Diastereoselective Synthesis of CF3-Substituted Spiroisochromans by [1,5]-Hydride Shift/Cyclization/Intramolecular Friedel-Crafts Reaction Sequence

Article abstract of DOI:10.1021/acs.orglett.9b00668

Developed herein is a diastereoselective synthesis of CF₃-substituted spiroisochromans via C(sp³)-H bond functionalization involving sequential transformations ([1,5]-hydride shift/cyclization/elimination of MeOH/intramolecular Friedel-Crafts reaction).

Full text of DOI:10.1021/acs.orglett.9b00668

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereoselective Synthesis of CF3‑Substituted Spiroisochromans
by [1,5]-Hydride Shift/Cyclization/Intramolecular Friedel−Crafts
Reaction Sequence
Risa Tamura,† Eriko Kitamura,‡ Ryosuke Tsutsumi,§ Masahiro Yamanaka,§ Takahiko Akiyama,*,‡
and Keiji Mori*,†
†Department of Applied Chemistry, Graduate School of Engineering, Tokyo University of Agriculture and Technology, 2-24-16
Nakacho, Koganei, Tokyo 184-8588, Japan
‡Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
§Department of Chemistry and Research Center for Smart Molecules, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku,
Tokyo 171-8501, Japan
S
* Supporting Information
ABSTRACT: Developed herein is a diastereoselective synthesis
of CF3-substituted spiroisochromans via C(sp3)−H bond
functionalization involving sequential transformations ([1,5]-
hydride shift/cyclization/elimination of MeOH/intramolecular
Friedel−Crafts reaction).
he direct transformation of C−H bonds has attracted
much attention because it provides an efficient strategy
for such a sequential system, and hence, the introduction of
new methodology is required.
T
for the synthesis of various organic molecules.1 Hydride-shift-
triggered C(sp3)−H bond functionalization, also called the
“internal redox process” (Scheme 1), has drawn a great deal of
Our strategy is shown in the top portion of Scheme 2. The
key point is the dual role of heteroatom X (shown in blue) as
(1) a driving force for the hydride shift and (2) an activator of
the resulting cyclized adduct by acting as a leaving group. We
envisioned that a carbonyl (Y = O)3j,4a,6l or imine (Y =
NR)3a,e,g,6d,o moiety with an o-phenethyl ether or amine
moiety would be suited for this purpose in terms of the
acceleration of the elimination of the XR group by the
electron-donating ability of another heteroatom (Y). This
would realize the further transformation of the cyclized adduct
in the internal redox process, that is, the geminal
functionalization of the carbon at the phenethyl position.
Herein we report the first realization of this concept in an
intramolecular reaction, which has enabled the diastereose-
lective synthesis of CF3-substituted spiroisochromans. This
reaction is interesting in that the diastereoselectivity is affected
by subtle structural differences in the starting materials.
Whereas CF3-ketones with a terminal nucleophilic aromatic
ring (R = H) gave spiroisochromans in favor of the cis isomers,
the trans isomers were favored in the case of substrates with
two methyl groups at the benzylic position (R = Me).
CF3-ketone 3a was selected as the suitable electrophilic
portion because of its high electrophilic character and the high
Scheme 1. C(sp3)−H Functionalization by the Internal
Redox Process
interest in the recent decade because of its unique features.2
The key feature of this transformation is the [1,5]-hydride shift
of the C(sp3)−H bond α to a heteroatom, which is induced by
the electronic assistance from the adjacent heteroatom. The
subsequent 6-endo cyclization affords fused heterocycle 2.3−7
Recent efforts by us3,4 and other groups5−7 have revealed the
high synthetic potential of this methodology, which has
enabled the construction of various polyheterocycles, such as
isoquinolines,3e,g,6o benzopyrans,3b,6i tetralins,3c,d,h,i,k,6h,7m spi-
rooxindoles,3i,6n,7n and indoles.3 The combination of this
reaction system and another process would be a promising
synthetic tool for the construction of complex polycyclic
skeletons. To the best of our knowledge, there is no precedent
Received: February 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00668
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
with high diastereoselectivity (91% yield with cis:trans = 13:1;
entry 1). The relative stereochemistry of the major isomer was
determined to be cis by X-ray analysis.8 Screening of catalysts
revealed that Sc(OTf)3 was the most effective catalyst, as
Scheme 2. Idea for Sequential Reaction and
Diastereoselective Synthesis of CF3-Substituted
Spiroisochromans
9
shown in Table 1. Both Yb(OTf)3 and Hf(OTf)4 resulted in
recovery of the starting material 3a (entries 2 and 3). TiCl4
was also ineffective (entry 4). Although Gd(OTf)3 promoted
the reaction, the chemical yield was moderate even with a
longer reaction time (57%, 100 h), and the diastereomeric
ratio also remained at a moderate level (cis:trans = 6.5:1)
(entry 5). A stronger Brønsted acid (TfOH) afforded seven-
membered-ring adduct 5 (17%),10 and the desired spirocycle
4a was not obtained. The selection of the solvent had a
dramatic effect on the diastereoselectivity, and ClCH2CH2Cl
was the solvent of choice: although good chemical yields were
achieved in aromatic solvents, such as toluene, benzene, and
mesitylene, the diastereoselectivity remained at a moderate
level in all cases (cis:trans = 5.0−7.8:1; entries 7−9). In the
case of MeOH, the reaction failed to proceed, and 3a was
recovered (95%; entry 10). Importantly, this reaction could be
performed on a 1.21 mmol scale while maintaining both the
chemical yield and diastereomeric ratio (entry 11)
Figure 1 shows the substrate scope of this reaction. At first,
the effect of a terminal aromatic ring was investigated under
utility of the resulting product. The latter point is intriguing. As
far as we know, there have been no reports of the synthesis of
CF3-substituted spiroisochromans, despite their potentially
high biological activities derived from the hybrid structure of a
CF3 group, a spiro structure, and an isochroman core. At first,
3a was treated with 5 mol % Sc(OTf)3, which exhibited
excellent catalytic performance in a recently reported reaction
of the substrate with a CF3-ketone as the electrophilic portion
(Table 1).3j Gratifyingly, the desired sequential reaction
proceeded smoothly under the specified conditions (refluxing
in ClCH2CH2Cl for 24 h) to afford the desired CF3-
substituted spiroisochroman 4a in excellent chemical yield
a
Table 1. Examination of the Reaction Conditions
b
entry
catalyst
time (h)
yield (%)
cis:trans
1
2
3
4
5
6
7
8
9
10
Sc(OTf)3
Yb(OTf)3
Hf(OTf)4
TiCl4
Gd(OTf)3
TfOH
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
18.5
42
70
45
100
23
4
21
23
63
91
13:1
−
−
−
6.5:1
c
c
c
0 (81)
0 (68)
0 (98)
57 (39)
− (5: 17%)
82
80
56
0 (95)
81
c
−
d
6.3:1
7.8:1
5.0:1
−
e
Figure 1. Substrate scope.
f
g
c
the optimized reaction conditions (entry 1, Table 1), which
suggested that an electronic factor was found to play a
significant role in promoting the desired sequential reaction,
particularly the final Friedel−Crafts reaction. In the case of
substrate 3b bearing an m-tolyl group, the chemical yield of
desired spirocycle 4b was moderate (42%, cis:trans = 9.5:1),
and a substantial amount of isochromene 6b, which was
produced by hydride shift/cyclization followed by the
elimination of MeOH (not involving the intramolecular
h
11
24
11:1
a
Unless otherwise noted, all reactions were conducted with 0.10
mmol of 3a in the presence of 5 mol % catalyst in ClCH2CH2Cl (1.0
mL) at refluxing temperature. The diastereomeric ratio was
determined by comparing the integration values for the methine
proton at C-1 for each diastereomer in the H NMR spectrum. The
recovery of 3a is shown in parentheses. In toluene. In benzene. In
mesitylene at 120 °C. In MeOH. 1.21 mmol scale.
b
c
1
d
e
f
g
h
B
DOI: 10.1021/acs.orglett.9b00668
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Letter
Friedel−Crafts reaction), was obtained (55%). This tendency
became even more remarkable in substrate 3c bearing a simple
phenyl group. Isochromene 6c was obtained exclusively (83%),
and no spirocycle 4c was generated. Increasing the catalyst
loading to 30 mol % led to the formation of 4b and 4c (85%
with cis:trans = 9.7:1 and 48% with cis:trans = 13:1,
respectively), which revealed that isochromenes 6 also
functioned as intermediates for the subsequent intramolecular
Friedel−Crafts reaction.
We propose two mechanisms for the high diastereoselectiv-
ity (Figure 3): (1) the stereoselective Friedel−Crafts reaction
The ring size was just as important. In contrast to the
excellent chemical yields of [6.6]-spirocycle 4a and [5.6]-
spirocycle 4d, no [6.7]-spirocycle 4e was obtained at all. This
is ascribed to the difficulty of forming a middle-sized (seven-
membered) ring even in the intramolecular reaction. No [6.7]-
spirocycle 4e was formed even when the catalyst loading was
increased to 30 mol %.
The substituents on the mother nucleus were almost
negligible. Spirocycles 4f−i with various substituents on the
aromatic ring (e.g., Me and OMe), and naphthyl-type
spirocycle 4j were obtained in good to high chemical yields
with high diastereoselectivities (62−99%, cis:trans = 8.2−
13:1). The relative stereochemistries of the major isomers were
surmised as shown in Figure 1, Scheme 2, and Table 1 by
analogy to 4a, 4d, and 4j, whose relative stereochemistries
were unambiguously established by X-ray crystallographic
analysis.8
Figure 3. Plausible mechanism for the cyclization reaction.
to give oxonium cation C (kinetic control) and (2) the
thermodynamic shift to a more stable isomer through the ring-
opening and ring-closing equilibrium between 4 (or 8) and D
(thermodynamic control). In order to clarify the mechanism,
isolated cis isomers 4a and 8a were subjected to the optimized
reaction conditions. The observation of the trans isomers of 4a
and 8a suggested the involvement of thermodynamic control
in the reaction, although we could not completely rule out the
kinetic control pathway.
An investigation of the substituent effect at the benzylic
position gave interesting information (Figure 2). Subjecting
To gain insights into the origin of the diastereoselectivity, we
conducted DFT calculations. Consistent with the experimental
results, cis-4a is more stable than trans-4a (Figure 4). After
careful analysis of these structures, the preference for cis-4a is
mainly attributed to stabilization by an intramolecular
Figure 2. Scope of substrates with two methyl groups at the benzylic
position.
substrate 7a having two methyl groups at the benzylic position
to the optimized reaction conditions afforded spirocycle 8a in
favor of the trans isomer (88% yield with cis:trans = 1:2.8; cf.
cis:trans = 13:1 in 4a). The relative stereochemistry of the
minor isomer of 8a was determined to be cis by X-ray analysis,
and that of the major isomer was assigned as trans.8 This
stereochemical tendency was also observed with substrates
7b−e, and the corresponding adducts 8b−e were obtained in
good chemical yields with a slight preference for the trans
isomers (77−95%, cis:trans = 1:2.2−4.7). The reaction with a
monomethyl group at the benzylic position resulted in high cis
selectivity (cis:trans = 6.7:1), which suggested that the
presence of two methyl groups was indispensable for achieving
the trans selectivity.
Figure 4. 3D structures and relative energies of cis-4a, trans-4a, cis-8a,
and trans-8a. Bond lengths are in Å.
C
DOI: 10.1021/acs.orglett.9b00668
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrogen-bonding interaction between a fluorine atom of the
CF3 group and a hydrogen atom on the methoxyphenyl group.
DFT calculations also revealed the key for the reversal of
diastereoselectivity between 4 and 8. Consistent with the
experimental results, trans-8a is more stable than cis-8a. The
reversal of the diastereoselectivity is ascribed to the greater
distortion of the spiroisochroman core structure in cis-8a by
the introduction of the two methyl groups at the benzylic
position compared with that in trans-8a (see the Supporting
Information for details).
In summary, we have developed an efficient diastereose-
lective synthesis of CF3-substituted spiroisochromans via
C(sp3)−H bond functionalization involving sequential trans-
formations ([1,5]-hydride shift/cyclization/elimination of
MeOH/intramolecular Friedel−Crafts reaction). A range of
substrates provided the desired CF3-substituted spirocycles
4a−j in good to excellent chemical yields with high cis
selectivities. Interestingly, the introduction of two methyl
groups at the benzylic position reversed the diastereoselectivity
to furnish the trans isomers preferentially. Further investigation
of the synthesis of useful polycyclic skeletons by the hydride
shift/cyclization-initiated sequential reaction is underway in
our laboratory
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00668.
Experimental procedures, analytical and spectroscopic
data for new compounds, computational details, and
Cartesian coordinates (PDF)
1H, 13C, and 19F NMR spectra of new compounds
(PDF)
Accession Codes
CCDC 1881483−1881486 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: takahiko.akiyama@gakushuin.ac.jp
*E-mail: k_mori@cc.tuat.ac.jp
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ORCID
Ryosuke Tsutsumi: 0000-0001-7785-8257
Masahiro Yamanaka: 0000-0001-7978-620X
Takahiko Akiyama: 0000-0003-4709-4107
Keiji Mori: 0000-0002-9878-993X
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Japan Society for the Promotion
of Science, and by grants from The Uehara Memorial
Foundation and The Naito Foundation.
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