Sonication and Microwave-Assisted Primary Amination of Potassium- Aryltrifluoroborates and Phenylboronic Acids under Metal-Free Conditions

Article abstract of DOI:10.1055/s-0036-1588148

The transition-metal-free generation of a series of primary arylamines from potassium aryltrifluoroborates and phenylboronic acids- is reported. The method uses a mild, inexpensive source of nitrogen (hydroxylamine-O-sulfonic acid) in cooperation with aqueous sodium hydroxide in acetonitrile. Both a sonication and a microwave-assisted method were developed, which are capable of converting ArBF₃K functionalities into primary arylamines (ArNH₂) in isolated yields of up to 78% (10 examples for each method). This report represents the first general method for the conversion of aryltrifluoroborates into primary arylamines under mild, transition-metal-free conditions in moderate to very good yields. The method is applicable to a wide array of substrates containing electron-donating, electron-neutral, or electron-withdrawing substituents. Both the sonication and microwave methods were also applied to the generation of anilines from phenylboronic acids in isolated yields of up to 96% (12 examples for each method) that were superior to existing room temperature methods in terms of yield, while also offering much shorter reaction times (15 min vs 16 h). In particular, the microwave method is the first to allow for the conversion of arylboronic acids containing strongly electron-withdrawing substituents into the corresponding anilines in good yields, along with electron-donating- substituents in very good to excellent yields.

Full text of DOI:10.1055/s-0036-1588148

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–G
paper
A
D. Kuik et al.
Paper
Synthesis
Sonication and Microwave-Assisted Primary Amination of
Potassium Aryltrifluoroborates and Phenylboronic Acids under
Metal-Free Conditions
Dale Kuika
J. Adam McCubbinb,c
Geoffrey K. Tranmer*a,c
NH2
X
H2N OSO3H
R
R
NaOH(aq), MeCN
Method A: rt, sonication, 1–3 h
Method B: 100 °C, MW, 15 min
a College of Pharmacy, University of Manitoba, 750
McDermot Ave., Winnipeg, Manitoba, R3E 0T5,
Canada
X = BF3K, 10 examples, up to 78%
X = B(OH)2, 12 examples, up to 96%
R = electron-donating & electron-withdrawing
b Department of Chemistry, University of Winnipeg,
599 Portage Ave., Winnipeg, Manitoba, R3B 2E9,
Canada
c Department of Chemistry, University of Manitoba,
360 Parker Building, Winnipeg, Manitoba, R3T 2N2,
Canada
geoffrey.tranmer@umanitoba.ca
Received: 13.12.2016
Accepted after revision: 27.01.2017
Published online: 22.02.2017
tractive in many cases, this behavior can pose problems
when transformation of the boron group is desired. These
properties can often manifest themselves in decreased re-
activities when compared to other organoboron com-
pounds.11 On the one hand, the stability of trifluoroborates
makes them inert to conditions that would normally modi-
fy boronic acids. On the other hand, their altered reactivity
often requires forcing reaction conditions (e.g., high tem-
peratures, longer reaction times) in order to allow the
transformation of a trifluoroborate functionality to proceed
towards completion, and can often lead to side-reactions or
decomposition of the desired product.
To date, the ability to use trifluoroborates as boronic
acid surrogates has found numerous applications in organic
synthesis and many aryltrifluoroborates are now commer-
cially available. New methods, however, are required that
will allow for the conversion of trifluoroborates into desir-
able functional groups, such as the generation of primary
C–NH2 bonds from C–BF3K functionalities. The synthesis of
primary aromatic amines from arylboronic acids under
copper-catalyzed conditions has been established, includ-
ing Cu-catalyzed azidonation reactions,12 however, the ami-
nation reactions generally require 12–24 hours to reach
completion.12–14 Indeed, only a single publication exists that
details the copper-catalyzed amination of aryltrifluorobo-
rates. The method described requires reaction times of 24
hours and has limited scope.14 To the best of our knowledge,
only four other publications have described an analogous
transformation where an aryltrifluoroborate is converted
into a primary arylamine. In each of these publications,
only a single example is reported for this type of conver-
sion, albeit with reaction times of 16 hours15 or 30 hours,16
in 13% yield as a by-product of the desired reaction,17 or
through the use of a toxic and potentially explosive azide as
a reagent (HN3).18 As a result, the literature is distinctly
lacking suitable methods that are capable of providing ac-
DOI: 10.1055/s-0036-1588148; Art ID: ss-2016-m0856-op
Abstract The transition-metal-free generation of a series of primary
arylamines from potassium aryltrifluoroborates and phenylboronic
acids is reported. The method uses a mild, inexpensive source of nitro-
gen (hydroxylamine-O-sulfonic acid) in cooperation with aqueous sodi-
um hydroxide in acetonitrile. Both a sonication and a microwave-assist-
ed method were developed, which are capable of converting ArBF3K
functionalities into primary arylamines (ArNH2) in isolated yields of up
to 78% (10 examples for each method). This report represents the first
general method for the conversion of aryltrifluoroborates into primary
arylamines under mild, transition-metal-free conditions in moderate to
very good yields. The method is applicable to a wide array of substrates
containing electron-donating, electron-neutral, or electron-withdraw-
ing substituents. Both the sonication and microwave methods were
also applied to the generation of anilines from phenylboronic acids in
isolated yields of up to 96% (12 examples for each method) that were
superior to existing room temperature methods in terms of yield, while
also offering much shorter reaction times (15 min vs 16 h). In particu-
lar, the microwave method is the first to allow for the conversion of ar-
ylboronic acids containing strongly electron-withdrawing substituents
into the corresponding anilines in good yields, along with electron-
donating substituents in very good to excellent yields.
Key words trifluoroborates, boronic acids, amination, sonication,
microwave synthesis
Organotrifluoroborate salts are readily available and
serve as convenient alternative substrates to boronic acids
and their esters.1–4 This is primarily due to the ease with
which they are handled and their relatively high chemical
stability. Indeed, trifluoroborates are inert to many sets of
reaction conditions that would be expected to adversely af-
fect conventional tricoordinate boron species. For example,
trifluoroborate containing substrates can undergo various
oxidation,5–7 reduction,8 and strong base-mediated reac-
tions9,10 without transformation of the boron functionality.
While the stability of these organoboron substrates is at-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

B
D. Kuik et al.
Paper
Synthesis
cess to aromatic primary amines from a wide variety of ar-
yltrifluoroborates. Ideally, a convenient method is required
for this transformation, which features short reaction
times, and mild, metal-free conditions. As part of a collabo-
rative effort, we set out to develop an efficient method that
is capable of converting potassium aryltrifluoroborates into
anilines, a key building block of biologically active agents.19
We expect the subsequent application of this general meth-
od to provide access to alternate primary arylamines, in ad-
dition to anilines, as a broader synthetic transformation.
The methods described herein will serve as general exam-
ples of a key functional group interconversion, the genera-
tion of aromatic C–NH2 moieties from trifluoroborates un-
der transition-metal-free conditions that can be applied to
the generation of alternate molecular frameworks, in addi-
tion to anilines.
The reactions were typically performed at a 0.5 mmol scale.
However, increasing the scale to 1.0 mmol had little effect
on the yields. The use of 1.5 equivalents of HSA gave good
isolated yields in combination with 5 equivalents of a 1 M
solution of aqueous sodium hydroxide. The ultrasound-
promoted reactions could be readily monitored by HPLC.
The microwave reactions, however, were normally too rap-
id to be monitored in this way. In most cases, commercially
available anilines were used as reference standards for
HPLC monitoring of reaction progress, and verification of
the desired products. Using the sonication method outlined
in Table 1, the sonication reactions were placed in the ultra-
sound bath for 30-minute intervals, at which time a small
aliquot was sampled for reaction monitoring via HPLC. This
process was repeated until the crude reaction HPLC trace
indicated the absence of any starting material, or that the
reaction had failed to progress any further, at which time
the crude reaction was prepared for column chromatogra-
phy purification. In general, the substrates with electron-
donating substituents reacted much faster than those with
electron-withdrawing substituents using the sonication
method. For example, 2,6-dimethoxyphenyltrifluoroborate
required only 1 hour of reaction time, while 4-chloro- and
4-iodophenyltrifluoroborate required 3 hours. Included in
the Supporting Information (SI) section are the HPLC chro-
matograms of both the crude reactions and the pure isolat-
ed products for the substrates listed in Table 1. As can be
seen through inspection of the HPLC chromatograms, the
majority of the reactions proceeded relatively cleanly, with
near complete consumption of starting material for the mi-
Previously, the McCubbin group had reported a single
example of the transformation of potassium 4-methoxy-
phenyltrifluoroborate into 4-methoxyaniline in 10% yield,
with a 16 hour reaction time.15 Following the addition of
excess silica gel, an enhancement of the yield was observed
(74%), presumably through the action of the silica gel in fa-
cilitating trifluoroborate hydrolysis.20 Unfortunately, this
publication provided only one example of this reaction, re-
quired long reaction times (16 hours), and necessitated the
use of 1.0 gram of silica gel per mmol of trifluoroborate,
limiting scale-up, and resulting in poor atom economy.21 As
a result, we set out to develop a robust reaction method
that would enable the conversion of aryltrifluoroborates to
primary arylamines with the benefit of microwave-assisted
organic synthesis (MAOS),22–24 and sonochemistry.25,26
+
Guided by the use of a common NH2 equivalent under
Table 1 Scope of Amination Reaction Using Microwave and Ultra-
basic aqueous conditions,15 we began our preliminary reac-
tion studies by treating potassium phenyltrifluoroborate
(1a) with hydroxylamine-O-sulfonic acid (HSA) and aque-
ous NaOH, in combination with acetonitrile at room tem-
perature, overnight. The corresponding reaction was moni-
tored via HPLC using aniline as a reference standard, and
very little conversion of the trifluoroborate was observed.
In a subsequent reaction, these reagents were combined
with potassium p-tolyltrifluoroborate (1b) and an excess of
silica gel, with some additional conversion to the aniline
derivative being observed, albeit in poor yield, with the ma-
jor product identified as p-tolylboronic acid by HPLC. At
this point, the use of a microwave synthesizer was em-
ployed to assist in this reaction and aid in the generation of
aryl primary amines. Concurrently, the use of an ultrasonic
cleaner (35 kHz, 90 W) was employed to investigate the po-
tential of an ultrasound-promoted rate enhancement of the
desired reaction. Initial studies for the microwave and ul-
trasound promoted reactions focused on method optimiza-
tion by varying reagent equivalence, solvent, and base. It
was quickly realized, however, that acetonitrile served as
the optimal solvent of choice, at concentrations of 0.2 M for
sonication reactions and 0.25 M for microwave processing.
sound Processing for Potassium Aryltrifluoroborates
H2N–OSO3H
NH2
BF3K
X
X
NaOH(aq), MeCN
1
2
Method A: ))), 1–3 h
Method B: MW, 100 °C, 15 min
Entry
2
Sonication Yield Microwave
(%)a
Yield (%)b
1
2
2a (X = H)
58
69
64
40
55
48
46
59
49
77
77
78
74
53
68c
55
76
73
45
74
2b (X = 4-Me)
3
2c (X = 4-MeO)
2d (X = 4-Cl)
4
5
2e (X = 3-thiophenyl)
2f (X = 2-naphthyl)
2g (X = 3-MeO)
2h (X = 3,4-methylenedioxy)
2i (X = 4-I)
6
7
8
9
10
2j [X = 2,6-(MeO)2]
a Isolated yields, 1–3 h, as monitored by HPLC.
b Isolated yields, 100 °C for 15 min.
c Reaction conducted using 3.0 equiv of HSA for 20 min.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

C
D. Kuik et al.
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Synthesis
crowave reactions. For the sonication reactions, in most
cases some starting material remained (<3 h), while the use
of microwave irradiation usually resulted in complete con-
version following 15 minutes of reaction time. Table 1 sum-
marizes the final results of the optimized reactions using
both microwave and ultrasound reaction processing.
conversion was observed when 1.5 equivalents of HSA was
used. The use of 3.0 equivalents of HSA, however, was found
to afford the desired product in a much higher yield of 68%.
For the majority of the microwave reactions, high conver-
sions were observed and the less than quantitative yields
obtained are likely a function of the slight water solubility
of anilines and their moderate volatility (aniline, bp
184 °C), resulting in product loss during aqueous workup
and purification.
The isolated yields for the sonication reactions were
found to be between 40% and 77%, and in general, the high-
er yielding reactions required less time in the ultrasound
bath to approach completion. In comparison to phenyltri-
fluoroborate (58%), the substrates possessing electron-
withdrawing groups (Cl, I) afforded products in lower yields
(40%, 49%, respectively), while those with electron-
donating substituents gave higher yields; 4-methyl- (69%),
4-methoxy- (64%), or 2,6-dimethoxy- (77%). 3,4-Meth-
ylenedioxyphenyltrifluoroborate was found to react with
similar isolated yield (59%) to that of the unsubstituted phe-
nyl (X = H) substrate, while the 2-naphthyl substrate afford-
ed the desired product in 48% yield, and the electron-rich
heteroaromatic 3-thiophenetrifluoroborate substrate af-
forded product in 55% yield. The majority of the reactions
proceeded relatively clean and gave products in good isolat-
ed yields. However, reaction of the 3-methoxyphenyl sub-
strate was found to produce an unidentified by-product
with a diminished isolated yield of 46% for the desired
product, in comparison to the other methoxy-bearing sub-
strates. The use of additional HSA (~3.0 equiv) provided for
increased conversion of starting material and shorter soni-
cation times. However, we found that the use of 1.5 equiva-
lents provided a good balance between yield, reaction time,
and reagent economy.
In general, higher isolated yields were obtained when
microwave irradiation was used to incubate the reactions,
as compared to sonication. In particular, for entries 1–8 in
Table 1, the yields were found to be 8% to 30% higher, while
the reactions shown in entries 9 and 10 occurred with sim-
ilar isolated yields. The increase in yields are presumably
due to an increase in the conversion of starting material to
product for the reactions as demonstrated by the crude re-
actions HPLC chromatograms (see SI). For instance, com-
paring the HPLC chromatograms of the crude reactions for
phenyltrifluoroborate (microwave vs sonication methods),
the ratio of product to starting material (Product/SM) for
the sonication method is ~1.8:1, while for the microwave
method it is ~6:1 (SM retention time 6.18 min, product re-
tention time 6.35 min). Additionally, the trends in the
yields were similar between the microwave and ultrasound
methods in terms of substituent effects. For electron-
donating groups, the isolated yields were found to be 73–
78% (Table 1, entries 2, 3, 7, 8, 10), while substrates bearing
electron-withdrawing substituents afforded products in
much lower yields, (entry 4, X = Cl, 53% and entry 9, X = I,
45%). Additionally, the 2-naphthyl substrate also afforded
product in moderate yield (55%, entry 6). It was also noted
that for the 3-thiophene substrate (entry 5) only moderate
Once the sonication and microwave methods had been
developed for the conversion of aryltrifluoroborates to pri-
mary arylamines, the methods were applied to provide for
similar transformations involving the conversion of arylbo-
ronic acids into analogous primary arylamines. Previously,
the McCubbin group had published a method that provided
for transition-metal-free access to primary anilines. How-
ever, this method required 16 hours of reaction time and
did not provide access to anilines possessing strongly deac-
tivating groups, such as nitro substituents.15 Thus, we pro-
posed to develop both sonication and microwave methods
that would allow for shortened reaction times for this
transformation, while also allowing access to anilines bear-
ing strong electron-withdrawing substituents. Using the
methods previously developed for the aryltrifluoroborates,
Table 2 represents the scope of these reactions, which di-
rectly compares the yields of the 16-hour room tempera-
ture reaction with sonication and microwave batch pro-
cessing techniques using the same concentrations and re-
agent equivalents. For each of the entries, the reactions
were performed at room temperature overnight (16 h) to
establish a baseline isolated yield in our hands,15 from
which the sonication and microwave methods can be com-
pared. In almost all cases, the sonication and microwave
methods offered an increase in isolated yield, with a corre-
sponding reduction in reaction times from 16 hours to 15
minutes for microwave processing. Additionally, boronic
acids refluxed for 5 hours under these conditions tended to
generate multiple by-product peaks via HPLC analysis,
demonstrating the advantage of microwave irradiation over
the use of conventional heating.
The results shown in Table 2 demonstrate the relative
improvement in yields, and reduction in reaction times,
that can be obtained through the use of sonication and mi-
crowave processing. Under otherwise identical reaction
conditions, a room temperature reaction required a mini-
mum of 16 hours to give acceptable yields for the desired
reaction. However, the use of ultrasound reduced the reac-
tion times to between one and three hours. Over time, the
temperature of the sonication bath was found to slowly in-
crease when active. This increase was negligible at 1 hour,
and the bath temperature rose to 35 °C at 3 hours. However,
reactions refluxed for 5 hours were found to afford lower
yields than the sonication reactions performed between
room temperature and 35 °C. These results suggest a sub-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

D
D. Kuik et al.
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Synthesis
Table 2 Comparison of Amination Reactions Using Room Tempera-
ture, Sonication, and Microwave Processing for Arylboronic Acids
minutes provided acceptable conversion of starting materi-
al. Under room temperature conditions, the reduced yields,
in comparison to the microwave method, were largely at-
tributed to unreacted starting material. Overall, both the
sonication and microwave methods afford products in very
good yields.
NH2
B(OH)2
H2N–OSO3H
X
X
NaOH(aq), MeCN
3
2
Method A: rt, 16 h
Method B: ))), 1–3 h
In conclusion, we have developed a simple, mild, transi-
tion-metal-free method for the transformation of aryltri-
fluoroborates and arylboronic acids into primary anilines
using sonication and microwave irradiation. The reaction
methods require only inexpensive, commercially-available
reagents (HSA, aq NaOH) that typically afford products in
good to excellent yields. For both the aryltrifluoroborates
and arylboronic acids, the methods are highly effective for
both electron-rich and electron-neutral substrates, while
also providing efficient access to primary anilines with
electron-withdrawing substituents. Additionally, micro-
wave irradiation allows for the conversion of phenylboronic
acids with strongly electron-withdrawing substituents
(X = NO2) to anilines, a first under metal-free conditions.
The primary advantage of this method over those previous-
ly reported is the ability to provide rapid access (1–3 hours
under sonication, or 15 minutes for microwave) to this im-
portant functional group interconversion (C–BXn to C–NH2).
This reduction in reaction times provides for a real-world
improvement in the synthetic methods that are available to
the typical organic chemist. The majority of synthetic labs
possess an ultrasonic cleaner, which is the only equipment
required to conduct the sonication method. Most industrial
synthetic labs do possess a microwave reactor, however,
some academic labs and chemists in developing nations do
not have access to this costly piece of equipment. Using the
methods developed herein, either the sonication and/or the
microwave methods can be utilized by scientists and pro-
vide useful acceleration of rates for this reaction, depending
upon laboratory resources. We are currently exploring the
nature of the observed rate enhancement for the sonication
reactions and believe that heterogeneous sonochemical ef-
fects may be in operation.27 For more information on the
relevance of the reaction medium and homo- versus het-
erogeneous sonochemistry, the corresponding reviews are
recommended.25,26 We are also extending our efforts in the
development of this transformation to include additional
heteroaromatic trifluoroborates and multicyclic scaffolds,
as well as efforts to avoid aqueous workup procedures. We
are also developing methods that would employ modern
flow chemistry techniques28–30 that would provide for the
generation of primary arylamines from arylboronic esters.
Method C: MW, 100 °C, 15 min
Entry
2
Room temp,
Sonication
Microwave
Yield (%)c
16 h Yield (%)a Yield (%)b
1
2
2a (X = H)
78
61
75
69
61
70
68
43
71
38
62
31
86
75
79
70
75
77
96
39
70
59
95
26d
88
76
72
74
87
87
80
60
63
53d
92
68d
2b (X = 4-Me)
3
2c (X = 4-MeO)
2d (X = 4-Cl)
4
5
2f (X = 2-naphthyl)
2g (X = 3-MeO)
2j [X = 2,6-(MeO)2]
2k (X = 2-Br)
6
7
8
9
2l (X = 4-Br)
10
11
12
2m (X = 2-I)
2n (X = 8-quinolinyl)
2o (X = 3-NO2)
a Isolated yields, 16 h at r.t.
b Isolated yields, 1–2.5 h, as monitored by HPLC.
c Isolated yields, 100 °C for 15 min.
d With an additional 1.0 equiv of HSA.
stantial rate enhancement for the sonication reactions be-
yond any temperature effects. The use of microwave pro-
cessing reduced this time even further to just 15 minutes.
Using the sonication method, 9 of the 12 entries in Table 2
allowed for isolation of products in yields between 70 and
96%, while the use of microwave processing provided prod-
ucts in yields between 60 and 92% for 11 of the 12 entries.
For the sonication method, only substrates that possessed
an electron-withdrawing substituent gave desired products
in yields less than 70%, entries 8 (X = Br, 39%), 10 (X = I, 59%)
and 12 (X = NO2, 26%). Using the microwave method, only
entry 10 (X = I, 53%) afforded the desired product in an iso-
lated yield less than 60%. For this reaction an additional 1.0
equivalent of HSA was added to provide for more complete
conversion. Of special note is the success of this method in
transforming an arylboronic acid possessing a strongly
electron-withdrawing substituent (X = NO2, 68%) into an
aniline, a reaction that has not appeared in the literature to
date under metal-free conditions. This particular reaction
required the addition of an extra 0.5 equivalent of HSA after
the initial 15 minutes of reaction time, followed by an extra
7 minutes of microwave irradiation, (repeated twice), to af-
ford the nitroaniline product in this yield. A microwave re-
action temperature of 100˚C was found to be optimal, since
higher temperatures produced additional peaks in the
crude reactions (confirmed by HPLC analysis) while 15
Automated flash chromatography was performed using a normal
phase disposable silica gel columns, (40–60 μm). For sonication reac-
tions, an ultrasonic cleaner 2.8 L was employed, operating frequency
35 kHz, power consumption 90 W. HPLC was performed using a 5 μm,
150 mm × 4.6 mm column, and a diode array detector. HPLC method
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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D. Kuik et al.
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Synthesis
(H2O/MeCN): 0–1.0 min, 95% H2O; 9.0–10.0 min, 95% MeCN, 11.0–
12.0 min 95% H2O. All solvents were purchased as ACS reagents and
used without further purification. All other chemicals and starting
materials, aryltrifluoroborates and arylboronic acids, were purchased
commercially and used as received.
DKB05-Purified),32 2f (39.6 mg, 55%, purified product chromatogram
DKB09-Purified),12 2g (performed on a 1.0 mmol scale, 94.3 mg, 76%,
purified product chromatogram DKB10-Purified),12 2h (50.0 mg, 73%,
purified product chromatogram DKB13-Purified),33 2i (39.0 mg, 45%,
purified product chromatogram DKB15-Purified),34 2j (56.9 mg, 74%,
purified product chromatogram DKB16-Purified),35 were prepared by
this method and afforded NMR data that matched those reported in
the literature.
HPLC chromatograms of all the reaction products with indicated
numbers (DKA or DKB) are provided in the Supporting Information.
Amination of Aryltrifluoroborates; General Procedures (Table 1)
Sonication; Method A
Amination of Arylboronic Acids; General Procedures (Table 2)
Room Temperature; Method A
Reactions were performed under sonication on a 0.5 mmol scale.
Aryltrifluoroborate 1 (1.0 equiv) and MeCN (2.5 mL) were added to a
25 mL microwave vial equipped with stir bar, followed by HSA (1.5
equiv) and aq 1 M NaOH (5 equiv). The vial was capped and set to stir
for 5 min, then placed in a VWR ultrasonic cleaner for 30 min (35 kHz,
90 W), at which time the vial was removed and a small aliquot was
taken for reaction monitoring via HPLC analysis. The mixture was
then placed back in the VWR sonication bath for 30 min. This process
was repeated until the reaction had either reacted completion, or the
reaction failed to progress any further, as monitored by HPLC. The re-
action mixture was then diluted with H2O (30 mL) and extracted with
EtOAc (2 × 30 mL). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. The residue was purified by flash chroma-
tography (EtOAc/hexanes) to afford the desired amine product 2.
Room-temperature reactions were performed on a 1.0 mmol scale.
Arylboronic acid 3 (1.0 equiv) and MeCN (5.0 mL) were added to a 25
mL round-bottomed flask equipped with stir bar, followed by HSA
(1.5 equiv) and aq 1 M NaOH (5 equiv). The mixture was capped and
set to stir for 16 h overnight, after which a small aliquot was taken for
reaction monitoring via HPLC analysis. The reaction mixture was di-
luted with H2O (30 mL) and extracted with EtOAc (2 × 30 mL). The
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The residue was purified by flash chromatography (EtO-
Ac/hexanes) to afford the desired amine product 2.
Compounds 2a (72.6 mg, 78%, purified product chromatogram
DKA29-Purified),12 2b (65.3 mg, 61%, purified product chromatogram
DKA20-Purified),31 2c (92.8 mg, 75%, purified product chromatogram
DKA60-Purified),31 2d (87.9 mg, 69%, purified product chromatogram
DKA54-Purified),31 2f (87.0 mg, 61%, purified product chromatogram
DKA33-Purified),12 2g (69.0 mg, 70%, purified product chromatogram
DKA30-Purified),12 2j (102.3 mg, 68%, purified product chromato-
gram DKA34-Purified),35 2k (74.0 mg, 43%, purified product chro-
matogram DKA39-Purified shows two peaks with a yield taken as ra-
tio of 37:63 for impurity/product, respectively),36 2l (122.1 mg, 71%,
purified product chromatogram DKA40-Purified),37 2m (83.8 mg,
38%, purified product chromatogram DKA45-Purified),35 2n (90.0 mg,
62%, purified product chromatogram DKA59-Purified),38 2o (42.6 mg,
31%, purified product chromatogram DKA53-Purified),39 were pre-
pared by this method and afforded NMR data that matched those re-
ported in the literature.
Compounds 2a (2.5 h sonication time, 27.3 mg, 58%, purified product
chromatogram DKB6-Purified),12 2b (2.5 h sonication time, 37.1 mg,
69%, purified product chromatogram DKA86-Purified),31 2c (2.5 h
sonication time, 39.4 mg, 64%, purified product chromatogram
DKA75-Purified),31 2d (3 h sonication time, 25.6 mg, 40%, purified
product chromatogram DKB02-Purified),31 2e (1.5 h sonication time,
27.4 mg, 55%, purified product chromatogram DKB07-Purified),32 2f
(2.5 h sonication time, 34.2 mg, 48%, purified product chromatogram
DKB08-Purified),12 2g (2.5 h sonication time and performed on a 1.0
mmol scale, 56.3 mg, 46%, purified product chromatogram DKB11-
Purified),12 2h (1.5 h sonication time, 40.4 mg, 59%, purified product
chromatogram DKB12-Purified),33 2i (3 h sonication time, 43.4 mg,
49%, purified product chromatogram DKB14-Purified),34 2j (1 h soni-
cation time, 39.3 mg, 77%, purified product chromatogram DKB17-
Purified),35 were prepared by this method and afforded NMR data
that matched those reported in the literature.
Sonication; Method B
Reactions facilitated by sonication were performed on a 1.0 mmol
scale. Arylboronic acid 3 (1.0 equiv) and MeCN (5.0 mL) were added
to a 25 mL microwave vial equipped with a stir bar, followed by HSA
(1.5 equiv) and aq 1 M NaOH (5 equiv). The mixture was capped and
set to stir for 5 min, then placed in an ultrasonic cleaner for 30 min
(35 kHz, 90 W), at which time the vial was removed and a small ali-
quot was taken for reaction monitoring via HPLC analysis. The mix-
ture was then placed back in the sonication bath for 30 min. This pro-
cess was repeated until the reaction had gone to completion, or the
reaction failed to progress, as monitored by HPLC. The reaction mix-
ture was diluted with H2O (30 mL) and extracted with EtOAc (2 × 30
mL). The combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. The residue was purified by flash chromatography
(EtOAc/hexanes) to afford the desired amine product 2.
Microwave; Method B
Reactions facilitated by microwave irradiation were performed on a
0.5 mmol scale. Aryltrifluoroborate 1 (1.0 equiv) and MeCN (2.0 mL)
were added to a 10 mL microwave vial equipped with stir bar, fol-
lowed by HSA (1.5 equiv) and aq 1 M NaOH (5 equiv). The mixture
was capped and set to stir for 5 min at r.t., then placed in a microwave
reactor and heated to 100 °C for 15 min, and then cooled. The vial was
removed from the microwave and a small aliquot was taken for reac-
tion monitoring via HPLC analysis. The reaction mixture was diluted
with H2O (30 mL) and extracted with EtOAc (2 × 30 mL). The com-
bined organic extracts were dried (Na2SO4) and concentrated in vac-
uo. The residue was purified by flash chromatography (EtOAc/
hexanes) to afford the desired amine product 2.
Compounds 2a (1 hour sonication time, 80.2 mg, 86%, purified prod-
uct chromatogram DKA25-Purified),12 2b (1.25 h sonication time,
79.9 mg, 75%, purified product chromatogram DKA21-Purified),31 2c
(1.5 h sonication time, 96.9 mg, 79%, purified product chromatogram
DKA55-Purified),31 2d (1.5 h sonication time, 89.2 mg, 70%, purified
product chromatogram DKA49-Purified),31 2f (1 h sonication time,
107.6 mg, 75%, purified product chromatogram DKA31-Purified),12 2g
Compounds 2a (36.0 mg, 77%, purified product chromatogram
DKB01-Purified),12 2b (42.0 mg, 78%, purified product chromatogram
DKA85-Purified),31 2c (45.6 mg, 74%, purified product chromatogram
DKA76-Purified),31 2d (33.6 mg, 53%, purified product chromatogram
DKB03-Purified),31 2e (reaction performed using 3.0 equiv of HSA and
heated for 20 min, 33.7 mg, 68%, purified product chromatogram
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

F
D. Kuik et al.
Paper
Synthesis
(1 h sonication time, 95.3 mg, 77%, purified product chromatogram
DKA27-Purified),12 2j (1 h sonication time, 146.8 mg, 96%, purified
product chromatogram DKA35-Purified),35 2k (2.5 h sonication time,
67.8 mg, 39%, purified product chromatogram DKA37-Purified),36 2l
(1.5 h sonication time, 121.5 mg, 70%, purified product chromato-
gram DKA41-Purified),37 2m (2.5 h sonication time, 128.5 mg, 59%,
purified product chromatogram DKA43-Purified),35 2n (1.5 h sonica-
tion time, 137.2 mg, 95%, purified product chromatogram DKA47-Pu-
rified),38 2o (2.5 total h sonication time with additional 0.5 equiv of
HSA added after 1 h and 0.5 equiv of HSA added after 1.5 h, 36.3 mg,
26%, purified product chromatogram DKA57-Purified),39 were pre-
pared by this method and furnished NMR data that matched those re-
ported in the literature.
References
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Microwave; Method C
Reactions facilitated by microwave irradiation were performed on a
1.0 mmol scale. Arylboronic acid 3 (1.0 equiv) and MeCN (5.0 mL)
were added to a 10 mL microwave vial equipped with stir bar, fol-
lowed by HSA (1.5 equiv) and aq 1 M NaOH (5 equiv). The mixture
was capped and set to stir for 5 min, then placed in a microwave reac-
tor, and heated to 100 °C for 15 min, and then cooled to r.t. The vial
was removed from the microwave and a small aliquot was taken for
reaction monitoring via HPLC analysis. The reaction mixture was di-
luted with H2O (30 mL) and extracted with EtOAc (2 × 30 mL). The
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo. The residue was purified by flash chromatography (EtOAc/
hexanes) to afford the desired amine product 2.
Compounds 2a (81.7 mg, 88%, purified product chromatogram DKA4-
Purified),12 2b (81.1 mg, 76%, purified product chromatogram DKA8-
Purified),31 2c (89.0 mg, 72%, purified product chromatogram DKA56-
Purified),31 2d (94.3 mg, 74%, purified product chromatogram DKA50-
Purified),31 2f (126.8 mg, 87%, purified product chromatogram
DKA32-Purified),12 2g (108.1 mg, 87%, purified product chromato-
gram DKA11-Purified),12 2j (122.6 mg, 80%, purified product chro-
matogram DKA36-Purified),35 2k (104.8 mg, 60%, purified product
chromatogram DKA38-Purified),36 2l (109.2 mg, 63%, purified prod-
uct chromatogram DKA42-Purified),38 2m (an additional 1.0 equiv of
HSA was added after 15 min, and heated for an additional 14 min,
117.0 mg, 53%, purified product chromatogram DKA61-Purified),35 2n
(132.2 mg, 92%, purified product chromatogram DKA48-Purified),38
2o (an additional 1.0 equiv of HSA was added after 15 min, and heated
for an additional 14 min, 94.6 mg, 68%, purified product chromato-
gram DKA58-Purified),39 were prepared by this method and fur-
nished NMR data that matched those reported in the literature.
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Acknowledgment
Acknowledgment is made to the University of Manitoba (G.K.T.), the
University of Winnipeg (J.A.M.), and the College of Pharmacy at the
University of Manitoba (Undergraduate Scholarship, D.K.; G.K.T.) for
financial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588148.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G

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D. Kuik et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G