Bis-terminal hydroxy polyethers as all-purpose, multifunctional organic promoters: A mechanistic investigation and applications

Full text of DOI:10.1002/anie.200903903

Angewandte
Chemie
DOI: 10.1002/anie.200903903
Cooperative Catalysis
Bis-Terminal Hydroxy Polyethers as All-Purpose, Multifunctional
Organic Promoters: A Mechanistic Investigation and Applications**
Ji Woong Lee, Hailong Yan, Hyeong Bin Jang, Hong Ki Kim, Sung-Woo Park, Sungyul Lee,*
Dae Yoon Chi,* and Choong Eui Song*
Catalysis is one of the central themes in chemical
science. The promotion of physicochemical and
biological processes, as demonstrated by enzymes in
living cells, is an extremely important subject to be
elucidated in all branches of science. Therefore, the
design and application of new and efficient types of
promoters for organic transformations are of fun-
damental importance.
A range of important classes of organic reac-
tions can be conducted with fluoride anions as a
catalyst or nucleophilic reagent.[1] Although alkali
Figure 1. Bis-terminal hydroxy polyethers (III) as multifunctional promoters.
metal fluorides are a readily available source of the
fluoride ion, their applications are limited because
of their low solubility in organic solvents. To increase the
solubility of alkali metal salts, crown ethers are frequently
employed to generate a “naked” fluoride ion (Figure 1 I).[2]
This simple but innovative concept of crown ethers helped lay
the foundation for the important fields of ion and molecular
recognition and has therefore had a profound impact on
science.[3] However, their application to chemical reactions is
often hampered by the strong basicity of fluoride, which
causes it to induce the formation of by-products. During the
course of our efforts to develop general catalyst (promoter)
systems employing alkali metal salts as nucleophilic sources, it
was observed that bulky protic solvents (e.g. tBuOH) can be
suitable to generate a “flexible” fluoride ion from CsF
through controlled hydrogen bonding to reduce the basicity of
the nucleophile, fluoride (Figure 1 II).[4] However, owing to
the strong Coulombic influence of K+ on Fꢀ, KF was observed
to be inactive toward SN2 reactions. Thus, the combination of
these two concepts—“naked” and flexible systems together in
one molecule (Figure 1 I and II)—became the focus of our
study to design a much more versatile promoter system for a
wide range of organic transformations. Herein, we describe
the phenomenal efficiency of bis-terminal hydroxy polyethers
as a new type of all-purpose promoter system (Figure 1 III),
which act as extremely efficient catalytic reaction media for
nucleophilic fluorination with alkali metal fluorides. More-
over, by using chiral bis-terminal hydroxy polyethers as
catalysts, the catalytic desilylative kinetic resolution of the
silyl ethers of racemic secondary alcohols with KF was
successfully achieved for the first time.
Cooperative catalysis,[5] the simultaneous binding and
activation of reacting partners resulting in both preorganiza-
tion of the substrates and stabilization of the transition state
structures, is a fundamental principle in modern catalysis.
Recently, much efforts in this field have focused on the
development of efficient multifunctional organocatalysts.[6]
We anticipated that bis-terminal hydroxy polyethers might
serve as a new type of multifunctional organic promoters in
various organic reactions through a cooperative activation
mechanism as depicted in Figure 1 III: The ether groups act as
a Lewis base toward K+, “freeing” the nucleophile, as well as
“enhancing” the solubility of the potassium salts. On the other
hand, one of the two OH groups forms controlled hydrogen
bonding with the fluoride anion, thus decreasing the basicity
of the nucleophile, whereas the other OH group may be able
to simultaneously activate the electrophile by hydrogen
bonding, thereby stabilizing the transition state (Figure 1
III). More importantly, this type of promoter can easily be
modified to produce “chiral variants”.
[*] S.-W. Park, Prof. S. Lee
Department of Applied Chemistry, Kyunghee University
Yongin, Gyeonggi, 446-701 (Korea)
E-mail: sylee@khu.ac.kr
Prof. D. Y. Chi
Department of Chemistry, Sogang University
1 Shinsudong, Mapogu, Seoul 121-742 (Korea)
E-mail: dychi@sogang.ac.kr
J. W. Lee, H. Yan, H. B. Jang, H. K. Kim, Prof. C. E. Song
Department of Chemistry, Sungkyunkwan University
300 Cheoncheon, Jangan, Suwon, Gyeonggi, 440-746 (Korea)
E-mail: s1673@skku.edu
Prof. C. E. Song
Department of Energy Science, Sungkyunkwan University
300 Cheoncheon, Jangan, Suwon, Gyeonggi, 440-746 (Korea)
[**] This work was supported by the MOEHRD (grant no. KRF-2008-
005J00701), the SRC program of MEST/KOSEF (grant no. R11-2005-
008-00000-0), the KOSEF basic research program (grant no. 2009-
0070597), and the WCU program (grant no. R31-2008-000-10029-0).
To prove the validity of this novel concept, we first
examined bimolecular nucleophilic fluorination, which is
considered to be one of the most difficult SN2 reactions. We
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903903.
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conducted the nucleophilic fluorination on the model sub-
strate 2-(3-methanesulfonyloxypropoxy)naphthalene (1) with
5 equivalents of potassium fluoride in triethylene glycol or
tetraethylene glycol as the solvent at 1008C. The results are
summarized in Table 1, together with those obtained in other
solvent systems reported previously by us[4,7] and other
Table 1: Nucleophilic fluorination with alkali metal fluoride in various
solvent systems.[a]
Scheme 1. Nucleophilic flourination of 3 with KF
yield, along with the alkene 4b in 5% yield. It is well
known that introducing fluorine into haloethyl or alkanesul-
fonyloxyethyl aromatic compounds is very difficult because of
their tendency to undergo elimination reactions to produce
styrenes.[9] All of the aforementioned results are certainly
consistent with our hypothesis of a cooperative mechanism
depicted in Figure 1 III.
To further verify the importance of the cooperative
multifunctionality of the promoters, the fluorination of the
mesylate 1 with KF (5 equiv) was carried out in various glycol
derivatives as the solvent. As shown in Scheme 2, when
triethylene glycol dimethyl ether (in which both terminal
Entry Solvent
Nucleophile (MF)
t
Yield [%][b]
1[c]
2[c]
3[d]
4
CH3CN
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
CsF
KF
CsF
24 h
24 h
1 h
0
40
4
0
0
93
92
95
94
[18]crown-6 in CH3CN
[18]crown-6 in DMF
tBuOH
1.5 h
1.5 h
1.5 h
1.5 h
1 min
1 min
1.5 h
1.5 h
1.5 h
1.5 h
5
6
7
tert-amyl alcohol
triethylene glycol
tetraethylene glycol
triethylene glycol
tetraethylene glycol
PEG 600
PEG 600
PEG 1000
PEG 1000
8[e]
9[e]
10
11
12
13
70[f]
>98[f]
39[f]
>98[f]
[a] Unless otherwise indicated, all reactions were carried out with 1
(0.1 mmol) and KF (5 equiv) at 1008C in 0.5 mL of solvent. [b] Yield of
isolated product. [c] See Ref. [7]. [d] See Ref. [8]. [e] Reactions were
carried out under microwave irradiation (700 W). [f] Yields were
1
determined by H NMR spectroscopy. DMF=N,N-dimethylformamide.
group.[8] Pleasingly, when using tri- or tetraethylene glycol
as solvent, the substitution reactions proceeded at an
unprecedented fast rate and were completed within 1.5 h to
afford the fluorinated product 2 in excellent yields (92–93%)
without forming any appreciable amount of by-products
(Table 1, entries 6 and 7). Moreover, by applying microwave
irradiation (700 W) to the same reaction, the fluorinated
product 2 could be obtained in nearly quantitative yields
within only 1 minute (Table 1, entries 8 and 9). In contrast to
these results, the same fluorination reaction with KF in
aprotic polar solvents such as acetonitrile in the presence or
absence of [18]crown-6 proceeded sluggishly (Table 1,
entries 1–3).[7,8] Bulky protic solvents such as tBuOH and
tert-amyl alcohol, which are known to be excellent media for
fluorination with CsF,[4] also showed no reactivity with KF
(Table 1, entries 4 and 5). Interestingly, PEG 600 or
PEG 1000 (containing ca. 13 and 22 ether units, respectively)
showed low reactivity for the same reaction (Table 1,
entries 10 and 12). Meanwhile the reaction of 1 with CsF in
PEG 600 or PEG 1000 proceeded smoothly to give the
desired fluorinated product 2 in nearly quantitative yields
(Table 1, entries 11 and 13). This result strongly indicates that
the effectiveness of alkali metal cation is determined by the
chain length of the bis-terminal hydroxy polyethers, as would
be expected. Moreover, as shown in Scheme 1, the fluorina-
tion of 2-(2-mesyloxyethyl)naphthalene (3) proceeded to give
predominantly 2-(2-fluoroethyl)naphthalene (4a) in 95%
Scheme 2. Nucleophilic fluorination with KF in triethylene glycol
derivatives.
hydroxy groups are methylated) was used as the solvent, the
reaction did not proceed at all. On the other hand, triethylene
glycol monoethyl ether showed about half of the reactivity of
triethylene glycol under the same reaction conditions. We also
carried out the same reaction in a mixed solvent system
consisting of triethylene glycol dimethyl ether and tBuOH
(1:1, v/v) on the assumption that the ether units of the former
can chelate the potassium cation and the latter can stabilize
the fluoride anion by controlled hydrogen bonding. However,
no conversion was observed. All of these experimental results
strongly suggest that, in the case of bis-terminal hydroxy
polyethers, the “intramolecular” cooperative activation
mechanism is responsible for the rate acceleration in nucle-
ophilic fluorinations.
Support for the proposed cooperative mechanism was
obtained from quantum chemical calculations carried out by
employing the accurate DFT (MPW1K/6-31 + + G**)
method.[10] Figure 2 depicts the reactions of C3H7OMs with
K+Fꢀ in tetraethylene glycol. In Figure 2, five oxygen atoms in
the tetraethylene glycol molecule act as a Lewis base toward
K+, thus drastically lowering its electrostatic effects and
thereby “freeing” the nucleophile, Fꢀ. The ion pair K+Fꢀ
resides in the hollow “pocket” formed by the five oxygen
atoms in the solvent (very much like an active site in an
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radiopharmaceuticals such as [18F]FLT, [18F]FP-CIT, and
[18F]BAY94-9172 by nucleophilic fluorination is still challeng-
ing, as this is one of the most difficult nucleophilic substitution
reactions. Thus, we believe that our fluorination protocol will
open up new perspectives for [18F] labeling chemistry:
because of its use of readily available alkali metal fluorides
as nucleophilic sources, its fast reaction rates, and excellent
product selectivity.
We also examined the scope of our protocol with a variety
of different potassium salts. As shown in Scheme 3, a range of
activated nucleophiles including carbon, nitrogen, oxygen,
Figure 2. Calculated mechanism of the reaction [K+Fꢀ + C3H7-OMs!
K+OMsꢀ + C3H7-F] in tetraethylene glycol by using DFT (MPW1K/6-
31++G**) methods. Energy and Gibbs free energy in kcalmolꢀ1 and
bond lengths in ꢀ.
enzyme). One of the two OH groups of tetraethylene glycol
forms a hydrogen bond with the fluoride nucleophile. The
other OH group interacts with the mesylate leaving group,
thus helping it to detach from the reactant. The calculated
energy barrier (E° = 18.6 kcalmolꢀ1, G°(1008C) = 19.9 kcal
molꢀ1) for the reaction with KF in tetraethylene glycol is
much lower than even those calculated by similar methods for
the same reaction with cesium and tetra-n-butylammonium
Scheme 3. SN2 reaction with various potassium salts.
sulfur, and other halogen nucleophiles can be simply gen-
erated from the corresponding potassium salts in the presence
of bis-terminal hydroxy polyethers. Thus, the substitution
reactions proceed extremely well with a diverse set of
nucleophiles to afford the corresponding substitution prod-
ucts in nearly quantitative yields. These results indicate that
bis-terminal hydroxy polyethers can be used to generate the
activated nucleophiles from potassium salts for diverse
organic reactions.
To demonstrate that our concept is generally applicable to
other organic reactions, we also examined the removal of
various silyl ether protecting groups in 5–8 with KF in
tetraethylene glycol at room temperature. As shown in
Table 2, the silyl groups could be cleanly removed to give
fluoride in tert-butyl alcohol and ethylene glycol;[11] [Cs+Fꢀ
+
C3H7OMs!Cs+OMsꢀ + C3H7F] in tert-butyl alcohol (E° =
23.5 kcalmolꢀ1, G° (808C) = 23.1 kcalmolꢀ1), [nBu4N+Fꢀ
+
C3H7OMs!nBu4N+OMsꢀ + C3H7F] in tert-butyl alcohol
(E° = 25.3 kcalmolꢀ1, G° (808C) = 22.3 kcalmolꢀ1),[12] and
[Cs+Fꢀ
+
C3H7OMs!Cs+OMsꢀ
+ C3H7F] in ethylene
glycol (E° = 20.0 kcalmolꢀ1, G° (808C) = 21.5 kcalmolꢀ1).[13]
Replacing one hydroxy group of tetraethylene glycol by a
methoxy group (see Figure S2) is calculated to increase the
activation barrier significantly (E° and G° by 1.2 and
1.7 kcalmolꢀ1, respectively): this increase is due to the much
lower acidity and tenuous interactions of OCH3 with the
leaving group compared with OH, which is in agreement with
the experimental observation of a corresponding decrease in
the reaction rate (see Scheme 2). In solvents containing two
terminal OCH3 groups, the reactant tends to separate away
from the “loose” solvent molecule, with no prereaction
complex being formed. These observations indicate that one
of the terminal OH groups acts as an “anchor” to the
nucleophile and the other acts as an “anchor” to the leaving
group, thus supporting the mechanism depicted in Figure 2. A
similar nucleophilic fluorination reaction with a metal fluo-
ride was observed in an enzymatic reaction, where the
controlled hydrogen bonding among the enzyme, fluoride,
Table 2: Removal of silyl groups using KF in tetraethylene glycol.[a]
Entry Substrate
KF [equiv]
t
Yield [%][b]
1
5
1.5
15 min 98
2
6
3
30 min 96
3
7
1.5
1.5
3 h
2 h
99
93
4[c]
(R)-8
ꢀ
and substrate plays a crucial role in the formation of C F
bonds.[14] Notably, labeling organic compounds with [18F]
isotope (t1/2 = 110 min) is a particularly important process for
the noninvasive imaging of molecular and biological process-
es in living subjects with positron emission tomography
(PET).[15] However, the mass production of [18F] labeled
[a] All reactions were carried out with 0.1 mmol of the substrate in
tetraethylene glycol (1.0 mL) at room temperature. [b] Yield of isolated
product. [c] Enantiopurity of the alcohol was determined by HPLC on a
chiral stationary phase (see the Supporting Information). TIPS=triiso-
propylsilyl, TES=triethylsilyl.
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the corresponding alcohols in nearly quantitative yields.
polyethers as multifunctional promoters for other organic
reactions, 2) developing efficient asymmetric variants, and
3) PET applications.
Notably, the base-sensitive silyl ether (R)-8 could also be
selectively deprotected without racemization (Table 2,
entry 4). It is well known that tetra-n-butylammonium
fluoride (TBAF), the most common reagent for the cleavage
of silyl ethers, is inappropriate for base sensitive substrates
because of the strong basicity of the fluoride anion.[1a,16]
Finally, we are also in the process of developing asym-
metric variants of the catalytic process using our multifunc-
tional promoter. For example, treating the racemic silyl ether
9 with 0.5 equivalents of KF at 158C for 24 hours in the
presence of the chiral variant (R)-11 (10 mol%) of tetra-
ethylene glycol as a catalyst furnished the resolved alcohol
(S)-10 with 73% ee (Scheme 4 and the Supporting Informa-
Received: July 16, 2009
Published online: September 8, 2009
Keywords: cooperativecatalysis·densityfunctionalcalculations·
.
kinetic resolution · nucleophilic fluorination · polyethers
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Scheme 4. Desilylative kinetic resolution of rac-9 with KF. TMS=trime-
thylsilyl.
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the desilylative kinetic resolution of the silyl ethers of racemic
secondary alcohols.[17] This process can certainly open up a
new avenue for asymmetric reactions catalyzed by chiral
fluoride,[1b,c] which have vast synthetic potential but remain a
relatively undeveloped field.
In conclusion, we have demonstrated that multifunctional
bis-terminal hydroxy polyether derivatives can strongly
promote a range of chemical reactions, in which alkali metal
salts are used as nucleophilic sources. Achiral bis-terminal
hydroxy polyether derivatives dramatically facilitated the
most difficult process of nucleophilic fluorination, even with
KF. We also described the first successful desilylative kinetic
resolution of the silyl ethers of racemic secondary alcohols
with KF by using the chiral variants of bis-terminal hydroxy
polyether derivatives as catalysts. Quantum chemical calcu-
lations provide detailed insight into the modes of action of
this type of organic promoter. On the basis of all these
remarkable results, we believe that our new promoter system
(bis-terminal hydroxy polyethers and their chiral variants) is a
new development that constitutes a significant step forward in
many important areas of science, e.g., solvent engineering,
enantioselective organocatalysis, and diagnostic medicine.
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