Scavenging of fluorinated N,N′-dialkylureas by hydrogen binding: A novel separation method for fluorous synthesis

Article abstract of DOI:10.1021/ol016165+

(matrix presented) A dramatic solubility increase in fluorous solvents is observed for N,N′-di(polyfluoroalkyl)ureas when hydrogen binding complexes are formed with commercially available perfluoroalkanoic acid scavengers. As a case example, analytically pure peptides and esters are obtained using this novel separation method.

Full text of DOI:10.1021/ol016165+

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2361-2364
Scavenging of Fluorinated
N,N′-Dialkylureas by Hydrogen Binding:
A Novel Separation Method for Fluorous
Synthesis
Claudio Palomo,* Jesus M. Aizpurua,* Iraida Loinaz,
Maria Jose Fernandez-Berridi, and Lourdes Irusta
Departamento de Qu´ımica Orga´nica-I, UniVersidad del Pa´ıs Vasco,
Facultad de Qu´ımica, Apdo 1072, 20080 San Sebastia´n, Spain
qppaiipj@sc.ehu.es
Received May 24, 2001
ABSTRACT
A dramatic solubility increase in fluorous solvents is observed for N,N′-di(polyfluoroalkyl)ureas when hydrogen binding complexes are formed
with commercially available perfluoroalkanoic acid scavengers. As a case example, analytically pure peptides and esters are obtained using
this novel separation method.
Fluorous Biphasic Catalysis1 and Fluorous Synthesis2 are
ensembles of synthetic techniques based on the selective
partition of perfluorinated catalysts, substrates, reagents,
products, or reagent byproducts in bilayer systems consisting
of an organic solvent and a “fluorous” fluid.3 The success
of such approachs relies on the efficient establishment of
different phase behavior at the reaction and purification
stages,3b which, under ideal conditions, should allow the
reaction to be conducted in a homogeneous liquid phase and
the purification in a multiphase (two or three) liquid system
by simple separation. This criterion is fulfilled to a great
extent by catalytic processes involving hydroformylation,4
hydroboration,5 C-C coupling,6 and oxidations,7 but its
application to stoichiometric fluorous syntheses, based on
phase-labeled substrates or reagents, is not trivial. Reagents
labeled with “light” fluorous tags8 (Figure 1), bearing one
or two perfluorinated medium-sized chains (e.g., C6F13), are
highly desirable when compared to “heavy” fluorous tags,
because of their lower molecular weight and their higher
solubility in polar organic solvents (A). However, the
purification stage for “light”-tagged fluorous byproducts
results in a poor separation from products (B). The introduc-
(4) Horvath, I. T.; Kiss, G.; Cook, R. A.; Bond, J. E.; Stevens, P. A.;
Rabai, J.; Mozeliski, E. J. J. Am. Chem. Soc. 1998, 120, 3133-3143.
(5) Juliette, J. J.; Horvath, I. T.; Gladysz, J. A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 1610-1612.
(1) Horvath, I. T.; Rabai, J. Science 1994, 266, 72-75.
(2) Suder, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Jeger, P.; Wipf, P.;
Curran, D. P. Science 1997, 275, 823-826.
(3) For reviews on this subject, see: (a) Cornils, B. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2057-2059. (b) Curran, D. P. Angew. Chem., Int. Ed.
1998, 37, 1174-1196. (c) Horva´th, I. T. Acc. Chem. Res. 1998, 31, 641-
650. (d) de Wolf, E.; van Koten, G.; Deelman, B.-J. Chem. Soc. ReV. 1999,
28, 37-41.
(6) Kleijn, H.; Rijnberg, E.; Jastrzebski, J. T. B. H.; van Koten, G. Org.
Lett. 1999, 1, 853-855.
(7) Klement, I.; Lu¨tjens, H.; Knochel, P. Angew. Chem., Int. Ed. Engl.
1997, 36, 1454-1456.
(8) Curran, D. P.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069-9072.
10.1021/ol016165+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/21/2001

and (c) perfluoroalkanoic acids are commercially available
compounds.
Thus, N,N′-dialkylureas 3 and 4 bearing, respectively, one
and two fluorous tags were readily prepared from amines
215 (Scheme 1) by addition to alkyl isocyanates or by
Scheme 1
Figure 1. The reaction/separation antagonism for the stoichiometric
reaction of a fluorous-labeled reagent (F-Re): increasing the number
of perfluorinated chains improves separation but hampers the
reaction.
carbonylation with triphosgene16 in overall yields ranging
from 41% to 98%. Polyfluorinated N,N′-dialkylureas 4a-d
were colorless or white solid compounds sparingly soluble
in CH2Cl2 (typically, 0.3-0.6% at 25 °C) and, surprisingly,
still less soluble in C6F14 (<0.1%). Our finding was that ureas
4a-d dissolved immediately upon the addition of 1 equiv
of most of the polyfluoroalkanoic acids 5a-d in a biphasic
CH2Cl2/C6F14 system (Scheme 2). The gravimetric determi-
tion of more heavily fluorinated labels is only an apparent
solution to this problem, because the large number of fluorine
atoms required to ensure efficient byproduct purification (D)9
has liabilities in the reaction step (C) which becomes very
slow (or does not take place at all) because it is difficult for
the fluorous reagent to cross the phase boundary.10
Herein we report on a novel scavenging method11 based
upon the unprecedented concept of intermolecular hydrogen-
binding interaction in fluorous medium12 that improves the
liquid-liquid separation step (B) for “light” fluorous tags.
To describe the “proof-of-principle” of our strategy, we
devised hydrogen acceptor/donor systems formed by N,N′-
dialkylureas and perfluoroalkanoic acids. This choice was
supported by the following facts: (a) N,N′-dialkylureas (i.e.,
N,N′-dicyclohexylurea) are the prototypical reaction byprod-
ucts of carbodiimide-promoted reactions, including the very
important peptide synthesis;13 (b) perfluoroalkanoic acids
have superior hydrogen-binding capabilities than their alkyl
or aryl homologues toward amide-like hydrogen acceptors;14
nation of the partition coefficients PC F
at 25 °C
14/CH2Cl2
6
revealed ratios as high as 99/1 for complex 4c‚5a, bearing
medium-size fluorinated chains (Rf ) C6F13).
Scheme 2
(9) Hughes, R. P.; Trujillo, H. A. Organometallics 1996, 15, 286-294.
(10) Three methods have been proposed to attain a homogeneous reaction
medium able to dissolve slightly polar organic substrates and fluorous
reactants bearing three or more perfluorinated chains: (a) Temperature-
promoted fusion of toluene/perfluorohexane or similar biphases: see ref 1.
(b) Supercritical CO2, see: Kainz, S.; Koch, D.; Baumann, W.; Leitner,
W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1628-1630. (c) Partially
fluorinated solvents, such as benzotrifluoride (BTF), see: Ogawa, A.;
Curran, D. P. J. Org. Chem. 1997, 62, 450-451.
(11) The fluorous amine [(C6F13CH2CH2)3SiCH2CH2CH2]2NH has been
used for an automated urea synthesis as isocyanate scavenger by covalent
bond formation. Linclau, B.; Sing, A. K.; Curran, D. P. J. Org. Chem. 1999,
64, 2835-2842.
2362
Org. Lett., Vol. 3, No. 15, 2001

Replacement of dichloromethane by more coordinating
solvents, such as acetonitrile, gave moderately lower partition
coefficients. Experiments to determine the minimum number
of fluorine atoms in the urea component to attain an efficient
partition indicated that less fluorinated ureas 4a and 4b gave
unsatisfactory values with either medium-sized (complex
4a‚5a) or long-sized perfluoroalkanoic acids (complex
4a‚5d). On the other hand, perfluoroheptanoic acid 5a was
also more efficient than their pony-tailed counterparts 5b or
5c bearing, respectively, one or two methylene spacers and
also than long-sized acid 5d. Urea/acid 1:1 complexes were
isolable waxy solids or viscous liquids. For instance, 4c‚5a
was a stable noncrystalline solid at room temperature but
dissociated slowly on heating under vacuum (90 °C/10-4
Torr; 4 h) allowing the quantitative recovery of the pure urea
4c (98%) and the sublimated perfluoroheptanoic acid 5a
(96%).
of the acid 5a, the autoaggregation of urea 4c, and the
formation of complex 4c‚5a. Urea 4c was present in CH2-
Cl2 essentially as a nonassociated species [3451 cm-1 (N-
H); 1686 cm-1 (CONH amide-I); 1540 cm-1 (CONH amide-
II)]. In C6F14, however, no free urea could be detected and
the N-H and CdO amide-I bands shifted to lower frequen-
cies [3371 cm-1 and 3324 cm-1 (N-H); 1630 cm-1 (CONH
amide-I)], while the CONH amide-II band appeared at higher
frequencies (1575 cm-1), consistent with the formation of
CdO‚‚‚H-N autoaggregation bindings.
A 1:1 mixture of 4c and 5a in CH2Cl2 showed, in addition
to the peaks previously mentioned, three strong bands in the
carbonyl region [1752 cm-1 (CdO of 5a, associated with
the urea NH); 1640 cm-1 (CONH amide-I), 1563 cm-1
(CONH amide-II)], assigned to 4c‚5a. In C6F14 a similar
behavior was observed, but the free 4c carbonyl band could
not be detected, indicating that the equilibrium was com-
pletely shifted to 4c‚5a. Furthermore, a new band at 3482
cm-1 appeared, which was consistent with the free N-H
stretching band present in 4c‚5a.17
Even though the precise nature of the urea-acid hydrogen
bindings is not fully clear at present, a FTIR comparative
analysis (Scheme 3) of 5 × 10-3 M solutions of 4c, 5a, and
To check the efficiency of this new separation technique
for “fluorous synthesis”, some exploratory reactions based
on the use of the dehydrated carbodiimide counterpart of
the urea 4c were investigated (Scheme 4). Carbodiimide 618
Scheme 3
Scheme 4a
a (a) Ph3PBr2, NEt3, CH2Cl2/C6F14; (b) 6, H2NR2; (c) 6, HOtBu,
DMAP (0.1 equiv). PMP: C6H4OMe-p.
was a stable and storable liquid, conveniently prepared by
the reaction of urea 4c with triphenylbromophosphonium
bromide and triethylamine19 in a CH2Cl2/C6F14 biphasic
(14) Crystalline adducts of linear oligomers of Nylon-6 precipitated from
trifloroethanol solution with perfluoroglutaric acid, but not with nonfluori-
nated diacids. See: Aharoni, S. M.; Wasserman, E. Macromolecules 1982,
15, 20-25.
(15) Trabelsi, H.; Szo¨nyi, F.; Michelangeli, N.; Cambon, A. J. Fluorine
Chem. 1994, 69, 115-117. None of ureas 4a-d has been described yet.
(16) Correa, A.; Denis, J.-N.; Greene, A. E. Synth. Commun. 1991, 21,
1-9.
(17) Application of the NMR titration method allowed the estimation of
a weak association constant (Ka ) 37 M-1; 25 °C) for 4c‚5a in CD2Cl2
observing the shift of the NH protons in fast dynamic exchange [δ(4c) )
4.53 ppm; δ(4c‚5a)) 5.01 ppm], whereas the autoaggregated nature of 4c
in C6F14 (CDCl3 as external standard) prevented from a reliable determi-
nation of Ka for 4c‚5a. In both solvents, no formation of complexes of
higher stoichiometry than 1:1 could be detected when an excess of 5a was
added. For methods of determination of association constants by NMR,
see: Fielding, L. Tetrahedron 2000, 56, 6151-6170.
1:1 mixtures of 4c and 5a showed that changing the solvent
from CH2Cl2 to C6F14 dramatically enhanced the dimerization
(12) Fully fluorocarbon-soluble coordination complexes of Mn(II) per-
fluorocarboxylates and perfluorinated triamines have been described
recently. See: Vincent, J.-M.; Rabion, A.; Yachandra, V. K.; Fish, R. H.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2346-2349.
(13) For reviews, see: (a) Mikolajczyk, M.; Kielbasinski, P. Tetrahedron
1981, 37, 233-284. (b) Williams, A.; Ibrahim, I. T. Chem. ReV. 1981, 81,
589-636.
Org. Lett., Vol. 3, No. 15, 2001
2363

solvent medium. Simple separation and evaporation of the
fluorous phase afforded the pure product 6 in 98% isolated
yield, thus setting the stage for the efficient recycling of urea
4c.
Table 1. Condensation Reactions Promoted by Carbodiimide 6
[see ref 20]
[R]25
yield residual 4c
Condensation reactions carried out in a biphasic CH2Cl2/
C6F14 medium proceeded to give good yields of dipeptides
7a-d after being washed twice with a solution of perfluoro-
heptanoic acid in perfluorohexane and once again with
perfluorohexane.20 This isolation technique was also compat-
ible with ternary systems, including acidic aqueous solutions,
to separate basic compounds (i.e., 4-(N,N-dimethylamino)-
pyridine), as illustrated in the case of tert-butyl esters 8a,b.
The 1H NMR (500 MHz) spectra of crude products showed
essentially epimerization-free pure products with no traces
of fluorous byproducts, whereas a more accurate determi-
nation of fluorous urea 4c by GC-MS analysis, using
phenanthrene as internal standard, gave concentrations in the
range 0.1-0.3% (Table 1).
(%)
(%)a
mp (°C)
exp. (solvent)
lit.
7a
7b
7c
7d
8a
8b
81
85
85
73
85
95
0.2
0.2
<0.1
<0.1
<0.1
0.3
100-101
94-95
82-84
oil
oil
55-56
-9.0 (EtOH)
+5.1 (CH2Cl2)
-27.9 (CHCl3)
-8.321
-30.822
-2323
-21.5 (EtOH)
+37.2 (CH2Cl2)
a Determined by GC-MS analysis of the reaction crude.
In conclusion, the examples described here illustrate a
novel solution to the reactivity/separation problem of
stoichiometric “fluorous synthesis” and set the basis for
further strategies based upon the new concept of fluorous
chain multiplication through hydrogen binding interactions.
(18) For another synthesis of carbodiimide 6, see: Trabelsi, H.; Bollens,
E.; Jouani, M. A.; Gaysinski, M.; Szo¨nyi, F.; Cambon, A. Phosphorous,
Sulfur Silicon 1994, 90, 185-191.
(19) Palomo, C.; Mestres, R. Synthesis 1981, 373-374.
Acknowledgment. This work was supported by CICYT
(Project: SAF 98-0159-C02-01), Universidad del Pa´ıs Vasco
(UPV: 170.215-G47/98), and Diputacio´n Foral de Gipuzkoa.
A grant from Gobierno Vasco to I. L. is gratefully acknowl-
edged.
(20) Preparation of peptides 7a-d: equimolar amounts of N-protected
amino acid, R-amino ester and 6 (3 × 10-4 mol each) in CH2Cl2 (1 mL),
and C6F14 (1 mL) were stirred at room temperature for 16 h. The mixture
was washed successively with perfluoroheptanoic acid (0.4 M in C6F14,
0.5 mL × 2) and C6F14 (0.5 mL), and the CH2Cl2 phase was separated and
evaporated. Preparation of tert-butyl esters 8a,b: a biphasic mixture (CH2-
Cl2/C6F14: 1.5/1.5 mL) of carboxylic acid (4.6 × 10-4 mol), tert-butyl
alcohol (5 × 10-4 mol), 4-(N,N-dimethylamino)pyridine (5 × 10-5 mol),
and 6 (5 × 10-4 mol) was stirred at room temperature for 18 h. Aqueous
HCl (1 M, 1 mL) and perfluoroheptanoic acid (5 × 10-4 mol) were added,
and the central CH2Cl2 phase was washed successively with perfluorohep-
tanoic acid (0.5 M in C6F14, 1 mL) and C6F14(0.5 mL). Evaporation of the
CH2Cl2 phase gave the product.
Supporting Information Available: Preparation proce-
dures and physical and spectroscopic data for compounds
3, 4a-d, and 6, FTIR spectra of 4c, 5a, and 4c‚5a, and
analytical methods to determine the purity of 7a-d and 8a,b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Gibson, F. G.; Park, M. S.; Rapoport, H. J. Org. Chem. 1994, 59,
7503-7507.
(22) Dudash, J.; Jiang, J.; Mayer, S. C.; Joullie´, M. M. Synth. Commun.
1993, 23, 349-356.
(23) Chevallet, P.; Garrouste, P.; Malawska, B.; Martinez, J. Tetrahedron
Lett. 1993, 34, 7409-7412.
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