TLC plates as a convenient platform for solvent-free reactions

Article abstract of DOI:10.1039/b616311d

Solvent-free oxidative couplings of naphthols have been optimized by co-spotting catalysts and substrates directly on silica TLC plates and heating, followed by chromatography, staining, and qualitative visualization. The Royal Society of Chemistry.

Full text of DOI:10.1039/b616311d

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TLC plates as a convenient platform for solvent-free reactions
Jonathan M. Stoddard,* Lien Nguyen, Hector Mata-Chavez and Kelly Nguyen
Received (in Austin, TX, USA) 10th November 2006, Accepted 30th November 2006
First published as an Advance Article on the web 4th January 2007
DOI: 10.1039/b616311d
Solvent-free oxidative couplings of naphthols have been
optimized by co-spotting catalysts and substrates directly on
silica TLC plates and heating, followed by chromatography,
staining, and qualitative visualization.
co-grinding the two components. 2-Naphthol was then co-ground
with the mixture, placed in an oven at 50 uC, eluted with chloro-
form, and analyzed with TLC. In all cases, the 2-naphthol–BINOL
reaction ratios were similar and it was concluded that added silica
does not hinder the oxidative coupling reaction.
Environmentally-friendly methods of solvent-free synthesis involve
reactions in the solid state, melt or vapor phases and reduce the
We found it necessary to optimize the application of FeCl and
3
2-naphthol onto TLC plates so that there is adequate mixing of the
two components and consistent results are obtained after heating
the TLC plates. We found two methods that worked equally well.
1
amount of waste from solvent. Inorganic materials such as
alumina and silica are common supports for reagents or catalysts
in heterogeneous reactions that effectively replace the solvent.
Silica, for example, can be a support for two reactants that
undergo reaction upon microwave irradiation or heating and the
resultant silica–product mixture directly subjected to chromato-
graphy without extractive work-up procedures. The development
of these reactions involves mixing the two components with silica
gel, providing the necessary heat, washing the product mixture
from the silica gel with solvent, and analyzing the product mixture
with thin-layer chromatography (TLC).
3 2
In the first method, FeCl ?6H O (0.1 M in water) was spotted onto
the baseline of a TLC plate. 2-Naphthol (0.1 M in acetone) was
immediately spotted on the same location of the TLC plate. In the
3 2
second method, the aqueous FeCl ?6H O was spotted onto
the TLC plate, heated at 100 uC for 5 minutes to evaporate most
of the water, and allowed to cool before 2-naphthol was co-
spotted. The key parameter affecting the efficiency of co-spotting,
was to ensure that the FeCl spot had a larger diameter than the
3
2-naphthol spot so that there was adequate interaction of
2-naphthol with the metal. It has been found that the Fe(III) is
3
catalytically regenerated by oxygen in a solvent-free reaction and
2
It has occurred to us, as well as others, that TLC plates contain
silica that, in principle, may act as a medium for solvent-free
reactions. Although TLC plates are commonly treated with stain-
ing reagents and heat to assist with the visualization of absorbed
components, the extension of this platform for developing solvent-
free organic reactions has rarely been explored. We have devised a
method for developing solvent-free reactions on silica TLC plates.
The use of TLC plates as a medium for solvent-free organic
synthesis enables the application of catalysts, reagents, and heat.
Without further manipulations, the results of the reaction may be
directly analyzed by chromatography, staining, and visualization.
This methodology allows the reaction development process to take
place completely on a disposable TLC plate, thereby further
reducing waste and time during the development phase.
thus it is not critical that the two spots perfectly overlap or are
applied in equimolar amounts on the silica TLC plate.
We started by screening different metals in parallel on the same
TLC plate and found FeCl
product. A TLC plate was spotted with 0.1 M aqueous solutions
of CuCl , FeCl , FeCl , NiCl , and CoCl , dried, then co-spotted
3 2 2
, FeCl , and CuCl catalysts to provide
2
2
3
2
2
with a smaller diameter of 0.1 M 2-naphthol in acetone. The TLC
plate was placed on a hotplate at 50 uC for 2 hours, cooled,
chromatographed with 80 : 20 hexanes–ethyl acetate and stained
with ceric ammonium molybdate. The FeCl , FeCl , and CuCl
2
3
2
catalysts indicated some product formation and were further
investigated.
The TLC-supported oxidative coupling reactions were further
optimized by placing TLC plates on hotplates at various
temperatures (50, 100, 150, and 200 uC) for different reaction
times (15, 30, 45, and 60 min). The TLC-based oxidative coupling
Herein, we report the use of TLC plates for the development of
oxidative couplings of naphthols. The oxidative coupling of
2
-naphthols is the first step in the synthesis of 2,29-binaphthol
BINOL)-based asymmetric ligands. The solid-phase synthesis of
BINOL has been accomplished in the solid state by co-grinding
(
2
of 2-naphthol with CuCl produced more side products while
3
FeCl and FeCl formed equal amounts of BINOL. Thus FeCl
3
2
3
2-naphthol with FeCl ?6H O and heating at 50 uC for 2 h. This
3
2
was selected for further optimization at different temperatures and
times (Table 1). The critical parameter affecting the relative
amounts of BINOL and 2-naphthol is the temperature, 100 uC
being optimal (Fig. 1). This is in contrast with the preparative
protocol results in a 95% yield that we have found convenient on
larger scales (10–100 g). We sought to reverse engineer this reaction
on silica TLC plates before extending the methodology to other
oxidative coupling reactions.
solid-phase reaction between FeCl and 2-naphthol where the ideal
3
The presence of added silica on the solid-phase oxidative
3
temperature is 50 uC. The relative amount of BINOL produced
3 3
coupling of 2-naphthol by FeCl had no effect. Different FeCl ?
with longer reaction times remained constant, with the exception
of reactions at 150 uC where a less polar side product becomes
prevalent with increasing reaction time. Furthermore, higher
temperatures cause decomposition of 2-naphthol that occurs in
6
H O–silica gel mixtures (50, 33, and 25 w/w%) were prepared by
2
Dept. of Chemistry and Biochemistry, California State University,
Fullerton, CA 92834-6866, USA. E-mail: jstoddard@fullerton.edu;
Fax: +1 714 5316; Tel: +1 714 278 5316
3
the absence of FeCl (Fig. 1).
1
240 | Chem. Commun., 2007, 1240–1241
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Table 1 Qualitative results of FeCl
on silica TLC plates
3
oxidative coupling of 2-naphthol
3
and FeCl , which does not allow the product to be analyzed by
TLC (R 5 0) 80 : 20 hexanes–ethyl acetate. Instead we optimized
f
b
the disappearance of 2-aminonaphthalene (R 5 0.24). Our initial
f
Relative amounts (%)
TLC-supported screens again indicated that FeCl was a better
3
a
Temperature uC
Time/min
2-Naphthol
BINOL
Impurity
catalyst than CuCl , which produced more side products. Upon
2
5
5
5
5
00
00
00
00
00
50
50
50
50
0
0
0
0
15
30
45
60
5
15
30
45
60
15
30
45
60
60
60
60
60
10
2
2
2
2
40
40
40
40
90
98
98
98
98
45
40
35
30
—
—
—
—
—
—
—
—
—
10
20
30
40
3
co-spotting 2-aminonaphthalene onto the silica-supported FeCl ,
there was immediate dark coloration which indicated a reaction
had taken place. Reactions using these two metals were carried out
at 25, 35, and 45 uC for 5 minutes.
1
1
1
1
1
1
1
1
1
a
Reactions at longer reaction times did not show improvement.
In addition, higher reaction temperatures showed increasing
2
amounts of side products, especially in the case of CuCl .
Interestingly, TLC reactions at 25 and 35 uC showed a small
45
40
35
30
b
amount of less-polar material (R 5 0.35), which may be an
f
intermediate in the oxidative coupling reaction. At 45 uC this
component was not detected after staining with ceric ammonium
molybdate. Preparative scale oxidative couplings of 2-amino-
Measured using an IR-thermometer. Chromatographed using
0 : 20 hexanes–ethyl acetate and stained using ceric ammonium
8
molybdate; 2-naphthol (R
5 0.58).
f
5 0.34), BINOL (R
f
5 0.16), impurity
3 2
naphthalene (1 equiv.) and FeCl ?6H O (2 equiv.) were carried out
(
R
f
by co-grinding the two in a mortar and pestle, placing in capped
vials, and heating in a thermostated oven. After work-up{ the
reactions were analyzed with TLC, without complications due to
3
the complexation of BINAM or 2-aminonaphthalene to FeCl .
Increasing the reaction temperature or increasing the reaction time
had no effect on the yield of the product ratio, which remained
fairly constant at 60 : 40 2-aminonaphthalene–BINAM. We
reasoned that the BINAM may coordinate strongly with the
Fe(III) and inactivate it. Alternatively, acid may form during the
reaction conditions and form 2-naphthylammonium chloride
which cannot coordinate with Fe(III) and allow the oxidative
3 2
coupling reaction to proceed. The amount of FeCl ?6H O was
increased in an effort to optimize the yields of the oxidative
coupling reaction.
We found that the amount of BINAM produced could be
optimized with 8 equivalents of FeCl ?6H
3
2
O. Solid-phase reactions
2
?6H O
Fig. 1 All TLC plates heated 15 min, developed with 80 : 20 hexanes–
of 2-aminonaphthalene with 2, 4, and 8 equivalents of FeCl
3
ethyl acetate, and stained using ceric ammonium molybdate. Lanes: (A)
produced 60 : 40, 20 : 80, and 10 : 90 ratios of 2-aminonaphtha-
lene–BINAM respectively. The latter reaction was carried out on a
2 3
2-naphthol; (B) CuCl –2-naphthol; (C) FeCl –2-naphthol.
1
g scale by co-grinding 2-aminonaphthalene with 8 equivalents of
We next screened a number of different naphthols in parallel for
their ability to undergo the oxidative coupling reaction on SiO2
TLC plates where 2,3-naphthalene diol serves as a representative
FeCl ?6H O for 5 minutes at 21 uC to produce analytically pure
BINAM in 33% yield after work-up,{ without chromatography.
An aqueous acid work-up did not increase the yield of recovered
3
2
example. CuCl
supported oxidative coupling of 2,3-naphthalene diol. FeCl
found to provide more product conversion compared with CuCl
and was further optimized. The FeCl ?6H O and 2,3-naphthalene
diol were co-spotted onto silica TLC plates and heated at 50, 75,
00 uC for 15 min. It was found that the reaction was complete at
00 uC and 15 min. Higher temperatures or longer reaction times
2
and FeCl
3
catalysts were screened for the TLC-
4
BINAM.
3
was
2
3
2
Notes and references
{
Solid-phase reactions were worked up by partitioning the reaction
1
mixture between ether and water, filtering through celite to remove
insoluble material, and washing the precipitate with ether. The ether
solution was separated and evaporated to afford the binaphthyl product,
1
did not appear to produce more coupled product. With these
results in hand, we undertook the preparative scale oxidative
coupling reaction by co-grinding 2,3-naphthalene diol (10 g) with
1
1,19-binaphthyl-2,29,3,39-tetraol: H NMR (400 MHz, DMSO-d ) d 6.81 (d,
6
J 5 8.4 Hz, 1H), 6.96 (ddd, J 5 1.2, 6.8, 8.2 Hz, 1H), 7.15 (ddd, J 5 1.2,
6.8, 9.1 Hz, 1H), 7.23 (s, 1H), 7.65 (d, J 5 7.9 Hz, 1H), 8.38 (bs, 1H), 10.04
(bs, 1H); C NMR (100 MHz, DMSO-d ) d 146.8, 145.3, 129.2, 129.0,
13
2
equivalents of FeCl ?6H O at 100 uC for 15 min to produce
6
3
2
21
126.3, 124.7, 123.1 (2), 116.7, 109.1; IR (ATR): 3459, 3400 cm ; mp
analytically pure tetraol in 66% yield.{
The oxidative coupling of 2-aminonaphthalene has been carried
.
275 uC.
out with CuCl
,29-diaminobinaphthyl (BINAM) in 45% yield, but a solvent-free
reaction has not yet been developed. We have prepared
2 2 2 2
and PhCH NH or tBuNH catalysts to afford
1
2
(a) G. W. V. Cave, C. L. Raston and J. L. Scott, Chem. Commun., 2001,
2159; (b) F. Toda, Acc. Chem. Res., 1995, 28, 480.
L. Williams, Chem. Commun., 2000, 435.
4
2
5
3 F. Toda, K. Tanaka and S. Iwata, J. Org. Chem., 1989, 54, 3007.
M. A. Smrcina, M. Lorenc, V. Hanus and P. Kocovsky, Synlett, 1991,
31.
2-aminonaphthalene via the Bucherer reaction of 2-naphthol
4
and investigated its TLC-supported oxidative coupling reactions.
2
The BINAM (R 5 0.24) product coordinates strongly to CuCl
f
5 H. Seeboth, Angew. Chem., Int. Ed. Engl., 1967, 6, 307–317.
2
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