A fluorous Mukaiyama coupling reagent for a concise condensation reaction: Utility of medium-fluorous strategy

Article abstract of DOI:10.1016/j.tet.2012.03.034

The entire study of condensation reactions using various fluorous Mukaiyama reagents, including a novel medium-fluorous strategy, is described. A Mukaiyama reagent bearing a medium-fluorous content tag, between 40 and 60% fluorine by weight, was prepared and examined in ester and amide-forming condensation reactions. At the end of the reactions, the fluorous pyridone by-product was effectively separated from non-fluorous components by increasing the water content of the crude reaction mixture and subsequent filtration of the precipitate. It is also shown that Mukaiyama reagents bearing a fluorous tag increase the reaction rate considerably when compared to their non-fluorous tagged counterpart. Interestingly, it was observed that the longer the fluorous chain, the higher the activity of the Mukaiyama reagent.

Full text of DOI:10.1016/j.tet.2012.03.034

Tetrahedron 68 (2012) 3885e3892
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A fluorous Mukaiyama coupling reagent for a concise condensation reaction:
utility of medium-fluorous strategy
Yuya Sugiyama a, Yuki Kurata a, Yoko Kunda a, Atsushi Miyazaki a, Junko Matsui a, Shuichi Nakamura b,
,
Hiromi Hamamoto a, Takayuki Shioiri a, Masato Matsugi a
*
a Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku-ku, Nagoya 468-8502, Japan
b Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The entire study of condensation reactions using various fluorous Mukaiyama reagents, including a novel
medium-fluorous strategy, is described. A Mukaiyama reagent bearing a medium-fluorous content tag,
between 40 and 60% fluorine by weight, was prepared and examined in ester and amide-forming con-
densation reactions. At the end of the reactions, the fluorous pyridone by-product was effectively sep-
arated from non-fluorous components by increasing the water content of the crude reaction mixture and
subsequent filtration of the precipitate. It is also shown that Mukaiyama reagents bearing a fluorous tag
increase the reaction rate considerably when compared to their non-fluorous tagged counterpart. In-
terestingly, it was observed that the longer the fluorous chain, the higher the activity of the Mukaiyama
reagent.
Received 17 February 2012
Received in revised form 8 March 2012
Accepted 9 March 2012
Available online 19 March 2012
Keywords:
Fluorous
Medium fluorous
Mukaiyama reagent
Condensation
Purification
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
there are many reports of its use in a key ester or amide-forming
step of a synthetic route. Since the reagent was reported in 1975,
Condensation reactions are some of the most important re-
actions in synthetic organic chemistry. Thus, not surprisingly,
a number of condensation reagents that enable condensation re-
actions have been developed to achieve high coupling yields, facile
experimental protocols and improved atom economy.1 The
a number of modified N-alkyl-2-halopyridinium salts have been
developed with the aim of achieving higher levels of efficiency.3
Often times though separation of the coupling reagent from the
desired coupling products can be challenging.
Organic molecules bearing small fluorous tags such as C6F13 and
C8F17 are called light-fluorous molecules. Light-fluorous reagents,4
scavengers5 and catalysts6 are especially convenient because in
addition to inducing the desired transformation under the same
conditions as their non-fluorous counterparts, they are also reliably
and predictably separated from the desired products out of the
crude reaction products by fluorous solid phase extraction (FSPE).7
In 2005, Nagashima et al. reported the first fluorous-tagged
Mukaiyama reagent 2 (Fig. 1) and demonstrated its ability to suc-
cessfully promote amide bond formation.8 In this report, a fluorous
benzyl group was used as the fluorous tag, and the reaction mixture
was purified by FSPE cleanly removing the resultant fluorous pyr-
idone by-product from the desired amide products. In this protocol,
the addition of 1-hydroxybenzotriazole (HOBT) was required to
decrease the formation of the carboxylic anhydride by-product and
so the purification protocol employed a resin-bound carbonate
scavenger to remove the excess HOBT.9
Mukaiyama reagent (N-methyl-2-chloropyridinium iodide)
1
(Fig. 1) is one of the more widely used condensation reagents2 and
Fig. 1. Original and fluorous Mukaiyama reagents.
Recently, we demonstrated that a new fluorous Mukaiyama
reagent 3a (Fig. 1) bearing a C8F17 tag with an ethylene spacer
shows higher reactivity than the non-fluorous variant, and the
* Corresponding author. Tel./fax: þ81 52 832 1151; e-mail address: matsugi@
meijo-u.ac.jp (M. Matsugi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.034

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Y. Sugiyama et al. / Tetrahedron 68 (2012) 3885e3892
purification is greatly simplified by using FSPE to isolate the desired
coupling products.10 Interestingly, we also showed that the struc-
ture of the fluorous tag could greatly influence the rates of the
condensation reaction.11 Furthermore, we introduced a new con-
cept of fluorous separation, namely a ‘medium-fluorous strategy,’
where condensation reactions employed a fluorous Mukaiyama
reagent bearing a slightly larger C10F21 tag.12 In the current publi-
cation, we detail our complete investigation towards condensation
reactions using various fluorous Mukaiyama reagents including the
use medium-fluorous Mukaiyama reagent 3d.
2. Results and discussion
2.1. Light-fluorous Mukaiyama reagent
Initially, we planned to prepare
a simple light-fluorous
Mukaiyama reagent with an ethylene spacer between the pyri-
dine and the fluorous tag. Our rationale behind using a simple
ethylene spacer, as opposed to a benzyl spacer as employed by
Nagashima, is that this type of coupling agent should be more ac-
tive in condensation reactions, given the closer proximity of the
strongly electron withdrawing fluorous tag to the pyridine in the
case of the simple ethylene variant. Furthermore the reactivity of
the ethylene based fluorous Mukaiyama reagent should be further
enhanced given the smaller steric demand of this group when
compared to the benzyl fluorous moiety. To test this hypothesis,
Mukaiyama reagent 3a was prepared from 2-chloropyridine in one
step as shown in Scheme 1 in 84% isolated yield after a single
recrystallisation.14 Utilizing the same conditions to prepare 3a, we
prepared fluorous reagents 3bed to investigate the effect of dif-
ferent fluorous tags on the rate of condensation reactions. All of the
fluorous Mukaiyama reagents that we prepared are white powders
and can be stored in a desiccator at ambient temperature for ex-
tended periods of time without decomposition. Elemental analysis
as well as 1H and 19F NMR analysis provide support for the salt
structures shown for compounds 3a15 and 3b. We chose to syn-
thesize a triflate salt of the pyridine because a non-nucleophilic
triflate counter ion is reportedly optimal for Mukaiyama-type
reagents.3c A non-fluorous Mukaiyama reagent 3e was also pre-
pared, using the same method, to serve as a control in the rate
studies.16
Fig. 2. Comparison of conversion for ester formation in CDCl3.
the same reactivity as the original Mukaiyama reagent 1 in this
particular ester forming reaction.
Synthetically, we envisioned separating the target product from
the fluorous pyridone 4a (Fig. 3) derived from the Mukaiyama re-
agent 3a, via FSPE after the condensation reaction.17 Facile and
predictable product purification is the most important feature of
the fluorous Mukaiyama reagent and the main reason for using
them in condensation reactions. Clearly when the Rf values of both
the product and the pyridone by-product are similar to each other,
it is difficult to separate these compounds effectively by typical
chromatography. As shown in Fig. 3, for example, when acetic acid
and N-methylaniline were used as the substrates in an amidation
reaction with fluorous Mukaiyama reagent 3a, the target product
could not be separated effectively from the corresponding pyridone
4a by standard column chromatography. The Rf values (AcOEt/
hexane¼1:1) of 4a and the product 5 were 0.30 and 0.33, re-
spectively by regular TLC (Silica Gel 60 F254; MERCK) as shown in
Fig. 3. As a result, complete resolution of adducts 4a and 5 by col-
umn chromatography was not trivial. On the other hand, there was
a remarkable difference in Rf values between 4a and 5 by fluorous
TLC18 (0.11 vs 0.83) when eluting with 80% aq MeOH as shown in
Fig. 3. This significant difference in Rf enabled facile separation of
the fluorous pyridone 4a and amide 5 when the FSPE strategy was
employed.
Scheme 1. Synthesis of the fluoroalkyl Mukaiyama reagents and alkyl reagent.
To test the reactivity of the Mukaiyama reagents, the esterifi-
cation reaction between 2-phenyl benzoic acid and isopropanol
was conducted in CDCl3. Three separate reactions were set up un-
der identical reaction conditions each with a different Mukaiyama
reagent 1, 2, or 3a. At given time points, the % conversion of the
reaction was determined by recording the 1H NMR spectra of the
reaction mixtures and measuring the relative integrals of the
methine proton of the isopropoxy ester and isopropanol, re-
spectively. A plot of % conversion versus time is shown in Fig. 2 with
the original Mukaiyama reagent 1 data points represented by cir-
cles, the ethylene spacer reagent 3a represented by squares, and
finally the ethylene benzyl derivative 2, data points shown using
triangles. It is clear that the ethylene spacer fluorous reagent 3a
has a significantly higher reactivity than 2, and displays almost
Fig. 3. Comparison of TLC between FSPE condition and regular conditions.
Table 1 shows a variety of acid and alcohol coupling partners
employed in an esterification reaction reagent 3a under mildly
basic conditions. The procedure for the condensation reaction was
simple and easily carried out. All reactions proceeded at room
temperature and were complete within 2 h. Upon completion, the
reaction mixture was washed with aq HCl to remove triethylamine
(TEA) and N,N-dimethylaminopyridine (DMAP) and then subjected

Y. Sugiyama et al. / Tetrahedron 68 (2012) 3885e3892
3887
Table 1
Table 2
Ester formation using 3a and FSPE
Amide formation using 3a and FSPE
Entry Carboxylic acid
Amine
Time (h) Yieldb (%) Purityc (%)
Entry Carboxylic acid
Alcohol
Time (h) Yieldb (%) Purityc (%)
1
2
3
CH3CO2H
PhCO2H
PhCO2H
PhNHMe
PhNH2
PhNHMe
2
4
1
92
Quant.
80
86
99
89
1
2
4-PhePhCO2H
4-PhePhCO2H
MeOH (10.0 equiv)
1
1
Quant.
99
99
99
4
PhCO2H
2
80
99
3
4
4-PhePhCH2CO2H MeOH (10.0 equiv) 0.5
Quant.
87
97
99
2-PhePhCO2H
MeOH (10.0 equiv)
1
5
6
4-MeOePhCO2H
4-MeOePhCO2H
4-NO2ePhCO2H
4-NO2ePhCO2H
2-PhePhCO2H
PhNH2
PhNHMe
PhNH2
PhNHMe
PhNH2
2
5
2
2
2
4.5
86
77
76
91
84
80
95
99
99
96
99
97
5
2-PhePhCO2H
2
80
92
7
8d
9
6
7
8
9
4-MeOePhCO2H
4-NO2ePhCO2H
MeOH (10.0 equiv) 1.5
MeOH (10.0 equiv) 1.5
94
52
71
Quant.
99
97
99
98
10
4-PhePhCH2CO2H PhNHMe
Boce
Boce
L
-tryptophan MeOH (10.0 equiv)
1
1
L-tryptophan 4-PhePhOH
tBuOH
24
No reaction
11
PhNHMe
4
2
72
97
10
PhCO2H
12
BoceL-tryptophan
84
99
11
PhOH
1
No reaction
a
a
The amount of fluorous silica used was 15 times weight of 3a.
Isolated yield.
Determined by HPLC.
The amount of fluorous silica gel used was 15 times weight of 3a.
Isolated yield.
Determined by HPLC.
b
c
b
c
d
0.2 equiv of DMAP was used.
to FSPE eluting with 80% aq MeOH to give the target products in
good yields and high purities.20 Unfortunately, an esterification
containing tert-butyl functional group (Table 1, entries 10 and 11)
failed to give any detectable levels of product.
Similarly, various amide-forming reactions without HOBT were
investigated and the results are shown in Table 2. Moderate to good
yields and easy purification were achieved in all cases.
bearing the same length of the carbon chain (3d vs 3e). (For in-
terpretation of the references to colour in this figure legend, the
reader is referred to the web version of this article.)
In order to explain this increase in reactivity with increasing
length of the fluorous chain we calculated the atomic charge (NBO
charge) and dipole moment of the cationic part of 3d and the cor-
responding non-fluorous reagent 3e using Gaussian 03 HF/6-
2.2. Effect of fluorous tags for the reactivity
During our investigations into the scope and limitations of the
modified fluorous Mukaiyama reagents, we noticed that the rate of
the coupling reaction was greatly influenced by the length of the
fluorous tag in the molecule. The esterification reaction between 2-
phenyl benzoic acid and isopropanol in CDCl3 was again used to
demonstrate this observation. Five separate reactions were set up
under identical conditions each with a different Mukaiyama re-
agent 3ae3e. At given time points, the % conversion of the reaction
was determined by recording 1H NMR spectra of the reaction
mixture and calculating the relative integration between the
methine proton of the isopropyl ester product and the isopropanol
starting material.19 A plot of % conversion versus time is shown in
Fig. 4 with the non-fluorous version of the Mukaiyama reagent
bearing C10H21 tag 3e shown in black, the C8F17 tag 3a shown in red,
the C4F9 tag 3b shown in green, the C6F13 tag 3c shown in purple,
and finally, the C10F21 tag 3d shown in blue. It is evident from Fig. 4
that the reaction rate is greatly affected by the nature of the fluo-
rous tag in the Mukaiyama reagent. The greater the number of
fluorines in the fluorous tag, the higher the reactivity of the reagent.
This is one of the rare examples where a fluorous tag remarkably
changes the reactivity of an organic molecule.20 Interestingly, we
also found that the fluorous version of the Mukaiyama reagent
promotes a faster reaction rate than the non-fluorous reagent
Fig. 4. Comparison of a family of Mukaiyama reagents containing different length
fluorous chains.

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Y. Sugiyama et al. / Tetrahedron 68 (2012) 3885e3892
31þG** method.21 The results of which are shown in Fig. 5 indicate
that there is no significant difference, in terms of the atomic charge
on the carbon atom where nucleophilic attack occurs, between the
fluorous and non-fluorous reagents.22 This can be explained by the
ethylene spacer attenuating the electron withdrawing effect of the
fluorous tag. On the other hand, when the dipole moments were
examined, a remarkable difference was observed between 3b and
3d when the fluorine content went from 47.4 to 60.4%, respectively.
Although it remains as a matter to be discussed and investigated
further, we guess that an aggregation state based on the fluo-
rophilic effect of the fluorous tag in solution, affects the reaction
rate of this coupling reaction. Although we tried some coupling
reactions in fluorous solvents such as FC-72,24 and a mixture of FC-
72 and HFE710025 in order to examine the effect of the aggregation
state of the reagent, reliable data were not obtained due to the
insolubility of the fluorous reagent in these solvents.
the heavy fluorous nature of the product pyridinone greatly facili-
tates purification.
Fig. 6 shows the difference in solubility of pyridones 4a (light
fluorous) and 4d (heavy fluorous) in aq DMF. During our in-
vestigation to find the optimum conditions for the separation, we
found that the medium-fluorous Mukaiyama reagent 3d, which
easily dissolved in N,N-dimethylformamide (DMF) during the
coupling reaction, was insoluble in 80% aq DMF.26 This observation
suggested that the fluorous pyridone 4d could be separated effec-
tively by increasing the water content of the crude product mixture
when DMF is used as the solvent. In practise, compound 4d was
effectively separated in 90% recovery yield as a precipitate by
adding water to the reaction mixture, after the coupling reaction
was complete and filtering (Fig. 7). The purification did not require
any further separation by FSPE using expensive fluorous silica gel.27
This method would be used as a complementary technique for the
light-fluorous strategy.
Fig. 5. Calculation of atomic charge and dipole moment of cation part of Mukaiyama
reagent using Gaussian (6-31þG**/HF) method.
2.3. A facile condensation reactions using medium-fluorous
Mukaiyama reagent
Fig. 6. The solubility of the pyridones 4a and 4d for aq DMF.
So far, we have demonstrated that the by-product derived from
a light-fluorous Mukaiyama reagent is easily separated from the
coupling products by FSPE, and that the fluorous reagent 3d, with
a C10F21 tag, showed the highest reactivity among the Mukaiyama
reagents for the esterification reaction. However we wanted to
further simplify the purification protocol whereby we would not
rely on FSPE but rather a liquideliquid extraction where the fluo-
rous containing by-products would reside in one phase and the
desired products in the other enabling purification by a simple
phase split. Typically though, this strategy requires a compound to
be classified as heavy fluorous.
The classification of light versus medium versus heavy fluorous
is determined by the % of molecular weight that is attributed to the
fluorines with light-fluorous compounds typically being in the
30e40 wt % range.13 Subsequently medium-fluorous compounds
are considered to be between 40 and 60 wt % fluorine and finally
heavy fluorous compounds are anything above 60%. For employing
Fig. 7. A concise separation of fluorous pyridone 4d.
Signals corresponding to fluorous pyridone 4d were not ob-
served in the 1H NMR of the crude product after filtration. In-
terestingly when the C8F17 tagged Mukaiyama reagent (light-
fluorous variant) was used in the typical procedure outlined above,
the reaction was successful, but the purification was not and a small
amount of the pyridone by-product was observed in the filtrate.
This illustrates that it is essential to use C10F21 tag (medium-fluo-
rous type) for effective separation and purification. Table 3 shows
the results of the purification for various coupling reactions
employing reagent 3d. All reactions proceeded at room tempera-
ture and were complete within 2 h to give the target products in
good yields and high purities.
a
liquideliquid purification strategy we envisioned using
Mukaiyama reagent 3d, which bears a C10F21 tag and is thus clas-
sified as a medium-fluorous compound23 given that it is 49 wt %
fluorine. Upon reaction completion, compound 3d is converted to
pyridone 4d with a concomitant reduction in molecular weight. As
a result, the fluorine content of 4d increases to 62% of its molecular
weight, and loses its medium-fluorous compound status and for-
mally becomes a heavy fluorous compound making it amenable to
liquideliquid type extractions. This feature provides a dual benefit
in that the reagent behaves like a medium-fluorous compound
during the reaction in terms of solubility and reactivity, and then

Y. Sugiyama et al. / Tetrahedron 68 (2012) 3885e3892
3889
Table 3
Amide and ester forming reactions with the medium-fluorous Mukaiyama
reagent 3d
Entry
R
R1
R2
Yield (%) Puritya (%)
Amidation
1
2
3
4
5
6
7
8d
Me
Ph
Ph
Ph
Ph
d
d
d
d
d
d
d
d
Quant.
99
98
86
99
Quant.
97
87
98
99
96
95
97
96
99
89
Ph
iPr
PhNHMeb
Ph
L
-ValineeOMec
4-MeOePh
4-NO2ePh
4-NO2ePh
Ph
Ph
PhNHMeb
Esterification
9e
Ph
Ph
Ph
d
d
d
d
d
d
d
d
Bn
94
Quant.
92
90
92
96
96
99
91
87
10
11
12
13
14
15
16
nC4H9
Fig. 8. Effect of counter-anions in medium-fluorous Mukaiyama reagent for coupling
reaction.
nC8H17 Quant.
4-PhePh
4-MeOePh
4-NO2ePh
Boce
Boce
Me
Me
Me
Me
Allyl
98
96
Quant.
Quant.
98
not be traced due to the low solubility for CDCl3. The tri-
fluoromethanesulfonate 3d showed a highest reactivity among
these reagents after 3 h in this esterification reaction. Although the
reason of the difference of the reactivity until 2 h is not elucidated, it
would be reasonable to suppose that a non-nucleophilic anion such
as trifluoromethanesulfonate was suitable in terms of the reactivity.
L
-tryptophanf
-tryptophanf
L
a
Determined by HPLC.
b
c
d
e
f
Phenylmethylamine was used.
-Valine methyl ester was used.
L
The reaction was conducted for 2 h at rt.
The reaction was conducted for 0.5 h at rt.
BoceL-tryptophan was used.
3. Conclusion
2.4. Regeneration of the fluorous Mukaiyama reagents
In summary, a new medium-fluorous Mukaiyama reagent 3d
was prepared and used in a variety of coupling reactions. We
demonstrated that facile purification of the coupling products was
possible by filtration without the need for fluorous solid phase ex-
traction. The reagent 3d was re-generated from pyridone 4d by the
facile procedure. We also conclude that a condensation strategy
using reagent 3d is one of the most practical methods for various
ester and amide-forming reactions in terms of process chemistry.
Finally, we examined a methods to re-generate the medium-
fluorous Mukaiyama reagent 3d from pyridone 4d. The treatment of
4d with phosphorus oxychloride28 and subsequent anion exchange
with sodium trifluoromethanesulfonate provided 3d in 78% yield
after recrystallization from ethyl acetate (Table 4, entry 1). For the
anion exchange reaction, DMF was found to be the most suitable
solvent. In addition, to find out the influence of the counter anion
for the coupling reaction, three medium-fluorous reagents (6e8)
that have different counter anion each were prepared. In the same
way as the previously 1H NMR experiment, these reagents were
tested by recording the 1H NMR spectra of the reaction aspect and
the results were shown in Fig. 8. The reaction using tosylate 8 could
4. Experimental section
4.1. General
All the laboratory chemicals were purchased and used without
purification. Solvents were removed at a heating bath temperature
of 40 ꢀC and reduced pressure by rotary evaporation. Non-volatile
compounds were dried in vacuo at 0.01 mbar. All reactions were
magnetically stirred and monitored by thin layer chromatography
(TLC) using silica gel plates. Purification by chromatography was
Table 4
Preparation of
counter-anions
a family of fluorous Mukaiyama reagents containing different
performed on silica gel (45e75 mm).
4.1.1. A typical procedure for amide formation and FSPE using 3a. To
a solution of benzoic acid (71 mg, 0.58 mmol), N,N-dimethylami-
nopyridine (71 mg, 0.58 mmol) in dry dichloromethane (15 ml)
were added triethylamine (0.24 ml, 1.74 mmol), aniline (0.053 ml,
0.58 mmol) and 3a (500 mg, 0.70 mmol) at room temperature then
the mixture was stirred for 4 h. After washing the organic layer
with aq HCl and removal of the volatile components by evapora-
tion, the mixture was submitted to separation by FSPE. A short
column was packed with fluorous silica gel (7.5 g, 15 times weight
for 3a) using 80% methanol as the solvent. The crude reaction
mixture was then loaded onto this column and eluted with 20 ml of
Entry
NaX
Yield (%)
1
2
3
4
NaOTf
NaBF4
Nal
78a
66b
37c
28c
NaOTs
a
Isolated yield after recryst from AcOEt.
Isolated yield after recryst from AcOEt/MeCN¼2:1.
Isolated yield after recryst from MeCN.
b
c

3890
Y. Sugiyama et al. / Tetrahedron 68 (2012) 3885e3892
80% methanol to give N-phenylbenzamide in quantitative yield
(116 mg) as a white solid.
White crystals; mp 118.0e119.0 ꢀC; 1H NMR (270 MHz, DMSO-d6)
3.02e3.22 (m, 2H), 5.06 (t, 2H, J¼7.4 Hz), 8.15e8.20 (m, 1H), 8.41
(dd,1H, J¼8.6,1.4 Hz), 8.63e8.69 (m,1H), 9.27 (dd,1H, J¼6.5,1.6 Hz);
d
4.1.2. A typical procedure for the coupling reaction and purification
using 3d. To a solution of benzoic acid (62.8 mg, 0.51 mmol), ani-
line (47 ml, 0.51 mmol) and DMAP (62.8 mg, 0.51 mmol) in dry DMF
13C NMR(67.8 MHz, DMSO-d6)
d
29.4(t, J¼21.5 Hz), 51.7,106e122 (m,
C10F21), 120.8 (q, J¼322.3 Hz), 126.9, 130.6, 146.9, 148.5; 19F NMR
(466 MHz, DMSO-d6) ppmꢁ77.7 (3F), ꢁ80.2 (3F), ꢁ112.8(2F), ꢁ121.5
(10F), ꢁ122.4 (2F), ꢁ122.9 (2F), ꢁ125.7 (2F); IR(KBr) nmax cmꢁ1:3059,
1620, 1279, 1153, 1030, 637. Anal. calcd for C18H8ClF24NO3S: C, 26.70,
H, 1.00, N, 1.73; found: C, 26.58, H, 0.94, N, 1.65.
(8 ml) was added the fluorous Mukaiyama reagent 3d (500 mg,
0.61 mmol) at room temperature. The reaction mixture was stirred
for 1 h at ambient temperature. After the addition of H2O (2 ml), the
reaction mixture was stirred for an additional 5 min and then fil-
tered. After washing the precipitate with 20% aq DMF (10 ml), 1.0 M
HCl was added to the filtrate, which was then extracted with
diethyl ether. The organic layer was then washed again with1.0 M
HCl and brine. After drying the organic layer with Na2SO4, con-
centration of the organic phase provided the coupling product in
quantitative yield (101 mg), in high purity (99%).
4.2.5. 2-Chloro-1-dodecyl-pyridinium
3e. White crystals; mp 24.0e25.0 ꢀC; 1H NMR (270 MHz, CDCl3)
0.88 (t, 3H, J¼6.6 Hz), 1.25e1.46 (m, 18H), 1.92e2.03 (m, 2H), 4.81
trifluoromethanesulfonate
d
(t, 2H, J¼7.8 Hz), 8.04e8.13 (m, 2H), 8.50e8.56 (m,1H), 9.21 (dd,1H,
J¼6.1, 1.5 Hz); 13C NMR (67.8 MHz, CDCl3)
d 14.0, 22.6, 26.0, 28.8,
29.2, 29.4, 29.5, 29.9, 31.8, 60.9, 120.6 (q, J¼319.4 Hz), 127.2, 130.4,
146.1, 147.5, 148.2; IR (KBr) nmax cmꢁ1: 3055, 2920, 2855, 1618, 1258,
1161, 1032, 641. Anal. calcd for C18H29ClF3NO3S: C, 50.05, H, 6.77, N,
3.24; found: C, 50.02, H, 6.41, N, 3.11.
4.2. Preparation of fluorous and non-fluorous Mukaiyama
reagents
To
a
solution of 1H,1H,2H,2H-1-perfluorodecanol (15.0 g,
4.2.6. 2-Chloro-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-
32.3 mmol), 2-chloropyridine (10.3 g, 77.1 mmol) in dry dichloro-
methane was added trifluoromethanesulfonic anhydride (10.7 g,
38.0 mmol) at 0 ꢀC and the mixture was stirred at 45 ꢀC for 24 h.
Diethyl ether (100 ml) was added and the mixture was stirred for
0.5 h at room temperature. After the filtration of the crude product,
the recrystallization from ethyl acetate gave 3a (19.0 g, 84%) as
a white powder.
henicosafluorododecyl)pyridinium tetrafluoroborate 6. White crys-
tals; mp 182.0e183.0 ꢀC; 1H NMR (270 MHz, DMSO-d6)
d 3.03e3.23
(m, 2H), 5.07 (t, 2H, J¼7.3 Hz), 8.17e8.22 (m,1H), 8.45 (dd, 1H, J¼8.1,
0.7 Hz), 8.65e8.71 (m, 1H), 9.28 (dd, 1H, J¼5.8, 1.5 Hz); 19F NMR
(466 MHz, DMSO-d6) ppm ꢁ81.2 (3F), ꢁ113.3 (2F), ꢁ122.0 (10F),
ꢁ123.1 (2F), ꢁ123.4 (2F), ꢁ126.5 (2F), ꢁ148.3 (4F); IR (KBr)
nmax cmꢁ1: 3090, 1618, 1217, 1153, 1059, 646.
4.2.1. 2-Chloro-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodec
yl)pyridinium trifluoromethanesulfonate 3a. White crystals; mp
4.2.7. 2-Chloro-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-
henicosafluorododecyl)pyridinium
iodide
7. Yellow crystals;
3.07e3.21 (m, 2H),
88.0e89.0 ꢀC;1H NMR(270 MHz,DMSO-d6)
d
3.03e3.24(m, 2H), 5.08
181.0e182.0 ꢀC; 1H NMR (270 MHz, DMSO-d6)
d
(t, 2H, J¼7.4 Hz), 8.16e8.22 (m, 1H), 8.45 (dd, 1H, J¼8.4, 1.1 Hz),
5.06 (t, 2H, J¼7.3 Hz), 8.17e8.22 (m, 1H), 8.45 (dd, 1H, J¼8.2, 0.9 Hz),
8.65e8.71 (m, 1H), 9.29 (dd, 1H, J¼5.9, 1.1 Hz); 19F NMR (466 MHz,
DMSO-d6) ppm ꢁ80.1 (3F), ꢁ112.7 (2F), ꢁ121.4 (10F), ꢁ122.3 (2F),
ꢁ122.9 (2F), ꢁ125.6 (2F); IR (KBr) nmax cmꢁ1: 3046, 1618, 1215, 1153,
644. Anal. calcd for C17H8ClF21IN: C, 25.93, H, 1.02, N, 1.78; found: C,
25.77, H, 1.30, N, 1.59.
8.65e8.71 (m, 1H), 9.30 (dd, 1H, J¼6.3, 1.8 Hz); 13C NMR (67.8 MHz,
DMSO-d6)
d
29.5 (t, J¼20.0 Hz), 51.7, 106e122 (m, C8F17), 120.7 (q,
J¼322.5 Hz), 126.9, 130.7, 146.9, 148.4, 148.6; 19F NMR (466 MHz,
DMSO-d6) ppm ꢁ78.0 (3F), ꢁ81.2 (3F), ꢁ112.8 (2F), ꢁ121.9 (2F),
ꢁ122.2 (4F), ꢁ123.1 (2F), ꢁ123.3 (2F), ꢁ126.5 (2F); IR (KBr) nmax cmꢁ1
:
3072,1618,1261,1204,1148,1031, 640. Anal. calcdforC16H8ClF20NO3S:
C, 27.08, H, 1.14, N, 1.97; found: C, 26.68, H, 1.10, N, 2.11.
4.2.8. 2-Chloro-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-
henicosafluorododecyl)pyridinium 4-metylbenzenesulfonate
8. White crystals; mp 96.0e97.0 ꢀC; 1H NMR (270 MHz, DMSO-
4.2.2. 2-Chloro-1-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)pyridinium tri-
fluoromethanesulfonate 3b. White crystals; mp 68.0e69.0 ꢀC; 1H
d6)
d
2.29 (s, 3H), 3.07e3.21 (m, 2H), 5.08 (t, 2H, J¼7.4 Hz), 7.11 (d,
NMR (270 MHz, DMSO-d6)
d
3.04e3.24 (m, 2H), 5.08 (t, 2H, J¼7.4 Hz),
2H, J¼8.1 Hz), 7.47 (d, 2H, J¼7.8 Hz), 8.16e8.21 (m, 1H), 8.45 (dd, 1H,
J¼9.0, 1.2 Hz), 8.64e8.70 (m, 1H), 9.29 (dd, 1H, J¼6.2, 1.6 Hz); 19F
NMR (466 MHz, DMSO-d6) ppm ꢁ80.1 (3F), ꢁ112.7 (2F), ꢁ121.5
8.16e8.22 (m, 1H), 8.45 (dd,1H, J¼8.4,1.4 Hz), 8.64e8.70 (m,1H), 9.29
(dd, 1H, J¼6.3, 1.2 Hz); 13C NMR (67.8 MHz, DMSO-d6)?
d 29.2 (t,
J¼21.2 Hz), 51.5, 106e122 (m, C4F9), 120.7 (q, J¼322.1 Hz), 126.7, 130.4,
(10F), ꢁ122.4 (2F), ꢁ122.9 (2F), ꢁ125.6 (2F); IR (KBr) nmax cmꢁ1
:
147.0, 148.2, 148.4; 19F NMR (466 MHz, DMSO-d6) ppm ꢁ77.6 (3F),
3046, 1620, 1217, 1151, 1124, 1011, 683, 563.
ꢁ80.5 (3F), ꢁ113.0 (2F), ꢁ124.0 (2F), ꢁ125.6 (2F); IR (KBr) nmax cmꢁ1
:
3098,1618,1255,1227,1136,1032, 640. Anal. calcd for C12H8ClF12NO3S:
C, 28.28, H, 1.58, N, 2.75; found: C, 28.02, H, 1.50, N, 2.65.
4.3. Recovered fluorous Mukaiyama pyridones
4.3.1. 1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-Heptadecafluorodecyl)pyr-
idin-2(1H)-one 4a. White crystal; mp 98.4e99.2 ꢀC; 1H NMR
4.2.3. 2-Chloro-1-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)pyr-
idinium trifluoromethanesulfonate 3c. White crystals; mp
(270 MHz, CDCl3)
d
2.59e2.73 (m, 2H), 4.21 (t, 2H, J¼7.0), 6.20 (t,1H,
83.0e85.0 ꢀC; 1H NMR (270 MHz, DMSO-d6)
d
3.04e3.25 (m, 2H),
J¼6.5 Hz), 6.58 (d, 1H, J¼9.2 Hz), 7.28 (d, 1H, J¼6.5 Hz), 7.37 (t, 1H,
5.08 (t, 2H, J¼7.4 Hz), 8.17e8.22 (m, 1H), 8.45 (dd, 1H, J¼8.1, 1.4 Hz),
J¼7.9 Hz); 13C NMR (67.8 MHz, CDCl3)
d
29.9 (t, J¼21.4 Hz), 43.5 (d,
8.64e8.71 (m, 1H), 9.30 (dd, 1H, J¼6.3, 1.8 Hz); 13C NMR (67.8 MHz,
J¼4.4 Hz), 106.7, 109.9e124.1 (m, C10F21), 121.3, 137.9, 140.3, 162.7;
19F NMR (466 MHz, CDCl3) ppm ꢁ80.6 (3F), ꢁ113.6 (2F), ꢁ121.5
(2F), ꢁ121.8 (4F), ꢁ122.6 (2F), ꢁ123.3 (2F),126.0 (2F); HRMS [EI] m/z
calcd for C15H8ONF17 541.0334, found: 541.0332.
DMSO-d6)
d
29.3 (t, J¼20.9 Hz), 51.5, 106e122 (m, C6F13), 120.7 (q,
J¼321.1 Hz), 126.7, 130.5, 147.0, 148.2, 148.5; 19F NMR (466 MHz,
DMSO-d6) ppm ꢁ77.7 (3F), ꢁ80.2 (3F), ꢁ112.7 (2F), ꢁ121.6 (2F),
ꢁ122.6 (2F), ꢁ123.0 (2F), ꢁ125.7 (2F); IR (KBr) nmax cmꢁ1: 3090,
1618, 1200, 1123, 1032, 642. Anal. calcd for C14H8ClF16NO3S: C,
27.58, H, 1.32, N, 2.30; found: C, 27.20, H, 1.19, N, 2.33.
4.3.2. 1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-
Henicosafluorododecyl)pyridin-2(1H)-one 4d. White crystal; mp
121.9e122.5 ꢀC; 1H NMR (270 MHz, CDCl3)
d 2.56e2.75 (m, 2H),
4.2.4. 2-Chloro-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-
henicosafluorododecyl) pyridinium trifluoromethanesulfonate 3d.
4.21 (t, 2H, J¼7.3 Hz), 6.20 (t, 1H, J¼6.8 Hz), 6.58 (d, 1H, J¼9.2 Hz),
7.28 (d, 1H, J¼7.3 Hz), 7.36 (t, 1H, J¼7.0 Hz); 13C NMR (67.8 MHz,

Y. Sugiyama et al. / Tetrahedron 68 (2012) 3885e3892
3891
CDCl3)
d
29.7 (t, J¼21.4 Hz), 43.4 (d, J¼4.9 Hz), 106.5, 109.8e123.5
2H, J¼10.8 Hz), 7.14 (t, 1H, J¼6.8 Hz), 7.37 (t, 2H, J¼8.1 Hz), 7.63 (dd,
2H, J¼4.4, 0.6 Hz), 7.85 (d, 2H, J¼4.1 Hz).
(m, C10F21), 121.3, 137.7, 140.1, 162.5; 19F NMR (466 MHz, CDCl3)
ppm ꢁ80.6 (3F), ꢁ113.6 (2F), ꢁ121.5 (5F), ꢁ121.8 (5F), ꢁ122.5 (2F),
ꢁ123.3 (2F), ꢁ125.9 (2F); HRMS [EI] m/z calcd for C17H8ONF21
641.0271, found: 641.0231.
4.4.15. 4-Methoxy-N-methyl-N-phenylbenzamide.35 Yellow oil; 1H
NMR (270 MHz, CDCl3)
d
3.52 (s, 3H), 7.03 (d, 2H, J¼7.0 Hz),
7.15e7.28 (m, 3H), 7.44 (d, 2H, J¼8.9 Hz), 8.03 (d, 2H, J¼7.0 Hz).
4.4.16. 4-Nitro-N-phenylbenzamide.36 Pale yellow crystals; mp
4.4. Coupling products
4.4.1. Methyl-biphenyl-4-carboxylate.3d Yellow
106.0e107.0 ꢀC; 1H NMR (270 MHz, CDCl3)
3.94 (s, 3H), 7.35e7.50
(m, 3H), 7.62e7.69 (m, 4H), 8.11 (d, 2H, J¼8.6 Hz).
crystals;
mp
212.0e213.0 ꢀC; 1H NMR (270 MHz, CDCl3)
d 7.21 (br s, 1H), 7.41 (t,
d
2H, J¼8.1 Hz), 7.64 (d, 2H, J¼8.1 Hz), 7.78 (s, 1H), 8.05 (d, 2H,
J¼8.1 Hz), 8.36 (d, 2H, J¼8.1 Hz).
4.4.2. Allyl-biphenyl-4-carboxylate.3d Brown oil; 1H NMR (270 MHz,
4.4.17. N-Methyl-4-nitro-N-phenylbenzamide.36 Yellow-brown
CDCl3)
d
4.84e4.87 (m, 2H), 5.29e5.45 (m, 2H), 5.99e6.12 (m, 1H),
crystals; mp 101.0e102.0 ꢀC; 1H NMR (270 MHz, CDCl3)
d 3.48 (s,
7.39e7.50 (m, 3H), 7.61e7.69 (m, 4H), 8.14 (d, 2H, J¼8.6 Hz).
3H), 3.74 (s, 3H), 6.66 (dd, 2H, J¼6.8, 2.2 Hz), 7.04 (d, 2H, J¼6.8 Hz),
7.14e7.39 (m, 5H).
4.4.3. Methyl-2-(biphenyl-4-yl)acetate.3d Brown oil; 1H NMR
(270 MHz, CDCl3)
d
3.60 (s, 2H), 3.64 (s, 3H), 7.27e7.52 (m, 9H).
4.4.18. N-Phenylbiphenyl-2-carboxamide.37 White crystals; mp
105.0e106.0 ꢀC; 1H NMR (270 MHz, CDCl3)
d 6.86 (s, 1H), 7.02e7.11
4.4.4. Methyl-biphenyl-2-carboxylate.29 Yellow oil; 1H NMR
(m, 4H), 7.21 (d, 2H, J¼7.3 Hz), 7.42e7.55 (m, 7H), 7.91 (d, 1H,
(270 MHz, CDCl3) 3.62 (s, 3H), 7.28e7.41 (m, 7H), 7.48e7.58 (m,
d
J¼8.1 Hz).
1H), 7.80e7.83 (m, 1H).
4.4.19. 2-(Biphenyl-4-yl)-N-methyl-N-phenylacetamide.3d White
4.4.5. Allyl-biphenyl-2-carboxylate. Pale yellow oil; 1H NMR
crystals; mp 57.0e58.0 ꢀC; 1H NMR (270 MHz, CDCl3)
3.42 (s, 3H), 7.04e7.37 (m, 12H), 7.40e7.50 (m, 2H).
d 3.22 (s, 2H),
(270 MHz, CDCl3)
d 4.52e4.55 (m, 2H), 5.06e5.14 (m, 2H),
5.57e5.72 (m, 1H), 7.30e7.44 (m, 7H), 7.50e7.56 (m, 1H), 7.85 (dd,
1H, J¼7.8, 1.4 Hz); 13C NMR (67.8 MHz, CDCl3)
d
65.6, 118.2, 127.17,
4.4.20. N-Methyl-2-(naphthalen-1-yl)-N-phenylacetamide.38 Brown
127.22, 128.1, 128.4, 129.9, 130.7, 130.9, 131.3, 131.7, 141.4, 142.6,
oil; 1H NMR (270 MHz, CDCl3)
d 3.31 (s, 3H), 3.91 (s, 2H), 7.09e7.45
168.4; HRMS [EI] m/z calcd for C16H14O2 238.0994, found: 238.0954.
(m, 9H), 7.69e7.82 (m, 3H).
4.4.6. Methyl-4-methoxybenzoate.30 Brown
crystals;
3.87 (d, 6H, J¼7.3 Hz),
mp
4.4.21. (S)-tert-Butyl-3-(1H-indol-3-yl)-1-(2-methoxybenzylamino)-
1-oxopropan-2-ylcarbamate.39 Pale
yellow crystals; mp
76.0e77.0 ꢀC; 1H NMR (270 MHz, CDCl3)
1.41 (s, 9H), 3.05e3.12
(m, 1H), 3.24e3.31 (m, 1H), 3.57 (s, 3H), 4.02e4.39 (m, 3H), 5.21 (s,
1H), 6.04 (s, 1H), 6.74e6.88 (m, 3H), 7.04e7.31 (m, 5H), 7.65e7.75
(m, 2H).
43.0e44.0 ꢀC; 1H NMR (270 MHz, CDCl3)
6.92 (d, 2H, J¼7.0 Hz), 8.00 (d, 2H, J¼8.9 Hz).
d
d
4.4.7. Methyl-4-nitrobenzoate.30 Yellow crystals; mp 89.0e90.0 ꢀC;
1H NMR (270 MHz, CDCl3)
3.99 (s, 3H), 8.19e8.32 (m, 4H).
d
4.4.8. (S)-Methyl-2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)
4.4.22. N-Phenylacetamide.32 Pale
107.0e108.0 ꢀC; 1H NMR (270 MHz, CDCl3)
J¼7.3 Hz), 7.32 (t, 2H, J¼7.8 Hz), 7.49 (d, 2H, J¼7.8 Hz).
yellow
crystals;
mp
propanoate.3d Brown crystals; mp 141.0e142.0 ꢀC; 1H NMR
d
2.18 (s, 3H), 7.11 (t, 2H,
(270 MHz, CDCl3)
d
1.42 (s, 9H), 3.28 (d, 2H, J¼5.1 Hz), 3.67 (s, 3H),
4.65 (d, 1H, J¼7.6 Hz), 5.09 (d, 1H, J¼7.6 Hz), 6.98 (d, 1H, J¼1.6 Hz),
7.08e7.21 (m, 2H), 7.55 (d, 1H, J¼7.6 Hz), 8.20 (s, 1H).
4.4.23. N-Isopropylbenzamide.40 Pale
yellow crystals;
mp
64.0e65.0 ꢀC; 1H NMR (270 MHz, CDCl3)
1.27 (d, 6H, J¼6.8 Hz),
d
4.4.9. (S)-Biphenyl-4-yl-2-(tert-butoxycarbonylamino)-3-(1H-indol-
4.18e4.36 (m, 1H), 5.89 (br s, 1H), 7.39e7.49 (m, 3H), 7.75 (d, 2H,
J¼6.5 Hz).
3-yl)propanoate.3d Brown crystals; mp 159.0e160.0 ꢀC; 1H NMR
(270 MHz, CDCl3)
J¼9.9 Hz), 5.12 (d, 1H, J¼8.6 Hz), 7.02e7.62 (m, 14H).
d
1.37 (s, 9H), 3.37 (d, 2H, J¼5.4 Hz), 4.82 (d, 1H,
4.4.24. (S)-Methyl-2-benzamido-3-methylbutanoate.41 Pale yellow
crystals; mp 115.0e116.0 ꢀC; 1H NMR (270 MHz, CDCl3)
d 1.01 (t, 6H,
4.4.10. N-Methyl-N-phenylacetamide.31 Pale yellow oil; 1H NMR
J¼6.7 Hz), 2.22e2.34 (m,1H), 3.78 (s, 3H), 4.79 (dd,1H, J¼8.9, 4.8 Hz),
(270 MHz, CDCl3)
d 1.87 (s, 3H), 3.27 (s, 3H), 7.17e7.44 (m, 5H).
6.63 (d, 1H, J¼7.8 Hz), 7.42e7.56 (m, 3H), 7.83 (d, 2H, J¼7.8 Hz).
4.4.11. N-Phenylbenzamide.32 Pale
yellow
158.0e159.0 ꢀC; 1H NMR (270 MHz, CDCl3)
crystals;
7.15 (br s, 1H),
mp
4.4.25. Benzyl benzoate.42 Yellow oil; 1H NMR (270 MHz, CDCl3)
d
d
5.37 (s, 2H), 7.31e7.65 (m, 8H), 8.06e8.12 (m, 2H).
7.32e7.41 (m, 2H), 7.45e7.59 (m, 3H), 7.63e7.66 (m, 5H).
4.4.26. Butyl benzoate.43 Pale yellow oil; 1H NMR (270 MHz, CDCl3)
4.4.12. N-Methyl-N-phenylbenzamide.33 Yellow oil; 1H NMR
d
1.01 (t, 3H, J¼7.0 Hz), 1.41e1.55 (m, 2H), 1.71e1.86 (m, 2H), 4.33 (t,
(270 MHz, CDCl3)
d
3.50 (s, 3H), 7.02e7.31 (m, 2H), 7.47 (dt, 3H,
2H, J¼7.0 Hz), 7.41e7.47 (m, 2H), 7.50e7.59 (m, 1H), 8.07 (d, 2H,
J¼7.9 Hz).
J¼7.2, 1.4 Hz), 7.58e7.64 (m, 2H), 8.10e8.14 (m, 3H).
4.4.13. N-(2-Methoxybenzyl)benzamide.34 Pale yellow crystals; mp
4.4.27. Octyl benzoate.44 Pale yellow oil; 1H NMR (270 MHz, CDCl3)
77.0 ꢀC; 1H NMR (270 MHz, CDCl3)
d
3.89 (s, 3H), 4.64 (d, 2H,
d
0.91 (t, 3H, J¼7.0 Hz), 1.18e1.31 (m, 8H), 1.41e1.71 (m, 2H),
J¼5.4 Hz), 6.62 (s, 1H), 6.89e6.96 (m, 3H), 7.28e7.48 (m, 4H),
1.74e1.82 (m, 2H), 4.32 (t, 2H, J¼7.0 Hz), 7.41e7.46 (m, 2H),
7.52e7.59 (m, 1H), 8.05 (d, 2H, J¼8.3 Hz).
7.74e7.77 (m, 2H).
4.4.14. 4-Methoxy-N-phenylbenzamide.33 White
158.0e159.0 ꢀC; 1H NMR (270 MHz, CDCl3)
3.88 (s, 3H), 6.98 (d,
crystals;
mp
4.4.28. (S)-Allyl-2-((tert-butoxycarbonyl)amino)-3-(1H-indol-3-yl)
d
propanoate.3d Pale yellow crystals; mp 112.0e113.0 ꢀC; 1H NMR

3892
Y. Sugiyama et al. / Tetrahedron 68 (2012) 3885e3892
120.7 (q, J¼322.5 Hz), 126.9, 130.7, 146.9, 148.4, 148.6; 19F NMR (466 MHz,
(270 MHz, CDCl3)
d
1.42 (s, 9H), 3.30 (d, 2H, J¼4.9 Hz), 4.56 (d, 2H,
DMSO-d6) ppm ꢁ78.0 (3F), ꢁ81.2 (3F), ꢁ112.8 (2F), ꢁ121.9 (2F), ꢁ122.2 (4F),
ꢁ123.1 (2F), ꢁ123.3 (2F), ꢁ126.5 (2F); IR (KBr) nmax cmꢁ1: 3072, 1618, 1261,
1204, 1148, 1031, 640. Anal. calcd for C16H8ClF20NO3S: C, 27.08, H, 1.14, N, 1.97;
found: C, 26.68, H, 1.10, N, 2.11.
J¼5.4 Hz), 4.67 (m, 1H), 5.08 (m, 1H), 5.19e5.31 (m, 2H), 5.76e5.91
(m, 1H), 7.02 (d, 1H, J¼2.2 Hz), 7.10e7.22 (m, 2H), 7.34 (d, 1H,
J¼7.8 Hz), 7.56 (d, J¼7.6 Hz, 1H), 8.18 (s, 1H).
16. 3e: white crystals; mp 24.0e25.0 ꢀC; 1H NMR (270 MHz, CDCl3)
d 0.88 (t, 3H,
J¼6.6 Hz), 1.25e1.46 (m, 18H), 1.92e2.03 (m, 2H), 4.81 (t, 2H, J¼7.8 Hz), 8.04e8.
Acknowledgements
13 (m, 2H), 8.50e8.56 (m, 1H), 9.21 (dd, 1H, J¼6.1, 1.5 Hz); 13C NMR (67.8 MHz,
CDCl3)
d
14.0, 22.6, 26.0, 28.8, 29.2, 29.4, 29.5, 29.9, 31.8, 60.9, 120.6 (q, J¼319.
4 Hz), 127.2, 130.4, 146.1, 147.5, 148.2; IR (KBr) nmax cmꢁ1: 3055, 2920, 2855,
1618, 1258, 1161, 1032, 641. Anal. calcd for C18H29ClF3NO3S: C, 50.05, H, 6.77, N,
3.24; found: C, 50.02, H, 6.41, N, 3.11.
This research was partially supported by the Ministry of Edu-
cation, Science, Sports and Culture, Grant-in-aid for Scientific Re-
search (C), 23580154, and the fund for Agriomics project. We thank
Prof. Dennis P. Curran, University of Pittsburgh, for the useful dis-
cussion and Mr. Masahiko Bando, Otsuka Pharmaceutical Co. Ltd.,
for the elemental analysis of the fluorous Mukaiyama reagents
3ae3d and 7. We also thank Wako Pure Chemical Industries, Ltd. for
funding this work.
17. Curran, D. P. Separations with fluorous silica gel and related materials In The
ꢀ
Handbook of Fluorous Chemistry; Gladysz, J., Horvath, I., Curran, D. P., Eds.;
Wiley-VCH: Weinheim, 2004; pp 101e127.
18. The fluorous TLC is TLC plate, which is coated with fluorous silica gel and
commercially available from Fluorous Technologies Inc; http://www.fluorous.
com/.
19. The control experiments to confirm the relative integration of the isopropyl
function were conducted. Isopropanol was mixed with 3a and DMAP in CDCl3
without 2-phenylbenzoic acid and traced for 2 h by NMR. As the result, the
integration from the isopropanol stayed the same. The same experiment with
the ester was also conducted.
References and notes
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14. There is a significant difference among isolated yields of the products due to
the marked difference in crystallinity of the different reagents. Preparation of
fluorous Mukaiyama reagent 3a: To
a
solution of 1H,1H,2H,2H-1-
perfluorodecanol (15.0 g, 32.3 mmol), 2-chloropyridine (10.3 g, 77.1 mmol) in
dry dichloromethane was added trifluoromethanesulfonic anhydride (10.7 g,
38.0 mmol) at 0 ꢀC and the mixture was stirred at 45 ꢀC for 24 h. Diethyl ether
(100 ml) was added and the mixture was stirred for 0.5 h at room temperature.
After the filtration of the crude product, the recrystallization from ethyl acetate
gave 3a (19.0 g, 84%) as a white powder.
42. Cronin, L.; Manoni, F.; O’ Connor, C. J.; Connon, S. J. Angew. Chem., Int. Ed. 2010,
15. Fluorous Mukaiyama reagent 3a: white crystals; mp 88.0e89.0 ꢀC; 1H NMR
49, 3045e3048.
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74, 5967e5974.
(270 MHz, DMSO-d6)
1H), 8.45 (dd, 1H, J¼8.4, 1.1 Hz), 8.65e8.71 (m, 1H), 9.30 (dd, 1H, J¼6.3, 1.8 Hz);
13C NMR (67.8 MHz, DMSO-d6)
29.5 (t, J¼20.0 Hz), 51.7, 106e122 (m, C8F17),
d
3.03e3.24 (m, 2H), 5.08 (t, 2H, J¼7.4 Hz), 8.16e8.22 (m,
d