Highly efficient "on water" catalyst-free nucleophilic addition reactions using difluoroenoxysilanes: Dramatic fluorine effects

Article abstract of DOI:10.1002/anie.201404432

A remarkable fluorine effect on "on water" reactions is reported. The C-FaH-O interactions between suitably fluorinated nucleophiles and the hydrogen-bond network at the phase boundary of oil droplets enable the formation of a unique microstructure to facilitate on water catalyst-free reactions, which are difficult to realize using nonfluorinated substrates. Accordingly, a highly efficient on water, catalyst-free reaction of difluoroenoxysilanes with aldehydes, activated ketones, and isatylidene malononitriles was developed, thus leading to the highly efficient synthesis of a variety of α,α- difluoro-β-hydroxy ketones and quaternary oxindoles. It's on! The C-FaH-O interactions between suitably fluorinated nucleophiles and a hydrogen-bond network at the phase boundary of an oil droplet facilitate "on water" catalyst-free reactions. Accordingly, the title reaction of difluoroenoxysilanes with aldehydes, activated ketones, and isatylidene malononitriles was developed, thus leading to α,α-difluoro-β-hydroxy ketones and quaternary oxindoles.

Full text of DOI:10.1002/anie.201404432

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DOI: 10.1002/anie.201404432
Heterogeneous Catalysis
Highly Efficient “On Water” Catalyst-Free Nucleophilic Addition
Reactions Using Difluoroenoxysilanes: Dramatic Fluorine Effects**
Jin-Sheng Yu, Yun-Lin Liu, Jing Tang, Xin Wang,* and Jian Zhou*
Dedicated to Professor Li-Xin Dai on the occasion of his 90th birthday
[4]
À
À
Abstract: A remarkable fluorine effect on “on water” reactions
Accordingly, we envisioned that C F···H O interactions
might bring about beneficial effects to on water reactions.
À
À
is reported. The C F···H O interactions between suitably
fluorinated nucleophiles and the hydrogen-bond network at the
phase boundary of oil droplets enable the formation of
a unique microstructure to facilitate on water catalyst-free
reactions, which are difficult to realize using nonfluorinated
substrates. Accordingly, a highly efficient on water, catalyst-
free reaction of difluoroenoxysilanes with aldehydes, activated
ketones, and isatylidene malononitriles was developed, thus
leading to the highly efficient synthesis of a variety of a,a-
difluoro-b-hydroxy ketones and quaternary oxindoles.
For example, through the interactions with hydrogen-
bond networks at the phase boundary, the fluorinated moiety
of the nucleophile and the hydrophilic part of the electrophile
might be organized at the periphery of the oil droplet, while
the hydrophobic part is positioned within the hydrophobic
interior (Scheme 1). As a result, the free hydroxy groups at
S
ince the landmark work of Sharpless and co-workers,[1a]
“on water” catalysis has been established as a powerful
strategy in organic synthesis.[1] It is very important to explore
the potential of this methodology in the synthesis of value-
added products, as water is a cheap, safe, and an environ-
mentally benign solvent. Generally, on water reactions rely on
the heterogeneity of reaction mixtures, and the rate accel-
eration is related to the unique chemistry between water and
reactants at the phase boundary, where hydrogen-bonding
interactions play an important role.[1] Many organic reactions
have been tried under on water conditions to improve
synthetic efficiency, however, the influences of fluorine
substitution[2] on a reaction under such conditions remains
to be explored.[3] In contrast to the hyper-hydrophobicity of
highly fluorinated compounds, a single fluorine substitution
on an aliphatic chain actually reduces the hydrophobicity.[2]
Scheme 1. Schematic of the fluorine effects on on water reactions.
the interface can only stabilize both the reactants and the
transition state,[1i] but importantly, they organize both reac-
tion partners into a favorable orientation to facilitate the
desired reaction. Therefore, it is possible to take advantage of
such effects to develop on water reactions, which could not be
realized by using nonfluorinated nucleophiles, even in the
absence of any catalyst, to enable the synthesis of valuable
fluorinated products.[5]
This hypothesis, along with our previous finding that
[*] J.-S. Yu, Y.-L. Liu, J. Tang, Prof. Dr. J. Zhou
Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, East China Normal University
À
À
C F···H N interactions dramatically affected the cyanation
of ketimines,[6ab] encouraged us to explore the possible effects
of fluorine substitution on on water reactions as part of our
work on selective introduction of fluoroalkyl groups.[6] The
difluoroenoxysilane 1[7] (for structures see Table 1) was used
as the ideal fluorinated nucleophile to initiate our study
because it only contained a CF2 group as the hydrophilic part,
and could simplify the analysis. The on water, catalyst-free
aldol reaction using 1 was first examined, in view of the
versatility of the product a,a-difluoro-b-hydroxy ketones 3,[8]
for the synthesis of difluoromethylated compounds[9] which
are of current interest in medicinal research.[10] In addition,
while several Lewis acid catalyzed protocols are known,[7a,8ab]
a metal-free version is lacking, and an on water, catalyst-free
method would avoid heavy-metal contamination of the
products. It should also be noted that although much progress
had been made in the Lewis acid catalyzed aldol reaction of
nonfluorinated trimethylsilyl (TMS) based nucleophiles in
3663N, Zhongshan Road, Shanghai 200062 (China)
E-mail: jzhou@chem.ecnu.edu.cn
Prof. Dr. X. Wang
College of Chemistry, Sichuan University
Chengdu, 610064 (China)
E-mail: wangxin@scu.edu.cn
Prof. Dr. J. Zhou
State Key Laboratory of Elemento-organic Chemistry
Nankai University, Tianjin 300071 (P. R. China)
[**] We thank Prof. Dr. Shu-Hua Li of Nanjing University and Prof. Dr.
Yu-Xue Li of Shanghai Institute of Organic Chemistry for their
constructive suggestions. Financial support from NSFC (21172075,
21222204), 973 program (2011CB808600), the Ministry of Educa-
tion (NCET-11-0147 and PCSIRT), and Program of SSCS
(13XD1401600) is appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404432.
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water,[11a] the corresponding on water, catalyst-free processes
are rare and limited to the reactions using highly active
aldehydes or TMS-based nucleophiles.[11b–d]
Table 2: Substrate scope of Mukaiyama aldol reaction.
To our delight, the on water reaction of 1a with the
aldehyde 2a was complete within 10 hours at 508C to give the
product 3a in 85% yield (entry 1, Table 1). Remarkably, the
Entry[a]
R1
R2
3
Yield
[%][b]
Table 1: Representative results.
1
1a: Ph
1a: Ph (6.0 mmol)
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1a: Ph
1b: p-ClC6H4
1c: m-MeC6H4
1d: 2-naphthyl
1e: p-MeOC6H4
1 f: PhCH2CH2
2a: p-ClC6H4
2a: p-ClC6H4
2b: o-ClC6H4
2c: m-ClC6H4
2d: p-NO2C6H4
2e: p-CF3C6H4
2 f: p-CNC6H4
2g: Ph
2h: m-MeC6H4
2i: p-MeOC6H4
2j: 2-naphthyl
2k: thienyl
2l: PhCH2CH2
2a: p-ClC6H4
2a: p-ClC6H4
2a: p-ClC6H4
2a: p-ClC6H4
2a: p-ClC6H4
3a
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
85
86
78
80
94
84
80
64
76
61
62
48
33
94
93
66
85
59
2[c]
3
4
5
6
7
8
9
10
11
12
13[d]
14
15
16[e]
17
18
Entry[a]
Solvent
Additive
t [h]
Yield [%][b]
1
2
H2O
THF
–
10
72
85
10
DMAP
3
THF
144
43
4
5
6
7
8
THF/H2O[c]
H2O
H2O
H2O
neat
–
24
10
10
10
10
21
70
77
79
–
PhSO3H
4-C12H25C6H4SO3H
C12H25SO3Na
–
[a] On a 0.25 mmol scale. [b] Yield of isolated product. [c] THF/H2O (7:1,
v/v). THF=tetrahydrofuran.
reaction was much more efficient than those run in organic
solvents (see the Supporting Information). We had previously
discovered that 4-dimethylaminopyridine (DMAP) could
effectively activate 1 to react with isatins or b,g-unsaturated
a-ketoesters in THF,[6de] however, it catalyzed the present
reaction very slowly (entry 2). The thiourea 4 [Ar= 3,5-
(CF3)2C6H3][12] was inefficient as well, thus affording 3a in
only 43% yield, even after six days (entry 3). These results
unambiguously showed that the development of a metal-free
protocol of this reaction was not trivial. The heterogeneity
proved to be very important,[13] as the homogeneous reaction
using a mixed solvent of THF/H2O (7:1, v/v) gave 3a in a low
yield (entry 4). The use of a Brønsted acid might affect the
microenvironment at the phase boundary, thus leading to
a reduced yield. For example, the use of PhSO3H decreased
the yield of 3a from 85% to 70% (entry 1 versus entry 5). The
use of a surfactant,[14] either p-dodecylbenzenesulfonic acid or
sodium dodecyl sulfonate, to improve the reaction efficiency
was tried, but resulted in no positive result (entries 6 and 7),
possibly because of the interference of the surfactant on the
microenvironment of the reaction. Noticeably, no reaction
took place under solvent-free conditions (entry 8), thus
indicating the rate acceleration was not a result of the
increase in the effective concentration of the reactants.
The scope of this on water, catalyst-free protocol with
respect to the difluoroenoxysilanes 1 and aldehydes 2 was
then examined by running the reaction at 508C (Table 2).
First, it should be pointed out that this catalyst-free, on water
protocol could be used for preparative synthesis, as demon-
strated by a scaled up reaction using 6.0 mmol of 2a, which
afforded 3a in 1.55 grams with 86% yield (entry 2). Gener-
ally, the benzaldehydes 2a–i worked well with 1a to give the
[a] On a 0.25 mmol scale. [b] Yield of the isolated product. [c] On
a 6.0 mmol scale. [d] Saturated NaCl (aq.) as the solvent and on
a 1.0 mmol scale. [e] Used 1.2 equiv of 1d.
products 3a–i in good to high yield (entries 1–10). 2-Naphthyl
aldehyde (2j) provided the product 3j in 62% yield
(entry 11), and thiophene-2-carbaldehyde (2k) gave the
desired product 3k in lower yield as well (entry 12). The
aliphatic aldehyde 2l gave 3l in higher yield by using
saturated NaCl (aq.) as the solvent. Both aryl and aliphatic
difluoroenoxysilanes (1a–f) worked well with 2a to give the
corresponding products 3a and 3m–q in good yield (entries 1
and 14–18), but the aryl-substituted 1a–e gave the corre-
sponding products in higher yields. The activated ketones 5,
such as isatins and b,g-unsaturated a-ketoesters, were also
viable substrates for this on water reaction, thus giving the
desired products 6a–h in high yield.
The a,a-difluoro-b-hydroxy ketones 3 are versatile build-
ing blocks, and could be readily transformed into difluoro-
methylated hydroxy esters, diols, anti-2,2-difluoropropane-
1,3-diols, aminoalcohol, and 3,3-difluoroazetidine (for full
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substrate scope of Mukaiyama aldol reaction and the product
elaborations, see the Supporting Information).
Interestingly, an unprecedented Mukaiyama–Michael
addition of the difluoroenoxysilanes 1 to the isatylidene
malononitriles 7 worked well on water, thus allowing efficient
construction of the quaternary oxindoles 8 featuring a CF2
group at the C3-position (Scheme 2). Remarkably, this
reaction represents a rare example of on water, catalyst-free
construction of quaternary carbon centers.[1] It should be
noted that the synthesis of quaternary oxindoles is of current
interest[15] because of the need for privileged scaffolds in
medicinal research.
interactions and hydrogen-bonding activation of 2a[17] could
be expected, the homogeneous reaction of 1a and 2a in
MeOH provided 3aa in only 29% yield, accompanied by side
products (see the Supporting Information for detailed dis-
cussion).
To account for why the reaction of 1a and 2a proceeded
much more efficiently on water (heterogeneous) than in
MeOH (homogeneous), but that of 9 and 2a worked
substantially better in MeOH than under on water conditions,
we propose that oil droplets, formed from 1a and 2a on water,
have a microstructure different from those formed between 9
and 2a. Through the hydrogen-bonding interactions with both
the CF2 group of 1 and the carbonyl group of 2, as suggested in
Scheme 1, the network of hydroxy groups at the phase
boundary elegantly preorganizes both reaction partners to
Scheme 2. Mukaiyama–Michael addition using 1.
The high efficiency of these catalyst-free, on water
reactions of difluoroenoxysilanes is impressive, and obviously
resulted from the difluorine substitution, as revealed by the
following control experiments. First, the on water reaction of
the nonfluorinated silyl enol ether 9 and 2a, although not
reversible,[16] gave only trace amounts of the product 11, with
almost complete hydrolysis of 9. In contrast, the presence of
enough fluorine atoms on the enol silyl ether was also
important, as the monofluorinated analogue 10 reacted with
2a sluggishly to give 12 in only 26% yield (NMR) under the
same reaction conditions. Noticeably, the difluoroenoxysilane
1a hydrolyzed at a much faster rate than both 9 and 10 in the
absence of the aldehyde 2a. These observations could not be
explained by the reactivity difference between 9 and 1a,
because although there is a difference in reactivity, it is not
that significant (9 is two times more reactive than 1a in
palladium-catalyzed arylation reactions,[7d] but is less reactive
in a Brønsted acid catalyzed Mannich reaction[7g]). In
addition, although chlorine is highly electronegative, the
dichloroenoxysilane 16 failed to react with 2a or the isatin 5a
to give the desired aldol adduct. More surprising results came
from the homogeneous reactions run in MeOH. Despite the
methanolysis of 9 within 20 minutes, the reaction of the
nonfluorinated 9 and 2a gave the adduct 11 in 8% yield upon
isolation, and is in sharp contrast to the fact that only trace
amounts of 11 were detected under on water conditions, even
though it took about 45 hours for the complete hydrolysis of 9
À
react with each other. Without such organization through C
À
F···H O interactions, the microstructure of the oil droplets
derived from 9 and 2a might result in an unfavorable
orientation of the reactants, thus making it difficult for 9 to
approach the aldehyde and leading to almost complete
hydrolysis of 9.
According to this mechanistic insight, the hydrophobic
TMS moiety of 1 should be positioned within the interior of
the oil droplet. Therefore, it was possible to use a chiral Lewis
base to activate 1a from the interior of the droplet and
cooperate with the hydrogen-bonding interactions at the
periphery to realize asymmetric synthesis. Indeed, when
(QD)2PYR[18] was used, 3aa was obtained in 73% yield and
39% ee. Increasing the loading of (QD)2PYR from 10 mol%
to 30 mol% resulted in the increase of the ee value of 3aa
from 39 to 53%,[19] possibly because (QD)2PYR was dis-
À
À
under on water conditions. In addition, while both C F···H O
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optimized TS in which only hydrogen-bonding interactions
between water and 2a existed) to 23.3 kcalmolÀ1. Calcula-
tions also revealed that without the assistance of water the
reaction proceeded through a concerted mechanism with
a reaction barrier of up to 41.6 kcalmolÀ1. These results
À
À
further showed the importance of C F···H O interactions in
lowering the activation barrier. Not unexpectedly, the tran-
sition state of the reaction using 9 and the dichloroenoxy-
silane 16 was not located, possibly because of the lack of
À
À
effective C F···H O interactions with water. For computa-
tional methods, data, and a detailed discussion, see pages 34–
56 of the Supporting Information.
In conclusion, we have demonstrated, by experimental
À
À
persed into more oil droplets, thus reducing the background
reaction. The rate acceleration effect of the on water
conditions was obvious, as reaction in THF gave 3aa in only
15% yield, albeit in 67% ee. These results further support the
proposed mechanism, even though there is ample room for
further improvements on the ee value of 3. It should be also
noted that the organocatalytic asymmetric aldol reaction of
1 with aldehydes is unprecedented.[20]
and theoretical studies, that the C F···H O interactions
between the fluorinated nucleophile and the hydrogen-bond
network at the phase boundary are able to cooperate with the
hydrogen-bonding activation of the electrophile to facilitate
on water reactions, which are unattainable by using non-
fluorinated substrates. An on water, catalyst-free reaction of
the difluoroenoxysilanes 1 with aldehydes, activated ketones,
and isatylidene malononitriles was developed, thus allowing
highly efficient synthesis of valuable a,a-difluoro-b-hydroxy
ketones and quaternary oxindoles. Further investigation of
this dramatic fluorine effects in other on water reactions is
now in progress in our laboratory.
À
À
À
The crucial role of the C F···H O interactions in the C C
bond-formation step of this protocol was further supported by
density functional theory (DFT) calculations using a five-
water model. The Gibbs free-energy profile and the opti-
mized structures of the transition state (TS) are shown in
Figure 1. The results reveal that in the transition-state TSII(5
Received: April 17, 2014
Revised: May 29, 2014
Published online: July 17, 2014
H O), a short C F···H O contact[4] (bond length 2.219 ꢀ; bond
angle of F···H O, 1458) does indeed exist between dangling
À
À
2
À
free OH groups of the five-water assembly and the CF2
moiety of 1a, together with double hydrogen bonds between
the carbonyl group of the aldehyde and water. On one hand,
hydrogen-bonding interactions activated 2a and stabilized the
negative charge developed at the oxygen atom in the
Keywords: fluorine · heterocycles · heterogeneous catalysis ·
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synthetic methods · water chemistry
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À
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