Selective Metalations of 1,4-Dithiins and Condensed Analogues Using TMP-Magnesium and -Zinc Bases

Article abstract of DOI:10.1021/acs.orglett.6b03539

TMPMgCl·LiCl and TMPZnCl·LiCl allow facile magnesiation and zincation, respectively, of the 1,4-dithiin scaffold, producing polyfunctionalized 1,4-dithiins. A subsequent metalation of these S-heterocycles can also be achieved with the same TMP bases, lead

Full text of DOI:10.1021/acs.orglett.6b03539

Letter
pubs.acs.org/OrgLett
Selective Metalations of 1,4-Dithiins and Condensed Analogues
Using TMP-Magnesium and -Zinc Bases
Alicia Castello-Mico,† Julia Nafe,† Kosuke Higashida,† Konstantin Karaghiosoff,† Marc Gingras,‡
́
́
and Paul Knochel*,†
†Department Chemie, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munchen, Germany
̈
̈
‡CNRS, Aix-Marseille Universite,
́
CINAM UMR 7325, 163 Avenue de Luminy, 13288 Marseille, France
S
* Supporting Information
ABSTRACT: TMPMgCl·LiCl and TMPZnCl·LiCl allow facile
magnesiation and zincation, respectively, of the 1,4-dithiin scaffold,
producing polyfunctionalized 1,4-dithiins. A subsequent metalation
of these S-heterocycles can also be achieved with the same TMP
bases, leading to 2,3-disubstituted-1,4-dithiins. The Mg- and Zn-
TMP bases allow as well the successful metalation of 1,4,5,8-
tetrathianaphthalene and 1,4,5,6,9,10-hexathiaanthracene.
ulfur heterocycles are important building blocks for
We have found that the metalation of 1 with 6 produces the
magnesiated 1,4-dithiin 8 at −40 °C within 0.5 h (Scheme 1).
S
applications in medicinal chemistry1 and materials science.2
Especially, 1,4-dithiins of type 1 (Figure 1) have attracted
Scheme 1. Synthesis of Mono- and Disubstituted 1,4-Dithiin
Derivatives Using TMP Bases
Figure 1. 1,4-Dithiin derivatives and condensed analogues.
Subsequent quenching of 8 with various electrophiles (E1−X)
leads to monosubstituted 1,4-dithiins of type 9. Further
functionalization of 9 can be achieved either with 6 or 7
depending on the nature of the substituent E1, leading to the
regioselectively metalated 2,3-disubstituted 1,4-dithiins 10.
Quenching with various eletrophiles produces a range of 2,3-
disubstituted 1,4-dithiins 11. Thus, the magnesiated 1,4-dithiin
8 was readily halogenated using iodine, tetrachlorodibromo-
ethane, or benzenesulfonyl chloride to afford 2-halo-1,4-dithiins
9a−c in 56−78% yield (Table 1, entries 1−3). Cyanation,
aminomethylation with Tietze’s reagent,12 and the reaction
with PhCHO were readily achieved, giving the corresponding
adducts 9d−f in 58−97% yield (entries 4−6). Acylation of 8
with NCCO2Et, benzoyl chloride, and cyclopropylcarbonyl
chloride provided the corresponding carbonyl-substituted 1,4-
dithiins 9g−i in 65−89% yield (entries 7−9). Copper-catalyzed
allylation and Pd-catalyzed arylation furnished the coupling
products 9j and 9k, respectively, in 73−94% yield (entries 10
attention because of their unique electronic and conducting
properties3 as well as their use for the preparation of other
sulfur heterocycles.4 Structural studies of 1,4-dithiin derivatives
have also been the subject of several publications, as to whether
1,4-dithiins are flat and to understand the electronic
delocalization.5 Nevertheless, the preparation of functionalized
1,4-dithiins remains a challenge since the metalation of these
scaffolds has been scarcely studied. The reaction of 1 with
nBuLi leads to ring opening unless this lithiation is performed
at −110 °C.6 Also, the treatment of 2 with tBuOK gives a
skeleton rearrangement affording 1,4-dithiafulvenes (3) due to
the harsh reaction conditions.7 We recently reported a set of
kinetically highly active bases such as TMPMgCl·LiCl (6)8 and
TMPZnCl·LiCl (7)9 for the magnesiation and zincation,
respectively, of various heterocyclic scaffolds.10 Herein we
report that these mild bases allow smooth metalation of the 1,4-
dithiin skeleton, enabling the preparation of mono-, di-, tri-, or
tetrasubstituted dithiins. Thereafter we will also show the
functionalization via magnesiation or zincation of the
condensed 1,4,5,8-tetrathianaphthalene (TTN, 4)11 and the
new 1,4,5,6,9,10-hexathiaanthracene (HTA, 5).
Received: November 28, 2016
© XXXX American Chemical Society
A
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Table 1. Preparation of 2-Substituted 1,4-Dithiins of Type 9
by Magnesiation of 1,4-Dithiin (1) with TMPMgCl·LiCl (6)
Table 2. Preparation of Disubstituted 1,4-Dithiin-Derivatives
of Type 11 by Metalation of Dithiins of Type 9 Using Mg-
and Zn-TMP Bases 6 and 7
a
b
Yields of isolated, analytically pure products. TMPMgCl·LiCl
c
(1.05−1.1 equiv, −78 °C, 0.5 h) was used. TMPZnCl·LiCl (1.1
d
a
b
equiv, −40 °C, 0.5 h) was used. TMPZnCl·LiCl (1.1 equiv, 0 °C, 0.5
Yield of isolated, analytically pure product. Obtained after
h) was used.
transmetalation with ZnCl2 (1.2 equiv, −40 °C, 15 min) and
c
CuCN·2LiCl (1.2 equiv, −40 °C, 15 min). Obtained after
Scheme 2. Synthesis of Tribrominated 1,4-Dithiin 12 and
Subsequent Metalation by TMPZnCl·LiCl (7) Leading to
Tetrasubstituted Dithiin 13
transmetalation with ZnCl2 (1.2 equiv, −40 °C, 15 min) using 3
mol % Pd(dba)2 and 6 mol % P(2-furyl)3.
and 11). Finally, the reaction of 8 with bis(phenylsulfonyl)
sulfide13 produced the pentathio derivative 9l in 75% yield
(entry 12).
Subsequent metalation of 1,4-dithiin derivatives of type 9 was
achieved using either TMPMgCl·LiCl (6) or TMPZnCl·LiCl
(7). In the case of less sensitive substituents E1, magnesiation
with 6 was readily performed at −78 °C (in only 0.5 h). In the
same way, 1,4-diithins 9e−g were magnesiated with 6 (1.05−
1.1 equiv) and quenched with standard electrophiles (I2, C2Cl6,
NCCO2Et, and Tietze’s reagent12), leading to 2,3-disubstituted
1,4-dithiins 11a−d in 43−90% yield (Table 2, entries 1−4).
Similarly, the more sensitive 1,4-dithiins 9a, 9b, 9d, and 9h
were zincated with 7 between −40 and 0 °C14 and quenched
with halogenated electrophiles, leading to 2,3-disubstituted 1,4-
dithiins 11e−i in 50−86% yield (entries 5−9). A third
metalation was achieved on 2,3,5-tribromo-1,4-dithiin (12),
previously obtained by bromination of 11g (84% yield, Scheme
2), as treatment of 12 with 7 at −78 °C for 10 min furnished
the corresponding zinc reagent, which provided tetrabromo-
1,4-dithiin 13 after bromination with (BrCCl2)2 in 56% yield.
The same metalation procedure was applied to the
condensed S-heterocycle TTN (4) using TMPMgCl·LiCl.
This magnesiation proceeded at −78 °C in 10 min and
produced a magnesiated TTN that reacted smoothly with
typical electrophiles (by iodolysis, bromination, cyanation,
thiomethylation, carbonylation, and acylation), leading to
monosubstituted TTNs 14a−f in 65−89% yield (Table 3). A
second metalation of the monosubstituted TTNs of type 14
was best achieved with TMPZnCl·LiCl (7) at −40 °C in 0.5 h,
Table 3. Preparation of Monosubstituted TTNs by
Metalation of 4 Using TMPMgCl·LiCl (6)
a
b
Yields of isolated, analytically pure products. CuCN·2LiCl was used.
B
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providing 3,4-disubstituted TTNs 15a−e in 55−83% yield after
quenching with allyl bromide, acyl chloride, aryl iodide
(Negishi cross-coupling), or iodine (Table 4). Finally, we
Table 4. Synthesis of Disubstituted TTN Derivatives of Type
15 Using TMPZnCl·LiCl (7)
Figure 2. Crystal structure of HTA (5).
Scheme 4. Ring Closure of 9k and 11c Leading to S-
Heterocycles
alkyne 18 in 77% yield. Treatment with iodine in CH2Cl2
produced the endo cyclization product 19 in 88% yield.
In summary, we have shown that TMPMgCl·LiCl (6) and
TMPZnCl·LiCl (7) are excellent bases for facile metalation of
the sensitive 1,4-dithiin scaffold. Interestingly, these metalation
procedures can be extended to the condensed heterocycles
TTN and HTA. The preparation of additional S-heterocycles
via metalation of 6 or 7 is currently underway in our
laboratories.
a
b
Yields of isolated, analytically pure products. CuCN·2LiCl was used.
c
Pd(dba)2 (6 mol %) and P(2-furyl)3 (12 mol %) were used.
prepared the new hexathiaanthracene (HTA, 5) using the
previously described dithiin 9l (Table 1, entry 9) by a
condensation with SCl2 in chloroform (0 °C, 3 h, 55% yield;
Scheme 3).15 X-ray analysis of this new condensed S-
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03539.
■
S
Scheme 3. Synthesis of 1,4,5,6,9,10-Hexathiaanthracene (5)
and Subsequent Functionalization by TMPZnCl·LiCl (7)
Detailed experimental procedures and characterization
data for new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.knochel@cup.uni-muenchen.de.
ORCID
heterocycle showed that this molecule is not planar but rather
that the conformation of 5 is best viewed as a fused boat system
of three units linked together (Figure 2).14,16 The mild Zn-
TMP base 7 reacted with 5 to provide a zincated intermediate
that was readily allylated, leading to S-heterocycle 16 in 51%
yield.
The substituted 1,4-dithiins prepared above are interesting
building blocks for the construction of more elaborated S-
heterocycles. Consequently, the treatment of 9k with 2-
thiophenecarboxaldehyde in EtOH under microwave irradi-
ation (130 °C, 15 min) produced tricyclic heterocycle 17 in
60% yield (Scheme 4). Moreover, 2,3-disubstituted dithiin 11c
was submitted to a Sonogashira cross-coupling leading to
Paul Knochel: 0000-0001-7913-4332
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research received funding from the Deutsche Forschungs-
gesellschaft. We also thank BASF AG (Ludwigshafen) and
Albemarle (Frankfurt) for generous gifts of chemicals.
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