Transmetalation of Z-telluroenynes: Stereoselective synthesis of Z-enynols and their application in palladium-catalyzed cyclization

Article abstract of DOI:10.1021/ol902896x

(Figure Presented) The synthesis of various Z-enynols via reaction of vlnyllithlum Intermediate with aldehydes and ketones Is described. The subsequent cyclizatlon of a wide variety of Z-enynols afforded substituted furans and dihydrofurans with high regl

Full text of DOI:10.1021/ol902896x

ORGANIC
LETTERS
2010
Vol. 12, No. 5
936-939
Transmetalation of Z-Telluroenynes:
Stereoselective Synthesis of Z-Enynols
and Their Application in
Palladium-Catalyzed Cyclization
Caroline C. Schneider,† Helton Caldeira,† Bibiana M. Gay,† Davi F. Back,‡ and
Gilson Zeni*,†
Laborato´rio de S´ıntese, ReatiVidade, AValiac¸a˜o Farmacolo´gica e Toxicolo´gica de
Organocalcogeˆnios, and Laborato´rio de Materiais Inorgaˆnicos, CCNE, UFSM,
Santa Maria, Rio Grande do Sul 97105-900, Brazil
gzeni@pq.cnpq.br
Received December 16, 2009
ABSTRACT
The synthesis of various Z-enynols via reaction of vinyllithium intermediate with aldehydes and ketones is described. The subsequent
cyclization of a wide variety of Z-enynols afforded substituted furans and dihydrofurans with high regioselectivity under mild reaction
conditions.
The stereospecific synthesis of conjugated enynes is of
great interest to organic chemists. They are considered to
be some of the most potent antitumoral agents known to
date and have other interesting biological activities as
well.1 In this context, Z-enynols are extremely versatile
structural units for drug lead discovery due to their wide
range of activity against different families of targets.2
Although considerable efforts have been devoted to the
development of efficient methods for the synthesis of
Z-enynols, the majority are focused on (1) zirconium-
mediated cross-coupling,3 (2) titanium complexes,4 and
(3) catalytic synthesis via Pd/Cu cross-coupling of the
terminal alkynes with vinylic halides.5 To the best of our
knowledge, the preparation of Z-enynols using vinylic
tellurides as substrate still remains an unexplored area.6
The chemistry of organotellurium compounds has devel-
oped in the past years, being the subject of many review
articles7 as well as books.8 From the many classes of
tellurium compounds, vinylic tellurides constitute one of
the most useful. Several methods have been developed
† Laborato´rio de S´ıntese, Reatividade.
‡ Laborato´rio de Materiais Inorgaˆnicos.
(1) (a) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene Chemistry;
Stang, P. J., Diederich, F., Eds.; VCH: Weinheim, 1995. (b) Grissom, J. W.;
Gunawardena, G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453.
(c) Nicolaou, K. C.; Da´ı, W. M. Angew. Chem., Int. Ed. Engl. 1991, 30,
1387. (d) Nicolaou, K. C.; Day´, W.-D.; Hong, Y. P.; Tsay, S.-C.; Baldridge,
J. S.; Siegel, J. S. J. Am. Chem. Soc. 1993, 115, 7944. (e) Danishefsky,
S. J.; Shair, M. D. J. Org. Chem. 1996, 61, 16. (f) Yang, C.; Nolan, S. P.
J. Org. Chem. 2002, 67, 591, and references cited therein.
(4) (a) Chen, J.; Liu, Y. Tetrahedron Lett. 2008, 49, 6655. (b) Liu, Y.;
Gao, H. Org. Lett. 2006, 8, 309.
(2) Havranek, M.; Sauerberg, P.; Mogensen, J. P.; Kratina, P.; Jeppesen,
C. B.; Pettersson, I.; Pihera, P. Bioorg. Med. Chem. Lett. 2007, 17, 4144.
(3) (a) Guo, S.; Zhang, H.; Song, F.; Liu, Y. Tetrahedron Lett. 2007,
63, 2009. (b) Liu, Y.; Song, F.; Cong, L. J. Org. Chem. 2005, 70, 6999. (c)
Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
(5) (a) Lu, Z.; Ma, S. AdV. Synth. Catal. 2007, 7, 1225. (b) Liu, F.; Ma,
D. J. Org. Chem. 2007, 72, 4844. (c) Lu, Z.; Ma, S. J. Org. Chem. 2006,
71, 2655.
(6) Dabdoub, M. J.; Dabdoub, V. B.; Comasseto, J. V. Tetrahedron Lett.
1992, 33, 2261.
10.1021/ol902896x  2010 American Chemical Society
Published on Web 02/04/2010

for their preparation;7,8 among them, one of the most
important is the hydrotelluration reaction of alkynes,9 which
furnishes exclusively the (Z)-vinylic telluride. These species
can be transmetalated with many organometallic reagents to
generate the corresponding (Z)-vinyl organometallics with
retention of the double-bond geometry, which can react with
several electrophiles like carbonyl compounds,10 enones,11
and epoxides.12 These and especially the knowledge that
Z-enynols are promising candidates for palladium-catalyzed
cyclization to form substituted furans prompted us to develop
a complete investigation on the synthesis of Z-enynols from
vinylic tellurides as the sequence showed in Scheme 1.
coupling, we conclude that the Te/Li exchange proceeded
with highly stereospecific retention of configuration.
After standardizing the conditions of the transmetalation,
the reaction of the (Z)-vinyllithium intermediate with
ketones and aldehydes was extensively screened in order
to determine the scope and limitations of our method.
Table 1 summarizes the reaction of various aryl and alkyl
ketones used as electrophile. Interestingly, all entries
provided the corresponding Z-enynols in acceptable yields.
Aromatic ketones having a neutral (Table 1, entry 6), an
electron-donating (Table 1, entry 3), or an electron-
withdrawing group (Table 1, entries 1, 2 and 4, 5) formed
the desired products in similar yields. These results
revealed that the reaction does not significantly depend
on the electronic effects of substituents in the aromatic
ring of ketones. In addition to aromatic ketones, the
reaction with alkyl ketones also led to the formation
of the desired products; however, a decrease in the
yields was observed (Table 1, entries 7-9). A significant
decrease in yields of enynols was also observed when the
reaction was performed with bulky ketones (Table 1,
entries 10 and 11). It is also worth noting that this reaction
can be performed using aldehydes as the electrophile
source. Most importantly, this method turned out to be
general with respect to a diverse array of functionality in
the aromatic ring at aryl aldehydes (Table 1, entries
20-23). In addition, alkyl aldehydes were effective in the
preparation of the corresponding enynols (Table 1, entry
24).13
Since functionalized heterocycles containing oxygen
exhibit a broad range of biological activities such as
anticancer, antiviral, antioxidative, insecticidal, anti-
inflammatory, and antifungal,14 their preparation becomes
a major challenge to organic chemists. During the past
years, numerous protocols have been reported in the
literature describing the synthesis of this class of com-
pounds based on gold- or iodo-catalyzed cyclization of
enynols.15 Nevertheless, only a few methods involving
palladium cyclization of enynols to furans have been
reported to the present.16 Here, we wish to report a new
approach to the synthesis of furan and 2,5-dihydrofuran
from enynols. Consequently, we investigated several
synthetic strategies to facilitate the synthesis.17 Thus, the
reaction of (Z)-enynols 3 (Table 2, entries 1-6) with
Scheme 1
The generation of the (Z)-vinyllithium reagent from vinylic
tellurides was attempted under a variety of reaction condi-
tions by changing the medium, temperature, and amount of
n-BuLi used for the transmetalation. On the basis of these
experiments, we concluded that the best condition for the
transmetalation was as follows: addition of n-BuLi (1.1
equiv) to a solution of Z-vinylic tellurides 1a (0.5 mmol) in
THF (3 mL) at -78 °C. After 15 min, the reaction was
quenched by H2O producing the corresponding Z-enyne 3′
in 84% yields (Scheme 2). Since we obtained 3′ as a single
Scheme 2
isomer and its stereochemistry is clearly indicated by
coupling constant (J ) 16 Hz) of the doublets attributed to
the vinylic hydrogens, which is characteristic of trans vinyl
(13) The enynol stereochemistry was determined by the NOESY NMR
experiment; see the Supporting Information.
(14) (a) Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Perez, C. J.
Nat. Prod. 2001, 64, 134. (b) Lambert, J. D.; Meyers, R. O.; Timmermann,
B. N.; Dorr, R. T. Cancer Lett. 2001, 171, 47.
(7) (a) Zeni, G.; Ludtke, D. S.; Panatieri, R. B.; Braga, A. L. Chem.
ReV. 2006, 106, 1032. (b) Vieira, M. L.; Zinn, F. K.; Comasseto, J. V. J.
Braz. Chem. Soc. 2001, 12, 586. (c) Comasseto, J. V.; Barrientos-
Astigarraga, R. E. Aldrichim. Acta 2000, 33, 66. (d) Comasseto, J. V.; Ling,
L. W.; Petragnani, N.; Stefani, H. A. Synthesis 1997, 373.
(8) (a) Petragnani, N. Tellurium in Organic Synthesis. Best Synthetic
Methods; Academic Press: London, UK, 1994. (b) Petragnani, N. In
Organotellurium Compounds in Organic Synthesis; McKillop, A., Ed.;
Pergamon Press: New York, 1994; Vol. 11, Chapter 14.
(9) Zeni, G.; Comasseto, J. V. Tetrahedron Lett. 2000, 41, 1311.
(10) Barros, S. M.; Comasseto, J. V.; Barriel, J. N. Tetrahedron Lett.
1989, 30, 7353.
(15) (a) Lu, Y.; Du, X.; Jia, X.; Liu, Y. AdV. Synth. Catal. 2009, 351,
1517. (b) Du, X.; Song, F.; Lu, Y.; Chen, H.; Liu, Y. Tetrahedron 2009,
65, 183. (c) Lu, Y.; Fu, X.; Chen, H.; Du, X.; Jia, X.; Liu, Y. AdV. Synth.
Catal. 2009, 351, 129. (d) Song, F.; Liu, Y. J. Organomet. Chem. 2009,
694, 502. (e) Liu, Y.; Song, F.; Guo, S. J. Am. Chem. Soc. 2006, 128,
11332. (f) Liu, Y.; Song, F.; Cong, L. J. Org. Chem. 2005, 70, 6999. (g)
Liu, Y.; Song, F.; Song, Z.; Liu, M.; Yan, B. Org. Lett. 2005, 7, 5409.
(16) (a) Larock, R. C.; Doty, M. J.; Han, X. Tetrahedron Lett. 1998,
39, 5143. (b) Gabriele, B.; Salerno, G. Chem. Commun. 1997, 1083. (c)
Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K. Tetrahedron 1985,
41, 3655. (d) Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki, H. J. Org.
Chem. 1991, 56, 5816. (e) Gabriele, B.; Salerno, G.; Lauria, E. J. Org.
Chem. 1999, 64, 7687.
(11) Tucci, F. C.; Chieffi, A.; Comasseto, J. V.; Marino, J. P. J. Org.
Chem. 1996, 61, 4975.
(12) Marino, J. P.; McLure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci,
F. C. J. Am. Chem. Soc. 2002, 124, 1664.
(17) Qing, F. L.; Gao, W. Z. Tetrahedron Lett. 2000, 41, 7727.
Org. Lett., Vol. 12, No. 5, 2010
937

Table 1. Synthesis of (Z)-Enynolsb
a Yields are given for isolated products. b Reaction performed in the presence of 1 (0.5 mmol), n-BuLi (1.1 equiv) in THF at -78 °C followed by
aldehydes or ketones addition (2.5 equiv). c These products were easily purified by column chromatography; however, they were unstable to obtain reliable
elemental analysis or HRMS.
PdCl2(CH3CN)2 (5 mol %) in THF at reflux for 30 min
produced the corresponding 2,5-dihydrofurans 4a-c,e-f
in good isolated yields. Concerning the group directly
bonded at the double or triple bond of enynols, we found
some limitations in this methodology. For example no
reaction was observed with enynol bearing an alkyl group
at double and triple bonds (Table 2, entry 4). Finally, when
this reaction condition was repeated with Z-enynols with
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Org. Lett., Vol. 12, No. 5, 2010

an hydrogen in the allylic position, furans 5a-c were
obtained, instead of 2,5-dihydrofuran (Table 2, entries
7-9). These results strongly suggest that the cyclization
was significantly influenced by nature of Z-enynols,
becoming our methodology highly regioselective.18 Re-
garding the five- versus six-membered ring, it is important
to point out that the unique product obtained during the
curse of this cyclization was the five-membered furan
derivatives, which were determined by X-ray diffraction
analysis (see the Supporting Information).
Table 2. Synthesis of Furans or Dihydrofuransb
In summary, we showed the synthesis of various
Z-enynols via reaction of the tellurium-lithium exchange
and the reaction of these vinyllithium intermediates with
aldehydes and ketones. Various aryl and alkyl groups
directly bonded to the carbonyl group were successfully
used as electrophiles. These enynols, bearing a hydroxyl
group, underwent highly selective intramolecular cycliza-
tions when treated with palladium salt affording 2,5-
dihydrofuran or furan. The results demonstrated that the
selectivity in the cyclization was significantly influenced
by the presence of a substituent in the allylic position.
Z-Enynols having a hydrogen at the allylic position gave
2,5-dihydronfurans, while Z-enynols without hydrogen in
this position gave furan derivatives. In this way, there are
some advantages to use vinylic tellurides instead of other
methods, such as easy access by stereoselective reactions
to (Z)-vinyllithium intermediate, low cost, and ease of
availability, which are crucial for commercial applications.
Acknowledgment. We are grateful to FAPERGS, CAPES
(SAUX), and CNPq (CNPq/INCT-catalise) for the finan-
cial support. CNPq is also acknowledged for the fellow-
ships (G.Z. and C.C.S.). We thank the LMI (Prof. Ernesto
Lang) for the X-ray crystal results.
Supporting Information Available: Spectroscopic data
for all new compounds, X-ray results, and detailed experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Isolated yields. b Reaction performed in the presence of 3 (0.5 mmol)
and PdCl2(CH3CN)2 (5 mol %) in THF. c These products were easily purified
by column chromatography; however, they were unstable to obtain reliable
elemental analysis or HRMS.
OL902896X
(18) For differentiation in the mechanism, see the Supporting Informa-
tion.
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