Synthesis of boron-containing primary amines

Article abstract of DOI:10.3390/molecules181012346

In this study, boron-containing primary amines were synthesized for use as building blocks in the study of peptoids. In the first step, Gabriel synthesis conditions were modified to enable the construction of seven different aminomethylphenyl boronate esters in good to excellent yields. These compounds were further utilized to build peptoid analogs via an Ugi four-component reaction (Ugi-4CR) under microwave irradiation. The prepared Ugi-4CR boronate esters were then successfully converted to the corresponding boronic acids. Finally, the peptoid structures were successfully modified by cross-coupling to aryl/heteroaryl chlorides via a palladium-mediated Suzuki coupling reaction to yield the corresponding derivatives in moderate to good yields.

Full text of DOI:10.3390/molecules181012346

Molecules 2013, 18, 12346-12367; doi:10.3390/molecules181012346
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Boron-Containing Primary Amines
Sheng-Hsuan Chung, Ting-Ju Lin, Qian-Yu Hu, Chia-Hua Tsai and Po-Shen Pan *
Department of Chemistry, Tamkang University, No. 151 Yingzhuan rd., Tamsui Dist.,
New Taipei City 25137, Taiwan
* Author to whom correspondence should be addressed; E-Mail: popan@mail.tku.edu.tw;
Tel.: +886-2-2621-5656 (ext. 2842); Fax: +886-2-2620-9924.
Received: 30 August 2013; in revised form: 27 September 2013 / Accepted: 30 September 2013 /
Published: 8 October 2013
Abstract: In this study, boron-containing primary amines were synthesized for use as
building blocks in the study of peptoids. In the first step, Gabriel synthesis conditions were
modified to enable the construction of seven different aminomethylphenyl boronate esters
in good to excellent yields. These compounds were further utilized to build peptoid analogs
via an Ugi four-component reaction (Ugi-4CR) under microwave irradiation. The prepared
Ugi-4CR boronate esters were then successfully converted to the corresponding boronic
acids. Finally, the peptoid structures were successfully modified by cross-coupling to
aryl/heteroaryl chlorides via a palladium-mediated Suzuki coupling reaction to yield the
corresponding derivatives in moderate to good yields.
Keywords: boron; multicomponent reactions; Gabriel synthesis; Ugi reaction; peptoid
1. Introduction
Peptides are a form of naturally occurring polymer [Figure 1(a)], which have many significant
pharmacological properties such as high specificity, high potency toward their target [1], and low
accumulation in the body [2]. As a result, many drugs currently on the market are based on the peptide
structure, including vancomycin (VancocinTM), oxytocin (OxytocinTM), enfuvirtide (FuzeonTM), and
eptifibatide (IntegrilinTM). However, peptides also have a number of drawbacks when used as
pharmaceuticals, including low cell permeability [3] and vulnerability to proteolytic degradation [4,5].
Peptoids, oligo-N-substituted glycines [Figure 1(b)], are a class of biomimetic molecule designed to
mimic peptides and proteins, whilst providing the advantages of protease resistance [6] and improved

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cell permeability [7]. These features have driven research into the application of peptoids as
therapeutic agents. Recent examples include transcription factor mimics [8], protein–protein interaction
inhibitors [9], antimicrobial agents [10,11], and lung surfactant mimics [12]. There are two major
strategies used for synthesizing peptoids. The first of these is the two stage sub-monomer method
developed by Zuckermann and co-workers [13]. The protocol proceeds via acylation of an amine with
an activated ester of 2-bromo (or chloro) acetic acid, followed by displacement of the halide with a
primary amine [Scheme 1(a)]. The second strategy is via the Ugi four-component reaction [Ugi-4CR,
Scheme 1(b)] [14,15], where a carboxylic acid, an isocyanide, an aldehyde (or ketone), and a primary
amine are reacted in a one-pot method to generate the desired peptoid. Aside from their different
synthetic approaches, both strategies rely on primary amines as the only source to introduce the side
chain to the peptoid backbone.
Figure 1. Structures of (a) peptide; (b) peptoid.
Scheme 1. (a) Zuckermann peptoid synthesis; (b) Ugi-4CR peptoid synthesis.
Many studies have shown that both inter- and intramolecular interactions between the side chains of
peptoid play a crucial role in determining its folding, conformation [16,17] and the functions [18,19].
Hence, primary amines can be used as the tool to investigate the role of individual monomer units
involved in the peptoid folding/helix-stabilizing process. Boron-containing primary amines have
unique properties for facilitating the study of this type of event, as they can be first incorporated into
the parent peptoid backbone, and then the boron moiety can be converted into a variety of functional
groups [20–26] (Figure 2). This transformation provides a valuable platform for evaluation of the
relationships between the side chains and the peptoid folding patterns.

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Figure 2. Functional group transformations from boronate ester.
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2. Results and Discussion
Although there are many synthetic methods that can be used to prepare amines [27,28], strategies
for the specific synthesis of primary amines are relatively limited. The use of a reductive amination
reaction is one such approach [29,30], whereby first an imine intermediate is formed and then a metal
hydride reducing agent such as sodium cyanoborohydride is employed to reduce the imine double
bond. The use of a protecting group is crucial when using this method in order to prevent over-alkylation,
as an unprotected starting material will often result in the formation of undesired secondary or tertiary
amine byproducts [31–33]. However, this need for the incorporation of a protecting group presents a
number of disadvantages, including an increase in the total number of synthetic steps (protection and
deprotection steps) and a decrease in atom economy. An alternative strategy for producing primary
amines is via Gabriel synthesis [34]. In this method, the potassium salt of phthalimide is reacted with a
primary alkyl halide to give the corresponding N-alkylphthalimide. This then reacts with hydrazine to
give the desired primary amine. This synthetic strategy avoids the formation of secondary or tertiary
amine byproducts without the need for a protecting group. Although this is one of the most commonly
used methods, the synthesis of boron-containing primary amines via Gabriel synthesis is relatively
unexplored [35]. This is partly because the reaction conditions are often harsh, and there are concerns
over whether the boron functional group can survive intact in such an environment. In this report, we
demonstrate the synthesis of boron-containing primary amines via a modified Gabriel synthesis.

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The synthesis proceeded via the mixing of formylphenyl boronic acid with pinacol and magnesium
sulfate in methanol to give the corresponding boronate ester. The progress was monitored using
11B-NMR spectroscopy, and when the reaction was seen to be completed, the crude solution was
filtered. Sodium borohydride was then added to the filtrate, and the reaction was allowed to react at
room temperature for 5 hours to afford the desired products 2a–g in good to excellent yields (Table 1).
Table 1. Synthesis of hydroxymethylphenyl boronate esters.
Enrty
Aldehyde
Product
Yields (%) a
1
88
2
86
3
4
5
69
90
95
6
7
94
97
a
b
c
In two steps; 2a was also prepared under similar synthetic conditions [36]; preparation of 2f using
different synthetic conditions was also reported [37].
Although THF is often used as the solvent in syntheses involving phthalimide, in the present study
the desired product could not be isolated using this as either the solvent or co-solvent (Table 2, entries 1
and 2). Instead DMF was found to be the optimal solvent for this reaction (Table 2, entry 3). The use
of 1.5 equiv. of potassium phthalimide gave the best yield (96%, entry 3), with a reduced amount

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resulting in lower yields (entries 4 and 5). In addition, six further analogs 3a–g were successfully
synthesized in moderate to excellent yields (entries 6–11).
Table 2. Optimization of phthalimidophenyl boronate esters synthesis.
Enrty
R1
Solvent
PhthK (equiv.)
1.5
Product
Yields (%)
1
THF
3a
N.R.
DMF/THF
(v:v=1:4)
2
3
4
1.5
1.5
1.2
3a
3a
3a
N.R.
96
DMF
DMF
87
5
6
7
8
DMF
DMF
DMF
DMF
1.0
1.5
1.5
1.5
3aa
3b
3c
80
80
75
85
Bpin
Bpin
Cl
3d
9
DMF
DMF
DMF
1.5
1.5
1.5
3e
3f
53
97
48
10
11
3g
a 3a was also synthesized by the similar synthetic condition [35].
The next step involved the use of the Ing-Manske procedure for the synthesis of the desired
aminomethylphenyl boronate ester from the phthalimidophenyl boronate ester, and optimization of the
reaction conditions. Initially, 3a was reacted with six equivalents of hydrazine in ethanol under reflux
for 8 h, giving the desired product 4a in poor yield (Table 3, entry 1). Increasing the reaction time in
addition to the amount of hydrazine used significantly improved the yield to 47% (Table 3, entry 2).

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Table 3. Synthesis of aminomethylphenyl boronate esters.
Time
(h)
Hydrazine
(equiv.)
Enrty
R1
Solvent
Product
4a
Yields (%)
1
EtOH
8
6
8
3
7
2
3
EtOH
12
12
4a
47
73
MeOH
4a a
4
5
THF
THF
THF
THF
12
12
12
12
3
3
3
3
4a
4b
4c
4d
87
82
98
36
6
Bpin
7
Cl
Bpin
8
THF
THF
THF
12
12
12
3
3
3
4e
4f
91
66
58
F
9
10
4g
a 4a was also synthesized by the similar synthetic condition [35].
Other solvent systems were also investigated, and it was found that the yield was improved from
47% to 73% when methanol was used instead of ethanol (entry 3). Additionally, the use of THF
improved the yield even further from 73% to 87% (entry 4). By employing these optimized conditions,
4b–g were obtained in good to excellent yield (entries 5–10). Interestingly, phthalimidophenyl
trifluoroborate failed to provide the desired aminomethylphenyl trifluoroborate under the same reaction
conditions, due to stability issues of the boron moiety.
Three of the synthesized boron-containing primary amines 4a–c were subsequently utilized as
building blocks for the microwave-assisted Ugi-4CR reaction, and the desired products 5a–d were
successfully obtained in moderate to good yields (Scheme 2).

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Scheme 2. Synthesis of peptoid boronate esters via Ugi-4CR.
After successful synthesis of Ugi-4CR boronate esters 5a–d, transformation into the corresponding
boronic acids 6a–c was performed. The boronate esters were first converted into potassium
organotrifluoroborates that then underwent hydrolysis to give the desired boronic acids. Although it
was possible to isolate each of the boronic acids, the substrate bearing an electron-withdrawing group
5c gave a particularly low yield over the two steps Scheme 3.
The structural diversity of the Ugi-4CR boronate esters was further increased by using a palladium-
mediated Suzuki coupling reaction, where aryl/heteroaryl chlorides were cross-coupled to the boron-
containing analogs to give 8a–b in moderate to good yields (Scheme 4).
Scheme 3. Synthesis of peptoid boronic acids from the corresponding boronate esters.
1. KHF2 (6 equiv),
0.1 M MeOH/H2O (1:1)
r.t., 5h
O
O
H
N
H
N
N
N
2. SiO2 (1.1 equiv),
EtOAc/H2O (1:1)(0.1 M )
r.t., 5h
O
O
Bpin
B(OH)2
5a-c
6a-c
O
O
O
H
N
H
N
N
H
N
N
N
O
O
O
B(OH)2
B(OH)2
F
B(OH)2
6a
6b
60 %
(over two-steps)
6c
10 %
(over two-steps)
49 %
(over two-steps)

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Scheme 4. Pd mediated Suzuki cross coupling of boron containing Ugi-4CR substrate.
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3. Experimental
3.1. General Information
All starting materials were obtained from commercial suppliers and used without further
purification unless otherwise noted. Reactions were performed on a CEM Co., Discovery microwave
13
reactor with sealed vessels. Unless otherwise specified 1H-, and C-NMR spectra were recorded on a
Bruker AC-300 FT-NMR spectrometer at 300 and 76 MHz, respectively. 11B-NMR spectra were
11
recorded on a Bruker Avance 600 FT-NMR spectrometer at 193 MHz. All B chemical shifts were
referenced to external BF3·OEt2 (0.0 ppm). Data is represented as follows: chemical shifts (ppm),
multiplicity: (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constant J (Hz).
Melting points were determined by using a Fargo MP-2D melting point apparatus and were
uncorrected. High resolution ESI mass spectra were obtained on a Finnigan MAT 95S instrument. The
desired products 4a–g were purified by a RP-HPLC using ODS-A C18 reverse phase column (5 μm,
10 mm × 250 mm) and following gradient elutions with solvent A: 0.1% TFA/ water, solvent B: 0.1%
TFA/acetonitrile; from 0% to 90% of B over 90 min, a flow rate: 2.0 mL/min; detection: UV, 215 and
254 nm.
3.2. General Procedure A for the Synthesis of Boron-Containing Primary Alcohols 2a–g
[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2a). To
a
mixture of
a
4-formylbenzenboronic acid (1a, 375 mg, 2.50 mmol), pinacol (355 mg, 3.00 mmol) and anhydrous
magnesium sulfate (625 mg, 5.00 mmol), methanol was added (12.50 mL). The mixture was stirred at
room temperature for 6 h. After the reaction was completed, the crude solution was filtered, and then

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sodium borohydride (47 mg, 1.25 mmol) was added to the filtrate. Afterwards, the reaction mixture
was stirred for an additional 5 h. Once the reaction was completed, the reaction mixture was filtered
and the filtrate was concentrated in vacuo to give the desired product 2a as a white solid (m.p. 75–77 °C) in
1
88% yield (513 mg); H-NMR (CD3OD-d4) δ ppm 7.71 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H),
4.62 (s, 2H), 1.34 (s, 12H); 13C-NMR (CD3OD-d4) δ ppm 146.23, 135.93, 127.26, 85.19, 65.24, 25.34;
11B-NMR (CDCl3) δ ppm 34.82.
[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2b). Following the General
Procedure A, the desired compound was synthesized utilizing 3-formylbenzenboronic acid (1b, 375 mg,
2.50 mmol), pinacol (355 mg, 3.00 mmol), anhydrous magnesium sulfate (601 mg, 5.00 mmol),
sodium borohydride (47 mg, 1.25 mmol), and methanol (12.50 mL) giving compound 2b as a white
1
solid (m.p. 48–50 °C) in 86% yield (502 mg); H-NMR (CD3OD-d4) δ ppm 7.74 (s, 1 H), 7.64 (d,
J = 7.2 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 4.60 (s, 2H), 1.34 (s, 12H);
11
13C-NMR (CD3OD-d4) δ ppm 142.11, 134.76, 134.50, 131.23, 128.93, 85.23, 65.35, 25.35; B-NMR
(CDCl3) δ ppm 30.97.
[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]phenyl)methanol (2c). Following the
General Procedure A, the desired compound was synthesized utilizing 2-fluoro-3-
formylbenzenboronic acid (1c, 420 mg, 2.50 mmol), pinacol (355 mg, 3.00 mmol), anhydrous
magnesium sulfate (601 mg, 5.00 mmol), sodium borohydride (47 mg, 1.25 mmol), and methanol
1
(12.50 mL) giving compound 2c as a white solid (m.p. 80–82 °C) in 69% yield (435 mg); H-NMR
(CD3OD-d4) δ ppm 7.68 (t, J = 3.4 Hz, 1H), 7.49–7.44 (m, 1H), 7.01 (t, J = 6.5 Hz, 1H), 4.57 (s, 2H),
1.34 (s, 12H); 13C-NMR (CD3OD-d4) δ ppm 166.42 (d, J = 249.0 Hz), 136.7, 135.1, 135.0, 131.9,
131.9, 114.7, 114.5, 114.2, 83.7, 62.9, 23.7, 23.7, 23.6; 11B-NMR (CDCl3) δ ppm 30.2.
[4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2d). Following the
General Procedure A, the desired compound was synthesized utilizing 2-chloro-5-
(hydroxymethyl)phenylboronic acid (1d, 242 mg, 1.30 mmol), pinacol (184 mg, 1.56 mmol),
anhydrous magnesium sulfate (313 mg, 2.60 mmol), sodium borohydride (25 mg, 0.65 mmol), and
methanol (6.50 mL) giving compound 2d as a oil in 90% yield (314 mg); 1H-NMR (CD3OD-d4) δ ppm
7.66 (d, J = 1.8 Hz, 1H), 7.39–7.31 (m, 2H), 4.57 (s, 2H), 1.39 (t, J = 18.1 Hz, 12H); 13C-NMR
(CDCl3) δ ppm 138.4, 138.1, 134.5, 130.2, 129.2, 84.0, 63.7, 24.5, 24.3; 11B-NMR (CDCl3)
δ ppm 30.6.

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[2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2e). Following the
General Procedure A, the desired compound was synthesized utilizing 4-fluoro-3-formylphenylboronic
acid (1e, 218 mg, 1.30 mmol), pinacol (184 mg, 1.56 mmol), anhydrous magnesium sulfate (313 mg,
2.60 mmol), sodium borohydride (25 mg, 0.65 mmol), and methanol (6.50 mL) giving compound 2e as
1
a white solid (m.p. 44–47 °C) in 95% yield (312 mg); H-NMR (CD3OD-d4) δ ppm 7.87 (d, J = 8.1
Hz, 1H), 7.71–7.09 (m, 1H), 7.05 (t, J = 10.4 Hz, 1H), 4.67 (s, 2H), 1.34 (s, 12H); 13C-NMR
(CD3OD-d4) δ ppm 164.4(d, J = 250.5 Hz), 137.6, 137.2, 137.1, 129.2, 129.1, 115.8, 115.7, 85.4, 58.9,
25.3, 25.2; 11B-NMR (CDCl3) δ ppm 30.6.
[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2f). Following the General
Procedure A, the desired compound was synthesized utilizing 2-fluoro-4-formylphenylboronic acid (1f,
218 mg, 1.30 mmol), pinacol (184 mg, 1.56 mmol), anhydrous magnesium sulfate (313 mg,
2.60 mmol), sodium borohydride (25 mg, 0.65 mmol), and methanol (6.50 mL) giving compound 2f as
1
a white solid (m.p. 35–38 °C) in 94% yield (308 mg); H-NMR (CDCl3) δ ppm 7.60 (t,
J = 6.8 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 10.4 Hz, 1H), 4.53 (s, 2H), 1.29 (s, 12H);
13C-NMR (CDCl3) δ ppm 167.4 (d, J = 250.5 Hz), 147.2, 136.9, 136.8, 121.5, 113.3, 113.1, 83.9, 64.2,
30.3, 24.8; 11B-NMR (CDCl3) δ ppm 29.9.
[2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (2g). Following the
General Procedure A, the desired compound was synthesized utilizing 3-formylbenzenboronic acid (1g,
213 mg, 1.30 mmol), pinacol (184 mg, 1.56 mmol), anhydrous magnesium sulfate (313 mg,
2.60 mmol), sodium borohydride (25 mg, 0.65 mmol), and methanol (6.50 mL) giving compound 2g
1
as a white solid (m.p. 60–63 °C) in 97% yield (312 mg); H-NMR (CD3OD-d4) δ ppm 7.74 (s, 1H),
7.55 (d, J = 7.4 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 4.62 (s, 2H), 2.36 (s, 3H), 1.34 (s, 12H); 13C-NMR
(CD3OD-d4) δ ppm 141.1, 139.8, 135.4, 135.1, 130.8, 85.1, 63.5, 25.3, 25.2, 19.1; 11B-NMR (CDCl3) δ
ppm 30.9.
3.3. General Procedure B for the Synthesis of Boron-Containing Primary Phthalimides 3a–g

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2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3a). Compound 2a
(585 mg, 2.50 mmol), and dichloromethane (25.00 mL) were added to a dry flask containing a
magnetic stir bar under a nitrogen atmosphere. The flask was cooled to 0 °C, then methanesulfonyl
chloroide (0.29 mL, 3.75 mmol) and N,N-diisopropylethylamine (DIPEA, 0.87 mL, 5.00 mmol) were
slowly added to the flask. The reaction mixture was stirred at 0 °C for 3 h. After the reaction was
completed, the reaction mixture was diluted with dichloromethane (25.00 mL) before H2O (25.00 mL)
was added. The organic layer was then washed with brine and dried with MgSO4. The resulting
organic layer was then filtered and the filtrate was concentrated in vacuo. The resulting crude material
was re-dissolved in DMF (4.68 mL) after which both potassium phthalimide salt (695 mg, 3.75 mmol),
and K2CO3 (1,036 mg, 7.50 mmol) were added to the solution. The reaction was then allowed to stir at
room temperature for 3 days. After the reaction was completed, the distilled H2O (20.00 mL) was
slowly added to the reaction mixture to afford the formation of a solid precipitate. The reaction mixture
was then filtered and the filtered cake was collected. The filtered cake was re-dissolved in tert-
butanol/H2O (4:1, v/v) (10.00 mL) before a freeze-drying process was applied to remove the remaining
DMF. The desired product 3a was obtained as a white solid (m.p. 166–169 °C) in 96% yield (872 mg);
1H-NMR (CDCl3) δ ppm 7.84–7.82 (m, 2 H), 7.74 (d, J = 7.85 Hz, 2 H), 7.71–7.68 (m, 2H), 7.42 (d,
J = 7.85 Hz, 2H), 4.85 (s, 2H), 1.34 (s, 12H); 13C-NMR (CDCl3) δ ppm 167.90, 139.26, 135.12,
133.93, 132.04, 127.76, 123.29, 83.73, 41.60, 24.77; 11B-NMR (CDCl3) δ ppm 30.94.
2-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3b). Following the
General Procedure B, the desired compound was synthesized utilizing 2b (767 mg, 3.28 mmol),
methanesulfonyl chloride (0.38 mL, 4.92 mmol), DIPEA (1.14 mL, 6.56 mmol), potassium
phthalimide salt (911 mg, 4.92 mmol), and potassium carbonate (1,360 mg, 9.84 mmol) giving
1
compound 3b as a white solid (m.p. 170–173 °C) in 80% yield (953 mg); H-NMR (CDCl3) δ ppm
7.76–7.83 (m, 3H), 7.72–7.68 (m, 3H), 7.51 (d, J = 7.70 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 4.85 (s, 2H),
1.33 (s, 12H); 13C-NMR (CDCl3) δ ppm 135.60, 134.78, 134.25, 133.91, 132.13, 131.36, 128.05,
123.31, 83.82, 41.59, 24.84; 11B-NMR (CDCl3) δ ppm 30.88.
2-[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3c). Following
the General Procedure B, the desired compound was synthesized utilizing 2c (378 mg, 1.50 mmol),
methanesulfonyl chloroide (0.17 mL, 2.25 mmol), DIPEA (0.52 mL, 3.00 mmol), potassium phthalimide
salt (417 mg, 2.25 mmol), and potassium carbonate (622 mg, 4.5 mmol) giving compound 3c as a
1
white solid (m.p. 55–58 °C) in 75% yield (429 mg); H-NMR (CDCl3) δ ppm 7.84–7.78 (m, 3H),
7.78–7.67 (m, 2H), 7.52–7.7.47 (m, 1H), 6.95 (t, J = 8.8 Hz, 1H), 4.80 (s, 2H), 1.34 (s, 12H);

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13C-NMR (CDCl3) δ ppm 167.93, 137.12, 137.07, 133.96, 133.73, 133,67, 132.03, 131.63, 123.47,
123.32, 115.61, 115.45, 83.95, 40.80, 24.75; 11B-NMR (CDCl3) δ ppm 30.19.
2-[4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3d). Following
the General Procedure B, the desired compound was synthesized utilizing 2d (348 mg, 1.30 mmol),
methanesulfonyl chloroide (0.15 mL, 1.95 mmol), DIPEA (0.45 mL, 2.60 mmol), potassium phthalimide
salt (360 mg, 1.95 mmol), and potassium carbonate (539 mg, 3.90 mmol). Compound 3d was obtained
1
as a white solid (m.p. 102–104 °C) in 85% yield (439 mg); H-NMR (CDCl3) δ ppm 7.78–7.74
(m, 2H), 7.71 (d, J = 2.0 Hz, 1H), 7.66–7.62 (m, 2H), 7.35 (q, J1 = 6.1 Hz, J2 = 2.1 Hz, 1H), 7.23 (d,
J = 8.3 Hz, 1H), 4.75 (s, 2H), 1.32 (s, 12H); 13C-NMR (CDCl3) δ ppm 167.8, 139.0, 136.5, 134.1,
134.0, 132.1, 131.9, 129.6, 123.3, 84.2, 40.9, 24.8; 11B-NMR (CDCl3) δ ppm 30.6.
2-[2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3e). Following
the General Procedure B, the desired compound was synthesized utilizing 2e (272 mg, 1.08 mmol),
methanesulfonyl chloroide (0.13 mL, 1.62 mmol), DIPEA (0.38 mL, 2.16 mmol), potassium
phthalimide salt(300 mg, 1.62 mmol), and potassium carbonate (447 mg, 3.24 mmol) giving 3e as a
1
white solid (m.p. 139–142 °C) in 53% yield (218 mg); H-NMR (CDCl3) δ ppm 7.85–7.79 (m, 3H),
7.73–768 (m, 3H), 7.02 (q, J1 = 1.8 Hz, J2 = 8.2 Hz, 1H), 4.91 (s, 2H), 1.32 (s, 12H); 13C-NMR
(CDCl3) δ ppm 167.8, 163.0 (d, J = 252.0 Hz), 137.2, 136.7, 136.6, 133.9, 132.1, 123.4, 122.5, 122.4,
115.1, 114.9, 83.9, 35.6, 35.5, 24.8; 11B-NMR (CDCl3) δ ppm 30.6.
2-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3f). Following
the General Procedure B, the desired compound was synthesized utilizing 2f (293 mg, 1.16 mmol),
methanesulfonyl chloroide (0.14 mL, 1.74 mmol), DIPEA (0.39 mL, 2.32 mmol), potassium phthalimide
salt (322 mg, 1.74 mmol), and potassium carbonate (480 mg, 3.48 mmol) giving compound 3f as a
1
white solid (m.p. 101–103 °C) in 97% yield (429 mg); H-NMR (CDCl3) δ ppm 7.85–7.81 (m, 2H),
7.73–7.66 (m, 3H), 7.17 (d, J = 7.7 Hz, 1H), 7.06 (d, J = 9.9 Hz, 1H), 4.82 (s, 2H), 1.32 (s, 12H);
13C-NMR (CDCl3) δ ppm 167.7, 167.2 (d, J = 252.0 Hz), 142.0, 141.9, 137.2, 137.2, 134.1, 131.9,
123.5, 123.4, 115.2, 114.9, 83.8, 40.9, 24.7; 11B-NMR (CDCl3) δ ppm 30.06.

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2-[2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]isoindoline-1,3-dione (3g). Following
the General Procedure B, the desired compound was synthesized utilizing 2g (598 mg, 2.41 mmol),
methanesulfonyl chloroide (0.28 mL, 3.62 mmol), DIPEA (0.83 mL, 4.83 mmol), potassium phthalimide
salt (670 mg, 3.62 mmol), and potassium carbonate (1,000 mg, 7.24 mmol) giving compound 3g as a
1
white solid (m.p. 168–171 °C) in 48% yield (438 mg); H-NMR (CDCl3) δ ppm 7.81–7.76 (m, 3H),
7.68–7.61 (m, 3H), 7.16 (d, J = 7.4 Hz, 1H), 4.86 (s, 2H), 2.49 (s, 3H), 1.29 (s, 12H); 13C-NMR
(CDCl3) δ ppm 167.8, 139.5, 134.9, 134.2, 133.7, 133.4, 131.8, 129.7, 126.5, 122.9, 83.4, 39.1, 24.6,
19.6; 11B-NMR (CDCl3) δ ppm 31.1.
3.4. General Procedure C for the Synthesis of Boron-Containing Primary Amines 4a–g
[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (4a). Compound 3a (196 mg,
0.54 mmol) was added to a dry flask containing magnetic stir and dissolved in THF (5.50 mL).
Afterwards, hydrazine hydrate (0.08 mL, 1.62 mmol) was added to the reaction mixture. The reaction
was stirred under a reflux for 12 h. The resulting dried crude material was then re-suspended with
chloroform (50.00 mL), filtered, and the filtrate was concentrated in vacuo. The crude material was
purified by High Performance Liquid Chromatography (HPLC) to give the desired product 4a as a
1
white solid (m.p. 85 °C) in 87% yield (111 mg); H-NMR (CDCl3) δ ppm 7.78 (d, J = 7.9 Hz, 2H),
7.32 (d, J = 8.0 Hz, 2H), 3.88 (s, 2H), 1.34 (s, 12H); 13C-NMR (CDCl3) δ ppm 136.72, 135.56, 127.18,
11
84.11, 43.94, 25.02; B-NMR (CD3OD-d4) δ ppm 30.90; HRMS (ESI, positive ion) (m/z): [M+H]+
calcd for C13H20BNO2, 234.1669; found, 234.1651.
[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (4b). Following the General
Procedure C, the desired compound was synthesized utilizing 3b (250 mg, 0.69 mmol), THF (7.00 mL),
and hydrazine hydrate (0.10 mL, 2.07 mmol) giving compound 4b as a white solid (m.p. 91 °C) in
1
82% yield (131 mg); H-NMR (CDCl3) δ ppm 7.74–7.68 (m, 2H), 7.42–7.32 (m, 2H), 3.86 (s, 2H),
13
1.34 (s, 12H); C-NMR (CDCl3) δ ppm 142.78, 133.58, 133.48, 130.30, 128.23, 84.03, 46.69, 25.07;
11B-NMR (CD3OD-d4) δ ppm 30.94; HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for C13H20BNO2,
234.1669; found, 234.1644.

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[4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (4c). Following the
General Procedure C, the desired compound was synthesized utilizing 3c (953 mg, 2.50 mmol), THF
(25.00 mL), and hydrazine hydrate(0.36 mL, 7.50 mmol) giving compound 4c as a white solid (m.p.
62 °C) with 98% yield (616 mg); 1H-NMR (CDCl3) δ ppm 7.66–7.63 (m, 1H), 7.40–7.34 (m, 1H), 6.99
13
(t, J = 5.9 Hz, 1H), 3.83 (s, 2H), 1.34 (s, 12H); C-NMR (CDCl3) δ ppm 166.44 (d, J = 249.9 Hz),
138.64, 135.58, 135.47, 132.37, 132.25, 116.48, 116.31, 84.13, 45.92, 25.03; 11B-NMR (CD3OD-d4) δ
ppm 30.12; HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for C13H19BFNO2, 252.1574; found,
252.1548.
[4-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (4d). Following the
General Procedure C, the desired compound was synthesized utilizing 3d (524 mg, 1.32 mmol), THF
(13.00 mL), and hydrazine hydrate (0.20 mL, 3.96 mmol) giving compound 4d as a white solid (m.p. 56
1
°C) in 36% yield (128 mg); H-NMR (CDCl3) δ ppm 7.59 (s, 1H), 7.31–7.26 (m, 2H), 4.19 (s, 2H),
13
1.27 (s, 12H); C-NMR (CDCl3) δ ppm 135.26, 134.97, 131.96, 130.91, 130.59, 84.37, 45.76, 24.95;
11B-NMR (CD3OD-d4) δ ppm 30.45; HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for
C13H19BClNO2, 268.1279; found, 268.1153.
[2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (4e). Following the
General Procedure C, the desired compound was synthesized utilizing 3e (679 mg, 1.78 mmol), THF
(18.00 mL), and hydrazine hydrate (0.26 mL, 5.34 mmol) giving compound 4e as a white solid (m.p. 78
1
°C) in 91% yield (405 mg); H-NMR (CDCl3) δ ppm 7.76–7.66 (m, 2H), 7.02 (t, 1H), 3.91 (s, 2H),
13
1.33 (s, 12H); C-NMR (CDCl3) δ ppm 163.27 (d, J = 126.8 Hz), 138.35, 136.29, 136.24, 124.02,
123.93, 83.96, 36.59, 24.88; 11B-NMR (CD3OD-d4) δ ppm 30.05; HRMS (ESI, positive ion) (m/z):
[M+H]+ calcd for C13H19BFNO2, 252.1574; found, 252.1549.
[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (4f). Following the
General Procedure C, the desired compound was synthesized utilizing 3f (907 mg, 2.38 mmol), THF
(24.00 mL), and hydrazine hydrate (0.34 mL, 7.15 mmol) giving compound 4f as a white solid (m.p.
52 °C) in 66% yield (396 mg); 1H-NMR (CDCl3) δ ppm 7.70 (t, J = 6.5 Hz, 1H), 7.10 (d, J = 7.8 Hz,
1H), 7.04 (d, J = 9.7 Hz, 1H), 3.93 (s, 2H), 1.30 (s, 12H); 13C-NMR (CDCl3) δ ppm 167.24 (d,
J = 252.2 Hz), 137.98, 137.87, 124.21, 116.05, 115.72, 84.37, 43.20, 25.02, 24.93; 11B-NMR (CDCl3-d3) δ

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ppm 30.16; HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for C13H19BFNO2, 252.1574;
found, 252.1549.
[2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (4g). Following the
General Procedure C, the desired compound was synthesized utilizing 3g (690 mg, 1.83 mmol), THF
(18.00 mL), and hydrazine hydrate (0.26 mL, 5.49 mmol) giving compound 4g as a white solid (m.p.
1
59 °C) in 58% yield (262 mg); H-NMR (CDCl3) δ ppm 7.62–7.60 (m, 2H), 7.17 (d, J = 6.7 Hz, 1H),
13
3.75 (s, 2H), 2.38 (s, 3 H), 1.34 (s, 12H); C-NMR (CDCl3) δ ppm 140.44, 136.90, 134.49, 134.32,
11
130.10, 83.71, 42.04, 24.91, 19.68; B-NMR (CDCl3) δ ppm 31.01; HRMS (ESI, positive ion) (m/z):
[M+H]+ calcd for C14H22BNO2, 248.1489; found, 248.9602.
3.5. General Procedure D for the Synthesis of Ugi-4CR Boronate esters 5a–c
O
H
N
N
O
Bpin
N-Cyclohexyl-2-phenyl-2-{N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl] acetamido}acetamide
(5a). A 10 mL glass tube containing 4a (396 mg, 1.70 mmol), benzylaldehyde (0.17 mL, 1.70 mmol)
and MeOH (3.40 mL) was first microwave irradiated for 120 min (50 °C, 150 W) under medium speed
magnetic stirring. Acetic acid (0.12 mL, 2.04 mmol) and cyclohexyl isocyanide (0.21 mL, 1.70 mmol)
were then added to the reaction mixture. Additional microwave irradiation was applied for 120 min
(50 °C, 150 W) under moderate magnetic stirring. After the reaction was completed, MeOH was
removed in vacuo. The crude material was re-dissolved in ethyl acetate and the resulting organic
solution was washed with 1 M aqueous HCl solution. This was followed by adding a saturated aqueous
solution of K2CO3 combined with brine. The resulting organic layer was collected, dried by MgSO4,
and then concentrated in vacuo. Afterwards, the crude material was purified by flash column
chromatography on silica gel using n-hexane/ethyl acetate = 1:1 as the eluent to afford the desired
1
product 5a as a white solid (m.p. 100 °C) in 69% yield (575 mg); H-NMR (CDCl3) δ ppm 7.59 (d,
J = 7.7 Hz, 2H), 7.44–7.18 (m, 5H), 7.10–6.90 (m, 2H), 6.08 (s, 0.55H), 5.79 (b, 0.45H), 4.66 (q,
13
J1 = 41.9, J2 = 18.1, 2H), 3.77 (br, 1H), 2.00–1.03 (m, 22H); C-NMR (CDCl3) δ ppm 172.9, 168.8,
141.1, 135.4, 135.0, 129.8, 128.9, 128.7, 128.6, 127.5, 125.5, 83.9, 62.3, 50.8, 48.7, 32.9, 26.1, 25.6,
11
25.0, 24.9, 24.9, 22.6; B-NMR (CD3OD-d4) δ ppm 31.2; HRMS (ESI, positive ion) (m/z): [M+H]+
calcd for C29H39BN2O4, 491.3079; found, 491.3067.

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N-Cyclohexyl-2-phenyl-2-{N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]acetamido}acetamide
(5b). Following the General Procedure D, the desired compound was synthesized utilizing 4b (394 mg,
1.69 mmol), benzylaldehyde (0.17 mL, 1.69 mmol), cyclohexyl isocyanide (0.21 mL, 1.69 mmol),
acetic acid (0.12 mL, 2.03 mmol), and MeOH (3.40 mL) giving compound 5b as a white solid (m.p. 91
1
°C) in 52% yield (430 mg); H-NMR (Bruker AC-600 FT-NMR spectrometer at 600 MHz, CDCl3) δ
ppm 7.57 (d, J = 7.2 Hz, 1H), 7.33–7.09 (m, 8 H), 5.92 (s, 1H), 5.67 (br, 0.45H), 4.65 (q, J1 = 46.5,
13
J2 = 17.4, 2H), 3.75 (br, 1H), 2.10 (s, 3H), 1.64–1.05 (m, 22H); C-NMR (Bruker AC-600 FT-NMR
spectrometer at 150.9 MHz, CDCl3) δ ppm 22.3, 24.8, 25.2, 32.6, 48.7, 50.9, 63.0, 83.8, 127.8, 128.7,
128.9, 129.0, 129.5, 132.4, 133.4, 134.8, 136.3, 168.7, 173.3; 11B-NMR (CD3OD-d4) δ ppm 31.08;
HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for C29H39BN2O4, 491.3079; found, 491.3057.
N-Cyclohexyl-2-{N-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]acetamido}-2-
phenylacetamide (5c). Following the General Procedure D, the desired compound was synthesized
utilizing 4c (733 mg, 2.92 mmol), benzylaldehyde (0.30 mL, 2.92 mmol), cyclohexyl isocyanide (0.36 mL,
2.92 mmol), acetic acid (0.20 mL, 3.50 mmol), and MeOH (4.00 mL) giving 5c a white solid (m.p.
1
110 °C) in 74% yield (1,100 mg); H-NMR (CDCl3) δ ppm 7.32–7.06 (m, 7H), 6.81(br, 1H), 6.00 (s,
0.50H), 5.66 (br, 0.50H), 4.62 (q, J1 = 44.0, J2 = 17.3, 2H), 3.76 (m, 1H), 2.06 (s, 3H), 1.85–1.06 (m,
22H); 13C-NMR (CDCl3) δ ppm 172.62, 168.62, 166.97, 165.31, 135.11, 134.32, 134.28, 132.68,
130.92, 130.87, 129.73, 128.76, 128.55, 115.15, 83.91, 62.39, 49.99, 48.61, 31.91, 29.34, 24.82, 24.58,
22.47; 11B-NMR (CDCl3) δ ppm 29.94; HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for
C30H40BFN2O4, 509.2985; found, 509.3139.
O
H
N
N
O
Bpin
N-Cyclohexyl-2-phenyl-2-{N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]
acetamido}
propionamide (5d). Following the General Procedure D, the desired compound was synthesized

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utilizing 4a (487 mg, 2.09 mmol), benzylaldehyde (0.21 mL, 2.09 mmol), cyclohexyl isocyanide
(0.26 mL, 2.09 mmol), propionic acid (0.19 mL, 2.50 mmol), and MeOH (4.00 mL) giving 5d as a
1
white solid (m.p. 102 °C) in 44% yield (464 mg); H-NMR (CDCl3) δ ppm 7.59 (d, J = 7.3 Hz, 2H),
7.34–7.23 (m, 5H), 6.93 (d, J = 7.2, 2H), 6.09 (s, 0.48H), 5.66 (b, 0.52H), 4.66 (q, J1 = 46.4,
J2 = 18.1, 2H), 3.78 (br, 1H), 2.37–1.04 (m, 27H); 13C-NMR (CDCl3) δ ppm 175.9, 168.8, 141.1,
135.2, 134.7, 129.7, 128.7, 128.5, 125.2, 83.7, 62.4, 49.9, 48.5, 32.7, 26.2, 25.4, 24.8, 24.7, 9.2;
11B-NMR (CDCl3) δ ppm 30.6; HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for C30H41BN2O4,
505.3157; found, 505.3219.
3.6. General Procedure E for the Synthesis of Ugi-4CR Boronic Acid Derivatives 6a–c
[4-({N-[2-(Cyclohexylamino)-2-oxo-1-phenylethyl]acetamido}methyl)phenyl]boronic
acid
(6a).
Compound 5a (917 mg, 1.87 mmol) and KHF2 (876 mg, 11.22 mmol) were added to a flask containing
magnetic stir, which was then suspended in MeOH/H2O (1:1, v/v, 9.35 mL). The reaction mixture was
stirred vigorously at room temperature for 6 hours, and the solvents were removed in vacuo. The
resulting mixture of solids were dried under a dry-freezing vacuum overnight and then subjected to
extraction with hot acetone (100.00 mL). The resulting acetone extracts were concentrated in vacuo.
SiO2 (123 mg, 2.05 mmol) was added to this crude material which was re-suspended in H2O/ethyl
acetate (1:1, v/v) (5.5 mL). The reaction was stirred at room temperature until 11B-NMR indicated
completion of the reaction (5 h). The reaction mixture was filtered to remove SiO2, and the filter cake
was thoroughly rinsed with ethyl acetate. The aqueous layer was separated from the organic layer, and
the aqueous layer was extracted with ethyl acetate (2 × 15 mL). The organic layer was collected and
dried with MgSO4. This organic solution was then filtered, and concentrated in vacuo to afford the
desired pure product 6a as a white solid (m.p. 177 °C) in 49% yield (374 mg); 1H-NMR (CD3OD-d4) δ
ppm 7.56–7.20 (m, 6H), 6.94–6.89 (m, 3H), 6.09 (s, 0.81H), 5.67 (br, 0.23H), 4.64 (q, J1 = 88.5,
13
J2 = 19.4, 2H), 3.69–3.54 (br, 1H), 2.08 (s., 3H), 1.96–1.06 (m, 10H); C-NMR (CD3OD-d4) δ ppm
175.4, 171.6, 136.4, 135.1, 134.7, 131.2, 130.2, 129.8, 129.7, 127.6, 126.3, 63.9, 51.3, 50.2, 33.6, 33.6,
11
26.7, 26.2, 26.2, 22.7; B-NMR (CD3OD-d4) δ ppm 28.09; HRMS (ESI, positive ion) (m/z): [M+H]+
calcd for C23H29BN2O4, 409.2297; found, 409.2310.

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[3-({N-[2-(Cyclohexylamino)-2-oxo-1-phenylethyl]acetamido}methyl)phenyl]boronic
acid
(6b).
Following the General Procedure E, the desired compound was synthesized utilizing 5b (431 mg,
0.88 mmol), KHF2 (412 mg, 5.28 mmol), SiO2 (58 mg, 0.96 mmol), and MeOH/H2O (1:1, v/v, 4.5 mL)
1
giving 6b as a white solid (m.p. 150 °C) in 60% yield (215 mg); H-NMR (CD3OD-d4) δ ppm
7.51–6.98 (m, 9H), 6.10 (s, 0.81H), 5.66 (br, 0.19H), 4.69 (q, J1 = 70.7, J2 = 18.1, 2H), 3.66 (br, 1H),
2.09 (s, 3H), 1.82–1.03 (m, 10H); 13C-NMR (CD3OD-d4) δ ppm 175.25, 171.43, 170.26, 138.30,
138.05, 136.65, 136.35, 133.93, 133.37, 133.08, 132.87, 132.46, 131.90, 131.01, 130.36, 130.08,
129.95, 129.65, 129.48, 128.85, 128.61, 128.46, 128.31, 66.41, 63.76, 51.21, 50.11, 33.46, 26.60,
11
26.09, 26.04, 22.56; B-NMR (CD3OD-d4) δ ppm 28.58; HRMS (ESI, positive ion) (m/z): [M+H]+
calcd for C23H29BN2O4, 409.2318; found, 409.2297.
[5-({N-[2-(Cyclohexylamino)-2-oxo-1-phenylethyl]acetamido}methyl)-2-fluorophenyl]boronic Acid
(6c). Following the General Procedure E, the desired compound was synthesized utilizing 5c (46 mg,
0.09 mmol), KHF2 (42 mg; 0.54 mmol), SiO2 (6 mg; 0.10 mmol), and MeOH/H2O (1:1, v/v, 2.0 mL)
1
giving compound 6c as a white solid (m.p. 61 °C) with 10% yield (4 mg); H-NMR (Bruker AC-600
FT-NMR spectrometer at 600 MHz, CD3OD-d4) δ ppm 7.27–7.20 (m, 5H), 6.97–6.82 (m, 3H), 6.10 (s,
0.72H), 5.66 (br, 0.28H), 4.65 (q, J1 = 127.8, J2 = 17.4, 2H), 3.65 (br, 1H), 2.19 (s, 0.89H), 2.08 (s,
2.11H), 1.85–1.59 (m, 5H), 1.34–1.14 (m, 5H); 13C-NMR (CD3OD-d4) δ ppm 175.21, 174.62, 171.36,
170.35, 136.51, 136.34, 135.62, 134.81, 134.08, 132.57, 131.10, 129.68, 115.57, 115.41, 114.83,
66.27, 63.48, 50.51, 50.02, 33.51, 33.46, 26.60, 26.10, 26.05, 22.49; 11B-NMR (CD3OD-d4) δ ppm
28.46; HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for C23H28BFN2O4, 427.2202; found, 427.2204
3.7. General Procedure F for the Synthesis 8a–b
2-[N-([1,1'-Biphenyl]-3-ylmethyl)acetamido]-N-cyclohexyl-2-phenylacetamid (8a). Compound 5b
(284 mg, 0.58 mmol), bromobenzene (0.08 mL, 0.75 mmol), and Pd(PPh3)2Cl2 (40 mg, 0.06 mmol)
were added to a flask containing a magnetic stir with EtOH (5.80 mL). Triethylamine (0.18 mL,
1.28 mmol) was then added to the reaction mixture and the reaction mixture was stirred under reflux
condition for 10 h under a N2 atmosphere. After cooling the mixture to room temperature, solvent was
removed in vacuo. The crude material was diluted with ethyl acetate (5.00 mL) and water (5.00 mL).
The aqueous layer was separated from the organic layer, and the aqueous layer was extracted with ethyl

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acetate (2 × 15 mL). Organic layers were then combined, washed with brine solution, and dried with
MgSO4, and solvent was removed in vacuo. The crude material was then purified by flash column
chromatography on silica gel using n-hexane/ethyl acetate = 1:1 as the eluent to give the desired
1
product 8a as a white solid (m.p. 180 °C) in 57% yield (146 mg); white solid; H-NMR (Bruker
AC-600 FT-NMR spectrometer at 600 MHz, CD3OD-d4) δ ppm 7.47–7.19 (m, 12H), 7.07 (s, 1H), 6.96
(d, J = 7.8 Hz, 1H), 6.15 (s, 0.77H), 5.68 (br, 0.23H), 4.75 (q, J1 = 115.8, J2 = 18.0, 2H), 3.65 (m, 1H),
13
2.11 (s, 3H), 1.82–1.08 (m, 10H); C-NMR (Bruker AC-600 FT-NMR spectrometer at 150.9 MHz,
CD3OD-d4) δ ppm 175.41, 171.51, 142.75, 142.33, 140.03, 136.65, 131.20, 130.26, 130.00, 129.93,
129.72, 128.56, 128.15, 126.67, 126.21, 125.77, 63.73, 51.35, 50.19, 33.63. 26.75, 26.25, 26.20, 22.72;
HRMS (ESI, positive ion) (m/z): [M+H]+ calcd for C29H32N2O2, 441.2543; found, 441.2542.
N-[2-(Cyclohexylamino)-2-oxo-1-phenylethyl]-N-[4-(6-methoxypyrimidin-4-yl)benzyl]propionamide
(8b). Following the General Procedure F, the desired compound was synthesized, utilizing N-[2-
(cyclohexylamino)-2-oxo-1-phenylethyl]-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-
propionamide (5d, 236 mg, 0.52 mmol), 4-chloro-6-methoxypyrimidine (105.24 mg, 0.728 mmol),
Pd(PPh3)2Cl2 (15 mg, 0.06 mmol), and triethylamine (0.17 mL, 1.23 mmol) giving compound 8b as a
1
white solid (m.p. 174 °C) in 82% yield (223 mg); H-NMR (CDCl3) δ ppm 8.76 (s, 1 H), 7.78 (d,
J = 8.2 Hz, 1H), 7.32–6.66 (m, 9H), 6.11 (s, 0.42H), 5.93 (b, 0.58H), 4.68 (q, J1 = 51.4, J2 = 18.2, 2H),
3.97 (s, 3H), 3.77 (m, 1H), 2.40–2.13 (m, 2H), 1.84–1.02 (m, 13H); 13C-NMR (CDCl3) δ ppm 176.29,
175.82, 169.97, 164.83, 158.44, 141.87, 135.43, 129.84, 128.87, 128.79, 128.71, 127.10, 126.57,
117.01, 103.40, 62.73, 54.01, 49.91, 48.76, 32.85, 27.41, 25.56, 24.91, 24.83, 9.46; HRMS (ESI,
positive ion) (m/z): [M+H]+ calcd for C29H34N4O3, 487.2710; found, 487.2702.
4. Conclusions
In summary, seven boron-containing primary amines were successfully synthesized from the
corresponding formylphenyl boronate esters. Further, the synthesized amines were incorporated into
the peptoid-like backbone in moderate to good yields via an Ugi-4CR reaction under microwave-
assisted conditions. The boronate ester group of the peptoid-like analogs was successfully transformed
to provide the corresponding boronic acids using a simple two-step protocol. In addition, the structure
of the peptoid-like boronate esters was further modified by coupling to aryl/heteroaryl chlorides via
palladium-mediated Suzuki cross-coupling reactions. These results suggest that boron-containing
primary amines could be a unique building block for use in the progression of the field of peptoid research.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/18/10/12346/s1.

Molecules 2013, 18
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Acknowledgments
This research was supported by the National Science Council in Taiwan (NSC-99-2113-032-002-
MY2, NSC-101-2113-M-032-001-MY2). We thank Department of Chemistry of Tamkang University
for the equipment and financial support. We thank Shen-Shen Chen for conducting 11B-NMR
experiments, and we thank Instrumentation Center of National Taiwan University for conducting
HRMS experiments.
Conflicts of Interest
The authors declare no conflict of interest.
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