as an internal standard. Isolated yield.
ylmethyl acrylate (3f) were also accommodated. In addition,
the 1,1-disubstituted acrylates could be used to deliver product
3g in 48% yield and 3q in 23% yield. Moreover, simple alkyl
acrylates were suitable substrates (3h−3l), and functional
groups such as epoxide (3m), alkenes (3n), and alkynes (3o)
moieties were tolerated. Lactones (3p) were compatible
affording the corresponding products in moderate yield.
Intriguingly, acrylamide (3r), vinylphosphonate (3s), and
vinylsulfone (3t) underwent the reaction smoothly to deliver
desired products.
We next investigated the substrate scope of amines with
benzyl acrylate as the partner (Scheme 4). As shown in
Scheme 4, employing symmetric aliphatic secondary amines,
such as diethylamine, diisobutylamine, bis(2-ethylhexyl)amine,
dioctylamine, dibenzylamine, and bis(4-methoxybenzyl)amine,
gave desired products in moderate to good yields (3u−3z).
The mixture of 3u and 3a was obtained employing N-
ethylbutan-1-amine as the substrate, due to the existence of
two reactive α positions. Interestingly, using isopropyl (1h and
1i) or methyl (1j) substituted amines, the reaction proceeded
with good regioselectivity. We reasoned that steric hindrance
of isopropyl and instability of methyl radical may suppress the
alkylation of the corresponding α-C(sp3)−H site. Finally, a
primary amine (1k) was subjected to the reaction providing
corresponding product 3a in a 30% yield, demonstrating the
broad substrates scope of the system.
found that using 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyano-
benzene (4CzIPN, 4 mol %) as the photoredox catalyst in
the mixture solution of toluene and H2O (3:1) under an air
(sealed) atmosphere at 80 °C provided the optimal result,
affording benzyl 4-oxoheptanoate (3a) in 82% yield (entry 1).
No product was obtained employing Ru(bpy)3(PF6)2 as the
photocatalyst (entry 2). And using Ir[df(CF3)ppy]2(dtbbpy)-
PF6 instead of 4CzIPN afforded a lower yield (entry 3). Using
toluene as the solvent gave 3a in 30% yield indicating that the
addition of H2O is essential (entry 4). Switching the reaction
solvent from toluene/H2O to CH3CN/H2O and CH2Cl2/H2O
delivered products in decreased yield (entries 5 and 6). When
the concentration of 1a was increased from 0.025 to 0.05 M,
the yield of product 3a decreased to 10% (entry 7).
Subsequently, using 1 equiv of K2CO3 or Cs2CO3 as the
additive resulted in lower yields (entries 8 and 9). When the
reaction was carried out using 2 equiv of 2a or at lower
temperature, a lower yield was obtained (entries 10 and 11).
Notably, the product 3a was afforded in only 28% yield
employing O2 instead of air, suggesting that the amount of O2
is of importance in this system. We reasoned that excessive
oxygen may lead to C−N bond cleavage of 1a. The control
experiments indicated that photocatalyst and light irradiation
are both critical for the reaction (entries 13 and 14).
With the optimal conditions in hand, the substrate scope of
alkenes was investigated (Scheme 3). As shown in Scheme 3,
benzyl acrylates bearing different functional groups on
aromatic rings were effective to afford products in good yields
(3b−3d). Naphthalen-1-ylmethyl acrylate (3e) and pyridin-3-
Various control experiments were conducted to understand
the reaction mechanism. Based on the result of Stern−Volmer
quenching studies, the excited photocatalyst [E1/2(*P/P−) =
+1.35 V vs SCE in MeCN]12 could be quenched by
dibutylamine (Ep = 1.09 V vs SCE in MeCN, Figure S3).
B
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mide (5) was synthesized and subjected to the standard
conditions, giving desired 1,4-dicarbonyl compounds (3r) in
48% yield (Scheme 5b). Secondary and primary amines could
be oxidized easily to generate aldehydes in the presence of
oxidants under photoredox conditions.11 And the addition of
acyl radical from aldehydes to electron-deficient alkenes has
been developed.13 Performing the reaction of 1a in the
presence of aldehydes (4b) under standard reaction conditions
afforded 3a and 3v in 75% and 10% yields, respectively
(Scheme 5c). Conversely, adding 4a to the reaction of 1v
afforded 3v and 3a in 58% and 13% yields (Scheme 5c). The
results of these two crossover experiments suggested that
aldehydes derived from direct oxidation of started amines may
contribute to the formation of 1,4-dicarbonyl compounds.
However, according to the ratios of 3a and 3v, the reaction
mainly went through γ-aminocarbonyl intermediates, rather
than aldehydes. In addition, 3a was not obtained when we used
the butyraldehyde (4a) as the substrate instead of dibutyl-
amine, indicating that the addition of the aldehydes to alkenes
could not occur without the amines (Scheme 5c).
Scheme 4. (a) Scope of Symmetric Secondary Amines; (b)
Scope of Unsymmetric Secondary Amines and Primary
Amines
a
Based on the aforementioned control experiments, we
propose a plausible mechanism for the transformation of
unprotected primary and secondary amines to 1,4-dicarbonyl
compounds under photoredox conditions (Scheme 6). The
Scheme 6. Proposed Mechanism
a
The standard reaction condition, isolated yields.
The formation of 3a was completely inhibited using TEMPO
as the additive, suggesting that radical intermediates were
generated during the transformation (Scheme 5a). The
postulated intermediate 4-(butylamino)-N,N-dimethylheptana-
Scheme 5. Control Experiments
exited-state 4CzIPN (II) can be reduced by the amine (IV) to
afford the α-amino radical (V). Addition of V to the electron-
deficient alkene gives rise to a radical adduct (VI). Subsequent
reduction of adduct (VI) and protonation of VII affords the γ-
aminocarbonyl intermediate (VIII) which can be oxidized to
generate (IX). Oxygen in the system can also oxidize III to I
and deliver oxygen radical anion species. Hydrogen atom
transfer from IX to oxygen radical anion provides an iminium
ion (X). Finally, hydrolysis of X occurs to furnish the 1,4-
dicarbonyl compound. The direct oxidation of started amines
to aldehydes and subsequent radical addition of acyl radical
C
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Notes
from aldehydes to electron-deficient alkenes may be the minor
pathway of the process (Scheme 6b).
The authors declare no competing financial interest.
To demonstrate the importance and utility of this method,
transformations of ethyl 4-oxopentanoate (3aa) to 4,5-
dihydropyridazin-3(2H)-one (6) and 5-methyldihydrofuran-
2(3H)-one (7) were conducted, giving desired products in
good yields (Scheme 7).
ACKNOWLEDGMENTS
■
The work was supported by the National Natural Science
Foundation of China (No. 21901118 and No. 21875109), the
Natural Science Foundation of Jiangsu Province (No.
BK20190430) and the Fundamental Research Funds for the
Central Universities (No. 30919011217).
Scheme 7. Transformations of 1,4-Dicarbonyl Compounds
REFERENCES
■
(1) (a) McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science 2011,
334, 1114−1117. (b) Kohls, P.; Jadhav, D.; Pandey, G.; Reiser, O.
Org. Lett. 2012, 14, 672−675. (c) Miyake, Y.; Nakajima, K.;
Nishibayashi, Y. J. Am. Chem. Soc. 2012, 134, 3338−3341.
(d) Nakajima, K.; Miyake, Y.; Nishibayashi, Y. Acc. Chem. Res.
2016, 49, 1946−1956. (e) Prier, C. K.; Rankic, D. A.; MacMillan, D.
W. C. Chem. Rev. 2013, 113, 5322−5363. (f) Beatty, J. W.;
Stephenson, C. R. Acc. Chem. Res. 2015, 48, 1474−1484.
(2) (a) Dinnocenzo, J. P.; Banach, T. E. J. Am. Chem. Soc. 1989, 111,
8646−8653. (b) Zhang, X.; Yeh, S.-R.; Hong, S.; Freccero, M.; Albini,
A.; Falvey, D. E.; Mariano, P. S. J. Am. Chem. Soc. 1994, 116, 4211−
4220.
(3) (a) Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. Engl. 1997,
36, 2550−2589. (b) Lewis, F. D.; Correa, P. E. J. Am. Chem. Soc.
1984, 106, 194−198. (c) Lewis, F. D.; Zebrowski, B. E.; Correa, P. E.
J. Am. Chem. Soc. 1984, 106, 187−193. (d) Fessenden, R. W.; Neta,
P.; Mellon Inst. Sci. J. Phys. Chem. 1972, 76, 2857−2859.
(4) (a) Wang, J.; Li, P.; Choy, P. Y.; Chan, A. S. C.; Kwong, F. Y.
ChemCatChem 2012, 4, 917−925. (b) Enders, D.; Wang, C.; Liebich,
J. X. Chem. - Eur. J. 2009, 15, 11058−11076.
In summary, we have developed a visible-light-driven
C(sp3)−H activation strategy to realize direct radical addition
of unprotected secondary and primary amines to electron-
deficient alkenes. This work represents a rare example of
visible-light-promoted direct functionalization of α-C(sp3)−H
of unmasked secondary amines. This protocol provides a novel
access to important 1,4-dicarbonyl compounds. Moreover, the
substrate scope of this method is broad and a wide array of
functional groups are tolerated.
ASSOCIATED CONTENT
* Supporting Information
■
(5) (a) Das, S.; Kumar, J. S. D.; Thomas, K. G.; Shivaramayya, K.;
George, M. V. J. Org. Chem. 1994, 59, 628−634. (b) Das, S.; Dileep
Kumar, J. S.; Shivaramayya, K.; George, M. V. J. Photochem. Photobiol.,
A 1996, 97, 139−150.
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02571.
(6) (a) Yoon, U. C.; Mariano, P. S. Acc. Chem. Res. 1992, 25, 233−
240. (b) Cho, D. W.; Yoon, U. C.; Mariano, P. S. Acc. Chem. Res.
2011, 44, 204−215. (c) Miyake, Y.; Ashida, Y.; Nakajima, K.;
Nishibayashi, Y. Chem. Commun. 2012, 48, 6966−6968. (d) Miyake,
Y.; Ashida, Y.; Nakajima, K.; Nishibayashi, Y. Chem. Commun. 2014,
50, 8900−8903. (e) Espelt, L. R.; McPherson, I. S.; Wiensch, E. M.;
Yoon, T. P. J. Am. Chem. Soc. 2015, 137, 2452−2455. (f) Lenhart, D.;
Experimental procedures, detailed mechanistic studies,
characterization data, and 1H NMR and 13C NMR
spectra for all new products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Bauer, A.; Pcţ hig, A.; Bach, T. Chem. - Eur. J. 2016, 22, 6519−6523.
Bin-Dong Li − College of Chemical Engineering, Nanjing
University of Science and Technology, Nanjing 210094, China;
Email: libindong@njust.edu.cn
Jing Hou − College of Chemical Engineering, Nanjing University
of Science and Technology, Nanjing 210094, China;
orcid.org/0000-0002-1892-2025; Email: chmhouj@
njust.edu.cn
(g) Yasu, Y.; Koike, T.; Akita, M. Adv. Synth. Catal. 2012, 354, 3414−
3420. (h) Miyazawa, K.; Koike, T.; Akita, M. Adv. Synth. Catal. 2014,
356, 2749−2755. (i) Fan, L.; Jia, J.; Hou, H.; Lefebvre, Q.; Rueping,
M. Chem. - Eur. J. 2016, 22, 16437−16440.
(7) (a) Ye, J.; Kalvet, I.; Schoenebeck, F.; Rovis, T. Nat. Chem. 2018,
10, 1037−1041. (b) Ashley, M. A.; Yamauchi, C.; Chu, J. C. K.;
Otsuka, S.; Yorimitsu, H.; Rovis, T. Angew. Chem., Int. Ed. 2019, 58,
4002−4006. (c) McManus, J. B.; Onuska, N. P. R.; Nicewicz, D. A. J.
Am. Chem. Soc. 2018, 140, 9056−9060.
Authors
(8) Ryder, A. S. H.; Cunningham, W. B.; Ballantyne, G.; Mules, T.;
Kinsella, A. G.; Turner-Dore, J.; Alder, C. M.; Edwards, L. J.; McKay,
B. S. J.; Grayson, M. N.; Cresswell, A. J. Angew. Chem., Int. Ed. 2020,
59, 14986−14991.
Qian Zhang − College of Chemical Engineering, Nanjing
University of Science and Technology, Nanjing 210094, China
Yan Huang − College of Chemical Engineering, Nanjing
University of Science and Technology, Nanjing 210094, China
Le-Wu Zhan − College of Chemical Engineering, Nanjing
University of Science and Technology, Nanjing 210094, China
Wan-Ying Tang − College of Chemical Engineering, Nanjing
University of Science and Technology, Nanjing 210094, China
(9) (a) Bernardes, L. S.; Kato, M. J.; Albuquerque, S.; Carvalho, I.
Bioorg. Med. Chem. 2006, 14, 7075−7082. (b) Piancatelli, G.; D’Auria,
M.; D’Onofrio, F. Synthesis 1994, 1994, 867−889. (c) Kaleta, Z.;
Makowski, B. T.; Soos, T.; Dembinski, R. Org. Lett. 2006, 8, 1625−
1628. (d) Baltazzi, E.; Krimen, L. I. Chem. Rev. 1963, 63, 511−556.
(e) Zheng, C.; Dubovyk, I.; Lazarski, K. E.; Thomson, R. J. J. Am.
Chem. Soc. 2014, 136, 17750−17756. (f) Furusaki, A.; Matsumoto,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02571
̅
T.; Ogura, H.; Takayanagi, H.; Hirano, A.; Omura, S. J. Chem. Soc.,
Chem. Commun. 1980, 698a−698a.
Author Contributions
†These authors contributed equally (Q.Z. and Y.H.).
(10) (a) Ros, F.; de la Rosa, J.; Enfedaque, J. J. Org. Chem. 1995, 60,
5419−5424. (b) Zhu, Y.; Zhang, L.; Luo, S. J. Am. Chem. Soc. 2014,
D
https://dx.doi.org/10.1021/acs.orglett.0c02571
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
136, 14642−14645. (c) Miura, K.; Fujisawa, N.; Saito, H.; Wang, D.;
Hosomi, A. Org. Lett. 2001, 3, 2591−2594. (d) Song, H. J.; Lim, C. J.;
Lee, S.; Kim, S. Chem. Commun. 2006, 2893−2895. (e) Zhao, J.-F.;
Tan, B.-H.; Loh, T.-P. Chem. Sci. 2011, 2, 349−352. (f) Matsubara,
R.; Doko, T.; Uetake, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2007,
46, 3047−3050. (g) Zhong, F.; Yao, W.; Dou, X.; Lu, Y. Org. Lett.
2012, 14, 4018−4021. (h) Tanaka, K.; Shibata, Y.; Suda, T.;
Hagiwara, Y.; Hirano, M. Org. Lett. 2007, 9, 1215−1218. For a
decarboxylativeacyl radical Michael addition, see: (i) Wang, G. Z.;
Shang, R.; Cheng, W. M.; Fu, Y. Org. Lett. 2015, 17, 4830−4833.
(j) Zhang, S. L.; Wang, X. J.; Yu, Z. L. Org. Lett. 2017, 19, 3139−
3142.
(11) (a) Iqbal, N.; Cho, E. J. Adv. Synth. Catal. 2015, 357, 2187−
2192. For other selected works on generation of iminium ions from
amines, see: (b) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson,
C. R. J. J. Am. Chem. Soc. 2010, 132, 1464−1465. (c) Zou, Y.; Lu, L.;
Fu, L.; Chang, N.; Rong, J.; Chen, J.; Xiao, W. Angew. Chem., Int. Ed.
2011, 50, 7171−7175. (d) Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B.
K. Org. Lett. 2013, 15, 1802−1805. (e) Gogoi, A.; Modi, A.; Guin, S.;
Rout, S. K.; Das, D.; Patel, B. K. Chem. Commun. 2014, 50, 10445−
10447. (f) Gogoi, A.; Sau, P.; Ali, W.; Guin, S.; Patel, B. K. Eur. J. Org.
Chem. 2016, 2016, 1449−1453.
(12) Luo, J.; Zhang, J. ACS Catal. 2016, 6, 873−877.
(13) Banerjee, A.; Lei, Z.; Ngai, M. Synthesis 2019, 51, 303−333.
E
https://dx.doi.org/10.1021/acs.orglett.0c02571
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