3,3,3-Trichloropropyl-1-triphenylphosphorane: A reagent for the synthesis of (Z)-1,3-enynes, (Z,Z)-1-chloro-1,3-dienes, and 1,3-diynes

Article abstract of DOI:10.1021/ja045112v

,3,3,3-Trichloropropyl-1-triphenylphosphonium chloride is conveniently prepared from 2-chloroethanol, triphenylphosphine, and trichloroacetic acid. Deprotonation of this reagent generates 3,3,3-trichloropropyl-1-triphenylphosphorane, which reacts with aldehydes to give trichloromethylated (Z)-olefins, which are useful for the synthesis of (Z)-1,3-enynes, (Z,Z)-1-chloro-1,3-dienes, and 1,3-diynes in high yields and stereospecificities. Copyright

Full text of DOI:10.1021/ja045112v

Published on Web 10/13/2004
3,3,3-Trichloropropyl-1-triphenylphosphorane: A Reagent for the Synthesis of
(Z)-1,3-Enynes, (Z,Z)-1-Chloro-1,3-dienes, and 1,3-Diynes†
Maheswaran S. Karatholuvhu and Philip L. Fuchs*
Department of Chemistry, Purdue UniVersity, 560 OVal DriVe, West Lafayette, Indiana 47907
Received August 13, 2004; E-mail: pfuchs@purdue.edu
Conjugated π-systems, including (Z)-1,3-enynes, (Z,Z)-1,3-
dienes, and 1,3-diynes, such as those found in histrionicotoxin 2,1
leustroduscin H 3,2 and the dialula diyne 4,3 are features which
may be advantageously employed as connective segments in
synthesis (Figure 1).
yields of the (E)-1,3-enyne, 8E, Peterson reactions with bis-silylated
propynylic anions, 11a,b, represent the current state-of-the-art
generation of 8Z with a three-carbon reagent. Alternatively, a
stepwise approach is often employed for construction of olefins
12a-d and followed by palladium-catalyzed coupling with 13 to
generate (Z)-1,3-enyne, 8Z (Scheme 1).
We reasoned that a reagent where the acetylene moiety was
present in latent form at the time of the Wittig reaction should favor
formation of the (Z)-olefin. Acetylene 6 is available from 1,1-
dibromoolefin 14, prepared from aldehyde 5 and ylide 13.6
Moreover, a group at DuPont has developed a beautiful and
economical one-carbon protocol, adding a trichloromethyl anion
to aldehyde 5 followed by transmetalation of adduct 17 to acetylene
6 (Scheme 2).7
Scheme 2
Figure 1. 3,3,3-Trichloropropyl-1-triphenylphosphorane and natural product
targets.
Our current study melded both of the above reactions. Stirring
a mixture of l.5 equiv of 16 and 16′ at 25 °C with the Schweizer
vinylphosphonium salt (20-Br)8 in acetonitrile delivers a 95% yield
of pure 1-Br. A more economical synthesis of vinylphosphonium
chloride (20-Cl) involves the heating of 2-chloroethanol (21) with
a slight excess of triphenylphosphine neat for 48 h at 100 °C to
afford â-hydroxyethyl phosphonium chloride (22).9
Natural products containing the 1,3-diyne moiety are fairly
common and have been synthesized by SN2 reactions with acetylene
followed by organocopper or palladium-mediated coupling (Scheme
1). An alternative introduction of the initial alkyne involves
conversion of an aldehyde 5 to acetylene 6 using a variety of one-
carbon reagents.4 Typically, the second acetylene is used in excess,
and TMS-acetylene offers the advantage that the product can often
be selectively semihydrogenated at the less-hindered alkyne5 to
generate a protected (Z)-1,3-enyne (8Z), suitable for subsequent
coupling operations after silyl deprotection to 9Z (Scheme 1). In
cases where several acetylenic functions reside in the target
molecule, the semihydrogenation approach may not be a realistic
option.
Scheme 3
Scheme 1
Dehydration of 22 was best accomplished by heating the mixture
with oxalyl chloride until gas evolution had ceased.10 Purification
delivered 20-Cl in 95% overall yield. Conversion of 20-Cl to 1-Cl
was equivalent to the formation of the more expensive 1-Br
(Scheme 3), without requiring purification for any of the intermedi-
ate steps.
Scheme 4
In such cases, an alternative approach to the (Z)-1,3-enyne, 8Z,
is required. While Wittig reagents, such as 10, provide excellent
† Conjunctive reagents for the Chiral Carbon Catalog 2 (for 1, see: Li, X.;
Lantrip, D.; Fuchs, P. L. J. Am. Chem. Soc. 2003, 125, 14262-14263).
9
14314
J. AM. CHEM. SOC. 2004, 126, 14314-14315
10.1021/ja045112v CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Reactions of Reagent 1-Cl
1
a Z/E ratio for trichloroethylenes and chloroenynes are from H NMR; however, for dichlorodienes, the Z/E ratio is reported based on the Z/E ratio of
trichloroethylenes. Most dichloro compounds show poor separation of isomers in NMR solvents, such as CDCl3, C6D6, and CD3OD. b LHMDS was used
instead of NaHMDS. c Yield corresponds to the transformation from 24k; see the Supporting Information. d Single enantiomer from chiral HPLC. e Acetate
hydrolyzed to methoxyphenol. f Yield is for the two steps starting from the corresponding propargyl alcohol. g See the Supporting Information.
Scheme 5
References
(1) Kotera, M. Bull. Soc. Chim. Fr. 1989, 370-397. (b) Davidson, E. C.;
Fox, M. E.; Holmes, A. B.; Roughley, S. D.; Smith, C. J.; Williams, G.
M.; Davies, J. E.; Raithby, P. R.; Adams, J. P.; Forbes, I. T.; Press, N. J.;
Thompson, M. J. J. Chem. Soc., Perkin Trans. 1 2002, 1494-1514. (c)
Stockman, R. A. Tetrahedron Lett. 2000, 41, 9163-9165.
(2) Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125,
4048-4049. (b) Buck, S. B.; Hardouin, C.; Ichikawa, S.; Soenen, D. R.;
Gauss, C. M.; Hwang, I.; Swingle, M. R.; Bonness, K. M.; Honkanen, R.
E.; Boger, D. L. J. Am. Chem. Soc. 2003, 125, 15694-15695.
(3) Walker, R. P.; Faulkner, D. J. J. Org. Chem. 1981, 46, 1475-1478. (b)
de Jesus, R. P.; Faulkner, D. J. J. Nat. Prod. 2003, 66, 671-674.
(4) Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521-
522 and references therein.
Metalation of 1-Cl in toluene (-78 °C) followed by the addition
of aldehyde gives Wittig adduct 23 or chloro (Z)-1,3-enyne 25 when
the reaction is conducted in THF using excess sodium hexa-
methyldisilazane (NaHMDS). Application of the Cr[II] vinylidene
carbenoid method of Falck and Mioskowski11 to (Z)-olefin 23 gives
the (Z,Z)-chlorodiene 26 in 80% yield. Alternatively, treatment of
23 with DBU in dichloromethane gives (Z)-dichlorodiene 24
(Scheme 4).
Transmetalation of 25 to lithioacetylide 27 (X ) Li), followed
by conversion to functionalized (Z)-1,3-enynes (27), was effected
by trapping with a variety of electrophiles (Table 1, last column).
Potassium tert-butoxide presumably effects bis-elimination of 25
to 1,3-diyne 29 via the cumulene intermediate 2812 (Scheme 5).
(5) Aerssens, M. H. P. J.; Brandsma, L. Chem. Commun. 1984, 735-736.
(6) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(7) Wang, Z.; Campagna, S.; Yang, K.; Xu, G.; Pierce, M. E.; Fortunak, J.
M.; Confalone, P. N. J. Org. Chem. 2000, 65, 1889-1891.
(8) Schweizer, E. E.; Bach, R. D. J. Org. Chem. 1964, 29, 1746-1751. (b)
Schweizer, E. E.; Smucker, L. D.; Votral, R. J. J. Org. Chem. 1966, 31,
467-471.
(9) Seyferth, D.; Fogel, J. J. Organomet. Chem. 1966, 6, 205-227. For a
modification of this procedure, see Supporting Information.
(10) Okuma, K.; Ono, M.; Ohta, H. Bull. Chem. Soc. Jpn. 1993, 66, 1308-
1311.
(11) Baati, R.; Barma, D. K.; Falck, J. R.; Mioskowski, C. J. Am. Chem. Soc.
2001, 123, 9196-9197.
Acknowledgment. Thanks are due to Dr. Douglas Lantrip for
assistance in manuscript preparation.
Supporting Information Available: Additional experiments, dis-
cussion, experimental procedures, and 1H and 13C spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(12) Negishi, E.; Okukado, N.; Lovich, S. F.; Luo, F.-T. J. Org. Chem. 1984,
49, 2629-2632. (b) Kende, A. S.; Smith, C. A. J. Org. Chem. 1988, 53,
2655-2657. (c) Yadav, J. S.; Maiti, A. Tetrahedron Lett. 2001, 42,
3909-3912.
JA045112V
9
J. AM. CHEM. SOC. VOL. 126, NO. 44, 2004 14315