Phase-Transfer Catalyzed O-Silyl Ether Deprotection Mediated by a Cyclopropenium Cation

Article abstract of DOI:10.1021/acs.joc.6b02733

The use of a cyclopropenium cation as a phase-transfer catalyst for O-silyl ether deprotection is reported. Mechanistic insight into this deprotection methodology derived by linear free-energy relationships (LFER), quantum theory of atoms in molecules (QTAIM), and density functional theory (DFT) calculations are also provided.

Full text of DOI:10.1021/acs.joc.6b02733

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Article
Phase-Transfer Catalyzed O-Silyl Ether
Deprotection Mediated by a Cyclopropenium Cation
Roya Mir, and Travis Dudding
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02733 • Publication Date (Web): 09 Dec 2016
Downloaded from http://pubs.acs.org on December 12, 2016
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The Journal of Organic Chemistry
PhaseꢀTransfer Catalyzed OꢀSilyl Ether Deprotection Mediated by a Cyclopropenium Cation
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Roya Mir and Travis Dudding,*
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Department of Chemistry, Brock University, 1812 Sir Isaac Brock Way, St. Catharines, Ontario, Canada, L2S
3A1.
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ABSTRACT: The use of a cyclopropenium cation as a phaseꢀtransfer catalyst for
Oꢀsilyl ether deprotection is
reported. Mechanistic insight into this deprotection methodology derived by linear freeꢀenergy relationships
(LFER), quantum theory of atoms in molecules (QTAIM), and density functional theory (DFT) calculations is
also provided.
KEYWORDS: Hꢀbonding, phaseꢀtransfer catalyst, deprotection, cyclopropenium cation, Hammett plot
Introduction
Protecting groups have a rich chemical history dating back to the lateꢀeighteenth century as attested for by
their use in Nobel laureate Emil Fischer’s syntheses of glucose, fructose, and mannose.1 Since this formative beꢀ
ginning, protecting groups have become an essential part of the synthetic chemist’s toolbox, and today find use
in nearly every branch of chemical synthesis. Owing to this fact, an array of protecting groups exist today with Oꢀ
silyl ethers being one of the most utilized, due to stability under various conditions, ease of installation and reꢀ
moval, functional group compatibility, and the commercial availability of countless silane precursors.
The use of Oꢀsilyl ether protecting groups, however, is not without drawbacks. This is particular evident with
respect to deprotection and product purification.2 For instance, the use of TBAF (tertꢀbutylammonium fluoꢀ
ride), a widely employed source of soꢀcalled ‘naked Fꢀ’3 for mediating silyl deprotection, is associated with severꢀ
al shortcomings, such as it (1) undergoes Hoffman E2ꢀelimation at temperatures between 40ꢀ77 °C (2 torr),4 (2)
has a poor fluoride to total reagent mass ratio (Fꢀ = 7.3 % of total mass of NBu4F), (3) is hydroscopic, and (4)
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stoichiometric or greater amounts are usually employed in practice. Making matters worse, the isolation of waꢀ
terꢀsoluble products, such as sugars from TBAF and its byꢀproducts is often challenging as standard workꢀup
protocols call for an aqueous acid/base wash. To address these shortcomings various desilylation procedures
have been introduced,5 yet owing to inherit limitations there remains a need for innovation. Relevant in this reꢀ
spect would be the advancement of more robust and operationally simple approaches that were catalytic.
Intrigued by this prospect we envisioned using a cyclopropenium cation as a phaseꢀtransfer catalyst (PTC) for
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O
ꢀsilyl ether deprotection. Notably, the advancement of this technology would build upon a rich history and
revitalized interest in bis(dialkylamino)cyclopropenium, while having the advantages of PTC protocols. That is,
being simple to perform, amenable to both large and smallꢀscale synthetic protocols, and utilizes mild reaction
conditions, as well as, the frequent use of inexpensive reagents and solvents.6
As such, in building upon our recent development and use of a Nꢀcentered cyclopropenium (1) and proton
sponge analogue DACNꢀ2H+ (2ꢀ2H+) as phaseꢀtransfer catalyst for fluorination and/or benzylation7 we were
intrigued by the prospect of using an alkali halide, such as KF and a catalytic amount of cyclopropenium 3•X‒ (X‒
‒
= BF4 , Cl‒, etc.) as a reaction platform for mediating
O
ꢀsilyl ether deprotection under biphasic (solid/solution)
conditions (Figure 1). To this end, the ability of 3•X‒ to function as a phaseꢀtransfer catalyst was projected to
arise from a discrete set of functionalities, which could be subdivided into (1) liphophilic alkyl groups, (2) a πꢀ
polarizable aromatic cyclopropenium cation with
Figure 1. Envisioned use of a cyclopropenium (3•X‒) as a phaseꢀtransfer catalysts for
Oꢀsilyl ether deprotection.
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organophilic character, and (3) a cyclopropenium C(sp2)–H moiety capable of shuttling Fꢀ into solution via
C(sp2)+–H•••F‒ Hꢀbonding. Accordingly, reported here is the use of cyclopropenium 3•Cl‒ as a PTC for
ꢀsilyl
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O
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ether deprotection.8 Catalytic conditions, operational simplicity, and ease of removal of the fluoride source by
simple filtration, typify evident strengthens of this novel methodology.
Results and Discussion
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‒
Initial efforts in this study focused on the reaction of substrate 4a (1 eq), catalyst 3•BF4 (10 – 20 mol%),
and solid KF (1.5 eq) as an easy to handle, inexpensive, latent source of nucleophilic fluoride in dichloroꢀ
methane (DCM). To our disappointment, only unreacted starting material was obtained under these conditions
(Table 1, entries 1 and 2). Reasoning this lack of reactivity stemmed, in part, from the poor solubility of KF
and/or a putative in situ derived species 3•F‒ in DCM, the desilylation of 4a was performed in CH3CN. To our
delight, the formation of alcohol 5a was observed in CH3CN, albeit in low isolated yield (Table 1, entry 3). The
‒
loading of 3•BF4 was then increased, manifesting in circa a twofold improvement in the yield of 5a (Table 1,
‒
entry 4), while a control reaction performed in the absence of 3•BF4 resulted in a negligible yield of 5a (Table 1,
entry 5).
Table 1. Desilylation of substrate 4a under various reaction conditions.
Entry
Solvent
Catalyst
(mol%)
KF
Time
Yielda
(%)
ꢀꢀꢀ
(mol%) (h)
‒
1
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4
4a DCM
4a DCM
3•BF4 ( 10)
1.5
1.5
1.5
1.5
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‒
3•BF4 (20)
ꢀꢀꢀ
‒
4a CH3CN
4a CH3CN
3•BF4 (10)
20
‒
3•BF4 (20)
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5
4a CH3CN
ꢀꢀꢀ
1.5
19
4.8
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a) Isolated yields.
4
‒
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6
While the ability of 3•BF4 to act as a phaseꢀtransfer catalyst for desilylation was encouraging, improvement
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was needed in terms of yield. Suspecting that the conversion of 3•BF4 to a reactive entity 3•F‒ capable of mediꢀ
‒
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ating desilylation was the root of the problem, density functional theory (DFT) calculations at the wB97XD/6ꢀ
311+G(d,p):(TZVP fitting set):(IEFPCM) implicit solvation model (CH3CN, ε = 37.5) were performed to
‒
gain insight into this assumption. More specifically, the relative energies of ion pairs 3•X‒ (X‒ = Br‒, Cl‒, BF4 ,
CF3SO3 , ClO4 ) vs 3•F‒ were computed using the lowest energy structures generated by optimization of several
starting geometries, wherein, the counterion was placed in one of four quadrants (i.e., top, front, back, and side
quadrants) at a 4 Å distance from the ring of bis(diisopropylamino)cyclopenium (BACI) 3, Figure 2a.9 As seen
from Figure 2b, there was an energetic preference for the counterions Cl‒, and F‒ to reside in front of the cation,
‒
‒
‒
‒
‒
while BF4 , Br‒ and CF3SO3 were on top and ClO4 was in back. Materializing further was the finding that the
‒
conversion of 3•BF4 to 3•F‒ was the least favored counterion exchange process, in terms of ꢀE, whereas the
conversion of 3•Cl‒ to 3•F‒ was the most favorable (eq. 1 and Figure 2b).
Armed with this insight, catalyst 3•Cl‒ (20 mol%), 4a (1 eq), and KF (1.5 eq) were reacted in CH3CN at
ambient temperature to afford the corresponding alcohol in 89% yield (Table 2, entry 1). Having identified
3•Cl‒ as an optimum catalyst for desilylation the substrate scope of this methodology was probed. Commencing
with the deprotection of trimethyl silyl (TMS) protected 4b and 4c, the rapid formation of 1°ꢀ and 2°ꢀbenzyl
alcohols 5b and 5c was observed (Table 2, entry 2ꢀ3). In comparison, TMSꢀOꢀprotected 4d was slow to react,
forming 3°ꢀbenzyl alcohol 5d in 89% after 17 h (Table 2, entry 4). The lack of reactivity in this case, most likely,
arising from the bulky PhC(Me)2Oꢀmoiety, which in being isostructural with a neoꢀpentyl group, adversely afꢀ
fected reactivity at the Siꢀatom of 4d.
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Figure 2. (a) Schematic of counterion X‒ relative to 3. (b) Calculated ꢀE values of eq. 1 and favored positioning
of counterion X‒ with respect to 3.
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On the other hand, substrate 4e underwent rapid desilylation in only 0.5 h to afford 5e in 95% (Table 2, entry
5). The desilylation of TMSꢀOꢀprotected natural products camphor 4f and quinine 4g were then investigated,
resulting in 5f and 5g in high yields of 92% and 94% (Table 2, entries 6 and 7). Next, to explore the influence of
silylꢀgroup size on the rate of desilylation, acid and base sensitive TES protected furanyl 4h was examined, reꢀ
sulting in the 5h in 91% (Table 2, entry 8). In contrast, TES protected benzoin 4i underwent desilylation in a
shorter timespan (Table 2, entry 9). The desilylation of aryl protected 4j and 4k having a bulky tert
ꢀ
butyldimethylsilyl (TBS) group were then carried out to afford 5j and 5k in 1 h and 0.5 h in high yields, whereas
TBS protected benzyl alcohol 4l required an extended reaction time to obtain 5l in 90% yield (Table 2, entries
10, 11 and 12). Notably, as attested for by substrates 5j and 5l, both aldehyde and iodo functionalities were
compatible with the reaction conditions. Finally, switching to the use of a large steric hindering tert
ꢀ
butyldiphenylsilyl (TBDPS) protecting group the desilyation of phenol protected 4m, 4n, and 4o was studied.
The desylilation of protected phenol 4m having a resonance donating and inductively electron withdrawing orꢀ
thoꢀbromo substituted occurred in 15 h with 94% yield (Table 2, entry 13). Meanwhile, orthoꢀ and metaꢀmethyl
substituted protected phenols 4n provided a lower product yield of 60%, whilst, 4o reacted more rapidly to afꢀ
ford 5o in 85% yield (Table 2, entry 14 and 15).
As for the mechanism of these reactions, the trends in Table 2 suggest that both the silyl group (region 1
)
and substructure R1 (region 2) have an impact on the rate of desilylation (Figure 3a). While the rate dependenꢀ
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cy arising from the silyl group (region 1) can be accounted for by known relative hydrolysis rates of
Oꢀsilyl
1
2
3
ethers in basic media (e.g., krel = TMS (1) < TES (10ꢀ100) < TBS ̴
TBDPS (20,000) < TIPS (100,000))10 the
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effect of the substrate (R1) substructure (region 2), especially in terms of electronics, is less obvious. As such, to
better understand the impact of substrate based (R1) electronics on the rate of desilylation the linear freeꢀenergy
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relationship (LFER) derived from activated, unactivated and deactivated paraꢀsubstituted tert
ꢀ
butyldimethylsilyl protected phenols 4pꢀw was explored, providing the Hammett plot depicted in Figure 4. To
this end, the positive ρ (rho) value (ρ = 0.22) of this Hammett plot is consistent with a modest degree of (δ–)ꢀ
charge buildꢀup in the rate determining transition state of these
Table 2. Deprotection of substrates 4bꢀo using catalysta 3•Cl‒.
Entry
Substrate
4a
Time
(h)
19
Yield
(%)b
89
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2
0.1
0.3
96
95
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17
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95
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0.5
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0.5
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85
a All reactions were carried out with 0.2 mmol of the substrate, catalyst 3•Cl‒ (20 mol%), and KF (1.5 eq) in aceꢀ
tonitrile at room temperature. b Isolated yields.
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desilylation reactions, thus suggesting the possible formation of a shortꢀlived fiveꢀcoordinate siliconate conformꢀ
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ꢀ
ing to a transition complex (TC) or a reaction mechanism involving a Sn2–type transition state (TS) with (δ )ꢀ
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charge accumulation at silicon (Figure 3b). Notably, the former scenario involving a TC would in all likelihood
evolve on a singleꢀ or tripleꢀwell potential energy surface (PES), while the latter would occur on a doubleꢀwell
PES.11
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Figure 3. (a) Generalized example of a silyl ether compound. (b) Transition complex (TC) and Sn2–type transiꢀ
tion state (TS).
Irrespective of whether a shortꢀlived TC or Sn2ꢀtype transition state (TS) is involved in these reactions, the
question remains what catalytic F‒ entity prompts their formation. While numerous offꢀcycle equilibria leading
to inactive catalyst resting states, in principle, might exist under the reaction conditions for desilylation reported
vide supra, it is suggested that a solutionꢀphase species conforming to 3•F‒ triggers the formation of the aforesaid
TC or Sn2ꢀTS structures.12 Considering F‒ is the smallest anion(ionic radius = 1.33 Å)13 and a powerful Brønsted
base with a strong propensity to form extremely strong Hꢀbonds (HꢀF BDE =136 kcal/mol) the catalytic role,
for instance, of 3•F‒ in these desilylations is reasonable, given the formation of 3•F‒ would be driven by the creaꢀ
tion of a favorable C(sp2)+–H•••F‒ Hꢀbond. Notably, this C(sp2)+–H•••F‒ interaction, which in the lexicon of Gilli14
typifies a heteronuclear negative/positive charge assisted Hꢀbond [(ꢀ/+)CAHB], would benefit from both ionic
and “partial covalent” character with the later arising from a margin degree of charge transfer Hꢀbonding. To
gain insight into this C(sp2)+–H•••F‒ interaction, natural bond order (NBO) analysis, quantum theory of atoms
in molecules (QTAIM), NBO charge populations were calculated. To this end, the closedꢀshell (ionic) characꢀ
ter of the C(sp2)+–H•••F‒ Hꢀbond of 1•F‒ was supported by a (+3, ꢀ1) bond critical point (BCP) residing near the
atomic basin of fluoride with density ρ = 0.080 au and Laplacian value ∇2⍴bcp = 0.055 au.15 In addition, the
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computed NBO charges of the hydrogen (0.337 e) and fluoride (ꢀ0.804 e) were consistent with an ionic interacꢀ
tion. The shared nature of this Hꢀbond, on the other hand, was uncovered by NBO analysis, which revealed a
substantial donorꢀacceptor ηF‒→σ∗(HꢀC) component amounting to 78.07 kcal/mol.
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0.2
CN
0.2
0.1
NO2
Cl
OCH3
OH
Br
0.1
H
0.0
-0.1
-0.1
-0.2
-0.2
-0.3
-0.3
y = 0.2424x - 0.0214
R² = 0.9817
N(CH3)2
-1
-0.5
0
Substituent constant, σ
0.5
1
Figure 4. Hammett plot derived from the desilylation of 4ꢀsubstituted tertꢀbutyldimethylsilyl phenols at rt. over
6 h.
On the basis of the above results a plausible catalytic cycle supported by DFT calculations is offered in Figure
5. Counterꢀion exchange between 3•Cl‒ and KF to generate the active catalyst 3•F‒ initiates the cycle, where after
precomplex 6 forms in the presence of substrate 4b. At that stage, low barrier (ꢀG≠ = ꢀ2.63 kcal molꢀ1) fluoride
addition transition state TS1 arises. Salient features of this transition state include a Si•••F‒ bond forming disꢀ
tance of 2.65 Å and a F‒ stabilizing Hꢀbond network originating from a C(sp2)+–H•••F‒ interaction (distance =
1.45 Å) and two C–H•••F‒ contacts involving H1 and H2 that measured 2.41 Å and 2.52 Å. An intrinsic reaction
coordinate (IRC) calculation revealed that pentavalent silicate transition complex TC was the direct product of
δ
TS1. Finally, Si•••O bond cleavage (distance = 3.30 Å) accompanied by C(sp2)+–H•••‒ OPh Hꢀbond stabilizaꢀ
tion of the developing phenoxy occurs via rate determining transition state TS2 (ꢀG≠ = 11.07 kcal/mol) resultꢀ
ing in the exergonic formation of 7, TMS–F and catalyst turnover.
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Figure 5. Proposed 3•Cl‒ catalyzed cycle for
Oꢀsilyl ether deprotection.
To recap, the use of a cyclopropenium as a phaseꢀtransfer catalyst for
O
ꢀsilyl ether deprotection was reported.
The origin of this reactivity was investigated by LFER analysis, and DFT calculations, which revealed the reꢀ
markable finding that cyclopropeniums offer promise as a catalytic platform for shuttling fluoride into solution
via C(sp2)+–H•••F‒ Hꢀbonding. No doubt, the potential of this Hꢀbonding motif as a means for attenuating fluoꢀ
ride basicity and nucleophilicity will be applicable to other modes of catalysis.
Experimental Section
1. General information.
Materials were obtained from commercial suppliers and were used without further purification. All reactions
were performed under an inert atmosphere. Reactions were monitored by thin layer chromatography (TLC)
using TLC silica gel 60 F254. Flash column chromatography was performed over Silicycle ultrapure silica gel
(230ꢀ400 mesh). NMR spectra were obtained with a 300 MHz or 400 MHz spectrometer (1H 300 MHz, 1H 400
MHz, 13C 75.5 MHz, and 13C 150.9 MHz) in CDCl3 or CD3CN. The chemical shifts are reported as δ values
(ppm) relative to tetramethylsilane. Mass analyzer magneticꢀelectrostatic sector used for the HRMS measurꢀ
ments.
2. General procedure for silyl protection of alcohols 5aꢀw
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General procedure16 for preparation of trimethylsilyl ether (4bꢀg). To a solution of benzyl alcohol (1.0 g, 9.2
mmol) in THF (5 mL) was added triethylamine (2.6 mL, 18.4 mmol) and trimethylsilyl chloride (1.4 mL, 11.04
mmol). The suspension was stirred for 5 h at room temperature. Subsequently, water (5 mL) was added, and
the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) three times. Comꢀ
bined organic layers were dried over anhydrous MgSO4 and concentrated under high vacuum. The crude prodꢀ
uct was purified by column chromatography on silica gel (hexanes:ethyl acetate, 10:1) to yield 4b (1.5 g, 92%
yield).
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General procedure17 for preparation of triethylsilyl ether (4hꢀi). To a stirred solution of benzoin (212.2 mg, 1
mmol) and imidazole (204.2 mg, 3 mmol) in DMF (2 mL) at 5 °C was added dropwise triethylsilyl chloride
(0.33 mL, 2 mmol). The reaction mixture was allowed to warm to room temperature over 1 h and then stirred
for 10 h. Subsequently, water (2 mL) was added and the resulting mixture extracted with diethyl ether (5 mL)
three times. Combined organic layers were dried over anhydrous MgSO4 and concentrated under high vacuum.
The crude product was purified by column chromatography on silica gel (hexanes:ethyl acetate, 10:1) to yield 4i
(293.8 mg, 90% yield).
General procedure18 for preparation of tertꢀbutyldiphenylsilyl ether (4a, 4mꢀw). tertꢀButyldiphenylsilyl chloride
(1.4 mL, 5.5 mmol) was added dropwise to a stirred solution of benzyl alcohol (540.7 mg, 5 mmol) and imidazꢀ
ole (749.1 mg, 11 mmol) in DMF (2 mL) at room temperature. The reaction mixture was stirred for 10 h. Subꢀ
sequently, water (2 mL) was added and the resulting mixture extracted with diethyl ether (5 mL) three times.
Combined organic layers were dried over anhydrous MgSO4 and concentrated under high vacuum. The crude
product was purified by column chromatography on silica gel (hexanes:ethyl acetate, 10:1) to yield 4a (1.6 g,
94% yield).
General procedure19 for preparation of ether (4jꢀl). To a stirred solution of 2ꢀiodobenzyl alcohol (585.1 mg, 2.5
mmol) and imidazole (374 mg, 5.5 mmol) in DMF (2 mL) at room temperature was added dropwise tert
ꢀ
butyldimethylsilyl chloride (414.5 mL, 2.7 mmol). The reaction mixture was stirred for 10 h. Subsequently, waꢀ
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ter (2 mL) was added and the resulting mixture extracted with diethyl ether (5 mL) three times. Combined orꢀ
ganic layers were dried over anhydrous MgSO4 and concentrated under high vacuum. The crude product was
purified by column chromatography on silica gel (hexanes:ethyl acetate, 10:1) to yield 4l (801.1 mg, 92% yield).
Benzyloxyꢀtertꢀbutyldiphenylsilane (4a): Registry number 139706ꢀ45ꢀ9. 1H NMR (400 MHz, CDCl3): δ 7.92ꢀ
7.98 (m, 4H), 7.44ꢀ7.61 (m,1H), 5.04 (s, 2H), 1.37 (s, 9H).
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(Benzyloxy)trimethylsilane (4b): Registry number 14642ꢀ79ꢀ6.
Trimethyl(1ꢀphenylethoxy)silane (4c)20: (1.6 g, 92% yield), 1H NMR (300 MHz, CDCl3): δ 7.36ꢀ7.44 (m,
5H), 4.94 (q, J = 6.4 Hz, 1H), 1.52 (d, J = 6.4Hz, 3H), 0.16 (s, 9H).
Trimethyl((2ꢀphenylpropanꢀ2ꢀyl)oxy)silane (4d) 20: (1.8 g, 92% yield), 1H NMR (300 MHz, CDCl3): δ 7.48ꢀ
7.52 (m, 2H), 7.34ꢀ7.39 (m, 2H), 7.23ꢀ7.29 (m, 1H), 1.64 (s, 6H), 0.16 (s, 9H).
(2,3ꢀDimethylphenoxy)triethylsilane (4e): (1.7 g, 94% yield), Colorless oil. 1H NMR (300 MHz, CDCl3): δ
7.11 (s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.84 (d, J
= 8.1 Hz, 1H), 2.41 (s, 3H), 2.33 (s, 3H), 0.43 (s, 9H). 13C
NMR (400 MHz, CDCl3): δ 151.4, 132.0, 130.5, 128.6, 127.1, 118.9, 20.6, 16.6, 0.5. HRMS (EI): m/z calcd for
C11H18OSi (M+): 194.1127; found: 194.1120.
(((1R,2S,5R)ꢀ2ꢀisopropylꢀ5ꢀmethylcyclohexyl)oxy)trimethylsilane (4f)21: (1.9 g, 90% yield), 1H NMR (300
MHz, CDCl3): δ 3.41 (td,
J
= 10.3, 4.4 Hz, 1 H), 2.16 (dsept,
J
= 7.0, 2.4 Hz, 1H), 1.84–1.90 (m, 1 H), 1.58–
= 7.0 Hz, 6 H), 0.75 (m, 3H), 0.82ꢀ0.87 (m,
1.68 (m, 2 H), 1.31–1.47 (m, 1 H), 1.00ꢀ1.20 (m, 3 H), 0.96 (d,
1H), 0.14 (s, 9).
J
(2S)ꢀ2ꢀ((R)ꢀ(6ꢀMethoxyquinolinꢀ4ꢀyl)((trimethylsilyl)oxy)methyl)ꢀ5ꢀvinylquinuclidine (4g)22: (3.3 g, 91%
yield), 1H NMR (300 MHz, CDCl3): δ 8.76 (d, J = 4.32 Hz, 1H), 8.04 (d, J = 9.24 Hz, 1H), 7.45ꢀ7.55 (m, 1H),
7.39 (dd, J = 8.34, 2.61 Hz, 2H), 5.62ꢀ6.80 (br, 1H), 4.87ꢀ5.00 (m, 2H), 3.96ꢀ4.06 (m, 3H), 3.36ꢀ3.69 (m, 1H),
2.92ꢀ3.30 (m, 2H), 2.49ꢀ2.86 (m, 1H), 2.17ꢀ2.49 (m, 1H), 1.74ꢀ1.83 (m, 4H), 1.47ꢀ1.62 (br, 1H), 1.26ꢀ1.29 (br,
1H), 0.84ꢀ0.97 (br, 1H), 0.085 (s, 9H).
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Triethyl(1ꢀ(furanꢀ2ꢀyl)ethoxy)silane (4h)23: (208.3 mg, 92% yield), 1H NMR (300 MHz, CDCl3): δ 7.33ꢀ7.32
(m, 1H), 6.27ꢀ 6.329 (m, 1H), 6.15 (d, = 3.24 Hz, 1H), 4.85 (q, = 19.5, 6.5 Hz, 1H), 1.47 (d, = 6.50 Hz,
3H), 0.92 (t, = 8.01 Hz , 9H), 0.46ꢀ0.62 (m, 6H).
1,2ꢀDiphenylꢀ2ꢀtriethylsilyloxyethanone (4i)24: 1H NMR (300 MHz, CDCl3): δ 8.02ꢀ8.05 (m, 2H), 7.53ꢀ7.56
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(m, 2H), 7.45ꢀ7.49 (m, 1H), 7.33ꢀ7.39 (m, 4H), 7.27ꢀ7.29 (m, 1H), 5.80 (s, 1H), 0.91 (t,
0.67 (m, 6H).
J = 8.0 Hz, 9H), 0.62ꢀ
4ꢀ(tertꢀButyldimethylsilyloxy)ꢀ3ꢀmethoxybenzaldehyde (4j)25: (619.4 g, 93% yield), 1H NMR (300 MHz,
CDCl3): δ 9.84 (s, 1H), 7.34ꢀ7.40 (m, 2H), 6.65 (d, = 7.95 Hz, 1H), 3.86 (s, 3H), 1.00 (s, 9H), 0.19 (s, 6H).
J
tertꢀButyldimethyl(naphthalenꢀ2ꢀyloxy)silane (4K)26: (587.9 g, 91% yield), 1H NMR (300 MHz, CDCl3): δ
7.88ꢀ7.95 (m, 3H), 7.57ꢀ7.62 (m, 1H), 7.48ꢀ7.53 (m, 1H), 7.40ꢀ7.46 (m, 1H), 7.27ꢀ7.31 (m, 1H), 1.24ꢀ1.27 (m,
9H), 0.46ꢀ0.48 (m, 6H).
tertꢀButyl(2ꢀiodobenzyl)oxy)dimethylsilane (4l)27: 1H NMR (300 MHz, CDCl3): δ 7.79 (dd,
1H), 7.54 (d, = 7.59 Hz, 1H), 7.39 (dt, = 7.62, 0.66 Hz, 1H), 7.00 (dt, = 7.92, 1.02 Hz, 1H), 4.65 (s, 2H),
0.99 (s, 9H), 0.16 (s, 6H).
J = 7.8, 0.99 Hz,
J
J
J
(2ꢀBromophenoxy)(tertꢀbutyl)diphenylsilane (4m)28: (2.1 g, 92% yield), 1H NMR (300 MHz, CDCl3): δ 7.73ꢀ
7.76 (m, 4H), 7.52ꢀ7.55 (m, 1H), 7.41 ꢀ 7.47 (m, 6H), 6.82 ꢀ 6.87 (m, 1H), 6.70 ꢀ 6.75 (m, 1H), 6.47 (dd,
J=7.92, 1.2 Hz, 1H), 1.15 (s, 9 H).
tertꢀButyl(2,3ꢀdimethylphenoxy)diphenylsilane (4n): (1.8 g, 90% yield), Viscus oil. 1H NMR (300 MHz,
CDCl3): δ 7.72ꢀ7.74 (m, 4 H), 7.34ꢀ7.43 (m, 6 H), 6.95ꢀ7.00 (m, 1 H), 6.56 (d, J = 8.07 Hz, 1 H), 6.31 (d, J =
8.16 Hz, 1 H), 2.37 (s, 3 H), 2.19 (s, 3 H), 1.11 (s, 9 H). 13C NMR (300 MHz, CDCl3): δ 151.5, 135.5, 133.2,
131.5, 129.9, 127.9, 127.8, 126.7, 118.2, 30.9, 26.7, 20.5, 19.7, 17.1. HRMS (EI): m/z calcd for C24H28OSi
(M+): 360.1909; found: 360.1895.
tertꢀButyl(2ꢀmethoxyphenoxy)diphenylsilane (4o)29: (1.8 g, 92% yield), 1H NMR (300 MHz, CDCl3): δ 7.71
(m, 4 H), 7.31ꢀ7.43 (m, 6 H), 6.74 (m, 4 H), 3.56 (s, 3 H), 1.11 (s, 9 H).
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tertꢀButyl(phenoxy)diphenylsilane (4p): (1.7 g, 92% yield), Viscus oil. 1H NMR (300 MHz, CDCl3): δ 7.73ꢀ
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7.61 (m, 4H) 7.36ꢀ7.48 (m, 6H), 7.09ꢀ7.14 (m, 2H), 6.86ꢀ6.93 (m, 1H), 6.78 (d, J = 7.71 Hz, 2H), 1.13 (s, 9
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H). 13C NMR (300 MHz, CDCl3): δ 155.7, 151.5, 153.6, 133.1, 131.6, 129.9, 129.3, 127.8, 126.8, 121.1, 119.8,
118.2, 26.6, 19.5. HRMS (EI): m/z calcd for C22H24OSi (M+): 332.1596; found: 332.1602.
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4ꢀtertꢀButyldiphenylsilyloxyꢀN,N
ꢀdimethylaniline (4q): (1.9 g, 90% yield), light yellow oil. 1H NMR (300 MHz,
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CDCl3): δ 7.74ꢀ7.77 (m, 4H) 7.35ꢀ7.47 (m, 6H), 6.70ꢀ6.73 (m, 2H), 6.54ꢀ6.60 (m, 2H), 2.83 (s, 6H), 1.12 (s,
9 H). 13C NMR (300 MHz, CDCl3): δ 147.6, 145.6, 135.6, 135.5, 134.9, 133.5, 129.8, 129.8, 129.6, 127.7, 119.9,
114.6, 41.7, 26.7, 19.5. HRMS (EI): m/z calcd for C24H29NOSi (M+): 375.2018; found: 375.2018.
4ꢀtertꢀButyldiphenylsilyloxyphenol (4r)30: (1.7 g, 91% yield), 1H NMR (300 MHz, CDCl3): δ 7.74ꢀ7.77 (m, 4
H), 7.37ꢀ7.49 (m, 6 H), 6.65ꢀ6.70 (m, 2 H), 6.55ꢀ6.61 (m, 2 H), 4.55 (br, 1 H), 1.14 (s, 9 H).
tertꢀButylꢀ4ꢀmethoxyphenoxydiphenylsilane (4s)30: (1.8 g, 90% yield), 1H NMR (300 MHz, CDCl3): δ 7.73ꢀ
7.76 (m, 4 H) 7.36ꢀ7.48 (m, 6 H), 6.64ꢀ6.74 (m, 4 H), 3.72 (s, 3 H), 1.13 (s, 9 H).
tertꢀButylꢀ4ꢀchlorophenoxyꢀdiphenylsilane (4t)31: (1.8 g, 93% yield), 1H NMR (300 MHz, CDCl3): δ 7.70ꢀ7.73
(m, 4H), 7.37ꢀ7.46 (m, 6H), 7.04ꢀ7.07 (m, 2H), 6.69ꢀ6.71 (m, 2H), 1.12 (s, 9H).
4ꢀBromophenoxyꢀtertꢀbutylꢀdiphenylsilane (4u)32: (2.1 g, 92% yield), 1H NMR (300 MHz, CDCl3): δ 7.71 (dd,
J
= 7.86, 1.47 Hz, 4H), 7.37ꢀ7.46 (m, 6H), 7.20 (m, 2H), 6.64ꢀ6.67 (m, 2H), 1.11 (s, 9H).
4ꢀtertꢀButylꢀdiphenylsilyloxybenzonitrile (4v)33: (1.8 g, 91% yield), 1H NMR (300 MHz, CDCl3): δ 7.67ꢀ7.69
(m, 4H), 7.43ꢀ7.44 (m, 2H), 7.39ꢀ7.41 (m, 6H), 6.78ꢀ6.81 (m, 2H), 1.11 (s, 9H).
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tertꢀButyl(4ꢀnitrophenoxy)diphenylsilane (4w): (1.9 g, 91% yield), White solid. MP = 106 °C. H NMR (400
MHz, CDCl3): δ 8.00 (dd, J = 9.15, 2.15 Hz, 2 H), 7.74ꢀ7.77 (m, 4 H), 7.42ꢀ7.52 (m, 6 H), 6.86 (d, J = 9.12Hz,
2 H), 1.18 (s, 9 H). 13C NMR (400 MHz, CDCl3): δ 161.4, 141.9, 135.4, 131.5, 130.5, 128.1, 125.7, 120.0, 26.4,
19.4. HRMS (EI): m/z calcd for C22H23NO3Si (M+): 377.1447; found: 377.1427.
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3. Procedure for deprotection of alcohol and phenols 4aꢀw
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An RBF was charged with reported34 cyclopropenium chloride (3•Cl‒) (11 mg, 0.04 mmol), and KF (17.4 mg,
0.3 mmol). Subsequently, a solution of (benzyloxy)(tertꢀbutyl)diphenylsilane 4a (69.3 mg, 0.2 mmol) in aceꢀ
tonitrile (1 mL) was added. The resulting mixture was stirred for 19 h, after which, the solvent was removed and
the residue dissolved in diethyl ether. The resulting suspension was filtered and the filtrate concentrated folꢀ
lowed by flash chromatography purification (hexanes to ethyl acetate = 10:1) to provide product benzyl alcohol
as a colorless oil (19.2 mg, 89% yield).
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4. Hammett correlation
A series of separate reactions were performed in which a solution of a respective 4ꢀRꢀtertꢀ
butyl(benzyloxy)diphenylsilane (R = NO2, CN, Br, Cl, OH, OMe, NMe2) (0.2 mmol) substrate in aceꢀ
tonitrile (1 ml) was added to catalyst 3•Cl‒ (11 mg, 0.04 mmol) and KF (17.4 mg, 0.3 mmol) and stirred
at room temperature. Each reaction was monitored (30 min intervals up to 6 h) by 1H NMR spectroscoꢀ
py using 2ꢀbromomesitylene (19.9 mg, 0.1 mmol) as an internal standard. The Kx was estimated from a
firstꢀorder plot of log [product] vs reaction time rather than log [tertꢀbutyl(benzyloxy)diphenylsilane] vs
reaction time.
ASSOCIATED CONTENT
Supporting Information
Spectroscopic data for all starting compounds, and computational details. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: tdudding@brocku.ca
ACKNOWLEDGMENT
We are grateful to the Natural Sciences and Engineering Research Council of Canada (NSERC) for funding of
this research.
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REFERENCES
1
2
3
4
5
1
2
Fischer, E. Ber. 1895, 28, 1145.
(a) Trost, B. M. Science 1991, 254, 1471. (b) Vaxelaire, C.; Winter, P. Christmann, M. Angew. Chem. Int.
6
7
8
Ed. 2011, 5, 3605.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
4
5
Kim, D.W.; Song, C. E.; Chi, D. Y., J. Am. Chem. Soc. 2012, 124, 10278.
Sharma, R. K.; Fry, J. L. J. Org. Chem. 1983, 48, 2112.
(a) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723ꢀ736. (b) Craig, J. C.; Everhart, E. T. Synth. Commun
.
1990, 20, 2147. (c) Parlow, J. J.; Vazquez, M. L.; Flynn, D. L. Bioorg. Med. Chem. Lett. 1998, 8, 2391.
6
(a) Weber, W. P.; Gokel, G. W. (1977). Phase Transfer Catalsis in Organic Synthesis. Berlin Heidelberg.
(b) Starks, C. M. (1994), Phase Transfer Catalysis, New York: Chapman & Hall.
(a) Mirabdolbaghi, R.; Dudding, T.; Stamatatos, T. Org. Lett. 2014, 16, 2790. (b) Belding, L.; Stoyanov,
P.; Dudding, T. J. Org. Chem. 2016, 81, 553.
7
8
(a) Lavallo, V.; Canac, Y.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. Science 2006, 312, 722. (b) Bidal,
Y. D.; Lesieur, M.; Melaimi, M.; Cordes, D. B.; Slawin, A. M. Z.; Bertrand, G.; Cazin, C. S. J. Chem. Comꢀ
mun. 2015, 51, 4778.
9
Mir, R.; Dudding, T. J. Org. Chem. 2016, 81, 2675.
10 Greene, T. W.; Wuts, P. G. M. (2014). Protective Groups In Organic Synthesis. New York: John Wiley &
Sons. p. 202.
11 Bento, A. P.; Bickelhaupt, M. J. Org. Chem. 2007, 72, 2201.
12 Engle, K. M.; Pfeifer, L.; Pidgeon, G. W.; Giu redi, G. T.; Thompson, A. L.; Paton, R. S.; Brown, J. M.;
Gouverneur, V. Chem. Sci. 2015, 6, 5293.
13 Haynes, W. M. (2015). CRC handbook of Chemistry and Physics. Boca Raton; CRC Press.
14 Gilli, P.; Pretto, L.; Bertolasi, V. Gilli, G. Acc. Chem. Res. 2009, 42, 33.
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The Journal of Organic Chemistry
15 Becke, A. The Quantum Theory of Atoms in Molecules: From Solid State to DNA and Drug De sign; Matꢀ
ta, C. F., Boyd, R. J., Eds.; Wiley: New York, 2007; pp 10.
1
2
3
4
5
6
16 Corey, E. J.; Snider B. B., J. Am. Chem. Soc. 1972, 94, 2549.
7
8
17 Oppolzer, W.; Snowden, R. L.; Simmons, D. P. Helv. Chim. Acta, 1981, 64, 2002.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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48
49
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51
52
53
54
55
56
57
58
59
60
18
Corey E. J.; Venkateswarlu, A. J. Am. Chem. Soc., 1972, 94, 6190.
19 (a) Hanessian S.; Lavallee, P. Can. J. Chem., 1975, 53, 2975. (b) Hanessian S.; Lavallee, P. Can.
J. Chem., 1977, 55, 562.
20
21
Gryparis, C.; Stratakis, M. Chem. Commun., 2012, 48, 10751.
Simonneau, A.; Friebel, J.; Oestreich, M. Eur. J. Org. Chem. 2014, 2077.
22 Belmessieri, D.; Cordes, D. B.; Slawin, A. M. Z.; Smith, A. D. Org. Lett. 2013, 15, 3472.
23 DíezꢀGonzález, S.; Kaur, H.; Kauer Zinn, F.; Stevens, E.D.; Nolan, S.P. J. Org. Chem. 2005, 70,
4784.
24
Linghu, X.; Bausch, C. C.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 1833.
25 Castaño, M.; Cardona, W.; Quiñones, W.; Robledo, S.; Echeverri, F. Molecules, 2009, 14, 2491.
26
27
28
29
30
31
Abri, A.; Assadi, M. G.; Pourreza, S. J. Chin. Chem. Soc. 2012, 59, 1449.
Lautens, M.; Paquin, J.ꢀF.; Piguel, S.; Dahlmann, M. J. Org. Chem. 2001, 66, 8127.
Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2009, 131, 10844.
Nicolaou, K. C.; Toh, Q.ꢀY.; Chen, D. Y.ꢀK. J. Am. Chem. Soc. 2008, 130, 11292.
Stern, A.; John S. Swenton, J. S. J. Org. Chem. 1987, 52, 2763
D’Sa, B. A.; McLeod, D.; Verkade, J. G. J. Org. Chem. 1997, 62, 5057.
32 Schuster, C.; Rönnefahrt, M.; JulichꢀGruner, K. K.; Jäger, A.; Schmidt, A. W.; Knölker, H.ꢀJ.
Synthesis 2016, 48, 150.
33
Zhou, W.; Zhang, L.; Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 7094.
34 (a) Lavallo, V.; Canac, Y.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G. Science, 2006, 312, 722.
(b) Bidal, Y. D.; Lesieur, M.; Melaimi, M.; Cordes, D. B.; Slawin, A. M. Z.; Bertrand, G.; Cazin,
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C. S. J. Chem. Commun., 2015, 51, 4778.
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