New thiochromans via reductive cyclization of thiophenol derivatives

Article abstract of DOI:10.1055/s-0032-1317922

Reductive cyclization of sulfur-containing substrates 1 and 5 with samarium diiodide afforded the corresponding thiochroman derivatives with excellent diastereoselectivities. Cyclization of 1 is facilitated by geminal dimethyl substitution, which accelera

Full text of DOI:10.1055/s-0032-1317922

LETTER
▌177
lNetteerw Thiochromans via Reductive Cyclization of Thiophenol Derivatives
Synthesis of New Thiochromans
André Niermann, Janine E. Grössel, Hans-Ulrich Reissig*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received: 01.11.2012; Accepted after revision: 23.11.2012
small amounts of bicyclic product 3 we mainly isolated
secondary alcohol 4 as a result of samarium diiodide me-
diated reduction of the carbonyl group. In contrast, pre-
cursor 5 bearing two methyl groups in the linker unit
Abstract: Reductive cyclization of sulfur-containing substrates 1
and 5 with samarium diiodide afforded the corresponding thiochro-
man derivatives with excellent diastereoselectivities. Cyclization of
1 is facilitated by geminal dimethyl substitution, which accelerates
the reductive coupling and prevents samarium diiodide induced de- underwent smooth reductive cyclization and furnished a
halogenation. Bromo-substituted dihydrothiochroman derivative 8
was further functionalized in subsequent reactions. Analogously,
bromo-substituted hexahydroquinoline derivative 10 was diastereo-
similar mixtures of regioisomers are regularly isolated
selectively prepared in satisfying yield.
mixture of the desired bicyclic compound 6 and the con-
jugated diene 7 in satisfying yield. It should be noted that
when substrates without additional substituents at the phe-
nyl ring are applied as precursors.2g,h The origin of the low
Key words: samarium diiodide, radical, cyclization, thiochroman,
geminal disubstitution, γ-aryl ketone
regioselectivity is still under investigation, but prelimi-
nary results indicate that a kinetically controlled unselec-
tive protonation of an anionic intermediate is responsible
for the generation of product mixtures.11 The relative con-
figuration of these compounds was established by NMR
spectroscopy and is analogous to that of cyclization prod-
ucts previously reported.2,5,6
Samarium diiodide is known as a very efficient reagent in
organic synthesis triggering the formation of new carbon–
carbon bonds.1 Our group is interested in the application
of samarium diiodide in the reductive cyclizations of (het-
ero)aryl ketones that deliver functionalized dearomatized
products with excellent diastereoselectivity.1e,i A broad
spectrum of substrates such as ketones with (substituted)
phenyl,2,3 naphthyl,4 aniline,5 indole, pyrrole6 and
quinoline7 moieties in γ-position were successfully used
as precursors. In the course of these studies we also inves-
tigated the influence of geminal disubstitution on these re-
ductive cyclizations of (substituted) phenyl ketones2h,i and
now present our results applying substrates containing a
sulfur or nitrogen atom in the linker unit. Compounds
such as 1 are easily prepared by conjugate addition of the
corresponding thiophenol derivative to mesityl oxide
(Scheme 1)8 and they are excellent precursors for the
preparation of unusually substituted thiochroman deriva-
tives.9
Comparison of the results of precursors 2 and 5 suggests
that geminal dialkyl substitution is very beneficial for ef-
ficient cyclizations. We therefore examined the conver-
sion of para-bromo-substituted precursor 1 and were
delighted to observe that the cyclization proceeds cleanly
and rapidly even at a lower temperature affording bromo-
substituted thiochroman derivative 8 in good yield.12 No
evidence was found for the generation of compounds 6 or
7, possible products of a reductive removal of the bromo
substituent. Thus, for the first time a bromo-substituted
aryl ketone was successfully applied in the samarium di-
iodide induced ketyl–aryl coupling process. Previous in-
vestigations towards cyclization of aryl ketones with a
para-chloro substituent predominantly led to dechlorinat-
ed products due to a fast reduction of the carbon–halogen
bond.2g Apparently, the geminal dimethyl substitution of
compound 1 strongly accelerates the cyclization and de-
halogenation does not occur.
Et3N
O
CH2Cl2
SH
S
r.t., 72 h
+
O
73%
Br
Br
We also explored the related para-bromoaniline-derived
ketone 9 as substrate and smoothly obtained hexahydro-
quinoline derivative 10 albeit in moderate yield (Scheme
3). Substrates without a bromo substituent and without the
dimethyl unit had been investigated previously and fur-
nished cyclization products in excellent diastereoselectiv-
ities.5 An attempt to cyclize the iodo analogue of 9 led to
a more complex product mixture containing only small
amounts of the desired cyclization products.11,13 The relat-
ed precursors with an oxygen atom in the linker unit were
not suitable with the reductive ketyl–aryl coupling as only
small amounts of cyclization products could be obtained.
1
Scheme 1 Preparation of bromo-substituted γ-aryl ketone 1 by conju-
gate addition
Scheme 2 summarizes our results on reductive cycliza-
tions.10 The attempted reductive cyclization of ketone 2,
bearing a thioether in the linker but no geminal dimethyl
unit, did not lead to a satisfying conversion. Along with
SYNLETT 2013, 24, 0177–0180
Advanced online publication: 11.12.2012
DOI: 10.1055/s-0032-1317922; Art ID: ST-2012-D0935-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Thiochroman derivatives such as 8 are promising candi-
dates for subsequent transformations, e.g. transition-met-

178
A. Niermann et al.
LETTER
S
the generation of epoxides.14 Nevertheless, the low yield
for this transformation indicates the formation of side
products.
H
OH
SmI2, HMPA
3, 8%
t-BuOH
THF, r.t.
17 h
S
S
TIPS-acetylene
Pd(PPh3)2Cl2
CuI, DIPA
DMF, 60 °C, 20 h
O
+
H
OH
OH
2
S
TIPS
91%
11
OH
tert-butyl acrylate
Pd(OAc)2
PPh3, LiCl, Et3N
DMF, 90 °C, 7 d
S
4, 58%
t-BuO
39%
S
12
S
O
PhB(OH)2
Pd(PPh3)4
Na2CO3, toluene
MW, 90 °C, 2.5 h
S
SmI2, HMPA
t-BuOH
THF, r.t.
60 min
H
OH
Br
H
S
OH
6
Ph
8
58%
H
O
OH
O
+
66%
13
S
5
O
m-CPBA
CH2Cl2
0 °C, 3 h
S
H
OH
Br
7
H
42%
OH
6/7 = 85:15
14
Scheme 4 Subsequent transformations of bromo-substituted com-
pound 8 leading to new thiochroman derivatives 11–14
SmI2, HMPA
t-BuOH
S
S
THF, –20 °C
20 min
In summary, we could demonstrate that the samarium di-
iodide induced cyclization of sulfur-containing precursors
constitutes a new and valuable approach to thiochroman
derivatives which are formed diastereoselectively. We
again could show that geminal dialkyl substitution of the
linker unit is essential to attain acceptable yields. This al-
lows the use of bromo-substituted precursors and hence
subsequent transformations utilizing this functional group
leading to a variety of new highly substituted thiochroman
derivatives.
Br
O
H
Br
OH
73%
1
8
Scheme 2 Samarium diiodide induced cyclizations of sulfur-contain-
ing γ-aryl ketones with different substitution patterns
Ac
SmI2, HMPA
N
Ac
t-BuOH
THF, –20 °C
35 min
N
Br
O
H
10
Br
OH
52%
9
Acknowledgment
Scheme 3 Samarium diiodide induced cyclization of aniline-derived
γ-aryl ketone 9
We thank the Deutsche Forschungsgemeinschaft and BayerHealth-
care for generous financial support. We gratefully acknowledge the
assistance of Dr. R. Zimmer during preparation of this manuscript.
al-catalyzed cross couplings or oxidations at the sulfur
atom. Our exemplary results are illustrated in Scheme 4.
Sonogashira reaction of 8 with TIPS–acetylene as cou-
pling partner afforded alkyne 11 in very good yield,
whereas a Heck coupling with tert-butyl acrylate required
high temperatures and long reaction times to furnish re-
aromatized thiochroman derivative 12 in modest yield.
Suzuki–Miyaura coupling of 8 and phenyl boronic acid
under standard conditions afforded compound 13 in mod-
erate yield. Sulfone 14 was obtained by oxidation of 8
with m-CPBA under mild conditions with no evidence for
References and Notes
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Synlett 2013, 24, 177–180
© Georg Thieme Verlag Stuttgart · New York

LETTER
(h) Procter, D. J.; Flowers, R. A. II.; Skrydstrup, T. Organic
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Cyclizations of Aryl Ketones: HMPA (10 equiv) was added
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compound 8 in 73% yield (265 mg) as a colorless oil.
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3,4,4a,7-tetrahydro-2H-thiochromen-4-ol (8): 1H NMR
(700 MHz, CDCl3): δ = 1.21, 1.30, 1.37 (3 × s, 3 H each,
CH3), 1.57 (br s, 1 H, OH), 1.99, 2.02 (AB system, JAB = 13.4
Hz, 1 H each, 3-H), 3.02 (mc, 1 H, 4a-H), 3.07 (dddd, J = 1.2,
3.8, 7.5, 22.4 Hz, 1 H, 7-H), 3.17 (dddd, J = 1.9, 3.4, 7.4,
22.4 Hz, 1 H, 7-H), 5.96 (ddd, J = 1.3, 3.4, 3.8 Hz, 1 H, 8-
H), 6.30 (ddd, J = 1.2, 1.9, 3.5 Hz, 1 H, 5-H). 13C NMR (176
MHz, CDCl3): δ = 24.6, 30.6, 32.7 (3 × q, CH3), 37.2 (t, C-
7), 43.6 (s, C-2), 53.7 (d, C-4a), 56.8 (t, C-3), 73.6 (s, C-4),
119.6 (s, C-6), 126.2 (d, C-5), 126.9 (d, C-8), 129.3 (s, C-8a).
IR (film): 3400 (O–H), 3010–2850 (=C–H, C–H), 1665
(C=C) cm–1. Anal. Calcd for C12H17BrOS (289.2): C, 49.83;
H, 5.92. Found: C, 49.78; H, 5.77.
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Analytical data of (4R*,4aS*)-6-Bromo-2,2,4-trimethyl-
1,1-dioxo-3,4,4a,7-tetrahydro-2H-benzo-thiopyran-4-ol
(14): mp 160–164 °C. 1H NMR (500 MHz, CDCl3): δ = 1.24,
1.34, 1.41 (3 × s, 3 H each, CH3), 1.83 (br s, 1 H, OH), 1.88,
2.38 (2 × d, J = 14.4 Hz, 1 H each, 3-H), 3.26 (dddd, J = 1.3,
3.9, 7.8, 23.6 Hz, 1 H, 7-H), 3.36 (dddd, J = 2.0, 3.1, 7.5,
23.6 Hz, 1 H, 7-H), 3.63 (mc, 1 H, 4a-H), 6.29 (mc, 1 H, 5-
H), 6.78 (mc, 1 H, 8-H). 13C NMR (126 MHz, CDCl3): δ =
22.0, 22.8, 24.5 (3 × q, Me), 36.0 (t, C-7), 49.7 (d, C-4a),
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 177–180

180
A. Niermann et al.
LETTER
51.9 (t, C-3), 57.2 (s, C-2), 72.9 (s, C-4), 118.8 (s, C-6),
125.5 (d, C-5), 132.8 (s, C-8a), 135.2 (d, C-8). IR (film):
3480 (O–H), 2990–2855 (=C–H, C–H), 1130 (S=O) cm–1.
HRMS (ESI–TOF–MS): m/z [M + Na]+ calcd for
C12H17BrO3SNa: 342.9979; found: 342.9977.
Synlett 2013, 24, 177–180
© Georg Thieme Verlag Stuttgart · New York