The facile and direct formylation of organoboron aromatic compounds with benzodithiolylium tetrafluoroborate

Article abstract of DOI:10.1002/ejoc.201300529

Organoboron compounds can be used to effect a direct formylation in the absence of transition metals. We report that the direct reaction between boronic derivatives and benzodithiolylium tetrafluoroborate, a commercially available carbenium ionic compound, is possible and provides access to many interesting compounds without the use of transition metals. The direct reaction of the carbenium ion with boronic derivatives results in the formation of substituted arylcarbenium ions, a number of which can be further utilized in materials chemistry or for the direct transformation into other compounds. In addition to the rich chameleonic chemical nature of the benzodithiol intermediate, such species can also undergo a metallation reaction and subsequent treatment with a wide range of electrophiles to access a variety of functional groups (aldehyde, ketone, acid, and alkyl groups). Copyright

Full text of DOI:10.1002/ejoc.201300529

FULL PAPER
DOI: 10.1002/ejoc.201300529
The Facile and Direct Formylation of Organoboron Aromatic Compounds with
Benzodithiolylium Tetrafluoroborate
Diego Petruzziello,[a] Andrea Gualandi,[a] Hamza Giaffar,[a] Veronica Lopez-Carrillo,[a] and
Pier Giorgio Cozzi*[a]
Keywords: Synthetic methods / Sulfur heterocycles / Boron / C–C coupling / Carbocations / Substituent effects
Organoboron compounds can be used to effect a direct
formylation in the absence of transition metals. We report
that the direct reaction between boronic derivatives and
arylcarbenium ions, a number of which can be further uti-
lized in materials chemistry or for the direct transformation
into other compounds. In addition to the rich chameleonic
benzodithiolylium tetrafluoroborate, a commercially avail- chemical nature of the benzodithiol intermediate, such spe-
able carbenium ionic compound, is possible and provides ac- cies can also undergo a metallation reaction and subsequent
cess to many interesting compounds without the use of tran-
sition metals. The direct reaction of the carbenium ion with
boronic derivatives results in the formation of substituted
treatment with a wide range of electrophiles to access a vari-
ety of functional groups (aldehyde, ketone, acid, and alkyl
groups).
Introduction
C–C bond forming reactions. Using the rule of thumb for
nucleophile-electrophile combinations,[6] a reaction between
an electrophile (E) and a suitable nucleophile (N) may take
a place at room temperature when E-N Ͼ –5 (for sN = 1
and 1 m concentration of both reagents to afford a 50%
conversion after 24 h at 20 °C). On the basis of the mea-
sured range of the nucleophilicity parameters for or-
ganoboron reagents, Mayr highlighted the possible scope of
organoboron compounds in new, reasonably tolerant, and
functional-group-compatible organic transformations,
which avoided the use of transition metals.[7]
Recently, we explored the reactivity of commercially
available and stable 1,3-benzodithiolylium tetrafluoroborate
(1)[8] in organocatalytic reactions.[9] The benzodithiolyl
group introduced by an organocatalytic strategy is chamele-
onic in nature and can be used to generate its anionic or
cationic equivalent. It can also be easily removed by Raney
nickel or transformed into a carbonyl or acid group. By
introducing the benzodithiolyl group in an organocatalytic
fashion and the successive treatment with Raney nickel, a
formal stereoselective α-methyl alkylation of aldehydes was
achieved, and this strategy was successfully applied to the
total syntheses of natural products.[10] With the favorable
stability and reactivity of the benzodithiolyl group, we
asked ourselves whether 1 could be used in the formylation
of organoboron reagents, that is, in a direct reaction real-
ized without any transition metal. The resulting substrates
are potentially useful intermediates, which could then allow
the direct transformation of boron reagents into other com-
pounds. In this report, we describe a full account of our
findings.
The transition-metal-catalyzed addition of organoboron
compounds to electrophilic C=X double bonds (X = N, O,
and C) has traditionally been one of the most important
methods for the construction of C–C bonds.[1] Aryl and alk-
enyltrifluoroborates as well as trialkoxyborates have been
used in the absence of transition metals,[2] whereas aryl-
boronic acids and arylboronates are commonly used in the
presence of Lewis base additives.[3] The formation of boron
ate complexes and their successive reaction with carbon
electrophiles such as iminium ions, Michael acceptors, and
stabilized carbocations have been recently explored.[4] To
quantify the nucleophilicity of arylboron compounds and
further explore the scope and limitations of organoboron
reagents in transition-metal-free carbon–carbon bond
forming reactions, Mayr and Knochel have recently applied
the benzhydrylium methodology to create a nucleophilicity
scale for these compounds.[5] Their results have confirmed
that the experimentally determined nucleophilicity values of
organoboron compounds are between those of organo-
lithium and organosilicon compounds. A particularly inter-
esting feature of this study was the establishment of new
nucleophilicity parameters to design transition-metal-free
[a] Dipartimento di Chimica “G. Ciamician”, Alma Mater
Studiorum Università di Bologna,
Via Selmi 2, 40126 Bologna, Italy
Fax: +39-051-2099456
E-mail: piergiorgio.cozzi@unibo.it
Homepage: www.unibo.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300529.
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this electrophile. The results for the process of screening the
solvent are shown in Table 1. Using acetonitrile resulted in
a significantly higher conversion in comparison to the other
solvents tested, for example, dichloroethane (DCE), tolu-
ene, and dioxane. No trace amounts of the product were
identified when N,N-dimethylformamide (DMF) was used.
In addition, the conversion in each of the examined solvents
did not increase as the reaction temperature was raised
above 80 °C, and, as such, 80 °C was selected as the opti-
mum reaction temperature.
Results and Discussion
Although transition-metal-free carbon–carbon bond
forming reactions between organoboronates as the nucleo-
philic partner and a stabilized carbenium ion are not well
established in the literature, they are potentially of great
interest to industry and academia. The Mayr scale[11] and
its relations provide a basis to combine an element of sys-
tematic rational design with the chemical intuition that has
guided previous efforts in this area of organic synthesis (see
Figure 1). The activation of the BF3K group is sufficient
for the organocatalytic Friedel–Crafts alkylation of α,β-un-
saturated iminium ions (–10 Ͻ E Ͻ –5, E = electrophilicity
according to Mayr[6b]), as described by MacMillan.[12] With
a wide range of nucleophilic boronate compounds from
which to choose and a quantitative correlation to govern
their reactivity in hand, the problem remains to select a
suitably versatile electrophilic partner.
Scheme 1. Direct formylation of 1 with boronic derivative 2a (THF
= tetrahydrofuran).
Table 1. Reaction conditions for the direct formylation of 2a with
electrophilic reagent 1.[a]
Entry
T [h]
Solvent
Temp. [°C]
% Yield[b]
1
2
3
4
16
48
24
24
16
16
10
DCE
DMF
THF
dioxane
toluene
CH3CN
CH3CN
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
80
60
0
10
17
50
73
74
5
6
7[c]
[a] The reaction was conducted under nitrogen atmosphere for the
indicated time. [b] Isolated yields after a fast chromatographic puri-
1
fication on neutral Al2O3. [c] The H NMR spectrum of the crude
reaction mixture showed almost complete conversion in CH3CN.
Figure 1. The nucleophilicity of boronic derivatives according to
Mayr scale rationalization.
This reaction was effective at room temperature, but
We have reported on other highly enantioselective α-alk- longer reaction times were necessary to achieve a satisfac-
ylations of aldehydes that have resulted from a carbenium tory conversion. The chemical properties of CH3CN are not
ion,[13] but benzodithiolylium 1 has a number of particu- thought to affect reaction rate. In fact, Mayr has observed
larly striking applications in the rapidly evolving field of only minor changes in the rate of the reaction when sp2-
organocatalysis.[9,10] The stability of 1 along with the pos- hybridized trivalent boron compounds were employed in
sibility of the benzodithiol to undergo a metallation fol- CH3CN compared to CH2Cl2, thereby excluding the pos-
lowed by treatment with an alkylating agent and then with sibility that acetonitrile coordinates to the sp2-hybridized
Raney Nickel for the simple elimination of this group boron center. The number of equivalents of 1 was impor-
prompted us to investigate the reactivity of 1 with a range tant to drive the reaction toward the desired product.
of organoboron reagents. As the electrophilicity of 1 falls
It is well known that carbenium ions can be obtained by
in a range (i.e., –4 Ͻ E Ͻ –3), we examined its reactivity in a hydride shift.[14] As soon as the aryl benzodithiol 3a was
the presence of a number of functionalized aryltrifluorob- obtained, the product was transformed into the correspond-
orate salts. From inspection of the Mayr nucleophilicity pa- ing cationic compound 4a (see Scheme 2). To drive the reac-
rameters that are published for organoboron reagents,[5] the tion toward the formation of the more stabilized cation 4a,
aryltrifluoroborate salts exhibit moderate nucleophilicity which is stable in air and isolatable by filtration, almost
(see Figure 1). However, the more nucleophilic boron ate 2.5 equiv. of 1 were necessary. To isolate the compound in
complexes were not suitable for the carbenium ion, as the its neutral form, the crude reaction mixture underwent a
alcohol that is in equilibrium with the ate complex is pre- reduction reaction by treatment with NaBH4 to afford de-
sumed to intercept the carbenium ion. The desired com- sired 3a in high yields. The isolation of a number of prod-
pounds were obtained after the reduction of the carbenium ucts proved to be challenging because of their tendency to
ion intermediate by treatment with NaBH4 (see Scheme 1). form stabilized cations. Fortunately, preparative TLC on
Because of the easy access to compound 1, the procedure neutral Al2O3 resulted in only minor decomposition (for-
to optimize this reaction was conducted with 2.5 equiv. of mation of the carbenium ion by a hydride shift).
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Formylation of Organoboron Aromatic Compounds
Scheme 2. Formation of the most stable cationic compounds by hydride shift.
The case of the reaction with aryltrifluoroborate 2a,
which demonstrated a successful conversion into the corre-
sponding coupled product in good yield, was extended to
other aryltrifluoroborates (see Scheme 3 and Table 2). All
the trifluoroborate salts were prepared from commercially
available boronic acid through a simple procedure described
by Molander.[15] Aryltrifluoroborates with electron-donat-
ing groups (i.e., 2g–2i) on the aromatic ring resulted in both
better conversions into the coupled products and better
yields of the isolated products in comparison to those with
electron-withdrawing groups (i.e., 2b and 2c). An explana-
tion for this is the increased nucleophilicity of the organic
residue in the case of an activated ring system that con-
tained electron-donating groups as opposed to a relatively
deactivated ring that contained electron-withdrawing
groups. This reaction was also tolerant of halide functional-
ities on the aromatic ring. Both 2e and 2f underwent the
coupling reaction with a high conversion, but only 3e was
successfully isolated as a pure product. Strongly electron-
deficient aromatic substrates (i.e., pyridine, formylthio-
phenes, etc.)[16] were unreactive under the reaction condi-
tions. The products were purified by preparative TLC on
neutral Al2O3.
Table 2. Addition of the benzodithiolylium 1 to electron-rich and
electron-poor aryltrifluoroborates.
Scheme 3. Reaction of 1 with different boronic derivatives.
The facile formation of the cation by a hydride shift can
be advantageously used for the preparation of new hydridic
reagents for organocatalytic reductions.[14] The ipso Friedel–
Crafts electrophilic aromatic substitution mechanism is pre-
sumed to be the prevalent reaction pathway in this class of
reactions. Mayr et al. reported that changing the counterion
in the reaction of a number of borates with a benzhy-
drylium cation did not result in a significant change in the
rate of the reaction.[5] This indicates a rate-determining car-
bon–carbon bond forming step in which the carbon–boron
bond is not yet fully broken, which is a result fully consis-
tent with the Friedel–Crafts SEAr mechanism. However,
electron-rich aromatic compounds can also undergo a di-
rect reaction with 1.[8b] In fact, when p-methoxybenzene
was treated with 1 in CH3CN, satisfactory yields of the
Friedel–Crafts product were achieved (70%). However, less
activated substrates such as toluene or xylenes were unreac-
tive. The facility of a direct reaction is determined by the
position of the arene compounds on the Mayr scale. For
[a] All the reactions were conducted in CD3CN. [b] Conversion was
determined by H NMR analysis of the crude reaction mixture in
CD3CN. The isolated yield after chromatographic purification on
neutral Al2O3 is reported in parenthesis. [c] Product was obtained
as inseparable mixture with benzodithiol 5. [d] Product obtained
was para substituted. [e] No reaction. [f] Trace amounts of the de-
1
the moderately activated substrates presented in Table 2, the sired compound was determined by GC–MS analysis.
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Friedel–Crafts type reaction was not possible. In addition, nism, can be effectively eliminated by amine scavengers to
we examined the possibility of a competition between the trap the proton that is released during the electrophilic at-
activating effect of the BF3K on the aromatic ring and the tachment. In fact, when 2l was treated with 1 in the pres-
ipso activation by the trifluoroborate. Substitution at the ence of NaH2PO4 or at room temperature, compound 6l
1
CH-position of a heterocycle and aromatic ring can be was characterized by H NMR spectroscopy.[18]
faster that ipso substitution. Mayr recently reported[17] that
The versatility and synthetically utility of the benzodi-
the BF3K group activates the position attached to boron thiol group is illustrated in the Scheme 5, where all the
by a factor of 103–104, whereas adjacent CH-positions are transformations investigated occurred in high yields. The
activated by a factor of 105–106. In fact, when we submitted benzodithiol group can be easily alkylated by an electro-
the potassium 3-methoxyphenyltrifluoroborate salt (2l, phile following its treatment with nBuLi. Therefore, aro-
meta substituted) to 1 under the optimized reaction condi- matic ketones can be easily obtained starting from an aryl-
tions, the reaction led to the isolation of the corresponding trifluoroborate. The benzodithiol group can also be oxid-
para-substituted compound 3l (see Scheme 4).
ized to the corresponding carboxylic acid.
The activating effects of the BF3K group on the vicinal
The benzodithiol is not only the masked form of a corre-
and more remote positions of indole, furan, benzofuran, sponding aldehyde, ketone, or acid, but it is also possible to
and thiophenes were also investigated by Mayr.[17] By select- eliminate the group by hydrogenation, which provides ac-
ing an electrophile as a reference compound, a quantitative cess to alkyl aryl compounds. The direct obtainment of a
structure–activity relationship showed that BF3K enhanced carbenium ion in the reaction can be advantageously used
the nucleophilic reactivity of the C-3 position of indole less for the successive addition of nucleophiles. This transforma-
when it was located at C-3 (ipso) than when it was located tion can be accomplished through a one-pot, two-step pro-
at another position, such as the vicinal C-2 or the remote cedure. The electrophilicity of intermediate cations such as
C-5 position. Similarly in furans, the nucleophilic reactivity 4a or 4h is not very high. This limited capacity to behave
of the heterocycle was enhanced more when the BF3K as a powerful electrophile restricts the range of nucleophiles
group was located in a remote position than when it was that can be used to intercept these arylbenzodithiolylium
located at the ipso position. Therefore, the ipso activation cations.[19] In fact, on the upper end of Mayr’s scale, en-
of the BF3K is less than its activation at a vicinal or remote amines appear as strong nucleophiles, and their reaction
position. In almost all the examples examined in Table 2, with appropriate electrophiles demonstrate rate constants
the vicinal or remote position of the aromatic compound in the diffusion-controlled region. Two separate, but direct,
was less activated compared to the ipso position. When 2l reactions of electrophilic compound 3a with two such en-
was considered, the competition of ipso versus vicinal sub- amines, 1-morpholinocyclohexene and 1-morpholinocyclo-
stitution was observed. Mayr reported that the proto-de- pentene, did not result in any further coupling product as
borylation, which is promoted by the Friedel–Crafts mecha- determined by 1H NMR analysis after 17 h. Only very reac-
Scheme 4. Reactions of electron-rich boronic acid derivative.
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Formylation of Organoboron Aromatic Compounds
Scheme 5. Multistep reaction sequences utilizing the chameleonic benzodithiol group.
tive nucleophiles, positioned at or below 18 on the Mayr
Conclusions
scale[7] could be used for a reaction to be obeserved. In fact,
In summary, by taking advantage of the results from the
when the anion of dimethyl 2-methylmalonate (prepared by
addition of NaH in THF) was added to compound 4h, we
isolated the desired adduct 7 in high yield. Interestingly, the
treatment of 7 with Raney-Ni resulted in the elimination
of the benzodithiol moiety and the reduction of the less
substituted benzene ring. When the reaction was repeated
with compound 11, the elimination of the benzodithiol
group occurred without this side reaction.
Heteroaromatic electron-poor substrates were also inves-
tigated under the optimal reaction conditions. In general,
they did not perform as well as the other substrates re-
ported in Table 2. Neither 3-pyridinyl trifluoroborate 2m
nor 5-formylthiophene trifluoroborate 2n underwent a suc-
cessful coupling reaction. Other trifluoroborate salts were
investigated as well. Potassium (phenylethenyl)trifluorobor-
ate was treated with 1,3-benzodithiolylium tetrafluorobor-
ate, but no trace of the reaction product was observed after
48 h at 80 °C. Unsaturated adducts such as the vinyl tri-
fluoroborate salt were unreactive. We also examined cyclo-
hexyl trifluoroborate 2o and hexyl trifluoroborates 2p. With
the latter, there were trace amounts of the desired adduct
that were observed by GC–MS analysis, but we were unable
to isolate it as decomposition occurred during chromatog-
raphy.
kinetic and synthetic studies described by Mayr, we were
able to design a simple and effective procedure for the direct
formylation of aryltetrafluoroborate salts. The advantage of
introducing the benzodithiol group stems from its chamele-
onic chemical nature, as this group can be used for further
transformations. The cationic aryl benzodithiolylium com-
pounds, accessible through a direct reaction of 1, are poten-
tially of use in materials science. We are currently expanding
the limitation of this chemistry by studying related reactions
that involve a variety of boronic derivatives and suitable
carbenium ion precursors.
Experimental Section
1
General Methods: The H NMR spectroscopic data were recorded
with Varian Gemini 200 and Varian MR 400 spectrometers. Chemi-
cal shifts are reported in ppm relative to TMS with the residual
solvent resonance as the internal standard (chloroform, δ =
7.27 ppm). Data are reported in the order of chemical shift, multi-
plicity [singlet (s), doublet (d), triplet (t), quartet (q), broad singlet
(br. s), and multiplet (m)], and coupling constants (Hz). The 13C
NMR spectroscopic data were recorded with Varian Gemini 200
and Varian MR 400 spectrometers. Chemical shifts are reported
in ppm relative to TMS with the solvent as the internal standard
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P. G. Cozzi et al.
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(deuterochloroform, δ = 77.0 ppm). LC–electrospray ionization
mass spectra were obtained with an Agilent Technologies
MSD1100 single-quadrupole mass spectrometer. Chromatographic
purification was performed with 240–400 mesh silica gel. Melting
points were measured with a Bibby Stuart Scientific Melting Point
Apparatus SMP 3. Reactions were carried out under inert gas and
anhydrous conditions. Anhydrous solvents were supplied by Ald-
rich in Sureseal® bottles and used without further purification.
(m, 2 H), 7.92 (s, 1 H) ppm. 19F NMR (377 MHz, [D6]acetone): δ
= –129.9 ppm.
Preparation of Potassium Benzo[b]thien-2-yltrifluoroborate (2j): The
general procedure was used with benzo[b]thien-2-ylboronic acid
(100 mg, 0.562 mmol) and KHF2 (131.5 mg, 1.686 mmol). The re-
action was completed in 30 min. Acetone (5 mL) was added to the
crude solid, and the resulting mixture was sonicated and then fil-
tered. This procedure was repeated (2ϫ). The combined filtrates
were concentrated in vacuo, and the crude solid was redissolved in
a minimal amount of hot acetone (2 mL). The addition of ether
(10 mL) led to the precipitation of the product, which was filtered,
collected, and dried in vacuo to afford the desired pure product
(94 mg, 0.393 mmol, 70% yield) as an off-white solid. 1H NMR
(400 MHz, [D6]acetone): δ = 7.09 (m, 1 H), 7.12–7.20 (m, 2 H), 7.63
(dt, J = 7.8, 1.0 Hz, 1 H), 7.74 (m, 1 H) ppm. 19F NMR (377 MHz,
CD3CN): δ = –138.36 ppm.
General Procedure for the Preparation of Potassium Aryl and Het-
eroaryl Trifluoroborates: To a solution of boronic acid (1 equiv.) in
MeOH (3.5 m solution) under nitrogen was added KHF2 (3 equiv.)
in one portion at 0 °C. To this suspension was added H2O dropwise
at 0 °C. The ice-water bath was removed, and the reaction was
stirred at room temperature for 1 h. The mixture was then concen-
trated and dried overnight in vacuo. The desired product was then
extracted from the crude solid with acetone (2ϫ5 mL) and sonic-
ation and then further extracted with hot acetone (2ϫ5 mL). The
collected extracts were then concentrated, and the residue was re-
dissolved in a minimal amount of acetone (5 mL). The addition of
ether (5 mL) encouraged precipitation of the product. The collected
product was isolated by filtration and dried in vacuo.
Potassium 3-Methoxyphenyltrifluoroborate (2l): The general pro-
cedure was used with 3-methoxyphenylboronic acid (200 mg,
1.316 mmol) and KHF2 (821 mg, 10.526 mmol). Relative to the ge-
neral procedure, this corresponds to an increase from 3 to 8 equiv.
in the amount of KHF2. The reaction was completed in 2 h. Ace-
tone (5 mL) was added to the crude solid, and the resulting mixture
was sonicated and then filtered. This procedure was repeated (2ϫ).
The combined filtrates were concentrated in vacuo, and the crude
solid was redissolved in a minimal amount of hot acetone (3 mL).
The addition of ether (5 mL) led to the precipitation of the product,
which was filtered, collected, and dried in vacuo to afford the de-
sired pure product (248 mg, 1.200 mmol, 91% yield) as a white so-
lid. 19F NMR (377 MHz, [D6]acetone): δ = –142.85 ppm.
Potassium 2,4-Difluorophenyltrifluoroborate (2f): The general pro-
cedure was used with 2,4-difluorophenylboronic acid (200 mg,
1.266 mmol) and KHF2 (290 mg, 3.723 mmol). The reaction was
completed in 1 h. Acetone (5 mL) was added to the crude solid,
and the resulting mixture was sonicated and then filtered. This pro-
cedure was repeated (2ϫ). The combined filtrates were concen-
trated in vacuo, and the crude solid was redissolved in a minimal
amount of hot acetone (2 mL). The addition of hexane (4 mL) led
to the precipitation of the product, which was filtered, collected,
and dried in vacuo to afford the desired pure product (267 mg,
1.212 mmol, 96% yield) as a white solid. 1H NMR (400 MHz, [D6]-
acetone): δ = 6.48 (td, J = 9.8, 2.4 Hz, 1 H), 6.59 (td, J = 8.5,
2.3 Hz,1 H), 7.35 (q, J = 7.8 Hz, 1 H) ppm. 19F NMR (377 MHz,
[D6]acetone): δ = –99.58, –111.17 (q, J = 8.3 Hz), –134.21 (q, J =
45.6 Hz) ppm.
Potassium Pyridin-3-yltrifluoroborate (2m): The general procedure
was used with 3-pyridylboronic acid (50 mg, 0.407 mmol) and
KHF2 (101 mg, 1.301 mmol). The reaction was completed in
10 min. Acetone (3 mL) was added to the crude solid, and the re-
sulting mixture was sonicated and then filtered. This procedure was
repeated (2ϫ). The combined filtrates were concentrated in vacuo,
and the crude solid was redissolved in a minimal amount of hot
acetone (1 mL). The addition of hexane (3 mL) led to the precipi-
tation of the product along with what was identified as the zwitter-
ionic form of the salt – potassium pyridiniumtrifluoroborate. The
product was filtered, collected, and dried in vacuo to afford the
desired pure product (56 mg, 0.301 mmol, 74% yield) as a white
solid. 1H NMR (400 MHz, [D6]acetone): δ = 6.99 (m, 1 H), 7.69
(d, 1 H), 8.24 (m, 1 H), 8.61 (s, 1 H) ppm. 19F NMR (377 MHz,
[D6]acetone): δ = –142.93 ppm.
Potassium 4-Biphenyltrifluoroborate (2g): The general procedure
was used with 4-biphenylboronic acid (100 mg, 0.505 mmol) and
KHF2 (315 mg, 4.039 mmol). The reaction was completed in 2 h.
Acetone (5 mL) was added to the crude solid, and the resulting
mixture was sonicated and then filtered. This procedure was re-
peated (2ϫ). The combined filtrates were concentrated in vacuo,
and the crude solid was redissolved in a minimal amount of hot
acetone (2 mL). The addition of ether (10 mL) led to the precipi-
tation of the product, which was filtered, collected, and dried in
vacuo to afford the desired pure product (108 mg, 0.414 mmol,
82% yield) as a white solid. 1H NMR (400 MHz, CD3CN): δ =
7.27–7.33 (m, 1 H), 7.39–7.49 (m, 4 H), 7.52 (d, J = 7.7 Hz, 2
H),7.61–7.66 (m, 2 H) ppm. 19F NMR (377 MHz, [D6]acetone): δ
= –138.7 ppm.
Potassium (5-Formyl-2-thienyl)trifluoroborate (2n): The general pro-
cedure was used with (5-formyl-2-thienyl)boronic acid (100 mg,
0.641 mmol) and KHF2 (160 mg, 2.051 mmol). The reaction was
completed in 30 min. Acetone (4 mL) was added to the crude solid,
and the resulting mixture was sonicated and then filtered. This pro-
cedure was repeated (2ϫ). The combined filtrates were concen-
trated in vacuo, and the crude solid was redissolved in a minimal
amount of hot acetone (2 mL). The addition of ether (5 mL) led to
the precipitation of the product, which was filtered, collected, and
dried in vacuo to afford the desired pure yellow-brown product
(101 mg, 0.462 mmol, 72% yield). 1H NMR (400 MHz, [D6]acet-
one): δ = 7.09 (s, 1 H), 7.68 (s, 1 H), 9.81 (s, 1 H) ppm. 19F NMR
(377 MHz, [D6]acetone): δ = –132.7 ppm.
Potassium Naphthalene-2-trifluoroborate (2h): The general pro-
cedure was used with naphthalene-2-boronic acid (200 mg,
1.163 mmol) and KHF2 (272 mg, 3.489 mmol). The reaction was
completed in 10 min. Acetone (3 mL) was added to the crude solid,
and the resulting mixture was sonicated and then filtered. This pro-
cedure was repeated (2ϫ). The combined filtrates were concen-
trated in vacuo, and the crude solid was redissolved in a minimal
amount of hot acetone (2 mL). The addition of hexane (3 mL) led
to the precipitation of the product, which was filtered, collected,
and dried in vacuo to afford the desired pure product (253 mg,
1.08 mmol, 93% yield) as a white solid. 1H NMR (400 MHz,
Potassium (Phenylethenyl)trifluoroborate: A solution of phenyl-
acetylene (300 mg, 2.94 mmol) in THF (5.88 mL) was cooled to
–78 °C under nitrogen. nBuLi (2.5 m in hexane, 1.176 mL,
2.94 mmol, 1 equiv.) was added dropwise, and the solution was
CD3CN): δ = 7.32–7.42 (m, 2 H), 7.62–7.71 (m, 2 H), 7.75–7.83 stirred for 1 h at this temperature. Trimethylborate (459 mg,
4914
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Formylation of Organoboron Aromatic Compounds
4.41 mmol, 1.5 equiv.) was then added dropwise at –78 °C. The
solution was stirred at this temperature for 1 h, and a saturated
aqueous solution of KHF2 (1.376 g, 17.64 mmol, 6 equiv.) was
added to the vigorously stirred solution. The resulting mixture was
stirred at –20 °C for 1 h and then was warmed to room temperature
for 1 h. The solvent was removed under reduced pressure, and the
resulting white solid was dried under high vacuum for 2 h. The
solid was then extracted with acetone (2ϫ5 mL) and hot acetone
(3ϫ5 mL). The combined organic mixtures were filtered, and the
solvent was removed to afford a fluffy white solid. This solid was
then dissolved in hot acetone and precipitated with the addition of
diethyl ether. The solution was cooled to –20 °C to complete the
precipitation of the solid. The product was collected to afford po-
tassium (phenylethenyl)trifluoroborate (330 mg, 1.59 mmol, 54%
2-(4-Bromophenyl)benzo[d][1,3]dithiole (3e): 1H NMR (400 MHz,
CDCl3): δ = 6.09 (s, 1 H), 7.07 (dd, J = 3.2, 5.8 Hz, 2 H), 7.20
(dd, J = 3.2, 5.8 Hz, 2 H), 7.47–7.38 (m, 4 H) ppm. 13C NMR
(100.76 MHz, CDCl3, 25 °C): δ = 139.3 (1 C), 137.1 (2 C), 131.8
(2 C), 128.7 (2 C), 125.9 (2 C), 125.6 (1 C), 122.0 (2 C), 55.6 (1
C) ppm. HRMS: calcd. for C13H9BrS2 307.93290; found 307.93312.
2-(2,4-Difluorophenyl)benzo[d][1,3]dithiole (3f): The compound was
obtained as a inseparable mixture with the benzodithiole. Chroma-
tographic purification was not possible in this as case. Many dif-
ferent eluent mixtures were used, but the compounds were not sep-
1
arable. H NMR (400 MHz, CDCl3): δ = 6.26 (s, 1 H), 6.85–6.75
(m, 2 H), 7.73–7.64 (m, 1 H), 7.24 (dd, J = 3.3, 5.9 Hz, 2 H),
7.08 (dd, J = 3.3, 5.9 Hz, 2 H) ppm. HRMS: calcd. for C13H8F2S2
266.00355; found 266.00333.
1
yield) as a white crystalline solid. H NMR (400 MHz, CD3CN):
2-([1,1Ј-Biphenyl]-4-yl)benzo[d][1,3]dithiole
(3g):
1H
NMR
δ = 7.31–7.22 (m, 2 H), 7.40–7.34 (m, 1 H) ppm. 19F NMR
(377 MHz, CD3CN): δ = –135.17 ppm.
(400 MHz, CDCl3): δ = 6.24 (s, 1 H), 7.08 (dd, J = 3.3, 5.8 Hz, 2
H), 7.23 (dd, J = 3.3, 5.8 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 2 H), 7.35
(t, J = 7.3 Hz, 1 H), 7.52–7.59 (m, 4 H), 7.44 (d, J = 8.0 Hz, 2
H) ppm. 13C NMR (100.76 MHz, CDCl3): δ = 56.3 (1 C), 122.0 (2
C), 125.9 (2 C), 127.2 (2 C), 127.5 (4 C), 127.6 (1 C), 128.9 (2 C),
137.6 (2 C), 139.0 (1 C), 140.5 (1 C), 141.8 (1 C) ppm. HRMS:
calcd. for C19H14S2 306.05369; found 306.05347.
2-(Naphthalen-2-yl)benzo[d][1,3]dithiole (3h): 1H NMR (400 MHz,
CDCl3): δ = 6.37 (s, 1 H), 7.07 (dd, J = 3.3, 5.9 Hz, 2 H), 7.23 (dd,
J = 3.3, 5.9 Hz, 2 H), 7.48 (dd, J = 3.3, 6.2 Hz, 2 H), 7.73 (d, J =
8.8 Hz, 1 H), 7.77–7.85 (m, 3 H), 7.89 (s, 1 H) ppm. 13C NMR
(100.76 MHz, CDCl3): δ = 56.8 (1 C), 122.0 (2 C), 124.9 (2 C),
125.9 (2 C), 126.5 (2 C), 127.7 (1 C), 128.1 (1 C), 129.0 (1 C), 132.5
(1 C), 133.4 (1 C), 137.1 (1 C), 137.6 (2 C) ppm. HRMS: calcd. for
C17H12S2 280.03804; found 280.03822.
General Procedure for the Coupling of Potassium Organotrifluoro-
borates with 1,3-Benzodithiolylium Tetrafluoroborate: To a stirred
solution of the potassium organotrifluoroborate (1 equiv.) in aceto-
nitrile (1 mL) under nitrogen was added 1,3-benzodithiolylium tet-
rafluoroborate (1, 2.5 equiv.). The mixture was heated at 80 °C and
then stirred overnight (16 h). The solvent was then removed under
reduced pressure. THF (1 mL) was added to dissolve the resulting
solid, and to the stirred mixture was added NaBH4 (10 equiv.) over
the course of 1 h at 0 °C. Water (5 mL) was added, and the mixture
was then transferred to a separatory funnel. EtOAc was added, and
the aqueous layer was thoroughly extracted with EtOAc
(3ϫ2.5 mL). The combined organic extracts were dried with
Na2SO4 and then filtered. Removal of the solvent under reduced
pressure and subsequent purification by preparative TLC (neutral-
alumina) afforded the product.
2-(4-Butoxyphenyl)benzo[d][1,3]dithiole (3i): 1H NMR (400 MHz,
CDCl3): δ = 0.95 (t, J = 7.4 Hz, 3 H), 1.67–1.79 (m, 2 H), 1.52–
1.40 (m, 2 H), 3.93 (t, J = 6.5 Hz, 2 H), 6.22 (s, 1 H), 6.82 (d, J =
8.7 Hz, 2 H), 7.03 (dd, J = 3.3, 5.7 Hz, 2 H), 7.17 (dd, J = 3.3,
1
2-Phenylbenzo[d][1,3]dithiole (3a): H NMR (400 MHz, CDCl3): δ
= 6.20 (s, 1 H), 7.06 (dd, J = 3.0, 5.8 Hz, 2 H), 7.21 (dd, J = 3.0,
5.8 Hz, 2 H), 7.29–7.37 (m, 3 H), 7.55 (dd, J = 2.0, 7.4 Hz, 2
H) ppm. 13C NMR (100.76 MHz, CDCl3): δ = 56.5 (1 C), 121.9 (2
C), 125.8 (2 C), 127.1 (2 C), 128.7 (2 C), 128.8 (1 C), 137.5 (2 C),
139.9 (1 C) ppm. HRMS: calcd. for C13H10S2 230.02239; found
230.02261.
5.7 Hz,
2 H), 7.48 (d, J =
8.7 Hz, 2 H) ppm. 13C NMR
(100.76 MHz, CDCl3): δ = 13.8 (1 C), 19.2 (1 C), 31.2 (1 C), 56.6
(1 C), 67.7 (1 C), 114.6 (2 C), 121.9 (2 C), 125.7 (2 C), 128.4 (2
C), 131.1 (1 C), 137.7 (2 C), 159.5 (1 C) ppm. HRMS: calcd. for
C17H18OS2 302.07991; found 302.08009.
2-(Benzo[b]thiophen-2-yl)benzo[d][1,3]dithiole (3j): 1H NMR
(400 MHz, CDCl3): δ = 6.37 (s, 1 H), 7.13–7.40 (m, 2 H), 7.21–
7.29 (m, 3 H), 7.28–7.33 (m, 2 H), 7.63–7.70 (m, 1 H), 7.70–7.77
(m, 1 H) ppm. 13C NMR (100.76 MHz, CDCl3): δ = 52.2 (1 C),
122.3 (2 C), 122.4 (2 C), 123.8 (1 C), 124.5 (1 C), 124.9 (1 C), 125.8
(1 C), 126.0 (2 C), 136.7 (1 C), 138.8 (1 C), 139.8 (1 C), 145.3 (1
C) ppm. HRMS: calcd. for C15H10S3 285.99446; found 285.99439.
Methyl 4-(Benzo[d][1,3]dithiol-2-yl)benzoate (3b): 1H NMR
(400 MHz, CDCl3): δ = 3.91 (s, 3 H), 6.13 (s, 1 H), 7.07 (dd, J =
3.0, 5.8 Hz, 2 H), 7.22 (dd, J = 3.0, 5.8 Hz, 2 H), 7.58 (d, J =
8.4 Hz,
2 H), 7.98 (d, J =
8.4 Hz, 2 H) ppm. 13C NMR
(100.76 MHz, CDCl3): δ = 52.2 (1 C), 55.6 (1 C), 122.0 (2 C), 125.7
(1 C), 126.0 (2 C), 127.0 (2 C), 130.1 (2 C), 137.2 (2 C), 151.0 (1 C),
198.0 (1 C) ppm. HRMS: calcd. for C15H12O2S2 288.02787; found
288.02809.
2-(Benzo[b]furan-2-yl)benzo[d][1,3]dithiole
(3k):
1H
NMR
Methyl 3-(Benzo[d][1,3]dithiol-2-yl)benzoate (3c): 1H NMR
(400 MHz, CDCl3): δ = 3.91 (s, 3 H), 6.21 (s, 1 H), 7.07 (dd, J =
3.3, 5.8 Hz, 2 H), 7.21 (dd, J = 3.3, 5.8 Hz, 2 H), 7.41 (t, J =
7.8 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.97 (d, J = 7.8 Hz, 1 H),
8.17 (s, 1 H) ppm. 13C NMR (100.76 MHz, CDCl3): δ = 52.2 (1
C), 55.9 (1 C), 122.0 (2 C), 125.9 (2 C), 128.2 (1 C), 129.0 (1 C),
129.9 (1 C), 130.5 (1 C), 131.6 (1 C), 137.2 (2 C), 140.6 (1 C),
166.5 (1 C) ppm. HRMS: calcd. for C15H12O2S2 288.02787; found
288.02765.
(400 MHz, CDCl3): δ = 6.02 (s, 1 H), 6.78 (s, 1 H), 7.00–7.11 (m,
2 H), 7.17 (t, J = 7.2 Hz, 1 H), 7.21–7.29 (m, 3 H), 7.39–7.50 (m,
2 H) ppm. 13C NMR (100.76 MHz, CDCl3): δ = 48.3 (1 C), 104.8
(1 C), 111.4 (1 C), 121.2 (1 C), 122.4 (2 C), 123.0 (1 C), 124.7 (1
C), 125.9 (2 C), 127.9 (1 C), 136.4 (2 C), 155.3 (1 C), 155.4 (1
C) ppm. HRMS: calcd. for C15H10OS2 270.01731; found
270.01715.
1
2-(4-Methoxyphenyl)benzo[d][1,3]dithiole (3l): H NMR (400 MHz,
CDCl3): δ = 3.79 (s, 3 H), 6.23 (s, 1 H), 6.84 (d, J = 8.7 Hz, 2 H),
2-(2,6-Dimethylphenyl)benzo[d][1,3]dithiole
(3d):
1H
NMR
(400 MHz, CDCl3): δ = 2.63 (s, 6 H), 7.08–6.98 (m, 4 H), 7.09– 7.49 (d, J = 8.7 Hz, 2 H), 7.04 (dd, J = 3.2, 5.8 Hz, 2 H), 7.19 (dd,
7.21 (m, 3 H), 7.22–7.34 (m, 1 H) ppm. 13C NMR (100.76 MHz,
J = 3.2, 5.8 Hz, 2 H) ppm. 13C NMR (100.76 MHz, CDCl3): δ =
CDCl3): δ = 21.8 (2 C), 52.1 (1 C), 121.8 (2 C), 125.4 (2 C), 125.9
55.3 (1 C), 56.5 (1 C), 114.0 (2 C), 121.8 (2 C), 125.7 (2 C), 128.4
(1 C), 128.6 (2 C), 129.8 (2 C), 131.1 (1 C), 139.0 (2 C) ppm. (2 C), 131.5 (1 C), 137.7 (2 C), 159.9 (1 C) ppm. HRMS: calcd. for
HRMS: calcd. for C15H14S2 258.05369; found 258.05347. C14H12OS2 260.03296; found 260.03287.
Eur. J. Org. Chem. 2013, 4909–4917
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4915

P. G. Cozzi et al.
FULL PAPER
Synthesis of 6: In a flask that was open to air was dissolved 2-
(naphthalen-2-yl)benzo[d][1,3]dithiole (30 mg, 0.1 mmol, 1 equiv.)
in CH3CN (1.0 mL, 0.1 m solution). To this mixture was added
H2O2 (70% solution, 0.57 mL, 0.4 mmol) followed by HBr
(0.022 mL, 0.2 mmol, 2 equiv.) at room temperature. After 24 h, the
reaction was quenched by the addition of a saturated solution of
NaHSO3 (1 mL) and a saturated solution of NaHCO3 (5 mL). The
aqueous phase was extracted with diethyl ether (2ϫ5 mL). The
aqueous phase was acidified with HCl (1 n solution, 5 mL) until
the pH = 1 and was then extracted with ethyl acetate (2ϫ5 mL).
The combined organic phases were evaporated under reduced pres-
sure to give the pure product (92% yield). Spectroscopic data were
in agreement with the published data.[20]
128.9 (1 C), 130.8 (1 C), 132.3 (1 C), 136.2 (1 C), 137.0 (1 C), 172.5
(2 C) ppm.
Supporting Information (see footnote on the first page of this arti-
cle): Evidence of ipso substitution of compound 3j and NMR spec-
tra.
Acknowledgments
MIUR (Rome) through the project PRIN (Progetto Nazionale
Stereoselezioni in Chimica Organica: Metodologie ed Applicazioni),
Bologna University, Fondazione Del Monte, European Commis-
sion through the project FP7-201431 (CATAFLU.OR) and the pro-
ject FP7-ITN-238434 (BioChemLig) are acknowledged for finan-
cial support.
Synthesis of 10: In a two-necked flask under nitrogen was dissolved
2-(naphthalen-2-yl)benzo[d][1,3]dithiole
(30 mg,
0.1 mmol,
1 equiv.) in THF (1.0 mL, 0.1 m solution). n-Butyllithium
(0.2 mmol, 2 equiv.) was added dropwise at 0 °C until the mixture
was a persistent yellow color. The reaction mixture was stirred at
0 °C for 15 min, and then MeI (0.5 mmol, 0.5 equiv.) was added
dropwise. The reaction was monitored by GC–MS and quenched
by the addition of water. The mixture was extracted with diethyl
ether (3ϫ2 mL). The combined organic phases were evaporated
under reduced pressure to give an oil. The crude product was dis-
solved in THF (1.0 mL), and the resulting solution was added to a
suspension of HgO (0.8 mmol, 0.8 equiv.) in H2O (1 mL) followed
by the addition of HBF4 (0.2 mL, 0.2 mL/mmol). After 15 h,
NaHCO3 was added until the solution was basic on the pH scale.
The reaction mixture was filtered through Celite and washed with
diethyl ether. The filtrate was extracted with diethyl ether
(2ϫ3 mL). The combined organic phases were evaporated under
reduced pressure to give the crude product. Purification by flash
chromatography on silica (cyclohexane/ethyl acetate, 95:5) provided
the pure product (81% yield). Spectroscopic data were in agreement
with the published data.[21]
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General Procedure for the Synthesis of Malonates 9 and 12: Under
nitrogen into a two-necked flask that contained NaH (20 mg,
0.5 mmol, 5 equiv.) was added THF (1 mL). Methyl dimethyl-
malonate (0.073 mL, 0.55 mmol, 5.5 equiv.) was subsequently
added dropwise at 0 °C. After 20 min, the reaction mixture was
added dropwise by cannula to a solution of 2-phenylbenzo[d][1,3]-
dithiolylium tetrafluoroborate (4a, 77 mg, 0.1 mmol, 1 equiv.) in
THF (0.5 mL, 0.05 m solution) under nitrogen. The reaction mix-
ture was stirred at room temperature for 15 h and then was
quenched by the addition of H2O (2 mL). The mixture was ex-
tracted with diethyl ether (2ϫ3 mL). The combined organic ex-
tracts were evaporated under reduced pressure, and the crude prod-
uct was dissolved in MeOH (3 mL). To this solution was added
Raney-Ni (slurry in water, 500 mg), and the mixture was stirred
under H2. After 48 h, the reaction mixture was filtered through
Celite, which was washed with MeOH. The MeOH was evaporated,
and H2O/diethyl ether was added to the residue. The aqueous phase
was extracted with diethyl ether (2ϫ3 mL). The combined organic
phases were evaporated under reduced pressure to give the crude
product. Purification by flash chromatography on silica (cyclohex-
ane/diethyl ether, 95:5) provided pure product 12 (78% yield). Spec-
troscopic data were in agreement with the published data.[22] Com-
pound 9 was prepared according to same procedure to give pure
product 9 (78% yield). Data for 9: 1H NMR (400 MHz, CDCl3): δ
= 1.34 (s, 3 H), 1.72–1.81 (m, 4 H), 2.76–2.64 (m, 4 H), 3.15 (s, 2
H), 3.73 (s, 6 H), 6.75–6.82 (m, 2 H), 6.94 (d, J = 7.6 Hz, 1 H) ppm.
13C NMR (100.76 MHz, CDCl3): δ = 19.7 (1 C), 23.2 (2 C), 29.0
(1 C), 29.4 (1 C), 40.9 (1 C), 52.4 (2 C), 54.9 (1 C), 127.1 (1 C),
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4916
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 4909–4917

Formylation of Organoboron Aromatic Compounds
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The aryl carbenium ion was isolated in the presence of an ex-
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For the more electrophilic 2-phenyl-1,3-dithiolan-2-ylium cat-
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philes (enamines, allylsilane, silyl enolates) and successfully pre-
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Published Online: June 21, 2013
A minor change has been made after publication in Early View.
Eur. J. Org. Chem. 2013, 4909–4917
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