Synthesis of 1-Aryltetralins and 1-Arylnaphthalenes via (4 + 2) Annulation of β-Ketosulfones with Styryl Bromides

Article abstract of DOI:10.1021/acs.orglett.6b00603

A novel route has been developed for the synthesis of various substituted 1-aryltetralins 6 and 1-arylnaphthalenes 8 via (1) K₂CO₃-mediated α-styrylation of β-ketosulfones 3 with bromostyryl bromides 4 and (2) stereocontrolled NaBH₄-promoted reduction of the resulting γ-alkenones 5, followed by BF₃·OEt₂-catalyzed intramolecular annulation of the corresponding γ-alkenols 7 under rt/5 h and reflux/10 h conditions, respectively. The key structures of 6 and 8 were confirmed by X-ray crystallographic analysis. A plausible mechanism has been proposed.

Full text of DOI:10.1021/acs.orglett.6b00603

Letter
pubs.acs.org/OrgLett
Synthesis of 1‑Aryltetralins and 1‑Arylnaphthalenes via (4 + 2)
Annulation of β‑Ketosulfones with Styryl Bromides
Meng-Yang Chang* and Yu-Chieh Cheng
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
S
* Supporting Information
ABSTRACT: A novel route has been developed for the
synthesis of various substituted 1-aryltetralins 6 and 1-
arylnaphthalenes 8 via (1) K2CO3-mediated α-styrylation of
β-ketosulfones 3 with bromostyryl bromides 4 and (2)
stereocontrolled NaBH4-promoted reduction of the resulting
γ-alkenones 5, followed by BF3·OEt2-catalyzed intramolecular
annulation of the corresponding γ-alkenols 7 under rt/5 h and reflux/10 h conditions, respectively. The key structures of 6 and 8
were confirmed by X-ray crystallographic analysis. A plausible mechanism has been proposed.
Scheme 2. Synthetic Route of 2,5-Diaryltetrahydrofurans, 1-
Aryltetralins, and 1-Arylnaphthalenes
etralin is a highly privileged core structure found in many
Tvaluable biologically active molecules, pharmaceuticals, and
natural products.1−4 With regard to the construction of this key
building block, the 90-year-old Darzens tetralin synthesis
(H2SO4-mediated intramolecular ring-closure of a 1-phenyl-4-
pentene)5 still stands out as one of the most direct and
convenient methods. It uses arenes with an allylic chain6 1 or an
unactivated alcohol7 2 as the starting materials; it is especially
effective when combined with the recent remarkable advances in
metal-catalyzed annulation. Various catalysts have been
employed to accelerate the formation of a carbon−carbon
bond via a carbocation-like intermediate (Scheme 1).8
Scheme 1. Intramolecular Friedel−Crafts Substitution
Reaction
functionalized 1-aryltetralins. However, to the best of our
knowledge, the bromo group-initiated intramolecular Friedel−
Crafts alkylation procedure for the preparation of 1-aryltetralins
has not been reported,11 nor has the intramolecular annulation of
bromostyryl β-ketosulfones been explored. Herein, we report our
studies12,13 on these two processes for aryltetralin synthesis.
K2CO3-mediated α-styrylation of β-ketosulfones 3a−r with
bromostyryl bromides 4a−d (prepared by p-TsOH-catalyzed
double bromination of styrene with 2.5 equiv of NBS in CH2Cl2
at reflux) in acetone at reflux provided 5a−x in a yield range of
78−89%, as shown in Table 1. The yields of 5a−x did not change
much as a function of the structure of 3a−r under these reaction
conditions. The bromo group promoted intramolecular ring
closure of 5 was examined via a two-step route: stereoselective
NaBH4-mediated reduction followed by BF3·OEt2-promoted
Friedel−Crafts annulation of the resulting sulfonyl 4-alkenols.
For different R substituents on 5, a diversity of electron-
As part of our recent studies of BF3·OEt2-promoted tandem
cyclization reactions,9 we devised an efficient stereocontrolled
synthesis of sulfonyl 2,5-diaryltetrahydrofurans in good yield via
the Lewis acid promoted intramolecular hydroalkoxylation of
sulfonyl γ-alkenols (X = H),10 as shown in Scheme 2. In this
paper, we report the BF3·OEt2-mediated intramolecular Friedel−
Crafts electrophilic substitution of sulfonyl γ-alkenols (X = Br)
by tethering a β-bromovinyl group to the aryl rings. In contrast to
a hydrogen atom, the weakly deactivating bromo group initiates
the stereospecific progression of the delocalized electron pair (in
an exo → endo → exo direction), leading to the formation of a six-
membered ring under metal-free catalyzed conditions. This
stereospecific annulation reaction provides facile access to
Received: March 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00603
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
suggests that NaBH4-mediated carbonyl reduction of 5a is
affected by the steric hindrance of the sulfonyl substituent such
that the hydride can only attack the less hindered carbonyl face,
yielding a single stereoisomer.12b Subsequently, complexation of
the resulting hydroxyl group by BF3·OEt2 gives I (Scheme 4).
Table 1. Synthesis of 5 and 6
Scheme 4. Proposed Annulation Mechanism
c
yield (%)
entry
3, Ar = , R =; 4, Y-Ar =
3a, Ph, Me; 4a, Ph
5
6
1
5a, 80
5b, 84
5c, 89
5d, 83
5e, 86
5f, 83
5g, 80
5h, 80
5i, 82
5j, 84
5k, 88
5l, 82
5m, 80
5n, 84
5o, 82
5p, 83
5q, 84
5r, 83
5s, 84
5t, 85
5u, 82
5v, 79
5w, 78
5x, 80
6a, 82
6b, 80
6c, 76
6d, 78
6e, 74
6f, 70
2
3b, Ph, Ph; 4a, Ph
3
3c, Ph, Tol; 4a, Ph
3d, 4-FC6H4, Tol; 4a, Ph
4
5
3e, 4-MeOC6H4, Tol; 4a, Ph
3f, 4-MeC6H4, Tol; 4a, Ph
3g, 4-CF3C6H4, Tol; 4a, Ph
3h, 4-NO2C6H4, Tol; 4a, Ph
3i, 3-NO2C6H4, Tol; 4a, Ph
3j, 4-PhC6H4, Tol; 4a, Ph
6
d
7
6g, −
6h, −
6i, −
d
8
d
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
6j, 74
3k, 2-naphthalene, Tol; 4a, Ph
3l, Ph, 4-FC6H4; 4a, Ph
6k, 70
6l, 78
Following model B, a stereocontrolled bromo group-initiated
intramolecular SN2 annulation leads to II via a six-membered
chairlike conformation having two adjacent equatorial protons.
An SN1 process can also be envisioned with III (model C),
deprotonation of II affording 6a via a sequential aromatization
process.
The BF3·OEt2-mediated intramolecular annulation of 5 was
investigated at elevated temperatures and longer reaction times,
as shown in Scheme 5. Specifically, changing the reaction
3m, Ph, 4-MeOC6H4; 4a, Ph
3n, Ph, 3-MeC6H4; 4a, Ph
3o, Ph, 4-EtC6H4; 4a, Ph
6m, 81
6n, 82
6o, 78
6p, 74
6q, 80
6r, 80
6s, 78
6t, 76
6u, 80
6v, 80
6w, 81
6x, 82
3p, Ph, 4-nBuC6H4; 4a, Ph
3b, Ph, Ph; 4b, 4-FC6H4
3c, Ph, Tol; 4b, 4-FC6H4
3b, Ph, Ph; 4c, 4-PhC6H4
3c, Ph, Tol; 4c, 4-PhC6H4
3c, Ph, Tol; 4d, 2-naphthalene
3k, 2-naphthalene, Tol; 4d, 2-naphthalene
3q, 3,4-Cl2C6H3, Tol; 4a, Ph
3r, 2-thiophene, Tol; 4a, Ph
Scheme 5. Synthesis of 8
a
Alkylation reaction: 3 (1.0 mmol), K2CO3 (2.9 mmol), 4 (1.05
b
mmol), acetone (15 mL), reflux, 10 h. Annulation reaction: 5 (0.2
mmol), NaBH4 (1.0 mmol), THF (5 mL)/MeOH (5 mL), 0 °C, 1 h,
c
then BF3·OEt2 (0.2 mmol), CH2Cl2 (5 mL), 25 °C, 5 h. Isolated
d
yields. No reaction; 7g (89%), 7h (92%), and 7i (90%) were
recovered.
withdrawing and electron-donating groups was well-tolerated.
However, when the Ar group was strongly electron-withdrawing,
none of the desired products 6g−i were formed, and only 7g−i
were observed. Thus, in the presence of 3- or 4-nitrophenyl and
4-(trifluoromethyl)phenyl groups, no intramolecular annulation
was observed. Moreover, for entries 7−9, different substituents
on 5 did not affect the annulation, and the isolated yield of 6 was
maintained. The structures of 5e, 6c, 6f, 6l, and 6u were all
determined by single-crystal X-ray crystallography.14
In accord with our previous experience, a single skeleton
derived from the sulfonyl 4-alkenol was obtained. On the basis of
the Felkin−Anh model A,15 the stereochemical centers of two
protons (green H−Cα and pink H−Cβ in 7a) are well
established. As shown in Scheme 3, a plausible mechanism
conditions from 25 °C and 5 h to CH2Cl2 at reflux for 10 h
generated substituted 1-bromomethyl naphthalenes 8a−e (66−
80%) and 1-bromomethyl phenanthrenes 8f,g (73% and 70%)
via BF3·OEt2-promoted cascade desulfonative aromatization of
5a,c,d,j,r,t−v. 1-Arylnaphthalene has been shown to exhibit a
wide range of potential biological activities.16 The present
protocol provides a novel synthetic route for the preparation of
substituted naphthalenes.17 The structure of 8d was determined
by single-crystal X-ray crystallography.14
By changing the α-substituent from a sulfonyl group to an
ethyl ester group (3s, Ar = Ph; 3t, Ar = 4-MeOC6H4), 9a and 9b
were isolated in 80% and 82% yields, respectively, as shown in
Scheme 6. Using the above synthetic protocol, 10a,b were
generated in 73% and 74% yields. Comparing the 1,3-dicarbonyl
synthons, both β-ketosulfones and β-ketoesters provided similar
yields of 1-aryltetralins. However, 9c containing a β-diketone
group (prepared by alkylation of 3u with 4a) failed to afford the
tetralin skeleton under the standard reaction conditions.
Scheme 3. Proposed Reduction Mechanism
B
DOI: 10.1021/acs.orglett.6b00603
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
for these cyclization reactions. The structures of the key products
6 and 8 have been confirmed by X-ray crystallography. Further
investigations regarding the asymmetric synthesis of chiral 6 will
be studied via the desymmetrical annulation of 5.
Scheme 6. Reaction of 4a with 3s−u
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00603.
X-ray analysis data of 5e (CIF)
X-ray analysis data of 5y (CIF)
X-ray analysis data of 6c (CIF)
X-ray analysis data of 6f (CIF)
In further work, the bromo group was replaced with a chloro or
iodo group, affording facile access to 1-aryltetralins. As shown in
Scheme 7, α-styrylation of 3c with chlorostyryl chloride 4e
X-ray analysis data of 6l (CIF)
X-ray analysis data of 6u (CIF)
X-ray analysis data of 8d (CIF)
Detailed experimental procedures and spectroscopic data
for all new compounds (PDF)
Scheme 7. Reaction of 3c with 4e,f
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mychang@kmu.edu.tw.
Notes
The authors declare no competing financial interest.
afforded 5y in a 77% yield. The formation of 6y (75%) was
achieved via intramolecular annulation of 5y using the above
protocol. The structure of 5y was determined by single-crystal X-
ray crystallography.14 However, when 3c was allowed to react
with 4f, a complex mixture was formed and no 5z was observed.
To examine the applicability of this synthetic route, a formal
synthesis of sertraline (Zoloft)18 was developed (Scheme 8).
ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology of the
Republic of China for financial support (MOST 104-2113-M-
037-012).
REFERENCES
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Scheme 8. Formal Synthesis of Sertraline
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In summary, we have developed a novel synthesis of various
substituted 1-aryltetralins 6 and 1-arylnaphthalenes 8 via (1)
K2CO3-mediated α-styrylation of substituted β-ketosulfones 3
with bromostyryl bromides 4 and (2) stereocontrolled NaBH4-
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D
DOI: 10.1021/acs.orglett.6b00603
Org. Lett. XXXX, XXX, XXX−XXX