Catalytic [2+2+1] Synthesis of Fused Thiophenes Using Thiocarbonyls as Sulfur Donors

Article abstract of DOI:10.1002/anie.201609545

The use of N-(p-chlorophenyl)methylbenzoxazole-2-thione as a sulfur-atom donor enables the catalytic [2+2+1] cycloaddition of diynes in wet DMF at 80 °C when open to air, thus affording diverse fused thiophenes with good yields and wide functional-group c

Full text of DOI:10.1002/anie.201609545

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International Edition: DOI: 10.1002/anie.201609545
German Edition: DOI: 10.1002/ange.201609545
Cycloaddition
Catalytic [2+2+1] Synthesis of Fused Thiophenes Using Thiocarbonyls
as Sulfur Donors
Kazuma Matsui, Masatoshi Shibuya, and Yoshihiko Yamamoto*
Abstract: The use of N-(p-chlorophenyl)methylbenzoxazole-
2-thione as a sulfur-atom donor enables the catalytic [2+2+1]
cycloaddition of diynes in wet DMF at 808C when open to air,
thus affording diverse fused thiophenes with good yields and
wide functional-group compatibility. A plausible mechanism,
involving a cationic ruthenacycle intermediate, was also
proposed on the basis of several control experiments.
T
hiophene is a privileged scaffold widely found in biologi-
cally active compounds and functional materials.[1] Although
transition-metal-catalyzed approaches have been extensively
developed to achieve diverse heterocycle syntheses under
neutral conditions,[2] the catalytic synthesis of substituted
thiophenes is underdeveloped because organosulfur com-
pounds often inhibit the catalytic turnover by strong coordi-
nation of the soft sulfur atom to the transition-metal
catalysts.[3,4]
Figure 1. [2+2+1] Approaches to multisubstituted thiophenes.
To establish a straightforward and versatile process, we
focused on the transition-metal-mediated [2+2+1] approach,
as it enables the construction of substituted thiophenes from
readily available alkynes in a single operation. However, the
requirement of stoichiometric amounts of preformed metal-
lacycles, low efficiency, and/or limited scope remain to be
addressed.[5] Although substituted thiophenes have been
synthesized via zirconacyclopentadienes using S2Cl2 as the
sulfur donor (Figure 1a),[6] the functional-group compatibility
is limited owing to the highly reducing character of “Cp2Zr”.
Moreover, a metal-free [2+2+1] synthesis of thiophenes
(Figure 1b)[7] and relevant methods using 1,3-diynes have
been developed.[8] However, the substrate scope is still limited
in previous methods.
transfer from thiocarbonyls to carbenoid carbon atoms (Fig-
ure 1c). Notably, the newly developed process is robust and
operationally simple, as the reaction can be performed in air
and neither a anhydrous solvent nor an inert atmosphere is
necessary.
The key to the successful realization of the elusive
catalytic [2+2+1] synthesis of thiophenes is the identification
of an optimal sulfur donor toward ruthenacycle intermediates
as electrophilic bis(carbenoid)s. To this end, conventional
sulfur donors (Lawessonꢀs reagent, thiirane, S8, Na2S, and
Na2S2O3) were screened. However, the expected product was
not sufficiently obtained. Then, we evaluated thiocarbonyls as
=
We have previously reported transition-metal-catalyzed
[2+2+1] cycloadditions of alkynes to afford substituted
furans.[9] In these reports, catalytically generated ruthenacycle
intermediates behaved as electrophilic bis(carbenoid)s to
undergo oxygen-atom transfer from either DMSO or nitro-
nes, thus allowing the catalytic formation of fused furans.
Based on these results, we assumed that the yet elusive sulfur-
atom transfer to similar ruthenacycle intermediates could be
realized by judicious optimization of a sulfur donor and
reaction conditions. Herein, we disclose a novel catalytic
[2+2+1] cycloaddition of diynes involving a sulfur-atom
tunable sulfur donors, because a C S bond has high polar-
izability owing to inefficient pp–pp overlap and, thus, is
sufficiently nucleophilic. After extensive screening of thio-
carbonyls (see Figure S1 in Supporting Information), we
found that the benzoxazole-2-thione 3a was a potent S donor
(Scheme 1). Therefore, the N-benzyl moiety was further
[*] K. Matsui, Dr. M. Shibuya, Prof. Dr. Y. Yamamoto
Department of Basic Medicinal Sciences, Graduate School of
Pharmaceutical Sciences, Nagoya University
Chikusa, Nagoya 464-8601 (Japan)
E-mail: yamamoto-yoshi@ps.nagoya-u.ac.jp
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609545.
Scheme 1. Optimization of sulfur donor. DMF=N,N-dimethylforma-
mide.
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optimized by performing the reaction of the diyne 1a with
1 mol% [CpRu(MeCN)3]PF6 (Ru1; Cp = h5-C5H5) at 808C
using DMF while open to air. It was revealed that an electron-
withdrawing group on the N-benzyl moiety of 3 has a favor-
able impact on the sulfur-atom transfer. The p-chlorinated
analogue 3b gave the best yield (71%), albeit with 21% of 1a
remaining. The m-chloro and p-fluoro analogues 3c and 3d,
respectively, also produced 2a, albeit in slightly lower yields,
and 3e, bearing an electron-donating methoxy group on the
N-benzyl moiety, was inefficient. Notably, the reaction was
sluggish in anhydrous DMF and the yield of 2a decreased to
35%, and unreacted 1a and 3b were recovered in 63 and 64%
yield, respectively. This result implies that water plays an
important role. Moreover, [Cp*Ru(MeCN)3]PF6, bearing the
bulky and electron-donating Cp* (h5-C5Me5) ligand, proved
to be a less efficient catalyst.
obtained in 62% yield from the stoichiometric reaction of
a preformed rhodacyclopentadiene with elemental sulfur.[5a]
The present protocol successfully improved the yield by using
catalytic amounts of the less expensive ruthenium complex.
The fused thiophene structure was unambiguously confirmed
by single-crystal X-ray analysis of 2k.
Next, the influence of the terminal aryl groups of diyne
substrates was investigated (Figure 3). The reactions of the
By using 3b as the optimal sulfur donor, the general
applicability of this method was investigated in terms of the
diyne substrates 1 (Figure 2). The reaction of 1a was repeated
Figure 3. Influence of terminal aryl groups.
diynes 1o–r, possessing electron-rich aryl terminals, pro-
ceeded with a 2 mol% catalyst loading, except for 1p, which
bears sterically demanding o-substituted aryl terminals
(10 mol%). The corresponding bicyclic thiophenes 2o–r
were obtained in high yields. In addition, the diynes 1s–u,
bearing p-fluoro, p-iodo, and p-boryl groups on the aryl
terminals, respectively, afforded the corresponding products
in greater than 90% yields, although 5 mol% catalyst
loadings were required for 1s and 1u. In contrast, the
reaction of the diyne 1v, possessing p-formylphenyl terminal
groups, hardly produced the desired thiophene under the
standard reaction conditions with a 2 mol% catalyst load-
ing.[10] This protocol enables the synthesis of unsymmetrical
push-pull thiophenes 2w, 2x, and 2y in high yields.[11]
Moreover, the tristhiophenes 2za–zc were synthesized in
67–92% yields. It is particularly significant that the reactive
Figure 2. Scope with respect to the diyne substrates. TBS=tert-butyldi-
methylsilyl, Ts=4-toluenesulfonyl.
with an increased catalyst loading (2 mol%) to observe
complete conversion in 5 hours, thus affording 2a in 90%
yield upon isolation. Similarly, other diynes (1b–j) were
subjected to the reaction with a 2–5 mol% catalyst loading,
thus affording the corresponding bicyclic thiophenes in 71–
90% yield. Notably, various functional groups, including
ester, ketone, amide, nitrile, sulfide, sulfone, and silyl ether,
were well tolerated under the reaction conditions.
The spirocyclic fluorene derivative 2k and acenaphtho-
[1,2-c]thiophene derivative 2l were also synthesized in high
yields (Figure 2). Moreover, this method proved to be
applicable to six-membered ring formations, as the 4H-
thieno[3,4-c]chromene derivative 2m and naphtho[2,3-c]thio-
phene-4,9-dione derivative 2n were obtained in 87 and 75%
yield, respectively. The latter compound was previously
ꢀ
ꢀ
ꢀ
C I, C Br, and C B bonds, which can be utilized for further
transformations, were preserved in the final products.
This method was also applicable to diyne substrates
bearing alkyl or silyl terminal groups (Scheme 2). The diynes
4a and 4b, each bearing at least one alkyl terminal group
afforded the corresponding bicyclic thiophenes 5a and 5b,
albeit in moderate yields. In our previous study, silyldiynes
could be converted into 2-silylfurans using nitrones as oxygen
donors.[9b] In striking contrast, TMS groups were not tolerated
under the present reaction conditions: the reaction of diyne
6a, bearing a TMS terminal group, afforded the desilylated
bicyclic thiophene 7 in 56% yield. Thus, the diyne 6b, bearing
a bulkier TBS terminal group was examined, and afforded the
2
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Scheme 2. Reactions of diynes bearing nonaromatic terminal groups.
TMS=trimethylsilyl.
expected 2-silylthiophene 8 in 49% yield, along with 7 (36%).
Taking advantage of the readily removed TMS groups, the
bis(silyl)diyne 9 was directly transformed into the bicyclic
thiophene 10, which could not be obtained from the
corresponding terminal diyne because of its facile [2+2+2]
cyclodimerization. Finally, diphenylacetylene and (3-methox-
yprop-1-ynyl)benzene were also subjected to the reaction
conditions, thus affording only trace amounts of the expected
thiophenes. Therefore, the catalytic [2+2+1] protocol is
dependent on the intramolecular settings.
To gain insight into the reaction mechanism, several
control experiments were conducted. The previously reported
ruthenacycle complex 11[12] was reacted with 3b upon treat-
ment with AgPF6 (1.1 equiv) in DMF at 808C for 1 hour, and
afforded 2a in 54% yield (Figure 4). This result corroborates
the involvement of cationic ruthenium bis(carbene) com-
plexes in the present [2+2+1] cycloaddition. Moreover,
careful inspection of the byproducts of the reaction of 1a
with 3b led to the identification of the formamide 12, which
was derived from 3b. It was proposed that one H2O molecule
was involved in the transformation of 3b into 12. Thus, the
reaction of 1a and 3b was repeated in the presence of D2O
(6 equiv) and H218O (6 equiv), with the other reaction
parameters remaining the same, thus affording [D]12 and
[18O]12, respectively. These results corroborate the involve-
ment of a water molecule in the sulfur-atom transfer and are
in good agreement with the fact that the reaction was sluggish
in anhydrous DMF. In the absence of H2O, only trace amounts
of 12 were detected and unidentifiable byproducts were also
observed. In contrast, the reactions efficiently proceeded in
wet DMF (H2O < 0.1%) in air. These results imply that H2O
was not essential, but dramatically improved the reaction
efficiency. Indeed, the reaction of 1a with 3b completed in
only 2 hours to afford 2a in 91% yield when the reaction was
carried out with 1.0 equivalent of H2O in anhydrous DMF
(H2O < 10 ppm) under Ar.
Based on these observations, a plausible mechanism was
deduced as shown in Figure 4. The catalytic cycle starts with
the oxidative cyclization of a diyne with the CpRu+ fragment
to generate the cationic ruthenacycle A as a key intermediate.
Subsequently, sulfur-atom transfer occurs from 3b to the
electrophilic carbene carbon atom of A to generate the
thiadienylcarbene complex C, which further undergoes cyc-
lization to provide thiophene complex D. A similar cyclo-
isomerization was proposed for the previous [2+2+1] furan
formations.[9] The final ligand exchange from the resultant
thiophene to a diyne restores A, thus closing the catalytic
Figure 4. Control experiments and proposed mechanism.
cycle. Although the details of the sulfur-atom-transfer step
(A!C) are unclear at this stage, it is suggested that the attack
of H2O on the thiocarbonyl group of 3b, which becomes
electrophilic upon coordination (B), triggers the sulfur-atom
transfer to the carbenoid carbon atom via the transition state
TSBC. An alternative route is the direct S transfer from the
coordinated thiocarbonyl to the ruthenacycle with the
concomitant formation of a free carbene, which reacts with
H2O to generate 12.
In conclusion, we developed a catalytic [2+2+1] cyclo-
addition route to produce diverse fused thiophenes using N-
(p-chlorophenyl)methylbenzoxazole-2-thione as the sulfur
donor in wet DMF at 808C. The optimized protocol tolerated
a wide variety of functional groups and enabled the reaction
to proceed when open to air, thus obviating inert atmosphere
and anhydrous conditions. A plausible mechanism, involving
a cationic ruthenacycle intermediate, for this catalytic process
was also deduced from several control experiments. Interest-
ingly, the sulfur-atom transfer from the thiocarbonyl group to
the cationic carbenoid carbon atom possibly occurs with the
attack of H2O on the coordinated thiocarbonyl group.
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[7] W. Liu, C. Chen, H. Liu, Adv. Synth. Catal. 2015, 357, 4050 –
4054.
Acknowledgments
[8] a) M. L. N. Rao, S. S. Islam, P. Dasgupta, RSC Adv. 2015, 5,
78090 – 78098; b) I. Talbi, C. Alayrac, J.-F. Lohier, S. Touil, B.
Witulski, Org. Lett. 2016, 18, 2656 – 2659.
[9] a) K. Yamashita, Y. Yamamoto, H. Nishiyama, J. Am. Chem.
Soc. 2012, 134, 7660 – 7663; b) K. Matsui, M. Shibuya, Y.
Yamamoto, ACS Catal. 2015, 5, 6468 – 6472.
This research is partially supported by AMED (Platform for
Drug Discovery, Information, and Structural Life Science)
and JSPS KAKENHI (Grand Number JP 16KT0051).
Keywords: alkynes · cycloaddition · reaction mechanisms ·
[10] The inefficiency of 1v can be ascribed to the electron-with-
drawing effect of the terminal groups. The reaction of 1a with 3b
was conducted in the presence of 2 equiv of benzaldehyde under
the standard reaction conditions, thus affording 2a in 83% yield.
This result indicates that the formyl group is tolerated under the
reaction conditions.
[11] Thiophene derivatives substituted by electron-donors and elec-
tron-acceptors at the 2- and 5-positions, respectively, have
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irradiated by a UV lamp (l = 365 nm). Fluorescence spectra of
2x and 2y with lmax at 464 and 430 nm, respectively, were
obtained when excited at l = 398 nm in CH2Cl2 (see Figure S4 in
the Supporting Information).
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Received: September 29, 2016
Published online: && &&, &&&&
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Communications
Cycloaddition
K. Matsui, M. Shibuya,
Y. Yamamoto*
&&&& — &&&&
Catalytic [2+2+1] Synthesis of Fused
Thiophenes Using Thiocarbonyls as
Sulfur Donors
The use of N-(p-chlorophenyl)methylben-
zoxazole-2-thione as a sulfur-atom donor
enables the catalytic [2+2+1] cycloaddi-
tion of diynes in DMF at 808C when open
to air, thus affording diverse fused thio-
phenes with good yields and wide func-
tional-group compatibility. A plausible
mechanism, involving a cationic ruthe-
nacycle intermediate, was also proposed
on the basis of several control experi-
ments.
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!