Fluorous Synthesis: Fluorous Protocols for the Ugi and Biginelli Multicomponent Condensations

Article abstract of DOI:10.1021/jo970095w

A new protocol for multicomponent condensation reactions that uses fluorous (highly fluorinated) substrates is introduced. This method takes advantage of the ease of purification of fluorous compounds by liquid-liquid extractions between fluorous and organic solvents. The application of this method to the Ugi and Biginelli reactions is described. The condensation products of these two reactions, amino acid amides and dihydropyrimidines, are easily obtained without chromatography in high purities, even though the other reagents are used in very large excesses. This is the first demonstration of the suitability of fluorous phase methods for combinatorial synthesis of "druglike" organic molecules.

Full text of DOI:10.1021/jo970095w

J . Org. Chem. 1997, 62, 2917-2924
2917
F lu or ou s Syn th esis: F lu or ou s P r otocols for th e Ugi a n d Bigin elli
Mu lticom p on en t Con d en sa tion s
Armido Studer, Patrick J eger, Peter Wipf,* and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
Received J anuary 17, 1997X
A new protocol for multicomponent condensation reactions that uses fluorous (highly fluorinated)
substrates is introduced. This method takes advantage of the ease of purification of fluorous
compounds by liquid-liquid extractions between fluorous and organic solvents. The application
of this method to the Ugi and Biginelli reactions is described. The condensation products of these
two reactions, amino acid amides and dihydropyrimidines, are easily obtained without chroma-
tography in high purities, even though the other reagents are used in very large excesses. This is
the first demonstration of the suitability of fluorous phase methods for combinatorial synthesis of
“druglike” organic molecules.
In tr od u ction
on the ability of a “fluorous” (highly fluorinated) molecule
to partition into the fluorous phase in a liquid-liquid
extraction between an organic solvent and a fluorous
solvent.11,12 We have introduced a number of fluorous
techniques for traditional and parallel liquid phase
syntheses as well,5,8,9,13 and we describe herein the full
details13 of our work on one of these techniques: “fluorous
multicomponent condensations”. These reactions are a
variant of fluorous synthesis, which more generally
encompasses all strategies in which the products parti-
tion into the fluorous phase during the purification.13
Figure 1 shows the analogy between solid phase
synthesis and fluorous synthesis. In fluorous synthesis,
the initial organic substrate is attached to a “fluorous
label”, which is of sufficient structure, size, and fluorine
content to render the attached organic molecule fluo-
rous.12 One or more reactions are then conducted, and
the fluorous components of the reaction are subsequently
separated from all non-fluorous (organic, inorganic, solid,
volatile) components by an appropriate phase separation
technique (extraction has been the focus of the early
work). At the desired stage, the fluorous label is cleaved
and the product is rendered organic. Unlike solid phase
techniques, fluorous synthesis allows the routine use of
standard reagents and reaction conditions. If solvents
are well chosen, it is possible to have a homogeneous
solution (that is, no phase separation) at the reaction
stage, but to readily induce phase separation by changing
solvents at the purification stage. Furthermore, “fluorous
labels” are much more robust than most polymers and
linkers in current use for solid phase synthesis.
Combinatorial chemistry has rapidly become an im-
portant method for the identification and optimization
of lead compounds in drug discovery.1 In contrast to
traditional solution organic synthesis, which often re-
quires time-consuming purification procedures, combi-
natorial chemistry has been conducted almost exclusively
on solid polymer supports.2 Solid phase synthesis allows
very simple product isolation by filtration, but this
advantage at the isolation stage can be a detraction at
the synthesis stage because reaction mixtures are inho-
mogeneous. To overcome these drawbacks, reactions of
polymers that are soluble under certain conditions and
insoluble under others have been introduced.3 It has also
been shown that imaginatively designed “traditional”
solution reactions of organic molecules can provide
powerful tools in combinatorial synthesis.4
The phase behavior of any reaction mixture, combina-
torial or otherwise, is a crucial feature that affects the
ease of purification.5 To avoid chromatographic purifica-
tion, reactions should be planned such that the phase of
the desired product is different from the phases of all the
other reaction components and undesired products. The
“fluorous phase” 6-10 has recently been used to advantage
in traditional organic synthesis. The new techniques rely
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) Reviews: (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor,
S. P. A.; Gordon, E. M. J . Med. Chem. 1994, 37, 1233, 1386. (b) Terrett,
N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J .; Steele, J .
Tetrahedron 1995, 51, 8135. (c) Thompson, L. A.; Ellman, J . A. Chem.
Rev. 1996, 96, 555. (d) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc.
Chem. Res. 1996, 29, 144. (e) Rinnova, M.; Lebl, M. Collect. Czech.
Chem. Commun. 1996, 61, 171.
(2) (a) Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. Tetrahe-
dron 1996, 52, 4527. (b) Fru¨chtel, J . S.; J ung, G. Angew. Chem., Int.
Ed. Engl. 1996, 35, 17.
(3) (a) Han, H.; Wolfe, M. M.; Brenner, S.; J anda, K. D. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 6419. (b)Han, H.; J anda, K. D. J . Am. Chem.
Soc. 1996, 118, 2539, 7632.
Resu lts a n d Discu ssion
Multicomponent condensation strategies are capable
of providing in a single step durable core structures and
(4) (a) Carell, T.; Wintner, E. A.; Bashir-Hashemi, A.; Rebek, J ., J r.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2059. Carell, T.; Wintner, E.
A.; Rebek, J ., J r. Angew. Chem., Int. Ed. Engl. 1994, 33, 2061. Carell,
T.; Wintner, E. A.; Sutherland, A. J .; Rebek, J ., J r.; Dunayevskiy, Y.
M.; Vourous, P. Chem. Biol. 1995, 2, 171. Shipps, G. W., J r.; Spitz, U.
P.; Rebek, J ., J r. Bioorg. Med. Chem. 1996, 4, 655. (b) Cheng, S.; Comer,
D. D.: Williams, J . P.; Myers, P. L.; Boger, D. L. J . Am. Chem. Soc.
1996, 118, 2567. Boger, D. L.; Tarby, C. M.; Myers, P. L.; Caporale, L.
H. J . Am. Chem. Soc. 1996, 118, 2109. Cheng, S.; Tarby, C. M.; Comer,
D. D.; Williams, J . P.; Caporale, L. H.; Myers, P. L.; Boger, D. L. Bioorg.
Med. Chem. 1996, 4, 727.
(7) (a) Gladysz, J . A. Science 1994, 266, 55. (b) Bergbreiter, D. E.
Chemtracts: Org. Chem. 1995, 8, 108.
(8) .Curran, D. P.; Hadida, S. J . Am. Chem. Soc. 1996, 118, 2531.
(9) Curran, D. P.; Hoshino, M. J . Org. Chem. 1996, 61, 6480.
(10) (a) Hughes, R. P.; Trujillo, H. A. Organometallics 1996, 15, 286.
(b) DiMagno, S. G.; Dussault, P. H.; Schultz, J . A. J . Am. Chem. Soc.
1996, 118, 5312.
(11) (a) Scott, R. L. J . Am. Chem. Soc. 1948, 70, 4090. Scott, R. L.
J . Phys. Chem. 1958, 62, 136. (b) Hildebrand, J . H.; Cochran, D. R. F.
J . Am. Chem. Soc. 1949, 71, 22.
(12) Hudlicky, M. Chemistry of Organic Fluorine Compounds; Ellis
Horwood: Chichester, U.K., 1992.
(5) Curran, D. P. Chemtracts: Org. Chem. 1996, 9, 75.
(6) (a) Horva´th, I. T.; Ra´bai, J . Science 1994, 266, 72. (b) Zhu, D.-
W. Synthesis 1993, 953.
(13) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; J eger, P.; Wipf,
P.; Curran, D. P. Science, in press.
S0022-3263(97)00095-9 CCC: $14.00 © 1997 American Chemical Society

2918 J . Org. Chem., Vol. 62, No. 9, 1997
Studer et al.
F igu r e 1.
Sch em e 1
Sch em e 2
highly variable side chains from simple starting materi-
als. Therefore, these strategies are rapidly becoming a
cornerstone of combinatorial syntheses of small-molecule
libraries in the pharmaceutical industry.1,16,17 The Ugi14
and the Biginelli15 reactions (Scheme 1) are two impor-
tant classes of multicomponent condensations that have
recently been adapted to solid phase techniques, and we
therefore selected these reactions to test the potential of
fluorous synthesis as a new strategy for multicomponent
condensation.
We designed a fluorous tag based on silane chemistry
because silanes are among the most useful substituents
and protecting groups in modern organic synthesis.18
Silane 1 is a new compound that was prepared by
following the literature procedure for a lower analog.19
The Grignard reagent derived from the commercially
available 1-iodo-1H,1H,2H,2H-perfluorododecane was re-
acted with trichlorosilane in Et2O (76%, Scheme 2).
Brominolysis of 1 in FC-7220 afforded bromosilane 2 in
quantitative yield. This bromosilane is a generally useful
fluorous labeling reagent. For the applications at hand,
we selected acid 7 as a suitable common precursor.
Bromine-lithium exchange of orthothiobenzoate 321 in
Et2O at -78 °C afforded the corresponding aryllithium
compound, which was then transferred to a solution of 2
in FC-72/benzotrifluoride (BTF, C6H5CF3) to provide the
silylated orthothioester 4. The fluorous orthothioester
4 was isolated by aqueous workup followed by partition-
ing of the crude product between benzene and FC-72.
(14) Ugi, I. Angew. Chem., Int. Ed. Engl. 1982, 21, 810.
(15) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) Kappe, C.
O. Tetrahedron 1993, 49, 6937 and references cited therein.
(16) See, for example: (a) Gordeev, M. F.; Patel, D. V.; Gordon, E.
M. J . Org. Chem. 1996, 61, 924. (b) Mjalli, A. M. M.; Sarshar, S.; Baiga,
T. J . Tetrahedron Lett. 1996, 37, 2943. (c) Hutchins, S. M.; Chapman,
K. T. Tetrahedron Lett. 1996, 37, 4869. (d) Gordeev, M. F.; Patel, D.
V.; Wu, J .; Gordon, E. M. Tetrahedron Lett. 1996, 37, 4643. (e)
Kolodziej, S. A.; Hamper, B. C. Tetrahedron Lett. 1996, 37, 5277. (f)
Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996,
37, 937.
(17) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123.
(18) (a) Greene, W. T.; Wuts, P. G. Protective Groups in Organic
Synthesis; J ohn Wiley & Sons, Inc: New York, 1991. (b) Armitage, D.
A. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone,
F. G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 2, p
1.
(19) Boutevin, B; Guida-Pietrasanta, F.; Ratsimihety, A.; Caporiccio,
G.; Gornowicz, G. J . Fluorine Chem. 1993, 60, 211.
(20) FC-72 is a commercially available (3M) fluorocarbon liquid
consisting mostly of isomers of C6F14 (bp 56 °C; price $389/1 gal).
(21) 3 was prepared according to Breslow, R.; Pandey, P. S. J . Org.
Chem. 1980, 45, 740.
(22) In the 1H NMR spectrum of orthothioester 4 we could always
observe some fluorous impurities. Attempts to purify 4 were not
successful.

Fluorous Synthesis: Ugi and Biginelli Condensations
J . Org. Chem., Vol. 62, No. 9, 1997 2919
Ta ble 1. Exa m p les of F lu or ou s Ugi Con d en sa tion s
Sch em e 3
yield
(%)
purity
(%)a
entry
R1
R2
R3
9
1
2
3
4
5
6
7
8
9
Bn
Bn
Bn
Pr
Bn
Pr
Bn
Bn
Bn
Pr
Ph
t-Bu
t-Bu
t-Bu
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
t-Bu
a
b
c
d
e
f
g
h
i
83
81
32
99
92
71
61
84
75
78
85
87
89
>95
80
>95
>95
>95
93
4-MeO-Ph
c-Hex
c-Hex
Ph
i-Pr
i-Pr
c-Hex
Et
i-Pr
Evaporation of the FC-72 phase provided 4, which was
used for the subsequent reaction without further puri-
fication.22 Treatment of 4 with AgNO3 in a mixture of
BTF, THF, acetone, and water yielded after column
chromatography thioester 5 in 40-60% overall yield.23
Oxidative cleavage of the thioester sulfur-carbon bond
with bromine in FC-72 afforded the corresponding acyl
bromide 6 (not characterized), which was hydrolyzed in
aqueous THF to provide the highly fluorinated acid 7 as
a white solid in 97% yield.
Th e F lu or ou s Ugi (or F lu gi) Rea ction . In the Ugi
four-component reaction, an acid, an aldehyde, an amine,
and an isonitrile are condensed to form the corresponding
amino acid amide, as shown in Scheme 1.14 Fluorous acid
7 can directly be used as the “labeled” component in the
Ugi reaction.24 To optimize the reaction conditions for
the multiple component condensation, the reactions of
acid 7 with a preformed imine (benzylbenzylideneamine)
and tert-butyl isocyanide in different solvents were
studied (Scheme 3). These trial reactions were run in
sealed tubes with large excesses (up to 17 equiv each) of
the imine and the isonitrile. After removal of the
solvents, the crude reaction mixture was diluted with
benzene and extracted three times with FC-72. Evapo-
ration of the fluorous phase yielded the desired fluorous
Ugi product 8 together with unreacted acid 7. No
resonances from these fluorous products could be identi-
fied in the 1H NMR spectrum of the residue from the
benzene layer, thereby proving the high efficiency of the
extraction process. With CH2Cl2 as the organic phase
for the extraction, more than 10% of the fluorous Ugi
product remained in the organic layer even after multiple
extractions with FC-72.
10
t-Bu
j
81
a
Determined by GC analysis.
fluorine atoms (4-tris((2-(perfluorohexyl)ethyl)silyl)ben-
zoic acid, 7-F39). However, the corresponding Ugi product
8-F39 obtained by three-component condensation with
benzylbenzylideneamine and tert-butyl isocyanide could
not efficiently be extracted from different organic solvents
into FC-72. After three extractions with FC-72, only 11%
(benzene), 9% (MeOH), and 8% (CH2Cl2) of 8-F39 could
be isolated from the fluorous phase. In simple terms,
8-F39 is an organic compound rather than a fluorous
compound.
The last step in the synthesis is desilylation, which
corresponds to the cleavage of the product from the
polymer in solid phase synthesis (see Figure 1). The silyl
group was surprisingly stable toward many common
desilylation procedures. No reaction occurred under
basic conditions with LiOH in a mixture of THF and
water. Exposure to HF‚pyridine in THF and CsF in THF/
MeOH also did not cleave the aryl-silicon bond, nor did
trifluoroacetic acid in CH2Cl2.25 However, with tetrabu-
tylammonium fluoride (TBAF, 1.5 equiv) in THF, cleav-
age was accomplished within 30 min at room tempera-
ture. After evaporation of the solvent, the crude product
was purified by two-phase extraction using benzene and
FC-72. The fluorous phase containing the fluorosilane
was discarded. The organic layer was additionally
washed with 0.1 N HCl, aqueous Na2CO3, and brine to
remove benzoic acid derived from unreacted acid 7, excess
TBAF, and any compounds derived from TBAF. The
desired benzoylated amino acid amide 9a was obtained
in 83% yield.
We applied these optimized conditions to the prepara-
tion of a small library of amino acids, and the results of
these experiments are summarized in Table 1. Reactions
were run on a 15 µmol scale to provide 2-5 mg of the
final benzoylated amino acids 9b-j. In two examples
(entries 1 and 5), preformed imine was used. For the
phenylglycine derivative 9a , the corresponding four-
component condensation reaction with benzaldehyde and
benzylamine gave similar results to those described in
entry 1. The yields of the overall process were modest
to high (32-99%). For comparison, authentic samples
of the products were synthesized by using the standard
Ugi protocol (see Experimental Section). Purities were
determined by GC analysis. The average purity of about
Three-component condensation reaction of 7, benzyl-
benzylideneamine, and tert-butyl isocyanide in BTF/THF
(1:1) at 90 °C for 38 h resulted in 30% conversion as
1
determined by H NMR analysis. In MeOH, the solvent
normally used in non-fluorous Ugi reactions, 60% conver-
sion was obtained after 48 h. Trifluoroethanol
(CF3CH2OH, TFE) was found to be the solvent of choice.
Like BTF,8 TFE serves as a “hybrid organic/fluorous”
solvent with the ability to dissolve both organic and
fluorous compounds. High conversion (>90%) in the Ugi
test reaction was obtained in 48 h by using TFE.
Acid 7 contains 63 fluorine atoms. We have also
synthesized a “lower homolog” of acid 7 containing 39
(23) Reactions were usually run on 0.5-0.7 mmol scale. If the
reaction sequence was performed on a larger scale, a decrease in the
yield was observed.
(25) NMR spectra of acid
trifluoroacetic acid.
7 were recorded in neat deuterated
(24) For Ugi reactions on solid polymer supports, see ref 17.

2920 J . Org. Chem., Vol. 62, No. 9, 1997
Studer et al.
Sch em e 4
product separation without chromatography are pre-
served. The use of fluorous labels in the separation
process allows for a greater flexibility in the choice of
anchoring functions and cleavage conditions.
In a typical reaction, the urea 13 (Rfh ) C10F21CH2CH2),
obtained in 89% yield by the acylation of urea alcohol 12
with acyl bromide 6, was stirred for 3 d at 50 °C with 10
equiv each of â-keto ester 10 and aldehyde 11 in the
presence of catalytic HCl (Scheme 5). As with the Ugi
reaction, the large excess of reactants was used both to
drive the reaction to completion and to deliberately
generate the separation of large amounts of organic
reaction products. Optimal solubility of all the reaction
components and a homogenous solution were achieved
in a 2:1 mixture of THF/BTF. The crude reaction mixture
was extracted with FC-72, and desilylation with TBAF
in THF/BTF provided dihydropyrimidines 14 in 47-71%
1
yield and >90% purity by H NMR. Table 2 presents a
range of examples of this method.
For comparison, the yields of standard Biginelli reac-
tions with urea 15 according to Scheme 5 are listed side-
by-side with the fluorous yields. In the absence of the
fluorous or solid phase linkages, the excess of aldehyde
and â-keto ester components had to be limited to 2 equiv
to reduce the number of tedious chromatographic separa-
tions. We noted, however, a slight decrease in the
reaction rate of the fluorous compared to the standard
Biginelli reactions that might require a more extensive
reaction optimization. In some fluorous Biginelli reac-
tions (entries 7-10), we obtained a mixture of products.
Our hypothesis is that in the case of a longer side chain
(R2 ) CH2Bn) or a less reactive aldehyde (R3 ) 4-MeO-
Ph), the Biginelli reaction proceeds only slowly, giving
rise to side products. This is reflected by a low product
yield under the corresponding standard reaction condi-
tions. The fluorous Biginelli heterocycles and the side
products, sharing the same phase, were not separated
in the liquid-liquid extraction step.
Attachment of one of the reactants in the Biginelli
reaction to a fluorous tag allows a straightforward
separation of the heterocyclic product by liquid-liquid
extraction. The dihydropyrimidine can be obtained in an
analytically pure form by cleavage of the fluorinated silyl
group with TBAF and renewed liquid-liquid extraction.
Compared to the standard protocol,15 this method allows
the rapid preparation of Biginelli products in comparable
yields without any chromatographic separations. Com-
pared to the solid phase procedure,26 the fluorous Bigi-
nelli condensation results in slightly lower reaction yields
but offers a greater flexibility in the selection of side-
chain functionalities.
90% is in line with current standards for combinatorial
synthesis. The purity seems to depend mainly on the
aldehyde component: alkyl aldehydes give higher puri-
ties than aryl ones. The yields and purities are impres-
sive considering that the Ugi products 9 are only minor
components of the reaction due to the large excesses of
reactants and the high molecular weight of the fluorous
tag. These products consist of only 4 of the 52 molar
equiv of reactants that are mixed in the Ugi reaction,
and they have less than 6% of the total mass after
desilylation.
Th e F lu or ou s Bigin elli (or F lu gin elli) Rea ction .
In the Biginelli dihydropyrimidine synthesis,15 the one-
pot cyclocondensation of â-keto esters, aldehydes, and
ureas provides heterocycles of well-established pharma-
cological potential. We have recently reported26 the first
solid phase version of the Biginelli reaction and demon-
strated its suitability for combinatorial chemistry.27
The solid phase Biginelli protocol uses a polymer bound
urea which is reacted with different â-keto esters 10 and
aldehydes 11 as shown in Scheme 4. This offers a
superior alternative to the standard solution-based ex-
perimental variations of this reaction. Yields are gener-
ally higher by a margin of 10-20%, and no crystallization
or chromatographic purification is necessary. We were
able to obtain dihydropyrimidines of >90% purity (1H
NMR) and 80-95% yield after cleavage from the resin
and filtration. However, this protocol has limitations
imposed by the nature of the linkage group to the resin
and the acidic conditions required in the cleavage reac-
tion.
Con clu sion s
This work shows that a highly fluorinated silyl group
containing 63 fluorine atoms can be used as a “fluorous
phase marker” to replace the solid polymer support in
combinatorial synthesis. “Organic” molecules with mo-
lecular weights of up to almost 500 were rendered
“fluorous” upon attachment to this fluorous tag. The
fluorous Ugi and Biginelli products have molecular
We have now developed a new protocol for the Biginelli
reaction that takes advantage of the extraction of the
product heterocycles into the fluorous phase. The major
advantages of the solid phase protocol26 such as the use
of an excess of two or more reaction components and
3
weights of about 2000, of which roughly /5 is fluorine,
1
1/5 is other atoms of the tag (C, H, Si), and /5 is the tagged
organic moiety itself.
(26) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819.
(27) For a related solid-phase modification of the Biginelli reaction,
see: Robinett, L. D.; Yager, K. M.; Phelan, J . C. 211th National
Meeting of the American Chemical Society, New Orleans, 1996;
American Chemical Society: Washington, DC, 1996; ORGN 122.
In contrast to most solid phase syntheses, reactions can
be run in homogeneous phase and can be followed by TLC
or other standard techniques. The products are single

Fluorous Synthesis: Ugi and Biginelli Condensations
J . Org. Chem., Vol. 62, No. 9, 1997 2921
Sch em e 5
Ta ble 2. Yield s of F lu or ou s a n d Sta n d a r d Bigin elli
Rea ction s a ccor d in g to Sch em e 5
a white solid (4.7 g, 76%): mp 76-78 °C; IR (FC-72) 2977,
2950, 2914, 2873, 2136, 1444, 1426 cm-1; 1H NMR (300 MHz,
FC-72 with benzene as internal lock) δ 1.15-1.22 (m, 6 H),
2.24-2.41 (m, 6 H), 4.14 (s, 1 H).
â-keto ester
aldehyde
yields of
dihydropyrimidine 14
10
11
Br om otr is(2-(p er flu or od ecyl)eth yl)sila n e (2). Tris(2-
(perfluorodecyl)ethyl)silane (1) (0.56 g, 0.34 mmol) was dis-
solved under argon in FC-72 (10 mL). Bromine (0.03 mL, 0.50
mmol) was added, and the mixture was stirred at 25 °C for 12
h. FC-72 (40 mL) was added, and the fluorous phase was
washed with CH2Cl2. Evaporation of the fluorous layer yielded
bromotris(2-(perfluorodecyl)ethyl)silane as a white solid (586
mg, 99%): mp 80-81 °C; IR (FC-72) 2980, 2953, 2907, 2847,
entry R1
R2
R3
fluorousa standardb [%] compd
1
2
3
Et
Et
Et
Me
Me
Me
Ph
71
74
62
78
90
66
73
38
56
33
18
a
b
c
d
e
f
2-naphthyl 55
(4-MeO)Ph 69
2-naphthyl 70
2-naphthyl 60
Ph
(4-MeO)Ph mixture
mixture
4
Me Me
5
6
7
Et
Et
Et
Et
Et
Et
47
g
h
l
1
1444, 1423 cm-1; H NMR (300 MHz, FC-72 with benzene as
8
Me Ch2Bn Ph
9
10
Me Ch2Bn 2-naphthyl mixture
Me Ch2Bn (4-MeO)Ph mixture
internal lock) δ 1.41-1.55 (m, 6 H), 2.33-2.44 (m, 6 H).
k
Tr ip r op yl 4-Br om oor th oth ioben zoa te (3). 4-Bromoben-
zoic acid (2.00 g, 9.95 mmol) was suspended in thionyl chloride
(3 mL, 41.2 mmol) and heated at reflux for 60 min. Removal
of the excess thionyl chloride and vacuum drying provided
4-bromobenzoyl chloride as a colorless solid. Propanethiol (10
mL, 109 mmol) was slowly added to a mixture of 4-bromoben-
zoyl chloride and anhydrous AlCl3 (5.30 g, 39.7 mmol). The
mixture was heated at 60 °C for 48 h, cooled, and poured slowly
with stirring into ice-cooled 4 N aqueous NaOH (75 mL).
Extraction with ether and washing of the organic phase with
brine afforded after drying (MgSO4) the crude product as a
red oil. Purification by flash column chromatography (SiO2,
hexanes containing 1% of NEt3) provided the orthothiobenzoate
3 as a colorless oil (1.78 g, 45%): IR (neat) 2962, 2929, 2871,
1582, 1483, 1456, 1391, 1378, 1337, 1291, 1237, 1076, 1008
a
b
With urea 13. With urea 15.
entities that can be characterized by standard spectro-
scopic methods as well. Purities can be assessed at any
stage. Detachment and extractive purification provide
the corresponding organic products in reasonable yields
and acceptable purities without using conventional sepa-
ration methods even when an unduly large excess of
reactants is added. Considering the simple experimental
techniques used in this fluorous chemistry, automation
should be feasible, thus allowing the preparation of
libraries of small molecules.
1
cm-1; H NMR (300 MHz, CDCl3) δ 0.93 (t, J ) 7.3 Hz, 9 H),
Exp er im en ta l Section
1.48-1.55 (m, 6 H), 2.54 (t, J ) 7.3 Hz, 6 H), 7.43 (d, J ) 8.7
Hz, 2 H), 7.73 (d, J ) 8.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3)
δ 13.80, 21.80, 33.82, 72.87, 121.53, 129.68, 130.94, 141.33.
MS (EI) m/ z 351 (M+ - propyl), 349, 319 (M+ - S(CH2)2CH3),
317, 201, 109; HRMS calcd for C13H18S281Br (M+ - S(CH2)2CH3)
m/ z 319.0013, found 319.0000.
Gen er a l. Anhydrous solvents were freshly distilled from
sodium benzophenone ketyl, P2O5, or CaH2. FC-72 and FC-
84 were obtained from 3M. FC-84 consists mostly of isomers
of C7F16 (bp 80 °C) and can be used instead of FC-72.
Tr is(2-(per flu or odecyl)eth yl)silan e (1). Magnesium pow-
der (0.45 g, 18.5 mmol) was suspended in dry Et2O (20 mL),
and 1-iodo-1H,1H,2H,2H-perfluorododecane (0.50 g, 0.77 mmol)
was added. The resulting suspension was sonicated for 30
min. A solution of 1-iodo-1H,1H,2H,2H-perfluorododecane
(9.50 g, 14.7 mmol) in Et2O (70 mL) was slowly added. The
mixture was heated at reflux for 2 h. Trichlorosilane (0.40
mL, 3.87 mmol) was slowly added, and the reaction mixture
was stirred under reflux for 16 h. After the mixture was cooled
to 25 °C, saturated aqueous NH4Cl and CH2Cl2 were added.
The cloudy biphase was extracted five times with FC-72.
Evaporation of the combined fluorous extracts yielded the
crude product as a white solid. Removal of the impurity
(dimer, Wurtz coupling product) by bulb-to-bulb distillation
(0.5 Torr, 210 °C) yielded tris(2-(perfluorodecyl)ethyl)silane as
4-Tr is((2-(p er flu or od ecyl)eth yl)silyl)th ioben zoic Acid
S-P r op yl Ester (5). Tripropyl 4-bromoorthothiobenzoate (3)
(250 mg, 0.66 mmol) was dissolved in Et2O (7.5 mL) and cooled
to -78 °C under argon. t-BuLi (1.7 molar in pentane, 0.82
mL, 1.39 mmol) was slowly added, and the resulting yellow
solution was stirred at that temperature for 45 min. The
yellow aryllithium solution was then transferred via canula
to a 25 °C mixture of bromo tris(2-(perfluorodecyl)ethyl)silane
(2) (500 mg, 0.29 mmol) in BTF (15 mL) and FC-72 (2.5 mL).
The reaction mixture was stirred at 25 °C for 30 min. After
addition of H2O, the reaction mixture was extracted three
times with CH2Cl2. The combined organic layers were dried
(MgSO4) and evaporated to afford an oil which was taken up
into FC-72 and washed with benzene. The benzene layer was

2922 J . Org. Chem., Vol. 62, No. 9, 1997
Studer et al.
additionally extracted twice with FC-72. The combined fluo-
rous layers were evaporated to yield the crude orthothioester
4 which was dissolved in BTF (7.5 mL), THF (7.5 mL), acetone
(5 mL), and H2O (0.5 mL) at 25 °C. AgNO3 (135 mg, 0.80
mmol) was added, and the resulting suspension was stirred
at 25 °C for 12 h. After filtration and evaporation of the
filtrate, the crude product was purified by flash column
chromatography (SiO2, Et2O/hexanes; 1/40) to afford 5 as a
colorless solid (319 mg, 60%): mp 69-71 °C; IR (CHCl3) 2970,
2935, 1668, 1246, 1193, 1157 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.04 (t, J ) 7.3 Hz, 3 H), 1.15-1.21 (m, 6 H), 1.68-1.75 (m,
2 H), 1.94-2.06 (m, 6 H), 3.08 (t, J ) 7.1 Hz, 2 H), 7.54 (d, J
) 8.0 Hz, 2 H), 8.03 (d, J ) 8.0 Hz, 2 H); 13C NMR (125 MHz,
CDCl3, 30 °C) δ 1.60, 13.43, 23.00, 25.60 (t, J ) 23.0 Hz), 31.19,
108.45-118.40 (m, CF2, CF3), 127.23, 133.99, 137.79, 139.27,
191.85.
4-Tr is((2-(p er flu or od ecyl)eth yl)silyl)ben zoic Acid (7).
4-Tris((2-(perfluorodecyl)ethyl)silyl)thiobenzoic acid S-propyl
ester (5) (210 mg, 0.11 mmol) was dissolved in FC-72 (15 mL).
Bromine (0.05 mL, 0.83 mmol) was added at 25 °C, and the
mixture was stirred for 3 h. After addition of FC-72 (15 mL)
and washing with CH2Cl2, the fluorous layer was evaporated
to afford 4-tris((2-(perfluorodecyl)ethyl)silyl)benzoic acid bro-
mide (6) as a colorless solid. The acid bromide 6 was dissolved
in THF (12 mL) and BTF (3 mL). H2O (1.5 mL) was added,
and the solution was stirred at 25 °C for 12 h. Evaporation of
the solvents afforded 7 as a colorless solid (196 mg, 97%): mp
134-136 °C; 1H NMR (300 MHz, TFA-d) δ 1.35-1.39 (m, 6
H), 2.10-2.35 (m, 6 H), 7.78 (d, J ) 8.1 Hz, 2 H), 8.27 (d, J )
7.9 Hz, 2 H); 13C NMR (75 MHz, TFA-d) δ 2.95, 27.42, 105-
120 (m, CF2, CF3), 131.78, 132.05, 136.15, 142.95, 175.38; MS
(EI) m/ z 1243 (M+ - CH2CH2(CF2)9CF3), 706, 601, 474, 423,
378, 175.
fluorosilylated amino acid amide. For desilylation, the amino
acid amide was dissolved at 25 °C in THF (2 mL); TBAF (1 M
in THF, 0.022 mL, 0.022 mmol) was added, and the resulting
solution was stirred at 25 °C for 30 min. After removal of the
solvent, the residue was diluted with benzene (30 mL) and
washed twice with FC-72 (15 mL). Et2O (30 mL) was added
to the organic layer which was washed with 0.1 N HCl,
saturated aqueous Na2CO3, and brine (15 mL each). The
organic phase was dried (MgSO4) and evaporated to yield the
benzoylated amino acid amide 9. The purity was checked by
GC analysis.
N-Ben zoyl-N-ben zylph en ylglycin e ter t-bu tylam ide (9a)
was prepared according to general procedure 1 with the acid
7 (26.2 mg, 0.015 mmol), benzylbenzylideneamine (51 mg, 0.25
mmol), and tert-butyl isocyanide (30 µL, 0.25 mmol) to afford
the silylated amino acid 8: IR (CHCl3) 1684, 1631, 1518, 1240,
1
1218, 1157 cm-1; H NMR (300 MHz, CDCl3) δ 1,14 (s br, 6
H), 1.34 (s, 9 H), 1.90-2.20 (br, 6 H), 4.35-4.50 (br, 1 H), 4.71
(d, J ) 17.6, 1 H), 5.52 (s, 1 H), 5.63 (s, 1 H), 6.91 (s br, 2 H),
7.26 (s br, 4 H), 7.30-7.49 (m, 8 H); 13C NMR (75 MHz, CDCl3)
δ 1.50, 25.54, 28.75, 51.93, 105-125 (m, CF2, CF3), 127.08,
127.15, 127.24, 128.45, 128.95, 129.15, 129.25, 129.98, 137.63,
138.89, 168.42, 172.70. Desilylation as described in general
procedure 1 in THF (2 mL) with TBAF (0.022 mL, 0.022 mmol)
afforded 9a (5.0 mg, 83%) with 85% purity: IR (CHCl3) 3424,
3066, 3032, 2969, 2934, 2907, 2246, 1681, 1635, 1514, 1496,
1
1453, 1430, 1409 cm-1; H NMR (300 MHz, CDCl3) δ 1.30 (s,
9 H), 4.47 (s br, 1 H), 4.73 (d, J ) 16.4 Hz, 1 H), 5.46 (s, 1 H),
5.40-5.75 (s br, 1 H), 7.03 (s br, 2 H), 7.13-7.16 (m, 4 H),
7.26-7.49 (m, 9 H); 13C NMR (75 MHz, CDCl3) δ 28.67, 51.74,
126.79, 127.02, 128.41, 128.66, 128.92, 129.73, 129.90, 135.33,
136.46, 168.53, 173.38; MS (EI) m/ z 328 (M+ - NHC(CH3)3),
300 (M+ - CONHC(CH3)3), 210, 191, 105, 91, 77; HRMS calcd
for C21H18NO (M+ - CONHC(CH3)3) m/ z 300.1388, found
300.1389.
4-Tr is((2-(p er flu or oh exyl)eth yl)silyl)ben zoic a cid (7-
F 39) was prepared according to the procedure for the prepara-
tion of acid 7: mp 64-65 °C; IR (CHCl3) 3500-2500 br, 1694,
1441, 1422, 1361, 1318, 1291, 1237, 1211 cm-1; 1H NMR (300
MHz, CDCl3) δ 1.17-1.23 (m, 6 H), 2.01-2.07 (m, 6 H), 7.59
(d, J ) 8.0 Hz, 2 H), 8.18 (d, J ) 8.0 Hz, 2 H); 13C NMR (75
MHz, CDCl3 and two drops of CD3OD) δ 1.18, 25.28 (t, J ) 24
Hz), 104.61-122.89 (m, CF2, CF3), 129.78, 132.41, 133.66,
N-Ben zoyl-N-ben zyl-4-m eth oxyp h en ylglycin e ter t-bu -
tyla m id e (9b) was prepared according to general procedure
1 with the acid 7 (26.1 mg, 0.015 mmol), benzylamine (27 µL,
0.25 mmol), anisaldehyde (30 µL, 0.25 mmol), and tert-butyl
isocyanide (30 µL, 0.25 mmol) to afford after desilylation 9b
(5.1 mg, 81%) with 87% purity: IR (CHCl3) 3423, 3066, 3031,
2968, 2937, 2911, 2246, 1681, 1633, 1581, 1512, 1455, 1412,
1395, 1366, 1339, 1306, 1252, 1224, 1179, 1033 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.30 (s, 9 H), 3.77 (s, 3 H), 4.43 (s br, 1
H), 4.72 (d, J ) 16.4 Hz, 1 H), 5.43 (s, 1 H), 5.40-5.70 (s br,
1 H), 6.79 (d, J ) 8.3 Hz, 2 H), 7.02-7.47 (m, 12 H); 13C NMR
(75 MHz, CDCl3) δ 28.70, 51.67, 55.42, 114.24, 126.77, 126.92,
127.25, 128.35, 128.58, 129.79, 131.18, 136.60, 159.76, 168.84,
173.28; MS (EI) m/ z 430 (M+), 358 (M+ - NHC(CH3)3), 330
(M+ - CONHC(CH3)3), 240, 224, 105, 91, 77; HRMS calcd for
C22H20NO2 (M+ - CONHC(CH3)3) m/ z 330.1494, found
330.1498.
137.50, 168.82; MS (EI) m/ z 1173 (M+ - OH), 843 (M+
CH2CH2(CF2)5CF3), 517, 414, 309, 239, 187.
-
N-(4-Tr is([2-p er flu or oh exyleth yl]silyl)ben zoyl)-N-ben -
zylp h en ylglycin e ter t-Bu tyla m id e (8-F 39). 4-Tris((2-(per-
fluorohexyl)ethyl)silyl)benzoic acid (7-F39) (0.070 g, 0.059
mmol), benzylbenzylideneamine (0.032 g, 0.164 mmol), and
tert-butyl isocyanide (16 µL, 0.l4 mmol) were dissolved in
MeOH (1 mL). The solution was heated at reflux for 46 h.
Removal of the solvent and purification by flash column
chromatography (SiO2, 1/5 gradient ether/hexanes to 1/3 ether/
hexanes) afforded the silylated amino acid amide as a foam
(82 mg, 86%): IR (CHCl3) 3424, 3067, 3031, 2969, 2934, 2245,
1682, 1636, 1515, 1498, 1451, 1364, 1350, 1315, 1294, 1238,
N-Ben zoyl-N-ben zylcycloh exylglycin e ter t-bu tyla m id e
(9c) was prepared according to general procedure 1 with the
acid 7 (24.0 mg, 0.013 mmol), benzylamine (27 µL, 0.25 mmol),
cyclohexanecarboxaldehyde (30 µL, 0.25 mmol), and tert-butyl
isocyanide (30 µL, 0.25 mmol) to afford after desilylation 9c
(1.7 mg, 32%) with 89% purity: mp 140-141 °C; IR (CHCl3)
1
1210, 1145, 1121, 921, 900 cm-1; H NMR (300 MHz, CDCl3)
δ 1.12-1.15 (m, 6 H), 1.33 (s, 9 H), 1.90-2.25 (m, 6 H), 4.44
(d br, J ) 16.4 Hz, 1 H), 4.72 (d, J ) 16.7 Hz, 1 H), 5.57 (s br,
1 H), 5.66 (s br, 2 H), 6.91 (s br, 2 H), 7.10 (s br, 4 H), 7.19-
7.49 (m, 8 H); 13C NMR (75 MHz, CDCl3) δ 1.35, 25.32 (t, J )
24 Hz), 28.53, 51.73, 105.47-121.24 (m, CF2, CF3), 126.91,
128.24, 128.74, 128.93, 129.75, 133.66, 135.10, 137.48, 138.75,
168.25, 172.49; MS (FAB) m/ z 1491 (M + Na)+, 1469 (M +
H)+, 1173 ((Rf)3SiC6H4CO)+. In extraction experiments, puri-
fied 8-F39 was dissolved in the organic solvent and extracted
three times with FC-72.
Gen er a l P r oced u r e for th e Ugi F ou r -Com p on en t Con -
d en sa tion (Gen er a l P r oced u r e 1). 4-Tris((2-(perfluorode-
cyl)ethyl)silyl)benzoic acid (7) (26.2 mg, 0.015 mmol), the
amine (0.25 mmol), the aldehyde (0.25 mmol), and the isoni-
trile (0.25 mmol) were added to a sealed tube with CF3CH2OH
(0.3 mL). (For some examples, the preformed imine was used.)
The suspension was heated under argon to 90 °C for 48 h. After
removal of the solvent, the residue was diluted with FC-72
(15 mL) and washed with benzene (15 mL). The benzene layer
was additionally extracted twice with FC-72 (15 mL). The
combined fluorous phases were evaporated to yield the per-
2964, 2935, 2858, 2249, 1674, 1618, 1510, 1452, 1363 cm-1
;
1H NMR (300 MHz, CDCl3) δ 0.90-2.00 (m, 10 H), 1.31 (s, 9
H), 2.38 (m, 1 H), 4.14 (d, J ) 10.5 Hz, 1 H), 4.44 (d, J ) 16.1
Hz, 1 H), 4.70 (d, J ) 16.1 Hz, 1 H), 5.30 (s br, 1 H), 6.90-
7.50 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 25.06, 25.88, 26.49,
28.80, 29.77, 30.32, 36.50, 51.19, 52.65, 126.72, 127.25, 127.64,
128.31, 128.53, 129.74, 136.99, 137.41, 169.42, 173.99; MS (EI)
m/ z 406 (M+), 306 (M+ - CONHC(CH3)3), 216, 197, 105, 91,
77; HRMS calcd for C26H34N2O2 m/ z 406.2620, found 406.2635.
N-Ben zoyl-N-p r op ylcycloh exylglycin e cycloh exyla -
m id e (9d ) was prepared according to general procedure 1 with
the acid 7 (26.4 mg, 0.015 mmol), propylamine (21 µL, 0.25
mmol), cyclohexanecarboxaldehyde (30 µL, 0.25 mmol), and
cyclohexyl isocyanide (31 µL, 0.25 mmol) to afford after
desilylation 9d (5.7 mg, 99%) with >95% purity: mp 110-
112 °C; IR (CHCl3) 2934, 2856, 2244, 1660, 1613, 1578, 1529,
1
1450, 1419, 1352 cm-1; H NMR (300 MHz, CDCl3) δ 0.61 (t,
J ) 7.3 Hz, 3 H), 0.85-1.84 (m, 22 H), 2.39 (m, 1 H), 3.20 (m,

Fluorous Synthesis: Ugi and Biginelli Condensations
J . Org. Chem., Vol. 62, No. 9, 1997 2923
2 H), 3.75-3.78 (m, 1 H), 4.00 (s br, 1 H), 7.34-7.43 (m, 5 H);
13C NMR (75 MHz, CDCl3) δ 11.21, 22.59, 24.71, 25.79, 26.50,
29.69, 30.47, 32.79, 32.97, 35.53, 47.75, 126.64, 128.61, 129.76,
N-Ben zoyl-N-p r op ylva lin e ter t-bu tyla m id e (9j) was
prepared according to general procedure 1 with the acid 7 (23.1
mg, 0.013 mmol), propylamine (21 µL, 0.25 mmol), isobutyral-
dehyde (23 µL, 0.25 mmol), and tert-butyl isocyanide (30 µL,
0.25 mmol) to afford after desilylation 9j (3.2 mg, 78%) with
81% purity: IR (CHCl3) 2967, 2935, 2875, 2245, 1679, 1668,
136.96, 170.27, 173.70; MS (EI) m/ z 384 (M+), 258 (M+
-
CONHC6H11), 223, 105, 77; HRMS calcd for C24H36N2O2 m/ z
384.2777, found 384.2781.
1613, 1578, 1550, 1535, 1496, 1458, 1419, 1340, 1225 cm-1
;
N-Ben zoyl-N-b en zylp h en ylglycin e cycloh exyla m id e
(9e) was prepared according to general procedure 1 with the
acid 7 (27.1 mg, 0.015 mmol), benzylbenzylideneamine (51 mg,
0.25 mmol), and cyclohexyl isocyanide (31 µL, 0.25 mmol) to
afford after desilylation 9e (5.2 mg, 92%) with 80% purity: IR
(CHCl3) 3422, 3066, 3031, 2935, 2857, 2246, 1673, 1634, 1603,
1515, 1497, 1452, 1431, 1411, 1349, 1313, 1253 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.07-2.20 (m, 10 H), 3.83 (m br, 1 H),
4.47 (s br, 1 H), 4.70 (s br, 1 H), 5.47 (s, 1 H), 5.67 (s br, 1 H),
7.12-7.49 (m, 15 H); 13C NMR (75 MHz, CDCl3) δ 24.91, 25.60,
32.84, 48.71, 126.83, 127.15, 128.51, 128.73, 128.99, 129.73,
129.96, 135.24, 136.34, 168.39, 173.36; MS (EI) m/ z 321 (M+
- PhCO), 300 (M+ - CONHC6H11), 217, 210, 105, 91, 77;
HRMS calcd for C21H18NO (M+ - CONHC6H11) 300.1388,
found 300.1398.
N-Ben zoyl-N-p r op ylva lin e cycloh exyla m id e (9f) was
prepared according to general procedure 1 with the acid 7 (25.8
mg, 0.014 mmol), propylamine (21 µL, 0.25 mmol), isobutyral-
dehyde (23 µL, 0.25 mmol), and cyclohexyl isocyanide (31 µL,
0.25 mmol) to afford after desilylation 9f (3.5 mg, 71%) with
>95% purity. The physical data are in agreement with those
reported in literature.
N-Ben zoyl-N-ben zylva lin e cycloh exyla m id e (9g) was
prepared according to general procedure 1 with the acid 7 (26.1
mg, 0.015 mmol), benzylamine (27 µL, 0.25 mmol), isobutyral-
dehyde (23 µL, 0.25 mmol), and cyclohexyl isocyanide (31 µL,
0.25 mmol) to afford after desilylation 9g (3.5 mg, 61%) with
>95% purity: mp 131-133 °C; IR (CHCl3) 3423, 3303, 3064,
3029, 2970, 2931, 2860, 2242, 1665, 1617, 1518, 1450, 1340,
1309 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.78-1.37 (m, 11 H),
1.51-1.79 (m, 5 H), 2.69 (m br, 1 H), 3.63 (m br, 1 H), 4.16 (d,
J ) 10.6 Hz, 1 H), 4.44 (d, J ) 15.8 Hz, 1 H), 4.67 (d, J ) 15.9
Hz, 1 H), 6.93 (s br, 2 H), 7.11-7.26 (m, 7 H); 13C NMR (75
MHz, CDCl3) δ 19.39, 19.91, 24.63, 25.53, 27.24, 32.58, 32.87,
47.76, 52.54, 68.17, 126.57, 127.20, 127.49, 128.17, 128.42,
129.64, 136.79, 137.08, 169.27, 173.92; MS (EI) m/ z 287 (M+
- PhCO), 266 (M+ - CONHC6H11), 211, 183, 105, 91, 77;
HRMS calcd for C18H27N2O (M+ - PhCO) m/ z 287.2123, found
287.2128.
1H NMR (300 MHz, CDCl3) δ 0.56 (t, J ) 7.1 Hz, 3 H), 0.75-
1.60 (m, 8 H), 1.31 (s, 9 H), 2.60 (m, 1 H), 3.17 (t, J ) 7.3 Hz,
2 H), 3.90 (s br, 1 H), 7.26-7.36 (m, 6 H); 13C NMR (75 MHz,
CDCl3) δ 11.27, 19.35, 20.08, 22.57, 26.54, 28.74, 50.93, 126.61,
128.62, 129.73, 136.95, 170.38, 173.67; MS (EI) m/ z 318 (M+),
246 (M+ - NHC(CH3)3), 218 (M+ - CONHC(CH3)3), 105, 91,
77; HRMS calcd for C19H30N2O2 (M+) m/ z 318.2307, found
318.2322.
Gen er a l P r oced u r e for Con ven tion a l Ugi Rea ction s.
Benzoic acid (122 mg, 1.00 mmol), the aldehyde (1 mmol), the
amine (1 mmol), and the isonitrile (1 mmol) were dissolved in
MeOH (2 mL) and stirred at room temperature (16-24 h).
After evaporation of the solvent, the residue was diluted with
Et2O and washed with 0.1 N HCl, saturated aqueous Na2CO3,
and brine. The organic phase was dried (MgSO4) and evapo-
rated to yield the crude product. Purification by flash column
chromatography (SiO2, Et2O/hexanes; 1/1) afforded the amino
acid amide 9.
(2-((4-(Tr is(2-(p e r flu or od e cyl)e t h yl)silyl)b e n zoyl)-
oxy)eth yl)u r ea (13). A solution of thioester 5 (88 mg, 47.6
µmol) in FC-72 (6 mL) was treated at 25 °C with bromine (30
µL, 0.58 mmol). After 0.5 h, the mixture was extracted with
dichloromethane (10 mL). The dichloromethane phase was
extracted with FC-72 (3 × 10 mL). The combined fluorous
phases were filtered and evaporated. The resulting acid
bromide 6 (88 mg) was diluted with BTF (1.0 mL) and added
to a suspension of (hydroxyethyl)urea 12 (27 mg, 0.26 mmol),
triethylamine (36 µL, 0.26 mmol), and 4-(dimethylamino)py-
ridine (3 mg, 25 µmol) in dry dioxane (0.50 mL) at 35 °C. After
the mixture was stirred for 22 h at 35 °C, the volatiles were
removed in vacuo and FC-72 (20 mL), water (10 mL), and
toluene (5 mL) were added. The combined water/toluene
phases were washed with FC-72 (5 × 10 mL). The combined
fluorous phases were filtered and concentrated to give 13 as a
white solid (79 mg, 89%): mp 101-103 °C; IR (neat) 3500-
3100, 1718, 1662, 1558, 1207, 1149, 896, 739, 665, 532 cm-1
1H NMR (acetone-d6) δ 8.10 (d, J ) 8.1 Hz, 2 H), 7.86 (d, J )
8.1 Hz, 2 H), 5.96 (bs, 1 H), 5.13 (bs, 2 H), 4.35 (t, J ) 5.5 Hz,
2 H), 3.53 (q, J ) 5.5 Hz, 2 H), 2.45-2.20 (m, 6 H), 1.50-1.40
(m, 6 H); 13C NMR (acetone-d6) δ 166.6, 159.3, 139.7, 135.2,
132.8, 129.8, 119.5-109.5 (m, CF2, CF3), 65.6, 39.6, 26.0 (t, J
;
N-Ben zoyl-N-b en zylcycloh exylglycin e cycloh exyla -
m id e (9h ) was prepared according to general procedure 1 with
the acid 7 (26.2 mg, 0.015 mmol), benzylamine (27 µL, 0.25
mmol), cyclohexanecarboxaldehyde (30 µL, 0.25 mmol), and
cyclohexyl isocyanide (31 µL, 0.25 mmol) to afford after
desilylation 9h (5.3 mg, 84%) with >95% purity: mp 181-
182 °C; IR (CHCl3) 2933, 2856, 2246, 1671, 1620, 1515, 1451,
) 23.9 Hz), 1.7; MS (El) m/ z (relative intensity) 1329 ([M+
-
CH2CH2C10F21], 4), 1268 (25), 1243 (8), 1225 (9), 740 (46), 615
(29), 509 (93), 439 (100).
Gen er a l P r oced u r e for F lu or ou s Bigin elli Rea ction s
(Gen er a l P r oced u r e 2). A solution of 13 (18 mg, 9.6 µmol)
in THF/BTF (2/1, 0.75 mL) was treated at 25 °C with 10 equiv
of â-keto ester 10, 10 equiv of aldehyde 11, and concentrated
HCl (1 µL). After 3 days at 50 °C, volatiles were removed in
vacuo and FC-84 and toluene (10 mL each) were added. The
toluene phase was extracted with FC-84 (5 × 5 mL). The
combined fluorous phases were filtered and concentrated. The
resulting white solid was diluted with THF/BTF (1:1, 0.50 mL)
and treated dropwise with a 1 M tributylammonium fluoride
(TBAF) solution in THF (10 µL, 10 µmol). After the mixture
was stirred for 0.5 h at 25 °C, volatiles were removed in vacuo
and FC-84 and toluene were added (10 mL each). The fluorous
phase was extracted with toluene (3 × 5 mL). The combined
toluene phases were extracted with saturated aqueous NaH-
CO3 solution (3 × 10 mL) and brine (3 × 10 mL), dried
(Na2SO4), filtered, and concentrated. The resulting dihydro-
pyrimidines 14 were spectroscopically (1H NMR) identical to
those prepared by the conventional procedure.
1
1415, 1351, 1329 cm-1; H NMR (300 MHz, CDCl3) δ 0.85-
1.84 (m, 20 H), 2.41 (m, 1 H), 3.65-3.71 (m, 1 H), 4.15 (d, J )
11.0 Hz, 1 H), 4.45 (d, J ) 15.8 Hz, 1 H), 4.67 (d, J ) 15.9 Hz,
1 H), 4.92 (s br, 1H), 6.96 (s br, 2 H), 7.15-7.43 (m, 8 H); 13C
NMR (75 MHz, CDCl3) δ 24.72, 25.62, 25.77, 26.41, 29.73,
30.32, 32.69, 32.99, 36.31, 47.85, 126.67, 127.25, 127.50,
128.25, 128.47, 129.70, 136.89, 137.24, 169.26, 174.01; MS (EI)
m/ z 432 (M+), 327 (M+ - PhCO), 306 (M+ - CONHC6H11),
223, 105, 91, 77; HRMS calcd for C28H36N2O2 (M+) m/ z
432.2793, found 432.2778.
N-Ben zoyl-N-ben zyleth ylglycin e ter t-bu tyla m id e (9i)
was prepared according to general procedure 1 with the acid
7 (26.3 mg, 0.015 mmol), benzylamine (27 µL, 0.25 mmol),
propanal (18 µL, 0.25 mmol), and tert-butyl isocyanide (30 µL,
0.25 mmol) to afford after desilylation 9i (3.9 mg, 75%) with
93% purity: IR (CHCl3) 3417, 2974, 2937, 2879, 2249, 1675,
1
1512, 1458, 1367 cm-1; H NMR (300 MHz, CDCl3) δ 0.80-
1.10 (m br, 3 H), 1.32 (s, 9 H), 1.70-2.10 (m, 2 H), 4.58 (s br,
2 H), 4.70-4.80 (br, 1H), 6.90-7.60 (m, 11 H); 13C NMR (75
MHz, CDCl3) δ 11.08, 21.52, 28.68, 51.25, 51.51, 126.67, 127.74,
128.41, 128.64, 129.98, 136.50, 168.68, 173.98; MS (EI) m/ z
352 (M+), 300, 280 (M+ - NHC(CH3)3), 252 (M+ - CONH-
C(CH3)3), 210, 105, 91, 77; HRMS calcd for C22H28N2O2 (M+)
m/ z 352.2151, found 352.2165.
1-(2-(Ben zoyloxy)eth yl)-6-m eth yl-2-oxo-4-ph en yl-1,2,3,4-
tetr ah ydr opyr im idin e-5-car boxylic acid eth yl ester (14a)
was prepared according to general procedure 2 to afford 14a
(2.8 mg, 6.9 µmol, 71%): mp 129 °C; IR (CHCl3) 3425, 3016,
1711, 1684, 1623, 1450, 1392, 1270, 1178 cm-1 1H NMR
;
(CDCl3) δ 7.96 (d, J ) 7.8 Hz, 2H), 7.60-7.10 (m, 8 H), 5.39

2924 J . Org. Chem., Vol. 62, No. 9, 1997
Studer et al.
(bs, 2 H), 4.50-4.40 (m, 3 H), 4.15-3.90 (m, 3 H), 2.60 (s, 3
H), 1.18 (t, J ) 7.1 Hz, 3 H); 13C NMR (CDCl3) δ 166.3, 165.9,
153.4, 148.0, 143.0, 133.1, 129.6, 128.6, 128.4, 127.7, 126.0,
105.3, 63.4, 60.2, 54.0, 40.9, 16.4, 14.1; MS (El) m/ z (relative
intensity) 408 (M+, 4), 393 (16), 331 (16), 303 (8), 286 (6), 259
(20), 209 (10), 149 (100), 105 (99), 77 (54); HRMS calcd for
C23H24N2O5 408.1672, found 408.1685.
afford 14e (2.7 mg, 5.7 µmol, 60%): IR (neat) 3340, 2981, 1704,
1681, 1614, 1454, 1382, 1269, 1182, 1108, 1067 cm-1; 1H NMR
(CDCl3) δ 7.85 (d, J ) 7.1 Hz, 2H), 7.70-7.25 (m, 10 H), 5.55
(d, J ) 3.3 Hz, 1 H), 5.52 (bs, 1 H), 4.55-4.45 (m, 3 H), 4.20-
4.05 (m, 2 H), 4.05-3.85 (m, 1 H), 3.55-3.35 (m, 1 H), 2.90-
2.75 (m, 1 H), 1.25 (t, J ) 7.2 Hz, 3 H), 1.20 (t, J ) 7.1 Hz, 3
H); 13C NMR (CDCl3) δ 166.4, 165.7, 154.4, 154.1, 140.4, 133.2,
133.0, 129.7, 129.5, 128.9, 128.4, 128.1, 127.7, 126.3, 126.1,
125.0, 124.3, 104.5, 63.7, 60.5, 53.9, 40.8, 22.1, 14.3, 13.1; MS
(El) m/ z (relative intensity) 472 (M+, 14), 443 (25), 350 (11),
323 (14), 277 (7), 223 (13), 149 (100), 105 (95), 77 (41); HRMS
calcd for C28H28N2O5 472.1980, found 472.1998.
1-(2-(Ben zoyloxy)eth yl)-6-m eth yl-2-oxo-4-(2-n a p h th yl)-
1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic a cid eth yl es-
ter (14b) was prepared according to general procedure 2 to
afford 14b (2.4 mg, 5.2 µmol, 55%): IR (neat) 3342, 2977, 1714,
1679, 1621, 1450, 1390, 1269, 1219, 1182, 1108, 1070 cm-1
;
1H NMR (CDCl3) δ 7.95-7.25 (m, 12 H), 5.58 (d, J ) 2.8 Hz,
1 H), 5.49 (d, J ) 2.8 Hz, 1 H), 4.60-4.35 (m, 3 H), 4.15-4.00
(m, 3 H), 2.63 (s, 3 H), 1.18 (t, J ) 7.1 Hz, 3 H); 13C NMR
(CDCl3) δ 166.4, 166.2, 153.7, 148.4, 140.5, 133.2, 132.9, 129.7,
128.8, 128.5, 128.0, 127.6, 126.3, 126.0, 125.0, 124.4, 105.3,
63.6, 60.4, 54.3, 41.2, 16.6, 14.3; MS (El) m/ z (relative
intensity) 458 (M+, 26), 443 (22), 412 (9), 385 (11), 353 (11),
331 (24), 309 (30), 263 (6), 209 (12), 149 (100), 105 (87), 77
(36); HRMS calcd for C27H26N2O5 458.1842, found 458.1842.
1-(2-(Be n zoyloxy)e t h yl)-6-m e t h yl-2-oxo-4-(4-m e t h -
oxyp h en yl)-1,2,3,4-t et r a h yd r op yr im id in e-5-ca r b oxylic
a cid eth yl ester (14c) was prepared according to general
procedure 2 to afford 14c (2.9 mg, 6.6 µmol, 69%): mp 75 °C;
IR (CHCl3) 3425, 3025, 1704, 1677, 1621, 1514, 1454, 1392,
1-(2-(Ben zoyloxy)eth yl)-6-eth yl-2-oxo-4-p h en yl-1,2,3,4-
tetr a h yd r op yr im id in e-5-ca r boxylic a cid eth yl ester (14f)
was prepared according to general procedure 2 to afford 14f
(1.9 mg, 4.5 µmol, 47%): mp 111 °C; IR (neat) 3340, 2981, 1714,
1687, 1616, 1450, 1383, 1269, 1209, 1172, 1108, 1074 cm-1
;
1H NMR (CDCl3) δ 7.94 (d, J ) 7.2 Hz, 2 H), 7.55-7.05 (m, 8
H), 5.41 (bs, 1 H), 5.36 (d, J ) 3.2 Hz, 1 H), 4.55-4.40 (m, 3
H), 4.20-4.00 (m, 2 H), 4.00-3.85 (m, 1 H), 3.50-3.30 (m, 1
H), 2.90-2.70 (m, 1 H), 1.23 (t, J ) 7.3 Hz, 3 H), 1.19 (t, J )
7.1 Hz, 3 H); 13C NMR (CDCl3) δ 166.4, 165.7, 154.2, 154.1,
143.2, 133.2, 129.7, 128.7, 128.5, 127.8, 126.2, 104.6, 63.7, 60.4,
53.7, 40.7, 22.0, 14.2, 13.0; MS (El) m/ z (relative intensity)
422 (M+, 5), 393 (95), 377 (10), 345 (31), 317 (14), 273 (35),
243 (8), 223 (36), 195 (11), 149 (100), 105 (92), 77 (52); HRMS
calcd for C24H26N2O5 422.1827, found 422.1842.
1
1270, 1174, 1114, 1069 cm-1; H NMR (CDCl3) δ 7.96 (d, J )
7.1 Hz, 2 H), 7.56 (t, J ) 7.6 Hz, 1 H), 7.41 (t, J ) 7.6 Hz, 2
H), 7.14 (d, J ) 8.7 Hz, 2 H), 6.62 (d, J ) 8.7 Hz, 2 H), 5.34
(bs, 2 H), 4.50-4.40 (m, 3 H), 4.15-3.95 (m, 3 H), 3.66 (s, 3H),
2.60 (s, 3 H), 1.19 (t, J ) 7.1 Hz, 3 H); 13C NMR (CDCl3) δ
166.4, 166.2, 159.0, 153.9, 147.9, 135.5, 133.2, 129.7, 128.5,
127.4, 113.9, 105.8, 63.6, 60.3, 55.1, 53.3, 40.9, 16.5, 14.3; MS
(El) m/ z (relative intensity) 438 (M+, 5), 423 (27), 365 (13),
331 (7), 316 (6), 289 (30), 243 (6), 209 (5), 149 (92), 105 (100),
77 (50); HRMS calcd for C24H26N2O6 438.1787, found 438.1791.
1-(2-(Ben zoyloxy)eth yl)-6-m eth yl-2-oxo-4-(2-n a p h th yl)-
1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic a cid m eth yl
ester (14d ) was prepared according to general procedure 2 to
afford 14d (3.0 mg, 6.8 µmol, 70%): mp 116 °C; IR (CHCl3)
3425, 3012, 1708, 1683, 1623, 1454, 1392, 1275, 1188, 1115,
1076 cm-1; 1H NMR (CDCl3) δ 7.88 (d, J ) 8.0 Hz, 2 H), 7.70-
7.30 (m, 10 H), 5.57 (d, J ) 2.6 Hz, 1 H), 5.52 (bs, 1 H), 4.55-
4.45 (m, 3 H), 4.10-3.95 (m, 1 H), 3.66 (s, 3 H), 2.63 (s, 3 H);
13C NMR (CDCl3) δ 166.5, 166.3, 153.9, 148.7, 140.3, 133.1,
132.8, 129.5, 128.7, 128.3, 128.0, 127.5, 126.1, 125.9, 124.7,
124.2, 104.9, 63.5, 53.8, 51.5, 41.0, 16.5; MS (El) m/ z (relative
intensity) 444 (M+, 10), 429 (10), 339 (6), 317 (12), 295 (15),
149 (81), 105 (100), 77 (35); HRMS calcd for C26H24N2O5
444.1686, found 444.1685.
Gen er a l P r oced u r e for Con ven tion a l Bigin elli Rea c-
tion s. A solution of ((benzoyloxy)ethyl)urea (15) (174 mg, 0.84
mmol) in THF (5 mL) was treated with â-keto ester 10 (2.52
mmol), aldehyde 11 (2.52 mmol), and concentrated HCl (25
µL). The solution was stirred at room temperature. The
reaction was followed by TLC, and after completion (1-2 d),
the reaction mixture was concentrated in vacuo and the
residue purified by chromatography on SiO2 (ethyl acetate/
hexanes 1:1) to provide the dihydropyrimidine 14.
Ack n ow led gm en t. P.W. acknowledges support from
the A. P. Sloan and Camille and Henry Dreyfus founda-
tions. P.J . and A.S. are recipients of a Swiss National
Science Foundation Postdoctoral Fellowship. We thank
the National Institutes of Health for funding and the
3M Corporation for a gift of FC-72.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
the precursors and products of the Ugi and Biginelli condensa-
tions (25 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
1-(2-(Ben zoyloxy)et h yl)-6-et h yl-2-oxo-4-(2-n a p h t h yl)-
1,2,3,4-tetr a h yd r op yr im id in e-5-ca r boxylic a cid eth yl es-
ter (14e) was prepared according to general procedure 2 to
J O970095W