Dithiane induced cycloaddition/aromatization tactic for the synthesis of multisubstituted furans

Article abstract of DOI:10.1021/acs.orglett.6b00699

The development of a new transition-metal-free tactic for convergent, one-pot synthesis of multisubstituted furans by β-chloro-vinyl dithiane cyclization with aldehydes is described. Key to the success was the development of a new vinylidene dithiane site

Full text of DOI:10.1021/acs.orglett.6b00699

Letter
pubs.acs.org/OrgLett
Dithiane Induced Cycloaddition/Aromatization Tactic for the
Synthesis of Multisubstituted Furans
Junshan Lai,† Yongping Liang,† Teng Liu,† and Shouchu Tang*,†,‡
†School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: The development of a new transition-metal-free
tactic for convergent, one-pot synthesis of multisubstituted
furans by β-chloro-vinyl dithiane cyclization with aldehydes is
described. Key to the success was the development of a new
vinylidene dithiane site as a donor allene that generates the
active dihydrofuran, which undergoes in situ aromatization
under mild conditions.
Scheme 1. Novel Strategies for Multisubstituted Furans
urans are common structural motifs in numerous bio-
logically active molecules as well as in various pharmaceuti-
F
cally active compounds, functional materials, and agrochem-
icals.1,2 Moreover, they are also particularly important building
blocks in synthetic organic chemistry.3 As a consequence, it is not
surprising that a large number of effective synthetic methods for
the formation of functionalized furans have been specifically
designed.4 In recent years, transition-metal-mediated cyclo-
isomerization reaction of allene derivatives has been shown to be
a powerful synthetic method for the preparation of furans.5,6 In
those transformations, the allenyl moieties are activated by
transition-metal catalysts (Scheme 1, eq 1). Additionally, access
to this class of compounds by an intermolecular approach
whereby the two substituents originate from different simple
starting materials would have advantages over traditional
strategies.7 As an example, Ellman and co-workers recently
reported a general strategy to access substituted furans via a Rh or
Co catalyzed alkenyl C−H bond addition to aldehydes (Scheme
1, eq 2).8 Consequently, the development of a facile and
environmentally attractive strategy for the direct intermolecular
[3 + 2] annulation of easily available compounds without
assistance of metal system is highly desirable.
Dithianes represent a highly valuable class of compounds
found in natural product synthesis and synthetic intermediates.9
As part of an ongoing research program aimed at developing new
methods for the synthesis of functionalized dithianes,10 we
recently reported that metal-free couplings of β-chloro-vinyl
dithianes with a variety of related nucleophiles can be achieved
under mild conditions (Scheme 1, eq 4).10e In addition, we have
been able to characterize a more reactive vinylidene dithiane
facilitated by a stoichiometric amount of base to induce the
elimination of HCl.11 This unique investigation provided a proof
of principle for vinylidene dithiane as a reactive acceptor/donor
intermediate induced coupling reaction. However, Oh group
recently disclosed a mild base-promoted vinylogous aldol-type
reaction of β-chlorovinyl ketones through an allenol/cumulenol-
(ate) intermediate (Scheme 1, eq 3).12 However, to the best of
our knowledge, direct additions of β-chloro-vinyl dithianes to
aldehydes are unknown; the synthetic versatility of vinylidene
dithiane as a donor allene has scarcely been studied.13 Herein, we
report a practical and highly efficient [3 + 2] cycloaddition of β-
chloro-vinyl dithianes to aldehydes leading to the construction of
highly substituted furans. This represents the first example of
synthesis of furans in which vinylidene dithianes were used as the
Received: March 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00699
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Organic Letters
Letter
a
electron-donor moieties for in situ use in the intermolecular [3 +
2] cycloaddition.
Scheme 3. Substrate Scope of Aldehydes
In our approach to furan synthesis, we reasoned that the
intermolecular [3 + 2] cycloaddition strategy could offer direct
access to highly substituted dihydrofurans that are amendable to
further aromatization by acid neutralized workup. In the
cyclization process, dithiane motif has the ability to “pump” in
which the transformation is determined by the relative
propensity of the vinylidene dithiane to participate in the
electron-transfer process, followed by a vinylogous addition to
aldehydes. Most importantly, the development of method may
address the regiochemistry problem in cyclization reaction.
Meanwhile, the dithiane moiety plays a key role in driving the
essential aromatization in situ via a standard neutralized workup.
To test our hypothesis, we investigated the reaction of β-
chloro-alkenyl dithiane 1a as a standard substrate and
benzaldehyde 2a (Scheme 2). An initial examination of the
Scheme 2. Standard Reaction Conditions for Multisubstituted
Furans
base-mediated reaction conditions revealed that using 1.2 equiv
of t-BuOK and DMSO as the solvent gave complete conversion
of the starting materials at room temperature, and to our delight,
we were able to isolate the 2,3,5-trisubstituted furan product 3aa
in 73% yield after standard workup. In DMSO, the examination
of other bases such as NaOMe, KOH and NaH was found to be
effective for this transformation, while the use of K2CO3 was
ineffective. It should also be noted that the use of Cs2CO3 at 50
°C gave the product in a comparable yield after 2 h (see Table S1
in the Supporting Information (SI)). With the result in hand, we
proceeded with screening of different commonly employed
solvents. It showed that the yield could be increased to an
excellent 89% with THF instead of DMSO (see Table S2 in SI for
further information). Moreover, the reaction in THF reached full
conversion within 5 min. Notably, the reaction without an
aldehyde present at room temperature afforded the reactive
vinylidene dithiane I-1 in moderate isolated yield.11
With a set of optimized reaction conditions in hand, we then
examined the substrate scope with respect to the aldehyde
component. The results are summarized in Scheme 3. Pleasingly,
it was found that a variety of functionalized aryl aldehydes could
be employed for the formation of furan product efficiently.
Substitutions are well tolerated at the 4-position (3ab−3ae), 3-
position (3af−3ah), and the 2-position (3ai−3ak), typically
giving the 2,3,5-trisubstituted furans in excellent yield after an
acidic workup. This aromatic ring was found to be tolerant of
both electron-rich groups, such as methyl (3af and 3ai) and
methoxy (3ab, 3ag, 3aj, 3am, and 3an), and electron-deficient
groups, such as trifluoromethyl (3ak). Importantly, the halogen-
containing motifs, such as F (3ah), Cl (3ad), and Br (3ae)
worked well in this transformation. To this end, several
a
Isolated yield. Reaction conditions: (i) 1a (58 mg, 0.225 mmol), 2a−
2r (0.25 mmol), t-BuOK (28 mg, 0.25 mmol), THF (2 mL), 5−10
min (ii) 1 N HCl work up.
heteroaryl (3ap and 3aq) and vinyl-substituted (3ar) substances
were also subjected to furan products. Unfortunately, alkyl
aldehydes such as t-butyl and n-butyl aldehydes remain
challenging substrates for this methodology under the current
conditions.
Next, a variety of dithiane derivatives with different
substitutions (1b−1h) were synthesized and used to investigate
the influence of electronic parameters on the transformation. To
our delight, the reactions proceeded well under the optimized
reaction conditions, thus affording versatile furan products in
good to excellent yields. The substituent on the aromatic ring has
little influence on this reaction. Both electron-donating and
electron-withdrawing groups were well tolerated in this trans-
formation (Scheme 4). We next tried to extend this methodology
to the analogues of dithioacetal. The substrate 1j underwent the
desired cycloaddition and aromatization cascade process in the
standard condition and provided the corresponding trisubstitu-
tied furans in satisfactory yields.
In probing the intermediates of the reaction, we were pleased
to find that the furan product resulted from the corresponding
dihydrofuran adduct by an irreversible aromatization.14 Gratify-
ingly, the cycloaddition of 1a with differently aldehydes 2a−2m
proceeded smoothly to provide good to high yields of
dihydrofurans 4aa-4am with excellent regioselectivities (Table
B
DOI: 10.1021/acs.orglett.6b00699
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Letter
a
NMR, the cyclization proceeded to completion without the
production of any byproducts.
Scheme 4. Substrate Scope of Vinylidene Dithiane Precusors
Alternatively, to gain insights into the dithiane induced
annulation process by control experiments, the substrate 1a′ was
independently synthesized and exposed to the standard reaction
conditions. As expected, the cycloaddition to 2a was observed.
Conversely, conversions into furan product was not observed
when 1k was used. These results obviously indicated that the
dithiane species are required for the cycloaddition processes
(Scheme 5).
Scheme 5. Mechanistic Experiments and Gram Scale
a
Experiment
a
Isolated yield. Reaction conditions: (i) 1a−1j (0.225 mmol), 2a−2s
(0.25 mmol), t-BuOK (28 mg, 0.25 mmol), THF (2 mL), 5−10 min
(ii) 1 N HCl work up.
1).6d,e The assignment of the structure of 4ab was confirmed by
X-ray crystallographic analysis. As indicated by GC/MS and
Table 1. Investigation of Dihydrofurans
a
Gram scale experiment reaction conditions: (i) 1a−1b (10 mmol), 2a
(1.24 g, 12 mmol), t-BuOK (1.4 g, 12 mmol), THF (50 mL), rt, 30
min (ii) 1 N HCl work up.
To illustrate the pharmaceutical utility of our method, we
exploited this strategy to conduct the potent rigid combretastatin
analogue 6 which displayed a better pharmacokinetic profile to
inhibit tubulin assembly (Scheme 6).15 The [3 + 2] annulation of
Scheme 6. Synthesis of Combretastatin Analogue 6
dithiane 1l and aldehyde 2u proceeded well to provide the
corresponding furan product 3lu. Subsequently, furan 3lu was
subjected to a Rainy-Ni mediated reaction to provide the
biologically active furan 6 in good yield over the two steps.
In summary, we have developed an extremely mild and
efficient method for the preparation of diversely substituted furan
scaffolds starting from simple and readily available substrates.
The first exploration of dithiane induced cycloadditions with
aldehydes has been accomplished without any additional
initiators and metal catalyst. The no catalytic method
demonstrates a broad range of functional group compatibility.
The implementation of the present method to the synthesis of
a
entry
R′
time (min)
product
yield (%)
1
2
3
4
5
H
5
4aa
4ab
4ac
4ak
4am
85
87
79
84
82
4-OMe
4-iPr
5
5
2-CF3
10
5
2,5-OMe
a
Isolated by flash Al2O3 column (EA/PE = 1:100−1:25). Reaction
conditions: 1a (58 mg, 0.25 mmol), 2a−2m (0.25 mmol), t-BuOK (28
mg, 0.25 mmol), THF (2 mL), 5−10 min.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00699.
■
S
Experimental details, characterization data for the
products, and copies of NMR spectra (PDF)
Crystallographic data for 4ab (CIF)
(8) (a) Lian, Y.; Huber, T.; Hesp, K. D.; Bergman, R. G.; Ellman, J. A.
Angew. Chem., Int. Ed. 2013, 52, 629. (b) Hummel, J. R.; Ellman, J. A. J.
Am. Chem. Soc. 2015, 137, 490.
AUTHOR INFORMATION
Corresponding Author
■
́
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(b) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365.
(c) Henrot, M.; Richter, M. E. A.; Maddaluno, J.; Herweck, C.; De
Paolis, M. Angew. Chem., Int. Ed. 2012, 51, 9587. (d) Mahapatra, S.;
Cater, R. G. J. Am. Chem. Soc. 2013, 135, 10792. (e) Chen, M. Z.;
Gutierrez, O.; Smith, A. B., III Angew. Chem., Int. Ed. 2014, 53, 1279.
(10) (a) Du, W.; Tian, L.; Lai, J.; Huo, X.; Xie, X.; She, X.; Tang, S. Org.
Lett. 2014, 16, 2470. (b) Du, W.; Lai, J.; Tian, L.; Xie, X.; She, X.; Tang,
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2015, 21, 14328.
*E-mail: tangshch@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the Qiaohong Foundation
and Fundamental Research Funds for Central Universities
(No.lzujbky-2015-309). We thank the State Key Laboratory of
Applied Organic Chemistry for assistance with NMR spectros-
copy.
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