Comparison of the relative reactivities of the triisopropylsilyl group with two fluorous analogs

Article abstract of DOI:10.1002/adsc.200900061

The relative stabilities of two fluorous analogs, diisopropyl(3,3,4,4,5,5, 6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)silyl and diisopropyl-(4,4,5,5,6, 6,7,7,8,8,9,9,10,10,11,11,11-heptadeca-fluoroundecyl)silyl [C₈F ₁₇(CH₂)_nSi(i-Pr)₂, where n = 2 or 3], of the standard triisopropylsilyl (TIPS) group are compared in the setting of alcohol protection. The fluorous silyl groups can be installed under standard conditions in comparable yields to the TIPS group, but the derived fluorous silyl ethers are more labile than TIPS ethers towards cleavage by both acids and fluoride.

Full text of DOI:10.1002/adsc.200900061

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DOI: 10.1002/adsc.200900061
Comparison of the Relative Reactivities of the Triisopropylsilyl
Group With Two Fluorous Analogs
Amador Garcia Sancho,a Xiao Wang,a Bin Sui,a and Dennis P. Currana,*
a
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Fax : (+1)-412-624-9861; e-mail: curran@pitt.edu
Received: January 29, 2009; Published online: May 5, 2009
Dedicated to Prof. Dr. Armin de Meijere in celebration of his 70th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900061.
Abstract: The relative stabilities of two fluorous an-
alogs, diisopropyl(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
of the parent triisopropylsilyl (TIPS) group that we
F
usually call TIPS (Figure 1).[11]
heptadecafluorodecyl)silyl
(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadeca-
fluoroundecyl)silyl [C8F17A(CH2)nSi(i-Pr)2, where n=
2 or 3], of the standard triisopropylsilyl (TIPS)
group are compared in the setting of alcohol pro-
tection. The fluorous silyl groups can be installed
under standard conditions in comparable yields to
the TIPS group, but the derived fluorous silyl
ethers are more labile than TIPS ethers towards
cleavage by both acids and fluoride.
and
diisopropyl-
An understanding of the relative reactivity and sta-
bility of fluorous protecting groups is essential for
synthetic planning. Fluorous groups that closely re-
semble the structure of their parents and that have
suitable spacers can be expected to have comparable
reactivities to the parent groups.[12] For example, the
fluorous PMB (FPMB) group in Figure 1 is structural-
ly very similar to the parent PMB group, and the pro-
tected functionality is relatively well insulated from
the perfluoroalkyl group (Rf) by a propylene spacer.
In contrast, the parent TIPS group may not be such
G
E
ACHTUNGTRENNUNG
F
Keywords: fluorous chemistry; protecting groups;
relative reactivity; triisopropylsilyl group
good model for the TIPS group for two reasons: 1)
F
the TIPS group is not an analog of a triisopropylsilyl
group but instead a 18-alkyl(diisopropylsilyl) group,
and 2) the ethylene spacer may not be a sufficient in-
F
sulator. Thus, the TIPS group may differ in reactivity
Fluorous protecting groups[1] have been extensively
used recently in diversity-oriented synthesis, natural
products synthesis and fluorous mixture synthesis.
Such groups typically serve a dual role of protecting a
given functional group and enabling a fluorous sepa-
ration. In diversity-oriented synthesis[2] and natural
products synthesis,[3] the separation method is usually
a fluorous solid-phase extraction,[4] which separates
fluorous components from non-fluorous ones. In fluo-
rous mixture synthesis,[5] the method is a fluorous
HPLC,[6] which resolves differentially tagged fluorous
components of a mixture into individual compounds.
Fluorous protecting groups are usually fashioned
after parent (standard) protecting groups, and avail-
able protecting groups for alcohols include fluorous
analogs of tetrahydropyranyl (THP),[7] p-methoxyben-
zyl (PMB),[8] and methoxymethyl (MOM) groups,[9]
among others. Assorted fluorous silyl groups are also
Figure 1. Comparision of fluorous TIPS (FTIPS) and fluo-
available,[10] and we have often used a fluorous analog rous PMB (FPMB) groups with their organic parents.
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Amador Garcia Sancho et al.
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and stability from TIPS for both steric and electronic group on the 28-alcohol and the fluorous TIPS group
reasons. We report here observations showing that on the 18-alcohol. These products originate from the
two fluorous TIPS groups differ in reactivity from two starting quasi-isomers with the standard TIPS
each other and from the parent TIPS group. These group on O5, but they are not the target products be-
F
observations will help in selection of suitable fluorous cause the TIPS group on O2 migrated to the primary
protecting groups during synthetic planning.
alcohol O1. The more polar spot was a mixture of
We first observed differences between TIPS and two products M-5, 36% yield, derived from the other
F
FTIPS groups during a fluorous mixture synthesis of a two starting quasi-isomers with the TIPS group on
F
natural product called SCH 725674.[13,14] A key step in O5. In addition to migration of the one TIPS group
the pilot (non-fluorous) synthesis of SCH 725674 was from O2 to O1, the other FTIPS group was lost entire-
selective desilylation of tris-silyl ether 1 bearing one ly. This allowed the partial separation of four products
tert-butyldimethylsilyl (TBS) group on the primary al- into two fractions since two of the compounds are
cohol and two TIPS groups on secondary alcohols. mono-ols (M-4, less polar) and two are diols (M-5,
Careful treatment of 1 with HCl in MeOH at À58C more polar).
for 1 h[15] removed the TBS group to provide primary
The combined mass balance of the two products
alcohol 2 in 87% yield with the benzyl group and the only accounted for about two-thirds of the starting
two TIPS groups intact. material and there were other unidentified products
A very different result was obtained when an analo- according to TLC analysis. Nonetheless, the results
gous reaction was tried in the fluorous mixture syn- show clear differences between the stable TIPS
F
thesis. Here the precursor was a mixture of four groups in 1 and the TIPS groups in M-3 which either
quasi-isomers[16] M-3 with configurations at C3 and migrated or fell off.
C5 coded to the combination of standard and fluorous
We also encountered untoward liability of the
TIPS groups as indicated. One of the quasi-isomers FTIPS group in a recently completed fluorous mixture
has the same configurations as 1, so the differing reac- synthesis of petrocortyne A.[17] In the pilot synthesis
tivities cannot primarily come from stereochemical of an individual compound, dialkynol (rac)-6a was
differences.
treated with 2 equiv. of BuLi to generate dianion
Treatment of M-3 with HCl and MeOH did not [(rac)-6b in situ], then iodide (S)-7 was added
give a clean product as above, but instead gave rise to (Scheme 2). Standard workup and chromatography
a rather complex mixture. Two spots predominated provided coupled product 8 in 30% yield. Substantial
on TLC analysis and these were isolated by flash starting material remained, and 8 was the only new
chromatography. Both samples lacked the TBS group, product of the reaction.
but neither contained the target products. The less
polar spot, 34% yield, was identified as a mixture of M-9 with configurations encoded by the TIPS groups
In the fluorous mixture version, the quasi-racemate
F
two quasi-isomers M-4 bearing the standard TIPS was added to the same dianion (S)-6b. Again, a single
F
Scheme 1. Differences between TIPS and TIPS groups – SCH 725674 setting.
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Comparison of the Relative Reactivities of the Triisopropylsilyl Group
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Table 1. Isolated yields of silyl ethers under the standard
silylation conditions.
Table 2. Percent conversions in competitive experiments
F
with equimolar amounts of two or three TES, TIPS, TIPS
F
or TIPS* silyl ethers.
TIPS FTIPS FTIPS*
R-OH
R’OTIPS
R’OFTIPS
R’OFTIPS*
Entry Rgt
t [h] TES
C6H5CH2
t-C4H9CH2
c-C5H9
80%
88%
76%
76%
79%
80%
76%
80%
74%
1
2
3
4
5
6
7
PPTS[b]
1
91%
100% NA
NA[a] 0%
0%
0%
81%
100%
AcOH[c] 0.5
0%
21%
35%
100% 55%
100% 3%
100% 27%
[d]
F6SiH2
FeCl3
0.5
1
1
NA
NA
NA
NA
0%
0%
NA
0%
NA
NA
[e]
TBAF[f]
TBAF[g] 0.5
new spot appeared on TLC analysis. However, this
time the chromographically isolated product (30%
yield) was not the pure quasi-racemate M-10. Instead,
this was contaminated by a substantial amount (about
50%) of a second component 11 resulting from trans-
fer of the TIPS groups of 9 to the terminal acetylide
of 6. These compounds were not separable, but the
structure of 11 was secured by MS and NMR analysis
TBAF[h]
1
[a]
[b]
[c]
[d]
[e]
[f]
NA is not added.
1 equiv, THF, room temperature.
THF/H2O, 0 8C.
0.6 equiv., THF/MeCN/H2O, 0 8C.
EtOH, room temperature.
2 equiv., THF, room temperature.
0.7 equiv., THF, 08C.
1 equiv., THF, room temperature.
F
1
[g]
[h]
of the mixture. In particular, the H NMR spectrum
of the mixture exhibited no terminal acetylide proton
resonance, so the TIPS group must be there and not
F
on the alcohol.
F
Scheme 2. Differences between TIPS and TIPS groups – petrocortyne setting.
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Amador Garcia Sancho et al.
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These results prompted us to conduct a short study
Table 2 summarizes the results of several of the
to more carefully compare the standard TIPS and the more informative competitive experiments. Competi-
F
first generation TIPS groups. We also included a new tions under acidic conditions are summarized in en-
F
second-generation FTIPS* group with a propylene tries 1–4. The TIPS group and both TIPS groups are
spacer, RfACHTUNGTRENNUNG(CH2)3SiACHTUNGTERN(NUNG i-Pr)2, to help sort out spacer ef- stable for at least 3 h under typical PPTS conditions
F
fects from steric effects. The TIPS* group should be used to cleave TES groups. The TES group is com-
more similar to an n-alkyldiisopropylsilane than the pletely cleaved under these conditions after 3 h (not
F
first generation TIPS group with the ethylene spacer. shown) and is 91% cleaved after 1 h. Likewise, expo-
The synthesis of the corresponding silane precursor, sure of the TES, FTIPS and FTIPS* silyl ethers to
C8F
forward and is detailed below (see Experimental Sec- group but returned the two TIPS ethers. The TIPS
tion). ether is also stable to these conditions (not shown).
17ACHTUNGTRENNUNG(CH2)3SiACHTUNGTRENNUNG(i-Pr)2H, of the silyl triflate was straight- acetic acid in THF/water for 30 min cleaved the TES
F
F
In a first stage, Table 1, we compared the perfor- Treatment of the three component TIPS, TIPS and
mance of the three silyl triflates under standard silyla- FTIPS* mixture with hexafluorosilicic acid (SiF6H2)
tion conditions. The goal here was to learn whether left the TIPS ether unscathed while cleaving most of
F
F
they gave comparable yields under comparable condi- the TIPS* ether (81%) and some of the TIPS ether
tions and whether the derived products were stable to (21%). Differences in reactivity between the two
standard work-up and chromatography. In a standard FTIPS ethers were also observed on treatment with
procedure (see below), the three silyl triflates (TIPS- FeCl3 in ethanol. After 1 h at room temperature, the
F
F
F
F
ACHTUNGTRENNUNG
CH2Cl2 at 08C. 2,6-Lutidine was added, the solutions
were divided into three, and one of the three alcohols
Competitive experiments with commercial tetra-
ACHTUNGTRENUNbNG utylammonium fluoride (TBAF) in THF are sum-
(benzyl alcohol, neopentyl alcohol, cyclopentanol) marized in entries 5–7. Treatment of the TIPS silyl
F
was added to each one. After 15 min at 08C, the mix- ether and the two TIPS ethers with 2 equiv. of TBAF
tures were warmed to ambient temperature and returned the TIPS ether unreactive while cleaving all
stirred for 2 h prior to standard aqueous workup.
of the FTIPS ether and 55% of FTIPS*. In a more
Each of the nine crude products was purified by carefully monitored reaction, treatment of the two
flash chromatography, and their isolated yields are FTIPS ethers with a limited amount (0.7 equiv.) of
summarized in Table 1. The yields were comparable TBAF at 08C for 30 min gave complete conversion of
F
(74–88%) and there was no evidence of product insta- FTIPS with only 3% conversion of TIPS*. Finally, in
bility during workup or chromatography. These are not a similar experiment but with the TES ether and
competitive experiments and provide no information 1 equiv. of TBAF, the TES ether was stable, the
F
of the relative reactivity of the three triflates; however, FTIPS ether was fully cleaved, and the TIPS* ether
we do learn that all three triflates can be installed was 27% cleaved.
under the same conditions in comparable yields.
These results provide helpful information about the
F
Next, we conducted a series of simple competitive relative reactivity of the two TIPS groups compared
experiments to assess the relative ease of cleavage of to each other and to standard silyl groups. Both the
the two FTIPS groups compared to either standard FTIPS groups are considerably more labile than TIPS
TIPS or triethylsilyl (TES). We first prepared the four to TBAF. FTIPS is more labile than FTIPS* and is even
silyl ethers shown in Table 2 by the same procedure more labile that TES. It should certainly be possible to
as above and with comparable isolated yields. In the cleave FTIPS in the presence of TIPS (as seen in
competitive experiments, an equimolar mixture of Scheme 1), and it may even be generally possible to
F
F
two or three of the silyl ethers was treated with a cleave TIPS in the presence of TIPS*. As implied by
standard desilylating reagent. The progress of each re- the observations of migration or cleavage during the
F
action was followed by GC as a percentage decrease two syntheses (Scheme 1, Scheme 2), TIPS has to be
of the starting amount of silyl ethers, and these values used with some care under nucleophilic conditions
are listed in Table 2 as percent conversion (% conv.) since its reduced steric hindrance (relative to TIPS)
relative to an internal standard (decane). The corre- and increased electron deficiency on Si (relative to
sponding alcohols were the only products of both both TIPS and TES) leave it susceptible to nucleophil-
competitive and control experiments, so the differ- ic attack. That said, we have used this group in many
ence between the product yield should be [100%À
(<10%), the percent conversion was instead estimat- stable of the four groups, as expected. Both FTIPS
(% typical synthetic transformations without problems.[11]
ACHTUNGTRENNUNG
conv.)] for each entry. In the case of low conversions
Under acidic conditions, TIPS is again the most
F
ed from the GC yield of the product. A conversion of and TIPS* are considerably more stable than TES,
0% means that the alcohol product was not detected presumably for steric reasons. However, the inductive
F
by GC.
effect of the perfluoroalkyl group of TIPS with the
1038
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Adv. Synth. Catal. 2009, 351, 1035 – 1040

Comparison of the Relative Reactivities of the Triisopropylsilyl Group
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References
ethylene spacer now provides stability over the
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Experimental Section
Preparation of Diisopropyl(4,4,5,5,6,6,7,7,8,8,9,9,10,10,
11,11,11-heptadecafluoroundecyl)silane
A solution of t-BuLi in pentane (1.7M, 100 mL, 170 mmol)
was added slowly to a solution of perfluorooctylpropyl
iodide (40 g, 68 mmol) in dry Et2O (510 mL) at À788C. The
internal temperature was maintained below À508C through-
out. After the addition was completed, the reaction mixture
was stirred 30 min at À608C, then warmed to À208C until
the solution became clear. Finally, the mixture was cooled to
À788C and chlorodiisopropylsilane (12.8 mL, 75 mmol) was
added. The reaction mixture was warmed to room tempera-
ture and stirred for additional 5 h, then quenched slowly
and carefully with water. The aqueous layer was extracted 3
times with Et2O. The combined organic layers were dried
over MgSO4, filtered and concentrated under vacuum. The
crude product was purified by distillation to afford diisopro-
pyl(perfluoroctylpropyl)silane as a colorless oil; yield: 29.4 g
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(75%), bp 95–1008C/0.1 mbar; H NMR (300 MHz, CDCl3):
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2.02–2.20 (m, 2H), 3.46 (br, 1H); 19F NMR (282.4 MHz,
CDCl3): d=81.58 (t, J=9.9, 2F), 114.97–115.08 (m, 2F),
122.46 (br, 6F), 123.38 (br, 2F), 124.27 (br, 2F), 126.81 (br,
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General Procedure for Silylation
To 1 mmol of the corresponding fluorous silane at 08C was
added 1.2 mmol of triflic acid. The mixture was stirred 1 h at
08C and then warmed to room temperature and stirred 15 h.
The resulting triflates were used directly in the protection
reaction.
To
a 0.1M solution of the corresponding alcohol
(1.1 equiv.) in dichloromethane (DCM) at 08C were added
2 equiv. of 2,6-lutidine and 1.0 equiv. of the corresponding
triflate (0.5M solution in DCM). The reaction mixture was
stirred at 08C for 15 min and then warmed to room temper-
ature. After 2 h, the reaction was quenched with NaHCO3
(aqueous solution). The aqueous layer was extracted several
times with Et2O, and the organic layers were combined,
dried over MgSO4, filtered and concentrated under vacuum.
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Acknowledgements
We thank the National Institute of General Medical Sciences
of the National Institutes of Health for funding this work.
A.G.S. thanks the CIPF for a predoctoral fellowship.
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pounds are commercially available from Fluorous Tech-
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Amador Garcia Sancho et al.
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