One-pot generation of lithium (lithiophenyl)trialkoxyborates from substituted dihalobenzenes (Hal = Br, I) and their derivatization with electrophiles

Article abstract of DOI:10.1002/ejoc.200800245

The simple one-pot approach to synthetically useful phenyltrialkoxyborates bearing lithium at the phenyl ring has been developed starting with 1,3- and 1,4-diiodobenzene, as well as several activated dibromobenzenes and bromoiodobenzenes. The general sequence of transformations involves halogen-lithium exchange by using nBuLi and subsequent boronation with a trialkylborate. The resulting lithium (halophenyl) trialkoxyborates were then subjected to halogen-lithium exchange in situ with a second equivalent of nBuLi to give dianionic lithium (lithiophenyl)trialkoxyborates. Treatment with selected electrophiles afforded substituted arylboronic acids and/or their pinacol esters as final products in moderate-to-good yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800245

FULL PAPER
DOI: 10.1002/ejoc.200800245
One-Pot Generation of Lithium (Lithiophenyl)trialkoxyborates from
Substituted Dihalobenzenes (Hal = Br, I) and Their Derivatization with
Electrophiles
Paweł Kurach,[a] Sergiusz Lulin´ski,*[a] and Janusz Serwatowski[a]
Keywords: Lithium / Borates / Arylboronic acids / Lithiation / Substituent effects / Dihalobenzenes
The simple one-pot approach to synthetically useful phenyl-
trialkoxyborates bearing lithium at the phenyl ring has been
developed starting with 1,3- and 1,4-diiodobenzene, as well
as several activated dibromobenzenes and bromoiodo-
benzenes. The general sequence of transformations involves
halogen–lithium exchange by using nBuLi and subsequent
boronation with a trialkylborate. The resulting lithium (halo-
phenyl)trialkoxyborates were then subjected to halogen–lith-
ium exchange in situ with a second equivalent of nBuLi to
give dianionic lithium (lithiophenyl)trialkoxyborates. Treat-
ment with selected electrophiles afforded substituted aryl-
boronic acids and/or their pinacol esters as final products in
moderate-to-good yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Furthermore, N-methyliminodiacetic acid[16] and 1,8-diami-
nonaphthalene[17] have been employed as boron-masking
reagents in the Pd-catalyzed arylation of haloarylboronic
acids. The conversion of arylboronic acids into azaesters by
using N-alkyldiethanolamines was used for the introduction
of lithium to the boronated aromatic ring.[18] The synthesis
and reactivity of closely related boron–lithium bimetallic
reagents, that is, potassium 3- and 4-lithiophenyltrifluoro-
borates,[19] as well as magnesiated arylboronic pinacol esters
were reported.[20] Our work deals with another class of lithi-
ated tetravalent arylboron complexes, which can be easily
converted into various functionalized arylboron derivatives.
Introduction
Recently, arylboronic acids and esters have become very
popular as they are versatile building blocks in organic syn-
thesis; they have also found applications in other fields.[1]
There is a growing interest in novel functionalized deriva-
tives. Hence, the development of new simple general syn-
thetic routes to arylboronic acids is an important task. The
classical synthetic routes to arylboronic acids involving
transmetalation of aryllithium[2] or arylmagnesium[3] com-
pounds with trialkylborates suffer from limited access to
these organometallics as they do not tolerate many popular
functional groups attached to the aryl ring. Very recently, a
significant progress in the use of arylmagnesium reagents
was achieved.[4] Many difficulties have been overcome with
a discovery of palladium-catalyzed coupling of aryl halides
with diboron derivatives[5] or hydroboranes.[6,7] In this con-
Results and Discussion
In our first attempts, consecutive reactions were per-
text, the CuI-catalyzed coupling of iodoarenes with pinac- formed starting with 1,3- and 1,4-diiodobenzene: they in-
olborane is the novel interesting alternative.[8] Aryl deriva- volved lithiation with nBuLi (1 equiv.), transmetalation
tives of silicon, mercury,[9] tin,[10] and thalium[11] have also with B(OiPr)3 (1 equiv.), and then the second lithiation
been used in combination with borane or tribromobor- (1.1 equiv.) followed by addition of the electrophile
ane.[12] Alternative strategies relying on a structural modifi- (1.2 equiv.) (Scheme 1). To avoid a potential coupling of 1-
cation of simple arylboronic acids were less explored in the iodobutane byproduct with iodophenyllithium and/or (lithio-
past years; classical examples include nitration of phenylbo- phenyl)triisopropoxyborate intermediates, diethyl ether
ronic acid and regiochemical oxidation of tolylboronic ac- was used as a solvent. After carboxylation and acidic hy-
ids.[13,14] Recently, a more advanced general protocol has drolysis, we isolated 4- and 3-carboxyphenylboronic acids,
been developed: it involves immobilization of substituted 1 and 3, respectively, in ca. 50% yield by simple solvent
arylboronic acids onto diethanolaminomethyl polysty- evaporation and washing the crude products with water and
rene[15] followed by derivatization of a remaining active sub- ether (Scheme 1). It should be noted that the precise control
stituent (formyl, bromomethyl, carboxy, amino groups). of stoichiometry during the first two steps (i.e., the first I–
Li exchange and boronation) is critical for a selective gener-
ation of lithium (iodophenyl)triisopropoxyborates, which is
in line with the desired removal of unreacted diiodobenzene
[a] Warsaw University of Technology, Faculty of Chemistry,
Noakowskiego 3, 00-664 Warsaw, Poland
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P. Kurach, S. Lulin´ski, J. Serwatowski
FULL PAPER
Scheme 1. The one-pot synthesis of meta- and para-substituted arylboronic acids from 1,3- and 1,4-diiodobenzene.
or iodophenyllithium from the reaction mixture. Derivati-
zation of lithium–boron reagents with appropriate electro-
philes may provide access to variously functionalized aryl-
boronic acids that are otherwise not easily accessible. Thus,
upon treatment with 2-methoxybenzaldehyde, boronated
carbinols 2 and 4 were isolated in moderate yields.
We attempted next to probe the above protocol by em-
ploying 1,3- and 1,4-dibromobenzene. Unfortunately, the
corresponding lithium (bromophenyl)triisopropoxyborates
do not undergo Br–Li exchange with nBuLi even at higher
temperatures (around –20 °C) and by employing THF as a
cosolvent, which is a better promoter of halogen–lithium
exchange when compared to Et2O.[21] In fact, iodine–lith-
ium exchange proceeds generally more smoothly than bro-
mine–lithium exchange. To give a simple example, dilithi-
ation of 1,3- and 1,4-diiodobenzene with nBuLi occurs
quantitatively in Et2O at –78 °C, whereas 1,3- and 1,4-di-
bromobenzene can only be monolithiated.[22]
We extended our work by using dibromobenzenes bear-
ing electron-withdrawing substituents (in terms of inductive
effect), as we assumed that the better stabilization of the
negative charge of the “ate” complex might be beneficial
for the Br–Li interconversion. In the case of 1,4-dibromo-2-
fluorobenzene, the first Br–Li exchange proceeds selectively
ortho to the fluorine atom when performed in Et2O at
–80 °C to produce lithium (4-bromo-2-fluorophenyl)trialk-
oxyborate as a gelatinous material after consecutive bo-
ronation (Scheme 2, Table 1). To improve its solubility, the
substantial addition of THF proved mandatory. Subse-
quent treatment with the next equivalent of nBuLi at ca
–60 °C resulted in the formation of lithium (4-lithio-2-fluo-
rophenyl)trialkoxyborate. This intermediate was trapped
with selected electrophiles to give functionalized 2-fluoro-
phenylboronic acids or their pinacol esters 5–7.
Scheme 2. The one-pot synthesis of 4-substituted 2-fluorophen-
ylboronic acids or their pinacol esters from 1,4-dibromo-2-fluoro-
benzene.
A similar approach proved also successful with 1,4-di-
bromo-2-methoxybenzene. The sequence of first lithiation/
boronation affords the “ate” complex (4-Br-2-MeOC6H3)-
B(OR)3Li as a result of selective Br–Li exchange ortho to a
methoxy group. However, to replace the remaining bromine
atom with lithium a higher temperature, that is, ca. –40 °C,
was necessary, as clearly evidenced by the precipitation of
the lithiated “ate” complex from an almost homogeneous
solution. Finally, we succeeded in the isolation of 4-substi-
Scheme 3. The one-pot synthesis of 4-substituted 2-methoxyphen-
ylboronic acids from 1,4-dibromo-2-methoxybenzene.
In 1,3-dibromo-2-alkoxybenzenes two bromine atoms
tuted 2-methoxyphenylboronic acids 8–10 after quench gain significant activation from the adjacent alkoxy group.
with electrophiles (Scheme 3). Hence, the Br–Li exchange in the preformed “ate” complex
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One-Pot Generation of Lithium (Lithiophenyl)trialkoxyborates
(3-Br-2-ROC6H3)B(OR)3Li (R = Me, Pr) proceeds effec-
The reactivity pattern of 1-bromo-4-iodo-2-(trifluoro-
tively at lower temperatures than in the previous case, that methyl)benzene is dictated by the tendency of iodine to be
is, at ca. –60 °C, providing easy access to acids 11–13 replaced much faster than bromine despite the fact that the
(Scheme 4).
latter is strongly activated by the adjacent strongly electron-
Table 1. The one-pot preparation of functionalized arylboronic acids and pinacol esters from dihalobenzenes.
Eur. J. Org. Chem. 2008, 3171–3178
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P. Kurach, S. Lulin´ski, J. Serwatowski
FULL PAPER
Table 1. (Continued)
[a] Lithiation of the halophenyl “ate” complex. [b] Used as a cosolvent.
Scheme 5.
Scheme 4. The one-pot synthesis of 3-substituted 2-alkoxyphen- the bromine atom, which would in turn result in lithiation
ylboronic acids from 1,3-dibromo-2-alkoxybenzenes.
of the borate. This prompted us to probe the reactivity of
some 5-substituted 1,3-dibromobenzenes.
The conversion of 1,3-dibromo-5-fluorobenzene into the
withdrawing trifluoromethyl group. Thus, the iodine–lith- “ate” complexes of the type (3-Br-5-FC6H3)B(OR)3Li was
ium exchange proceeds cleanly in Et2O (importantly, THF performed smoothly by using Et2O at –70 °C as a solvent,
must be completely avoided, as a mixture of products is whereas the addition of THF and a slight heating (to ca.
formed[23]) in the first step to give the “ate” complex (4-Br- –50 °C) were applied to induce the subsequent Br–Li in-
3-CF3C6H3)B(OiPr)3Li after consecutive boronation. This terconversion. The resultant lithiated intermediate was
complex undergoes facile bromine–lithium exchange at ca. trapped with CO2 to give the pinacol ester of 3-carboxy-5-
–70 °C without any activation by the addition of THF. The fluorophenylboronic acid 15 in moderate yield. This result
resultant lithiated species was carboxylated to give 4-car- demonstrates that fluorine is capable of activating remote
boxy-3-(trifluoromethyl)phenylboronic acid (14) after meta positions quite strongly,[24–26] which enables an effec-
acidic hydrolysis (Scheme 5).
tive Br–Li exchange in the “ate” complex. An even better
It should be noted that in all the above cases either the situation was observed for 1,3,5-tribromobenzene, where
anionic borate moiety is stabilized by the neighboring ortho the lithiation of the “ate” complex (3,5-Br2C6H3)B(OR)3Li
substituent or the halogen atom in the “ate” complex is was observed already at –60 °C in Et2O/THF (ca. 2:1) pro-
strongly ortho activated (in syntheses of 11–14). In addition, viding compounds 16 and 17 (Scheme 6) after derivati-
we were interested in evaluating whether long-range elec- zation. Finally, the conversion of 1,3-dibromo-5-methoxy-
tron-withdrawing effects are sufficiently strong to activate benzene into 3-carboxy-5-methoxyphenylboronic acid (18;
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One-Pot Generation of Lithium (Lithiophenyl)trialkoxyborates
Scheme 7) failed almost completely, as 3-bromo-5-methoxy- 11 and 16. In general, this degradation could not be easily
phenylboronic acid (19) was identified as a major product, monitored by using VT 11B NMR, as only the spectra of
and it was only contaminated with a small amount (ca. the dianionic precursor of 11 showed changes pointing to
15%) of 18. Clearly, the lithiation of the (3-Br-5-OMeC6H3)- degradation starting at ca. 0 °C, whereas for 16 they were
B(OR)3Li complex is not effective even at higher tempera- not significantly temperature dependent.
tures (ca. –15 °C), which confirms the reputation of the
methoxy group being only weakly activating and/or anion
stabilizing when located at a remote meta position,[27,28] es-
Conclusions
pecially in comparison with fluorine.[29,30]
The halogen–lithium interconversion in lithium
(haloaryl)trialkoxyborates is straightforward by using
nBuLi for iodides and moderately activated bromides. The
resultant lithium (lithioaryl)trialkoxyborates can be re-
garded as equivalents of lithiated arylboronic acids or es-
ters, which can be subsequently derivatized by the treatment
with an appropriate electrophile, which provides access to a
wide range of functionalized arylboronic acids and esters.
It should be stressed that the proposed one-pot protocol
uses readily available and relatively cheap dihalobenzenes
as starting materials.
Experimental Section
General Comments: All reactions involving air- and moisture-sensi-
tive reagents were carried out under an argon atmosphere. Et2O
and THF were stored over sodium wire before use. Starting materi-
als: diiodobenzenes, substituted dibromobenzenes, and other im-
portant reagents including tert-butyl isocyanate, dimethyl carbon-
ate, N,N-dimethylformamide, iodine, dimethyl disulfide, nBuLi
(10  in hexanes), triisopropoxyborane, and 2-methoxy-4,4,5,5-tet-
ramethyl[1,3,2]dioxaborolane were received from Aldrich. 1,3-Di-
bromo-2-methoxybenzene, 1,3-dibromo-2-propoxybenzene, and 1-
bromo-4-iodo-2-(trifluoromethyl)benzene were prepared according
to literature procedures.[31,32]
Scheme 6. The one-pot synthesis of 3-substituted 5-halophenyl-
boronic acids (X = F, Br) or their pinacol esters from correspond-
ing 1,3-dibromo-5-halobenzenes.
The NMR chemical shifts are given relative to TMS by using
known chemical shifts of residual proton (1H) or carbon (13C) sol-
vent resonances. In the 13C NMR spectra of arylboronic acids, the
resonances of boron-bound carbon atoms were not observed in
most cases as a result of their broadening by a quadrupolar boron
nucleus. New compounds gave satisfactory elemental analyses ex-
cept for acids 14 and 16, because of the formation of air-stable
hydrates.
Scheme 7.
4-Carboxyphenylboronic acid (1): To a stirred suspension of 1,4-
diiodobenzene (16.5 g, 50 mmol) in Et2O (300 mL) was slowly
added nBuLi (2  in hexanes, 25 mL, 50 mmol) at –70 °C. The mix-
ture was stirred for 30 min, followed by the dropwise addition of
B(OiPr)3 (8.9 g, 50 mmol). The resultant mixture was stirred for ca.
15 min and then treated with nBuLi (2  in hexanes, 30 mL,
In addition, we investigated the thermostabilities of both
types of “ate” complexes existing in the reaction pathway
by using VT 11B NMR spectroscopy under reaction condi-
tions. We selected 1,3-dibromo-2-methoxybenzene and
1,3,5-tribromobenzene (Table 1, compounds 11 and 16, 60 mmol) to give a gelatinous slurry. The mixture was stirred for
1 h at –60 °C and then poured onto freshly crushed dry ice covered
with Et2O (50 mL). After evaporation of the excess CO2, the mix-
ture was hydrolyzed with aqueous sulfuric acid (1.5 , 50 mL). The
organic phase was separated and concentrated under reduced pres-
sure. The residue was filtered and washed consecutively with water
(2ϫ10 mL), ether (2ϫ5 mL), and hexane (10 mL). Drying in
vacuo afforded the title compound as a white powder. M.p. 236–
237 °C (decomp.) (ref.[33] m.p. 240 °C). Yield: 4.3 g (52%). 1H
NMR (400 MHz, [D6]acetone): δ = 7.91 (m, 4 H, Ph), 4.03 [br., 3
H, B(OH)2 + COOH] ppm. 11B NMR (64.2 MHz, [D6]acetone): δ
respectively) as starting materials. We found that lithium (3-
bromo-2-methoxyphenyl)triisopropoxyborate
(δ11B
=
4 ppm) is stable at 0 °C but decomposes quite rapidly at
room temperature to give diisopropyl boronate (δ11B =
27 ppm). In contrast, lithium (3,5-dibromophenyl)triiso-
propoxyborate is more stable under comparable conditions
and does not split to form the corresponding boronate.
(Lithiophenyl)triisopropoxyborates are apparently too reac-
tive when warmed up (0–20 °C), as subsequent attempted
carboxylation (at –70 °C) did not afford desired products = 27.0 ppm.
Eur. J. Org. Chem. 2008, 3171–3178
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P. Kurach, S. Lulin´ski, J. Serwatowski
FULL PAPER
4-[(2Ј-Methoxyphenyl)hydroxymethyl]phenylboronic acid (2):
A
1 H, Ph), 7.84 (dd, J = 8.0, 5.5 Hz, 1 H, Ph), 7.75 (dd, J = 9.5,
1.0 Hz, 1 H, Ph) 1.38 (s, 12 H, Me) ppm. 13C{1H} NMR
(100.6 MHz, CDCl3): δ = 170.9 (d, J = 2.5 Hz), 166.8 (d, J =
250 Hz), 137.0 (d, J = 8.5 Hz), 133.8 (d, J = 8.5 Hz), 125.0 (d, J =
3.0 Hz), 116.7 (d, J = 26.0 Hz) 84.4, 24.8 ppm. 11B NMR
(64.2 MHz, CDCl3): δ = 25.4 ppm. C13H16BFO4 (266.08): calcd. C
58.68, H 6.06; found C 58.45, H 6.27.
slurry of 1,4-diiodobenzene (6.6 g, 20 mmol) in Et2O (100 mL) was
treated consecutively with nBuLi (2  in hexanes, 10 mL, 20 mmol),
B(OiPr)3 (3.8 g, 20 mmol), and again with nBuLi (2  in hexanes,
11 mL, 22 mmol) by employing a protocol similar to that described
for 1. The resultant mixture was stirred for ca. 30 min at –75 °C,
and it was then treated with a solution of 2-methoxybenzaldehyde
(3.25 g, 22 mmol) in Et2O (20 mL). The mixture was stirred for 1 h
at –75 °C and then hydrolyzed with aqueous sulfuric acid (1.5 ,
20 mL). The organic phase was separated and concentrated under
reduced pressure. Toluene (10 mL) and hexane (10 mL) were
added, and a resultant slurry was filtered and washed with water
(2ϫ5 mL) and hexane (2ϫ5 mL). The title compound was ob-
tained as a white powder. M.p. 126–130 °C (decomp.). Yield: 3.35 g
4-Methoxycarbonyl-2-fluorophenylboronic acid (6): This compound
was prepared as described for the preparation of 5 by using B(OiPr)
(8.9 g, 50 mmol) for the boronation and an excess amount of
3
dimethyl carbonate (6.8 g, 75 mmol) as the electrophile (added be-
low –80 °C). The crude product was washed with water (3ϫ10 mL)
and toluene (2ϫ5 mL) to give the title compound as a white crys-
talline material. M.p. 137–140 °C. Yield: 6.7 g (68%). 1H NMR
(400 MHz, [D6]acetone): δ = 7.85–7.76 (m, 2 H, Ph), 7.58 (dd, J =
10.0, 1.5 Hz, 1 H, Ph), 7.50 [br., 2 H, B(OH)2], 3.89 (s, 3 H, CO-
OMe) ppm. 13C{1H} NMR (100.6 MHz, [D6]acetone): δ = 167.1
(d, J = 244 Hz), 166.1 (d, J = 3.0 Hz), 137.0 (d, J = 9.0 Hz), 134.7
(d, J = 8.0 Hz), 125.3 (d, J = 3.0 Hz), 116.1 (d, J = 26.5 Hz),
52.6 ppm. 11B NMR (64.2 MHz, [D6]acetone): δ = 28.0 ppm.
C8H8BFO4 (197.96): calcd. C 48.54, H 4.07; found C 48.67, H 4.10.
1
(65%). H NMR (400 MHz, [D6]acetone + D2O): δ = 7.76 (d, J =
8.0 Hz, 2 H, Ph), 7.49 (dd, J = 7.5, 1.5 Hz, 1 H, PhЈ), 7.36 (d, J =
8.0 Hz, 2 H, Ph), 7.18 (td, J = 7.5, 1.5 Hz, 1 H, PhЈ), 6.93–6.88 (m,
2 H, PhЈ), 6.12 (s, 1 H, CHOH), 3.75 (s, 3 H, OMe) ppm. 13C{1H}
NMR (100.6 MHz, [D6]acetone + D2O): δ = 156.8, 147.9, 134.5,
134.0, 128.8, 127.5, 126.4, 121.1, 111.2, 69.7, 55.6 ppm. 11B NMR
(64.2 MHz, [D6]acetone + D2O): δ = 28.0 ppm. IR (KBr): 3460,
1608, 1316, 1244, 1032, 760 cm–1. C14H15BO4 (258.08): calcd. C
65.15, H 5.86; found C 64.81, H 5.90.
2-(2Ј-Fluoro-4Ј-iodophenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaborolane
(7): This compound was prepared as described for the preparation
of 5 by using iodine (12.7 g, 50 mmol) as the electrophile dissolved
in THF (30 mL) at –80 °C. After hydrolysis with aqueous sulfuric
acid (1.5 , 50 mL), the organic phase was consecutively separated,
washed with water (50 mL) and aqueous Na2S2O3 (20 wt.-%,
30 mL), and concentrated under reduced pressure. The oily residue
was diluted with hexane and washed with water (2ϫ10 mL). After
removal of hexane, the residue was distilled under reduced pressure
to give the crude product as an oil. B.p. 95–105 °C (0.5 Torr).
Recrystallization from hexane (30 mL) at –40 °C afforded the title
compound as colorless crystals. M.p. 56–58 °C. Yield: 10.4 g (60%).
1H NMR (400 MHz, CDCl3): δ = 7.49 (dd, J = 8.0, 1.5 Hz, 1 H,
Ph), 7.45–7.41 (m, 2 H, Ph), 1.34 (s, 12 H, Me) ppm. 13C{1H}
NMR (100.6 MHz, CDCl3): δ = 166.3 (d, J = 256 Hz), 137.7 (d, J
= 8.0 Hz), 133.0 (d, J = 3.0 Hz), 124.7 (d, J = 26.5 Hz), 98.1 (d,
J = 8.0 Hz), 84.0, 24.7 ppm. 11B NMR (64.2 MHz, CDCl3): δ =
25.3 ppm. C12H15BFIO2 (347.96): calcd. C 41.42, H 4.35; found C
41.55, H 4.65.
3-Carboxyphenylboronic acid (3): This compound was prepared
similarly by starting with 1,3-diiodobenzene (6.6 g, 20 mmol) and
obtained as a white powder. M.p. 245–247 °C (decomp.) (ref.[33]
m.p. 250 °C). Yield: 1.65 g (50%). 1H NMR ([D6]acetone,
400 MHz): δ = 8.54 (s, 1 H, Ph), 8.10–8.06 (m, 2 H, Ph), 7.48 (t, J
= 8.0 Hz, 1 H, Ph), 3.60 [br., 3 H, B(OH)2] ppm. 11B NMR
(64.2 MHz, [D6]acetone + D2O): δ = 28.0 ppm.
3-[(2Ј-Methoxyphenyl)hydroxymethyl]phenylboronic acid (4): This
compound was prepared as described for the preparation of 3 from
1,3-diiodobenzene (6.6 g, 20 mmol) and obtained as a white pow-
der. M.p. 140–144 °C (decomp.). Yield: 2.9 g (55%). 1H NMR
(400 MHz, [D6]acetone + D2O): δ = 7.91 (s, 1 H, Ph), 7.67 (d, J =
7.5 Hz, 1 H, Ph), 7.50 (dd, J = 7.5, 1.5 Hz, 1 H, Ph), 7.39 (d, J =
7.5 Hz, 1 H, Ph), 7.21–7.16 (m, 2 H, PhЈ), 6.91–6.87 (m, 2 H, PhЈ),
6.11 (s, 1 H, CHOH), 3.73 (s, 3 H, OMe) ppm. 13C{1H} NMR
(100.6 MHz, [D6]acetone + D2O): δ = 156.8, 144.6, 134.2, 133.2,
129.3, 128.7, 127.7, 127.5, 121.0, 111.2, 70.0, 55.6 ppm. 11B NMR
(64.2 MHz, [D ]acetone + D O): δ = 29.0 ppm. IR (KBr): ν = 3332,
˜
6
2
4-Carboxy-2-methoxyphenylboronic acid (8): This compound was
prepared as described for 6 from 1,4-dibromo-2-methoxybenzene
(5.32 g, 20 mmol) except the higher temperature (–40 °C) was ap-
plied to perform the lithiation of the “ate” complex. The crude
product was washed with water (2ϫ10 mL), ether (2ϫ10 mL), and
hexane (10 mL) to give the title compound as a white crystalline
material. M.p. 181–182 °C. Yield: 3.4 g (87 %). 1H NMR
(400 MHz, [D6]DMSO): δ = 7.94 [br., 2 H, B(OH)2], 7.58 (d, J =
7.5 Hz, 1 H, Ph), 7.51 (dd, J = 7.5, 1.0 Hz, 1 H, Ph), 7.43 (s, 1 H,
Ph), 3.83 (s, 3 H, OMe) ppm. 13C{1H} NMR (100.6 MHz, [D6]-
DMSO): δ = 167.4, 162.9, 134.9, 133.4, 128.1 (br.), 121.2, 110.3,
55.3 ppm. 11B NMR (64.2 MHz, [D6]DMSO): δ = 29.8 ppm.
C8H9BO5 (195.97): calcd. C 49.03, H 4.63; found C 48.63, H 4.70.
1600, 1356, 1240, 1008, 756 cm–1. C14H15BO4 (258.08): calcd. C
65.15, H 5.86; found C 64.70, H 5.78.
2-(4Ј-Carboxy-2Ј-fluorophenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaboro-
lane (5): To a stirred solution of nBuLi (10  in hexanes, 5 mL,
50 mmol) in Et2O (50 mL) was slowly added a solution of 1,4-di-
bromo-2-fluorobenzene (12.7 g, 50 mmol) in Et2O (30 mL) at
–80 °C. The mixture was stirred for 30 min, followed by the drop-
wise addition of PinBOMe (7.9 g, 50 mmol). The resultant gelati-
nous mixture was diluted with THF (70 mL) and stirred for ca.
30 min at –70 °C to give an almost clear solution. It was then
treated with nBuLi (2  in hexanes, 27 mL, 54 mmol) to give a
gelatinous slurry. The slurry was stirred for 30 min at ca. –65 °C.
After cooling to –80 °C, the mixture was carboxylated by passing
through a stream of dried gaseous CO2 with rapid stirring. After
saturation, the mixture was left to warm up to ca. 0 °C to evaporate
the excess CO2, followed by the careful hydrolysis with aqueous
sulfuric acid (1.5 , 50 mL). The organic phase was separated and
concentrated under reduced pressure. The crude product was
washed with water (3ϫ10 mL) and hexane (10 mL) to give the title
compound as a white powder. M.p. 193–195 °C. Yield: 11.0 g
4-tert-Butylaminocarbonyl-2-methoxyphenylboronic acid (9): This
compound was prepared as described for the preparation of 8 by
using tBuNCO as the electrophile. The crude product was washed
with water (2ϫ10 mL), toluene (2ϫ5 mL), and hexane (2ϫ5 mL)
to give the title compound as a white crystalline material. M.p.
189–191 °C. Yield: 2.7 g (54%). 1H NMR (400 MHz, [D6]acetone):
δ = 7.76 (d, J = 7.5 Hz, 1 H, Ph), 7.42 (d, J = 1.0 Hz, 1 H, Ph),
7.39 (dd, J = 7.5, 1.0 Hz, 1 H, Ph), 7.35 (br., 1 H, NH), 3.93 [s, 2
(83%). 1H NMR (400 MHz, CDCl3): δ = 7.87 (dd, J = 7.5, 1.0 Hz, H, B(OH)2], 1.42 (s, 9 H, tBu) ppm. 13C{1H} NMR (100.6 MHz,
3176
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Eur. J. Org. Chem. 2008, 3171–3178

One-Pot Generation of Lithium (Lithiophenyl)trialkoxyborates
[D6]acetone): δ = 167.3, 165.2, 140.7, 136.9, 119.8, 109.8, 55.9, 52.0,
28.8 ppm. 11B NMR (64.2 MHz, [D6]acetone): δ = 28.8 ppm.
C12H18BNO4 (251.09): calcd. C 57.40, H 7.23, N 5.58; found C
57.30, H 7.23, N 5.56.
8.18 (d, J = 8.0 Hz, 1 H, Ph), 7.85 (d, J = 8.0 Hz, 1 H, Ph), 7.7
(br., 1 H), 5.5 (br., 2 H) ppm. 13C{1H} NMR (100.6 MHz, [D6]-
acetone): δ = 168.2, 138.6, 134.2 (q, J = 2.0 Hz), 132.6 (q, J =
5.5 Hz), 129.9, 127.7 (q, J = 31.0 Hz), 124.9 (q, J = 271 Hz) ppm.
1 1 B N M R ( 6 4 . 2 M H z , [ D 6 ] a c e t o n e ) : δ = 2 7 . 9 p p m .
C8H6BF3O4·H2O (255.96): calcd. C 38.14, H 3.20; found C 37.73,
H 3.57.
4-Formyl-2-methoxyphenylboronic acid (10): This compound was
prepared as described for the preparation of 8 by using Me2NCHO
as the electrophile. The crude product was washed with water
(2ϫ10 mL), toluene (2ϫ5 mL), and hexane (2ϫ5 mL) to give the
title compound as a white crystalline material. M.p. 152–155 °C.
Yield: 2.4 g (67%). 1H NMR (400 MHz, [D6]acetone): δ = 10.01 (s,
1 H, CHO), 7.95 (d, J = 7.5 Hz, 1 H, Ph), 7.52 (dd, J = 7.5, 1.0 Hz,
1 H, Ph), 7.47 (d, J = 1.0 Hz, 1 H, Ph), 7.24 [s, 2 H, B(OH)2], 3.98
(s, 3 H, OMe) ppm. 13C{1H} NMR (100.6 MHz, [D6]acetone): δ =
193.1, 165.5, 140.6, 137.7, 123.5, 109.8, 56.0 ppm. 11B NMR
(64.2 MHz, [D6]acetone): δ = 28.6 ppm. C8H9BO4 (179.97): calcd.
C 53.39, H 5.04; found C 53.70, H 4.83.
2-(3Ј-Carboxy-5Ј-fluorophenyl)-4,4,5,5-tetramethyl[1,3,2]dioxaboro-
lane (15): This compound was prepared as described for the prepa-
ration of 5 from 1,3-dibromo-5-fluorobenzene (12.7 g, 50 mmol)
except a slightly higher temperature (–50 °C) was applied to per-
form the lithiation of the “ate” complex. The crude product was
washed with water (3ϫ10 mL) and hexane (10 mL) to give the title
compound as pale yellow crystals. M.p. 212–215 °C. Yield: 6.1 g
(46%). 1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 1.0 Hz, 1 H,
Ph), 7.86 (ddd, J = 9.0, 2.5, 1.0 Hz, 1 H, Ph), 7.73 (dd, J = 9.0,
2.5 Hz, 1 H, Ph), 1.37 (s, 12 H, Ph) ppm. 13C{1H} NMR
(100.6 MHz, CDCl3): δ = 170.9, 162.3 (d, J = 247 Hz), 138.2 (br.),
132.1 (d, J = 2.5 Hz), 130.9 (d, J = 7.0 Hz), 126.6 (d, J = 20.0 Hz),
119.5 (d, J = 23.0 Hz), 84.5, 24.8 ppm. 11B NMR (64.2 MHz,
CDCl3): δ = 25.6 ppm. C13H16BFO4 (266.08): calcd. C 58.68, H
6.06; found C 58.46, H 6.06.
3-Carboxy-2-methoxyphenylboronic acid (11): This compound was
prepared as described for the preparation of 6 from 1,3-dibromo-
2-methoxybenzene (5.32 g, 20 mmol). The crude product was
washed with water (2 ϫ10 mL), toluene (2ϫ5 mL), and hexane
(2ϫ5 mL) to give the title compound as a white crystalline mate-
rial. M.p. 156–159 °C. Yield: 2.8 g (72 %). 1H NMR (400 MHz,
[D6]acetone + D2O): δ = 7.90–7.85 (m, 2 H, Ph), 7.20 (t, J = 7.5 Hz,
1 H, Ph), 3.89 (s, 3 H, OMe) ppm. 13C{1H} NMR (100.6 MHz,
[D6]acetone + D2O): δ = 167.7, 165.4, 140.5, 134.6, 124.8, 124.2,
63.4 ppm. 11B NMR (64.2 MHz, [D6]acetone + D2O): δ =
28.8 ppm. C8H9BO5 (195.97): calcd. C 49.03, H 4.63; found C
49.19, H 4.73.
3-Bromo-5-carboxyphenylboronic acid (16): This compound was
prepared as described for the preparation of 5 from 1,3,5-tribromo-
benzene (9.45 g, 30 mmol) except that nBuLi was added to a stirred
slurry of the substrate in Et2O. The crude product was washed with
water (3ϫ10 mL) and toluene (2ϫ5 mL) to give the title com-
pound as a white crystalline material. M.p. 260–263 °C. Yield: 6.5 g
1
(82%). H NMR (400 MHz, [D6]acetone): δ = 8.48 (t, J = 1.0 Hz,
3-Carboxy-2-propoxyphenylboronic acid (12): This compound was
prepared as described for the preparation 11 from 1,3-dibromo-2-
propoxybenzene (5.88 g, 20 mmol). The crude product was washed
with water (2ϫ10 mL), toluene (2ϫ5 mL), and hexane (2ϫ5 mL)
to give the title compound as a white crystalline material. M.p.
142–144 °C. Yield: 3.8 g (85%). 1H NMR (400 MHz, [D6]acetone):
δ = 11.3 (br., 1 H, COOH), 7.92 (m, 2 H, Ph), 7.30 [br., 2 H, B(OH)
2], 7.22 (t, J = 7.5 Hz, 1 H, Ph), 4.02 (t, J = 7.0 Hz, 2 H, OCH2Et),
1.82 (sextet, J = 7.0 Hz, 2 H, OCH2CH2CH3), 1.00 (t, J = 7.0 Hz,
3 H, OCH2CH2CH3) ppm. 13C{1H} NMR (100.6 MHz, [D6]ace-
tone): δ = 167.2, 164.5, 140.6, 134.7, 124.8, 124.3, 78.9, 24.0,
10.5 ppm. 11B NMR (64.2 MHz, [D6]acetone): δ = 28.8 ppm.
C10H13BO5 (224.02): calcd. C 53.62, H 5.85; found C 53.69, H 5.89.
1 H, Ph), 8.20 (dd, J = 2.0, 1.0 Hz, 1 H, Ph), 8.17 (dd, J = 2.0,
1.0 Hz, 1 H, Ph), 7.61 [br., 2 H, B(OH)2] ppm. 13C{1H} NMR
(100.6 MHz, [D6]acetone): δ = 166.6, 141.8, 134.8, 134.6, 133.0,
122.6 ppm. 11B NMR (64.2 MHz, [D6]acetone): δ = 28.0 ppm.
C7H6BBrO4·H2O (262.853): calcd. C 31.99, H 3.07; found C 31.57,
H 3.57.
2-[3Ј-Bromo-5Ј-(tert-butylaminocarbonyl)phenyl]-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (17): This compound was prepared as de-
scribed for the preparation of 16 by using PinBOMe for the bo-
ronation. The crude product was washed with water (3ϫ10 mL)
and recrystallized from hexane (30 mL) to give the title compound
1
as a white powder. M.p. 217–220 °C. Yield: 6.3 g (55%). H NMR
(400 MHz, CDCl3): δ = 7.72 (dd, J = 7.5, 1.0 Hz, 1 H, Ph), 7.64
(dd, J = 7.5, 6.0 Hz, 1 H, Ph), 7.53 (dd, J = 9.0, 1.0 Hz, 1 H, Ph)
ppm. 13C{1H} NMR (100.6 MHz, CDCl3): δ = 165.4, 139.9, 137.3,
133.2, 130.4, 122.8, 84.5, 51.9, 28.8, 24.8 ppm. 11B NMR
(64.2 MHz, CDCl3): δ = 25.5 ppm. C17H25BBrNO3 (382.11): calcd.
C 53.44, H 6.59, N 3.67; found C 53.69, H 6.66, N 3.81.
3-(Methylthio)-2-propoxyphenylboronic acid (13): This compound
was prepared as described for the preparation of 12 by using (MeS)
as the electrophile. The crude product was washed with water
2
(2ϫ10 mL), toluene (2ϫ5 mL), and hexane (2ϫ5 mL) to give the
title compound as a white crystalline material. M.p. 97–99 °C.
Yield: 2.9 g (64%). 1H NMR (400 MHz, [D6]acetone): δ = 7.53 (dd,
J = 7.5, 1.5 Hz, 1 H, Ph), 7.31 (dd, J = 7.5, 1.5 Hz, 1 H, Ph), 7.17
[br., 2 H, B(OH)2], 7.14 (t, J = 7.5 Hz, 1 H, Ph), 3.92 (t, J = 7.0 Hz,
2 H, OCH2Et), 2.43 (s, 3 H, SMe), 1.82 (sextet, J = 7.0 Hz, 2 H,
OCH2CH2CH3), 1.04 (t, J = 7.0 Hz, 3 H, OCH2CH2CH3) ppm.
13C{1H} NMR (100.6 MHz, [D6]acetone): δ = 161.5, 132.8, 129.1,
125.4, 76.6, 24.1, 14.2, 10.6 ppm. 11B NMR (64.2 MHz, [D6]ace-
tone): δ = 29.0 ppm. C10H15BO3S (226.10): calcd. C 53.12, H 6.69;
found C 53.11, H 6.74.
3-Carboxy-5-methoxyphenylboronic acid (18): This compound was
prepared as described for the preparation of 8 from 1,3-dibromo-
5-methoxybenzene (5.32 g, 20 mmol) except a higher temperature
(–15 °C) was applied to perform the lithiation of the “ate” complex.
The crude product was washed with water (3ϫ10 mL) and toluene
(2ϫ5 mL) to give a mixture containing the title compound as a
1
minor component (ca. 15%) and acid 19 as the major product. H
NMR (400 MHz, [D6]acetone): δ = 8.15 (t, J = 1.5 Hz, 1 H, Ph),
7.66 (dd, J = 2.5, 1.0 Hz, 1 H, Ph), 7.59 (dd, J = 2.5, 1.5 Hz, 1 H,
Ph), 3.86 (s, 3 H, OMe) ppm.
4-Carboxy-3-(trifluoromethyl)phenylboronic acid (14): This com-
pound was prepared as described for the preparation of 1 from
1-bromo-4-iodo-2-(trifluoromethyl)benzene (7.02 g, 20 mmol). The
crude product was washed with water (2 ϫ 10 mL), toluene
(2ϫ10 mL), and hexane (10 mL) to give the title compound as a
white crystalline material. M.p. 253–254 °C (decomp.). Yield: 3.1 g
(61%). 1H NMR (400 MHz, [D6]acetone): δ = 8.27 (s, 1 H, Ph),
Acknowledgments
This work was supported by the Warsaw University of Technology
and by the Polish Ministry of Science and Higher Education (Grant
Eur. J. Org. Chem. 2008, 3171–3178
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3177

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Published Online: May 6, 2008
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3178
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Eur. J. Org. Chem. 2008, 3171–3178