Regioselective synthesis of: Ortho -iodobiphenylboronic acid derivatives: A superior catalyst for carboxylic acid activation

Article abstract of DOI:10.1039/c9nj05708k

An efficient and versatile synthesis of ortho-iodobiphenylboronic acids via the highly regioselective metal-iodine exchange (MIE) of 2,3-diiodobiphenyls is reported. The site-selectivity is very much controlled by the size of the biphenyl fragment, providing only the terminal arylboronic acid derivatives in excellent site-selectivity. The nature of the substituents (R¹ and R²) on the biphenyls is found to have an influence on the reactivity but not on the regioselectivity. The best reactivity and the highest isolated yields were furnished with products bearing electron-donating groups. The synthesized derivatives were also tested for in vitro antimicrobial activity against four strains of bacteria and one fungal strain. This revealed that (2-iodo-4′-isopropyl-[1,1′-biphenyl]-3-yl)boronic acid 6_A and (3-(benzo[d][1,3]dioxol-5-yl)-2-iodo-5-methoxyphenyl)boronic acid 22_A possess the most potent antibacterial and antifungal activity with MICs of 0.10 and 0.3 mg mL^-1 for B. cereus and C. albicans respectively. The catalytic activity was also examined towards an amidation reaction at ambient temperature and this revealed a new optimal catalyst, (2-iodo-4′,5-dimethoxy-[1,1′-biphenyl]-3-yl)boronic acid 19_A providing a remarkable increase in the amide yields, including α-aminoacids. This work discloses a protocol for the first synthesis of hitherto unknown ortho-iodobiphenylboronic acid derivatives that is scalable, and general in scope, where no chromatographic purification is necessary and the products are indeed potential organocatalysts.

Full text of DOI:10.1039/c9nj05708k

View Article Online
View Journal
NJC
New Journal of Chemistry
Accepted Manuscript
A journal for new directions in chemistry
This article can be cited before page numbers have been issued, to do this please use: R. Al-Zoubi, W. K.
Al-Jammal and R. McDonald, New J. Chem., 2020, DOI: 10.1039/C9NJ05708K.
Volume 42
This is an Accepted Manuscript, which has been through the
Number
6
21 March 2018
Pages 3963-4776
Royal Society of Chemistry peer review process and has been
accepted for publication.
NJC
New Journal of Chemistry
rsc.li/njc
A journal for new directions in chemistry
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 1144-2546
PAPER
Chechia Hu, Tzu-Jen Lin et al.
Yellowish and blue luminescent graphene oxide quantum dots
prepared via a microwave-assisted hydrothermal route using
H2O2 and KMnO4 as oxidizing agents
rsc.li/njc

Page 1 of 15
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
7
8
Regioselective Synthesis of ortho-Iodobiphenylboronic Acid Derivatives: A
Superior Catalyst for Carboxylic Acid Activation
Raed M. Al-Zoubi,*a Walid K. Al-Jammala and Robert McDonaldb
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aDepartment of Chemistry, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan
bDepartment of Chemistry, Gunning-Lemieux Chemistry Centre, University of Alberta, Edmonton, Alberta, T6G2G2, Canada
*Corresponding author. Tel.: + 962-2-7201000-Ext 23651; fax: + 962-2-7201071; e-mail: rmzoubi@just.edu.jo
Keywords: ortho-iodobiphenylboronic acids, Grignard reactions, MIC, Regioselectivity, Metal-iodine exchange, Substituent effect,
Organocatalyst, Amidation, Antibacterial, Antifungal
Abstract: An efficient and versatile synthesis of ortho-iodobiphenylboronic acids via highly regioselective Metal-Iodine Exchange (MIE) of 2,3-
diiodobiphenyls is reported. The site-selectivity is extremely controlled by the size of the biphenyl fragment providing only the terminal
arylboronic acid derivatives in excellent site-selectivity. The nature of substituents (R1 and R2) on the biphenyls is found to have influence on the
reactivity but not the regioselectivity. The best reactivity and the highest isolated yields were furnished with products bearing electron donating
groups. The synthesized derivatives were also tested for in vitro antimicrobial activity against four strains of bacteria and one fungal strain. It
revealed that (2-iodo-4'-isopropyl-[1,1'-biphenyl]-3-yl)boronic acid 6A and (3-(benzo[d][1,3]dioxol-5-yl)-2-iodo-5-methoxyphenyl)boronic acid
22A possess the most potent antibacterial and antifungal activity with MIC of 0.10 and 0.3 mg/mL for B. cereus and C. albicans respectively. The
catalytic activity was also examined towards amidation reaction at ambient temperature and revealed a new optimal catalyst, 2-iodo-4',5-
dimethoxy-[1,1'-biphenyl]-3-yl)boronic acid 19A providing a remarkable increase in the amide yields including - mino cids. This work discloses
a protocol for the first synthesis of hitherto unknown ortho-iodobiphenylboronic acid derivatives that is scalable, general in scope, no
chromatographic purification is necessary and indeed potential organocatalysts.
Introduction
Arylboronic acids and particularly halogenated motifs are largely utilized intermediates in pharmaceutical chemistry and in
chemical industry. The unique chemical and
electronic properties of boronic acid as mild Lewis
acids let to interact reversibly with cis-diol
OH
MeO
B
functionality found in ribonucleosides and
F
B
OH
carbohydrates.[1] Industrially, ortho-halogenated
OH
I
arylboronic acids were reported to have
a
MIBA
remarkable bifunctional organocatalytic activity for
“green” chemical transformation of alcohols and
carboxylic acids.[2] It is believed that ortho-halo can
be harnessed to further tune the boron oxophilicity
for better reactivity.[3] Several examples where
found in literature. For example, 2-iodo-5-
methoxyphenylboronic acid MIBA (1, Fig. 1) is an
ortho-iodinated arylboronic acid contains a methoxy
group the aryl ring, is reported as a superior
organocatalytic activity for amide bond formation at
ambient temperature providing only water as
OH
1
2
(2-iodo-5-
(2-fluoro-5-(4-methylcyclohexyl)-
[1,1'-biphenyl]-3-yl)boronic acid
methoxyphenyl)boronic acid
Amidation Catalyst
Phosphorescent OLED material
for luminescent application
OH
F
OH
F
B
B
OH
OH
CN
Br
byproduct.[2b-d]
Additionally,
(2-fluoro-5-(4-
4
3
(4-bromo-2-fluoro-4'-propyl-[1,1'-
biphenyl]-3-yl)boronic acid
methylcyclohexyl)-[1,1'-biphenyl]-3-yl)boronic acid
2, is an ortho-fluorinated biphenylboronic acid
derivative, contains a fluoro group at C2 on the aryl
ring, is reported as a phosphorescent OLED material
for luminescent application.[4] Furthermore, (2'-
cyano-2-fluoro-[1,1'-biphenyl]-3-yl)boronic acid 3, a
small fluorinated biphenylboronic acid derivative
(2'-cyano-2-fluoro-[1,1'-biphenyl]-
3-yl)boronic acid
GABA receptor for anxiety
disorders
Liquid Crystal application
Figure 1.
Some biologically and chemically active halogenated organoboron compounds
in medicine and industry

New Journal of Chemistry
Page 2 of 15
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
7
8
9
that contains a cyano group at C2 on the second aromatic ring, is reported to have a selective and orally bio-available GABA
Aα2/3α binding site in rats and dogs.[5] Lastly, (4-bromo-2-fluoro-4'-propyl-[1,1'-biphenyl]-3-yl)boronic acid (4, Fig. 1), a doubly
ortho-halogenated biphenylboronic acid, is discovered to have extremely high negative dielectric anisotropy and relatively low
rotary viscosity for liquid crystal application.[6] The status quo of these compounds and other halogenated boronic acids[7] like
Tavaborole (AN-2690) have initiated great attention and enthusiasm for developing halogenated boron-based molecules for
their novel applications in industry and medicine.[8] Although there are a number of published protocols for the synthesis of
halogenated arylboronic acids,[2c, 2e, 2h, 9] a practical protocol to access ortho-iodobiphenylboronic acid derivatives has not been
reported yet.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Herein, we report the first method for the synthesis of hitherto unknown ortho-iodobiphenylboronic acid derivatives via site-
selective metal iodine exchange of 5-substituted-2,3-diiodobiphenyls in a single step that is wide in scope, readily scalable and
provides good isolated yields. A number of 5-substituted-2,3-diiodobiphenyls bearing electron donating, neutral and electron
withdrawing groups were examined under the optimal conditions affording the desired iodinated biphenylboronic acid
products in excellent site-selectivity and indeed are hard to be made by other means.
Results and discussion
Owing to the known biological and chemical activities of halogenated phenyl and biphenylboronic acid derivatives in literature
and also to our interest in the industrial catalytic activity of ortho-iodinated arylboronic acids for green chemical
transformations, we felt charmed to examine the metal-iodine exchange (MIE) on 5-substituted-2,3-diiodobiphenyls aiming
forward to make the iodobiphenylboronic acid derivatives.
A handful examples on regioselective functionalization of 1,2-diiodo- and 1,2,3-triiodoarenes is reported in literature. Togni and
co-workers reported the synthesis of ortho-iodobenzyl alcohol derivatives using isopropylmagnesium chloride via metal-iodine
exchange reaction from 1,2-diiodobenzene.[10] We also reported three regioselective Metal-Iodine exchange reaction of 1,2,3-
triiodobenzene derivatives with isopropylmagnesium chloride for the synthesis of diiodobenzyl alcohols, diiodophenylboronic
acids and iodinated benzoboroxoles.[11] The desired products were isolated in good yields where the regioselectivity and
reactivity of the reactions per se are controlled by both the nature of the substituent at C-5 on the aryl group and the type of
electrophile favoring the displacement to occur either at the terminal or internal position. Other works on regioselective Metal-
bromine/iodine exchange reaction are also reported.[12]
The metal-iodine exchange/functionalization with only two regiochemically different C-I positions on 5-substituted-2,3-
diiodobiphenyls provide no more than two possible biphenylboronic acid products, the terminal and the internal
biphenylboronic acid products (Scheme 1). Therefore, the adequate use of only one mole equivalent of a base is theoretically
sufficient to exchange one of the two iodo groups, making arylmetal intermediate that quenched with borate reagent making
the desired iodinated biphenylboronic acid products.
Terminal
Internal
HO
OH
OH
I
I
B
Metal-Halogen Exchange
reaction
I
B
I
OH
+/or
R1
Ar
followed by (MeO)3B
R1
Ar
R1
Ar
5 - 25
A
B
R1 = EDG, EWG, Neutral, H
2-iodobiphenylboronic
acid derivative
3-iodobiphenylboronic
acid derivative
Scheme 1
Possible iodinated biphenylboronic acid regioisomers from Metal-Iodine Exchange (MIE)
of 5-substituted-2,3-diiodobiphenyls
Therefore, to examine this hypothesis, 2,3-diiodobiphenyl 5 and trimethylborate were used as model substrates as shown in
Table 1. The reaction with 2,3-diiodobiphenyl 5 using different alkyl lithium reagents like tert-BuLi, sec-BuLi or n-BuLi at -78
oC/THF provided non-clean reactions (Table 1, entries 1-3). The use of isopropylmagnesium chloride at -78 oC, as expected from
our previous work, gave a clean reaction in THF and provided only one biphenylboronic acid product as found by NMR. The
displacement occurred clearly at C-3 position forming the terminal product as a sole regioisomer (2-iodo-[1,1'-biphenyl]-3-
yl)boronic acid 5A in 51% yield, which is also supported by X-ray crystallography (Table 1, entry 4). The regioselectivity of
reaction using isopropylmagnesium chloride with 2,3-diiodobiphenyl 5 confirmed the stability of the terminal arylmagnesium
intermediate, the less hindered and the more accessible site. Changing the reaction conditions by using other solvents was

Page 3 of 15
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
found to be unsuccessful providing lower isolated yields (Table 1, entries 5-6). Lowering the temperature of the reaction to -50
oC/THF provided unwanted side products together with the desired boronic acid 5A and in lower isolated yield 33% (Table 1,
entry 7). The higher isolated yield for this reaction was obtained by using 1.1 equivalents of isopropylmagnesium chloride at -78
oC in THF (Table 1, entry 8). The reaction also performed well on gram scale (Table 1, entry 10).
7
8
9
Table 1.
Conditions for the regioselective Metal-Iodine Exchange reaction of 2,3-diiodo-1,1'-biphenyl
5 followed by trimethylborate
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HO
OH
I
I
OH
B
B
1. Metal-Iodine Exchange
reaction conditions
I
I
OH
+
2. (MeO)3B
5B
5
5A
d
Yield of 5 (%)b
Yield of 5A (%)c Ratio 5A:5B
Conditionsa
Entry
tert-BuLi (2.0 equiv.), -78 oC, THF
sec-BuLi (1.0 equiv.), -78 oC, THF
n-BuLi (1.0 equiv.), -78 oC, THF
i-PrMgCl (1.0 equiv.), -78 oC, THF
i-PrMgCl (1.0 equiv.), -78 oC, diethylether
i-PrMgCl (1.0 equiv.), -78 oC, toluene
i-PrMgCl (1.0 equiv.), -50 oC, THF
1
2
3
4
5
-
-
-
-
-
-
-
-
-
21
51
40e
35
33e
>99:1
>99:1
>99:1
23
29
11
12
7
6
7
8
>99:1
>99:1
>99:1
>99:1
60 (62f)
i-PrMgCl (1.1 equiv.), -78 oC, THF
i-PrMgCl (1.2 equiv.), -78 oC, THF
i-PrMgCl (1.1 equiv.), -78 oC, THF
49
9
10g
8
58
aConditions: All reactions were carried out using 1.0 mmol (1.0 equiv., 0.05 M) of 2,3-diiodo-1,1'-
biphenyl 5 starting material in 20 mL solvent. bRecovered starting material. cIsolated yield. dRatio of
regioisomers. eUnknown mixture of products were isolated along with 5A. f BORSM yield . g1.0 gram
scale (2.46 mmol).
The superb site-selectivity and promising isolated yield (Table 1, entry 8) encouraged us to examine our previously synthesized
5-substituted-2,3-diiodobiphenyls under the optimized conditions aiming to expand the scope of ortho-iodinated arylboronic
acids for their application in industry and medicine.[13] Therefore, a variety of 5-substituted-2,3-diiodobiphenyls were subjected
to the optimized conditions and gladly provided the desired products with superior regioselectivity (Scheme 2). It is worth to
note that several purification techniques were examined and found that phase-switch technique is the most efficient one to
purify these products.[14] On the other hand, flash chromatography provided decomposition and ipso-deboronation side
products.
We found that the nature of substituents on the biphenyls (Scheme 2: R1 and R2) has a large influence on the reactivity and no
influence on the regioselectivity of MIE reaction. The scope is summarized in Scheme 2. It is found that 2,3-diiodobiphenyls
bearing electron-donating groups afforded the desired products in good to high yields (Scheme 2: 14A-24A). In contrast, neutral
and electron-withdrawing 2,3-diiodobiphenyls gave low to moderate isolated yields (Scheme 2: 5A -13A). The formation of the
internal regioisomer (Scheme 2: B) is not observed by NMR after phase-switch purification in all cases. Furthermore, The best
reactivity and the highest isolated yields were furnished with products bearing electron-donating groups at both R1 and R2 on
2,3-diiodobiphenyls (Scheme 2: 15A, 19A and 21A). Gladly, no exchange reaction with bromo or chloro groups was observed
(Scheme 2: 12A and 13A) and the reaction was tolerant to a broad range of functional groups. Unfortunately, a derivative
bearing methyl ester group at C-5 was found to be unstable and quickly decomposed upon phase-switch purification step
(Scheme 2: 25A).

New Journal of Chemistry
Page 4 of 15
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
7
8
9
Terminal
Internal
X
X
X
HO
OH
I
i) iPrMgCl (2M, 1.1 equiv.)
THF, -78 °C, 1h
OH
B
I
I
B
R2
R2
R2
I
OH
+
ii) B(OCH3)3
(
3.0 equiv.)
A
B
THF, -78 °C, 12h
R1
R1
R1
OH
Not Formed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
F
I
H3CO
B
OH
OH
B
OH
I
I
I
OH
B
B
OH
OH
OH
CH3
5
6
7
8
A, 47%
A, 60%
A, 54%
A, 63%
F
H3CO
OH
B
OH
I
I
OH
B
OH
B
I
I
B
OH
OH
OH
OH
CH3
A, 40%
CH3
F
Cl
12
A, 53%
9
10
A, 60%
11
A, 38%
OCH3
OH
OH
OH
B
I
I
I
OH
B
I
B
B
OH
OH
OH
OH
OCH3
OCH3
OCH3
Br
16
13
14
A, 63%
A, 65%
A, 83%
15
A, 86%
OCH3
OCF3
H3CO
F
H3CO
OH
OH
B
OH
B
OH
I
I
I
I
B
B
OH
OH
OH
OH
OCH3
A, 77%
OCH3
A, 80%
OCH3
A, 92%
OCH3
20
17
18
A, 67%
19
O
O
O
PhO
H3CO
OH
OH
B
OH
OH
B
I
I
I
I
B
B
N
OH
OH
OH
OH
OCH3
A, 88%
OCH3
OCH3
23
OCH3
A, 65%
24
21
22
A, 66%
A, 53%
OH
I
B
aYields are given for isolated compounds (reaction scale: 1.0
mmol). Phase-Switch technique is used to purify the products.
bDecomposed upon phase-switch purification
OH
H3CO
25
O
A, 0%b
Scheme 2.
Terminal vs Internal iodobiphenylboronic acid derivatives via regioselective Metal-Iodine exchange of
5-substituted-2,3-diiodobiphenyls and trimethylboratea

Page 5 of 15
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
The structure of ortho-iodobiphenylboronic acid derivatives are supported by X-ray diffraction methods for four products, (2-
iodo-[1,1'-biphenyl]-3-yl)boronic acid 5A, (2-iodo-5-methoxy-[1,1'-biphenyl]-3-yl)boronic acid 14A, (2-iodo-4',5-dimethoxy-[1,1'-
biphenyl]-3-yl)boronic acid 19A and (2-iodo-5-methoxy-4'-phenoxy-[1,1'-biphenyl]-3-yl)boronic acid 21A as shown in Figure 2. It
shows clearly the position of both the iodo and the boronic acid groups.[15]
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
14A
5A
19A
21A
Figure 2.
ORTEP view of (2-iodo-[1,1'-biphenyl]-3-yl)boronic acid 5A, (2-iodo-5-methoxy-[1,1'-biphenyl]-3-yl)boronic acid 14A,
(2-iodo-4',5-dimethoxy-[1,1'-biphenyl]-3-yl)boronic acid 19A and (2-iodo-5-methoxy-4'-phenoxy-[1,1'-biphenyl]-3-
yl)boronic acid 21A . Thermal Gaussian ellipsoids at 30% probability level.
A plausible mechanism for the regioselective formation of ortho-iodobiphenylboronic acids is proposed in Scheme 3. Several
approaches for metal-iodine exchange of diiodo intermediates using isopropylmagnesium chloride/bromide have been
previously studied and reported,[16] The treatment of 2,3-diiodobiphenyl with isopropylmagnesium chloride at -78oC in THF
provided immediately the yellow-color ate complex C with the less hindered and more accessible iodo group. It became an
intense yellow color within ~1 min and faded within 1-2 h based on the nature of the R-substituent. It is believed that the ortho-
iodine atom convey much thermodynamic stability of the ate complex by stabilizing the negative charge on the ortho-carbon.
Electron-withdrawing groups (R) were found to further increase the thermodynamic stability by preserving the intense yellow-
color for longer time (~2 h). The addition of trimethylborate reagent, which is known as a fast reacting electrophile,[17]
decolorized the mixture by transforming the ate complex C to the new Grignard D (off-white color) that immediately quenched
with borate reagent to form the desired boronic acid.
ate-complex
_
+
MgCl
E+
(fast reacting
B(OMe)3
)
THF, -78 oC
Fast step
~1 min
THF, -78 oC
Slow step
~1-2 h
Mg
I
I
I
I
I
+
I
Cl
THF, -78 oC
R
R
R
MgCl
R
B(OH)2
R
D
Dependant
C
Less hindered & more
accessible site
Yellow color
Off-White color
Scheme 3
Plausible mechanism for the formation of ortho-iodobiphenylboronic acids

New Journal of Chemistry
Page 6 of 15
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
Antimicrobial activity
The ortho-iodinated biphenylboronic acid products 5A-24A were then examined for in vitro antibacterial and antifungal
activities. A panel of four bacterial strains was used comprising one drug-resistant Gram negative Escherichia coli (ATCC 25922)
and three Gram positive Staphylococcus aureus (ATCC 29213), Micrococcus Luteus (ATCC 9341) and Bacillus cereus (ATCC
11778) and one fungal strain Candida albicans (a clinical sample from KAUH hospital of Jordan). Based on the diversity of the
products, selected ortho-iodobiphenylboronic acid compounds were examined (Table 2). The antimicrobial activity was
measured by the inhibition zone on the agar disk. Even though the mechanisms of activity have not been identified till now, the
microbial data obviously shows a broad-spectrum antimicrobial activity against both Gram-positive strains of bacteria as well as
antifungal activity for tested ortho-iodobiphenboronic acids (Table 2). Remarkably, no inhibition was observed for most tested
derivatives against E. coli (ATCC 25922).
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2:
The inhibition zone exhibited by synthetic ortho-iodobiphenylboronic acids 5A - 6A, 9A, 14A - 15A and 17A - 22A
against three gram-positive and one gram-negative bacteria strains as well as one fungus strain using well-
diffusion method
Synthetic ortho-iodobiphenylboronic acid compounds
Microbiological
Species
5A
6A
9A
14A
15A
17A
18A
19A
20A
21A
22A
+
+
+
13 ( 4.9)

+
+
+
+
+
+
13 ( 4.9)

18 ( 4.9) 20 ( 4.9)
20 ( 4.2) 20 ( 2.1) 12 ( 4.9) 15 ( 3.5) 10 ( 6.3)
Micrococcus Luteus
Bacillus Cereus
NI
NI







+
20 ( 7.7)

+
+
+
19 ( 4.8)

+
17 ( 4.2)

+
20 ( 3.5)

+
+
+
+
25 ( 4.2)

20 ( 4.2) 22 ( 4.2)
13 ( 5.0)
+
21 ( 4.2) 15 ( 4.2) 23 ( 4.2)


NI
+

NI
+



+
10 ( 4.2)

+
20 ( 3.5)

Escherichia Coli
NI
NI
NI
NI
NI
NI
NI
+
+
20 ( 4.2)

+
22 ( 3.5)

+
+
+
+
15 ( 1.5)

Staphylococcus aureus
Candida albicans
+
20 ( 1.5)

NI
18 ( 1.5) 22 ( 1.5)
11 ( 3.5)
15 ( 1.5) 10 ( 1.5) 18 ( 1.5)






+
15 ( 4.4)

+
17 ( 3.5)

+
20 ( 2.5)

+
12 ( 2.8)

NI
NI
NI
NI
NI
NI
NI
Zone of inhibition in mm
NI: No Inhibition
The minimum inhibition concentration (MIC) for iodinated biphenylboronic acid products against three bacteria strains and one
fungal strain are summarized in Table 3. The data clearly identified two lead derivatives. (2-iodo-4'-isopropyl-[1,1'-biphenyl]-3-
yl)boronic acid 6A and (3-
(benzo[d][1,3]dioxol-5-yl)-2-
Table 3:
Minimum inhibitory concentration (MIC, mg/mL) for synthesized ortho-iodobiphenyl
iodo-5-
boronic acid derivatives against Micrococcus Luteus, Bacillus cereus, Staphylococcus
methoxyphenyl)boronic acid
aureus and Candida albicans
22A bearing hydrogen and
methoxy substituents at C-5
Microbial Species
Iodobiphenyl
on the aryl ring (R1)
R1 Group
boronic acid
Compounds
respectively. Compound 6A
possesses the most potent
antibacterial activities toward
Gram-positive Bacellus cereus,
M. luteus
B. cereus
S. aureus
C. albicans
5A
6A
9A
0.45
0.15
0.80
3.2
3.0
NT
NT
1.5
0.8
0.6
0.48
0.10
0.16
1.6
0.37
0.16
026
1.4
NT
0.8
0.9
0.48
NT
3.0
NT
NT
NT
NT
NT
NT
0.3
H
HA
Me
Micrococcus
Staphylococcus
whereas
luteus
and
aureus,
22A
14A
15A
17A
18A
19A
20A
21A
22A
OMe
OMe
Me
OMe
OMe
OMe
OMe
OMe
compound
1.4
possesses the most antifungal
activity against Candida
0.75
0.62
0.96
0.49
0.4
0.7
0.78
0.75
0.48
0.15
albicans. These promising
results illustrated that the
iodo and boronic acid groups
have great influence on the
antimicrobial activity and
0.2
0.15
NT: Not Tested
further investigations are still ongoing with our collaborators.

Page 7 of 15
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
7
8
9
Organocatalytic activity
The catalytic activity of ortho-iodinated biphenylboronic acids was investigated towards direct amidation reaction at ambient
temperature appraising both steric and electronic factors. The optimized conditions and mechanistic studies were previously
3]
reported.[2c,2h, It reveled that the role of iodo substituent at the ortho position is crucial for catalytic activity of ortho-
iodophenylboronic acids and their activity as bifunctional Lewis acid/Lewis base catalysts. As a result of Marcelli DFT-
calculations,[3] the removing of water molecule from the orthoaminal intermediate was found to be the rate-determining step,
which was calculated to be assisted by internal iodine-hydrogen bond. Accordingly, a derivative like 5-methoxy-2-
iodophenylboronic acid (MIBA) with a more basic iodide was found to be more reactive catalyst by forming a stronger iodine-
hydrogen bond and therefore, providing a lower activation energy.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We envisioned that the addition of an aryl group at C-3 next to the iodo substituent is expected to further activate the catalyst
by tuning the proximity between iodo and boronic acid groups. Conveniently, model amidation reactions between phenylacetic
acid and benzylamine or pyrrolidine were used under the optimized reaction conditions.[2c] Up to 6 hour long side-by-side
reactions were performed including MIBA (1, Table 4) to examine their catalytic activity at room temperature. The results are
summarized in Table 4. Initially, the effectiveness of having a phenyl unit next to the iodo group was not clear by comparing the
reactivity between catalyst 14A and MIBA. Adding a substituent to the phenyl ring on 14A such as 3-methoxy or 4-
methoxymethyl 16A and 18A respectively proved to be slightly more efficient than 14A and similar to reactivity of MIBA.
Table 4.
Comparative study for amide synthesis catalyzed by ortho-iodobiphenylboronic acid derivatives at ambient temperaturea
Ph
NH2
NH
O
O
O
Catalyst
(10 mol%)
or
Ph
Ph
Ph
+
or
N
OH
N
Ph
4 Å mol. sieves (1.0 g), 0.1M
CH2Cl2, 25 oC, 1-6 h
H
25
26
OMe
OMe
Catalysts
MeO
I
I
I
I
I
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
OMe
1,
OMe
OMe
OMe
16A
OMe
14A
MIBA
19A
18A
F
O
O
MeO
I
I
I
I
B(OH)2
B(OH)2
B(OH)2
B(OH)2
F
Cl
CH3
OMe
22A
10A
11A
12A
b
b
25
26
NMR conversion (%) of amide
NMR conversion (%) of amide
Catalyst
Catalyst
1h
3h
6h
1h
3h
6h
1
1
48%
41%
46%
44%
63%
21%
39%
30%
31%
75%
68%
73%
70%
88%
33%
62%
41%
44%
93%
88%
90%
82%
>99%
41%
71%
52%
58%
76%
73%
95%
89%
91%
85%
99%
42%
79%
59%
61%
>99%
97%
98%
95%
>99%
74%
86%
75%
82%
14A
16A
18A
19A
22A
10A
11A
12A
14A
16A
18A
19A
22A
10A
11A
12A
74%
68%
89%
34%
63%
42%
49%
aConditions: All reactions were carried out using 0.55 mmol (1.1 equiv.) of phenylacetic acid, 0.50 mmol (1.0 equiv.) of amine, 10 mol% of
BA, activated 4 Å mol. sieves (1.0 g) in 5.0 mL dry DCM at room temp. bNMR yields.

New Journal of Chemistry
Page 8 of 15
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
7
8
A clear progress in catalytic activity was achieved with 19A with good conversion of 63% of the amide product 26 after 60 mins.
To further improve the catalytic activity, we then examined 22A with more electronically enriched aryl group. Unfortunately, it
found to be less efficient catalyst giving lower conversion than 14A. The difference in catalytic activity between 19A and 22A
implies an ideal Lewis basicity of the iodo atom adopted by the catalyst in the transition state as shown in DFT studies by
Marcelli.[3] Consequently, the replacement of methoxy group with a methyl, fluoro or chloro led to the less efficient catalysts
10A-12A respectively.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Having recognized 19A as the optimal organocatalyst and using the optimal conditions in hands, we started to explore specific
carboxylic acids (Scheme 4). Glycine tert-butyl ester coupled with phenylacteic acid to obtain the desired amide product 26 in
74%. A COX-II inhibitor Indomethacin amide 27 was also formed in excellent yield. Other α- mino cids such as Z-alanine,
caprylylglycine and N-phenylglycine were used and successfully formed the corresponding amides 28-30 in 95%, 40% and 50%
yields respectively. The optically active ibuprofen amide 31 was also made in 71% with less than 5% epimerization.
H3CO
O
OH
B
I
O
19
ArB(OH)2 A (10 mol%)
+
H2NR2
R1
OH
OH
NHR2
R1
4 Å mol. sieves (1.0 g), 0.1M
CH2Cl2, 25 oC, 6 h
0.55 mmol
0.5 mmol
19A
OCH3
O
Ph
N
O
H
H
N
O
MeO
Ph
O
N
O
O
Me
N
H
O
H
N
28
27
26
O
Cl
Z-Alanine amide
tert-butyl ester amide
Indomethacin amide
Glycine
95%
COX-II inhibitor
74%
94%
O
H
O
H
O
N
N
N
N
H
N
Ph
Ph
Ph
H
H
O
29
31
30
Caprylylglycine amide
Ibuprofen amide
N-phenylglycine amide
NSAID with reduced toxicity
40%
50%
71% >96%ee
,
Scheme 4.
19
Direct amidation scope catalyzed by (2-iodo-4',5-dimethoxy-[1,1'-biphenyl]-3-yl)boronic acid A at ambient
temperature
Conclusion
In conclusion, the synthesis, X-ray structure, biological and catalytic activity of hitherto unknown iodinated biphenylboronic acid
derivatives are reported. 5-substituted-2-iodobiphenylboronic acid products were synthesized in one-step through metal-iodine
Exchange reaction of 5-substituted-2,3-diiodobiphenyls and isolated in 38%-92% yields and without chromatography. Phase-
switch technique is found to be the best method to purify these products and with excellent purity. The structure of the
products is confirmed by X-ray diffraction methods for four derivatives. The antimicrobial examinations of iodinated
biphenylboronic acids were found to have broad-spectrum of antibacterial activity against Gram-positive strains and with no
activity against Escherichia coli. The most potent iodinated biphenylboronic acid derivatives as antibacterial and antifungal are

Page 9 of 15
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
7
8
9
found to be (2-iodo-4'-isopropyl-[1,1'-biphenyl]-3-yl)boronic acid (compound 6A) and (3-(benzo[d][1,3]dioxol-5-yl)-2-iodo-5-
methoxyphenyl)boronic acid (compound 22A) with MIC of 0.10 and 0.3 mg/mL for B. cereus and C. albicans respectively. The
catalytic activity of iodinated biphenylboronic acids were also examined towards amidation reaction at ambient temperature. It
revealed a new optimal catalyst, 2-iodo-4',5-dimethoxy-[1,1'-biphenyl]-3-yl)boronic acid 19A providing a remarkable increase in
the amide yields including -aminoacids. We disclosed an efficient, scalable and regioselective method for the synthesis of
hitherto unknown ortho-iodobiphenylboronic acid derivatives, which are valuable in industry, medicine and indeed are hard to
be made by other means. Other chemical transformations could be easily performed with the other iodo group on the biphenyl
ring.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental
General
All commercial reagents and chromatography solvents were used as obtained unless otherwise stated. Diethyl ether, ethyl acetate, hexanes, anhydrous
sodium sulfate (Na2SO4, BDH), iso-propylmagnesium chloride (iPrMgCl, 2M/THF) and trimethylborate (MeO)3B. Anhydrous solvents were distilled over
appropriate drying agents prior to use. Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60 F254. Merck Silica gel 60 (0.063 -
0.2 mm) was used for column chromatography. Visualization of TLC was accomplished with UV light (254 nm). NMR spectra were recorded on a Bruker-
Avance 400 MHz spectrometer. The residual solvent protons (1H) or the solvent carbon (13C) were used as internal standards. 1H-NMR data are presented
as follows: chemical shift in ppm (δ) downfield from trimethylsilane (multiplicity, integration, coupling constant). The following abbreviations are used in
reporting NMR data: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; dq, doublet of quartets; dd, doublet of doublets; m, multiplet. High
resolution mass spectra were recorded using Chemical Ionization (CI) and Electrospray ionization (ESI) techniques.
Antibacterial Assays
The antibacterial activities of diodinated arylboronic acids were tested against three Gram-positive bacterial strains: Staphylococcus aureus (ATCC
29213), Bacillus Cereus (ATCC 11778) and Micrococcus luteus (ATCC 9341) and one Gram-negative bacterial strains: Escherichia coli (ATCC 25922) and one
fungal strain Candida albicans using the method recommended by the National Committee for Clinical Laboratory Standards (NCCLS).[18]
General procedure for MIE Reaction of 5-substituted-2,3-diiodobiphenyl and trimethylborate
To a solution of 5-substituted-2,3-diiodobiphenyl derivative (1.00 mmol) in 20.0 mL anhyd. THF at -78 oC was added dropwize isopropyl
magnesium chloride (2M in THF, 1.10 mmol, 1.10 equiv.). The mixture was stirred at that temperature for 1 h and then, trimethylborate (3.0
equiv.) was added. The solution was slowly warmed up to room temperature and stirred overnight. Saturated NH4Cl was added and the
resulting mixture was stirred 30 min at room temperature. The aqueous layer was extracted with Et2O (2 x 50 mL). Organic layers were
combined and then concentrated under reduced pressure using a rotary evaporator. A 20 mL diethylether was added and then extracted
twice with 20 mL of aqueous NaOH (0.25M). Aqueous basic layers were combined; acidified using HCl solution (0.25M) and the resulting
precipitate was then extracted with 30 mL diethylether. Organic layers were combined, dried with anhyd. Sodium sulfate, filtered and
concentrated under reduced pressure using a rotary evaporator yield the pure desired boronic acid product.
Synthesis of (2-iodo-[1,1'-biphenyl]-3-yl)boronic acid (5A)
The title compound was prepared using the general procedure for MIE reaction of 5-substituted-2,3-diiodobiphenyl derivative with trimethylborate and
isolated as a white solid (60% yields). IR (cast film, cm-1) 3421, 3095, 3025, 2955, 1601, 1598, 1106, 954, 782. H (400MHz, d6-DMSO) : 8.31 (s, 2H), 7.37-
7.46 (m, 4H), 7.24-7.28 (m, 2H), 7.21 (dd, 1H, J = 1.5 Hz, J = 7.4 Hz), 7.12 (dd, 1H, J = 1.5 Hz, J = 7.2 Hz). C (100 MHz, d6-DMSO) : 149.2, 145.5, 144.7,
131.4, 129.2, 129.1, 128.0, 127.5, 127.3, 102.6 . B (128 MHz, d6-acetone) : 29.2. M.p: 91-94 °C. HRMS (ESI) m/z for C12H11BIO2 [M+H] : calcd. 324.9897;
found, 324.9894.
Synthesis of (2-iodo-4'-isopropyl-[1,1'-biphenyl]-3-yl)boronic acid (6A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (54% yields). IR (cast film, cm-1) 3346, 3045, 2998, 1612, 1597, 1179, 1078, 967, 862. H (400 MHz, d6-DMSO) : 8.27 (s, 2H), 7.33
(dd, 1H, J = 7.4 Hz, J = 7.3 Hz) , 7.25 (d, 2H, J = 8.0 Hz), 7.12-7.15 (m, 3H), 7.05 (d, 1H, J = 7.0 Hz), 2.45 (sept, 1H, J = 6.4 Hz), 1.19 (d, 6H, J = 6.7 Hz) . C
(100 MHz, d6-DMSO) : 149.5, 147.5, 145.5, 142.2, 131.2, 129.4, 129.1, 127.4, 125.9, 102.8, 33.2, 23.9. B (128MHz, d6-acetone) : 29.5. M.p: 114-116 °C.
HRMS (ESI) m/z for C15H17BIO2 [M+H] : calcd. Exact 367.0366; found, 367.0358.
Synthesis of (3'-fluoro-2-iodo-4'-methoxy-[1,1'-biphenyl]-3-yl)boronic acid (7A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (63% yield). IR (cast film, cm-1) 3396, 3097, 3017, 2986, 2934, 1619, 1597, 1547, 1352, 1247, 1101, 937, 782. H (400 MHz, d6-
DMSO) : 8.30 (s, 2H), 7.38 (t, 1H, J = 7.4 Hz), 7.20-7.26 (m, 2H), 7.13 (dd, 1H, J = 1.6 Hz, J = 7.2 Hz), 7.08 (dd, 1H, J = 2.0 Hz, J = 12.2 Hz), 7.01(d, 1H, J =

New Journal of Chemistry
Page 10 of 15
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
8.3 Hz), 3.39 (s, 3H). C (100 MHz, d6- DMSO) : 151.9, 149.5, 146.5, 146.5, 144.1, 137.5, 137.5, 131.5, 129.3, 127.4, 125.6, 125.6, 116.9, 116.7, 113.4,
113.4, 102.7, 56.1. B (128 MHz, d6-acetone) : 29.7. M.p: 119-121 °C. HRMS (ESI) m/z for C13H12BFIO3 [M+H] : calcd. 372.9908; found, 372.9897.
5
6
Synthesis of (2-iodo-5-methyl-[1,1'-biphenyl]-3-yl)boronic acid (8A)
7
8
9
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (47% yield). IR (cast film, cm-1) 3304, 3086, 3055, 2986, 2942, 1614, 1597, 1157, 1024, 935, 824. H (400 MHz, d6-DMSO) : 8.12
(s, 2H), 7.06 (s, 1H), 7.33-7.46 (m, 5H), 7.13 (s, 1H), 2.29 (s, 3H). C (100 MHz, d6-DMSO) : 145.8, 142.4, 139.1, 138.5, 128.7, 128.3, 128.2, 127.1, 99.9,
20.2. B (128 MHz, d6-acetone) : 29.3. M.p: 126-128 °C. HRMS (ESI) m/z for C13H13BIO2 [M+H] : calcd. 339.0053; found, 339.0046.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of (2-iodo-4'-isopropyl-5-methyl-[1,1'-biphenyl]-3-yl)boronic acid (9A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (40% yields). IR (cast film, cm-1) 3318, 3104, 3095, 2984, 2812, 1601, 1575, 886, 776. H (400 MHz, d6-DMSO) : 8.24 (s, 2H), 7.29
(d, 2H, J = 8.0 Hz), 7.16 (d, 2H, J = 7.8 Hz), 7.02 (s, 1H), 6.93 (s, 1H), 2.62 (sept, 1H, J = 6.8 Hz), 2.25 (s, 3H), 1.23 (d, 6H, J = 6.8 Hz). C (100 MHz, d6-
DMSO) : 147.4, 145.3, 142.2, 136.6, 132.1, 130.3, 129.1, 125.9, 98.8, 33.2, 23.9, 20.3. B (128 MHz, d6-acetone) : 29.5. M.p: 117-119 °C. HRMS (ESI)
m/z for C16H19BIO2 [M+H] : calcd. 381.0523; found, 381.0520.
Synthesis of (3'-fluoro-2-iodo-4'-methoxy-5-methyl-[1,1'-biphenyl]-3-yl)boronic acid (10A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (60% yields). IR (cast film, cm-1) 3406, 3120, 3089, 3009, 2979, 1596, 1442, 1243, 1124, 1106, 912, 795. H (400 MHz, d6-DMSO)
: 8.25 (s, 2H), 7.21 (dd, 1H, J = 8.8 Hz , J = 8.7 Hz), 7.00-7.09 (m, 3H), 6.9 (d, 1H, J = 1.7 Hz), 3.88 (s, 3H), 2.25 (s, 3H). C (100 MHz, d6-DMSO) :151.9,
149.4, 149.1, 146.5, 146.4, 143.9, 137.5, 137.5, 136.9, 132.4, 130.2, 125.6, 125.6, 116.8, 116.7, 113.4, 98.9, 56.1, 20.3. B (128 MHz, d6-acetone) : 29.3.
M.p: 132-134 °C. HRMS (ESI) m/z for C14H14BFIO3 [M+H] : calcd. 387.0065; found, 387.0059.
Synthesis of (5-fluoro-2-iodo-[1,1'-biphenyl]-3-yl)boronic acid (11A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (38% yields). IR (cast film, cm-1) 3298, 3084, 3068, 2994, 1631, 1599, 1425, 1348, 1275, 1186, 1015, 784. H (400 MHz, d6-DMSO)
: 8.44 (s, 2H), 7.35-7.50 (m, 3H) , 7.27 (d, 2H, J = 6.9 Hz), 7.11 (dd, 1H, J = 2.9 Hz, J = 9.4 Hz), 7.01 (dd, 1H, J = 2.9 Hz, J = 8.6 Hz) . C (100 MHz, d6-DMSO)
: 162.9, 160.5, 147.8, 147.7, 143.6, 129.0, 128.3, 128.2, 128.1, 127.9, 118.0, 117.8, 116.2, 116.0, 96.2, 96.1. B (128 MHz, d6-acetone) : 29.4. M.p: 135-
137 °C. HRMS (ESI) m/z for C12H10BFIO2 [M+H] : calcd. 342.9803; found, 342.9799.
Synthesis of (5-chloro-2-iodo-[1,1'-biphenyl]-3-yl)boronic acid (12A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (53% yields). IR (cast film, cm-1) 3314, 3109, 3058, 3017, 1621, 1597, 1414, 1283, 1138, 1017, 973, 712. H (400 MHz, d6-DMSO)
: 8.50 (s, 2H), 7.40-7.48 (m, 4H), 7.25-7.29 (m, 2H), 7. 29 (d, 1H, J = 2.3 Hz), 7. 17 (d, 1H, J = 7.8 Hz). C (100 MHz, d6-DMSO) : 151.4, 147.6, 143.4, 132.7,
130.7, 128.9, 128.4, 128.1, 127.9, 100.5. B (128 MHz, d6-acetone) : 28.9. M.p: 138-140 °C. HRMS (ESI) m/z for C12H10BClIO2 [M+H] : calcd. 358.9507;
found, 358.9505.
Synthesis of (5-bromo-2-iodo-[1,1'-biphenyl]-3-yl)boronic acid (13A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (65% yields). IR (cast film, cm-1) 3274, 3108, 3061, 2941, 1612, 1599, 1296, 1101, 862, 697. H (400 MHz, d6-DMSO) : 8.47 (s,
2H), 7.40-7.48 (m, 3H), 7. 36 (d, 1H, J = 2.3 Hz), 7. 29 (d, 1H, J = 2.3 Hz), 7. 26 (d, 2H, J = 6.7 Hz). C (100 MHz, d6-DMSO) : 152.1, 147.9, 143.3, 133.5,
131.2, 128.9, 128.2, 127.9, 121.4, 101.3. B (128 MHz, d6-acetone) : 29.3. M.p: 140-144 °C. HRMS (ESI) m/z for C12H10BBrIO2 [M+H] : calcd. 402.9002;
found, 402.8997.
Synthesis of (2-iodo-5-methoxy-[1,1'-biphenyl]-3-yl)boronic acid (14A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (83% yields). IR (cast film, cm-1) 3288, 3087, 3025, 2984, 1601, 1587, 1289, 1148, 1012, 937, 812. H (400 MHz, d6-DMSO) : 8.32
(s, 2H), 7.38-7.45 (m, 3H), 7.27 (d, 2H, J = 6.8 Hz), 6.78 (d, 1H, J = 2.9 Hz), 6.75 (d, 1H, J = 2.9 Hz), 3.75 (s, 3H). C (100 MHz, d6-DMSO) : 158.6, 150.1,
146.7, 144.6, 129.1, 128.0, 127.6, 117.3, 115.2, 91.2, 55.3. B (128 MHz, d6-acetone) : 29.4. M.p: 119-121 °C. HRMS (ESI) m/z for C13H13BIO3 [M+H] :
calcd. 355.0002; found, 354.9997.

Page 11 of 15
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
Synthesis of (2-iodo-4'-isopropyl-5-methoxy-[1,1'-biphenyl]-3-yl)boronic acid (15A)
5
6
7
8
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (86% yields). IR (cast film, cm-1) 3369, 3107, 3081, 2932, 1621, 1598, 1272, 1133, 1098, 986, 862. H (400 MHz, d6-DMSO) : 8.30
(s, 2H), 7.30 (d, 2H, J = 8.0 Hz), 7.19 (d, 2H, J = 8.0 Hz), 6.77 (d, 1H, J = 2.9 Hz), 6.71 (d, 1H, J = 2.9 Hz), 3.75 (s, 3H), 2.95 (sep, 1H, J = 6.9Hz), 1.24 (d, 6H, J =
6.9Hz). C (100 MHz, d6-DMSO) :158.6, 150.0, 147.5, 146.6, 141.9, 128.9, 125.9, 117.2, 115.2, 91.3, 55.3, 33.1, 23.8. B (128 MHz, d6-acetone) : 28.1.
M.p: 91-93 °C. HRMS (ESI) m/z for C16H19BIO3 [M+H] : calcd. 397.0472; found, 397.0464.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of (2-iodo-3',5-dimethoxy-[1,1'-biphenyl]-3-yl)boronic acid (16A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (63% yields). IR (cast film, cm-1) 3312, 3087, 3014, 2998, 2888, 1642, 1609, 1299, 1283, 1114, 1107, 983. H (400 MHz, d6-DMSO)
: 8.30 (s, 2H), 7.34 (dd, 1H, J = 7.9 Hz, J = 7.8 Hz), 6.95 (dd, 1H, J = 2.1 Hz, J = 8.3 Hz), 6.81 (d, 1H, J = 7.6 Hz), 6.73-6.78 (m, 2H), 6.73 (d, 1H, J = 2.9 Hz),
3.78 (s, 3H), 3.75 (s, 3H). C (100 MHz, d6-DMSO) : 158.7, 158.6, 146.5, 145.8, 129.2, 121.5, 117.3, 115.2, 114.9, 112.9, 91.1, 55.3, 55.1. B (128 MHz, d6-
acetone) : 29.2. M.p: 129-131 °C. HRMS (ESI) m/z for C14H15BIO4 [M+H] : calcd. 385.0108; found, 385.0105.
Synthesis of (3'-fluoro-2-iodo-4',5-dimethoxy-[1,1'-biphenyl]-3-yl)boronic acid (17A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (77% yields). IR (cast film, cm-1) 3297, 3086, 3078, 3027, 2996, 1617, 1589, 1588, 1418, 1207, 1167, 1117, 862. H (400 MHz, d6-
DMSO) : 8.31 (s, 2H), 7.23 (dd, 1H, J = 8.6 Hz, J = 8.7 Hz), 7.10 (dd, 1H, J = 1.7 Hz, J = 12.2 Hz), 7.04 (d, J = 8.4 Hz, 2H), 6.80 (d, 1H, J = 2.9 Hz), 6.75 (d, 1H,
J = 2.9 Hz), 3.89 (s, 3H), 3.76 (s, 3H) . C (100 MHz, d6-DMSO) : 158.6, 151.8, 150.1, 149.4, 146.6, 146.5, 145.2, 137.3, 137.2, 125.6, 125.6, 117.4, 116.8,
116.7, 115.3, 113.3, 91.4, 56.0, 55.3. B (128 MHz, d6-acetone) : 29.2. M.p: 134-136 °C. HRMS (ESI) m/z for C14H14BFIO4 [M+H] : calcd. 403.0014; found,
403.0005.
Synthesis of (2-iodo-5-methoxy-4'-(methoxymethyl)-[1,1'-biphenyl]-3-yl)boronic acid (18A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (80% yields). IR (cast film, cm-1) 3213, 3099, 3085, 2988, 1621, 1608, 1598, 1249, 1120, 1108, 1096, 877, 648. H (400 MHz, d6-
DMSO) : 8.31 (s, 2H), 7.37 (d, 2H, J = 7.8 Hz), 7.24 (d, 2H, J = 7.8 Hz), 6.78 (d, 1H, J = 2.8 Hz), 6.74 (d, 1H, J = 2.7 Hz), 4.46 (s, 2H), 3.75 (s, 3H), 3.32 (s, 3H).
C (100 MHz, d6-DMSO) : 158.6, 150.1, 146.5, 143.6, 137.6, 128.9, 127.1, 117.3, 115.2, 91.2, 73.4, 57.7, 55.3. B (128 MHz, d6-acetone) : 30.0. M.p: 142-
144 °C. HRMS (ESI) m/z for C15H17BIO4 [M+H] : calcd. 399.0265; found, 399.0258.
Synthesis of (2-iodo-4',5-dimethoxy-[1,1'-biphenyl]-3-yl)boronic acid (19A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (85% yields). IR (cast film, cm-1) 3295, 3076, 3028, 2981, 1623, 1601, 1573, 1253, 1208, 1147, 1129, 837, 728. H (400 MHz, d6-
DMSO) : 8.31 (s, 2H), 7.18 (d, 2H, J = 8.2 Hz), 6.98 (d, 2H, J = 8.3 Hz), 6.75 (d, 1H, J = 2.0 Hz), 6.70 (d, 1H, J = 2.0 Hz), 3.79 (s, 3H), 3.74 (s, 3H) . C (100
MHz, d6-DMSO) : 158.7, 158.6, 150.2, 146.4, 136.9, 130.3, 117.0, 115.4, 113.4, 91.9, 55.3, 55.2. B (128 MHz, d6-acetone) : 29.4. M.p: 124-126 °C.
HRMS (ESI) m/z for C14H15BIO4 [M+H] : calcd. 385.0108; found, 385.0101.
Synthesis of (2-iodo-5-methoxy-3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)boronic acid (20A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (67% yields). IR (cast film, cm-1) 3312, 3097, 3058, 2942, 2828, 1589, 1546, 1427, 1343, 1242, 1168, 1127, 852, 742. H (400 MHz,
d6-DMSO) : 8.32 (s, 2H), 7.59 (dd, 1H, J = 8.0 Hz , J = 7.9 Hz), 7.40 (d, 1H, J = 7.6 Hz), 7.30 (d, 1H, J = 7.6 Hz), 7.20 (s, 1H), 6.84 (d, 1H, J = 2.9 Hz), 6.77 (d,
1H, J = 2.9 Hz), 3.77 (s, 3H). C (100 MHz, d6-DMSO) : 158.6, 150.2, 147.8, 146.5, 144.9, 130.2, 128.3, 123.9, 121.7, 121.4, 120.1, 118.9, 117.9, 116.3,
115.2, 90.7, 55.4. B (128 MHz, d6-acetone) : 29.6. M.p: 126-128 °C. HRMS (ESI) m/z for C14H12BF3IO4 [M+H] : calcd. 438.9825; found, 438.9814.
Synthesis of (2-iodo-5-methoxy-4'-phenoxy-[1,1'-biphenyl]-3-yl)boronic acid (21A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (59% yields). IR (cast film, cm-1) 3348, 3124, 3109, 3058, 2956, 1597, 1586, 1579, 1282, 1214, 1175, 1127, 812. H (400 MHz, d6-
DMSO) : 8.36 ( s, 2H), 7.43 (dd, 2H, J = 8.0 Hz, J = 7.8 Hz), 7.26 (d, 2H, J = 8.5 Hz), 7.18 (dd, 1H, J = 7.4 Hz, J = 7.3 Hz), 7.07 (d, 2H, J = 7.8 Hz), 7.03 (d, 2H, J
= 8.5 Hz), 6.80 (d, 1H, J = 3.0 Hz), 6.72 (d, 1H, J = 3.0 Hz), 3.75 (s, 3H). C (100 MHz, d6-DMSO) : 158.6, 156.4, 156.3, 146.1, 139.6, 160.9. 130.2, 123.9,
119.1, 117.7, 117.4, 115.3, 91.6, 55.4. B (128 MHz, d6-acetone) : 29.4. M.p: 129-131 °C. HRMS (ESI) m/z for C19H17BIO4 [M+H] : calcd. 447.0265; found,
447.0262.

New Journal of Chemistry
Page 12 of 15
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
Synthesis of (3-(benzo[d][1,3]dioxol-5-yl)-2-iodo-5-methoxyphenyl)boronic acid (22A)
5
6
7
8
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (66% yields). IR (cast film, cm-1) 3298, 3108, 3068, 3028, 2994, 1619, 1578, 1348, 1286, 1274. 1208, 1142, 1115, 921, 689. H (400
MHz, d6-DMSO) : 8.23 (s, 2H), 6.96 (d, 1H, J = 7.9 Hz), 6.69-6.78 (m, 3H), 6.53 (s, 1H), 6.06 (s, 2H), 3.75 (s, 3H). C (100 MHz, d6-DMSO) : 158.5, 150.0,
146.7, 146.6, 146.3, 138.5, 122.7, 117.2, 115.3, 109.7, 107.9, 101.1, 91.7, 55.3. B (128 MHz, d6-acetone) : 29.3. M.p: 108-110 °C. HRMS (ESI) m/z for
C14H13BIO5 [M+H] : calcd. 398.9901; found, 398.9893.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of (3-(2,3-dihydrobenzofuran-5-yl)-2-iodo-5-methoxyphenyl)boronic acid (23A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (53% yields). IR (cast film, cm-1) 3368, 3108, 3088, 3042, 2995, 1632, 1614, 1586, 1312, 1277, 1148, 986, 834. H (400 MHz, d6-
DMSO) : 8.27 (s, 2H), 7.11 (s, 1H), 6.97 (dd, 1H, J = 1.6 Hz, J = 8.2 Hz), 6.80 (d, 1H, J = 8.2 Hz), 6.76 (d, 1H, J = 3.1 Hz), 6.71 (d, 1H, J = 3.0 Hz), 4.56 (t, 2H, J
= 8.7 Hz ), 3.75 (s, 3H), 4.56 (t, 2H, J = 8.6 Hz ). C (100 MHz, d6-DMSO) : 159.1, 158.6, 150.1, 146.8, 136.9, 128.8, 126.9, 125.8, 116.9, 115.3, 108.2, 92.1,
71.1, 55.2, 29.1. B (128 MHz, d6-acetone) : 29.8. M.p: 137-139 °C. HRMS (ESI) m/z for C15H15BIO4 [M+H] : calcd. 397.0108; found, 397.0104.
Synthesis of (2-iodo-5-methoxy-3-(6-methoxypyridin-3-yl)phenyl)boronic acid (24A)
The title compound was prepared using the general procedure for MIE reaction of 2,3-diiodo-5-substituted biphenyl derivatives with trimethylborate and
isolated as a white solid (65% yields). IR (cast film, cm-1) 3307, 3109, 3086, 3062, 2997, 1614, 1598, 1388, 1286, 1214, 1178, 1137, 899. H (400 MHz, d6-
DMSO) : 8.33 (s, 2H), 8.08 (d, 1H, J = 1.8 Hz), 7.61 (dd, 1H, J = 2Hz, J = 8.4 Hz), 6.89 (d, 1H, J = 8.5 Hz), 6.89 (d, 1H, J = 2.8 Hz), 6.76 (d, 1H, J = 2.8 Hz) 3.90
(s, 3H), 3.77 (s, 3H). C (100 MHz, d6-DMSO) : 162.8, 158.7, 150.1, 146.5, 143.1, 140.1, 133.8, 117.6, 115.6, 109.6, 92.1, 55.4, 53.3. B (128 MHz, d6-
acetone) : 29.3. M.p: 139-141 °C. HRMS (ESI) m/z for C13H14BINO4 [M+H] : calcd. 386.0061; found, 386.0058.
General Procedure for Organocatalytic Amidations
Into a 25 mL round bottom flask equipped with a stir bar were added carboxylic acid ( 0.55 mmol, 0.1 M, 1.1 equiv), ortho-iodobiphenylboronic acid
derivative (0.05 mmol, 10 mol%) and 1.0 g of activated 4Å molecular sieves (preactivation overnight in an oven at ~250 oC or by Kugelrohr for 2h at 250
oC under high vacuum). Dichloromethane (7 mL) was added and the mixture was stirred for 10 min. Then, amine (0.5 mmol, 1.0 equiv) was added (in
order to get reproducible results, it was necessary to use a gastight 100 L syringe). The resulting mixture was stirred for 6 h at room temperature (24-25
oC). The reaction mixture was filtered through a pad of Celite® 545, the filtrate was washed with aqueous hydrochloric solution (pH = 4), aqueous sodium
hydroxide solution (pH = 10-11) and brine, respectively. The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to yield
the title amide product.
Synthesis of tert-butyl (2-phenylacetyl)glycinate (26)
The title compound was prepared using the general procedure for organocatalytic amidation reaction and isolated as pale yellow oil (74% yields). IR (cast
film, cm-1) 3285, 3024, 3012, 1764, 1652, 1614, 1520, 864, 662. H (400 MHz, d6-DMSO) : 7.26-7.35 (m, 5H), 6.16 (bs, 1H), 3.86 (d, 2H, J = 5.0 Hz), 3.58 (s,
2H), 1.42 (s, 9H). C (100 MHz, d6-DMSO) : 171.1, 168.8, 134.7, 129.5, 128.9, 127.3, 82.2, 43.4, 42.2, 28.0. HRMS (ESI) m/z for C14H19NO3Na [M+Na] :
calcd. 272.1263; found, 272.1269.
Synthesis of benzyl (S)-(1-(benzylamino)-1-oxopropan-2-yl)carbamate (28)
The title compound was prepared using the general procedure for organocatalytic amidation reaction and isolated as off-white solid (95% yields). IR (cast
film, cm-1) 3304, 3295, 3095, 3021, 2997, 1712, 1648, 1623, 1594, 824, 725. H (400 MHz, d-CDCl3) : 7.20-7.50 (m, 10H), 6.71 (d, 1H, J = 5.4 Hz), 5.00 (s,
2H), 5.74 (s, 1H), 3.94 (s, 2H), 3.72 (t, 1H, J = 6.6 Hz), 1.20 (d, 3H, J = 6.6 Hz). C (100 MHz, d-CDCl3) : 175.2, 155.2, 137.4, 136.7, 128.5, 128.4, 127.8,
127.8, 127.7, 65.1, 54.9, 51.1, 42.8, 18.9. M.p: 129-131 °C. HRMS (ESI) m/z for C18H20N2O3Na [M+Na] : calcd. 335.1372; found, 335.1383.
Synthesis of N-(2-(benzylamino)-2-oxoethyl)octanamide (29)
The title compound was prepared using the general procedure for organocatalytic amidation reaction and isolated as colorless oil (40% yields). IR (cast
film, cm-1) 3314, 3294, 3015, 3007, 2997, 1654, 1642, 1610, 1607, 1594, 945, 687. H (400 MHz, d-CDCl3) : 7.23-7.32 (m, 5H), 7.07 (s, 1H), 6.61 (s, 1H),
4.40 (d, 2H, J = 5.7 Hz), 3.94 (d, 2H, J = 5.1 Hz), 2.18 (t, 2H, J = 7.5 Hz), 1.56 (s, 2H), 1.10-1030 (m, 8H), 0.87 (t, 3H, J = 6.3 Hz). C (100 MHz, d-CDCl3) :
174.1, 169.2, 138.0, 128.8, 127.8, 127.6, 43.7, 43.5, 36.5, 31.8, 29.4, 29.1, 25.7, 22.7, 14.2, . HRMS (ESI) m/z for C17H26N2O2Na [M+Na] : calcd. 313.1892;
found, 313.1907.

Page 13 of 15
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
Acknowledgements
This work was generously funded by Jordan University of Science and Technology (JUST) - Deanship of Research - Jordan (Grant
No. 338/2015 for R.M.A.). We thank the department of chemistry at University of Alberta for X-ray diffraction methods. The
authors thank Dr. Mazher S. Al-Zoubi for his help in screening the microbial activity.
5
6
7
8
9
Supplementary Material
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting information for this article is available on the WWW under………………………………
References and notes
[1]
D. G. Hall, Ed. Boronic Acids; Wiley-VCH: Weinheim, 2005
[2]
a) H. Zheng, D. G. Hall, Aldrichimica Acta 2014, 47, 41-51; b) D. Hall, N. Gernigon, R. Al-Zoubi, P. D. Thornton,
University of Alberta, GreenCentre Canada, World Patent WO2012109749A1, 2012, p. 86; c) N. Gernigon, R. M. Al-
Zoubi, D. G. Hall, J. Org. Chem. 2012, 77, 8386-8400; d) R. M. Al-Zoubi, D. G. Hall, Synfacts 2010, 9, 1049-1049; e) R.
M. Al-Zoubi, D. G. Hall, Org. Lett. 2010, 12, 2480-2483; f) D. Hall, O. Marion, R. Al-Zoubi, University of Alberta, World
Patent WO2009030022A1, 2009, p. 34; g) D. Hall, N. Gernigon, R. Al-Zoubi, P. D. Thornton, University of Alberta,
GreenCentre Canada, US Patent US9284270B2, 2016; h) R. M. Al-Zoubi, O. Marion, D. G. Hall, Angew. Chem. Int. Ed.
2008, 47, 2876-2879; i) H. Tsuji, H. Yamamoto, Synlett 2018, 29, 318-321; j) X. Mo, T. D. R. Morgan, H. T. Ang, D. G.
Hall, J. Am. Chem. Soc. 2018, 140, 5264-5271; k) G. E. Garrett, K. Tanveer, M. S. Taylor, J. Org. Chem. 2017, 82, 1085-
1095; l) X. Mo, D. G. Hall, J. Am. Chem. Soc. 2016, 138, 10762-10765; m) H. S. Geethanjali, R. M. Melavanki, D.
Nagaraja, N. R. Patil, J. Thipperudrappa, R. A. Kusanur, Luminescence 2016, 31, 1046-1053; n) C. L. Ricardo, X. Mo, J. A.
McCubbin, D. G. Hall, Chem. - Eur. J. 2015, 21, 4218-4223; o) T. Mohy El Dine, W. Erb, Y. Berhault, J. Rouden, J.
Blanchet, J. Org. Chem. 2015, 80, 4532-4544; p) K. Ishihara, Top. Organomet. Chem. 2015, 49, 243-270; q) Y. Lu, K.
Wang, K. Ishihara, Asian J. Org. Chem. 2017, 6, 1191-1194; r) T. Maki, K. Ishihara, H. Yamamoto, Tetrahedron 2007, 63,
8645-8657; s) T. Maki, K. Ishihara, H. Yamamoto, Org. Lett. 2006, 8, 1431-1434; t) T. Maki, K. Ishihara, H. Yamamoto,
Org. Lett. 2005, 7, 5043-5046; u) T. Maki, K. Ishihara, H. Yamamoto, Synlett 2004, 1355-1358; v) K. Ishihara, S. Ohara,
H. Yamamoto, D. T. Amos, R. L. Danheiser, Org. Synth. 2002, 79, 167-183; w) K. Ishihara, S. Ohara, H. Yamamoto, D. T.
Amos, R. L. Danheiser, Org. Synth. 2002, 79, 176-183; x) K. Ishihara, S. Kondo, H. Yamamoto, Synlett 2001, 1371-1374;
y) K. Ishihara, S. Ohara, H. Yamamoto, J. Org. Chem. 1996, 61, 4196-4197.
[3]
[4]
T. Marcelli, Angew. Chem. Int. Ed. 2010, 49, 6840-6843.
a) J. Cao, Shijiazhuang Chengzhi Yonghua Display Material Co., Ltd., Patent CN105503961A, 2016, p. 25; b) J. Guo, J.
Cao, Y. Sui, R. Hua, Shijiazhuang Chengzhi Yonghua Display Material Co., Ltd., Patent CN103058886A, 2013, p. 14.
a) S. C. Goodacre, L. J. Street, D. J. Hallett, J. M. Crawforth, S. Kelly, A. P. Owens, W. P. Blackaby, R. T. Lewis, J. Stanley,
A. J. Smith, P. Ferris, B. Sohal, S. M. Cook, A. Pike, N. Brown, K. A. Wafford, G. Marshall, J. L. Castro, J. R. Atack, J. Med.
Chem. 2006, 49, 35 - 38; b) M. S. Chambers, S. C. Goodacre, D. J. Hallett, A. Jennings, P. Jones, R. T. Lewis, K. W.
Moore, M. G. N. Russell, L. J. Street, H. J. Szekeres, Merck Sharp & Dohme Limited, World Patent WO2002074773A1,
2002, p. 197.
[5]
[6]
[7]
[8]
H. Tian, T. Jiang, S. Chu, X. Tan, Q. Ban, L. Gao, X. Su, H. Chen, X. Wei, Beijing Bayi Space LCD Technology Co., Ltd.,
Patent CN106811208A, 2017, p. 24.
F. Barany, M. Pingle, D. E. Bergstrom, S. F. Giardina, L. D. Arnold, Cornell University; Purdue Research Foundation;
Coferon, Inc. World Patent WO2013058824A1, 2013, p. 368.
a) K. Babaoglu, G. Brizgys, J. Cha, X. Chen, H. Guo, R. L. Halcomb, X. Han, R. Huang, H. Liu, R. McFadden, M. L. Mitchell,
Y. Qi, P. A. Roethle, L. Xu, H. Yang, Gilead Sciences, Inc., World Patent WO2013159064A1, 2013, p. 633; b) J. Y. Winum,
A. Innocenti, A. Scozzafava, J. L. Montero, C. T. Supuran, Bioorg. Med. Chem. 2009, 17, 3649-3652; c) J. Adams, Drug
Discov. Today 2003, 8, 307-315; dJ. Adams, Curr. Opin. Chem. Biol. 2002, 6, 493-500; e) J. Adams, M. Behnke, S. Chen,
A. A. Cruickshank, L. R. Dick, L. Grenier, J. M. Klunder, Y. T. Ma, L. Plamondon, R. L. Stein, Bioorg. Med. Chem. Lett.
1998, 8, 333-338; f) T. Mc Cormack, W. Baumeister, L. Grenier, C. Moomaw, L. Plamondon, B. Pramanik, C. Slaughter,
F. Soucy, R. Stein, F. Zuhl, L. Dick, J. Bio. Chem. 1997, 272, 26103-26109; g) M. M. Hansen, R. A. Jolly, R. J. Linder, Org.
Process Res. Dev. 2015, 19, 1507-1516; h) T. Glinka, R. Higuchi, S. Hecker, B. Eastman, O. Rodny, Rempex
Pharmaceuticals, Inc., World Patent WO2012109164A1, 2013, p. 149; i) M. R. O’Donovan, C. D. Mee, S. Fenner, A.
Teasdale, D. H. Phillips, Mutat. Res. Genet. Toxicol. Environ. Mutagen. 2011, 724, 1-6; j) R. T. Jacobs, J. J. Plattner, B.

New Journal of Chemistry
Page 14 of 15
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
7
8
9
Nare, S. A. Wring, D. Chen, Y. Freund, E. G. Gaukel, M. D. Orr, J. B. Perales, M. Jenks, R. A. Noe, J. M. Sligar, Y.-K.
Zhang, C. J. Bacchi, N. Yarlett, R. Don, Future Med. Chem. 2011, 3, 1259-1278.
[9]
a) V. Obermoser, R. Mauersberger, D. Schuster, M. Czifersky, M. Lipova, M. Siegl, U. Kintscher, R. Gust, Eur. J. Med.
Chem. 2017, 126, 590-603; b) W. Erb, A. Hellal, M. Albini, J. Rouden, J. Blanchet, Chem. Eur. J. 2014, 20, 6608-6612; c)
K. Durka, S. Luliński, M. Dąbrowski, J. Serwatowski, Eur. J. Org. Chem. 2014, 2014, 4562-4570; d) M. Filthaus, I. M.
Oppel, H. F. Bettinger, Org. Biomol. Chem. 2008, 6, 1201-1207; e) M. J. Smith, M. J. Lawler, N. Kopp, D. D. McLeod, A.
H. Davulcu, D. Lin, K. Katipally, C. Sfouggatakis, Org. Process Res. Dev. 2017, 21, 1859-1863; f) N. Gernigon, H. Zheng,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
D. G. Hall, Tetrahedron Lett. 2013, 54, 4475-4478; g) M. D ̧browski, P. Kurach, S. Luliński, J. Serwatowski, Appl.
Organomet. Chem. 2007, 21, 234-238; h) Coghlan, S. W.; Giles, R. L.; Howard, J. A. K.; Patrick, L. G. F.; Probert, M. R.;
Smith, G. E.; Whiting, A. J. Organomet. Chem. 2005, 690, 4784-4793; i) S. Liu, Y. Yang, X. Liu, F. K. Ferdousi, A. S.
Batsanov, A. Whiting, Eur. J. Org. Chem. 2013, 2013, 5692-5700; j) H. Charville, D. Jackson, G. Hodges, A. Whiting,
Chem. Commun. 2010, 46, 1813-1823; k) I. Georgiou, G. Ilyashenko, A. Whiting, Acc. Chem. Res. 2009, 42, 756-768; l)
K. Arnold, B. Davies, D. Hérault, A. Whiting, Angew. Chem. Int. Ed. 2008, 47, 2673-2676.
[10]
[11]
J. Cvengroš, D. Stolz, A. Togni, Synthesis 2009, 2009, 2818-2824.
a) R. M. Al-Zoubi, A. Ibdah, W. K. Al-Jammal, M. S. Al-Zoubi, A. A. Almasalma, R. McDonald, Synthesis 2018, 50, 384-
390; b) R. M. Al-Zoubi, M. S. Al-Zoubi, K. T. Jaradat, R. McDonald, Eur. J. Org. Chem. 2017, 2017, 5800-5808; c) R. M.
Al-Zoubi, M. S. Al-Zoubi, A. H. Abazid, R. McDonald, Asian J. Org. Chem. 2015, 4, 359-367; d) R. M. Al-Zoubi, H. Al-
Mughaid, R. McDonald, Aust. J. Chem. 2015, 68, 912-918; e) R. M. Al-Zoubi, H. Al-Mughaid, R. McDonald, Aust. J.
Chem. 2015, 68, 912-918.
a) C. Sämann, B. Haag, P. Knochel, Chem. Eur. J. 2012, 18, 16145-16152; b) A. Unsinn, C. J. Rohbogner, P. Knochel,
Adv. Synth. Catal. 2013, 355, 1553-1560; c) D. Teclechiel, M. Sundström, G. Marsh, Chemosphere 2009, 74, 421-427;
d) A. Unsinn, S. H. Wunderlich, P. Knochel, Adv. Synth. Catal. 2013, 355, 989-995. e) K. Menzel, P. M. Mills, D. E.
Frantz, T. D. Nelson, M. H. Kress, Tetrahedron Lett. 2008, 49, 415-418; f) K. Menzel, E. L. Fisher, L. DiMichele, D. E.
Frantz, T. D. Nelson, M. H. Kress, J. Org. Chem. 2006, 71, 2188-2191; g) K. Menzel, L. Dimichele, P. Mills, D. E. Frantz, T.
D. Nelson, M. H. Kress, Synlett 2006, 1948-1952; h) L. DiMichele, K. Menzel, P. Mills, D. Frantz, T. Nelson, Magn.
Reson. Chem. 2006, 44, 1041-1043; i) F. Cottet, E. Castagnetti, M. Schlosser, Synthesis 2005, 798-803; j) F. Mongin, E.
Marzi, M. Schlosser, Eur. J. Org. Chem. 2001, 2001, 2771-2777; k) I. Sapountzis, H. Dube, P. Knochel, Adv. Synth. Catal.
2004, 346, 709-712; l) C. J. F. Du, H. Hart, K. K. D. Ng, J. Org. Chem. 1986, 51, 3162-3165; m) J. F. Bunnett, R. R. Victor,
J. Am. Chem. Soc. 1968, 90, 810-811. n) Y. Liu, J. Kim, H. Seo, S. Park, J. Chae, Adv. Synth. Catal. 2015, 357, 2205-2212;
o) D. Wang, Q. Cai, K. Ding, Adv. Synth. Catal. 2009, 351, 1722-1726.
R. M. Al-Zoubi, W. K. Al-Jammal, M. Y. El-Khateeb, R. McDonald, Eur. J. Org. Chem. 2015, 2015, 3374-3384.
S. Mothana, J. M. Grassot, D. G. Hall, Angew. Chem. Int. Ed. 2010, 49, 2883-2887.
CCDC-1881916-1881919 contain the supplementary crystallographic data for compounds 5A, 14A, 19A and 21A
respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
a) V. P. W. Boehm, V. Schulze, M. Broenstrup, M. Mueller and R. W. Hoffmann, Organometallics 2003, 22, 2925-
2930; b) R. W. Hoffmann, M. Broenstrup and M. Mueller, Org. Lett. 2003, 5, 313-316; c) M. Mueller, M. Broenstrup, O.
Knopff, V. Schulze and R. W. Hoffmann, Organometallics 2003, 22, 2931-2937; d) V. Schulze, M. Bronstrup, V. P. W.
Bohm, P. Schwerdtfeger, M. Schimeczek and R. W. Hoffmann, Angew. Chem., Int. Ed. 1998, 37, 824-826.
M. Schnuerch, M. Spina, A. F. Khan, M. D. Mihovilovic and P. Stanetty, Chem. Soc. Rev. 2007, 36, 1046-1057.
a) J. D. MacLowry, M. J. Jaqua, S. T. Selepak, Appl. Microbiol. 1970, 20, 46; b) F. Smaill, J. Can, Gastroenterology 2000,
14, 871.
[12]
[13]
[14]
[15]
[16]
[17]
[18]

Page 15 of 15
New Journal of Chemistry
View Article Online
DOI: 10.1039/C9NJ05708K
1
2
3
4
5
6
Graphical Abstract
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Regioselective Synthesis of ortho-Iodobiphenylboronic Acid Derivatives: A
Superior Catalyst for Carboxylic Acid Activation
Raed M. Al-Zoubi,*a Walid K. Al-Jammala and Robert McDonaldb
aDepartment of Chemistry, Jordan University of Science and Technology, P.O.Box 3030, Irbid, 22110, Jordan
bDepartment of Chemistry, Gunning-Lemieux Chemistry Centre, University of Alberta, Edmonton, Alberta, T6G2G2, Canada
*Corresponding author. Tel.: + 962-2-7201000-Ext 23651; fax: + 962-2-7201071; e-mail: rmzoubi@just.edu.jo
Key Topic: Ortho-Iodobiphenylboronic Acids in One-step
Superior catalyst for
Crystalline solids
> 99 : 1
carboxylic acid activation
including -aminoacid

X
X
i. iPrMgCl (2M),
THF, - 78 oC
I
OH
B
MeO
I
R2
R2
OH
B
I
I
OH
OH
ii. (MeO)3B, THF,
-78 oC to r.t.
R1
R1
OMe
R1 = F, Cl, Br, H, CH3, OCH3, CO2CH3
R2 = H, F, OCH3, i-Pr, CH2OCH3, OPh
X = C, N
21 examples
38% - 92%
Compound 19A
Highlights
Gram-Scale synthesis
Chromatography free
High regioselective
High functional group tolerance
Broad substrate scope
Antimicrobial Activities
Amidation Catalysts
Four X-ray crystal structures
Efficient and versatile synthesis of ortho-iodobiphenylboronic acids with remarkable catalytic and microbial activities
.