Diastereoselective and Stereodivergent Synthesis of 2-Cinnamylpyrrolines Enabled by Photoredox-Catalyzed Iminoalkenylation of Alkenes

Article abstract of DOI:10.1002/anie.202016941

A photoredox-catalyzed iminoalkenylation of γ-alkenyl O-acyl oximes has been developed. Readily available alkenylboronic acids serve as alkenylation reagents, leading to densely functionalized pyrrolines. Both (E)- and (Z)-cinnamylpyrrolines are accessible depending on the reaction solvent. In dichloromethane, (E)-cinnamylpyrrolines are produced through a photoredox-mediated single-electron-transfer process. In tetrahydrofuran, (Z)-cinnamylpyrrolines are generated by photocatalytic contra-thermodynamic E-to-Z isomerization of (E)-cinnamylpyrrolines though an energy-transfer pathway. Two stereocenters are established with complete diastereoselectivity and only one diastereomer is isolated.

Full text of DOI:10.1002/anie.202016941

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doi.org/10.1002/anie.202016941
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Photocatalysis
Diastereoselective and Stereodivergent Synthesis of 2-
Cinnamylpyrrolines Enabled by Photoredox-Catalyzed
Iminoalkenylation of Alkenes
Xu Shen, Congcong Huang, Xiang-Ai Yuan,* and Shouyun Yu*
Abstract:
A
photoredox-catalyzed iminoalkenylation of
construction of (E)- and (Z)-isomers from the same set of
starting materials is attractive, but challenging.[5]
g-alkenyl O-acyl oximes has been developed. Readily available
alkenylboronic acids serve as alkenylation reagents, leading to
densely functionalized pyrrolines. Both (E)- and (Z)-cinna-
mylpyrrolines are accessible depending on the reaction solvent.
In dichloromethane, (E)-cinnamylpyrrolines are produced
through a photoredox-mediated single-electron-transfer pro-
cess. In tetrahydrofuran, (Z)-cinnamylpyrrolines are generated
by photocatalytic contra-thermodynamic E-to-Z isomerization
of (E)-cinnamylpyrrolines though an energy-transfer pathway.
Two stereocenters are established with complete diastereose-
lectivity and only one diastereomer is isolated.
Photo-induced single-electron transfer (SET)[6] and en-
ergy transfer (EnT)[7] processes have provided powerful
strategies to access novel reactivity manifolds. The utility of
iminyl radicals has long been appreciated over the years.[8]
The Narasaka group synthesized pyrrolines through UV-
=
mediated iminyl radical addition to C C bonds intramolec-
ularly.[9] In 2015, we reported that iminyl radicals could be
generated from O-acyl oximes with fac-Ir(ppy)3 as a photo-
redox catalyst under visible light irradiation.[10] The iminyl
radicals underwent intramolecular homolytic aromatic sub-
stitution (HAS) to give pyridine-based heteroarenes. Hence-
forth, photoredox-mediated imino functionalization of al-
kenes via iminyl radicals was developed by the groups of
Leonori,[11] Studer,[12] and Loh/Feng,[13] respectively, using
a variant of oxime derivatives as iminyl radical precursors.
These methods provide an efficient strategy leading to
pyrrolines. One of major limitations of these established
methods is diastereoselectivity issue. When two stereocenters
are constructed during these processes, the diastereoselectiv-
ity is out of control.[11,12] Herein, we report a photoredox-
catalyzed iminoalkenylation of g-alkenyl O-acyl oximes with
alkenylboronic acids (Figure 1). Our strategy does possess
Introduction
Pyrrolines, also named as dihydropyrroles, are frequently
spread in biologically or pharmaceutically important mole-
cules.[1] Alkenes were widely used in the realm of chemical
synthesis because of their rich reactivity and abundance.[2]
Therefore, the exploration of highly efficient new strategies
for the elaboration of the alkenylpyrrolines framework have
the potential to greatly facilitate the discovery of new
function and reactivity agents.[3] In the past few years,
Narasaka and Bower discovered several elegant catalytic
methods for the synthesis of substituted pyrrolines.[4] These
methods were enabled by transition-metal-catalyzed cycliza-
tion of oxime esters with pendant alkenes. Nevertheless, these
methods are mostly stereospecific and provide thermody-
namically stable (E)-alkenes as major products. The (Z)-
isomers are usually inaccessible under these catalytic con-
ditions. The catalytic stereodivergent protocol allowing the
Figure 1. Diastereoselective and stereodivergent synthesis of 2-cinna-
mylpyrrolines. PC=photocatalyst.
[*] X. Shen, Prof. Dr. S. Yu
State Key Laboratory of Analytical Chemistry for Life Science
Jiangsu Key Laboratory of Advanced Organic Materials
Chemistry and Biomedicine Innovation Center (ChemBIC)
School of Chemistry and Chemical Engineering, Nanjing University
Nanjing 210023 (China)
some interesting features: 1) Two stereocenters are estab-
lished with complete diastereoselectivity and only one
diastereomer is observed; 2) Both (E)- and (Z)-isomers of
cinnamylpyrrolines are accessible, which is enabled by the
solvents employed in the reactions; 3) Readily available
alkenylboronic acids serve as alkenylation reagents, which
secures high diastereoselectivity; 4) Both visible light-induced
SET and EnT processes are involved in this reaction.
E-mail: yushouyun@nju.edu.cn
Homepage: http://hysz.nju.edu.cn/yusy/
C. Huang, Prof. Dr. X.-A. Yuan
School of chemistry and chemical engineering
Qufu Normal University
Qufu 273165 (China)
E-mail: xiang_aiyuan@qfnu.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016941.
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Results and Discussion
methane (DCM) solution with 2 mol% of Ir(t-Buppy)3 as
a photocatalyst (conditions A). The desired cinnamylpyrro-
line 3a was isolated in an 83% yield with excellent E-
selectivity (E/Z > 20:1). Very interestingly, when reaction
parameters were slightly changed, i.e., the solvent was shifted
from DCM to tetrahydrofuran (THF) (conditions B), (Z)-
cinnamylpyrroline 4a was produced in a 72% yield and
> 20:1 Z/E selectivity. It was worthy to note that the reaction
was completely diastereoselective and only one diastereomer
was observed in both cases.
Reaction discovery
Recently, we reported photoredox-catalyzed remote
C(sp3)-H vinylation via hydrogen atom transfer (HAT) using
alkenylboronic acids as alkenylation reagents.[14] Based on
these works, it was envisaged that photoredox-catalyzed
iminoalkenylation of g-alkenyl O-acyl oximes with alkenyl-
boronic acids could be achieved and highly functionalized
pyrroline derivatives were thus delivered. Therefore, the
reaction between O-acyl oxime ester (1a) and (E)-(4-
methoxystyryl) boronic acid (2a) was then investigated. After
systematic evaluation of all reaction parameters (for details,
see the Supplementary information (SI)), the optimal reac-
tion conditions were established (Scheme 1). It was found that
the reaction proceeded smoothly under visible-light irradi-
ation (l = 456 nm, blue LEDs) for 12 hours in a dichloro-
Experimental mechanistic studies
To gain some mechanistic insights into these excellent
stereoselective transformations, a series of experimental
mechanistic studies were carried out. First, Stern–Volmer
quenching studies of the excited state of photocatalyst Ir(t-
Buppy)3 were performed in the presence of varying concen-
trations of O-acyl oxime ester 1a and (E)-cinnamylpyrroline
3a in DCM and THF solutions, respectively (see Figures S4
and S5). It was found that both 1a and 3a could quench the
excited photocatalyst Ir(t-Buppy)3*. The quenching rates of
1a and 3a in THF were faster than those in DCM.
Cinnamylpyrroline 3a was more efficient quencher than O-
acyl oxime ester 1a. Based on these observation and the fact
that photocatalytic contra-thermodynamic E to Z isomer-
ization of alkenes is well-known,[15] photocatalytic isomer-
ization of (E)-cinnamylpyrrolines to (Z)-cinnamylpyrrolines
is feasible.
In order to confirm this hypothesis, a series of kinetic
experiments were conducted (Figure 2). We monitored the
Scheme 1. Optimal reaction conditions.
Figure 2. Real-time monitoring experiment. The yields are based on the GC analysis using tetradecane as the internal standard.
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Figure 3. Proposed mechanism and computed Gibbs free-energy profile for the iminoalkenylation reaction catalyzed by Ir(t-Buppy)3 at DFT/B3LYP-
D3/6–311G(d,p) (C,H,O,N,B,F)/SDD (Ir) level in THF with SMD solvation model, and spin-density graph (isovalue=0.04) of intermediate II.
Selected bond lengths are given in [Š].
reaction of 1a and 2c in DCM and THF, respectively. As
shown in Figure 3a, iminoalkenylation of O-acyl oxime 1a
with boronic acid 2c gave (E)-cinnamylpyrroline 3c rapidly in
DCM (conditions A) and almost no (Z)-cinnamylpyrroline 4l
was detected at the beginning of the reaction. After complete
consumption of 1a, the yield of 3c decreased and the yield of
4l increased. The overall yield of 3c and 4l decreased slowly,
indicating the slow decomposition of cinnamylpyrrolines
under reaction conditions. When the reaction of 1a and 2c
carried out in THF (conditions B), the yield of 3c went up
quickly and then went down. Pyrroline 4l could be observed
at the beginning of the reaction and the yield increased
gradually (Figure 3b). These phenomena suggest that 3c
might convert to 4l. Photocatalytic conversion of (E)-
cinnamylpyrroline 3c to (Z)-cinnamylpyrroline 4l could be
observed directly. Irradiation of isolated 3c in the presence of
photocatalyst Ir(t-Buppy)3 in DCM led to slow isomerization
to 4l while this isomerization was much faster in THF. These
experiments clearly show that the reaction of the O-acyl
oxime and boronic acid give the (E)-cinnamylpyrroline first
and then (E)-cinnamylpyrroline converts into (Z)-cinnamyl-
pyrroline under the same photocatalytic conditions. This E to
Z isomerization is more efficient in THF than that in DCM.
To gain more details of this reaction, (Z)-alkenyl O-acyl
oxime 1p was prepared and subjected into conditions A with
boronic acid 2c, (E)-cinnamylpyrroline 3c was isolated as the
sole product (90% yield, dr > 20:1, E/Z > 20:1), whereas the
other diastereomer 3c’ was not detected (Scheme 2). This
phenomenon suggests that (Z)-O-acyl oxime ester 1p might
share the same intermediate with its (E)-isomer 1a.
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isomerization.[15] The triplet energy of 3a is better matched
with the emissive energy of the excited *IrIII complex in THF
than that in DCM (Figure S10). Therefore, this isomerization
is more efficient in THF than that in DCM.[7,18]
Scheme 2. The reaction of 1p with 2c.
Substrate scope of the reaction
With the optimized reaction conditions established, we
examined the substrate scope of this process. First, we focused
on constructing (E)-cinnamylpyrrolines under conditions A
(Scheme 3). A variety of (E)-styrylboronic acids 2a–2l
bearing diverse substituents were transformed into the
corresponding pyrrolines 3a–3l in high yields (61–95%) and
stereoselectivity (Scheme 3, top). (E)-styrylboronic acids with
Theoretical studies and the proposed mechanism
Based on the aforementioned experimental observations
and relevant studies on iminyl radicals,[11–13,16] a plausible
mechanism was posited (Figure 3a). The energy profiles were
also provided to support this proposed mechanism (Fig-
ure 3b). Photoexcitation of IrIII by visible light leads to an
excited *IrIII complex. SET reductive cleavage of O-acyl
oxime 1a by *IrIII produces an iminyl radical I’, an acyl anion
t
either electron-donating (Me, OMe, Bu, and NHBoc) or
electron-withdrawing groups (F, Cl, Br, CF3, and CO2Me) on
the phenyl ring provided the corresponding products 3a–3l.
Variation of the O-acyl oxime esters provided access to a wide
range of densely functionalized pyrrolines (Scheme 3, bot-
tom). Generally, the desired pyrrolines 3m–3ab were ob-
tained in high yields (67–98%) no matter of the position and
electronic property of substituents of O-acyl oxime esters.
The stereoselectivity of these reactions were excellent.
Only one diastereomer was isolated in all cases. E/Z ratios
were greater than 20:1 in most of cases except the substrates
with conjugated substituents, e.g., ester (3h, E/Z = 3:1) and
naphthalene (3q, E/Z = 3:1). The stereochemistry of the
products was unambiguously established by X-ray diffraction
analysis of 3d.[19] The reaction could be scaled up to 2 mmol in
the case of 3a without affecting the isolated yield significantly
(78% vs. 82%).
We next turned our attention to iminoalkenylation of
O-acyl oximes with boronic acids under conditions B, giving
(Z)-cinnamylpyrrolines 4 (Scheme 4). When (E)-(4-methox-
ystyryl) boronic acid 2a was used as the carbon-centered
radical receptor, a wide variety of O-acyl oximes bearing
methoxyl, methyl, fluoro, tifluoromethyl, and naphthyl
groups on the benzene ring underwent this iminoalkenylation
smoothly to give (Z)-cinnamylpyrrolines 4a–4k in a range of
61–81% yields (Scheme 4, top). The final investigation of the
substrate scope was focused on various (E)-styrylboronic
acids coupled with O-acyl oxime 1a (Scheme 4, bottom). No
significant substituent effect was observed and the corre-
sponding (Z)-cinnamylpyrrolines 4l–4t were prepared in 60–
79% yields. Relatively lower yields than those for (E)-
cinnamylpyrrolines were obtained due to slow decomposition
of the pyrrolines under these photocatalytic conditions.
Similar to the synthesis of (E)-cinnamylpyrrolines, only one
diastereomer was isolated in all cases and E/Z ratios were
generally good. The stereochemistry was also determined by
X-ray diffraction analysis of 4h.[19]
À
(Ar’CO2 ) and oxidated state photocatalyst IrIV. Density
functional theory (DFT) calculations suggest that this SET
process is exergonic by 33.4 kcalmolÀ1 with an activation free
energy of 1.6 kcalmolÀ1 (Figure S6), estimated according to
Marcus theory,[17] which indicates this SET event is feasible.
After conformation adjustment of iminyl radical I’ to radical
I, 5-exo-trig cyclization of iminyl radical I gives a carbon-
centered radical II. This step is exergonic by 13.0 kcalmolÀ1
and has a relatively low barrier (5.8 kcalmolÀ1). The radical II
=
is expected to intermolecularly add to C C bond of vinyl
boronic acid 2a giving the corresponding radical III. Calcu-
lation results reveal that a hydrogen bond Complex I between
radical II and vinyl boronic acid 2a forms before intermo-
lecular radical addition. This step is believed to be diastereo-
selective step, leading to the formation of the final product as
sole diastereomer. There are four possible addition modes
considering the addition of the re/si face of radical II to the
two different prochiral faces of vinyl boronic acid 2a. The
energy profile for the C-radical addition suggests that the
most favorable addition mode corresponds to the addition of
the si face of radical II to the si face of 2a. This step has
a moderate barrier of 14.4 kcalmolÀ1. The other addition
modes are kinetically unfavored and are shown in Figure S7.
Further oxidation of radical III by IrIV produces a cation IV.
Subsequently, the cation IV combines with anion Ar’CO2À to
form a stable intermediate V which then undergoes the B-O
elimination via TS3-1 to give a low energy complex II. This
elimination process needs to overcome an activation barrier
of 22.6 kcalmolÀ1, which is the highest barrier in the whole
iminoalkenylation reaction. Finally, the removal of boron
complex [Ar’COOB(OH)2] gives the final product 3a. Alter-
natively, the boron migration pathway (from C to N in V,
Figure S8) is kinetically less favored.
The conjugated (E)-cinnamylpyrroline 3a is excited by
the excited *IrIII complex through EnT process.[7] Subsequent
Interestingly, when geminal disubstituted g-alkenyl
O-acyl oxime 1s was subjected into conditions Awith boronic
acid 2c, the desired 5-exo-trig cyclization and coupling
product 5 was only isolated in 13% yield, together with
42% yield of pyridine 6. Pyridine 6 was the product of 6-endo-
trig cyclization followed by oxidation and deprotonation
(Scheme 5a). When d-alkenyl O-acyl oxime 1t coupled with
À
rotation of C C bond in the transient intermediate VII can
give rise to both (E)-cinnamylpyrroline 3a and (Z)-cinna-
mylpyrroline 4a. The p system of (Z)-cinnamylpyrroline 4a is
deconjugated due to allylic strain and thus reactivation of 4a
is inefficient. Therefore, this process enables an intrinsic
directionality in favor of the contra-thermodynamic E to Z
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Scheme 3. Scope of the reactions leading to (E)-cinnamylpyrrolines. Reaction conditions A: A mixture of 1 (0.05 mmol, 1.0 equiv), 2 (0.1 mmol,
2.0 equiv), Ir(t-Buppy)3 (2 mol%) in DCM (1.0 mL) was irradiated by blue LEDs at RT for 7–12 h. The dr and E/Z ratios were determined by
1H NMR spectroscopy. [a] 2.0 mmol scale of 1a.
boronic acid 2c, no desired 6-endo-trig cyclization and
coupling product 8 was detected. Instead, the iminyl radical
underwent 1,5-hydrogen atom transfer (HAT) followed by
homolytic aromatic substitution (HAS). Benzocyclohexa-
none 7 was finally produced, which is consistent with
Nevadoꢀs observation (Scheme 5b).[20] This result suggests
that 1,5-HAT is favored than 6-endo-trig cyclization.
3a using DIBAL-H at À788C followed by N-tosylation with
tosyl chloride gave pyrrolidine 9 in 84% yield with > 20:1
diastereoselectivity. Furthermore, reduction of pyrroline 3c
followed by N-allylation provided pyrrolidine 10 in 73%
overall yields for two steps and > 20:1 diastereoselectivity.
Indolizidine 11 was delivered in a 67% yield through Grubbs-
Hoveyda catalyst (GH-II)-catalyzed alkene metathesis.[4g]
Both pyrrolidine and indolizidine motifs are widely presented
in a number of natural alkaloids.[21]
Synthetic application
The potential utility of pyrrolines 3a and 3c was
demonstrated (Figure 4). Reduction of the imine moiety in
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Scheme 4. Scope of the reactions leading to (Z)-cinnamylpyrrolines. Reaction conditions B: A mixture of 1 (0.05 mmol, 1.0 equiv), 2 (0.1 mmol,
2.0 equiv), Ir(t-Buppy)3 (2 mol%) in THF (1.0 mL) was irradiated by blue LEDs at RT for 12–24 h. The dr and E/Z ratios were determined by
1H NMR spectroscopy.
Figure 4. Synthetic application.
Conclusion
In summary, we have described photoredox-catalyzed
iminoalkenylation of g-alkenyl O-acyl oximes with alkenyl-
boronic acids. Both (E)- and (Z)-cinnamylpyrrolines are
accessible depending on the reaction solvent. (E)-cinnamyl-
pyrrolines are produced in DCM through photoredox-medi-
ated SET process while (Z)-cinnamylpyrrolines are generated
Scheme 5. Extension of substrates and chemoselectivity investigation.
Ar’=4-CF3C6H4.
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isomerization of (E)-cinnamylpyrrolines though EnT path-
way. Two stereocenters are established with complete diaste-
reoselectivity and only one diastereomer is observed. Readily
available alkenylboronic acids serve as alkenylation reagents,
leading to densely functionalized pyrrolines. The studies on
enantioselective version of this reaction are ongoing and will
be reported in the due course.
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Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (21732003, 21971110, and 21703118) is
acknowledged. We are also grateful to the High Performance
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The authors declare no conflict of interest.
Keywords: iminoalkenylation ·iminyl radicals ·
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[19] Deposition Numbers 2045809 (3d) and 2045810 (4h) contain the
supplementary crystallographic data for this paper. These data
are provided free of charge by the joint Cambridge Crystallo-
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Manuscript received: December 21, 2020
Revised manuscript received: January 24, 2021
Accepted manuscript online: February 5, 2021
Version of record online: March 10, 2021
Angew. Chem. Int. Ed. 2021, 60, 9672 –9679
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