Stille couplings catalytic in tin: a "Sn-F" approach.

Article abstract of DOI:10.1021/ol016792z

A new tin recycling method for Stille couplings catalytic in tin is reported. PMHS made hypercoordinate by KF((aq)) allows Me(3)SnH to be efficiently recycled during a Pd(0)-catalyzed hydrostannation/Stille cascade. Relative to previously disclosed protoc

Full text of DOI:10.1021/ol016792z

ORGANIC
LETTERS
2001
Vol. 3, No. 26
4173-4176
Stille Couplings Catalytic in Tin:
A “Sn−F” Approach
Robert E. Maleczka, Jr.,* and William P. Gallagher
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
maleczka@cem.msu.edu
Received September 21, 2001
ABSTRACT
A new tin recycling method for Stille couplings catalytic in tin is reported. PMHS made hypercoordinate by KF(aq) allows Me3SnH to be efficiently
recycled during a Pd(0)-catalyzed hydrostannation/Stille cascade. Relative to previously disclosed protocols, reaction times are shorter and
because this process is believed to proceed through a Me3SnF intermediate the hazards and problems associated with trimethyltins are also
diminished.
The Stille reaction is a commonly employed tactic in organic
synthesis.1 Despite its wide use, the reaction’s reliance on
organostannanes has traditionally been viewed negatively
given the toxicity,1b,2 associated purification problems,1b,3 and
expense of these chemicals. To address the concerns over
organotin use, new organotin derivatives1a,b,4 and tech-
niques1b,3a,b have been designed to facilitate removal of the
tin waste.5
We have pursued a complementary approach to solving
the Stille “tin problem”; the development of a Pd(0)-catalyzed
hydrostannation/Stille coupling that is catalytic in tin. First
examples of such a process proved reasonably successful as
reactions employing only 0.06 equiv. of Me3SnCl often
afforded cross-coupled products in 51-91% yield.6 Unfor-
tunately, reaction yields suffered greatly when Bu3SnCl was
substituted for Me3SnCl or when tin loads were lowered.6
This was significant since organotin toxicity and volatility
increase as the alkyl group size decreases.2 Trimethyltin
halides (Cl, Br, I) and the presumed trimethyltin carbonate
intermediate (Scheme 1, “Sn-O” approach) are also water
soluble,1b thereby complicating disposal of aqueous phases
produced during workup. Furthermore, the reactivity and
structure of (Me3SnO)CO is not well defined,7 bringing into
question its competence within the catalytic cycle.
Thus, we set out to develop a new but equally efficient
way to recycle Me3SnH that did not involve tin carbonates
and/or minimized the hazards and problems associated with
trimethyltins. In pursuing this goal, we became attracted to
the possibility of a catalytic cycle mediated by Me3SnF.
Organotin fluorides are nonvolatile aggregated solids not
easily absorbed through the skin and sparingly soluble in
(1) (a) Mitchell, T. N. In Metal-catalyzed Cross-coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter
4. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50,
1-652. (c) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-523.
(2) (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. (c) Krigman, M. R.; Silverman, A. P. Neurotoxi-
cology 1984, 5, 129-140.
(3) (a) Saloman, C. J.; Danelon, G. O.; Mascaretti, O. A. J. Org. Chem.
2000, 65, 9220-9222 and references cited. (b) Crich, D.; Sun, S. J. Org.
Chem. 1996, 61, 7200-7201. (c) Farina, V. J. Org. Chem. 1991, 56, 4985-
4987.
K. C.; Winssinger, N.; Pastor, J.; Murphy, F. Angew. Chem., Int. Ed. 1998,
37, 2534-2537 and references cited), and (d) alkyltrichlorostannanes
(Bumagin, N. A.; Roshchin, A. I. Russ. J. Gen. Chem. 2000, 70, 57-63
and references cited).
(5) Tin toxicity has also spurred development of reactions with Zn
(Negishi) and B (Suzuki) compounds (ref 1a, Chapters 1-2) as well as
advances in Si (Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123,
6439-6440 and references cited. Lee, H. M.; Nolan, S. P. Org. Lett. 2000,
2, 2053-2055. Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 1684-
1688) and In-based cross-couplings (Perez, I.; Sestelo, J. P.; Sarandeses,
L. A. J. Am. Chem. Soc. 2001, 123, 4155-4160).
(4) Examples include: (a) monoorganotins (Fouquet, E.; Rodriguez, A.
L. Synlett 1998, 1323-1324), (b) stannatranes (Yang, C.; Jensen, M. S.;
Conlon, D. A.; Yasuda, N.; Hughes, D. L. Tetrahedron Lett. 2001, 41,
8677-8681 and references cited), (c) polymer bound organotins (Nicolaou,
(6) (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. (c) Gallagher, W. P.; Terstiege, I.; Maleczka, R.
E., Jr. J. Am. Chem. Soc. 2001, 123, 3194-3204.
10.1021/ol016792z CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/07/2001

Scheme 1
Table 1
most solvents.2a,b As such, the risks posed by organotin
fluorides are less than those of other organotins. Indeed, tin-
mediated reactions are often subjected to a fluoride workup
so as to convert the organotin waste into the relatively benign
and easily filterable organotin fluorides.8
In 1986, Scott and Stille9 showed that the presence of CsF
during the efficient cross-coupling of organostannanes with
vinyltriflates allowed for 80% of the tin waste to be removed
by filtration. More recently, we reported on Pd(0)-mediated
hydrostannations via R3SnH generated in situ by reduction
of R3SnF or R3SnCl with hypercoordinate polymethyl-
hydrosiloxane (PMHS + fluoride).10
On the basis of these precedents, we considered a “Sn-
F” approach to Stille reactions catalytic in tin such as that
illustrated by Scheme 1 (“Sn-F” approach). A Me3SnF-
mediated sequence would lessen the aforementioned prob-
lems associated with our prior use6 of trimethyltins.11
Furthermore, fluoride-activation of vinylstannanes can fa-
cilitate their coupling;12 therefore we wanted to explore if
fluoride would positively impact reaction effectiveness.
In practice, a variety of alkynes and electrophiles under-
went a successful hydrostannation/Stille reaction in the
presence of KF, catalytic TBAF,13,14 catalytic Pd(0), and 0.06
equiv of Me3SnCl (Table 1). We were pleased to find that
compared to our original “Sn-O” method,6 the “Sn-F”
approach afforded the Stille products in similar yields but
a “Sn-F” conditions: 6 mol % of Me3SnCl, aqueous KF, catalytic TBAF,
PMHS, 1 mol % of PdCl2(PPh3)2, 1 mol % of Pd2dba3, 4 mol % of (2-
furyl)3P, Et2O, 37 °C, 11 h. b Average isolated yield of three runs.
in approximately 25% less time (11 vs 15 h). Beyond the
key substitution of fluoride for Na2CO3, this new approach
required only minor alterations to our original procedure.
Instead of adding the electrophile last (per our “Sn-O”
protocol), a solution of alkyne and PMHS in Et2O was slowly
added to the reaction mixture via syringe pump. This reverse
addition minimized electrophile reduction and generally gave
cleaner and higher yielding reactions.
In terms of substrate tolerance, the “Sn-F” and “Sn-O” 6
approaches proved similar. Reaction efficiency was highly
influenced by the regioselectivity of the Pd(0)-catalyzed
hydrostannation step.15 Alkynes that were trisubstituted at
the propargylic position (entries 1-6 and 9) worked better
than those that are disubstituted (entries 7-8), while
unhindered alkynes required the regiochemical assistance of
a 1-bromo group6c,15a,16 (entry 10). As for electrophiles, vinyl,
aryl, and benzyl halides were amenable to the new conditions,
while allyl bromide, methyl iodide, and an aryl nonaflate
were not.
(7) Ku¨mmerlen, J.; Sebald, A. J. Organomet. Chem. 1992, 427, 309-
323.
(8) (a) Leibner, J. E.; Jacobus, J. J. Org. Chem. 1979, 44, 449-450. (b)
Edelson, B. S.; Stoltz, B. M.; Corey, E. J. Tetrahedron Lett. 1999, 40, 6729-
6730.
(9) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-3040.
(10) (a) 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. (b)
Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 1999, 64, 342-343. (c)
Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 2000, 65, 930.
(11) Applying tributyltins to this approach proved disappointing (see ref
10b).
(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) Hydrostannations with R3SnX/PMHS/KF generated R3SnH are
accelerated by adding a catalytic amount of TBAF which presumably
facilitates phase transfer (ref 10).
(14) Reaction of stoichiometric TBAF with R3SnH can give R3SnSnR3
(Kawakami, T.; Shibata, I.; Baba, A. J. Org. Chem. 1996, 61, 82-87), a
terminating event for the catalytic cycle.
To further test the synthetic utility of the “Sn-F”
approach, we sought to synthesize diene 1, a key intermediate
from Jauch’s17 recently reported synthesis of the reverse
transcriptase inhibitor kuehneromycin A.18 While Jauch
formed 1 via Horner-Wadsworth-Emmons olefination of
(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. (c) Rice, M. B.; Whitehead, S. L.; Horvath, C. M.;
Muchnij, J. A.; Maleczka, R. E., Jr. Synthesis 2001, 1495-1504 and
references cited.
(16) Boden, C. D. J.; Pattenden, G.; Ye, T. J. Chem. Soc., Perkin Trans.
1 1996, 2417-2419.
(17) Jauch, J. Angew. Chem., Int. Ed. 2000, 39, 2764-2765.
(18) Erkel, G.; Lorenzen, K.; Anke, T.; Velten, R.; Gimenez, A.; Steglich,
E. Z. Naturforsch. C 1995, 50, 1-10.
4174
Org. Lett., Vol. 3, No. 26, 2001

aldehyde 2 (Scheme 2), our route started with 4,4-dimeth-
ylhex-5-yn-1-ol (4).
source of Bu3SnH10 provided a separable 11:1 mixture of
(E)-vinylstannane 7 and its proximal isomer. Tin-halogen
exchange with NBS ultimately afforded (3-bromoallyloxy)-
tert-butyldiphenylsilane (8)23 in 58% combined yield from
propargyl alcohol. Vinyl bromide 824 and alkyne 4 were then
reacted via the Me3SnF-mediated hydrostannylation25/Stille
protocol to afford diene 126 in 72% yield. This example
highlights the method’s tolerance toward silyl protective
groups.
Scheme 2. Jauch’s Retrosynthesis of Kuehneromycin A
Tin loading requirements were similar for both the “Sn-
F” and “Sn-O” approaches. Dropping below 6 mol % of
tin resulted in substantial yield reduction (Table 2), while
higher loads (up to 20 mol %) offered little advantage.
In our hands, the reported synthesis19 of 4 proved tedious.
Therefore a dianion alkylation20 based construction was
investigated. Exposing isopropylacetylene (3) to 2 equiv of
n-BuLi and 1 equiv of TMEDA in Et2O at 50 °C resulted in
formation of a red dianion solution (Scheme 3). This solution
Table 2. Tin Loading Experiments
Scheme 3. Synthesis of Jauch Intermediate 1a
For entry 1 in Table 1, 6 mol % of Me3SnF or the
corresponding vinylstannane could be substituted for Me3-
SnCl as the initial tin source with very little effect on the
yield of the cross-coupled product. Furthermore, stoichio-
metric experiments followed by 1H NMR indicated that the
reduction of Me3SnCl (δ 0.60 ppm in CD3OD) to Me3SnH
(δ 0.14) proceeds through Me3SnF (δ 0.45). Thus while the
presence of multiple aggregates of Me3SnF, [Me3SnF(Cl)]K,
or related “ate” intermediates has not been completely ruled
out, we believe the spectroscopic and chemical data suggest
the sequence to be proceeding via a cycle like that illustrated
in Scheme 1. Work to further identify reaction intermediates
continues.
In summary, we have developed a modified protocol for
carrying out Stille reactions with catalytic amounts of tin.
In comparison to our original “Sn-O” route, the “Sn-F”
approach offers several advantages. Reactions can be com-
pleted in 25% less time with little loss in yield. Although
trimethylstannanes are still required, the reaction proceeds
via the less hazardous organotin fluoride,2 which can be
filtered off at the end of the reaction sequence.9 In contrast,
trimethyltin residue from the “Sn-O” approach resides in
both the organic and aqueous phases, requiring additional
manipulation and/or creating undesirable exposure and
disposal problems.
a Reagents and conditions: (a) n-BuLi (2 equiv), Et2O, 0 °C then
TMEDA (1 equiv), 50 °C, 15 h then oxetane, BF3‚EtO2, -78 °C,
6 h; (b) BPSCl, imidazole, DMF, 25 °C, 5 h; (c) NBS, AgNO3, 8
h; (d) Bu3SnCl, aqueous KF, PMHS, TBAF, PdCl2(PPh3)2, rt, THF,
2 h; (e) NBS, CH2Cl2, 1 h, 0 °C; (f) 4, 6 mol % of Me3SnCl,
catalytic TBAF, 1 mol % of PdCl2(PPh3)2, 1 mol % of Pd2dba3, 4
mol % of (2-furyl)3P, aqueous KF, PMHS, Et2O, 37 °C, 11 h.
was treated with oxetane21 followed by slow addition22 of
BF3‚Et2O at -78 °C. The oxetane was thus ring opened and
alkyne (4) was formed in 35% yield.
Synthesis of the electrophilic partner (8) began with the
protection of propargyl alcohol as its tert-butyldiphenylsilyl
(TBDPS) ether (Scheme 3). Conversion to 1-bromoalkyne
6 was carried out to enhance selectivity during the subsequent
Pd(0)-catalyzed vinyltin formation.15a,16 In practice, hy-
drostannation of 6 using Bu3SnCl/KF/PMHS as an in situ
(23) Although tin-free preparations of 8 can be envisaged, prior work
by us and the immediate availablity of intermediates favored the chosen
route.
(24) Under traditional Stille conditions the analogous vinyl iodide gave
an intrusive amount of homocoupling.
(25) Pd(0)-catalyzed hydrostannation of 4 exclusively gave the (E) isomer
(88% yield).
(26) Spectral data for 1 was not reported (ref 17); however its structure
as well as those assigned all new compounds are in accord with their
infrared, 300- or 500 MHz 1H NMR, and 62.5- or 125-MHz 13C NMR
spectral data, as well as appropriate ion identification by high-resolution
mass spectrometry. See Supporting Information for details.
(19) Harada, T.; Iwazaki, K.; Otani, T.; Oku, A. J. Org. Chem. 1998,
63, 9007-9112.
(20) (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.
(21) Yamaguchi, M.; Nobayashi, Y.; Hirao, I. Tetrahedron 1984, 40,
4261-4266 and references cited.
(22) Adding BF3‚EtO2 in one portion resulted in a 20% yield of 4.
Org. Lett., Vol. 3, No. 26, 2001
4175

Acknowledgment. We thank the Yamanouchi USA
Foundation, NIH (HL-58114) and NSF (CHE-9984644) for
their generous support. W.P.G. thanks Pfizer and Dow
Chemical for sponsorship of ACS Division of Organic
Chemistry and MSU graduate fellowships, respectively.
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.
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