Efficient preparation of α-aminoboronic acid derivatives via boroalkyl group migration

Article abstract of DOI:10.1055/s-0033-1340502

A reaction demonstrating migration of boron-substituted carbon is presented. It is shown that α-boroalkyl groups of transient boroalkyl acyl azide intermediates migrate readily from carbon to nitrogen. This transformation allows access to a novel class of stable molecules, α-boryl isocyanates, from easily preparable α-borylcarboxylic acid precursors. The protocol enables the synthesis of a diverse range of α-aminoboronic acid derivatives, including α,α-disubstituted analogues.

Full text of DOI:10.1055/s-0033-1340502

PRACTICAL SYNTHETIC PROCEDURES
▌445
pErafctficiacliseynnthtetiPc prroecepduarersation of α-Aminoboronic Acid Derivatives via Boroalkyl
Group Migration
Building Blocks for the Synthesis of Aminoboronic Acid Derivatives
Adam Zajdlik, Zhi He,1 Jeffrey D. St. Denis, Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George St.,
Toronto, Ontario, M5S 3H6, Canada
Fax +1(416)9467676; E-mail: ayudin@chem.utoronto.ca
PSP
Received: 05.11.2013; Accepted after revision: 09.12.2013
No266
Abstract: A reaction demonstrating migration of boron-substituted carbon is presented. It is shown that α-boroalkyl groups of transient
boroalkyl acyl azide intermediates migrate readily from carbon to nitrogen. This transformation allows access to a novel class of stable mol-
ecules, α-boryl isocyanates, from easily preparable α-borylcarboxylic acid precursors. The protocol enables the synthesis of a diverse range
of α-aminoboronic acid derivatives, including α,α-disubstituted analogues.
Key words: boron, isocyanates, Curtius rearrangement, boroalkyl shift
O
O
MeN
O
HNR2R3 (1.5 equiv)
THF, 23 °C
O
O
B
R2
R1
N
N
R3
up to 95% yield
procedure 1B
H
O
O
87% yield for
O
O
DPPA (1.1 equiv)
Et3N (1.1 equiv)
MeCN, 50 °C, 1 h
R
1 = PhCH2CH2 and
R
2R3NH = t-BuNH2
MeN
MeN
O
O
O
O
B
B
R1
COOH
R1
NCO
up to 91% yield
procedure 1A
O
O
R4OH (3.0 equiv)
CuCl (1.0 equiv)
DMF, 23 °C
91% yield for
1 = PhCH2CH2
MeN
O
O
R
O
B
R1
N
OR4
up to 90% yield
procedure 1C
R1 = Ph, 4-MeC6H4, 4-FC6H4, Cy, i-Bu, n-Bu, Bn, (CH2)2Ph
H
R
R
2 or R3 = H, Et, i-Pr, t-Bu, Ph
90% yield for
1 = PhCH2CH2 and
R4OH = PhCH2OH
4 = (CH2)2TMS, (fluorenyl)methyl, t-Bu, CH2CH=CH2, Bn
R
DPPA = diphenylphosphoryl azide
Scheme 1 Preparation and application of α-boryl isocyanates in the synthesis of α-aminoboronic acid derivatives
with Lewis basic species including those at an enzyme’s
active site. While desirable in biological settings, the
Introduction
Organoboronic acids have found widespread application Lewis acidity of organoboron compounds complicates
both as synthetic building blocks2 and as biologically ac- their synthesis by limiting the reaction conditions under
tive targets of chemical synthesis.3 A subset of these com- which they are stable. Thus, late-stage boron installation
pounds containing a gem-aminoboronic acid motif have is common during synthesis but chemoselectivity issues
been recognized for their utility as both probes3e,4 and in- still impose restrictions on compatible functional groups.2
hibitors of enzyme function.3g The utility of these mole-
Our group’s approach to the preparation of organoboronic
cules is exemplified by the recent FDA-approval of
acid derivatives involves installation of boron at an early
bortezomib, a boropeptide currently used as a front-line
stage of the synthesis, followed by manipulation of adja-
therapeutic in the treatment of multiple myeloma.5 The bi-
cent functionalities and transposition of the boron frag-
ological activity of boron-containing peptide derivatives
ment. This has allowed access to novel amphoteric
results from boron’s tendency to undergo interactions
building blocks containing a nucleophilic C–B bond di-
rectly adjacent to various electrophilic groups.6 Among
these compounds are the α-boryl aldehydes.6a These re-
SYNTHESIS 2014, 46, 0445–0454
Advanced online publication: 21.01.2014
agents contain a C–B bond directly adjacent to an alde-
hyde, which can be functionalized leaving the boronate
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340502; Art ID: SS-2013-Z0731-PSP
© Georg Thieme Verlag Stuttgart · New York

446
A. Zajdlik et al.
PRACTICAL SYNTHETIC PROCEDURES
moiety intact for access to a variety of α-borylated func-
tionalities. In this report, we highlight the synthesis of sta-
ble, isolable α-boryl isocyanates via 1,2-migration of a
boroalkyl fragment to establish the gem-aminoboron mo-
tif (Scheme 1). These unique boron building blocks are
useful precursors to aminoboronic acids and their deriva-
tives including boryl ureas, carbamates, isocyanides, and
peptides, and are readily available from commercially
available materials.
Table 1 Preparation of α-Boryl Isocyanates via Curtius Rearrange-
menta
O
O
O
O
C
MeN
MeN
O
O
DPPA, Et3N
O
O
B
B
MeCN, 50 °C
O
R
COOH
R
N
1
2
Entryb
1
1
R
Product
Yield (%)c
71
Scope and Limitations
1a
1b
2a
Recent commercial availability of α-boryl aldehydes has
fueled extensive investigations of their synthetic utility.
The aldehyde participates in a diverse range of function-
alizations including mild oxidative conversion to the
corresponding α-boryl carboxylic acids 1. These configu-
rationally stable molecules are easily converted to the cor-
responding isocyanates 2 under mild conditions (50 °C, 1
h) via Curtius rearrangement using a slight excess of both
diphenylphosphoryl azide (DPPA) and Et3N (Table 1).7
This protocol tolerates all commercially available boryl
aldehydes including a variety of aromatic and alkyl sub-
stituted compounds. The presence of the isocyanate func-
tional group is confirmed by IR (isocyanate stretch at
~2200 cm–1) and NMR (13C signal at ~120 ppm) spectros-
copy.
2
2b
57
3
4
1c
2c
62
91
F
1d
2d
Ph
Ph
5
6
1e
1f
2e
2f
84
86
7
1g
2g
71
The carbon-to-nitrogen migration of the boryl fragment
occurs with complete retention of stereochemistry for the
phenylethyl-substituted acid 3b as determined by an in-
vestigation of enantiomerically pure substrates prepared
using the chiral PIDA (pinene-derived iminodiacetic acid)
ligand (Scheme 2).6e However, the phenyl substrate 3a ex-
hibits slight erosion of stereochemistry, which we attri-
bute to the increased susceptibility of the α-proton to base
under the reaction conditions.
8
1h
2h
73
a Reactions were carried our using 1.0 equiv of α-boryl carboxylic
acid 1, 1.1 equiv of DPPA, and 1.1 equiv of Et3N in anhydrous MeCN
at 50 °C for 1 h.
b Carboxylic acids were prepared by oxidation of commercially avail-
able α-boryl aldehydes.
c Yield of isolated product after silica gel chromatography.
under the reaction conditions; however, identification of
the product by crude 1H NMR spectroscopy is made diffi-
cult by the lack of coupling partners for the α-proton.
O
O
O
O
N
N
O
O
O
O
DPPA, Et3N
B
O
O
B
O
MeCN, 50 °C
C
R
N
R
COOH
MeN
O
O
B(OH)2
NH4Cl
3a R = Ph (dr > 95:5)
3b R = CH2CH2Ph (dr > 95:5)
4a R = Ph (dr = 85:15)
4b R = CH2CH2Ph (dr > 95:5)
B
3.0 M HCl(aq)
O
C
Ph
MeCN, 23 °C
quantitative yield
Ph
N
Scheme 2 Stereochemical investigation of the Curtius rearrange-
ment. Diastereomeric ratios (dr) were determined by 1H NMR analy-
sis of the crude reaction mixtures.
5
2d
Scheme 3 Acidic hydrolysis of α-boryl isocyanates
Under acidic hydrolysis conditions, α-boryl isocyanate 2d
undergoes quantitative conversion into the corresponding
ammonium chloride salt (Scheme 3). Of note is the con-
comitant hydrolysis of the MIDA (methyliminodiacetic
acid) group to give the corresponding free boronic acid.
Boryl ammonium salt 5 is difficult to separate from the
free MIDA component and could not be applied in down-
stream transformations. Isocyanate 2a behaves similarly
Nucleophilic attack at the isocyanate carbon by either
amines or alcohol yields the corresponding ureas and car-
bamates, respectively. Amine addition to the isocyanate
occurs smoothly at room temperature in THF with com-
plete selectivity for the isocyanate carbonyl over the
MIDA ester (Table 2). A variety of amine nucleophiles
are tolerated including primary, secondary, aliphatic, and
aromatic. The use of aniline results in decreased yields
Synthesis 2014, 46, 445–454
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Building Blocks for the Synthesis of Aminoboronic Acid Derivatives
447
Table 2 Preparation of α-Boryl Ureasa
Table 3 Preparation of α-Boryl Carbamatesa
O
O
O
O
O
O
O
O
O
O
MeN
O
MeN
MeN
MeN
O
O
O
O
O
O
O
R2OH
HNR2R3
B
B
B
B
O
O
C
R3
C
THF, 23 °C
CuCl, DMF, 23 °C
R1
N
R1
N
H
N
R2
R1
N
R1
N
H
OR2
2
7
2
6
Entry R1
R2
Product
Yield
(%)b
Entry R1
R2
R3
Product
Yield
(%)b
O
O
O
O
MeN
B
O
MeN
O
O
O
B
O
1
Ph
75
1
Ph
H
Et
93
TMS
Teoc
Et
Ph
N
H
Ph
N
H
N
H
7a
6a
O
O
O
O
O
MeN
B
O
MeN
O
O
O
2
n-Bu
n-Bu
Ph
80
60
67
90
B
2
3
Ph
H
H
i-Pr
95
87
Fmoc
n-Bu
N
H
i-Pr
Ph
N
H
N
H
7b
6b
O
O
O
O
MeN
B
O
O
MeN
O
O
3c
B
O
Boc
PhCH2CH2
t-Bu
n-Bu
N
H
t-Bu
Ph
N
H
N
H
7c
6c
O
O
O
O
O
MeN
B
O
O
MeN
O
O
4
B
Alloc
Ph
N
H
4
PhCH2CH2 Et
Et
77
Et
Ph
N
H
N
7d
Et
O
O
6d
MeN
O
O
O
O
O
B
Ph
5
PhCH2CH2
MeN
O
Cbz
O
Ph
N
H
B
5
PhCH2CH2
H
Ph
30
Ph
Ph
N
H
N
H
7e
a Reactions were carried out using 1.0 equiv of α-boryl isocyanate, 3.0
equiv of alcohol, and 1.0 equiv of CuCl in anhydrous DMF at 23 °C
for 3 h.
6e
a Reactions were carried out using 1.0 equiv of α-boryl isocyanate and
1.5 equiv of amine in anhydrous THF at 23 °C for 1–12 h.
b Yield of isolated product after silica gel chromatography.
b Yield of isolated product after silica gel chromatography.
c Reaction was carried out using 10.0 equiv of t-BuOH at 70 °C for
24 h.
due to its decreased nucleophilicity relative to aliphatic
amines. Alcohol addition requires a more polar solvent
(DMF) and an equimolar amount of CuCl (Table 3).8 A
variety of alcohols are tolerated including those required
to prepare typical carbamate protecting groups for amines
[Teoc (trimethylsilylethoxycarbonyl), Fmoc (fluorenyl-
methyloxycarbonyl), Boc (tert-butyloxycarbonyl), Alloc
(allyloxycarbonyl), and Cbz (carboxybenzyl)]. Both aro-
matic 2a and aliphatic 2d, 2f side chains of the isocyanate
are tolerated. Quaternary centers adjacent to the isocya-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 445–454

448
A. Zajdlik et al.
PRACTICAL SYNTHETIC PROCEDURES
O
O
O
O
O
O
O
O
NaH2PO4
NaClO2
cyclohexene
OH
MeN
MeN
Ph
MeN
Ph
O
O
O
O
O
O
Pd(PPh3)4 (5.0 mol%)
B
B
B
t-BuOH–H2O
Et3N, Et3B
4 Å MS, THF
65%
Ph
COOH
11
12
B(OH)2
NH4Cl
6.0 M HCl
Ph
14
O
O
MeCN, 23 °C, 48 h
quantitative yield
MeN
Ph
O
O
DPPA, Et3N
B
O
O
MeCN, 50 °C, 2 h
70%
O
C
N
MeN
Ph
O
O
13
EtNH2
B
O
THF, 23 °C, 5 h
85%
Et
N
H
N
H
15
Scheme 4 Preparation of α-aminoboronic acid derivatives with a quaternary carbon center
nate are also amenable to this protocol as exemplified by In short, amphoteric α-boryl isocyanates have proven to
the allyl-substituted isocyanate 13 (Scheme 4).9 The free be useful tools in the streamlined preparation of various
boronic acid of boryl urea 6c can be obtained in high yield gem-aminoboronic acids and their derivatives. These
by treatment with 1.0 M aqueous NaOH (Scheme 5).
bench-stable building blocks are readily available in two
steps form commercially available materials via oxidation
and subsequent Curtius rearrangement. α-Boryl amines
and ammonium salts can be obtained in one step as well
as ureas and carbamates via nucleophilic attack. These
transformations occur readily under mild conditions to
yield stable, isolable products with potential downstream
functionalizations and biological applications.
O
O
MeN
Ph
O
O
HO
Ph
OH
B
B
O
O
1.0 M NaOH(aq)
t-Bu
t-Bu
N
N
THF, 23 °C
(90%)
N
H
N
H
H
H
Scheme 5 Preparation of unprotected α-boryl urea via alkaline hy-
drolysis of the MIDA group
Anhydrous CH2Cl2, MeCN, and CHCl3 were purchased and used as
received. Anhydrous THF was distilled from sodium benzophenone
ketyl under argon. All other solvents were of reagent grade quality.
Flash column chromatography was carried out using Silicycle 230–
400 mesh silica gel. TLC was performed on Macherey-Nagel pre-
coated glass backed TLC plates (SIL G/UV254, 0.25 mm) and vi-
sualized using a UV lamp (254 nm) or KMnO4 stain in case of no
UV activity. 1H NMR and 13C NMR spectra were recorded on Var-
Deprotection of the Cbz-protected amine of boryl carba-
mate 7d can be achieved via Pd(0) catalysis. The resulting
primary amine is stable under coupling conditions and af-
fords the corresponding borodipeptide in a 1:1 mixture of
diastereomers when coupled with N(Cbz)-leucine using
PyBOP as a coupling agent (Scheme 6). An important
limitation to this protocol is that attempted deallylation of
alkyl-substituted boryl carbamates results in decomposi-
tion. The desired free amines could not be isolated.
1
ian Mercury 400 MHz spectrometer. H NMR spectra chemical
shifts (δ) are reported in parts per million (ppm) referenced to TMS
(0 ppm) or residual protium in the NMR solvent. Note: Carbons ex-
hibiting significant line broadening brought about by boron substit-
uents were not reported (quadrupolar relaxation). 11B NMR was
recorded using Varian VNMRS 400 MHz spectrometer or Bruker
O
O
O
O
O
O
O
MeN
Ph
MeN
Ph
MeN
Ph
O
O
O
O
O
O
DMBA, Pd(PPh3)4
(Cbz)NH-Leu-OH
B
B
B
CH2Cl2–MeOH
23 °C, 1 h
50%
PyBOP, DIPEA
CHCl3
H
N
NHCbz
NH2
N
Cbz
80%
H
7d
9
10
Scheme 6 Preparation and coupling of α-boryl amine
Synthesis 2014, 46, 445–454
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Building Blocks for the Synthesis of Aminoboronic Acid Derivatives
449
Avance III 400 MHz spectrometer and referenced to an external
standard of Et2O·BF3. IR spectra were recorded on a PerkinElmer
Spectrum 100 instrument equipped with a single-reflection dia-
mond/ZnSe ATR accessory. High-resolution mass spectra were ob-
tained on a VG 70-250S (double focusing) mass spectrometer at 70
eV or on an ABI/Sciex Qstar mass spectrometer with ESI source,
MS/MS and accurate mass capabilities or on Jeol AccuTOF-DART
instrument.
HRMS (DART-TOF): m/z [M + NH4]+ calcd for C13H16BFN3O5:
324.11670; found: 324.11736.
1-(MIDA boryl)-3-phenylpropyl Isocyanate (2d)
The reaction was carried out on a 4.70 mmol scale; yield: 1.37 g
(4.33 mmol, 92%); white solid; mp 133 °C (dec.); Rf = 0.80
(EtOAc).
IR (film): 2254, 1752, 1497, 1454, 1337, 1284, 1245, 1193, 1111,
1032, 990, 952, 897, 861, 820, 725, 700 cm–1.
α-Boryl Isocyanates 2a–h; Procedure 1A (Table 1)
1H NMR (400 MHz, DMSO-d6): δ = 7.32–7.28 (m, 2 H), 7.23–7.17
(m, 3 H), 4.34 (d, J = 17.2 Hz, 1 H), 4.27 (d, J = 17.2 Hz, 1 H), 4.11
(d, J = 17.2 Hz, 1 H), 4.04 (d, J = 17.2 Hz, 1 H), 3.04 (dd, J = 10.5,
3.2 Hz, 1 H), 2.97 (s, 3 H), 2.87–2.80 (m, 1 H), 2.67–2.56 (m, 1 H),
1.94–1.85 (m, 1 H), 1.83–1.73 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.6, 168.4, 141.2, 128.4,
128.3, 125.8, 121.5, 62.5, 62.3, 45.9, 34.3, 32.8.
To a solution (or suspension) of α-boryl carboxylic acid 1 (5.0
mmol) in anhydrous MeCN (30 mL) was added Et3N (6.0 mmol, 1.2
equiv) and subsequently DPPA (6.0 mmol, 1.2 equiv). The resulting
solution was stirred at r.t. under N2 for 15 min, and then heated at
1
50 °C for 1 h until the reaction was complete as indicated by H
NMR analysis of the crude mixture. The mixture was cooled to r.t.
and evaporated under reduced pressure to remove the solvent. The
crude residue was purified by flash column chromatography on sil-
ica gel [hexanes–EtOAc (80:20) → hexanes–EtOAc (50:50) →
EtOAc] to afford the respective pure product.
11B NMR (128 MHz, DMSO-d6): δ = 10.7.
HRMS (DART-TOF): m/z [M + H]+ calcd for C15H18BN2O5:
317.13088; found: 317.13060.
(MIDA boryl)(phenyl)methyl Isocyanate (2a)
The reaction was carried out on a 0.66 mmol scale; yield: 707 mg
(2.46 mmol, 71%); white solid; mp 125 °C (dec.); Rf = 0.55
(EtOAc).
1-(MIDA boryl)-2-phenylethyl Isocyanate (2e)
The reaction was carried out on a 0.85 mmol scale; yield: 214 mg
(0.71 mmol, 84%); white solid; mp 130 °C (dec.); Rf = 0.56
(EtOAc).
IR (film): 2244, 1752, 1453, 1341, 1297, 1252, 1100, 1039, 948,
904, 868, 770, 718, 701 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.39–7.24 (m, 5 H), 4.39 (d,
J = 17.2 Hz, 1 H), 4.31 (d, J = 17.2 Hz, 1 H), 4.31 (s, 1 H), 4.16 (d,
J = 17.2 Hz, 1 H), 4.07 (d, J = 17.2 Hz, 1 H), 3.09 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.4, 168.4, 140.7, 128.3,
126.8, 126.7, 122.9, 62.6, 62.3, 46.1.
IR (film): 3065, 3027, 2953, 2904, 2257, 2170, 1773, 1741, 1709,
1590, 1511, 1489, 14551448, 1426, 1343, 1327, 1294, 1252, 1237,
1200, 1183, 1161, 1117, 1072, 1041, 1010, 991, 960, 944, 904, 873,
822, 781, 754, 739, 724, 695 cm–1.
1H NMR (400 MHz, CD3CN): δ = 7.38–7.32 (m, 4 H), 7.29–7.25
(m, 1 H), 4.06 (d, J = 17.2 Hz, 1 H), 4.05 (d, J = 17.0 Hz, 1 H), 3.95
(d, J = 17.0 Hz, 1 H), 3.91 (d, J = 17.2 Hz, 1 H), 3.37 (dd, J = 12.0,
2.8 Hz, 1 H), 3.11 (dd, J = 14.2, 2.8 Hz, 1 H), 3.02 (s, 3 H), 2.77 (dd,
J = 14.2, 12.0 Hz, 1 H).
11B NMR (128 MHz, DMSO-d6): δ = 10.5.
HRMS (DART-TOF): m/z [M + NH4]+ calcd for C13H17BN3O5:
13C NMR (100 MHz, CD3CN): δ = 169.1, 168.7, 140.6, 130.2,
306.12613; found: 306.12679.
129.5, 127.7, 118.4, 63.7, 63.4, 47.0, 39.4.
11B NMR (128 MHz, CD3CN): δ = 10.6.
HRMS (DART-TOF): m/z [M + NH4]+ calcd for C14H19BN3O5:
(MIDA boryl)(p-tolyl)methyl Isocyanate (2b)
The reaction was carried out on a 3.05 mmol scale; yield: 114 mg
(0.38 mmol, 57%); white solid; mp 149 °C (dec.); Rf = 0.72 (EtOAc).
320.14178; found: 320.14186.
IR (film): 2242, 1756, 1513, 1455, 1336, 1292, 1102, 1071, 1038,
949, 902, 886, 868, 810, 761, 736 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.18 (app br s, 4 H), 4.37 (d,
J = 17.2 Hz, 1 H), 4.30 (d, J = 17.2 Hz, 1 H), 4.24 (s, 1 H), 4.15 (d,
J = 17.2 Hz, 1 H), 4.05 (d, J = 17.2 Hz, 1 H), 3.06 (s, 3 H), 2.29 (s,
3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.4, 168.4, 137.6, 135.9,
128.9, 126.7, 123.0, 62.6, 62.3, 46.1, 20.6.
11B NMR (128 MHz, DMSO-d6): δ = 10.3.
HRMS (DART-TOF): m/z [M + NH4]+ calcd for C14H19BN3O5:
1-(MIDA boryl)pentyl Isocyanate (2f)
The reaction was carried out on a 3.69 mmol scale; yield: 859 mg
(3.20 mmol, 86%); white solid; mp 163–164 °C; Rf = 0.60 (EtOAc).
IR (film): 2959, 2261, 1742, 1465, 1339, 1294, 1230, 1160, 1141,
1099, 1069, 1045, 1026, 990, 954, 900, 861, 726 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.34 (d, J = 17.2 Hz, 1 H), 4.26
(d, J = 17.2 Hz, 1 H), 4.09 (d, J = 17.2 Hz, 1 H), 4.04 (d, J = 17.2
Hz, 1 H), 3.03 (dd, J = 10.0, 3.2 Hz, 1 H), 2.98 (s, 3 H), 1.68–1.56
(m, 1 H), 1.56–1.42 (m, 2 H), 1.40–1.25 (m, 3 H), 0.90 (t, J = 6.9
Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.7, 168.5, 121.5, 62.4,
62.2, 45.9, 31.8, 28.8, 21.7, 13.9.
320.14178; found: 320.14169.
(MIDA boryl)(4-fluorophenyl)methyl Isocyanate (2c)
The reaction was carried out on a 0.65 mmol scale; yield: 122 mg
(0.40 mmol, 62%); white solid; mp 113 °C (dec.); Rf = 0.75 (EtO-
Ac).
11B NMR (128 MHz, DMSO-d6): δ = 10.6.
HRMS (DART-TOF): m/z [M + NH4]+ calcd for C11H21BN3O5:
285.15743; found: 286.15789.
IR (film): 2246, 1756, 1603, 1508, 1465, 1336, 1279, 1218, 1158,
1100, 1071, 1035, 954, 897, 824, 739 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.34–7.29 (m, 2 H), 7.24–7.18
(m, 2 H), 4.39 (d, J = 17.2 Hz, 1 H), 4.35 (s, 1 H), 4.32 (d, J = 17.2
Hz, 1 H), 4.18 (d, J = 17.2 Hz, 1 H), 4.08 (d, J = 17.2 Hz, 1 H), 3.08
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.3(8), 168.3(6), 161.1 (d,
1JCF = 242.6 Hz), 136.8 (d, 4JCF = 3.0 Hz), 128.6 (d, 3JCF = 8.2 Hz),
122.9, 115.1 (d, 2JCF = 21.4 Hz), 62.7, 62.3, 46.2.
3-Methyl-1-(MIDA boryl)butyl Isocyanate (2g)
The reaction was carried out on a 0.66 mmol scale; yield: 127 mg
(0.47 mmol, 71%); white solid; mp 160–161 °C; Rf = 0.55 (EtOAc).
IR (film): 3016, 2961, 2873, 2266, 2139, 1742, 1705, 1517, 1469,
1451, 1338, 1289, 1249, 1197, 1161, 1102, 1081, 1070, 1045, 1018,
992, 956, 915, 898, 866, 816, 776, 725, 687 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.34 (d, J = 17.2 Hz, 1 H), 4.25
(d, J = 17.2 Hz, 1 H), 4.09 (d, J = 17.2 Hz, 1 H), 4.04 (d, J = 17.2
11B NMR (128 MHz, DMSO-d6): δ = 10.2.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 445–454

450
A. Zajdlik et al.
PRACTICAL SYNTHETIC PROCEDURES
Hz, 1 H), 3.09 (dd, J = 11.8, 2.9 Hz, 1 H), 2.99 (s, 3 H), 1.79–1.69
(m, 1 H), 1.53 (ddd, J = 14.0, 11.8, 3.8 Hz, 1 H), 1.28 (ddd, J = 14.0,
10.3, 2.9 Hz, 1 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 6.6 Hz, 3
H).
4.26 (d, J = 17.1 Hz, 1 H), 4.25 (d, J = 16.9 Hz, 1 H), 4.15 (d,
J = 17.1 Hz, 1 H), 3.89 (d, J = 16.9 Hz, 1 H), 2.98 (s, 3 H), 2.97–
2.91 (m, 2 H), 0.94 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.8, 168.5, 158.0, 144.6,
13C NMR (100 MHz, DMSO-d6): δ = 168.7, 168.4, 121.4, 62.5,
127.4, 126.9, 125.0, 62.3, 62.3, 45.7, 34.1, 15.5.
62.3, 45.9, 41.0, 24.8, 23.4, 20.6.
11B NMR (128 MHz, DMSO-d6): δ = 10.7.
HRMS (DART-TOF): m/z [M + NH4]+ calcd for C11H21BN3O5:
11B NMR (128 MHz, DMSO-d6): δ = 11.5.
HRMS (DART-TOF): m/z [M + H]+ calcd for C15H21BN3O5:
334.15743; found: 334.15849.
286.15743; found: 286.15807.
1-Isopropyl-3-[(MIDA boryl)(phenyl)methyl]urea (6b)
The reaction was carried out on a 0.17 mmol scale; yield: 56 mg
(0.16 mmol, 95%); white solid; mp 160–162 °C; Rf = 0.22 (EtOAc).
Cyclohexyl(MIDA boryl)methyl Isocyanate (2h)
The reaction was carried out on a 0.66 mmol scale; white solid;
yield: 137 mg (464 mmol, 69%); mp 175–176 °C; Rf = 0.39
(EtOAc).
IR (film): 3405, 2965, 1747, 1639, 1539, 1495, 1451, 1338, 1282,
1239, 1152, 1099, 1028, 950, 896, 817, 704 cm–1.
IR (film): 2925, 2852, 2261, 1749, 1449, 1338, 1292, 1233, 1109,
1030, 969, 894, 862, 818, 729 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.29 (d, J = 17.2 Hz, 1 H), 4.25
(d, J = 17.1 Hz, 1 H), 4.05 (d, J = 17.2 Hz, 1 H), 4.03 (d, J = 17.1
Hz, 1 H), 2.96 (s, 3 H), 1.76–1.73 (m, 3 H), 1.64–1.56 (m, 4 H),
1.30–1.17 (m, 3 H), 1.29–1.00 (m, 2 H).
1H NMR (400 MHz, DMSO-d6): δ = 7.25–7.21 (m, 2 H), 7.17–7.08
(m, 3 H), 6.00 (d, J = 9.6 Hz, 1 H), 5.95 (d, J = 7.6 Hz, 1 H), 4.33
(d, J = 9.6 Hz, 1 H), 4.26 (d, J = 17.0 Hz, 1 H), 4.25 (d, J = 17.1 Hz,
1 H), 4.16 (d, J = 17.1 Hz, 1 H), 3.88 (d, J = 17.0 Hz, 1 H), 3.60–
3.52 (m, 1 H), 2.98 (s, 3 H), 0.99 (d, J = 6.5 Hz, 3 H), 0.96 (d,
J = 6.5 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.6(3), 168.6(0), 121.0,
13C NMR (100 MHz, DMSO-d6): δ = 168.8, 168.4, 157.5, 144.6,
62.0, 61.8, 45.9, 39.9, 31.4, 27.8, 26.1, 25.7(5), 25.7(2).
127.4, 126.9, 125.0, 62.4, 62.3, 45.6, 40.9, 23.3, 23.2.
11B NMR (128 MHz, DMSO-d6): δ = 10.6.
11B NMR (128 MHz, DMSO-d6): δ = 11.7.
HRMS (DART-TOF): m/z [M + NH4]+ calcd for C13H23BN3O5:
HRMS (DART-TOF): m/z [M + H]+ calcd for C16H23BN3O5:
312.17308; found: 312.17444.
348.17308; found: 348.17306.
α-Aminoboronic Acid; (1-Amino-3-phenylpropyl)boronic Acid
(5) (Scheme 3)
1-(tert-Butyl)-3-[1-(MIDA boryl)-3-phenylpropyl]urea (6c)
The reaction was carried out on a 0.32 mmol scale; yield: 107 mg
(0.27 mmol, 87%); white solid; mp 120–125 °C; Rf = 0.25 (EtOAc).
In a vial equipped with a stirring bar and a screw-cap lid was dis-
solved the α-boryl isocyanate 2d (50 mg, 0.158 mmol, 1.0 equiv) in
MeCN (2 mL). Aq 3.0 M HCl (0.53 mL, 10 equiv) was added drop-
wise and the reaction mixture was stirred at r.t. for 12 h until the re-
action was complete as judged by TLC (eluent: EtOAc). The
resulting solution was evaporated to remove the solvent under re-
duced pressure. The residue was azeotroped with MeCN three times
to obtain the desired product as a white powder; yield: 34 mg (0.158
mmol, ~100%); white solid (a 1:1 mixture with MIDA).
IR (film): 3381, 2963, 1762, 1747, 1644, 1549, 1497, 1453, 1337,
1285, 1216, 1110, 993, 952, 896, 862, 749, 699 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.28–7.23 (m, 2 H), 7.18–7.13
(m, 3 H), 5.32 (br s, 1 H), 4.24 (d, J = 17.1 Hz, 1 H), 4.20 (d,
J = 16.7 Hz, 1 H), 4.04 (d, J = 17.1 Hz, 1 H), 3.75 (d, J = 16.7 Hz,
1 H), 3.26 (app d, J = 6.3 Hz, 1 H), 2.89 (s, 3 H), 2.64–2.55 (m, 1
H), 2.52–2.45 (m, 1 H), 1.76–1.67 (m, 1 H), 1.51–1.41 (m, 1 H),
1.22 (s, 9 H).
1H NMR (400 MHz, CD3OD): δ = 7.31–7.17 (m, 5 H), 4.11 (s, 4 H)
(MIDA α-CH2), 3.05 (s, 3 H) (MIDA CH3), 2.91 (br s, 1 H), 2.72 (t,
J = 7.9 Hz, 2 H), 2.03–1.97 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.8, 168.7, 158.3, 143.1,
128.2, 128.2, 125.4, 62.2, 62.1, 49.1, 45.4, 35.1, 32.5, 29.3.
11B NMR (128 MHz, DMSO-d6): δ = 11.5.
HRMS (ESI): m/z [M + H]+ calcd for C19H29BN3O5: 390.2200;
13C NMR (100 MHz, CD3OD): δ = 168.7 (MIDA C=O), 142.1,
129.7, 129.6, 127.5, 57.4 (MIDA α-CH2), 43.4 (MIDA CH3), 33.7,
32.6.
11B NMR (128 MHz, CD3OD): δ = 28.3.
HRMS (ESI): m/z [M + H]+ calcd for C9H15BNO2: 180.1196; found:
found: 390.2202.
1,1-Diethyl-3-[1-(MIDA boryl)-3-phenylpropyl]urea (6d)
The reaction was carried out on a 0.32 mmol scale; yield: 95 mg
(0.24 mmol, 77%); white solid; mp 150–152 °C; Rf = 0.40 (EtOAc–
MeOH, 9:1).
180.1199.
α-Boryl Ureas 6a–e; Procedure 1B (Table 2)
IR (film): 3382, 2979, 2933, 1770, 1740, 1617, 1521, 1496, 1455,
1401, 1334, 1293, 1247, 1198, 1122, 1080, 1061, 1017, 1000, 955,
897, 856, 757, 702 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.27–7.23 (m, 2 H), 7.19–7.12
(m, 3 H), 5.07 (d, J = 9.1 Hz, 1 H), 4.24 (d, J = 17.2 Hz, 1 H), 4.17
(d, J = 16.8 Hz, 1 H), 4.01 (d, J = 17.2 Hz, 1 H), 3.70 (d, J = 16.8
Hz, 1 H), 3.50–3.44 (m, 1 H), 3.30–3.23 (m, 2 H), 3.20–3.11 (m, 2
H), 2.92 (s, 3 H), 2.64–2.56 (m, 1 H), 2.46–2.38 (m, 1 H), 1.74–1.68
(m, 2 H), 1.01 (t, J = 7.0 Hz, 6 H).
In a vial equipped with a stirring bar and a screw-cap lid was dis-
solved the appropriate α-boryl isocyanate 2 (0.30 mmol, 1.0 equiv)
in THF (2 mL). The respective amine (0.36 mmol, 1.2 equiv) was
added and the reaction mixture was stirred at r.t. for 1–5 h until the
reaction was complete as judged by TLC (eluent: EtOAc). The re-
sulting cloudy mixture was concentrated under reduced pressure to
remove the solvent to obtain the desired product as a white solid.
The crude product was subjected to purification by flash column
chromatography on silica gel.
13C NMR (100 MHz, CDCl3): δ = 167.7, 167.6, 157.6, 142.6, 128.6,
128.5, 125.9, 62.8, 62.2, 46.0, 41.6, 34.3, 33.4, 14.2.
11B NMR (128 MHz, DMSO-d6): δ = 12.3.
1-Ethyl-3-[(MIDA boryl)(phenyl)methyl]urea (6a)
The reaction was carried out on a 0.17 mmol scale; yield: 54 mg
(162 mmol, 93%); white solid; mp 150–153 °C; Rf = 0.20 (EtOAc).
IR (film): 3374, 2967, 1748, 1634, 1547, 1494, 1451, 1338, 1282,
1244, 1107, 1075, 1028, 991, 950, 895, 878, 802, 703 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.25–7.09 (m, 5 H), 6.05 (d,
J = 9.7 Hz, 1 H), 6.02 (t, J = 5.5 Hz, 1 H), 4.34 (d, J = 9.7 Hz, 1 H),
HRMS (ESI): m/z [M + H]+ calcd for C19H29BN3O5: 390.2200;
found: 390.2181.
Synthesis 2014, 46, 445–454
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Building Blocks for the Synthesis of Aminoboronic Acid Derivatives
451
1-[1-(MIDA boryl)-3-phenylpropyl]-3-phenylurea (6e)
The reaction was carried out on a 0.32 mmol scale; yield: 31 mg (75
μmol, 30%); white solid; mp 130–134 °C; Rf = 0.45 (EtOAc).
13C NMR (100 MHz, DMSO-d6): δ = 168.7, 168.6, 156.8, 143.9(5),
143.9(1), 140.7(0), 140.6(8), 127.6, 127.0, 125.3, 125.2, 120.0(3),
120.0(1), 65.1, 62.2, 46.9, 45.5, 30.9, 28.4, 22.2, 14.0.
11B NMR (128 MHz, DMSO-d6): δ = 11.6.
HRMS (DART-TOF): m/z [M + H]+ calcd for C25H30BN2O6:
IR (film): 3382, 2943, 1762, 1745, 1646, 1597, 1540, 1497, 1440,
1292, 1230, 1119, 1075, 1046, 1029, 991, 952, 895, 861, 749, 694
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.55 (s, 1 H), 7.38 (d, J = 7.7
Hz, 2 H), 7.31–7.13 (m, 7 H), 6.87 (app t, J = 7.2 Hz, 1 H), 5.83 (d,
J = 9.6 Hz, 1 H), 4.26 (d, J = 17.1 Hz, 1 H), 4.24 (d, J = 17.1 Hz, 1
H), 4.10 (d, J = 17.1 Hz, 1 H), 3.90 (d, J = 17.1 Hz, 1 H), 3.46–3.40
(m, 1 H), 2.91 (s, 3 H), 2.69–2.60 (m, 1 H), 2.60–2.51 (m, 1 H),
1.85–1.75 (m, 1 H), 1.61–1.51 (m, 1 H).
465.21969; found: 465.22061.
tert-Butyl [1-(MIDA boryl)pentyl]carbamate (7c)
The reaction was carried out on a 0.10 mmol scale; yield: 21 mg (60
μmol, 60%); white solid; mp 89–91 °C; Rf = 0.50 (EtOAc).
IR (film): 2959, 1763, 1688, 1503, 1457, 1365, 1336, 1296, 1243,
1165, 1101, 1079, 1023, 991, 947, 896, 863, 731 cm–1.
13C NMR (100 MHz, DMSO-d6): δ = 168.9, 168.7, 155.6, 142.8,
140.7, 128.6, 128.2, 128.1, 125.5, 120.7, 117.2, 62.1(8), 62.1(7),
45.6, 34.9, 32.5.
11B NMR (128 MHz, DMSO-d6): δ = 11.4.
HRMS (ESI): m/z [M + H]+ calcd for C21H25BN3O5: 410.1881;
1H NMR (400 MHz, acetone-d6): δ = 5.20 (d, J = 10.5 Hz, 1 H),
4.22 (d, J = 17.0 Hz, 1 H), 4.20 (d, J = 16.7 Hz, 1 H), 4.12 (d,
J = 17.0 Hz, 1 H), 3.89 (d, J = 16.7 Hz, 1 H), 3.24 (ddd, J = 10.5,
9.8, 3.5 Hz, 1 H), 3.15 (s, 3 H), 1.65–1.56 (m, 1 H), 1.39 (s, 9 H),
1.47–1.23 (m, 5 H), 0.89 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, acetone-d6): δ = 168.8, 168.7, 157.5, 78.5,
63.3, 63.2, 46.3, 32.6, 29.6, 28.7, 23.4, 14.6.
found: 410.1880.
α-Boryl Carbamates 7a–e; Procedure 1C (Table 3)
11B NMR (128 MHz, DMSO-d6): δ = 11.5.
In a vial equipped with a stirring bar and a screw-cap lid was dis-
solved the appropriate α-boryl isocyanate 2 (0.30 mmol, 1.0 equiv)
in anhydrous DMF (2 mL). Alcohol (0.90 mmol, 3.0 equiv) and
CuCl (0.30 mmol, 1.0 equiv) were added subsequently and the re-
action mixture was stirred at r.t. for 3 h until the reaction was com-
plete as judged by TLC (eluent: EtOAc) or crude 1H NMR analysis.
The resulting green mixture was diluted with EtOAc (10 mL) and
the CuCl suspension was filtered off. The filtrate was washed with
H2O (2 × 3 mL) and brine (3 mL). The organic layers were concen-
trated to remove the solvent. The crude residue was purified by flash
column chromatography on silica gel [hexanes–EtOAc (50:50) →
EtOAc → EtOAc–MeCN (90:10)] to afford the pure product.
HRMS (DART-TOF): m/z [M + H]+ calcd for C15H28BN2O6:
343.20404; found: 343.20510.
Allyl [(MIDA boryl)(phenyl)methyl]carbamate (7d)
The reaction was carried out on a 0.69 mmol scale; yield: 160 mg,
(0.46 mmol, 67%); white solid; mp 240 °C (dec.); Rf = 0.45
(EtOAc).
IR (film): 3423, 3372, 1753, 1700, 1524, 1496, 1452, 1342, 1299,
1239, 1146, 1101, 1072, 1046, 1022, 992, 945, 882, 817, 804, 746,
710 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.46 (d, J = 8.6 Hz, 1 H), 7.27–
7.20 (m, 4 H), 7.14–7.10 (m, 1 H), 5.92–5.82 (m, 1 H), 5.26 (dd,
J = 17.3, 1.5 Hz, 1 H), 5.13 (dd, J = 10.6, 1.5 Hz, 1 H), 4.46–4.37
(m, 2 H), 4.25 (d, J = 17.1 Hz, 1 H), 4.23 (d, J = 17.1 Hz, 2 H), 4.20
(s, 1 H), 3.87 (d, J = 17.1, 1 H), 3.00 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.9, 168.2, 156.2, 143.6,
133.8, 127.5, 127.1, 125.3, 116.6, 64.2, 62.7, 62.5, 45.9.
11B NMR (128 MHz, DMSO-d6): δ = 11.1.
HRMS (ESI): m/z [M + H]+ calcd for C16H20BN2O6: 347.1414;
Note: For the preparation of compound 7c, 10.0 equiv of t-BuOH
was used. The reaction was carried out at 70 °C for 24 h.
2-(Trimethylsilyl)ethyl [(MIDA boryl)(phenyl)methyl]carba-
mate (7a)
The reaction was carried out on a 0.35 mmol scale; yield: 123 mg
(0.26 mmol, 75%); white solid; mp 84–87 °C; Rf = 0.55 (EtOAc).
IR (film): 2958, 1760, 1696, 1496, 1337, 1284, 1246, 1136, 1102,
1074, 1031, 1003, 952, 896, 858, 834, 702 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.25–7.19 (m, 5 H), 7.13–7.09
(m, 1 H), 4.24 (d, J = 17.1 Hz, 1 H), 4.22 (d, J = 17.1 Hz, 2 H), 4.19
(s, 1 H), 3.97 (t, J = 7.3 Hz, 2 H), 3.85 (d, J = 17.1 Hz, 1 H), 2.99 (s,
3 H), 0.88 (t, J = 7.3 Hz, 2 H), –0.01 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.9, 168.2, 156.6, 143.8,
127.4, 127.1, 125.2, 62.6, 62.5, 61.5, 45.9, 17.4, –1.5.
11B NMR (128 MHz, DMSO-d6): δ = 10.2.
HRMS (DART-TOF): m/z [M + NH4]+ calcd for C18H31BN3O6Si:
found: 347.1418.
Benzyl [1-(MIDA boryl)-3-phenylpropyl]carbamate (7e)
The reaction was carried out on a 0.63 mmol scale; yield: 242 mg
(0.57 mmol, 90%); white solid; mp 78–80 °C; Rf = 0.55 (EtOAc).
IR (film): 3328, 3030, 2947, 1761, 1694, 1517, 1497, 1454, 1335,
1291, 1234, 1124, 1076, 1017, 954, 896, 859, 741, 697 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.31 (m, 5 H), 7.27–7.23 (m,
2 H), 7.17–7.14 (m, 3 H), 5.10 (d, J = 12.2 Hz, 1 H), 5.06 (d,
J = 12.2 Hz, 1 H), 4.68 (d, J = 10.3 Hz, 1 H), 3.76 (d, J = 16.5 Hz,
1 H), 3.72 (d, J = 16.1 Hz, 1 H), 3.67 (d, J = 16.5 Hz, 1 H), 3.52 (d,
J = 16.1 Hz, 1 H), 3.33 (ddd, J = 10.3, 10.1, 3.3 Hz, 1 H), 2.91 (s, 3
H), 2.77–2.69 (m, 1 H), 2.62–2.54 (m, 1 H), 2.07–1.99 (m, 1 H),
1.80–1.70 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 167.9, 167.7, 157.3, 142.2, 136.9,
128.7, 128.6, 128.5, 128.4, 128.2, 126.0, 67.0, 62.7, 62.3, 46.0,
33.9, 32.9.
424.20752; found: 424.20952.
(9H-Fluoren-9-yl)methyl [1-(MIDA boryl)pentyl]carbamate
(7b)
The reaction was carried out on a 0.96 mmol scale; yield: 358 mg
(0.77 mmol, 80%); white solid; mp 72–73 °C; Rf = 0.70 (EtOAc).
IR (film): 2955, 1761, 1695, 1515, 1450, 1335, 1293, 1234, 1161,
1101, 1080, 1023, 990, 896, 856, 759, 739 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.88 (d, J = 7.4 Hz, 2 H), 7.72
(dd, J = 7.1, 3.9 Hz, 2 H), 7.41 (dd, J = 7.4, 7.1 Hz, 2 H), 7.31 (dd,
J = 11.1, 7.1 Hz, 2 H), 6.73 (d, J = 9.4 Hz, 1 H), 4.29–4.15 (m, 5 H),
4.04 (d, J = 17.3 Hz, 1 H), 3.67 (d, J = 16.8 Hz, 1 H), 3.09 (ddd,
J = 11.3, 9.4, 2.5 Hz, 1 H), 2.85 (s, 3 H), 1.54–1.41 (m, 1 H), 1.40–
1.18 (m, 5 H), 0.83 (t, J = 5.8 Hz, 3 H).
11B NMR (128 MHz, DMSO-d6): δ = 12.6.
HRMS (ESI): m/z [M + H]+ calcd for C22H26BN2O6: 425.1884;
found: 425.1894.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 445–454

452
A. Zajdlik et al.
PRACTICAL SYNTHETIC PROCEDURES
α-Aminoboronic Acid Derivatives with a Quaternary Carbon
Center (Scheme 4)
to obtain the desired product; yield: 17 mg (76 μmol, ~100%); white
solid (1:1 mixture with MIDA).
1H NMR (400 MHz, CD3OD): δ = 7.48–7.43 (m, 4 H), 7.41–7.32
(m, 1 H), 5.88–5.76 (m, 1 H), 5.34 (d, J = 17.1 Hz, 1 H), 5.27 (d,
J = 9.8 Hz, 1 H), 4.11 (s, 4 H, MIDA α-CH2), 3.05 (s, 3 H, MIDA
CH3), 3.00–2.90 (m, 2 H).
13C NMR (100 MHz, CD3OD): δ = 168.7 (MIDA C=O), 140.0,
133.1, 130.4, 129.6, 127.7, 121.6, 57.4 (MIDA α-CH2), 43.4
(MIDA CH3), 22.2.
2-(MIDA boryl)-2-phenylpent-4-enoic Acid (12)
To a suspension of α,α-disubstituted α-boryl aldehyde 11 (250 mg,
0.79 mmol, 1 equiv) in t-BuOH (5 mL) was added cyclohexene
(2.38 mmol, 0.24 mL, 3.0 equiv). A solution of NaClO2 (80% puri-
ty, 0.107 g, 0.95 mmol, 1.2 equiv) and NaH2PO4 (0.131 g, 0.95
mmol, 1.2 equiv) in H2O (5 mL) was added dropwise at r.t. The
mixture was vigorously stirred at r.t. for 12 h. The reaction solution
was then diluted with brine (10 mL) and extracted with EtOAc
(3 × 5 mL). The combined organic layers were concentrated to re-
move the solvent. The crude product was purified by flash column
chromatography on silica gel [hexanes–EtOAc (50:50) → EtOAc
→ EtOAc–MeCN (90:10)] to afford the pure product as a white
foam; yield: 162 mg (0.51 mmol, 65%); Rf = 0.37 (EtOAc).
11B NMR (128 MHz, CD3OD): δ = 28.5.
HRMS (ESI): m/z [M + H]+ calcd For C10H15BNO2: 192.1196;
found: 192.1191.
1-Ethyl-3-[1-(MIDA boryl)-1-phenylbut-3-en-1-yl]urea (15)
In a vial equipped with a stirring bar and a screw-cap lid was dis-
solved the α-boryl isocyanate 13 (13.1 mg, 0.0399 mmol, 1.0 equiv)
in anhydrous THF (1 mL). EtNH2 (2.0 M in THF, 0.0479 mmol, 1.2
equiv) was added and the reaction mixture was stirred at r.t. for 5 h
until the reaction was complete as judged by TLC (eluent: EtOAc).
The resulting solution was concentrated to remove the solvent under
reduced pressure. The crude product was subjected to purification
by flash column chromatography on silica gel to obtain the pure
product; yield: 13 mg (34 μmol, 85%); white solid; mp 112–115 °C;
Rf = 0.33 (EtOAc).
IR (film): 2926, 1765, 1743, 1467, 1447, 1344, 1291, 1243, 1195,
1162, 1096, 1066, 1022, 992, 962, 899, 874, 827, 734, 703 cm–1.
1H NMR (400 MHz, acetone-d6): δ = 7.43–7.33 (m, 2 H), 7.33–7.23
(m, 2 H), 7.22–7.11 (m, 1 H), 5.88 (dddd, J = 17.1, 10.2, 8.0, 5.8 Hz,
1 H), 4.86 (ddt, J = 17.1, 2.6, 1.5 Hz, 1 H), 4.75 (ddt, J = 10.2, 2.6,
1.2 Hz, 1 H), 4.30 (d, J = 17.5 Hz, 1 H), 4.13 (d, J = 16.3 Hz, 1 H),
4.06 (d, J = 16.3 Hz, 1 H), 3.92 (d, J = 17.5 Hz, 1 H), 3.01 (ddt,
J = 14.4, 5.8, 1.5 Hz, 1 H), 2.78 (dd, J = 14.4, 8.0 Hz, 1 H), 2.62 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 180.7, 168.9, 168.3, 140.4, 135.8,
129.0, 127.6, 126.7, 117.7, 65.1, 64.5, 48.6, 41.3.
11B NMR (128 MHz, CDCl3): δ = 11.5.
IR (film): 3389, 2973, 1762, 1740, 1667, 1542, 1493, 1444, 1347,
1303, 1271, 1193, 1111, 1024, 1003, 953, 906, 864, 824, 766, 724,
704 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.26–7.19 (m, 4 H), 7.15–7.11
(m, 1 H), 6.21 (t, J = 3.5 Hz, 1 H), 5.82–5.71 (m, 1 H), 5.57 (br s, 1
H), 5.01 (dd, J = 18.4, 2.3 Hz, 1 H), 4.97 (dd, J = 10.1, 2.3 Hz, 1 H),
4.11 (d, J = 17.0 Hz, 1 H), 4.02 (d, J = 17.1 Hz, 1 H), 3.97 (d,
J = 17.1 Hz, 1 H), 2.79 (d, J = 17.0 Hz, 1 H), 2.99 (qd, J = 7.1, 3.5
Hz, 2 H), 2.94 (dd, J = 13.9, 7.5 Hz, 1 H), 2.72 (dd, J = 13.9, 6.8 Hz,
1 H), 2.64 (s, 3 H), 1.00 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.2, 168.2, 157.9, 145.1,
135.6, 127.5, 126.2, 125.1, 117.1, 63.1, 62.9, 46.0, 43.2, 33.9, 15.7.
11B NMR (128 MHz, DMSO-d6): δ = 11.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H25BN3O5: 374.1887;
HRMS (ESI): m/z [M + H]+ calcd for C16H19BNO6: 332.1306;
found: 332.1304.
1-(MIDA boryl)-1-phenylbut-3-en-1-yl Isocyanate (13)
To a solution of 12 (75 mg, 0.227 mmol) in anhydrous MeCN (1
mL) was added Et3N (38 μL, 0.273 mmol, 1.2 equiv) and subse-
quently DPPA (59 μL, 0.273 mmol, 1.2 equiv). The resulting solu-
tion was stirred at r.t. under N2 for 15 min, and then heated at 50 °C
for 2 h until the reaction was complete as indicated by the 1H NMR
analysis of the crude mixture. The reaction mixture was cooled to
r.t. and evaporated under reduced pressure to remove the solvent.
The crude residue was purified by flash column chromatography on
silica gel [hexanes–EtOAc (80:20) → hexanes–EtOAc (50:50) →
EtOAc] to afford the pure product; yield: 53 mg (0.16 mmol, 70%);
white solid; mp 164–165 °C; Rf = 0.70 (EtOAc).
found: 374.1882.
α-Ureido Boronic Acid; {1-[3-(tert-Butyl)ureido]-3-phenylpro-
pyl}boronic Acid (Scheme 5)
IR (film): 3009, 2964, 2250, 1773, 1746, 1494, 1448, 1347, 1303,
1253, 1197, 1162, 1127, 1082, 1061, 1033, 993, 976, 963, 926, 901,
874, 803, 759, 712 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.48 (m, 2 H), 7.38–7.34 (m,
2 H), 7.29–7.23 (m, 1 H), 5.43–5.33 (m, 1 H), 5.22 (d, J = 17.1 Hz,
1 H), 5.12 (d, J = 9.9 Hz, 1 H), 3.85 (d, J = 16.3 Hz, 1 H), 3.77 (d,
J = 16.3 Hz, 1 H), 3.62 (d, J = 16.2 Hz, 1 H), 2.97 (d, J = 16.2 Hz,
1 H), 3.02 (ddt, J = 14.3, 5.2, 1.3 Hz, 1 H), 2.95 (dd, J = 14.3, 8.8
Hz, 1 H), 2.68 (s, 3 H).
In a vial equipped with a stirring bar and a screw-cap lid was dis-
solved the α-boryl urea 6c (87 mg, 0.225 mmol, 1.0 equiv) in THF
(3 mL). Aq 1.0 M NaOH (0.676 mL, 3.0 equiv) was added dropwise
and the reaction mixture was stirred at r.t. for 15 min. The reaction
was then quenched with sat. aq NH4Cl (3 mL). Et2O (3 mL) was
added, the product extracted, and the layers were separated. The
aqueous layer was further extracted with a mixed solvent E2O–THF
(1:1) (2 × 3 mL). The organic phases were combined and concen-
trated to dryness under reduced pressure to afford the desired free
boronic acid product as a white powder; yield: 55.8 mg (0.20 mmol,
90%); mp 95 °C (dec.).
13C NMR (100 MHz, CDCl3): δ = 167.2, 166.8, 140.7, 131.9, 129.1,
127.1, 126.0, 124.9, 121.0, 63.8, 63.3, 46.9, 45.8.
IR (film): 3369, 2964, 2931, 1627, 1595, 1526, 1496, 1453, 1387,
1365, 1316, 1192, 1098, 811, 747, 697 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.19–7.15 (m, 2 H), 7.10–7.06
(m, 3 H), 6.49 (br s, 1 H), 6.16 (br s, 1 H), 2.57–2.50 (m, 2 H), 2.45–
2.39 (m, 1 H), 1.80–1.69 (m, 1 H), 1.63–1.53 (m, 1 H), 1.21 (s, 9 H).
13C NMR (100 MHz, DMSO-d6): δ = 160.7, 143.4, 128.1, 127.9,
125.1, 50.0, 33.3, 30.4, 29.2.
11B NMR (128 MHz, CDCl3): δ = 10.8.
HRMS (DART-TOF): m/z [M + H]+ calcd for C16H18BN2O5:
329.13088; found: 329.12999.
(1-Amino-1-phenylbut-3-en-1-yl)boronic Acid (14)
In a vial equipped with a stirring bar and a screw-cap lid was dis-
solved α-boryl isocyanate 13 (25 mg, 0.0762 mmol, 1.0 equiv) in
MeCN (2 mL). Aq 6.0 M HCl (0.127 mL, 10 equiv) was added
dropwise and the reaction mixture was stirred at r.t. for 48 h until
the reaction was complete as judged by TLC (eluent: EtOAc). The
resulting solution was evaporated to remove the solvent under re-
duced pressure. The residue was azeotroped with MeCN three times
11B NMR (128 MHz, DMSO-d6): δ = 16.7.
HRMS (DART-TOF): m/z [(M
C14H22BN2O2: 261.17743; found: 261.17655.
– H2O) +
H]+ calcd for
Synthesis 2014, 46, 445–454
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES Building Blocks for the Synthesis of Aminoboronic Acid Derivatives
453
Preparation and Coupling of α-Boryl Amine 9 (Scheme 6)
IR (film): 3328, 2959, 1760, 1706, 1668, 1518, 1454, 1337, 1287,
1251, 1111, 1038, 950, 895, 843, 739, 698 cm–1.
2-Amino(phenyl)methyl MIDA Boronate (9)
1H NMR (400 MHz, CD3CN): δ = 7.39–7.32 (m, 5 H), 7.30–7.24
(m, 4 H), 7.21–7.17 (m, 1 H), 6.97 (d, J = 9.9 Hz, 1 H), 5.91 (d,
J = 5.4 Hz, 1 H), 5.10 (d, J = 12.2 Hz, 1 H), 5.03 (d, J = 12.2 Hz, 1
H), 4.65 (d, J = 9.9 Hz, 1 H), 4.07–4.00 (m, 1 H), 4.00 (d, J = 17.0
Hz, 1 H), 3.99 (d, J = 17.1 Hz, 1 H), 3.93 (d, J = 17.0 Hz, 1 H), 3.83
(d, J = 17.1 Hz, 1 H), 2.97 (s, 3 H), 1.66–1.54 (m, 1 H), 1.46–1.42
(m, 2 H), 0.88 (d, J = 7.1 Hz, 3 H), 0.86 (d, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CD3CN): δ = 173.2, 169.1, 168.5, 157.6,
143.6, 137.9, 129.6, 129.0(9), 129.0(6), 128.4, 127.17, 67.6, 63.7,
63.5, 55.3, 47.0, 41.1, 25.6, 23.3, 21.8.
To a solution of carbamate 7d (0.664 g, 1.92 mmol, 1.0 equiv) in
CH2Cl2–MeOH (2:1, 60 mL, predegassed with N2) was added 1,3-
dimethylbarbituric acid (DMBA; 0.599 g, 3.84 mmol, 2.0 equiv)
and subsequently Pd(PPh3)4 (44 mg, 0.0384 mmol, 0.02 equiv). The
reaction mixture was stirred at r.t. under N2 for 1 h until the reaction
was complete as judged by TLC (eluent: EtOAc–MeCN–MeOH–
H2O, 70:10:10:5). The reaction mixture was concentrated to remove
the solvent. The residue was diluted with EtOAc (100 mL) and
quickly washed with sat. aq Na2CO3 (2 × 25 mL) and brine (25 mL).
The organic phase was separated and concentrated to dryness to af-
ford the crude product as a yellowish solid. The crude product was
purified using a short pad of silica gel [hexanes–EtOAc (50:50) →
EtOAc → EtOAc–MeCN–MeOH (70:10:10) → EtOAc–MeCN–
MeOH–H2O (70:10:10:5)] to afford the pure product 9 as a beige
solid; yield: 252 mg (0.96 mmol, 50%); mp 90–91 °C; Rf = 0.15
(EtOAc–MeCN–MeOH–H2O, 70:10:10:5).
11B NMR (128 MHz, DMSO-d6): δ = 11.1.
HRMS (ESI): m/z [M + H]+ calcd for C26H33BN3O7: 510.2412;
found: 510.2404.
Acknowledgment
IR (film): 1762, 1747, 1599, 1448, 1339, 1290, 1246, 1194, 1155,
1106, 1073, 1046, 1004, 949, 898, 862, 773, 703 cm–1.
1H NMR (400 MHz, CD3CN): δ = 7.34–7.27 (m, 4 H), 7.20–7.15
(m, 1 H), 4.02 (d, J = 16.3 Hz, 1 H), 3.95 (d, J = 16.3 Hz, 1 H), 3.94
(d, J = 17.3 Hz, 1 H), 3.84 (d, J = 17.3 Hz, 1 H), 3.41 (s, 1 H), 3.19
(s, 3 H).
We thank the Natural Sciences and Engineering Research Council
of Canada (NSERC) for financial support of this work.
References
13C NMR (100 MHz, CD3CN): δ = 169.6, 169.1, 148.1, 129.0,
127.9, 126.6, 63.7, 63.5, 46.7.
11B NMR (128 MHz, DMSO-d6): δ = 11.5.
HRMS (ESI): m/z [M + H]+ calcd for C12H16BN2O4: 263.1203;
(1) Updated address: Massachusetts Institute of Technology,
Department of Chemistry 77 Massachusetts Ave., Bldg 18-
590 Cambridge, MA 02139, USA.
(2) Boronic Acids: Preparation and Applications in Organic
Synthesis, Medicine and Materials; Hall, D. G., Ed.; Wiley-
VCH: New York, 2011.
found: 263.1192.
(3) (a) Fevig, J. M.; Abelman, M. M.; Britelli, D. R.; Kettner, C.
A.; Knabb, R. M.; Weber, P. C. Bioorg. Med. Chem. Lett.
1996, 6, 295. (b) Dominguez, C.; Carini, D. J.; Weber, P. C.;
Knabb, R. M.; Alexander, R. S.; Kettner, C. A.; Wexler, R.
R. Bioorg. Med. Chem. Lett. 1997, 7, 79. (c) Fevig, J. M.;
Buriak, J. Jr.; Cacciola, J.; Alexander, R. S.; Kettner, C. A.;
Knabb, R. M.; Pruitt, J. R.; Weber, P. C.; Wexler, R. R.
Bioorg. Med. Chem. Lett. 1998, 8, 301. (d) Shevni, A. B.
Biochemistry 1986, 25, 1286. (e) Touchet, S.; Carreaux, F.;
Carboni, B.; Bouillon, A.; Boucher, J.-L. Chem. Soc. Rev.
2011, 40, 3895. (f) Rao, R. J. R.; Rao, A. K. S. B.; Swapna,
K.; Rani, B. B.; Kumar, S. P.; Awantika, S.; Murthy, Y. L.
N. J. Korean Chem. Soc. 2011, 55, 765. (g) For a review,
see: Rentsch, A.; Landsberg, D.; Brodmann, T.; Bülow, L.;
Girbig, A.-K.; Kalesse, M. Angew. Chem. Int. Ed. 2013, 52,
2.
Benzyl [(2S)-4-Methyl-1-({[MIDA boryl)(phenyl)methyl]ami-
no}-1-oxopentan-2-yl)]carbamate (10)
To a solution of Cbz-Leu-OH (69 mg, 0.261 mmol, 1.2 equiv) and
α-amino MIDA boronate 9 (57 mg, 0.217 mmol, 1.0 equiv) in an-
hydrous CHCl3 (5 mL) was added PyBop (147 mg, 0.283 mmol, 1.3
equiv) and subsequently DIPEA (75 μL, 0.434 mmol, 2 equiv). The
reaction mixture was stirred at r.t. under N2 for 5 h. The reaction so-
lution was washed with aq 10% citric acid (2 mL) and sat. aq
NaHCO3 (2 mL). The organic layer was concentrated and the resi-
due was purified by flash column chromatography on silica gel
[hexanes–EtOAc (50:50) → EtOAc → EtOAc–MeCN (90:10)] to
afford the two diastereoisomers of the desired coupling products.
Diastereomer 1
Yield: 53 mg (0.10 mmol, 40%); white solid; mp 140–147 °C;
Rf = 0.60(EtOAc).
(4) Reviews: (a) Baker, S. J.; Tomsho, J. W.; Benkovic, S. J.
Chem. Soc. Rev. 2011, 40, 4279. (b) Dembitsky, V. M.;
Srebnik, M. Tetrahedron 2003, 59, 579. (c) Baker, S. J.;
Ding, C. Z.; Akama, T.; Zhang, Y. K.; Hernandez, V.; Xia,
Y. Future Med. Chem. 2009, 1, 1275. (d) Hiratake, J.; Oda,
J. Biosci. Biotechnol. Biochem. 1997, 61, 211.
(5) Greener, B.; Millan, D. S. In Modern Drug Synthesis; Li, J.
J.; Johnson, D. S., Eds.; Wiley: Hoboken, 2010, Chap. 8, 99–
110.
IR (film): 3303, 2956, 1758, 1705, 1656, 1532, 1453, 1338, 1290,
1236, 1114, 1036, 950, 896, 736, 699 cm–1.
1H NMR (400 MHz, CD3CN): δ = 7.41–7.33 (m, 5 H), 7.30–7.24
(m, 4 H), 7.20–7.16 (m, 1 H), 7.10 (d, J = 10.0 Hz, 1 H), 5.89 (d,
J = 6.5 Hz, 1 H), 5.10 (d, J = 12.6 Hz, 1 H), 5.02 (d, J = 12.6 Hz, 1
H), 4.68 (d, J = 10.0 Hz, 1 H), 4.06 (d, J = 16.0 Hz, 1 H), 4.08–4.00
(m, 1 H), 3.96 (d, J = 17.1 Hz, 1 H), 3.93 (d, J = 16.0 Hz, 1 H), 3.89
(d, J = 17.1 Hz, 1 H), 2.86 (s, 3 H), 1.58–1.48 (m, 1 H), 1.46–1.30
(m, 2 H), 0.86 (d, J = 6.6 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3 H).
(6) (a) He, Z.; Yudin, A. K. J. Am. Chem. Soc. 2011, 133,
13770. (b) He, Z.; Zajdlik, A.; St. Denis, J. D.; Assem, N.;
Yudin, A. K. J. Am. Chem. Soc. 2012, 134, 9926. (c) He, Z.;
Trinchera, P.; Adachi, S.; St. Denis, J. D.; Yudin, A. K.
Angew. Chem. Int. Ed. 2012, 51, 11092. (d) Zajdlik, A.;
Wang, Z.; Hickey, J. L.; Aman, A.; Schimmer, A. D.; Yudin,
A. K. Angew. Chem. Int. Ed. 2013, 52, 8411. (e) Li, J.;
Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774.
(7) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203. (b) Ninomiya, K.; Shioiri, T.; Yamada, S.
Tetrahedron 1974, 30, 2151. (c) Wolff, O.; Waldvogel, S. R.
13C NMR (100 MHz, CD3CN): δ = 173.5, 169.1, 168.7, 157.5,
143.7, 138.3, 129.6, 129.0, 128.7, 128.4, 127.0, 67.2, 63.86, 63.3,
54.8, 46.7, 41.1, 25.4, 23.324, 22.0.
11B NMR (128 MHz, DMSO-d6): δ = 11.1.
HRMS (ESI): m/z [M+ H]+ calcd for C26H33BN3O7: 510.2412;
found: 510.2404.
Diastereomer 2
Yield: 53 mg (0.10 mmol, 40%); white solid; mp 119–121 °C;
Rf = 0.37 (EtOAc).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 445–454

454
A. Zajdlik et al.
PRACTICAL SYNTHETIC PROCEDURES
Synthesis 2004, 1303. Recent modification of the Curtius
rearrangement: (d) Lebel, H.; Leogane, O. Org. Lett. 2005,
7, 4107. (e) Lebel, H.; Leogane, O. Org. Lett. 2006, 8, 5717.
(f) Leogane, O.; Lebel, H. Synthesis 2009, 1935.
(g) Leathen, M. L.; Peterson, E. A. Tetrahedron Lett. 2010,
51, 2888.
(8) Acid-catalyzed reactions of hindered isocyanates with
alcohols: (a) Duggan, M. E.; Imagire, J. S. Synthesis 1989,
131. (b) Benalil, A.; Roby, P.; Carboni, B.; Vaultier, M.
Synthesis 1991, 787. (c) Spino, C.; Joly, M.-A.; Godbout, C.;
Arbour, M. J. Org. Chem. 2005, 70, 6118.
(9) St. Denis, J. D.; Yudin, A. K. Org. Biomol. Chem. 2012, 10,
7900.
Synthesis 2014, 46, 445–454
© Georg Thieme Verlag Stuttgart · New York