Deprotonation-Triggered Heavy-Halogen Migrations as a Key to the Structural Elaboration of 2,2 -Difluoro-1,3-benzodioxole

Article abstract of DOI:10.1002/ejoc.200300553

Although proton abstraction from the 4-position of 2,2-difluoro-1,3-benzodioxole occurs with exceptional ease, lithiation of the more-remote 5-position can only be brought about if no oxygen-adjacent site remains unoccupied. Thus, unlike 4-bromo-2,2-diflu

Full text of DOI:10.1002/ejoc.200300553

FULL PAPER
Deprotonation-Triggered Heavy-Halogen Migrations as a Key to the Structural
Elaboration of 2,2-Difluoro-1,3-benzodioxole
[a]
[a]
[a,b]
´ ´
Joanna Gorecka, Frederic Leroux, and Manfred Schlosser*
Keywords: Carboxylations / Deprotonation / Halogen migration / Iodine / Protective groups
Although proton abstraction from the 4-position of 2,2-di-
fluoro-1,3-benzodioxole occurs with exceptional ease,
lithiation of the more-remote 5-position can only be brought
about if no oxygen-adjacent site remains unoccupied. Thus,
unlike 4-bromo-2,2-difluoro-1,3-benzodioxole (1), (7-bromo-
2,2-difluoro-1,3-benzodioxol-4-yl)triethylsilane (5b) does re-
2,2-difluoro-1,3-benzodioxole (8) and 5-bromo-2,2-difluoro-
1,3-benzodioxole-4-carboxylic acid (3) are formed nearly
quantitatively. A similar basicity gradient-driven heavy-hal-
ogen migration can be accomplished starting from 2,2-di-
fluoro-4,7-diiodo-1,3-benzodioxole (11). These results pro-
cure a deeper insight in the acidifying effects of fluoroalkoxy
act with lithium diisopropylamide to generate an interme- groups and their distance dependence.
diate that isomerizes instantaneously by heavy-halogen
migration. Upon neutralization and carboxylation, 5-bromo-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
lithium compound resulting from deprotonation at the
oxygen-activated 7-position would afford 7-bromo-2,2-di-
Having discovered the first clean and, hence, synthetically fluoro-1,3-benzodioxole-4-carboxylic acid (2). In fact, only
useful deprotonation-promoted heavy-halogen migration in the latter product 2 (96%) was obtained when 4-bromo-2,2-
the arene series,[1,2] we embarked on a systematic explo- difluoro-1,3-benzodioxole was treated consecutively with
ration[3,4] of the scope and the limitations of this kind of lithium diisopropylamide (LIDA) and dry ice before the
process. 2,2-Difluoro-1,3-benzodioxole, the key intermedi- mixture was neutralized.
ate for the manufacture of an important herbicide,[5,6] pro-
vided us with a prototypical model substrate because its
exceptionally strong inherent acidity makes lithiation at the
4-position,[5Ϫ7] and the subsequent introduction of a wide
range of electrophiles at this site, extremely facile.[8] The
main objective of the present work was to probe the proton
mobility at the heteroatom-remote 5-position relative to the
4-position.
We chose 4-bromo-2,2-difluoro-1,3-benzodioxole (1)[8] to
serve as the test compound. If it behaves as an ordinary 1-
bromo-2,3-dialkoxyarene, deprotonation by a lithium di-
alkylamide should occur simultaneously at the halogen- and
oxygen-adjacent positions because bromine or chlorine
atoms and alkoxy or aryloxy substituents belong to the
Obviously LIDA is basic enough to make the depro-
least-acidifying neighboring groups.[2] Lithiation at the
tonation of 4-bromo-2,2-difluoro-1,3-benzodioxole (1) at
the 7-position virtually irreversible. When we employed a
position next to the bromine atom would generate an inter-
mediate doomed to undergo basicity gradient-driven
weaker base, lithium piperidide, proton abstraction oc-
halogen migration. Upon carboxylation, the isomerized
curred concomitantly also at the 5-position, thus triggering
species would provide 5-bromo-2,2-difluoro-1,3-benzo-
the intended heavy-halogen migration. 5-Bromo-2,2-di-
dioxole-4-carboxylic acid (3). Alternatively, the organo-
fluoro-1,3-benzodioxole-4-carboxylic acid (3), however, was
formed in only small amounts (8%) along with the isomeric
[a]
´
Institute de Chimie moleculaire et biologique, Ecole
7-bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid
(2) and numerous by-products. Since bromobenzene is
totally inert towards any lithium dialkylamide in the
presence or absence of potassium tert-butoxide, the present
´ ´
Polytechnique Federale, BCh
1015 Lausanne, Switzerland
[b]
´
Faculte des Sciences, Universite, BCh
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
64
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300553
Eur. J. Org. Chem. 2004, 64Ϫ68

Deprotonation-Triggered Heavy-Halogen Migrations
FULL PAPER
findings reveal an acidifying effect of the fluoroalkoxy unit, bromine-adjacent position. The organolithium intermediate
which is, of course, strongest at the 4- and 7-positions, but thus generated isomerized instantaneously through heavy-
extends also to the 5- and 6-positions.
halogen migration. Carboxylation, neutralization, and
iodination of the resulting species gave the 5-bromo-2,2-di-
fluoro-7-trialkylsilyl-1,3-benzodioxole-4-carboxylic acids 6
(both 6a and 6b: 82%), the bromosilanes 7 (7a: 86%, 7b:
85%), and the iodobromosilane 9b (73%), respectively. Pro-
todesilylation of the acids 6 and the bromosilanes 7 af-
forded 5-bromo-2,2-difluoro-1,3-benzodioxole (8; 79%) and
5-bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic acid
(3; 91%), respectively.
The heavy-halogen migration did take place smoothly
once the 7-position was blocked by a trialkylsilyl group.
This transformation was first attempted by treating the
bromo compound 1 consecutively with LIDA and the chlo-
roalkylsilane ClSiR3 (R ϭ CH3, C2H5), but the yields of
bromosilanes 5a (12%) and 5b (50%) were poor. Satisfac-
tory results (5a: 83%; 5b: 95%) were achieved when trial-
kyl(2,2-difluoro-1,3-benzodioxolan-4-yl)silane 4 (a: R ϭ
CH3; b: R ϭ C2H5) was allowed to react consecutively with
LIDA and molecular bromine. The resulting bromosilanes
5 (5a: 83%, 5b: 95%) underwent clean proton abstraction
from the
This bis(silanes) 10 (10a: 85%; 10b: 83%) were obtained
each time upon simultaneous exposure of 2,2-difluoro-1,3-
benzodioxole to two equivalents of LIDA and chlorotri-
alkylsilane ClSiR3 (R ϭ CH3 or C2H5). The reaction pro-
ceeds stepwise under such in situ trapping conditions.[9] The
attempted double metalation of 2,2-difluoro-1,3-benzodiox-
ole using LIDA, butyllithium, or N,N,NЈ,NЈЈ,NЈЈ-penta-
methyldiethylenetriamine-activated sec-butyllithium failed,
as evidenced by the absence of any 2,2-difluoro-4,7-diiodo-
1,3-benzodioxole (13; see below) after the addition of the
reaction mixture to a solution of molecular iodine.
Iododesilylation of the bis(silanes) 10 produced 2,2-di-
fluoro-4,7-diiodo-1,3-benzodioxole (11) in nearly quantita-
tive yields (95 and 94% from 10a and 10b, respectively).
Monolateral halogen/metal permutation followed by car-
boxylation gave 2,2-difluoro-7-iodo-1,3-benzodioxane-4-
carboxylic acid (12; 64%). The same acid 12 was formed in
64% yield when the organolithium precursor was generated
[8]
by incubating 2,2-difluoro-4-iodo-1,3-benzodioxole
with
LIDA in tetrahydrofuran for 2 h at Ϫ100 °C. LIDA-pro-
moted deprotonation of the diiodo compound 11 triggered
a heavy-halogen migration. The isomerized aryllithium
species afforded 2,2-difluoro-5,7-diiodo-1,3-benzodioxole-
4-carboxylic acid (14; 91%) upon carboxylation and 2,2-
difluoro-4,6-diiodo-1,3-benzodioxole (13; 86%) upon neu-
tralization. When butyllithium was added to the latter com-
pound, the metal replaced the oxygen-adjacent iodine atom
exclusively. Subsequent neutralization or carboxylation af-
forded 2,2-difluoro-5-iodo-1,3-benzodioxole[7] (15; 62%)
and 2,2-difluoro-6-iodo-1,3-benzodioxole-4-carboxylic acid
(16; 72%).
Eur. J. Org. Chem. 2004, 64Ϫ68
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
65

J. Gorecka, F. Leroux, M. Schlosser
FULL PAPER
deuteriochloroform (if not specified otherwise). Mass spectra were
obtained at a 70-eV ionization potential while maintaining a source
temperature of 200 °C. Whenever no molecular peak was observed
under such conditions, chemical ionization (‘‘c.i.’’) was applied in
an ammonia atmosphere at source temperature of 100 °C. To avoid
redundancy, only the [79Br] fragments, and not the [81Br] isotopo-
mers, are listed in all cases.
2,2-Difluoro-1,3-benzodioxole and 5-bromo-2,2-difluoro-1,3-
benzodioxole are commercially available. The preparation of 4-
bromo-2,2-difluoro-1,3-benzodioxole and 2,2-difluoro-4-iodo-1,3-
benzodioxole are described in ref.[8] (spec. on p. 460).
7-Bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic Acid (2): Diiso-
propylamine (1.4 mL, 1.0 g, 10 mmol) and 4-bromo-2,2-difluoro-
1,3-benzodioxole (1; 2.4 g, 10 mmol) were added consecutively to
butyllithium (10 mmol) in tetrahydrofuran (15 mL) and hexanes
(5.0 mL) at Ϫ100 °C. After 2 h at Ϫ100 °C the mixture was poured
onto an excess of freshly crushed carbon dioxide. Extraction with
dichloromethane (20 mL) and, after acidification to pH 1, with di-
ethyl ether (3 ϫ 10 mL) followed by evaporation and crystallization
from pentanes gave colorless prisms; m.p. 208Ϫ210 °C; yield 2.73 g
(96%). 1H NMR: δ ϭ 7.64 (d, J ϭ 8.8 Hz, 1 H), 7.34 (d, J ϭ
8.8 Hz, 1 H) ppm. 13C NMR: δ ϭ 167.8, 144.0, 143.2, 131.3 (t, J ϭ
258 Hz), 127.1, 126.2, 112.2, 107.8 ppm. MS (c.i.): m/z (%) ϭ 298
(35) [Mϩ ϩ NH4], 280 (100) [Mϩ], 220 (38), 199 (24), 197 (25).
C8H3BrF2O4 (281.01): calcd. C 34.19, H 1.08; found C 34.26, H
1.10.
5-Bromo-2,2-difluoro-1,3-benzodioxole-4-carboxylic Acid (3): 5-
Bromo-2,2-difluoro-7-triethylsilyl-1,3-benzodioxole-4-carboxylic
acid (6b; 3.9 g, 10 mmol) and tetrabutylammonium fluoride tri-
hydrate (TBAF, 3.2 g, 10 mmol) in tetrahydrofuran (20 mL) were
kept for 30 min at 25 °C. After evaporation of the solvent, the resi-
due was dissolved in water (15 mL), and extracted with diethyl
ether (2 ϫ 10 mL); colorless stars (cryst. from pentanes); m.p.
159Ϫ160 °C (ref.[7] m.p. 148Ϫ149 °C); yield 2.52 g (91%). 1H
NMR: δ ϭ 7.45 (d, J ϭ 8.5 Hz, 1 H), 7.09 (d, J ϭ 8.0 Hz, 1 H)
ppm. 13C NMR: δ ϭ 167.4, 144.2, 143.4, 131.7 (t, J ϭ 258 Hz),
129.1, 115.4, 115.3, 113.4 ppm. The same compound was formed
in a small amount (8%) when piperidine (1.0 mL, 0.85 g, 10 mmol)
and 4-bromo-2,2-difluoro-1,3-benzodioxole (1; 2.4 g, 10 mmol)
were added consecutively to butyllithium (10 mmol) in tetrahydro-
furan (15 mL) and hexanes (5.0 mL) at Ϫ75 °C. The product was
identified by gas chromatography [30 m, DB-Wax, 75 °C (20 min);
30 m, DB-23, 75 °C (20 min)] upon comparison with the
authentic compound.
Being unleashed by the proton abstraction from the 5-
position, the basicity gradient-driven isomerization of the
diiodo compound 11 testifies again the far-reaching acidify-
ing effect of the fluoroalkoxy unit. Iodine atoms hardly ever
stabilize electron excess at adjacent ortho positions. For ex-
ample, 1,3-diiodobenzene is inert toward both LIDA and
lithium 2,2,6,6-tetramethylpiperidide.[10]
Even if this may sometimes be nothing more than an un-
warranted precaution, we often prefer triethylsilyl to tri-
methylsilyl protective groups. Strong bases are known to be
capable of deprotonating the latter, but not the
former.[11Ϫ13] Although in the present study the triethyl(2,2-
difluoro-1,3-benzodioxolan-4-yl)silane (4b) gave excellent
yields of the bromo derivative 5b whatever the base, the
trimethyl analog 4a performed well only toward sec-butyl-
lithium, whereas an inextricable mixture of compounds re-
sulted, including protodesilylation products, when LIDA
was employed. Moreover, the bulkiness of the triethylsilyl
entity appears to facilitate the reaction of the bis(silane) 10b
(R ϭ C2H5) with iodine monochloride. It is complete after
2 h. In contrast, the same iododesilylation of bissilane 10a
(R ϭ CH3) requires 20 h.
(2,2-Difluoro-1,3-benzodioxol-4-yl)trimethylsilane (4a): sec-Butyllith-
ium (0.10 mol) in cyclohexanes (75 mL) and 2,2-difluoro-1,3-benzo-
dioxole (16 g, 0.10 mol) in tetrahydrofuran (0.12 L) were mixed at
Ϫ75 °C. After 2 h in a dry ice/methanol bath, chlorotrimethylsilane
(13 mL, 11 g, 0.10 mol) was added. Distillation under reduced
pressure afforded the product as a colorless liquid; b.p. 64Ϫ66 °C/
1
9 Torr; n2D0 ϭ 1.4587; yield 19.3 g (83%). H NMR: δ ϭ 7.09 (dd,
J ϭ 6.7, 2.2 Hz, 1 H), 7.0 (m, 2 H), 0.34 (s, 9 H) ppm. 13C NMR:
δ ϭ 148.2, 142.6, 131.3 (t, J ϭ 253 Hz), 128.3, 123.3, 121.8, 110.0,
Ϫ1.4 (3 C) ppm. MS (c.i.): m/z (%) ϭ 232 (21) [Mϩ ϩ 2], 231 (10)
[Mϩ
ϩ
1], 230 (51) [Mϩ], 215 (27), 149 (100), 130 (21).
C10H12F2O2Si (230.28): calcd. C 52.16, H 5.25; found C 52.25, H
5.38.
Experimental Section
Details concerning standard operations and abbreviations can be
found in previous publications from this laboratory.[14,15] 1H and
(1H-decoupled) 13C NMR spectra were recorded at 400 and
(2,2-Difluoro-1,3-benzodioxol-4-yl)triethylsilane (4b): Formed anal-
ogously to the procedure above using chlorotriethylsilane (17 mL,
15 g, 0.10 mol); colorless liquid; b.p. 107Ϫ109 °C/14 Torr; nD20
ϭ
1
101 MHz, respectively, with the samples having been dissolved in 1.4737; yield 25.3 g (92%). H NMR: δ ϭ 7.0 (m, 3 H), 1.0 (m, 9
66
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Eur. J. Org. Chem. 2004, 64Ϫ68

Deprotonation-Triggered Heavy-Halogen Migrations
FULL PAPER
H), 0.9 (m, 6 H) ppm. 13C NMR: δ ϭ 148.5, 142.7, 131.2 (t, J ϭ 256 Hz), 130.8, 128.0, 115.7, 113.5, Ϫ1.5 (3 C) ppm. MS (c.i.): m/z
253 Hz), 129.2, 123.3, 119.2, 110.0, 7.2 (3 C), 3.2 (3 C) ppm. MS
(CI): m/z (%) ϭ 273 (19) [Mϩ ϩ 1], 272 (57) [Mϩ], 260 (100), 232
(14). C13H18F2O4Si (272.36): calcd. C 57.33, H 6.66; found C 57.26,
H 6.61.
(%) ϭ 308 (27) [Mϩ], 293 (26), 227 (100), 107 (40). C10H11BrF2O2Si
(309.18): calcd. C 38.85, H 3.59; found C 38.77, H 3.35.
(6-Bromo-2,2-difluoro-1,3-benzodioxol-4-yl)triethylsilane (7b): Pre-
pared analogously using the procedure above, starting from (7-
bromo-2,2-difluoro-1,3-benzodioxol-4-yl)triethylsilane (5b; 8.8 g,
25 mmol); colorless liquid; b.p. 135Ϫ137 °C/11 Torr; n2D0 ϭ 1.5002;
yield 7.48 g (85%). 1H NMR: δ ϭ 7.18 (symm. m, presumably 2 ϫ
d, J ϭ 1.8 Hz, 2 H), 1.0 (m, 9 H), 0.9 (m, 6 H) ppm. 13C NMR:
δ ϭ 147.5, 143.2, 131.5, 131.3 (t, J ϭ 255 Hz), 121.6, 115.8, 113.5,
7.1 (3 C), 3.1 (3 C) ppm. MS (c.i.): m/z (%) ϭ 350 (55) [Mϩ], 321
(100), 293 (36), 227 (46), 199 (62). C13H17BrF2O2Si (351.26): calcd.
C 44.45, H 4.88; found C 44.96, H 4.73.
(7-Bromo-2,2-difluoro-1,3-benzodioxol-4-yl)trimethylsilane
(5a):
(2,2-Difluoro-1,3-benzodioxol-4-yl)trimethylsilane (4a; 11.5 g,
50 mmol) was added to sec-butyllithium (50 mmol) in tetrahydrofu-
ran (60 mL) and cyclohexanes (40 mL) kept in a dry ice/methanol
bath. After 2 h at Ϫ75 °C the reaction mixture was treated with
bromine (2.6 mL, 8.0 g, 50 mmol). Upon distillation, the product
was isolated as a colorless liquid; b.p. 94Ϫ96 °C/7 Torr; nD20
ϭ
1
1.4914; yield 12.8 g (83%). H NMR: δ ϭ 7.18 (d, J ϭ 8.2 Hz, 1
H), 6.96 (d, J ϭ 8.2 Hz, 1 H), 0.34 (s, 9 H) ppm. 13C NMR: δ ϭ
148.2, 141.2, 130.8 (t, J ϭ 256 Hz), 129.3, 128.0, 126.8, 102.3, Ϫ1.5
(3 C) ppm. MS (c.i.): m/z (%) ϭ 308 (34) [Mϩ], 302 (81), 286 (100),
227 (28). C10H11BrF2O2Si (309.18): calcd. C 38.85, H 3.59; found
C 39.18, H 3.48.
5-Bromo-2,2-difluoro-1,3-benzodioxole (8): (6-Bromo-2,2-difluoro-
1,3-benzodioxol-4-yl)triethylsilane (7b; 3.5 g, 10 mmol) and TBAF
(3.2 g, 10 mmol) in tetrahydrofuran (20 mL) were kept for 30 min
at 25 °C. After evaporation of the solvent, the residue was dissolved
in water (15 mL), and extracted with diethyl ether (2 ϫ 10 mL).
Upon distillation under reduced pressure, a colorless liquid was
collected; b.p. 58Ϫ60 °C/10 Torr; n2D0 ϭ 1.4718 (ref.[16] b.p. 78Ϫ79
°C/20 Torr; n2D0 ϭ 1.4722); yield 1.86 g (79%).
(7-Bromo-2,2-difluoro-1,3-benzodioxol-4-yl)triethylsilane (5b): Pre-
pared analogously using the procedure above, starting from (2,2-
difluoro-1,3-benzodioxol-4-yl)triethylsilane (4b; 13.6 g, 50 mmol);
colorless liquid; b.p. 138Ϫ140 °C/16 Torr; n2D0 ϭ 1.5084; yield 16.6 g
(95%). 1H NMR: δ ϭ 7.19 (d, J ϭ 8.2 Hz, 1 H), 6.96 (d, J ϭ
8.4 Hz, 1 H), 1.0 (m, 9 H), 0.9 (m, 6 H) ppm. 13C NMR: δ ϭ 148.5,
141.3, 130.7 (t, J ϭ 256 Hz), 130.1, 126.9, 118.0, 102.3, 7.2 (3 C),
3.1 (3 C) ppm. MS (c.i.): m/z (%) ϭ 350 (10) [Mϩ], 341 (56), 338
(55), 250 (27). C13H17BrF2O2Si (351.26): calcd. C 44.45, H 4.88;
found C 44.93, H 4.84.
(6-Bromo-2,2-difluoro-7-iodo-1,3-benzodioxol-4-yl)triethylsilane
(9b): Diisopropylamine (9.1 mL, 6.6 g, 65 mmol) and (6-bromo-
2,2-difluoro-1,3-benzodioxol-4-yl)triethylsilane (5b; 23 g, 65 mmol)
were added consecutively to a solution of butyllithium (65 mmol)
in tetrahydrofuran (0.12 L) and hexanes (45 mL) kept in a dry ice/
methanol bath. After 2 h at Ϫ75 °C, a solution of iodine (16 g,
65 mmol) in tetrahydrofuran (40 mL) was added. The solvents were
evaporated and the residue was dissolved in diethyl ether (0.10 L).
After washing with 10% aqueous sodium thiosulfate (50 mL), the
organic layer was dried before being evaporated to dryness. Color-
less cubes were obtained upon crystallization from methanol; m.p.
5-Bromo-2,2-difluoro-7-trimethylsilyl-1,3-benzodioxole-4-carboxylic
Acid (6a): Diisopropylamine (3.5 mL, 2.5 g, 25 mmol) and (7-
bromo-2,2-difluoro-1,3-benzodioxol-4-yl)trimethylsilane (5a; 7.7 g,
25 mmol) were added consecutively to butyllithium (25 mmol) in
tetrahydrofuran (35 mL) and hexanes (13 mL). After 2 h at Ϫ75
°C, the mixture was poured onto an excess of freshly crushed car-
bon dioxide. Extraction with dichloromethane (50 mL) and, after
acidification to pH 1, with diethyl ether (3 ϫ 30 mL) followed by
evaporation and crystallization from hexanes gave colorless
1
34Ϫ35.5 °C; yield 22.6 g (73%). H NMR: δ ϭ 7.35 (s, 1 H), 1.0
(m, 9 H), 0.9 (m, 6 H) ppm. 13C NMR: δ ϭ 146.0, 145.3, 131.9,
130.3 (t, J ϭ 257 Hz), 123.7, 121.1, 80.6, 7.1 (3 C), 2.9 (3 C) ppm.
C13H16BrF2IO2Si (477.16): calcd. C 32.72, H 3.38; found C 32.84,
H 3.41.
1
needles; m.p. 134Ϫ135 °C; yield 7.21 g (82%). H NMR: δ ϭ 7.39
(s, 1 H), 0.37 (s, 9 H) ppm. 13C NMR: δ ϭ 167.5, 147.6, 142.8,
133.4, 131.4 (t, J ϭ 253 Hz), 127.9, 115.3, 115.1, Ϫ1.7 (3 C) ppm.
MS (c.i.): m/z (%) ϭ 370 (31) [Mϩ ϩ NH4], 352 (100) [Mϩ], 337
(67), 271 (58). C11H11BrF2O4Si (353.19): calcd. C 37.41, H 3.14;
found C 37.65, H 2.82.
2,2-Difluoro-4,7-bis(trimethylsilyl)-1,3-benzodioxole (10a): Diiso-
propylamine (14 mL, 10 g, 0.10 mol), 2,2-difluoro-1,3-benzodiox-
ole (7.9 g, 50 mmol), and chlorotrimethylsilane (13 mL, 11 g, 0.10
mol) were added consecutively to butyllithium (100 mmol) in hex-
anes (50 mL) and tetrahydrofuran (50 mL). After 2 h at Ϫ75 °C,
direct distillation under reduced pressure gave a colorless liquid
that slowly crystallized upon standing; m.p. 35Ϫ36 °C; b.p. 89Ϫ91
°C/10 Torr; yield 12.8 g (85%). 1H NMR: δ ϭ 7.07 (s, 2 H), 0.33
(s, 18 H) ppm. 13C NMR: δ ϭ 147.1 (2 C), 131.0 (t, J ϭ 253 Hz),
127.9 (2 C), 122.2 (2 C), Ϫ1.4 (6 C) ppm. MS (c.i.): m/z (%) ϭ 303
(37) [Mϩ ϩ 1], 302 (100) [Mϩ], 301 (56) [Mϩ Ϫ 1], 287 (54), 221
(35), 193 (66). C13H20F2O2Si2 (302.46): calcd. C 51.62, H 6.66;
found C 51.65, H 6.79.
5-Bromo-2,2-difluoro-7-triethylsilyl-1,3-benzodioxole-4-carboxylic
Acid (6b): Prepared analogously using the procedure above, starting
from (7-bromo-2,2-difluoro-1,3-benzodioxol-4-yl)triethylsilane (5b;
8.8 g, 25 mmol); colorless prisms (from pentanes); m.p. 142Ϫ144
1
°C; yield 8.12 g (82%). H NMR: δ ϭ 7.37 (s, 1 H), 1.0 (m, 9 H),
0.9 (m, 6 H) ppm. 13C NMR: δ ϭ 167.4, 147.8, 142.8, 134.1, 131.3
(t, J ϭ 258 Hz), 125.7, 115.3, 115.1, 7.1 (3 C), 2.9 (3 C) ppm.
C14H17BrF2O4Si (395.27): calcd. C 42.54, H 4.33; found C 42.83,
H 4.19.
(6-Bromo-2,2-difluoro-1,3-benzodioxol-4-yl)trimethylsilane (7a): Di- 2,2-Difluoro-4,7-bis(triethylsilyl)-1,3-benzodioxole (10b): Prepared
isopropylamine (3.5 mL, 2.5 g, 25 mmol) and (7-bromo-2,2-di- analogously using the procedure described above, using chlorotri-
fluoro-1,3-benzodioxol-4-yl)trimethylsilane (5a; 7.7 g, 25 mmol) ethylsilane (17 mL, 15 g, 0.10 mol); colorless liquid; b.p. 165Ϫ167
1
were added consecutively to butyllithium (25 mmol) in tetrahydrofu- °C/9 Torr; n2D0 ϭ 1.4865; yield 16.0 g (83%). H NMR: δ ϭ 7.05 (s,
ran (35 mL) and hexanes (13 mL). After 2 h at Ϫ75 °C, the mixture 2 H), 1.0 (m, 18 H), 0.9 (m, 12 H) ppm. 13C NMR: δ ϭ 147.4 (2
was treated with methanol (5.0 mL). Direct distillation gave a color-
C), 130.9 (t, J ϭ 253 Hz), 128.8 (2 C), 119.6 (2 C), 7.3 (6 C), 3.2
less liquid; b.p. 86Ϫ88 °C/7 Torr; n2D0 ϭ 1.4916; yield 6.62 g (86%). (6 C) ppm. MS (c.i.): m/z (%) ϭ 387 (25) [Mϩ ϩ 1], 386 (64) [Mϩ],
1H NMR: δ ϭ 7.18 (symm. m, presumably 2 ϫ d, J ϭ 2.0 Hz, 2 357 (100), 235 (38), 207 (58). C19H32F2O2Si2 (386.62): calcd. C
H), 0.34 (s, 9 H) ppm. 13C NMR: δ ϭ 147.2, 143.2, 131.4 (t, J ϭ
www.eurjoc.org
59.02, H 8.34; found C 58.54, H 8.38.
Eur. J. Org. Chem. 2004, 64Ϫ68
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
67

J. Gorecka, F. Leroux, M. Schlosser
FULL PAPER
2,2-Difluoro-4,7-diiodo-1,3-benzodioxole (11): A mixture of 2,2-di-
2,2-Difluoro-5-iodo-1,3-benzodioxole (15): 2,2-Difluoro-4,6-diiodo-
fluoro-4,7-bis(trimethylsilyl)-1,3-benzodioxole (10a; 15 g, 50 mmol) 1,3-benzodioxole (13; 4.0 g, 10 mmol) was added to butyllithium
and iodine monochloride (5.0 mL, 16 g, 0.10 mol) in tetrachloro-
methane (50 mL) was heated under reflux for 20 h. After washing
(10 mmol) in hexanes (5.1 mL) and tetrahydrofuran (15 mL) at Ϫ75
°C. After 45 min at Ϫ75 °C, methanol (5.0 mL, 0.12 mol) was in-
with sodium thiosulfate solution (2 ϫ 20 mL), the organic phase jected. Distillation under reduced pressure afforded a colorless
1
was dried and the solvents evaporated; colorless needles (from pen-
liquid; b.p. 70Ϫ71 °C/6 Torr; n2D0 ϭ 1.5416; yield 1.72 g (62%). H
1
tanes); m.p. 110Ϫ111 °C; yield 19.3 g (95%). H NMR: δ ϭ 7.15 NMR: δ ϭ 7.42 (dd, J ϭ 8.3, 1.6 Hz, 1 H), 7.40 (d, J ϭ 1.6 Hz, 1
(s, 2 H) ppm. 13C NMR: δ ϭ 144.7 (2 C), 133.6 (2 C), 129.3 (t,
J ϭ 258 Hz), 70.8 (2 C) ppm. MS (c.i.): m/z (%) ϭ 411 (8) [Mϩ
H), 6.84 (d, J ϭ 8.3 Hz, 1 H) ppm. 13C NMR: δ ϭ 144.3, 143.7,
132.6, 131.3 (t, J ϭ 258 Hz), 118.6, 111.3, 84.6 ppm. MS (c.i.): m/
ϩ
1], 410 (100) [Mϩ], 409 (90) [Mϩ Ϫ 1], 344 (5), 189 (10). z (%) ϭ 285 (14) [Mϩ ϩ 1], 284 (100) [Mϩ], 218 (15), 158 (7).
C7H2F2I2O2 (409.90): calcd. C 20.51, H 0.49; found C 20.49, H
0.59. The same product was obtained in 94% yield (18.9 g) after
heating 2,2-difluoro-4,7-bis(triethylsilyl)-1,3-benzodioxole (10b;
19 g, 50 mmol) and iodine monochloride (5.0 mL, 16 g, 0.10 mol)
in tetrachloromethane (50 mL) for 1 h under reflux.
C7H3F2IO2 (284.00): calcd. C 29.60, H 1.06; found C 29.71, H 1.14.
2,2-Difluoro-6-iodo-1,3-benzodioxole-4-carboxylic Acid (16): 2,2-Di-
fluoro-4,6-diiodo-1,3-benzodioxole (13; 4.0 g, 10 mmol) was added
to butyllithium (10 mmol) in tetrahydrofuran (15 mL) and hexanes
(5.0 mL) at Ϫ75 °C. After 45 min at Ϫ75 °C, the reaction mixture
was poured onto an excess of freshly crushed carbon dioxide. Ex-
traction with dichloromethane (20 mL) and, after acidification of
the aqueous phase to pH 1, with diethyl ether (3 ϫ 10 mL), fol-
lowed by evaporation and crystallization from chloroform, gave
colorless prisms; m.p. 167Ϫ168 °C; yield 2.36 g (72%). 1H NMR
(CD3COCD3): δ ϭ 7.85 (d, J ϭ 8.5 Hz, 1 H), 7.25 (d, J ϭ 8.5 Hz,
1 H) ppm. 13C NMR (CD3COCD3): δ ϭ 164.8, 145.6, 143.5, 137.6,
133.1 (t, J ϭ 255 Hz), 124.2, 115.0, 86.5 ppm. MS (c.i.): m/z (%) ϭ
329 (47) [Mϩ ϩ 1], 328 (100) [Mϩ], 245 (11). C8H3F2IO4 (328.01):
calcd. C 29.29, H 0.92; found C 29.13, H 0.99.
2,2-Difluoro-7-iodo-1,3-benzodioxole-4-carboxylic Acid (12): 2,2-Di-
fluoro-4,7-diiodo-1,3-benzodioxole (4.1 g, 10 mmol) was added to
butyllithium (10 mmol) in tetrahydrofuran (15 mL) and hexanes
(5.0 mL) at Ϫ75 °C. Immediately afterwards, the reaction mixture
was poured onto an excess of freshly crushed carbon dioxide. Ex-
traction with dichloromethane (25 mL) and, after acidification of
the aqueous phase to pH 1, with diethyl ether (3 ϫ 15 mL), fol-
lowed by evaporation and crystallization from chloroform, gave
1
colorless needles; m.p. 201Ϫ202 °C; yield 2.52 g (77%). H NMR
(CD3COCD3): δ ϭ 7.69 (d, J ϭ 8.6 Hz, 1 H), 7.53 (d, J ϭ 8.6 Hz,
1 H) ppm. 13C NMR (CD3COCD3): δ ϭ 164.4, 148.2, 143.6, 134.4,
132.5 (t, J ϭ 256 Hz), 128.4, 116.4, 78.6 ppm. MS (c.i.): m/z (%) ϭ
329 (53) [Mϩ ϩ 1], 328 (100) [Mϩ], 311 (11), 262 (35), 245 (24), 79
(16). C8H3F2IO4 (328.01) calcd. C 29.29, H 0.92; found C 29.49,
H 0.98. Acid 12 (2.10 g, 64%) was also obtained when 2,2-difluoro-
4-iodo-1,3-benzodioxole[8] (2.8 g, 10 mmol) was treated consecu-
tively with lithium diisopropylamide (10 mmol) in tetrahydrofuran
(15 mL) and hexanes (5.0 mL), for 2 h at Ϫ100 °C, and dry ice.
Acknowledgments
This work was supported financially by the Schweizerische Nation-
alfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20Ϫ55Ј303Ϫ98) and the Bundesamt für Bildung und Wis-
senschaft, Bern (grant 97.0083 linked to the TMR project
FMRXCT-970129).
2,2-Difluoro-4,6-diiodo-1,3-benzodioxole (13): Diisopropylamine
(1.4 mL, 1.0 g, 10 mmol) and 2,2-difluoro-4,7-diiodo-1,3-benzo-
dioxole (11; 4.0 g, 10 mmol) were added consecutively to butyllith-
ium (10 mmol) in tetrahydrofuran (15 mL) and hexanes (5.1 mL)
kept in a dry ice/methanol bath. After 2 h at Ϫ75 °C, methanol
(5.0 mL, 0.10 mol) was injected. Upon steam distillation, a yellow
liquid was collected that crystallized from pentanes; colorless
[1]
F. Mongin, O. Desponds, M. Schlosser, Tetrahedron Lett. 1996,
37, 2767Ϫ2770.
[2]
M. Schlosser, in Organometallics in Synthesis: A Manual (Ed.:
M. Schlosser), 2nd edition, Wiley, Chichester, 2002, pp. 1Ϫ352,
see p. 252Ϫ265.
F. Mongin, E. Marzi, M. Schlosser, Eur. J. Org. Chem. 2001,
2771Ϫ2777.
T. Rausis, M. Schlosser, Eur. J. Org. Chem. 2002, 3351Ϫ3358.
P. Ackermann, H.-R. Känel, B. Schaub, Eur. Pat. Appl. EP
333658 (to Ciba Geigy; filed on 20 Sept. 1989); Chem. Abstr.
1990, 112, 13901n.
B. Schaub, H.-R. Känel, P. Ackermann, Eur. Pat. Appl. EP
333661 (to Ciba Geigy; filed on 20 Sept. 1989); Chem. Abstr.
1990, 112, 12901n.
E. Castagnetti, M. Schlosser, Eur. J. Org. Chem. 2001,
691Ϫ695.
M. Schlosser, J. Gorecka, E. Castagnetti, Eur. J. Org. Chem.
[3]
[4]
1
prisms; m.p. 51Ϫ52 °C; yield 3.44 g (86%). H NMR: δ ϭ 7.74 (d,
[5]
J ϭ 1.5 Hz, 1 H), 7.34 (d, J ϭ 1.5 Hz, 1 H) ppm. 13C NMR: δ ϭ
146.0, 142.8, 140.0, 130.2 (t, J ϭ 258 Hz), 118.4, 85.4, 72.2 ppm.
MS (c.i.): m/z (%) ϭ 411 (8) [Mϩ ϩ 1], 410 (87) [Mϩ], 206 (25),
189 (100), 188 (43). C7H2F2I2O2 (409.90): calcd. C 20.51, H 0.49;
found C 20.18, H 0.64.
[6]
[7]
2,2-Difluoro-5,7-diiodo-1,3-benzodioxole-4-carboxylic Acid (14):
The reaction mixture obtained by consecutive addition of diisopro-
pylamine (3.2 mL, 2.5 g, 25 mmol) and 2,2-difluoro-4,7-diiodo-1,3-
benzodioxole (11; 10 g, 25 mmol) in tetrahydrofuran (35 mL) and
hexanes (15 mL) was poured, after 2 h at Ϫ75 °C, onto an excess
of freshly crushed dry ice. After evaporation of the volatiles, the
residue was treated with 2.0  hydrochloric acid (20 mL) and the
solid material collected by filtration. Crystallization from chloro-
form gave colorless prisms; m.p. 224Ϫ226 °C; yield 10.0 g (91%).
1H NMR: δ ϭ 8.18 (s, 1 H) ppm. 13C NMR: δ ϭ 163.7, 147.3,
143.8, 141.2, 131.2 (t, J ϭ 258 Hz), 121.6, 87.0, 76.4 ppm. MS (c.i.):
m/z (%) ϭ 455 (15) [Mϩ ϩ 1], 454 (100) [Mϩ], 453 (86) [Mϩ Ϫ 1],
371 (11), 77 (13). C8H2F2I2O4 (453.90): calcd. C 21.17, H 0.44;
found C 21.23, H 0.97.
[8]
2003, 452Ϫ462.
[9]
M. Schlosser, L. Guio, F. Leroux, J. Am. Chem. Soc. 2001,
123, 3822Ϫ3823.
[10]
C. Heiss, E. Marzi, M. Schlosser, Eur. J. Org. Chem. 2003,
4625Ϫ4629.
A. Mordini, M. Schlosser, Chimia 1986, 40, 309Ϫ310.
J. E. Macdonald, G. S. Poindexter, Tetrahedron Lett. 1987,
28, 1851Ϫ1852.
F. Mongin, M. Schlosser, unpublished results.
[11]
[12]
[13]
[14]
C. Heiss, M. Schlosser, Eur. J. Org. Chem. 2003, 447Ϫ451.
[15]
M. Schlosser, M. Marull, Eur. J. Org. Chem. 2003, 1569Ϫ1575.
[16]
E. L. Stogryn, J. Org. Chem. 1972, 37, 673Ϫ673.
Received September 2, 2003
68
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 64Ϫ68