Preparation and condensation reactions of a new light-fluorous Mukaiyama reagent: reliable purification with fluorous solid phase extraction for esters and amides

Article abstract of DOI:10.1016/j.tetlet.2007.03.173

A modified light-fluorous Mukaiyama reagent bearing a C₈F₁₇ tag was prepared and examined in ester and amide forming condensation reactions. Following the reactions, the desired product was effectively separated from the fluorous pyridone by-product using a simple fluorous solid phase extraction.

Full text of DOI:10.1016/j.tetlet.2007.03.173

Tetrahedron Letters 48 (2007) 4147–4150
Preparation and condensation reactions of a new light-fluorous
Mukaiyama reagent: reliable purification with fluorous solid
phase extraction for esters and amides
Masato Matsugi,a,* Masakazu Hasegawa,a Daisuke Sadachika,a Sachina Okamoto,a
Mami Tomioka,a Yoshimi Ikeya,a Araki Masuyamab and Yuji Moric
aFaculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
bFaculty of Engineering, Osaka Institute of Technology, 5-16-1 Omiya, Asahi, Osaka 535-8585, Japan
cFaculty of Pharmacy, Meijo University, 150, Yagotoyama, Tempaku, Nagoya 464-8606, Japan
Received 19 February 2007; revised 19 March 2007; accepted 23 March 2007
Available online 6 April 2007
Abstract—A modified light-fluorous Mukaiyama reagent bearing a C8F17 tag was prepared and examined in ester and amide form-
ing condensation reactions. Following the reactions, the desired product was effectively separated from the fluorous pyridone
by-product using a simple fluorous solid phase extraction.
Ó 2007 Published by Elsevier Ltd.
The Mukaiyama condensation reagent (N-methyl-2-
chloropyridinium iodide)1 1 is one of the most useful re-
N+ Cl
agents in organic synthesis and there are many reports
of its use for the key ester or amide forming step of
the synthetic route. Since the reagent was reported in
1975, various N-alkyl-2-halopyridinium salts have been
developed, with the aim of achieving higher levels of effi-
ciency.2 Recently, fluorous-tagged 2-chloropyridinium
hexafluorophosphate 2 was reported by Nagashima
et al.3 and shown to successfully promote amide bond
formation (see Fig. 1). A fluorous benzyl group was
used as the fluorous tag, and fluorous solid phase extrac-
tion (FSPE)4 of the reaction mixture cleanly removed
the corresponding fluorous pyridone by-product. In
this protocol, the addition of 1-hydroxybenzotriazole
(HOBT) is required to decrease the formation of the car-
boxylic anhydride by-product, so a resin-bound carbon-
ate scavenger was used to remove excess HOBT.5
Herein, we report a simple procedure for the condensa-
tion reaction using a new light-fluorous6 Mukaiyama
reagent 3, which is more reactive than 2 and easily
removable from the desired product using FSPE.
Cl
F6P-
N+
I-
Me
2
1
C9F19
Figure 1.
Scheme 12d in 72% isolated yield after recrystallisation.7
Elemental analysis as well as the 1H and 19F NMR spec-
tra provide support for the salt structure 3.8 Compound
3 is a white powder that can be stored in the desiccator
without decomposition for over one year. We chose the
triflate as the counterion for the pyridinium salt because
a triflate anion is reportedly a good counter anion for
Mukaiyama-type reagents.2c
OH
C8F17
Tf2O
The light-fluorous Mukaiyama reagent 3 was easily pre-
pared from 2-chloropyridine in a one step as shown in
N+ Cl
TfO-
CH2Cl2, 45 °C, 24 h
N
Cl
72% (from AcOEt)
3
C8F17
*
Corresponding author. Tel.: +81 52 832 1151; e-mail: matsugi@
ccfms.meijo-u.ac.jp
Scheme 1. Synthesis of the fluoroalkyl Mukaiyama reagent.
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.03.173

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M. Matsugi et al. / Tetrahedron Letters 48 (2007) 4147–4150
reagent (1.2 eq)
OH
We expected that the fluorous Mukaiyama reagent with
the ethylene spacer, 3, to be more active in the conden-
sation reaction than the ethylene benzyl spacer because
the inductive effect of the fluorous tag should be stron-
ger and because its fluorous tag is not bulky. To test this
hypothesis, we compared the reactivity of the three
Mukaiyama reagents in question 1–3 in an esterification
reaction between 2-phenyl benzoic acid and isopropanol
(1 eq)
Et3N (3 eq)
DMAP (1 eq)
i
CO2H
Ph
CO2 Pr
CDCl3 (0.3 M), rt
Ph
1
in CDCl3 as the solvent to allow for H NMR monitor-
ing of reaction aliquots. Three separate reactions were
90
80
70
60
50
40
30
20
10
0
Me
N
Me
1
2
3
N
O
O
C8F17
5
4
4 5
4 5
silica gel
TLC
fluorous
TLC
0
20
40
60
time (min)
80
100
(AcOEt/hexane=1/1) (80% aq.MeOH)
Figure 3. Comparison of TLC between FSPE conditions and regular
Figure 2. Comparison of conversion for ester formation in CDCl3.
conditions.
Table 1. Ester formation using 3 and FSPE
3 (1.2 eq)
Et3N (3 eq)
DMAP (1 eq)
R'OH (1 eq)
1) washing with aq. HCl
2) FSPE (80% MeOH)a
RCO2H
RCO2R'
CH2Cl2
rt
Entry
1
Carboxylic acid
Alcohol
Time (h)
Yieldb (%)
Quant.
Purityc (%)
99.0
CO2H
MeOH (10 equiv)
1
Ph
CO2H
2
3
1
99
99.1
97.4
OH
Ph
CH2CO2H
MeOH (10 equiv)
0.5
Quant.
Ph
CO2H
4
MeOH (10 equiv)
1
87
98.9
Ph
CO2H
5
6
2
1
80
94
92.0
99.8
OH
Ph
CO2H
MeOH (10 equiv)
MeO
NHBoc
CO2H
7
8
MeOH (10 equiv)
1
1
71
99.0
98.0
N
H
NHBoc
CO2H
OH
Quant.
Ph
N
H
a The amount of fluorous silica gel used was 15 times the weight of 3.
b Isolated yield.
c Determined by HPLC.

M. Matsugi et al. / Tetrahedron Letters 48 (2007) 4147–4150
4149
set up under identical conditions each with a different
Mukaiyama reagent either 1, 2 or 3. At given time points
the % conversion of the reaction was determined by
recording 1H NMR spectra of the reaction mixtures
and calculating the relative integrals of the methine pro-
ton of isopropoxy ester. A plot of % conversion versus
time is shown in Figure 2 with the original Mukaiyama
reagent 1 shown in red, the ethylene spacer version 3
shown in blue, and finally the ethylene benzyl derivative,
2, shown in green. It is clear that fluorous reagent 3 has
a higher reactivity than 2, and almost the same reactivity
as the original Mukaiyama reagent 1 in this particular
ester forming reaction. Interestingly, the solubility of
2, which showed the lowest activity, was the highest
among these reagents.
ous Mukaiyama reagent 3, the target product could
not be separated effectively from the corresponding pyri-
done 4 by standard column chromatography. The Rf
values (AcOEt/hexane = 1/1) of 4 and product 5 were
0.30, and 0.33, respectively, by regular TLC (Silica gel
60 F254; MERCK) as shown in Figure 3. As a result
complete resolution of adducts 4 and 5 by column chro-
matography was not trivial. On the other hand, there
was a remarkable difference in Rf values between 4
and 5 on fluorous TLC10 (0.11 vs 0.83) when eluting
with 80% MeOH as shown in Figure 3. This significant
difference in Rf enabled facile separation of fluorous
pyridone 4 and amide 5 when the FSPE strategy was
employed.
Table 1 shows the various ester formation reactions
using 3 under mild basic conditions. The procedure of
the condensation reaction was simple and easily carried
out. All reactions proceeded at room temperature and
were complete in under 2 h. Upon completion, the reac-
tion mixture was washed with aq HCl to remove the
TEA and DMAP and then subjected to FSPE eluting
with 80% MeOH to give the target products in good
yields and high purities.11 Similarly, various amide
forming reactions without HOBT were investigated
and the results are shown in Table 2. Although the
Synthetically, we envisioned separating the target prod-
uct from fluorous pyridone 4, derived from the Mukai-
yama reagent, via FSPE after the condensation reaction.9
The ability of simple product purification is the most
important feature of the fluorous Mukaiyama reagent.
When the Rf values of both the product and the pyri-
done by-product are similar to each other, it is difficult
to separate these compounds effectively by the usual
chromatography. For example, when acetic acid and
N-methylaniline were used as the substrates with fluor-
Table 2. Amido formation using 3 and FSPE
3 (1.2 eq)
Et3N (3 eq)
DMAP (1 eq)
R'R''NH (1 eq)
1) washing with aq. HCl
RCO2H
RCONR'R''
2) FSPE (80% MeOH)a
CH2Cl2
rt
Entry
1
Carboxylic acid
Amine
Time (h)
2
Yieldb (%)
80
Purityc (%)
99.1
CO2H
NH2
OMe
CO2H
2
3
PhNH2
PhNH2
4
2
Quant.
86
99.8
95.1
CO2H
MeO
MeO
CO2H
NHMe
4
5
77
98.9
CO2H
CO2H
5
PhNH2
NHMe
2
2
76
91
99.7
95.8
O2N
O2N
6d
CO2H
7
8
PhNH2
2
2
84
84
99.8
98.9
Ph
NHBoc
CO2H
NH2
OMe
N
H
a The amount of fluorous silica gel used was 15 times the weight of 3.
b Isolated yield.
c Determined by HPLC.
d 0.2 equiv of DMAP was used.

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M. Matsugi et al. / Tetrahedron Letters 48 (2007) 4147–4150
Lindsley, C. W.; Zhao, Z.; Leister, W. H.; Strauss, K. A.
Tetrahedron Lett. 2002, 43, 6319–6323; (d) Zhang, W.;
Chen, C. H.-T.; Nagashima, T. Tetrahedron Lett. 2003, 44,
2065–2068.
by-products that did not move on TLC were slightly
observed, moderate to good yields and easy purification
were achieved in all cases.
6. Curran, D. P. A User’s Guide to Light Fluorous Chem-
istry. In The Handbook of Fluorous Chemistry; Gladysz, J.,
In summary, a new fluorous Mukaiyama reagent 3 was
prepared and it was found that the reactivity was higher
than known fluorous Mukaiyama reagent 2. Further-
more, we demonstrated that 3 is a useful reagent for
condensation reactions when the Rf values of both the
product and the pyridone by-product are similar on
regular TLC. We conclude that a condensation strategy
using reagent 3 and FSPE is one of the most conve-
nient methods for various ester and amide forming
reactions.
´
Horvath, I., Curran, D. P., Eds.; Wiley-VCH: Weinheim,
2004; pp 128–155, Light fluorous molecules typically
contain 21 fluorines or fewer, and molecular weights can
range from 400 to about 900 mu. They may exhibit little or
even no solubility in fluorous solvent, so separations with
fluorous solid phase are often the only practical methods.
7. Preparation of fluorous Mukaiyama reagent 3: To a
solution of 1H,1H,2H,2H-1-perfluorodecanol (68.4 g,
85.3 mmol), 2-chloropyridine (33.5 g, 171 mmol) in dry
dichloromethane was added trifluoromethanesulfonic
anhydride (50.0 g, 177 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
recrystallisation from ethyl acetate gave 1 (68.2 g, 72%) as
a white powder.
8. Fluorous Mukaiyama reagent 3: white powder; mp 131.0–
132.0 °C; 1H NMR (270 MHz, DMSO-d6) d: 3.04–3.29
(2H, m), 5.07 (2H, t, J = 7.4 Hz), 8.19 (1H, m), 8.45 (1H,
d, J = 8.2 Hz), 8.64–8.70 (1H, m), 9.28 (1H, d, J = 6.3
Hz); 19F NMR (465 MHz, DMSO-d6) ppm À125.7 (2F),
À123.0 (2F), À122.5 (2F), À121.7 (4F), À121.4 (2F),
À112.8 (2F), À80.2 (3F), À77.8 (3F); Anal. Calcd for
C16H8ClF20NO3S: C, 27.08; H, 1.14; N, 1.97. Found: C,
26.68; H, 1.10; N, 2.11.
Acknowledgements
This work was supported by Grant-in-Aids for Creative
Scientific Research (No. 14GS0214) from the Japan
Society for the Promotion of Science. We thank Profes-
sor Dennis P. Curran, University of Pittsburgh, for the
useful discussion and Professor Shuji Akai, Shizuoka
Pharmaceutical University, for the elemental analysis
of the fluorous Mukaiyama reagent 3. We also thank
Wako Pure Chemical Industries, Ltd, for funding this
work.
References and notes
9. Curran, D. P. Separations with Fluorous Silica Gel and
Related Materials. In The Handbook of Fluorous Chemis-
´
1. (a) Mukaiyama, T.; Usui, M.; Shimada, E.; Saigo, K.
Chem. Lett. 1975, 1045–1048; (b) Mukaiyama, T.; Toda,
H.; Kobayashi, S. Chem. Lett. 1976, 13–14; (c) Mukai-
yama, T.; Narasaka, K.; Kikuchi, K. Chem. Lett. 1977,
441–444.
2. For examples: (a) Mukaiyama, T.; Aikawa, Y.; Koba-
yashi, S. Chem. Lett. 1976, 57–60; (b) Kametani, T.; Sekine,
H.; Honda, T. Heterocycles 1983, 20, 1577–1580; (c)
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Chem. 1998, 63, 8170–8182; (d) Crosignani, S.; Gonzalez,
J.; Swinnen, D. Org. Lett. 2004, 6, 4579–4582; (e) Donati,
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3. Nagashima, T.; Lu, Y.; Petro, M. J.; Zhang, W. Tetra-
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4. (a) Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997,
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2002, 58, 3871–3875; (b) Lindsley, C. W.; Zhao, Z.;
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try; Gladysz, J., Horvath, I., Curran, D. P., Eds.; Wiley-
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10. The fluorous TLC is a TLC plate, which is coated with
fluorous silica gel and commercially available from Flu-
orous Technologies Incorporated; <http://www.fluorous.
com/>.
11. A typical procedure for amide formation and FSPE: To a
solution of benzoic acid (71 mg, 0.58 mmol), N,N-dimeth-
ylaminopyridine (71 mg, 0.58 mmol) in dry dichloro-
methane (15 ml) were added triethylamine (0.24 ml, 1.74
mmol), aniline (0.053 ml, 0.58 mmol) and 3 (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 3) using 80% methanol as the solvent. The
crude reaction mixture was then loaded onto this column
and eluted with 20 ml of 80% methanol to give N-
phenylbenzamide in quantitative yield (116 mg) as a white
solid.