Long-range effects in the metalation/boronation of functionalized 1,4-dihalobenzenes

Article abstract of DOI:10.1002/ejoc.200600541

The lithiation/boronation of 1,4-dihalobenzenes (Hal = F, Cl, Br) bearing various functional groups in the 2-position was investigated using lithium diisopropylamide (LDA) as the metalating agent and trialkyl borate B(OR) ₃ (R = Et, iPr) as the

Full text of DOI:10.1002/ejoc.200600541

FULL PAPER
DOI: 10.1002/ejoc.200600541
Long-Range Effects in the Metalation/Boronation of Functionalized
1,4-Dihalobenzenes
Sergiusz Lulin´ski,*[a] Janusz Serwatowski,[a] and Anna Zaczek[a]
Keywords: Metalation / Long-range inductive effects / Substituent effects / Buttressing effects / Aryl halides / Aryl
boronic acids
The lithiation/boronation of 1,4-dihalobenzenes (Hal = F, Cl,
Br) bearing various functional groups in the 2-position was
investigated using lithium diisopropylamide (LDA) as the
metalating agent and trialkyl borate B(OR)3 (R = Et, iPr) as
the electrophile. It was demonstrated that sufficient steric
hindrance precludes effective ortho-lithiation at the 3-posi-
halobenzenes was observed. Moreover, competition experi-
ments using 2,3-bifunctional 1,4-dihalobenzenes were per-
formed to determine the relative meta-directing ability of
carboxylate or fluorine in competition with a methoxy group.
A significant buttressing effect is responsible for the course
of metalation of 2-(dimethoxymethyl)-1,4-dihalobenzenes
tion. In such cases, a strong meta-directing effect of an oxy- (Hal = Cl, Br).
gen- or sulfur-based substituent (OMe, OSiMe3, SMe), re- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
sulting in the preferred formation of 2,6-disubstituted 1,4-di-
Germany, 2006)
zene may be problematic due to a formation of other kin-
etically favoured products.[10] This result has prompted us
to evaluate more precisely the influence of steric and elec-
tronic factors on the regioselectivity of the metalation of 2-
functionalized 1,4-dihalobenzenes with special emphasis on
the role of long-range inductive effects.
Introduction
There is growing interest in the metalation of haloge-
nated aromatics and heteroaromatics as a useful tool for
their diverse functionalization.[1] Their reactivity depends
strongly on the kind and number of halogens attached to
the aromatic ring. Thus, halogenated fluorobenzenes are
more susceptible to deprotonation than the parent com-
pound due to an enhanced acidifying effect provided by the
second halogen.[2] For instance, 1,4-difluorobenzene un-
dergoes metalation using LTMP 80 times more rapidly than
fluorobenzene.[3] Similar rules are applicable for the met-
alation of heavier halogen analogues,[4] e.g., lithiation of
1,4-dichlorobenzene is feasible using nBuLi at –78 °C,
whereas chlorobenzene requires sBuLi to be converted into
2-chlorophenyllithium.[5] The role of long-range inductive
effects in the metalation of arenes has been studied less ex-
tensively when compared to ortho-directed deprotonations.
For instance, the lithiation of benzotrifluorides can proceed
in the position meta or para with respect to a CF3 group.[6]
It is known that a bulky trialkylsilyloxy group prevents or-
tho-lithiation.[5,7] Tricarbonylchromium(0) complexes of si-
lylated phenols and anilines are preferentially metalated at
the meta-position of the ring, but such regioselectivity is
rationalized in terms of chelation of the lithating agent by
a carbonyl or an increased electron deficiency at the
eclipsed ring carbons[8,9] rather than by long-range induc-
tive effects of oxygen or nitrogen operating within the aro-
matic ring. Recently, we have shown that the proton ab-
straction from a 3-position of 1,4-dibromo-2-methoxyben-
Results and Discussion
Long-Range Inductive Effects
1,4-Difluoro-2-methoxybenzene is metalated selectively
at the 3-position with LDA. Treatment with B(OEt)3 gave
the corresponding boronic acid 1 whereas carboxylation af-
forded 3,6-difluoro-2-methoxybenzoic acid 2 (Scheme 1). A
similar result was found previously for nBuLi mediated de-
protonation.[11] This is not surprising since the acidifying
effects of fluorines and a methoxy group are expected to
cumulate to the highest extent in the 3-position which is
reflected by the increased proton mobility. In order to de-
termine the effect of a heavier halogen, we subjected the
closely related 1,4-dichloro-2-methoxybenzene to LDA-me-
diated deprotonation followed by a B(OEt)3 quench,
whereas the bromo analogue was boronated using either a
sequential or a modified in situ[12,13] quench with B(OiPr)3.
A progressive shift in the regioselectivity is observed as the
former reaction gave an approximately equimolar mixture
of substituted boronic acids 3 and 4. We attribute this result
to a substantial steric hindrance impeding the access of a
lithium base to the 3-position of a substrate and thus dis-
favouring the formation of 3. Accordingly, the formation of
4, we interpret as a result of a longe-range meta-directing
[a] Warsaw University of Technology, Faculty of Chemistry,
Noakowskiego 3, 00-664 Warsaw, Poland
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S. Lulin´ski, J. Serwatowski, A. Zaczek
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effect (i.e. in a 6-position) of the methoxy group as an iso-
meric acid resulting from the metalation in the 5-position,
was not found to a detectable extent. In the case of 1,4-
dibromo-2-methoxybenzene, the only acid isolated upon
workup of the reaction mixture was 2,6-dibromo-3-meth-
oxyphenylboronic acid 5, although the yield was moderate
(39%). This is in line with our recent results concerning the
synthesis of 2,5-dibromo-3-methoxybenzaldehyde,[10] and
indicates that the 6-position is preferentially metalated. As
we proposed previously, these results can be rationalized
assuming conformational restrictions of the methoxy group
imposed by an adjacent halogen atom. This effect leads to
an increased stability of an anti-conformation of the meth-
oxy group, thus making in turn an approach by the bulky
deprotonating agent more difficult. This is an interpretation
involving kinetic control conditions, i.e., it can be applicable
in a case when an internal electrophile, immediately reacting
with aryllithium, is used. However, in the absence of a trap-
ping electrophile, LDA-mediated deprotonations are gen-
erally able to reach a thermodynamic equilibrium. If so, a
composition of the reaction mixture must reflect a relative
stability of aryllithium isomers. It is plausible that, a
thermodynamic stability of 3-lithio-1,4-dihalo-2-meth-
oxyanisoles (Hal = Cl, Br) is decreased by conformational
restrictions of the methoxy group due to their lower aggre-
gation state and/or solvent stabilization. Hence, despite the
assumed higher thermodynamic acidity of a hydrogen in
the 3-position (i.e., a more negative ∆G of formation of a
corresponding carbanion under gas phase conditions), a 6-
lithiated species can be formed to a significant extent or
Scheme 1. Lithiation/boronation of 1,4-dihalo-2-methoxybenzenes.
even as a major product. However, at this point we have to ternal electrophile, aryllithium intermediates undergo a re-
stress that there is no evidence that LDA-mediated lithi- versible reprotonation with the byproduct diisopropylamine
ation of 1,4-dihalo-2-methoxyanisoles is actually controlled and hence they can interconvert with each other but one of
by thermodynamics.
them (lithiated ortho to the Me3SiO group) is kinetically
Results concerning the metalation of 2,5-dihaloanisoles unstable and undergoes an aromatic [1,3]retro-Brook re-
have prompted us to investigate the reactivity of related 1,4- arrangement[15] to form a silylated phenolate via silyl group
dihalo-2-(trimethylsilyloxy)benzenes. It is known that trial- migration from the oxygen to the metalated carbon
kylsilyloxy groups effectively prevent ortho-lithiation.[14] In- (Scheme 3). Apparently, this intramolecular reaction pro-
deed, the metalation of 1,4-difluoro-2-(trimethylsilyloxy) ceeds more rapidly than trapping with B(OiPr)3, which is
benzene 6 with LDA using a B(OiPr)3 internal quench af- probably hampered by the substantial steric effect of the
forded
2,5-difluoro-3-hydroxyphenylboronic
acid
7
adjacent Me3SiO group. The metalation/in situ boronation
(Scheme 2) in 38% yield resulting from lithiation at a less of the analogous dichloro derivative 10 gave the acid 11
hindered meta-position with respect to the Me3SiO group. with good purity and moderate yield (66%). In a similar
A substantial amount of 3,6-difluoro-2-(trimethylsilyl)phe- reaction, a dibromo compound was converted into the acid
nol 8 (42%) was isolated too. However, when a stepwise 12, which was contaminated with some (ca. 10%) of the
protocol was employed, i.e., the lithiation was performed isomeric acid 13. It is clear that proton abstraction from a
followed by trapping with the electrophile [B(OEt)3, DMF] position between the halogen and the Me3SiO group does
and hydrolysis, no trapping products were found, and the not proceed effectively due to significant steric hindrance,
only isolated product was the phenol 8. In another experi- whereas the relatively strong long-range acidifying effect of
ment LDA (1.1 equiv.) was added to a solution of 6 in the oxygen enables a preferred kinetic deprotonation at the 6-
presence of TMSCl as the electrophile (1.2 equiv.). GC/MS position. To summarize, the metalation/boronation of diha-
analysis revealed that comparable amounts of 3- and 6-si- logenated (trimethylsilyloxy)benzenes provides (after subse-
lylated derivatives of 6 were formed (both ca 20%) together quent hydrolysis/deprotection step) access to synthetically
with a substantial amount (27%) of 2,5-difluoro-1,4-bis(tri- useful boronated dihalophenols.
methylsilyl)-3-(trimethylsilyloxy)benzene and unreacted 6
The effect of the replacement of a methoxy group with a
(15%). These results suggest unequivocally that the LDA- related methylthio group was subsequently studied em-
mediated metalation proceeds with comparable rates ortho ploying 1,4-dichloro-2-(methylthio)benzene 7 and its bromo
and meta to the Me3SiO group. In the absence of an in- analogue 8. It is known that SMe has weaker ortho-direct-
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Metalation/Boronation of 1,4-Dihalobenzenes
FULL PAPER
is impeded by steric hindrance and the major product is the
acid 16 resulting from a preferred lithiation at the less
crowded 6-position. However, the formation of the isomeric
acid 17, albeit not exceeding 10% with respect to 16, points
to a difference in acidities of 6-H and 5-H (meta and para
with respect to SMe) is not large enough to provide a per-
fect regioselectivity. Nevertheless, it is clear that a meth-
ylthio group does acidify aromatic hydrogen atoms in the
meta-position by long-range inductive effects to an extent
not expected for such a weak ortho-director.
Scheme 2. Lithiation/boronation of 1,4-dihalo-2-(trimethyl-
silyloxy)benzenes.
Scheme 4. Lithiation/boronation of 1,4-dichloro-2-(methylthio)-
benzene.
We have extended our study by performing long-range
effect competition experiments. We were interested in the
comparison of the meta-directing power of methoxy and
carboxylate groups. The ortho-directed metalation of re-
lated 2-methoxybenzoic acid was studied recently; it was
demonstrated that with LTMP or sBuLi/TMEDA it pro-
ceeds ortho to a carboxylate whereas the superbase nBuLi/
tBuOK deprotonates ortho to a methoxy group.[19] In our
protocol the related 3,6-difluoro-2-methoxybenzoic acid 2
Scheme 3. LDA-induced rearrangement of 1,4-difluoro-2-(trimeth-
ylsilyloxy)benzene.
ing properties when compared to the methoxy group[16] and was subjected to a double deprotonation using a threefold
may undergo α-deprotonation to a significant extent.[17] In- excess of LDA. A quench with (EtO)3B gave 4-carboxyl-
deed, the latter was a major reaction pathway for the LDA- 2,5-difluoro-3-methoxyphenylboronic acid 18 selectively
mediated deprotonations of 14 and 15 as the in situ Me3- with good yield (84%) as shown in Scheme 1. Based on
SiCl trapping (1.1 equiv.) gave, in both cases, non-resolved conclusions concerning metalation of 2-methoxy- and 2-
mixtures of isomeric SMe-silylated and disilylated dihalo- (trimethylsilyloxy)-1,4-dihalobenzenes we believe that the
thioanisoles. Whereas, with internal B(OiPr)3 most of the orientation in the reaction is dictated by the meta-directing
starting material was recovered, presumably due to the hy- methoxy group acting by a long-range negative inductive
drolytic cleavage of a boron–carbon bond in a SMe-bo- effect. A contribution from a positive long-range inductive
ronated product during aqueous workup. With nBuLi, effect of electron-rich carboxylate reducing the relative pro-
howewer, it was possible to lithiate 14 at the ring preferen- ton mobility in a meta-position with respect to this anionic
tially (Scheme 4). The selectivity of ring metalation is again group may also be taken into account. Presumably, the well-
influenced by a combination of steric and electronic effects known kinetic activation of the aromatic ring by a carboxyl-
imposed by the SMe group. Its steric parameters are re- ate[20] is purely due to the precomplexation of the lithiating
markably different to those of the methoxy group; Carom–S agent, which obviously is limited to the adjacent ortho-posi-
bond lengths in thioanisoles are longer by ca. 0.3 Å with tion. In another experiment, 1,4-dibromo-2-fluoro-3-me-
respect to Carom–O bond lengths in anisoles, while the C– thoxybenzene 19 was subjected to lithiation/in situ bo-
S–C angle is significantly smaller than the corresponding ronation with LDA/B(OiPr)3. In this case, we found that
C–O–C angle.[18] As a result, the lithiation at the 3-position fluorine outperforms the methoxy group in its meta-direct-
Scheme 5. Lithiation/boronation of 1,4-dibromo-2-fluoro-3-methoxybenzene.
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S. Lulin´ski, J. Serwatowski, A. Zaczek
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Scheme 6. Lithiation/boronation of 1,4-dihalo-2-(dimethoxymethyl)benzenes.
ing ability as the major product 2,5-dibromo-3-fluoro-4- oxymethyl)benzene with sBuLi/THF at –100 °C gives an
methoxyphenylboronic acid 20 was contaminated with only approximately equimolar mixture of ortho- and meta-lithi-
a small amount (ca 5%) of the regioisomeric byproduct 21 ated species as comparable proportions of corresponding
(Scheme 5). This shows that the long-range inductive effect boronic acids were obtained after trapping with (EtO)3B.[29]
of fluorine is significantly stronger than that of oxygen, The buttressing effect caused by dimethoxymethyl groups is
which is in line with the lithiation results of isomeric 1,2- not as strong as that observed for trialkylsilyl groups, and
dibromo-4-fluoro-5-methoxybenzene by means of Li/Br ex- hence it is of a lower synthetic value. However, in conjunc-
change.[21] For comparison, nBuLi/THF slowly depro- tion with the strong meta-directing effect of fluorine it was
tonates the parent 2-fluoroanisole ortho to the methoxy used to convert 1,4-dibromo-2-(dimethoxymethyl)-3-fluoro-
group, whereas a selective metalation ortho to fluorine re- benzene into 2,5-dibromo-3-fluoro-4-formylphenylboronic
quires a superbase such as nBuLi premixed with PMDTA acid 26 free of its regioisomer in 40% yield (Scheme 6).
or KOtBu.[22]
Conclusion
The Impact of Buttressing Effects
In conclusion, the metalation of functionalized 1,4-di-
halobenzenes proceeds with varying regioselectivity. Depro-
The lithiation/in situ boronation of 1,4-halo-2-(dimeth-
oxymethyl)benzenes (Hal = Cl, Br) using LDA/B(OiPr)3
tonation of functionalized 1,4-dichloro- and dibromoben-
showed that the metalation does not proceed selectively as
zenes at the 3-position is generally sluggish and occurs pref-
mixtures of corresponding 2,5-dihalo-4-formyl- and 2,5-di-
erably at the less hindered 6-position, which gains an ad-
halo-3-formylphenylboronic acids were formed (Scheme 6).
ditional activation when compared to the 5-position due
We rationalize the preferred formation of compounds 22
and 24 in terms of two factors. Standard steric hindrance
to long-range inductive effects exerted by heteroatom-based
substituents (OMe, OSiMe3, SMe, F). On the other hand,
precludes deprotonation ortho to
a dimethoxymethyl
the buttressing effect of the dimethoxymethyl group leads
to a reversal of such regioselectivity. In many cases a combi-
nation of various effects proved synthetically useful and
gave selective access to novel dihalophenylboronic acids
bearing valuable functionalities (OH, OMe, CHO, COOH)
with satisfactory yields. There is also potential for a broad
range of other dihalogenated aromatics by employing vari-
ous electrophilic reagents.
CH(OMe)2 group. A secondary but still significant but-
tressing effect exerted by the CH(OMe)2 group on the adja-
cent halogen seems to be operative in decreasing the extent
of the metalation at the meta-position with respect to it.
The concept of a buttressing effect is not new[23] but it was
employed only recently to explain the reduced mobility of
a proton located ortho to a halogen in some fluoro- (albeit
to a small extent),[24] chloro- and bromoarenes bearing ad-
jacent bulky groups such as iodine[25] and trialkylsilyl.[25,26]
More advanced studies revealed that this is a purely kinetic
phenomenon[27] whose synthetic potential is remarkable.[28]
As expected, a comparison of product distributions 22/23
(2:1) and 24/25 (4:1) shows that this effect is more pro-
nounced for the dibromo compound due to the increased
van der Waals radius of this halogen. However, when the
dibromo acetal was replaced with its more bulky diethyl
analogue, the regioselectivity was not improved in favour
of the product 23 due to a potential enhancement of the
buttressing effect. In this context it is also interesting to
Experimental Section
General Comments: All reactions involving air and moisture sensi-
tive reagents were carried out in an argon atmosphere. THF was
stored with sodium wire before use. All starting materials: 2,5-di-
halophenols, 2,5-dibromoanisole, 2,5-dihalobenzaldehydes, 3,6-di-
bromo-2-fluorophenylboronic acid, and other important reagents
including hexamethyldisilazane HN(SiMe3)2, dimethyl sulfate, tri-
methyl orthoformate, diisopropylamine, n-butyllithium (10  solu-
tion in hexanes), triethyl and triisopropyl borates were received
from Aldrich. 2,5-Difluoroanisole,[11] 2,5-dichloroanisole,[30] 1,4-
note that the metalation of related 1,3-dichloro-2-(dimeth- dichloro-2-(dimethoxymethyl)benzene,[31] 1,4-dibromo-2-(dimeth-
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Metalation/Boronation of 1,4-Dihalobenzenes
FULL PAPER
oxymethyl)benzene,[21] 1,4-dibromo-2-(dimethoxymethyl)-3-fluoro-
benzene[21] have been prepared according to literature procedures.
The NMR chemical shifts are given relative to TMS using known
chemical shifts of residual proton (1H) or carbon (13C) solvent reso-
nances. In the 13C NMR spectra of aryl boronic acids, the reso-
nances of boron-bound carbon atoms were not observed due to
their broadening by a quadrupolar boron nucleus. New compounds
gave satisfactory elemental analyses except for the acid 7, presum-
ably due to formation of an air-stable hydrate. In addition, for mix-
tures 3–4, 12–13, 16–17, 20–21, 22–23 and 24–25 a characterization
by their 1H NMR spectra in [D6]acetone (with ca 5 wt.-% D2O
–105 °C. The mixture was stirred for 15 min and hydrolyzed with
water. The organic phase was separated, and the water phase was
extracted with diethyl ether. Evaporation of the combined organic
solution left a crude solid product. The product was washed with
water, dried and recrystallized from ethanol (50 mL), and dried to
give white crystals, m.p. 59–60 °C. Yield 14.7 g (52%). 1H NMR
(400 MHz, CDCl3): δ = 7.36 (d, J = 8.0 Hz, 1 H, Ph), 7.18 (d, J =
2.0 Hz, 1 H, Ph), 7.11 (dd, J = 8.0, 2.0 Hz, 1 H, Ph), 2.47 (s, 3 H,
SMe). 13C{1H} NMR (100.6 MHz, CDCl3): δ = 142.1, 133.6,
128.3, 127.4, 121.7, 119.8, 15.7 ppm. C7H6Br2S (282.00): calcd. C
29.82, H 2.14; found C 29.95, H 2.03.
1
added to simplify spectra by exchanging H from boronic groups)
3,6-Dibromo-2-fluoroanisole (19): 3,6-Dibromo-2-fluorophenylbo-
ronic acid (29.8 g, 0.1 mol) was oxidized with acetic acid (50 mL)/
H2O2 (30 wt.-% solution in water, 10.7 g, 0.11 mol) at 35–38 °C.
After evaporation of solvents a crude 3,6-dibromo-2-fluorophenol
was filtered and washed with a little water. Then it was dissolved
in 2  aq. NaOH (55 mL) followed by the addition of Me2SO4
(12.6 g, 0.10 mol). The mixture was stirred for 2 h at 70 °C and the
crude product was separated as a thick, oily liquid. It was washed
with 2  aq. NaOH (10 mL) and water. Distillation in vacuo gave
the title compound, b.p. 90–92 °C (2 Tr) as oil crystallizing after
standing at room temperature, m.p. 42–44 °C. Yield 20.5 g (72%).
1H NMR (400 MHz, CDCl3): δ = 7.21 (dd, J = 8.5, 2.0 Hz, 1 H,
Ph), 7.15 (dd, J = 8.5, 6.5 Hz, 1 H, Ph), 3.97 (d, J = 1.5 Hz, 3 H,
OMe) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ = 153.2 (d, J
= 251.5 Hz), 146.3 (d, J = 14.0 Hz), 128.3 (t, J = 4.0 Hz), 127.9,
116.3 (d, J = 2.0 Hz), 109.2 (d, J = 20.0 Hz), 61.6 (d, J = 5.0 Hz)
ppm. C7H5Br2FO (283.92): calcd. C 29.62, H 1.77; found C 29.65,
H 1.80.
is provided.
1,4-Difluoro-2-(trimethylsilyloxy)benzene (6): (Me3Si)2NH (17.05 g,
0.11 mol) was added during 1 h to 1,4-difluorophenol (26.02 g,
0.20 mol) at 170 °C. The crude liquid product was distilled in vacuo
to give the title compound, b.p. 70–72 °C (2 Torr), as a colourless
liquid. Yield 40.0 g (99%). 1H NMR (400 MHz, CDCl3): δ = 6.96–
6.89 (m, 1 H, Ph), 6.60–6.51 (m, 2 H, Ph), 0.22 (d, J = 1.0 Hz, 9
H, SiMe3) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ = 158.5
(dd, J = 242.0, 2.5 Hz), 150.8 (dd, J = 239.5, 3.0 Hz), 143.6 (dd, J
= 14.5, 11.5 Hz), 116.3 (dd, J = 22.0, 10.0 Hz), 109.7 (dd, J = 24.0,
1.5 Hz), 108.1 (dd, J = 24.0, 7.5 Hz), 0.0 (d, J = 2.0 Hz) ppm.
C9H12F2OSi (202.28): calcd. C 53.46, H 5.98; found C 53.29, H
6.04.
1,4-Dichloro-2-(trimethylsilyloxy)benzene (9): This compound was
prepared using procedure described for 6 starting from 2,5-dichlo-
rophenol (8.15 g, 0.05 mol); colourless liquid, b.p. 88–91 °C
1
(2 Torr). Yield 11.5 g (98%). H NMR (400 Hz, CDCl3): δ = 7.25
(d, J = 9.2 Hz, 1 H, Ph), 6.89 (m, J = 2.4 Hz, 2 H, Ph), 0.30 (s, 9
H, SiMe3) ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ = 151.9,
132.5, 130.6, 124.3, 122.4, 121.4, 0.2 ppm. C9H12Cl2OSi (235.18):
calcd. C 45.96, H 5.14; found C 46.31, H 5.23.
3,6-Difluoro-2-methoxyphenylboronic Acid (1): A solution of 1,4-
fluoro-2-methoxybenzene (2.88 g, 20 mmol) in THF (10 mL) was
added dropwise to a solution of LDA freshly prepared from diiso-
propylamine (2.42 g, 24 mmol) and nBuLi (10  solution in hex-
anes, 2.4 mL, 24 mmol) in THF (20 mL) at –70 °C. The resultant
solution was stirred for 15 min followed by slow addition of
B(OEt)3 (3.50 g, 24 mmol). The mixture was stirred for 15 min and
then hydrolyzed with dilute aqueous H2SO4. The organic phase was
separated. Evaporation of the combined organic solutions left a
solid that was washed with water and hexane, and dried to give
white crystals, m.p. 99–101 °C. Yield 2.97 g (79%). 1H NMR
(400 MHz, [D6]acetone): δ = 7.13 (m, 1 H, Ph), 6.75 (m, 1 H, Ph),
3.91 (d, J = 1.5 Hz, 3 H, OMe) ppm. 13C{1H} NMR (100.6 MHz,
[D6]acetone): δ = 159.9 (d, J = 239.0 Hz), 151.2 (d, J = 242.0 Hz),
149.5 (dd, J = 14.0, 11.0 Hz), 117.4 (dd, J = 22.0, 10.5 Hz), 109.7
(dd, J = 28.0, 7.0 Hz), 60.5 (d, J = 6.0 Hz) ppm. 11B NMR
(64.3 MHz, [D6]acetone): δ = 28 ppm. C7H7BF2O3 (187.94): calcd.
C 44.74, H 3.75; found C 44.71, H 4.06.
1,4-Dibromo-2-(trimethylsilyloxy)benzene (11): This compound was
prepared using procedure described for 6 starting from 2,5-dibro-
mophenol (12.6 g, 0.05 mol); colourless liquid, b.p. 112–115 °C (2
1
Tr). Yield 15.9 g (98%). H NMR (400 Hz, CDCl3): δ = 7.34 (d, J
8.0 Hz,1 H, Ph), 6.98–6.92 (m, 2 H, Ph), 0.28 (s, 9 H, SiMe3) ppm.
13C{1H} NMR (100.6 MHz, CDCl3): δ = 153.2, 134.0, 125.8, 123.8,
121.0, 114.6, 0.3 ppm. C9H12Br2OSi (324.09): calcd. C 33.33, H
3.73; found C 33.31, H 3.87.
2,5-Dichlorothioanisole (14): A solution of 1,4-dichlorobenzene
(22.05 g, 0.15 mol) in THF (50 mL) was added dropwise to a solu-
tion of nBuLi (10  solution in hexanes, 0.15 mol, 15 mL) in THF
(100 mL) at –80 °C. The resultant solution was stirred for 15 min
followed by the addition of Me2S2 (14.13 g, 0.15 mol). The mixture
was stirred for 15 min and hydrolyzed with water. The organic
phase was separated, and the water phase was extracted with di-
ethyl ether. Evaporation of the combined organic solution left a
crude solid product. The product was filtered, washed with water,
and recrystallized from hexane (30 mL), to give white crystals, m.p.
64–67 °C. Yield 12.1 g (63%). 1H NMR (400 MHz, CDCl3): δ =
7.24 (d, J = 8.5 Hz, 1 H, Ph), 7.07 (d, J = 2.5 Hz, 1 H, Ph), 7.03
(dd, J = 8.5, 2.5 Hz,1 H, Ph), 2.47 (s, 3 H, SMe) ppm. 13C{1H}
NMR (100.6 MHz, CDCl3): δ = 139.9, 133.1, 130.1, 129.6, 125.2,
124.7, 15.5 ppm. C7H6Cl2S (193.10): calcd. C 43.54, H 3.13; found
C 43.45, H 3.52.
3,6-Difluoro-2-methoxybenzoic Acid (2): A solution of 1,4-difluoro-
2-methoxybenzene (7.2 g, 50 mmol) in THF (15 mL) was added to
a solution of LDA freshly prepared from nBuLi (10  solution in
hexanes, 5.5 mL, 55 mmol) and diisopropylamine (5.7 g, 57 mmol)
in THF (50 mL) at –60 °C. After 30 min stirring a freshly prepared
solution of CO2 in diethyl ether (50 mL) was quickly added. After
hydrolysis with dilute aq. H2SO4 the organic phase was separated,
and the water phase was extracted with diethyl ether. The organic
phase was concentrated and the residue was dissolved in 2  aq.
NaOH (50 mL). The resultant solution was washed with hexane
(2×25 mL) and acidified with dilute aq. H2SO4 to precipitate a
solid that was filtered, washed with water (2×5 mL), and dried, to
give the title compound as white crystals, m.p. 82–83 °C. Yield
4.75 g (51%). 1H NMR (400 MHz, CDCl3): δ = 9.62 (br., 1 H,
2,5-Dibromothioanisole (15): A solution of 1,2,4-tribromobenzene
(31.5 g, 0.1 mol) in THF (50 mL) was added dropwise to a solution
of nBuLi (10  solution in hexanes, 0.10 mol, 10 mL) in THF/Et2O
(4:1, 150 mL) at –105 °C. The resultant solution was stirred for
15 min followed by the addition of Me2S2 (10.3 g, 0.11 mol) at COOH), 7.20 (m, 1 H, Ph), 6.85 (td, J = 9.0, 3.5 Hz, 1 H, Ph),
Eur. J. Org. Chem. 2006, 5167–5173
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S. Lulin´ski, J. Serwatowski, A. Zaczek
FULL PAPER
4.06 (d, J = 2.0 Hz, 3 H, OMe) ppm. 13C{1H} NMR (100.6 MHz,
CDCl3): δ = 167.6, 155.9 (dd, J = 251.5, 2.5 Hz), 151.5 (dd, J =
245.0, 3.0 Hz), 146.5 (dd, J = 13.5, 5.5 Hz), 119.8 (dd, J = 21.5,
10.0 Hz), 115.9 (dd, J = 17.5, 2.5 Hz), 110.9 (dd, J = 24.0, 7.0 Hz),
62.4 (d, J = 7.0 Hz) ppm. C8H6F2O3 (188.13): calcd. C 51.07, H
3.21; found C 50.64, H 3.52.
the addition of B(OEt)3 (2.92 g, 20 mmol). The mixture was stirred
for 15 min and then hydrolyzed with dilute aq H2SO4. The organic
phase was separated, and the water phase was extracted with di-
ethyl ether. Evaporation of the combined organic solution left a
solid that was washed with acidic water (2×5 mL) and hexane
(2×5 mL), and dried to give white crystals, m.p. 140–143 °C. Yield
1.82 g (84%). 1H NMR (200 MHz, [D6]acetone): δ = 7.13 (dd, J =
9.0, 4.0 Hz, 1 H, Ph), 3.92 (d, J = 1.0 Hz, 3 H, OMe), 3.47 (s, 3 H,
OH) ppm. 13C{1H} NMR (100.6 MHz, [D6]acetone): δ = 163.9 (d,
J = 2.5 Hz), 155.9 (dd, J = 243.5, 3.0 Hz), 154.9 (d, J = 248.5 Hz),
145.9 (dd, J = 15.0, 6.0 Hz), 121.1 (d, J = 20.5 Hz), 116.1 (dd, J =
21.5, 9.0 Hz), 62.5 (d, J = 5.5 Hz) ppm. 11B NMR (64.3 MHz,
[D6]acetone): δ = 28 ppm. C8H7BF2O5 (231.95): calcd. C 41.43, H
3.04; found C 40.98, H 2.90.
2,5-Dibromo-3-methoxyphenylboronic Acid (5): A solution of LDA
freshly prepared from diisopropylamine (2.42 g, 24 mmol) and
nBuLi (10  solution in hexanes, 2.4 mL, 24 mmol) in THF
(20 mL) at –70 °C was added dropwise to a solution of 2,5-dibro-
moanisole (5.32 g, 20 mmol) in THF (20 mL) containing B(OiPr)3
(4.51 g, 5.50 mL) at –70 °C. A resultant solution was stirred for
15 min and then hydrolyzed with dilute aq. H2SO4. The organic
phase was separated, and the water phase was extracted with Et2O
(10 mL). Evaporation of combined organic solutions left a solid
that was washed with water (2×5 mL), hexane (2×5 mL), and
recrystallized from toluene (10 mL) to give white crystals, m.p. 357–
360 °C. Yield 2.44 g (39%). 1H NMR (400 MHz, [D6]acetone): δ =
7.60 [broad, B(OH)2], 7.17 (d, J = 2.0 Hz, 1 H, Ph), 7.14 (d, J =
2.0 Hz, 1 H, Ph),3.90 (s, 3 H, OMe), 3.10 [broad, B(OH)2] ppm.
2,5-Dibromo-3-fluoro-4-formylphenylboronic Acid (26): This com-
pound was prepared using procedure described for 5, starting
form 1,4-dibromo-2-dimethoxymethyl-3-fluorobenzene (6.58 g,
20 mmol). Evaporation of the combined organic solution left an
oily residue that was heated at 60 °C with water acidified with a
few drops aq. HCl in order to cleave a dimethoxymethyl group.
The resultant solid was filtered and washed with water (2×5 mL)
13C{1H} NMR: δ = 157.0, 128.5, 121.9, 116.3, 114.3, 56.9 ppm. 11
B
NMR (64.3 MHz, [D6]acetone): δ = 29 ppm. C7H7BBr2O3 (309.75): and toluene (2×5 mL), and dried to give white crystals, m.p. 231–
calcd. C 27.14, H 2.28; found C 27.57, H 2.60.
234 °C. Yield 2.25 g (40%). 1H NMR (400 MHz, [D6]acetone): δ =
10.23 (d, J = 1.0 Hz, 1 H, CHO), 7.61 (d, J = 1.5 Hz,1 H, Ph), 3.13
(s, 2 H, OH) ppm. 13C{1H} NMR (100.6 MHz, [D6]acetone): δ =
188.3, 159.1 (d, J = 264.0 Hz), 134.6 (d, J = 4.5 Hz), 124.3, 123.5,
113.2 (d, J = 20.0 Hz) ppm. 11B NMR (64.3 MHz, [D6]acetone): δ
= 28 ppm. C7H4BBr2FO3 (325.72): calcd. C 25.81, H 1.24; found
C 25.84, H 1.55.
2,5-Difluoro-3-hydroxyphenylboronic Acid (7): This compound was
prepared using a procedure described for 5, starting from 1,4-di-
fluoro-2-(trimethylsilyloxy)benzene (4.04 g, 20 mmol). Evaporation
of the combined organic solution obtained after acidic hydrolysis
and extraction of the water phase gave a crude solid product and
an oily residue. Hexane (5 mL) was added and the mixture was
filtered. The solid product was washed with water (2×5 mL) and
toluene (2×5 mL), and dried to give the title compound as white
crystals, m.p. 179–183 °C. Yield 1.32 g (38%). 1H NMR (400 MHz,
3,6-Dichloro-2-methoxyphenylboronic Acid (3) and 2,5-Dichloro-3-
methoxyphenylboronic Acid (4): The procedure described for 1 was
employed starting from 1,4-dichloro-2-methoxybenzene (3.54 g,
[D6]acetone): δ = 6.80–6.74 (m, 2 H, Ph), 3.14 (broad, 3 H, OH) 20 mmol). Yield 3.12 g (71%), 3/4 = 1:1. 1H NMR (400 MHz,
ppm. 13C{1H} NMR (100.6 MHz, [D6]acetone): δ = 159.2 (d, J = [D6]acetone + D2O): δ = 7.35 (d, 1 H, J = 8.0 Hz, 3), 7.11–7.09
240.0 Hz), 152.4 (d, J = 233.5 Hz), 145.1 (d, J = 27.0 Hz), 110.8 (m, 3 & 4), 7.18 (s, 1 H, 17), 3.91 (s, 3 H, 3), 3.87 (s, 3 H, 4) ppm.
(dd, J = 22.0, 7.5 Hz), 107.2 (d, J = 27.5 Hz) ppm. 11B NMR
(64.3 MHz, [D6]acetone): δ = 28 ppm.
2,5-Dibromo-3-hydroxyphenylboronic Acid (12, major component)
and 2,5-Dibromo-4-hydroxyphenylboronic Acid (13, minor compo-
The toluene filtrate was concentrated under reduced pressure and
distilled in vacuo to give 3,6-difluoro-2-(trimethylsilyl)phenol (8),
b.p. 75–80 °C (2 Torr), as a colourless liquid. Yield 0.85 g (42%).
1H NMR (400 MHz, CDCl3): δ = 6.98 (m, 1 H, Ph), 6.46 (m, 1 H,
Ph), 5.30 (broad, 1 H, OH), 0.37 (dd, J = 5.0, 3.0 Hz, 9 H, SiMe3)
ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ = 162.8 (d, J =
237.0 Hz), 148.1 (dd, J = 30.0, 13.0 Hz), 147.2 (dd, J = 233.0,
3.5 Hz), 116.4 (dd, J = 21.0, 11.5 Hz), 114.3 (d, J = 36.0 Hz), 106.7
(dd, J = 31.0, 6.0 Hz), 0.2 (d, J = 4.0 Hz) ppm. C9H12F2OSi
(202.28): calcd. C 53.46, H 5.98; found C 53.13, H 6.24.
nent): The procedure described for 5 was employed starting from
11 (9.75 g, 30 mmol). Yield 7.1 g (80%), 12/13 = 9:1. 1H NMR
(400 MHz, [D6]acetone + D2O): δ = 7.69 (s, 1 H, 13), 7.17 (s, 1 H,
13), 7.11 (d, 1 H, J = 2.0 Hz, 12), 7.02 (d, 1 H, J = 2.0 Hz, 12)
ppm.
2,5-Dichloro-3-(methylthio)phenylboronic Acid (16, major compo-
nent) and 2,5-Dichloro-4-(methylthio)phenylboronic Acid (17, minor
component): A solution of 14 (3.86 g, 20 mmol) in THF (15 mL)
was added dropwise to a solution of nBuLi (10  solution in hex-
anes, 2 mL, 20 mmol) in THF (30 mL) at –80 °C. The resultant
slurry was stirred for 15 min followed by the addition of (EtO)3B
(3.2 g, 22 mmol). The mixture was stirred for 15 min and hy-
drolyzed 1.5  aq. H2SO4. The organic phase was separated, and
the water phase was extracted with diethyl ether. Evaporation of
the combined organic solution left a crude solid product. The prod-
uct was filtered, washed with water (2×5 mL) and toluene
2,5-Dichloro-3-hydroxyphenylboronic Acid (10): This compound
was prepared using the procedure described for 5 starting from 1,4-
dichloro-2-(trimethylsilyloxy)benzene (7.05 g, 30 mmol) as a white
powder, m.p. 241–246 °C. Yield 4.10 g (66%). 1H NMR (400 MHz,
[D6]acetone): δ = 7.00 (d, 1 H, J = 2.5 Hz, Ph), 6.97 (d, 1 H, J =
2.5 Hz, Ph), 3.12 (s, 3 H, OH) ppm. 13C{1H} NMR (100.6 MHz,
[D6]acetone): δ = 154.3, 132.7, 124.8, 122.9, 117.4 ppm. 11B NMR
1
(2×5 mL). Yield 2.95 g (63%), 16/17 = 10:1. H NMR (400 MHz,
(64.3 MHz, [D6]acetone): δ = 28 ppm. C6H5BCl2O3 (206.82): calcd. [D6]acetone + D2O): δ = 7.57 (s, 1 H, 17), 7.23 (d, 1 H, J = 2.0 Hz,
C 34.84, H 2.44; found C 35.20, H 2.25.
16), 7.19 (d, 1 H, J = 2.0 Hz, 16), 7.18 (s, 1 H, 17), 2.54 (s, 3 H,
17), 2.52 (s, 3 H, 16) ppm.
4-Carboxy-2,5-difluoro-3-methoxyphenylboronic Acid (18): A solu-
tion of LDA freshly prepared from diisopropylamine (3.03 g,
30 mmol) and nBuLi (10  solution in hexanes, 3 mL, 30 mmol) in
THF (30 mL) at –70 °C was added dropwise to a solution of 3,6-
difluoro-2-methoxybenzoic acid (1.88 g, 10 mmol) in THF
(10 mL). The resultant solution was stirred for 15 min followed by
2,5-Dibromo-3-fluoro-4-methoxyphenylboronic Acid (20, major com-
ponent) and 2,5-Dibromo-4-fluoro-3-methoxyphenylboronic Acid (21,
minor component): The procedure described for 5 was employed
starting from 19 (2.84 g, 10 mmol). Yield 1.42 g (44%), 20/21 =
1
20:1. H NMR (400 MHz, [D6]acetone + D2O): δ = 7.51 (d, 1 H,
5172
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Eur. J. Org. Chem. 2006, 5167–5173

Metalation/Boronation of 1,4-Dihalobenzenes
FULL PAPER
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J = 2.0 Hz, 20), 7.45 (d, 1 H, J = 8.0 Hz, 21), 3.94 (d, 3 H, J =
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2.9 g (66%), 22/23 = 2:1. 1H NMR (400 MHz, [D6]acetone + D2O):
δ = 10.41 (s, 1 H, CHO, 23), 10.35 (s, 1 H, CHO, 22), 7.77–7.75
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2,5-Dibromo-4-formylphenylboronic Acid (24, major component) and
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The procedure described for 26 was employed starting from 1,4-
dibromo-2-(dimethoxymethyl)benzene (3.10 g, 10 mmol). Yield
1.6 g (53%), 24/25 = 4:1. 1H NMR (400 MHz, [D6]acetone + D2O):
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This work was supported by the Warsaw University of Technology.
The support by Aldrich Chemical Co., Milwaukee, WI, U.S.A.,
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Published Online: September 14, 2006
Eur. J. Org. Chem. 2006, 5167–5173
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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