Fluorous analogues of DMAP (F-DMAP): Reusable organocatalysts for acylation reaction

Article abstract of DOI:10.1016/j.jfluchem.2008.06.008

A short and facile preparation of analogues of DMAP (F-DMAPs) labelled with fluorous chains is reported. These catalysts efficiently promote the acylation of alcohols with anhydrides (Ac₂O, (i-PrCO)₂O) and can be partially recovered and reused. The effectiveness of F-DMAP is similar to that of DMAP.

Full text of DOI:10.1016/j.jfluchem.2008.06.008

Journal of Fluorine Chemistry 129 (2008) 974–977
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Fluorous analogues of DMAP (F-DMAP): Reusable organocatalysts
for acylation reaction
Julien Legros *, Benoit Crousse, Dani e` le Bonnet-Delpon
Laboratoire BioCIS-CNRS, Facult e´ de Pharmacie, Univ Paris-Sud, Rue J. B. Cl e´ ment, F-92296 Ch aˆ tenay-Malabry, France
A R T I C L E I N F O
A B S T R A C T
Article history:
A short and facile preparation of analogues of DMAP (F-DMAPs) labelled with fluorous chains is reported.
Received 31 March 2008
Received in revised form 5 June 2008
Accepted 5 June 2008
These catalysts efficiently promote the acylation of alcohols with anhydrides (Ac
be partially recovered and reused. The effectiveness of F-DMAP is similar to that of DMAP.
ß 2008 Elsevier B.V. All rights reserved.
2 2
O, (i-PrCO) O) and can
Available online 20 June 2008
Keywords:
4
4
-(Dimethylamino)pyridine
-Pyrrolidinopyridine
PPY
Organocatalysis
Fluorous tag
1
. Introduction
2. Results and discussion
Since the pioneer work of Litvinenko and Kirichenko, followed
Many studies have been devoted to the structural effects of
DMAP and its derivatives on their catalytic properties. From these
reports, two major facts can be underlined: the lone pair of the
amino moiety at C-4 of the pyridine ring plays a decisive role [3],
and the sites C-2 have to be non-substituted [4]. Considering that
fluoroalkyl groups are bulky and electron withdrawing, grafting
the fluorous ponytails on the amino group with an adequate spacer
seems to be the best design for efficient fluorous analogues of
DMAP. It is generally admitted that a two- to three-methylene
spacer avoids excessive electronic and steric perturbations, while
keeping fluorophilicity properties [14]. Our first idea was thus to
by Steglich, in the late 1960s [1], DMAP (4-(dimethylamino)pyr-
idine) has been widely used as organocatalyst for synthetic
transformations [2]. One of the most striking effect of DMAP is
exhibited in the acylation reaction of poorly reactive alcohols with
carboxylic anhydrides for which catalytic amounts of this
organocatalyst cause great rate accelerations [3,4]. However,
due to its acute toxicity [5] the search for recyclable analogues
is of great interest. For this purpose, various derivatives of DMAP
have been supported on organic [6] as well as on inorganic
supports [7], and used as recoverable catalysts [8]. In this
connection, tagging DMAP with fluorous ponytails could represent
a very attractive alternative to common supporting methods
react 4-aminopyridine 1 with C
6
F
2 2
13(CH ) I, both commercially
available (Scheme 1, path (a)).
[
9,10]. Indeed, fluorous compounds can often be easily removed
However in the substrate 1, the NH moiety is poorly reactive
2
from an organic mixture by various methods: liquid–liquid
extraction [11], solid phase extraction (SPE) [12], or even
precipitation [13]. Herein, we report the synthesis of fluorous
analogues of DMAP (F-DMAP) and their application in the acylation
reaction of alcohols with anhydrides.
while the nitrogen atom of the pyridine is more nucleophilic and a
mixture of alkylated products was obtained. However, attempts to
use selective protection methods remained also unsuccessful. We
then turned to another strategy by using the 4-(diallylamino)pyr-
idine 2 as an easily accessible starting material [15]: we reasoned
that one perfluoroalkyl chain could be added onto both double
bonds of 2 through a radical path (Scheme 1, path (b)) [16]. When
4 9 8
placed in presence of perfluoroalkyl iodide (C F I or C F17I) and
sodium dithionite under basic conditions, the 4-(diallylamino)-
pyridine 2 was completely converted as shown by NMR analyses
[17]. Surprisingly, instead of the expected products resulting from
*
Corresponding author. Tel.: +33 1 46 83 57 44; fax: +33 1 46 83 57 40.
E-mail address: julien.legros@u-psud.fr (J. Legros).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.06.008

J. Legros et al. / Journal of Fluorine Chemistry 129 (2008) 974–977
975
Scheme 1.
Scheme 2.
a di-addition of R
probably come from the monoaddition of R
double bond, and the resulting compound undergoes further
cyclisation to afford the pyrrolidino derivative. The crude products
F
I, the cyclic products 3 was formed. These latter
I onto one of the
mixture, allowing the reaction to proceed almost under homo-
geneous conditions. The following point to be assessed was the
recovery and recycling of F-DMAPs. Despite the acceptable fluorine
content of our F-DMAP catalysts (%F = 44% for 4a, and 55% for 4b),
they are completely insoluble in fluorous solvents (perfluoro-
methylcyclohexane, perfluorodecaline), probably due to their high
polarity, precluding thus the use of liquid extraction for recovery
F
3
a and 3b [18] are then submitted to dehydrohalogenation in
presence of DBU [19], to yield F-DMAP 4a and 4b (40% and 34%
yield, respectively; Scheme 2). While the obtained products 4a and
4
b are structurally different from those initially designed, they fit
with our requirements (site of grafting and spacer). Moreover, 4-
pyrrolidinopyridine itself (PPY) is also known as a very effective
acylation catalyst [20].
Table 2
a
Acylation of alcohols with F-DMAP 4a with isobutyric and acetic anhydrides
Having in hands our F-DMAPs 4a and 4b, we tested their
potential as catalyst in the acylation of phenyl ethanol with the
sterically hindered isobutyric anhydride under neat conditions
[
6a]. Results are presented in Table 1.
As expected from the structure of our compounds, 10 mol% of
a or 4b is largely enough to promote the acylation in a very short
0
4
Entry Alcohol
R
Time Product
h)
Conversion Yield
b
(
(%)
(%)
reaction time: after only 15 min, more than 98% conversion were
obtained (entries 1 and 4). Comparison with DMAP afforded
similar results, while the conversion was extremely low without
any catalyst (5% conversion after 15 min and almost no evolution
after 1 h). Besides their intrinsic catalytic power the efficiency of F-
DMAPs is also due to their partial miscibility in the reaction
1
i-Pr
0.4
>98
85
-
2
3
CH
CH
3
0.4
>98
>98
90
75
Table 1
Assessment of F-DMAPs 4 in the acylation of phenylethanol with (i-PrCO)
2
O and
a
recovery
3
0.4
4
5
i-Pr
0.4
0.4
6.0
>98
95
82
–
b
Entry
Catalyst
Run
Conversion (%)
1
2
3
4a
1
2
3
>98
80
45
CH
CH
3
4
5
6
7
4b
1
2
3
–
>98
75
47
c
6
3
43
–
DMAP
>98
8
No catalyst
–
5
a
Reactions performed on a 1-mmol scale of substrate.
a
b
c
Reactions performed on a 1-mmol scale of substrate.
Monitored by GC. Only the acylation product was obtained.
2 eq. of Ac O and 3 eq. of Et N were used.
b
Monitored by GC. Only the acylation product was obtained.
2
3

9
76
J. Legros et al. / Journal of Fluorine Chemistry 129 (2008) 974–977
1
9
[
21]. However, the addition of n-hexane to the reaction mixture
F NMR (acetone d-6, 188 MHz)
d
ꢁ81.10 (tt, J = 2.0 Hz,
caused a partial precipitation of the catalysts (ca. 60%). After
removal of the hexane phase (containing the organic products), the
remaining catalyst was reused. Unfortunately, the second run
showed a significant drop in the reactivity for both catalysts (80%
and 75% conversion with 4a and 4b, respectively), and even more
at the third run (ca. 45%), as shown in entries 2–3 and 5–6.
Nevertheless F-DMAP 4a was successfully used in the acylation
of various alcohols (secondary and tertiary) with isobutyric and
acetic anhydrides (Table 2). Like phenyl ethanol (entries 1 and 2),
cyclohexanol (entries 3 and 4) and diphenyl methanol (entry 5)
reacted remarkably fast with both anhydrides (15 min) to afford
the corresponding esters. More sluggish is the acetylation of the
tertiary alcohol 1-adamantanol with only 43% conversion after 6 h
J = 10.1 Hz, 3F), ꢁ112.5 (m, 2F), ꢁ121.8 (m, 6F), ꢁ122.5 (m, 2F),
1
ꢁ123.0 (m, 2F), ꢁ126.2 (m, 2F); H NMR (acetone d-6, 200 MHz)
d
3.28 (m, 4H), 4.10 (m, 3H), 5.25 (m, 2H), 6.55 (d, J = 6.3 Hz, 2H), 8.20
1
3C
2
(d, J = 6.3 Hz, 2H);
= 21 Hz, CH CF ), 37.2 (CH), 53.1 (CH
109.2 (CH), 106.0–128.0 (m, C 17), 148.9 (C), 150.7 (CH), 153.8 (C);
NMR (acetone d-6, 75 MHz)
d 34.18 (t, J
C–
F
2
2
2
), 54.3 (CH ), 108.7 (C=CH ),
2
2
8
F
+
APCI m/z (rel. int.): 593 [M+H] (100).
4.3. Acylation of phenyl ethanol with isobutyric anhydride catalysed
by F-DMAP 4a: typical procedure
A test tube was charged with F-DMAP 4a (39 mg, 0.1 mmol),
and phenyl ethanol (122 mg, 1 mmol), Et
3
N (202 mg, 2 mmol) and
(entry 6). However, it is worth noting that it has been reported that
(i-PrCO) O (190 mg, 1.2 mmol) were successively added. After
2
the use of DMAP as catalyst for this later reaction gave similar
results under closed reaction conditions (45% conversion after
15 min stirring, n-hexane was added to the reaction mixture
(4 mL) and stirring was maintained for 10 min. After decantation,
the hexane phase was removed, and the remaining catalyst (brown
paste) can be reused for a further catalysis. The acylation product
contained in the hexane phase was purified by chromatography
over silica gel (cyclohexane/AcOEt, 90:10) to afford 163 mg of
5
.2 h) [4a].
3
. Conclusions
In summary, we have designed and synthesized fluorous
isobutyric acid 1-phenyl ethyl ester (85% yield).
1
analogues of DMAP (F-DMAPs). When used as catalysts to promote
acylation reaction of alcohols with anhydrides, F-DMAPs exhibit an
excellent effectiveness similar to that of the original DMAP.
However, these catalysts are not yet conveniently recycled. This
latter point could be improved by using fluorous silica gel for solid-
phase extraction, or by increasing the fluorophilicity of the catalyst
through the grafting of a second fluoroalkyl chain on the double
bond. This work is currently in progress and will be reported in due
course.
3
H NMR (CDCl , 200 MHz) d 1.16 (d, J = 6.9 Hz, 6H), 1.52 (d,
J = 6.6, 3H), 2.56 (sept, J = 6.9 Hz, 1H), 5.87 (q, J = 6.6, 1H), 7.22–7.36
(m, 5H) [22].
Acknowledgements
Almir Bronja (undergraduate student, University of Paris—Val
de Marne) is gratefully acknowledged for his active participation to
this work, as well as Daniela Vuluga for her kind help. Michele
Danet from the SAMM is thanked for mass spectroscopy analyses.
We are grateful to Elf Atochem for kind gift of perfluoralkyl iodides.
4
. Experimental
4.1. Synthesis of F-DMAP 4a: typical procedure
References
[
1] L.M. Litvinenko, A.I. Kirichenko, Dokl. Akad. Nauk. SSSR 176 (1967) 97–100;
W. Steglich, G. H o¨ fle, Angew. Chem., Int. Ed. Engl. 8 (1969) 981.
2] For reviews on applications of DMAP and its derivatives as organocatalysts, see:
(a) R.P. Wurz, Chem. Rev. 107 (2007) 5570–5595;
A 250-mL flask was loaded with a solution of 4-(diallylami-
no)pyridine 2 [15] (1.0 g, 5.75 mmol) in a mixture of CH
3
CN/H
I (4.37 g,
(2.6 g, 14.94 mmol) and NaHCO (1.9 g,
3.0 mmol), and the mixture was vigorously stirred. After 2 h,
2
O
[
(
1
2
25:15 mL). To this solution, were successively added C F
4 9
(
(
(
b) A.C. Spivey, S. Arseniyadis, Angew. Chem. Int. Ed. 43 (2004) 5436–5441;
c) R. Murugan, E.F.V. Scriven, Aldrichim. Acta 36 (2003) 21–27;
d) D.J. Berry, C.V. DiGiovanna, S.S. Metrick, R. Murugan, ARKIVOC (2001) 201–226;
2.64 mmol), Na
2
S
2
O
4
3
brine was added (100 mL) to the reaction mixture, and it was
(e) U. Ragnarsson, L. Grehn, Acc. Chem. Res. 31 (1998) 494–501.
extracted with AcOEt (3 ꢀ 200 mL). The combined organic phases
[3] For studies in the role of DMAP in rate acceleration, see:
M. Baidya, S. Kobayashi, F. Brotzel, U. Schmidhammer, E. Riedle, H. Mayr, Angew.
Chem., Int. Ed. 46 (2007) 6176–6179.
4
were dried over MgSO , filtered and the solvents were removed in
vacuo. The crude residue 3a (orange paste, 1.79 g) was then
dissolved in THF (20 mL) and DBU (1.57 g, 10.35 mmol) was added.
After stirring for 2 h, the reaction mixture was filtered and the
solvent was eliminated in vacuo. The residue was then purified by
[4] For more potent DMAP analogues for acylation reaction, see:
(a) S. Singh, G. Das, O.V. Singh, H. Han, Org. Lett. 9 (2007) 401–404;
(
(
(
b) S. Singh, G. Das, O.V. Singh, H. Han, Tetrahedron Lett. 48 (2007) 1983–1986;
c) I. Held, S. Xu, H. Zipse, Synthesis (2007) 1185–1196;
d) M.R. Heinrich, H.S. Klisa, H. Mayr, W. Steglich, H. Zipse, Angew. Chem. Int. Ed.
flash chromatography over silica gel neutralized with Et
3
N
42 (2003) 4826–4828.
[
5] According to the Material Safety Data Sheet (MSDS) provided by chemical
suppliers, DMAP (CAS [1122-58-3]) is classified as ‘‘very toxic T + ’’ (Oral, rat:
LD50 = 250 mg/kg; Skin, rabbit: LD50 = 13 mg/kg).
(CH
2 2
Cl /MeOH, 85:15) to afford F-DMAP 4a as a dark brown paste
(
0.95 g, 40% over 2 steps).
19
F NMR (acetone d-6, 188 MHz)
J = 9.5 Hz, 3F), ꢁ112.7 (m, 2F), ꢁ124.0 (m, 2F), ꢁ125.7 (m, 2F); H
NMR (acetone d-6, 200 MHz) 3.26 (m, 4H), 4.02 (m, 3H), 5.25 (m,
H), 6.55 (d, J = 6.3 Hz, 2H), 8.18 (d, J = 6.3 Hz, 2H);
d
ꢁ81.10 (tt, J = 3.2 Hz,
[6] (a) A. Sakakura, K. Kawajiri, T. Ohkubo, Y. Kosugi, K. Ishihara, J. Am. Chem. Soc.
29 (2007) 14775–14779;
1
1
(
(
b) J.-H. Yuang, M. Shi, Adv. Synth. Catal. 345 (2003) 953–958;
c) A. Corma, H. Garcia, A. Leyva, Chem. Commun. (2003) 2806–2807;
d
1
3C
2
NMR
), 37.0 (CH),
), 109.1 (CH), 106.5–125.6 (m,
), 148.8 (C), 150.7 (CH), 153.7 (C); APCI m/z (rel. int.): 393
(d) B. Pelotier, G. Priem, S.J.F. Macdonald, M.S. Anson, I.B. Campbell, Synlett
(2003) 679–683;
2
(acetone d-6, 75 MHz)
d
34.17 (t, JC–F = 21 Hz, CH
2 2
CF
(
(
e) F. Guendouz, R. Jacquier, J. Verducci, Tetrahedron 44 (1988) 7095–7108;
f) F.M. Menger, D.J. McCann, J. Org. Chem. 50 (1985) 3928–3930;
5
3.1 (CH
2
), 54.4 (CH
2
), 108.7 (C=CH
2
C
4
F
9
(g) W. Storck, G. Manecke, J. Mol. Catal. 30 (1985) 145–169;
(h) E.J. Delaney, L. Wood, I.M. Klotz, J. Am. Chem. Soc. 104 (1982) 799–807;
+
[
M+H] (100).
(i) M. Tomoi, Y. Akada, H. Kakiuchi, Makromol. Chem. Rapid Commun. 3 (1982)
5
37–542;
4.2. F-DMAP 4b
(
(
j) S. Shinkai, H. Tsuji, Y. Hara, O. Manabe, Bull. Chem. Soc. Jpn. 54 (1981) 631–632;
k) M.A. Hierl, E.P. Gamson, I.M. Klotz, J. Am. Chem. Soc. 101 (1979) 6020–6022.
[
7] (a) C. O´ . D a´ laigh, S.A. Corr, Y. Gun’ko, S.J. Connon, Angew. Chem. Int. Ed. 46 (2007)
329–4332;
b) S. Rubinsztajn, M. Zeldin, W.K. Fife, Macromolecules 24 (1991) 2682–2688;
(c) S. Rubinsztajn, M. Zeldin, W.K. Fife, Macromolecules 23 (1990) 4026–4027.
8 17
The same procedure was followed but starting from C F I
4
(
(
(
12.64 mmol, 6.90 g). The product 4b was obtained as a black paste
34% yield over 2 steps).

J. Legros et al. / Journal of Fluorine Chemistry 129 (2008) 974–977
977
[
[
8] For reviews on supported organocatalysts, see:
[16] For a review on perfluoroalkyl halides, see:
G.G. Furin, Russian Chem. Rev. 69 (2000) 491–522.
3
[17] This reaction has also been attempted with some other initiators: with Et B
(0.2 equiv.; 1 M solution in hexanes) in dichloroethane or under neat conditions;
or with AIBN (0.1–1 equiv., in toluene or in benzene at reflux). In all the cases, the
starting material remained unchanged and was fully recovered after work up.
[18] The addition products 3a and 3b have not been isolated and fully characterized.
Their structures have been assumed from that of dehydrohalogenation products
4a and 4b.
(
(
a) F. Cozzi, Adv. Synth. Catal. 348 (2006) 1367–1390;
b) M. Benaglia, A. Puglisi, F. Cozzi, Chem. Rev. 103 (2003) 3401–3429.
9] J.A. Gladysz, D.P. Curran, I.T. Horv a´ th (Eds.), Handbook of Fluorous Chemistry,
Wiley-VCH, New York, 2004.
[
10] For examples of fluorous organocatalysts, see:
(
(
a) L. Zu, H. Xie, H. Li, J. Wang, W. Wang, Org. Lett. 10 (2008) 1211–1214;
b) Q. Chu, W. Zhang, D.P. Curran, Tetrahedron Lett. 47 (2006) 9287–9290.
[
[
[
[
[
11] J.A. Gladysz, C. Emmet, in: J.A. Gladysz, D.P. Curran, I.T. Horv a´ th (Eds.), Handbook
of Fluorous Chemistry, Wiley-VCH, New York, 2004, pp. 11–23.
12] D.P. Curran, in: J.A. Gladysz, D.P. Curran, I.T. Horv a´ th (Eds.), Handbook of Fluorous
Chemistry, Wiley-VCH, New York, 2004, pp. 101–126.
13] J.A. Gladysz, R. Corr eˆ a da Costa, in: J.A. Gladysz, D.P. Curran, I.T. Horv a´ th (Eds.),
Handbook of Fluorous Chemistry, Wiley-VCH, New York, 2004, pp. 24–40.
14] J.A. Gladysz, in: J.A. Gladysz, D.P. Curran, I.T. Horv a´ th (Eds.), Handbook of Fluorous
Chemistry, Wiley-VCH, New York, 2004, pp. 41–55.
15] J. Campos, M. delCarmen N u´ n˜ ez,V. Rodr ı´ guez, A. Entrena,R. Hern a´ ndez-Alcoceba, F.
Fern a´ ndez, J.C. Lacal, M.A. Gallo, A. Espinosa, Eur. J. Med. Chem. 36 (2001) 215–225.
[19] The use of other bases (e.g. NaH, t-BuOK), or hydride reduction (Bu3SnH) afforded
complex mixtures.
[20] (a) A. Hassner, L.R. Krepski, V. Alexanian, Tetrahedron 34 (1978) 2069–2076;
(b) W. Steglich, G. H o¨ fle, Tetrahedron Lett. 54 (1970) 4727–4730.
[21] For a review and discussion on the particular case of nitrogen-containing fluorous
catalysts, see:
F. Fache, New J. Chem. 28 (2004) 1277–1283.
[22] D. Klomp, K. Djanashvili, N.C. Svennum, N. Chantapariyavat, C.-S. Wong, F. Vilela,
T. Maschmeyer, J.A. Peters, U. Hanefeld, Org. Biomol. Chem. 3 (2005) 483–489.