Concise synthesis of α-amino cyclic boronates: Via multicomponent coupling of salicylaldehydes, amines, and B2(OH)4

Article abstract of DOI:10.1039/d0gc00346h

We report here a concise synthesis of α-amino cyclic boronates via multicomponent coupling of readily available salicylaldehydes, amines, and B₂(OH)₄. The process can be carried out at room temperature in ethanol, does not require ca

Full text of DOI:10.1039/d0gc00346h

View Article Online
View Journal
Green
Chemistry
Cutting-edge research for a greener sustainable future
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: W. Ming, X. Liu, A.
Friedrich, J. Krebs, Y. P. Budiman, M. Huang and T. B. Marder, Green Chem., 2020, DOI:
10.1039/D0GC00346H.
Volume 20
This is an Accepted Manuscript, which has been through the
Number
May 2018
Pages 1919-2160
9
7
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Cutting-edge research for a greener sustainable future
rsc.li/greenchem
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1463-9262
PAPER
Paul T. Anastas et al.
The Green ChemisTREE: 20 years after taking root with the 12
principles
rsc.li/greenchem

Page 1 of 10
Green Chemistry
View Article Online
DOI: 10.1039/D0GC00346H
Concise synthesis of α-amino cyclic boronates via multicomponent coupling
of salicylaldehydes, amines, and B2(OH)4
Wenbo Ming,a Xiaocui Liu,a Alexandra Friedrich,a Johannes Krebs,a Yudha P. Budiman,a,b Mingming Huang,a
Todd B. Marder*a
a
Institute of Inorganic Chemistry and Institute for Sustainable Chemistry & Catalysis with Boron,
Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
b
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, 45363
Jatinangor, Indonesia
E-mail: todd.marder@uni-wuerzburg.de
KEYWORDS: aminoboronic acids · benzoxaboroles · borylation · catalyst-free · cyclic boronic acids
Abstract: We report here a concise synthesis of α-amino cyclic boronates via multicomponent coupling of
readily available salicylaldehydes, amines, and B2(OH)4. The process can be carried out at room
temperature in ethanol, does not require catalysts or additives, and is easy to scale up. Aminals and
ligated boroxines are intermediates in this reaction.
Organoboron compounds have numerous applications in organic synthesis, pharmaceuticals and
functional materials.1 In particular, α-aminoboronic acids and their derivatives are important due to their
roles as bio-active agents, functional materials, and synthetic building blocks.2 For example, α-amino
cyclic boronate A, and its macrocyclic derivative B, are HCV NS3 serine protease inhibitors (IC50 23 nM
and 43 nM, respectively) (Scheme 1).3 Vaborbactam, approved by the FDA in 2017, is a β-lactamase
inhibitor based on a cyclic boronic acid pharmacophore. It has been used in trials investigating the
treatment of bacterial infections in subjects with varying degrees of renal insufficiency (Scheme 1, C).4
Taniborbactam is a new-generation cyclic boronate β-lactamase inhibitor, which has a unique
broad-spectrum activity, covering both serine-β-lactamases and metallo-β-lactamases (Scheme 1, D).5
1

Green Chemistry
Page 2 of 10
F
O
N
N
H
OH
B
O
O
H
N
View Article Online
DOI: 10.1039/D0GC00346H
O
N
N
S
O
O
B
N
H2N
O
HN
HO
O
N
O
H
O
COOH
O
B
H
N
O
CO2H
O
HO
O
B
OH
O
N
O
H
O
N
C, vaborbactam
approved by the FDA in 2017
D, taniborbactam
Phase III clinical trial
O
H
A
B
HCV NS3 protease inhibitor
macrocyclic HCV NS3 protease inhibitor


-lactamase inhibitor
-lactamase inhibitor
Scheme 1 Examples of enzyme inhibitors possessing an α-amino cyclic boronate motif.
The therapeutic potential of α-amino cyclic boronates provides a driving force to develop and refine
efficient and green methods for their synthesis. However, compared with their non-cyclic derivatives,6
relatively few methods are available for the preparation of α-amino cyclic boronates. Traditional synthetic
methods are based on multi-step reactions, including Ir-catalysed borylation, Matteson’s boronic ester
homologation, nucleophilic amination, cyclization, etc. (Scheme 2a).4a,7 In 2017, Parra, Tortosa and
coworkers synthesized a series of chiral α-aminoboronic esters by a Cu-catalysed asymmetric
hydroboration of β-amidoacrylates. With these borylated products in hand, hemiboronates were prepared
by hydrolysis of the pinacol boronic ester, and an N-Boc protected derivative was transformed into a
primary α-aminoboronate (Scheme 2b).8 These useful methods require harsh conditions, multi-step
procedures, and/or metal catalysts. Additionally, the starting materials usually require several steps to
prepare. Thus, development of efficient and versatile chemical transformations for synthesizing α-amino
cyclic boronates from readily available starting materials is highly desirable.
Aldehydes and amines have been widely utilised in multicomponent Mannich, Strecker, and Petasis
reactions, etc., and are ideal starting materials as they are abundant, inexpensive and readily available
from commercial suppliers. Bypassing the isolation of imine or iminium intermediates increases the
product scope, reduces the number of steps, and is thus more economical and sustainable.
2

Page 3 of 10
Green Chemistry
a) Reported synthetic route to Vaborbactam.4a,7
O
Bpin
TBDMS
O
TBDMSCl
[Ir(cod)Cl]2, dppb
HBpin, CH2Cl2
O
O
O
O
O
View Article Online
DOI: 10.1039/D0GC00346H
Imidazole, CH2Cl2
OH
O
TBDMS
OH
OH
Cl
nBuLi, DCM
-95 °C, THF
O
O
O
B
B
O
O
THF
O
O
O
O
TBDMS
O
TBDMS
O
S
1) LiHMDS, THF,
-78 °C to rt
OH
B
H
N
HN
3 N HClaq, dioxane
reflux
S
O
O
O
B
2) 2-Thiopheneacetic acid
EDCl, HOBT, NMM, CH2Cl2
O
COOH
O
O
O
TBDMS
b) Parra and Tortosa’s protocol to synthesize α-amino cyclic boronates.8
HO
CuCl (10 mol %)
O
O
B
O
R = Ph
(R)-SEGPHOS (11 mol %)
O
O
NaOtBu (1.0 equiv)
iBu(OH)2, pentane
MeOH, 1N HClaq
O
O
O
Bpin O
N
H
Ph
PPh2
PPh2
R
N
R
N
OEt
H
HO
B2pin2 (1.1 equiv)
MeOH (4.0 equiv)
THF, rt, 3 h
H
R = OtBu
O
B
O
OEt
O
O
(R)-SEGPHOS
ClH3N
c) Catalyst- and additive-free synthesis of α-amino cyclic boronates via multicomponent coupling (this
work).
R1
R1
R2
Cl
O
H
R2
N
OH
O
N
R1 R2
1 N HClaq
H
EtOH, rt, 1 h
O B
+
+
B2(OH)4
H
N
H
R3
B
R3
B OH
O
O B
OH
O
5
OH
1
2
3
4
One-pot
Scheme 2 Previously reported methods for the synthesis α-amino cyclic boronates, and our method.
We report here the synthesis of diverse α-amino cyclic boronates via the multicomponent coupling of
commercially available salicylaldehydes, amines, and tetrahydroxydiboron [B2(OH)4]. The process is
simple, can be run in a green solvent, and does not require catalysts or additives (Scheme 2c).
Our initial studies showed that a novel ligated boroxine 4a was formed in 24 h, when salicylaldehyde 1a,
morpholine 2a and B2(OH)4 were mixed in toluene at room temperature (Table 1, Entry 1). Optimisation of
the reaction showed that polar solvents were better than non-polar ones, giving the product in 94%
isolated yield, when CH3CN was used (Entries 2-7). Compound 4a was formed in 93% yield in only 12 h
(Entry 8) and, due to its low solubility in CH3CN, the product can be easily separated via filtration.
3

Green Chemistry
Page 4 of 10
Table 1 The development of optimized conditions for ligated boroxine formation[a]
O
O
CHO
OH
N
OH
H
conditions
View Article Online
B2(OH)4
+
+
O B
DOI: 10.1039/D0GC00346H
N
H
B
O
O B
O
1a
2a
3
OH
4a
Entry Solvent Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
toluene
Et2O
24
24
24
24
24
24
24
12
6
49
38
65
68
72
89
94
93
72
CH2Cl2
THF
EtOAc
acetone
MeCN
MeCN
MeCN
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol, 1.0
equiv), 3 (0.75 mmol, 1.5 equiv), solvent (2 mL), in air at
ambient temperature, with isolated yields of product.
With optimised conditions in hand, the substrate scope was then systematically studied, and the results
are compiled in Scheme 3. Secondary aliphatic amines, including piperidine, pyrrolidine, Bn2NH,
BnMeNH, Me2NH, Et2NH, and nPr2NH were suitable substrates for this reaction. Both electron-donating
methyl, methoxy, and t-butyl, and electron-withdrawing bromide and fluoride substituents on the
salicylaldehyde were tolerated (Scheme 3). A convenient gram-scale reaction (10 mmol) of 1a gives 4a in
91% yield (2.791 g). The structures of the products were exemplified by single-crystal X-ray diffraction
studies of 4a, 4d, and 4p (Figure 1).
4

Page 5 of 10
Green Chemistry
R1
R2
N
OH
O
CHO
OH
H
MeCN
R1 R2
O
B
R3
B2(OH)4
+
+
N
H
R3
B
rt, 12 h
O
O
B
View Article Online
OH
1
2
3
4
DOI: 10.1039/D0GC00346H
O
Bn
H
Bn
N
OH
O
N
OH
O
B
OH
N
OH
O
B
OH
N
OH
O
B
OH
H
H
H
O
B
O
O
B
O
B
O
O
B
B
B
B
B
O
O
O
B
O
O
O
OH
4a
4b
4c
4d
, 71%
, 93%
, 88%
, 82%
10 mmol scale, 2.791 g, 91%
nPr
H
Et
H
nPr
N
O
B
Bn
Et
N
O
B
N
N
O
B
OH
O
OH
O
B
OH
OH
O
B
OH
OH
O
B
OH
H
H
O
B
B
B
B
B
O
O
O
O
B
O
O
O
O
OH
4e
4f
4g
4h
, 65%
, 79%
, 84%
, 72%
O
O
O
N
O
B
O
N
N
N
O
B
OH
O
B
OH
OH
B
O
B
OH
B
O
B
OH
B
H
H
H
H
MeO
F
O
O
B
O
B
O
B
O
B
OH
O
O
O
O
O
O
Br
OH
OH
4i
4j
4k
4l
, 89%
, 84%
, 75%
O
, 77%
O
N
O
B
O
O
N
N
OH
B
O
B
OH
O
OH
O
N
H
OH
O
B
OH
tBu
H
H
H
O
O
B
O
O
B
O
O
B
B
B
B
O
O
O
O
B
B
O
MeO
tBu
4p
, 68%
OH
OH
OH
OMe
4n
F
4m
4o
, 83%
, 72%
, 82%
Reaction conditions: 1 (0.5 mmol, 1.0 equiv), 2 (0.5 mmol, 1.0 equiv) and 3 (0.75 mmol, 1.5 equiv) in
MeCN (2 mL) in air at ambient temperature unless otherwise specified, with isolated yields of target
product.
Scheme 3 Substrate scope of synthesis of boroxines.
4a
4d
4p
Figure 1. Molecular structures of 4a, 4d, and 4p.
Given its low price, low boiling point and low toxicity, ethanol is widely used as a green solvent in organic
synthesis.9 With ethanol as the solvent for our reaction, one or both hydroxyls were substituted by EtO-,
5

Green Chemistry
Page 6 of 10
as confirmed by NMR spectroscopy and HRMS (Scheme 4 and Figures S7 to S11). However, the
products were formed faster and in higher yields and, after work up with 1N HClaq, a
View Article Online
DOI: 10.1039/D0GC00346H
benzoxaborole-derived α-amino cyclic boronate was isolated in 79% yield.10,11 As depicted in Scheme 5,
a series of α-amino cyclic boronates were prepared via this multicomponent reaction.
O
O
O
O
O
EtOH
rt, 1 h
N
N
N
H
OEt
O
B
OH
OH
O
B
OEt
OEt
O
B
OEt
H
H
+
+
B2(OH)4
+
+
H
O
B
O
B
O
B
N
H
B
B
B
O
O
OH
O
O
O
O
1a
2a
3
4a-EtO
4a-EtO'
4a-2EtO
Scheme 4 Reaction conducted in ethanol.
R1
Cl
O
EtOH, rt, 1 h
work up with 1N HClaq
R2
N
R1 R2
H
+
+
B2(OH)4
H
N
H
R3
R3
B OH
OH
O
1
2
3
5
O
Cl
Cl
Cl
Bn
H
Bn
H
Cl
Cl
Bn
N
N
N
N
H
N
H
H
B OH
, 85%
B OH
B OH
B OH
B OH
O
O
O
O
O
5a
5b
5c
5d
5e
, 72%
, 79%
, 75%
, 83%
O
Cl
O
N
Cl
Et
nPr
H
Cl
Cl
Cl
Et
nPr
N
N
N
N
H
H
H
H
F
B OH
B OH
B OH
B OH
B OH
O
O
O
O
O
F
5f
5g
5h
5i
5j
, 81%
, 55%
, 75%
, 69%
, 74%
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol, 1.0 equiv) and 3 (0.75 mmol, 1.5 equiv), ethanol (2 mL), in air under
ambient temperature for 1h, then 2 mL 1N HClaq was added, with isolated yields of target product.
Scheme 5 Substrate scope of the one-pot synthesis of α-amino cyclic boronates.
To gain insight into the mechanism, the reaction was conducted stepwise, and aminal intermediate 4a’
was formed in 26% yield immediately upon mixing salicylaldehyde 1a and morpholine 1b in CH3CN,
1
confirmed by H NMR spectroscopy (Figure S1). Prolonging the reaction time to 12 h did not lead to an
improvement in the yield of 4a’, indicating that the formation of aminals is reversible (Figures S2–S6).
B2(OH)4 was then added to the reaction mixture, and boroxine 4a was isolated in 92% yield after stirring
for 12 h. Then, 4a was hydrolysed with 1N HClaq to give α-amino cyclic boronate 5a in 94% yield
(Scheme 6).
6

Page 7 of 10
Green Chemistry
O
O
N
O
Cl
O
O
1 N HClaq
rt, 15 min
CH3CN (2 mL)
rt, 12 h
B2(OH)4 (0.75 mmol)
N
OH
O
H
N
H
+
H
O B
B
O B
View Article Online
N
H
rt, 12 h
N
DOI: 10.1039/D0GC00346H
B OH
OH
O
O
O
OH
, 26% NMR yield
1a
2a
, 0.5 mmol
, 0.5 mmol
OH
4a'
4a
5a
, 92% isolated yield
, 94% isolated yield
1
Scheme 6
Stepwise reaction process; the yield of intermediate 4a’ was monitored by H NMR
spectroscopy (300 MHz, CDCl3, rt) using 1,3,5-trimethoxybenzene as an internal standard.
The Petasis three-component reaction between an amine, an aldehyde and an organoboron compound,
has evolved into a versatile process for the synthesis of amino acids, amino alcohols, and various
heterocycles.12 Matteson first reported ligand-facilitated trimerisation of arylboronic acids as early as
1962, when they prepared the 1 : 1 pyridine complex of vinylboronic acid anhydride, the boroxine being
generated spontaneously in a high yield.13
O
O
N
O
N
O
O
- H2O
+ H2O
- morpholine
+ morpholine
N
B2(OH)4
OH
+
H
OH
B
B
N
H
N
OH
OH
O
O
OH
4a'
O
OH
1a
2a
A
B
O
O
N
O
O
Cl
1N HClaq
hydrolysis
H2O
2 B(OH)3
-3 H2O
N
OH
O
H
N
N
H
H
O B
O B
- B(OH)3
OH
OH
B(OH)2
B
B
B OH
O
O
O
OB(OH)2
OH
4a
5a
C
D
Scheme 7 Proposed mechanism.
Based on the above, and our observations, we propose the mechanism for this multicomponent coupling
reaction shown in Scheme 7. Salicylaldehyde 1a reacts with morpholine 1b to form aminal intermediate
4a’. The key intermediate B is assembled by formation of iminium ion A, and coordination of its phenolate
oxygen to B2(OH)4.1d,14 Intramolecular boryl group transfer provides C, the immediate precursor to ligated
α-aminoboronic acid D, which can react with boric acid to give boroxine 4a. Finally, hydrolysis with 1N
HClaq affords α-amino cyclic boronate 5a.
In conclusion, we have developed a green and economical process for the synthesis of α-amino cyclic
boronates. The desired products can be obtained via a one-step multicomponent reaction from the readily
available starting materials, salicylaldehydes, amines, and B2(OH)4. Our protocol has several advantages
over previous routes including mild reaction conditions (room temperature, in air), no catalysts or
additives, easy product isolation, and green solvents (ethanol and water). Further explorations of the
7

Green Chemistry
Page 8 of 10
scope of this multicomponent reaction and applications of the benzoxaborole-derived α-amino cyclic
boronates are currently underway, and will be reported in due course.
View Article Online
DOI: 10.1039/D0GC00346H
Acknowledgement
T.B.M. thanks the Julius-Maximilians-Universität Würzburg for support. W.M., X.L., and M.H. are grateful
to the China Scholarship Council (CSC) for providing Ph.D. scholarships. Y.P.B. thanks the Indonesia
Endowment Fund for Education (LPDP) for a Ph.D. scholarship. We thank AllyChem Co. Ltd. (Dalian, P.
R. China) for a generous gift of B2(OH)4, and Jan Maier and Dr. Rüdiger Bertermann
(Julius-Maximilians-Universität Würzburg) for helpful discussions.
Reference and notes
1. (a) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010,
110, 890-931; (b) Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and
Materials, ed. D. G. Hall, Wiley-VCH, Weinheim, 2nd edn., 2011; (c) Synthesis and Application of
Organoboron Compounds, eds. E. Fernández and A. Whiting, Springer, Berlin, 2015; (d) E. C.
Neeve, S. J. Geier, I. A. I. Mkhalid, S. A. Westcott and T. B. Marder, Chem. Rev., 2016, 116,
9091-9161; (e) Handbook of Boron Science with Applications in Organometallics, Catalysis,
Materials and Medicine, World Scientific Publishing Europe Ltd., London, 2018.
2. (a) D. S. Matteson, Med. Res. Rev., 2008, 28, 233-246; (b) S. Touchet, F. Carreaux, B. Carboni, A.
Bouillon and J.-L. Boucher, Chem. Soc. Rev., 2011, 40, 3895-3914; (c) P. Andres, G. Ballano, M. I.
Calaza and C. Cativiela, Chem. Soc. Rev., 2016, 45, 2291-2307; (d) A. Šterman, I. Sosič, S. Gobec
and Z. Časar, Organic Chemistry Frontiers, 2019, 6, 2991-2998; (e) S. Jin, C. Zhu, M. Li and B.
Wang, Bioorg. Med. Chem. Lett., 2009, 19, 1596-1599; (f) S. Jin, C. Zhu, Y. Cheng, M. Li and B.
Wang, Bioorg. Med. Chem., 2010, 18, 1449-1455; (g) S. R. Inglis, M. Strieker, A. M. Rydzik, A.
Dessen and C. J. Schofield, Anal. Biochem., 2012, 420, 41-47; (h) T. Ohmura, T. Awano and M.
Suginome, J. Am. Chem. Soc., 2010, 132, 13191-13193; (i) T. Awano, T. Ohmura and M. Suginome,
J. Am. Chem. Soc., 2011, 133, 20738-20741; (j) W. Ming, H. S. Soor, X. Liu, A. Trofimova, A. K.
Yudin and T. B. Marder, Chem. Soc. Rev., submitted.
3. (a) X. Li, Y.-K. Zhang, Y. Liu, C. Z. Ding, Q. Li, Y. Zhou, J. J. Plattner, S. J. Baker, X. Qian, D. Fan, L.
Liao, Z.-J. Ni, G. V. White, J. E. Mordaunt, L. X. Lazarides, M. J. Slater, R. L. Jarvest, P. Thommes,
M. Ellis, C. M. Edge, J. A. Hubbard, D. Somers, P. Rowland, P. Nassau, B. McDowell, T. J.
Skarzynski, W. M. Kazmierski, R. M. Grimes, L. L. Wright, G. K. Smith, W. Zou, J. Wright and L. E.
Pennicott, Bioorg. Med. Chem. Lett., 2010, 20, 3550-3556; (b) X. Li, Y.-K. Zhang, Y. Liu, C. Z. Ding,
Y. Zhou, Q. Li, J. J. Plattner, S. J. Baker, S. Zhang, W. M. Kazmierski, L. L. Wright, G. K. Smith, R. M.
Grimes, R. M. Crosby, K. L. Creech, L. H. Carballo, M. J. Slater, R. L. Jarvest, P. Thommes, J. A.
Hubbard, M. A. Convery, P. M. Nassau, W. McDowell, T. J. Skarzynski, X. Qian, D. Fan, L. Liao, Z.-J.
8

Page 9 of 10
Green Chemistry
Ni, L. E. Pennicott, W. Zou and J. Wright, Bioorg. Med. Chem. Lett., 2010, 20, 5695-5700.
4. (a) S. J. Hecker, K. R. Reddy, M. Totrov, G. C. Hirst, O. Lomovskaya, D. C. Griffith, P. King, R.
Tsivkovski, D. Sun, M. Sabet, Z. Tarazi, M. C. Clifton, K. Atkins, A. Raymond, K. T. Potts, J.
View Article Online
DOI: 10.1039/D0GC00346H
Abendroth, S. H. Boyer, J. S. Loutit, E. E. Morgan, S. Durso and M. N. Dudley, J. Med. Chem., 2015,
58, 3682-3692; (b) O. Lomovskaya, D. Sun, D. Rubio-Aparicio, K. Nelson, R. Tsivkovski, D. C.
Griffith and M. N. Dudley, Antimicrob. Agents Chemother., 2017, 61, e01443-01417.
5. (a) J. Brem, R. Cain, S. Cahill, M. A. McDonough, I. J. Clifton, J.-C. Jiménez-Castellanos, M. B.
Avison, J. Spencer, C. W. G. Fishwick and C. J. Schofield, Nat. Comm., 2016, 7, 12406; (b) S. T.
Cahill, R. Cain, D. Y. Wang, C. T. Lohans, D. W. Wareham, H. P. Oswin, J. Mohammed, J. Spencer,
C. W. G. Fishwick, M. A. McDonough, C. J. Schofield and J. Brem, Antimicrob. Agents Chemother.,
2017, 61, e02260-02216; (c) S. T. Cahill, J. M. Tyrrell, I. H. Navratilova, K. Calvopiña, S. W.
Robinson, C. T. Lohans, M. A. McDonough, R. Cain, C. W. G. Fishwick, M. B. Avison, T. R. Walsh,
C. J. Schofield and J. Brem, Biochim. Biophys. Acta, 2019, 1863, 742-748; (d) A. Krajnc, J. Brem, P.
Hinchliffe, K. Calvopiña, T. D. Panduwawala, P. A. Lang, J. J. A. G. Kamps, J. M. Tyrrell, E. Widlake,
B. G. Saward, T. R. Walsh, J. Spencer and C. J. Schofield, J. Med. Chem., 2019, 62, 8544-8556; (e)
G. W. Langley, R. Cain, J. M. Tyrrell, P. Hinchliffe, K. Calvopiña, C. L. Tooke, E. Widlake, C. G.
Dowson, J. Spencer, T. R. Walsh, C. J. Schofield and J. Brem, Bioorg. Med. Chem. Lett., 2019, 29,
1981-1984.
6. Reported methods for the preparation of α-amino boronates from imines, alkenes, α-boryl
isocyanates etc., see: (a) D. Nishikawa, K. Hirano and M. Miura, J. Am. Chem. Soc., 2015, 137,
15620-15623; (b) N. Hu, G. Zhao, Y. Zhang, X. Liu, G. Li and W. Tang, J. Am. Chem. Soc., 2015,
137, 6746-6749; (c) S. Kawamorita, T. Miyazaki, T. Iwai, H. Ohmiya and M. Sawamura, J. Am.
Chem. Soc., 2012, 134, 12924-12927; (d) G. Mann, K. D. John and R. T. Baker, Org. Lett., 2000, 2,
2105-2108; (e) K. Hong and J. P. Morken, J. Am. Chem. Soc., 2013, 135, 9252-9254; (f) M. A.
Beenen, C. An and J. A. Ellman, J. Am. Chem. Soc., 2008, 130, 6910-6911; (g) C. Sole, H. Gulyas
and E. Fernández, Chem. Commun., 2012, 48, 3769-3771; (h) D. S. Matteson, J. Org. Chem., 2013,
78, 10009-10023; (i) Z. He, A. Zajdlik, J. D. St. Denis, N. Assem and A. K. Yudin, J. Am. Chem. Soc.,
2012, 134, 9926-9929; (j) W. Ming, X. Liu, A. Friedrich, J. Krebs and T. B. Marder, Org. Lett., 2020,
22, 365-370.
7. D. Fan, R. L. Jarvest, L. Lazarides, Q. Li, X. Li, Y. Liu, L. Liao, J. E. Mordaunt, Z.-J. Ni, J. Plattner, X.
Qian, M. J. Slater, G. V. White and Y. K. Zhang, World Pat., WO2009046098A1, 2009..
8. A. López, T. B. Clark, A. Parra and M. Tortosa, Org. Lett., 2017, 19, 6272-6275.
9. C. Capello, U. Fischer and K. Hungerbühler, Green Chem., 2007, 9, 927-934.
10. Due to its physicochemical and drug-like properties, benzoxaborole is a privileged structure in
medicinal chemistry, which has been widely applied as antifungal, antibacterial, antiviral,
anti-parasite, and anti-inflammatory agents. See: (a) S. J. Baker, Y.-K. Zhang, T. Akama, A. Lau, H.
Zhou, V. Hernandez, W. Mao, M. R. K. Alley, V. Sanders and J. J. Plattner, J. Med. Chem., 2006, 49,
4447-4450; (b) F. L. Rock, W. Mao, A. Yaremchuk, M. Tukalo, T. Crépin, H. Zhou, Y.-K. Zhang, V.
Hernandez, T. Akama, S. J. Baker, J. J. Plattner, L. Shapiro, S. A. Martinis, S. J. Benkovic, S.
Cusack and M. R. K. Alley, Science, 2007, 316, 1759-1761; (c) Q.-H. Hu, R.-J. Liu, Z.-P. Fang, J.
Zhang, Y.-Y. Ding, M. Tan, M. Wang, W. Pan, H.-C. Zhou and E.-D. Wang, Sci. Rep., 2013, 3, 2475;
(d) J. Zhang, M. Zhu, Y. Lin and H. Zhou, Sci. China Chem., 2013, 56, 1372-1381; (e) E. Sonoiki, C.
9

Green Chemistry
Page 10 of 10
L. Ng, M. C. S. Lee, D. Guo, Y.-K. Zhang, Y. Zhou, M. R. K. Alley, V. Ahyong, L. M. Sanz, M. J.
Lafuente-Monasterio, C. Dong, P. G. Schupp, J. Gut, J. Legac, R. A. Cooper, F.-J. Gamo, J. DeRisi,
Y. R. Freund, D. A. Fidock and P. J. Rosenthal, Nat. Comm., 2017, 8, 14574; (f) A. Nocentini, C. T.
View Article Online
DOI: 10.1039/D0GC00346H
Supuran and J.-Y. Winum, Expert Opin. Ther. Pat., 2018, 28, 493-504.
11. A reported synthetic route7 to benzoxaborole-derived α-amino cyclic boronates is outlined below.
Cl
O
O
DCM, nBuLi
O
B
O
B
MOM-Cl
B
O
O
DMF, 0 °C to rt, 2 h
THF, -100 °C to rt, 12 h
O
OMe
OH
O
OMe
TMS
N
TMS
O
B
NH3Cl
B OH
LiHMDS
HCl (4M in dioxane)
hexane, -78 °C to rt, overnight
O
THF, -78 °C to rt, 2 h
O
O
OMe
12. (a) N. A. Petasis and S. Boral, Tetrahedron Lett., 2001, 42, 539-542; (b) Q. Wang and M. G. Finn,
Org. Lett., 2000, 2, 4063-4065; (c) N. R. Candeias, F. Montalbano, P. M. Cal and P. M. Gois, Chem.
Rev., 2010, 110, 6169-6193; (d) C. A. Guerrera and T. R. Ryder, in Boron Reagents in Synthesis, ed.
A. Coca, American Chemical Society, Washington, DC, 2016, ch. 9, pp. 275-311; (e) P. Wu, M.
Givskov and T. E. Nielsen, Chem. Rev., 2019, 119, 11245-11290.
13. D. S. Matteson, J. Org. Chem., 1962, 27, 3712-3712.
14. (a) S. Pietsch, E. C. Neeve, D. C. Apperley, R. Bertermann, F. Mo, D. Qiu, M. S. Cheung, L. Dang, J.
Wang, U. Radius, Z. Lin, C. Kleebergꢀ and T. B. MarderꢀChem. Eur. J., 2015, 21, 7082-7098; (b) R. D.
Dewhurst, E. Neeve, T. B. Marder and H. Braunschweig, Chem. Commun., 2015, 51, 9594-9607; (c)
C. Kleeberg, L. Dang, Z. Lin and T. B. Marder, Angew. Chem. Int. Ed., 2009, 48, 5350-5354; (d) A. B.
Cuenca, R. Shishido, H. Ito and E. Fernández, Chem. Soc. Rev., 2017, 46, 415-430.
10