Potassium fluoride on calcium fluoride - A practical reagent for removal of organotin residues from reaction mixtures

Article abstract of DOI:10.1016/j.mencom.2013.09.006

Potassium fluoride deposited on calcium fluoride serves as an easily available and convenient reagent for the removal of all major types of organotin residues from reaction mixtures by a simple filtration.

Full text of DOI:10.1016/j.mencom.2013.09.006

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 257–259
Potassium fluoride on calcium fluoride – a practical reagent
for removal of organotin residues from reaction mixtures
Margarita A. Lapitskaya, Ljudmila L. Vasiljeva and Kasimir K. Pivnitsky*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: +7 499 135 5328; e-mail: kpiv@mail.ru
DOI: 10.1016/j.mencom.2013.09.006
Potassium fluoride deposited on calcium fluoride serves as an easily available and convenient reagent for the removal of all major
types of organotin residues from reaction mixtures by a simple filtration.
Various organotin reagents, especially Bu3SnH, Bu3SnX (X = F,
Cl, Br), (Bu3Sn)2O and (Bu3Sn)2, have found wide application in
modern organic synthesis as indispensable reagents for a variety
of radical and ionic reactions.1(a),(b) The common drawback of
these reactions is the necessity to remove the reaction mixtures
from all organotin residues (OTR) originating in the excesses
and chemical transformations of the organotin reagents. This type
of purification is important not only to gain a high purity of the
synthetic product but also in connection with the high toxicity of
organotin compounds.1(c) The problem of OTR removal arises
from the similarity of OTR and the reaction products in some
physical properties, very often resulting in an inadequate effective-
ness of common extractive treatment followed by chromatography
(for excellent illustration, see ref. 2).
In the period of more than the last 30 years this problem and
its solutions were the main object of several articles2–8 and sections
in reviews9,10 as well as valuable episodes in many papers.11–17
The majority of the purification methods were based on a chemical
transformation of OTR to facilitate its removal. The reagents
being proposed for this transformation include Me3Al,5 DBU,14
NaBH3CN,4 NaOH,5 KOH17 and CsOH,6 which are not chemo-
selective and not acceptable for the variety of target products.
The most widely-used method is the treatment with fluoride
ion which converts some types of OTR into the corresponding
insoluble stannyl fluorides.3 The source of fluoride ion is usually
KF in aqueous3,7 or alcoholic11 solution, or as a mixture with
silica gel,2 but sometimes CsF,6,12 Bu4NF17 and Py·HF13 were
used as well.
The methods with fluoride ion are experimentally simple and
chemoselective, however, sometimes they do not provide a suf-
ficiently complete (<1%) removal of OTR.2,12,17,18 Moreover, with
the single exception of chromatography on a mixture of silica
gel with KF,2 the methods with fluoride ion imply an extractive
treatment of reaction mixtures.
The treatment of reaction mixtures with a suspension of a
solid source of fluoride ion in an inert solvent followed by
filtration appears to be a much more convenient method to OTR
removal. This method has been realized yet only with a help of
hygroscopic and alkaline solid solution CsF·CsOH as a reagent.6
Herein, we found that potassium fluoride deposited on calcium
fluoride (KF/CaF2, 20–22% KF) could serve as a very effective
source of fluoride ion in this method. The system KF/CaF2 is a
cheap and easily available reagent,† and can be readily prepared
in the laboratory by evaporation of a CaF2 suspension in aqueous
KF solution.‡
The relative effectiveness of various solid ‘forms’ of KF as a
heterogeneous source of fluoride ion has already been investigated
in the reactions of nucleophilic substitution. Exactly KF/CaF2 was
found to be the most active ‘form’,19 followed by the mechanical
19,20
mixture KF + CaF2
and fine-powdered ‘spray-dried’ KF.20,21
Other studied supports for KF, namely silica gel,22 celite,22,23
Al2O322,24 and analogues,22 diminish fluoride ion nucleophilicity25
and are not chemically inert to a contact with KF.§ As an example,
highly alkaline ‘KF/Al2O3’ is in fact (K3AlF6 + KAlO2 + KOH)/
Al2O3.26 In KF/CaF2 any chemical interaction of the components
is absent.19,27
Additional favorable properties of KF/CaF2 are its essential
neutrality and non-hygroscopicity. A sample of the completely
dried reagent contained only 0.4% of water after 5 years of the
occasional using. The same quantity of water was absorbed by
anhydrous KF/CaF2 exposed to air within 24 h with a relative
humidity 22% at 25°C. Similar unexpected negligible hygro-
scopicity of fine-powdered KF has already been known but
remained unexplained.21,24,28 Mechanical mixtures of KF with
CaF220 or silica gel2 are hygroscopic.8
Some time ago KF/CaF2 was used as a reagent for the hydrolysis
of dibutylchlorostannyl ethers.16 In the course of that study we
discovered a significant increase of the KF/CaF2 activity on the
addition of 1 equiv. of water. A similar effect of small water
quantities was reported for KF on other supports.19,22,23 Therefore,
it is expedient and convenient to moisten the reagent in advance up
to a ratio KF:H2O = 1:1.‡ The following discussion in this paper
assumes KF/CaF2 containing KF and H2O 3.5 mmol g–1 each.
A practical, without chromatography, general method of OTR
removal from reaction mixtures with the aid of KF/CaF2 is very
simple. It consists in stirring (6–12 h) of a mixture containing
OTR (for example, ~1 mmol of [Sn]) with suspended KF/CaF2
(600–900 mg, ~2–3 mmol of KF), dilution (2–5 times) with
‡
Preparation of KF/CaF2. The powdered (20–100 mm) CaF2 (66.69 g)
was added portionwise to a solution of KF·2H2O (30.0 g) in water (30 ml)
with mixing by spatula. The formed thick wet mass was dried in air
first at room temperature and then at 130–140°C for 2 h. The brittle
dry mass was then finely powdered by a short grinding in a mortar (yield
84.89 g of white anhydrous KF/CaF2). This reagent (30.0 g) was stored
in desiccator containing a cup with 3–4 ml of water until it reached
the weight 32.0–32.1 g which corresponds to the contents of KF and H2O
3.5 mmol g–1 each.
†
§
Potassium fluoride on calcium fluoride (20% KF) (Cat. No. 316636)
The appearance of an unpleasant, potentially toxic odour was sensed
could be found in the electronic catalogue on Sigma-Aldrich site, but at
present this reagent ‘has been discontinued’.
during preparation of KF/SiO2 by grinding of silica gel in a mortar together
with a concentrated aqueous solution of KF.
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 257–259
Example 1
O
Example 2
Example 3
Example 4
Me
Me
Me
H
H
Me
H
O
OH
O
Me
Me
H
Me
H
Me
H
H
O
H
H
H
H
MeO
O
4-RC6H4COO
ButMe2SiO
1
+
2
3 (R = Br)
+
5
+
+
Bu3SnCl
(Bu3Sn)2O
Bu3SnH
(Bu3Sn)2
+ Silica gel
+ I2
KF/CaF2, silica gel filtration
+ Chromatography
1 (95%)
2 (100%)
3 (R = H, 91%)
5 (100%)
Scheme 1 Examples of various organotin residue removals.
ButOMe, Et2O, MeCN or EtOAc (depending on the product
polarity), and filtering through a short plug of silica gel¶ (1–2 g).
If some traces of OTR remained in a product the same filtering
should be repeated in the pure chosen solvent. Specific details of
this general method as well as a pre-treatment of reaction
mixtures needed for some types of OTR are commented below.
In all fluoride-based methods of OTR removal the final opera-
tion is filtering off of insoluble Bu3SnF formed. However, the
complete removal of Bu3SnF by filtering may be problematic
because the filtrate is usually saturated with Bu3SnF which remains
in the product. The quantity of remained Bu3SnF depends critically
on the solubility of this substance in the solvent(s) used. Et2O,3,18
EtOAc,12 MeCN and Me2CO10 are recommended in the literature as
the solvents for Bu3SnF removal by filtering. Nevertheless, we were
unable to find in the literature any quantitative data on the Bu3SnF
solubility in the mentioned solvents,†† and therefore we deter-
mined the solubility in these as well as in some other solvents
(Table 1). The data show that the solubility in Me2CO is too high
and ButOMe appears to be an optimal solvent for the purpose.
Filtering through a short plug of silica gel is an important
additional factor which makes it possible to diminish Bu3SnF
concentration in filtrates down to <<0.1 mg cm–3. Silica gel was
reported to irreversibly absorb (Bu3Sn)2O thus removing its last
traces.8,10,14 We found that Bu3SnF possesses the same ability –
1 g of silica gel can irreversibly absorb up to 11 mg of Bu3SnF
from solutions during filtrations.
Removal of Bu3SnCl and (Bu3Sn)2O (and their homologues)
from reaction mixtures with KF/CaF2 needs no pre-treatment of
the mixtures. To compare the activities of KF/CaF2 and CsF·CsOH
we reproduced the model experiment6 with a replacement of
CsF·CsOH by an equivalent quantity of KF/CaF2 (Example 1 in
S
cheme 1).‡‡ The result, i.e. the complete purification of 6-methoxy
-
1-tetralone 1 from an equimolar admixture of Bu3SnCl, remained
unchanged. An increased quantity of silica gel (3.5 g mmol–1
[Sn]) made it possible to fulfill the Bu3SnF filtering off in
CH2Cl2 despite significant solubility of Bu3SnF in this solvent
(see Table 1).
Oxide (Bu3Sn)2O is probably the most common component
of OTR despite its only limited application as a reagent for organic
synthesis.12,15,30 Nevertheless, various quantities of (Bu3Sn)2O
could be formed in the reactions with all other types of tributyl-
stannanes due to main or side oxidative or hydrolytic reactions.
The transformation of (Bu3Sn)2O on contact with KF/CaF2 pro-
ceeds according to the equation (Bu3Sn)2O + KF + H2O ®
® Bu3SnF + KOH generating a strong base. Indeed, we observed
the appearance of a medium alkaline condition in the process.
Therefore with alkali-sensitive substrates it is advisable to add
some silica gel to a reaction mixture of (Bu3Sn)2O for removal by
the general method. This small modification was demonstrated
in the model experiment of the quantitative testosterone 2 isola-
tion from its mixture with an equimolar quantity of (Bu3Sn)2O
(Example 2§§).
Two other popular organotin reagents, Bu3SnH and (Bu3Sn)2,
do not react under mild conditions with KF/CaF2 or other sources
of fluoride ion. An attempt to get around this obstacle was made
in Example 3,¶¶ during the treatment of a reaction mixture after
Table 1 Solubility of Bu3SnF in organic solvents at 24°C.a
Solvent
Solubilityb/mg cm–3
Solvent
Solubilityb/mg cm–3
C6H6
0.4c
0.8
Et2O
ButOMe
0.2
§§ Example 2. The suspension of KF/CaF2 (862 mg, 3 mmol KF) and
silica gel (431 mg) in a solution of testosterone 2 (145 mg, 0.50 mmol)
and (Bu3Sn)2O (300 mg, 0.5 mmol) in CH2Cl2 (8.6 ml) was stirred for
6 h, then diluted with EtOAc (20 ml) and filtered through silica gel (1 g).
Filtrate evaporation remained 184 mg of crystalline mass incompletely
soluble in 0.5 ml of EtOAc. This mass in EtOAc (3 ml) was filtered again
through silica gel (500 mg) affording crystalline hydroxyketone 2 (145 mg,
100%), pure according to TLC and NMR, Sn content <0.1% (semi-
quantitative atom-emission analysis).
¶¶ Example 3. The solution of bromobenzoate 3 (200 mg, 0.33 mmol),
Bu3SnH (290 mg, 1.0 mmol) and AIBN (8 mg, 0.05 mmol) in toluene
(6.3 ml) was heated for 4 h at 80°C in Ar atmosphere. Extractive work-up
and evaporation at 100°C (0.4 Torr) produced 302 mg (174%) of semi-
solid mass. This mass was vigorously stirred for 6 h in air with KF/CaF2
(740 mg, 2.6 mmol KF) in toluene (7 ml). Filtration through silica gel
(500 mg, CH2Cl2 elution) gave 253 mg (146%) of crystalline mass heavily
contaminated by OTR (NMR spectrum). Repeated treatment with KF/CaF2
(in THF) did not change anything. Only by chromatography on silica gel
(6 g) in toluene, Bu3SnH (64 mg, Rf 0.95, toluene) and pure benzoate 4
(158 mg, 91%, Rf 0.10) were isolated.
Toluene
CH2Cl2
CHCl3
EtOAc
0.1
2.8
>20d
THF
6.9
MeCN
Me2CO
0.24
0.50
0.26
aA suspension of Bu3SnF (50–300 mg) in a solvent (15 ml) was stirred for
1 h at 40°C (30°C for Et2O) and then stored at least 24 h at 24°C. Supernatant
aliquots (5.00 ml) were evaporated in vacuum to dryness and the crystalline
residues were weighted. b 1 mg cm–3 = 3.24×10–3 mol dm–3
(25°C). d Lit.,29(a) ~20 mg cm–3 (37°C).
.
c Lit.,29(b): ~0
¶
Deactivated silica gel 20–100 mm (Chemapol) with water content 9–10%
was used.
†† The only published solubilities of Bu3SnF are >10 mg cm–3 at 37°C in
MeOH, n-hexane, CHCl3, CCl4 and Cl2C=CCl2.29
‡‡ Example 1. The suspension of KF/CaF2 (330 mg, 1.14 mmol KF)
and silica gel (120 mg) in a solution of 6 methoxy-1-tetralone 1 (100 mg,
0.57 mmol) and Bu3SnCl (153 ml, 0.57 mmol) in CH2Cl2 (2 ml) was stirred
overnight. Filtering through a short plug of silica gel (2 g) with CH2Cl2
elution afforded crystalline ketone 1 (95 mg, 95%), pure by NMR.
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Mendeleev Commun., 2013, 23, 257–259
2 D. C. Harrowven and I. L. Guy, Chem. Commun., 2004, 1968.
reductive debromination of diosgenin p-bromobenzoate 3 with
3 equiv. of Bu3SnH. Neither stripping off at 100°C (0.4 Torr)
of the excessive volatile Bu3SnH [bp 80°C (0.4 Torr)], nor the
double treatment with KF/CaF2 according to the general method
in the air [for oxidation of Bu3SnH into (Bu3Sn)2O] did result in
complete purification of the formed benzoate 4. The remained
Bu3SnH, very unpolar compound, can be removed by chromato-
graphy, with a significant decrease in a preparative value of the
synthesis.4
3 J. E. Leibner and J. Jacobus, J. Org. Chem., 1979, 44, 449.
4 D. Crich and S. Sun, J. Org. Chem., 1996, 61, 7200.
5 P. Renaud, E. Lacote and L. Quaranta, Tetrahedron Lett., 1998, 39, 2123.
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K. J. Stenning, B. Tang, E. Packard and L. Nanson, Chem. Commun.,
2010, 46, 6335.
The similar situation is observed with high-boiling (Bu3Sn)2,18
which could be present in OTR not only as an excess of the
reagent but very often as a product of Bu3SnH transformation
under diverse reaction conditions.31 For both of these OTR com-
ponents the best modification of the general method is pre-treat-
ment of reaction mixtures with iodine solution.6,7,14 This pre-
treatment smoothly converts both Bu3SnH and (Bu3Sn)2 into Bu3SnI
which is easily removed on subsequent KF/CaF2 treatment by the
general method. In a model experiment an equimolar quantity of
(Bu3Sn)2 was successfully removed from the mixture with silyl
ether 5 using this modification of the method (Example 4†††).
Moreover, the choice of an optimal (by solubility of Bu3SnF)
solvent (ButOMe) in this experiment made it possible to use a
single silica gel filtration only. Simultaneously the stability of
ButMe2SiO group towards KF/CaF2 was found.
9 W. P. Neumann, Synthesis, 1987, 665.
10 F. Guibe, Tetrahedron, 1998, 54, 2967.
11 D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1978, 100, 3636.
12 D. N. Harpp and M. Gingras, J. Am. Chem. Soc., 1988, 110, 7737.
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Int. Ed., 2007, 56, 1648 (Izv. Akad. Nauk, Ser. Khim., 2007, 1586).
17 B. O. Tasch, E. Merkul, W. Frank and T. J. J. Muller, Synthesis, 2010,
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18 G. Muller, G. Durner, J. W. Bats and M. W. Gobel, Liebigs Ann. Chem.,
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19 J. H. Clark, A. J. Hyde and D. K. Smith, J. Chem. Soc., Chem. Commun.,
1986, 791.
In summary, KF/CaF2 is an easily available and convenient
reagent in this simple method of organotin residue removal from
reaction mixtures without chromatography.
20 J. Ichihara, T. Matsuo, T. Hanafusa and T. Ando, J. Chem. Soc., Chem.
Commun., 1986, 793.
21 N. Ishikawa, T. Kitazume, T. Yamazaki, Y. Mochida and T. Tatsuno,
Chem. Lett., 1981, 761.
22 J. Yamawaki and T. Ando, Chem. Lett., 1979, 755.
23 T. Ando and J. Yamawaki, Chem. Lett., 1979, 45.
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R. B. Jobson and D. F. Reinhold, Tetrahedron Lett., 1986, 27, 3845.
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J. Chem. Soc., Chem. Commun., 1986, 657.
28 N. Ishikawa, T. Kitazume and M. Nakabayashi, Chem. Lett., 1980, 1089.
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This work was supported by the Presidium of the Russian
Academy of Sciences (program 2011–2012). Authors are grateful
to Dr. O. D. Vernidub (Metaltest, Moscow) for atom-emission
analyses.
References
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Compounds, vol. 2, ed. Z. Rappoport, John Wiley and Sons, Chichester,
2002, p.1333; (b) M. W. Carland and C. H. Schiesser, in The Chemistry of
Organic Germanium, Tin and Lead Compounds, vol. 2, ed. Z. Rappoport,
John Wiley and Sons, Chichester, 2002, p.1401; (c) E. Lukevics and
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p.1685.
††† Example 4. The solution of iodine in ButOMe (0.25 mol dm–3, ~2 ml)
was added dropwise to the solution of silyl ether 5 (201 mg, 0.50 mmol)
and (Bu3Sn)2 (290 mg, 0.50 mmol) in ButOMe (5 ml) until appearance of
light-yellow coloration. Thereafter KF/CaF2 (714 mg, 2.5 mmol KF) was
added and thickening white suspension was stirred for 6 h. The filtration
through silica gel (1 g) with ButOMe elution afforded crystalline silyl
ether 5 (201 mg, 100%), according to TLC and NMR not contaminated
neither by OTR nor by desilylation product, with Sn content <0.05%
(semi-quantitative atom-emission analysis).
Received: 8th July 2013; Com. 13/4152
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