Coupling of alkynylTMS derivatives with vinylic iodides. An efficient route to 1,3-enynes and dienes

Article abstract of DOI:10.1021/ol016899m

matrix presented CuCl-promoted coupling of alkynylTMS derivatives with vinyl iodides leads to 1,3-enynes in high yield. Enynes prepared from homopropargylic alcohols undergo intramolecular hydrosilylation and subsequent silyl cleavage with TBAF to afford

Full text of DOI:10.1021/ol016899m

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4107-4110
Coupling of AlkynylTMS Derivatives with
Vinylic Iodides. An Efficient Route to
1,3-Enynes and Dienes
James A. Marshall,* Harry R. Chobanian, and Mathew M. Yanik
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904
jam5x@Virginia.edu
Received October 11, 2001
ABSTRACT
CuCl-promoted coupling of alkynylTMS derivatives with vinyl iodides leads to 1,3-enynes in high yield. Enynes prepared from homopropargylic
alcohols undergo intramolecular hydrosilylation and subsequent silyl cleavage with TBAF to afford 1,3-dienes.
We recently developed an efficient procedure for the reso-
lution of 4-TMS-3-butyn-2-ol and found that the mesylate
derivative (e.g., 1) can be used for the in situ preparation of
allenylindium reagents that undergo facile additions to
branched and unbranched achiral and chiral aldehydes to
afford adducts 2 in high yield with excellent diastereo- and
enantiomeric selectivity (eq 1).1 Pursuant to our interest in
developing seamless integration of this methodology with
reactions that further elaborate the alkynyl moiety, we
explored the possibility for direct coupling of these adducts
with vinylic halides along the lines of 2 f 3.
also been reported to participate in Pd-catalyzed cross-
couplings in the presence of CuCl.3,4 This latter application
seemed to be especially well suited to our objectives, and
accordingly, we decided to examine its applicability to
various alkynylsilane adducts derived from allenylindium
reagents and aldehydes.
Before targeting these applications, we conducted feasibil-
ity studies of vinylic cross-coupling with the simple non-
volatile alkynylTMS derivative 4 and (E)-1-iodo-1-hexene
(Table 1).5 Adopting the procedure of Nishihara et al.,3a but
substituting 1,3-dimethylimidazolidin-2-one (DMI) for DMF
along the lines of Hosomi and co-workers,3c we obtained
enyne 6 in 40% yield. Variations in the Pd(0) catalyst or
catalyst precursor either caused decomposition or had little
(2) (a) Denmark, S. E.; Wang, Z. Org. Lett. 2001, 3, 1073. (b) Denmark,
S. E.; Pan, W. Org. Lett. 2001, 3, 61.
(3) (a) Alkynylsilanes with aryl halides and triflates, alkynyl chlorides,
and alkenyl triflates: Nishihara, Y.; Ikegashira, K.; Hirabayashi, K.; Ando,
J.-I.; Mori, A.; Hiyama, T. J. Org. Chem. 2000, 65, 1780. (b) Alkynylsilanols
with aryl iodides: Chang, S.; Yang, S. H.; Lee, P. H. Tetrahedron Lett.
2001, 42, 4833. (c) Alkynylsilanes with acyl chlorides: Ito, H.; Arimoto,
A.; Sensui, H.-O.; Hosomi, A. Tetrahedron Lett. 1997, 38, 3977. (d)
Arylsilanes with aryl iodides: Ito, H.; Kikuo, A.; Muira, K.; Hosomi, A.
Chem. Lett. 1997, 639.
(4) Couplings of TMSalkynes with vinyl iodides in the presence of
(Et2N)3S+Me3SiF2- have been reported (Hatanaka, Y.; Matsui, T.; Hiyama,
T. Tetrahedron Lett. 1989, 30, 2403). Our intended application of the present
methodology to silyl-protected polyol derivatives precludes the use of
fluoride-assisted silyl cleavage procedures.
Denmark and co-workers have shown that vinylsiloxanes
undergo Pd-catalyzed cross-coupling reactions with aryl and
vinyl iodides, bromide, and triflates.2 Alkynylsilanes have
* Corresponding author. Fax: + 01-804-924-7993.
(1) Marshall, J. A.; Chobanian, H. R.; Yanik, M. M. Org. Lett. 2001, 3,
3369.
(5) Brown, H. C.; Hamaoka, T.; Ravindran, N. J. Am. Chem. Soc. 1973,
95, 5786.
10.1021/ol016899m CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/16/2001

1 equiv of CuCl in DMF at 60 °C after 3 h. We observed
moderate amounts of homocoupling product from reactions
in which Pd(0) catalysts were present (Table 1) but detected
no homocoupling of TMSalkyne 4 in their absence. We made
one further modification to the procedure by substituting
Bu3N for Et3N. Results were comparable, but the lower
volatility of Bu3N was more compatible with the higher-
temperature procedure. This modification was applied to the
racemic adducts 7a-c1 with excellent results (Table 2).
The homopropargylic alcohol adducts 2 (eq 1) afforded
cross-coupled products in low yield. However, TBS ether
or acetate derivatives of 2 could be readily converted to
enynes as illustrated in Table 2 and eqs 4 and 5. It is possible
that the alcohols coordinate with the CuCl promoter in a
five-membered alkyne complex (Figure 1, A vs B) thereby
shutting down the formation of Cu acetylide intermediates.
Table 1. Alkynylsilane Cross-Coupling Reactions
CuCl, equiv
Pd catalyst (equiv)
t, h
T, °C
yield, %
1.1
1.1
1.1
2.0
2.2
2.2
2.2
2.2
2.2
2.2
Pd(PPh3)4 (0.05)
Pd(PPh3)2Cl2 (0.025)
Pd2(dba)3 (0.025)
Pd(PPh3)2Cl2 (0.05)
Pd(PPh3)4 (0.05)
Pd2(dba)3 (0.05)
none
none
none
none
15
15
15
8
1.5
24
3.5
40
20
6
85
85
85
85
85
85
85
85
100
130
40c
dec
dec
55c
40c
30c
10
83
88
87
a From 1.3 to 1.5 equiv. b DMI ) 1,3-dimethyl-2-imidazolidinone. c From
10 to 20% of the 1,3-diyne product was formed.
effect. In the absence of Pd, addition of 1 equiv of CuCl in
DMI to acetylene 4 resulted in a pale yellow-green solution
that gave no cross-coupling product with the vinyl iodide.
Addition of Et3N caused the solution to become deep red,
but again no coupling was observed. Attempts to force a
reaction by increasing the temperature led to decomposition
products. However, when 2 equiv of CuCl in DMI were
added to acetylene 4, a yellow precipitate gradually formed.
This precipitate is presumed to be the copper acetylide
complex.6 Treatment of the mixture with Et3N and the vinyl
iodide afforded the coupled product in 10% yield after 3.5
h at 85 °C (Table 1). After a reaction time of 40 h, the enyne
could be isolated in 83% yield. Increasing the reaction
temperature to 100 or 130 °C significantly shortened the
reaction time with no decrease in yield. When less than 2
equiv of CuCl were employed, the coupling reactions were
markedly slower and decomposition products were produced.
Nishihara et al.3a obtained the 1,3-diyne homocoupling
product in 80% yield upon treatment of 1-TMS-1-octyne with
Figure 1. Possible reactivity differences between homopropargylic
alcohols and derivatives toward Si-Cu exchange.
Aryl iodide couplings were briefly examined. Methyl
p-iodobenzoate afforded the coupled product 10a in high
yield but iodobenzene coupling proceeded sluggishly, af-
fording 10b in 60% yield and the desilylated terminal alkyne
as the only other isolated product. p-Iodoanisole yielded
negligible quantities of coupled product with the TMSalkyne
4 after prolonged reaction times. Interestingly, o-iodobenzoic
acid (11) coupled efficiently to yield the isocoumarin 12,7
but p-iodobenzoic acid gave the coupled product in only 16%
yield along with numerous decomposition products.8
Table 2. Coupling of Alkynylsilanes with Vinyl Iodides
R1
R2
t, h
yield, %
c-C6H11 (a )
c-C6H11 (a )
i-Pr (b)
C7H15 (a )
H (b)
C7H15 (a )
H (b)
C7H15 (a )
H (b)
Bu (c)
3
14
5
19
4
90 (a )
87 (b)
73 (c)
94 (d )
97 (e)
80 (f)
91 (g)
i-Pr (b)
Ph(CH2)2 (c)
Ph(CH2)2 (c)
Ph(CH2)2 (c)
16
3.5
Couplings between homopropargylic acetates and vinylic
iodides also proceeded smoothly (eqs 4 and 5). The starting
4108
Org. Lett., Vol. 3, No. 25, 2001

enantiopure alkynylsilanes were prepared as previously
described.1 The examples in eq 5 show that the methodology
can be applied to relatively complex polyfunctional alkynyl-
silanes. As already stated, both TBS ethers and acetates are
superior to the free alcohols as coupling substrates.
Scheme 2
Key: (a) TBSOTf, Et3N, CH2Cl2 (87%); (b) TBAF, THF (90%);
(c) (Me2SiH)2NH, 60 °C; (d) H2PtCl6 0.5 mol %, THF (85%, 2
steps); (e) TBAF, THF (73%).
allenylindium reagent.1 The TBS ether 22 underwent efficient
coupling with vinyl iodide to afford enyne 23. TBS ether
cleavage followed by silylation and intramolecular hydro-
silylation led to the cyclic siloxane 26, which was treated
without purification with TBAF to afford the pure (Z)-1,3-
diene 27 in high overall yield.
We recently disclosed methodology for the conversion of
homopropargylic alcohols to â-hydroxy ketones through
intramolecular hydrosilylation followed by Tamao oxidation
of the intermediate cyclic siloxane (eq 6).9,10 It was of interest
to examine a modification of this sequence on the enynes
23 and 30 as a possible route to the C17-C24 1,3-diene
terminus 27 of discodermolide11 and the analogue 34
(Schemes 1 and 2).
Scheme 1
The anti,anti homopropargylic alcohol 28 was prepared
analogously from aldehyde 19 and mesylate ent-20 (Scheme
2). CuCl-promoted coupling of the TBS ether derivative 29
with (E)-1-iodo-1-hexene afforded the enyne 30, which was
subjected to the foregoing hydrosilylation-TBAF sequence
to afford the (Z,E)-1,3-diene 34 free of isomeric byproducts.
The methodology described in this report expands the list
of useful reactions that can be performed on homopropargylic
alcohol derivatives. The ability to prepare the TMSalkyne
intermediates through highly diastereo- and enantioselective
addition reactions and to seamlessly append vinylic substit-
uents is of particular interest for applications to the polyketide
family of natural products. It should be noted that the use of
the corresponding 4-butyn-2-ol mesylates as precursors to
Key: (a) TBSOTf, Et3N, CH2Cl2 (79%); (b) TBAF, THF (91%);
(c) (Me2SiH)2NH, 60 °C; (d) H2PtCl6 0.5 mol %, THF (94%, 2
steps); (e) TBAF, THF (74%).
The anti,syn (right-to-left) homopropargylic alcohol 21 was
prepared from aldehyde 19 and mesylate 20 via the derived
(10) Tamao, K.; Kumada, M.; Maeda, K. Tetrahedron Lett. 1984, 25,
321.
(6) The structure of this solid has been formulated as [Cu2Cl(CtCPh)]n:
Nishihara, Y.; Takemura, M.; Mori, A.; Osakada, A. J. Organomet. Chem.
2001, 620, 282. We thank a reviewer for bringing this reference to our
attention.
(7) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313.
(8) A recent paper by Nagasaka and co-workers describes Pd(0)-catalyzed
couplings of aryl iodides with TMSalkynes and an equivalent of Ag2CO3
and several other silver salts. Alkenyl iodides were not included in their
study: Koseki, Y.; Omino, K.; Anzai, S.; Nagasaka, T. Tetrahedron Lett.
2000, 41, 2377.
(11) (a) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem.
Soc. 1996, 118, 11054. (b) Smith, A. B., III; Qui, Y.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011. (c) Smith, A. B., III;
Kaufman, M. D.; Beauchamp, T. J.; LaMarche, M. J.; Arimoto, H. Org.
Lett. 1999, 1, 1823. (d) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D.
C. J. Org. Chem. 1997, 62, 6098. (e) Marshall, J. A.; Johns, B. A. J. Org.
Chem. 1998, 63, 7885. (f) Paterson, I.; Schlapbach, A. Synlett 1995, 498.
(g) Clark, D. L.; Heathcock, C. H. J. Org. Chem. 1993, 58, 5878. (h) Golec,
J. M. C.; Jones, S. D. Tetrahedron Lett. 1993, 34, 8159.
(12) Sonogashira, K. ComprehensiVe Organic Synthesis; Pergamon
Press: Elsmford, NY, 1990; Vol. 3, p 521.
(9) Marshall, J. A.; Yanik, M. M. Org. Lett. 2000, 2, 2173.
Org. Lett., Vol. 3, No. 25, 2001
4109

the allenylindium reagents leads to mixtures of anti and syn
isomers (ca. 90:10-80:20) with unbranched and conjugated
aldehydes. Thus, the TMS substituent plays a significant role
in the present methodology vis-a`-vis the alternative sequence
in which a terminal alkyne adduct is converted to the 1,3-
enyne through a Sonogashira coupling.12,13
Acknowledgment. Support for these studies was provided
by NIH Research Grant R01 CA90383 and NSF Grant CHE-
9901319.
Supporting Information Available: Additional experi-
1
mental procedures and H NMR spectra for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Experimental procedures: (2S,3S,4S)-(+)-1-Benzyloxy-2,4-di-
methyl-6-trimethylsilyl-5-hexyn-3-ol (21). The standard allenylindium
addition procedure was followed using aldehyde 191 (120 mg, 0.67 mmol),
mesylate 20 (179 mg, 0.81 mmol), InI beads (212 mg, 0.88 mmol),
Pd(OAc)2 (9.1 mg, 0.04 mmol), PPh3 (10.6 mg, 0.04 mmol) in THF (6
mL), and HMPA (2 mL) at 0 °C for 15 min before the solution was warmed
to room temperature to give 146 mg (71%) of alcohol 21 and its syn
diastereomer as a 99:1 inseparable mixture: [R]20D +12.2 (c ) 2.15, CHCl3);
OL016899M
mg (91%) of alcohol 24: [R]20 -14.0 (c ) 1.73, CHCl3); IR (film) υ
D
3477, 2964, 2229 cm -1; H NMR (500 MHz, CDCl3) δ 0.99 (d, J ) 6.5
1
Hz, 3H), 1.21 (d, J ) 7.5 Hz, 3H), 2.01 (m, 1H), 2.34 (d, J ) 4.5 Hz, 1H),
2.78 (m, 1H), 3.47 (m, 1H), 3.57 (m, 2H), 4.51 (d, J ) 4.5 Hz, 2 H), 5.41
(dd, J ) 2.0, 9.0 Hz, 1H), 5.57 (dd, J ) 2.0, 15.5 Hz, 1H), 5.79 (m, 1H),
7.34 (m, 5H); 13C NMR (125 MHz, CDCl3) δ 10.9, 17.8, 17.6, 31.2, 36.3,
73.2, 73.8, 75.7, 81.6, 91.9, 117.2, 126.3, 127.6, 127.5, 128.3, 138.3. Anal.
Calcd for C17H22O2: C, 79.03; H, 8.58. Found: C, 79.11; H, 8.84.
(2S,3S,4S,Z)-(+)-1-Benzyloxy-2,4-dimethyl-5,7-octadien-3-ol (27). Al-
cohol 24 (218 mg, 0.85 mmol) in (Me2SiH)2NH (TMDS) (1.5 mL) was
heated to 60 °C. After 12 h, IR analysis indicated complete conversion to
silane 25. The excess TMDS was removed under reduced pressure for 12
h; the residue was taken up in THF (2 mL), and 35 µL (0.5 mol %) of
0.053 M H2PtCl6 solution in THF was added. The solution was heated to
60 °C and monitored by IR. After 1 h, conversion to siloxane 26 was
complete. The solution was cooled to room temperature, diluted with Et2O
(5 mL), filtered through Celite, and concentrated under reduced pressure
to yield 250 mg (94%) of siloxane 26. A portion of this material (100 mg,
0.32 mmol) in THF (2 mL) was treated with TBAF (1.15 mL, 1.15 mmol).
After 7 h, the product was isolated by extraction with Et2O and purified by
chromatography on silica gel (8:1 hexanes/Et2O) to afford 61 mg (74%) of
1
IR (film) υ 3548, 2975, 2162 cm -1; H NMR (300 MHz, CDCl3) δ 0.15
(s, 9H), 0.96 (d, J ) 6.9 Hz, 3H), 1.17 (d, J ) 7.2 Hz, 3H), 1.62 (d, J )
6.6 Hz, 1H), 1.97 (m, 1H), 2.68 (m, 1H), 3.45 (m, 1H), 3.56 (m, 2 H), 4.52
(s, 2H), 7.33 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 0.10, 10.7, 17.6, 22.4,
31.8, 36.3, 73.1, 73.7, 75.0, 86.7, 108.4, 127.5, 128.3, 137.9. Anal. Calcd
for C18H28O2Si: C, 71.00; H, 9.27. Found: C, 70.84; H, 9.39. (2S,3S,4S)-
(-)-1-Benzyloxy-2,4-dimethyl-7-octene-5-yn-3-ol (24). To a stirred solu-
tion of alcohol 21 (569 mg, 1.87 mmol) in CH2Cl2 (4 mL) was added Et3N
(0.52 mL, 3.74 mmol) and TBSOTf (0.60 mL, 2.20 mmol) at room
temperature. The reaction was monitored by TLC analysis and quenched
with saturated NH4Cl upon completion. The organic layer was separated,
dried over MgSO4, filtered, and concentrated under reduced pressure to
yield 615 mg (79%) of silyl ether 22. The oil was taken on with no further
purification and subjected to standard coupling conditions with CuCl (288
mg, 2.94 mmol), DMI (2.0 mL), Bu3N (630 mg, 4.41 mmol), and vinyl
iodide 8b (294 mg, 1.91 mmol). After 10 h at 120 °C, the mixture was
cooled, and the product was isolated and purified by filtration through silica
gel affording 498 mg (91%) of enyne 23 as a pale yellow oil that was
dissolved in THF and treated with TBAF (2 mL, 2.00 mmol). After 10 h,
reaction was judged to be complete by TLC analysis. The mixture was
diluted with saturated NH4Cl and Et2O. The organic layer was separated,
dried over MgSO4, filtered, and concentrated under reduced pressure. The
residue was chromatographed on silica gel (10:1 hexanes/Et2O) to give 218
diene 27: [R]20 +21.3 (c ) 3.85, CHCl3); IR (film) υ 3477, 2964, 2344
D
1
cm -1; H NMR (500 MHz, CDCl3) δ 0.96 (d, J ) 7.0 Hz, 3H), 1.00 (d,
J ) 7.0 Hz, 3H), 2.01 (m, 1H), 2.22 (s, 1H), 2.80 (m, 1H), 3.48-3.57 (m,
3H), 4.52 (d, J ) 3.0 Hz, 2H), 5.13 (d, J ) 10 Hz, 1 H), 5.23 (d, J ) 17
Hz, 1H), 5.38 (t, J ) 10.5, 1H), 6.13 (t, J ) 10.5 Hz, 1H), 6.62 (m, 1H),
7.34(m, 5H); 13C NMR (125 MHz, CDCl3) δ 9.9, 17.2, 17.6, 35.1, 35.7,
35.8, 73.3, 74.6, 76.2, 118.0, 127.6, 128.2, 130.4, 132.2, 135.3, 138.2.
4110
Org. Lett., Vol. 3, No. 25, 2001