Fluorinated analogues of tert-butyl alcohol as novel protecting groups for use in fluorous synthesis

Article abstract of DOI:10.1021/ol0166505

Figure presented A series of fluorous derivatives of tert-butyl alcohol were prepared and evaluated as reagents for the protection of carboxylic acids for use in fluorous synthesis. Alcohol 3b can be employed efficiently to protect and immobilize medium-size nonpolar carboxylic acids in a fluorous phase.

Full text of DOI:10.1021/ol0166505

ORGANIC
LETTERS
2
001
Vol. 3, No. 23
711-3714
Fluorinated Analogues of tert-Butyl
Alcohol as Novel Protecting Groups for
Use in Fluorous Synthesis
3
Juan Pardo, Agust ´ı n Cobas,* Enrique Guiti a´ n,* and Luis Castedo
Departamento de Qu ´ı mica Org a´ nica, Facultade de Ciencias, UniVersidade de Santiago
de Compostela, Campus UniVersitario, 27002 Lugo, Spain
agcobas@lugo.usc.es
Received August 26, 2001
ABSTRACT
A series of fluorous derivatives of tert-butyl alcohol were prepared and evaluated as reagents for the protection of carboxylic acids for use
in fluorous synthesis. Alcohol 3b can be employed efficiently to protect and immobilize medium-size nonpolar carboxylic acids in a fluorous
phase.
1
Since the initial works of Horvath and R a´ bai, fluorous-phase
separation techniques are emerging as an alternative to solid-
phase techniques in organic synthesis. These techniques are
based on the immiscibility of perfluorinated solvents with
of fluorous techniques are the utilization of fluorous re-
6
7
agents, fluorinated scavenging agents, nonmetallic cata-
8
lysts, etc. The Curran group also envisioned using fluori-
9
nated protecting groups in fluorous synthesis.
2
water and most organic solvents. Most organic compounds
In this context we considered the possibility of creating a
new generation of fluorinated protecting groups derived from
the traditional ones by attaching perfluoroalkyl chains as
pony tails. Two requirements should be met by these novel
compounds to be useful in fluorous synthesis: First, they
should serve to protect and deprotect the substrates as
are insoluble in the fluorous phase; however, introduction
of perfluorinatealkyl chains (pony tails) convert them into
fluorous soluble materials that can be partitioned in the
fluorous phase. This proccess can be employed for the
selective extraction of fluorous components from reaction
3
mixtures.
Fluorous-phase separation techniques can be applied in
several ways, depending on which is the fluorous component
(5) (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S. Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823-826. (b) Studer, A.; Curran, D.
P. Tetrahedron 1997, 62, 6681-6696. (c) Studer, A.; Jeger, P.; Wipf, P.;
Curran, D. P. J. Org. Chem. 1997, 62, 2917-2924.
of the reaction mixture. In the fluorous biphasic catalysis
4
(
FBC), a homogeneous catalyst is immobilized into the
(6) (a) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531-
2
532. (b) Curran, D. P.; Hoshino, M. J. Org. Chem. 1996, 61, 6480-6481.
fluorous phase by attaching fluoro pony tails to the ligand.
In fluorous synthesis, the starting substrate of the synthesis
(c) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg, A. J.
Org. Chem. 1997, 62, 5583-5587. (d) Hoshino, M.; Degenkolb, P.; Curran,
D. P. J. Org. Chem. 1997, 62, 8341-8349. (e) Curran, D. P.; Hadida, S.;
He, M. J. Org. Chem. 1997, 62, 6714-6715. (f) Olofsson, K.; Kim, S.-Y.;
Larhed, M.; Curran, D. P.; Hallberg, A. J. Org. Chem. 1999, 64, 4539-
4541.
(7) Linclau, B.; Sing, A. K.; Curran, D. P. J. Org. Chem. 1999, 64, 2835-
2842.
5
is immobilized into the fluorous phase. Other applications
(
(
(
1) Horv a´ th, I. T.; R a´ bai, T. Science 1994, 266, 72-75.
2) Zhu, W. Synthesis 1993, 953-954.
3) (a) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174-1196. (b)
Horv a´ th, I. T. Acc. Chem. Res. 1998, 31, 641-650.
(8) Betzemeier, B.; Lhermitte, F.; Knochel, P. Synlett 1999, 4, 489-
491.
(4) FBS has been reviewed in several publications: (a) Cavazzini, M.;
Montanari, F.; Pozzi, G.; Quici, S. J. Fluorine Chem. 1999, 94, 183. (b)
Fish, R. Chem. Eur. J. 1999, 5, 1677-1680. (c) de Wolf, E.; van Koten,
G.; Deelman, B.-J. Chem. Soc. ReV. 1999, 28, 37-41. (d) BarthelRosa, L.;
Gladysz, J. A. Coord. Chem. ReV. 1999, 192, 587.
(9) (a) Curran, D. P.; Ferritto, R.; Hua, Y. Tetrahedron Lett. 1998, 39,
4937-4940. (b) Curran, D. P.; Luo, Z. Y. J. Am. Chem. Soc. 1999, 121,
9069-9072. (c) Lou, Z.; Williams, J.; Read, R. W.; Curran, D. P. J. Org.
Chem. 2001, 66, 4261-4266.
1
0.1021/ol0166505 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/19/2001

efficiently as the original protecting groups. Second, they
should have the ability to immobilize the protected substrate
into a fluorous phase, thus allowing its separation by simple
extraction with a fluorous solvent.
In this communication we report our preliminary efforts
toward the preparation of perfluorinated analogues of tert-
butyl alcohol,10 as reagents for the protection of carboxylic
acids in fluorous synthesis.
butyl alcohol: First, the strong electron-withdrawing proper-
ties of the perfluoroalkyl groups must decrease the nucleo-
philicity of the oxygen despite the presence of the ethylene
spacer. Second, these alcohols have very low solubility in
common organic solvents. We started our study assaying the
reaction of phenylacetic acid (5) with 2 and 3.
Esterification of 5 with the alcohol 2 was easily carried
out under standard conditions (DCC/DMAP in dichlo-
romethane), giving the corresponding ester 6 in 80% yield
(Scheme 2). However, protection of 5 with alcohols 3a and
1
3
As potential candidates for fluorous analogues of tert-butyl
alcohol, we selected compound 2, containing one perfluo-
roalkyl chain attached to the quaternary carbon through an
ethylene spacer, and compounds 3a and 3b, having two
perfluoroalkyl chains of different lengths. It is well-known
that the length and number of perfluoroalkyl groups influence
the solubility of perfluoroalkylated compounds in a fluorous
Scheme 2
3
,5a,11
solvent.
2
Also the presence of several CH insulating
groups is necessary to minimize the effects of the perflu-
orinated chains in the reactivity of the modified alcohols.
During the preparation of this manuscript, alcohol 3a and
very similar alcohols were prepared and were used for
9c
carbamate (BOC) rather than acyl based protecting groups.
It was also shown how the fluorous solid-liquid extraction
methods are much more practical and efficient than the
fluorous liquid-liquid extraction methods.9
c
Alcohols 2 and 3a were conveniently prepared by reaction
of Grignard 1 with acetone and ethyl acetate, respectively.
Similarly, treatment of Grignard 4 with ethyl acetate afforded
alcohol 3b in good yield (Scheme 1). Grignards 1 and 4 were
Scheme 1. Fluorinated Analogues of tert-Butyl Alcohol
3
b was more difficult, and poor yields of 7a and 7b were
obtained under these conditions, a more thorough study of
this reaction being necessary. Preliminary assays showed that
coupling reagents such as DPC, PyBPO, HBTU, TBTU, and
BOPCl were ineffective, whereas carbodiimides DCC and
DIC, in combination with DMAP, gave better results,
allowing the isolation of 7a and 7b in reasonable yields,
depending on the solvent used. It is remarkable to point out
that the use of common solvents such as DMF, CHCl
Cl , and THF for these reactions gave poor yields of product
even after raising the temperature to solubilize the reagents).
Instead, the use of benzotrifluoride, a partially fluorinated
solvent that is employed as substitute for CH Cl in reactions
3 2
, CH -
2
(
2
2
1
4
with perfluorinated compounds, allowed the isolation of
7a and 7b in moderate yields (75% and 60%) using DIC/
DMAP as coupling reagent at 40 °C.
generated from the corresponding commercially available
iodides.
1
2
The esterification of carboxylic acids with alcohols 2 and
has two difficulties compared with the reaction with tert-
A preliminary evaluation of the effectiveness of alcohols
2, 3a, and 3b as protecting groups for 5 showed that 3b was
3
(
10) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
(13) Farnhan, B. W. Chem. ReV. 1996, 96, 1633-1640.
Synthesis, 2nd ed.; Wiley-Interscience: New York, 1991. (b) Kocienski,
P. J. Protecting Groups; Thieme: Stuttgart, 1994.
(14) See for example: (a) Maul, J. J.; Ostrowski, P. J.; Ublacker, G. A.;
Linclau, B.; Curran, D. P. Benzotrifluoride and Derivatives: Useful Solvent
for Organic Synthesis and Fluorous Synthesis. In: Topics in Current
Chemistry, Modern SolVents in Organic Synthesis; Knochel, P., Ed.;
Springer-Verlag: Berlin-Heidelberg, 1999; Vol. 206, p 79. (b) Colonma,
S.; Gaggero, N.; Montanari, F.; Pozzi, G.; Quici, S. Eur. J. Org. Chem.
2001, 181-186. (c) Ogawa, A.; Curran, D. P. J. Org. Chem 1997, 62, 450-
451 and ref 6a.
(11) (a) de Wolf, E.; Richter, B.; Deelman, B.-J.; van Koten, G. J. Org.
Chem. 2000, 65, 5424-5427. (b) Rocaboy, C.; Rutherford, D.; Bennett, B.
L.; Gladysz, J. A. J. Phys. Org. Chem. 2000, 13, 596-603. (c) Rocaboy,
C.; Bauer, W.; Gladysz, J. A. Eur. J. Org. Chem. 2000, 2621-2628. (d)
Hughes, R. P.; Trujillo, H. A. Organometallics 1996, 15, 286.
(12) See refs 6a and 5a for the preparation of Grignard 1 and 4.
3712
Org. Lett., Vol. 3, No. 23, 2001

the most appropriate for our purposes (see below). To
complete this study, a series of aliphatic acids 8a-c were
protected with alcohol 3b using the optimized coupling
reaction conditions described above. So, reaction of 8a-c
with 3b, using DIC and DMAP as coupling reagents in
benzotrifluoride, gave the corresponding esters 9a-c in 92%,
The length of the perfluorinated chain has also a great
effect on the partition coefficients, and as expected, the use
of labels with more fluorine atoms favors the partition into
the fluorous phase.
Ester 7b acted as a “fluorous compound” for all solvent
pairs. The protected acid showed the highest partition
coefficients when either lowly polar (cyclohexane, toluene)
or highly polar (methanol, acetonitrile, ethanol) organic
solvents were used. Also it was observed that the extraction
power of perfluoromethylcyclohexane is superior to that of
FC-72.
75% and 72% yields, respectively (Scheme 2).
One important issue was to prove that these substrates
could be readily deprotected. Treatment of esters 7a,b and
9
a-c with trifluoroacetic acid for 15 h gave the original
unprotected acids in quantitative yields, which could be
isolated from the crude reaction mixture by means of simple
washing with perfluoromethylcyclohexane. Also it was
proven that these esters remained unaltered in basic media
From a synthetic point of view, for the extraction to be of
D
practical utility, the K values must be higher than 4,
indicating that after three extractions more than 99% of the
and under hydrogenation conditions (H
2
/Pd-C).
17
substrate draws into the fluorous phase. Analysis of our
Once we found the methods to protect and deprotect the
acids, the next step was to study if the protected substrates
were suitable to be used in fluorous synthesis. To select the
most efficient protecting group, the partition coefficients
results showed that with protecting group 3a (ester 7a) it is
possible, at least, to choose a polar organic solvent and a
nonpolar organic solvent to carry out the extraction in a
practical way. With protecting group 3b (ester 7b), a greater
number of organic solvents can be chosen for an efficient
extraction, particularly when perfluoromethylcyclohexane is
employed as fluorous solvent. Again it is possible to employ
a polar or a nonpolar organic solvent but also a solvent of
intermediate polarity as dichloromethane, which has a great
extracting power for most organic compounds.
15
(K
D
)
of esters 6 and 7a,b in several fluorous biphasic
16
solvent combinations were determined. As fluorous sol-
vents, FC-72 (a mixture of perfluorohexanes) and perfluo-
romethylcyclohexane were used. The results of these ex-
periments, shown in Table 1, helped us to evaluate these
Once we verified that 3b was the most efficient protecting
group for our purposes, the partition coefficients of aliphatic
esters 9a-c were determined (Table 1). We observed that
with the aliphatic series 9a-c the partition coefficients are
higher and so the number of pairs of solvents that can be
used for a practical extraction is increased. Again perfluo-
romethylcyclohexane showed a greater extracting power than
FC-72, and the extraction is best carried out with very polar
solvents such as methanol, ethanol, and acetonitrile and with
nonpolar solvents such as cyclohexane and toluene. It is also
interesting to observe how the length of the hydrocarbon
Table 1. Partition Coefficients of Esters 7a,b and 9a-c
organic
solvent
fluorous
solvent
7a
7b
9a
9b
9c
cyclohexane
cyclohexane
toluene
toluene
CH2Cl2
CH2Cl2
chloroform
chloroform
ethyl acetate FC-72
ethyl acetate CF3C6F11
FC-72
CF3C6F11
FC-72
CF3C6F11
FC-72
CF3C6F11
FC-72
8.26 14.62
5.37 13.92
8.10
9.58 12.4
7.75
6.46 17.2
6.72
0.91
2.86
1.13
3.84
1.22
4.68
0.53
1.64
1.06
2.08
0.50
1.04
1.77
2.69
1.78
2.87
0.61
1.96
0.69
0.86
0.29
0.58
0.37
0.55
0.25
0.57
3.42
5.49
9.53
4.00
5.28
9.08
4.53
13.6
2.63
5.74
2.74
9.86
1.70
4.79
2.92
5.55
6.21 15.4
2.55
2.70
1.32
2.04
1.30
3.02
1.50
2.46
9.00
3.06
CF3C6F11
5.93
2.59
3.25
2.70
5.26
3.33
6.28
chain affects the K
an increase in the molecular weight of the aliphatic esters
leads to a decrease in K , an expected result because of the
D
values. In general, for nonpolar solvents,
THF
THF
FC-72
CF3C6F11
FC-72
CF3C6F11
FC-72
CF3C6F11
FC-72
CF3C6F11
FC-72
CF3C6F11 11.1
D
decrease in fluor percentage, but also because the esters
adquire a nonpolar character as a result of the longer
hydrocarbon chain.
However, the situation changes for polar solvents where
D
in general, the K values increase with the increase in the
length of the aliphatic chain, due to the loss of polar character
and therefore their affinitity in polar solvents.
This behavior suggests that we must use polar organic
solvents for extractions with nonpolar esters and also that
increasing the molecular weight of an aliphatic ester must
acetone
acetone
acetonitrile
acetonitrile
ethanol
ethanol
methanol
methanol
6.42 11.2
16.9 29.9
4.19 5.98
4.46 10.24 16.0 11.0
4.65 11.7 4.78 8.89 19.5
20.7 10.8 27.3 33.7
14.3
16.4
8.35
11.2
4.81 16.2
3.29 7.69
protecting groups with regard to their immobilization capa-
bility in a fluorous phase and also to determine the most
adequate pair of solvents for the extraction.
Not surprisingly, ester 6 showed no affinity for the fluorous
phase, demonstrating that at least two perfluorinated chains
were necessary in the protecting group. Esters 7a and 7b,
having two pony tails, showed higher affinities for the
fluorous phase.
(16) The partition coefficients were determined by dissolving a known
amount of the fluorous compound (40-70 mg) in the biphasic system (4
mL, 1:1 v/v). The resulting mixture was vigorously stirred for 15 min in a
10 mL vial, immersed in a 25 °C oil bath. After two clear layers were
obtained, a 1 mL aliquot was removed from each layer with a syringe.
This was evaporated to dryness, and the weight (( 0.1 mg) of each residue
was determined. The partition coefficients were calculated as the ratio of
the amount of residue from each layer.
(17) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.
Vogel’s, Textbook of Practical Organic Chemistry, 5th ed.; ELBS: London,
1989.
(15) KD ) C(fluorous phase)/C(organic phase), at 25 °C.
Org. Lett., Vol. 3, No. 23, 2001
3713

not be indicative of loss in fluorous affinity, despite the
decrease in fluor percentage.18 This result is significant
because it demonstrates that it should be possible to extract
nonpolar compounds of medium molecular weight or even
larger compounds, as the trend of Table 1 shows, in an
effective way without the necessity of increasing the length
of the pony tails. Therefore, it could be feasible to apply
these techniques to a great variety of interesting compounds
such as terpenes, carotenes, etc.
In short, the results shown here prove that perfluorinated
alcohol 3b can be employed as reagent for carboxylic acid
protection to be used in fluorous synthesis. Also we
demonstrated that it is possible to use fluorous synthesis to
immobilize medium-sized nonpolar substrates without using
a large amount of fluor.
Acknowledgment. Financial support from the Xunta de
Galicia (grant Xuga-26201A98) is gratefully acknowledged.
(18) Polar compounds need a larger percentage of fluor than nonpolar
compounds to be soluble in fluorous solvent because the fluorous solvents
keep some nonpolar character (Guillevic, M. A.; Rocaboy, C.; Arif, A. M.;
Horvath, I. T.; Gladysz, J. A. Organometallics 1998, 17, 707-717. Also,
ref 7). For polar compounds it will be necessary to increase the length of
the pony tails of the alcohol to get adequate fluorous solubility and affinity.
Otherwise other nobel fluorous techniques referred to as light fluorous
techniques, allow the separation of fluorous compounds readily without
increasing the length of the pony tails. See ref 9c and (a) Zhang, Q.; Luo,
Z.; Curran, D. P. J. Org. Chem. 2000, 65, 8866-8876. (b) Luo, Z.; Zhang,
Q.; Oderaotoshi, Y.; Curran, D. P. Science 2001, 291, 1766-1769 and
references therein.
Supporting Information Available: Detailed experi-
1
13
mental procedures and H and C NMR data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0166505
3714
Org. Lett., Vol. 3, No. 23, 2001