Discovery of Oxygen α-Nucleophilic Addition to α,β-Unsaturated Amides Catalyzed by Redox-Neutral Organic Photoreductant

Article abstract of DOI:10.1021/jacs.0c10707

The conjugate additions of oxygen-centered nucleophiles to conjugate acceptors are among the most powerful C-O bond formation reactions. The conjugate addition normally takes place at the β-position carbon to the electron-withdrawing group, resulting in the formation of a stabilized carbanion intermediate that can be quenched by proton or electrophiles to form the β-addition (i.e., hetero-Michael addition) products. On the contrary, the formation of α-hydroxyl or alkoxyl amides through conjugate addition needs an α,β-inverse addition. Nevertheless, a regio-inversed nucleophilic α-addition of oxygen-centered nucleophiles to α,β-unsaturated carbonyl compounds still remains less explored because of the electronic mismatch. In this research, we discovered the first α-specific nucleophilic addition of α,β-unsaturated amides with oxygen and fluoride nucleophiles. This region-inversed nucleophilic addition is enabled by the catalysis of a novel redox-neutral nondonor-acceptor organic photoreductant (CBZ6). As low as 0.5 mol % of visible light photoreductant was employed. The mechanistic insights were also explored. The oxidative potential of the excited state of CBZ6 is obtained in -1.92 V (vs SCE), presenting a stronger reductive potential than representative metal-cored or organic photoredox catalysts. This feature enabled the umpolung of α,β-unsaturated amides to take place α-nucleophilic addition other than the normal β-addition.

Full text of DOI:10.1021/jacs.0c10707

pubs.acs.org/JACS
Communication
Discovery of Oxygen α‑Nucleophilic Addition to α,β-Unsaturated
Amides Catalyzed by Redox-Neutral Organic Photoreductant
Zi-Hong Luan, Jian-Ping Qu, and Yan-Biao Kang*
Cite This: https://dx.doi.org/10.1021/jacs.0c10707
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The conjugate additions of oxygen-centered nucleophiles to conjugate acceptors are among the most powerful C−O
bond formation reactions. The conjugate addition normally takes place at the β-position carbon to the electron-withdrawing group,
resulting in the formation of a stabilized carbanion intermediate that can be quenched by proton or electrophiles to form the β-
addition (i.e., hetero-Michael addition) products. On the contrary, the formation of α-hydroxyl or alkoxyl amides through conjugate
addition needs an α,β-inverse addition. Nevertheless, a regio-inversed nucleophilic α-addition of oxygen-centered nucleophiles to
α,β-unsaturated carbonyl compounds still remains less explored because of the electronic mismatch. In this research, we discovered
the first α-specific nucleophilic addition of α,β-unsaturated amides with oxygen and fluoride nucleophiles. This region-inversed
nucleophilic addition is enabled by the catalysis of a novel redox-neutral nondonor−acceptor organic photoreductant (CBZ6). As
low as 0.5 mol % of visible light photoreductant was employed. The mechanistic insights were also explored. The oxidative potential
of the excited state of CBZ6 is obtained in −1.92 V (vs SCE), presenting a stronger reductive potential than representative metal-
cored or organic photoredox catalysts. This feature enabled the umpolung of α,β-unsaturated amides to take place α-nucleophilic
addition other than the normal β-addition.
he nucleophilic conjugate additions of oxygen-centered
nucleophiles to conjugate acceptors are among the most
T
powerful carbon−oxygen bond formation reactions.1 Such
reactions have been the key steps in the syntheses of numerous
natural products and pharmaceutically relevant compounds.2 A
conjugate addition reaction involves the addition of a
nucleophile to an electron-deficient double or triple bond
(Figure 1a). The conjugate addition normally takes place at the
β-position carbon to the electron-withdrawing group (EWG),
resulting in the formation of a stabilized carbanion
intermediate. At this point, the carbanion can be quenched
by proton or electrophiles to form the β-addition (hetero-
Michael addition) products. Nevertheless, a regioselectivity-
reversed nucleophilic addition, namely, α-addition of oxygen-
centered nucleophiles to α,β-unsaturated carbonyl compounds
still remains less explored because of the electronic mismatch.3
To our delight, the emergence of visible light-induced
photochemical reaction provides an opportunity to introduce
functional groups into organic substrates, which could not
otherwise be possible owing to the low reactivity or the
electronic mismatch, by changing the reaction pathway.4,5 In
our continuing efforts to develop novel and practical oxidation
reactions,6 we found that a novel and general α,β-umpolung
strategy by employing a new redox-neutral nondonor−
acceptor type organophotocatalyst enables a general regiose-
lectivity-reversed α-specific addition of oxygen-centered
nucleophiles (water, alcohol, etc.) or fluorides to α,β-
unsaturated amides under mild conditions. This could realize
the inversion of reactivity on the α-position of α,β-unsaturated
amides from nucleophilic to electrophilic affording α-specific
oxygen-substituted quaternary carbon centers. For the first
time, a large variety of alcohols,2 H2O, D2O, H218O,3 and HF,4
Figure 1. β-Nucleophilic addition reaction to acrylamides (well
studied) (a), regioreversed α-nucleophilic oxygenation of acrylamides
(this research) (b), and molecular structure of CBZ6 (CCDC
2041767) (c).
Received: October 13, 2020
https://dx.doi.org/10.1021/jacs.0c10707
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
could be utilized as effective oxygen or fluorine nucleophiles
without prefunctionalization (Figure 1b). Here we report our
results in detail.
Diphenyldibenzocarbazole CBZ6, the photocatalyst (PC) in
this research, is a new redox neutral visible light organo-
photocatalyst bearing six six-membered rings, which is a highly
twisted single carbazole-cored nondonor−acceptor type PC.
CBZ6 was readily available from the hydroisoxazole rearrange-
ment and cyclization developed by our group.7 It could be
synthesized in large scale and recyclable after reaction, which
illustrates a great advantage as a redox photocatalysis (Figure
2a).
Figure 3. Oxygen and fluorine α-nucleophilic addition to α,β-
unsaturated amides catalyzed by CBZ6 (a), working model (b), and
control reactions (c).
Acrylamide 1 catches an electron from exited CBZ6* to form
radical anion A or A′ along with radical cation of CBZ6,
followed by protonation to afford radical B. The EToxidation
of B with the radical cation of CBZ6 to cation C, which can
easily be quenched by a nucleophile such as H2O or alcohol,
etc. Consequentially, CBZ6 returns to the ground state.
In the further study of the nucleophilic α-addition reaction
of 1a with water or MeOH as a nucleophile (Figure 3), CBZ6
and several common PCs such as fac-Ir(ppy)3, Ru(bpy)3Cl2,
Eosin Y, Rhodamine B, and Rhodamine 6G have been
investigated, whereas only CBZ6 (90% yield) was found
reactive. Other organic reductants such as N-phenylpheno-
thiazine or phenoxazine9 were found much less reactive and
only 14% yield of 2r was obtained. This redox catalysis
involves reduction 1 to A and oxidation radical B to cation C.
The strong photoreductants might be able to accomplish the
reduction step but probably failed in oxidation step. The failure
of metal-core PCs might be due to the instability under acidic
conditions. CBZ6 can be recovered without losing the
reactivity whereas Ir(ppy)3 cannot. Standard reaction con-
ditions were then established by using 0.5 mol % of CBZ6 in
the presence of 0.2 equiv of triflic acid in CH3CN under the
irradiation of 9 W LEDs (λmax = 407 nm) (Figure 3c). Control
experiments confirm the necessity of all the components for
the reaction as no conversion of 1a was observed in the
absence of either CBZ6 or light irradiation (Figure 3c). The
yield of 2r drops dramatically to 33% in the absence of triflic
acid, indicating triflic acid is not necessary but can increase the
yields.
Figure 2. Synthesis of CBZ6 (a), absorption spectrum (b), and cyclic
voltammetry (c).
The excited state energy of CBZ6 as well as its absorption
spectrum and cyclic voltammetry is demonstrated in Figure 2.
The energy of the first singlet excited state E00 of CBZ6 is
estimated from the position of the long wavelength tail of the
absorption spectrum, along with cyclic voltammetry of CBZ6
(Figure 2). The oxidative potential of the excited state of
CBZ6 is obtained in −1.92 V (vs SCE), presenting a stronger
reductive potential than metal-core photoredox catalysts (e.g.,
2+
3+
Ru(bpy)3 −0.87/1.26; Ir(ppy)3 −1.73/0.78; etc.) and
some organophotocatalyst (4CzBN −1.29/1.61; Eosin Y
−1.58/2.31; 4DPAIPN −1.28/1.34; etc.).8−10 This feature
enabled the umpolung of α,β-unsaturated amides to take place
α-nucleophilic addition other than the normal β-addition
(Figure 3a). The working model is demonstrated in Figure 3b.
With the standard reaction conditions in hand, the scope of
substrates was explored (Figure 4). First, various amides were
B
https://dx.doi.org/10.1021/jacs.0c10707
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Figure 4. Scope of alcohol for the α-oxygenation of α,β-unsaturated amide. Reaction conditions: CBZ6 (0.5 mol %), 1 (0.5 mmol), alcohol (5
mmol), TfOH (20 mol %) in 2 mL of CH3CN, 9 W (3 W × 3) LEDs (407 nm), Ar atmosphere, about 32 °C, isolated yields. Variations to
b
conditions for 2a−2d: 1 (0.2 mmol), CBZ6 (5 mol %), TfOH (50 mol %) in 4 mL of MeOH, 18W (3W × 6) LEDs (407 nm). 0.5 equiv of
TfOH. bDCM (4 mL) as solvent. c2 equiv of dihydrocholesterol, 0.5 equiv of TfOH and DCM (5 mL) as solvent. d1 (0.2 mmol), CBZ6 (1 mol %),
without TfOH, 18W (3W × 6) LEDs (407 nm).
examined using methanol as an oxygen nucleophile and the
corresponding α-methoxyl amides 2a−2l were obtained in
moderate to high yields. α-Aryls are better substituents for
stabilizing α-carbon cations; therefore, better yields are
achieved from α-aryl substrates. The N-substituents of amides
were also investigated. Either simple or complex substitutes or
even benzyl group are suitable and as high as 94% yields were
obtained (2m−2q). A wide spectrum of alcohol nucleophiles
have been subjected to the standard reaction conditions and all
alcohols were found suitable (2r−2z and 2A−2G). Phenol and
acetic acid are less reactive nucleophiles under acidic
conditions and the corresponding products were obtained in
C
https://dx.doi.org/10.1021/jacs.0c10707
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
low yields. For example, the reaction of 4-methoxylphenol in
the absence of TfOH afforded the corresponding product 2H
in 27% yield.
functionalization of unsaturated amides, various α-fluoro
amides (4a−4h) can be obtained (Figure 6). This reaction
provides a feasible method for α-fluorination of amides.
Water was next surveyed as a nucleophile instead of alcohols.
Using deuterated water (D2O) as a nucleophile, the
corresponding α-hydroxyl amides (3a−3j) were obtained in
generally high deuterium incorporation (Figure 5). Besides
Figure 6. Conditions: 1 (0.5 mmol), 3HF·Et3N (3 mmol), CBZ6 (1
mol %), TfOH (20 mol %) in 2 mL of CH3CN, 3W × 6 LEDs (407
nm), argon, ∼32 °C, isolated yields.
Fluorescence quenching experiments of CBZ6 show the
quenching effect with 1a (Figure 7a). The Stern−Volmer plot
indicates that the excited state of the sensitizer was quenched
by 1a and the quenching effect increased with the increase of
the concentration of 1a (Figure 7b).
Figure 5. Scope for β-deuterative α-oxygenation of α,β-unsaturated
amide. Reaction conditions: 1 (0.5 mmol), D2O (5 mmol), CBZ6 (2
mol %), p-TsOH·H2O (20 mol %) in 2 mL of CH3CN, 18W (3W ×
6) LEDs (407 nm), argon, about 32 °C, isolated yields.
D2O, H218O was also tested and the corresponding α-18OH
amide 3A was obtained in 77% yield (eq 1). The α-hydroxyl
amides bearing either simple or complex substituents are
available. This reaction provides an efficient and practical
method for synthesis deuterated hydroxyl amides as well as
α-18OH amides.
After establishing oxygen nucleophiles, fluoride was also
tested. The halogenation of either electron-rich alkenes with
NXS (X = Cl, Br, I) or electron-deficient alkenes with HX (X =
Cl, Br, I) has well been established. The analogical fluorination
normally involves more hazardous and expensive electrophilic
reagents such as diethylaminosulfur trifluoride (DAST),
selectfluor, PhIF2, XeF2, etc. By CBZ6-catalyzed nucleophilic
Figure 7. Fluorescence quenching effect (a) and Stern−Volmer plot
(b).
D
https://dx.doi.org/10.1021/jacs.0c10707
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Control experiments were carried out to gain insight into the
reaction mechanism. The reaction without of CBZ6 did not
afford the addition product (Figure 8a). The reaction in the
low as 0.5 mol % photoreductant, the corresponding α-
hydroxyl amides and α-alkoxyl amides were obtained in up to
94% yields under the standard reaction conditions and more
than 50 examples have been presented. Besides α-oxygenation
products, α-fluoro amides could also be achieved. The
mechanistic insights based on experimental evidence were
also explored. The oxidative potential of the excited state of
CBZ6 is obtained in −1.92 V (vs SCE), presenting a stronger
reductive potential than representative metal-cored and other
organic photoredox catalysts. This feature enabled the
umpolung of α,β-unsaturated amides to take place α-
nucleophilic addition other than the normal β-addition.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10707.
■
sı
Experimental procedures, tables of conditions, chemical
structures and characterization data, UV−vis absorption
spectrum, fluorescence spectra, and luminescence
quenching experiments, CV, molecular structures, crystal
data, and NMR spectra (PDF)
Crystal data for 2j (CIF)
Crystal data for 2p (CIF)
Crystal data for 3a (CIF)
Crystal data for CBZ6 (CIF)
Crystal data for CBZ6 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Yan-Biao Kang − Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026,
China; State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China; orcid.org/0000-0002-
7537-4627; Email: ybkang@ustc.edu.cn
Authors
Figure 8. Control experiments.
Zi-Hong Luan − Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026,
China
Jian-Ping Qu − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech
University, Nanjing 211816, China; orcid.org/0000-
0002-5002-5594
presence of radical trapping reagents inhibited the reaction
(Figure 8b,c). A radical cyclization product 6 from amide 1a
and 1,1-diphenylethene was also observed. The TEMPO
trapping adduct was obtained in 10% yield (Figure 8c). In the
absence of alcohols, the cyclization product 7 through radical
anion A was obtained in 6% yield (Figure 8d). In the
meantime, an aryl nucleophilic addition product 8 via cation B
was also obtained (Figure 8d). The isomerization of (E)-9
together with the control reactions demonstrated in Figure 8d
and Figure 8b,c are all the evidence for involving radical anion
intermediates. Therefore, the working model demonstrated in
Figure 3b is rational. The synergistic catalytic role of CBZ6 as
a photoredox catalyst and TfOH as a proton catalyst enabled
the α,β-inversed nucleophilic oxygenation and fluorination of
α,β-unsaturated amides. CBZ6 is highly twisted heteroarene.
The influence of the geometry to the exited state properties is
not clear yet and still under study.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10707
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21922109, 21672196, 21602001, 21831007), and the
Fundamental Research Funds for the Central Universities of
China (WK2060190086) for financial support.
In conclusion, we discovered the first α-specific nucleophilic
addition of α,β-unsaturated amides with oxygen and fluoride
nucleophiles. This region-inversed nucleophilic addition is
enabled by the catalysis of a novel redox-neutral non-donor−
acceptor organic photoreductant (CBZ6). By employing as
REFERENCES
■
̈
(1) (a) Nising, C. F.; Brase, S. The oxa-Michael reaction: from
recent developments to applications in natural product synthesis.
Chem. Soc. Rev. 2008, 37, 1218−1228. (b) Resch, V.; Hanefeld, U.
E
https://dx.doi.org/10.1021/jacs.0c10707
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
The selective addition of water. Catal. Sci. Technol. 2015, 5, 1385−
1399.
photocuring reactions in the visible region. Beilstein J. Org. Chem.
2018, 14, 3025−3046. (b) Fagnoni, M.; Dondi, D.; Ravelli, D.; Albini,
A. Photocatalysis for the formation of the C-C bond. Chem. Rev. 2007,
107, 2725−2756. (c) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C.
Visible Light Photoredox Catalysis with Transition Metal Complexes:
Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322−5363.
(d) Marin, M. L.; Santos-Juanes, L.; Arques, A.; Amat, A. M.;
Miranda, M. A. Organic Photocatalysts for the Oxidation of Pollutants
and Model Compounds. Chem. Rev. 2012, 112, 1710−1750.
(2) (a) Liang, Y.-J.; Wei, J.-L.; Qiu, X.; Jiao, N. Homogeneous
Oxygenase Catalysis. Chem. Rev. 2018, 118, 4912−4945. (b) Alsters,
P. L.; Jary, W.; Nardello-Rataj, V.; Aubry, J.-M. Dark” Singlet
Oxygenation of β-Citronellol: A Key Step in the Manufacture of Rose
Oxide. Org. Process Res. Dev. 2010, 14, 259−262.
(3) For an example of direct α-oxidation of saturated amides:
Gonca̧ lves, C. R.; Lemmerer, M.; Teskey, C. J.; Adler, P.; Kaiser, D.;
́
Maryasin, B.; Gonzalez, L.; Maulide, N. Unified Approach to the
Chemoselective α-Functionalization of Amides with Heteroatom
Nucleophiles. J. Am. Chem. Soc. 2019, 141, 18437−18443.
́
(4) (a) Jahjah, R.; Gassama, A.; Dumur, F.; Marinkovic, S.; Richert,
̀
S.; Landgraf, S.; Lebrun, A.; Cadiou, C.; Selles, P.; Hoffmann, N.
Photochemical Electron Transfer Mediated Addition of Naphthyl-
amine Derivatives to Electron-Deficient Alkenes. J. Org. Chem. 2011,
76, 7104−7118. (b) Oelgemoller, M.; Hoffmann, N. Studies in
organic and physical photochemistry-an interdisciplinary approach.
Org. Biomol. Chem. 2016, 14, 7392−7442. (c) Ando, Y.; Kamatsuka,
T.; Shinokubo, H.; Miyake, Y. Selective α-arylation of α,β-unsaturated
imides mediated by a visible light photoredox catalyst. Chem.
Commun. 2017, 53, 9136−9138. (d) Vidyasagar, A.; Shi, J.;
Kreitmeier, P.; Reiser, O. Bromo- or Methoxy-Group-Promoted
Umpolung Electron Transfer Enabled, Visible-Light-Mediated Syn-
thesis of 2-Substituted Indole-3-glyoxylates. Org. Lett. 2018, 20,
6984−6989.
(5) (a) Hoffmann, N. Photochemical Reactions as Key Steps in
Organic Synthesis. Chem. Rev. 2008, 108, 1052−1103.
(6) (a) Dai, P.-F.; Ning, X.-S.; Wang, H.; Cui, X.-C.; Liu, J.; Qu, J.-
P.; Kang, Y.-B. Cleavage of C(aryl)-CH3 bonds in the absence of
directing groups under transition metal free conditions. Angew. Chem.,
Int. Ed. 2019, 58, 5392−5395. (b) Dai, P.-F.; Qu, J.-P.; Kang, Y.-B.
Organocatalyzed Aerobic Oxidation of Aldehydes to Acids. Org. Lett.
2019, 21, 1393−1396. (c) Liu, J.; Zheng, H.-X.; Yao, C.-Z.; Sun, B.-
F.; Kang, Y.-B. Pharmaceutical-oriented selective synthesis of
mononitriles and dinitriles directly from methyl(hetero)arenes: access
to chiral nitriles and Citalopram. J. Am. Chem. Soc. 2016, 138, 3294−
3297.
(7) Xiao, Z.-F.; Ding, T.-H.; Mao, S.-W.; Shah, Z.; Ning, X.-S.; Kang,
Y.-B. Iridium-Catalyzed Cyclization of Isoxazolines and Alkenes:
Divergent Access to Pyrrolidines, Pyrroles, and Carbazoles. Org. Lett.
2016, 18, 5672−5675.
(8) (a) Romero, N. A.; Nicewicz, D. A. Organic Photoredox
Catalysis. Chem. Rev. 2016, 116, 10075−10166. (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. (c) Hosokai, T.;
Matsuzaki, H.; Nakanotani, H.; Tokumaru, K.; Tsutsui, T.; Furube,
A.; Nasu, K.; Nomura, H.; Yahiro, M.; Adachi, C. Evidence and
mechanism of efficient thermally activated delayed fluorescence
promoted by delocalized excited states. Sci. Adv. 2017, 3,
No. e1603282. (d) Ahn, J. M.; Peters, J. C.; Fu, G. C. Design of a
Photoredox Catalyst that Enables the Direct Synthesis of Carbamate-
Protected Primary Amines via Photoinduced, Copper-Catalyzed N-
Alkylation Reactions of Unactivated Secondary Halides. J. Am. Chem.
Soc. 2017, 139, 18101−18106.
(9) (a) Pearson, R. M.; Lim, C.-H.; McCarthy, B. G.; Musgrave, C.
B.; Miyake, G. M. Organocatalyzed Atom Transfer Radical Polymer-
ization Using N-Aryl Phenoxazines as Photoredox Catalysts. J. Am.
Chem. Soc. 2016, 138, 11399−11407. (b) McCarthy, B. G.; Pearson,
R. M.; Lim, C.-H.; Sartor, S. M.; Damrauer, N. H.; Miyake, G. M.
Structure-Property Relationships for tailoring Phenoxazines as
Reducing Photoredox Catalysts. J. Am. Chem. Soc. 2018, 140,
́
5088−5101. (c) Vega-Penaloza, A.; Mateos, J.; Companyo, X.;
̃
Escudero-Casao, M.; DellAmico, L. A Rational Approach to Organo-
Photocatalysis: Novel Designs and Structure-Property Realationships.
Angew. Chem., Int. Ed. 2020, 59, 2−18.
(10) (a) Bonardi, A. H.; Dumur, F.; Noirbent, G.; Lalevee, J.;
Gigmes, D. Organometallic vs organic photoredox catalysts for
F
https://dx.doi.org/10.1021/jacs.0c10707
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX