A homologous series of O- and N-functionalized 2,2-difluoro-1,3-benzodioxoles: An exercise in organometallic methodology

Article abstract of DOI:10.1002/ejoc.200390079

The conversion of 2,2-difluoro-1,3-benzodioxole, an exceptionally acidic arene, via a 4-lithiated intermediate into more than three dozen new derivatives was conceived as a case study. The lithiated species was trapped by C₀-electrophiles (4-toluenesulfonyl azide, fluorodimethoxyborane, iodine), C₁-electrophiles (carbon dioxide, N,N-dimethylformamide, formaldehyde, dimethyl sulfate), C₂-electrophiles (oxalic acid diesters, oxirane), C₃-electrophiles (oxetane), and higher alkyl iodides. The resulting carboxylic acid 1a may be treated with organolithium compounds to afford ketones (e.g. 10) and the aldehyde 9 can be condensed with nitromethane or acetic anhydride under basic conditions. If not oxidized with chromium trioxide to the corresponding carboxylic acids, the alcohols 2b, 2c, and 2d can be transformed into the corresponding bromides (12) or sulfonates (13). Their condensation with nitrogen-containing C₀-nucleophiles (hydroxylamine, sodium azide, potassium phthalimide), C₁-nucleophiles (potassium cyanide), and C₂-nucleophiles (aceto-nitrile) opens a convenient access to the amines 3. Other reactions gave, despite a proven track record in other areas, only moderate yields. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390079

FULL PAPER
A Homologous Series of O- and N-Functionalized 2,2-Difluoro-
1,3-benzodioxoles: an Exercise in Organometallic Methodology
Manfred Schlosser,*[a,b] Joanna Gorecka,[a] and Eva Castagnetti[a]
Keywords: Lithiation / Alcohols / Aldehydes / Acids / Amines
The conversion of 2,2-difluoro-1,3-benzodioxole, an excep- with chromium trioxide to the corresponding carboxylic ac-
tionally acidic arene, via a 4-lithiated intermediate into more
than three dozen new derivatives was conceived as a case
study. The lithiated species was trapped by C0-electrophiles
(4-toluenesulfonyl azide, fluorodimethoxyborane, iodine),
C1-electrophiles (carbon dioxide, N,N-dimethylformamide,
formaldehyde, dimethyl sulfate), C2-electrophiles (oxalic
acid diesters, oxirane), C3-electrophiles (oxetane), and
higher alkyl iodides. The resulting carboxylic acid 1a may be
treated with organolithium compounds to afford ketones (e.g.
10) and the aldehyde 9 can be condensed with nitromethane
or acetic anhydride under basic conditions. If not oxidized
ids, the alcohols 2b, 2c, and 2d can be transformed into the
corresponding bromides (12) or sulfonates (13). Their con-
densation with nitrogen-containing C0-nucleophiles (hy-
droxylamine, sodium azide, potassium phthalimide), C1-nu-
cleophiles (potassium cyanide), and C2-nucleophiles (aceto-
nitrile) opens a convenient access to the amines 3. Other
reactions gave, despite a proven track record in other areas,
only moderate yields.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
In the literal sense, ‘‘methodology’’ means the knowledge
of methods and, by extension, also their critical evaluation.
Organometallic reactions have become favorite tools of
modern organic synthesis, and therefore we deemed it ap-
propriate to embark on a systematic investigation of how
efficiently metal-bearing intermediates can be func-
tionalized and chain-lengthened. In other words, rather
than scrutinize various possibilities for the generation of or-
ganometallic species,[1] we wanted this time to put elec-
trophiles, in particular carboelectrophiles, to the test.
2,2-Difluoro-1,3-benzodioxole, a technical bulk product,
was selected as the substrate for structural elaboration, as
it undergoes metalation at the 4-position with extraordinary
ease.[2] We set ourselves the task to explore, in a compara-
tive study, the various ways for converting it into the carb-
oxylic acids 1, the phenolic or alcoholic hydroxy derivatives
2 and the aromatic or aliphatic amines 3.
81% yield.[3] As this reaction is of unmatched simplicity, we
did not attempt to find a second route to product 1a.
Results
Carboxylic Acids
The carboxylation of (2,2-difluoro-1,3-benzodioxol-4-yl)-
lithium has already been reported to afford the acid 1a in
[a]
Institute of Chemistry and Molecular Sciences, Ecole
´ ´
Polytechnique Federale, BCh
1015 Lausanne, Switzerland
[b]
´
Institut de Cristallographie, BSP, Universite
1015 Lausanne, Switzerland
E-mail: manfred.schlosser@epfl.ch
452
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0452 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 452Ϫ462

A Homologous Series of O- and N-Functionalized 2,2-Difluoro-1,3-benzodioxoles
FULL PAPER
An expedient transformation was achieved when the 4-
lithiated 2,2-difluoro-1,3-benzodioxole was trapped with di-
ethyl oxalate and the resulting α-oxo ester 4 (83%) sub-
sequently submitted to a WolffϪKishnerϪHuang reduction
and concomitant saponification to (2,2-difluoro-1,3-benzo-
dioxol-4-yl)acetic acid (1b; 82%). The latter compound
could also be prepared in a most straightforward manner
by Jones oxidation of 2-(2,2-difluoro-1,3-benzodioxol-4-
yl)ethanol (2c)[3] or by hydrolysis of (2,2-difluoro-1,3-
benzodioxol-4-yl)acetonitrile (20b; see below). In contrast,
the attempted conversion of the aromatic acid 1a into its
rearranged homolog 1b by means of the ArndtϪEistert se-
quence failed completely.
sium cyanide to give the nitrile 20c (87% and 88%, respect-
ively), the alkaline hydrolysis of which produced the acid 1c
(82%). The same compound was obtained by submitting
the aldehyde 9 to a Perkin condensation. The resulting α,β-
unsaturated acid
6
(88%), also accessible by
a
HeckϪMorizawa reaction between 2,2-difluoro-4-iodo-1,3-
benzodioxole (11) and acrylic acid in 96% yield, was either
completely reduced to the arylpropanol 2d (84%), which
then had to be reoxidized to the acid 1c (92%), or the latter
was obtained in 99% yield by partial hydrogenation of the
unsaturated acid 6. Finally, acid 1c was isolated in 48%
yield after the bromo compound 12c was subjected to a
substitution[12,13] reaction with disodium tetracarbonyl-
ferrate followed by oxidation with air.
The acid 1b and the alcohol 2c could be finally accessed
via 2,2-difluoro-4-methyl-1,3-benzodioxole (8), readily ob-
tained by condensation of the lithiated intermediate with
dimethyl sulfate in 71% yield. Deprotonation with lithium
diisopropylamide (LIDA) in the presence of potassium tert-
butoxide (KOR),[4Ϫ8] followed by carboxylation or by addi-
tion to formaldehyde, gave the products 1b (71%) and 2c
(35%), respectively. However, substrate 8 offered another
impressive example of ‘‘optional site selectivity’’.[9Ϫ11]
When LIDA/KOR was replaced by either sec-butyllithium
or lithium 2,2,6,6-tetramethylpiperidide (LITMP) in the
presence of N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine
(PMDTA) and potassium tert-butoxide as the base, proton
abstraction occurred exclusively at the aromatic 7-position.
Consequently, the acid 5 (93%) and the benzyl alcohol 7
(64%) were formed with carbon dioxide and formalde-
hyde, respectively.
Alcohol 2c was also the starting point for an expedient
preparation of the next higher acid homologue 1c. The cor-
responding bromide 12c and benzenesulfonate 13c (Bes ϭ
SO2C6H5) underwent nucleophilic substitution with potas-
Eur. J. Org. Chem. 2003, 452Ϫ462
453

M. Schlosser, J. Gorecka, E. Castagnetti
FULL PAPER
The 3-aryl-1-propanol 2d was converted via the corres- the alcohol 2c in almost quantitative yield (85% being isol-
ponding benzenesulfonate 13d (OBes ϭ OSO2C6H5) into
the nitrile 20d (82%) in the same way as described above
for the lower homolog 20c. Alkaline hydrolysis of nitrile
20d afforded the acid 1d (87%).
ated). Alternatively, alcohol 2c was found to be accessible
in 35% yield by deprotonation of the methyl derivative 8 at
the benzylic position (see above), followed by the addition
of paraformaldehyde.
Phenols and Alcohols
The phenol 2a was readily prepared by consecutive
lithiation, borylation (using fluorodimethoxyborane[14,15]),
and oxidation. Product 2a was isolated in high yield (92%)
and purity.
The homologous 3-(2,2-difluoro-1,3-benzodioxol-4-yl)-
propanol (2d; 72%) was prepared similarly by benzylic de-
protonation of 2,2-difluoro-4-methyl-1,3-benzodioxole (8)
followed by addition to oxirane. Alternatively, alcohol 2d
could be prepared by the reaction of (2,2-difluoro-1,3-
benzodioxol-4-yl)lithium with oxetane in 41% yield. Finally,
the Perkin condensation product 6 was cleanly reduced with
lithium aluminum hydride to the alcohol 2d (84%).
The benzyl alcohol 2b was formed in only moderate yield
(27%) when the lithiated species was treated with paraform-
aldehyde. It proved preferable to formylate the intermediate
with N,N-dimethylformamide to obtain, after hydrolysis,
the aldehyde 9 (88%), which then was reduced with sodium
borohydride in methanol to the alcohol 2b (95%).
A chain length of three methylene units does not set
limits for the accessibility of ω-(2,2-difluoro-1,3-benzo-
dioxol-4-yl)alkanols. To prepare higher homologs one has
simply to replace oxirane or oxetane by suitably acetal-
protected ω-haloalkanols.[16] Thus, 1-iodo-4-(methoxy-
methoxy)butane was smoothly condensed with the 4-
lithiated 2,2-difluoro-1,3-benzodioxole to afford, after
deprotonation with acid, the alcohol 2e in 18% yield.
Alcohol 2c has previously been prepared by the reaction
with oxirane in only 54% yield.[3] Apparently, the organo-
lithium intermediate acts as both a nucleophile and as a base,
thus causing deprotonation of the electrophile and ring-
opening to the acetaldehyde enolate. The supernucleophilic,
but only marginally basic, cuprates avoid this kind of prob-
lem. Readily prepared by treatment of the lithium species
with cuprous iodide, the resulting copper reagent afforded
454
Eur. J. Org. Chem. 2003, 452Ϫ462

A Homologous Series of O- and N-Functionalized 2,2-Difluoro-1,3-benzodioxoles
FULL PAPER
The poor yield suggests the occurrence of β-eliminations
and other side reactions. Improved results could presum-
ably be achieved by first attaching an (ωϪ1)-alkenyl side
chain[17] and its subsequent hydroboration and oxidation.
Aromatic and Aliphatic Amines
Using lithium methoxyamide,[18Ϫ20] (2,2-difluoro-1,3-
benzodioxol-4-yl)lithium could be directly converted into
the aniline 3a although only in moderate yield (40%). The
more lengthy route through the ketone 10 (68% from the
carboxylic acid 1a), condensation with hydroxylamine and
Beckmann rearrangement of the resulting oxime 18 (84%)
proved to be more expedient (83% of 3a in the last step).
Superior still was the reaction of the organolithium inter-
mediate with p-toluenesulfonyl azide followed by the reduc-
tion of the azido derivative 14a (94%) to the amine 3a
(80%).
Similar principles were applied to prepare the homolog-
ous amine 3c. This compound was obtained by reduction
of the nitrile 20b (86% from the benzyl bromide 12b) and
by hydrazinolysis of the phthalimide 15c (86% from the al-
cohol 2c via the bromide 12c or sulfonate 13c) in 89% and
77% yield, respectively. In addition, a Henry condensation
was accomplished between the aldehyde 9 and nitrometh-
ane, and the nitro compound 16 (75%) thus formed was
catalytically hydrogenated to the amine 3c (89%).
The most straightforward route to the benzylamine 3b
proceeds via the aldehyde 9 and the oxime 17 (96%). The
latter compound was reduced to 3b either with lithium alu-
The sequences aiming at the amine 3d also featured a
minum hydride (89%) or by catalytic hydrogenation (93%). method not yet tested in the given context. Acetonitrile was
The detour via the nitrile 20a (91% by dehydration with deprotonated[21Ϫ23] particularly smoothly when the su-
cyanuric chloride in the presence of pyridine) did not offer perbasic mixture of lithium diisopropylamide and potas-
any practical advantage. Nevertheless, nitrile 20a, readily sium tert-butoxide (LIDA/KOR[4Ϫ8]) or of butyllithium and
accessible (in 91% yield) by dehydration of the carboxamide potassium tert-butoxide (LIC/KOR[24Ϫ26]) was applied and
19 (from the carboxylic acid 1a through the acyl chloride the metal keteneimide was alkylated[22,27] with the bromide
and concentrated aqueous ammonia in 92% yield), could 12b (from 8 in 65% yield) to afford the nitrile 20c in moder-
be smoothly reduced with lithium aluminum hydride to give ate yield (58%). This precursor to the amine 3d (92% by
the amine 3b (86%). Direct reduction of carboxamide 19 reduction with lithium aluminum hydride) could also be ef-
with lithium aluminum hydride afforded the amine 3b in ficaciously prepared by nucleophilic substitution of the sul-
80% yield. Attempts to subject the carboxamide 19 to a fonate 13c or the bromide 12c, as already mentioned above.
Hofmann rearrangement failed completely. Finally, amine The final remaining option was the replacement of the hy-
3b could also be obtained by means of the Gabriel method. droxy group in alcohol 2d by the amino function. For sake
Starting from the benzyl alcohol 2b or 2,2-difluoro-4- of variation, the sulfonate 13d was this time treated with
methyl-1,3-benzodioxole (8), the benzyl bromide 12b (86%) sodium azide rather than with potassium phthalimide. The
or sulfonate 13b (89%) and the N-alkylphthalimide 15b resulting azido compound 14d (85%) was eventually trans-
(75%) were the intermediates.
formed into amine 3d (93%) by catalytic hydrogenation.
Eur. J. Org. Chem. 2003, 452Ϫ462
455

M. Schlosser, J. Gorecka, E. Castagnetti
FULL PAPER
As can be deduced from the reactions presented above,
the cyano group is evidently the optimal precursor function
to a primary amino group. It can be introduced quite read-
ily by an SN2 process using potassium cyanide or the an-
ionized acetonitrile as a C1- and C2-nucleophile, respect-
ively. The transition metal catalyzed addition of hydrogen
cyanide to olefinic double bonds,[28Ϫ32] an economically
most attractive option, should not remain unmentioned in
this context.
Experimental Section
General: Details concerning standard operations and abbreviations
can be found in previous publications from this laboratory.[33Ϫ35]
1H and 13C NMR spectra were recorded at 400 and 101 MHz, re-
spectively, samples having been dissolved in deuterochloroform.
1. Carboxylic Acids and Esters
2,2-Difluoro-1,3-benzodioxole-4-carboxylic Acid (1a): The synthesis
of 1a has already been reported.[3] It was obtained by the consecu-
tive reaction of 2,2-difluoro-1,3-benzodioxole with sec-butyllithium
and dry ice in 81% yield.
Methyl 2,2-Difluoro-1,3-benzodioxole-4-carboxylate: A solution of
2,2-difluoro-1,3-benzodioxole-4-carboxylic acid[3] (1a; 10 g,
50 mmol) and boron trifluorideϪdiethyl etherate (6.3 mL, 7.1 g,
50 mmol) was allowed to stand for 48 h at ϩ25 °C. Distillation
afforded a colorless liquid which solidified in an ice bath; needles;
m.p. 14Ϫ15 °C; b.p. 100Ϫ102 °C/14 Torr; n2D0 ϭ 1.4800; yield: 9.7 g
(90%). 1H NMR: δ ϭ 7.69 (dd, J ϭ 8.2, 1.4 Hz, 1 H), 7.25 (dd,
J ϭ 8.1, 1.4 Hz, 1 H), 7.15 (t, J ϭ 8.0 Hz, 1 H), 3.97 (s, 3 H) ppm.
13C NMR: δ ϭ 163.5, 144.5, 143.5, 131.8 (t, J ϭ 257 Hz), 125.1,
123.3, 114.2, 113.5, 52.5 ppm. C9H6F2O4 (216.14): calcd. C 50.01,
H 2.80; found C 49.87, H 2.67. The methyl ester was formed di-
rectly in a yield of 81% when a solution of 2,2-difluoro-1,3-benzo-
dioxole (2.9 mL, 4.0 g, 25 mmol) and sec-butyllithium (25 mmol)
in tetrahydrofuran (30 mL) and cyclohexane (15 mL), after having
been kept at Ϫ75 °C for 2 h, was transferred dropwise, in the course
of 20 min, through a cannula into a solution of methyl chloro-
formate (5.0 mL, 6.1 g, 65 mmol) in tetrahydrofuran (20 mL), kept
in a methanol/dry ice bath. Immediate distillation gave a colorless
liquid; yield: 4.32 g (81%).
(2,2-Difluoro-1,3-benzodioxol-4-yl)acetic Acid (1b): 2-(2,2-Difluoro-
1,3-benzodioxol-4-yl)ethanol[3] (2c; 2.0 g, 10 mmol) in acetone
(50 mL) was added to potassium dichromate (5.9 g, 20 mmol) in
50% aqueous sulfuric acid (10 mL), cooled in an ice bath. After 1 h
at 0 °C, the mixture was concentrated before being poured into
water (0.10 L) and extracted with diethyl ether (3 ϫ 25 mL). The
combined organic layers were washed with brine (2 ϫ 25 mL),
dried, and concentrated. The residue was crystallized from hexanes;
colorless star-shaped crystals; m.p. 88Ϫ89 °C; b.p. 144Ϫ146 °C/
The higher homolog 3e was also found to be readily ac-
cessible. All it needed was again to convert the alcohol 2d,
via the corresponding bromide 12d (88%), into the cyanide
20d (91%) and to reduce the latter with lithium aluminum
hydride to the desired amine 3e (94%).
1
6 Torr; yield: 1.79 g (82%). H NMR: δ ϭ 7.0 (m, 3 H), 3.73 (s, 2
H) ppm. 13C NMR: δ ϭ 176.1, 143.5, 142.5, 131.3 (t, J ϭ 250 Hz),
456
Eur. J. Org. Chem. 2003, 452Ϫ462

A Homologous Series of O- and N-Functionalized 2,2-Difluoro-1,3-benzodioxoles
FULL PAPER
125.1, 123.5, 115.7, 108.7, 34.1 ppm. C9H6F2O4 (216.14): calcd. C
50.01, H 2.80; found C 49.81, H 2.80. The same compound was
prepared from the cyanide 20b (see Section 6; 2.0 g, 10 mmol) and
potassium hydroxide (1.7 g, 30 mmol) in 65% aqueous ethanol
(30 mL) by heating under reflux for 3 h in 88% yield and sub-
sequent reduction of ethyl (2,2-difluoro-1,3-benzodioxol-4-
yl)oxoacetate (4; see below; 2.6 g, 10 mmol) with hydrazine hydrate
(50 mL) in the presence of potassium hydroxide (14 g, 0.25 mol),
dissolved in diethylene glycol (0.10 L), heated to 190 °C for 6 h, in
82% yield. Finally, the acid 1b was obtained by the treatment of
2,2-difluoro-4-methyl-1,3-benzodioxole (8; see Section 4; 1.7 g,
10 mmol) with lithium diisopropylamide (10 mmol) and potassium
tert-butoxide (1.1 g, 10 mmol) in tetrahydrofuran (20 mL) and hex-
anes (6.2 mL) for 2 h at Ϫ75 °C followed by carboxylation with
dry ice in 71% yield.
(50 mL), cooled in a methanol/dry ice bath. After 1 h at Ϫ75 °C,
the product 6 was isolated by distillation as a colorless liquid; b.p.
132Ϫ134 °C/6 Torr; n2D0 ϭ 1.4829; yield: 5.29 g (83%). 1H NMR:
δ ϭ 7.67 (dd, J ϭ 8.2, 1.2 Hz, 1 H), 7.34 (dd, J ϭ 8.0, 1.2 Hz, 1
H), 7.23 (t, J ϭ 8.1 Hz, 1 H), 4.47 (q, J ϭ 7.2 Hz, 3 H), 1.43 (t,
J ϭ 7.2 Hz, 2 H) ppm. 13C NMR: δ ϭ 182.1, 162.9, 144.6, 143.8,
131.8 (t, J ϭ 258 Hz), 124.2, 124.0, 116.8, 115.2, 63.0, 13.9 ppm.
C11H8F2O5 (258.17): calcd. C 51.18, H 3.12; found C 50.85, H 3.17.
2,2-Difluoro-7-methyl-1,3-benzodioxole-4-carboxylic Acid (5): Po-
tassium tert-butoxide (1.7 g, 15 mmol) and 2,2-difluoro-4-methyl-
1,3-benzodioxole (8; 2.6 g, 15 mmol) were added consecutively to a
solution of butyllithium (15 mL) in tetrahydrofuran (30 mL) and
hexanes (10 mL), kept in a dry ice/methanol bath. After 30 min of
vigorous stirring and a further 90 min of storing at Ϫ75 °C, the
mixture was poured onto an excess of freshly crushed pieces of
solid carbon dioxide. After evaporation of the solvent, a 1.0 
aqueous solution (30 mL) of sodium hydroxide was added and the
organic material extracted with diethyl ether (3 ϫ 15 mL). After
drying, the solvent was removed and the residue crystallized; color-
less prisms; m.p. 201Ϫ202 °C (ref.[36] m.p. 200 °C); yield: 2.8 g
(85%). 1H NMR: δ ϭ 7.63 (d, J ϭ 8.3 Hz, 1 H), 6.98 (d, J ϭ
8.4 Hz, 1 H), 2.39 (s, 3 H) ppm. 13C NMR: δ ϭ 163.7, 143.0, 142.8,
131.6 (t, J ϭ 254 Hz), 125.2, 125.0 (2 C), 111.9, 14.3 ppm.
C9H6F2O4 (216.14): calcd. C 50.01, H 2.80; found C 49.99, H 2.73.
The yield was raised to 93% (3.0 g) when 2,2,6,6-tetramethylpiper-
idine (2.6 mL, 2.1 g, 15 mmol) and N,N,NЈ,NЈЈ,NЈЈ-pentamethyldi-
ethylenetriamine (3.0 mL, 2.6 g, 15 mmol) were added together
with compound 8 and potassium tert-butoxide (15 mmol) to the
solution of butyllithium (15 mmol).
3-(2,2-Difluoro-1,3-benzodioxol-4-yl)propanoic Acid (1c): Under ni-
trogen, palladium (0.27 g, 0.25 mmol; 10 wt.-% on charcoal) was
added to a solution of (E)-3-(2,2-difluoro-1,3-benzodioxol-4-yl)-2-
propenoic acid (6; see below; 1.1 g, 5.0 mmol) in methanol (20 mL).
Hydrogen gas was bubbled into the stirred reaction mixture until,
after 6 h, the uptake ceased. The catalyst was removed by filtration,
the solvent evaporated and the residue crystallized from pentanes;
1
colorless platelets; m.p. 65Ϫ67 °C; yield: 1.10 g (99%). H NMR:
δ ϭ 7.0 (m, 1 H), 6.9 (m, 1 H), 3.01 (t, J ϭ 7.7 Hz, 2 H), 2.75 (t,
J ϭ 7.8 Hz, 2 H) ppm. 13C NMR: δ ϭ 177.4, 143.6, 142.1, 131.4 (t,
J ϭ 256 Hz), 124.2, 123.6, 122.6, 107.8, 33.2, 24.2 ppm. C10H8F2O4
(230.16): calcd. C 52.18, H 3.50; found C 52.01, H 3.33. The acid
1c was independently obtained when a suspension of the disodium
tetracarbonylferrateϪdioxane (2:3) adduct (8.7 g, 25 mmol) in
tetrahydrofuran (50 mL) was vigorously stirred at ϩ25 °C for 2 h
after the addition of 4-(2-bromoethyl)-2,2-difluoro-1,3-benzodiox-
ole (6.6 g, 25 mmol), for a further 2 h while air was bubbled in and
for a further 6 h after water (0.10 L) had been added. The product
was purified by extraction with diethyl ether (3 ϫ 25 mL) and crys-
tallization from pentanes; yield: 2.75 g (48%). The acid 1c was also
prepared from 3-(2,2-difluoro-1,3-benzodioxol-4-yl)propanenitrile
(20c; see Section 6) by hydrolysis in alkaline medium (for reaction
conditions, see above: 20b Ǟ 1b) in 82% yield and from the alcohol
2d by oxidation with potassium dichromate (for reaction condi-
tions, see above: 2c Ǟ 1b) in 92% yield.
(E)-3-(2,2-Difluoro-1,3-benzodioxol-4-yl)-2-propenoic Acid (6): A
mixture of 2,2-difluoro-4-iodo-1,3-benzodioxole (11; see Section 4;
14 g, 50 mmol), acrylic acid (4.1 mL, 4.3 g, 60 mmol), palladium()
acetate (0.11 g, 0.49 mmol), and triethylamine (17 mL, 12 g, 0.12
mol) in acetonitrile (20 mL) was heated at 80 °C for 4 h before
being poured into 10% hydrochloric acid (0.25 L). The white pre-
cipitate formed was collected by filtration, thoroughly washed with
water (0.2 L) and dried; colorless needles; m.p. 192Ϫ194 °C (from
chloroform); yield: 10.9 g (96%). 1H NMR: δ ϭ 7.72 (d, J ϭ
16.1 Hz, 1 H), 7.20 (dd, J ϭ 6.9, 2.5 Hz, 1 H), 7.1 (m, 2 H), 6.67
(d, J ϭ 16.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 170.7, 144.1, 142.2,
139.2, 131.6 (t, J ϭ 256 Hz), 124.5, 123.9, 122.0, 118.0, 111.1 ppm.
C10H6F2O4 (228.15): calcd. C 52.65, H 2.65; found C 52.46, H 2.61.
When 2,2-difluoro-4-bromo-1,3-benzodioxole (12a; see below) was
used instead of the iodo compound 11 under otherwise identical
conditions, acid 6 was formed only in trace amounts. When 2,2-
difluoro-4-iodo-1,3-benzodioxole (50 mmol) was allowed to react
with tert-butyl acrylate (7.3 mL, 6.4 g, 50 mmol) under otherwise
identical conditions, tert-butyl (E)-3-(2,2-difluoro-1,3-benzodioxol-
4-yl)-1-propenate was obtained in 81% yield {11.5 g; colorless
prisms; m.p. 90Ϫ91 °C (from pentanes); 1H NMR: δ ϭ 7.51 (d,
J ϭ 16.2 Hz, 1 H), 7.15 (dd, J ϭ 7.6, 1.7 Hz, 1 H), 7.09 (t, J ϭ
7.8 Hz, 1 H), 7.05 (dd, J ϭ 7.9, 1.8 Hz, 1 H), 6.58 (d, J ϭ 16.2 Hz,
1 H), 1.55 (s, 9 H) ppm; 13C NMR: δ ϭ 165.8 (s), 144.1 (s), 141.9
(s), 135.8 (s), 131.5 (t, J ϭ 258 Hz), 125.1 (s), 124.3 (s), 123.8 (s),
118.6 (s), 110.3 (s), 81.0 (s), 28.2 (s, 3 C) ppm; MS: m/z (%) ϭ 302
(91) [Mϩ ϩ NH4], 284 (47) [Mϩ], 224 (100), 223 (99), 171 (32);
C14H14F2O4 (284.26): calcd. C 59.15, H 4.96; found C 59.25, H
5.01}. The ester was converted into the α,β-unsaturated acid 6 (ap-
prox. 100%) by heating to 100 °C in the presence of one drop of
formic acid for 2 h, until the gas evolution had ceased, and into
4-(2,2-Difluoro-1,3-benzodioxol-4-yl)butanoic Acid (1d): Potassium
hydroxide (1.7 g, 30 mmol) in water (10 mL) was added to a solu-
tion of 4-(2,2-difluoro-1,3-benzodioxol-4-yl)butanenitrile (2.2 g,
10 mmol) in ethanol (20 mL). The mixture was refluxed for 4 h.
Ethanol was then distilled off and the residue was dissolved in
water (20 mL), washed with diethyl ether, and filtered. The water
phase was acidified to pH ϭ 1 with an aqueous solution of hydro-
chloric acid and then extracted with diethyl ether (2 ϫ 10 mL). The
ethereal phase was dried with sodium sulfate and the solvents were
evaporated. The product was crystallized from hexanes as colorless
1
prisms; m.p. 56Ϫ57 °C; yield: 2.08 g (87%). H NMR: δ ϭ 7.00 (t,
J ϭ 7.9 Hz, 1 H), 6.9 (m, 2 H), 2.73 (t, J ϭ 7.6 Hz, 2 H), 2.41 (t,
J ϭ 7.4 Hz, 2 H), 2.00 (quint, J ϭ 7.5 Hz, 2 H) ppm. 13C NMR:
δ ϭ 179.8, 143.5, 142.2, 131.5 (t, J ϭ 252 Hz), 124.4, 123.7, 123.5,
107.5, 33.3, 28.3, 24.2 ppm. C11H10F2O4 (244.19): calcd. C 54.10,
H 4.13; found C 54.24, H 4.20.
Ethyl (2,2-Difluoro-1,3-benzodioxol-4-yl)oxoacetate (4): A solution
of 2,2-difluoro-1,3-benzodioxole (2.9 mL, 3.9 g, 25 mmol) and sec-
butyllithium (25 mmol) in tetrahydrofuran (50 mL) and cyclohex-
ane (20 mL) was kept for 2 h at Ϫ75 °C before being transferred
through a cannula slowly, in the course of 5 min, into a flask con- tert-butyl 3-(2,2-difluoro-1,3-benzodioxol-4-yl)propanoate by palla-
taining diethyl oxalate (6.8 mL, 7.3 g, 50 mmol) in tetrahydrofuran
dium-catalyzed hydrogenation in methanol in 99% yield [colorless
457
Eur. J. Org. Chem. 2003, 452Ϫ462

M. Schlosser, J. Gorecka, E. Castagnetti
FULL PAPER
oil; b.p. 107Ϫ109 °C/10 Torr; n2D0 ϭ 1.4604; H NMR: δ ϭ 6.99 (t,
1
when the same reaction was repeated in the absence of copper()
J ϭ 7.8 Hz, 1 H), 6.9 (m, 2 H), 2.96 (t, J ϭ 7.7 Hz, 2 H), 2.60 (t, iodide. Alcohol 2c was isolated in 35% yield when a solution of
J ϭ 7.7 Hz, 2 H), 1.42 (s, 9 H) ppm; 13C NMR: δ ϭ 171.5 (s), butyllithium (20 mmol) and potassium tert-butoxide (20 mmol) in
143.4 (s), 142.0 (s), 131.4 (t, J ϭ 253 Hz), 124.2 (s), 123.3 (s), 123.3
tetrahydrofuran (40 mL) and hexanes (15 mL) was consecutively
(s), 107.4 (s), 80.6 (s), 34.7 (s), 27.9 (s, 3 C), 24.6 (s) ppm; treated with diisopropylamine (2.8 mL, 2.0 g, 20 mmol) and 2,2-
C14H16F2O4 (286.27): calcd. C 58.74, H 5.63; found C 59.09, H
5.32]. The latter compound was subsequently heated in the pres-
ence of formic acid (see above) to afford the free acid 1c (98%)
and reduced with lithium aluminum hydride in diethyl ether to the
alcohol 2d (91%). Acid 6 was also obtained by the condensation
of 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde (9; see Section 4;
4.6 g, 25 mmol) with acetic anhydride (4.7 mL, 5.1 g, 50 mmol) in
the presence of sodium acetate (2.05 g, 25 mmol). After 4 h of heat-
ing at 250 °C, the yield reached 88%.
difluoro-4-methyl-1,3-benzodioxole (8; 3.4 g, 20 mmol) while
cooled in a methanol/dry ice bath. After 2 h at Ϫ75 °C, dry para-
formaldehyde (0.6 g, 20 mmol) was added and the reaction was
worked up as described for the lower homolog 2b (see above).
3-(2,2-Difluoro-1,3-benzodioxol-4-yl)-1-propanol (2d): A solution of
2,2-difluoro-1,3-benzodioxole (2.8 mL, 3.9 g, 25 mmol) and sec-bu-
tyllithium (25 mmol) in tetrahydrofuran (50 mL) and cyclohexane
(15 mL) was kept for 2 h at Ϫ75 °C before oxetane (1.7 mL, 1.5 g,
25 mmol) and boron trifluorideϪdiethyl ether (3.2 mL, 3.5 g,
25 mmol) were added consecutively. At ϩ25 °C, the mixture was
neutralized with a slight excess of ethereal hydrogen chloride and
concentrated. Distillation afforded a colorless oil; b.p. 111Ϫ113 °C/
5 Torr; n2D0 ϭ 1.4801; yield: 2.2 g (41%). 1H NMR: δ ϭ 6.99 (t, J ϭ
7.9 Hz, 1 H), 6.9 (m, 2 H), 3.67 (t, J ϭ 6.3 Hz, 2 H), 2.76 (t, J ϭ
7.6 Hz, 2 H), 2.91 (m, 2) ppm. 13C NMR: δ ϭ 143.4, 142.0, 131.4
(t, J ϭ 254 Hz), 124.3, 124.2, 123.4, 107.2, 61.9, 32.1, 25.4 ppm.
C10H10F2O3 (216.19): calcd. C 55.56, H 4.66; found C 55.52, H
4.67. Alcohol 2d was isolated in 61% yield by deprotonation of 2,2-
difluoro-4-methyl-1,3-benzodioxole (8; 3.4 g, 20 mmol) with li-
thium diisopropylamide (20 mmol) in the presence of potassium
tert-butoxide (20 mmol) as described above (see the end of the pre-
ceding paragraph dealing with alcohol 2c) followed by the addition
of oxirane (20 mmol). The alcohol 2d was finally obtained in 84%
yield when a solution of (E)-3-(2,2-difluoro-1,3-benzodioxol-4-yl)-
2-propenoic acid (6; see Section 1; 2.3 g, 10 mmol) and lithium
aluminum hydride (0.76 g, 20 mmol) in diethyl ether (20 mL) was
heated for 2 h under reflux and nitrogen before being poured onto
ice, extracted with diethyl ether (3 ϫ 10 mL) and distilled.
2. Phenols and Alcohols
2,2-Difluoro-1,3-benzodioxol-4-ol (2a): A solution containing 2,2-
difluoro-1,3-benzodioxole (5.7 mL, 7.9 g, 50 mmol) and sec-butyl-
lithium (50 mmol) in tetrahydrofuran (65 mL) and cyclohexane
(35 mL) was kept for 2 h at Ϫ75 °C before fluorodimethoxy-
boraneϪdiethyl ether[14,15] (9.4 mL, 8.2 g, 50 mmol) and, at ϩ25
°C, sodium hydroxide (2.0 g, 50 mmol) and a 30% aqueous solution
(10 mL) of hydrogen peroxide (3.4 g, 0.10 mol), were added. After
2 h of vigorous stirring, the mixture was acidified with hydrochloric
acid to pH ϭ 3 and extracted with diethyl ether (3 ϫ 20 mL). Dis-
tillation afforded a colorless liquid; m.p. 29Ϫ30 °C (from hexanes
at Ϫ25 °C); b.p. 68Ϫ70 °C/14 Torr; yield: 8.0 g (92%). 1H NMR:
δ ϭ 6.95 (t, J ϭ 8.3 Hz, 1 H), 6.69 (d, J ϭ 8.5 Hz, 1 H), 6.66 (d,
J ϭ 8.0 Hz, 1 H), 5.43 (s, 1 H) ppm. 13C NMR: δ ϭ 144.8, 139.1,
131.5 (t, J ϭ 256 Hz), 131.2, 124.0, 112.7, 102.2 ppm. C7H4F2O3
(174.10): calcd. C 48.29, H 2.32; found C 48.20, H 2.21.
(2,2-Difluoro-1,3-benzodioxol-4-yl)methanol (2b): A solution con-
taining 2,2-difluoro-1,3-benzodioxole (5.7 mL, 7.9 g, 50 mmol) and
sec-butyllithium (50 mmol) in tetrahydrofuran (65 mL) and cyclo-
hexane (35 mL) was kept for 2 h at Ϫ75 °C before dry paraformal-
dehyde (1.5 g, 50 mmol) was added and the suspension stirred for
1 h at Ϫ75 °C before the temperature was allowed to raise to ϩ25
°C. After dilution with diethyl ether (0.10 L), the mixture was
washed with brine (2 ϫ 50 mL). Upon steam distillation a colorless
liquid was collected, which solidified; colorless needles; m.p. 30Ϫ31
°C (from hexanes at Ϫ75 °C); b.p. 72Ϫ74 °C/3 Torr; yield: 2.6 g
(27%). 1H NMR: δ ϭ 7.13 (d, J ϭ 8.0 Hz, 1 H), 7.08 (t, J ϭ 7.9 Hz,
1 H), 7.00 (dd, J ϭ 7.8, 1.3 Hz, 1 H), 4.77 (s, 2 H), 1.91 (s, 1 H)
ppm. 13C NMR: δ ϭ 143.6, 141.2, 131.6 (t, J ϭ 253 Hz), 123.7,
123.4, 122.8, 108.8, 59.1 ppm. C8H6F2O3 (188.13): calcd. C 51.08,
H 3.21; found C 51.06, H 3.16. The alcohol 2b was obtained in
95% yield by reduction of the aldehyde 9 (9.6 g, 50 mmol) with
sodium borohydride (1.9 g, 50 mmol) in methanol (50 mL) at 0 °C
for 15 min. The mixture was neutralized with 2.0  ethereal hydro-
gen chloride and distilled directly.
4-(2,2-Difluoro-1,3-dioxol-4-yl)-1-butanol (2e): From 2,2-difluoro-
1,3-benzodioxole (2.9 mL, 4.0 g, 25 mmol) and, 2 h later, 1-iodo-4-
(methoxymethoxy)butane (see below; 6.1 g, 25 mmol) in tetrahy-
drofuran (30 mL) and cyclohexane (15 mL) cooled in a methanol/
dry ice bath. When, after 2 h, the mixture was allowed to attain
ϩ25 °C, it was neutralized with a slight excess of ethereal hydrogen
chloride and distilled under reduced pressure; colorless liquid; b.p.
1
144Ϫ146 °C/19 Torr; n2D0 ϭ 1.4879; yield: 1.02 g (18%). H NMR:
δ ϭ 6.98 (t, J ϭ 7.9 Hz, 1 H), 6.9 (m, 2 H), 3.67 (t, J ϭ 6.5 Hz, 2
H), 2.69 (t, J ϭ 7.6 Hz, 2 H), 1.90 (s, 1 H), 1.7 (m, 2 H), 1.6 (m, 2
H) ppm. 13C NMR: δ ϭ 143, 142.1, 131.5 (t, J ϭ 253 Hz), 124.9,
124.4, 123.4, 107.1, 62.4, 32.1, 28.9, 25.7 ppm. MS (c.i.): m/z (%) ϭ
248 (100) [Mϩ ϩ NH4], 231 (25) [Mϩ ϩ 1], 230 (52) [Mϩ], 207
(52), 184 (60), 171 (30). C11H12F2O3 (230.21): calcd. C 57.39, H
5.25; found C 57.10, H 5.32.
1-Iodo-4-(methoxymethoxy)butane: At 0 °C, chloromethyl methyl
ether (4.6 mL, 4.8 g, 60 mmol; ‘‘technical grade’’ quality) was ad-
ded to a solution of 4-iodo-1-butanol[37] (10 g, 50 mmol) and N-
ethyldiisopropylamine (13 mL, 9.7 g, 75 mmol) in anhydrous
dichloromethane (25 mL). The mixture was immediately absorbed
onto silica gel (25 mL) and the powder, once dry, poured on top of
a column filled with more silica (0.20 L) from which the product
was eluted with hexanes; colorless oil; n2D0 ϭ 1.4876; yield: 9.6 g
2-(2,2-Difluoro-1,3-benzodioxol-4-yl)ethanol (2c): A solution of 2,2-
difluoro-1,3-benzodioxole (5.7 mL, 7.9 g, 50 mmol) and sec-butyl-
lithium (50 mmol) in tetrahydrofuran (65 mL) and cyclohexane
(35 mL) was stored 2 h at Ϫ75 °C before copper() iodide (4.8 g,
25 mmol) was added. The mixture was stirred at Ϫ75 °C until, after
about 45 min, it became homogeneous. Oxirane was then added
(2.5 mL, 2.2 g, 50 mmol) and the mixture was then allowed to at-
tain slowly, in the course of 2 h, ϩ25 °C. Neutralization with a
small excess of ethereal hydrogen chloride and immediate distilla-
tion gave the product 2c as a colorless liquid; b.p. 114Ϫ115 °C/
1
(79%). H NMR: δ ϭ 4.61 (s, 2 H), 3.55 (t, J ϭ 6.3 Hz, 2 H), 3.36
(s, 3 H), 3.23 (t, J ϭ 7.0 Hz, 2 H), 1.94 (symm. m, 2 H), 1.7 (m, 2
H) ppm. 13C NMR: δ ϭ 96.4, 66.4, 55.2, 30.6, 30.4, 6.6 ppm.
C6H13IO2 (244.07): calcd. C 29.53, H 5.37; found C 29.72, H 5.07.
6 Torr (ref.[3] b.p. 99Ϫ101 °C/4 Torr); n2D0 ϭ 1.4962 (ref.[3] n2D0
ϭ
(2,2-Difluoro-7-methyl-1,3-benzodioxol-4-yl)methanol (7): At Ϫ75
°C, sec-butyllithium (25 mmol) in cyclohexane (18 mL) was added
1.4966); yield: 4.19 g (82%). Alcohol 2c formed in a mere 54% yield
458
Eur. J. Org. Chem. 2003, 452Ϫ462

A Homologous Series of O- and N-Functionalized 2,2-Difluoro-1,3-benzodioxoles
to a solution of 2,2-difluoro-4-methyl-1,3-benzodioxole (4.3 g, 142.4, 131.5 (t, J ϭ 256 Hz), 124.8, 123.5, 122.6, 107.6, 41.8, 33.6
FULL PAPER
25 mmol) in tetrahydrofuran (32 mL). After 2 h at Ϫ75 °C, para-
formaldehyde (1.5 g, 50 mmol) was added to the reaction mixture
and the mixture was then warmed up to 25 °C. After steam distilla-
ppm. C9H9F2NO2 (201.17): calcd. C 53.74, H 4.51, N 6.96; found
C 53.44, H 4.48, N 6.99. Amine 3c was obtained in 89% yield when
the same lithium aluminum reduction protocol was applied to (E)-
tion, an oil was collected which was then distilled under reduced 2,2-difluoro-4-(2-nitroethenyl)-1,3-benzodioxole (16, see Section 6).
pressure as colorless liquid and crystallized from pentanes as color-
3-(2,2-Difluoro-1,3-benzodioxol-4-yl)-1-propanamine (3d): As above,
less needles; m.p. 55Ϫ57 °C; b.p. 112Ϫ114 °C/15 Torr; yield: 3.23 g
(64%). 1H NMR: δ ϭ 7.01 (d, J ϭ 8.1 Hz, 1 H), 6.88 (d, J ϭ
8.1 Hz, 1 H), 4.73 (s, 2 H), 2.31 (s, 3 H), 1.81 (s, 1 H) ppm. 13C
NMR: δ ϭ 142.2, 140.9, 131.6 (t, J ϭ 252 Hz), 125.3, 126.6, 120.5,
119.7, 59.1, 14.3 ppm. C9H8F2O3 (202.16): calcd. C 53.47, H 3.99;
found C 53.40, H 3.93.
from 3-(2,2-difluoro-1,3-benzodioxol-4-yl)propanenitrile (20c; see
Section 6; 2.1 g, 10 mmol); colorless oil; b.p. 104Ϫ106 °C/12 Torr;
n2D0 ϭ 1.4806; yield: 1.97 g (92%). 1H NMR: δ ϭ 6.99 (t, J ϭ 7.8 Hz,
1 H), 6.9 (m, 2 H), 2.7 (m, 4 H), 1.81 (quint, J ϭ 7.4 Hz, 2 H), 1.4
(s, 2 H) ppm. 13C NMR: δ ϭ 143.3, 142.0, 131.3 (t, J ϭ 258 Hz),
124.5, 124.2, 123.3, 107.0, 41.3, 33.1, 26.4 ppm. C10H11F2NO2
(215.20): calcd. C 55.81, H 5.15; found C 55.24, H 5.15.
3. Amines
(2,2-Difluoro-1,3-benzodioxol-4-yl)amine (3a): Under nitrogen, pal-
ladium (1.33 g, 1.25 mmol; 10 wt.-% on charcoal) was added to a
solution of 4-azido-2,2-difluoro-1,3-benzodioxole (14a; see Section
6; 5.0 g, 25 mmol) in methanol (50 mL). Hydrogen gas was bubbled
into the stirred reaction mixture until, after 6 h, the uptake ceased.
The catalyst was removed by filtration, the solvent evaporated and
the residue distilled under reduced pressure as a colorless liquid;
4-(2,2-Difluoro-1,3-benzodioxol-4-yl)-1-butanamine (3e): As above,
from 4-(2,2-difluoro-1,3-benzodioxol-4-yl)butanenitrile (20d; see Sec-
tion 6; 2.3 g, 10 mmol); colorless oil; b.p. 110Ϫ111 °C/6 Torr; nD20
ϭ
1.4788; yield: 2.20 g (94%). 1H NMR: δ ϭ 7.0 (m, 1 H), 6.9 (m, 2 H),
2.74 (t, J ϭ 7.0 Hz, 2 H), 2.67 (t, J ϭ 7.6 Hz, 2 H), 1.7 (m, 2 H), 1.5
(m, 4 H) ppm. 13C NMR: δ ϭ 143.4, 142.0, 131.5 (t, J ϭ 254 Hz),
125.0, 124.3, 123.4, 107.1, 41.9, 33.2, 29.0, 26.8 ppm. C11H13F2NO2
(229.23): calcd. C 57.64, H 5.72; found C 56.78, H 5.63.
b.p. 78Ϫ80 °C/8 Torr; n2D0 ϭ 1.4600; yield: 3.48 g (80%). H NMR:
1
δ ϭ 6.86 (t, J ϭ 8.2 Hz, 1 H), 6.5 (m, 2 H), 3.7 (s, 2 H) ppm. 13C
NMR: δ ϭ 144.2, 131.4 (t, J ϭ 256 Hz), 131.1, 130.2, 124.0, 111.7, 4. Methyl Derivative, Aldehyde, Ketone, and Iodo Compound
99.6 ppm. C7H5F2NO2 (173.12): calcd. C 48.57, H 2.91; found C
2,2-Difluoro-4-methyl-1,3-benzodioxole (8): A solution of 2,2-di-
fluoro-1,3-benzodioxole (11.4 mL, 15.8 g, 0.10 mol) and sec-butyl-
lithium (0.10 mol) in tetrahydrofuran (0.15 L) and cyclohexane
(60 mL) was kept at Ϫ75 °C before dimethyl sulfate (9.5 mL, 12.6 g,
0.10 mol) was added. Upon direct distillation, the product was col-
lected as a colorless liquid; b.p. 79Ϫ81 °C/6 Torr; n2D0 ϭ 1.4496;
yield: 12.2 g (71%). 1H NMR: δ ϭ 6.91 (m, 3 H), 2.31 (s, 3 H)
ppm. 13C NMR: δ ϭ 143.4, 142.5, 131.5 (t, J ϭ 251 Hz), 125.3,
123.2, 120.4, 106.9, 14.3 ppm. C8H6F2O2 (172.13): calcd. C 55.82,
H 3.51; found C 55.55, H 3.34.
49.04, H 2.80. Amine 3a was formed in 40% yield when 2,2-di-
fluoro-1,3-benzodioxole (10 mmol), after lithiation with sec-butylli-
thium (10 mmol), was added to O-methylhydroxylamine (0.94 g,
20 mmol) which had beforehand been treated dropwise with a 1.7
 ethereal solution of methyllithium (20 mol); the mixture was kept
for 2 h at Ϫ15 °C. Amine 3a was obtained in 82% yield when a
mixture containing (2,2-difluoro-1,3-benzodioxol-4-yl)ethanone
oxime (18; see Section 6; 2.2 g, 10 mmol) and phosphorus penta-
chloride (6.2 g, 30 mmol) in benzene (50 mL) was heated under
reflux for 15 min and, after addition of 32% hydrochloric acid
(5.0 mL) and ethanol (0.10 L), heated again for 6 h. The solid
residue left behind upon evaporation of the solvents was dissolved
in water (10 mL) and basified with sodium hydroxide until pH ϭ
12 was attained. The product 3a was isolated by extraction with
diethyl ether and distillation.
2,2-Difluoro-1,3-benzodioxole-4-carbaldehyde (9): A solution of 2,2-
difluoro-1,3-benzodioxole (5.7 mL, 7.9 g, 50 mol) and sec-butyl-
lithium (50 mol) in tetrahydrofuran (70 mL) and cyclohexane
(30 mL) was kept at Ϫ75 °C before N,N-dimethylformamide
(3.9 mL, 3.7 g, 50 mmol) was added. The solvents were evaporated
and the residue was treated with 2.0  hydrochloric acid (50 mL)
before being extracted with diethyl ether (3 ϫ 25 mL). The com-
bined organic layers were washed with brine (2 ϫ 25 mL), dried,
and distilled; colorless liquid; b.p. 73Ϫ74 °C/6 Torr; n2D0 ϭ 1.4988;
yield: 8.2 g (88%). 1H NMR: δ ϭ 10.20 (s, 1 H), 7.58 (d, J ϭ 7.9 Hz,
(2,2-Difluoro-1,3-benzodioxol-4-yl)methanamine (3b): 2,2-Difluoro-
1,3-benzodioxole-4-carbonitrile (20a; see Section 6; 1.8 g, 10 mol)
and lithium aluminum hydride (0.76 g, 20 mmol) in diethyl ether
(20 mL) were heated under reflux for 2 h before being poured onto
crushed ice (25 g). The organic layer was decanted, dried and con-
centrated. Distillation gave product 3b as a colorless liquid; b.p.
1 H), 7.33 (d, J ϭ 8.0 Hz, 1 H), 7.23 (t, J ϭ 8.0 Hz, 1 H) ppm. 13
C
1
94Ϫ95 °C/6 Torr; n2D0 ϭ 1.4860; yield: 1.58 g (86%). H NMR: δ ϭ
NMR: δ ϭ 186.0, 144.6, 144.2, 132.1 (t, J ϭ 259 Hz), 123.9, 123.1,
119.8, 114.7 ppm. C8H4F2O3 (186.12): calcd. C 51.63, H 2.17;
found C 51.52, H 2.27.
7.1 (m, 2 H), 7.0 (m, 1 H), 3.95 (s, 2 H), 1.68 (s, 2 H) ppm. 13C
NMR: δ ϭ 143.6, 141.5, 131.6 (t, J ϭ 251 Hz), 125.9, 123.7, 122.8,
108.1, 40.5 ppm. C8H7F2NO2 (187.15): calcd. C 51.34, H 3.77; found
C 50.98, H 3.91. Amine 3b was formed in 80% and 89% yield, re-
spectively, when 2,2-difluoro-1,3-benzodioxole-4-carboxamide (19;
see Section 6; 2.0 g, 10 mmol) and 2,2-difluoro-1,3-benzodioxole-4-
carbaldehyde oxime (17; see Section 6; 4.0 g, 20 mmol) were submit-
ted to the same lithium hydride reduction protocol.
(2,2-Difluoro-1,3-benzodioxol-4-yl)ethanone (10): At Ϫ75 °C, an
ethereal solution (75 mL) of methyllithium (0.11 mol) was added
to 2,2-difluoro-1,3-benzodioxole-4-carboxylic acid (10 g, 50 mmol).
The mixture was kept for 3 h at ϩ25 °C before being neutralized
with a slight excess of ethereal hydrogen chloride. Upon distillation,
first of the solvents and eventually of the product, a viscous liquid
was collected that solidified in the refrigerator; colorless star-
shaped crystals; m.p. 32Ϫ33 °C (from pentanes at Ϫ75 °C); b.p.
87Ϫ89 °C/12 Torr; yield: 6.8 g (68%). 1H NMR: δ ϭ 7.65 (dd, J ϭ
(2,2-Difluoro-1,3-benzodioxol-4-yl)ethanamine (3c): Exactly as de-
scribed in the preceding paragraph, (2,2-difluoro-1,3-benzodioxol-
4-yl)acetonitrile (20b; see Section 6; 2.0 g, 10 mmol) was reduced
with lithium aluminum hydride (20 mmol) to afford product 3c as 8.1, 1.3 Hz, 1 H), 7.26 (dd, J ϭ 8.0, 1.3 Hz, 1 H), 7.17 (t, J ϭ
a colorless liquid; b.p. 80Ϫ82 °C/6 Torr; n2D0 ϭ 1.4866; yield: 1.75 g
8.0 Hz, 1 H), 2.67 (s, 3 H) ppm. 13C NMR: δ ϭ 193.5, 144.5, 143.2,
(86%). 1H NMR: δ ϭ 7.0 (m, 1 H), 6.9 (m, 2 H), 3.02 (t, J ϭ 131.5 (t, J ϭ 256 Hz), 123.6, 123.5, 120.9, 113.7, 30.3 ppm.
7.0 Hz, 2 H), 2.81 (t, J ϭ 6.9 Hz, 2 H) ppm. 13C NMR: δ ϭ 143.6, C9H6F2O3 (200.14): calcd. C 54.01, H 3.02; found C 53.76, H 2.95.
Eur. J. Org. Chem. 2003, 452Ϫ462
459

M. Schlosser, J. Gorecka, E. Castagnetti
FULL PAPER
2,2-Difluoro-4-iodo-1,3-benzodioxole (11): A solution of 2,2-di-
fluoro-1,3-benzodioxole (5.7 mL, 7.9 g, 50 mmol) and sec-butyl-
lithium (50 mol) in tetrahydrofuran (70 mL) and cyclohexane
(30 mL) was kept for 2 h at Ϫ75 °C before a precooled solution of
iodine (13 g, 50 mmol) was added. The solvents were evaporated
ϩ25 °C. The organic layer was washed with brine (2 ϫ 25 mL),
dried, and the solvents were evaporated. The oil left behind crystal-
lized spontaneously when put in an ice bath; colorless star-shaped
crystals; m.p. 34Ϫ35 °C; yield: 7.30 g (89%). 1H NMR: δ ϭ 7.9 (m,
2 H), 7.64 (t, J ϭ 7.5 Hz, 1 H), 7.52 (t, J ϭ 7.8 Hz, 2 H), 7.0 (m,
and the residue was treated with water (0.10 L) and extracted with 3 H), 5.14 (s, 2 H) ppm. 13C NMR: δ ϭ 143.6, 141.9, 135.9, 134.0,
diethyl ether (3 ϫ 25 mL). The combined organic layers were
washed with a saturated aqueous solution (25 mL) of sodium thio-
sulfate and brine (25 mL) before being concentrated. Low temper-
ature crystallization afforded the product 11 as colorless star-
shaped crystals; m.p. 39Ϫ40 °C (from ethanol); yield: 13.8 g (97%).
1H NMR: δ ϭ 7.39 (d, J ϭ 8.3 Hz, 1 H), 7.03 (d, J ϭ 8.1 Hz, 1
H), 6.86 (t, J ϭ 8.0 Hz, 1 H) ppm. 13C NMR: δ ϭ 145.8, 142.7,
132.5, 130.3 (t, J ϭ 262 Hz), 125.1, 109.4, 70.9 ppm. C7H3F2IO2
(284.00): calcd. C 29.61, H 1.06; found C 29.55, H 1.19.
131.4 (t, J ϭ 258 Hz), 129.3 (2 C), 127.9 (2 C), 124.3, 123.8, 116.0,
110.4, 65.3 ppm.
2-(2,2-Difluoro-1,3-benzodioxol-4-yl)ethyl Benzenesulfonate (13c):
As above, from alcohol 2c (see Section 2; 2.0 g, 10 mmol); colorless
star-shaped crystals; m.p. 26Ϫ28 °C; yield: 2.61 g (77%). 1H NMR:
δ ϭ 7.79 (dd, J ϭ 8.4, 1.2 Hz, 2 H), 7.62 (tt, J ϭ 7.5, 1.2 Hz, 1 H),
7.49 (t, J ϭ 8.0 Hz, 2 H), 6.98 (t, J ϭ 7.9 Hz, 1 H), 6.92 (dd, J ϭ
8.0, 1.4 Hz, 1 H), 6.87 (dm, J ϭ 8.4 Hz, 1 H), 4.30 (t, J ϭ 6.6 Hz,
2 H), 3.01 (t, J ϭ 6.6 Hz, 2 H) ppm. 13C NMR: δ ϭ 143.5, 142.1,
135.7, 133.8, 131.3 (t, J ϭ 258 Hz), 129.2 (2 C), 127.7 (2 C), 125.0,
123.6, 118.9, 108.3, 68.4, 29.1 ppm.
5. Bromo Compounds and Sulfonates
4-Bromo-2,2-difluoro-1,3-benzodioxole (12a): After 2 h at Ϫ75 °C,
bromine (1.3 mL, 4.0 g, 25 mmol) was added to a solution initially
3-(2,2-Difluoro-1,3-benzodioxol-4-yl)propyl Benzenesulfonate (13d):
containing 2,2-difluoro-1,3-benzodioxole (2.8 mL, 3.9 g, 25 mmol) As above, from alcohol 2d (see Section 2; 5.4 g, 25 mmol); colorless
and sec-butyllithium (25 mmol) in tetrahydrofuran (35 mL) and
cyclohexane (15 mL). Immediate distillation gave a colorless oil; b.p.
75Ϫ77 °C/16 Torr; nD20 ϭ 1.4966; yield: 4.21 g (71%). 1H NMR: δ ϭ
oil (after chromatography); n2D0 ϭ 1.5214 yield: 7.21 g (81%). 1H
NMR: δ ϭ 7.92 (d, J ϭ 8.5 Hz, 2 H), 7.67 (tt, J ϭ 7.5, 1.3 Hz, 1
H), 7.56 (t, J ϭ 7.4 Hz, 2 H), 6.95 (t, J ϭ 7.8 Hz, 1 H), 6.89 (dd,
7.22 (dd, J ϭ 8.1, 1.6 Hz, 1 H), 6.9 (m, 2 H) ppm. 13C NMR: δ ϭ J ϭ 8.0, 1.3 Hz, 1 H), 6.79 (dm, J ϭ 7.9 Hz, 1 H), 4.11 (t, J ϭ
143.7, 131.0 (t, J ϭ 260 Hz), 127.1, 124.5, 108.5, 106.6, 101.4 ppm.
6.1 Hz, 2 H), 2.72 (t, J ϭ 7.6 Hz, 2 H), 2.0 (m, 2 H) ppm. 13C
C7H3BrF2O2 (237.01): calcd. C 35.47, H 1.28; found C 35.42, H 1.38. NMR: δ ϭ 143.5, 142.0, 136.0, 133.9, 131.4 (t, J ϭ 258 Hz), 129.3
(2 C), 127.9 (2 C), 124.4, 123.6, 122.9, 107.7, 69.5, 28.4, 25.3 ppm.
4-(Bromomethyl)-2,2-difluoro-1,3-benzodioxole (12b): A solution of
triphenylphosphane (6.6 g, 25 mmol) in acetonitrile (50 mL) was
cooled in an ice bath and treated with bromine (1.3 mL, 4.0 g,
25 mmol) before 4-(2,2-difluoro-1,3-benzodioxol-4-yl)methanol
(2b; see Section 6; 4.7 g, 25 mmol) was added. The solution was
heated for 2 h at ϩ50 °C. Immediate distillation afforded a color-
less liquid; m.p. 24Ϫ25 °C (from hexanes at Ϫ75 °C); b.p. 86Ϫ88
°C/6 Torr; yield: 5.40 g (86%). 1H NMR: δ ϭ 7.10 (dd, J ϭ 7.9,
1.7 Hz, 1 H), 7.06 (t, J ϭ 7.8 Hz, 1 H), 7.00 (dd, J ϭ 7.8, 1.7 Hz,
1 H), 4.48 (s, 2 H) ppm. 13C NMR: δ ϭ 143.7, 141.7, 131.5 (t, J ϭ
256 Hz), 124.7, 123.9, 120.4, 109.6, 24.4 ppm. C8H5BrF2O2
(251.03): calcd. C 38.28, H 2.01; found C 37.99, H 2.26. The same
compound 12b was prepared in 65% yield from 2,2-difluoro-4-
methyl-1,3-benzodioxole (8; see Section 4; 4.3 g, 25 mmol) and
bromine (1.3 mL, 4.0 g, 25 mmol) in tetrachloromethane (50 mL).
6. Azido Compounds, Phthalimides, Nitro Compounds, Carbox-
amides, and Nitriles
4-Azido-2,2-difluoro-1,3-benzodioxole (14a): A solution of 2,2-di-
fluoro-1,3-benzodioxole (2.9 mL, 4.0 g, 25 mmol) and sec-butyl-
lithium (25 mmol) in tetrahydrofuran (50 mL) and cyclohexane
(20 mL) was kept for 2 h at Ϫ75 °C. After the addition of p-tolu-
enesulfonyl[38] azide (4.9 g, 25 mmol), the mixture was allowed to
stand at ϩ25 °C for 2 h. Immediate distillation afforded the prod-
uct 14a as an orange-colored, solidifying oil; m.p. 20Ϫ22 °C (from
pentanes); b.p. 80Ϫ82 °C/10 Torr; yield: 4.74 g (94%). 1H NMR:
δ ϭ 7.06 (t, J ϭ 8.2 Hz, 1 H), 6.84 (dd, J ϭ 8.1, 1.0 Hz, 1 H), 6.80
(dd, J ϭ 8.4, 1.0 Hz, 1 H) ppm. 13C NMR: δ ϭ 144.9, 132.4, 131.6
(t, J ϭ 258 Hz), 124.4, 123.8, 114.9, 105.9 ppm. C7H3F2N3O2
(199.12): calcd. C 42.23, H 1.52; found C 42.40, H 1.68.
3-(2-Bromoethyl)-2,2-difluoro-1,3-benzodioxole (12c): Prepared and
worked-up as its lower homolog 12b (see below; 5.0 g, 25 mmol);
colorless liquid; b.p. 131Ϫ133 °C/12 Torr; n2D0 ϭ 1.5029; yield: 5.83 g
4-(3-Azidopropyl)-2,2-difluoro-1,3-benzodioxole (14d): A mixture of
3-(2,2-difluoro-1,3-benzodioxol-4-yl)propyl
benzenesulfonate
(3.6 g, 10 mmol) and sodium azide (0.65 g, 10 mmol) in ethanol
(20 mL) was refluxed for 6 h. The reaction mixture was then
cooled, the ethanol was evaporated, the residue dissolved in diethyl
ether (20 mL) and washed with water (2 ϫ 10 mL). After drying
with sodium sulfate, the solvents were evaporated from the ethereal
phase and the product was distilled under reduced pressure as a
colorless liquid; b.p. 117Ϫ119 °C/12 Torr; n2D0 ϭ 1.4877; yield:
1
(89%). H NMR: δ ϭ 7.03 (t, J ϭ 7.9 Hz, 1 H), 6.97 (dd, J ϭ 8.2,
1.4 Hz, 1 H), 6.94 (d, J ϭ 8.6 Hz, 1 H), 3.61 (t, J ϭ 7.3 Hz, 2 H),
3.24 (t, J ϭ 7.3 Hz, 2 H) ppm. 13C NMR: δ ϭ 143.6, 141.3, 130.6 (t,
J ϭ 252 Hz), 124.7, 123.6, 121.4, 108.3, 32.8, 30.3 ppm. C9H7BrF2O2
(265.05): calcd. C 40.78, H 2.66; found C 40.71, H 2.62.
4-(3-Bromopropyl)-2,2-difluoro-1,3-benzodioxole (12d): As above,
1
from alcohol 2d (5.4 g, 25 mmol); colorless oil; b.p. 102Ϫ103 °C/
2.07 g (85%). H NMR: δ ϭ 7.01 (t, J ϭ 7.9 Hz, 1 H), 6.9 (m, 2
6 Torr; n2D0 ϭ 1.4988; yield: 6.12 g (88%). H NMR: δ ϭ 6.9 (m, 3 H), 3.33 (t, J ϭ 6.7 Hz, 2 H), 2.76 (t, J ϭ 7.7 Hz, 2 H), 1.9 (symm.
H), 3.42 (t, J ϭ 6.5 Hz, 2 H), 2.84 (t, J ϭ 7.4 Hz, 2 H), 2.2 (m, 2 m, 2 H) ppm. 13C NMR: δ ϭ 143.6, 142.1, 131.5 (t, J ϭ 253 Hz),
H) ppm. 13C NMR: δ ϭ 143.6, 142.1, 131.4 (t, J ϭ 251 Hz), 124.5, 124.4, 123.6, 123.5, 107.6, 50.6, 28.6, 26.4 ppm. C10H9F2N3O2
1
123.6, 123.1, 107.6, 32.6, 32.0, 27.7 ppm. C10H9BrF2O2 (279.08):
calcd. C 43.04, H 3.25; found C 42.79, H 3.42.
(241.19): calcd. C 49.80, H 3.76; found C 50.35, H 3.74.
N-[(2,2-Difluoro-1,3-benzodioxol-4-yl)methyl]phthalimide {2-[(2,2-
Difluoro-1,3-benzodioxol-4-yl)methyl]-1H-isoindole-1,3(2H)-dione;
15b}: A mixture of (2,2-difluoro-1,3-benzodioxol-4-yl)methyl ben-
(2,2-Difluoro-1,3-benzodioxol-4-yl)methyl Benzenesulfonate (13b): A
biphasic mixture of (2,2-difluoro-1,3-benzodioxol-4-yl)methanol
(2b; Section 2; 4.7 g, 25 mmol) and benzenesulfonyl chloride zenesulfonate (13b; 8.2 g, 25 mmol), potassium phthalimide (18.5 g,
(3.2 mL, 4.4 g, 25 mmol) in diethyl ether (50 mL) and potassium 100 mmol) and 18-crown-6 (0.66 g, 2.5 mmol) in N,N-dimethyl-
hydroxide (4.2 g, 75 mmol) in water (10 mL) was stirred for 15 h at formamide (50 mL) was stirred under reflux for 3 h. Then, the
460
Eur. J. Org. Chem. 2003, 452Ϫ462

A Homologous Series of O- and N-Functionalized 2,2-Difluoro-1,3-benzodioxoles
FULL PAPER
solvent was distilled under reduced pressure and the solid residue
was dissolved in dichloromethane (40 mL) and washed with water
(2 ϫ 20 mL). The organic phase was separated, dried with sodium
sulfate, and the solvents were evaporated. The product crystallized
(2,2-Difluoro-1,3-benzodioxol-4-yl)ethanone Oxime (18): In the
same way as described in the preceding paragraph, (2,2-difluoro-
1,3-benzodioxol-4-yl)ethanone (10; see Section 4; 2.0 g, 10 mmol)
was condensed with hydroxylamine (15 mmol) to afford colorless
needles; m.p. 110Ϫ111 °C (from methanol); yield: 1.80 g (84%). 1H
from pentanes as colorless needles; m.p. 118Ϫ119 °C; yield: 5.94 g
1
(75%). H NMR: δ ϭ 7.87 (m, 2 H), 7.74 (m, 2 H), 7.05 (dd, J ϭ NMR: δ ϭ 7.31 (dd, J ϭ 7.4, 2.0 Hz, 1 H), 7.1 (m, 2 H), 2.35 (s,
7.8, 1.2 Hz, 1 H), 7.01 (t, J ϭ 8.0 Hz, 1 H), 6.96 (dd, J ϭ 7.9,
3 H) ppm. 13C NMR: δ ϭ 152.1, 144.2, 141.4, 131.7 (t, J ϭ
1.3 Hz, 1 H), 4.93 (s, 2 H) ppm. 13C NMR: δ ϭ 167.6 (2 C), 143.6, 258 Hz), 123.7, 122.0, 120.2, 110.0, 12.7 ppm. C9H7F2NO3
141.6, 134.2 (2 C), 131.9 (2 C), 131.4 (t, J ϭ 258 Hz), 123.7, 123.55,
123.5 (2 C), 118.8, 108.8, 35.1 ppm. C16H9F2NO4 (317.25): calcd.
C 60.58, H 2.86; found C 60.53, H 2.81.
(215.16): calcd. C 50.24, H 3.28; found C 50.47, H 3.19.
2,2-Difluoro-1,3-benzodioxole-4-carboxamide (19): A mixture of
methyl
2,2-difluoro-1,3-benzodioxole-4-carboxylate
(5.4 g,
N-[2-(2,2-Difluoro-1,3-benzodioxol-4-yl)ethyl]phthalimide {2-[(2,2-
Difluoro-1,3-benzodioxol-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione;
15c}: As above, from 2-(2,2-difluoro-1,3-benzodioxol-4-yl)ethyl
benzenesulfonate (13c; 8.5 g, 25 mmol); colorless needles (hexanes/
25 mmol) and freshly distilled formamide (4.0 mL, 4.5 g,
100 mmol) in anhydrous N,N-dimethylformamide (30 mL) were
heated to 100 °C and sodium methoxide solution (1.1 g, 20 mmol)
was added slowly as small portions over 20 min to the reaction
mixture. The mixture was then heated at 100 °C for 6 h, cooled
and 2-propanol was added. The solvents were then distilled under
reduced pressure and the product was obtained as a white powder
that was recrystallized from a methanol/water (4:1) mixture giving
colorless star-shaped crystals; m.p. 132Ϫ133 °C; yield: 2.81 g
(56%). 1H NMR: δ ϭ 7.81 (dd, J ϭ 7.5, 1.9 Hz, 1 H), 7.2 (m, 2
H), 6.5 (s, 1 H), 6.0 (s, 1 H) ppm. 13C NMR: δ ϭ 163.2, 143.7,
141.3, 131.2 (t, J ϭ 251 Hz), 125.0, 124.0, 116.0, 113.1 ppm.
C8H5F2NO3 (201.13): calcd. C 47.78, H 2.51, N 6.96; found C
47.65, H 2.88, N 6.99. The yield increased to 92% when 2,2-di-
fluoro-1,3-benzodioxole-4-carboxylic acid (1a; 25 mmol) was first
converted into the acyl chloride (employing an excess of thionyl
chloride for 2 h at reflux temperature) before treating the latter with
a concentrated aqueous solution of ammonia, collecting the precip-
itate formed and recrystallizing it.
1
chloroform, 5:1); m.p. 116Ϫ118 °C; yield: 6.1 g (74%). H NMR:
δ ϭ 7.8 (m, 2 H), 7.7 (m, 2 H), 7.00 (t, J ϭ 7.8 Hz, 1 H), 6.9 (m,
2 H), 4.02 (t, J ϭ 7.0 Hz, 2 H), 3.09 (t, J ϭ 7.0 Hz, 2 H) ppm. 13C
NMR: δ ϭ 168.0 (2 C), 143.3, 142.4, 133.9 (2 C), 131.9 (2 C), 131.2
(t, J ϭ 254 Hz), 124.7, 123.6, 123.2 (2 C), 120.8, 108.0, 37.3, 28.3
ppm. C17H11F2NO4 (331.28): calcd. C 61.64, H 3.35; found C
61.77, H 3.38.
N-[3-(2,2-Difluoro-1,3-benzodioxol-4-yl)propyl]phthalimide
{2-[3-
(2,2-Difluoro-1,3-benzodioxol-4-yl)propyl]-1H-isoindole-1,3(2H)-
dione; 15d}: As above, from 3-(2,2-difluoro-1,3-benzodioxol-4-yl)-
propyl benzenesulfonate (13d; 8.9 g, 25 mmol); colorless prisms
(from pentanes); m.p. 86Ϫ88 °C; yield: 6.12 g (71%). 1H NMR:
δ ϭ 7.8 (m, 2 H), 7.7 (m, 2 H), 6.9 (m, 2 H), 6.86 (dd, J ϭ 7.5,
1.7 Hz, 1 H), 3.77 (t, J ϭ 7.1 Hz, 2 H), 2.74 (t, J ϭ 7.8 Hz, 2 H),
2.09 (quint, J ϭ 7.6 Hz, 2 H) ppm. 13C NMR: δ ϭ 168.3 (2 C),
143.4, 142.0, 134.0 (2 C), 132.1 (2 C), 131.4 (t, J ϭ 250 Hz), 124.1,
123.5 (2 C), 123.2 (2 C), 107.3, 37.5, 27.8, 26.6 ppm. MS: m/z (%) ϭ
363 (51) [Mϩ ϩ NH4], 346 (11) [Mϩ ϩ 1], 345 (11) [Mϩ], 327 (23),
326 (96), 324 (39), 323 (100). C18H13F2NO4 (345.30): calcd.C 62.61,
H 3.79; found C 62.68, H 3.70.
2,2-Difluoro-1,3-benzodioxole-4-carbonitrile (20a): A solution of
2,2-difluoro-1,3-benzodioxole-4-carbaldehyde oxime (17; 4.0 g,
20 mmol), cyanuric chloride (2,4,6-trichloro-1,3,5-triazine, 1.8 g,
10 mmol) and pyridine (1.6 mL, 1.6 g, 20 mmol) in dichloro-
methane (20 mL) was kept for 2 h at ϩ25 °C before being poured
into water (50 mL). The organic layer was decanted and the aque-
ous one extracted with diethyl ether (2 ϫ 15 mL). The combined
organic phases were dried and concentrated. Distillation gave the
product as a solidifying liquid; colorless needles; m.p. 32Ϫ34 °C
(E)-2,2-Difluoro-4-(2-nitroethenyl)-1,3-benzodioxole (16): A 1.0 
aqueous solution (30 mL) of sodium hydroxide was added dropwise
to a stirred solution of 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde
(9; see Section 4; 4.6 g, 25 mmol) and nitromethane (1.4 mL, 1.5 g,
25 mmol) in methanol (0.10 L), cooled in a ice/salt bath at such a
rate that the temperature remained below ϩ15 °C. After an addi-
tional 15 min of stirring at 0 °C, the mixture was added dropwise
to 10% hydrochloric acid (15 mL, 50 mmol). The yellow precipitate
formed was collected by filtration, washed with water (50 mL) and
dried. Recrystallization from methanol gave yellow star-shaped crys-
tals; m.p. 91Ϫ92 °C; yield: 4.25 g (75%). 1H NMR: δ ϭ 7.93 (d, J ϭ
13.8 Hz, 1 H), 7.79 (d, J ϭ 13.8 Hz, 1 H), 7.2 (m, 3 H) ppm. 13C
NMR: δ ϭ 144.2, 142.3, 140.6, 131.7, 131.5 (t, J ϭ 251 Hz), 125.9,
124.5, 114.0, 112.6 ppm. C9H5F2NO4 (229.14): calcd. C 47.18, H
2.20, N 6.11; found C 47.21, H 2.06, N 6.11.
1
(from hexanes); b.p. 84Ϫ86/10 Torr; yield: 3.31 g (91%). H NMR:
δ ϭ 7.35 (dd, J ϭ 8.0, 1.1 Hz, 1 H), 7.32 (dd, J ϭ 8.1, 1.2 Hz, 1
H), 7.20 (t, J ϭ 8.1 Hz, 1 H) ppm. 13C NMR: δ ϭ 145.2, 144.2,
131.4 (t, J ϭ 261 Hz), 126.6, 124.5, 114.1, 112.7, 95.2 ppm.
C8H3F2NO2 (183.11): calcd. C 52.48, H 1.65, N 7.65; found C
52.16, H 1.98, N 7.62. The same product 20a was obtained when
a solution of the aldehyde 9 (see Section 4; 4.7 g, 25 mmol) in tetra-
hydrofuran (25 mL) was simultaneously treated with iodine (6.3 g,
25 mmol) and 28% aqueous ammonia (0.10 L) for 2 h at ϩ25 °C.
The mixture was decolorized with sodium thiosulfate (2.5 g) and
extracted with diethyl ether (3 ϫ 15 mL). After washing with brine
(2 ϫ 10 mL), the combined organic layers were dried, and the vol-
atiles evaporated. Upon distillation, nitrile 20a was isolated in 68%
yield. Finally, nitrile 20a was formed in 91% yield when the carbox-
amide 19 (5.0 g, 25 mmol) and thionyl chloride (15 mL, 24 g, 0.20
mol) were heated under reflux for 6 h before the volatiles were evap-
orated and the residue was purified by crystallization.
2,2-Difluoro-1,3-benzodioxol-4-carbaldehyde Oxime (17): A solu-
tion of 2,2-difluoro-1,3-benzodioxol-4-carbaldehyde (9; see Section
4; 9.3 g, 50 mmol), hydroxylamine hydrochloride (5.2 g, 75 mmol),
and sodium acetate trihydrate (10 g, 75 mmol) in methanol (0.10 L)
was heated under reflux for 30 min. When the mixture was poured
into water (0.12 L), a white mass precipitated. This was collected
by filtration, washed with water, and dried; colorless needles; m.p.
(2,2-Difluoro-1,3-benzodioxol-4-yl)acetonitrile (20b):
A mixture
120Ϫ121 °C (from methanol); yield: 9.7 g (96%). 1H NMR: δ ϭ containing 4-(bromomethyl)-2,2-difluoro-1,3-benzodioxole (12b;
8.21 (s, 1 H), 7.29 (dd, J ϭ 7.2, 1.8 Hz, 1 H), 7.1 (m, 2 H) ppm. see Section 5; 6.3 g, 25 mmol) and potassium cyanide (1.6 g,
13C NMR: δ ϭ 144.4, 144.3, 141.2, 131.7 (t, J ϭ 252 Hz), 123.9, 25 mmol) in 80% aqueous ethanol (60 mL) was heated under reflux
122.4, 115.7, 110.5 ppm. C8H5F2NO3 (201.13): calcd. C 47.78, H
2.51, N 6.96; found C 47.69, H 2.89, N 6.99.
for 6 h before being concentrated to about one sixth of the volume.
After the addition of water (20 mL), the organic product was ex-
Eur. J. Org. Chem. 2003, 452Ϫ462
461

M. Schlosser, J. Gorecka, E. Castagnetti
FULL PAPER
tracted with diethyl ether (2 ϫ 25 mL) and purified by distillation;
b.p. 106Ϫ108 °C/13 Torr; crystallization from hexanes at Ϫ75 °C
gave colorless star-shaped crystals; m.p. 31Ϫ32 °C; yield: 2.14 g
(43%). 1H NMR: δ ϭ 7.1 (m, 2 H), 7.07 (dd, J ϭ 7.3, 1.7 Hz, 1
H), 3.81 (s, 2 H) ppm. 13C NMR: δ ϭ 143.7, 141.6, 131.4 (t, J ϭ
257 Hz), 124.3, 123.5, 115.8, 112.5, 109.6, 17.6 ppm. C9H5F2NO2
(197.14): calcd. C 54.83, H 2.56, N 7.10; found C 54.90, H 2.77, N
7.09. Alternatively, the benzenesulfonate 13b (see Section 5; 3.3 g,
10 mmol), potassium cyanide (1.3 g, 20 mmol), 1,4,7,10,13,16-
hexaoxacyclooctadecane (‘‘18-crown-6’’, 0.26 g, 1.0 mmol), and
acetonitrile (20 mL) were heated under reflux for 20 h. Nitrile 20b
was again isolated as colorless star-shaped crystals; m.p. 31Ϫ32 °C
(from hexanes at Ϫ75 °C); yield: 1.4 g (71%).
[1]
M. Schlosser, in: Organometallics in Synthesis: A Manual (Ed.:
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E. Castagnetti, M. Schlosser, Eur. J. Org. Chem. 2001,
691Ϫ695, spec. 694.
C. Margot, M. Schlosser, Tetrahedron Lett. 1985, 26,
1035Ϫ1038.
A. Mordini, E. Ben Rayana, C. Margot, M. Schlosser, Tetra-
hedron 1990, 46, 2401Ϫ2410.
C. Margot, M. Rizzolio, M. Schlosser, Tetrahedron 1990, 46,
2411Ϫ2424.
C. Margot, H. Matsuda, Tetrahedron 1990, 46, 2425Ϫ2430.
S. Takagishi, M. Schlosser, Synlett 1991, 119Ϫ121.
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[11]
3-(2,2-Difluoro-1,3-benzodioxol-4-yl)propanenitrile (20c): A solution
of 3-(2-bromoethyl)-2,2-difluoro-1,3-benzodioxole (12c; see Section
5; 6.6 g; 25 mmol) and potassium cyanide (3,2 g, 50 mmol) in 75%
aqueous ethanol (75 mL) was heated under reflux for 6 h. Upon
distillation a colorless liquid was collected; b.p. 123Ϫ124 °C/
[12]
[13]
[14]
[15]
12 Torr; n2D0 ϭ 1.4810; yield: 4.58 g (87%). H NMR: δ ϭ 7.06 (t,
1
J ϭ 7.9 Hz, 1 H), 7.0 (m, 2 H), 3.04 (t, J ϭ 7.4 Hz, 2 H), 2.72 (t,
J ϭ 7.4 Hz, 2 H) ppm. 13C NMR: δ ϭ 143.6, 141.9, 131.4 (t, J ϭ
256 Hz), 124.2, 124.0, 120.3, 118.4, 108.7, 25.3, 17.3 ppm.
C10H7F2NO2 (211.17): calcd. C 56.88, H 3.34, N 6.63; found C
56.77, H 3.35, N 6.73. Under the same conditions as specified at
the end of the preceding paragraph, benzenesulfonate 13c (see Sec-
tion 5; 3.4 g, 10 mmol) was converted into the nitrile 20c in 88%
yield. The nitrile 20c was produced again when potassium tert-bu-
toxide (2.8 g, 25 mmol) and acetonitrile (2.3 mL, 1.0 g, 25 mmol)
were added consecutively to a vigorously stirred solution of butyl-
lithium (25 mmol) in tetrahydrofuran (40 mL) and hexanes (15 mL)
kept in a methanol/dry ice bath before, after 15 min at Ϫ75 °C, 4-
(bromomethyl)-2,2-difluoro-1,3-benzodioxole (6.3 g, 25 mmol) was
dissolved in the mixture which was warmed up to ϩ25 °C and then
distilled; b.p. 123Ϫ124 °C/12 Torr; yield: 3.1 g (59%). When not
only the alkoxide and acetonitrile but, in between these two ingredi-
ents, also diisopropylamine (3.5 mL, 2.5 g, 25 mmol) was added to
the butyllithium-containing reaction mixture, the yield of products
20c remained unchanged (58%).
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[24]
[25]
[26]
[27]
[28]
[29]
4-(2,2-Difluoro-1,3-benzodioxol-4-yl)butanenitrile (20d): Analog-
ously as described above for the lower homologs 20b and 20c, ni-
trile 20d was prepared from the bromo compound 12d (25 mmol)
and the benzenesulfonate 13d (10 mmol) in 91% and 82% yield,
respectively. It was purified by distillation: colorless oil; b.p.
[30]
[31]
[32]
1
134Ϫ136 °C/10 Torr; n2D0 ϭ 1.4756; yield: 5.14 g (91%). H NMR:
δ ϭ 7.03 (t, J ϭ 7.9 Hz, 1 H), 6.95 (dd, J ϭ 8.1, 1.3 Hz, 1 H), 6.91
(d, J ϭ 8.0 Hz, 1 H), 2.84 (t, J ϭ 7.6 Hz, 2 H), 2.38 (t, J ϭ 7.1 Hz,
2 H), 2.04 (quint, J ϭ 7.2 Hz, 2 H) ppm. 13C NMR: δ ϭ 143.6,
142.1, 131.4 (t, J ϭ 254 Hz), 124.4, 123.8, 122.3, 119.1, 108.0, 28.2,
25.0, 16.6 ppm. C11H9F2NO2 (225.19): calcd. C 58.67, H 4.03;
found C 58.72, H 4.02.
[33]
[34]
[35]
[36]
[37]
Acknowledgments
This work was financially supported by the Schweizerische Na-
tionalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20-55Ј303-98) and the Bundesamt für Bildung und Wissen-
schaft, Bern (grant 97.0083 linked to the TMR project
FMRXCT-970129).
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H.-S. Dang, B. P. Roberts, J. Chem. Soc., Perkin Trans. 1 1996,
13, 1493Ϫ1498.
Received August 7, 2002
[O02461]
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Eur. J. Org. Chem. 2003, 452Ϫ462