Tertiary amines acting as Alkyl radical equivalents enabled by a P/N heteroleptic Cu(I) photosensitizer

Article abstract of DOI:10.1021/acs.orglett.0c03236

An unprecedented exploration of tertiary amines as alkyl radical equivalents for cross-coupling with aromatic alkynes to access allylarenes has been achieved by a P/N heteroleptic Cu(I)based photosensitizer under photoredox catalysis conditions. Mechanist

Full text of DOI:10.1021/acs.orglett.0c03236

pubs.acs.org/OrgLett
Letter
Tertiary Amines Acting as Alkyl Radical Equivalents Enabled by a
P/N Heteroleptic Cu(I) Photosensitizer
Limeng Zheng,§ Qinfang Jiang,§ Hanyang Bao, Bingwei Zhou, Shu-Ping Luo, Hongwei Jin, Huayue Wu,*
and Yunkui Liu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03236
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An unprecedented exploration of tertiary amines as
alkyl radical equivalents for cross-coupling with aromatic alkynes to
access allylarenes has been achieved by a P/N heteroleptic Cu(I)-
based photosensitizer under photoredox catalysis conditions.
Mechanistic studies reveal that the reaction might undergo radical
addition of in situ-generated α-amino radical intermediates to
alkynes followed by 1,5-hydrogen transfer, C−N bond cleavage,
and concomitant isomerization of the resulting allyl radical species.
n the past two decades, visible-light-driven photoredox
reactions have developed rapidly and emerged as an
unfriendly reaction conditions.10 To circumvent these
problems, recently, alkylation strategies involving active alkyl
radical species produced from corresponding alkyl sources via
the one-electron transfer process (SET) under visible-light-
driven photoredox catalysis conditions have received special
attention and become important tools for the incorporation of
alkyl groups into organic molecules. So far, a variety of alkyl
precursors have been explored to serve as active alkyl radical
equivalents under visible-light-driven photoredox catalysis
conditions, including alkyl halides,10a,11 carboxylic acids and
their derived esters,12 alkyl alcohol-derived compounds,13
Katritzky salts,14 hypervalent iodine(III) reagents,15 alkyl
trifluoroborates,10b,16 alkyl boronic acids,17 organosilicon
compounds,18 Hantzsch esters,19 ketones and aldehydes20
(Scheme 1a), etc. Despite their merits, one or more limitations
are still associated with some of these reagents with respect to
the toxicity of halo-containing precursors, low atom economy,
tedious preparation, high costs, explosiveness, production of
undesired byproducts, etc. To realize efficient and practical
alkylation reactions, exploring and developing cost-effective,
easily available, safe, and low-toxicity alkyl radical equivalents
are in high demand.
I
attractive and powerful platform for the construction of
carbon−carbon or carbon−heteroatom bonds.1 In this regard,
most visible-light-driven photoredox catalysts predominantly
rely on complexes of noble and heavy metals such as
ruthenium or iridium. However, the fact that several innate
limitations are associated with the metal centers of these
photocatalysts, including poor reserves in the earth, high
prices, and high toxicities, has stimulated chemists to explore
alternative photocatalysts based on metals with characteristic
features of lower costs, greater safety, and environmental
friendliness. In this area, copper complexes represent the most
attractive and promising alternative candidates.2 Indeed, over
the past two decades, there have been increasingly more
reports about the copper-based photoactive complexes and
their applications in visible-light-driven organic synthesis.3−5
Despite the impressive progress, it is still highly desirable to
develop novel and efficient organic transformations involving
the direct use of copper-based photosensitizers under visible-
light-driven catalysis conditions.
In view of the ubiquity of alkyl motifs in bioactive
molecules,6,7 the selective and efficient introduction of alkyl
groups into organic molecules from alkyl precursors is very
important, yet challenging due to the difficulty of introducing
alkyl groups into organic molecules from alkyl precursors
through the traditional transition-metal-catalyzed cross-cou-
pling reactions.8,9 It is well-known that transition-metal-
catalyzed alkyl coupling partner-involved cross-couplings
always suffer from a high energy barrier to activate alkyl
precursors via the two-electron transfer process, easy β-hydride
elimination, harsh reaction conditions, and environmentally
Tertiary amines play important roles in visible-light-driven
photoredox catalytic reactions. In fact, tertiary amines were
Received: September 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03236
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
reaction conditions (Table 1 and Table S1). When 1a and PS4
(5 mol %) were subjected to the mixture of MeCN (1.6 mL),
Scheme 1. Various Precursors Used as Alkyl Radical
Equivalents in Visible-Light-Driven Photocatalytic
Reactions
a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
b
entry
1
deviation from standard conditions
none
3aa (E/Z)
4aa
13
75 (10/1),
c
d
72, 67
2
3
4
5
6
7
8
9
PS5 instead of PS4
PS1 or PS2 instead of PS4
PS3 instead of PS4
PS6 instead of PS4
PS7 instead of PS4
Ru(bpy)3Cl2·6H2O instead of PS4
PS8 instead of PS4
PS9 instead of PS4
64 (10/1)
0
49 (10/1)
48 (10/1)
47 (10/1)
trace
20
0
24
36
39
12
trace
35
0
0
identified as faithful partners of excited photosensitizers and
different types of reactivity have arisen from their combination
(Scheme 1b): (1) merely used as electron sacrificial agents for
the completion of a photocatalytic cycle in which they
themselves are not incorporated into the final pro-
ducts,4c,d,g−i,21 (2) acting as reductants for quenching photo-
catalyts as well as precursors for the generation of nucleophilic
α-amino radicals that are capable of reacting with various
electrophilic reagents (Scheme 1b-I),21 and (3) used as two-
electron donors to reduce photocatalysts as well as precursors
for the generation of electrophilic iminium cations that are
capable of reacting with various nucleophilic reagents (Scheme
1b-II).22 To the best of our knowledge, to date, no studies of
the utilization of tertiary amines as alkyl radical equivalents
involving C−N bond cleavage under photoredox catalysis
conditions have been reported (Scheme 1b-III). Very recently,
we have realized alkyl aldehydes as alkyl radical equivalents in
the cross-coupling with alkynes enabled by a P/N heteroleptic
Cu(I) photosensitizer, mechanistically involving in situ-
generated alkyl-substituted α-amino radical species.4m How-
ever, in the reaction, excessive amounts of dipropylamine and
Hantzsch ester must be used. Because tertiary amines could be
used as both quenching agents and precursors of alkyl-
substituted α-amino radicals (Scheme 1b),21,22 we envisioned
that P/N heteroleptic Cu(I) photosensitizers might also enable
cross-coupling of tertiary amines with alkynes to deliver
allylarenes, thus leading to unprecedented exploration of
tertiary amines as alkyl radical equivalents in photoredox
catalytic reactions (Scheme 1b-III and Scheme 1c).23
10
11
12
13
14
Rose Bengal instead of PS4
4CzIPN instead of PS4
0.6 mL of Et3N
0.1 mL of H2O
3.0 mL of Et3N was used in the absence of 10
MeCN and H2O
THF instead of MeCN
1,4-dioxane instead of MeCN
without a photosensitizer
in the dark
0
trace
trace
11
13
trace
35 (10/1)
57 (10/1)
45 (10/1)
15
16
17
18
50 (10/1)
66 (10/1)
0
0
31
18
0
0
a
Standard conditions: 1a (0.2 mmol), PS4 (5 mol %), MeCN (1.6
mL)/Et3N (2a) (1.2 mL)/H2O (0.2 mL), irradiated with a 60 W
CFL under a nitrogen atmosphere at 38 °C for 18 h unless otherwise
noted. Yields and E/Z ratios were determined by GC analysis using
biphenyl as the internal standard. Isolated yield. Yield of 1 mmol-
scale synthesis.
b
c
d
Et3N (1.2 mL), and H2O (0.2 mL) and irradiated with a 60 W
CFL at 38 °C for 18 h, allylbenzene 3aa was obtained in an
acceptable yield (GC yield, 75%; isolated yield, 72%), along
with a small amount of C−N bond intact product 4aa (13%,
entry 1, Table 1). The most effective Cu(I) photosensitizer
PS5 previously reported for the cross-coupling of aldehydes
and alkynes4m gave results inferior to those of PS4 in the
reaction presented here (64%, entry 2 vs entry 1, Table 1).
Several other P/N heteroleptic Cu(I) photosensitizers (PS1-
PS3, PS6, and PS7) generally gave results inferior to those of
PS4 (entries 3−6 vs entry 1, Table 1). Popular photocatalysts
such as Ru(bpy)3Cl2·6H2O (entry 8) and Ir(III) photo-
sensitizers PS8 (entry 8) and PS9 (entry 9) all failed to deliver
3aa, albeit a 35% yield of byproduct 4aa was obtained with
Initially, 4-ethynyl-1,1′-biphenyl (1a) and Et3N (2a) were
selected as the model substrates for the optimization of
B
https://dx.doi.org/10.1021/acs.orglett.0c03236
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 2. Scope of Alkynes 1 and Amines 2
a
Conditions: (a) 1,4-dioxane used instead of MeCN.
PS9 as a photocatalyst (entry 9, Table 1). For organo-
photosensitizers, Rose Bengal showed no catalytic activity for
the reaction, while 4CzIPN [2,4,5,6-tetrakis(carbazol-9-yl)-1,3-
dicyanobenzene] could exhibit some photocatalytic activity but
delivering only a low yield of 3aa (entries 10 and 11, Table 1).
It was found that an appropriate ratio of Et3N, MeCN, and
H2O is important for obtaining a satisfactory yield of 3aa
(entries 12−14, Table 1). Solvent screening experiments
indicated that the combination of MeCN and water is the most
suitable medium for the reaction (entries 15 and 16, Table 1).
Controlled experiments indicated that the photosensitizer and
light irradiation are indispensable for this alkylation reaction
(entries 17 and 18, Table 1). Note that the E/Z ratios of 3aa
always remained around 10/1, not influenced much by the
parameters investigated above.
With the optimized reaction conditions in hand, we next set
out to investigate the scope of alkynes 1 and tertiary amines 2
(Scheme 2). A variety of aromatic terminal alkynes 1 were
compatible with this transformation and could deliver
corresponding products in acceptable yields with modest E/
Z selectivities. Generally, aromatic terminal alkynes 1 bearing
electron-withdrawing groups or a neutral group [e.g., Cl, Br,
CF3, CN, COOMe group, and phenyl (1a−1d and 1h−1m,
Scheme 2)] furnished the desired products in yields higher
than the yields of those bearing electron-donating groups [e.g.,
n-propyl, n-pentyloxy, and acylamino (1e−1g, Scheme 2)]. It
seems that the steric hindrance of substituents on phenyl rings
had no significant influence on the reaction outcome in terms
of yield (1a vs 1j and 1b vs 1k). Aromatic alkynes 1 bearing a
naphthalene ring (1n and 1o), a heteroarene ring such as
thiophene (1p), furan (1q), or pyridine (1r), or a
benzothiophene backbone (1s, 1t) were also viable substrates
for the reaction. In addition, aliphatic alkynes (1u and 1v)
were used for the reaction; unfortunately, no desired products
were obtained in these cases. Furthermore, internal alkyne 1w
was also proven to be a suitable candidate for this reaction,
delivering the desired product 3wa in 70% yield, but with a
poor E/Z selectivity. Note that in the reaction of 1w with
Et3N, the regioisomers predominantly arose from the addition
of the α-amino radical to the more electron-deficient sp carbon
of 1w (see the Supporting Information). Finally, the substrate
scope of tertiary amines 2 was explored. As shown in Scheme
2, for tertiary amines consisting of the same alkyl moieties
(2b−2e), single desired products could be obtained in modest
yields; however, the reaction may deliver different alkylated
products when tertiary amines consisting of different alkyl
moieties were used (2f and 2g). Interestingly, when N,N-
dibutyl-4-fluorobutan-1-amine (2h) was used, the reaction
selectively delivered n-butyl-incorporated product 3ac in 43%
yield while no 4-fluorobutyl-incorporated product 3ah was
obtained. Note that 1,4-dioxane was a more suitable solvent in
the cases of 2b and 2c as the substrates.
To gain some insights into the mechanism of the reaction
presented here, several mechanistic experiments were carried
out (Scheme 3). First, the reaction was performed in the
presence of a radical scavenger. As a result, the reaction was
suppressed thoroughly when 2 equiv of TEMPO (eq 1,
Scheme 3) or 1,1-diphenylethylene 5 (eq 2, Scheme 3) was
used. To our delight, the α-amino radical was successfully
trapped by 1,1-diphenylethylene to produce 6 in 67%
C
https://dx.doi.org/10.1021/acs.orglett.0c03236
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
2a [E1/2(Et3N•+/Et3N) = 0.83 V vs SCE in MeCN]25 to
generate α-amino radical 7 and Cu(0) species. Addition of α-
amino radical 7 to alkyne 1a afforded vinyl radical species 10,
which could further undergo a key 1,5-HAT process to
produce radical 11.4m,26 Subsequently, β-fission of 11 resulted
in C−N bond cleavage and formation of radical intermediate
14 and imine 12 (path a).4m,27 Alternatively, 11 might be
oxidized by Cu(I)* to produce intermediate 13, which was
then reduced by the active Cu(0) species [E1/2(CuI/Cu0) =
−1.73 V vs SCE in MeCN (see the Supporting Information)]
to yield 14 and imine 12 (path b).4m,14,26a 14 could be
isomerized to 15. Finally, the reduction of 15 by the active
Cu(0) species via the SET process followed by the protonation
of the resulting anion species 16 by H2O delivered 3aa.4m
Allylarenes are versatile building blocks in organic synthesis
and could be easily converted into valuable synthons and fine
chemicals via various transformations.28−30 With 3aa as a
model substrate, it could be epoxidized by m-CPBA to deliver
epoxide 17 in 91% yield (see Scheme S1a) and hydroborylated
by B2(pin)2 to afford 18 in 65% yield under the catalysis of
Fe(OAc)2 (Scheme S1b).28c,d 3aa could also undergo oxidative
cycloaddition with N-phenylmaleimide to deliver 19 in a
stereoselective manner (Scheme S1c).30c
Scheme 3. Preliminary Mechanistic Experiments
yield.22a,24 Next, when the reaction was conducted under the
standard conditions except in MeCN and D2O, deuterium-
incoporated 3aa-d5 that comprises 92% D enrichment of one
benzyl hydrogen at position 1, nearly 100% D enrichment of
the vinyl hydrogen at position 2, and total 25% D enrichment
of the methyl hydrogens at position 4 were obtained in 70%
yield (eq 3, Scheme 3).4m As a comparison, no D/H exchange
occurred when preparative 3aa was subjected to the standard
reaction conditions except with D2O instead of H2O (eq 4,
Scheme 3). These results indicated that water participated in
the reaction. Finally, a deuterium labeling experiment of the
model reaction using deuterated Et3N-d15 (>99% D enrich-
ment) was carried out (eq 5, Scheme 3). It was found that a
99% D incorporation rate for one of the benzyl hydrogens at
position 1 in the resulting 3aa-d5 was achieved, suggesting that
the 1,5-HAT process should occur.4m Meanwhile, because we
used H2O in the reaction medium, an H/D exchange for the
deuterated methyl group (CD3) at position 4 of 3aa-d5 was
also observed.
In summary, for the first time we have realized tertiary
amines as alkyl radical equivalents exemplified in the alkylation
of alkynes to access allylarene derivatives enabled by a P/N
heteroleptic Cu(I) photosensitizer under photoredox catalysis
conditions. In the reaction, tertiary amines play dual roles,
namely, quenching agents for the photoexcited Cu(I) complex
and alkylating equivalents for the cross-coupling with alkynes.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03236.
Experimental details, full characterization data, mecha-
nistic experiments, and copies of NMR spectra for
compound 3 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
On the basis of the experiments presented above and
previous studies,4m,14,25−27 a plausible mechanism is presented
in Scheme 4. First, the excited state of PS4 Cu(I)*
[E1/2(CuI*/Cu0) = 1.04 V vs SCE in MeCN (see the
Supporting Information)] could be quenched by triethylamine
Yunkui Liu − State Key Laboratory Breeding Base of Green
Chemistry-Synthesis Technology, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou
310014, P. R. China; orcid.org/0000-0001-8614-458X;
Email: ykuiliu@zjut.edu.cn
Huayue Wu − College of Chemistry and Materials
Engineering, Wenzhou University, Wenzhou 325027, P. R.
China; orcid.org/0000-0003-3431-561X;
Scheme 4. Proposed Mechanism
Email: huayuewu@wzu.edu.cn
Authors
Limeng Zheng − State Key Laboratory Breeding Base of
Green Chemistry-Synthesis Technology, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou
310014, P. R. China
Qinfang Jiang − State Key Laboratory Breeding Base of Green
Chemistry-Synthesis Technology, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou
310014, P. R. China
Hanyang Bao − State Key Laboratory Breeding Base of Green
Chemistry-Synthesis Technology, College of Chemical
D
https://dx.doi.org/10.1021/acs.orglett.0c03236
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(d) Mejía, E.; Luo, S.-P.; Karnahl, M.; Friedrich, A.; Tschierlei, S.;
Surkus, A.-E.; Junge, H.; Gladiali, S.; Lochbrunner, S.; Beller, M.
Chem. - Eur. J. 2013, 19, 15972−15978. (e) Fischer, S.; Hollmann, D.;
Tschierlei, S.; Karnahl, M.; Rockstroh, N.; Barsch, E.; Schwarzbach,
P.; Luo, S.-P.; Junge, H.; Beller, M.; Lochbrunner, S.; Ludwig, R.;
Engineering, Zhejiang University of Technology, Hangzhou
310014, P. R. China
Bingwei Zhou − State Key Laboratory Breeding Base of Green
Chemistry-Synthesis Technology, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou
310014, P. R. China; orcid.org/0000-0002-8014-5482
Shu-Ping Luo − State Key Laboratory Breeding Base of Green
Chemistry-Synthesis Technology, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou
310014, P. R. China
Bruckner. ACS Catal. 2014, 4, 1845−1849. (f) Wang, B.; Shelar, D.
̈
P.; Han, X.-Z.; Li, T.-T.; Guan, X.; Lu, W.; Liu, K.; Chen, Y.; Fu, W.-
F.; Che, C.-M. Chem. - Eur. J. 2015, 21, 1184−1190. (g) Lennox, A. J.
J. J.; Fischer, S.; Jurrat, M.; Luo, S.-P.; Rockstroh, N.; Junge, H.;
Ludwig, R.; Beller, M. Chem. - Eur. J. 2016, 22, 1233−1238.
(h) Michelet, B.; Deldaele, C.; Kajouj, S.; Moucheron, C.; Evano, G.
Hongwei Jin − State Key Laboratory Breeding Base of Green
Chemistry-Synthesis Technology, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou
310014, P. R. China
Org. Lett. 2017, 19, 3576−3579. (i) Call, A.; Casadevall, C.; Acuna-
̃
́
Pares, F.; Casitas, A.; Lloret-Fillol, J. Chem. Sci. 2017, 8, 4739−4749.
(j) Minozzi, C.; Caron, A.; Grenier-Petel, J.-C.; Santandrea, J.;
Collins, S. K. Angew. Chem., Int. Ed. 2018, 57, 5477−5481. (k) Wang,
C.; Guo, M.; Qi, R.; Shang, Q.; Liu, Q.; Wang, S.; Zhao, L.; Wang, R.;
Xu, Z. Angew. Chem., Int. Ed. 2018, 57, 15841−15846. (l) Lyu, X.-L.;
Huang, S.-S.; Song, H.-J.; Liu, Y.-X.; Wang, Q.-M. Org. Lett. 2019, 21,
5728−5732. (m) Bao, H.; Zhou, B.; Luo, S.-P.; Xu, Z.; Jin, H.-W.;
Liu, Y. ACS Catal. 2020, 10, 7563−7572.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03236
Author Contributions
§L.Z. and Q.J. contributed equally to this work.
Notes
(5) For selected recent examples of copper/substrate complex-
induced photocatalytic reactions, see: (a) Kainz, Q. M.; Matier, C. D.;
Bartoszewicz, A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016,
351, 681. (b) Lei, W.-L.; Wang, T.; Feng, K.-W.; Wu, L.-Z.; Liu, Q.
ACS Catal. 2017, 7, 7941−7945. (c) Ahn, J. M.; Peters, J. C.; Fu, G.
C. J. Am. Chem. Soc. 2017, 139, 18101−18106. (d) Li, Y.; Zhou, K.;
Wen, Z.; Cao, S.; Shen, X.; Lei, M.; Gong, L. J. Am. Chem. Soc. 2018,
140, 15850−15858. (e) Xiao, P.; Li, C.-X.; Fang, W.-H.; Cui, G.;
Thiel, W. J. Am. Chem. Soc. 2018, 140, 15099−15113. (f) Yu, X.-Y.;
Zhao, Q.-Q.; Chen, J.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed.
2018, 57, 15505−15509. (g) Mao, R.; Balon, J.; Hu, X. Angew. Chem.,
Int. Ed. 2018, 57, 9501−9504. (h) Sagadevan, A.; Pampana, V. K. K.;
Hwang, K. C. Angew. Chem., Int. Ed. 2019, 58, 3838−3842.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Natural Science Foundation of China
(21772176 and 21372201) and the Natural Science
Foundation of Zhejiang Province (LY20B020013) for financial
support.
REFERENCES
■
(6) For selected recent reviews of alkylation, see: (a) Proctor, R. S.
J.; Phipps, R. J. Angew. Chem., Int. Ed. 2019, 58, 13666−13699.
(b) Irrgang, T.; Kempe, R. Chem. Rev. 2019, 119, 2524−2549.
(1) (a) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527−
532. (b) Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T. Angew.
Chem., Int. Ed. 2015, 54, 3872−3890. (c) Shaw, M. H.; Twilton, J.;
MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898−6926. (d) Ravelli,
D.; Protti, S.; Fagnoni, M. Chem. Rev. 2016, 116, 9850−9913.
̈
(7) For selected reviews of methylation, see: (a) Schonherr, H.;
Cernak, T. Angew. Chem., Int. Ed. 2013, 52, 12256−12267. (b) Dor,
Y.; Cedar, H. Lancet 2018, 392, 777−786. (c) Chen, Y. Chem. - Eur. J.
2019, 25, 3405−3439. For selected examples, see: (d) Feng, K.;
Quevedo, R. E.; Kohrt, J. T.; Oderinde, M. S.; Reilly, U.; White, M. S.
Nature 2020, 580, 621−627. (e) DiRocco, D. A.; Dykstra, K.; Krska,
S.; Vachal, P.; Conway, D. V.; Tudge, M. Angew. Chem., Int. Ed. 2014,
53, 4802−4806.
̈
̈
(e) Karkas, M. D.; Porco, J. A., Jr.; Stephenson, C. R. J. Chem. Rev.
2016, 116, 9683−9747. (f) Twilton, J.; Le, C.; Zhang, P.; Shaw, M.
H.; Evans, R. W.; MacMillan, D. W. C. Nat. Rev. Chem. 2017, 1, 0052.
(g) Xie, J.; Jin, H.; Hashmi, A. S. K. Chem. Soc. Rev. 2017, 46, 5193−
̈
5203. (h) Marzo, L.; Pagire, S.; Reiser, O.; Konig, B. Angew. Chem.,
Int. Ed. 2018, 57, 10034−10072. (i) Pitre, S. P.; Weires, N. A.;
Overman, L. E. J. Am. Chem. Soc. 2019, 141, 2800−2813.
(8) (8) A review of the limitation of nucleophilic substitution that is
the most classic method for alkylation: Fu, G. C. ACS Cent. Sci. 2017,
3, 692−700.
(2) For selected reviews of copper-based photocatalysts, see:
(a) Knorn, M.; Rawner, T.; Czerwieniec, R.; Reiser, O. ACS Catal.
2015, 5, 5186−5193. (b) Reiser, O. Acc. Chem. Res. 2016, 49, 1990−
1996. (c) Hernandez-Perez, A. C.; Collins, S. K. Acc. Chem. Res. 2016,
49, 1557−1565. (d) Larsen, C. B.; Wenger, O. S. Chem. - Eur. J. 2018,
24, 2039−2058. (e) Hossain, S.; Bhattacharyya, A.; Reiser, O. Science
2019, 364, No. eaav9713.
(3) For selected recent examples of homoleptic Cu(I) photo-
sensitizer-catalyzed reactions, see: (a) Hossain, A.; Vidyasagar, A.;
Eichinger, C.; Lankes, C.; Phan, J.; Rehbein, J.; Reiser, O. Angew.
Chem., Int. Ed. 2018, 57, 8288−8292. (b) Rawner, T.; Lutsker, E.;
Kaiser, C. A.; Reiser, O. ACS Catal. 2018, 8, 3950−3956. (c) Ng, Y.
Y.; Tan, L. G.; Ng, S. M.; Chai, Y. T.; Ganguly, R.; Du, Y.; Yeow, E. K.
L.; Soo, H. S. ACS Catal. 2018, 8, 11277−11286. (d) Smirnov, V. O.;
Maslov, A. S.; Kokorekin, V. A.; Korlyukov, A. A.; Dilman, A. D.
Chem. Commun. 2018, 54, 2236−2239. (e) Hossain, A.; Engl, S.;
Lutsker, E.; Reiser, O. ACS Catal. 2019, 9, 1103−1109.
(4) For selected examples of heteroleptic Cu(I) photosensitizer-
catalyzed reactions, see: (a) Cuttell, D. G.; Kuang, S.-M.; Fanwick, P.
E.; McMillin, D. R.; Walton, R. A. J. Am. Chem. Soc. 2002, 124, 6−7.
(b) Hernandez-Perez, A. C.; Vlassova, A.; Collins, S. K. Org. Lett.
2012, 14, 2988−2991. (c) Luo, S.-P.; Mejía, E.; Friedrich, A.; Pazidis,
A.; Junge, H.; Surkus, A. E.; Jackstell, R.; Denurra, S.; Gladiali, S.;
Lochbrunner, S.; Beller, M. Angew. Chem., Int. Ed. 2013, 52, 419−423.
(9) For selected reviews of the limitation of transition-metal-
catalyzed cross-coupling reactions for alkylation, see: (a) Ye, S.; Xiang,
T.; Li, X.; Wu, J. Org. Chem. Front. 2019, 6, 2183−2199. (b) Tellis, J.
C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander,
G. A. Acc. Chem. Res. 2016, 49, 1429−1439.
(10) (a) Wang, G.-Z.; Shang, R.; Cheng, W.-M.; Fu, Y. J. Am. Chem.
Soc. 2017, 139, 18307−18312. (b) Tellis, J. C.; Primer, D. N.;
Molander, G. A. Science 2014, 345, 433−436.
(11) (a) Zhang, P.; Le, C.; MacMillan, D. W. C. J. Am. Chem. Soc.
2016, 138, 8084−8087. (b) McCallum, T.; Barriault, L. Chem. Sci.
2016, 7, 4754−4758. (c) Kurandina, D.; Parasram, M.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2017, 56, 14212−14216. (d) Nuhant, P.;
́
Oderinde, M. S.; Genovino, J.; Juneau, A.; Gagne, Y.; Allais, C.;
Chinigo, G. M.; Choi, C.; Sach, N. W.; Bernier, L.; Fobian, Y. M.;
Bundesmann, M. W.; Khunte, B.; Frenette, M.; Fadeyi, O. O. Angew.
Chem., Int. Ed. 2017, 56, 15309−15313. (e) Zhou, W.; Cao, G.; Shen,
G.; Zhu, X.; Gui, Y.; Ye, J.; Sun, L.; Liao, L.; Li, J.; Yu, D. Angew.
Chem., Int. Ed. 2017, 56, 15683−15687. (f) Kurandina, D.; Rivas, M.;
Radzhabov, M.; Gevorgyan, V. Org. Lett. 2018, 20, 357−360.
(12) (a) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A.
G.; MacMillan, D. W. C. Science 2014, 345, 437−440. (b) Cornella, J.;
Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C.-M.;
E
https://dx.doi.org/10.1021/acs.orglett.0c03236
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P. S. J. Am.
Chem. Soc. 2016, 138, 2174−2177. (c) Murarka, S. Adv. Synth. Catal.
2018, 360, 1735−1753. and references cited therein (d) Le, C.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 11938−11941.
(13) (a) Jamison, C. R.; Overman, L. E. Acc. Chem. Res. 2016, 49,
1578−1586. and references cited therein (b) Nawrat, C. C.; Jamison,
C. R.; Slutskyy, Y.; MacMillan, D. W. C.; Overman, L. E. J. Am. Chem.
Soc. 2015, 137, 11270−11273. (c) Zhang, X.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2016, 138, 13862−13865.
Zhao, L.-J.; Tan, B.; Liu, X.-Y. Angew. Chem., Int. Ed. 2014, 53,
11890−11894.
(27) (27) Turecek, F.; Julian, R. R. Chem. Rev. 2013, 113, 6691−
6733. and references cited therein (b) Zubarev, R. A.; Kelleher, N. L.;
Mclafferty, F. W. J. Am. Chem. Soc. 1998, 120, 3265−3266.
(28) (a) Yadav, J. S.; Rajendar, G.; Rao, R. S.; Pabbaraja, S. J. Org.
Chem. 2013, 78, 8524−8530. (b) Abazid, A. H.; Clamor, N.;
Nachtsheim, B. J. ACS Catal. 2020, 10, 8042−8048. (c) Mulzer, M.;
Whiting, B. T.; Coates, G. W. J. Am. Chem. Soc. 2013, 135, 10930−
10933. (d) Yu, X.; Zhao, H.; Xi, S.; Chen, Z.; Wang, X.; Wang, L.;
Lin, L. Q. H.; Loh, K. P.; Koh, M. J. Nat. Catal. 2020, 3, 585−592.
(29) (a) Lebold, T. P.; Kerr, M. A. Org. Lett. 2007, 9, 1883−1886.
(b) Wang, J.; Zhou, P.; Wang, Y. Eur. J. Org. Chem. 2011, 2011, 264−
270.
(14) (a) He, F.-S.; Ye, S.; Wu, J. ACS Catal. 2019, 9, 8943−8960.
̈
(b) Rossler, S. L.; Jelier, B. J.; Magnier, E.; Dagousset, G.; Carreira, E.
M.; Togni, A. Angew. Chem., Int. Ed. 2020, 59, 9264−9280. (c) Klauck,
F. J. R.; James, M. J.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56,
12336−12339.
(30) (a) Qi, C.; Cong, H.; Cahill, K. J.; Muller, P.; Johnson, R. P.;
̈
(15) (a) Liang, Y.; Zhang, X.; MacMillan, D. W. C. Nature 2018,
559, 83−88. (b) Yang, Z.-K.; Xu, N.-X.; Wang, C.; Uchiyama, M.
Chem. - Eur. J. 2019, 25, 5433−5439. (c) Genovino, J.; Lian, Y.;
Porco, J. A., Jr Angew. Chem., Int. Ed. 2013, 52, 8345−8348. (b) Xu,
W.-L.; Zhang, H.; Hu, Y.-L.; Yang, H.; Chen, J.; Zhou, L. Org. Lett.
2018, 20, 5774−5778. (c) Xu, W.-L.; Tang, L.; Ge, C. Y.; Chen, J.;
Zhou, L. Adv. Synth. Catal. 2019, 361, 2268−2273.
́
Zhang, Y.; Hope, T. O.; Juneau, A.; Gagne, Y.; Ingle, G.; Frenette, M.
Org. Lett. 2018, 20, 3229−3232.
(16) (a) Yasu, Y.; Koike, T.; Akita, M. Adv. Synth. Catal. 2012, 354,
3414−3420. (b) El Khatib, M.; Serafim, R. A. M.; Molander, G. A.
Angew. Chem., Int. Ed. 2016, 55, 254−258. (c) Lima, F.; Kabeshov, M.
A.; Tran, D. N.; Battilocchio, C.; Sedelmeier, J.; Sedelmeier, G.;
Schenkel, B.; Ley, S. V. Angew. Chem., Int. Ed. 2016, 55, 14085−
14089. (d) Huo, H.; Harms, K.; Meggers, E. J. Am. Chem. Soc. 2016,
138, 6936−6939. (e) Primer, D. N.; Molander, G. A. J. Am. Chem. Soc.
2017, 139, 9847−9850.
(17) Dong, J.; Yue, F.; Song, H.; Liu, Y.; Wang, Q. Chem. Commun.
2020, 56, 12652−12655.
(18) (a) Jouffroy, M.; Primer, D. N.; Molander, G. A. J. Am. Chem.
Soc. 2016, 138, 475−478. (b) Deng, Y.; Liu, Q.; Smith, A. B., III J.
́
Am. Chem. Soc. 2017, 139, 9487−9490. (c) Corce, V.; Chamoreau, L.-
M.; Derat, E.; Goddard, J.-P.; Ollivier, C.; Fensterbank, L. Angew.
Chem., Int. Ed. 2015, 54, 11414−11418. (d) Lang, S. B.; Wiles, R. J.;
Kelly, C. B.; Molander, G. A. Angew. Chem., Int. Ed. 2017, 56, 15073−
15077.
(19) (a) Huang, W.; Cheng, X. Synlett 2017, 28, 148. and references
cited therein (b) Wang, P.-Z.; Chen, J.-R.; Xiao, W.-J. Org. Biomol.
Chem. 2019, 17, 6936−6951. and references cited therein (c) Zhang,
H.-H.; Zhao, J.-J.; Yu, S. J. Am. Chem. Soc. 2018, 140, 16914−16919.
(d) van Leeuwen, T.; Buzzetti, L.; Perego, L. A.; Melchiorre, P. A.
́
́
Angew. Chem., Int. Ed. 2019, 58, 4953−4957. (e) Gutierrez-Bonet, A.;
Remeur, C.; Matsui, J. K.; Molander, G. A. J. Am. Chem. Soc. 2017,
139, 12251−12258.
(20) (20) Dong, J.; Wang, Z.; Wang, X.; Song, H.; Liu, Y.; Wang, Q.
Sci. Adv. 2019, 5, No. eaax9955.
(21) (a) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am.
Chem. Soc. 2008, 130, 12886−12887. (b) Narayanam, J. M. R.;
Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2009, 131,
8756−8757.
(22) (a) Nakajima, K.; Miyake, Y.; Nishibayashi, Y. Acc. Chem. Res.
2016, 49, 1946−1956. (b) Zhu, S.; Das, A.; Bui, L.; Zhou, H.; Curran,
D. P.; Rueping, M. J. Am. Chem. Soc. 2013, 135, 1823−1829.
(c) Thullen, S. M.; Rovis, T. J. Am. Chem. Soc. 2017, 139, 15504−
15508.
(23) (a) Zou, Y.; Xiao, W. Visible Light Mediated α-Amino C-H
Functionalization Reactions; Wiley-VCH: Berlin, 2018; Chapter 4, pp
93−128. (b) Xuan, J.; Xiao, W. Angew. Chem., Int. Ed. 2012, 51,
6828−6838. (c) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc.
Rev. 2011, 40, 102−113. (d) Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41,
́
́
7687−7697. (e) Condie, A. G.; Gonzalez-Gomez, J. C.; Stephenson,
C. R. J. J. Am. Chem. Soc. 2010, 132, 1464−1465.
(24) (a) Albeniz, A. C.; Espinet, P.; Lopez-Fernandez, R.; Sen, A. J.
Am. Chem. Soc. 2002, 124, 11278−11279. (b) Winterle, J. S.; Mill, T.
J. Am. Chem. Soc. 1980, 102, 6336−6338.
(25) Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Synlett 2016, 27,
714−723.
(26) (a) Trowbridge, A.; Reich, D.; Gaunt, M. J. Nature 2018, 561,
522−527. (b) Yu, P.; Lin, J.-S.; Li, L.; Zheng, S.-C.; Xiong, Y.-P.;
F
https://dx.doi.org/10.1021/acs.orglett.0c03236
Org. Lett. XXXX, XXX, XXX−XXX