A flexible radical-based approach to tms-substituted propargyl alcohols and to 2,3-allenols

Article abstract of DOI:10.1021/ol900739x

The radical reaction of TMS-substituted xanthates with 2,2-dlchlorovlnyl ethyl sulfone afforded TMS-substltuted homodichlorovinyl compounds that can be transformed Into TMS-substituted propargyl alcohols. Various 2,3-allenols were efficiently prepared fro

Full text of DOI:10.1021/ol900739x

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2868-2871
A Flexible Radical-Based Approach to
TMS-Substituted Propargyl Alcohols and
to 2,3-Allenols
Zhi Li and Samir Z. Zard*
´
Laboratoire de Synthe`se Organique, UMR 7652 CNRS-Ecole Polytechnique, Route de Saclay,
91128 Palaiseau CEDEX, France
zard@poly.polytechnique.fr
Received April 7, 2009
ABSTRACT
The radical reaction of TMS-substituted xanthates with 2,2-dichlorovinyl ethyl sulfone afforded TMS-substituted homodichlorovinyl compounds
that can be transformed into TMS-substituted propargyl alcohols. Various 2,3-allenols were efficiently prepared from the reaction of these
TMS-substituted propargyl alcohols with TBAF.
2,3-Allenols1 are versatile building blocks for the synthesis
of 2,5-dihydrofurans,2 vinylic epoxides,3 R,ꢀ-unsaturated
ketones,4 and numerous other valuable compounds. They
represent important intermediates in the total synthesis of
natural products such as the (+)-furanomycin5 and peridinin.6
Furthermore, 2,3-allenols are substructures in a number of
natural products or pharmaceutical substances,7a such as
mimulaxanthin,7b “Grasshopper Ketone”,7c (R)-cytallene,7d
and (R)-adenallene.7e
able, as indicated in Scheme 1, which summarizes previously
described synthetic routes.
Scheme 1. Approaches to TMS-Substituted Propargyl Alcohols
One efficient method for accessing 2,3-allenols 1 is the
reaction of TMS-substituted propargyl alcohols 2 with TBAF
(tetra-n-butylammonium fluoride).8 However, except for the
simplest derivatives, these precursors are not readily avail-
(1) For general reviews, see: (a) Ma, S. Acc. Chem. Res. 2003, 36, 701.
(b) Ma, S. Chem. ReV. 2005, 105, 2829. (c) Deng, Y. Q.; Gu, Z. H.; Ma,
S. Chin. J. Org. Chem. 2006, 26, 1468.
(2) (a) Gelin, R.; Gelin, S.; Albrand, M. Bul1. Soc. Chim. Fr. 1972,
1946. (b) Olsson, L. I.; Claesson, A. Synthesis 1979, 743.
(3) (a) Kang, S.-K.; Yamaguchi, T.; Pyun, S.-J.; Lee, Y.-T.; Bail, T.-G.
Tetrahedron Lett. 1998, 39, 2127. (b) Ma, S.; Zhao, S. J. Am. Chem. Soc.
1999, 121, 7943.
The most frequently explored approach relies on the
generation of the propargylic anion from alkyne 3 followed
by its capture with TMSCl to give key intermediate 4.9
Selective removal of the terminal TMS group requires
treatment with silver nitrate followed by destruction of the
(4) Shimizu, I.; Sugiura, T.; Tsuji, J. J. Org. Chem. 1985, 50, 537.
(5) Vanbrunt, M. P.; Standaert, R. F. Org. Lett. 2000, 2, 705.
(6) (a) Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S. Angew.
Chem., Int. Ed. 2002, 41, 1023. (b) Furuichi, N.; Hara, H.; Osaki, T.;
Nakano, M.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 7949.
10.1021/ol900739x CCC: $40.75
Published on Web 06/09/2009
 2009 American Chemical Society

corresponding silver acetylide with cyanide. Finally, the
resulting alkyne 5 is transformed into the desired allenyl
alcohol 2 in the usual manner.
The two alternative approaches start with the rather
inaccessible R- and ꢀ-TMS-substituted aldehydes 6 and 8.
The former is transformed into dibromide 7, which is then
converted into propargylic alcohol 2 through the Corey-Fuchs
reaction.10,11 The formation of the desired alkyne 2 from
aldehyde 8 proceeds via enol triflate 9.12
C-C bond next to the bulky TMS group by radical addition
to the somewhat sterically hindered dichloro-vinyl ethyl
sulfone was far from obvious. It was therefore necessary to
ascertain the viability of this key step in our proposed
strategy.
The radical addition of xanthate 10a-c to trimethyl vinyl
silane proceeded smoothly as shown by the results in Table
1. In the case of xanthate 10c, a 1:1 separable mixture of
As part of our work on the degenerative xanthate transfer
reaction,13 we examined a potentially more flexible and more
general route to allenyl alcohols 1. Our synthetic approach,
outlined in Scheme 2, hinges on the possibility of performing
Table 1. Synthesis of TMS-Substituted Xanthates 11
Scheme 2. Strategy to Synthesis of 2,3-Allenols from Xanthates
a Isolated yield. b Total yield of 11c and 11c′, 11c/11c′ ) 1/1. 11c, Rf
) 0.6, petroleum ether/EtOAc ) 20:1. 11c′, Rf ) 0.5, petroleum ether/
EtOAc ) 20:1. This reaction was conducted in a mixture of EtOAc and
DME (1:1 v/v).
a radical addition of a xanthate 10 onto trimethyl vinyl silane
to give the corresponding adduct 11 and then exchanging
the xanthate group with a dichloro vinyl motif through
reaction with dichlorovinyl ethyl sulfone.14 The resulting
product 12 could subsequently be processed into the desired
allenyl alcohol 1 through the powerful Corey-Fuchs reac-
tion.
diastereoisomers 11c/11c′ was obtained. The lack of dias-
tereoselectivity is not surprising, being typical of most
intermoleculer radical additions.
While we had previously performed additions of various
xanthates to trimethyl vinyl silane,15 the creation of a new
Table 2. Synthesis of Dichlorovinyl Compounds 12
(7) (a) Krause, N.; Hoffmann-Ro¨der, A. In Modern Allene Chemistry;
Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 2,
p 997. (b) Nitsche, H. Phytochemistry 1972, 11, 401. (c) Isoe, S.; Katsmura,
S.; Hyeon, S. B. Tetrahedron Lett. 1971, 16, 1089. (d) Jones, B. C. N. M.;
Silverton, J. V.; Simons, C. J. Med. Chem. 1995, 38, 1397. (e) Megati, S.;
Goren, Z.; Silverton, J. V.; et al. J. Med. Chem. 1992, 35, 4098
.
(8) (a) Pornet, J.; Randrianoelina, B.; Miginiac, L. Tetrahedron Lett.
1984, 25, 651. (b) Pornet, J.; Damour, D.; Randrianoelina, B.; Miginiac, L.
Tetrahedron 1986, 42, 2501. (c) Chow, H.-F.; Cao, X.-P.; Leung, M.-K.
J. Chem. Soc., Chem. Commun. 1994, 2121. (d) Chow, H.-F.; Cao, X.-P.;
Leung, M.-K. J. Chem. Soc., Perkin Trans. 1 1995, 193. (e) Wang, K. K.;
Liu, B.; Lu, Y.-D. J. Org. Chem. 1995, 60, 1885. (f) Wang, K. K.; Liu, B.;
Lu, Y.-D. Tetrahedron. Lett. 1995, 36, 3785. (g) Taing, M.; Moore, W. H.
J. Org. Chem. 1996, 61, 329
(9) (a) Rajagopalan, S.; Zweifel., G. Synthesis 1984, 111. (b) Fleming,
I.; Morgan, I. T.; Sarkar, A. K. J. Chem. Soc., Perkin Trans. 1 1998, 2749
.
.
(10) (a) Tietze, L. F.; Neumann, T.; Kajino, M.; Pretor, M. Synthesis
1995, 1003. (b) Haley, M. M.; Biggs, B.; Looney, W. A.; Gilbertson, R. D.
Tetrahedron Lett. 1995, 36, 3457
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769
(12) Fleming, I.; Mwaniki, J. M. J. Chem. Soc., Perkin Trans. 1 1998,
1237.
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.
a Isolated yield. b Total yield of 12c and 12c′, 12c/12c′ ) 1/1. 12c, Rf
) 0.6, petroleum ether/EtOAc ) 30:1. 12c′, Rf ) 0.5, petroleum ether/
EtOAc ) 30:1. The ratio of 12c and 12c′ was determined from the 1H
NMR of the crude product. For reaction details, see Supporting Information.
(13) For general reviews, see: (a) Zard, S. Z. Angew. Chem., Int. Ed.
Engl. 1997, 36, 672. (b) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur
Silicon Relat. Elem. 1999, 153, 137. (c) Zard, S. Z. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001;
Vol. 1, p 90. (d) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264,
201. (e) Quiclet-Sire, B.; Zard, S. Z. Chem. Eur. J. 2006, 12, 6002. (f)
Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205.
With the TMS-substituted xanthates 11 in hand, we set
out to assemble the R-TMS-substituted dichlorovinyl com-
pounds 12 via the radical reaction of 11 with 2,2-dichlo-
(14) Bertrand, F.; Quiclet-Sire, B.; Zard, S. Z. Angew. Chem., Int. Ed.
1999, 38, 1943.
Org. Lett., Vol. 11, No. 13, 2009
2869

rovinyl ethyl sulfone.16 After some extensive experimenta-
tion, we were pleased to find that it was possible to
accomplish the desired transformation leading to R-TMS-
substituted dichlorovinyl compounds 12, albeit in moderate
yield (Table 2). No diastereoselectivity was observed in the
formation of 12c/12c′, but it was possible to separate the
two diastereoisomers by chromatography. It is worth noting
that only a few instances of synthesis of R-TMS-substituted
dichlorovinyl compounds17a or related derivatives10a,17b-d
have been reported to date.
Table 4. Synthesis of TMS-Substituted Propargyl Alcohols 2
Prior to conducting the Corey-Fuchs reaction, it was
necessary to protect the ketone group as the corresponding
ketal. This was accomplished by treatment with ethylene
glycol under standard acid catalysis. Unfortunately, under
these conditions, the two separated diastereoisomers 12 and
12c′ gave the same mixture of 13c/13c′ (Table 3, entries 3
Table 3. Protection of Dichlorovinyl Compounds 12
a Isolated yield. b dr ) 1:1.
a Isolated yield. b Total yield of 13c and 13c′. 13c, Rf ) 0.5, petroleum
ether/EtOAc ) 30:1. 13c′, Rf ) 0.4, petroleum ether/EtOAc ) 30:1. The
ratio of 13c and 13c′ was determined from the 1H NMR of the crude product.
For reaction details, see Supporting Information.
(Table 5, entries 1 and 5), naphth-2-yl (entry 10), aliphatic
alkyl (entry 9), and cyclic alkyl (entries 2, 4, and 7). The
alcohols can be secondary (entries 1, 2, 4, 5, 7, 9, and 10)
or tertiary (entries 3, 6, and 8). The presence of the masked
ketone allows the installation of a carbonyl group that might
have further reaction potential in combination with the allene
moiety.18,19
The stability of the allyl trimethylsilyl motif in 12a-c
toward acidic conditions, allowing ready formation of ketals
13a-c, is remarkable. One of the initial aims of this project
and 4) through epimerization of the center vicinal to the
acetal group.
Acetals 13 were subjected to the general procedure of the
Corey-Fuchs reaction, and the acetylide was subsequently
quenched with various aldehydes (Table 4, entries 1, 2, 4,
5, 7, 9, and 10) or ketones (entries 3, 6, and 8). Consequently,
a broad assortment of TMS-substituted propargyl alcohols
2 were obtained in moderate to good yield (Table 4).
After reacting with 1.5 equiv of TBAF in THF at room
temperature, the TMS-substituted propargyl alcohols 2 were
transformed into the 2,3-allenols 1 in good to excellent yields
(Table 5). The R position of the 2,3-allenols can bear aryl
(15) For some recent examples, see: (a) Corbet, M.; Ferjancic, Z.;
Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2008, 10, 3579. (b) Quiclet-Sire,
B.; Zard, S. Z. Org. Lett. 2008, 10, 3279. (c) Corbet, M.; Zard, S. Z. Org.
Lett. 2008, 10, 2861. (d) Corbet, M.; de Greef, M.; Zard, S. Z. Org. Lett.
2008, 10, 253
.
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Org. Lett., Vol. 11, No. 13, 2009

Table 5. Synthesis of 2,3-Allenols 1
Scheme 3. Reaction of 12a and 12b with TBAF
xanthate transfer process to bring together the various
components, which then could be subjected to the Corey-
Fuchs reaction. This flexibility opens access to a large variety
of structures and complements existing strategies. Further-
more, it is interesting to note that converting the alcohol
group in adduct 2 (Table 4) into a strong nucleofuge, such
as a triflate, followed by treatment with fluoride, provides
1,2,3-trienes (see ref 8e). The present approach should allow
a convenient entry to otherwise inaccessible [3]cumulenes.
Acknowledgment. Z.L. thanks Ecole Polytechnique for
financial support.
Supporting Information Available: Experimental pro-
1
cedures, full spectroscopic data, and copies of H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900739X
a Isolated yield. b dr ) 1:1. c dr ) 1:1:1:1.
(16) For the synthesis of dichlorovinyl ethyl sulfone, see: (a) Schultz,
H. S.; Freyermoth, H. B.; Buc, S. R. J. Org. Chem. 1963, 28, 1140. (b)
Kay, I. T.; Ponja, N. J. Chem. Soc. C 1968, 3011.
(17) (a) Seyferth, D.; Mammarella, R. E. J. Organomet. Chem. 1978,
156, 299. (b) Cunico, R. F.; Zhang, C.-P. Tetrahedron. Lett. 1992, 33, 6751.
(c) Cunico, R. F.; Zhang, C.-P. Tetrahedron 1995, 51, 9823. (d) Takeda,
K.; Ohtani, Y.; Ando, E.; Fujimoto, K.; Yoshii, E.; Koizumi, T. Chem.
Lett. 1998, 1157.
was to exploit the proximity of the ketone group to induce
ring closure into dichlorocyclohexenol 14 by exposure to
Lewis acid as indicated in Scheme 3. However, treatment
of allylsilane 12a with BF3·OEt2 in CH2Cl2 did not result in
any reaction. Indeed, compound 12a was recovered es-
sentially intact. When we attempted to promote the same
ring formation with fluoride anion, we observed a different
reaction. With 12a, a simple desilylation took place to give
unsaturated dichloro ketone 15 in 44% yield. In the case of
12b, containing slightly more acidic hydrogen, the reaction
proceeded further to furnish monochlorovinyl cyclopropane
16 in moderate yield via enolate B.
(18) For recent examples of the intramolecular coupling reaction of allene
with carbonyl, see: (a) Kang, S.-K.; Ha, Y.-H.; Ko, B.-S.; Lim, Y.; Jung,
J. Angew. Chem., Int. Ed. 2002, 41, 343. (b) Kang, S.-K.; Kim, K.-J.; Hong,
Y.-T. Angew. Chem., Int. Ed. 2002, 41, 1584. (c) Kang, S.-K.; Yoon, S. K.
Chem. Commun. 2002, 2634. (d) Kang, S.-K.; Lee, S.-W.; Jung, J.; Lim,
Y. J. Org. Chem. 2002, 67, 4376. (e) Ha, Y.-H.; Kang, S.-K. Org. Lett.
2002, 4, 1143. (f) Montgomery, J.; Song, M. Org. Lett. 2002, 4, 4009. (g)
Kang, S.-K.; Hong, Y.-T.; Lee, J.-H.; Kim, W.-Y.; Lee, I.; Yu, C.-M. Org.
Lett. 2003, 5, 2813. (h) Molander, G. A.; Cormier, E. P. J. Org. Chem.
2005, 70, 2622. (i) Tsukamoto, H.; Matsumoto, T.; Kondo, Y. J. Am. Chem.
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(19) For the intramolecular coupling reaction of allene with acetal, see:
Kang, S.-K.; Kim, Y.-M.; Ha, Y.-H.; Yu, C.-M.; Yang, H.; Lim, Y.
Tetrahedron. Lett. 2002, 43, 9105.
In summary, we have established an efficient route to
polyfunctional 2,3-allenols by exploring the potential of the
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