Perfluoro-tagged benzyloxycarbonyl protecting group and its application in fluorous biphasic systems

Article abstract of DOI:10.1002/1522-2675(200201)85:1<255::AID-HLCA255>3.0.CO;2-5

The synthesis of a new perfluoro-tagged benzyloxycarbonyl protecting group is reported, as well as its application in the parallel protection of amines. Isolation of the protected amines was performed by simple liquid-liquid extraction between perfluorinated and organic solvents. Deprotection was achieved by standard hydrogenolysis. The novel protecting group was also applied to cyclization protocols leading to quinazoline-2,4-diones. These products were isolated by simple extraction procedures.

Full text of DOI:10.1002/1522-2675(200201)85:1<255::AID-HLCA255>3.0.CO;2-5

Helvetica Chimica Acta Vol.85 (2002)
255
Perfluoro-Tagged Benzyloxycarbonyl Protecting Group and Its Application in
Fluorous Biphasic Systems
by DominikSchwinn and Willi Bannwarth*
Institut f¸r Organische Chemie und Biochemie, Universit‰t Freiburg, Albert-Str.21, D-79104 Freiburg,
Germany (Phone: ‡‡ 49761203-6073; fax: ‡‡ 49761203-8705; e-mail: willi.bannwarth@organik.chemie.uni-
freiburg.de)
The synthesis of a new perfluoro-tagged benzyloxycarbonyl protecting group is reported, as well as its
application in the parallel protection of amines.Isolation of the protected amines was performed by simple
liquid-liquid extraction between perfluorinated and organic solvents.Deprotection was achieved by standard
hydrogenolysis.The novel protecting group was also applied to cyclization protocols leading to quinazoline-2,4-
diones.These products were isolated by simple extraction procedures
1. Introduction. With the challenge to build up large libraries of compounds of
pharmacological interest, the task for organic chemists is to efficiently synthesize great
numbers of diverse molecules for high-throughput screening [1].One way to achieve
this goal is to perform synthesis on solid supports.This offers the advantage that the
reagents can be used in excess and washed off without any loss of product [2].
Nevertheless, solid-phase synthesis also entails a number of disadvantages, most
notably the lack of suitable linkers.Furthermore, it is difficult to identify the
compounds attached to the solid-phase and to follow the course of reactions on the
solid support.Thus, a number of alternative strategies have been developed to speed up
chemical synthesis mainly by simplifying the work-up procedures after parallel
synthesis [3].
One such method comprises the use of polymer-supported reagents or solid-phase-
bound scavengers.The strategy combines the benefits of solution chemistry with the
advantages of solid-phase synthesis.Alternative methods comprise the use of super-
critical CO2 (scCO2) [4] or ionic liquids [5] as reaction media.
Recently, it was demonstrated, that −fluorous techniques× provide new options for
efficient separation and isolation steps in conducting solution chemistry.Perfluoro-
tagged compounds can be easily separated from organic compounds via liquid-liquid
extraction between a common organic and a perfluorinated solvent.Alternatively,
solid-phase extraction on fluorinated reversed-phase silica gel can be performed.The
approach can be used for the straightforward recycling of perfluoro-tagged catalysts
and in combinatorial chemistry.
In combinatorial chemistry, the perfluoro entities are best introduced via protecting
groups that render the parent compounds soluble in perfluorinated solvents and lead to
a strong interaction with fluorinated reversed-phase silica gel.Hence, separation from
non-perfluoro-tagged molecules is easily achieved.Finally, the protection group is
cleaved off and can be removed from the desired compound by one of the
aforementioned methods.

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One of the most prominent protecting groups in organic synthesis is the
benzyloxycarbonyl (Z) group, which is widely being used for the protection of amines
and amino acids.It is stable under acidic and basic conditions and can be cleaved under
orthogonal conditions by hydrogenolysis.
Here, we report on the synthesis of a perfluoro-tagged benzyloxycarbonyl group to
be applied in fluorous-biphasic-systems (FBS) [6].Its structure derives from a
perfluoro-tagged benzyl alcohol, that carries a tris[2-(perfluorohexyl)ethyl]silyl group.
We now demonstrate the utility of our protecting group for masking amines via
carbamates and their cleavage by hydrogenolysis.Furthermore, we are going to show
that certain protected amines are amenable to cyclization leading to quinazolinediones
[7] and that they can be used for efficient parallel syntheses due to the simple
separation of the cyclic products.
2. Results and Discussion. The initial strategy for the synthesis of the perfluoro-
tagged benzyl unit 6 is outlined in Scheme 1.The commercially available, fluorinated
octyliodide 1 was converted into a Grignard reagent and reacted with Cl3SiH to provide
2 in moderate yield.Bromination of 2 proceeded almost quantitatively to yield
compound 3 [8].The latter was reacted with the Grignard compound of 4-
bromotoluene providing 4 in both high yield and excellent purity [9].Bromination
of 4 with N-bromosuccinimide (NBS) led to the desired compound 5 together with
unreacted 4 and a dibrominated side-product.Compound 5 was not purified but
transformed with the help of an anion-exchange resin to 6, which was obtained after
chromatographic purification in modest yield [10].
Scheme 1
Due to the rather low yields in the last two steps, we were looking for a more
efficient preparation of 6.The alternative we devised is outlined in Scheme 2.The
synthetic pathway started with 4-bromobenzyl alcohol (7), which was protected with
the 2-(methoxyethoxy)methyl (MEM) group according to the procedure of Corey et al.

Helvetica Chimica Acta Vol.85 (2002)
257
[11] thus providing compound 8.The latter was reacted first with BuLi at À788,
followed by addition of 3 to yield the MEM-protected benzyl alcohol 9 in high yield.
The MEM group was removed with concentrated HCl in THF to produce 6 in high
yield [12].This procedure is also amenable to the synthesis of 6 on a multi-gram scale.
Scheme 2
To demonstrate the advantage of 6 for the parallel protection of amines, it was
transformed into the carbamate 10, which readily reacted with primary amines such as
furfurylamine or benzylamine after addition of catalytic amounts of 4-(dimethylami-
no)pyridine (DMAP) (Scheme 3) [13].
Scheme 3

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Helvetica Chimica Acta Vol.85 (2002)
For the protection of less nucleophilic or secondary amines, 10 had to be activated
via N-methylation using methyl trifluoromethane sulfonate (MeOTf).Since CH Cl2
2
was used as a solvent, (1,1,1-trifluoromethyl)benzene (BTF) had to be added to
solubilize the fluorinated compounds [14].
The protected amines were obtained via extraction with perfluorohexane (FC-72)
both in excellent yields and high purity (Table).
Table. Protection and cleavage of amines
Amines
Protection
Cleavagea)
furfurylamine
benzylamine
isopropylamine
n-butyl-ethyl-amine
piperidine
13a
13b
13c
13d
13e
13f
quant.80%
quant.60%
70%b)
not isolated
80%
88%
91%b)
98%b)
glycine ethyl ester
98%b)
62%
a) Yields of isolated amines. b) Methylation with methyl trifluoromethanesulfonate.
In order to determine the ease of deprotection, a solution of the substrates 13a f in
MeOH, containing Pd/C, was exposed to H2.The deprotected amines were recovered
together with silane 4 after liquid-liquid phase extraction (Scheme 4).The results are
summarized in the Table.
Scheme 4
Parallel synthesis on solid support represents an elegant way of accessing
heterocyclic compounds [15].Molecules that do not contain the necessary functional
groups for cyclization remain bound to the resin and can be easily separated via
filtration.In a similar way, we have used the perfluoro-tagged benzyloxycarbonyl entity
to synthesize quinazoline-2,4-diones (15) via intramolecular cyclization.This class of
heterocycles represents a group of attractive pharmacophores with a wide range of
pharmacological activities [16].Since the desired products lack any perfluoro-tags, they
can be easily separated via extraction from by-products.The corresponding synthetic
pathway is outlined in Scheme 5.
The first step comprises the coupling of anthranilic acid derivatives.This was
achieved in two different ways. N-Methylation of the carbamate 10, leading to 11, and
reaction with the anthranilic acid was one possibility.The preferred route however, was
the activation of 10 with diphosgene [17], leading to 12, which reacted smoothly to the

Helvetica Chimica Acta Vol.85 (2002)
259
Scheme 5
desired intermediates 13g,h.Next, a primary amine was coupled to the carboxylic acid
function of 13g,h to yield the amides 14a,b [18].The final cyclization step by means of
intramolecular carbamate cleavage was initiated by Et3N.This method allowed an easy
workup (even under conditions where all the steps prior to the cyclization did not
proceed quantitatively), since all the perfluoro-tag-containing products could be
separated from the desired heterocycles by liquid-liquid extraction.
Conclusions. In summary, we were able to establish a straightforward route for the
(large scale) synthesis of the perfluoro-tagged benzyl alcohol 6, which was successfully
used for the parallel protection of different amines.Isolation of the products was
achieved by simple liquid-liquid extraction between perfluorinated and organic
solvents, thereby omitting time-consuming chromatographic steps.Deprotection could
be performed by standard hydrogenolysis.The perfluoro-tagged protecting group was
also applied to cyclization protocols, leading to quinazoline-2,4-diones, which could
again be isolated by extraction procedures.Our strategy should therefore be generally
applicable to the rapid parallel synthesis of different heterocyclic cores, a project that is
currently being pursued in our group.
We would like to thank Dr. Hunkler, Mrs. Schonhard, and Mr. Reinbold for recording NMR spectra, Mr.
Warth and Mr. Wˆrth for recording MS spectra, and Mr. Hickl for performing elemental analyses.

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Experimental Part
General.All reagents were obtained from Acros or Aldrich and were of highest purity available.THF was
dried over Na and freshly distilled before use.CH 2Cl2 and 1,1,1-(trifluoromethyl)benzene (BTF) were dried
over molecular sieves 4 ä.Diethyl ether (Et 2O) was dried over KOH.Mp..were measured with the
electrothermal digital melting device IA 9200 and are uncorrected.Column chromatography (CC): SiO 2 KG 60
from Baker.NMR Spectra: 250 or 400 MHz ( 1H), 100 MHz (13C); chemical shifts d in ppm rel.to Me 4Si
(ˆ0 ppm) for 1H-NMR and rel.to CHCl (ˆ 77.00 ppm) for 13C-NMR, respectively. J in Hz.MS: Finnigan
3
MAT8200 (EI), MAT312 (Cl), and TSQ-7000 (ESI) mass spectrometer.
Tris-[2-(perfluorohexyl)ethyl]silane (2). A soln. of 25.0 g (52.7 mmol) of 1-iodo-1H,1H,2H,2H-perfluoro-
octane (1) in anh.Et 2O was carefully added within 1 h to a vigorously stirred suspension of 1.28 g (52.7 mmol) of
Mg powder in 5 ml of anhydrous Et2O.The suspension was refluxed for 3 h.After cooling to ,tr.
6.6 ml (13 mmol) of a 2m soln.of Cl 3SiH were slowly added, and the mixture was refluxed for 70 h.The
solvent was evaporated and the residue was taken up in 40 ml of CH2Cl2 and in 50 ml of a sat.NH 4Cl soln.
The cloudy two-phase mixture was extracted with perfluorohexane (FC-72, 5 Â 10 ml).The FC-72 phases
were combined and evaporated.The crude silane was purified by bulb-to-bulb distillation (180 8, 5 mbar)
to give 9.0 g (65%) of 2. 1H-NMR (400 MHz, FC-72/C6D6-capillary): 1.15 1.27 (m, 3 CH2Si); 2.28 2.43
(m, 3 CH2CF2); 4.16 (s, SiÀH).Anal.calc.for C
24H13F39Si (1070.02): C 26.93, H 1.22; found: C 26.92,
H 1.27.
Bromo{tris[2-(perfluorohexyl)ethyl]}silane (3).Br 2 (0.24 ml, 4.7 mmol) was added dropwise to a soln. of
4.87 g (4.60 mmol) of 2 in 10 ml of FC-72.The mixture was stirred at rt..for 18 h, and HBr was constantly
removed by a stream of Ar.FC-72 (10 ml) was added.The fluorous phase was washed with anh.CH 2Cl2 (3 Â
2 ml) and concentrated in vacuo to yield 5.09 g (97%) of 3. 1H-NMR (400 MHz, FC-72/C6D6-capillary): 1.42
1.55 ppm (m, 3 CH2Si); 2.38 2.50 (m, 3 CH2CF2).Anal.calc.for C 24H12BrF39Si (1149.93): C 25.08, H 1.05;
found: C 25.01, H 0.97.
[4-Methyl(phenyl)]{tris[2-(perfluorohexyl)ethyl]}silane (4). A soln. (5 ml), made of 0.34 g (2.0 mmol) of
4-bromotoluene in 50 ml of anh. THF, was added to 0.05 g (2.00 mmol) of Mg powder. The suspension was
stirred at 358 until the reaction started.Then the remaining soln.of 4-bromotoluene was added dropwise within
0.5 h. Then, the mixture was refluxed for 3 h. A soln. of 2.00 g (1.75 mmol) of 3 in 20 ml of anh.THF was added
to the Grignard reagent within 10 min.The resulting mixture was refluxed for 6 d.The solvent was evaporated,
the residue taken up in 20 ml of MeCN and extracted with FC-72 (5 Â 10 ml).The combined fluorous layers
1
were concentrated in vacuo to yield 1.94 g (96%) of 4. H-NMR (400 MHz, FC-72/C6D6-capillary): 1.32 1.39
(m, 3 CH2Si); 2.21 2.32 (m, 3 CH2CF2); 2.50 (s, Me); 7.40 (d, J ˆ 8.5, 2 arom. H); 7.53 (d, J ˆ 8.5, 2 arom. H).
Anal.calc.for C 31H19F39Si (1160.51): C 32.08, H 1.65; found: C 31.92, H 1.52.
[4-(Bromomethyl)phenyl]{tris[2-(perfluorohexyl)ethyl]}silane (5). Under Ar, 9.0 g (7.8 mmol) of 4 were
taken up in 50 ml of anh.CCl 4. N-bromo-succinimide (NBS) (1.4 g, 7.8 mmol) and 20 mg of azo[bis(isobutyr-
onitrile)] (AIBN) were added, and the mixture was carefully heated until the exothermic reaction started.Once
the reaction had subsided, the mixture was refluxed for 4 h, then cooled to r.t., and filtered. The solvent was
removed in vacuo.The residue was taken up in MeCN (30 ml) and extracted with FC-72 (5 Â 10 ml).The
combined fluorous layers were concentrated in vacuo to give 5.78 g of a yellowish oil, containing 70% of 5, 20%
of starting material and 10% of a dibromo derivative (see Scheme 1). 1H-NMR (400 MHz, FC-72/C6D6-
capillary): 1.38 1.45 (m, 3 CH2Si); 2.21 2.38 (m, 3 CH2CF2); 4.50 (s, CH2Br); 7.61 (s, 4 arom.H).EI-MS
‡
‡
(2308, 70 eV): 1239 (18, [M ]), 1159 (14, [M À Br] ), 503 (32), 399 (58), 309 (45), 289 (29), 263 (20), 245 (54),
239 (63), 195 (30), 175 (100), 91 (32), 77 (29), 69 (29), 59 (18), 51 (29).
4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl alcohol (6).A soln.of K 2CO3 (1 l, 1m) was slowly percolated
through a column filled with Amberlite IRA 900 (ClÀ-form) until a negative test for ClÀ was obtained by adding a
soln.of AgNO 3 to the eluate.Then, the resin was washed with 200 ml of MeOH, 100 ml of Et O, and dried in
2
vacuo for 4 h at r.t. Amberlite 900 (CO23À-form, 1.0 g, 3 eq.) and 0.7 g of the crude mixture, containing 0.5 g of 5
(0.4 mmol), were diluted in benzene and refluxed for 4 h. After cooling, the resin was filtered off and washed
with 20 ml of Et2O and 10 ml of FC-72.The combined filtrates were concentrated in vacuo to produce a
yellowish oil, which was purified by CC (cyclohexane/AcOEt 9 :1): 0.15 g (31%). 1H-NMR (400 MHz, FC-72/
C6D6-capillary): 1.34 1.42 (m, 3 CH2Si); 2.21 2.38 (m, 3 CH2CF2); 4.72 (s, CH2ÀOH); 7.53 (d, J ˆ 8.5,
‡
2 arom.H); 76. 5 ( d, J ˆ 8.5, 2 arom. CH). CI-MS (NH3, 2208, 240 eV): 1174 (100, [M À 2 H] ), 867 (36).Anal.
calc.for C 31H19F39OSi (1176.06): C 31.65, H 1.63; found: C 31.74, H 2.07.
1-Bromo-4-{[(2-methoxyethoxy)methoxy]methyl}benzene (8). To a stirred soln. of 1.0 g (5.4 mmol) of
benzyl alcohol 7 in 20 ml of anh. THF, 0.22 g (5.50 mmol) of NaH (60% in oil) were added under Ar at 08.The

Helvetica Chimica Acta Vol.85 (2002)
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resulting suspension was stirred for 15 min, then 0.8 g (6.4 mmol) of MEM-Cl were added dropwise, and the
mixture was stirred for 0.5 h at 08.The solvent was removed in vacuo, and the residue was taken up in 20 ml of
Et2O.The organic phase was washed with H 2O (2 Â 50 ml), dried over Na2SO4, and concentrated in vacuo.The
yellowish oil was purified by CC (cyclohexane/AcOEt 8 :2) to yield 0.77 g (52%) of 8. 1H-NMR (250 MHz,
CDCl3): 3.33 (s, MeO); 3.52 (t, J ˆ 4, CH2OMe); 3.67 (t, J ˆ 4, MeOCH2CH2); 4.50 (s, PhCH); 4.72 (s, OCH2O);
7.15 (d, J ˆ 7.5, 2 arom. H); 7.40 (d, J ˆ 7.5, 2 arom. H). 13C-NMR (CDCl3): 59.1 (OMe); 67.1 (CH2); 68.6 (CH2);
71.8 (PhCH2); 94.9 (OCH2O); 121.6, 129.5, 131.6, 137.0 (4 arom. C). Anal. calc. for C11H15BrO3 (260.00):
C 48.02, H 5.49; found: C 48.08, H 5.30.
(4-{[(2-Methoxyethoxy)methoxy]methyl}phenyl){tris[2-(perfluorohexyl)ethyl]}silane (9).To a stirred soln.
of 100 mg (0.36 mmol) of 8 in 40 ml of anh.THF at À788, 0.18 ml (0.45 mmol) of BuLi (2.5m in toluene) were
added dropwise.The soln.was stirred at À788 for 0.5 h. Then 300 mg (0.26 mmol) of 3 were added and the
mixture was allowed to warm up to r.t. within 1.5 h. A sat. soln of aq. NH4Cl was added, and the org.solvent was
removed in vacuo.After addition of 20 ml of CH Cl2, the cloudy biphasic mixture was extracted with FC-72
2
(5 Â 10 ml).The combined fluorous layers were concentrated in vacuo to give 0.29 g (87%) of 9. 1H-NMR
(400 MHz, FC-72/C6D6-capillary): 1.35 1.42 (m, 3 CH2Si); 2.21 2.37 (m, 3 CH2CF2); 3.46 (s, OMe); 3.63
(t, J ˆ 4, CH2); 3.82 (t, J ˆ 4, CH2); 4.79 (s, OCH2O); 4.89 (s, PhCH2); 7.63 (s, 4 arom.H).EI-MS: (230 8, 70 eV):
1231 (3), 1176 (10), 1175 (24), 1159 (17), 437 (16), 309 (22), 239 (31), 89 (100).
Synthesis of 6 from 9.To a mixture of 100 mg (00. 8 mmol) of 9 in 20 ml of THF, 5 ml of conc.HCl were
added.The emulsion was refluxed for 3 h.After cooling, the soln.was concentrated
in vacuo, and to the
remaining aq.layer was added 20 ml of CH 2Cl2.The binary mixture was extracted with FC-72 (5 Â 10 ml), and
the combined fluorous layers were dried over Na2SO4.FC-72 was removed in vacuo to give 91 mg (97%) of 6,
which was identical to a sample prepared by the previous route.This procedure is amenable to the synthesis of 6
on multigram scale.
(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl) 1H-Imidazole-1-carboxylate (10).To a stirred soln.of 55 mg
(0.34 mmol) of CDI1) in 5 ml of anh.THF, a soln.of 200 mg (0.17 mmol) of 6 in 5 ml of anh.THF was added at
08.The mixture was stirred at 0 8 for 1 h and for another at r.t. The solvent was removed in vacuo, and the residue
was taken up in 20 ml of FC-72.The fluorous layer was washed with a diluted soln.of aq.NH 4Cl (2 Â 10 ml) and
concentrated by bulb-to-bulb condensation in vacuo to yield 210 mg (97%) of 10. 1H-NMR (400 MHz, FC-72/
C6D6-capillary): 1.40 1.45 (m, 3 SiCH2); 2.25 2.37 (m, 3 CH2CF2); 5.50 (s, PhCH2); 7.05 (s, 1 H, imid.); 7.41
‡
(s, 1 H, imid.); 7.67 ( d, J ˆ 7.0, 2 arom. H); 7.73 (d, J ˆ 7.0, 2 arom. H); 8.04 (s, N H).ESI-MS (MeOH, 100 ml/
‡
‡
min, 70 eV): 1271 (100, [M ‡ H] ), 1227 (26, [M À C2H5N] ).
General Procedure for the Protection of Amines With 10.The imidazole-1-carboxylate 10 (0.13 g,
0.10 mmol) was taken up in 20 ml of anh. CH2Cl2, and 3 ml of BTF 2), 0.13 mmol of amine, and 5 mg of DMAP3)
were added.The mixture was stirred at rt..for 10 h.The solvent was removed
in vacuo, and the residue was
extracted with FC-72 (4 Â 5 ml).The combined fluorous layers were washed with 10 ml of aq.solns.of citric acid
(10%), dried over Na2SO4, and concentrated in vacuo to give both the carbamates 13a and 13b in quantitative
yield.
1
(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl) Furfurylcarbamate (13a): H-NMR (400 MHz, FC-72/C6D6-
capillary): 1.35 1.42 (m, 6 H, CH2Si); 2.22 2.36 (m, 3 CH2CF2); 4.35 (d, J ˆ 3.5, NCH2); 5.16 (s, PhCH2); 5.67
(t, J ˆ 3.5, NH); 6.25 (s, 1 H, furan); 6.33 (s, 1 H, furan); 7.34 (s, 1 H, furan); 7.50 (d, J ˆ 7.5, 2 arom. H); 7.60
(d, J ˆ 7.5, 2 arom. H). EI-MS (2308, 70 eV): 1176 (16), 1175 (41), 1159 (68), 399 (100), 96 (14), 91 (86).
(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl) Benzylcarbamate (13b): 1H-NMR (400 MHz, FC-72/C6D6-
capillary): 1.30 1.41 (m, 3 CH2Si); 2.20 2.35 (m, 3 CH2CF2); 4.38 (d, J ˆ 5.0, NCH2); 5.19 (s, OCH2); 5.43
(s, NH); 7.28 7.37 (m, 5 arom.H); 74. 9 ( d, J ˆ 7.0, 2 arom. H); 7.57 (d, J ˆ 7.0, 2 arom. H). EI-MS (2308, 70 eV):
‡
‡
1205 (12, [M À C7H7] ), 1159 (100, [M À C6H5CH2NHCO2] ), 437 (58), 239 (41), 175 (95).
General Procedure for the Protection of Amines with in situ Generated 11.Compound 10 (0.16 mmol) was
treated with 5 ml of anh.CH 2Cl2 and 1 ml of BTF.MeOTf 4) (1.6 mmol) was slowly added and the soln. was
stirred at r.t. for 1 h. The excess reagent and the solvent were removed in vacuo by bulb-to-bulb condensation.
Then, 10 ml of anh.CH 2Cl2, 2 ml of BTF, 0.48 mmol of amine, and 5 mg of DMAP3) were added to the residue.
The mixture was stirred at r.t. for 16 h. The solvent was removed in vacuo, and the residue was extracted with
1
)
)
)
)
1-[(1H-Imidazol-1-yl)carbonyl]-1H-imidazole (−carbonyldiimidazole×).
1,1,1-(Trifluoromethyl)benzene.
4-(N,N-Dimethylamino)pyridine.
2
3
4
Methyl trifluoromethylsulfonate.

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Helvetica Chimica Acta Vol.85 (2002)
FC-72 (4 Â 5 ml).The combined fluorous layers were washed with solns.of aq.citric acid (10%) (2 Â 10 ml),
dried over Na2SO4, and concentrated in vacuo to yield the carbamates 13c f.All compounds described below
were synthezised in parallel.The yields are outlined in the Table.
(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl) Isopropylcarbamate (13c). 1H-NMR (400 MHz, FC-72/C6D6-
capillary): 1.28 (d, J ˆ 6.0, 2 Me); 1.38 1.44 (m, 3 CH2Si); 2.22 2.37 (m, 3 CH2CF2); 4.00 (m, Me2CH); 4.56
(m, NH); 5. 21 (s, PhCH2); 7.56 (d, J ˆ 7.5, 2 arom. H); 7.62 (d, J ˆ 7.5, 2 arom. H). EI-MS (2008, 70 eV): 1261 (2,
‡
M ), 1176 (18), 811 (5), 399 (19), 239 (20), 175 (55), 107 (100).
1
(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl) (Butyl)(ethyl)carbamate (13d). H-NMR (400 MHz, FC-72/
C6D6-capillary): 1.13 (t, J ˆ 7.0, Me); 1.28 (t, J ˆ 7.0, Me); 1.35 1.42 (m, 3 CH2Si); 1.49 (m, CH2); 1.70 (m, CH2);
2.22 2.38 (m, 3 CH2CF2); 3.43 3.51 (m, 2 CH2); 5.27 (s, PhCH2); 7.54 (d, J ˆ 8.0, 2 arom. H); 7.63 (d, J ˆ 8.0,
‡
2 arom.H).EI-MS (200 8, 70 eV): 1303 (100, M ), 994 (79), 850 (6), 144 (8).
1
(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl) Piperidine-1-carboxylate (13e). H-NMR (400 MHz, FC-72/
C6D6-capillary): 1.35 1.42 (m, 3 CH2Si); 1.65 1.71 (m, 4 H, pip.); 1.76 1.82 (m, 2 H, pip.); 2.22 2.36
(m, 3 CH2CF2); 3.60 3.66 (m, 4 H, pip. ); 5. 28 (s, PhCH2); 7.50 (d, J ˆ 7.5, 2 arom. H ) ; 7.58 ( d, J ˆ 7.5,
‡
2 arom.H).EI-MS (230 8, 70 eV): 1287 (100, M ), 978 (91), 128 (5).
Ethyl 2-({[(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl)oxy]carbonyl}amino)acetate (13f). 1H-NMR
(400 MHz, FC-72/C6D6-capillary): 1.31 (t, J ˆ 8.5, Me); 1.35 1.42 (m, 3 CH2Si); 2.22 2.36 (m, 3 CH2CF2);
3.99 (d, J ˆ 3.0, NHCH2); 4.32 (q, J ˆ 8.5, MeCH2O); 5.21 (s, PhCH2); 5.49 (t, J ˆ 3.0, NH); 7.57 (d, J ˆ 7.5,
‡
2 arom.H); 76. 3 ( d, J ˆ 7.5, 2 arom. H). EI-MS (2008, 70 eV): 1305 (7, M ), 1159 (23), 811 (15), 483 (36), 239
(32), 175 (100).
General Procedure for the Hydrogenolytic Cleavage of the Carbamates 13a f.To a soln.of 00.9 mmol
amine in 10 ml of MeOH and 2 ml of BTF, 10 mg Pd on charcoal (10%) were added under Ar.The atmosphere
was saturated with H2 and shaken at r.t. for 16 h. The catalyst was filtered off, and the solvent was evaporated.
The residue was taken up in FC-72 (4 Â 5 ml), and the fluorous phase was extracted with 5 ml of MeCN.The two
phases were concentrated separately in vacuo to yield 4 and the parent amine.The latter were identified by
1H-NMR.The yields are outlined in the Table.
2-({[(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl)oxy]carbonyl}amino)benzoic Acid (13g).Compound 10
(0.20 g, 0.16 mmol) was taken up in 10 ml of anh. CH2Cl2 and 2 ml of BTF.Methyl trifluoromethane sulfonate
(MeOTf) (0.18 ml, 1.6 mmol) was slowly added and the soln. was stirred at r.t. for 1 h. The excess of MeOTf and
the solvent were removed in vacuo by bulb-to-bulb condensation.Then, 10 ml of anh.CH 2Cl2, 2 ml of BTF,
0.48 mmol of amine, and 5 mg of DMAP3) were added to the residue.The mixture was stirred at r.t.for 16 h.The
solvent was removed in vacuo, and the residue was extracted with FC-72 (4 Â 5 ml).The combined fluorous
layers were washed with solns.of aq.citric acid (10%) (2 Â 10 ml), dried over Na2SO4, and concentrated in
vacuo to yield 167 mg (78%) of 13g. 1H-NMR (400 MHz, FC-72/C6D6-capillary): 1.25 1.34 (m, 3 CH2Si); 2.18
2.36 (m, 3 CH2CF2); 5.12 (s, PhCH2); 6.92 (t, J ˆ 5.0, 1 arom. H); 7.40 7.49 (m, 3 arom.H); 7.60 ( m,
2 arom.H); 79. 1 ( d, J ˆ 5.0, 1 arom. H); 8.48 (d, J ˆ 6.5, 1 arom. H); 10.59 (s, NH).EI-MS (230 8, 70 eV):
‡
1339 (7, M ), 1295 (13), 1159 (13), 399 (89), 239 (71), 175 (100).
4-Chloro-2-({[(4-{tris[2-(perfluorohexyl)ethyl]silyl}benzyl)oxy]carbonyl}amino)benzoic Acid (13h).A
suspension of 63 mg (0.32 mmol) of trichloromethyl chloroformate and 5 mg of activated charcoal in 25 ml
of anh. THF were stirred under Ar for 10 min. A soln. of 0.5 g (0.43 mmol) of 6 in 10 ml of anh.THF was added
dropwise within 1 h.After stirring at rt..for 15 h, the mixture was filtered over 2 g of SiO 2.The filtrate was
concentrated in vacuo to give 52 mg (0.42 mmol, 98%) of 12.(In the 1H-NMR spectrum of 12, the peak for the
benzylic methylene group was shifted from 4.72 to 5.88 ppm. The MS spectrum showed fragments of the
molecule, but not the mass peak itself.The product was directly converted to 13h, because of its sensitivity to
moisture.) The chloroformate 12 (0.49 g, 0.40 mmol), 86 mg (0.50 mmol) of 4-chloroanthranilic acid, and 0.2 ml
(1.6 mmol) of H¸nig×s base (NEt(i-Pr)2) were taken up in 10 ml of anh.THF.The soln.was stirred at r.t.for 16 h.
The solvent was removed in vacuo and the residue was taken up in 30 ml of FC-72.The fluorous phase was
washed with 0.1m HCl soln.(3 Â 10 ml), dried over Na2SO4, and concentrated in vacuo to yield 451 mg (84%) of
13h. 1H-NMR (400 MHz, FC-72/C6D6-capillary): 1.25 1.34 ppm (m, 3 CH2Si); 2.18 2.36 (m, 3 CH2CF2); 5.25
(s, PhCH2); 6.92 (m, 1 arom. H); 7.40 7.70 (m, 4 arom.H); 79. 5 ( s, 1 arom.H); 85. 1 ( s, 1 arom.H); 109. 0
‡
(s, NH).EI-MS (230 8, 70 eV): 1373 (8, M ), 1329 (36), 1159 (80), 399 (57), 239 (52), 175 (87), 91 (100).
General Procedure for the Preparation of 14a,b.The carbamates 13g,h (0.15 mmol), 15 ml (0.17 mmol) of
furfurylamine, 22 mg (0.17 mmol) of H¸nig×s base, and 55 mg (0.17 mmol) of TBTU5) were taken up in 20 ml of
5
)
O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate.

Helvetica Chimica Acta Vol.85 (2002)
263
anh.THF under Ar.The soln.was stirred at r.t.for 16 h.The solvent was removed
in vacuo, and the residue was
taken up in 20 ml of FC-72.The fluorous phase was washed with aq.citric acid solns.(10%) (2 Â 5 ml), dried
over Na2SO4, and concentrated in vacuo.
(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl) 2-{[(Furfuryl)amino]carbonyl}phenylcarbamate (14a):
160 mg (87%). 1H-NMR (400 MHz, FC-72/C6D6-capillary): 1.28 1.42 (m, 3 CH2Si); 2.21 2.39 (m, 3 CH2CF2);
4.55 (s, NCH2); 5.21 (s, PhCH2); 6.29 (d, J ˆ 1.5, 1 arom. H (furan)); 6.31 (d, J ˆ 1.5, 1 arom. H (furan)); 6.79
(t, J ˆ 5.0, NH); 7.25 (t, J ˆ 5.0, 1 arom. H); 7.32 (s, 1 arom.H (furan)); 74. 0 ( d, J ˆ 7.0, 1 arom. H); 7.51 (d, J ˆ
7.5, 2 arom. H); 7.60 (d, J ˆ 7.5, 2 arom. H); 7.72 (m, 1 arom.H); 83. 4 ( d, J ˆ 6.5, 1 arom. H); 10.88 (s, NH).CI-
‡
MS (2208, 50 eV): 1419 (13, M ), 1158 (53), 399 (7), 243 (100), 147 (14).
(4-{Tris[2-(perfluorohexyl)ethyl]silyl}benzyl) 4-Chloro-2-{[(furfuryl)amino]carbonyl}phenylcarbamate
(14b): 175 mg (82%). 1H-NMR (400 MHz, FC-72/C6D6-capillary): 1.31 1.40 (m, 3 CH2Si); 2.21 2.41
(m, 3 CH2CF2); 4.60 (s, NCH2); 5.25 (s, PhCH2); 6.34 (d, J ˆ 1.5, 2 arom. H (furan)); 6.82 (d, J ˆ 4.5, NH);
7.35 ( m, 2 arom. H); 7.55 (d, J ˆ 7.5, 2 arom. H); 7.64 (d, J ˆ 7.5, 2 arom. H); 7.80 (m, 1 arom.H); 8.38
‡
(s, 1 arom.H); 109. 5 ( s, NH).EI-MS (230 8, 70 eV): 1452 (4, M ), 1175 (10), 1159 (34), 399 (41), 175 (51),
96 (100).
General Procedure for the Cyclization of the Amides 14a,b to the Quinazoline-2,4-diones 15a,b.To a soln.of
0.1 mmol of 14a,b in 10 ml of DMF, 0.2 ml (0.14 mg, 1.0 mmol) of Et3N were added.The cloudy mixture was
heated in a vial with a screw cap to 1108 for 16 h.After cooling to rt.,. the vial was carefully opened, and the
contents were poured into 50 ml of H2O.The aq.phase was extracted with FC-72 (2 Â 10 ml) and with AcOEt
(2 Â 10 ml).The org.phase 6) was washed with 0.5m solns.of aq.HCl (2 Â 5 ml), dried over Na2SO4, and
concentrated in vacuo to yield the quinazoline-2,4-diones as colorless crystalline powders.
3-Furfurylquinazoline-2,4-dione (15a): 16 mg (66%).Mp. .245 8. 1H-NMR (400 MHz, (CD3)2SO): 5.06 (s,
PhCH2); 6.29 (d, J ˆ 2.6, 1 arom. H (furan)); 6.38 (t, J ˆ 2.5, 1 arom. H (furan)); 7.20 (m, 2 arom.H); 75. 2
(s, 1 arom.H (furan)); 76. 5 ( t, J ˆ 7.8, 1 arom. H); 7.93 (d, J ˆ 8.0, 1 arom. H); 11.00 (s, NH). 13C-NMR
(100 MHz, (CD3)2SO): 36.1 (NCH2); 108.1 (arom. C); 109.8 (arom. C); 113.6 (arom. C); 114.9 134.3
(4 arom. C); 139.0 (arom. C); 141.2 (arom. C); 149.9 (arom. C); 150.0 (CˆO); 161.7 (CˆO).EI-MS (230 8,
‡
70 eV): 242 (100, M ), 213 (16), 146 (22), 81 (45).Anal.calc.for C 13H10N2O3 (242.07): C 64.46, H 4.16, N 11.56;
found: C 64.33, H 4.10, N 11.52.
7-Chloro-3-furfurylquinazoline-2,4-dione (15b): 24 mg (90%).Mp. .256 8. 1H-NMR (500 MHz, (CD3)2SO):
5.06 (s, PhCH2); 6.30 (d, J ˆ 2.6, 1 arom. H (furan)); 6.37 (t, J ˆ 2.5, 1 arom. H (furan)); 7.20 (s, 1 arom.H); 72. 5
(d, J ˆ 7.8, 1 arom. H); 7.54 (s, 1 arom.H (furan)); 79. 3 ( d, J ˆ 8.0, 1 arom. H); 11.60 (s, NH). 13C-NMR
(100 MHz, (CD3)2SO): 36.6 (NCH2); 108.0 (arom. C); 110.5 (arom. C); 112.6 (arom. C); 114.6 139.5
(4 arom. C); 140.5 (arom. C); 142.1 (arom. C); 149.6 (arom. C); 150.1 (CˆO); 160.8 (CˆO).EI-MS (230 8,
‡
70 eV): 276 (100, M ), 247 (13), 180 (36), 129 (76), 81 (91).Anal.calc.for C 13H9ClN2O3 (276.03): C 56.43,
H 3.28, N 10.13; found: C 55.98, H 3.02, N 9.83. FC-72 phase: 105 mg.
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Received August 13, 2001