Anti-Diastereoselective Synthesis of CF3-Containing Spirooxazolines and Spirooxazines via Regiospecific Trifluoromethylative Spirocyclization by Photoredox Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b01694

A novel synthesis of CF₃-containing spirooxazolines and spirooxazines has been developed. Regiospecific trifluoromethylative spirocyclization (CF₃-spirocyclization) of cyclic alkenes bearing an amide pendant mediated by photoredox ca

Full text of DOI:10.1021/acs.orglett.5b01694

Letter
pubs.acs.org/OrgLett
Anti-Diastereoselective Synthesis of CF3‑Containing Spirooxazolines
and Spirooxazines via Regiospecific Trifluoromethylative
Spirocyclization by Photoredox Catalysis
Naoki Noto, Kazuki Miyazawa, Takashi Koike,* and Munetaka Akita*
Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
S
* Supporting Information
ABSTRACT: A novel synthesis of CF3-containing spiroox-
azolines and spirooxazines has been developed. Regiospecific
trifluoromethylative spirocyclization (CF3-spirocyclization) of
cyclic alkenes bearing an amide pendant mediated by
photoredox catalysis is a useful strategy for construction of a
C(sp3)−CF3 bond and an spirooxazoline or spirooxazine ring
onto CC bonds via a single step. The key intermediate is α-
CF3-substituted carbocationic species smoothly generated
from single-electron-transfer (SET) photoredox processes, which results in diastereoselective spirocyclization. This is the first
example of synthesis of CF3-containing spirooxazolines and spirooxazines in anti-fashion with respect to the CF3 group and the
oxygen atom of the spirocycles.
synthesis of spirooxazolines and spirooxazines has been limited.5
pirooxazoline and spirooxazine scaffolds are useful structural
1
In 2011, the group of Toste reported that anion-based chiral
Smotifs in many biologically active molecules.
Thus,
phase transfer catalyst (PTC) induced asymmetric fluoro-
spirocyclization of allylic amides, leading to fluorinated
spirooxazolines (the upper process in Scheme 1b).5d But useful
synthetic protocols for spiro-fused rings through cyclization
accompanied by functionalization, especially carbo-spirocycliza-
tion, are still rare.4
development of synthetic methodologies for their derivatives
has attracted great interest from synthetic chemists for years.
One of the most useful strategies for synthesis of function-
alized spirooxazoline and spirooxazine is regioselective cycliza-
tion of cyclic alkenes with an amide pendant induced by
electrophilic activation of the olefinic moiety. Another good
aspect for the reaction of internal alkenes is an opportunity for
the construction of two stereogenic centers via a single step.
While synthesis of oxazolines and oxazines through cyclization of
allylic amides triggered by strongly electrophilic reagents such as
halogen and selenium electrophiles has been well-documentated
so far (Scheme 1a),2−4 application of this strategy to the
The trifluoromethyl group (CF3) is widespread in pharma-
ceutical and agrochemical fields because it influences chemical
and metabolic stability, lipophilicity, and binding selectivity,
resulting in unique bioactive properties.6,7 Recently, photoredox
catalysis8 with ruthenium(II) polypyridine complexes (e.g.,
[Ru(bpy)3]2+: bpy = 2,2′-bipyridine) and the relevant cyclo-
metalated iridium(III) derivatives has been recognized as a
powerful tool for radical trifluoromethylation.9,10 For the past
few years, our group has been extensively developing photo-
redox-catalyzed trifluoromethylative difunctionalization of ole-
fins.11 Our protocol is featured by (i) the use of shelf-stable
electrophilic trifluoromethylating reagents such as Umemoto’s
reagent 112 as a trifluoromethyl radical source and (ii)
regioselective generation of α-CF3-substituted carbocationic
intermediate from olefins through single-electron-transfer
(SET) photoredox processes, which is rather difficult to generate
by other methods. We expected that application of photoredox-
catalyzed trifluoromethylation to cyclic alkenes bearing a
nucleophilic amide moiety leads to CF3-containing spirooxazo-
lines and spirooxazines through intramolecular nucleophilic
attack of the oxygen atom in the amide functionality to an α-CF3-
substituted carbocationic intermediate.
Scheme 1. Synthesis of Heterocycles through
Functionalization−Cyclization Sequence of Alkenes Bearing
an Amide Pendant
Received: June 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01694
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Herein we describe the regiospecific trifluoromethylative
spirocyclization (CF3-spirocyclization) of cyclic alkenes bearing
an amide pendant mediated by photoredox catalysis, i.e.,
photoredox-catalyzed oxytrifluoromethylation,4c,10e,l,11a,g to be
a versatile protocol for access to CF3-containing spirooxazolines
and spirooxazines. In addition, this is the first report on
predominant formation of anti-diastereomers of CF3-containing
spirocyclic compounds.13
Scheme 2. Scope of the Present Photocatalytic CF3-
Spirocyclization of Allylic Amides (2)
a b c
, ,
We initially examined the photocatalytic reaction of N-((3,4-
dihydronaphthalen-1-yl)methyl)benzamide (2a) with Umemo-
to’s reagent 1 in the presence of 5 mol % [Ru(bpy)3](PF6)2 in
acetone-d6 at room temperature under visible light irradiation
with blue LED lamps (λmax = 425 15 nm). After 1.5 h, 2a was
completely converted but the corresponding spirooxazoline 3a
was not formed at all (Table 1, entry 1). Instead, a N-protonated
Table 1. Optimization of the Photocatalytic CF3-
a
Spirocyclization of Allylic Amide (2a)
b
b
entry
base
none
solvent
temp
rt
% yield of 3a
dr
c
1
2
3
4
5
acetone-d6
acetone-d6
acetone-d6
acetone-d6
CD2Cl2
−
−
−
−
c
K2CO3
rt
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
none
rt
91
91
90
0
77:23
84:16
74:26
−
−78 °C
−78 °C
−78 °C
−78 °C
−78 °C
d
6
acetone-d6
acetone-d6
acetone-d6
e
7
e
0
−
f
f
8
2,6-lutidine
28, 37
74:26
a
Reaction conditions: A mixture of [Ru(bpy)3](PF6)2 (1.25 μmol, 5
mol %), 1 (28 μmol, 1.1 equiv), 2a (25 μmol, 1.0 equiv), and solvent
a
b
b
Reaction conditions: see the Supporting Information. Yields were
(0.4 mL) was irradiated by 3 W blue LEDs (λ = 425 15 nm). Yields
c
and diastereomer ratios (dr) were determined by 1H NMR
obtained after purification. Diastereomer ratios (dr) were determined
d
by 1H and 19F NMR spectra of crude reaction mixtures. CH2Cl2 was
c
spectroscopy using SiEt4 as an internal standard. Protonated 3a was
e
d
e
f
used as a solvent due to solubility of substrate. Reaction was carried
out in the presence of 1.7 equiv of 1 at 0 °C for 4 h.
formed. In the dark. No photocatalyst. Reaction time = 8 h.
compound type of 3a was likely to be formed (see the Supporting
Information). Therefore, addition of a base, K2CO3 and 2,6-
lutidine, was tested. K2CO3 showed a result similar to entry 1
possibly due to its low solubility (entry 2). In contrast, to our
delight, 2,6-lutidine yielded the product 3a in a good yield (91%)
with good diastereoselectivity (77:23 dr) (entry 3). Next, to
improve the diastereoselectivity, the reaction was conducted at
−78 °C (in a dry ice−methanol bath), resulting in better
diastereoselectivity (84:16 dr) (entry 4). Use of CD2Cl2 as a
solvent also afforded the product smoothly (90% yield) but with
a slightly lower diastereoselectivity (74:26 dr) (entry 5). Finally,
the reaction did not proceed at all either in the dark or in the
absence of a photocatalyst (entries 6 and 7). To our surprise, 2,6-
lutidine also promoted the reaction to some extent even in the
absence of the photocatalyst (entries 7 and 8).14 But, even after a
longer reaction time, the yield was much lower than that obtained
by photoredox catalysis, suggesting that the reaction promoted
by 2,6-lutidine is not the main reaction pathway of the present
photocatalysis.
First, substituents on the amide pendants were explored.
Substrates with benzene rings bearing halogens, Br (2b) and I
(2c), and an electron-donating group, MeO (2d), and aliphatic
t
groups, Me (2e) and Bu (2f), afforded the corresponding
spirooxazoline products (3b−f) in good to high yields (59−
86%) with moderate to good diastereoselectivities (72:28−86:14
dr). Amide functionalities with an alkoxy group, OEt (2g), a
trichloromethyl group (2h), a naphthyl group (2i), and a pyridyl
group (2j) tolerated the present photocatalytic system (3g−3j:
52−85%, 75:25−86:14 dr). Remarkably, the alkene with a bulky
mesitylamide pendant (2k) gave 3k in a 73% yield with excellent
diastereoselectivity (97:3 dr). Next, structures of cyclic alkenes
were investigated. Reactions of N-((2H-benzopyran-4-yl)-
methyl)benzamide (2l) and N-((2H-thiocromen-4-yl)methyl-
benzamide (2m) proceeded without any retardation regardless
of the ether and sulfide functionalities to give the corresponding
CF3-spirocyclized products in good yields (3l: 71%, 88:12 dr and
3m: 64%, 89:11 dr) in a diastereoselective manner, respectively.
The reaction of N-((1H-inden-3-yl)methyl)benzamide (2n) also
afforded a good yield of the CF3-containing spirooxazoline (3n:
77%) but with slightly lower diastereoselectivity (77:23 dr)
compared to the dihydronaphthalenyl skeleton (3a). A
tetrasubstituted alkene, ((1H-2-methyl-inden-3-yl)methyl)-
With the optimal reaction conditions in hand, the preparative
scale experiments were performed. Then, we found that the
catalyst loading can be reduced to 0.5 mol %. The obtained CF3-
containing spirooxazolines 3 were summarized in Scheme 2.
B
DOI: 10.1021/acs.orglett.5b01694
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
benzamide (2o), could be also applied to the present reaction,
leading to the CF3-spirooxazoline with a quaternary carbon atom
3o (46%) but virtually with no diastereoselectivity (52:48 dr).
These results suggest that the present photocatalytic system is
amenable to diastereoselective synthesis of CF3-containing
spirooxazolines from cyclic alkenes with various amide pendants.
Diastereoselectivity is considerably dependent on the substituent
of the amide group and the structure of the cyclic alkenes.
The stereochemistry of the major diastereomer of CF3-
spirooxazolines 3c and 3n was unequivocally confirmed by
single-crystal X-ray analysis.15 An ORTEP drawing of the major
diastereomer (1R*,2S*)-3n is depicted in Figure 1. These results
revealed anti-stereochemistry for the nucleophilic cyclization
process with respect to the CF3 group.
by [Ru(bpy)3]2+ for the reaction of Umemoto’s reagent 1 with
cyclic alkenes 2 or 4 generates an α-CF3-substituted
carbocationic intermediate regiospecifically. This key intermedi-
ate undergoes intramolecular nucleophilic attack of the dangling
amide moiety in an anti-fashion presumably due to the steric
factor of the CF3 substituent. These regiospecific trifluorome-
thylation and anti-selective cyclization processes lead to the
predominant formation of anti-diastereomers of CF3-containing
spirooxazolines 3 or spirooxazines 5 (Scheme 4).
Scheme 4. A Plausible Reaction Mechanism for Anti-
Diastereoselectivity
Figure 1. An ORTEP drawing of the major diastereomer of CF3-
containing spirooxazoline (1R*,2S*)-3n. The thermal ellipsoids are set
at a 50% probability level.
In conclusion, we have developed a simple synthesis of both
CF3-containing spirooxazolines and spirooxazines from cyclic
alkenes bearing an amide pendant through trifluoromethylative
spirocyclization (CF3-spirocyclization) mediated by photoredox
catalysis under mild conditions. Regiospecific radical trifluor-
omethylation and anti-selective nucleophilic attack of the amide
pendant to the α-CF3-substituted carbocationic intermediate
lead to the formation of CF3-spirocycles in good to excellent
diastereoselectivity. This is the first example of an access to anti-
diastereomers of CF3-containing spirooxazolines and spiroox-
azines. Further studies on stereoselective trifluoromethylation
are underway in our laboratory.
Extension to amides with longer tethers, N-(2-(3,4-dihydro-
naphthalen-1-yl)ethyl)benzamides 4, was further examined
(Scheme 3). It was observed that the corresponding CF3-
Scheme 3. Diastereoselective Synthesis of CF3-Containing
Spirooxazines
ASSOCIATED CONTENT
■
S
* Supporting Information
Details of experimental procedures, control experiments and full
spectroscopic data for all new compounds, crystallographic data
for (1R*,2S*)-3c (CCDC 1049302), (1R*,2S*)-3n (CCDC
1049303), and (1R*,2S*)-5b (CCDC 1049304). The Support-
ing Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01694.
containing spirooxazines 5 were obtained in good yields (51−
67% yield).15 It should be noted that diastereomer ratios of the
products (5a, 5b, 5d) (89:11−91:9 dr) were substantially
enhanced compared to the above-mentioned spirooxazolines
with the five-membered rings (3a, 3b, 3d) with the same
substituent on the amide pendant. Single-crystal X-ray analysis
for the major diastereomer of 5b revealed the present
spirocyclization also proceeded in an anti-fashion (see the
Supporting Information). These results show that the present
reaction system serves as a facile synthetic method for both anti-
CF3-spirooxazolines and -spirooxazines from cyclic alkenes with
amide tethers.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: koike.t.ad@m.titech.ac.jp.
*E-mail: makita@res.titech.ac.jp.
Notes
The authors declare no competing financial interest.
The reaction appears to proceed through a mechanism similar
to that of the previously reported photocatalytic oxytrifluoro-
methylation11a (for the full proposed mechanism, see the
Supporting Information). SET photoredox processes mediated
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Numbers
(26288045 and 15K13689) and the Naito Foundation.
C
DOI: 10.1021/acs.orglett.5b01694
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Letter
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