Cross-coupling reactions of alkenylsilanols with fluoroalkylsulfonates.

Article abstract of DOI:10.1021/ol026900x

[reaction: see text] The design and development of an effective protocol for the palladium-catalyzed cross-coupling of (E)- and (Z)-heptenyldimethylsilanols with organo-triflates and nonaflates is described. Optimization of this coupling focused on the is

Full text of DOI:10.1021/ol026900x

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3771-3774
Cross-Coupling Reactions of
Alkenylsilanols with
Fluoroalkylsulfonates
Scott E. Denmark* and Ramzi F. Sweis
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
600 South Mathews AVenue, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received September 13, 2002
ABSTRACT
The design and development of an effective protocol for the palladium-catalyzed cross-coupling of (E)- and (Z)-heptenyldimethylsilanols with
organo-triflates and nonaflates is described. Optimization of this coupling focused on the issues of both reactivity and stability of the
psuedohalides in the presence of the nucleophilic fluoride promoter for the coupling. The crucial role of varying amounts of water to modulate
the reactivity of the fluoride ion is highlighted.
Palladium-catalyzed cross-coupling reactions are among the
most highly revered methods for the efficient construction
of carbon-carbon bonds. Soon after the breakthroughs in
organostannane (Stille-Migita-Kosugi)1 and organoboron
(Suzuki-Miyuara)2 cross-coupling with organohalides, an
extremely valuable alternative to these protocols was rec-
ognized, namely, the cross-coupling to sulfonate electro-
philes.3-5 Since such “pseudohalides” are readily prepared
from aryl alcohols or ketones,6 this development significantly
expanded the range of compatible electrophiles in cross-
coupling reactions and further enhanced the synthetic utility
of this method.
The recent development of organosilanol cross-coupling
presents a viable (often superior) alternative to the use of
organotin or organoboron compounds.7 The advantages of
these agents include the ease of synthesis of organosilanols,
their mild coupling conditions, and the harmless byproducts
that they generate. To date, most reports have described the
versatility of this reaction with regard to the silanol coupling
partner. Herein, we disclose our initial studies on the
extension to nonhalide-based electrophiles (Scheme 1).8
(5) Other nonhalide coupling partners for palladium-catalyzed cross-
couplings include iodonium salts: (a) Hinkle, R. J.; Poulter, G. T.; Stang,
P. J. J. Am. Chem. Soc. 1993, 115, 11626. (b) Moriarty, R. M.; Epa, W. R.
Tetrahedron Lett. 1992, 33, 4095. (c) Kang, S. K.; Lee, H. W.; Jang, S. B.;
Ho, P. S. J. Org. Chem. 1996, 61, 4720. (d) Kang, S. K.; Yamaguchi, T.;
Hong, R. K.; Kim, T. H.; Pyun, S. J. Tetrahedron 1997, 53, 3027. Diazonium
salts: (e) Sengupta, S.; Bhattacharyya, S. J. Org. Chem. 1997, 62, 3405.
(f) Andrus, M. B.; Song, C. Org. Lett. 2001, 3, 3761. (g) Willis, D. M.;
Strongin, R. M. Tetrahedron Lett. 2000, 41, 6271. (h) Babudri, F.; Farinola,
G. M.; Naso, F.; Panessa, D. J. Org. Chem. 2000, 65, 1554.
(6) For reviews on the synthesis of organo-triflates and nonaflates, see:
(a) Stang, P. J.; Hanack, M.; Subrmanian, L. R. Synthesis 1982, 85. (b)
Ritter, K. Synthesis 1993, 735.
(7) (a) Hirabayashi, K.; Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama,
T. Org. Lett. 1999, 1, 299. (b) Hirabayashi, K.; Mori, A.; Kawashima, J.;
Suguro, M.; Nishihara, Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342. (c)
Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565. (d) Denmark, S. E.;
Sweis, R. F. Acc. Chem. Res. 2002, 35, 835.
(1) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b) Farina,
V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1998, 50, 1. (c) Mitchell,
T. N. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 4.
(2) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Chapter 2. (c) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147.
(3) For organotin coupling to triflates, see: (a) Echavarren, A. M.; Stille,
J. K. J. Am. Chem. Soc. 1987, 109, 5478. (b) Scott, W. J.; Stille, J. K. J.
Am. Chem. Soc. 1986, 108, 3033. (c) Kwon, H. B.; McKee, B. H.; Stille,
J. K. J. Org. Chem. 1990, 55, 3114. For organoboron coupling to triflates,
see: (d) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201.
(e) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(4) Vinylstannane coupling to phosphates has also been reported: (a)
Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.; Gartner, P.; Yang, Z. J. Am.
Chem. Soc. 1997, 119, 5467.
(8) Hiyama has reported the cross-coupling of fluorosilanes to aryl and
alkenyl triflates. Hatanaka, Y.; Hiyama, T. Tetrahedron Lett. 1990, 31, 2719.
10.1021/ol026900x CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/25/2002

Scheme 1
Table 1. Optimization of the Cross-Coupling of (E)-1 with
Phenyl Sulfonates
phenol
time, (E)-2 yield, yield,
fluoride
sourcea
Our approach toward development of a successful protocol
addressed two obstacles associated with this type of coupling.
First, the low reactivity of triflates relative to the iodides
employed in our previously developed coupling methods was
immediately apparent. Second, aryl triflates were expected
to be unstable under the reaction conditions in the presence
of a nucleophilic promoter (Scheme 2). Because these cross-
couplings require a promoter, our challenge was clearly
defined: to devise a system wherein the difference between
the rate of desired C-O bond cleavage for cross-coupling
(path a) was significantly greater than the rate of undesired
S-O bond cleavage (path b) back to the aryl alcohol.
b
b
entry
R
X
solvent
h
%
%
1
2
3
4
5
6
7
8
9
Nf TBAF‚3H2O Cl dioxane 12
Nf TMAF‚4H2O Cl DMF 24
Nf TBAF‚4H2O Cl dioxane 12
Nf TBAF‚6H2O Cl dioxane 12
Nf TBAF‚8H2O Cl dioxane 12
Nf TBAF‚10H2O Cl dioxane 12
40
95
71
95
89
76
1
99
83
97
78
84
93
97
22d
5
19d
5
1d
1d
20d
1
Nf TMAFc
Nf TMAF‚6H2O Cl DMF
Nf TMAF‚8H2O Cl DMF
Cl DMF
24
24
24
8
3
8
1
3
22d
16
7
10 Nf TBAF‚6H2O Br dioxane
11 Tf TBAF‚3H2O Br dioxane
12 Tf TBAF‚4H2O Br dioxane
13 Tf TBAF‚6H2O Br dioxane
14 Tf TBAF‚8H2O Br dioxane
8
8
3
Scheme 2
a Hydrated levels of TBAF and TMAF were made by premixing the
appropriate amount of water with either TMAF‚4H2O or TBAF‚3H2O.
b Yields calculated by GC conversion relative to naphthalene as an internal
standard. c Prepared by dehydration of TMAF‚4H2O. d Mass balance is
unreacted starting material.
The optimal promoter, solvent, catalyst, and ligand com-
bination were then employed in the cross-coupling between
(E)-1 and phenyl nonaflate. At 12 h, the product ratio was
approximately 2:1 in favor of the cross-coupling compared
to the phenolic cleavage product (Table 1, entry 1). Although
encouraging, this was not a synthetically useful result.
However, when we employed tetramethylammonium fluoride
(TMAF), which is supplied as a crystalline tetrahydrate, a
dramatically improved product ratio of 95:5 in favor of the
desired cross-coupling product was observed (Table 1, entry
2).
This striking result prompted an investigation into the
origin of the superiority of TMAF over TBAF. The two
limiting possibilities would be the effect of either the alkyl
group or the extra water contained within the crystalline
tetraalkylammonium salt (TMAF‚4H2O and TBAF‚3H2O).12
These factors were easily addressed by adding water to the
coupling reaction to achieve various levels of hydration of
the nucleophilic salt (Table 1, entries 3-6). By comparing
the tetrahydrate of TBAF with the trihydrate (Table 1, entries
1 and 3), it became apparent that the addition of water
reduces the amount of phenol formation (from 22 to 19%)
and also increases the extent of cross-coupling (from 40 to
79%).13 Using TBAF as a hexahydrate (Table 1, entry 4)
At the outset, we chose to employ phenyl nonaflate in the
cross-coupling reaction with (E)-1, rather than the corre-
sponding triflate, because it was less prone to phenol
formation.9 A survey of promoters also revealed that tet-
rabutylammonium fluoride (TBAF), supplied as a crystalline
trihydrate, in either dioxane or DMF was unique in its ability
to effectively induce this type of coupling.10
The particular palladium catalyst/ligand combination em-
ployed was crucial to the success of this coupling. In addition
to the unique properties of TBAF as a promoter, high
conversion could only be obtained when either PdBr2 or
PdCl2 was used in conjunction with 1,1-di-tert-butylphos-
phinobiphenyl (BPDTBP), a crystalline air-stable ligand
developed by Buchwald (Table 1).11
(9) It has been reported that nonaflates are less susceptible than triflates
to nucleophilic attack at the sulfur atom, which we believe to be the source
of undesired phenol formation. See: Neuville, L.; Bigot, A.; Dau, M. E. T.
H.; Zhu, J. J. Org. Chem. 1999, 64, 7638.
(10) Other potential promoters surveyed include KOSiMe3, KH, KF,
KHF2, KOt-Bu, CsF, Cs2CO3, CsOH, and NaOMe.
(11) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 9550.
(12) For a review on water-accelerated organic transformations, see:
Ribe, S.; Wipf, P. Chem. Commun. 2001, 299.
3772
Org. Lett., Vol. 4, No. 21, 2002

Table 2. Palladium-Catalyzed Coupling of (E)- and (Z)-1 with Aryl Triflates and Nonaflatesa
time,
hb
yield,
%
entry
silanol
aryl
R
promoter
solvent
product
E/Zc
1
2
3
4
5
6
7
8
9
(E)-1
(Z)-1
(E)-1
(Z)-1
(E)-1
(Z)-1
(E)-1
(Z)-1
(E)-1
(Z)-1
C6H5
C6H5
1-naphthyl
SO2CF3
SO2C4F9
SO2CF3
SO2CF3
SO2CF3
SO2CF3
SO2CF3
SO2CF3
SO2C4F9
SO2C4F9
TBAF‚8H2O
TBAF‚6H2O
TBAF‚6H2O
TBAF‚6H2O
TBAF‚6H2O
TBAF‚6H2O
TBAF‚6H2O
TBAF‚6H2O
TMAF‚30H2O
TMAF‚30H2O
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
8
14
14
15
16
25
5
13
27
24
(E)-2a
(Z)-2a
(E)-2b
(Z)-2b
(E)-2c
(Z)-2c
(E)-2d
(Z)-2d
(E)-2e
(Z)-2e
91d
99.5/0.5
2.9/97.1
99.1/0.9
1.1/98.9
>99.9/0.1
0.4/99.6
98.9/1.1
1.5/98.5
93.2/6.7
80.0/20.0
88d
82d
82d
85e,f
86e,f
93d
87d
87d,g
91d,h,i
1-naphthyl
2-(CH3)C6H4
2-(CH3)C6H4
4-(CH3O)C6H4
4-(CH3O)C6H4
4-(CH3CO)C6H4
4-(CH3CO)C6H4
10
DMF
a Reactions employed 1.1 equiv of silanol. b Solvent: TBAF, dioxane; TMAF, DMF. c Crude product contained less than 6% of the corresponding aryl
alcohol. d Determined by GC analysis. e Yield of chromatographed, distilled products. f Yield of analytically pure material. g 10 mol % Pd, 20 mol % ligand.
h 50 °C. i 70 °C. j Crude product contained 26% 4-hydroxyacetophenone, 49% product, and 25% nonaflate; yield was based on 49% conversion to product.
resulted in a 95:5 ratio of the desired product to phenol.14
Further addition of water reduces the amount of phenol to
1% or less. However, the yield of coupling product also
begins to decrease due to the reduced rate of cross-coupling
(Table 1, entries 5 and 6).
more phenol (7%) than the nonaflate (3%) under similar
reaction conditions (Table 1, entries 10 and 13). Nonetheless,
the triflate proved to be a viable coupling partner and
responded in a similar way, with respect to TBAF hydration
levels, as the nonaflate. In this case, TBAF octahydrate gave
the lowest amount of phenol formation (3%) relative to cross-
coupling product (97%) (Table 1, entry 14).
From these optimization studies, it is apparent that there
is not one optimal set of conditions. If short reaction time is
desired, then high levels of fluoride hydration are not
necessary. On the other hand, if the starting psuedohalide is
precious, then high levels of hydration are imperative to
completely suppress phenol formation, albeit at the expense
of the coupling rate. Either a nonaflate or a triflate can be
used with either TBAF or TMAF hydrates, and the starting
points will be substrate dependent.
On the basis of these results, we next investigated a series
of aryl nonaflates and triflates possessing different electronic
and steric properties to establish the generality of the coupling
reaction and the ability to customize the procedure for
different substrates. The results of this survey are collected
in Table 2. As in our previously reported cross-couplings of
silanols to aryl iodides,7c-d these reactions were generally
high-yielding, proceeded under mild conditions, and showed
a high degree of stereospecificity (e.g., Table 2, entries 1
and 2). We observed slightly lower rates of coupling for more
sterically demanding substrates such as the 1-naphthyl and
2-methylphenyl derivatives (Table 2, entries 3-6). In general,
the rate of coupling with silanol (Z)-1 was slower than that
with (E)-1. With sterically demanding (Table 2, entries 3-6)
and electron-rich substrates (Table 2, entries 7-8), the TBAF
hexahydrate was sufficient to promote that coupling since
the rate of aryl alcohol formation was not competitive. In
the case of electron-deficient arenes, however, the more
A similar effect of water was observed when using TMAF
(Table 1, entries 7-9). Unlike TBAF, however, TMAF can
be obtained in an anhydrous form.15 The absence of water
almost completely suppressed the coupling reaction while
still promoting a significant amount of phenol formation
(Table 1, entry 7). The TMAF hexahydrate, on the other
hand, is not only superior to the tetrahydrate (Table 1, entries
2 and 8), but it is superior to TBAF hexahydrate in
minimizing phenol formation (1 vs 5%) (Table 1, entries 4
and 8). However, the rate of cross-coupling with TMAF‚
6H2O is much lower than that with TBAF‚6H2O. As was
the case with TBAF, increasing the amount of water further
reduces the rate and, hence, yields of cross-coupling products
(Table 1, entry 9).
Having established the importance of fluoride hydration,
we next examined the TBAF‚6H2O-promoted coupling using
PdBr2 instead of PdCl2. A significant increase in the reaction
rate was observed, with the cross-coupling now complete in
8 h compared to 12 h with PdCl2 (Table 1, entries 4 and
10). A re-examination of the hydration of TBAF employing
PdBr2 was then conducted with phenyl triflate (Table 1,
entries 11-14). As stated above, the triflate yielded slightly
(13) Reduced nucleophilicity of tetrahexylammonium fluoride with
increasing levels of hydration has been reported: Landini, D.; Maia, A.;
Rampoldi, A. J. Org. Chem. 1989, 54, 328.
(14) It has been suggested that a stable geometry exists as six water
molecules around the fluoride ion of TBAF in an aqueous solution. See:
Craig, J. D. C.; Booker, M. H. J. Solution Chem. 2000, 29, 879.
(15) Christe, K. O.; Wilson, W. W.; Wilson, R. D.; Bau, R.; Feng, J. J.
Am. Chem. Soc. 1990, 112, 7619.
Org. Lett., Vol. 4, No. 21, 2002
3773

robust nonaflate had to be used with the milder promoter,
TMAF (Table 2, entries 9-10). In addition, 30 equiv of water
was necessary to suppress the cleavage of the triflate. Since
this also attenuated the cross-coupling rate, the reaction had
to be heated to 50 °C to reach completion (Table 2, entry
9). With the corresponding coupling of (Z)-1, however, an
effective balance between the rates of cross-coupling and
aryl alcohol formation could not be achieved. This case
notwithstanding, the cross-coupling between silanols and aryl
sulfonates proves to be quite general, tolerating functional
groups as well as arenes possessing various steric and
electronic properties.
corresponding hexahydrate was necessary for the slower
coupling to (Z)-1 to reduce ketone formation to ∼10%.
The work presented here demonstrates that silanols are
capable of undergoing mild and facile palladium-catalyzed
cross-coupling reactions to alkenyl and aryl triflates. Unlike
most prior examples, these particular pseudohalide coupling
reactions generally do not require elevated temperatures.17
With few exceptions, the high yields and stereospecificity
obtained with substrates possessing a wide range of steric
and electronic properties exemplify the generality of this
method. As a result of our initial optimizations, the variables
affecting the success of this reaction have been delineated,
providing the user with clear guidelines by which to employ
this method for a particular sulfonate substrate of choice.
Finally, this method is also compatible with alkenyl
triflates. The cross-coupling (E)- and (Z)-1 proceeded readily
and with high stereospecificity at 50 °C with cycloalkenyl
triflate, 3, in the presence of TBAF (Scheme 3).16 While
TBAF trihydrate was adequate for the coupling to (E)-1, the
Acknowledgment. We are grateful to the Institutes of
Health (R01 GM63167-01A1) for generous financial support.
R.F.S. thanks R. W. Johnson Pharmaceutical Research
Institute for a graduate fellowship.
Scheme 3
Supporting Information Available: Representative pro-
cedures for optimization studies and coupling reactions. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026900X
(16) Lower yields of these couplings result from problematic separation
of the hydrocarbon product from the polymethylsiloxane byproducts.
(17) Fu has developed a mild, general method for the Suzuki coupling
of triflates.3e
3774
Org. Lett., Vol. 4, No. 21, 2002