Copper-catalyzed complete regio- and stereoselective cyclization of 1-aryl-3-sulfanyl-4-oxahepta-1,6-diynes triggered by alkynylation

Article abstract of DOI:10.1021/ol3011453

Copper(I)-catalyzed alkynylation-cyclization of 4-oxahepta-1,6-diynes 1 with a wide variety of terminal alkynes proceeded to give (3E,4Z)-3- (phenylsulfanylmethylene)-4-(2-propynylidene)tetrahydrofuran-2-yl]benzenes 2aa-he in high yields with complete regio- and stereoselectivity.

Full text of DOI:10.1021/ol3011453

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3190–3193
Copper-Catalyzed Complete Regio- and
Stereoselective Cyclization of
1-Aryl-3-sulfanyl-4-oxahepta-1,6-diynes
Triggered by Alkynylation
Mitsuhiro Yoshimatsu,*,† Hitomi Sasaki,† Yuko Sugimoto,† Yuya Nagase,†
Genzoh Tanabe,‡ and Osamu Muraoka‡
Department of Chemistry, Faculty of Education, Gifu University, Yanagido 1-1, Japan,
and School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-osaka,
Osaka 577-8502, Japan
yoshimae@gifu-u.ac.jp
Received May 10, 2012
ABSTRACT
Copper(I)-catalyzed alkynylationꢀcyclization of 4-oxahepta-1,6-diynes 1 with a wide variety of terminal alkynes proceeded to give (3E,4Z)-
3-(phenylsulfanylmethylene)-4-(2-propynylidene)tetrahydrofuran-2-yl]benzenes 2aaꢀhe in high yields with complete regio- and stereoselectivity.
During the past decade, the direct utilization of 1,6-
diynes in cyclizations and cycloisomerizations has been a
significant challenge, and the application ofthese strategies
to construct polysubstituted furans is especially attractive.
A novel strategy of transition-metal-catalyzed cyclization
of 1,6-diynes using alkynes such as [2 þ 2 þ 2] cycload-
ditions leading to benzenoides has been established.1
The challenge is tuning the approach to a more attrac-
tive cyclization including a wide variety of functionaliza-
tions such as catalytic hydrogenation,2 rhodium-catalyzed
arylation,3 carbonꢀcarbon bond formation with ketones
and enones leading to 1,2-dialkylidenecycloalkanes,4 and
ruthenium-catalyzed decarbonylation leading to alkyli-
denecycloalkanes.5
Scheme 1. Alkynylative Cyclization
† Gifu University.
‡ Kinki University.
(1) Recent reviews for [2 þ 2 þ 2] cycloaddition reactions: (a)
Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503. (b) Gandon, V.; Aubert,
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´ ´
ꢀ
Castedo, L.; Saa, C. Chem.ꢀEur. J. 2008, 14, 9772.
Although some progress has been made in this field,
there still remains a significant challenge in discovering a
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127, 1094.
r
10.1021/ol3011453
Published on Web 06/06/2012
2012 American Chemical Society

highly efficient cyclization and cycloisomerization trig-
gered by other useful functionalizations.
cyclization reaction did not proceed (entry 4), and the
starting diyne was recovered. On further screening of cata-
lysts, amines, and solvents, we found that copper(I) and
tributylamine were the most suitable catalyst and amine for
alkynylationꢀcyclizations, respectively. The optimized con-
ditions were used as shown in entry 6. In addition, we in-
vestigated the role of the solvent. Toluene was found to be
the most effective solvent for the alkynylationꢀcyclizations.
Other solvents such as dioxane, DMF, and DMSO gave
poorer yields of 2aa.
Our previous investigations of sulfur-substituted 1,6-
diynes with nucleophiles afforded cyclized furans through
an alkoxylation or aryloxylationꢀcyclization process, even
in metal-free reactions.6 Next, we focused on the cyclization
of 1,6-diynes triggered by alkynylation reactions because
enynes, dienynes, and enediynes are the key units of a
wide variety of important pharmacores such as neocarzi-
nostatin,7 C-1027,8 calicheamicin,9 kedarcidin chromo-
phore,10 and other enediyne chromophores.11 Meanwhile,
recent advances in alkynylations have explored the metal-
catalyzed cross-dimerization of alkynes, which is a practical
and direct method for generating enynes.12 In continuation
of our studies on the cyclizations of sulfur-substituted
1,6-diynes, which have a unique reactivity, we initially
investigated the copper-catalyzed cyclization of sulfanyl
1,6-diynes. Surprisingly, the cyclization of phenyl-substituted
1,6-diyne did not proceed, as shown in Scheme 1. Here, we
report a new copper(I)-catalyzed regio- and stereoselective
alkynylationꢀcyclization of sulfanyl 1,6-diynes leading to
3,4-dialkylidenefurans bearing an alkynyl group.
Table 1. Screening for Suitable Reaction Condition
entry
conditions
% yieldb
1
2
Pd(PPh3)4 (5), CuI (20), Et3N (5), toluene, 5 h
CuI (20), Et3N (5), toluene, 5 h
37
20
3
CuBr (10), Bu3N (2.5), toluene, 1 h
Pd(PPh3)4 (10), Et3N (5), toluene, 5 h
Cu(OAc)2 (10), Bu3N (2.5), toluene, 5 h
Cu(OTf)a (10), Bu3N (2.5), toluene, 20 min
CuOTf (10), Bu3N (2.5), dioxane, 15 min
CuOTf (10), Bu3N (2.5), DMF, 15 min
CuOTf (10), C5H5N (6), DMF, 2 h
33
First, we examined the reaction of diyne 1a, which was
easily prepared through the propargylation of 1-aryl-3-
sulfanylpropargyl alcohol, with 3,3-dimethyl-1-butyne un-
der typical conditions for usual coupling reactions; namely
5 mol % of Pd(PPh3)4ꢀ20 mol % CuI in toluene to give
4-[(4,4-dimethylpent-2-ynylene)-3-(phenylsulfanylmethyl-
ene)-2-furyl]-1-methoxybenzene (2aa) in 37% yield. As
shown in entry 2 of Table 1, the same reaction in the
presence of CuI alone gave a yield similar to that of 2aa.
Using the palladium catalyst in the absence of CuI, the
4
recov
recov
100
37
5
6
7
8
49
9
5
10
11
12
CuOTf (10), Et3N (5), toluene, 10 min
CuOTf (10), DIPEA (3.5), DMF, 45 min
CuOTf (10), Bu3N (2.5), Bu4NHSO4 (0.1),
tolueneꢀH2O (10:1), 15 min
48
29
76
13
14
CuOTf (10), Bu3N (2.5), benzene, 20 min
CuOTf (10), Bu3N (2.5), DMSO, 20 min
48
ꢀ
ꢀ
(5) Decarbonylative: (a) Gonzalez-Rodrıguez, C.; Varela, J. A.;
´
a CuOTf was used as benzene complex. b The yield of the product 2aa
was the isolated yield.
ꢀ
Castedo, L.; Saa, C. J. Am. Chem. Soc. 2007, 129, 12916. Dehydrative:
(b) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763.
Acetoxy: (c) Tanaka, K.; Saitoh, S.; Hara, H.; Shibata, Y. Org. Biomol.
Chem. 2009, 7, 4817.
Furthermore, including water asanadditive resultedin a
minor increase in the yield (entry 12). To clarify the unique
alkynylationꢀcyclizations with complete regio- and stereo-
selectivity, we further investigated the copper-catalyzed
alkynylation of 4-oxahepta-1,6-diyne bearing no sulfur
functional groups with p-tolyl- and tert-butylacetylene;
however, the corresponding dienynes were not obtained,
and most of the diynes were recovered (Scheme 2). This
shows that the organosulfur functional group on the
terminal acetylene of the diynes plays an important role
in catalytic alkynylationꢀcyclization. In all cases, the
homocoupling product of 1a was not observed.
(6) Yoshimatsu, M.; Watanabe, H.; Koketsu, E. Org. Lett. 2010, 12,
4192.
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1996, 272, 5270. (b) Hensens, O. D.; Chin, D.-H.; Stassinopoulos, A.;
Zink, D. L.; Kappen, L. S.; Goldberg, I. H. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 4534.
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Sci. U.S.A. 2009, 106, 4183. (c) Zhan, J.; Van Lanen, S. G.; Ju, J.; Liu,
W.; Dorrestein, P. C.; Li, W.; Kelleher, N. L.; Shen, B. Proc. Natl. Acad.
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B.; Beerman, T. A. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 17632.
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2822.
Scheme 2. Attempts of 1,3-diphenyl-4-oxahpeta-1,6-diyne to
alkynylationꢀcyclyzation
(11) (a) Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad.
Sci. U.S.A. 1993, 90, 5881. (b) Sugiura, Y.; Shiraki, T.; Konish, M.; Oki,
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Synlett 2008, 2663.
Org. Lett., Vol. 14, No. 12, 2012
3191

Next, we investigated the scope of the alkynylationꢀ
cyclization reaction of 1,6-diynes with terminal acetylenes,
and the results are shown in Table 2. In most cases, the reac-
tion of diynes with aromatic acetylenes proceeded smoothly;
however, the reaction with ethynylpyridine was totally in-
effective (entries 1ꢀ4). Propargyl aldehyde diethyl acetal and
propargyl alcohol formed adducts 2af and 2ag, entries 5 and
6, respectively, in a stereospecific manner. Notably, the
reactions with 3-methyl-1-butyn-3-ol and ethynylcycloalk-
anols, for example, were complete in 10ꢀ20 min at room
temperature. The reactions with bulky cyclododecanol and
ethynylestradiol were also effective in giving both dienynes
2al and 2am in good yields (entries 11 and 12, respectively).
The reaction with the secondary propargylic alcohol exclu-
sively formed dienyne 2an (entry 13). However, 4-azahepta-
6-en-1-yne, a secondary propargylamine, did not undergo
tandem cyclization to give the corresponding dienyne 2ao in
good yield (entry 14). We also examined reactions of diynes
bearing other aromatic substituents in conjunction with
similar acetylenes. The introduction of electron-withdrawing
substituents in 1b (Ar = p-FC6H4), 1c (Ar = p-ClC6H4),
and 1d (Ar=p-BrC6H4) had a positive effect on the reaction
outcome and formed the corresponding products after a
relatively short reaction time (1ꢀ4 h) (entries 15ꢀ21).
All of the cyclized compounds 2aaꢀhe showed similar
NMR spectroscopic properties. The NMR spectrum of
2ba indicated the presence of two trisubstituted olefin
moieties, and the observed small J values (J = 1.7 Hz
for the single-proton doublet at δH 6.07 and J = 2.6 and
2.3 Hz for the one-proton doublet of doublets at δH 6.34,
which correlates to the two olefinic protons at C30 and C40,
respectively) were ascribed to allylic couplings between the
R-methine proton at C2 and the methylene protons at C5.
Finally, the structure of 2ba was confirmed by single-
crystal X-ray analysis, as shown in Figure 1.13
Figure 1. Perspective view of compound 2ba with 50% ellipsoide
probability.
The mechanism for the copper-catalyzed cyclizations
of 1,6-diynes would be significantly different from that
of base-mediated cyclization.14 We propose a plausible mech-
anism for the copper-catalyzed alkynylationꢀcyclization, as
shown in Scheme 3. First, the terminal acetylene is acti-
vated by the Cu(I) catalyst to form the alkynylcopper
reagent 4, which reacts with the diyne 3, via an anti-
addition at the terminal acetylene, to give an enyne copper
species 5. Second, intramolecular cyclization of 5 occurs in
a stereospecific manner, resulting in dienyne 6, which is
highly stabilized by the organosulfur functional group.
Third, the π-alkyne complex between the dienyl copper 6
and another acetylene-forming intermediate 7 undergoes
ligand coupling to give product 8. Finally, the alkynylcop-
per reagent 4 regenerated to induce the next catalytic cycle
of the alkynylative cyclization. To obtain further informa-
tion supporting this mechanism, we performed the reaction
of diyne 1a with phenylacetylene-d1 to form doubly deu-
terated product 8a (deuterated at both H30 and H40) with a
high deuterium ratio. The results show that interconver-
sion between acetylene 3 and acetylide 30 takes place under
the reaction conditions and that the last step involves the
ligand coupling of intermediate 7 via the π-complex with
the intermolecular acetylene or a simple deuteration in the
presence of a large excess of phenylacetylene-d1.15
Finally, we investigated a similar additionꢀcyclization of
4-oxahepta-1,6-diynes, as shown in Scheme 4. The details
of reactions with alkoxides and aryl oxides are described in
our previous paper.6 To clarify the trends of the reactions,
other nucleophiles were examined. Under basic conditions,
some nucleophiles such as tosyl hydrazide, ammonium
acetate, and ammonium benzoate reacted with diynes to
give 4-hydrazinomethyl 9, acetoxymethyl 10, and benzoyl-
oxymethylfurans 11, respectively. We further explored the
palladium-catalyzed hydroaminationꢀcyclizations leading
to pyrrolidinomethyl 12a (n = 0), piperidinomethyl 12b
(n = 1), and benzimidazolylfurans 13.
The substrate 3-(2-thienyl)-4-oxahepta-1,6-diyne 1h was
highly reactive in the alkynylationꢀcyclizations; therefore,
p-tolyl-, 2-thienyl-, and cycloalkanol-substituted 1,3-dien-
5-ynes (2haꢀhd, respectively) were readily formed (entries
26ꢀ29). In addition, 1-octyn-3-ol participated effectively
and exclusively afforded the adduct 2he (entry 30).
(13) X-ray crystallographic analysis: single crystals of products 2ba
were obtained by slow crystallization from a mixture of CH2Cl2 and
n-hexane as pale yellow prisms. Data of 2ba were taken on a Rigaku
RAXIS RAPID imaging plate area detector with graphite monochro-
mated Mo-Ka radiation (λ = 0.71075 A). A total of 11010 reflections
(5056 unique, Rint = 0.015) were collected at a temperature of 23 °C to a
maximum 2θ value of 55°. The structure of 2ba was solved by heavy-
atom Patterson methods, and full-matrix least-squares refinement on F2
was employed with anisotropic thermal parameters for all non-hydrogen
atoms. All calculations were performed using the CrystalStructure 3.8
crystal structure analysis package, Rigaku and Rigaku/MSC. ORTEP
drawings of 2ba are shown in Figure 1. Crystal data for 2ba: triclinic,
space group P-1, a = 10.1433(11) A, b = 10.4317(9) A, c = 12.4818(12)
A, R = 76.579(3)°, β = 65.075(3)°, γ = 69.380(3)°, V = 1115.53(19) A3,
Z = 2, μ(Mo KR) = 1.68 cmꢀ1, F(000) = 432, Dc = 1.228 g/cm3, crystal
dimensions: 0.35 ꢁ 0.22 ꢁ 0.20 mm. Final R1 [I > 2.00σ>(I)], R (all
reflections) and Rw2 (all reflections) values were 0.0578, 0.0904, and
0.1845, respectively. The maximum and minimum peaks in the differ-
Inconclusion, wehave demonstrated the firstcyclization
of terminal alkynes and 1,6-diynes leading to sulfanyl-
substituted 1,3-dien-5-ynes catalyzed by copper(I). We
ence map were 0.35 and ꢀ0.45 eꢀ
A
ꢀ3, respectively. The data for 2ba
have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC842918. For further details on
the crystal structure, see the CIF of compound 2ba.
(14) Kudoh, T.; Mori, T.; Shirahama, M.; Yamada, M.; Ishikawa,
T.; Saito, S.; Kobayashi, H. J. Am. Chem. Soc. 2007, 129, 4939.
(15) Hattori, G.; Matsuzawa, H.; Tanabe, Y.; Miyake, Y.;
Nishibayashi, Y. J. Am. Chem. Soc. 2010, 132, 10592.
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Org. Lett., Vol. 14, No. 12, 2012

Table 2. Cyclization of 4-Oxahepta-1,6-diynes Using Versatile
Terminal Alkynes
Scheme 3. Proposed Mechanism for Cyclization
Scheme 4. Transformations of Alkynylated Tetrahydrofurans
are now investigating further reactions of alkynylationꢀ
cyclizations of sulfur-substituted 1,6-diynes bearing non-
aromatic substituents and other cyclizations triggered by
aminations. These results will be reported elsewhere.
Acknowledgment. This paper is dedicated to Professor
Shinzoh Kagabu on the occasion of his retirement from
Gifu University.
Supporting Information Available. Experimental de-
tails and spectral data for all of the new compounds,1H
and 13C NMR spectral data of all compounds, and X-ray
data for compound 2ba (CIF). This material is avail-
able free of charge via the Internet via Internet at http://
pubs.acs.org.
a 3E-Isomer was observed in 16%.
Org. Lett., Vol. 14, No. 12, 2012
The authors declare no competing financial interest.
3193