Hydrocarbon Soluble Recyclable Silylation Reagents and Purification Auxiliaries

Article abstract of DOI:10.1021/acs.orglett.6b00263

Procedures using heptane-phase-selectively soluble octadecyldimethylsilyl groups to facilitate separations and silyl reagent regeneration are described. These results show that alcohols and alkynes protected by these groups are phase-selectively soluble in hydrocarbon solvents. In a thermomorphic cyclohexane/DMF system, >96% of the silylated alcohols are in the cyclohexane phase, allowing these compounds to be purified by a simple liquid/liquid extraction. Applications of these silylating agents in a Grignard synthesis and Sonogashira reaction are described.

Full text of DOI:10.1021/acs.orglett.6b00263

Letter
pubs.acs.org/OrgLett
Hydrocarbon Soluble Recyclable Silylation Reagents and Purification
Auxiliaries
Chih-Gang Chao, Ashley M. Leibham, and David E. Bergbreiter*
Department of Chemistry, Texas A&M University, College Station, Texas 77842-3012, United States
S
* Supporting Information
ABSTRACT: Procedures using heptane-phase-selectively soluble octadecyl-
dimethylsilyl groups to facilitate separations and silyl reagent regeneration are
described. These results show that alcohols and alkynes protected by these
groups are phase-selectively soluble in hydrocarbon solvents. In a
thermomorphic cyclohexane/DMF system, >96% of the silylated alcohols
are in the cyclohexane phase, allowing these compounds to be purified by a
simple liquid/liquid extraction. Applications of these silylating agents in a
Grignard synthesis and Sonogashira reaction are described.
hlorosilanes are widely used in organic synthesis as
reactions and a separation without affecting reactivity by
anchoring catalysts or ligands onto soluble polymers.8 In this
strategy, separations are most often effected after completion of
the reaction, using a biphasic liquid/liquid separation where the
soluble polymer supported species is by design selectively soluble
in a phase that does not contain the product. Alternatively,
separations can be carried out using an extractive workup. These
methods have been used by us and others to recycle precious
metal catalysts and in synthesis.7,9−12 Here we show how a
similar strategy can address the issue of recycling organosilicon
species and as a strategy in purification of intermediates.
Our initial studies showed the feasibility of using a hydro-
carbon phase anchored silylating agent−octadecyldimethyl-
chlorosilane (1)as an analog of trimethylchlorosilane. After
synthesizing silyl ethers of a variety of alcohols, we showed that
the products of silylation that either had an n-octadecyl group or
contained a mixture of octadecyl isomers are soluble in alkanes
such as hexane and heptane, but poorly soluble in common polar
organic solvents such as dimethylformamide, 90% aqueous
ethanol, and acetonitrile. We further showed that this phase-
selective solubility can be used to assist in the extractive
purification of compounds containing this protecting group and
to subsequently separate and recycle a spent organosilyl species.
To study the separability of silyl ethers of 1 and the
recyclability of octadecylsilyl groups of 1, we first prepared silyl
ethers from a series of primary alcohols. As shown in Scheme 1,
alcohols with side chains of various sizes reacted with 1 under
1
Cprotecting groups. For example, trialkylsilyl chlorides are
used to form silyl ethers to protect alcohols, and trimethylsilyl
groups are used to monoprotect one C−H of ethyne in cross-
coupling chemistry. These organosilicon reagents are particularly
useful because their installation and removal can be performed
with high chemoselectivity under mild conditions. However,
when a silyl group is removed, often with a fluoride reagent, it is
typically discarded. Here, we show how techniques we developed
for the separation and recycling of phase-selectively soluble
homogeneous catalysts can be adapted to recycle protecting
groups. We also show that these same protecting groups can
serve as phase handles in a simple extractive purification method
for silyl-protected alcohols and alkynes, a strategy that has
precedent in liquid/liquid separations that employ fluorous silyl
groups.2
The chemistry described here highlights the potential of
heptane soluble silyl groups in recycling as well as purification.
Surprisingly few studies have been carried out to recycle
organosilyl species by regenerating chlorosilanes. Lickiss showed
that tert-butyldimethylsilanol (TBS−OH) could be recycled and
converted to tert-butyldimethylchlorosilane. However, in this
chemistry, the volatility of the hemihydrate of TBS−OH leads to
losses of product during distillation.3 Darling and co-workers
described cross-linked polystyrene supported chlorosilanes that
could be used as protecting groups in solid-phase synthesis and
regenerated by treatment with BCl3. However, the heterogeneity
of the support resulted in low loading of the silicon reagent,
difficult characterization, and modest efficiency in subsequent
silylation chemistry.4 Our experience with hydrocarbon soluble
catalyst ligands and others’ work with hydrocarbon phase tags
that employ octadecyl groups suggested alternative biphasic
schemes for separating and recycling silicon reagents might be
useful alternatives.5−7
Scheme 1. Synthesis of Silyl Ethers 2a−e
Our group has a longstanding interest in phase-selectively
soluble polymer-supported catalysts.7 We have shown that it is
possible to prepare catalysts or ligands that effect homogeneous
Received: January 26, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b00263
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Organic Letters
Letter
mild conditions to give the corresponding silyl ethers with
excellent yields. Notably, these products could be purified by a
simple liquid/liquid separation using heptane and 90% aqueous
ethanol due to the phase-selective solubility of the products in
heptane. In these cases, the products could be isolated by
removal of the heptane under reduced pressure. After the ethers
were synthesized, we next quantitatively determined the phase-
selective solubility of silyl ethers in a thermomorphic system of
DMF and cyclohexane, which is biphasic at room temperature
but forms a monophasic solution on heating. We then analyzed
the leaching of the silyl ethers into the polar phase of this
Figure 1. Recycling of 1 after a protection/deprotection sequence.
Scheme 4. Use of 1 To Trap Intermediates in Grignard
Reactions
1
thermomorphic system using H NMR spectroscopy. Using
methoxy(octadecyldimethyl)silane (2a), ethoxy(octadecyl-
dimethyl)silane (2b), and butoxy(octadecyldimethyl)silane
(2c) as examples, we found that 2a showed 3.8% leaching, 2b
showed 2.1% leaching, and 2c showed 2.0% leaching into the
DMF phase of a cyclohexane/DMF thermomorphic system.
1
Similar results were seen in H NMR experiments using 2c in
cyclooctane/DMF, hexane/DMF, heptane/DMF, and cyclo-
octane/90% aqueous ethanol where 2.2%, 4.6%, 3.2%, and 0.7%
leaching of 2c into the polar phase was seen. These results show
that 1 is effective at forming products that are reasonably phase-
selectively soluble in nonpolar solvents and suggest that 1 can be
used as a purification auxiliary.
yloxy)(octadecyldimethyl)silane (5) which after a workup
using heptane afforded a 91% yield of 5. A subsequent fluoride
deprotection and liquid/liquid separation procedure afforded
dodec-11-en-2-ol (6) in 75% yield that was pure by 1H and 13
C
Next, we examined ways to reform the alcohol and to recycle
the octadecyldimethylsilyl group (Scheme 2). In this case, we
NMR spectroscopy. This same strategy was used to form an 83%
yield of (1-(4-methoxyphenyl)ethoxy)(octadecyldimethyl)-
silane (7) when 1 was added to the product of the reaction of
methylmagnesium bromide and 4-methoxybenzaldehyde
The Sonogashira reaction is a widely used catalytic reaction
that leads to alkynes via a Pd-catalyzed cross-coupling reaction.19
A common variant of this procedure uses trimethylsilyl-protected
ethyne as a reagent to form terminal alkyne products.20,21 In
these cases, the protected alkyne coupling products are purified
by column chromatography to separate them from catalyst
residues. To illustrate the broader potential of 1, we have shown
that 1 can replace trimethylsilyl groups in these sorts of
Sonogashira coupling reactions, providing both recyclable silyl
protecting groups and a simpler way to isolate the intermediate
protected alkyne product.
Scheme 2. TBAF Cleavage of 2e To Form 3 and Decanol
used 2e as an example, cleaving the silyl ether using TBAF in a
heptane/THF solution. The octadecyldimethylsilyl groups were
recovered as a mixture of the silanol and silyl ether (3) in 94%
yields. The decanol (4) yield was lower, as some decanol was lost
during the extractions that were used to remove the TBAF
residues. The octadecyldimethylsilyl residue mixture 3 could be
further purified to form 3b, but the mixture of 3a and 3b was
typically used directly in recycling experiments.
There are a number of reactions that could in principle
regenerate 1 from 3. Some, like Sommer’s route using chlorine
gas, are likely experimentally inconvenient.13 Other procedures
including chlorination with acetyl chloride,14 thionyl chloride,15
oxalyl chloride,16 phosphorus pentachloride,17 and concentrated
hydrochloric acid18 are better choices. In our case, we found that
1 can be regenerated quantitatively from 3 by allowing 3 to react
with thionyl chloride in the presence of a catalytic amount of
DMF (Scheme 3). With these results in hand, a procedure for the
cleavage of organosilyl protecting groups and regeneration of 1
was established (Figure 1).
As shown in Scheme 5, the reaction of 1 with sodium
acetylide22 formed octadecyldimethylsilylacetylene (8) which
Scheme 5. Use of 1 in a Sonogashira Reaction Followed by
Regeneration and Reuse of 1
These recyclable hydrocarbon-soluble silylating reagents can
also be used in other types of reactions. For example, regenerable
1 can be used to phase tag the alkoxide product of a Grignard
reaction. This is shown in Scheme 4 where 10-undecenal was
allowed to react with methylmagnesium bromide. Addition of 1
to the alkoxide product solution formed (dodec-11-en-2-
could then be coupled with 4-iodoacetophenone to obtain 4-
(dimethyloctadecylsilyl)ethynylacetophenone (9). While a
trimethylsilyl analog of 9 previously had to be purified by
column chromatography,23 9 was purified by simple liquid/liquid
extraction. The result shows that 8 is a potential replacement for
Me3SiCCH and a purification handle for the intermediate
Scheme 3. Regeneration of 1 from 3
B
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Letter
product. In this example, 4-ethynylacetophenone (10) was
obtained in 95% yield after cleavage of the silyl group. The
starting 1 was then regenerated from 3. We also showed that
regenerated 1 could be used in other chemistry, specifically in a
reaction with ethanol to afford a 92% yield of 2b. The product 2b
formed from regenerated 1 was identical to that formed from
fresh 1 and contained no Sonagashira coupling products.
While we were successful in using 1 as a phase anchor as shown
in the examples above, 1 has limitations. If the substrate that is
appended to 1 has a molar mass comparable to 1 and is
significantly polar, leaching levels will exceed 10%. This is
illustrated visually in Figure 2 with an octadecyldimethylsilyl-
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: bergbreiter@tamu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (Grant CHE-
1362735) and the Robert A. Welch Foundation (Grant A-0639)
for support of this research. A.M.L. also acknowledges the
Department of Chemistry of Texas A&M University for financial
support.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00263.
Experimental procedures and NMR spectra (PDF)
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DOI: 10.1021/acs.orglett.6b00263
Org. Lett. XXXX, XXX, XXX−XXX