Catalytic Asymmetric Dearomatization by Visible-Light-Activated [2+2] Photocycloaddition

Article abstract of DOI:10.1002/anie.201802891

A novel method for the catalytic asymmetric dearomatization by visible-light-activated [2+2] photocycloaddition with benzofurans and one example of a benzothiophene is reported, thereby providing chiral tricyclic structures with up to four stereocenters including quaternary stereocenters. The benzofurans and the benzothiophene are functionalized at the 2-position with a chelating N-acylpyrazole moiety which permits the coordination of a visible-light-activatable chiral-at-rhodium Lewis acid catalyst. Computational molecular modeling revealed the origin of the unusual regioselectivity and identified the heteroatom in the heterocycle to be key for the regiocontrol.

Full text of DOI:10.1002/anie.201802891

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Accepted Article
Title: Catalytic Asymmetric Dearomatization by Visible-Light-Activated
[2+2] Photocycloaddition
Authors: Naifu Hu, Hoimin Jung, Yu Zheng, Juhyeong Lee, Lilu Zhang,
Zakir Ullah, Xiulan Xie, Klaus Harms, Mu-Hyun Baik, and Eric
Meggers
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10.1002/anie.201802891
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Catalytic Asymmetric Dearomatization by Visible-Light-Activated
[2+2] Photocycloaddition
Naifu Hu,[a] Hoimin Jung,[b] Yu Zheng,[a] Juhyeong Lee,[b] Lilu Zhang,[a] Zakir Ullah,[b] Xiulan Xie,[a]
Klaus Harms,[a] Mu-Hyun Baik,[b]* and Eric Meggers[a]*
Abstract:
A
novel method for the catalytic asymmetric
dearomatization by visible-light-activated [2+2] photocycloaddition
with benzofurans and one example of a benzothiophene is reported,
providing chiral tricyclic structures with up to four stereocenters
including quaternary stereocenters. The benzofurans and the
benzothiophene are functionalized at the 2-position with a chelating
N-acylpyrazole moiety which permits the coordination of a visible
light activatable chiral-at-rhodium Lewis acid catalyst. Computational
molecular modeling revealed the origin of the unusual
regioselectivity and identified the heteroatom in the heterocycle to be
key for the regiocontrol.
Aromatic and heteroaromatic compounds are ubiquitous
synthetic starting materials and many types of reactions have
been developed for their functionalization and transformation. A
recently emerging highly useful class of reactions are catalytic
asymmetric dearomatizations (CADA reactions), a term coined
by the You group.[1-3] This synthetic methodology is highly
appealing because it converts readily available aromatic
moieties into enantio-enriched three-dimensional cyclic
molecules in a catalytic fashion, which is an important objective
in contemporary organic synthesis.
Figure 1. Catalytic asymmetric dearomatization by visible-light-activated [2+2]
photocycloaddition reported in this study and comparison with state of the art.
We started our study with benzofurans[13] functionalized in
2-position with 2-acylimidazole (1a,b) or N-acylpyrazole (1c-h)
moieties for interacting with the photoactivatable chiral-at-metal
Rh catalyst Δ-RhS[14] (Table 1).[15,16] Initial experiments were
disappointing; when 2-acyl imidazoles (1a or 1b) with styrene 2a
were subjected to blue LEDs together with Δ-RhS (2 mol%),
nearly no conversion occurred (entries 1,2). Gratifyingly, when
N-acylpyrazole 1c was employed instead, 68% conversion was
observed for the dearomative [2+2] photocycloaddition and the
main product 3c was formed with 97% ee together with
diastereomer 3c' (5.4:1 dr) and regioisomer 3c'' (7.3:1 rr) (entry
3). To our surprise, the main product features a head-to-tail
Asymmetric cycloadditions enable
a
straightforward
access to complex architectures with multiple stereocenters in a
single step and thereby generate structural complexity in a rapid
and economical fashion.[4] Recently, Bach,[5] Yoon,[6] and our
groups[6c,7] reported visible-light-activated catalytic asymmetric
[2+2] photocycloadditions[8,9] which occur directly from an
electronically excited substrate/catalyst complex without the
involvement of charge separation. This chemistry is attractive
because it employs visible light as an abundant and mild source
of energy and at the same time circumvents drawbacks resulting
from radical ion intermediates which are typically generated in
the course of photoredox processes.[10]
regioselectivity in contrast to
a tail-to-tail regioselectivity
observed in related previous rhodium-catalyzed [2+2]
photocycloadditions.[7]
The substituents at the pyrazole have a profound effect on
this reaction (entries 4-8). The best results were obtained with a
Ph group in 3-position of the pyrazole (1f) which gave complete
conversion after 18 hours of irradiation and afforded the main
product 3f with 98% ee together with diastereomer 3f' (6.2:1 dr)
and regioisomer 3f'' (5.3:1 rr) (entry 6). Due to the lability of the
Herein we report the first application of visible-light-
activated [2+2] photocycloadditions to catalytic asymmetric
dearomatizations
and
we
investigate
the
observed
regioselectivity by computational modeling (Figure 1).[11,12]
N-acylpyrazole moiety in this structural context,
a prior
conversion to its methyl ester allowed to isolate the main product
together with its regioisomer in an overall yield of 78%. The
reaction is quite robust and performs well under air (entry 9).
However, the choice of solvent is important and the best results
are obtained with CH2Cl2 (compare entries 6, 10 and 11). The
catalyst loading can be reduced to 1 mol% with almost
unchanged performance (entry 12). As a control, in the absence
of light or catalyst, no conversion was observed (entries 13,14).
Likewise, the related Ir complex Δ-IrS[17] was not able to catalyze
this reaction (entry 15).
[a]
[b]
Dr. N. Hu, Y. Zheng, Dr. L. Zhang, Dr. K. Harms, Dr. X. Xie, Prof. Dr.
E. Meggers
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-
Strasse 4, 35043 Marburg, Germany
E-mail: meggers@chemie.uni-marburg.de
H. Jung, J. Lee, Z. Ullah, Prof. Dr. M-H. Baik
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 34141, Republic of Korea
Center for Catalytic Hydrocarbon Functionalizations, Institute for
Basic Science (IBS), Daejeon 34141, Republic of Korea
Supporting information for this article can be found under:
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10.1002/anie.201802891
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product.[19] The subsequent release of product 3f and
coordination of a new equivalent of substrate complete the
catalytic cycle. Our calculations confirm the location of the
Table 1. Initial experiments and optimization of conditions.
3
unpaired electrons across the ene moiety of photoexcited A as
a 1,2-biradical species, as indicated with red dots in Figure 3,
which reacts with the alkene substrate in a stereocontrolled
fashion. During this process, the enantioselectivity[20] is well-
controlled by the chiral Rh catalyst (see SI for a structure of the
transition state 3A-TS) and the regioselectivity is probably
determined by the stability of the 1,4-biradical intermediate
although other factors such as the rate of the back reaction to
the ground state precursors have been determined to play an
important role.[9b,21,22]
Entry
1
X
Reaction conditions[a]
Conv. (%)[b] dr[c]
rr[d]
ee (%)[e]
—
1a standard
< 5
< 5
68
—
—
2
1b standard
—
—
—
3
1c standard
5.4 : 1
4.7 : 1
—
7.3 : 1
4.3 : 1
—
97
4
1d standard
89
98
5
1e standard
< 5
100 (78)[f]
98
—
6
1f standard
6.2 : 1
6.1 : 1
5.9 : 1
5.7 : 1
3.4 : 1
4.0 : 1
6.1 : 1
—
5.3 : 1
5.0 : 1
4.3 : 1
4.7 : 1
5.0 : 1
3.4 : 1
5.1 : 1
—
98[g]
98
7
1g standard
8
1h standard
100
98
82
9
1f under air
97
10
11
12[h]
13
14
15
1f acetone as solvent
1f THF as solvent
1f 1.0 mol% -RhS
1f no light
65
95
49
92
100
0
98
—
1f no catalyst
1f 2.0 mol% -IrS
0
—
—
—
0
—
—
—
[a] Deviations from standard conditions are shown. Standard conditions:
Benzofuran 1a-h (0.1 mmol), styrene 2a (0.3 mmol) and 2.0 mol% -RhS in
CH2Cl2 (0.1 M, 1 mL) were stirred at r.t. under N2 for 18 h with blue LEDs (24
W) irradiation. [b] Conversion determined by 1H NMR of the crude product. [c]
Dr values determined by 1H NMR of the crude product. [d] Rr values
determined by 1H NMR of the crude product. [e] Ee values determined by
HPLC analysis on chiral stationary phase. [f] Total isolated yield of the main
product 4a with its regioisomer 4a'' (6.7:1 rr) after the conversion to the
corresponding methyl esters. [g] Ee value was unchanged after converting the
main product to the corresponding methyl ester. [h] Reaction time was 36 h.
Figure 2. Substrate scope with styrene derivatives. Isolated yields of
combined regioisomers are provided. [a] 8 mol% catalyst and 48 h reaction
time instead. [b] 4 mol% catalyst and 48 h reaction time instead. [c] The
absolute configuration of
a derivative of 4i was determined by X-ray
crystallography and all other products assigned by analogy.
With optimized reaction conditions in hand, we next
investigated the scope of substituted styrenes and determined
isolated yields after conversion of the initial N-acylpyrazole
products into their methyl esters (Figure 2). Overall, electron-
withdrawing and electron-donating groups as well as sterically
bulky groups in para- and meta-position of the phenyl moiety are
well tolerated; the dearomatization products 4b-g were obtained
with 96-98% ee and 68-88% yields as single diastereomers but
as regioisomeric mixtures (4.3:1 to >20:1 rr). The phenyl moiety
can also be replaced with a naphthyl (4i) or a thiophene moiety
(4j). However, ortho-substituents strongly affect the reactivity so
that for 2-methylstyrene (4h) the catalyst loading was doubled to
4 mol% in order to obtain satisfactory results.
Generally, the reaction is expected to proceed as seen in
previous Rh catalyzed [2+2] photocycloadditions as summarized
in Figure 3.[7,18] The catalytic cycle begins with the association of
the N-acylpyrazole substrate (11f) with the chiral Rh catalyst Δ-
RhS. The reactant complex 1A absorbs blue light to reach its
singlet excited state, 1A*. After intersystem crossing (ISC) to
form the triplet reactant complex 3A, it reacts with the alkene
substrate to generate the 1,4-biradical intermediate 3B, which
then recombines to form the desirable photocycloaddition
Figure 3. Proposed catalytic cycle.
We sought to understand the origin of the unusual
regioselectivity of this dearomatization using DFT calculations
for the reaction with catalyst Δ-RhS, substrate 1f, and styrene
(Figure 4).[23] Once the substrate-bound Rh complex 1A is
photoexcited and undergoes ISC into the triplet state to form the
reactive 1,2-biradical species 3A, the styrene substrate can
approach the 1,2-biradical from two possible faces. Since the
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formation of the benzyl radical is much more favorable than the
generation of the methyl radical, we focused on identifying the
transition state that couples the terminal carbon of styrene with
one of the 1,2-biradical carbons in the benzofuran fragment to
afford a 1,4-biradical product. As illustrated in Figure 4a, the
head-to-tail addition (solid black line) has a barrier that is 2.0
kcal/mol lower in energy than the tail-to-tail addition (dashed,
blue line). The thermodynamic stability of two analogous 1,4-
biradical intermediates shows the same trend, as 3B is 5.5
kcal/mol lower in free energy than 3B''. To complete the
cycloaddition, the 1,4-biradical species must undergo radical
recombination and cross-over to the singlet surface to produce
1C and 1C'', respectively. These processes will occur at the
minimum energy crossing point (MECP), where the triplet and
singlet surfaces cross.
The observation that styrene engages the 1,2-biradical
with the terminal methylene moiety to generate a benzyl radical
is plausible. However, the energy difference of 5.5 kcal/mol
between the 1,4-biradical intermediates 3B and 3B'' is not as
easy to understand, but it is a key feature leading to the
regioselectivity. To separate the impact of the chiral Rh-fragment
from the intrinsic energy differences of the two possible
intermediate isomers, we deleted the Rh-fragment and
evaluates the relative energies of the two biradicals, labeled as
3
3
3b and b''. Interestingly, our calculations indicate that b is 6.2
3
kcal/mol lower in energy than b'', as illustrated in Figure 4b. An
inspection of the underlying electronic structure reveals a simple
reason for this energy difference, outlined in Figure 4c. When
the unpaired electron is placed at the benzylic C3-position, it is
resonance-stabilized by the phenyl group. At the tertiary C2-
position, however, the unpaired electron is stabilized by the
neighboring carbonyl group and, more importantly, by the
oxygen lone-pair orbital, shown in blue and red in Figure 4c,
respectively.[24]
A more detailed energy decomposition is
provided in the SI. Thus, the calculations suggest that the
regiocontrol is based on an intrinsic electronic preference of
placing an unpaired electron of the 1,4-biradical intermediate at
the tertiary carbon next to an oxo functionality.
Figure 4. (a) Gibbs free energy profile. (b) Energy differences of two
analogous 1,4-biradical intermediates. (c) Schematic illustrations of the radical
stabilizations.
Finally, we investigated reactions with internal alkenes
which provide an additional stereocenter. To our delight, when
(E)-β-methylstyrene 5a was tested with benzofuran 1f and
subsequently converted to its methyl ester, the dearomatization
product 6a was obtained in 90% yield and 99% ee as a single
diastereomer (> 20:1 dr) and as a single regioisomer (> 20:1 rr)
(Figure 5). With the geometrical isomer (Z)-β-methylstyrene 5a'
the dearomatization product 6a' was formed as the main product
instead, albeit with a low dr of 1.8:1. Gratifyingly, when
performed at -30 °C, only a single diastereomer was obtained
(>20:1 dr). This strong temperature dependence of the
diastereoselectivity supports
a
mechanism through an
intermediate but very short-lived 1,4-biradical intermediate in
which the temperature affects the rotation around the single C-C
bond before the radical recombination occurs and thus
conserves the memory of the radical conformation.[25]
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alkene substrates, almost perfect head-to-tail regioselectivity
was observed with the formation of a single diastereomer and a
very high enantioselectivity for benzofuran substrates of 98-99%
ee to provide. The N-acylpyrazole moiety of the tricyclic
structures with up to four stereocenters including one quaternary
stereocenter can be easily further functionalized (see SI for
examples), thus indicating the potential synthetic value of this
new methodology.[27]
Acknowledgements
Funding from the Deutsche Forschungsgemeinschaft (ME
1805/13-1) and the LOEWE Research Cluster SynChemBio of
the Federal State of Hessen, Germany is gratefully
acknowledged. This research was supported by the Institute for
Basic Science (IBS-R10-D1) in Korea.
Figure 5. Asymmetric dearomatization with (E)- and (Z)-β-methylstyrene. For
the reaction at -30 °C, 5 W blue LEDs were employed (see SI for setup) and
reaction time was 60 h. The absolute configuration of a derivative of 6a was
determined by X-ray crystallography. The relative configuration of its
diastereoisomer 6a' was determined by NMR studies.
Encouraged by these results, the substrate scope with
internal (E)-alkenes was investigated (Figure 6). A variety of
substituents at the benzene moiety of the benzofurans were well
tolerated (6b-g) and the methyl group of (E)-β-methylstyrene
could also be replaced by long-chain and functionalized alkyl
groups without affecting the outcome (6h-i). All these
dearomatization products were formed with high yields (80-93%),
excellent enantioselectivities (98-99% ee) and virtually with
complete diastereo- and regioselectivities, except for 6g (16.7:1
dr). This catalytic asymmetric dearomatization can also be
applied to benzothiophene[26] to give the dearomatization
product 6j in 87% yield with >20:1 dr and >20:1 rr, albeit with a
diminished enantioselectivity (73% ee).
Keywords: photocycloaddition • dearomatization • asymmetric
catalysis • chiral-at-metal
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asymmetric dearomatizations by visible-light-activated [2+2]
photocycloadditions and investigated the observed regio-
selectivity with computational molecular modeling. With internal
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Entry for the Table of Contents
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N. Hu, H. Jung, Y. Zheng, J. Lee, L.
Zhang, Z. Ullah, X. Xie, K. Harms, M.-H.
Baik*, E. Meggers*
Page No. – Page No.
Catalytic Asymmetric
Dearomatization by Visible-Light-
Activated [2+2] Photocycloaddition
A catalytic asymmetric dearomatization of benzofurans and one benzothiophene
was accomplished by visible-light-activated [2+2] photocycloaddition using a chiral-
at-rhodium Lewis acid catalyst, providing chiral tricyclic structures with up to four
stereocenters including
a quaternary stereocenter. Computational modeling
revealed the origin of the observed regioselectivity.
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