Catalytic Allylation of Aldehydes Using Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.0c04735

Simple feedstock organic molecules, especially alkenes, are attractive starting materials in organic synthesis because of their wide availability. Direct utilization of such bulk, inert organic molecules for practical and selective chemical reactions, however, remains limited. Herein, we developed a ternary hybrid catalyst system comprising a photoredox catalyst, a hydrogen-atom-transfer catalyst, and a chromium complex catalyst, enabling catalytic allylation of aldehydes with simple alkenes, including feedstock lower alkenes. The reaction proceeded under visible-light irradiation at room temperature and with high functional group tolerance. The reaction was extended to an asymmetric variant by employing a chiral chromium complex catalyst.

Full text of DOI:10.1021/jacs.0c04735

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Catalytic Allylation of Aldehydes Using Unactivated Alkenes
Shun Tanabe, Harunobu Mitsunuma,* and Motomu Kanai*
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ABSTRACT: Simple feedstock organic molecules, especially alkenes, are
attractive starting materials in organic synthesis because of their wide
availability. Direct utilization of such bulk, inert organic molecules for
practical and selective chemical reactions, however, remains limited. Herein,
we developed a ternary hybrid catalyst system comprising a photoredox
catalyst, a hydrogen-atom-transfer catalyst, and a chromium complex
catalyst, enabling catalytic allylation of aldehydes with simple alkenes,
including feedstock lower alkenes. The reaction proceeded under visible-
light irradiation at room temperature and with high functional group
tolerance. The reaction was extended to an asymmetric variant by
employing a chiral chromium complex catalyst.
chemoselective allylation of aldehydes using simple alkenes,
including feedstock alkenes, is in high demand. The catalytic in
situ generation of nucleophilic allylmetal species from simple
and unactivated alkenes via allylic sp3 C−H bond activation
would be a straightforward approach. Earlier methods
involving this activation mode, however, suffered from the
generation of stoichiometric waste and/or a narrow substrate
scope.9−11 In particular, catalytic and stereocontrolled addition
reactions between simple aldehydes and gaseous lower
feedstock alkenes have not been reported.
We report herein a catalytic allylation of aldehydes with
various alkenes involving the development of ternary hybrid
catalysis12 comprising a photoredox catalyst, a hydrogen-atom-
transfer (HAT) catalyst, and a chromium complex catalyst
(Figure 1).13 The substrate scope covers feedstock lower
alkenes and densely functionalized aldehydes. This method is
further applicable to asymmetric catalysis by introducing a
chiral ligand to the chromium catalyst.
INTRODUCTION
■
The efficient production of fine chemicals from simple and
readily available bulk materials represents a fundamental
research goal in synthetic organic chemistry.1 Simple alkenes
are attractive starting materials for various transformations
because of their wide availability. Specifically, lower alkenes are
produced by one of the most common chemical processes,
hydrocarbon cracking.2 Over 500 million metric tons of raw
organic materials, such as kerogens and longer-chain hydro-
carbons, are converted to lower alkenes per year. As an
example, 1-butene and 2-butene are typical C4 alkene
feedstocks annually produced on a 105 metric ton scale.3
Catalytic methods enabling the direct utilization of these
abundant organic molecules as carbon sources would be highly
useful for practical and selective chemical reactions. Despite
several previous examples, the use of feedstock alkenes in
synthetically useful transformations remains a challenging
task.4
Catalytic allylation of aldehydes to produce secondary
homoallylic alcohols is a fundamentally important and
synthetically useful reaction.5 Traditionally, this catalytic
process has utilized nucleophilic allylmetal species as
stoichiometric starting materials. Although this approach is
reliable, there is room for improvement in the overall
efficiency, redox/atom/step economy, and environmental
sustainability,6 especially considering the use of bulk alkenes
as starting materials. Krische’s group established transfer
hydrogenative couplings between primary alcohols and feed-
stock dienes or allenes to produce homoallylic secondary
alcohols.7,8 This direct byproduct-free protocol bypasses the
use of premetalated reagents for carbonyl allylation. Consid-
ering that alkene substrates are generally more readily available
than allenes or dienes, however, a one-step, catalytic, and
RESULTS AND DISCUSSION
■
Reaction Design. Previously, Glorius’s group and our
group independently reported chromium/photoredox binary
hybrid catalysis promoting the allylation of aldehydes using
relatively simple alkenes as allyl sources (Figure 2).10 These
reactions proceeded under mild and redox-neutral conditions.
Received: April 30, 2020
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© XXXX American Chemical Society
A

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a
Table 1. Optimization of Reaction Conditions
Figure 1. (a) Catalytic allylation of aldehydes using simple
unactivated alkenes developed in this study. (b) Proposed catalytic
cycle.
a
General reaction conditions: 5a (0.25 mmol), 1a (5.0 mmol), CrCl2
(0.0125 mmol), HAT catalyst (0.025 mmol), photoredox catalyst
(0.0125 mmol), and K2HPO4 (0.025 mmol) were reacted in
dichloromethane (DCM; 1.5 mL) and acetonitrile (1 mL) at room
temperature under blue LED irradiation for 24 h. Yield and dr were
1
determined by H NMR analysis of the crude mixture using 1,1,2,2-
tetrachloroethane as an internal standard. dr = diastereomeric ratio.
b
c
n.d. = not determined. Without CrCl2. Without photoirradiation.
Without K2HPO4.
d
hybrid catalysis to activate the alkenes through the HAT
process of an allylic C−H bond (Figure 1b).
The design for ternary hybrid catalysis is shown in Figure 1b.
We planned to use a combination of an acridinium photoredox
catalyst (Mes-Acr+) and a thiophosphoric imide (TPI) HAT
catalyst to activate the alkenes through the HAT process of an
Figure 2. Previous approach using chromium/photoredox binary
hybrid catalysis.10 The alkene scope was limited by the oxidation
potential. PC = photoredox catalyst.
The key of these reactions was the in situ, catalytic generation
of allylchromium(III) species14 from alkenes through allyl
radical intermediates. The scope of these previous achieve-
ments, however, was limited to relatively electron-rich alkenes:
α-aryl- and α-amino alkenes for Glorius’s reaction and cyclic or
tri- and tetrasubstituted hydrocarbon alkenes for our reaction.
The limitation in the alkene scope is attributable to the
fundamental mechanism for the activation of alkenes, namely,
single-electron oxidation of alkenes by excited photoredox
catalysts to generate radical cation species (red arrow in Figure
2), followed by deprotonation to afford allyl radical
intermediates. Because of this mechanism, the scope of alkenes
depended on the oxidation potential, and the application of
simple alkenes with a much higher oxidation potential than
that of the excited photoredox catalysts (>2.5 V vs SCE) was
difficult.15,16 In particular, despite their availability and
synthetic utility, simple α-olefins are unreactive under these
reaction conditions. To broaden the alkene scope, we planned
to incorporate sulfur HAT catalysis17 into the previous binary
allylic C−H bond, on the basis of our previous studies.18,19
A
sulfur-centered radical (RS•) is generated through single-
electron oxidation of TPI by a photoexcited acridinium catalyst
(*Mes-Acr+).18 The RS• radical abstracts a hydrogen atom
from the allylic C−H bond of alkene substrates 1, generating
allyl radicals 2. Judging from the comparison between the bond
dissociation energies (BDEs) of an allylic C−H bond (ca. 85
kcal/mol)20 and an S−H bond (ca. 87 kcal/mol),21 this HAT
process (1 to 2) is plausible.18 Then the chromium(II)
b
complex catalyst 3 oxidatively intercepts 2, giving
allylchromium(III) species 4. This species reacts with
aldehydes 5 via a six-membered chair transition state to
produce chromium alkoxides 6 in an anti-selective manner.14
Protonolysis of 6 by the proton generated in the HAT catalysis
should then afford the target homoallylic alcohols 7 and an
oxidized chromium(III) complex 8. Finally, single-electron
reduction of 8 by the reduced form of the photoredox catalyst
(Mes−Acr•) would regenerate 3 and the oxidized form of the
B
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a
Table 2. Substrate Scope of Alkenes
a
General reaction conditions: 5a (0.25 mmol), 1 (5.0 mmol), CrCl2 (0.0125 mmol), HAT1 (0.025 mmol), PC1 (0.0125 mmol), and K2HPO4
(0.025 mmol) were reacted in DCM (1.5 mL) and acetonitrile (1 mL) at room temperature under blue LED irradiation for 24 h. Yield was the
b
c
isolated yield. 1 mL of alkene as a liquid was used. Alkene (3 equiv) was used. Reaction time was 48 h. Yield and dr were determined by 1H NMR
d
e
f
analysis of the crude mixture using 1,1,2,2-tetrachloroethane as an internal standard. Reaction time was 36 h. Reaction time was 72 h. TMS
group was removed after workup with 1 N HCl.
photoredox catalyst (Mes−Acr+), thus closing the catalytic
cycle.22
with the chromium atom at the terminal position.14 If the
chromium catalyst was absent (entry 3), however, 7a was
obtained in only 8% yield, accompanied by the linear product
(1-phenylhept-3-en-1-ol) in 42% yield. The observed moderate
regioselectivity in the absence of the Cr catalyst is consistent
with the coupling reactions of allyl radicals with persistent
radicals or radical acceptors, such as imines and Michael
acceptors.23 Other sulfur HAT catalysts17 showed low to no
reactivity (HAT2−4, entries 4−6). We also examined several
photoredox catalysts. Use of acridinium analogues PC2 and
PC3 slightly decreased the yield, likely because of the partial
catalyst decomposition during the reaction (entries 7 and
8).16b,24 Ruthenium- and iridium-based photoredox catalysts
were not effective (entries 9 and 10). Control experiments
confirmed that both the photoredox catalyst and photo-
irradiation were essential for the reaction progress (entries 11
Optimization of the Reaction Conditions. According to
this hypothesis, we commenced optimization of the reaction
conditions using benzaldehyde (5a) and 1-hexene (1a: 20
equiv) as model substrates (Table 1). The reaction was
conducted with a combination of 5 mol % CrCl2, 10 mol %
HAT catalysts, 5 mol % acridinium photoredox catalysts, and
10 mol % base (K2HPO4) under 430 nm visible-light
irradiation at room temperature. In the absence of the HAT
catalysts, which was the previous condition for the binary
hybrid catalysis,10b 7a was not obtained at all (entry 1). The
addition of TPI (HAT1) dramatically improved the reactivity
(85%, entry 2). The high branch- and anti-selectivity (>20/1
regio- and diastereoselectivity) was due to a six-membered
chair transition state involving (E)-2-hexenylchromium species
C
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a
Table 3. Substrate Scope of Aldehydes
Table 4. Functional Group Tolerance in Allylation of
Structurally Elaborated Aldehydes with 2-Butenes
a
a
General reaction conditions: 5 (0.25 mmol), 1c (1 mL as a liquid),
CrCl2 (0.0125 mmol), HAT1 (0.025 mmol), PC1 (0.0125 mmol),
and K2HPO4 (0.025 mmol) were reacted in DCM (1.5 mL) and
acetonitrile (1 mL) at room temperature under blue LED irradiation
b
c
for 24 h. Yield was the isolated yield. 1.0 mmol scale. MsOH (1
equiv) was added.
and 12). In the absence of the base, 7a was obtained in 76%,
accompanied by linear product in 12% (entry 13). We
speculate that the addition of base was effective for reducing
side reactions by neutralizing the reaction media.25
a
General reaction conditions: 5 (0.25 mmol), 1c (1 mL as a liquid),
CrCl2 (0.0125 mmol), HAT1 (0.025 mmol), PC1 (0.0125 mmol),
and K2HPO4 (0.025 mmol) were reacted in DCM (1.5 mL) and
acetonitrile (1 mL) at room temperature under blue LED irradiation
for 24 h. Yield was the isolated yield. Yield and dr were determined
by H NMR analysis of the crude mixture using 1,1,2,2-tetrachloro-
Substrate Scope. We next studied the substrate scope
under the optimized conditions. The scope of alkenes was first
investigated using 5a as an aldehyde substrate (Table 2). The
regioselectivity was completely controlled in all cases (>20/1),
exclusively producing the branched constitutional isomer. The
reactions of C4 feedstocks, 1-butene (1b) and 2-butenes (1c:
cis- and trans-mixture26), with benzaldehyde (5a) afforded 7b
in 94% and 100% yield, respectively, both with high
diastereoselectivity (14−16/1). Carbonyl crotylation using
butenes as a starting material will significantly contribute to
polyketide synthesis.5 For reactions with C5 alkenes, linear 1-
pentene (1d) afforded 7d in 81% yield with >20/1
diastereoselectivity, whereas branched 3-methyl-1-butene
(1e) selectively afforded 7e containing a quaternary carbon.
Regioselective formation of 7e was not possible under the
b
1
c
ethane as an internal standard. Reaction time was 72 h.
previous conditions without an HAT catalyst.10b Linear and
branched C6 alkenes (1a, 1f, and 1g) were also competent
substrates.27 Other alkenes, including vinylcyclohexane (1h),
cyclic (1i), halide-containing (1j), styrene derivative (1k), and
allylbenzene (1l), all afforded the product in high yield and
diastereoselectivity. (Z)-Allylchromium species from 1i
afforded syn-homoallylic alcohol 7i selectively. Allyl ethers
1m and 1n provided 1,2-diol derivatives, although the
diastereoselectivity requires further improvement.27 The
amount of alkenes could be reduced to 3 equiv (7a, 7f, and
D
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Table 5. Catalytic Asymmetric Allylation of Aldehydes with
Alkenes
Scheme 1. Mechanistic Studies
a
a
1
Yield and dr were determined by H NMR analysis of the crude
mixture using 1,1,2,2-tetrachloroethane as an internal standard.
a
General reaction conditions: 5 (0.25 mmol), 1 (5.0 mmol), CrCl2
(0.0125 mmol), ligand 8 (0.0125 mmol), HAT1 (0.025 mmol), PC1
(0.0125 mmol), and K2HPO4 (0.025 mmol) were reacted in DCM
(2.5 mL) at room temperature under blue LED irradiation for 48 h.
Yield is the isolated yield. The enantiomeric excess was determined by
chiral stationary HPLC analysis after isolation. 1 mL of 1c as a liquid
was used. ee = enantiomeric excess.
position of 1c was the exclusive pathway in the presence of
potentially reactive C−H bonds in the aldehyde substrates
(e.g., highlighted C−H bonds in 7ab and 7ac, the formyl C−H
bonds of aldehydes 5, and the allylic and benzylic C−H bonds
of products 7). Increasing the reaction scale to 1 mmol did not
affect the results (7q).
Next, we studied the reactions between more functionalized
aldehydes and 1c (Table 4). The natural product citronellal
was a competent substrate (7ad). An indometacin-conjugated
aldehyde provided product 7ae in 89% yield with high
diastereoselectivity. A cholesterol derivative containing allylic
C−H bonds also tolerated the reaction conditions (7af). The
free hydroxy group in propranolol did not affect the reaction
progress (7ag). A dipeptide and a nucleic acid derivative
containing coordinating polar functional groups (i.e., amides
and an adenine heterocycle) did not interfere with the reaction
(7ah and 7ai). Therefore, the allylation of aldehydes mediated
by ternary hybrid catalysis realized high functional group
compatibility and chemoselectivity using easily available
feedstock alkenes.
Catalytic Asymmetric Allylation. We applied this
method to a catalytic asymmetric allylation of aldehydes
(Table 5). The optimized chiral ligand was identified as
Indane-BOX ligand 8.10b,30,31 A series of alkenes afforded the
products in up to 88% ee ((S,S)-7a, 7b, 7f, (S,R)-7k). Both
aromatic and aliphatic aldehydes were also applicable ((S,S)-
7aj). In all the cases, regioselectivity was perfectly controlled to
favor branch selectivity (>20/1), although the diastereoselec-
tivity varied depending on the alkenes.32 To demonstrate the
b
7h). The C3 alkene feedstock, propene, was much less reactive
than other alkenes under the current conditions, however,
probably because of higher BDE of its allylic C−H bond (3%
yield from 5a).20,28
The aldehyde scope was then investigated by fixing the
alkene substrate to 1c (Table 3). A series of aromatic
aldehydes bearing halogens (7o−7q), electron-withdrawing
groups (7r), and a boronate ester (7s) reacted with 1c,
affording the corresponding products with high diastereose-
lectivity. A methyl substituent at the ortho, meta, and para
positions of the aromatic aldehydes did not affect the results
(7t−7v). The reactions of aliphatic aldehydes, including those
containing potentially sensitive functional groups, also
proceeded with high diastereoselectivity (7w−7y). Tertiary
amines (e.g., 7z) are generally susceptible to oxidative
conditions, providing N-cation radical or α-amino C-radical
species.29 Addition of 1 equiv of MsOH to the reaction
mixture, however, was effective for efficient reaction progress,
affording amino alcohol 7z. Sulfide moieties are also vulnerable
to various oxidative conditions; in this case, however, the
reaction proceeded in high yield without oxidizing the sulfide
moiety (7aa). When more than one C−H bond was
comparably reactive, the site selectivity was affected by the
relative concentration of the substrates: reaction at the allylic
E
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synthetic utility, we applied those conditions to the synthesis of
a key chiral intermediate of dictyostatin analogues reported by
Leighton’s group ((R,S)-7ak: Table 5b).33 The catalytic
asymmetric reaction between commercially available alkene
1j and aldehyde 5b proceeded, and (R,S)-7ak was obtained in
47% yield with a 3.6/1 dr and 82% ee after hydrolysis of the
acetal.
Mechanistic Studies. To gain insights into the reaction
mechanism, we conducted the following studies. First,
cyclopropanecarboxaldehyde 5c was subjected to the opti-
mized reaction conditions. No cyclopropane ring opening was
observed, suggesting that ketyl radical intermediates were not
involved (Scheme 1a). Next, a radical-trapping experiment was
conducted by the addition of TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy, free radical). There was no production of
desired product 7a in this case (Scheme 1b). These results are
consistent with the proposed reaction mechanism of the
ternary hybrid catalysis (Figure 1b). Furthermore, kinetic
studies for the reaction between 5a and 1-decene (1o) or 1-
decene-d2 (1o-D2) were conducted (Scheme 1c). A kinetic
isotope effect (KIE = 3.7) was observed, suggesting that the
HAT process of an allylic C−H bond is a rate-limiting step.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS KAKENHI Grant
Nos. JP17H06442 (M.K.) (Hybrid Catalysis) and
JP18H05969 (H.M.).
REFERENCES
■
(1) (a) Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.;
Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W.
Critical Assessment of Pharmaceutical Processes-A Rationale for
Changing the Synthetic Route. Chem. Rev. 2006, 106, 3002−3027.
(b) Sheldon, R. A. The E Factor: fifteen years on. Green Chem. 2007,
9, 1273−1283. (c) Gaich, T.; Baran, P. S. Aiming for the Ideal
Synthesis. J. Org. Chem. 2010, 75, 4657−4673. (d) Nguyen, K. D.;
Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.; Krische, M. J. Metal-
catalyzed reductive coupling of olefin-derived nucleophiles: Reinvent-
ing carbonyl addition. Science 2016, 354, No. aah5133. (e) Doerksen,
R. S.; Meyer, C. C.; Krische, M. J. Feedstock Reagents in Metal-
Catalyzed Carbonyl Reductive Coupling: Minimizing Preactivation
for Efficiency in Target-Oriented Synthesis. Angew. Chem., Int. Ed.
2019, 58, 14055−14064.
(2) Alfke, G.; Irion, W. W.; Neuwirth, O. S. Oil Refining. In
Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Wein-
heim, 2007.
(3) Geilen, F. M. A.; Stochniol, G.; Peitz, S.; Schulte-Koerne, E.
Butenes. In Ullmann’s Encyclopedia of Industrial Chemistry; Obenaus,
F., Droste, W., Neumeister, J., Eds.; Wiley: New York, 2014; pp 1−13.
(4) There are elegant catalytic processes using feedstock alkene
substrates in complex organic molecule synthesis (e.g., Wacker
process, alkene metathesis, alkene hydroformylation, and Heck
reaction). For recent representative reports and reviews on the use
of ethylene, propylene, and butenes in synthetically versatile catalytic
asymmetric transformations, see: (a) Saini, V.; Stokes, B. J.; Sigman,
M. S. Transition-Metal-Catalyzed Laboratory-Scale Carbon-Carbon
Bond-Forming Reactions of Ethylene. Angew. Chem., Int. Ed. 2013, 52,
11206−11220. (b) Yang, Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S.
L. Catalytic Asymmetric Hydroamination of Unactivated Internal
Olefins to Aliphatic Amines. Science 2015, 349, 62−66. (c) Pagar, V.
V.; RajanBabu, T. V. Tandem Catalysis for Asymmetric Coupling of
Ethylene and Enynes to Functionalized Cyclobutanes. Science 2018,
361, 68−72. (d) Silva Costa, D. C. Additions to non-activated
alkenes: Recent advances. Arabian J. Chem. 2020, 13, 799−834.
(e) Li, Y.; Wu, D.; Cheng, H.-G.; Yin, G. Difunctionalization of
Alkenes Involving Metal Migration. Angew. Chem., Int. Ed. 2020, 59,
7990−8003.
CONCLUSION
■
In conclusion, we developed ternary hybrid catalysis
comprising a photoredox catalyst, an HAT catalyst, and a
chromium complex catalyst, enabling the catalytic allylation of
aldehydes using simple alkenes, including feedstock alkenes,
under visible-light irradiation at room temperature. Incorpo-
rating a proper HAT catalytic cycle significantly broadened the
substrate scope of alkenes. Because of the high chemo-
selectivity, the reaction was applicable to multiple function-
alized substrates. By introduction of a chiral ligand to the
chromium catalyst, the asymmetric variant of this hybrid
catalysis enabled facile access to enantiomerically and
diastereomerically enriched homoallylic alcohols.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c04735.
■
sı
(5) For selected recent reviews on stereoselective allylation of
carbonyl compounds, see: (a) Denmark, S. E.; Fu, J. Catalytic
Enantioselective Addition of Allylic Organometallic Reagents to
Aldehydes and Ketones. Chem. Rev. 2003, 103, 2763−2794.
(b) Yamamoto, H.; Wadamoto, M. Silver-Catalyzed Asymmetric
Allylation: Allyltrimethoxysilane as a Remarkable Reagent. Chem. -
Asian J. 2007, 2, 692−698. (c) Yus, M.; Gonzalez-Gomez, J. C.;
Foubelo, F. Catalytic Enantioselective Allylation of Carbonyl
Compounds and Imines. Chem. Rev. 2011, 111, 7774−7854.
(d) Huo, H.-X.; Duvall, J. R.; Huang, M.-Y.; Hong, R. Catalytic
Asymmetric Allylation of Carbonyl Compounds and Imines with
Allylic Boronates. Org. Chem. Front. 2014, 1, 303−320. (e) Wang, P.-
S.; Shen, M.-L.; Gong, L.-Z. Transition-Metal-Catalyzed Asymmetric
Allylation of Carbonyl Compounds with Unsaturated Hydrocarbons.
Synthesis 2018, 50, 956−967. (f) Sedgwick, D.; Grayson, M.; Fustero,
S.; Barrio, P. Recent Developments and Applications of the Chiral
Brønsted Acid Catalyzed Allylboration of Carbonyl Compounds.
Synthesis 2018, 50, 1935−1957. (g) Spielmann, K.; Niel, G.; de
Figueiredo, R. M.; Campagne, J.- M. Catalytic Nucleophilic
‘Umpoled’ π-Allyl Reagents. Chem. Soc. Rev. 2018, 47, 1159−1173.
(h) Holmes, M.; Schwartz, L. A.; Krische, M. J. Intermolecular Metal-
Catalyzed Reductive Coupling of Dienes, Allenes, and Enynes with
Carbonyl Compounds and Imines. Chem. Rev. 2018, 118, 6026−
6052.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Harunobu Mitsunuma − Graduate School of Pharmaceutical
Sciences, The University of Tokyo, Tokyo 113-0033, Japan;
orcid.org/0000-0001-7609-905X; Email: h-mitsunuma@
mol.f.u-tokyo.ac.jp
Motomu Kanai − Graduate School of Pharmaceutical Sciences,
The University of Tokyo, Tokyo 113-0033, Japan;
orcid.org/0000-0003-1977-7648; Email: kanai@mol.f.u-
tokyo.ac.jp
Author
Shun Tanabe − Graduate School of Pharmaceutical Sciences,
The University of Tokyo, Tokyo 113-0033, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c04735
Notes
The authors declare no competing financial interest.
F
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(6) (a) Trost, B. M. The atom economy–a search for synthetic
efficiency. Science 1991, 254, 1471−1477. (b) Wender, P. A.; Croatt,
M. P.; Witulski, B. New reactions and step economy: the total
synthesis of ( )-salsolene oxide based on the type II transition metal-
catalyzed intramolecular [4 + 4] cycloaddition. Tetrahedron 2006, 62,
7505−7511. (c) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Redox
Economy in Organic Synthesis. Angew. Chem., Int. Ed. 2009, 48,
2854−2867.
(7) For representative reports, see: (a) Zbieg, J. R.; Yamaguchi, E.;
McInturff, E. L.; Krische, M. J. Enantioselective C-H Crotylation of
Primary Alcohols via Hydrohydroxyalkylation of Butadiene. Science
2012, 336, 324−327. (b) McInturff, E. L.; Yamaguchi, E.; Krische, M.
J. Chiral Anion Dependent Inversion of Diastereo- and Enantiose-
lectivity in Carbonyl Crotylation via Ruthenium Catalyzed Butadiene
Hydrohydroxyalkylation. J. Am. Chem. Soc. 2012, 134, 20628−20631.
(c) Kim, S. W.; Meyer, C. C.; Mai, B. K.; Liu, P.; Krische, M. J.
Inversion of Enantioselectivity in Allene Gas vs Allyl Acetate
Reductive Aldehyde Allylation Mediated by 2-Propanol Guided by
Metal-Centered Stereogenicity: An Experimental and Computational
Study. ACS Catal. 2019, 9, 9158−9163. For details please also see ref
1d.
12705−12709. (b) Mitsunuma, H.; Tanabe, S.; Fuse, H.; Ohkubo, K.;
Kanai, M. Catalytic Asymmetric Allylation of Aldehydes with Alkenes
Mediated by Organophotoredox and Chiral Chromium Hybrid
Catalysis. Chem. Sci. 2019, 10, 3459−3465.
(11) Intermolecular carbonyl ene reactions are classified in this
category. However, the scope of the carbonyl group is limited to
highly reactive aldehydes or ketones. For selected reviews, see:
(a) Mikami, K.; Shimizu, M. Asymmetric ene reactions in organic
synthesis. Chem. Rev. 1992, 92, 1021−1050. (b) Berrisford, D. J.;
Bolm, C. Catalytic Asymmetric Carbonyl-Ene Reactions. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1717−1719. (c) Mikami, K., Terada,
M., Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. Comprehensive
Asymmetric Catalysis; Springer; Berlin, 1999: p 1143. (d) Carlos Dias,
L. Chiral Lewis Acid Catalyzed Ene-Reactions. Curr. Org. Chem. 2000,
4, 305−342. (e) Mikami, K.; Nakai, T. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: New York; 2000: p 543.
(f) Clarke, M. L.; France, M. B. The carbonyl ene reaction.
Tetrahedron 2008, 64, 9003−9031.
(12) Sancheti, S. P.; Urvashi; Shah, M. P.; Patil, N. T. Ternary
Catalysis: A Stepping Stone toward Multicatalysis. ACS Catal. 2020,
10, 3462−3489.
(8) Recently, Buchwald’s group developed Cu−H-catalyzed
asymmetric allylations using feedstock allenes or dienes. Although a
stoichiometric amount of silicon reagent was produced as a
byproduct, the reactions proceeded in high reactivity, stereoselectivity,
and functional group compatibility. See: (a) Yang, Y.; Perry, I. B.; Lu,
G.; Liu, P.; Buchwald, S. L. Copper-Catalyzed Asymmetric Addition
of Olefin- Derived Nucleophiles to Ketones. Science 2016, 353, 144−
150. (b) Tsai, E. Y.; Liu, R. Y.; Yang, Y.; Buchwald, S. L. A Regio- and
Enantioselective CuH-Catalyzed Ketone Allylation with Terminal
Allenes. J. Am. Chem. Soc. 2018, 140, 2007−2011. (c) Liu, R. Y.;
Zhou, Y.; Yang, Y.; Buchwald, S. L. Enantioselective Allylation Using
Allene, a Petroleum Cracking Byproduct. J. Am. Chem. Soc. 2019, 141,
2251−2256. (d) Li, C.; Liu, R. Y.; Jesikiewicz, L. T.; Yang, Y.; Liu, P.;
Buchwald, S. L. CuH-Catalyzed Enantioselective Ketone Allylation
with 1,3-Dienes: Scope, Mechanism, and Applications. J. Am. Chem.
Soc. 2019, 141, 5062−5070. (e) Li, C.; Shin, K.; Liu, R. Y.; Buchwald,
S. L. Engaging Aldehydes in CuH-Catalyzed Reductive Coupling
Reactions: Stereoselective Allylation with Unactivated 1,3-Diene
Pronucleophiles. Angew. Chem., Int. Ed. 2019, 58, 17074−17080.
(9) (a) Tao, Z.-L.; Li, X.-H.; Han, Z.-Y.; Gong, L.-Z.
Diastereoselective Carbonyl Allylation with Simple Olefins Enabled
by Palladium Complex-Catalyzed C-H Oxidative Borylation. J. Am.
Chem. Soc. 2015, 137, 4054−4057. (b) Mita, T.; Hanagata, S.;
Michigami, K.; Sato, Y. Co-Catalyzed Direct Addition of Allylic
C(sp3)-H Bonds to Ketones. Org. Lett. 2017, 19, 5876−5879.
(c) Wang, Y.; Zhu, J.; Durham, A. C.; Lindberg, H.; Wang, Y.-M. W-
C-H Functionalization of π-Bonds Using Iron Complexes: Catalytic
Hydroxyalkylation of Alkynes and Alkenes. J. Am. Chem. Soc. 2019,
141, 19594−19599. For related one-pot allylic sp3 C−H borylation
(13) In general, chromium(II) and chromium(III) compounds
exhibit low toxicity. See: (a) Steib, A. K.; Kuzmina, O. M.; Fernandez,
S.; Flubacher, D.; Knochel, P. Efficient Chromium(II)-Catalyzed
Cross-Coupling Reactions between Csp2 Centers. J. Am. Chem. Soc.
2013, 135, 15346−15349. (b) Egorova, K. S.; Ananikov, V. P.
Toxicity of Metal Compounds: Knowledge and Myths. Organo-
metallics 2017, 36, 4071−4090.
(14) For selected reviews on reactivity of organochromium(III)
species, see: (a) Furstner, A. Carbon-Carbon Bond Formations
̈
Involving Organochromium(III) Reagents. Chem. Rev. 1999, 99,
991−1046. (b) Hargaden, G. C.; Guiry, P. J. The Development of the
Asymmetric Nozaki-Hiyama-Kishi Reaction. Adv. Synth. Catal. 2007,
349, 2407−2424. (c) Hargaden, G. C.; Guiry, P. J. In Stereoselective
Synthesis of Drugs and Natural Products; Andrushko, V., Andrushko,
N., Eds.; John Wiley & Sons, Inc.: Hoboken, NJ, 2013; pp 347−368.
(d) Tian, Q.; Zhang, G. Recent Advances in the Asymmetric Nozaki-
Hiyama-Kishi Reaction. Synthesis 2016, 48, 4038−4049. (e) Gil, A.;
́
Albericio, F.; Alvarez, M. Role of the Nozaki-Hiyama-Takai-Kishi
Reaction in the Synthesis of Natural Products. Chem. Rev. 2017, 117,
8420−8446.
(15) Schepp, N. P.; Johnston, L. J. Reactivity of Radical Cations.
Effect of Radical Cation and Alkene Structure on the Absolute Rate
Constants of Radical Cation Mediated Cycloaddition Reactions. J.
Am. Chem. Soc. 1996, 118, 2872−2881.
(16) (a) 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. (b) Romero, N. A.; Nicewicz, D. A. Organic Photoredox
Catalysis. Chem. Rev. 2016, 116, 10075−10166.
(17) Breder, A.; Depken, C. Light-Driven Single-Electron Transfer
Processes as an Enabling Principle in Sulfur and Selenium
Multicatalysis. Angew. Chem., Int. Ed. 2019, 58, 17130−17147.
(18) From the electrochemical and photochemical experiments, we
confirmed the generation of a TPI-derived, sulfur-centered radical
under photoirradiation in the presence of Acr-Mes+. See: Kato, S.;
Saga, Y.; Kojima, M.; Fuse, H.; Matsunaga, S.; Fukatsu, A.; Kondo,
M.; Masaoka, S.; Kanai, M. Hybrid Catalysis Enabling Room-
Temperature Hydrogen Gas Release from N-Heterocycles and
Tetrahydronaphthalenes. J. Am. Chem. Soc. 2017, 139, 2204−2207.
(19) For the use of TPI and its analogue thiophosphoric acid (TPA)
in HAT catalysis, see: (a) Fuse, H.; Kojima, M.; Mitsunuma, H.;
Kanai, M. Acceptorless Dehydrogenation of Hydrocarbons by Noble-
Metal-Free Hybrid Catalyst System. Org. Lett. 2018, 20, 2042−2045.
(b) Fuse, H.; Mitsunuma, H.; Kanai, M. Catalytic Acceptorless
Dehydrogenation of Aliphatic Alcohols. J. Am. Chem. Soc. 2020, 142,
4493−4499.
́
and carbonyl allylation protocols, see: (d) Olsson, V. J.; Szabo, K. J.
Selective One-Pot Carbon-Carbon Bond Formation by Catalytic
Boronation of Unactivated Cycloalkenes and Subsequent Coupling.
́
Angew. Chem., Int. Ed. 2007, 46, 6891−6893. (e) Olsson, V. J.; Szabo,
K. J. Functionalization of Unactivated Alkenes through Iridium-
Catalyzed Borylation of Carbon-Hydrogen Bonds. Mechanism and
Synthetic Applications. J. Org. Chem. 2009, 74, 7715−7723. (f) Deng,
3
́
H. P.; Eriksson, L.; Szabo, K. J. Allylic sp C-H borylation of alkenes
via allyl-Pd intermediates: an efficient route to allylboronates. Chem.
Commun. 2014, 50, 9207−9210. (g) Li, L.-L.; Tao, Z.-L.; Han, Z.-Y.;
Gong, L.-Z. Double Chiral Induction Enables a Stereoselective
Carbonyl Allylation with Simple Alkenes under the Sequential
Catalysis of Palladium Complex and Chiral Phosphoric Acid. Org.
Lett. 2017, 19, 102−105. (h) Mao, L.; Bertermann, R.; Rachor, S. G.;
́
Szabo, K. J.; Marder, T. B. Palladium-Catalyzed Oxidative Borylation
of Allylic C-H Bonds in Alkenes. Org. Lett. 2017, 19, 6590−6593.
̈
̈
(10) (a) Schwarz, J. L.; Schafers, F.; Tlahuext-Aca, A.; Luckemeier,
L.; Glorius, F. Diastereoselective Allylation of Aldehydes by Dual
Photoredox and Chromium Catalysis. J. Am. Chem. Soc. 2018, 140,
G
https://dx.doi.org/10.1021/jacs.0c04735
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(20) Khursan, S. L.; Mikhailov, D. A.; Yanborisov, V. M.; Borisov, D.
I. AM1 Calculations of bond dissociation energies. Allylic and
benzylic C-H bonds. React. Kinet. Catal. Lett. 1997, 61, 91−95.
(21) Denisov, E.; Chatgilialoglu, C.; Shestakov, A.; Denisova, T.
Rate constants and transition-state geometry of reactions of alkyl,
alkoxyl, and peroxyl radicals with thiols. Int. J. Chem. Kinet. 2009, 41,
284−293.
Catalytic Fluorinations and the Nozaki-Hiyama-Kishi Reaction. Chem.
- Eur. J. 2011, 17, 14922−14928.
(33) Ho, S.; Sackett, D.; Leighton, J. A. Methyl Extension” Strategy
for Polyketide Natural Product Linker Site Validation and Its
Application to Dictyostatin. J. Am. Chem. Soc. 2015, 137, 14047−
14050.
(22) The single-electron reduction of Cr(III) species by the reduced
form of the photoredox catalyst would be feasible based on the redox
potentials of intermediates ([Cr(III)/Cr(II)] = −0.41 V vs SCE,
[Mes-Acr+/Mes-Acr•] = −0.46 V vs SCE). See: (a) Fu
̈
rstner, A.; Shi,
N. Nozaki-Hiyama-Kishi Reactions Catalytic in Chromium. J. Am.
Chem. Soc. 1996, 118, 12349−12357. (b) Tsudaka, T.; Kotani, H.;
Ohkubo, K.; Nakagawa, T.; Tkachenko, N. V.; Lemmetyinen, H.;
Fukuzumi, S. Photoinduced Electron Transfer in 9-Substituted 10-
Methylacridinium Ions. Chem. - Eur. J. 2017, 23, 1306−1317.
(23) For representative reports on acyclic allylic C−H functionaliza-
tion through allyl radicals using photoredox catalysis, see:
(a) Cuthbertson, J. D.; MacMillan, D. W. C. The Direct Arylation
of Allylic sp3 C-H Bonds via Organic and Photoredox Catalysis.
Nature 2015, 519, 74−77. (b) Zhou, R.; Liu, H.; Tao, H.; Yu, X.; Wu,
J. Metal-Free Direct Alkylation of Unfunctionalized Allylic/Benzylic
sp3 C-H Bonds via Photoredox Induced Radical Cation Deprotona-
tion. Chem. Sci. 2017, 8, 4654−4659. (c) Vu, M. D.; Das, M.; Guo, A.;
́
Ang, Z.-E.; D̵ okic, M.; Soo, H. S.; Liu, X.-W. Visible-Light Photoredox
Enables Ketone Carbonyl Alkylation for Easy Access to Tertiary
Alcohols. ACS Catal. 2019, 9, 9009−9014. (d) Li, Y.; Lei, M.; Gong,
L. Photocatalytic regio- and stereoselective C(sp3)-H functionalization
of benzylic and allylic hydrocarbons as well as unactivated alkanes.
Nat. Catal. 2019, 2, 1016−1026.
(24) (b) White, A. R.; Wang, L.; Nicewicz, D. A. Synthesis and
Characterization of Acridinium Dyes for Photoredox Catalysis. Synlett
2019, 30, 827−832.
(25) TPI is a strong Brønsted acid with a pKa value of −3.83. See:
Yang, C.; Xue, X.-S.; Li, X.; Cheng, J.-P. Computational Study on the
Acidic Constants of Chiral Brønsted Acids in Dimethyl Sulfoxide. J.
Org. Chem. 2014, 79 (10), 4340−4351.
(26) Industrially produced 2-butene is a mixture of cis- and trans-
isomers. Becasue of their similar boiling points, separation is difficult.
(27) Possible reasons for low diastereoselectivity of 7g, 7m, and 7n
are discussed in the Supporting Information.
(28) For detailed results, see the Supporting Information.
(29) Nakajima, K.; Miyake, Y.; Nishibayashi, Y. Synthetic Utilization
of α-Aminoalkyl Radicals and Related Species in Visible Light
Photoredox Catalysis. Acc. Chem. Res. 2016, 49, 1946−1956.
(30) Desimoni, G.; Faita, G.; Jørgensen, K. A. C2-Symmetric Chiral
Bis(Oxazoline) Ligands in Asymmetric Catalysis. Chem. Rev. 2006,
106, 3561−3651.
(31) Schwarz, J. L.; Huang, H. M.; Paulisch, T. O.; Glorius, F.
Dialkylation of 1,3-Dienes by Dual Photoredox and Chromium
Catalysis. ACS Catal. 2020, 10, 1621−1627.
(32) In general, diastereoselectivity of the catalytic asymmetric
Nozaki-Hiyama-Takai allylations is low to moderate. For representa-
tive examples, see: (a) Inoue, M.; Suzuki, T.; Nakada, M. Asymmetric
Catalysis of Nozaki-Hiyama Allylation and Methallylation with A New
Tridentate Bis(oxazolinyl)carbazole Ligand. J. Am. Chem. Soc. 2003,
125, 1140−1141. (b) McManus, H. A.; Cozzi, P. G.; Guiry, P. J.
Application of Tridentate Bis(oxazoline) Ligands in Catalytic
Asymmetric Nozaki - Hiyama Allylation and Crotylation: An Example
of High Enantioselection with a Non-Symmetric Bis(oxazoline)
Ligand. Adv. Synth. Catal. 2006, 348, 551−558. (c) Xia, G.;
Yamamoto, H. Catalytic Enantioselective Nozaki-Hiyama Allylation
Reaction with Tethered Bis(8-quinolinolato) (TBOx) Chromium
Complex. J. Am. Chem. Soc. 2006, 128, 2554−2555. (d) Miller, J. J.;
Sigman, M. S. Design and Synthesis of Modular Oxazoline Ligands for
the Enantioselective Chromium-Catalyzed Addition of Allyl Bromide
to Ketones. J. Am. Chem. Soc. 2007, 129, 2752−2753. (e) Deng, Q.-
H.; Wadepohl, H.; Gade, L. H. The Synthesis of a New Class of
Chiral Pincer Ligands and Their Applications in Enantioselective
H
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