Microwave-assisted one-pot hydrostannylation/Stille couplings.

Article abstract of DOI:10.1021/ol006559l

In a fraction of the time required by conventional methods, microwave-accelerated one-pot hydrostannylation/Stille coupling allows 1-alkynes to be efficiently transformed into 1,3-dienes or styrenes.

Full text of DOI:10.1021/ol006559l

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3655-3658
Microwave-Assisted One-Pot
Hydrostannylation/Stille Couplings
Robert E. Maleczka, Jr.,* Je´roˆme M. Lavis, Damon H. Clark, and
William P. Gallagher
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
maleczka@cem.msu.edu
Received September 7, 2000
ABSTRACT
In a fraction of the time required by conventional methods, microwave-accelerated one-pot hydrostannylation/Stille coupling allows 1-alkynes
to be efficiently transformed into 1,3-dienes or styrenes.
The Stille cross-coupling1 of organic halides with vinylstan-
nanes has become an attractive method in modern organic
synthesis. Under classical Stille conditions, most substrates
cross-couple at reaction temperatures of 45-100 °C with
reaction times ranging from hours to days. Recently Larhed,
Hallberg, and others2 have shown that the cross-coupling time
for fluorous and organic-phase Stille couplings can be
reduced to only minutes by using microwave flash heating.3
Of course, the overall speed in which a Stille product can
be accessed is also dependent on the time required to (a)
prepare the starting materials and (b) isolate the product.
Thus, we viewed applying microwave assistance to a one-
pot hydrostannylation/Stille sequence4 as an advance of both
methodologies. We also sought to carry out these transfor-
mations in an easily removable solvent (THF as opposed to
DMF or NMP) so as to facilitate product isolation and
thereby further condense the time line to prepare 1,3-dienes
from 1-alkynes.
To achieve efficient one-pot palladium-mediated hy-
drostannylation/Stille couplings, it is crucial that Pd(0)-
catalyzed conversion5 of Bu3SnH into Bu3SnSnBu3 be
minimized. Therefore, we decided to employ Bu3SnCl,
aqueous KF, polymethylhydrosiloxane (PMHS), and catalytic
TBAF as an in situ source of Bu3SnH.6 In addition to being
relatively cheap and mild, these reagents allow a controlled
production of tin hydride, thereby decreasing the opportunity
for Pd(0)-mediated tin dimerization.7
Initial experiments involved irradiating a pressure tube
containing a THF solution of Bu3SnCl, aqueous KF, PMHS,
an alkyne, electrophile, and Pd(0) in a commercial micro-
wave oven.8,9 Although this led to the formation of Stille
products within minutes, yields varied widely and could not
be consistently reproduced. Furthermore, electrophile reduc-
(1) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-523.
(b) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813-817. (c)
Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1-652.
(2) (a) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582-9584.
(b) Olofsson, K.; Kim, S.-Y.; Larhed, M.; Curran, D. P.; Hallberg, A. J.
Org. Chem. 1999, 64, 4539-4541. (c) Larhed, M.; Hoshino, M.; Hadida,
S.; Curran, D. P.; Hallberg, A. J. Org. Chem. 1997, 62, 5583-5587.
(3) For other methods of accelerating Stille reactions, see: (a) Han, X.
J.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600-7605.
(b) Fugami, K.; Ohnuma, S.-y.; Kameyama, M.; Saotome, T.; Kosugi, M.
Synlett 1999, 63-64. (c) Fouquet, E.; Rodriguez, A. L. Synlett 1998, 1323-
1324. (d) Farina, V. Pure Appl. Chem. 1996, 68, 73-78. (e) Allred, G. D.;
Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748-2749.
(5) Mitchell, T. N.; Amamria, A.; Killing, H.; Rutschow, D. J. Orga-
nomet. Chem. 1986, 304, 257-265.
(6) Terstiege, I.; Maleczka, R. E., Jr. J. Org. Chem. 1999, 64, 342-343.
(7) 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.
(8) See cautionary notes (vide infra).
(9) Kenmore (model 721.69182) variable power 700 W microwave oven.
(10) (a) Taniguchi, M.; Takeyama, Y.; Fugami, K.; Oshima, K.; Utimoto,
K. Bull. Chem. Soc. Jpn. 1991, 64, 2593-2595. (b) Baillargeon, V. P.;
Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452-461. (c) Pri-Bar, I.; Buchman,
O. J. Org. Chem. 1986, 51, 734-738. (d) Pri-Bar, I.; Buchman, O. J. Org.
Chem. 1984, 49, 4009-4011.
(11) (a) Zapf, A.; Beller, M. Chem. Eur. J. 2000, 6, 1830-1833. (b)
Albisson, D. A.; Bedford, R. B.; Lawrence, S. E.; Scully, P. N. J. Chem.
Soc., Chem. Commun. 1998, 2095-2096.
(4) (a) Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 1998, 63, 9622-
9623. (b) Maleczka, R. E., Jr.; Gallagher, W. P.; Terstiege, I. J. Am. Chem.
Soc. 2000, 122, 384-385.
10.1021/ol006559l CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/24/2000

portion of catalyst was added and the reaction irradiated for
an additional 5 min.12
Table 1
Via this modified procedure, a variety of alkynes13
underwent microwave-accelerated hydrostannylation/Stille
couplings with aryl, benzyl, and vinyl electrophiles.14 The
expected dienes or styrenes were provided in good yields
after totals of 8-13 min of microwave irradiation (Table
1). In comparison, Stille coupling of 2-methyl-3-butyn-2-ol
with bromobenzene took 16 h in THF at reflux and afforded
the diene in 60% yield.
Most of the alkynes employed in Table 1 (entries 1-8)
were trisubstituted at the propargylic position. Such highly
substituted alkynes are strongly biased toward formation of
the E-distal stannane upon palladium-mediated addition of
tributyltin hydride,4,7,15 and thus subsequent cross-couplings
were not complicated by a nonregioselective hydrostan-
nylation. In contrast, palladium-catalyzed hydrostannylations
of unhindered alkynes typically afford mixtures of both distal
and proximal vinylstannanes. As such, it is not surprising
that less substituted alkynes (entries 9 and 10) gave cross-
coupled products in somewhat lower yields or as isomeric
mixtures. What did surprise us was the observation of the
Z-isomer in entry 10. Pd(PPh3)4-catalyzed hydrostannylation
of 5-hexyn-1-ol unassisted by microwave irradiation affords
a 2.7:1 ratio of E- to internal stannane without any observable
formation of the Z-isomer. As postproduction isomerization
seemed unlikely (vide infra), this result suggests that under
the high microwave temperatures free radical hydrostan-
nylation may be competing with the Pd-catalyzed reaction.
Phenyl acetylene and methyl propiolate (entries 11 and
12) gave cross-coupled products corresponding to those
expected from the distal vinyltins. Yet, product analysis after
the hydrostannylation portion of the sequence indicated a
2.5/1 to 10/1 (entries 11 and 12, respectively) preference for
the proximal vs distal vinyltins. These substrates may, in
part, be reacting via a mechanism similar to that proposed
by Busacca16 for the cross-coupling of methyl R-tributyl-
stannylacrylate (Scheme 1).
Scheme 1
tion10 often accompanied cross-coupling. The reactions also
produced a black participate, suggesting thermal decomposi-
tion of the palladium catalyst.11
To circumvent these problems, we ran the hydrostan-
nylation with 1 mol % Pd(PPh3)4 in the absence of the
electrophile. After 3 min of microwave irradiation at 140
W, the reaction vessel was either air cooled8 or cooled by
placement in tepid water, after which another 1 mol % of
Pd(PPh3)4 was added along with the electrophile. After
reheating in the microwave for an additional 5 min the
reaction progress was checked. If not complete, a third
As entry 10 of Table 1 suggests the possible occurrence
of free radical processes, we next sought to purposely carry
out the hydrostannylation portion of the sequence under free
radical conditions. As indicated by Table 2, substituting
(12) In an attempt to eliminate the need to add the Pd(0) in portions, we
investigated the use of the thermally more robust Pd[P(OAr)3]2 (ref 11).
However, no clear preparative advantage over Pd(PPh3)4 was realized with
this catalyst.
3656
Org. Lett., Vol. 2, No. 23, 2000

and 4) gave the cross-coupled products in relatively good
yields with only minor contamination by other geometric or
regioisomers.
Table 2
In fact, E/Z product ratios were greater than those obtained
during the hydrostannylation step alone. AIBN-initiated19
hydrostannylation of 2-methyl-3-butyn-2-ol reaches a 20:
8:1 (E/Z/internal) ratio of vinylstannanes after 3 min of
microwave irradiation, whereas the cross-coupled product
displayed an E/Z/internal ratio of 20:1:1 (Table 2, entry 1).20
To investigate this in more detail, isomerically pure
vinylstannanes were irradiated for 10 min in the presence
of bromobenzene and Pd(0). As illustrated in Scheme 2,
Scheme 2
AIBN for Pd(PPh3)4 during the first stage of the reaction
gave similar results with 2-methyl-3-butyn-2-ol and phenyl
acetylene (entries 1 and 2).17
microwave-assisted cross-coupling of pure Z-vinyltin and
bromobenzene afforded a 1:1.7 mixture of E- and Z-cross-
coupled product in 68% yield (eq 1), whereas attempted Stille
coupling of these partners gave no reaction after 24 h in
refluxing THF (eq 2).
A possible explanation of these results would be that in
the high temperatures of the microwave, reaction byproducts
(Bu3SnBr, Bu3SnSnBu3, etc.) or other components were
facilitating geometric isomerization of the vinylstannane by
a free radical (or other) processes. Thus, preferential cross-
coupling of the E-vinyltin would lead to a kinetic resolution
and stereoselective formation of the E-product. Alternatively,
the product itself could be undergoing an isomerization
leading to the observed E/Z ratio.
We also wished to establish that the protocol did not
require the Bu3SnH to be derived from our Bu3SnCl/aqueous
KF/PMHS combination. Thus, several reactions were run
using commercial Bu3SnH (Table 2, entries 3-5). In these
cases, it proved critical that water be included in the reaction
mixture, as in an anhydrous environment the reaction did
not proceed. Apparently, the water serves as a microwave
heat sink.
In principle, formation of the vinylstannanes under free
radical conditions also allows for an added element of
regiocontrol. In contrast to palladium-mediated hydrostan-
nylations, free radical hydrostannylations strongly favor distal
vinyltin formation even when the alkynes are unhindered.18
As indicated by Table 2, unsubstituted alkynes (entries 3
(19) Reactions without AIBN proceeded but were less stereoselective.
(20) For reports of geometric isomerization during the course of Stille
cross-couplings, see ref 1c and articles cited therein.
(21) Representative procedure: To a thick walled Pyrex tube containing
5 mL of THF were added Pd(PPh3)4 (12 mg, 0.01 mmol), 2-methyl-3-
butyn-2-ol (0.10 mL, 1 mmol), Bu3SnCl (0.33 mL, 1.2 mmol), PMHS (90
mg, 1.5 mmol), KF (174 mg, 3.0 mmol), 1 mL of H2O, and catalytic TBAF
(1 drop of a 1 M THF solution). The reaction was closed,8 placed in a
250-mL beaker set in the center of a domestic microwave oven9 (glass
turntable removed), and heated for 3 min at 140 W (20% power setting on
a 700 W microwave oven). After the mixture was allowed to air cool for
10 min, Pd(PPh3)4 (12 mg, 0.01 mmol)22 and bromobenzene (0.16 mL, 1.5
mmol) were added, and the sealed tube was irradiated at 140 W for 5 min.
Upon cooling, the reaction was checked by TLC before a third portion of
Pd(PPh3)4 (12 mg, 0.01 mmol) was added, and the sealed tube was again
irradiated at 140 W for another 5 min. After cooling, TLC showed the
reaction to be complete. A saturated aqueous solution of KF (2 mL) was
added, and the mixture was stirred for 30 min. The phases were separated,
and the organics were combined, washed with brine, dried over MgSO4,
filtered, and concentrated. The resulting residue was purified by flash
chromatography (silica gel; 90/10 pentane/EtOAc with 1% TEA) to afford
153 mg (94%) of E-2-methyl-4-phenyl-but-3-en-2-ol.23
(13) Subjecting internal alkynes to the reaction conditions resulted in
the formation of complex mixtures.
(14) Cinnamyl chloride and p-chloroaniline were also examined as
potential coupling partners. However, under our standard conditions no Stille
reactions were observed with these electrophiles. The performance of
catalysts specifically designed to couple chlorides (see: Littke, A. F.; Fu,
G. C. Angew. Chem., Int. Ed. 1999, 38, 2411-2413) will be discussed in
a full account of this work.
(15) (a) Zhang, H. X.; Guibe´ F.; Balavoine, G. J. Org. Chem. 1990, 55,
1857-1867. (b) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. ReV. 2000,
100, 3257-3282.
(16) Busacca, C. A.; Swestock, J.; Johnson, R. E.; Bailey, T. R.; Musza,
L.; Rodger, C. A. J. Org. Chem. 1994, 59, 7553-7556.
(17) For entry 2, the reaction was contaminated by a minor amount of
trans-stilbene.
(18) (a) Chemistry of Tin; Smith, P. J., Ed.; Blackie Academic &
Professional: New York, 1998. (b) Davies, A. G. In Organotin Chemistry;
VCH: New York, 1997.
Org. Lett., Vol. 2, No. 23, 2000
3657

To explore these possibilities, Z-enriched vinyltins and
cross-coupled products were both subjected to microwave
irradiation in the presence of the experimental reagents and/
or Bu3SnBr (Scheme 3, eq 1). Under such conditions no
latter conditions, the bias for trans products is greater than
the inherent selectivity of the hydrostannylation. Irrespective
of the hydrostannylation method employed, this protocol
allows commercially available 1-alkynes to be transformed
into purified 1,3-dienes or styrenes with a bottle-to-bottle
time of approximately 2.5 h.21
Cautionary Notes: Extreme caution should be taken when
heating a sealed tube in a microwave. Do not fill the reaction
vessel beyond half volume and avoid highly concentrated
reactions.24 High pressures and temperatures are generated
which have led to explosions. In the event of such explo-
sions, glass shards from the reaction vessel can penetrate
the walls of the oven. Thus, all reactions must be run in a
fume hood with appropriate blast shielding in place. Pressure
tubes were purchased from Ace glass and fitted with Teflon
plugs and Teflon encapsulated O-rings. These O-rings were
discarded after approximately 250 min of microwave ir-
radiation. (Using non-Teflon coated O-rings often resulted
in catastrophic failure of the seal.) When cleaning the
pressure tube, we recommend soaking and not scrubbing the
tube, as scratches from metal brushes can weaken the vessel
and facilitate its rupture.
Scheme 3
isomerization was observed. However, addition of radical
scavenger butylhydroxytoluene (BHT) to the Stille reaction
of bromobenzene and Z-(1-tributylstannyl)-3-methyl-but-1-
en-3-ol did lessen the extent to which isomerization was
observed in the product (E/Z ) 1:3) (Scheme 3, eq 2). This
indicates that some adventitious free radical source may be
contributing to the observed isomerizations. However, these
results also suggest that the reaction conditions brought about
by microwave irradiation may be leading to a nonradical
isomerization process occurring during the course of the Stille
coupling. Additional mechanistic investigations are currently
underway.
Acknowledgment. Support was provided by the NIH
(HL-58114), NSF (CHE-9984644 and the MSU/REU pro-
gram), and MSU from an Intramural Research Grant and
start-up funds for R.E.M. D.H.C. thanks the generous
providers of an NHLBI minority undergraduate student
supplement and a UNCF‚Merck Undergraduate Science
Research Scholarship Award. We thank Samantha M. Shore
for performing important control experiments.
In conclusion, we have developed an efficient microwave-
assisted one-pot hydrostannylation/Stille coupling protocol.
The hydrostannylation portion of the sequence can be carried
out under Pd-catalyzed or free radical conditions. Under the
Supporting Information Available: Spectroscopic data
for all new compounds pictured, as well as detailed experi-
mental procedures. This material is available free of charge
via the Internet at http://pubs.acs.org.
(22) Different commercial batches of Pd(PPh3)4 varied in activity;
occasionally necessitating a doubling of the catalyst load.
(23) For spectroscopic data, see: Marko, I. E.; Leung, C. W. J. Am.
Chem. Soc. 1994, 116, 371-372.
(24) Reactions run with 5 mmol alkyne in 5 mL of THF were prone to
explode.
OL006559L
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Org. Lett., Vol. 2, No. 23, 2000