Chemo- and Regioselective Ring Construction Driven by Visible-Light Photoredox Catalysis: an Access to Fluoroalkylated Oxazolidines Featuring an All-Substituted Carbon Stereocenter

Article abstract of DOI:10.1002/adsc.201900585

The unique advantages conferred by incorporation of all-substituted carbon stereocenters in organic molecules have gained widespread recognition. In this work, we describe a three-component cyclization to access C-2 fluoroalkylated oxazolidines by fragments assembly of readily available silyl enol ether, fluoroalkyl halide, and chiral amino alcohol in a single reaction vessel, which provides an efficient strategy for expanding the pool of pharmaceutically important heterocycles featuring an all-substituted carbon stereocenter. This process proceeds efficiently in a chemo-, regio-, and stereoselective fashion under mild reaction conditions at room temperature and exhibits broad functional group tolerance. The successful realization of this controlled heteroannulation sequence relies on distinctive perfluoroalkylation, regio- and stereoselective radical cyclization through visible-light photoredox catalysis. Moreover, a one-pot procedure directly employing ketone as substrate has also been achieved. (Figure presented.).

Full text of DOI:10.1002/adsc.201900585

Title: Chemo- and Regioselective Ring Construction Driven by Visible-
Light Photoredox Catalysis: an Access to Fluoroalkylated
Oxazolidines Featuring an All-Substituted Carbon Stereocenter
Authors: Xue-Qiang Chu, Danhua Ge, Mao-Lin Wang, Weidong Rao,
Teck-Peng Loh, and Zhi-Liang Shen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900585
Link to VoR: http://dx.doi.org/10.1002/adsc.201900585

10.1002/adsc.201900585
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Chemo- and Regioselective Ring Construction Driven by
Visible-Light Photoredox Catalysis: an Access to
Fluoroalkylated Oxazolidines Featuring an All-Substituted
Carbon Stereocenter
a
a
a
b
a,c
,
Xue-Qiang Chu, Danhua Ge, Mao-Lin Wang, Weidong Rao, Teck-Peng Loh, *
and Zhi-Liang Shena,*
a
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic
Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China.
E-mail: ias_zlshen@njtech.edu.cn.
Jiangsu Key Laboratory of Biomass-based Green Fuels and Chemicals, College of Chemical Engineering, Nanjing
b
Forestry University, Nanjing 210037, China.
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
c
Technological University, Singapore 637371, Singapore.
E-mail: teckpeng@ntu.edu.sg.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The unique advantages conferred by incorporation room temperature and exhibits broad functional group
of all-substituted carbon stereocenters in organic molecules tolerance. The successful realization of this controlled
have gained widespread recognition. In this work, we heteroannulation
sequence
relies
on
distinctive
describe a three-component cyclization to access C-2 perfluoroalkylation, regio- and stereoselective radical
fluoroalkylated oxazolidines by fragments assembly of cyclization through relay visible-light photoredox catalysis.
readily available silyl enol ether, fluoroalkyl halide, and Moreover, a one-pot procedure directly employing ketone
chiral amino alcohol in a single reaction vessel, which as substrate has also been achieved.
provides an efficient strategy for expanding the pool of
pharmaceutically important heterocycles featuring an all-
substituted carbon stereocenter. This process proceeds
efficiently in a chemo-, regio-, and stereoselective fashion
under mild reaction conditions at
Keywords: Photoredox catalysis; Multicomponent
reaction; Oxazolidines; All-substituted carbon stereocenter;
Fluoroalkylation
consequence of lengthy procedure, limited
commercial availability of precursors (e.g., specific
organic halides and carbonyl compounds), and
undesirable side reactions (Scheme 1, 2A).[5] While
the functionalization of saturated cyclic amines
relying on the activation of -C–H bond adjacent to
nitrogen atom by using transition metal catalysis[6] or
via radical-type reactions[7] promised to provide new
entries (Scheme 1, 2B),[8] unlike the functionalization
of their aromatic counterparts, attempts to derivatize
N-unprotected cyclic amines by using the same cross-
couplings are often faced with the lack of directing
groups.[9] To address the paucity of existing methods
towards these valuable chemicals containing an
additional heteroatom, research efforts have been
continuously made for the construction of
oxazolidines and oxazoles via cyclization,[10-11]
aminohydroxylation,[12] and tin amine protocol
(SnAP).[13] Typically, the precise placement of C-
Introduction
Saturated N-heterocycles, especially the highly
functionalized
oxazolidines,
have
attracted
consideration attentions both in academia and
industry, in view that they frequently revolutionize
privileged
pharmaceuticals
and
important
biologically active molecules[1,2] and are also widely
used in asymmetric synthesis as an invaluable
template in the pool of chiral catalysts and auxiliaries
(Scheme 1, 1).[3] Considering the increasing demands
in drug discovery for flexible modulations of
oxazolidines with structural complexity,[4] the
development of new synthetic strategies to access a
wider class of these important frameworks from
ubiquitous starting materials that could be assembled
in an easily accessible fashion are highly sought after.
Conventionally, the synthesis of densely
substituted oxazolidine derivatives could be achieved
via the direct alkylation of vicinal amino alcohols, but
the laborious routes suffered from well-recognized
limitations, such as low overall yields as a
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900585
Advanced Synthesis & Catalysis
still a particularly daunting task even in the field of
asymmetric synthesis.[14]
On the other hand, it is well-known that installing
fluorine atoms or higher homologue fluoroalkyl
groups (Rf) on organic molecules might exert
profound changes on chemical and physical
properties of organic molecules with minor spatial
alteration.[15] However, to the best of our knowledge,
few of the above reported methods deal with the
synthesis of fluorinated oxazolidines which might
exhibit improved biological and pharmaceutical
activity as a result of the incorporation of fluorine
atom in the molecules. Therefore, the strategic
exploitation of fluorine-containing building blocks[16]
for rapid assembly of oxazolidines pharmacophores
bearing Rf group and an all-substituted carbon center
will be of great value and highly desirable.[17] In
continuation of our task to develop efficient strategies
for the construction of fluoro-containing heterocycles
from readily available starting materials,[18] herein we
Scheme 1. Representative compounds featuring
oxazolidines skeletons and strategies for the synthesis of
oxazolidine derivatives.
describe
an
unprecedented
three-component
heteroannulation for directly constructing modular C-
2 fluoroalkylated oxazolidines by taking advantage of
visible-light photoredox catalysis under mild reaction
conditions (Scheme 1, 3). This protocol distinguishes
itself by broad functional group tolerance with
spatially defined substituents and heteroatoms in a
chemo-, regio-, and diastereoselective manner, which
provides an attractive complement to the existing
methods for the synthesis of organofluorine
compounds where preformed or commercially
available saturated N-heterocycles were directly
employed for fluoro-functionalization.
substituents on N-heterocycles has been readily
achieved by Bode[13] by means of combining carbonyl
compounds with bespoke SnAP reagents. However,
the requirement of stoichiometric copper, the toxicity
of organotin compound, and the necessity of
prefunctionalization of SnAP reagents have
somewhat limited the implementation of this strategy.
More importantly, one of the apparent difficulties of
these approaches is the generation of all-substituted
stereogenic centres in oxazolidine skeleton, which is
Results and Discussion
Table 1. Optimization of reaction conditions[a]
Entry
Photocatalyst [x mol%]
Base
Solvent
Yield [%][b]
1
2
3
4
5
Rose Bengal (3)
Ru(bpy)3Cl26H2O (3)
Eosin Y (3)
DABCO
DABCO
DABCO
DABCO
DABCO
MeCN
MeCN
MeCN
MeCN
MeCN
5
34
52
28
64
Eosin B (3)
Acriflavine (3)
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900585
Advanced Synthesis & Catalysis
--
DABCO
DABCO
DABCO
DABCO
DABCO
-
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
trace
trace
trace
72
6
Phloxine B (3)
7
Benzophenone (3)
Acriflavine (1.5)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
Acriflavine (0.3)
8
9
75 (68)[c]
10
11
12
13
14
15
16
17
18
19
20
21
22
0
DBU
trace
22
Et3N
iPr2NH
Cs2CO3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
48
0
54
DCE
18
DMF
58
acetone
MeCN
MeCN
MeCN
34
<5[d]
56[e]
58[f]
[a] Reaction conditions: 1a (0.6 mmol), 2a (0.9 mmol), 3a (0.3 mmol), photocatalyst (0.0009-0.009
mmol) and base (1.2 mmol) in solvent (2.0 mL) at room temperature by irradiation with blue LEDs
(4.5 W) under N2 for 24 h. [b] Yields and diastereoselectivities (>20:1 dr) were determined by NMR
analysis of crude reaction mixture (1,4-dimethoxybenzene as an internal standard). [c] Isolated yield.
[d] TMS enol ether was used in place of TIPS enol ether 1a. [e] TES enol ether was used in place of
TIPS enol ether 1a. [f] TBS enol ether was used in place of TIPS enol ether 1a.
With the optimized reaction conditions in hand, we
Initially, we investigated the model reaction of set out to investigate the substrate scope of the reaction
triisopropylsilyl (TIPS) enol ether 1a, perfluorobutyl by using a broad range of silyl enol ethers 1. As
iodide (2a), and (1S,2R)-1-amino-2,3-dihydro-1H- summarized
inden-2-ol (3a) in the presence of 3 mol% of rose phenylvinyl)oxy)silanes
bengal as catalyst and 4.0 equiv of substituents of varying electronic character and steric
in
Table
2,
triisopropyl((1-
1
containing
diverse
a
triethylenediamine (DABCO) as a base in acetonitrile hindrance on aromatic rings were smoothly converted
at room temperature under the irradiation of white into the corresponding products 4a-l in satisfactory
LEDs for 24 h, which fortunately delivered 5% NMR yields with excellent diastereoselectivities (>20:1 dr).
yield of fluoroalkylated oxazolidine 4a with good C-2 Notably, functional groups, such as halogens (Cl, Br, I,
selectivity (Table 1, entry 1). Evaluation of various 1b-d), cyano (1k), and methoxycarbonyl (1l) were
visible-light photoredox catalysts (entries 2-8) led to well
the discovery of acriflavine as a more efficient catalyst
for the desired annulation, whose loading could be
Table 2. Substrate scope of various silyl enol ethers[a]
decreased as low as 0.3 mol%, affording the N-
unprotected heterocycle 4a in 75% NMR yield and
68% isolated yield (entry 10). Notably, all the
reactions
proceeded
with
excellent
diastereoselectivities (>20:1 dr), which probably could
be attributed to the cis-addition mode of chiral amino
alcohol 3a.[5b] Additionally, attempts to use other bases
(entries 12-15) and solvents (entries 16-19) did not
lead to any improvement of product yield, and
noticeable decomposition of enolsilanes were observed
under these conditions (entries 12-19).[19] Moreover,
based on previous works,[18] we envisaged hat the
relative stability and the appropriate steric hindrance of
Si-protective groups should be beneficial to the
reaction. As expected, employment of trimethylsilyl
(TMS, entry 20), triethylsilyl (TES, entry 21), or tert-
butyldimethylsilyl (TBS, entry 22) groups remarkably
impaired the reaction efficiency, as compared to the
use of TIPS as protecting group (entry 10).
[a]
Standard conditions; yields of isolated products;
1
diastereoselectivity was determined by H NMR analysis of
crude reaction mixture. [b] For 24 h. [c] 1 mmol scale for 24 h.
tolerated under the mild reaction conditions, which
could be retained for late-stage manipulation. In a
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900585
Advanced Synthesis & Catalysis
same streamlined manner, substrates featuring observation that the use of (1R, 2S)-1-amino-2,3-
polycyclic and heteroaromatic motifs, such as dihydro-1H-inden-2-ol (3b) with opposite
naphthalene (1m), benzo[b]thiophene (1n), and configuration also led to the corresponding product 5a
pyridine (1o) also worked without difficulty to afford with reversed stereochemistry in 59% yield with >20:1
the densely functionalized oxazolidines 4m-o in 35- dr. It should be noted that the use of (1R, 2S)-2-amino-
56% yields. In addition, structural variation with the 1,2-diphenylethan-1-ol as substrate only resulted in the
presence of an α-substituent in cyclic enolsilane 1p did exclusive formation of alkenylated product 5b' in 75%
not interfere with the intermolecular formal [4+1] yield, no anticipated product 5b was obtained which
annulation, which provided access to a spirocyclic might be owing to the negative influence of steric
oxazolidine nuclei 4p bearing an all-substituted carbon effects. In contrast, other enantiopure amino alcohols
center at C-3 position in 34% yield. However, alkyl possessing potentially epimerizable stereogenic centers,
variant 1q was proven to be an inappropriate candidate such as phenylglycinol, phenylalaninol, valinol, and
for our reaction system (4q). It should be mentioned methyl serinate, could be transformed into
that the relative configuration of heterocycle 4i was synthetically useful oxazolidine derivatives 5c-f
tentatively assigned from the COSY and NOESY without any detectable racemization under mild
analysis (see Supporting Information for details). The reaction conditions, albeit in slightly decreased yields.
ability to facilely assemble special N-heterocycles These results will resonate with drug discovery
from simple and readily available acyclic building programs from chiral amino alcohols concerning N-
blocks, as demonstrated by the present protocol, will heterocycles synthesis.[4] Unfortunately, simple amino
provide efficient means for the construction and alcohol of 2-aminoethan-1-ol almost could not react
derivatization of valuable products.
under the optimal reaction conditions (5g).
Furthermore, we were able to accomplish the
conversion of related N-alkyl-protected amino alcohols
to heterocyclic products 5h and 5i in 25% and 69%
yields, respectively. Finally, various perfluoroalkyl
halides (except bromodifluoroacetate) with 3-10
carbon chain length were amenable to the mild
reaction conditions, producing C-2 perfluoroalkylated
products 6a-d in appreciable yields with >20:1
diastereoselectivities. Unfortunately, other types of di-
Table 3. Substrate scope of various β-amino alcohols and
perfluoroalkyl halides[a]
nucleophiles,
including
(1R,2R)-N1,N2-
dimethylcyclohexane-1,2-diamine (3k), cyclohexane-1,2-
diamine (3l), N1,N2-dimethylethane-1,2-diamine (3m),
ethane-1,2-diol (3n), (R)-3-(tert-butylamino)propane-1,2-
diol (3o), and ethyl D-cysteinate (3p), failed to produce
any products under the optimized reaction conditions.
[a]
Standard conditions; yields of isolated products;
Scheme 2. Transformation of propranolol to oxazolidine 7
and one-pot heteroannulation.
1
diastereoselectivity was determined by H NMR analysis of
crude reaction mixture.
shown.
[b]
Only major diastereomers are
Impressively, propranolol hydrochloride 3q as an
amino alcohol exhibited good reactivity and well
participated in this photocatalytic multicomponent
heteroannulation to produce the oxazolidine-modified
adduct 7 in 64% yield (Scheme 2, A). This result
indicates that the present methodology will not only be
useful in synthetic chemistry, but also be beneficial to
drug discovery for the rational design of drug for
Subsequently, the present catalytic protocol was
successfully extended to the use of various β-amino
alcohols with different degrees of substitution and
stereochemistry (Table 3). It was found that the
configuration of amino alcohols 3 only has a slight
impact on the reactivity, as elucidated by the
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900585
Advanced Synthesis & Catalysis
treating high blood pressure.[20] Additionally, product 8 under the standard conditions (Scheme 3, E).
considering procedural simplicity and synthetically Moreover, when the isolated intermediate 4a' was
ready accessibility, a two-step, one-flask procedure subjected to cyclization with amino alcohol under
was designed by utilizing in situ prepared enolsilanes optimized reaction conditions in the absence of visible
from related ketones (1k' and 1l') with TIPSOTf in the light, the formation of product 4a was almost
presence of Et3N, followed by exposure to the present unaffected (Scheme 3, F), thereby indicating that the
photocatalytic conditions. Gratifyingly, the one-pot ring-closure step mostly takes place via a conventional
reaction proceeded efficiently as well, giving rise to Michael addition route rather than a radical-type
the corresponding products 4k and 4l both in 56% reaction pathway.
yields in a succinct way (Scheme 2, B).
Scheme 4. Proposed reaction mechanism and rationale for
the high diastereoselectivity obtained.
On the basis of above control experiments and
literature
survey,[21,22]
a
radical-type
Scheme 3. Control experiments.
fluoroalkylation/defluorination/annulation mechanism
driven by relay visible-light photoredox catalysis is
depicted in Scheme 4a. First, the postulated
photocatalytic cycle begins with single electron
transfer (SET) from excited-state acriflavine* (Ered = -
1.19 V vs SCE in MeCN) to perfluorobutyl iodide (2a,
Ered = -1.10 V vs SCE in MeCN) to produce an
electrophilic n-C4F9 radical and a radical cation PC•+
by irradiation with visible light (see Supporting
Information for details). Addition of the formed
perfluoroalkyl radical to silyl enol ether 1 affords
tertiary radical species A, which is subsequently
oxidized by PC•+ to close the first photocatalytic cycle
and generate α-perfluoroalkylated ketone C after rapid
attack by an I- ion through carbocation B. Next, α,β-
desaturation of unstable carbonyl compound C is
enabled to give intermediate 4a' by means of
To gain insights into the putative mechanism of the
above reaction, several control experiments were
performed (Scheme 3). When the model reaction was
treated with radical scavengers of 2,2,6,6-
tetramethylpiperidin-1-oxyl (TEMPO, 3 equiv) under
standard reaction conditions, no anticipated product 4a
was detected (Scheme 3, A), indicative of the
involvement of a radical-type mechanism in the
reaction. In addition, control experiment B showed that
when enolsilane 1a was reacted with 2a under well-
established reaction conditions, (Z)-3,4,4,5,5,6,6,6-
octafluoro-1-phenylhex-2-en-1-one (4a'), which is
considered to be the key intermediate of the reaction,
could be isolated in 16% yield. The intermediacy of
4a' was further demonstrated by the fact that piperidine
could trap the possible intermediate 4a' to produce -
aminated ketone 4a'' in 13% yield (Scheme 3C).
Treatment of this intermediate 4a' with amino alcohol
3a did lead to the product 4a in 65% yield (Scheme 3,
D), suggesting that the three-component model
reaction should proceed via the formation of
intermediate 4a' through an intermolecular α-
perfluoroalkylation followed by ensuing defluorination.
Notably, the fluoro-substituent was also crucial for the
reactivity, in light of the fact that chalcone (4a''')
could not be converted into the corresponding cyclized
eliminating
a
molecule of HF under basic
conditions.[18a] Subsequently, amino alcohol
3
undergoes Michael-type reaction with intermediate 4a'
followed by fast β-F elimination to generate the enone
E. The observed regioselectivity results from the
comparatively stronger nucleophilicity of nitrogen
atom over oxygen one. The key species of alkenylated
compound E undergoes intramolecular Michael
addition to produce the cyclized product 4. Other
alternative rationales for the formation of alkoxy
radical via a proton coupled electron transfer (PCET)
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900585
Advanced Synthesis & Catalysis
process[21,22] or the formation of the radical-cation
intermediate via oxidizing the double bond of
diaza[2.2.2]bicyclooctane (DABCO, 168 mg, 1.5 mmol) in
MeCN (2.0 mL) was stirred under nitrogen atmosphere (by
compound
E
could
be
excluded.[23]
The
3
times’ vacuum evacuation/N2 backfill cycles) by
diastereoselectivity of this transformation is set during
the course of cyclization mainly due to the
configuration of chiral amino alcohol, enabling the
intramolecular addition to occur preferentially from the
less hindered front face (Scheme 4b).[24]
irradiation with 4.5 W white LEDs at room temperature for
28 h. Upon completion of the reaction (indicated by TLC),
solvent was removed under vacuum and the residue was
purified by flash silica gel column chromatography (300-
400 mesh) using petroleum ether/ethyl acetate (50:1) as
eluent to afford the pure methyl 4-(2-(3-isopropyl-5-
((naphthalen-1-yloxy)methyl)-2-
Conclusion
(perfluoropropyl)oxazolidin-2-yl)acetyl)benzoate (7, 118
mg, 64% yield).
In summary, an efficient strategy involving relay
visible-light photoredox catalysis has been developed
for accessing modular fluoroalkylated oxazolidines
with spatially defined substituents commencing from
readily available silyl enol ethers, fluoroalkyl halides,
and chiral amino alcohols. This process enables
annulation in a chemo-, regio-, and diastereoselective
manner under metal-free, ambient conditions and
exhibits broad functional group tolerance, which
represents a valuable entry to the divergent synthesis
of saturated N-heterocycles. Moreover, the one-pot
procedure directly employing ketones as an enolsilane
precursor also has been achieved with good synthetic
efficiency. Mechanistic studies showed that the
reaction presumably proceeded through a radical-type
reaction pathway via the formation of β-fluoro-
substituted enone 4a' as a key intermediate.
Acknowledgements
We gratefully acknowledge the Natural Science Foundation of
Jiangsu Province, China (BK20180690), the financial support from
Nanjing Tech University (Start-up Grant No. 39837118, 39837101,
and 39837146), the SICAM Fellowship from Jiangsu National
Synergetic Innovation Center for Advanced Materials, Nanjing
Forestry University, and Nanyang Technological University.
References
[1] a) B. S. Davidson, Chem. Rev. 1993, 93, 1771; b) Z. Jin,
Nat. Prod. Rep. 2006, 23, 464; c) J. D. Scott, R. M.
Williams, Chem. Rev. 2002, 102, 1669.
[2] a) G. P. Moloney, D. J. Craik, M. N. Iskander, T. L.
Nero, J. Chem. Soc., Perkin Trans. 2 1998, 199; b) Y.-C.
Wu, M. Liron, J. Zhu, J. Am. Chem. Soc. 2008, 130,
7148; c) C. Zhang, D. L. Zink, M. Ushio, B. Burgess, R.
Onishi, P. Masurekar, J. F. Barrett, S. B. Singh, Bioorg.
Med. Chem. 2008, 16, 8818; d) K. Ii, S. Ichikawa, B. Al-
Dabbagh, A. Bouhss, A. Matsuda, J. Med. Chem. 2010,
53, 3793; e) A. Monge, I. Aldana, H. Cerecetto, A.
Rivero, J. Heterocycl. Chem. 1995, 32, 1429; f) S. F.
Andrade, C. S. Teixeiraa, J. P. Ramosb, M. S. Lopesa, R.
M. Páduaa, M. C. Oliveiraa, E. M. Souza-Fagundes, R. J.
Alves, Med. Chem. Commun. 2014, 5, 1693; g) S. F.
Andrade, B. G. Oliveira, L. C. Pereira, J. P. Ramos, A. R.
Joaquim, M. Steppe, E. M. SouzaFagundes, R. J. Alves,
Eur. J. Med. Chem. 2017, 138, 13.
Experimental Section
Synthesis
of
2-((2R,3aS,8aR)-2-(perfluoropropyl)-
3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-yl)-1-
phenylethan-1-one (4a).
A solution of triisopropyl((1-phenylvinyl)oxy)silane (1a,
165 mg, 0.6 mmol), perfluorobutyl iodide (2a, 311 mg, 0.9
mmol), (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (3a, 45
mg, 0.3 mmol), acriflavine (0.2 mg, 0.0009 mmol), and 1,4-
diaza[2.2.2]bicyclooctane (134.5 mg, 1.2 mmol) in MeCN
(2.0 mL) was stirred under nitrogen atmosphere (by 3 times’
vacuum evacuation/N2 backfill cycles) by irradiation with
4.5 W white LEDs at room temperature for 24-48 h. Upon
completion of the reaction (indicated by TLC), solvent was
removed under vacuum and the residue was purified by
flash silica gel column chromatography (300-400 mesh)
using petroleum ether/ethyl acetate (200/1) as eluent to
afford the pure 2-((2R,3aS,8aR)-2-(perfluoropropyl)-
3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-yl)-1-
phenylethan-1-one (4a, 91 mg, 68%).
[3] For selected examples, see: a) G. C. Hargaden, P. J.
Guiry, Chem. Rev. 2009, 109, 2505; b) C. Wolf, H. Xu,
Chem. Commun. 2011, 47, 3339; c) Y.-J. Zhao, T.-P.
Loh, J. Am. Chem. Soc. 2008, 130, 10024; d) O. A.
Mukhina, A. G. Kutateladze, J. Am. Chem. Soc. 2016,
138, 2110.
[4] V. S. C. Yeh, Tetrahedron 2004, 60, 11995.
[5] a) E. D. Bergmann, Chem. Rev. 1953, 53, 309; b) C.
Agami, F. Couty, Eur. J. Org. Chem. 2004, 677.
Synthesis of methyl 4-(2-(3-isopropyl-5-((naphthalen-1-
yloxy)methyl)-2-(perfluoropropyl)oxazolidin-2-
yl)acetyl)benzoate (7).
[6] a) S. J. Pastine, D. V. Gribkov, D. Sames, J. Am. Chem.
Soc. 2006, 128, 14220; b) J. E. Spangler, Y. Kobayashi,
P. Verma, D.-H. Wang, J.-Q. Yu, J. Am. Chem. Soc.
2005, 137, 11876; c) H. Prokopcová, S. D. Bergman, K.
Aelvoet, V. Smout, W. Herrebout, B. Van der Veken, L.
Meerpoel, B. U. W. Maes, Chem.–Eur. J. 2010, 16,
A
solution
of
methyl
4-(1-
((triisopropylsilyl)oxy)vinyl)benzoate (1l, 201 mg, 0.6
mmol), perfluorobutyl iodide (2a, 311 mg, 0.9 mmol),
propranolol hydrochloride (3q, 89 mg, 0.3 mmol),
Acriflavine (0.2 mg, 0.0009 mmol), and 1,4-
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900585
Advanced Synthesis & Catalysis
13063; d) N. Yoshikai, A. Mieczkowski, A. Matsumoto,
L. Ilies, E. Nakamura, J. Am. Chem. Soc. 2010, 132,
5568; e) I. D. Jurberg, B. Peng, E. Wöstefeld, M.
Wasserloos, N. Maulide, Angew. Chem. Int. Ed. 2012, 51,
1950; Angew. Chem. 2012, 124, 1986; f) P. R. Payne, P.
Garcia, P. Eisenberger, J. C. H. Yim, L. L. Schafer, Org.
Lett. 2013, 15, 2182.
2016, 116, 422; b) A. Studer, Angew. Chem. Int. Ed.
2012, 51, 8950; Angew. Chem. 2012, 124, 9082; c) C.-P.
Zhang, Q.-Y. Chen, Y. Guo, J.-C. Xiao, Y.-C. Gu, Chem.
Soc. Rev. 2012, 41, 4536; d) H. Egami, M. Sodeoka,
Angew. Chem. Int. Ed. 2014, 53, 8294; Angew. Chem.
2014, 126, 8434; e) E. Merino, C. Nevado, Chem. Soc.
Rev. 2014, 43, 6598; f) D. E. Yerien, S. Barata-Vallejo,
A. Postigo, Chem.–Eur. J. 2017, 23, 14676; g) F. Zhou,
Y. Cheng, X.-P. Liu, J.-R. Chen, W.-J. Xiao, Chem.
Commun. 2019, 55, 3117; h) Q. Guo, M. Wang, Y.
Wang, Z. Xu, R. Wang, Chem. Commun. 2017, 53,
12317.
[7] For selected examples, see: a) T. Yoshimitsu, Y. Arano,
H. Nagaoka, J. Am. Chem. Soc. 2005, 127, 11610; b) A.
McNally, C. K. Prier, D. W. C. MacMillan, Science
2011, 334, 1114; c) L. Shi, W. Xia, Chem. Soc. Rev.
2012, 41, 7687.
[17] a) K. Matoba, H. Kawai, T. Furukawa, A. Kusuda, E.
Tokunaga, S. Nakamura, M. Shiro, N. Shibata, Angew.
Chem. Int. Ed. 2010, 49, 5762; Angew. Chem. 2010, 122,
5898; b) J. Chen, S. Meng, L. Wang, H. Tang, Y. Huang,
Chem. Sci. 2015, 6, 4184; c) A. Sanz-Marco, G. Blay, C.
Vila, J. R. Pedro, Org. Lett. 2016, 18, 3538.
[8] For selected reviews, see: a) K. R. Campos, Chem. Soc.
Rev. 2007, 36, 1069; b) E. A. Mitchell, A. Peschiulli, N.
Lefevre, L. Meerpoel, B. U. W. Maes, Chem.–Eur. J.
2012, 18, 10092; c) P. Beak, A. Basu, D. J. Gallagher, Y.
S. Park, S. Thayumanavan, Acc. Chem. Res. 1996, 29,
552; d) C.-V. T. Vo, J. W. Bode, J. Org. Chem. 2014, 79,
2809; e) Y. Qin, J. Lv, S. Luo, Tetrahedron Lett. 2014, [18] a) X.-Q. Chu, T. Xie, L. Li, D. Ge, Z.-L. Shen, T.-P.
55, 551.
Loh, Org. Lett. 2018, 20, 2749; b) T. Xie, Y.-W. Zhang,
L.-L. Liu, Z.-L. Shen, T.-P. Loh, X.-Q. Chu, Chem.
Commun. 2018, 54, 12722; c) X.-Q. Chu, B.-Q. Cheng,
Y.-W. Zhang, D. Ge, Z.-L. Shen, T.-P. Loh, Chem.
Commun. 2018, 54, 2615.
[9] P. Jain, P. Verma, G. Xia, J.-Q. Yu, Nat. Chem. 2017, 9,
140.
[10] a) K. R. Gaisina, A. F. Khlebnikov, M. S. Novikov,
Org. Biomol. Chem. 2017, 15, 4579; b) S. Murru, C. S.
Lott, B. McGough, D. M. Bernard, R. S. Srivastava, Org.
Biomol. Chem. 2016, 14, 3681.
[19] Acetophenone was detected as the major by-product.
[20] G. Vaiva, F. Ducrocq, K. Jezequel, B. Averland, P.
Lestavel, A. Brunet, C. R. Marmar, Biol. Psychiat. 2003,
54, 947.
[11] a) V. Rauniyar, A. D. Lackner, G. L. Hamilton, F. D.
Toste, Science 2011, 334, 1681; b) N. Arai, M. Mizota,
T. Ohkuma, Org. Lett. 2015, 17, 86; c) N. Noto, K. [21] a) J. J. Warren, T. A. Tronic, J. M. Mayer, Chem. Rev.
Miyazawa, T. Koike, M. Akita, Org. Lett. 2015, 17,
3710; d) A.-J. Cai, Y. Zheng, J.-A. Ma, Chem. Commun.
2015, 51, 8946; e) W.-C. Gao, F. Hu, Y.-M. Huo, H.-H.
Chang, X. Li, W.-L. Wei, Org. Lett. 2015, 17, 3914.
2010, 110, 6961; b) D. R. Weinberg, C. J. Gagliardi, J. F.
Hull, C. F. Murphy, C. A. Kent, B. C. Westlake, A. Paul,
D. H. Ess, D. G. McCafferty, T. J. Meyer, Chem. Rev.
2012, 112, 4016; c) H. G. Yayla, H. Wang, K. T.
Tarantino, H. S. Orbe, R. R. Knowles, J. Am. Chem. Soc.
2016, 138, 10794; d) A. Pannwitz, O. S. Wenger, Chem.
Commun. 2019, 55, 4004; e) M. Zhang, L. Yang, H.
Yang, G. An, G. Li, ChemCatChem 2019, 11, 1606.
[12] D. J. Michaelis, C. J. Shaffer, T. P. Yoon, J. Am. Chem.
Soc. 2007, 129, 1866.
[13] a) C.-V. T. Vo, M. U. Luescher, J. W. Bode, Nat. Chem.
2014, 6, 310; b) M. U. Luescher, C.-V. T. Vo, J. W.
Bode, Org. Lett. 2014, 16, 1236; c) W.-Y. Siau, J. W.
Bode, J. Am. Chem. Soc. 2014, 136, 17726.
[22] For examples with the use of organic photocatalyst as
hydrogen atom transfer (HAT) reagents, see: a) G. Zhao,
T. Wang, Angew. Chem. Int. Ed. 2018, 57, 6120; Angew.
Chem. 2018, 130, 6228; b) X.-Z. Fan, J.-W. Rong, H.-L.
Wu, Q. Zhou, H.-P. Deng, J.-D. Tan, C.-W. Xue, L.-Z.
Wu, H.-R. Tao, J. Wu, Angew. Chem. Int. Ed. 2018, 57,
8514; Angew. Chem. 2018, 130, 8650; c) D.‐ M. Yan,
J.‐ R. Chen, W.‐ J. Xiao, Angew. Chem. Int. Ed. 2019,
58, 378; Angew. Chem. 2019, 131, 384.
[14] a) J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593;
b) Y. Zhu, J. Han, J. Wang, N. Shibata, M. Sodeoka, V.
A. Soloshonok, J. A. S. Coelho, F. D. Toste, Chem. Rev.
2018, 118, 3887; c) B. M. Trost, C.-I. Hung, T. Saget, E.
Gnanamani, Nat. Catal. 2018, 1, 523; d) J. Nie, H.-C.
Guo, D. Cahard, J.-A. Ma, Chem. Rev. 2011, 111, 455.
[23] a) G. Qin, X. Chen, L. Yang, H. Huang, ACS Catal.
2015, 5, 2882; b) G. Qin, Y. Wang, H. Huang, Org. Lett.
2017, 19, 6352.
[15] a) G.-J. Mei, F. Shi, Chem. Commun. 2018, 54, 6607; b)
C. Cadicamo, J. Courtieu, H. Deng, A. Meddour, D.
O’Hagan, ChemBioChem 2004, 5, 685; c) M. Hird,
Chem. Soc. Rev. 2007, 36, 2070; d) K. L. Kirk, Org.
Process Res. Dev. 2008, 12, 305.
[24] a) J. V. Matlock, T. D. Svejstrup, P. Songara, S.
Overington, E. M. McGarrigle, V. K. Aggarwal, Org.
Lett. 2015, 17, 5044; b) M. Yar, E. M. McGarrigle, V. K.
Aggarwal, Angew. Chem. Int. Ed. 2008, 47, 3784.
[16] a) Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L.
Aceña, V. A. Soloshonok, K. Izawa, H. Liu, Chem. Rev.
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900585
Advanced Synthesis & Catalysis
FULL PAPER
Chemo- and Regioselective Ring Construction
Driven by Visible-Light Photoredox Catalysis: an
Access to Fluoroalkylated Oxazolidines Featuring
an All-Substituted Carbon Stereocenter
Adv. Synth. Catal. Year, Volume, Page – Page
Xue-Qiang Chu, Danhua Ge, Mao-Lin Wang,
Weidong Rao, Teck-Peng Loh,* and Zhi-Liang
Shen*
8
This article is protected by copyright. All rights reserved.