Photo-induced energy transfer relay of N-heterocyclic carbene catalysis: an asymmetric α-fluorination/isomerization cascade

Article abstract of DOI:10.1039/d0cc07264h

The geometric configuration of olefin products is often driven by thermodynamic control in synthesis. Methods enabling switching of cis/trans selectivity are rare. Recently, photosensitized approaches have emerged as a powerful tool for accomplishing this task. In this report, we report an in situ isomerization of an N-heterocyclic carbene (NHC)-bound intermediate by a photo-induced energy transfer process that leads to selective access of chiral allylic fluorides with a cis-olefin geometry. In the absence of a photocatalyst or light, the reaction proceeds smoothly to give (E)-olefin products, while the (Z)-isomer can be obtained under photosensitizing conditions. Preliminary mechanistic experiments suggest that an energy transfer process might be operative. This journal is

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Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC07264H
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Photo-induced energy transfer relay of N-heterocyclic carbene
catalysis: An asymmetric α-fluorination/isomerization cascade
Xinhang Jiang,a, d En Li, a, d Jiean Chen*c, d and Yong Huang*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Geometric configuration of olefin products is often complementary
electrophilic
fluorination
using
driven by thermodynamic control in synthesis. Methods organocatalysts have also been developed.4 For example,
enabling switching cis/trans selectivity are rare. Toste and co-workers reported asymmetric fluorination of
Recently, photosensitized approaches emerge as a allylic alcohol using a chiral phosphoric acid as phase
powerful tool for accomplish this task. In this report, we transfer catalyst.4c In this case, thermodynamically more
report an in situ isomerization of N-heterocyclic carbene stable olefin isomers were obtained as well. So far, access
(NHC)-bound intermediate by a photo-induced energy to chiral allylic fluorides with kinetic olefin geometry
transfer process that leads to selective access of chiral remains highly challenging. We were wondering whether
allylic fluorides with cis-olefin geometry. In the absence cooperative catalysis merging visible-light-chemistry and
of a photocatalyst or light, the reaction proceeds organocatalysis would yield a straightforward solution to
smoothly to give (E)-olefin products, while the (Z)- address this problem.
A. Geometrical isomerisation for synthesis of Z-alkenes
isomer can be obtained under photosensitizing
conditions. Preliminary mechanistic experiments
suggest an energy transfer process might be operative.
R
Ar
biradical
Ar
180 rotation
Ar
(Z)-isomer
R
photo-induced
ET
R
R
Ar
(E)-feedstock
Allylic fluorides are important structural motifs that are not
only versatile synthetic intermediates towards complexed
structures but are also prevalent among bioactive
molecules.1 Chiral allylic fluorides are particularly useful
synthons for radioactive probes for positron emission
intermediate
B. Energy transfer relay of NHC-bound
(this work)
O
acyl azolium
(E)-isomer
Ph
NHC
+
O
O
H
LG
NHC+
OR
base
F+
F
F
tomography
(PET)
imaging,
pharmaceuticals,
O
O
N
agrochemicals and materials.1,2,3 Towards this important
class of molecules, asymmetric installation of a fluorine
atom at the allylic position of an olefin have made
substantial progress in the past decade.2 Transition-metal-
catalyzed allylic fluorination, mostly via an electrophilic -
allyl-metal intermediate, has been developed as a powerful
strategy to chiral allylic fluorides.3 Products with (E)-
olefinic geometry were frequently obtained. The
N
O
O
N


NHC+
OR
F
F
vinylogous enolate
isomerization
(Z)-isomer
H
+
blocki
X
ng
 synergistic process
Z)-allylic fluoride
high enantioselectivity
high chemoselectivity
H
O
NHC+
NHC+
O
H
kinetically competitive
Scheme 1. Energy transfer relay of NHC-bound intermediate.
It has been well established that photosensitized energy
transfer processes can manipulate olefin geometry that often
leads to energetically unfavorable alkene isomers (Scheme
1A).5,6 In 2014, Weaver et al. reported photosensitized
isomerization of aryl-substituted (E)-allylamines to
thermodynamically less stable (Z)-isomers.6a Inspired by (-
)-riboflavin mediated (Z→E) isomerization, Gilmour and
coworkers accomplished (E/Z) inversion of polarized
a. State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen
Graduate School, Shenzhen, 518055, China.
b. Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Hong Kong SAR, China
c. Pingshan Translational Medicine Center, Shenzhen Bay Laboratory, Shenzhen,
518055, China
d. Shenzhen Public Platform of Drug Screening and Preclinical Evaluation, Peking
University Shenzhen Graduate School, Shenzhen, 518055, China
E-mail: chenja@szbl.ac.cn; yonghuang@ust.hk
†Electronic Supplementary Information (ESI) available. See DOI:
10.1039/x0xx00000x
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alkenes, a strategy that was further expanded to allylic We started our investigation using a model reaction between
View Article Online
alcohols and styrenyl boron compounds.6c However, substrate 1a and Selectfluor. Initial attempt using NHC-A
DOI: 10.1039/D0CC07264H
photosensitized isomerization of allylic fluorides remains and [Ir(dF-CF3-ppy)2(dtbbpy)]PF6 (PS-A) was encouraging
elusive. Recently, Rueping et al. reported a double that (Z)-allylic fluoride 3a was obtained in moderate yield
functionalization of terminal alkynes using a combination (33%), good Z/E ratio (6.8:1) and decent ee (83%). The
of photoredox/nickel catalysis.6f The authors observed combined yield of the undesired side products, (E)-2a, (Z)-
complete (E)-olefin selectivity when a Ru photocatalyst was 2a and (E)-3a, was 10%. Reaction parameters were
used. In sharp contrast, switching to an Ir-based screened orthogonally to identify key factors for the desired
photosensitizer led to the corresponding (Z)-olefin. The reaction pathway. Presumably, triplet–triplet energy
authors postulated that double bond (Z→E) isomerization transfer for the isomerization is operative. The triplet state
might be operative before the second functionalization. This energy (ET) of photosensitizer might impact both
development inspired us to probe a reaction involving chemoselectivity and efficiency of the double bond
energy-transfer-mediated double bond isomerization of an isomerization. Photocatalysts with ET of 50~55 kcal mol-1
NHC-derived vinylogous enolate intermediate that might afforded the highest (Z/E) ratio and yield.6g Those with low
lead to access to chiral (Z)-allylic fluorides.
ET, Ru(bpy)3Cl2 (ET = 46.8 kcal mol-1) failed to promote
It has been reported that vinylogous enolates can react with formation of the (Z)-allylic fluoride.6f Both the (E)-3a and
an electrophilic fluorinating reagent to give the (E)-2a were isolated in 17% and 19%, respectively. PS-C
corresponding allylic fluorides.7 Such chiral enolates can be was found to improve this process (Z/E = 9.2:1) without
generated from a chiral NHC catalyst and an α,β- eroding yield and enantioselectivity (see Table S1 for more
unsaturated aldehyde bearing a -leaving group. We details). Noteworthily, alternating Selectfluor with its type-
envisioned that upon fluorination, the olefinic acyl azolium II variant and NFSI resulted in dramatically decreased (Z/E)
intermediate might undergo photosensitized energy transfer ratio (0.5:1 and 1.5:1, respectively) and yield (10% and
to invert the double bond geometry before releasing the 12%, respectively).9 In order to suppress the competing α-
NHC catalyst. This in-cycle contra-thermodynamic protonation process, various additives were examined. In
isomerization might allow us to access chiral (Z)-allylic agreement with our previous reports on hydrofluorination
fluorides selectively. Several issues need to be addressed, reactions, PivONa delivered the highest H vs F selectivity
however. Although reports merging NHC and (Table S2).7d Screening the ratio of the mixed solvents
photocatalysis is evolving rapidly, robust systems allowing revealed that CHCl3 (1.5 mL)/MeOH (25.0 eq.) was ideal
for precise control of the photoactivation step within the for this reaction (Table S3). Further increasing the amount
NHC-catalytic cycle are still lacking.8 Photosensitizers are of methanol erodes (Z/E)-selectivity, likely due to rapid
generally redox reactive and might promote single-electron- NHC turnover so that the (E)-acylazolium intermediate is
transfer processes that disrupt the initial fluorination step. In converted into (E)-3a before undergoing olefin
addition, racemization might be a serious problem as the α- isomerization. The results also indicated that using
allyl-α-fluoro ester moiety is quite acidic and the reaction Selectfluor as limiting reagent could dexterously balance
is basic.
the reactivity and controllability via avoiding the start
material decomposition. (Table S4). Further tuning reaction
variables other than NHC led to a suboptimum reaction with
77% yield, 83% ee and 7.8:1 (Z/E) ratio (Scheme 2).
O
O
O
O
O
primary
Ph
Ph
Ph
H
OMe
OMe
OMe
OMe
condition
H
H
F
F
OCO2Me
Ph
Ph
1a
(1.0 eq.)
2a
2a
3a
(E)-
3a
(E)-
(Z)-
• primary condition
• orthogonal variation
At this stage, we believed that further improving yield and
selectivity might be accomplished by modification of the
NHC catalyst. A series of NHC precursors were explored
under the optimized α-fluorination/isomerization cascade
reaction (Table S5).10 The N-aryl substituent was
systematically modified. Electron-withdrawing groups on
N-Ar improved yield, but negatively impacted ee. Higher
(Z/E) ratio and ee was generally observed for N-Ar with
electron-donating groups. Two ortho-substituents on N-Ar
were essential for high (Z/E)-selectivity and
enantioselectivity. More sterically hindered N-aryl groups,
those with ortho-substituted MeO or Et group, afforded
particularly high (Z/E) ratio (> 10:1). The indanol motif of
the NHC was further optimized. Gratifyingly, we
demonstrated NHC-N, with a meta-NO2 group at the
indanol aryl, demonstrated an overall balanced catalytic
profile (92% yield, 94% ee, 7.9:1 Z/E ratio). The
particularly high ee might be attributed to possible -
interaction between the electron-deficient indanol arene and
A
B C
NHC- : 36%, 69% ee, 6.4:1; NHC- : 45%, 38% ee, 6.8:1
B C
PS- : 27%, 83% ee, 9.3:1; PS- : 32%, 83% ee, 9.2:1
NHC- (10 mol%)
A
PS- (1 mol%)
selectfluor (1.5 eq.)
NaOAc (4.0 eq.)
NFSI: 10%, 92% ee, 0.5:1; selectfluor II: 12%, 81% ee, 1.5:1
iPrCO2Li: 24%, 84% ee, 6.5:1; PivONa: 39%, 83% ee, 6.8:1
1a
CHCl3 (1.5 mL), MeOH (5.0 eq.)
45 W blue LEDs, r. t., 12 h
MeOH (25.0 eq.): 45%, 84% ee, 6.5:1;
(1.5 eq.): 58%, 83% ee, 6.8:1
(1.5 eq.) + selectfluor (1.0 eq.) + MeOH (25.0 eq.):
C
1a
PS- + PivONa +
3a
: 33%, 83% ee, 6.8:1
77%, 83% ee, 7.8:1
R1
X
BF4
BF4
O
N
NHC- : R1 = Me
N
N
PhO2S
SO2Ph
A
N
N
N
1
=
iPr
B
NHC- : R
F
R1
F
NHC- : R1 = Cl
BF4
C
R1
X = Cl: Selectfluor
X = H: Selectfluor II
NFSI
PF6
PF6
PF6
CF3
F
F
F
F
tBu
tBu
tBu
N
IrIII
N
N
N
IrIII
N
N
N
N
N
F
F
F
F
F
F
IrIII
N
N
N
tBu
F
F
CF3
A
B
C
PS- : [Ir(dF-CF3-ppy)2(dtbbpy)]PF6
PS- : [Ir(dF-ppy)2(dtbbpy)]PF6
PS- : [Ir(dF-ppy)2(bpy)]PF6
ET = 60.1 kcal•mol-1
ET = 55.4 kcal•mol-1
ET = 54.2 kcal•mol-1
Scheme 2. First round of conditions survey for synergistic energy transfer
catalysis.
2 | J. Name., 2012, 00, 1-3
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the electron-rich dienolate.11 The stereoselectivity can be
further improved by lowering reaction temperature to -5 oC.
Under the optimized reaction conditions, the substrate scope
of enals were explored in the α-fluorination/isomerization
cascade process. As shown in Table 3, substitutions are well
tolerated at the para- (3b-3g), meta- (3h-3m), and ortho-
position (3p-3r) of the γ-aryl group. An ortho-substituted
halogen atom did not infer with photosensitized geometric
isomerization (3p-3r). It appears that electro-deficient
aromatic substituents generally led to slightly higher yield
and (Z/E) ratio. A second substituent on the γ-aryl was also
examined and most of such substrates performed similarly
as their mono-substituted counterparts. Lower ee was
observed for substrates with two electro-withdrawing
groups on the γ-aryl (3r and 3s), which might be due to
weakened - interaction with the electron-deficient
indanol aryl. When the phenyl group being expanded to a
naphthyl group, geometric isomerization was affected and
the (E)-olefinic product was isolated as the major isomer
(3w). However, the reaction channel was totally obstructed
when an alkyl group being forged in lieu of the
aforementioned γ-aryl moiety. The optically enriched (Z)-
allylic fluoride 3a can be reduced under Luche reduction
conditions and further derivatized by sulfonylation and
acylation.12 Upon acylation using 1-pyrenoic acid, the
resulting ester 4c was crystalline and its structure was
confirmed by X-ray crystallography.
72 (96), 6;1
73 (96), 5:1
25 (97), 1:2
Structural confirmation
View Article Online
Reaction conditions: enal 1 (0.15 mmol), DSOeIl:e1c0tf.1l0u3o9r/D(00.C1Cm07m26o4lH),
NHC-N (10 mol%), PS-C (1 mmol%), PivONa (0.4 mmol),
CHCl3/MeOH (1.5 mL/0.1 mL), irradiation with 45 W blue LEDs, -5
oC, 18 h. Numbers outside parentheses are isolated yield using
Selectfluor as limiting reagent, and numbers inside parentheses are ee
value for isolated product (determined by chiral GC), followed by
(Z/E) ratio (determined by GC).
To further understand the isomerization details, several
control experiments were carried out (Scheme 3). In the
absence of either light or PS-C, the reaction proceeded with
high (E)-selectivity and ee. A trace amount of (Z) -product
was observed, likely due to internal electron transfer
processes via formation of electron-donor-acceptor (EDA)
complexes. When the (E)-isomer, allylic fluoride (E)-3a,
was subjected to the standard reaction conditions,
decomposition was predominant, and the corresponding
(Z)-isomer was obtained in 20% yield as racemates. This
result strongly suggests that the (Z)-selectivity of this
reaction is not a result of photosensitized isomerization of
the (E)-product. The olefin isomerization likely occurred
prior to the NHC-turnover step. Presumably, a homoenolate
intermediate A is generated by nucleophilic addition of
NHC to the enal substrate, followed by a hydride shift.
Upon releasing of CO2 and methanol, dienolate B is formed
that reacts with Selectfluor to give the acyl azolium
intermediate C. The (E)-acyl azolium intermediate C is
speculated as the key species that undergoes double bond
isomerization by energy transfer from the triplet state of the
excited photocatalyst, [Ir]*III. Finally, the dominant (Z)-acyl
azolium E react with MeOH to yield the product and
regenerate the NHC catalyst. At this stage, we cannot rule
Table 1. Substrate scope of the enantioselective α-
fluorination/isomerization cascade.
O
N
O
O
N
PS-C
(1 mol%)
NHC- (10 mol%),
N
N
Ar
Selectfluor (1.0 eq.), PivONa (4.0 eq.)
H
OMe
BF4
F
OCO2Me
Ar
CHCl3 (1.5 mL), MeOH (25.0 eq.)
45 W blue LEDs, -5 °C
1
3
(1.5 eq.)
N
NHC-
NO2
O
O
O
O
O
OMe
OMe
OMe
OMe
OMe
F
F
F
F
F
3a
3b
3c
3d
3e
O
O
(E) 3a
-
: 60% (94% ee)
: 3% (96% ee)
O
F
Cl
OCF3
Me
(Z)-3a
Ph
Ph
X
OMe
OMe
H
F
F
Ph
OCO2Me
1a
PS-C (E) 3a
-
: 76% (95% ee)
: 3% (97% ee)
81 (98), 9:1
70 (97), 10:1
71 (92), 6:1
61 (94), 9:1
58 (98), 6:1
X
(E) 3a
(Z)-3a
-
(Z)-3a
O
O
O
O
O
OMe
F
OMe
F
OMe
F
OMe
F
OMe
F
O
O
O
standard conditions
Ph
Ph
OMe
OMe
OMe
3f
3g
3h
3i
3j
iPr
tBu
F
F
F
Ph
Me
nBu
tBu
(E)-3a
(E)-3a
(Z)-3a
, 20% (0% ee)
, 96% ee
, trace
50 (94), 5:1
75 (95), 6:1
84 (95), 9:1
68 (96), 8:1
52 (97), 8:1
O
O
O
O
O
O
O
Ar
H
OR
OMe
OMe
OMe
OMe
OMe
OCO2Me
N
N
Ar
F
F
F
F
F
F
R N
R
3
1
3k
3l
3m
3n
3o
Cl
MeO
iPrO
Me
Me
tBu
tBu
ROH
63 (94), 7:1
75 (93), 8:1
73 (95), 7;1
79 (97), 7:1
55 (96), 5:1
O
N
OH
NHC- + base
R
R
O
O
O
O
O
Ar
N
N
OMe
OMe
OMe
OMe
OMe
F
N
N
N
Ar
F
OCO2Me
N
F
F
F
F
Cl
F
F
R
R
E
A
3p
3q
3r
3s
3t
Cl
Me
O
Me
Cl
F
F
olefin isomerization
Ar
CO2, MeOH
O
NHC+
52 (95), 9:1
68 (94), 9:1
69 (88), 9:1
60 (88), 3:1
73 (96), 8:1
F
D
O
R
O
O2
N
N
O
O
O
O
 interaction
Ar
N
[Ir]III
N
N
OMe
OMe
OMe
F
OMe
N
F
N
F
F
F
R
energy
transfer
C
B
3u
3v
3w
3a
4c (CCDC: 2005670)
F
Me
*[Ir]III
Me
Cl
Selectfluor
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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S. A. 2013, 110, 13729; (d) R. Guo, J. Huang, X. Zhao, ACS
Scheme 3. Control experiments and speculated catalytic cycle.
View Article Online
Catal. 2018, 8, 926.
DOI: 10.1039/D0CC07264H
out the possibility of olefin isomerization might also occur
to dienolate intermediate B. From steric perspective, α-
fluorination might have been slower for the (Z)-isomer of B
than its (E)-isomer (A1,3-strain) and therefore less likely.
In conclusion, we report an NHC/photosensitization relay
catalysis that promotes photo-induced energy transfer of an
NHC-bounded intermediate to yield (Z)-allylic fluorides
with good stereochemical control. Systematic investigations
of influence by both NHC catalysts and photosensitizers
were carried out. Upon a highly enantioselective α-
fluorination step, the key (E)-acyl azolium intermediate
undergoes in situ photoisomerization prior to NHC turnover.
It is suspected that π-π interactions between NHC and olefin
may enhance asymmetric control and the choice of
photocatalyst is important to control the rate and stage of
isomerization. The unprecedented cooperation of
photosensitization with NHC organocatalysis demonstrates
unique advantages for accessing thermodynamically
unfavored olefin isomers, especially those bearing multiple
functional groups.
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This work was financially supported by the National Natural Science
Foundation of China (21825101), Guangdong Basic and Applied
Basic Research Foundation (2019A1515011641) and Shenzhen
Science
and
Technology
Innovation
Commission
(SGDX2019081623241924, JCYJ20170818085510474).
Conflicts of interest
The authors declare no competing financial interests.
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Photo-induced energy transfer relay of N-heterocyclic carbene catalysis: An asymDmOeI:t1r0ic.103α9-/D0CC07264H
fluorination/isomerization cascade.
O
acyl azolium
Ph
O
NHC
+
O
H
LG
NHC+
F
OR
base
F+
F
O
(Z)-isomer
O
N
 synergistic process
 Z)-allylic fluoride

N
O
N


NHC+
isomerization
F
high enantioselectivity
vinylogous enolate
 high chemoselectivity