Noncryogenic preparation of functionalized arylboronic esters through a magnesium-iodine exchange with in situ quench

Article abstract of DOI:10.1021/op2000089

Various functionalized aryl boronic esters derived from hexylene glycol and pinacol were prepared in excellent yields according to a simple, safe procedure. The metal-halogen exchange reaction between ⁱPrMgCl? LiCl and aryl iodides is performed

Full text of DOI:10.1021/op2000089

TECHNICAL NOTE
pubs.acs.org/OPRD
Noncryogenic Preparation of Functionalized Arylboronic Esters
through a Magnesium-Iodine Exchange with in Situ Quench
Emilien Demory, Vꢀeronique Blandin, Jacques Einhorn, and Pierre Y. Chavant*
Dꢀepartement de Chimie Molꢀeculaire, UMR-5250, ICMG FR-2607, CNRS, Universitꢀe Joseph Fourier, BP 53, 38041 Grenoble Cedex 09,
France.
S Supporting Information
b
ABSTRACT: Various functionalized aryl boronic esters derived from hexylene glycol and pinacol were prepared in excellent yields
according to a simple, safe procedure. The metal-halogen exchange reaction between iPrMgCl LiCl and aryl iodides is performed
3
at 0 °C in the presence of a cyclic borate ester (MPBOiPr or PinBOiPr); the organomagnesium intermediate is immediately trapped
in situ so that no accumulation of hazardous reactive species can occur. The reaction is very selective, and particularly clean crude
products are obtained. The scope of the procedure and the tuning of reaction parameters are investigated.
’ INTRODUCTION
cases with organolithium species and triisopropyl borate, but
yields are still inadequate for challenging substrates such as ethyl
p-bromobenzoate.10 Regarding the magnesium-halogen ex-
change reaction, scarce examples of in situ trapping with trialk-
ylborates can be found, with varying degrees of success.11
Among boronic acid derivatives, arylboronic hexylene glycol
esters emerged as interesting compounds. Murata’s team12 and
ours13 have shown that they exhibit excellent stability toward air,
water, and chromatography,14 and undergo Suzuki-Miyaura
reactions with aryl iodides, bromides, and triflates in excellent
yields. Advantageously, hexylene glycol—a solvent—is much
less expensive than pinacol.15 We thus wondered whether 2-iso-
propoxy-4,4,6-trimethyl-1,3,2-dioxaborinane16 (MPBOiPr, 1)
could be an efficient in situ trapping agent for arylmagnesium
species issuing from a magnesium-halogen exchange.
Arylboronic acids and esters have found a prominent place in
the synthetic chemist’s toolbox, the latter being often preferred
for convenience in their purification and characterization and for
their ability to be observed via gas or liquid chromatography.1
Despite the recent developments in transition metal-catalyzed
borylation,1-4 the cheapest and most common way of synthesiz-
ing arylboronic acids and esters remains the reaction of an
organolithium or organomagnesium intermediate with a trialk-
ylborate at low temperature, typically -78 °C (Li) up to -10 °C
(Mg).1,5 An attractive method in this context is the generation of
the aryl Grignard reagent by metal-halogen exchange using
i
i
reagents such as PrMgBr or PrMgCl LiCl.6 Compared to the
3
historic Grignard synthesis from Mg0, this procedure, introduced
by Knochel and Cahiez,7 allows the preparation of the reagent at
milder temperatures (-40 °C to room temperature), which
broadly enlarges the functional group compatibility: for instance,
arylmagnesium halides bearing ester or nitrile substituents become
accessible. The exchange reaction is generally completed within
hours, and the organomagnesium species can then be reacted
with an electrophile at temperatures below 0 °C, typically -30
to -10 °C in the case of a trialkylborate.8
’ RESULTS AND DISCUSSION
Reagent 1 was easily prepared from boric acid, hexylene glycol,
and isopropanol by azeotropic removal of water (see Experi-
mental Section),17 and methyl 4-iodobenzoate 2a was chosen as
the first substrate. The magnesium-iodine exchange reaction
was carried out with in situ quench, at 0 °C, through gradual
addition of a THF solution of iPrMgCl LiCl to the mixture of 1
The functionalized Grignard reagents are intrinsically unstable,
even if they can be kept for several hours at low temperature.6a
Furthermore, with the expanding use of this magnesium-halo-
gen method for the preparation of arylmagnesium reagents, some
concerns have been raised regarding the stability of the reaction
mixture. Process safety evaluation studies9 revealed that an
exothermic decomposition of the solution is possible—even
for phenylmagnesium chloride—and that onset temperatures
as low as 55 °C can be found. The structure of the aromatic ring
and the concentration of the solution have a strong influence on
the severity of the event, fluorine substituents and concentrated
media being detrimental. A solution to avoid the prolonged
coexistence of the aryl Grignard reagent, reactive functional
3
and 2a in THF (Scheme 1).18 Monitoring the reaction by GC
analysis showed that the transformation of 2a into arylboronic
ester 3a was complete by the end of the addition. Hydrolysis of
the reaction mixture led to a dramatically clean crude product19
and to the corresponding boronic ester in 77% isolated yield after
a simple filtration over silica gel.
This first result was very promising, given the competitive
reactions at stake (Scheme 2): magnesium-iodine exchange,
nucleophilic addition of the organomagnesium species onto the
electrophilic MPBOiPr20 or onto the carboxylic ester.6b Once the
exchange has occurred, the aryl Grignard reagent does not
accumulate but instantaneously reacts with 1 to give the
i
groups, and PrX, the byproduct of the magnesium-halogen
exchange, would be to directly trap the reactive species by the
Received: January 12, 2011
Published: March 14, 2011
electrophile in situ. Such a procedure has proven efficient in some
r
2011 American Chemical Society
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dx.doi.org/10.1021/op2000089 Org. Process Res. Dev. 2011, 15, 710–716
|

Organic Process Research & Development
Scheme 1. First result for the in situ borylation of methyl 4-halobenzoate with MPBOiPr through a magnesium-halide exchange
TECHNICAL NOTE
Scheme 2. Competitive reactions for the in situ borylation with 1 through a magnesium-halide exchange
Scheme 3. In situ borylation of aryl iodides with MPBOiPr in
(∼1%) of the diborylated compound were detected only in the
case of the para-disubstituted 2e, by 1H NMR and GC analysis of
the crude material.24 The borylation of o-halo iodobenzene
occurs at the iodine position, and no product resulting from
aryne formation25 could be detected (Table 1, entries 6-8).
Running the reaction at lower temperature slightly improved the
yield in arylboronic ester 3f (Table 1, entry 6). The o-trifluoro-
methyl arylboronic ester 3i was prepared in quantitative yield up
to a 100 mmol scale using only a slight excess (10 mol %) of
reagents (Table 1, entry 9). This excellent result is particularly
interesting as the corresponding aryl Grignard reagent is re-
ported to be prone to a highly exothermic decomposition.9b The
very clean crude product was engaged without further purifica-
tion in a Suzuki-Miyaura coupling leading to biaryl 5 bearing
electron-withdrawing substituents on both aryl rings in 80%
unoptimised yield (Scheme 4).26 2-Pyridyl boronic acids are
notoriously unstable, and ester derivatives are therefore attractive
compounds;27 we were thus pleased to obtain 6-bromopyridin-
2-yl boronic ester 3j in excellent yield (Table 1, entry 10).
Electron-donating substituents proved detrimental to the
reaction: the slower rate of the magnesium-iodine exchange28
(constant k1 in Scheme 2) made the nucleophilic addition of the
the presence of iPrMgCl LiCl
3
arylboronic ester. Indeed, we did not detect any methyl benzoate
by GC analysis of hydrolyzed aliquots sampled during the
addition of iPrMgCl LiCl. The selectivity in the case of 2a can
3
be partly explained by the presence of the electron-withdrawing
substituent, known to strongly accelerate the magnesium-halo-
gen exchange.21 However, the nature of the halogen is crucial.
Indeed, in the case of aryl bromide 20a, the exchange proved too
slow22 compared to the nucleophilic addition onto 1, and methyl
4-bromobenzoate 20a was recovered unchanged when submitted
to the protocol from Scheme 1.
We then investigated the nature of the aryl iodides that could
undergo the magnesium-iodine exchange in the presence of
MPBOiPr 1 (Scheme 3 and Table 1). The reaction proceeds
smoothly with aryl iodides bearing electron-withdrawing reactive
substituents such as ester and nitrile groups, leading to arylboronic
hexylene glycol esters 3a-c in high yields (Table 1, entries 1-3).
alkylmagnesium species onto 1 competitive. iPrMgCl LiCl was
3
consumed to give MPBiPr and the conversion of aryl iodide 2 was
therefore incomplete; no synthetically useful yield of arylboronic
ester 3 could be obtained at 0 °C (Table 1, entries 11-13).
As we can see from the above results, the electronic nature of
the aryl iodide plays an important part in the outcome of the
borylation, by modifying the rate constant k1 in Scheme 2. For a
given aryl iodide, other parameters can favor the exchange
reaction over the nucleophilic addition, by changing either the
rate constants (k1, k2) or the reaction rates. To test the influence
of the reaction conditions, we chose 2-iodoanisole as a borderline
substrate for which k1 is close to k2;29 some aryl iodide remained
unreacted, and we used the conversion of 2m into arylboronic
ester 3m as a measure of effectiveness (Scheme 5 and Table 2).
The use of iPrMgCl LiCl was not suitable for a nitro group and led
3
to a complex mixture. PhMgCl is known to allow magnesium-
iodine exchange in the presence of an o-nitro group, but to react on
a nitro group in meta- or para- position.23 In the present system,
the only reaction that takes place is between PhMgCl and
MPBOiPr: a mixture of unreacted 1-iodo-3-nitrobenzene 2d and
phenylboronic ester was obtained (Table 1, entry 4).
Starting from diiodobenzenes, the monoborylated products
3e-f are selectively obtained (Table 1, entries 5-6); traces
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Organic Process Research & Development
TECHNICAL NOTE
Table 1. Borylation of aryl iodides 2 with MPBOiPr in the
by Knochel, LiCl accelerates the magnesium-halogen exchange
presence of iPrMgCl LiCla
(higher k1);6b we observed in our case that iPrMgCl LiCl signifi-
3
3
cantlyimproved the conversion of 2m into 3m (compare Table 2,
entries 1, 4, and 6). Decreasing the amount of MPBOiPr 1 (1.1
equiv vs 1.9 equiv) slows down the rate of the direct addition of
iPrMgCl LiCl onto 1. As a result, a better, albeit still low,
3
conversion of the aryl iodide was achieved (compare Table 2,
entries 2 vs 1 and 5 vs 4). More generally, decreasing the amount
of MPBOiPr 1 has a practical consequence: crude materials even
cleaner than usual are obtained and can be directly engaged in
further transformation (Scheme 4).30
Withtherateconstantk2 being directly correlated to the structure
of the trapping agent, we wondered whether our procedure for
the preparation of functionalized arylboronic esters could be
applied to the corresponding pinacol derivative 2-isopropoxy-
4,4,5,5-tetramethyl[1,3,2]dioxaborolane (PinBOiPr, 6).31 Indeed,
pinacol esters are the best-known arylboronic esters for Suzuki-
Miyaura reactions.1 We chose o-iodo trifluoromethylbenzene 2i
and o-iodo anisole 2m as representative substrates (Scheme 6
and Table 3). In the case of the aryl iodide bearing an electron-
withdrawing substituent, an excellent 93% yield in the pinacol
ester 7i was obtained (Table 3, entry 1). In the borderline case of
substrate 2m, PinBOiPr 6 gave better results than MPBOiPr 1,
whichever alkyl Grignard reagent was used (compare Table 3,
entries 3 vs 2 and 5 vs 4). The extent of nucleophilic addition of
the isopropylmagnesium species onto 6 is probably lessened by
the increased steric hindrance around the boron atom compared
to 1. Finally, as seen in Table 2, the effect of the borate ester
stoichiometry proved significant (compare Table 3, entries 6 vs 5).
’ CONCLUSION
Combining the generation, at 0 °C, of the aryl Grignard
reagent by magnesium-iodine exchange with its in situ trapping
by a cyclic borate ester proved to be a very simple, safe, and
selective procedure for the preparation, in excellent yields and
crude purity, of functionalized arylboronic esters from electron-
deficient aryl iodides. Regarding arylboronic hexylene glycol
esters, the present procedure is complementary to the Pd-
catalyzed borylation of electron-rich aryl halides with 4,4,6-
trimethyl-1,3,2-dioxaborinane (methyl pentanediol borane).12,13
’ EXPERIMENTAL SECTION
General Experimental Methods. THF was freshly distilled
from sodium benzophenone ketyl. Reagents and solvents were
purchased from commercial sources and were used as received.
Alkylmagnesium reagents were titrated according to literature.32
GC analyses were performed on a Shimadzu C17 apparatus
equipped with a flame ionization detector and a BPX1 column
(15 m ꢀ 0.25 mm, SGE; 2.5 min at 150 °C, then 150 to 250 at
15 °C per min; He). Infrared spectra (IR) were recorded on a
Nicolet iS10 spectrometer using attenuated total reflection (ATR),
and the data are reported as absorption maxima in cm-1. Unless
otherwise stated, 1H NMR (400 MHz), 13C NMR (101 MHz),
11B NMR (128 MHz) and 19F NMR (282 MHz) spectra were
recorded on a Varian 400MR spectrometer in CDCl3 (δC 77.2
a Reaction conditions, unless otherwise stated: iPrMgCl LiCl (1.1-1.2
3
equiv, 1.3 M in THF (addition rate: 0.2 mL/min)) was added at 0 °C to a
solution of aryl iodide 2 (1 mmol) and MPBOiPr 1 (1.9 equiv) in THF
i
([ArI] = 0.5 M). b 1.1 equiv MPBOiPr, PrMgCl LiCl (addition rate:
3
0.2-0.5 mL/min). c 1.1 equiv MPBOiPr; isolated yield not determined.
d PhMgCl (1.7 M in THF, 1.1 equiv, addition rate: 0.2 mL/min) was
i
f
employed; 1.5 equiv MPBOiPr. e 1.4 equiv PrMgCl LiCl. 1.1 equiv
3
MPBOiPr, iPrMgCl LiCl (0.8 M in THF, addition rate: 4.8 mL/min).
3
g Isolated yield not determined; conversion of 2 determined on the basis
of the 1H NMR spectrum of the crude product.
1
ppm; standard for H spectra: tetramethylsilane δH 0.0 ppm).
Data for 1H NMR are presented as follows: chemical shift (ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet,
hept = heptuplet, m = multiplet), coupling constant J (Hz) and
integration. Data for 13C NMR are reported in terms of chemical
The conversion reached 25% when conditions from Table 1
were applied (Table 2, entry 1). Running the reaction at lower
temperature was again beneficial (Table 2, entry 3). As stressed
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Organic Process Research & Development
TECHNICAL NOTE
Scheme 4. Suzuki-Miyaura coupling of o-trifluoromethyl arylboronic ester 3i
Scheme 5. Borylation of 2-iodoanisole with MPBOiPr
Table 2. Influence of reaction conditions on the borylation of
Scheme 6. Influence of the trapping agent
2-iodoanisole 2m with MPBOiPra
entry MPBOiPr (equiv) Mg(II) reagent T (°C) conversion of 2m (%) b
1
2
3
4
5
6
1.9
1
iPrMgCl LiCl
0
0
25
30
65
11
24
10
3
iPrMgCl LiCl
3
1.9
1.9
1.1
1.9
iPrMgCl LiCl -20
3
iPrMgCl
iPrMgCl
iPrMgBr
0
0
0
a Reaction conditions: aryl iodide 2m (1 mmol), MPBOiPr, THF
([2m] = 0.5 M), T (°C), Mg(II) reagent (1.1-1.2 equiv, [iPrMgCl
LiCl] = 1.3 M in THF (addition rate: 0.2 mL/min) or [iPrMgCl] = 2 M in
3
1
THF (addition rate: 0.1 mL/min) or [iPrMgBr] = 0.9 M in THF (addition
rate: 0.2 mL/min)). b Determined on the basis of the 1H NMR spectrum of
the crude product.
2933 and 2908 (CH3), 1304 and 1126 (B-O). H NMR δ 4.34
(hept, J = 6.2, 1H), 4.23 (dqd, J = 11.7, 6.2 and 2.8, 1H), 1.73 (dd, J =
13.9 and 2.8, 1H), 1.46 (dd, J = 13.9 and 11.7, 1H), 1.29 (s, 3H), 1.27
(s, 3H), 1.24 (d, J = 6.2, 3H), 1.16 (d, J = 6.2, 6H). 13C NMR δ 71.6
(Cq), 65.5 (CH), 64.9 (CH), 45.9 (CH2), 31.2 (CH3), 27.8 (CH3),
24.4 (CH3), 24.3 (CH3), 23.1 (CH3). 11B NMR δ 17.8.
shifts (ppm), and multiplicity (as above) followed by coupling
constant (Hz) for fluorine-containing compounds. Note that the
13C NMR signals of the boron-bound carbon atoms are very
broad and remain undetected. Mass spectra (LRMS) were
recorded on a ThermoFinnigan PolarisQ EI/CI ion-trap spectro-
meter (DCI: methane) or an Esquire 300 Plus Bruker Daltonics
spectrometer (ESI). The isotopic distribution of the base peak is
reported.
General Procedure for Borylation via Magnesium-Iodine
Exchange. A dry and nitrogen-flushed 10-mL flask equipped
with a magnetic stirrer and a septum was charged with iodoaryl 2
(1 mmol) and MPBOiPr 1 (353 mg, 1.9 mmol). THF was then
added (2 mL). The reaction mixture was cooled to 0 °C (water-
ice bath), and iPrMgCl LiCl (0.85 mL, 1.3 M in THF, 1.1 mmol)
3
2-Isopropoxy-4,4,6-trimethyl-1,3,2-dioxaborinane (MPBOiPr)
1. A 500 mL Erlenmeyer flask equipped with a magnetic stirrer was
charged with boric acid (25 g, 0.40 mol) and 2-methylpentan-2,4-diol
(48 g, 0.40 mol). Pentane was then added (q.s. 250 mL), and the
heterogeneous reaction mixture was stirred overnight at room
temperature. The solid was filtered and dried under reduce pressure,
thentransferredintoa250 mL round-bottomedflaskequippedwitha
magnetic stirrer. Isopropanol (100 g) was added, and the mixture was
stirred overnight at room temperature. The reaction flask was
equipped with a Cadiot distillation system, and water was removed
azeotropically with isopropanol (2 ꢀ 100 g) under atmospheric
pressure. The residue was finally distilled under reduced pressure to
afford MPBOiPr as a colorless liquid (41 g, 0.22 mol, 55% yield).
MPBOiPr can be stored for months under exclusion of air and
moisture. Bp: 92 °C, 24 Torr (lit.16 47 °C, 0.6 Torr). IR: 2972 (CH),
was added portionwise over 5 min. At the end of addition, the
conversion was verified by GC analysis of a hydrolyzed reaction
aliquot. The reaction mixture was quenched with a saturated
aqueous NH4Cl solution (20 mL), diluted with ethyl acetate
(30 mL), and the two phases were separated. The organic layer
was washed with a saturated aqueous NH4Cl solution (20 mL).
The combined aqueous phases were extracted with ethyl acetate
(20 mL). The combined organic phases were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was filtered through a thin pad of silica gel (Macherey Nagel silica
gel 60 M (230-400 mesh), eluent DCM) to afford the desired
product 3. Compounds 3a,c,l13a and 3m12a have been previously
described.
Methyl 2-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)benzo-
ate 3b. 3b was prepared according to general procedure starting
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Organic Process Research & Development
TECHNICAL NOTE
Table 3. Influence of the trapping agenta
entry
ArI
borate ester
Nb. equiv borate ester
Mg(II) reagent
ArMPB
conversion of ArI (%)b
1
2
3
4
5
6
2i
6
1
6
1
6
6
1.8
1.8
1.8
2
iPrMgCl LiCl
iPrMgCl
iPrMgCl
7i
100 (93)c
3
2m
2m
2m
2m
2m
3m
7m
3m
7m
7m
13
38
25
53
71
iPrMgCl LiCl
3
2
iPrMgCl LiCl
3
1.5
iPrMgCl LiCl
3
a Reaction conditions: aryl iodide (1 mmol), borate ester, THF ([ArI] = 0.5 M), 0 °C, Mg(II) reagent (1.1-1.2 equiv, [iPrMgCl LiCl] = 1.3 M in THF
3
(addition rate: 0.2 mL/min) or [iPrMgCl] = 2 M in THF (addition rate: 0.1 mL/min)). b Determined on the basis of the 1H NMR spectrum of the crude
product. c Isolated yield.
from methyl 2-iodobenzoate (262 mg, 1 mmol): yellow oil (236
mg, 89%). IR: 3057 and 3016 (CH ar.), 3973 (CH3), 1716
(CdO), 1598 and 1566 (CdC ar.), 1391 (B-C), 1301 (B-O
asym.), 1166 (B-O sym.). 1H NMR δ 7.90 (dt, J = 7.9 and 0.8,
1H), 7.50-7.43 (m, 2H), 7.34 (ddd, J = 7.9, 5.4 and 3.5, 1H),
4.38 (dqd, J = 11.5, 6.2 and 3.2, 1H), 3.88 (s, 3H), 1.85 (dd, J =
13.8 and 3.2, 1H), 1.76 (dd, J = 13.8 and 11.5, 1H), 1.43 (s, 3H),
1.34 (s, 3H), 1.30 (d, J = 6.2, 3H). 13C NMR δ 168.7 (Cq), 132.9
(Cq), 131.8 (CH), 131.5 (CH), 128.8 (CH), 128.2 (CH), 71.5
(Cq), 65.4 (CH), 52.0 (CH3), 45.8 (CH2), 31.2 (CH3), 27.8
(CH3), 23.1 (CH3). 11B NMR δ 28.2. LRMS (CI) m/z: 262.9
([M þ H]þ, 100).
(CH), 132.6 (CH), 130.8 (CH), 127.3 (Cq), 126.4 (CH), 72.0
(Cq), 65.8 (CH), 46.0 (CH2), 31.2 (CH3), 28.2 (CH3), 23.2
(CH3). 11B NMR δ 27.0. LRMS (EI) m/z: 281.1 (28), 282.0
(100), 283.0 (35), 284.0 (94), 285.0 (18).
2-(2-Chlorophenyl)-4,4,6-trimethyl-1,3,2-dioxaborinane
3h. 3h was prepared according to general procedure starting
from 2-iodo-1-chlorobenzene (241 mg, 1 mmol): yellow oil (182
mg, 76%). IR: 3063 (CH ar.), 2974 (CH3), 1592 and 1561
(CdC ar.), 1395 (B-C), 1305 (B-O asym.), 1167 (B-O
sym.). 1H NMR δ 7.58 (dd, J = 7.2 and 1.9, 1H), 7.29 (dd, J = 7.8
and 1.3, 1H), 7.23 (td, J = 7.8 and 1.9, 1H), 7.17 (td, J = 7.2 and
1.3, 1H), 4.35 (dqd, J = 11.8, 6.2 and 3.0, 1H), 1.85 (dd, J = 13.9
and 3.0, 1H), 1.61 (dd, J = 13.9 and 11.8, 1H), 1.38 (s, 3H), 1.36
(s, 3H), 1.33 (d, J = 6.2, 3H). 13C NMR δ 138.7 (Cq), 135.3
(CH), 130.8 (CH), 129.4 (CH), 125.8 (CH), 71.9 (Cq), 65.7
(CH), 46.0 (CH2), 31.2 (CH3), 28.2 (CH3), 23.2 (CH3). 11B
NMR δ 26.9. LRMS (EI) m/z: 236.2 (3), 237.1 (25), 238.1
(100), 239.1 (19), 240.1 (46), 241.1 (4).
2-(4-Iodophenyl)-4,4,6-trimethyl-1,3,2-dioxaborinane 3e.
3e was prepared according to general procedure starting from
1,4-diiodobenzene (1.65 g, 5 mmol), MPBOiPr (1.02 g, 5.5
mmol) and iPrMgCl LiCl (4.4 mL, 1.3 M in THF, 5.5 mmol):
3
yellow oil (1.66 g, quantitative). IR: 3069 and 3037 (CH ar.),
2972 (CH3), 1583 (CdC ar.), 1399 (B-C), 1301 (B-O asym.),
1163 (B-O sym.). 1H NMR δ 7.66 (d, J = 8.1, 2H), 7.51 (d, J =
8.1, 2H), 4.30 (dqd, J = 11.8, 6.2 and 2.9, 1H), 1.83 (dd, J = 13.8
and 2.9, 1H), 1.55 (dd, J = 13.8 and 11.8, 1H), 1.35 (s, 3H), 1.33
(s, 3H), 1.32 (d, J = 6.2, 3H). 13C NMR δ 136.7 (CH), 135.7
(CH), 97.9 (Cq), 71.4 (Cq), 65.2 (CH), 46.1 (CH2), 31.4 (CH3),
28.3 (CH3), 23.3 (CH3). 11B NMR δ 26.8. LRMS (EI) m/z:
329.0 (29), 330.0 (100), 331.0 (14).
4,4,6-Trimethyl-2-(2-(trifluoromethyl)phenyl)-1,3,2-diox-
aborinane 3i. The 2.5-g Scale Preparation. 3i was prepared
according to general procedure starting from 2-iodo-1-trifluor-
omethylbenzene (2.72 g, 10 mmol), MPBOiPr (2.06 g, 11
mmol), and iPrMgCl LiCl (8.7 mL, 1.3 M in THF, 11 mmol):
3
yellow oil (quantitative) that was used without further purifica-
tion for the synthesis of 5.
The 25-g Scale Preparation. A dry and nitrogen-flushed 500-mL
three-neckround-bottom flask equipped with a magnetic stirrer, a
thermometer, a 250-mL pressure-equalizing dropping funnel,
and a septum was charged with 2-iodobenzotrifluoride 2i (24.7 g,
91 mmol) and MPBOiPr 1 (18.9 g, 102 mmol). THF was then
2-(2-Iodophenyl)-4,4,6-trimethyl-1,3,2-dioxaborinane 3f.
3f was prepared according to general procedure starting from
1,2-diiodobenzene (330 mg, 1 mmol): yellow oil (270 mg, 82%).
IR: 3062 (CH ar.), 2973 and 2932 (CH3), 1584 and 1553 (CdC
1
ar.), 1395 (B-C), 1304 (B-O asym.), 1166 (B-O sym.). H
added (100 mL). iPrMgCl LiCl (prepared according to ref 6b,
NMR δ 7.78 (d, J = 7.8, 1H), 7.45 (dd, J = 7.4 and 1.7, 1H),
7.30-7.24 (m, 1H), 6.98 (td, J = 7.8 and 1.7, 1H), 4.37 (dqd, J =
11.9, 6.2 and 3.0, 1H), 1.85 (dd, J = 13.8 and 3.0, 1H), 1.65 (dd,
J = 13.8 and 11.9, 1H), 1.40 (s, 3H), 1.39 (s, 3H), 1.35 (d, J = 6.2,
3H). 13C NMR δ 139.3 (CH), 134.8 (CH), 130.9 (CH), 127.1
(CH), 100.2 (Cq), 72.2 (Cq), 65.9 (CH), 46.2 (CH2), 31.2
(CH3), 28.3 (CH3), 23.2 (CH3). 11B NMR δ 26.9. LRMS (EI)
m/z: 329.0 (34), 330.0 (100), 331.0 (15).
3
130 mL, 0.8 M in THF, 104 mmol) was charged in the dropping
funnel. The reaction mixture was cooled to -10 °C (NaCl-ice
i
bath), PrMgCl LiCl was added portionwise over 27 min. The
3
internal temperature remained under þ1 °C. The dropping
funnel was charged with a saturated aqueous NH4Cl solution
(50 mL) that was added to the reaction mixture in two portions;
the temperature rose to þ15 °C, and a solid precipitated. The
mixture was diluted with 50 mL water (dissolution of the solid)
and was transferred into a 500-mL separating funnel. The organic
phase was separated, and the aqueous phase was extracted with
Et2O (150 mL). The combined organic phases were then washed
with a saturated aqueous NH4Cl solution (20 mL) and a
saturated aqueous NaCl solution (40 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure, affording 3i as
a yellow oil (24.7 g, quantitative).
2-(2-Bromophenyl)-4,4,6-trimethyl-1,3,2-dioxaborinane
3g. 3g was prepared according to general procedure starting
from 2-iodo-1-bromobenzene (283 mg, 1 mmol): yellow oil (204
mg, 86%). IR: 3063 and 3048 (CH ar.), 2974 and 2932 (CH3),
1588 and 1557 (CdC ar.), 1396 (B-C), 1305 (B-O asym.),
1167 (B-O sym.). 1H NMR δ 7.52 (dd, J = 7.3 and 1.8, 1H),
7.48 (dd, J = 7.5 and 1.1, 1H), 7.23 (td, J = 7.3 and 1.1, 1H), 7.15
(td, J = 7.5 and 1.8, 1H), 4.36 (dqd, J = 11.8, 6.2 and 3.0, 1H),
1.85 (dd, J = 13.9 and 3.0, 1H), 1.63 (dd, J = 13.9 and 11.8, 1H),
1.39 (s, 3H), 1.37 (s, 3H), 1.34 (d, J = 6.2, 3H). 13C NMR δ 135.1
IR: 3063 and 3028 (CH ar.), 2976 (CH3), 1401 (B-C), 1316
1
(B-O asym.), 1159 (B-O sym.). H NMR δ 7.66-7.57 (m,
714
dx.doi.org/10.1021/op2000089 |Org. Process Res. Dev. 2011, 15, 710–716

Organic Process Research & Development
TECHNICAL NOTE
2H), 7.51-7.36 (m, 2H), 4.37 (dqd, J = 11.8, 6.2 and 3.0, 1H),
1.88 (dd, J = 13.9 and 3.0, 1H), 1.65 (dd, J = 13.9 and 11.8, 1H),
1.39 (s, 3H), 1.35 (s, 3H), 1.32 (d, J = 6.2, 3H). 13C NMR δ 133.6
(CH), 133.0 (q, 2J = 31.0, Cq), 130.8 (CH), 129.0 (CH), 125.4
(q, 3J = 4.8, CH), 124.9 (q, 1J = 273.5, Cq), 72.0 (Cq), 65.9 (CH),
46.0 (CH2), 31.1 (CH3), 27.9 (CH3), 23.1 (CH3). 11B NMR δ
27.8. 19F NMR δ -59.2. LRMS (EI) m/z: 172.1 (28), 173.1
(100), 174.1 (8), 271.2 (3), 272.2 (9), 273.2 (1).
’ AUTHOR INFORMATION
Corresponding Author
Telephone: (þ)33 476635796. Fax: (þ)33 476635983. E-mail:
Pierre-Yves.Chavant@ujf-grenoble.fr.
’ ACKNOWLEDGMENT
We are grateful to Universitꢀe Joseph Fourier and the CNRS
for financial support. We thank Laure Jullien, Rodolphe Guꢀeret,
and Dr. Bernard Brasme for Mass Spectrometry analysis and Dr.
Jean-Franc-ois Poisson, DCM, for fruitful discussion.
2-Bromo-6-(4,4,6-trimethyl-1,3,2-dioxaborinan-2-yl)pyridine
3j. 3j was prepared according to general procedure starting from
6-iodo-2-bromopyridine (284 mg, 1 mmol): yellow oil (260 mg,
92%). IR: 3044 (CH ar.), 2973 (CH3), 1575 and 1548 (CdC
1
ar.), 1403 (B-C), 1299 (B-O asym.), 1164 (B-O sym.). H
NMR δ 8.58 (d, J = 1.7, 1H), 7.80 (dd, J = 7.9 and 1.7, 1H), 7.35
(d, J = 7.9, 1H), 4.28 (dqd, J = 10.8, 6.2 and 3.0, 1H), 1.82 (dd, J =
14.4 and 3.0, 1H), 1.53 (dd, J = 14.4 and 10.8, 1H), 1.31 (s, 3H),
1.30 (s, 3H), 1.27 (d, J = 6.2, 3H). 13C NMR δ 155.5 (CH), 144.5
(Cq), 143.9 (CH), 127.3 (CH), 71.8 (Cq), 65.5 (CH), 46.0
(CH2), 31.2 (CH3), 28.2 (CH3), 23.1 (CH3). 11B NMR δ 26.4.
LRMS (EI) m/z: 282.0 (25), 283.0 (100), 284.0 (25), 285.0
(92), 286.0 (15).
’ REFERENCES
(1) Hall, D. G., Ed. Boronic Acids: Preparation and Applications in
Organic Synthesis and Medicine; Wiley-VCH Verlag GmbH: Weinheim,
2005.
(2) Borylationofareneswithpinacolboraneorbis(pinacolato)diboron:
(a) Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000,
287, 1995–1997. (b) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.,
Jr.; Smith, M. R., III Science 2002, 295, 305–308. For a recent
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J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890–931.
4,4,5,5-Tetramethyl-2-(2-(trifluoromethyl)phenyl)-1,3,2-diox-
aborolane 7i. 7i was prepared according to general procedure
starting from 2-iodo-1-trifluoromethylbenzene (281 mg, 1 mmol)
and PinBOiPr (335 mg, 1.8 mmol): yellow oil (250 mg, 93%). IR:
3063 (CH ar.), 2981 (CH3), 1354 (B-C), 1316 (B-Oasym.),
1140 (B-O sym.). 1H NMR δ 7.76-7.69 (m, 1H), 7.68-7.61
(m, 1H), 7.55-7.45 (m, 2H), 1.37 (s, 12H). 13C NMR δ 134.9
(CH), 134.0 (q, 2J = 31.4, Cq), 130.9 (CH), 130.1 (CH), 125.4
(3) Borylation of aryl halides with tetraoxydiboron reagents: (a)
Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508–7510.
For reviews, see:(b) Ishiyama, T.; Chen, H. 4,4,40,40,5,5,50,50-Octa-
methyl-2,20-bi-1,3,2-dioxaborolane. In e-EROS Encyclopedia of Reagents
for Organic Synthesis; 10.1002/047084289X.rn00188.pub2. (c) Merino,
P.; Tejero, T. Angew. Chem., Int. Ed. 2010, 49, 7164–7165. See also:(d)
Billingsley, K. L.; Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed.
2007, 46, 5359–5363. (e) Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J.
Am. Chem. Soc. 2010, 132, 17701–17703. Nevertheless, applicability on
a large scale remains hampered by the access to the tetraoxydiboron
reagents themselves:(f) Ishiyama, T.; Murata, M.; Ahiko, T.-a.; Miyaura,
N. Organic Syntheses; Wiley & Sons:New York, 2004; Collect. Vol. 10, pp
115-119.
(4) Borylation of aryl halides with dialkoxyborane reagents: Pd
catalysis: (a) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem.
1997, 62, 6458–6459. Cu:(b) Zhu, W.; Ma, D. Org. Lett. 2006,
8, 261–263. Ni:(c) Morgan, A. B.; Jurs, J. L.; Tour, J. M. J. Appl. Polym.
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Lett. 2008, 10, 2597–2600. For bibliography, see: (e) Moldoveanu, C.;
Wilson, D. A.; Wilson, C. J.; Leowanawat, P.; Resmerita, A.-M.; Liu, C.;
Rosen, B. M.; Percec, V. J. Org. Chem. 2010, 75, 5438-5452 and
references therein. (f) Lam, K. C.; Marder, T. B.; Lin, Z. Organometallics
2010, 29, 1849-1857 and references therein. See also:(g) Doux, M.;
Mꢀezailles, N.; Melaimi, M.; Ricard, L.; Le Floch, P. Chem. Commun.
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Sturgill, C. D. Org. Process Res. Dev. 2007, 11, 359–364.
3
1
(q, J = 5.0, CH), 124.6 (q, J = 273.4, Cq), 84.6 (Cq), 24.8
(CH3). 11B NMR δ 31.2. 19F NMR (376 MHz) δ -59.7. LRMS
(ESIþ) m/z: 295.0 (100, [M þ Na]þ).
Suzuki coupling: Preparation of 40-Methyl-30-nitro-2-(tri-
fluoromethyl)-1,10-biphenyl 5. A dry, nitrogen-flushed 10-mL
flask equipped with a magnetic stirrer and a septum was charged
with 4-bromo-2-nitrotoluene (216 mg, 1 mmol), 3i (408 mg, 1.5
mmol), Pd(OAc)2 (2.2 mg, 0.01 mmol), S-Phos (8.2 mg, 0.02
mmol), and K3PO4 (848 mg, 4 mmol). Toluene (2 mL) and
water (0.4 mL) were then added, and the reaction mixture was
heated at 100 °C. The consumption of the bromide was followed
by GC. The completion was obtained after 3 h. The crude
mixture was filtered through a thin pad of silica gel. After
concentration of the filtrate, purification of the residue by flash
chromatography (eluent: cyclohexane/ethyl acetate, 99:1)
yielded 5 as a yellow oil (226 mg, 80%). IR: 3069 (CH ar.),
2971 and 2932 (CH3), 1530 (nitro ar.), 1125 and 1112 (CF3).
1H NMR δ 7.96 (d, J = 1.5, 1H), 7.78 (d, J = 7.6, 1H), 7.60 (t, J =
7.6, 1H), 7.53 (t, J = 7.6, 1H), 7.50-7.45 (m, 1H), 7.38 (d, J =
7.9, 1H), 7.33 (d, J = 7.6, 1H), 2.66 (s, 3H). 13C NMR δ 148.8
(Cq), 138.9 (Cq), 138.7 (q, 3J = 2.0, Cq), 133.6 (q, 4J = 1.2, CH),
133.1 (Cq), 132.5 (CH), 132.0 (CH), 131.8 (CH), 128.8 (q, 2J =
30.1, Cq), 128.4 (CH), 126.4 (q, 3J = 5.3, CH), 125.2 (q, 4J = 1.4,
CH), 124.1 (q, 1J = 273.9, Cq), 20.3 (CH3). 19F NMR δ -56.8.
LRMS (ESIþ) m/z: 304.0 ([M þ Na]þ, 100).
(5) Recent examples. Organolithium reagents: (a) Huang, S.; Pe-
tersen, T. B.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 14021–14023.
(b) Clapham, K. M.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B. Org. Biomol.
Chem. 2009, 7, 2155–2161. Aryl Grignard reagent:(c) Gerbino, D. C.;
Mandolesi, S. D.; Schmalz, H.-G.; Podestꢀa, J. C. Eur. J. Org. Chem.
2009, 3964–3972. For a 1.5-mol scale synthesis of an arylboronic acid
via an organomagnesium species, see:(d) Cladingboel, D. E. Org. Process
Res. Dev. 2000, 4, 153–155.
(6) For a review, see: (a) Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.,
’ ASSOCIATED CONTENT
Int. Ed. 2003, 42, 4302–4320. For iPrMgCl LiCl, see:(b) Krasovskiy, A.;
3
Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 3333–3336.
(7) Boymond, L.; Rottl€ander, M.; Cahiez, G.; Knochel, P. Angew.
Chem., Int. Ed. 1998, 37, 1701–1703.
S
Supporting Information. Copies of NMR spectra for all
b
new compounds; 1H, 11B (and 19F) NMR spectra of the crude
products for 3a and 3i; 1H NMR spectra of the crude product for
the borylation of 2m (Table 2, entry 3). This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) See for instance: (a) Liu, C.-Y.; Gavryushin, A.; Knochel, P.
Chem. Asian J. 2007, 2, 1020–1030. (b) Hawkins, V. F.; Wilkinson,
M. C.; Whiting, M. Org. Process Res. Dev. 2008, 12, 1265–1268.
715
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Organic Process Research & Development
TECHNICAL NOTE
(9) (a) Reeves, J. T.; Sarvestani, M.; Song, J. J.; Tan, Z.; Nummy,
L. J.; Lee, H.; Yee, N. K.; Senanayake, C. H. Org. Process Res. Dev. 2006,
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M. S.; Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider, P. J. J. Org. Chem.
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(11) (a) Meudt, A.; Nerdinger, S.; Erbes, M.; Vogt, W. Method for
producing 2-formylfuran-4-boronic acid by the metalation of 4-halofur-
fural acetals in the presence of suitable boronic acid esters or anhydrides.
WO/2006/122683, 2006. The magnesium-bromine exchange be-
tween 4-bromofurfural diethyl acetal and isopropylmagnesium bromide
is performed in the presence of triisopropyl borate at low temperature
(<-60 °C); after deprotection of the acetal, the corresponding aryl-
boronic acid is recovered in 73% yield.(b) Collibee, S. E.; Yu, J.
Tetrahedron Lett. 2005, 46, 4453–4455. The “in situ quench” of an aryl
Grignard reagent, prepared by magnesium-iodine exchange with
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Knochel, P.; Mayr, H. J. Org Chem. 2009, 74, 2760–2764. (d) Shi, L.;
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temperature, and even at -78 °C, has been hypothesized: (a) Hart, H.;
Harada, K.; Du, C.-J. F. J. Org. Chem. 1985, 50, 3104–3110. (b)
Ghosh, T.; Hart, H. J. Org. Chem 1988, 53, 3555–3558. Formation
of 2-halo arylmagnesium species via magnesium-iodine exchange
before addition of a trialkylborate was performed at low temperature:
-78 °C:(c) Baron, O.; Knochel, P. Angew. Chem., Int. Ed. 2005,
44, 3133–3135. (d) Wegner, H. A.; Reisch, H.; Rauch, K.; Demeter,
A.; Zachariasse, K. A.; de Meijere, A.; Scott, L. T. J. Org. Chem. 2006,
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Chem., Int. Ed. 2008, 47, 2876–2879. (f) Diemer, V.; Leroux, F. R.;
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J.; Stolz, D.; Togni, A. Synthesis 2009, 2818–2824.
(26) The Suzuki-Miyaura coupling was performed according to
Buchwald’s procedure: Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685–4696, using 1.5 equiv
of boronic ester. Interestingly, 0.3 equiv of unreacted arylboronic ester
were recovered after chromatography, indicating that a lower excess
could have been used.
(27) (a) Fischer, F. C.; Havinga, E. Recl. Trav. Chim. Pays-Bas 1974,
93, 21–24. Bibliography, see:(b) Campeau, F.-C.; Fagnou, K. Chem. Soc.
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Burke, M. D. Org. Lett. 2010, 12, 2314–2317.
(12) (a) Murata, M.; Oda, T.; Watanabe, S.; Masuda, Y.
Synthesis 2007, 351–354. (b) Murata, M.; Sambommatsu, T.; Oda, T.;
Watanabe, S.; Masuda, Y. Heterocycles 2010, 80, 213–218.
(13) (a) PraveenGanesh, N.; Chavant, P. Y. Eur. J. Org. Chem.
2008, 4690–4696. (b) PraveenGanesh, N.; Demory, E.; Gamon, C.;
Blandin, V.; Chavant, P. Y. Synlett 2010, 2403–2406.(c) Chavant, P. Y.;
PraveenGanesh, N. 4,4,6-Trimethyl-1,3,2-dioxaborinane. In e-EROS
Encyclopaedia of Reagents for Organic Synthesis; John Wiley & Sons,
Ltd.: New York; 2008; 10.1002/047084289X.rn01065.
(28) See in particular refs 6a and 21c.
(29) It is worth noting that anisyl halides are among the best
substrates for all variants of Pd-catalyzed-borylation (which is fast and
high-yielding with electron-rich substrates).
(14) See also: (a) PraveenGanesh, N.; d’Hondt, S.; Chavant, P. Y. J.
Org. Chem. 2007, 72, 4510–4514. (b) PraveenGanesh, N.; de Candia, C.;
Memboeuf, A.; Lendvay, G.; Gimbert, Y.; Chavant, P. Y. J. Organomet.
Chem. 2010, 695, 2447–2454.
(15) For instance: hexylene glycol 99%, 500 g, Aldrich, h29.80;
pinacol 98%, 500 g, Aldrich, h394.60.
(30) On small laboratory scales, a slight excess (10 mol %) of
MPBOiPr 1 should be kept so that accidental excess of isopropylmag-
nesium halide will be trapped by 1.
(31) PinBOiPr (5) is commercially available (for instance: 2-iso-
propoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 98%, 5 mL, Aldrich,
h54.10) or can be prepared (see for instance the recent example: Lin, Q.;
Meloni, D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard, S.; Li, M.; Galya, L.;
Metcalf, B.; Yue, T.-Y.; Liu, P.; Zhou, J. Org. Lett. 2009, 11, 1999–2002.
Note that MPBOiPr (1) is also commercially available (2-isopropoxy-
4,4,6-trimethyl-1,3,2-dioxaborinane, 99%, 5 mL, Aldrich, h20.20).
(32) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967,
9, 165–168.
(16) Mehrotra, R. C.; Srivastava, G. J. Chem. Soc. 1962, 1032–1034.
(17) MPBOiPr was originally prepared from MPBOEt and propan-
2-ol (ref 16). More recently (Suginome, M.; Matsuda, T.; Ito, Y.
Organometallics 2000, 19, 4647-4649), MPBOiPr was prepared from
triisopropyl borate and hexylene glycol following the procedure for the
pinacol derivative described in: Hoffmann, R. W.; Metternich, R.; Lanz,
J. W. Liebigs Ann. Chem. 1987, 881-887.
(18) Reaction conditions: aryl iodide (1 mmol), MPBOiPr (3 equiv),
THF ([ArI] = 0.5 M), 0 °C, iPrMgCl LiCl (1.4 equiv, 1.3 M in THF,
3
addition rate: 0.2 mL/min).
(19) The excess of MPBOiPr 1 is hydrolyzed to give water-soluble
products, most of which are eliminated during the aqueous workup. The
product resulting from nucleophilic addition of (possible) excess
iPrMgCl LiCl onto 1, namely MPBiPr, is present in the reaction mixture
3
(as detected by GC analysis) but is easily eliminated under vacuum
together with the solvents. Traces of polar boric acid derivatives are
removed by filtration over silica gel.
(20) We verified that the reaction between MPBOiPr and iPrMgCl
3
LiCl, leading to MPBiPr occurred instantaneously in the absence of the
aryl iodide.
(21) (a) Delacroix, T.; Bꢀerillon, L.; Cahiez, G.; Knochel, P. J. Org.
Chem. 2000, 65, 8108–8110. (b) Shi, L.; Chu, Y.; Knochel, P.; Mayr,
H. Angew. Chem., Int. Ed. 2008, 47, 202–204. (c) Shi, L.; Chu, Y.;
716
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