Urea as a Redox-Active Directing Group under Asymmetric Photocatalysis of Iridium-Chiral Borate Ion Pairs

Article abstract of DOI:10.1021/jacs.0c09468

The development of a photoinduced, highly diastereo- and enantioselective [3 + 2]-cycloaddition of N-cyclopropylurea with α-alkylstyrenes is reported. This asymmetric radical cycloaddition relies on the strategic placement of urea on cyclopropylamine as a redox-active directing group (DG) with anion-binding ability and the use of an ion pair, comprising an iridium polypyridyl complex and a weakly coordinating chiral borate ion, as a photocatalyst. The structure of the anion component of the catalyst governs reactivity, and pertinent structural modification of the borate ion enables high levels of catalytic activity and stereocontrol. This system tolerates a range of α-alkylstyrenes and hence offers rapid access to various aminocyclopentanes with contiguous tertiary and quaternary stereocenters, as the urea DG is readily removable.

Full text of DOI:10.1021/jacs.0c09468

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Urea as a Redox-Active Directing Group under Asymmetric
Photocatalysis of Iridium-Chiral Borate Ion Pairs
Daisuke Uraguchi, Yuto Kimura, Fumito Ueoka, and Takashi Ooi*
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ABSTRACT: The development of a photoinduced, highly diastereo- and enantioselective [3 + 2]-cycloaddition of N-
cyclopropylurea with α-alkylstyrenes is reported. This asymmetric radical cycloaddition relies on the strategic placement of urea on
cyclopropylamine as a redox-active directing group (DG) with anion-binding ability and the use of an ion pair, comprising an iridium
polypyridyl complex and a weakly coordinating chiral borate ion, as a photocatalyst. The structure of the anion component of the
catalyst governs reactivity, and pertinent structural modification of the borate ion enables high levels of catalytic activity and
stereocontrol. This system tolerates a range of α-alkylstyrenes and hence offers rapid access to various aminocyclopentanes with
contiguous tertiary and quaternary stereocenters, as the urea DG is readily removable.
irecting groups (DGs) are commonly polar functional
significant implication for the effectiveness of DGs in
Dgroups situated in the vicinity of the reaction site of the controlling one-electron-mediated processes,2 DGs have
substrate and are expected to participate in attractive or
repulsive nonbonding interactions with reagents or catalysts,
which often plays a pivotal role in accelerating/retarding the
ensuing bond formation, as well as dictating regio- and
stereochemical outcomes.1 The use of DGs is a traditional
strategy, yet among the most reliable for attaining otherwise
difficult reactivity and selectivity in metal-mediated/catalyzed
transformations and other polar reactions to access structurally
and stereochemically defined organic molecules (Figure 1a). In
contrast, the utility of DGs in radical chemistry remains
obscure. In fact, although chiral Lewis- and Brønsted-acid
catalysis in establishing stereoselective radical reactions has
mainly been utilized for the development of transition metal-
catalyzed asymmetric reactions involving radical intermedi-
ates.3,4 In general, the intermolecular forces exploited in DG-
assisted selective two-electron processes are deemed less
effective when employing DGs to guide the reaction pathway
and stereochemistry of highly reactive radical intermediates
because they are apt to spontaneously engage in possible bond-
forming events without assistance (Figure 1b). While this
perception mirrors the stringent difficulty in taming radical
species for target bond construction, particularly in a catalytic
stereoselective manner, we envisioned that the judicious use of
DGs to achieve control over the reactivity and/or selectivity of
radical reactions would provide a powerful means to address
this important and challenging problem.
Considering the difficulty in the precise recognition of
radical species by a chiral catalyst and the behavior of chiral
acid catalysts in the asymmetric radical reactions,2 we sought
to develop a system for the generation of a reactive radical
intermediate in a molecular assembly built through non-
bonding interactions between a chiral catalyst and a substrate
bearing an appropriate DG, anticipating the subsequent bond
formation to occur without destructing this preorganization.
With the advantage of photoinduced generation of radical-ion
species in mind, we conceived a strategic use of DG for
anchoring a photocatalyst (PC) to a substrate prior to electron
transfer (Figure 1c).5 For the pursuit of this possibility, we
regarded widely used cationic iridium (Ir)-polypyridyl
Figure 1. Directing-group (DG) approach for stereoselective
transformation. (a) Schematic illustration of DG-assisted, metal
(M) reagent-mediated ionic reaction. (b) Difficulty in radical reaction.
(c) Working hypothesis of DG strategy in photoredox system with
cationic photocatalyst (PC)-chiral anion ion pair. FG = functional
group to be transformed, Nu = nucleophilic component, SET =
single-electron transfer.
Received: September 9, 2020
https://dx.doi.org/10.1021/jacs.0c09468
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Journal of the American Chemical Society
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Communication
complexes as a suitable class of PCs because of two
considerations: (1) the requisite chiral information can be
introduced into the structure of the pairing anion, which would
not affect the photocatalytic activity of the PC;6 (2) the
installation of DGs with an anion-recognition ability onto the
substrate would ensure its association with the PC. Assuming a
case with an electron-rich substrate embedded with such DG
functionality, we reasoned that capturing the chiral anion
component of the PC by the DG moiety would form a chiral
supramolecular ion pair. Upon light irradiation, single-electron
transfer (SET) from the substrate to the accompanying
excited-state cationic Ir complex could generate the corre-
sponding radical-ion pair with a defined three-dimensional
arrangement. This would enable the resultant radical cation to
undergo ensuing stereoselective bond formation within the
asymmetric environment created by the chiral anion. Herein,
we report the successful operation of this system using urea as
an anion-recognizable, redox active DG, and a cationic Ir
complex-chiral borate ion pair as a PC in achieving an efficient
and highly diastereo- and enantioselective [3 + 2]-cyclo-
addition of cyclopropylamine with alkenes under visible-light
irradiation.
To substantiate our hypothesis, we chose the [3 + 2]-
cycloaddition of cyclopropylamines with alkenes as a model
reaction,7−10 which is initiated by single-electron oxidation of
the amine reactant, primarily because N-carbamoylation of the
amine readily sets the urea functionality that is expected to act
as an oxidizable DG with a distinct anion-binding capability.
Importantly, the affinity of the urea moiety toward an anion
would be increased in the corresponding radical cation
generated via single-electron oxidation by an appropriate PC,
such as an Ir-polypyridyl complex. As an anionic component of
the PC, we employed weakly coordinating chiral borate 111,12
(Table 1 scheme) in anticipation that its negligible
nucleophilicity would be beneficial for the pairing Ir complex
to exert full potential as a PC,13 while its characteristic as a
hydrogen-bond acceptor would allow interaction with the urea
moiety. A preparatory step of the presumed reaction pathway
is the assembly of the photoactive Ir-chiral borate ion pair,
[PC][1], and N-cyclopropylurea derivative 2 into the supra-
molecular ion pair [PC] [1⊂2] (Figure 2). The excitation of
the Ir complex [PC]+ with irradiation of visible light followed
by SET leads to the generation of the radical-ion pair [1⊂2]•
with concomitant release of the reduced, noncharged Ir
complex [PC]. In this assembly, the radical cation derived
from 2 is considered to exist as a formal equilibrium mixture of
N-radical cation and distonic radical cation,14 and the latter
would react with alkene 3. The intermediary alkyl radical
would undergo stereoselective five-exo cyclization under the
guidance of accompanying 1 to afford aminocyclopentane 4 as
a form of N-radical cation pairing with 1. After single-electron
reduction of the N-radical cation by the reduced Ir complex
[PC], the desired product 4 is liberated via the transfer of
chiral anion 1 to 2 to complete the catalytic cycle. An
alternative chain process could also be operative if the N-
radical cation of 4 acts as an oxidant of 2 to directly generate
the key radical-ion pair [1⊂2]• via simultaneous transfer of the
hole and 1, although the same transition-state structure would
be involved in the stereodetermining step.
Figure 2. Proposed catalytic cycle. PC = photocatalyst (chromo-
phore), B* = chiral borate ion 1.
[rac-Ir(dFCF3ppy)2(dtbbpy)][1a] (*Ered = 1.42 V vs SCE)15
(5 mol %) in dichloromethane under irradiation with blue
LEDs (470 nm) at −30 °C. After stirring for 24 h, the desired
[3 + 2]-cycloadduct 4a was isolated in 40% yield as a mixture
of diastereomers (1.6:1), and a certain enantiomeric excess
(ee) was detected (18% ee for the major diastereomer) (Table
1, entry 1). Interestingly, the parallel reaction with [rac-
Ir(dFCF3ppy)2(dtbbpy)][PF6] as the PC under otherwise
similar conditions for obtaining racemic 4a was very sluggish
(<10% yield), suggesting that the property of the anionic
component of the PC is tightly associated with the reaction
efficiency. This observation prompted us to evaluate the
relationship between the anion structure and the catalytic
activity of the iridium-based PC by examining the reaction with
a series of iridium complexes possessing various anions. This
revealed that the reactivity trend was indeed dependent on the
anion characteristics (Table S1). Considering the anion effect
reported for ruthenium-based photocatalysis,13 we assumed
that the observed reactivity difference could be ascribed to the
stabilization of the excited-state iridium complex by the
counterion and thus we measured the fluorescence spectrum
of each iridium complex. However, all the complexes exhibited
essentially identical spectra (Figure S1), unlike the case with
ruthenium complexes. Therefore, we considered the influence
of the ability of the anion to coordinate with the urea on
reactivity and determined the association constants (Ka) of the
anions with 2 by 1H NMR titration experiments (Figure S2).16
By plotting the Ka values against cycloaddition conversion, an
evident correlation was revealed (Figure 3). While the reaction
with the iridium complex bearing a noncoordinating anion
afforded very low conversion, the conversion gradually
increased as the Ka value increased, reaching a maximum
when Ka was approximately 60 M−1, and then declined with
further increases in Ka. Although elucidation of the origin of
this profile should await detailed mechanistic studies, one
possibility is that the equilibrium between the radical cation of
2 and the corresponding distonic radical cation would favor the
The validity of this mechanistic blueprint was initially
assessed by attempting the cycloaddition of 3,5-xylyl cyclo-
propylurea (2) (Eox = 1.37 V vs saturated calomel electrode
(SCE)) and α-methylstyrene (3a) with a catalytic amount of
B
https://dx.doi.org/10.1021/jacs.0c09468
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Table 1. Optimization of Reaction Conditions
b
c
d
entry
Ar
G
1
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
Ph
H
H
H
H
Ph
1a
1b
1c
1d
1e
1f
40
53
41
99
95
99
95
98
1.6:1
2.4:1
2.5:1
7.4:1
6.7:1
9.9:1
12:1
12:1
18
16
32
84
81
90
92
93
4-MeOC6H4
3,5-(MeO)2C6H3
3,5-(nBuO)2C6H3
3,5-(nBuO)2C6H3
3,5-(nBuO)2C6H3
3,5-(nBuO)2C6H3
3,5-(nBuO)2C6H3
2,4,6-Me3C6H2
2,4,6-iPr3C6H2
2,4,6-iPr3C6H2
1g
1g
e
8
a
Unless otherwise noted, the reaction was performed with 2 (0.1 mmol), 3a (0.5 mmol), and [rac-Ir(dFCF3ppy)2(dtbbpy)][1] (5 mol %) in
b
c
CH2Cl2 (0.1 M) for 24 h under blue LEDs (470 nm) irradiation at −30 °C. Isolated yield. The diastereomeric ratio (dr) was determined by 1H
d
e
NMR analysis of the crude aliquot. The enantiomeric excess (ee) of the major diastereomer was determined by chiral HPLC. [Δ-
Ir(dFCF3ppy)2(dtbbpy)]+ was used as a counterion of 1g− instead of the corresponding racemate.
of the PC prompted us to obtain the Ka value of 1d, which was
determined to be 52 M−1, slightly higher than that of 1a, as
expected. To further improve relative and absolute stereo-
control, we continued to modify the borate ion by introducing
aromatic substituents to the 6,6′-position of the binaphthyl
backbone. The installation of sterically demanding 2,4,6-
trimethylphenyl appendages (1f) was particularly beneficial,
compared to that of simple phenyl groups (1e) (entries 5 and
6), and 1g, consisting of a borate ion with 2,4,6-
triisopropylphenyl groups, delivered a critical enhancement
in diastereo- and enantioselectivity without affecting catalytic
activity, enabling the isolation of 4a in 95% yield with a
diastereomeric ratio of 12:1 and 92% ee for the major isomer
Figure 3. Anion effect on the correlation between catalytic efficiency
of [Ir-complex]+ and association constant with 2.
(entry 7). It should be noted that the chirality of the cationic
iridium component played no part in the stereocontrol, as the
respective use of Δ- and Λ-isomers of the iridium complex
gave essentially the same results (entry 8 and Table S2).
Having established the optimal conditions, the scope and
limitation of this protocol were explored with a series of α-
substituted styrenes. With respect to α-methylstyrenes,
incorporation of substituted phenyl groups of different
electronic and steric attributes was generally tolerated (Table
2, entries 1−8). Variation of α-alkyl substituents was also
feasible (3j−m) without detrimental impact on the stereo-
chemical outcome (entries 9−12). Moreover, α-alkylstyrenes
bearing functional groups were amenable to the present
photocatalytic system (entries 13−16). It is noteworthy that
aliphatic conjugated diene 3r was accommodated with a
comparable degree of reactivity and selectivity (entry 17),
while a certain decrease in enantiocontrol was inevitable in the
reaction with simple styrene (3s) (entry 18).
distonic form by stabilization of the iminium ion through the
formation of hydrogen bonds with the anion of PC. In fact,
methylation of one or both of the nitrogen atoms in 2 inhibited
the reaction to a significant extent, supporting the relevance of
hydrogen-bonding interactions between the anion and 2
(Table S2).
With this information in mind, we next pursued the
structural modification of the borate ion of 1, as the
enantioselectivity of the 1a-catalyzed reaction was insufficient.
The strategy entailed the introduction of electron-donating
groups, such as alkoxy groups, to the geminal aromatic
substituents (Ar) with the expectation that it would lead to an
improvement in both catalytic activity and stereoselectivity.
While the effect of attaching 4-methoxyphenyl groups (1b)
was marginal (entry 2), improved enantioselectivity was
attained with 1c having 3,5-dimethoxyphenyl groups (entry
3). Notably, 3,5-bis-n-butoxylphenyl-substituted 1d exerted
significantly higher catalytic activity and stereocontrolling
ability, affording 4a in near quantitative yield with 84% ee
for the major diastereomer (entry 4). This distinct relationship
between the borate-ion structure and the catalytic performance
Finally, we confirmed that the urea DG could be readily
removed using a literature procedure to liberate the primary
amine functionality (Scheme 1).17 Thus, treatment of
cycloadduct 4a (92% ee) with diethylenetriamine at 130 °C
for 19 h furnished aminocyclopentane 5 in 86% yield with
complete preservation of enantiomeric purity (92% ee).18
C
https://dx.doi.org/10.1021/jacs.0c09468
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Table 2. Reaction Scope
AUTHOR INFORMATION
Corresponding Author
■
Takashi Ooi − Institute of Transformative Bio-Molecules (WPI-
ITbM) and Department of Molecular and Macromolecular
Chemistry, Graduate School of Engineering, Nagoya University,
Nagoya 464-8601, Japan; orcid.org/0000-0003-2332-
0472; Email: tooi@chembio.nagoya-u.ac.jp
yield
prod
(4)
b
c
d
Ar1, R
3
(%)
dr
ee (%)
Authors
entry
Daisuke Uraguchi − Department of Molecular and
Macromolecular Chemistry, Graduate School of Engineering,
Nagoya University, Nagoya 464-8601, Japan; orcid.org/
0000-0002-6584-797X
Yuto Kimura − Department of Molecular and Macromolecular
Chemistry, Graduate School of Engineering, Nagoya University,
Nagoya 464-8601, Japan
Fumito Ueoka − Department of Molecular and Macromolecular
Chemistry, Graduate School of Engineering, Nagoya University,
Nagoya 464-8601, Japan
1
2
3
4-BrC6H4, Me
4-FC6H4, Me
4-Me3SiC6H4, Me
4-pinBC6H4, Me
3-BrC6H4, Me
3-MeC6H4, Me
3-MeOC6H4, Me
2-FC6H4, Me
Ph, Et
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
98
99
95
95
94
96
99
98
98
94
96
86
94
95
80
81
96
92
8.4:1
6.7:1
12:1
14:1
16:1
14:1
19:1
>20:1
13:1
11:1
11:1
>20:1
13:1
>20:1
8.3:1
7.5:1
12:1
17:1
94/91
94/90
92
93
93
90
93
93
94
97
90
96
96
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
e
4
5
6
7
8
e
9
10
11
12
13
14
15
16
17
18
Ph, (CH2)5Me
i
Ph, Bu
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c09468
Ph, CH2Ph
Ph, (CH2)3CHCH2
Ph, (CH2)2Cl
Ph, (CH2)2OAc
Ph, (CH2)2CO2Me
2-propenyl, Me
Ph, H
96
Notes
e
88/47
92/48
90
The authors declare no competing financial interest.
e
ACKNOWLEDGMENTS
■
76
Financial support was provided by CREST-JST
(JPMJCR13L2:13418441 to T.O.) and a Grant-in-Aid for
Scientific Research on Innovative Areas “Hybrid Catalysis”
(No. 17H06444 to T.O.), and Grants of JSPS for Scientific
Research. This work was also supported by Program for
Leading Graduate Schools “Integrative Graduate Education
and Research Program in Green Natural Sciences” in Nagoya
University and WISE Program (Doctoral Pro-gram for World-
leading Innovative & Smart Education) “Graduate Program of
Transformative Chem-Bio Research” in Nagoya University.
a
Unless otherwise noted, the reaction was performed with 2 (0.1
mmol), 3 (0.5 mmol), and [rac-Ir(dFCF3ppy)2(dtbbpy)][1g] (5 mol
%) in CH2Cl2 (0.1 M) for 24 h under blue LEDs (470 nm) irradiation
at −30 °C. Isolated yield. dr was determined by H NMR analysis
of the crude aliquot. ee was determined by chiral HPLC. The
reaction was conducted at −20 °C.
b
c
1
d
e
Scheme 1. Removal of DG
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c09468.
Experimental procedures and spectral data (PDF)
Crystal structure of 6 (CIF)
D
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E
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F
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