Construction of 1,3-Dithio-Substituted Tetralins by [1,5]-Alkylthio Group Transfer Mediated Skeletal Rearrangement

Article abstract of DOI:10.1021/acs.orglett.8b01610

A novel skeletal rearrangement involving a [1,5]-alkylthio group transfer/cyclization sequence is described. Treatment of benzylidene malonates having a thioketal moiety at the homobenzyl position with a catalytic amount of Sc(OTf)₃ afforded alkylthio group rearranged adducts in good chemical yields. Detailed investigation of the reaction mechanism revealed that an intramolecular conjugate addition/ring opening sequence (not through-space transfer) is the key to achieving this reaction.

Full text of DOI:10.1021/acs.orglett.8b01610

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of 1,3-Dithio-Substituted Tetralins by [1,5]-Alkylthio
Group Transfer Mediated Skeletal Rearrangement
Naoya Hisano,† Yuto Kamei,‡ Yaoki Kansaku,‡ Masahiro Yamanaka,*,‡ 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 and Research Center for Smart Molecules, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku,
Tokyo 171-8501, Japan
S
* Supporting Information
ABSTRACT: A novel skeletal rearrangement involving a [1,5]-alkylthio group
transfer/cyclization sequence is described. Treatment of benzylidene malonates
having a thioketal moiety at the homobenzyl position with a catalytic amount of
Sc(OTf)3 afforded alkylthio group rearranged adducts in good chemical yields.
Detailed investigation of the reaction mechanism revealed that an intramolecular
conjugate addition/ring opening sequence (not through-space transfer) is the
key to achieving this reaction.
nterest in skeletal rearrangements has persisted for several
decades.1 Skeletal rearrangements enable the construction
high feasibility of the transfer of other substituents besides
hydrogen, which would open doors to novel skeletal
rearrangements. In this context, the Alajarin and Vidal group
found that the [1,4]-alkylthio group transfer was also a viable
process (Scheme 2).8 Although their results were intriguing,
I
of highly fused, complicated skeletons from relatively simple
organic compounds. Besides their utility as synthetic methods,
several features, such as (1) cleavage of relatively inert
chemical bonds (e.g., C−C bond) and (2) formation of a
different bond relative to the starting material, have fascinated
synthetic organic chemists. Because of the useful features
described above, the development of novel skeletal rearrange-
ment reactions remains one of the most sought after topics in
modern synthetic organic chemistry.
Scheme 2. Skeletal Rearrangement via Alkylthio Group
Transfer/Cyclization Sequence
Recently, our group has been interested in the development
of hydride shift triggered C(sp3)−H bond functionalization,
namely, the “internal redox reaction” (Scheme 1).2−7 The key
Scheme 1. C(sp3)−H Functionalization by Internal Redox
Process
detailed investigation of both substrate scope and reaction
mechanism of the transfer process was not conducted.
Furthermore, the development of another mode of transfer
process ([1,5]-transfer type reaction) is not a trivial issue
because SR group is susceptible to the elimination due to the
presence of benzylic hydrogens.
Herein, we report our recent efforts toward the development
of a novel skeletal rearrangement reaction involving a [1,5]-
alkylthio group transfer/cyclization sequence. Careful tuning of
the reaction conditions revealed that the [1,5]-transfer of the
to achieving this reaction is the through-space [1,5]-hydride
shift triggered by electronic assistance from the adjacent
heteroatom (X). In the early stage, this method was limited to
amino substrates having strong electron-donating ability.
Recent efforts by our group5 as well as the Sames,7a−d Urabe,7e
and Fillion groups4d revealed that both less reactive oxygen
analogues (X = O) and carbon analogues without an adjacent
heteroatom (X = CH2) were also good candidates for the
transformation.
The high tolerance to an electronic environment in the
hydride shift process (X = N, O, CH2) strongly implies the
Received: May 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
alkylthio group occurred effectively, and corresponding
adducts were obtained in good to excellent chemical yields
under Sc(OTf)3 catalysis. Computational investigation of the
reaction mechanism indicated that the [1,5]-alkylthio group
transfer occurred intramolecularly and mostly proceeded via
intramolecular conjugate addition/ring opening (not the
through-space transfer) pathway.
Table 1 illustrates the examination of the reaction
conditions. When a solution of 3a in ClCH2CH2Cl was
a
Table 1. Examination of Reaction Conditions
b
entry
catalyst
time (h)
yield (%)
dr
1
2
3
4
5
6
7
8
9
Gd(OTf)3
Zn(OTf)2
Mg(OTf)2
Tf2NH
Hf(OTf)4
Yb(OTf)3
TiCl4
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
48
48
48
48
48
48
4
48
24
48
48
no reaction
no reaction
no reaction
no reaction
trace
1.4:1
1.7:1
1:1.3
1:1.5
1:1.5
1:1.5
1:1.5
trace
50
88
76 (13)
9 (86)
c
d
c
10
11
e
75
a
Unless otherwise noted, all reactions were conducted with 0.10
mmol of 3a in the presence of 10 mol % of catalyst in ClCH2CH2Cl
b
(1.0 mL) at room temperature. Diastereomeric ratio was determined
by comparing the integration value of methine proton at the C-1
c
position for each diastereomer in the 1H NMR. The recovery of 3a is
d
e
shown in parentheses. In toluene. 1.1 mmol scale.
Figure 1. Substrate scope.
treated with 10 mol % of Gd(OTf)3 at room temperature, the
reaction did not proceed at all (entry 1). Compound 3a was
recovered completely under Zn(OTf)2 and Mg(OTf)2 catalysis
(entries 2 and 3). Use of a strong Brønsted acid (Tf2NH) was
likewise ineffective (entry 4). A trace amount of the desired
adduct 4a was obtained with low diastereoselectivity by using
Hf(OTf)4 (dr = 1.4:1, entry 5).9 The same situation was noted
when Yb(OTf)3 was employed as the catalyst (trace with dr =
1.7:1 at 50 °C, entry 6). Fortunately, TiCl4 promoted the
desired reaction, and corresponding adduct 4a was obtained in
50% yield with 1:1.3 diastereomeric ratio (entry 7). Although
the reaction was completed within 4 h, the chemical yield was
difficult to improve by changing the reaction conditions
(temperature, solvent, concentration, and so on). Further
screening for the catalyst revealed that Sc(OTf)3 was effective
for achieving excellent chemical yield, and corresponding
adduct 4a was obtained in 88% yield with 1:1.5 diaster-
eoselectivity (entry 8). Both prolonged reaction time (48 h)
and employment of ClCH2CH2Cl were essential for achieving
a satisfactory chemical yield, and the chemical yield of 4a was
decreased under other conditions (entries 9 and 10).10
Importantly, this reaction could be performed on a 1.1 mmol
scale with keeping both chemical yield and diastereomer ratio
(entry 11).
group (F), and corresponding adducts 4b−f were obtained in
good to excellent chemical yields (74−92%). Naphthyl-type
product 4g was obtained in excellent chemical yield (99%).
Terminal alkyl groups (R1) were also examined. Not only alkyl
groups (Me, Et, Pr) but also phenyl groups afforded adducts
4a,h−j in moderate to good chemical yields. In particular, the
reactivity of 3j (R1 = Ph) was extremely high, and the reaction
was completed within 4 h (cf. 48 h for 4a). In sharp contrast,
substrate 3k (R1 = H) derived from an aldehyde did not give
adduct 4k at all. To our surprise, both S-transfer and hydride
shift were not observed in the case of 3k, even though 3k had
two electron-donating groups (SEt group). A substituent on an
ester moiety had a negligible effect on the transformation, and
4l (R3 = Et) was obtained in 81% yield with increased catalyst
loading (20 mol %).
The employment of substrates with an acyclic alkylthio
group was indispensable for the reaction: although SPr- and
bulky SiPr-substituted products 4m and 4n were obtained in
moderate to good chemical yields, 1,3-dithiane derivative 3o
did not afford adduct 4o at all as reported by Alajarin and
Vidal.8
To confirm the intramolecular nature of alkylthio group
transfer process, crossover experiments with 3f and 3m were
conducted (Scheme 3). The observation of only two products
(4f and 4m) clearly indicates that key thio group transfer
proceeds intramolecularly.
Figure 1 summarizes the substrate scope of this reaction.
This reaction was applied to substrates 3b−f with electron-
donating groups (Me and OMe) and an electron-withdrawing
B
DOI: 10.1021/acs.orglett.8b01610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
planarity of the thiacarbenium moiety (Figure 3). These
computational results are qualitatively consistent with the
Scheme 3. Crossover Experiments
On the basis of the above results, two reaction pathways
could be assumed for the formation of key zwitterionic
intermediate B (Scheme 4): (1) through-space transfer of SR
Scheme 4. Two Possible Reaction Pathways
Figure 3. 3D structures of TS1, TS2, and TS3. Bond lengths are in Å.
experimentally observed substituent effect on R1 and the
substrate scope (Figure 1). The introduction of a Ph group on
R1 (3j) would stabilize TS2 by conjugation with the generated
thiacarbenium moiety, significantly accelerating the reaction
rate. In contrast, cyclic 1,3-dithiane moiety (3o) needs to be
considerably deformed for the C−S bond cleavage, signifi-
cantly destabilizing TS2. The thiacarbenium intermediate
INT2 directly connecting to TS3 is eventually formed through
the sequential C1−C2/C2−C3/C4−C5 bond rotation. At this
stage, such free bond rotation would occur with a low energy
barrier, resulting in low diastereoselectivity (Figure S1). The
relatively low energy barrier (3.6 kcal/mol) is attributed to the
small structural distortion between INT2 and TS3 (Figure 3).
In summary, we have developed a skeletal rearrangement
reaction involving a [1,5]-alkylthio group transfer/cyclization
sequence. Various substituents, such as electron-donating and
electron-withdrawing groups on the aromatic ring, had a
negligible effect on the reaction, and a wide variety of thio
group transfer adducts were obtained in good to excellent
chemical yields. Detailed investigation of the reaction
mechanism based on theoretical calculations revealed that
[1,5]-alkylthio group transfer occurred in the intramolecular
conjugate addition/ring opening pathway unlike the case of the
hydride shift process (through-space transfer), and ring
opening of cyclic thionium was the rate-determining step.
Further investigations of other group transfer/cyclization
processes are under way in our laboratory, and the results
will be reported in due course.
group (path 1) and (2) intramolecular conjugate addition to
electrophilic vinylic carbon (cyclic thionium C formation)
followed by ring opening (path 2). To gain a deeper insight
into the mechanistic details, DFT calculations were conducted
using a TiCl4-catalyzed reaction model (entry 7 in Table 1) to
reduce computational cost.11
After exploring transition state (TS) structures on both
reaction pathways, no TS was found along path 1 and path 2
was identified as the promising reaction pathway. Path 2
proceeds through a sequential mechanism: intramolecular
conjugate addition (TS1), ring opening of cyclic thionium
(TS2), and C−C bond formation (TS3), affording adduct 4
(Figure 2). The lower lying TS1 (+1.7 kcal/mol) indicates that
the formation of cyclic thionium INT1 is a reversible process.
TS2 located at the highest energy level (+12.2 kcal/mol) is
identified as the rate-determining step. In TS2, the C−S bond
cleavage is assisted by the C2−C3 bond rotation, enhancing the
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.8b01610.
Experimental procedures, analytical and spectroscopic
data for new compounds, computational details,
Cartesian coordinates (PDF)
1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Figure 2. Gibbs free energy profile (in kcal/mol) of the intra-
molecular conjugate addition/ring opening process (path 2).
*E-mail: k_mori@cc.tuat.ac.jp.
C
DOI: 10.1021/acs.orglett.8b01610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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*E-mail: myamanak@rikkyo.ac.jp.
ORCID
Masahiro Yamanaka: 0000-0001-7978-620X
Keiji Mori: 0000-0002-9878-993X
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, The Naito Foundation, and the Inoue Foundation
of Science.
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D
DOI: 10.1021/acs.orglett.8b01610
Org. Lett. XXXX, XXX, XXX−XXX