Tailoring atropisomeric maleimides for stereospecific [2 + 2] photocycloaddition-photochemical and photophysical investigations leading to visible-light photocatalysis

Article abstract of DOI:10.1021/ja5034638

Atropisomeric maleimides were synthesized and employed for stereospecific [2 + 2] photocycloaddition. Efficient reaction was observed under direct irradiation, triplet-sensitized UV irradiation, and non-metal catalyzed visible-light irradiation, leading to two regioisomeric (exo/endo) photoproducts with complete chemoselectivity (exclusive [2 + 2] photoproduct). High enantioselectivity (ee > 98%) and diastereoselectivity (dr > 99:1%) were observed under the employed reaction conditions and were largely dependent on the substituent on the maleimide double bond but minimally affected by the substituents on the alkenyl tether. On the basis of detailed photophysical studies, the triplet energies of the maleimides were estimated. The triplet lifetimes appeared to be relatively short at room temperature as a result of fast [2 + 2] photocycloaddition. For the visible-light mediated reaction, triplet energy transfer occurred with a rate constant close to the diffusion-limited value. The mechanism was established by generation of singlet oxygen from the excited maleimides. The high selectivity in the photoproduct upon reaction from the triplet excited state was rationalized on the basis of conformational factors as well as the type of diradical intermediate that was preferred during the photoreaction.

Full text of DOI:10.1021/ja5034638

Article
pubs.acs.org/JACS
Tailoring Atropisomeric Maleimides for Stereospecific [2 + 2]
PhotocycloadditionPhotochemical and Photophysical
Investigations Leading to Visible-Light Photocatalysis
Elango Kumarasamy,†,§ Ramya Raghunathan,†,§ Steffen Jockusch,‡ Angel Ugrinov,† and J. Sivaguru*,†
†Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58108, United States
‡Department of Chemistry, Columbia University, New York, New York 10027, United States
S
* Supporting Information
ABSTRACT: Atropisomeric maleimides were synthesized
and employed for stereospecific [2 + 2] photocycloaddition.
Efficient reaction was observed under direct irradiation, triplet-
sensitized UV irradiation, and non-metal catalyzed visible-light
irradiation, leading to two regioisomeric (exo/endo) photo-
products with complete chemoselectivity (exclusive [2 + 2]
photoproduct). High enantioselectivity (ee > 98%) and
diastereoselectivity (dr > 99:1%) were observed under the
employed reaction conditions and were largely dependent on
the substituent on the maleimide double bond but minimally
affected by the substituents on the alkenyl tether. On the basis
of detailed photophysical studies, the triplet energies of the maleimides were estimated. The triplet lifetimes appeared to be
relatively short at room temperature as a result of fast [2 + 2] photocycloaddition. For the visible-light mediated reaction, triplet
energy transfer occurred with a rate constant close to the diffusion-limited value. The mechanism was established by generation
of singlet oxygen from the excited maleimides. The high selectivity in the photoproduct upon reaction from the triplet excited
state was rationalized on the basis of conformational factors as well as the type of diradical intermediate that was preferred during
the photoreaction.
have successfully demonstrated the efficacy of this strategy in
various photochemical transformations,6 including 6π photo-
cyclization,6a,b 4π photocyclization,6c,d [2 + 2] photocycloaddi-
INTRODUCTION
■
The importance of synthesizing optically pure molecules has
placed asymmetric organic synthesis among the most explored
areas in chemistry.1 However, the absence of a single universal
method to access desired chiral scaffold(s) has forced chemists
to develop strategies that are both elegant and effective. In the
gamut of methodologies developed in organic synthesis,
asymmetric photochemical transformations2 hold a unique
place as they can provide access to molecules with unique
stereochemical and structural complexity, thus serving as a
complementary avenue to thermal transformations.3 Photo-
transformations are inherently fast processes that present
challenges to manipulate the excited-state reactivity and
product stereochemistry in the desired reaction. Recent
advances such as photoreactions in confined media, photo-
reactions controlled by supramolecular templates, and solid-
state photoreactions have addressed this bottleneck to some
extent and have led to improvements in the control of product
selectivity.4 In spite of the improvement obtained by employing
organized assemblies, achieving stereoselectivity in photo-
reactions that occur in solution has presented formidable
challenges. In that regard, we have embraced a strategy that
employs atropisomeric compounds,5 where axial chirality in the
reactant is transferred to point chirality in the product upon
excitation in the desired photochemical transformation.6 We
tion,6e Norrish−Yang cyclization,6f,g and Paterno
̀
−Buchi
̈
reactions.6h To broaden the scope of this strategy to access
chirally enriched photoproducts, we looked at [2 + 2]
photocycloaddition of atropisomeric maleimides. In this report,
we disclose our results on the stereospecific [2 + 2]
photocycloaddition of atropisomeric maleimides (Scheme 1)
that can be performed by visible-light meditated energy
transfer, in which we were able to achieve high enantiose-
Scheme 1. Intramolecular [2 + 2] Photocycloaddition of
Atropisomeric Maleimides 1
Received: April 7, 2014
© XXXX American Chemical Society
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lectivity (ee > 98%), diastereoselectivity (exo/endo selectivity),
and chemoselectivity ([2 + 2] vs [5 + 2] cycloaddition) in the
product by appropriate substitution on the atropisomeric
maleimides.
Scheme 3. Synthesis of Maleimides 1g−k, 1p, and 1q
Maleimides display rich and versatile chemistry in both the
ground state (thermal reactions) and the excited state
(photochemical reactions). [2 + 2], [4 + 2], and [5 + 2]
cycloadditions are a few of the reactions that are initiated by
photons.7 Depending on the substrate, type of irradiation
(sensitized vs direct irradiation), and wavelength, one can
switch from one product to another.7c,8 Booker-Milburn and
others have extensively investigated [2 + 2] and [5 + 2]
photocycloadditions of maleimides to access certain complex
organic scaffolds with multiple stereogenic centers.7c,9 They
have also elegantly demonstrated the possibility of large-scale
synthesis by merging photoreactions with a flow setup and
extending this technique to natural product synthesis.10
However, stereoselective photoreactions of maleimides have
been only scarcely investigated. We felt that incorporating our
methodology of axial-to-point chiral transfer in maleimides
would enable us to perform stereospecific photocycloaddition
reactions and further increase the scope and versatility of the
maleimides.
One of the characteristic features of atropisomeric com-
pounds (compounds whose chirality originates from restricted
rotation around a single bond) is their tendency to racemize at
elevated temperature. Such racemization erodes the absolute
configuration, resulting in poor selectivity in the desired
stereospecific transformations. On the basis of computational
analysis, it was reasoned that N-phenylmaleimides prefer a
twisted orientation with respect to the N−C(aryl) axis to avoid
steric crowding between the imide carbonyls and the ortho
hydrogens of the aryl group.13 Additionally, suitable sub-
stitutions at the ortho positions (i.e., the 2- and 6-positions) of
the N-phenyl ring should result in atropisomeric maleimides
with a stable chiral axis that would enable us to transfer/trap
the axial chirality in the reactant to point chirality in the
photoproduct.11,14 In this regard, the methyl group at the 6-
position of the N-phenyl ring in newly synthesized maleimides
1 was crucial in providing stable atropisomers by increasing the
energy barrier for the N−C(aryl) bond rotation. Maleimides
lacking the Me group at the 6-position (analogues of
maleimides 1a, 1g, and 1j) were not axially chiral at room
temperature.14a Analysis of the kinetic parameters for the newly
synthesized atropisomeric maleimides 1a−c and 1g provided
insights into the energy barrier to rotation around the N−
C(aryl) chiral axis (Table 1). For example, in the case of 1a
RESULTS AND DISCUSSION
■
Atropisomeric maleimides11 with varying substitution patterns
were synthesized to evaluate how substituent(s) on (a) the
maleimide ring (R1 = alkyl, aryl, halogen), (b) the N-aryl ring
(X = CH2, O, O2SiPh2), and (c) the alkenyl tether (R2, R3, R4 =
H or alkyl) influence the [2 + 2] photocycloaddition. Most of
the maleimides were synthesized using one of the two methods
shown in Schemes 2 and 3. For example, maleimides 1a−e and
1n (R1 = Me) were easily obtained by the reaction of 2-amino-
3-methylphenol (4) with citraconic anhydride (5a) followed by
allylation in the presence of a base (Scheme 2). However,
Scheme 2. Synthesis of Maleimides 1a−e and 1n
Table 1. Racemization Kinetics of Optically Pure
Atropisomeric Maleimides 1 in Toluene at 100 °C
a
entry
compd
krac (s−1
)
τ1/2 (days)
ΔG⧧rac (kcal mol−1
)
1
2
3
4
1a
1b
1c
1g
2.27 × 10−6
2.22 × 10−6
2.33 × 10−6
2.40 × 10−6
3.5
3.6
3.5
3.4
31.6
31.7
31.6
31.6
a
The racemization kinetics was followed by HPLC analysis on a chiral
stationary phase. Values carry an error of 5%.12
maleimide derivatives 1g−k, 1p, and 1q with bromo or phenyl
substituents (R1 = Ph, Br) underwent decomposition by this
approach, so these compounds were accessed starting from
allylated aniline derivatives 7a−d (Scheme 3). The yields of
these methods were generally good for two-step reactions.12
(Table 1, entry 1), the half-life for racemization (τ1/2) was 3.5
days at 100 °C, corresponding to a racemization rate constant
(krac) of 2.27 × 10−6 s−1 and an activation energy barrier
(ΔG⧧rac) of ∼31.6 kcal mol−1. The racemization energy barrier
was not affected significantly by variation of the R1 substituent
on the maleimide double bond or the substituent on the alkenyl
tether with 1a-c and 1g (Table 1; entries 1−4) having similar
energy barriers for racemization. Inspection of Table 1 suggests
that the newly synthesized atropisomeric maleimides have fairly
high energy barriers and can be employed effectively for
1
The atropisomeric maleimides were then characterized by H
and 13C NMR spectroscopy, high-resolution mass spectrometry
(HRMS), circular dichroism, and specific rotation values.12 The
optically pure isomers of the atropisomeric maleimides for the
study were easily secured through preparative separations on a
chiral stationary phase using HPLC and usually had >98%
enantiomeric purity.12
B
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photoreactions at ambient temperature without the loss of
absolute configuration.
Table 3. Solvent Screening Studies under Triplet-Sensitized
Irradiation of 1a
a
The [2 + 2] photocycloadditions of the atropisomeric
maleimides were carried out under different irradiation
conditions and proceeded smoothly in excellent isolated yields
and mass balance (Tables 2−4). Three different sets of
irradiation conditions were examined: (a) direct irradiation; (b)
sensitized irradiation under UV light (e.g., using xanthone as a
sensitizer); and (c) sensitization under metal-free visible-light
irradiation (e.g., using thioxanthone as a sensitizer). After the
photoreaction, the solvent was removed under reduced
pressure, and the product(s) were purified by column
chromatography. The HPLC, NMR, and X-ray diffraction
(XRD) analyses revealed that the major photoproduct was the
exo-photoadduct 2 (where exo indicates that the terminal
carbon of the alkene tether is oriented away from the carbon
bearing the R1 substituent of the maleimide) and the minor
photoproduct was endo-photoadduct 3 (where endo indicates
that the terminal carbon of the alkene tether is oriented toward
the carbon bearing the R1 substituent of the maleimide). We
employed 1a as a model system to optimize the irradiation
conditions (Tables 2 and 3). Direct irradiation of 1a in
acetonitrile gave a 2:3 diastereomeric ratio (dr) of 79:21 (Table
2, entries 1−3). The dr was unaffected but the conversion was
% conversion (% mass balance)
entry
solvent
xanthone
thioxanthone
1
2
3
4
5
6
7
8
methanol
MeCN
>98 (>98)
>98 (>98)
>98 (95)
>98 (>98)
>98 (>98)
83 (>98)
−
ethyl acetate
THF
b
−
chloroform
CH2Cl2
benzene
MCH
>98 (81)
>98 (>98)
44 (78)
>98 (>98)
>98 (>98)
73 (>98)
26 (>98)
27 (>98)
a
[1a] ≈ 3.9 mM; wavelengths of ∼350 and ∼420 nm were used for
xanthone- and thioxanthone-sensitized irradiation in a Rayonet reactor
at room temperature. Conversion and mass balance were determined
by 1H NMR spectroscopy using triphenylmethane as an internal
b
standard ( 5% error). The product decomposed after sensitized
irradiation with xanthone.
The irradiation conditions for maleimides 1a−n were
carefully chosen after several optimization studies to obtain
the best results.12 For example, irradiation in acetone was very
efficient for all of the maleimides except 1g, 1j, and 1m, which
partially decomposed,15 resulting in significantly lower isolated
yields. To overcome this decomposition, we employed
xanthone and thioxanthone as sensitizers in MeCN, which
resulted in very high isolated yields. This set of conditions also
worked with equal efficiency for other maleimides as well,
enabling us to develop visible-light mediated photocatalytic
conditions for our transformations. The reaction optimization
was done to minimize the established [5 + 2] photo-
cycloaddition that typically competes with the [2 + 2]
dimerization reaction.16 Under our reaction conditions (direct
or triplet-sensitized irradiation), we did not observe photo-
products corresponding to [5 + 2] cycloaddition. We believe
that the observed chemoselectivity ([5 + 2] vs [2 + 2]) was a
reflection of the molecular constraints that enforced reactivity
between the maleimide double bond and the alkenyl tether.
The reaction efficiency/conversion was higher under triplet
sensitization, as the reaction proceeded to complete conversion
in 1−2 h while 8−12 h was required for direct irradiation, with
no appreciable change in the observed selectivities (ee and dr
values) in the photoproduct.
a
Table 2. Direct and Sensitized Irradiation of 1a
entry
irradiation conditions
solvent
2:3 (% conv.)
1
2
3
4
5
6
7
bb/Pyrex cutoff, 12 h
∼300 nm, N2, 6 h
∼300 nm, O2, 6 h
∼300 nm, −30 °C, 12 h
bb/Pyrex cutoff, N2, 1.5 h
∼350 nm, xanthone, 1 h
∼420 nm, thioxanthone, 1 h
MeCN
MeCN
MeCN
MeCN
79:21 (>98)
79:21 (93)
79:21 (88)
79:21 (31)
b
c
acetone
MeCN
MeCN
79:21 (84 )
79:21 (>98)
79:21 (>98)
a
Irradiation was performed at room temperature, unless otherwise
1
noted. Values are based on H NMR spectroscopy ( 5% error). [1a]
≈ 3.9 mM. bb/Pyrex cutoff = broadband irradiation performed using a
450 W mercury lamp with a Pyrex cutoff filter (<295 nm cutoff); ∼300
nm, ∼350 nm, and ∼420 nm irradiations were carried out in a Rayonet
reactor. Acetone was used as the solvent and sensitizer. Isolated
yield.
b
c
affected by a decrease in temperature (Table 2, entry 4). In
addition, the efficiency of the reaction and the dr were similar
under oxygen- and nitrogen-saturated atmospheres (Table 2;
compare entries 2 and 3). When the solvent was changed to
acetone, which acted both as a solvent and a triplet sensitizer,
the reaction efficiency was significantly improved, and the
reaction required a shorter irradiation time (Table 2, entry 5)
and afforded an excellent isolated yield of the photoproducts.
The reaction was equally efficient when the triplet sensitizer
was changed to xanthone (∼350 nm irradiation) or
thioxanthone (∼420 nm irradiation). There was no change in
the dr when the irradiation conditions were changed from
direct irradiation to triplet sensitization. To study the effect of
solvent on the reaction, we employed different solvents for
xanthone and thioxanthone sensitization (Table 3). Excellent
mass balance and very high to moderate conversions were
observed for all of the solvents except tetrahydrofuran (THF),
in which decomposition was observed. The conversion was
slightly lower in benzene and in methylcyclohexane (MCH).
Investigation of Table 4 reveals several interesting features of
the [2 + 2] photocycloaddition reaction of atropisomeric
maleimides. The enantioselectivities of all the atropisomeric
maleimides investigated were >98% (Table 4, 1a−d and 1g).
This was due to the high energy barrier to rotation around the
N−C(aryl) chiral axis (Table 1), which prevented racemization
during the photoreaction and enabled efficient axial-to-point
chirality transfer, leading to excellent enantiomeric excess in the
photoproduct(s). Satisfied with the excellent enantiocontrol in
the [2 + 2] photocycloaddition reaction, we screened several
atropisomeric maleimides to analyze the exo/endo ratio (i.e., the
dr) in the resulting photoproducts. To understand the origin of
the diastereoselectivity between 2 and 3, we systematically
varied the R1 substituent on the maleimide double bond, the
R2−R4 substituents on the alkenyl tether, and the X group that
links the alkenyl tether to the N-aryl ring. The X group had very
little influence over the dr (Table 4; compare 1a with 1i and 1h
with 1k). Even a longer alkenyl tether as in the case of 1f did
not result in better dr (Table 4, entry 6). This was a slight
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a b
,
Table 4. Intramolecular [2 + 2] Photocycloaddition of Atropisomeric Maleimides
a
Irradiation of 1b was performed with 30 mol % xanthone as the triplet sensitizer in acetonitrile solvent at room temperature using a Rayonet reactor
equipped with 300 nm lamps. Irradiations of 1g, 1j, and 1m were performed with 30 mol % thioxanthone as the triplet sensitizer in acetonitrile
solvent at room temperature using a Rayonet reactor equipped with 420 nm lamps. For all other substrates, the photoreactions were performed in
b
acetone at room temperature using a 450 W medium-pressure Hg lamp with a Pyrex cutoff filter. The ee values were obtained from HPLC analysis
on a chiral stationary phase, and the results are averages of three runs with an error of 3%. The absolute configuration was determined by XRD with
c
d
Flack parameters. The ratios were determined by 1H NMR spectroscopy of the crude samples. A and B refer to the order of HPLC elution for a
e
1
given pair of enantiomers. Yield based on H NMR spectroscopy using triphenylmethane as an internal standard.
D
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disappointment in our case, as the silyl tether was established to
have control over the diastereoselectivity during photo-
cycloaddition.17 However, to our delight, when phenyl
derivatives 1g (X = O) and 1j (X = CH2) and imidazole
derivative 1m were subjected to [2 + 2] photocycloaddition,
complete control of the dr was observed, and the exo
photocycloadduct 2 was obtained as the sole product (Table
4, entries 7, 10, and 13). In the case of 1g (Table 4, entry 7), in
addition to the excellent diastereomeric ratio (dr > 99:1),
excellent enantiomeric excess (ee > 98%) and isolated yield
(90%) of the exo photoproduct 2 were observed during the [2
+ 2] photocycloaddition. These results allowed us to believe
that the substituent at the maleimide double bond (the R1
substituent) plays a more significant role in controlling the dr in
the photoproducts than the X group in the alkenyl tether. For
example, in the reactions of 1a, 1g, 1h, and 1m with varying R1
substitution (Table 4, entries 1, 7, 8, and 13), the dr varied
significantly: 69:31 for substrate 1h with R1 = Br (entry 8);
79:21 for substrate 1a with R1 = Me (entry 1); and >99:1 for
substrates 1g and 1m with phenyl and imidazole substituents,
respectively (entries 7 and 13). Surprisingly, disubstitution at
the maleimide double bond as in 1l gave a dr of 42:58 favoring
the endo product 3l in 94% isolated yield (Table 4, entry 12).
Having ascertained the role of the R1 and X substituents during
intramolecular [2 + 2] photocycloaddition in maleimides, we
then turned our attention to substituents on the alkene portion
of the tether (R2−R4) to understand the scope and limitations
of our substrates. We designed four different substrates 1b−e
and compared the dr values to gain insights into the role of the
alkene geometry during the [2 + 2] photocycloaddition.
Comparison of the exo/endo ratios from the [2 + 2]
photocycloaddition of 1a and 1b revealed that gem-dimethyl
substitution at the terminal alkene carbon atom did not alter
the dr value (2:3 = 79:21 in both cases; Table 4, entries 1 and
2). On the other hand, monomethyl substitution on the
terminal carbon of the alkene resulted in a slight increase in the
dr value from 79:21 for 1a to 87:13 for 1c and 84:16 for 1d
(Table 4; compare entries 1, 3 and 4). Internal substitution on
the alkene double bond as in substrate 1e resulted in a lower dr
value (2:3 = 62:38) compared with 1a (Table 4; compare
entries 1 and 5). Interestingly, changing the reaction partner
from alkene to alkyne in the case of maleimide 1n did not yield
the desired cyclobutene photoproducts,17 although complete
consumption of the starting material was observed. Careful
analysis of the products by HRMS and 1H NMR studies
revealed that dimeric products were formed along with
significant decomposition. Placement of oxygen on the alkenyl
tether in the maleimide allowed us to cleave the tether after the
photoreaction. The ether cleavage of the photoproducts
proceeded smoothly with BBr3 or 1:1 v/v concd. HCl/TFA
(Scheme 4) to yield the corresponding N-arylphenols in
isolated yields of 62−70%. However, to our disappointment the
imide cleavage proved to be rather difficult under different
conditions.12
Detailed photophysical investigations were carried out in
order to gain more insight into the excited state(s) of the
maleimides and the mode of reactivity involving sensitized
visible-light irradiation.13,18 Fluorescence and phosphorescence
measurements on maleimides were futile as the newly
synthesized atropisomeric maleimides were poor luminophores.
Even at 77 K the luminescence of the atropisomeric maleimides
was negligible, indicating very fast decay of the excited state.
Considering the reactivity of the maleimides, we designed
maleimides 10 and 11 with a saturated alkenyl tether so that we
could overcome the fast excited-state reactivity/deactivation
and decipher the excited-state behavior/spin state involved
using laser flash photolysis experiments (Figures 1−3).12
Laser excitation (λex = 355 nm, pulse width = 7 ns) of an
argon-saturated solution of 10 in acetonitrile generated a
transient absorption spectrum (Figure 1A, red). The transient
Figure 1. (A) Transient absorption spectrum monitored 0−3 μs after
pulsed laser excitation (355 nm, 7 ns pulse length) of an argon-
saturated MeCN solution of 10. (B) Absorbance kinetic traces
(monitored at 410 nm) for argon-saturated MeCN solutions of 10
(red) and 1g (green) with matching absorbance of 0.3 at 355 nm.
absorption centered around 400 nm decayed with a lifetime of
50 μs, was quenched by molecular oxygen (kq = 2 × 109 M−1
s−1), and was assigned to the triplet−triplet absorption of the
maleimide chromophore. The triplet transient of 10 was further
confirmed by triplet energy transfer from excited thioxanthone
(TX).
The initial triplet absorption of TX at 620 nm (Figure 2A,
3
blue spectrum) was quenched by 10 to generate 10* (Figure
2A, red spectrum) at later times. Having ascertained the triplet
transient of maleimide 10, we were able to investigate the
triplet quantum yield by monitoring the efficiency of singlet
oxygen generation in aerated CCl4 solution (Figure 3). With
phenalenone as the reference (ΦΔ = 0.98),19 the relative
quantum yield for the generation of singlet oxygen from 10
upon pulsed laser irradiation was ascertained to be ΦΔ ≈ 0.04.
This clearly established that the maleimides we investigated
have a very poor intersystem crossing quantum yield and
generate very low amounts of the triplet upon direct excitation.
Comparison of the triplet−triplet absorbance at 410 nm
upon laser excitation at 355 nm for 10 (maleimide with a
saturated alkyl tether) and 1g (the corresponding maleimide
with an alkenyl tether) under identical conditions showed only
3
3
negligible amounts of detectable 1g* compared with 10*
(Figure 1B). The absence of detectable 31g* is likely due to the
reactivity of the alkene double bond in 1g, resulting in
deactivation of the triplet state by the [2 + 2] photo-
cycloaddition reaction. While maleimides reacted efficiently
from the triplet excited state, as evidenced by the weak
transient absorbance of 1g, the generation of the triplet species
by direct irradiation was inefficient, as ascertained by the low
quantum yield of singlet oxygen generation from 10, indicating
Scheme 4. Cleavage of Photoproduct 2b
E
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absorbance intensity at 620 nm and the increase in the
absorbance intensity centered around 410 nm (Figure 2B,
green). This was again reflected in the absorbance kinetic
profile monitored at 410 nm. On the basis of the decay of 31g*,
the triplet lifetime in argon-saturated acetonitrile was
established to be 450 ns (Figure 2C) using laser excitation
(λex = 355 nm) of TX in a short optical path length of 2 mm
with the front-face optical geometry.12 Comparison of the
triplet lifetimes of 1g (τT = 450 ns) and 10 (τT = 50 μs)
showed that the alkenyl functionality in 1g deactivated the
excited triplet state of the maleimide, presumably by under-
going [2 + 2] photocycloaddition efficiently.
Bimolecular rate constants for quenching of the sensitizer’s
triplet states by maleimides (kq) were determined by laser flash
photolysis (see the Supporting Information), and the results are
summarized in Table 5. Inspection of Table 5 reveals that
Figure 2. (A) Transient absorption spectra monitored at 0−0.8 μs
(blue) and 10−20 μs (red) after pulsed laser excitation (355 nm, 7 ns
pulse length) of argon-saturated MeCN solutions of TX and 10 (0.05
mM). (B) Absorbance kinetic traces (monitored at 410 nm) for argon-
saturated MeCN solutions of TX containing 0.1 mM 10 (red) or 1g
(green). (C) Absorbance kinetic traces monitored at 620 nm (blue)
and 410 nm (green) after pulsed laser excitation using the front-face
geometry and a 2 mm optical path length.
Table 5. Bimolecular Rate Constants for Quenching of
Excited Triplet States of Sensitizers by Maleimides (kq)
a
entry
triplet sensitizer
maleimide
kq (M−1 s−1
)
1
2
3
4
5
6
7
8
thioxanthone
thioxanthone
thioxanthone
xanthone
1a
1i
(3.6 0.1) × 109
(3.5 0.1) × 109
(3.5 0.1) × 109
(6.3 0.1) × 109
(8.3 0.4) × 109
(8.2 0.3) × 109
(7.9 0.4) × 109
(7.6 0.2) × 109
11
11
1g
1j
thioxanthone
thioxanthone
thioxanthone
xanthone
10
10
a
Determined by laser excitation (λex = 355 nm) of thioxanthone or
xanthone (absorbance at 355 nm = 0.3) in the presence of varying
concentrations of maleimides in argon-saturated MeCN. For details,
see the Supporting Information.12
triplet excited states of xanthone and thioxanthone are
efficiently quenched by maleimides with very high quenching
rate constants that are close to the diffusion-limited values. The
distinct quenching rate constants observed for maleimides 10
(R1 = Ph) and 11 (R1 = Me) toward xanthone and
thioxanthone likely reflect the efficiencies of energy transfer
from the excited sensitizers to the maleimides. For example, the
triplet excited states of xanthone and thioxanthone were
efficiently quenched by 10 with roughly the same rate constant
(Table 5, entries 7 and 8). On the other hand, the rate constant
for quenching of triplet-excited thioxanthone by 11 [kq = (3.5
0.1) × 109 M−1 s−1; Table 5, entry 3] was almost half of the
rate constant for quenching of triplet-excited xanthone [kq =
(6.3 0.1) × 109 M−1 s−1; Table 5, entry 4]. This decrease in
the quenching rate constant reflects similar triplet energies for
thioxanthone and methyl-substituted maleimides (∼63 kcal/
mol). On the other hand, phenyl-substituted maleimides
quenched the triplet states of both xanthone and thioxanthone
efficiently because their triplet energies are likely well below the
triplet energy of thioxanthone as a result of the extended
conjugation of the maleimide chromophores with the phenyl
ring.
Figure 3. (A) Singlet oxygen phosphorescence decay traces
(monitored at 1270 nm) generated by pulsed laser excitation (355
nm, 7 ns pulse length) of air-saturated CCl4 solutions of 10 (red) and
phenalenone (black) with matching absorbance of 0.3 at 355 nm. (B)
Normalized singlet oxygen phosphorescence spectrum generated by
steady-state irradiation of 10 at 355 nm in air-saturated CCl4 solution.
a very low efficiency of intersystem crossing from the singlet
excited state to the triplet excited state of the maleimides
(Figure 3). To improve the efficiency for generation of the
triplet excited state, different sensitizers were employed to
promote the chemical transformation. Considering the
experimental aspects and the viability of using visible-light
irradiation, we selected thioxanthone as the triplet sensitizer
because its photophysical characteristics are well-established.
Laser excitation (λex = 355 nm) of TX in the presence of
maleimide 10 in argon-saturated acetonitrile solution gave the
3
corresponding triplet species 10*, as ascertained by the decay
of the absorbance at 620 nm (corresponding to 3TX*) and the
rise in the absorbance centered around 400 nm (corresponding
to 310*) (Figure 2B, red). Similarly, laser excitation (λex = 355
nm) of TX in the presence of 1g (the parent maleimide with
the alkenyl double bond) in argon-saturated acetonitrile
On the basis of our photophysical investigations, we believe
that the intramolecular [2 + 2] photocycloaddition of
maleimides 1a−m occurs via a triplet pathway. Mechanistically,
the exo/endo photoproduct selectivity and the stereospecific
chiral transfer need to be addressed. The electron-rich nature of
the alkene tether likely triggers the photocyclization by the
interaction with the half-filled π orbital of the ππ* excited state
3
solution produced the corresponding triplet transient 1g*. In
3
the presence of 1g, TX* acted as a triplet-excited-state donor
and 1g acted as an acceptor, as reflected in the decrease in the
F
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Journal of the American Chemical Society
Article
of the maleimide.20 We will first address the mechanistic
aspects of triplet-sensitized reactions then discuss the
mechanism of direct irradiation. We conjecture that the
triplet-sensitized reaction (with UV or visible light) proceeds
by a two-step process (Scheme 5) from the triplet excited state:
a
Scheme 6. Scrambling Studies with Maleimides 1c and 1d
Scheme 5. Mechanistic Rationale for [2 + 2]
Photocycloaddition of Atropisomeric Maleimides 1
a
For clarity, the endo photocycloadduct 3 has been omitted from the
scheme.
alkene geometry indicates that during the formation of
photoproduct 2 the 1,4-diradical DR1 is likely preferred over
DR2. In the second scenario, if indeed DR2 is formed during
the reaction, the lack of scrambling indicates that the cyclization
occurs at a higher rate, so that the relative orientation of the
substituents is maintained in the photoproduct in order for the
reaction to maintain stereospecificity as observed. As the
sensitized reaction occurs from the triplet state, the two
diradicals DR1 and DR2 will be in the triplet manifold. For the
cyclization step, this triplet 1,4-diradical has to undergo
intersystem crossing to the corresponding singlet diradical so
that it can recombine to form the exo product. Because of this
spin-restricted recombination, it is likely that DR2 is not
preferred, as it would have sufficient time to scramble the
alkene geometry, which would be reflected in the product
distribution. In other words, the formation of the exo product 2
could be rationalized on the basis of the formation of DR1 as
the likely 1,4-diradical intermediate. While this is not direct
evidence that conclusively rules out the formation of DR2, the
absence of scrambling products suggests that the formation of
DR1 may be the likely pathway, as the molecular restriction will
not scramble the relative orientation of the substituents on the
alkenyl tether. Similar arguments may be extended to the
formation of endo product 3, where the preferential formation
of DR3 over DR4 (Scheme 6) could be rationalized for the
observed lack of scrambling in substrates 1c and 1d.
Having hypothesized the likely mechanistic rationale for
triplet-sensitized irradiations, we turned our attention to direct
irradiations, which gave the same selectivity in the photo-
product (ee and dr values) as the triplet-sensitized reactions,
albeit with longer irradiation times. It is well-established in the
literature that upon direct irradiation N-alkylmaleimides
undergo [5 + 2] photocycloaddition from the singlet excited
state.8 In the case of atropisomeric maleimides 1, direct
irradiation resulted exclusively in [2 + 2] photocycloaddition.
The results could be a manifestation of two different scenarios:
(a) direct irradiation results in the triplet excited state as a
result of fast intersystem crossing from the excited singlet state
or (b) atropisomeric maleimides react from the singlet excited
state to give the same photoproduct. To decipher this, we
designed o-allyl-substituted maleimide 12 (Scheme 7), which
upon photoexcitation gave [5 + 2] cycloaddition products 13
and 14 exclusively, while the corresponding butenyl analogue 1i
(with an additional CH2) as well as the O-allyl derivative 1a
gave the [2 + 2] photoadduct exclusively (Table 2, entries 1
and 9). This clearly indicated that the chemoselectivity in
maleimides 1 is dictated by the length of the alkenyl chain at
the ortho position. Additionally our photophysical studies
revealed a very low intersystem crossing efficiency for the
the first step is the formation of the triplet 1,4-diradical (labeled
as DR1−DR4), and the second step is the cyclization, in which
the triplet 1,4-diradical undergoes intersystem crossing to the
corresponding singlet 1,4-diradical, which recombines to form
the cyclobutane photoproduct 2 or 3. While this general
mechanism is applicable to the formation of the photoproduct,
the type of diradical that is preferred would dictate the exo/endo
photoproduct selectivity (Scheme 5). To appreciate this aspect,
one has to determine the carbon atoms involved in the initial
bond-forming step. In the present case, the exo photoproduct 2
could be rationalized on the basis of the conformation “1-
conf(A)” in which the terminal CH2 in the alkenyl side chain is
oriented away from the maleimide R1 substituent, leading to
diradical intermediate DR1 or DR2 depending on the initial
bond formation between the alkene units. Similarly, formation
of the endo photoproduct 3 could be rationalized on the basis of
the conformation “1-conf(B)” in which the terminal CH2 in the
alkenyl side chain is oriented toward the maleimide R1
substituent, leading to diradical intermediate DR3 or DR4
depending on the initial bond formation between the alkene
units.
To understand the initial bond-forming step, we performed
scrambling studies on atropisomeric maleimides 1c and 1d that
are monosubstituted at the terminal carbon (Scheme 6). For
simplicity, we will rationalize our observations for the exo
photoproduct 2, as one can extend similar arguments for the
formation of the endo product 3. For both monosubstituted
maleimides, we did not observe any scrambling of the alkene
geometry in the photoproduct (Scheme 6). For example, in the
case of 1c we observed the exclusive formation of 2c as the
major product, with only a trace amount of 2d.21 Scrambling
studies on 1d also displayed similar preferential formation of 2d
(Scheme 6). This could be explained by only two plausible
scenarios. In the first scenario, the lack of scrambling in the
G
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appealing, as the reaction would be redox-neutral and metal-
free. We were also successful in merging visible-light
photolysis22 with a flow setup, as it increased the efficiency
and scalability of the photoreaction relative to conventional
batch mode.10b,23 With the simplest setup available at our
disposal, we built a custom flow setup, optimized the
conditions, and subjected maleimides 1a and 1g to visible-
light photoreaction using a 40 W compact fluorescent lamp
(CFL) as the light source.12 Complete conversion of maleimide
1a was achieved (3.9 mM with 10 mol % sensitizer and a flow
rate of 0.83 mL/min) within 35 min of irradiation, while the
batch mode for the similar scale gave 23% conversion in 35
min. Similarly, complete conversion of 1g was achieved (1.9
mM with 20 mol % sensitizer and a flow rate of 0.45 mL/min)
in less than 60 min (18% conversion for batch mode). These
results clearly illustrated the efficiency of [2 + 2] photo-
reactions of maleimides even under visible-light conditions.
Scheme 7. Alkenyl Chain Length-Dependent
Chemoselectivity in Atropisomeric Maleimides
maleimides (Figure 3). These observations point to the likely
involvement of a singlet excited state upon direct irradiation of
the maleimides (with the maleimide chromophore absorbing
light), with the reaction occurring in a concerted fashion
leading to the [2 + 2] photocyclization.20 The involvement of
the singlet excited state upon direct irradiation is further
reflected in the similar conversions observed under N2- and O2-
saturated atmospheres. In addition, the involvement of the
singlet excited state has literature precedent, as intramolecular
photodimerization of maleimides was postulated to occur from
the singlet excited state through exciplex formation.16 We
believe that upon direct excitation, a similar scenario is
manifested in our system, leading to the photoproduct. As it
involves a concerted mechanism, the bond formation is once
again likely dictated by the conformational preference as well as
the electron density of the interacting orbitals. As the alkene
tether is electron-rich (as a result of alkyl substitution), the
concerted cyclization is likely triggered by the interaction of the
half-filled π orbital of the ππ* excited state of the maleimide
with the π orbital of the terminal alkene.20 This π(maleimide)
← π(alkene) interaction is dictated by the R1 substituent and is
manifested in the exo/endo selectivity.
Thus, unlike N-alkenylmaleimides, which react differently
from the singlet and triplet excited states leading to [5 + 2] and
[2 + 2] cycloadditions, respectively,8 atropisomeric maleimides
with N-aryl substitution with an alkenyl tether at the ortho
position exclusively undergo [2 + 2] photocycloaddition. We
believe this chemoselectivity is a direct manifestation of
molecular restraints placed on the reacting double bonds by
the high barrier for N−C(aryl) bond rotation.
Our photophysical studies clearly established thioxanthone as
an effective triplet sensitizer, which prompted us to evaluate
visible-light irradiation conditions for [2 + 2] photocycloaddi-
tion of maleimides (Scheme 8). Such an attempt seemed very
CONCLUSION
■
Our present study demonstrates the efficient stereospecific [2 +
2] photocycloaddition of atropisomeric maleimides with
excellent stereocontrol in the photoproduct. The axial chirality
was efficiently transferred during [2 + 2] photocycloaddition,
leading to very high enantioselectivity in the photoproducts.
On the other hand, the diastereoselectivity in the photo-
products is dictated by the substituents on the double bonds.
Substitution at the maleimide double bond exerts a greater
influence over the diastereoselectivity (exo/endo) than sub-
stitution on the alkenyl tether. The photoreactivity can be
efficiently scaled up using visible-light mediated metal-free
photocatalytic conditions under flow without any loss of
selectivity in the photoproducts compared with batch-mode
irradiations. As maleimides are potential targets for the
construction of useful synthetic blocks (e.g., indolines), our
study opens up the possibility to build complex molecular
architectures with these systems with excellent stereocontrol.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, single-crystal XRD data (CIF),
characterization data, analytical conditions, flow setup, and
photophysical studies. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sivaguru.jayaraman@ndsu.edu
■
Author Contributions
§E.K. and R.R. contributed equally.
Notes
The authors declare no competing financial interest.
Scheme 8. Visible-Light Photocatalysis of Atropisomeric
Maleimides 1a and 1g under Flow Conditions
ACKNOWLEDGMENTS
■
The authors from NDSU thank NSF for generous support
(CHE-1213880). E.K. and J.S. thank the NSF ND-EPSCoR for
a doctoral dissertation fellowship (EPS-0814442). S.J. thanks
NSF for support (CHE-1111392). The authors also thank
NSF-CRIF (CHE-0946990) for the purchase of the depart-
mental X-ray diffractometer. This manuscript is dedicated to
Dr. D. K. Srivastava, Professor of Chemistry and Biochemistry,
North Dakota State University, an esteemed colleague and
friend on the occasion of his 60th birthday.
H
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Article
(15) HRMS analysis of the crude photolysate showed mass peaks
corresponding to addition products of acetone to phenylmaleimide 1g.
(16) Put, J.; De Schryver, F. C. J. Am. Chem. Soc. 1973, 95, 137−145.
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