An alternative and facile purification procedure of amidation and esterification reactions using a medium fluorous Mukaiyama reagent

Article abstract of DOI:10.1016/j.tetlet.2008.09.016

A convenient methodology for the separation of a fluorous by-product using fluorous chemistry is described. A Mukaiyama coupling reagent bearing a medium fluorous tag, between 40% and 60% fluorine by weight, can be effectively separated from non-fluorous components by increasing the water content of the crude reaction mixture and subsequent filtration. Additional fluorous solid phase extraction is not necessary.

Full text of DOI:10.1016/j.tetlet.2008.09.016

Tetrahedron Letters 49 (2008) 6573–6574
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An alternative and facile purification procedure of amidation and
esterification reactions using a medium fluorous Mukaiyama reagent
*
Masato Matsugi , Misaki Suganuma, Shoko Yoshida, Shohei Hasebe, Yoko Kunda,
Kotaro Hagihara, Sayaka Oka
Faculty of Agriculture, Meijo University, 1-501 Shiogamaguchi, Tempaku, Nagoya 468-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient methodology for the separation of a fluorous by-product using fluorous chemistry is
described. A Mukaiyama coupling reagent bearing a medium fluorous tag, between 40% and 60% fluorine
by weight, can be effectively separated from non-fluorous components by increasing the water content of
the crude reaction mixture and subsequent filtration. Additional fluorous solid phase extraction is not
necessary.
Received 22 August 2008
Revised 3 September 2008
Accepted 5 September 2008
Available online 9 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Organic molecules bearing small fluorous tags (C6F13 and C8F17
)
a heavy fluorous compound. This feature provides a dual benefit in
that the reagent behaves like a light fluorous compound during the
reaction in terms of solubility and reactivity, and then the almost
heavy fluorous nature of the product pyridone greatly facilitates
purification. During our investigation to find the optimum condi-
tions for the separation, we found that the medium fluorous
Mukaiyama reagent 1, which easily dissolved in N,N-dimethyl-
formamide (DMF) during the coupling reaction, was insoluble in
20% aq DMF.10 This observation suggested that the fluorous pyri-
done 2 could be separated effectively by increasing the water con-
tent in the crude product mixture when DMF is used as the solvent.
In practice, compound 2 was effectively separated as a precipitate
by adding water to the reaction mixture after the coupling reaction
was complete and filtering. The purification did not require any
further separation by fluorous solid phase extraction using expen-
sive fluorous silica gel.11 A typical procedure for the coupling reac-
tion and purification is as follows: To a solution of benzoic acid
(62.8 mg, 0.51 mmol), aniline (47 ml, 0.51 mmol), Et3N (0.215 ml,
1.54 mmol) and DMAP (4-dimethylaminopyridine: 62.8 mg,
0.51 mmol) in dry DMF (8 ml: 16 volume/weight for 1) was added
the fluorous Mukaiyama reagent 1 (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:4 volume/weight for
1), the reaction mixture was stirred for an additional 5 min and
then filtered (Scheme 1). After washing the precipitate with 20%
aq DMF (10 ml), 1.0 M. HCl (10 ml) was added to the filtrate which
was then extracted with diethyl ether. The organic layer was then
washed again with 1.0 M HCl and brine. After drying the organic
layer with Na2SO4, concentration of the organic phase provided
the coupling product in quantitative yield (101 mg, in high purity
(98.8%) (Table 1 entry 3)).
are called light fluorous molecules. Light fluorous reagents,1 scav-
engers2 and catalysts3 are especially convenient since they typi-
cally induce reactions of organic substrates under the same
conditions as their non-fluorous counterparts, but are reliably re-
moved from the crude reaction products by fluorous solid phase
extraction.4 In the field of amidation and esterification, some fluor-
ous reagents have been developed, and these reagents are separa-
ble due to their fluorous properties in a fluorous biphasic system
(FBS) and on fluorous silica gel supports.5 Recently, we reported
that the by-product derived from a light fluorous Mukaiyama cou-
pling reagent6 can be easily separated from the coupling products
by fluorous solid phase extraction.7 During our investigations into
the scope and limitations for the coupling reagent, we discovered
that a simple separation of the fluorous pyridone by-product,
where fluorous solid phase extraction is not necessary, is possible
when a medium weight fluorous version of Mukaiyama reagent is
used. Herein, we report an alternative useful separation technique
of the fluorous component from the reaction products.
The adjective ‘medium’ refers qualitatively to the weight of the
fluorous tag. Representative light fluorous molecules have fluorine
contents in the range of 30–40% of their molecular weight.8 We
prepared a Mukaiyama coupling reagent 1 bearing a C10F21 fluor-
ous tag, giving it a fluorine content around 49% of its molecular
weight, and accordingly named it ‘medium fluorous Mukaiyama
reagent’.9 Upon completion of the coupling reaction, the reagent
is converted to the corresponding fluorous pyridone 2, with a con-
comitant reduction in the molecular weight. As a result, the fluo-
rine content of 2 increases to 62% of its molecular weight, and
loses its medium fluorous compound status and formally becomes
Signals corresponding to fluorous pyridone 2 were not observed
* Corresponding author.
E-mail address: matsugi@ccmfs.meijo-u.ac.jp (M. Matsugi).
in the 1H NMR of the crude product after filtration. Interestingly,
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.016

6574
M. Matsugi et al. / Tetrahedron Letters 49 (2008) 6573–6574
+
N
Cl
-
TfO
N
O
PhCO2H
+
PhNH2
1 C
F
10 21
2
C
F
10 21
1) Et3N
filtration
DMAP
PhCONHPh
DMF (16 v/w)
(99%, 98.8%purity)
rt, 1 h
extraction
2) H2O (4 v/w)
with ether
rt, 5min
Scheme 1. A facile separation of fluorous pyridone 2.
Table 1
In summary, a new medium fluorous Mukaiyama reagent 1 was
prepared and used in coupling reactions. We demonstrated that
facile purification of the coupling products was possible by filtra-
tion without the need for fluorous solid phase extraction. We also
conclude that a condensation strategy using reagent 1 is one of the
most practical methods for various ester and amide forming reac-
tions in terms of process chemistry.
Amide and ester forming reactions with the medium fluorous Mukaiyama reagent 1
1
(1.2 eq)
1)
DMAP (1 eq)
Et3N (3 eq)
dry DMF, rt, 1 hr
R1NH2
or
R2OH
RCONHR1
or
+
RCO2H
Acknowledgements
2) H2O, rt, 5 min
RCO2R2
This research was partially supported by the Ministry of Educa-
tion, Science, Sports and Culture, Grant-in-aid for Scientific Re-
search (C), 20580115. We thank Professor Dennis P. Curran,
University of Pittsburgh, for the useful discussion. We also thank
Wako Pure Chemical Industries, Ltd for funding this work.
Entry
R
R1
R2
Yield (%) Puritya (%)
Amidation
1
2
3
4
5
6
7c
Me
Ph
Pr
Ph
—
—
—
—
—
—
—
Quant.
98
99
Quant.
Quant.
97
98.2
95.6
98.8
97.0
96.2
98.6
89.3
Ph
Ph
Ph
L
-Valine methyl esterb
4-MeO-Ph
4-NO2-Ph
4-NO2-Ph
Ph
References and notes
Ph
PhNHMed
87
1. Light Fluorous Chemistry—A User’s Guide. In The Handbook of Fluorous
Chemistry; Gladysz, J., Horváth, I., Curran, D. P., Eds.; Wiley-VCH: Weinheim,
2004; pp 128–155.
Esterrification
8e
9
10
11
12
13
14
Ph
Ph
Ph
—
—
—
—
—
—
—
Bn
94
92.2
90.1
92.0
95.5
96.0
98.7
91.3
Butyl 99
Octyl Quant.
Me
Me
Me
Me
2. Fluorous Scavengers. In The Handbook of Fluorous Chemistry; Gladysz, J.,
Horváth, I., Curran, D. P., Eds.; Wiley-VCH: Weinheim, 2004; pp 236–246.
3. Examples: (a) Schneider, S.; Bannwarth, W. Angew. Chem., Int. Ed. 2000, 39,
4142–4145; (b) Tian, Y.; Yang, Q. C.; Mak, T. C. W.; Chan, K. S. Tetrahedron 2002,
58, 3951–3961; (c) Matsugi, M.; Curran, D. P. J. Org. Chem. 2005, 70, 1636–1642;
(d) Yi, W.-B.; Cai, C.; Wang, X. Eur. J. Org. Chem. 2007, 3445–3448.
4. Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837–11865.
5. (a) Del Pozo, C.; Keller, A. I.; Nagashima, T.; Curran, D. P. Org. Lett. 2007, 9,
4167–4170; (b) Yoshida, A.; Hao, X.; Yamazaki, O.; Nishikido, J. QSAR Comb. Sci.
2006, 25, 697–702.
6. (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)
Mukaiyama, T.; Narasaka, K.; Kikuchi, K. Chem. Lett. 1977, 441–444.
7. Matsugi, M.; Hasegawa, M.; Sadachika, D.; Okamoto, S.; Tomioka, M.; Ikeya, Y.;
Masuyama, A.; Mori, Y. Tetrahedron Lett. 2007, 48, 4147–4150.
4-Ph-Ph
4-MeO-Ph
4-NO2-Ph
98
96
Quant.
Quant.
Boc-
L-
tryptophanf
15
Boc-
L
-
—
Ally
89
87.1
tryptophanf
a
Determined by HPLC.
b
c
d
e
f
L
-Valine methyl ester was used.
The reaction was conducted for 2 h at rt.
Phenylmethylamine was used.
The reaction was conducted for 0.5 h at rt.
8. 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 solvents, so separations with fluorous solid phases are
often the only practical methods; see Ref. 1.
Boc-L-tryptophan was used.
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 slightly amounts of the
pyridone were observed in the filtrate. Furthermore, no precipita-
tion of the pyridone was observed in 20% aq DMF when original
Mukaiyama reagent (non-fluorous-type) was used. These illustrate
that it is essential to use C10F21 tag (medium fluorous type) for
effective separation and purification. Table 1 shows the results of
the purification for various coupling reactions employing reagent
1. All reactions proceeded at room temperature and were complete
in 2 h to give the target products in good yields and high puri-
ties.The esterification worked well even in the case of using
9. Preparation of medium fluorous Mukaiyama reagent 1: To
a solution of
1H,1H,2H,2H-1-perfluorododecan-1-ol (25.0 g, 44.3 mmol), 2-chloropyridine
(12.0 g, 53.2 mmol) in dry dichloromethane (80 ml) was added
trifluoromethanesulfonic anhydride (15.0 g, 53.2 mmol) at 0 °C and the
mixture was stirred at 45 °C for 30 h. Diethyl ether (100 ml) was added and
the mixture was stirred for 0.5 h at room temperature. After filtration of the
crude product, the recrystallization from ethyl acetate gave the 1 (29.9 g,
83.4%) as a white powder; mp 118.0–119.0 °C; 1H NMR (270 MHz, DMSO-d6) d:
3.07 (2H, m), 5.02 (2H, t, J = 7.4 Hz), 8.19 (1H, m), 8.41 (1H, d, J = 7.4 Hz), 8.65
(1H, m), 9.26 (1H, d, J = 5.1 Hz); 19F NMR (466 MHz, DMSO-d6) ppm À125.7
(2F), À122.9 (2F), À122.4 (2F), À121.6 (4F), À121.4 (6F), À112.8 (2F), À80.2
(3F), À77.8 (3F).
10. (a) Yu, M. S.; Curran, D. P.; Nagashima, T. Org. Lett. 2005, 7, 3677–3680; (b) Chu,
Q.; Yu, M. S.; Curran, D. P. Tetrahedron 2007, 63, 9890–9895.
11. (a) Kamiusuki, T.; Monde, T.; Yano, K.; Yoko, T.; Konakahara, T.
Chromatographia 1999, 49, 649–656; (b) Kamiusuki, T.; Monde, T.; Yano, K.;
Yoko, T.; Konakahara, T. J.Chromatogr. Sci. 1999, 37, 388–394; (c) Curran, D. P.;
Dandapani, S.; Werner, S.; Matsugi, M. Synlett 2004, 1545–1548.
Boc-L-tryptophan, which has indole ring in the molecule (Table 1
entries 14 and 15).