A water soluble, recyclable organostannatrane

Article abstract of DOI:10.1016/S0040-4039(01)01148-0

Synthesis of a water-soluble recyclable organostannatrane has been accomplished via a straightforward three-step synthesis. The organostannatrane exhibits excellent water-solubility (0.33 M) and can be recovered from aqueous solutions via removal of water in vacuo. The compound can be readily converted by standard transformations into reagents suitable for Stille cross-coupling reactions. The reagent can also be transformed into a reactive, water-soluble organotin hydride.

Full text of DOI:10.1016/S0040-4039(01)01148-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5837–5839
A water soluble, recyclable organostannatrane
†
‡
§
Xiaojun Han, Gregory A. Hartmann, Antony Brazzale and Rick D. Gaston*
Department of Chemistry and Biochemistry, Southern Illinois University at Carbondale, Carbondale, IL 62901, USA
Received 28 March 2001; revised 25 June 2001; accepted 27 June 2001
Abstract—Synthesis of a water-soluble recyclable organostannatrane has been accomplished via a straightforward three-step
synthesis. The organostannatrane exhibits excellent water-solubility (0.33 M) and can be recovered from aqueous solutions via
removal of water in vacuo. The compound can be readily converted by standard transformations into reagents suitable for Stille
cross-coupling reactions. The reagent can also be transformed into a reactive, water-soluble organotin hydride. © 2001 Elsevier
Science Ltd. All rights reserved.
Metal-mediated cross-coupling reactions leading to the
formation of CꢀC bonds have become very important
methods in organic synthesis. Metal-mediated cross-
coupling reactions which are utilized most often include
the Negishi–Knochel coupling (utilizing organozinc
reagents), the Suzuki coupling (utilizing organoboron
reagents), and the Stille coupling (utilizing organotin
Despite the myriad of positive attributes, the use of
problematic tributyl- and trimethylstannanes has
caused the Stille reaction to remain underutilized in the
pharmaceutical industry. Tributylstannanes are cheap
and versatile reagents in the cross-coupling reaction.
Tributyltin halide, the byproduct of the Stille reaction,
has moderate toxicity (LD50 122–349 mg/kg for
1
2
reagents). While all three are synthetically useful,
Bu SnCl), but its main drawback is that it is extremely
3
undoubtedly the most versatile of these reactions is the
Stille coupling. The organostannanes typically
employed are easy to handle; most are air- and mois-
ture-insensitive; can be distilled, recrystallized, or chro-
matographed; and can be used in the presence of
other reactive functionalities (amines, aldehydes, car-
boxylic acids, etc.). A wide range of organostan-
nanes have been successfully used in cross-coupling
reactions.
difficult to completely remove from a reaction mixture.
In contrast, trimethylstannanes are readily removed
from reaction mixtures via an aqueous wash and are
usually more reactive than the complimentary tributyl-
stannanes. Unfortunately, the residue has a higher toxi-
2
city (LD50 9–20 mg/kg for Me SnCl) and the starting
3
materials for making trimethylstannane reactants are
quite expensive. Further complicating this picture is
that neither the tributyl- nor trimethyltin residues gen-
Scheme 1.
*
Corresponding author. Present address: NitroMed, Inc., 12 Oak Park Drive, Bedford, MA 01730-1414, USA. Tel.: 781-685-9751;
e-mail: rgaston@nitromed.com
†
Present address: Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Medicinal Chemistry Department 403, 5 Research
Parkway, Wallingford, CT 06492, USA.
Present address: Monsanto, Building W3A, St Louis, MO 63167, USA.
Present address: Wyeth-Ayerst Research, CN8000, Princeton, NJ 08543-8000, USA.
‡
§
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01148-0

5
838
X. Han et al. / Tetrahedron Letters 42 (2001) 5837–5839
1
2
erated during the cross-coupling reaction are typically
recycled. This results in hazardous waste disposal issues
and its associated costs.
dark. Removal of solvent in vacuo affords 1 as a pale
yellow solid in 95% yield (mp 162–165°C).
Compound 1’s crystal structure and unit cell are shown
13
We were interested in research performed by Tzachach
in Fig. 1. The molecule has a plane of symmetry and
an NꢀSnꢀI bond angle of 169.4(3)°. More interesting is
that a strong dative bond exists between the N and Sn
3
on the formation of stannatranes. In these systems, a
pendant nitrogen atom forms a dative bond to tin
generating trigonal bipyramidal geometry on the metal,
which results in an increased bond length of the opposing
axial ligand. This lengthened bond leads to enhanced
reactivity of the axial group, especially during the Stille
atoms (SnꢀN 2.38(1) A
of 3.0567(6) A. This bond length is longer than the atomic
radii of both Sn and I, thus imparting salt-like character-
istics on the molecule. The stannatrane has excellent
water-solubility (0.33 M at ambient temp.) and can be
readily recovered from water via removal of solvent in
vacuo. The material can be heated in boiling water for
over 6 h and still be recovered quantitatively and
completely unchanged.
,
) resulting in a very long SnꢀI bond
,
14
4
cross-coupling reaction’s transmetalation step. We
wanted to take advantage of this phenomenon and
generate a stannatrane that was water soluble, easily
recyclable, and synthetically easy to produce. A stanna-
trane of this kind would permit complete removal of tin
residues from Stille reactions via an aqueous wash during
work-up as is common when using trimethylstannanes.
Maintaining water-solubility while decreasing volatility
would permit recovery of the spent haloorganostanna-
trane by simple removal of water in vacuo. This would
drastically reduce hazardous waste disposal costs and
allow continual recycling of the stannatrane. Finally, an
easily recyclable stannatrane synthesized in a short
straightforward manner would be preferred over current
recycling methods, which use perfluorinated solvents to
While iodide 1 can be converted to reagents for Stille
15
cross-coupling reactions, more importantly it can be
transformed into a new reactive, water-soluble tin hydride
(
Scheme 2). Thus, treatment of 1 with borane in THF
followed by a pH 7 phosphate buffer work-up as per the
16
conditions of Breslow readily affords the water-soluble
17
tin hydride 4 as a clear colorless oil.
Hydride 4 has excellent water-solubility (0.22 M at
ambient temperature) thus representing a 7-fold increase
in water-solubility compared to Breslow’s tris[3-(2-
methoxyethoxy)propyl]tin hydride (0.03 M). The internal
activation of the tin hydride causes it to be highly reactive
in dehalogenation processes. Treatment of simple
iodobenzoic acids with 4 in water at ambient temperature
effects dehalogenation (<1 h) in high yields (84–87%)
5
remove perfluorinated tin residues or another organo-
stannatrane which is more difficult to make and is
6
recovered after a complex work-up. Thus, we chose to
synthesize the small molecule organostannatrane 1 which
we anticipated as having all of the desired properties.
Synthesis of 1 (Scheme 1) starts via reaction of N,N-
15
without addition of an initiator. While the hydride does
7
dimethylpropargylamine (2.6Msolutionincyclohexane)
not require special handling, it should be used as soon
as possible after its formation. Dilute solutions of 4 in
pentane (0.1 M) can be made and stored at −20°C with
8
with trimethyltin hydride (0.95 equiv., 60°C, 6 h). This
afforded an 80–90% yield of the vinylstannane 2 as a 2:1
to 1:2 mixture of Z/E isomers upon concentration of the
18
minimal decomposition. It may be more feasible to
generate 4 in situ although this was never attempted.
9
reactionmixtureinvacuo. Diimidereductionoftheolefin
mixture is accomplished by careful addition of NaIO (5
4
equiv., 0.6 M aqueous solution) via syringe pump over
a 2 h period to a 0°C solution of the Z/E vinylstannanes
Recycling of compound 1 is readily accomplished by
extracting into water followed by removal of water in
vacuo. This affords a material suitable for use in most
reactions. If necessary, the iodide can be recrystallized
(benzene) prior to reuse. For reactions performed in
water, the iodide can conveniently be extracted into
normal organic solvents such as diethyl ether or
chloroform.
(
(
0.17 M solution in THF) containing hydrazine hydrate
40 equiv.), copper (II) sulfate (saturated aqueous, 0.2
1
0
equiv.) and glacial acetic acid (3.5 equiv.). Immediate
extraction into CH Cl and removal of solvent in vacuo
2
2
affords a yellow oil. Distillation under reduced pressure
bp 45–55°C/1.5–2.0 torr) gives 3 as a clear colorless oil
(
1
1
in 80% yield. Selective cleavage of the axial methyl group
In conclusion, we have synthesized a water-soluble,
recyclable organostannatrane. This compound is readily
synthesized in high yield via a straightforward synthetic
pathway. Although this pathway involves the use of the
relatively expensive trimethyltin hydride, the fact that the
reagent is continuously recycled from the reaction mix-
is accomplished by treating 3 (1.2 M in benzene) with I2
(
0.95 equiv., 0.57 M in benzene) at 0°C overnight in the
Figure 1.
Scheme 2.

X. Han et al. / Tetrahedron Letters 42 (2001) 5837–5839
5839
tures dramatically reduces both the overall cost of the
reagent as well as the hazardous waste disposal of
organotin residues. Finally, the iodostannatrane can be
readily converted to reagents useful in Stille cross-cou-
pling reactions in addition to an extremely water-solu-
ble tin hydride which, with the addition of a
stereocenter, could conceivably be utilized as a chiral
hydride source.
N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2000, 2, 1081.
7. Smith, R. A.; Coffman, K. J. Synth. Commun. 1982, 12,
801.
8. Huivila, H. G.; Dixon, J. E.; Maxfield, P. L.; Scarpa, N.
M.; Topka, T. M.; Tsai, K. H.; Wursthorn, K. R. J.
Organomet. Chem. 1975, 86, 89.
9. Cochran, J. C.; William, L. E.; Bronk, B. S.; Calhoun, J.
C.; Fassberg, J.; Clark, K. G. Organometallics 1989, 8,
8
04.
0. van Tamelen, E. E.; Dewey, R. S. J. Am. Chem. Soc.
961, 83, 3729.
1. A solid residue (5–10%, mp 104–106°C) was left in the
still pot during distillation corresponding to a polymeric
intermolecularly coordinated stannatrane.
2. (a) Jousseaume, B.; Villeneuve, P. J. Chem. Soc., Chem.
Commun. 1987, 513; (b) Jastrzebski, J. T. B. H.;
Boersma, J.; Esch, P. M.; van Koten, G. Organometallics
1
1
Acknowledgements
1
The authors gratefully acknowledge Dr. Paul Robinson
of Southern Illinois University at Carbondale for per-
forming the X-ray crystallographic work. We also
thank the Hazardous Waste Research and Information
Center (HWRIC), Champaign, IL for funding this
research.
1
1991, 10, 930.
1
3. Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 161014. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
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