Stille reactions catalytic in tin: A "Sn-F" route for intermolecular and intramolecular couplings

Article abstract of DOI:10.1021/jo0484169

(Chemical Equation Presented) Polymethylhydrosiloxane (PMHS) made hypercoordinate by KF_(aq) allows Me₃SnH to be recycled during a Pd(0)-catalyzed hydrostannation/Stille cascade. Starting with a variety of alkynes, in situ vinyltin formation is followed by Stille reaction with aryl, styryl, benzyl, or vinyl electrophiles present in the reaction mixture. Both inter- and intramolecular versions of the process are possible with tin loads of approximately 6 mol %. Regeneration of the organotin hydride is believed to proceed through a Me₃SnF intermediate. Given the aggregated nature of organotin fluorides and the ability to use these organotins in substoichiometric quantities, the hazards and purification problems associated with the removal of organotin wastes from reaction mixtures are minimized.

Full text of DOI:10.1021/jo0484169

Stille Reactions Catalytic in Tin: A “Sn-F” Route for
Intermolecular and Intramolecular Couplings†
William P. Gallagher and Robert E. Maleczka, Jr.*
Department of Chemistry, Michigan State University, 540 Chemistry, East Lansing, Michigan 48824
maleczka@cem.msu.edu
Received September 8, 2004
Polymethylhydrosiloxane (PMHS) made hypercoordinate by KF(aq) allows Me3SnH to be recycled
during a Pd(0)-catalyzed hydrostannation/Stille cascade. Starting with a variety of alkynes, in situ
vinyltin formation is followed by Stille reaction with aryl, styryl, benzyl, or vinyl electrophiles present
in the reaction mixture. Both inter- and intramolecular versions of the process are possible with
tin loads of approximately 6 mol %. Regeneration of the organotin hydride is believed to proceed
through a Me3SnF intermediate. Given the aggregated nature of organotin fluorides and the ability
to use these organotins in substoichiometric quantities, the hazards and purification problems
associated with the removal of organotin wastes from reaction mixtures are minimized.
Introduction
tins as well as the general difficulty of their removal from
reaction mixtures.3 Such problems have, in part, driven
the development of cross-coupling reactions that replace
the tin with other metals, boron, silicon, zinc, and indium
among them.4 Despite the clear value of these other cross-
coupling methods, recognition of the aforementioned
positive features of the tin-mediated process has prompted
the invention of more appealing organostannane deriva-
tives for use in Stille reactions5 and better methods for
the removal of tin-containing byproducts.6 We too have
The palladium-catalyzed cross-coupling of organostan-
nanes with a variety of organic electrophiles is commonly
referred to as the Stille reaction.1 Due to its versatility
and functional group compatibility, the Stille reaction has
long been a popular method for the construction of sp2-
sp2 carbon-carbon bonds via σ bond formation.2 That
said, Stille reactions typically demand the management
of stoichiometric amounts of tin before, during, and after
the cross-couplings. This is unattractive because of
troubles associated with the cost and toxicity of organo-
(3) (a) Krigman, M. R.; Silverman, A. P. Neurotoxicology 1984, 5,
129-140. (b) Chemistry of Tin; Smith, P. J., Ed.; Blackie Academic &
Professional: New York, 1998. (c) Davies, A. G. In Organotin Chem-
istry; VCH: New York, 1997.
† Dedicated to Professor Amos B. Smith, III, in honor of his 60th
birthday and 40 years in organic chemistry.
(1) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-
523. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction;
John Wiley & Sons: New York, 1998.
(4) Boron: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-
2483. Silicon: (b) Hatanaka, T.; Hiyama, T. Synlett 1991, 845-853.
(c) Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531-
1541. Zinc: (d) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719-
2724. Indium: (e) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am.
Chem. Soc. 2001, 123, 4155-4160.
(5) (a) Stannatranes: Yang, C.; Jensen, M. S.; Conlon, D. A.; Yasuda,
N.; Hughes, D. L. Tetrahedron Lett. 2001, 41, 8677-8681 and refer-
ences cited therein. (b) Alkyltrichlorostannanes: Bumagin, N. A.;
Roshchin, A. I. Russ. J. Gen. Chem. 2000, 70, 57-63 and references
cited therein. (c) Monoorganostannanes: Fouquet, E.; Rodriguez, A.
L. Synlett 1998, 1323-1324. (d) Polymer-bound organotins: Nicolaou,
K. C.; Winssinger, N.; Pastor, J.; Murphy, F. Angew. Chem., Int. Ed.
1998, 37, 2534-2537.
(2) For some recent examples of the employment of the Stille
reaction in medicinal chemistry, materials science, and natural product
synthesis, see: (a) Elzein, E.; Palle, V.; Wu, Y.; Maa, T.; Zeng, D.;
Zablocki, J. J. Med. Chem. 2004, 47, 4766-4773. (b) Romo, D.; Choi,
N. S.; Li, S.; Buchler, I.; Shi, Z.; Liu, J. O. J. Am. Chem. Soc. 2004,
126, 10582-10588. (c) Liu, J.; Kadnikova, E. N.; Liu, Y.; McGehee, M.
D.; Frechet, J. M. J. J. Am. Chem. Soc. 2004, 126, 9486-9487. (d)
Zhang, X.; Kohler, M.; Matzger, A. J. Macromolecules 2004, 37, 6306-
6315. (e) Durham, T. B.; Blanchard, N.; Savall, B. M.; Powell, N. A.;
Roush, W. R. J. Am. Chem. Soc. 2004, 126, 9307-9317. (f) Stangeland,
E. L.; Sammakia, T. J. Org. Chem. 2004, 69, 2381-2385.
10.1021/jo0484169 CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/07/2005
J. Org. Chem. 2005, 70, 841-846
841

Gallagher and Maleczka
SCHEME 1. Tin-Catalyzed Stille Reactions: The
“Sn-O” Approach
SCHEME 2. Tin-Catalyzed Stille Reactions: The
“Sn-F” Approach
focused on this more direct approached to the “tin
problem” by developing a Stille reaction that is catalytic
in tin.7,8
Results and Discussion
Our early efforts toward such a process focused on
connecting a one-pot Pd-mediated alkyne hydrostanna-
tion and cross-coupling sequence by recycling the or-
ganotin halide Stille byproduct back to tin hydride via
polymethylhydrosiloxane (PMHS) reduction of a putative
tin carbonate intermediate (Scheme 1).8 While this first-
generation protocol proved to be reasonably successful,
improvements were sought by others and us. Kilburn and
co-workers nicely addressed the continuing issue of tin
residue removal by employing polymer-supported dialkyl-
tin chlorides in the cycle.9 Similarly, Shay has explored
adapting our protocol for operation in room-temperature
ionic liquids.10 In contrast, our development efforts cen-
tered on replacing the ill-defined “Sn-O” species in the
catalytic cycle.
Early on, the use of fluoride in Stille reactions was
investigated by Stille himself,11 who showed that the use
of CsF allowed ∼80% of the tin waste to be removed by
filtration. It is now common practice to perform a fluoride
workup to remove any tin byproducts by converting them
to easily filterable organotin fluorides. Moreover, as
aggregated solids that are sparingly insoluble in most
solvents, organotin fluorides are neither volatile nor
easily absorbed through the skin. Given organotin fluo-
ride’s lowered health risk and ease of removal and our
awareness of more recent studies demonstrating that
fluoride-activation of vinylstannanes facilitates their
cross-coupling,12 we decided to investigate a “Sn-F” vs
“Sn-O” approach to recycling the tin during our reaction
sequence.
In initiating this study, we immediately focused on
prior work from our labs that showed how a combination
of Bu3SnCl, aqueous KF, and PMHS produced Bu3SnH
in high yield13 and how organotin hydrides prepared in
this way could efficiently hydrostannylate alkynes in situ
when formed in the presence of a palladium catalyst.14
We also knew that aqueous KF and PMHS could regen-
erate Bu3SnH from Bu3SnX produced during dehaloge-
nations, thus rendering those reactions catalytic in tin.13
Finally, as all evidence pointed to Bu3SnF as the primary
intermediary for these reactions, we hypothesized that
the appropriate combination of R3SnX, PMHS, and
fluoride would enable a one-pot hydrostannation/Stille
cascade requiring only catalytic amounts of tin (Scheme
2).
In practice, mixing a THF solution of 2-methyl-3-butyn-
2-ol (1) and iodobenzene with PMHS, aqueous KF and
catalytic amounts of Pd2dba3, tri-2-furylphosphine, and
6 mol % Bu3SnCl, for 48 h, produced the cross-coupled
product in 21% yield (Scheme 2).13 The results of this
experiment indicated that the tin was being recycled,
albeit in unacceptably low turnover numbers. While
disappointing, the relatively poor performance of this
reaction was not surprising in light of earlier observa-
tions. During our “Sn-O” studies,8 the use of Me3SnCl
instead of Bu3SnCl proved to be essential for the success
of the reaction sequence. Thus, rather than exploring
higher tin loads or modifying other reaction conditions,
we moved immediately to experiments with Me3SnCl.
(6) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 7200-7201. (b)
Saloman, C. J.; Danelon, G. O.; Mascaretti, O. A. J. Org. Chem. 2000,
65, 9220-9222.
(7) Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 1998, 63, 9622-
9623.
(8) (a) Maleczka, R. E., Jr.; Gallagher, W. P.; Terstiege, I. J. Am.
Chem. Soc. 2000, 122, 384-385. (b) Gallagher, W. P.; Maleczka, R.
E., Jr.; Terstiege, I. J. Am. Chem. Soc. 2001, 123, 3194-3204.
(9) Herna´n, A. G.; Guillot, V.; Kuvshinov, A.; Kilburn, J. D.
Tetrahedron Lett. 2003, 3, 8601-8603.
This proved to be rather successful,15 as reacting
alkyne 3 in the presence of KF, catalytic TBAF, catalytic
Pd(0), bromostyrene, and 6 mol % Me3SnCl afforded diene
4 in 90% yield, representing a minimum of 15 tin
turnovers (Scheme 3). Examination of other reaction
parameters also revealed aqueous KF as the best fluoride
(10) Shay, W. R.; Ngwendson, J. N.; Mawo, R. 226th National
Meeting of the American Chemical Society, Sept 7-11, 2003, New
York; American Chemical Society: Washington, DC, 2003; ORGN 455.
(11) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-
3040.
(12) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1999, 38,
2411-2413. (b) Fugami, K.; Ohnuma, S.; Kameyama, M.; Saotome,
T.; Kosugi, M. Synlett 1999, 63-64.
(13) (a) Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 1999, 64,
342-343. (b) Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 2000,
65, 930.
(14) Maleczka, R. E., Jr.; Terrell, L. R.; Clark, D. H.; Whitehead, S.
L.; Gallagher, W. P.; Terstiege, I. J. Org. Chem. 1999, 64, 5958-5965.
(15) Maleczka, R. E., Jr.; Gallagher, W. P. Org. Lett. 2001, 3, 4173-
4176.
842 J. Org. Chem., Vol. 70, No. 3, 2005

Stille Reactions Catalytic in Tin
TABLE 1. Scope and Limitations Studies
SCHEME 3
source. Replacing KF with CsF or a CsF:CsOH fused salt
afforded high yields of Sonogashira-like enynes instead
of the desired Stille products.16 TBAF also could not be
used as the sole fluoride source since reaction of stoichio-
metric TBAF with R3SnH affords intrusive amounts of
17
R3SnSnR3 in what is a terminating event for the
catalytic cycle. Despite previous successes with microwave-
accelerated one-pot hydrostannation/Stille reactions us-
ing stoichiometric amounts of R3SnH,18 reactions with
catalytic quantities of tin carried out in a conventional
microwave oven afforded low yields of the expected
dienes. Finally, while higher loads of Me3SnCl led to little
improvement, loadings below 6 mol % resulted in fairly
significant reductions in yield (Scheme 3). Thus, 6 mol
% would become the standard amount of organotin
employed in subsequent explorations of the reaction
sequence.
In an effort to gain an appreciation of the reaction’s
scope, a variety of alkynes and electrophiles were sub-
jected to the hydrostannation/Stille sequence (Table 1).
Vinyl and aryl iodides and bromides acted as good
electrophiles, as did benzyl bromide (entry 6). In contrast,
methyl iodide, allyl bromide, and an aryl nonaflate did
not couple under these conditions (entries 5, 7, and 8).
Importantly, despite the presence of fluoride, the elec-
trophilic partners could possess TBS ethers (entries 2 and
3). As with our “Sn-O” protocol,8 R-trisubstituted alkynes
(entries 1-11) and R-disubstituted alkynes (entries 12
and 13) coupled well, but reactions with monosubstituted
alkynes proceeded poorly (entry 14). To efficiently couple
these substrates they were transformed into their bro-
moalkyne derivatives.19 These 1-bromoalkynes proved to
be successful, giving us the coupled products in modest
61 and 52% yields, respectively (entries 15 and 16).
a “Sn-F” conditions: 6 mol % Me3SnCl, aq KF, ca. 0.8 mol %
TBAF, PMHS, 1 mol % PdCl2(PPh3)2, 1 mol % Pd2dba3, 4 mol %
(2-furyl)3P, Et2O, 37 °C, 11 h. b Average isolated yield of three
runs. c See Supporting Information for preparation of the starting
1-bromoalkyne.
SCHEME 4
Of course the Stille reactions detailed in Table 1 are
all intermolecular in nature. Over the past decade the
intramolecular Stille reaction has emerged as a mild and
useful way to form variously sized rings.20 Thus, we
wondered if our protocol could be made amenable to a
one-pot Pd-mediated hydrostannation/intramolecular Stille
coupling. To answer this question we first needed to
obtain a suitable starting compound. Alkyne-aryl iodide
26 was targeted for this purpose; its synthesis being
shown in Scheme 4.
(16) Use of CsF in combination with PMHS has been explored to
produce enynes; see: (a) Gallagher, W. P.; Maleczka, R. E. Synlett 2003,
537-541. (b) Gallagher, W. P.; Maleczka, R. E. J. Org. Chem. 2003,
68, 6775-6779 and references cited therein.
10-Undecenol (24) was subjected to a Wacker-type
oxidation21 to afford the keto-alcohol in 93% yield. Treat-
ment with ethynylmagnesium bromide afforded the
desired alkynol 25 in 88% yield. Finally, DCC-mediated
coupling of 25 with 2-iodobenzoic acid produced the target
alkyne-aryl iodide 26 in 88% yield.
(17) Kawakami, T.; Shibata, I.; Baba, A. J. Org. Chem. 1996, 61,
82-87.
(18) Maleczka, R. E.; Lavis, J. M.; Clark, D. H.; Gallagher, W. P.
Org. Lett. 2000, 2, 3655-3658.
(19) Boden, C. D. J.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1
1996, 2417-2419.
(20) (a) Duncton, M. A. J.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1999, 1235-1246. (b) Pattenden, G.; Sinclair, D. J. J.
Organomet. Chem. 2002, 653, 261-268.
(21) Nishimura, T.; Kakiuchi, N.; Onoue, T.; Ohe, K.; Uemura, S.
J. Chem. Soc., Perkin Trans. 1 2000, 11, 1915-1918.
J. Org. Chem, Vol. 70, No. 3, 2005 843

Gallagher and Maleczka
SCHEME 5a
SCHEME 6. Intersecting Jauch’s Retrosynthesis
of Kuehneromycin A
a All Stille reactions were carried out with 3 mol % Pd2dba3 and
12 mol % ligand at a concentration of 0.005 M. For the “normal”
intramolecular Stille conditions: (a) R ) Bu, AsPh3, NMP, 60 °C,
22 h, (60% yield); (b) R ) Bu, AsPh3, THF, 70 °C, 28 h, (52% yield);
(c) R ) Bu, (2-furyl)3P, NMP, 60 °C, 24 h, (61% yield); (d) R ) Bu,
(2-furyl)3P, THF, 70 °C, 27 h, (63% yield). (e) R ) Me, AsPh3, NMP,
60 °C, 14 h, (72% yield); (f) R ) Me, AsPh3, THF, 70 °C, 15 h,
(63% yield); (g) R ) Me, (2-furyl)3P, NMP, 60 °C, 10 h, (74% yield);
(h) R ) Me, (2-furyl)3P, THF, 70 °C, 12 h, (73% yield). For the
“tin-catalyzed” intramolecular Stille conditions: (i) 5 mol %
Me3SnCl, aq KF, PMHS, THF, 70 °C, 14 h, (23% yield); (j) same
as conditions i except for the addition of 26 by syringe pump over
8 h (29% yield); (k) 5 mol % Me3SnF, aq Na2CO3, PMHS, THF, 70
°C, 12 h, (41% yield); (l) same as conditions k except for the
addition of 26 by syringe pump over 8 h (47% yield).
proach (see Scheme 1) to Stille reactions catalytic in tin
were superior in the intramolecular version as applied
to 26. A 0.005 M THF solution of 5 mol % Me3SnF,25 Pd-
catalyst, ligand, PMHS, and Na2CO3 with all of 26 added
at the beginning of the reaction afforded a 41% yield of
29 after 12 h at 70 °C. Again, the slow addition of 26
netted a small gain in yield (47%). It should also be noted
that the Na2CO3-based conditions did not produce any
detectable amounts of dehalogenated material. Further-
more, in the absence of tin, only starting material was
recovered, thus ruling out the occurrence of Heck-type
reaction pathways to 29.
To conclude our evaluation of scope and synthetic
utility, we sought to apply our “Sn-F” method to the
synthesis of a literature target molecule, namely, diene
30. Several years ago, Jauch reported the synthesis of
the reverse transcriptase inhibitor kuehneromycin A.26
His total synthesis proceeds through diene 30, which was
formed via a Horner-Wadsworth-Emmons olefination
of aldehyde 31 (Scheme 6). Thus, the synthesis of diene
30 from 4,4-dimethylhex-5-yn-1-ol (7) became our test
case.
Alkyne 727 had been synthesized before, but in our
hands the prior preparation proved too time consuming.
Thus, we chose to investigate a dianion alkylation28 route
to this molecule. After some experimentation (Table 2),
we found that treating isopropylacetylene 33 with 2 equiv
of n-BuLi and 1 equiv of TMEDA in Et2O at 50 °C
resulted in the formation of a red dianion solution. This
solution was then treated with oxetane,29 followed by slow
addition of BF3‚Et2O at -78 °C. The oxetane was thus
ring opened, and alkyne 7 was formed in a synthetically
useable 35% yield.
Although Grigg22 had previously demonstrated the
hydrostannation of an alkyne in the presence of an aryl
iodide, it was deemed prudent to learn if 26 could be
converted into its vinyltin without reduction of the iodide
moiety.23 Furthermore, as intramolecular Stille reactions
tend to be more substrate dependent than their inter-
molecular counterparts, we also thought it sensible to sort
out efficient cross-coupling conditions with any vinyltin-
aryl iodides prepared from 26.
In practice, Pd-mediated hydrostannation with PMHS/
KF/R3SnCl generated tin hydride afforded vinylstan-
nanes 27 and 2824 in excellent yield (Scheme 5) and
without hydrodehalogenation of the aryl iodide. Next, a
survey of catalyst/ligand combinations and conditions
was conducted. On the basis of this assessment, Pd2dba3/
TFP in THF was chosen as the catalyst/ligand/solvent
mix for attempts at the tin-catalyzed one-pot hydrostan-
nation/intramolecular Stille sequence (Scheme 5).
Thus, first experiments were carried out under these
Pd-catalyst conditions in union with the general “Sn-F”
conditions noted in Table 1. When all reagents were
added at once to a 70 °C 0.005 M THF solution (Scheme
5) and the ensuing reaction was allowed to proceed for
14 h, a 23% yield of macrocycle 29 was obtained along
with traces of the dehalogenated starting material (GC-
MS). Adding 26 via a syringe pump over 8 h slightly
improved the process, as 29 was produced in 29% yield
and no dehalogenated starting material was detected.
Interestingly, and in contrast to the intermolecular
results, a modified version of our original “Sn-O” ap-
(24) Both 27 and 28 were also prepared via a separate route to
confirm their structure: (1) hydrostannation of 25 followed by (2) DCC
coupling with 2-iodobenzoic acid. See Supporting Information for full
details.
(25) Similar results were observed when, per our original protocol,
Me3SnCl was used as the starting material.
(26) (a) Jauch, J. Angew. Chem., Int. Ed. 2000, 39, 2764-2765. For
the isolation, see: Erkel, G.; Lorenzen, K.; Anke, T.; Velten, R.;
Gimenez, A.; Steglich, E. Z. Naturforsch. C. 1995, 50, 1-10.
(27) Harada, T.; Iwazaki, K.; Otani, T.; Oku, A. J. Org. Chem. 1998,
63, 9007-9112.
(28) (a) Bhanu, S.; Scheinman, F. J. Chem. Soc., Chem. Commun.
1975, 817. (b) McMurry, J. E.; Matz, J. R.; Kees, K. L. Tetrahedron
1987, 43, 5489-5498.
(29) Yamaguchi, M.; Nobayashi, Y.; Hirao, I. Tetrahedron 1984, 40,
4261-4266 and references cited therein.
(22) Casaschi, A.; Grigg, R.; Sansano, J. M.; Wilson, D.; Redpath,
J. Tetrahedron 2000, 56, 7541-7551.
(23) Combination of PMHS/aq KF and Pd are known to facilitate
dehydrohalogenations. Studies are ongoing in our labs. For recent
work, see: (a) Maleczka, R. E., Jr.; Rahaim, R. J., Jr.; Teixeira, R.
Tetrahedron Lett. 2002, 43, 7087-7090. (b) Pri-Bar, I.; Buchman, O.
J. Org. Chem. 1986, 51, 734-735. (c) Maleczka, R. E., Jr.; Rahaim, R.
J., Jr. Tetrahedron Lett. 2002, 43, 8823-8826.
844 J. Org. Chem., Vol. 70, No. 3, 2005

Stille Reactions Catalytic in Tin
TABLE 2. Modified Synthesis of Alkyne 7
TABLE 3. Evaluating Different Initial Sources of Tin
entry
1
method of addition
yield
35%
addition of oxetane to dianion followed by
BF3‚OEt2 dropwise at -78 °C
4
3
2
addition of dianion to a solution of
oxetane/BF3‚OEt2 at -45 °C
addition of dianion to a solution of
oxetane/BF3‚OEt2 at -78 °C
22%
27%
20%
addition of oxetane to dianion followed by
BF3‚OEt2 in one portion at -78 °C
a See Supporting Information for preparation of vinylstannane
34.
SCHEME 7
of multiple aggregates of Me3SnF, [Me3SnF(Cl)]K or
related “ate” intermediates cannot be completely ruled
out.
ICP Analysis. Finally, we scrutinized the end of the
reaction to determine the final fate of the tin. During the
course of the reaction, a solid material was always
present. Filtration and analysis suggested this material
to be Me3SnF, but somewhat surprisingly this recovered
solid accounted for only ∼20% of the possible tin. ICP
analysis of the organic and aqueous phases separated
from the reaction mixture indicated that ∼75% of the tin
used in the reaction could be accounted for in the aqueous
phase. The crude organics contained ∼0.5% of the
reaction’s tin or 4.8 ppb.32 Significantly, after column
chromatography, ICP analysis of the purified product
measured no detectable amounts of tin.
The electrophile for our key tin-catalyzed Stille process
was synthesized by first protecting propargyl alcohol as
its tert-butyldiphenylsilyl (BPS) ether (Scheme 7). To
enhance the selectivity during the subsequent Pd(0)-
catalyzed hydrostannation,19 the BPS propargyl ether
was converted to its 1-bromoalkyne. Hydrostannation
under our standard conditions14 provided the correspond-
ing (E)-vinylstannane and a trace of its proximal isomer
(∼95:5). After chromatography, treatment of the vinyltin
with NBS afforded (3-bromoallyloxy)-tert-butyldiphenyl-
silane 32 in 58% combined yield from propargyl alcohol.
Subjecting vinyl bromide 3230 and alkyne 7 to our Me3-
SnF-catalyzed protocol afforded diene 30 in 80% yield.
In addition to providing a very modest example of the
method’s performance in target synthesis, the prepara-
tion of 30 again highlights this chemistry’s tolerance
toward silyl ethers.
Summary
In conclusion, we have developed a complementary
method for performing one-pot hydrostannation/Stille
reactions with catalytic amounts of tin. In addition to
lowering the typical tin requirements of these reactions
by ∼94%, the use of the organotin fluorides allows for
removal of most tin byproducts by a straightforward
combination of filtration and extraction. Moreover, after
column chromatography, the cross-coupled products can
be completely isolated from any measurable amounts of
tin.
Experiments were also carried out with the intention
of providing support for our putative catalytic cycle
(Scheme 2). For the reaction described in entry 1 of Table
1, we could start the reaction with 6 mol % of any of the
proposed tin intermediates. Indeed, using Me3SnCl, Me3-
SnF, Me3SnH, or vinylstannane 34 as the initial tin
source had very little effect on the outcome of the reaction
(Table 3).31 Stoichiometric experiments that were fol-
Experimental Section
General Procedure for the Me3SnCl-Catalyzed One-
Pot Hydrostannation/Stille Coupling. Tri-2-furylphos-
phine (9.3 mg, 0.04 mmol) was added to a solution of Pd2bda3
(9.2 mg, 0.01 mmol) in Et2O (5 mL). After the solution was
stirred at room temperature for 15 min, electrophile (1.5
mmol), Me3SnCl (0.06 mL, 0.06 mmol; 1 M solution in THF),
aq KF (0.1743 g, 3 mmol, 1 mL H2O), TBAF (1 drop of a 1 M
solution in THF (ca. 8 µL or 0.8 mol %)), and PdCl2(PPh3)2
(7.0 mg, 0.01 mmol) were all added to the solution. The solution
was heated to reflux, and then a solution of alkyne (1 mmol)
and PMHS (0.09 mL, 1.5 mmol) in Et2O (4 mL) was added via
a syringe pump over 11 h. The phases were separated and the
organics washed with brine, dried over MgSO4, filtered, and
concentrated. The resulting residue was purified by column
chromatography. Full experimental details are given in Sup-
porting Information.
1
lowed by H NMR indicated that the reduction of Me3-
SnCl (δ 0.06 ppm in CD3OD) to Me3SnH (δ 0.14 ppm)
proceeds through Me3SnF (δ 0.45 ppm). We believe that
the spectroscopic and chemical data suggest the sequence
to be proceeding via a cycle like that illustrated in
Scheme 2. However, it must be stated that the presence
(30) The corresponding vinyl iodide gave intrusive amounts of
homocoupling under traditional Stille conditions.
(31) See Supporting Information for full experimental details.
(32) The remaining ∼4.5% of the tin was unaccounted for.
J. Org. Chem, Vol. 70, No. 3, 2005 845

Gallagher and Maleczka
Supporting Information Available: Experimental pro-
cedures for Schemes 2-5 and 7 and Tables 1 and 2, additional
experimental details for the preparations of compounds 5, 8,
10, 27, 28, and 34, descriptions of control experiments and
Acknowledgment. We thank the Yamanouchi USA
Foundation, NIH (HL-58114), and NSF (CHE-9984644)
for their generous support. W.P.G thanks Pfizer, Dow
Chemical, and MSU for sponsorship of ACS Division of
Organic Chemistry and MSU graduate and dissertation
completion fellowships, respectively. We thank Professor
Lina C. Patino (MSU Department of Geological Sci-
ences) for performing the ICP analysis.
1
ligand surveys, and H and 13C NMR spectra for all reaction
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0484169
846 J. Org. Chem., Vol. 70, No. 3, 2005