A rapid synthesis of aminoboranes from amine-boranes utilizing an iodination/dehydroiodination sequence is described. Monomeric aminoboranes are generated exclusively from several substrate adducts, following an E2-type elimination, with the added base playing a critical role in monomer vs dimer formation. Diisopropylaminoborane formed using this methodology has been applied to a one-pot palladium-catalyzed conversion of iodo- and bromoarenes to the corresponding boronates. Additionally, modification of the workup allows for isolation of the boronic acid and recovery of the utilized amine.
A rapid synthesis of aminoboranes from amine-boranes utilizing an iodination/dehydroiodination sequence is described. Monomeric aminoboranes are generated exclusively from several substrate adducts, following an E2-type elimination, with the added base playing a critical role in monomer vs dimer formation. Diisopropylaminoborane formed using this methodology has been applied to a one-pot palladium-catalyzed conversion of iodo- and bromoarenes to the corresponding boronates. Additionally, modification of the workup allows for isolation of the boronic acid and recovery of the utilized amine.
Aminoboranes of the
type R2N-BH2,[1] commonly
obtained from amine-boranes (R2NH-BH3), have
received considerable attention as valuable
precursors for organic and material chemistry applications.[2−13] Borylations employing a variety of metal catalysts[2] and leaving groups[2a,2b,3] have been developed, including for C–H borylation.[2d] Suitable aryl,[2a−2d,3,4] alkenyl,[4a,5] and alkynyl[2e,2f] substrates can be converted to boronate esters,[2b−2d,3b,6] their complexes,[7] and boronic and borinic acids.[3a,7,8] They have been used for the preparation
of polyaminoboranes[9] and boron nitride
ceramics,[10] with recent uses in the production
of molecular sensors,[11] mechanochromic
materials,[12] and metal thin films.[13]Despite all of these developments, there
is still a need for a
convenient synthesis of aminoboranes. One of the earliest routes involved
the reduction of aminodihaloboranes with lithium aluminum hydride
[Scheme . (i)].[14] Large-scale synthesis of aminoboranes using
this protocol is limited by the highly reactive nature of the hydride
and boron halide reagents. This method has since been supplanted by
the thermal dehydrogenation of amine-boranes [Scheme . (ii)][2a] and
reaction of lithium aminoborohydrides with suitable organohalides
[Scheme . (iii)].[15] These routes, however, require elevated temperatures
(160–220 °C) or the use of highly sensitive reagents (n-BuLi). Recently, Pucheault and co-workers reported the
dehydrohalogenation of monochloroborane–amine complexes (which
have been reported elsewhere[16]) for the
preparation of aminoboranes [Scheme . (iv)].[6b] The dry, ethereal
HCl utilized in this preparation is cumbersome to prepare,[17] and although it is commercially available, it
is expensive relative to other halogen sources. Ethereal HCl is typically
prepared at concentrations of 1–2 M, as more concentrated solutions
tend to expel the highly corrosive HCl gas. Release of the solute
gas and the low boiling point of the solvent necessitate frequent
titration, as precise stoichiometry is critical for the preparation
of monochloroborane-amines. Treatment of amine-boranes with N-halosuccinimides[18] or molecular
halogens[16a,19] and the disproportionation reaction of BH3- and BX3-amines (X = halogen)[16a] are some of the other procedures that exist for the conversion
of amine-boranes to haloborane–amine complexes.
Scheme 1
Preparation
of Aminoboranes and One-Pot Borylation
As part of our ongoing projects on amine-boranes,[20] we were interested in developing a simple protocol for
the preparation of aminoboranes. It occurred to us that the halogenation
of amine-boranes with molecular halogens might provide a more convenient
protocol. Although known for several decades,[16a] the potential utility of this protocol has not been exploited
fully in organic synthesis. Described herein are the details of a
simple route to aminoboranes via dehydrohalogenation of appropriate
monoiodoborane–amine complexes [Scheme . (v)], avoiding the limitations of the previous
protocols. This methodology has been extended to a modified Pd-catalyzed one-pot borylation of aryl halides [Scheme . (vi)].
Results and Discussion
Halogenation
Over 60 years ago, Nöth described
the monoiodination of trimethylamine-borane with molecular iodine
in benzene.[16a] A similar procedure to prepare
alkylhaloboranes from alkylboranes has also been reported.[21] Our initial attempts sought to optimize the
conditions for the halogenation of a dialkylamine-borane by reacting
dimethylamine-borane (1c) with 0.5 and 1.0 equiv of either
bromine or iodine in CH2Cl2 or toluene and following
the reaction by 11B NMR spectroscopy.With bromine,
the nearly instantaneous halogenation readily went past the monohaloborane
(Table (2)) stage,
providing appreciable quantities of the di- (Table (3)) and trihalogenated boranes (Table (4)), as detected
in the 11B NMR spectrum. Using 0.5 equiv of Br2 also led to the formation of a mixture of di- and monobromoborane-amine
in a 3:1 ratio. On the other hand, when 0.5 equiv of iodine was utilized,
the amine-monohaloborane could be reliably produced in either solvent.
Even a stoichiometric equivalent of iodine provided the monoiodoborane
predominantly (80%). Halogenation of diisopropylamine-borane (1f) using N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS) was also examined as a potential
route to the amine monohaloborane complexes. A full equivalent of
NCS provided the desired monochloroborane, whereas NBS gave a mixture
of mono- and dihalogenated products (Table ).
Table 1
Optimization of Halogen
and Solvent
Studya
entry
halogen (equiv)
amine-borane
solvent
11B NMR peak ratio (1:2:3:4)b
1
I2 (0.5)
1c
DCM
0:1:0:0
2
I2 (1.0)
1c
DCM
0:4:1:0
3
Br2 (0.5)
1c
DCM
1.25:1:3:0
4
Br2 (1.0)
1c
DCM
0:1:1:0.75
5
I2 (0.5)
1c
CHCl3
indeterminate
6
I2 (0.5)
1c
Et2O
indeterminate
7
I2 (0.5)
1c
PhMe
0:1:0:0
8
I2 (0.5)
1c
Pentane
1c insoluble
9
NCS (1.0)
1f
DCM
0:1:0:0
10
NBS (1.0)
1f
DCM
1:1.6:2.1:0
Reactions were performed at a 2
mmol scale with respect to the amine-borane.
Ratio determined by 11B NMR (96 MHz)
spectroscopy.
Reactions were performed at a 2
mmol scale with respect to the amine-borane.Ratio determined by 11B NMR (96 MHz)
spectroscopy.The scope
of the iodination was demonstrated with a series of amine-boranes
(1a–1q), prepared from sodium borohydride via
a bicarbonate-promoted reaction of the desired amine (1b–1q)[20c] or by salt
metathesis of the corresponding ammonium hydrochloride (1a).[22] As detailed in Table , all of the primary and secondary amine-borane
complexes underwent quantitative iodination without any difficulty.[23]
Table 2
Amine-Boranes Subjected
to the Iodination/Dehydroiodination
Sequence and Resulting Aminoboranesa,b,c
Reactions
were performed at a 2
mmol scale with respect to the amine-borane.
Conversions were >99% by 11B NMR
(96 MHz) spectroscopy.
Composition
determined by 11B NMR (96 MHz) spectroscopy.
Reactions
were performed at a 2
mmol scale with respect to the amine-borane.Conversions were >99% by 11B NMR
(96 MHz) spectroscopy.Composition
determined by 11B NMR (96 MHz) spectroscopy.
Dehydrohalogenation
The dehydrohalogenation
of these
monoiodoborane–amine complexes was readily accomplished by
the addition of a sufficiently bulky amine [i-Pr2NEt (Hünig’s base) or i-Pr2NH] to the reaction mixture.[6b,16b] Quantitative
conversion to the elimination products was observed in the 11B NMR spectra. The monomeric or dimeric aminoborane species were
typically produced, along with an equivalent of the corresponding
ammonium iodide during the E2-type reaction (Table ). Several groups[2a,14,15,24] previously
used NMR spectroscopy, mass spectrometry, and X-ray crystallography
to fully characterize both the aminoborane monomer[14,24a] and dimer[24,25] products. The assignment of 11B NMR peaks to either monomer or dimer products in the present
reaction was based on the similarity of 11B NMR values
observed from the fully characterized prior products. Similar complete
characterizations have previously been made of the other proposed
species detected in the present reaction including diaminoborane,[26] aminodiborane,[27] polyaminoborane
and amine-exchange products.[9,28] The proposed identities
of these species are based on agreement between the 11B
NMR chemical shifts observed and those previously reported for similar
fully characterized products. The iodination of pyrrolidine-borane
and subsequent dehydroiodination using N,N-diisopropylethylamine
(Scheme ) followed
by analysis using 11B NMR spectroscopy revealed the formation
of each of these products.
Scheme 2
Products of the Dehydrohalogenation Step
The spectrum obtained from the above reaction
(Scheme ) and the
proposed identities of the chemical species represented by the peaks
present in the spectrum are shown in Figure .
Figure 1
11B NMR (96 MHz) spectrum showing
peaks that correspond
to each of the dehydrohalogenation products.
11B NMR (96 MHz) spectrum showing
peaks that correspond
to each of the dehydrohalogenation products.It was noted that the reaction of Hünig’s base with
each of the amine-iodoborane complexes, other than isopropylamine-monoiodoborane,
provided at least some amount of the aminoborane monomer. However,
the primary iodoborane-amines (1a, 1b) yielded
very little of either the monomeric or dimeric aminoborane, but primarily
a mixture of other boron species arising from the exchange of the
amines present. The iodoborane complexes of secondary amines provided
primarily aminoborane products, in either the monomeric or dimeric
form, with the ratio dependent on the sterics of the amine in the
borane complex. Compact or rigidly constrained amines, such as dimethylamine
or piperidine, resulted in a higher proportion of dimeric aminoboranes
(58 and 70%, respectively). Many of the iodoborane complexes of cyclic
and acyclic secondary amines gave primarily the aminoborane monomer
(3d–3q), with minimal formation of
dimers or other products. Diisopropylaminoborane (3f),
dicyclohexylaminoborane (3j), 2,6-dimethylpiperidinoborane
(3l), and dibenzylaminoborane (3q) (entries
6, 10, 12, and 17 in Table ) were each detected exclusively as the monomer (by 11B NMR). The monochloroborane example produced from 1f and NCS provided minimal monomer formation (∼1%) with 1 or
2 equiv of i-Pr2NEt, likely due to interference
of the still present succinimide.
Influence of the Amines
on Dehydrohalogenation
To assess
the influence of the amine added as a base for the elimination, another
series of dehydrohalogenation reactions was performed (Table ). Iodoborane-amines with varying steric environments were
reacted with amine bases with a range of substitutions (0° (NH3), 1, 2, 3°) and sterics. The iodoboranes were prepared
from diisopropylamine- (1f), dimethylamine- (1c), and piperidine-borane (1k), and their reactions with
the added amines allowed for the identification of several trends
in reactivity. The highly bulky iodoborane complex with diisopropylamine
(2f) reacted with bulky amines, including diisopropyl-,
dicyclohexyl-, diisobutyl-, and N,N-diisopropylethylamines
to produce the diisopropylaminoborane monomer 3f with
98–99% conversion. Slightly less hindered triethylamine and
dibenzylamine provided 80–90% conversion to 3f. The remainder of the 1° and less hindered 2° amines tested
with 2f gave what are presumed to be polyaminoboranes
or amine coordination products based on prior reports of these compounds
made from diisopropylaminoborane.[9,28] A similar
species was observed when unhindered 2c was reacted with
piperidine.
Table 3
Aminoboranes Formed Using Various
Aminesa,b
entry
amine-borane
added amine
monomer
(%)
dimer (%)
other (%)
1
1f
i-Pr2NH
≥99
0
0
2
1f
Et2NH
0
0
≥99
3
1f
Propylamine
0
0
≥99
4
1f
t-BuNH2
0
0
≥99
5
1f
BnNH2
0
0
≥99
6
1f
Bn2NH
90
0
10
7
1f
Chx2NH
≥99
0
0
8
1f
i-Bu2NH
98
0
2
9
1f
Azepane
0
0
≥99
10
1f
Piperidine
0
0
≥99
11
1f
Morpholine
0
0
≥99
12
1f
Ammonia
0
0
≥99
13
1f
Et3N
80
0
20
14
1f
i-Pr2EtN
≥99
0
0
15
1f
Pyridine
0
0
≥99
16
1c
Piperidine
0
0
≥99
17
1c
Et3N
1
40
59
18
1c
i-Pr2EtN
7
77
16
19
1k
Piperidine
0
0
≥99
20
1k
i-Pr2EtN
2
89
9
Reactions were performed at the
2 mmol scale with respect to the amine-borane.
Ratio determined by 11B NMR (96 MHz)
spectroscopy.
Reactions were performed at the
2 mmol scale with respect to the amine-borane.Ratio determined by 11B NMR (96 MHz)
spectroscopy.In the reactions
of 2c, increasing the bulk of the
added amine (triethylamine and N,N-diisopropylethylamine)
led to the partial formation of the dimeric dimethylaminoborane, 40%
and 77%, respectively. A small amount of monomeric aminoborane was
additionally detected in each case, 1% and 7%, respectively. The reaction
of 2k with piperidine gave the polyaminoborane exclusively,
while N,N-diisopropylethylamine gave mainly (89%)
dimeric aminoborane, with traces (2%) of the monomer present.
One-Pot
Borylation
Arylboronates and boronic acids
have traditionally been prepared by the reaction of trialkoxyboranes
with aryl lithium[29] or Grignard reagents.[30] However, these organometallic reagents are highly
reactive, making them incompatible with many functional groups. More
recently, Miyaura and co-workers have reported the palladium-catalyzed
cross-coupling reaction between aryl halides and bis(pinacolato)diboron
(B2pin2).[31] This
was later extended by Masuda to utilize pinacolborane (HBpin).[32] Although both B2pin2 and
HBpin are commercially available, these reagents are costly and half
of the B2pin2 reagent goes unused in the cross-coupling
reaction. The preparation of B2pin2[33] is lengthy and uses highly reactive reagents
(BBr3, Na) and HBpin[34] uses
unpleasant borane-dimethylsulfide. In 2003, Alcaraz and Vaultier utilized
diisopropylaminoborane as an efficient source of boron for palladium
catalyst borylation.[2a] Although the aminoborane
precursor amine-boranes were expensive in 2003, there are now several
simple procedures for their preparation from the corresponding amines
using sodium borohydride and benign activators such as NaHCO3[20c] and CO2.[35]As a further confirmation of the formation of aminoboranes
from the iodination/dehydroiodination sequence, the presumed aminoboranes
were subjected to palladium-catalyzed borylation of aryl halides,
as described by Pucheault and Vaultier.[6b] To simplify the protocol, and further persuade organic chemists
to embrace this process for Suzuki coupling,[36] we made two modifications to the above borylation protocol. (i)
Separation of the ammonium salt formed during the dehydrohalogenation
reaction was excluded since the salt from the borylation catalytic
cycle does not interfere in the reaction.[6a,37,21] Reactions were performed with and without
filtration of the salt, and identical overall yields (95%) were observed
for the borylation of 4-iodoanisole with 3f. This change
makes the process one-pot. Also, (ii) “quenching” of
the arylaminoborane intermediate with methanol, followed by transesterification
with pinacol, was replaced with a direct pinacol “quench”
without any loss in yield of the pinacol boronate (Scheme ).
Scheme 3
Proposed Pathway
for the One-Pot Synthesis of Pinacol Arylboronates
from Amine-Boranes
The progress of the
borylation of 4-iodoanisole was monitored,
and the proposed intermediates, shown in Scheme , were confirmed by 11B NMR spectroscopy.
Starting from diisopropylamine-borane (δ −21.80 (q): Figure a), iodine and amine
addition leads to the peaks at δ −17.34 (t) and δ
34.40 (t) (Figure b,c, respectively). After reflux, the amino(aryl)borane intermediate
was detected at δ 38.20 (Figure d). Addition of pinacol results in a slight upfield
shift to δ 30.21 (s) (Figure e), representative of the pinacol boronate.
Figure 2
11B NMR (96 MHz) spectra depicting the progress of the
one-pot conversion of amine-borane to arylboronates.
11B NMR (96 MHz) spectra depicting the progress of the
one-pot conversion of amine-borane to arylboronates.The optimized conditions shown in Scheme were tested with several amine-boranes,
such as monomer-forming dicyclohexylamine- (1j) and dibenzylamine-borane
(1q), as well as the primarily dimer-forming dimethylamine-borane
(1c) for the reaction. These complexes gave 90%, 91%,
and 58% yields, respectively, as compared to the 95% yield with 1f (Table ).
Table 4
Study of Amine-Boranes as Boron Sources
for One-Pot Borylation of Aryl Halidesa
entry
amine-borane
monomer (%)
product obtained
yieldb (%)
1
1c
7–22
4a
58
2
1f
≥99
4a
95
3
1j
≥99
4a
90
4
1q
≥99
4a
91
Reactions were
performed using 4-iodoanisole
at the 1 mmol scale with respect to the aryl halide.
Isolated yields after flash chromatography
are shown.
Reactions were
performed using 4-iodoanisole
at the 1 mmol scale with respect to the aryl halide.Isolated yields after flash chromatography
are shown.With the 58%
product recovery when using dimeric aminoborane 3c, we
have demonstrated that dimers also participate in the
borylation, albeit at a slower rate. Attempts are
under way to improve the yields. Examination of bromine- and chlorine-containing
arenes was also carried out with 4-bromo- and 4-chloroanisole. While
the former provided 95% of the borylated product, the latter was unreactive,
indicating that chlorine is not a suitable leaving group under the
current reaction conditions (Table ).[37,38]
Table 5
Leaving
Groups Studied for One-Pot
Borylationa
entry
amine-borane
starting material
product obtained
yieldb (%)
1
1f
MeOC6H4-Cl
none
2
1f
MeOC6H4-Br
9a
95
3
1f
MeOC6H4-I
9a
95
Reactions were performed at the
1 mmol scale with respect to the aryl halide.
Isolated yields after flash chromatography
are shown.
Reactions were performed at the
1 mmol scale with respect to the aryl halide.Isolated yields after flash chromatography
are shown.Following confirmation
of the reaction pathway, a series of aryl
iodides or bromides were subjected to the above-described reaction
conditions where 4-iodoanisole provided the boronate 4a in 95% yield. Other ether-containing 4-ethoxy- (4b),
4-methoxy-2-methyl- (4c), 6-methoxynaphthyl- (4d), and 2,3-dihydrobenzofuryl- (4e) aryl halides gave
equally high yields (96%, 94%, 97%, and 98%, respectively). Unadorned
bromobenzene (4f), as well as its counterparts with systems
of extended conjugation, 2-naphthyl- (4g), 1-naphthyl-
(4h), and 9-phenanthyl- (4i) halides, and
hydrocarbon substituents, 4-methyl- (4j), 4-phenyl- (4k), and 3,5-di-t-butyl- (4l) aryl halides, all
gave the corresponding boronates in excellent yields (97–99%).
However, the 2,4,6-substituted bromomesitylene proved to be too sterically
encumbered to undergo the reaction, and no product was isolated.Boronates of functionalized aryl halides with methylthio- (4m), nitrile- (4n), and dimethylamino- (4o) groups were obtained in 96, 65, and 70%, respectively.
However, substrates with reducible functionalities (keto-, formyl-,
amido-, and nitro) provided mixtures of other products along with
small quantities of the expected borylated products. Borylation of
aryl halides with other ring halogens (chlorine or fluorine) was also
shown to be feasible. 4-Chloro- (4p), 3,5-dichloro- (4q), 4-fluoro- (4r), and 4-trifluoromethyl- (4s) iodobenzenes gave the corresponding boronates in 89–99%
yields. Attempted borylation of pentafluoroiodobenzene, however, gave
none of the boronate ester. The results from the study of the substrate
scope are summarized in Figure .
Figure 3
Scope of the one-pot borylation from amine-boranes.a,b aReactions were performed at the 1 mmol scale with respect to the
aryl halide. bIsolated yields after flash chromatography
are shown.
Scope of the one-pot borylation from amine-boranes.a,b aReactions were performed at the 1 mmol scale with respect to the
aryl halide. bIsolated yields after flash chromatography
are shown.
Amine Recycling
The reaction sequences in Scheme suggested that the
ammonium salt byproduct from both the borylation cycle and aminoborane
synthesis could be recovered and recycled to regenerate the amine-borane.
Applying an alteration in the workup procedure (Scheme ) for the borylation of 4-iodoanisole provided
83% of 4-methoxyphenylboronic acid (5a) along with 86%
of diisopropylammonium chloride. The recovered ammonium salt can be
converted to the starting amine-borane via the salt metathesis protocol.[19] Though diisopropylamine is relatively inexpensive,
the demonstrated recovery of the amine can be useful when a more valuable
amine is utilized.
Scheme 4
Recovery of Diisopropylammonium Salt/Boronic Acid,
and Regeneration
of Amine-Borane,
Reaction
was performed at the
1 mmol scale with respect to the aryl halide.
Isolated yields after aqueous workup are shown.
Recovery of Diisopropylammonium Salt/Boronic Acid,
and Regeneration
of Amine-Borane,
Reaction
was performed at the
1 mmol scale with respect to the aryl halide.Isolated yields after aqueous workup are shown.
Conclusions
In summary, we have
described the preparation of aminoboranes,
within minutes, at room temperature, in reagent-grade solvents from
amine-boranes via an iodination-dehydroiodination sequence. Monomeric
or dimeric aminoboranes can be produced by alteration of the coordinated
amine, and the amine used for dehydrohalogenation, with the monomers
being formed exclusively in several cases. Application of these monomeric
aminoboranes has been demonstrated for a one-pot palladium-catalyzed
conversion of aryl iodides and bromides containing substituents with
varying steric and electronic environments to the corresponding boronate
esters and boronic acids.
Experimental Section
General Information
Unless otherwise noted, all manipulations
were carried out under open air conditions. 11B,19F,13C, and 1H NMR spectra were recorded at
room temperature, on a Varian INOVA 300 MHz NMR spectrophotometer.
Chemical shifts (δ values) are reported in parts per million
relative to BF3·Et2O for 11B
NMR. Data are reported as: δ value, multiplicity (s, singlet;
d, doublet; t, triplet; q, quartet; p, pentet; h, hextet; hept, heptet;
m, multiplet; br, broad) and integration. All solvents for routine
isolation of products were reagent-grade. Sodium borohydride (powder,
purity >99% by hydride estimation 1) was purchased from Oakwood
Chemical.
Tetrahydrofuran (THF, ACS reagent >99.0% containing 0.004% water
and
0.025% BHT), toluene (anhydrous, ≥99.8%), iodine (ACS reagent,
≥99.8%), bromine (reagent grade), N-chlorosuccinimide
(ReagentPlus, 99%), and N-bromosuccinimide (ReagentPlus,
99%) were purchased from Sigma-Aldrich. All amines, aryl halides,
and pinacol were purchased from commercial sources and used without
further purification. Flash chromatography was performed using silica
gel 40–63 um, 60 Å with diethyl ether as the eluent.
Preparation of Amine Boranes via Sodium Bicarbonate (AB Procedure
1)
Sodium borohydride (1.51 g, 2 equiv, 40 mmol) and powdered
sodium bicarbonate (6.72 g, 4 equiv, 80 mmol) were transferred to
a 100 mL dry round-bottom flask, charged with a magnetic stir-bar.
The corresponding amine (1 equiv, 20 mmol) was charged into the reaction
flask followed by addition of reagent-grade tetrahydrofuran (20 mL)
at rt. Under vigorous stirring, water (0.36 mL, 4 equiv, 80 mmol)
was added dropwise to prevent excessive frothing. Reaction progress
was monitored by 11B NMR spectroscopy. (Note: A drop of
anhydrous DMSO is added to the reaction aliquot before running the 11B NMR experiment to solubilize NaBH4.) Upon completion
of the reaction (4–48 h, as determined by 11B NMR),
the reaction contents were filtered through sodium sulfate and celite
and the solid residue was washed with THF. Removal of the solvent
in vacuo from the filtrate yielded the corresponding amine-borane
(1b, 1d–1r). The residual
solvent was removed by placing under a high vacuum for ∼12
h.
Isopropylamine-borane (1b)
1b was
synthesized using AB Procedure 1, obtained as a white solid
(91%, 1.327 g). 1H NMR (300 MHz, chloroform-d) δ 3.75 (s, 2H), 2.98 (dp, J = 12.9, 6.4
Hz, 1H), 1.22 (d, J = 6.5 Hz, 6H); 13C
NMR (75 MHz, chloroform-d) δ 50.2, 21.8; 11B NMR (96 MHz, chloroform-d) δ −20.99
(q, J = 95.3 Hz).
Preparation of Amine Boranes via Salt Metathesis
(AB Procedure
2)
Sodium borohydride (0.76 g, 20 mmol) and the appropriate
ammonium salt (20 mmol) were transferred to a 100 mL dry round-bottom
flask, charged with a magnetic stir-bar. This was followed by addition
of reagent-grade tetrahydrofuran (20.0 mL) at rt. Reaction progress
was monitored by 11B NMR spectroscopy. (Note: A drop of
anhydrous DMSO is added to the reaction aliquot before running the 11B NMR experiment to solubilize NaBH4.) Upon completion
of the reaction (1–24 h, as determined by 11B NMR),
the reaction contents were filtered through sodium sulfate and celite
and the solid residue was washed with THF. Removal of the solvent
in vacuo from the filtrate yielded the corresponding amine-borane.
No further purification was necessary in the examples (1a, 1c) presented here.
1c was synthesized using AB
Procedure 2, obtained as a white solid
(93%, 1.096 g). 1H NMR (300 MHz, chloroform-d) δ 4.30 (s, 1H), 2.46 (d, J = 5.8 Hz, 6H),
1.42 (dd, J = 188.2, 91.9 Hz, 3H). 13C
NMR (75 MHz, chloroform-d) δ 44.4. 11B NMR (96 MHz, chloroform-d) δ −14.76
(q, J = 95.5 Hz).
General Amine-Iodoborane
Synthesis Procedure
In a 25
mL round-bottom flask, containing a stir-bar, the amine-borane (2
mmol, 1 equiv) was weighed. This was followed by addition of dichloromethane
(4 mL). After dissolution of the amine-borane, iodine (1 mmol, 0.5
equiv) was added portionwise at rt. After stirring for 5 min at rt,
the reaction mixture was analyzed using 11B NMR spectroscopy.
(All iodoboranes are unisolated intermediates identified by 11B NMR spectroscopy.)
In a 25 mL
round-bottom flask containing a stir-bar, the amine-borane (2 mmol,
1 equiv) was weighed. This was followed by addition of dichloromethane
(4 mL). After dissolution of the amine-borane, iodine (1 mmol, 0.5
equiv) was added portionwise at rt. After complete formation of the
amine-iodoborane complex, as evidenced by a return to colorlessness
of the reaction mixture, diisopropylethylamine (2 mmol, 1 equiv) was
added dropwise to the stirred reaction mixture at rt. After stirring
for 5 min at rt, the reactions were complete. (All aminoboranes are
unisolated intermediates identified by 11B NMR spectroscopy.)
General Procedure for Boronate Ester Synthesis
(General Procedure
1)
In a 25 mL round-bottom flask containing a stir-bar, the
amine-borane (2 mmol, 2 equiv) was weighed. This was followed by addition
of dichloromethane (5 mL). After dissolution of the amine-borane,
iodine (1 mmol, 1 equiv) was added portionwise at rt. After complete
formation of the iodoborane–amine complex, as evidenced by
a return to colorlessness of the reaction mixture, diisopropylamine
(5 mmol, 5 equiv) was added to the stirred reaction mixture at rt.
After stirring for 5 min at rt, the reaction was complete. Then, by
stirring toluene (5 mL), the aryl halide substrate (1 mmol, 1 equiv)
and PdCl2(dppp) (0.05 mmol, 0.05 equiv) were added to the
reaction mixture at rt. A reflux condenser was affixed to the flask,
and the mix was brought to reflux. After completion (∼12–16
h), the reaction mixture was cooled to rt and then brought to 0 °C
using an ice-water bath. At 0 °C, diethyl ether (3 mL) was added
to the mixture, followed by pinacol (1.1 mmol, 1.1 equiv). The mixture
was stirred for 4 h while being allowed to warm to rt. After completion,
the reaction mixture was diluted with diethyl ether (10 mL) and the
crude mixture was passed through a pad of silica gel contained in
a fritted glass Büchner funnel and eluted with diethyl ether
as necessary. The resulting filtrate was condensed by rotary evaporation
followed by drying in vacuo for 12 h.
Procedure for Synthesis of Boronic Acid and
Amine Recovery (General
Procedure 2)
In a 25 mL round-bottom flask containing a stir-bar,
the amine-borane (2 mmol, 2 equiv) was weighed. This was followed
by addition of dichloromethane (5 mL). After dissolution of the amine-borane,
iodine (1 mmol, 1 equiv) was added portionwise at rt. After complete
formation of the iodoborane–amine complex, as evidenced by
a return to colorlessness of the reaction mixture, diisopropylamine
(5 mmol, 5 equiv) was added to the stirred reaction mixture at rt.
After stirring for 5 min at rt, the reaction was complete. Then, by
stirring toluene (5 mL), the aryl halide substrate (1 mmol, 1 equiv)
and PdCl2(dppp) (0.05 mmol, 0.05 equiv) were added to the
reaction mixture at rt. A reflux condenser was affixed to the flask,
and the mix was brought to reflux. After completion (∼12–16
h), the reaction mixture was cooled to rt and then brought to 0 °C
using an ice-water bath. At 0 °C, methanol (8 mL) was added to
the mixture, and the solvent was removed by rotary evaporation. The
residue was then dissolved with sodium hydroxide (3 M, 8 mL). The
aqueous layer was washed with hexanes (3 × 10 mL), and the hexane
layers were set aside. The aqueous layer was then acidified with 3
M HCl until reaching a pH of 1. The slurry was extracted with diethyl
ether (4 × 15 mL). The combined organic portions were dried over
sodium sulfate, filtered through cotton, and condensed via rotary
evaporation followed by drying in vacuo for 12 h to retrieve the boronic
acid. To the earlier separated hexane fractions was added 2 M ethereal
HCl (5 mL) precipitating the ammonium salt. The salt was collected
on a filter paper in a Hirsch funnel and washed with hexanes (2 ×
10 mL). The solid was transferred to a preweighed flask and dried
in vacuo for 12 h.
(4-Methoxyphenyl)boronic Acid (5a)
5a was synthesized using General Procedure
2, obtained as
an off-white solid (83%, 126 mg). 1H NMR (300 MHz, chloroform-d) δ 8.15 (d, J = 8.3 Hz, 2H), 7.01
(d, J = 8.4 Hz, 2H), 3.88 (s, 3H). 13C
NMR (75 MHz, chloroform-d) δ 162.98, 137.38,
113.42, 55.19. 11B NMR (96 MHz, chloroform-d) δ 29.25. Compound characterization is in accordance with
previous reports.[3a]
Diisopropylammonium
Chloride
Diisopropylammonium chloride
was recovered using General Procedure 2, obtained as a white solid
(86%, 828 mg). 1H NMR (300 MHz, chloroform-d) δ 9.17 (s, 2H), 3.38 (hept, J = 6.4 Hz,
2H), 1.48 (d, J = 6.5 Hz, 12H). 13C NMR
(75 MHz, chloroform-d) δ 47.42, 19.24.
Authors: Lubov Pasumansky; Dustin Haddenham; Jacob W Clary; Gary B Fisher; Christian T Goralski; Bakthan Singaram Journal: J Org Chem Date: 2008-01-24 Impact factor: 4.354
Scheme 1
Scheme 2
Figure 1
Scheme 3
Figure 2
Figure 3
Scheme 4