The role of neat substrates in phase-vanishing and tandem phase-vanishing reactions

Article abstract of DOI:10.1016/j.tetlet.2008.09.007

Phase-vanishing reactions are triphasic reactions, which involve a reagent, a liquid perfluoroalkane as a phase screen and a substrate. Aromatization, isomerization and halogenation of neat substrates under phase-vanishing conditions gave the expected products in good to excellent yields. In tandem single-phase-phase-vanishing reaction, two reactants, placed in the top phase, afforded the intermediate, which in a subsequent phase-vanishing reaction reacted with the reagent from the bottom phase to give the final product. The reaction worked well under solvent-free conditions on liquid substrates and intermediates. With solids, results were better if an additional solvent was employed.

Full text of DOI:10.1016/j.tetlet.2008.09.007

Tetrahedron Letters 49 (2008) 6543–6546
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Tetrahedron Letters
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The role of neat substrates in phase-vanishing and
tandem phase-vanishing reactions
Nicole Windmon a, Veljko Dragojlovic b,
*
a Department of Chemistry, Florida Atlantic University, 777 Glades Road, Boca Raton, Florida 33431, USA
b Wilkes Honors College of Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Phase-vanishing reactions are triphasic reactions, which involve a reagent, a liquid perfluoroalkane as a
phase screen and a substrate. Aromatization, isomerization and halogenation of neat substrates under
phase-vanishing conditions gave the expected products in good to excellent yields. In tandem single-
phase–phase-vanishing reaction, two reactants, placed in the top phase, afforded the intermediate, which
in a subsequent phase-vanishing reaction reacted with the reagent from the bottom phase to give the
final product. The reaction worked well under solvent-free conditions on liquid substrates and inter-
mediates. With solids, results were better if an additional solvent was employed.
Received 21 August 2008
Revised 30 August 2008
Accepted 2 September 2008
Available online 6 September 2008
Keywords:
Aromatization
Halocyclization
Ó 2008 Elsevier Ltd. All rights reserved.
Halogenation
Iodine monochloride
Phase-vanishing reactions
Solvent-free reactions
Phase-vanishing reactions, introduced by Ryu, Curran and Verk-
ade,1–4 are triphasic reactions, which involve a reagent, a liquid
perfluoroalkane and a substrate. The perfluoroalkane, which is in
the layer between the two, does not dissolve either of the reactants
and is used to separate them. As the reagent in the bottom layer
diffuses through the perfluoroalkane layer, it reaches the top layer
and reacts with it. Thus, the reaction proceeds at a moderate rate,
instead of a vigorous and often violent reaction if the two reactants
were mixed without a solvent. In the course of the reaction, the
reagent disappears (‘vanishes’). Phase-vanishing (PV) reaction
allows for reactions that otherwise would be too vigorous without
a solvent to be done on neat reagents.5 This considerably simplifies
the work up and makes the reactions environmentally friendly. We
40 W incandescent light bulb and gave a mixture of naphthalene
(4), 1-bromonaphthalene (5) and 1,4-dibromonaphthalene (6)
(Table 1, entry 2). These results are similar to bromination of
tetralin in carbon tetrachloride.6 cis-Stilbene (7) was cleanly
isomerized into trans-stilbene (8) when treated either with a
catalytic amount of iodine in FC-72 or upon treatment with
gaseous hydrogen bromide delivered through a tube immersed in
FC-72 (Table 1, entries 3 and 4). Phenanthrene (9) and dimerization
products, such as 10, that often accompany iodine-catalyzed
isomerization in benzene7 were not observed. Advantage of a
phase-vanishing isomerization with HBr is that delivery tube,
immersed into FC-72, was not plugged with the solid product as
was the case when HBr was bubbled directly into a neat cis-
stilbene. Iodine-catalyzed isomerization of dimethyl maleate (11)
under phase-vanishing conditions, upon exposure to a visible light
(40 W light bulb), gave a mixture of dimethyl maleate (11) and
dimethyl fumarate (12) (Table 1, entry 5). Reproducibility of this
isomerization was poor, and extended reaction times did not
change the ratio of the isomers in any consistent manner.
used FC-72 (perfluorohexane, C6F14
) as a phase screen and
examined phase-vanishing isomerization and addition reactions
that involve halogen reagents as well as a combination of tradi-
tional single-phase (SP) reactions with phase-vanishing reactions
into tandem single-phase–phase-vanishing (SP–PV) reactions.
Phase-vanishing aromatization and isomerization reactions
involving halogens and hydrogen halides worked well on neat
liquid substrates. Thus, reaction of dimethyl 4,5-dimethyl-1,4-
cyclohexadien-1,2-dicarboxylate (1) gave the aromatized product
2 cleanly and in a good yield (Table 1, entry 1). Reaction of tetralin
3 with bromine required irradiation with a projector lamp or a
Iodine, as a catalyst, is not consumed in the course of the reac-
tion and HBr reactions involved bubbling of a gas, the reagent
phase did not ‘vanish’ and, therefore, some of the procedures were
Ph
Ph
Ph
Ph
* Corresponding author. Tel.: +1 561 799 8012; fax: +1 561 799 8602.
E-mail address: vdragojl@fau.edu (V. Dragojlovic).
10
9
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.007

6544
N. Windmon, V. Dragojlovic / Tetrahedron Letters 49 (2008) 6543–6546
Table 1
Phase-vanishing aromatization and isomerization
Entry
1
Substrate
Conditions
Product (yield %)
CO2CH3
CO2CH3
CO2CH3
Br2 (1.1 equiv), 1 h
(88)
2
1
CO2CH3
Br
Br
Br
2
Br2 (1.1 equiv), 40 min
3
4
5
6
Ph
3b
4
I2 (0.1 equiv), 1 h
(94)
Ph Ph
Ph
7
8
7
HBr (g) (1.0 equiv), 1 h
I2 (0.1 equiv), 3 h
8
(91)
CO2CH3
5
+
11
12
11
H3CO2C CO2CH3
H3CO2C
not strict phase-vanishing reactions. Common to all the procedures
was that the substrate was in a separate phase and that the reagent
was delivered through the FC-72 phase.
ditions was exceptionally vigorous and fast for a solid substrate.
Product was a mixture of cis- and trans-1,2-dibromo-1,2-diphenyl-
ethenes (20) (Table 2, entry 5). Reaction was accompanied by for-
mation of a tribromo compound (ꢀ7%, GC), and the corresponding
amount of the starting diphenylacetylene (19) (ꢀ8%) was recov-
ered. Halogenation of neat solid trans-stilbene (8) did not give good
results. A large amount of the starting material was recovered and
two isomeric dibromostilbenes were obtained in various ratios.
That was the case even though trans-stilbene was finely powdered.
In the course of bromination of cis-stilbene (7) (Table 2, entry 6),
there was a competing isomerization into the solid trans-stilbene.
Isomerization reaction appears to be considerably faster than bro-
mination, and the product appears to be mainly a result of bromin-
Phase-vanishing halogenation of neat liquid alkenes worked
very well and at a high reaction rate, but not as well on neat solid
substrates. Thus, bromination of neat 2,3-dimethyl-2-butene (13)
(Table 2, entry 1) was very fast (<5 min). PV reaction was vigorous,
with formation of some tri- and tetra-bromo derivatives, and 2,3-
dibromo-2,3-dimethylbutene (14) was isolated in a modest yield.
This reaction should be done with a reasonably vigorous stirring
to prevent the solid product from forming a barrier between the
two layers. Alternatively, if the barrier does form, it can be broken
up with a glass rod. Cyclohexene (15) reacted slowly in the dark to
give the expected product, trans-1,2-dibromocyclohexane (16) (Ta-
ble 2, entry 3). In the presence of even a weak light source, allylic
bromination became an important side reaction. Dimethyl acetyl-
enedicarboxylate (17) (Table 2, entry 4) reacted at a high rate to
give a mixture of cis and trans isomers (18). Reaction of neat
diphenylacetylene (19) with bromine under phase-vanishing con-
ation of trans-stilbene. Besides the bromination products,
relatively large amount of trans-stilbene was isolated.
a
Reaction times can be controlled by the amount of FC-72, with a
larger depth of FC-72 resulting in a slower reaction, and the rate of
stirring. A reaction can be done without any stirring, or the
reaction rate can be increased by slow stirring. Fast stirring is not
Table 2
Phase-vanishing halogenation of alkenes and alkynes
Entry
1
Substrate
Conditions
Product (yield %)
Br
Br2 (1.1 equiv), 5 min
(72)
13
14
Br
Br
2
Br2 (1.1 equiv), dark, 2 h
Br2 (1.1 equiv), 10 min
Br2 (1.1 equiv), 1 min
(78)
(94)
(81)
15
16
Br
Br
H3CO2C
CO2CH3
3b
CO2CH3
H3CO2C
17
18
Br
Br
Ph
Ph
Ph
4
20
19
Ph Br
5
6
7
8
8
8
7
7
Br2 (1.1 equiv), 1 h
ICl (2.2 equiv), 3 h
Br2 (1.1 equiv), 1 h
ICl (2.2 equiv), 3 h
( )-Dibromostilbene (4–28%) meso-dibromostilbene (35–69%)
( )-Chlorostilbene (5–39%) meso-chlorostilbene (28–52%)
( )-Dibromostilbene (21–41%) meso-dibromostilbene (21–35%)
( )-Chlorostilbene (11%) meso-chlorostilbene (23%)

N. Windmon, V. Dragojlovic / Tetrahedron Letters 49 (2008) 6543–6546
6545
recommended as it may lead to mixing of the top and bottom
phases and a reaction running out of control. Usually, solubility
of the reaction products in FC-72 is negligible, and it can be reused.
However, that is not always the case particularly when the prod-
ucts are polyhalogenated compounds.
Further development of phase-vanishing procedure was inte-
gration of a traditional single-phase reaction with a phase-vanish-
ing reaction into a tandem single-phase–phase-vanishing (SP–PV)
reaction. We selected Diels–Alder reaction as a single-phase reac-
tion, and reaction of the resulting Diels–Alder adduct with a halo-
gen as a phase-vanishing reaction. Although Diels–Alder reactions
under solvent-free conditions (SFCs) have received relatively little
attention,8–10 we found them suitable for SP–PV process as long as
the resulting Diels–Alder adduct was a liquid.
a less reactive diene and a dienophile under SFC takes considerably
longer, frequently days, to go to completion. Such reaction can be
adapted to SP–PV conditions provided that the halogen reagent is
added upon the completion of SP reaction. Thus, 2,3-dimethyl-
1,3-butadiene (30), dimethyl acetylenedicarboxylate (17) and FC-
72 were combined in a vial. Diels–Alder reaction took 3 d. Next,
bromine was added to the bottom of the vial and the aromatized
product, dimethyl 4,5-dimethylphthalate (2), was obtained after
1 h (Table 3, entry 4).
Br
Br
Br
Br
Br
Br
Br
CO2H
Br
CO2H
26
CO2H
29
CO2H
27
28
A halogen reagent was placed at the bottom of the reaction ves-
sel, a phase screen (FC-72) was added and Diels–Alder reactants (a
diene and a dienophile) were placed on the top of the phase screen.
Thus, a relatively fast, SFC Diels–Alder reaction occurred first in the
top phase, and was followed by a slower phase-vanishing reaction
between the resulting Diels–Alder adduct and the halogen reagent.
Reaction outcome of an SP–PV was similar to a separate SP fol-
lowed by a VP reaction. Thus, reaction between cyclopentadiene
(21) and dimethyl fumarate (12) followed by reaction with iodine
monochloride (Table 3, entry 1) gave the resulting iodolactone 22
in 92% yield compared to 94% for separate reactions.5 Interestingly,
in one run reaction temperature of SP–PV reaction inadvertently
went out of control (stirring was set too high and iodine monochlo-
ride and Diels–Alder adduct came into a direct contact). The tem-
perature was so high that all of the FC-72 evaporated. Still,
iodolactone 22 was isolated in 96% yield (>95% pure according to
1H NMR). Even though dienes are highly reactive toward the halo-
gens, with a sufficient depth of the FC-72 phase screen and in the
absence of stirring there was little or no reaction between the hal-
ogen and either starting diene or dienophile. Thus, less than 2% of
the bromination products of the original staring materials were ob-
served in the GC–MS of the crude product. SP–PV reaction of cyclo-
pentadiene (21) and acrylic acid (24) followed by treatment with
bromine also gave essentially the same results as separate SP and
PV reactions.5 The major product was bromolactone 25 that was
isolated in a modest yield (Table 3, entry 3), and it was accompa-
nied by the four dibromo derivatives 26–29. A reaction between
While this short study proves the concept, the procedure in its
present form has some limitations. Reactions that proceeded
through liquid Diels–Alder adducts worked well, but with some
scale limitations. SFC Diels–Alder reactions are exothermic, and
the reaction temperature should be maintained below the boiling
point of FC-72 (58–60 °C) by selecting reaction vessel of the appro-
priate size (as large as possible to allow heat dissipation) and doing
the reaction on the appropriate scale. For example, Diels–Alder
reactions of cyclopentadiene (21) and some unsaturated esters,
such as dimethyl maleate and fumarate, on a very small scale
(<10 mmol) do not generate much heat, are very slow (take days),
and often do not go to completion. With an increase in scale, such
reactions release considerably more heat and usually go to comple-
tion in 1 h or less, which makes them suitable for SP–PV reactions.
Further increase in scale results in an out of control runaway reac-
tion that is not practical. In addition, size and shape of the reaction
vessel affects the reaction temperature. Thus, a reaction on a smal-
ler scale should be done in as small vessel as possible in order to
retain the heat and to ensure that reaction proceeds at a reasonable
rate and goes to completion, while a reaction on a larger scale
should be done in much larger vessels to allow dissipation of
excess heat. A detailed study of SFC Diels–Alder reactions will be
published elsewhere. Diels–Alder reactions that gave solid prod-
ucts did not give good results under SFC. The product would form
either clumps or a single solid piece, which did not react very well
with the reagent. Such reactions can be done if an additional sol-
vent, such as ethyl acetate, is employed to dissolve the intermedi-
ate Diels–Alder adduct (Table 3, entry 5). Work on optimization
and expanding the scope of SP–PV reactions is in progress.
In a typical procedure, to a 40 mL (28 Â 95 mm) vial equipped
with a stirring bar, 5.50 mL (55 mmol) of ICl and 10 mL of FC-72
were added. Cyclopentadiene (21) (4.15 mL, 50 mmol) and di-
methyl fumarate (12) (7.20 g, 50 mmol) were carefully added to
the top of FC-72 layer. SP reaction was allowed to proceed without
stirring for 12 min. After the exothermic Diels–Alder reaction was
completed, VP reaction was continued with stirring for another
24 h.
Table 3
Tandem SP–PV reactions
Entry
1
Substrates
Conditions
Product
I
CO2CH3
+
12
ICl, SP 12 min, VP 24 h
‘(92)
(94)
O
O
21
22
Br
O
CO2CH3
2
21 + 12
Br2, SP 12 min, VP 12 h
23
O
In conclusion, both PV and tandem SP–PV reactions avoided use
of any solvent, and the work up consisted of mechanical separation
of the product from the phase screen. SP–VP Diels–Alder-halogena-
tion reactions work well on a moderate (multi-gram) scale on
liquid Diels–Alder intermediates, and compare favorably to
running separate SP and VP reactions.
Br
CO2H
+
3b
Br2, SP 8 min, VP 1 h
Br2, SP 3 d, VP 1 h
(45)
(90)
(63)
21
O
24
25
O
+ 17
4
2
30
Acknowledgment
Br
Br
O
O
O
O
We thank Salvatore Lepore (Department of Chemistry,
Florida Atlantic University) for use of his facilities and helpful
discussions.
5
Br2, SP 10 min, VP 2 h
+
21
O
31
32
O

6546
N. Windmon, V. Dragojlovic / Tetrahedron Letters 49 (2008) 6543–6546
6. Çakmak, O.; Kahveci, I.; Demirtaßs, Í.; Hökelek, T.; Smith, K. Collect. Czech. Chem.
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