Selective and efficient generation of ortho-brominated para-substituted phenols in ACS-grade methanol

Article abstract of DOI:10.3390/molecules21010088

The mono ortho-bromination of phenolic building blocks by NBS has been achieved in short reaction times (15-20 min) using ACS-grade methanol as a solvent. The reactions can be conducted on phenol, naphthol and biphenol substrates, giving yields of >86% on gram scale. Excellent selectivity for the desired mono ortho-brominated products is achieved in the presence of 10 mol % para-TsOH, and the reaction is shown to be tolerant of a range of substituents, including CH₃/ F,and NHBoc.

Full text of DOI:10.3390/molecules21010088

molecules
Article
Selective and Efficient Generation of
ortho-Brominated para-Substituted Phenols in
ACS-Grade Methanol
David Georgiev, Bartholomeus W. H. Saes, Heather J. Johnston, Sarah K. Boys, Alan Healy
and Alison N. Hulme *
Received: 28 September 2015; Accepted: 7 January 2016; Published: 13 January 2016
Academic Editor: Kerry Gilmore
EaStCHEM School of Chemistry, The University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, UK;
D.Georgiev@sms.ed.ac.uk (D.G.); bartsaes@live.nl (B.W.H.S.); hjohnst2@exseed.ed.ac.uk (H.J.J.);
boys.sarah@gmail.com (S.K.B.); alan.healy@yale.edu (A.H.)
*
Correspondence: Alison.Hulme@ed.ac.uk; Tel.: +44-131-650-4711; Fax: +44-131-650-4743
Abstract: The mono ortho-bromination of phenolic building blocks by NBS has been achieved in short
reaction times (15–20 min) using ACS-grade methanol as a solvent. The reactions can be conducted on
phenol, naphthol and biphenol substrates, giving yields of >86% on gram scale. Excellent selectivity
for the desired mono ortho-brominated products is achieved in the presence of 10 mol % para-TsOH,
and the reaction is shown to be tolerant of a range of substituents, including CH , F, and NHBoc.
3
Keywords: ortho-bromination; ACS-grade methanol; NBS
1
. Introduction
Brominated phenols and their derivatives constitute important building blocks for a range of
synthetic targets (Figure 1), with recent examples of pharmaceutical interest including: (i) synthesis
of aryl 1-indanylketone inhibitors of the human peptidyl prolyl cis/trans isomerase Pin1, such as
using a domino coupling reaction starting from the methylated derivative of 2-bromo-4-fluorophenol
]; (ii) synthesis of alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists, such as library
members , by Sonogashira coupling to the tert-butyl protected phenoxyacetic acid derivative
of 3-bromo-[1,1 -biphenyl]-4-ol
product bisebromoamide
derivatives such as 6 [4,5].
1,
2 [1
3
1
4 [2]; and (iii) synthesis of the cytotoxic peptidic marine natural
5
[
3], through modification and peptide coupling of brominated D-tyrosine
(i)
(ii)
OH
O
OH
Br
x 2
OH
NO
O
Br
F
O
Ar
OH
F
2
1
2
HO
3
4
(iii)
O
OMe
N
O
O
BocHN
N
O
O
H
O
Me
N
N
S
N
Me
N
N
H
O
OH
O
Br
OH
Br
bisebromoamide 5
6
Figure 1. Recent applications of mono ortho-brominated phenols to the synthesis of biologically
active targets.
Molecules 2016, 21, 88; doi:10.3390/molecules21010088
www.mdpi.com/journal/molecules

Molecules 2016, 21, 88
2 of 8
As part of our own synthetic efforts directed towards the efficient solid-phase synthesis of
bisebromoamide ], gram-scale syntheses of each of the component building blocks was
required [ ]. For the bromotyrosine derivative a number of recently published methods for the
5 [6,7
8,9
N-bromosuccinimide (NBS) promoted mono-ortho-bromination reaction were surveyed with a view to
applying them to the amino acid derivative Boc-D-Tyr-OMe (7Ñ6, Scheme 1). Of particular concern
was minimization of over-bromination which results in the dibromo derivative
chromatography greatly reduced synthetic efficiency.
8, removal of which by
Scheme 1. Building block synthesis for the marine natural product bisebromoamide
Conditions: ( ) NBS (100 mol %), In(OTf) (10 mol %), MeCN, rt, 10 min; ( ) NBS (100 mol %), pTsOH
10 mol %), EtOAc, rt, 30 h.
5. Reagents and
a
b
3
(
Initial attempts to brominate Boc-D-Tyr-OMe
reaction of NBS in acetonitrile [10]. However, the major product of the reaction was found to be the
dibrominated material , even when the reaction was conducted in the dark and at reduced temperature
0 C). The Chhattise group have demonstrated rapid (<10 min) photochemical bromination of aromatic
compounds (including para-substituted phenols) under UV-vis irradiation at ambient temperatures [11].
Reaction of Boc-D-Tyr-OMe with one equivalent of NBS in ethyl acetate under UV-vis irradiation
365 nm; 6 W, F6T5/BL lamp) resulted in rapid consumption of the starting material, but again gave
7 focused on indium(III) triflate catalysis of the
8
˝
(
7
(
predominantly the undesired dibrominated product 8.
In an attempt to minimize the dibromination reaction, attention then shifted to the
p-toluene-sulfonic acid (pTsOH)-mediated NBS bromination reaction [12,13]. Leykajarakul and
co-workers have proposed a mechanism for this reaction in which the pTsOH conjugates to the
phenolic alcohol directing bromination to the para position, or in the case of para-substituted phenols
to give selective mono ortho-bromination [11
the presence of pTsOH (10 mol %) in ethyl acetate a moderate yield (58%) of the mono-brominated
material was obtained after 30 h reaction time. UV-vis irradiation (365 nm; 6 W, F6T5/BL lamp) of
this reaction gave full conversion to the desired monobrominated product in times ranging from
0 min to 4 h, depending on the reaction scale and light source used. However, it was suspected
,13,14]. When Boc-D-Tyr-OMe 7 was reacted with NBS in
6
6
4
that the extended reaction times also led to UV-mediated debromination of the desired product,
complicating the reaction still further. For these reasons, reproducible reaction conditions which were
readily amenable to scale-up were sought. Flow chemistry, and in particular photochemical flow
chemistry with its short path lengths allowing efficient irradiation, readily controlled residence times
and scaleability [15–19], was initially considered as a potential solution.
2
. Results and Discussion
2
.1. Investigation of the Mono ortho-Bromination Flow Reaction
Investigation of the mono ortho-bromination reaction by NBS in the presence of pTsOH (10 mol %)
under flow conditions was carried out using a UV photoreactor (365–366 nm; 125 W, Hg lamp) based
on those reported by the Booker-Milburn and Seeberger groups [16 19]. The initial batch reactions
–
had been conducted in ethyl acetate, but NBS shows only limited solubility in this solvent making it
incompatible with a flow modality for the reaction. For this reason the flow reaction was explored in
both acetonitrile and methanol; two solvents which are commonly used in bromination reactions on
other classes of substrates. Although higher concentrations of NBS could be achieved in acetonitrile

Molecules 2016, 21, 88
3 of 8
than in methanol (0.5 M and 0.1 M respectively) which would lead to increased production rates in
flow, the reactions in acetonitrile were noticeably slower with longer residence times required in the
UV photoreactor to achieve full conversion. Indeed, across a range of substrates the observed rates of
reaction in methanol were so fast that it led us to suspect that exposure to the UV light source was
not required. This was confirmed by reactions conducted under standard flow conditions but in the
absence of UV light (the so-called “dark reaction”), in which reactive substrates showed full conversion
to the mono ortho-brominated products in methanol, but only minimal conversion in acetonitrile.
These observations led us to look more closely at the NBS-mediated mono ortho-bromination reaction
in methanol.
2
.2. Investigation of Batch Reaction Conditions Using ACS-Grade Methanol
There are very few reports of ortho-bromination reactions of phenols conducted in methanol; and
those which have been reported to give mono selectivity rely on blocking of the second ortho position
to achieve this [14]. However, a similar dramatic rate acceleration for the NBS-mediated bromination
of the polyalkylated aromatic durene in the presence of pTsOH has been reported when this reaction
was conducted in methanol rather than acetonitrile, or ethyl acetate [20]. The facile chlorination of
˝
aromatic substrates in water at 40 C using a combination of NCS/NaCl reagents in the presence of
pTsOH has also been reported [21 22]. It has been proposed that under these polar protic conditions
,
the pTsOH accelerates the reaction through protonation of the N-halosuccinimide to provide a more
reactive electrophile [20,21].
In investigating the selective mono ortho-bromination reaction by NBS in the presence of pTsOH
in methanol, the reaction of p-cresol
available and the reaction to give the desired mono ortho-brominated product 10 (and the undesired
dibrominated product 11) could be easily followed by HPLC (SI Figure S1). The p-cresol was
9 (Table 1) was used as a test substrate, as it was both readily
9
premixed with pTsOH prior to addition of NBS as this has been shown to give better selectivity for
mono ortho-bromination [12]. HPLC analysis of samples taken directly from the reaction mixture at
timed intervals rapidly established that the batch reaction of
9 in methanol reached completion in
under 5 min, even in the absence of light. When the reaction was carried out with NBS addition in a
single portion at the beginning of the reaction, bromination of p-cresol
9 gave conversion to 9:10:11 in
a ratio of 6:87:7 (Table 1, entry 1).
Table 1. Optimization of batch conditions for the mono ortho-bromination reaction.
H C
H C
H C
Br
3
3
3
NBS, pTsOH
OH ACS-grade MeOH
rt, 25 min
OH
OH
Br
Br
9
10
11
Ratio (Relative % at 285 nm)
Isolated Yield
Entry
NBS (mol %)
pTsOH (mol %)
1
0 (%)
9
10
11
a,b
1
100
100
100
110
100
100
10
10
10
10
0
6
5
3
0
15
3
87
93
94
88
77
93
7
2
3
12
8
4
–
–
92%
86%
74%
90%
2 b
3
4
5
6
20
a
NBS added as a single portion at the start of the reaction and then reaction stirred for 25 min; b Reaction
conducted in dry methanol.
When the bulk concentration of NBS was reduced through its controlled addition in solution
by cannula, an overall increase in conversion to the desired mono ortho-brominated product 10 was
observed (Table 1, entry 2). The reaction was found to be tolerant of moisture (Table 1, entries 2 and 3);
when the reaction was conducted in ACS-grade methanol, under ambient conditions (air and room

Molecules 2016, 21, 88
4 of 8
temperature) an excellent isolated yield of 10 was achieved and no significant change in the ratio of
products was observed. Selectivity for the desired mono ortho-brominated product was shown to
depend heavily on the number of equivalents of NBS used (Table 1, entries 3 and 4), but also to be
influenced by the presence of pTsOH (Table 1, entries 5 and 6) as previously reported [12,13].
Optimum conditions involved pre-mixing the substrate and pTsOH (10 mol %) in a minimal
amount of ACS-grade methanol and controlled addition of a solution of NBS (100 mol %) as a 0.1 M
˝
solution in methanol over 20 min, then stirring for a further 5 min, at ambient temperature (~20 C)
under air; giving a ratio of 10 11 of 3:94:3 and an isolated yield of of 92%. These conditions were
9:
:
9
then successfully applied to a range of substrates on gram scale as shown in Table 2.
Table 2. Gram scale mono ortho-bromination reaction in ACS-grade methanol.
Ratio (SM:mono:di) b
Isolated Yield c (%)
Entry
Starting Material a
Major Product
1
p-Cresol 9
1:95:4
92
2
4-Fluorophenol
4:89:7
86
3
4
5
Vanillin
2-Naphthol
5:95:–
0:99:1
2:92:6
90
98
90
4-tert-Butylphenol
1
6
7
8
[1,1 -Biphenyl]-4-ol
4:90:6
4:92:4
2:94:4
89
90
89
1
1
1
3 -Fluoro-6 -methoxy-[1,1 -biphenyl]-4-ol
Boc-Tyr-OMe ent-7
a
Method A: NBS (100 mol %), pTsOH (10 mol %), MeOH, rt, 25 min; b Ratio SM:mono:di = starting
material:mono ortho-brominated:di ortho-brominated; c Major product.
Phenol derivatives with alkyl and aryl para-substituents (entries 1, 5–7, Table 2) and Boc-Tyr-OMe
ent-7, entry 8, Table 2) were shown to give high selectivity for the mono ortho-brominated products
(
under these conditions, facilitating separation to give excellent yields of the major product. Vanillin
and 2-naphthol (entries 3 and 4, Table 2), both known to react readily to bromination, also gave
excellent conversion. Electron withdrawing para-substituents (entry 2, Table 2, and p-CF not shown)
3
generally induced poorer selectivity for the mono ortho-brominated products resulting in somewhat
reduced isolated yields of the major products.

Molecules 2016, 21, 88
5 of 8
3
. Experimental Section
3
.1. General Information
ACS-grade methanol was obtained from Fischer Scientific and was used without further
purification or drying; all other chemicals were used as obtained from the supplier unless otherwise
1
13
19
stated. H-, C- and F-NMR spectra were obtained on an AVA 500 or a PRO 500 instrument (Bruker,
Coventry, UK) using TMS as a reference and residual solvent as an internal standard. The data
are presented as follows: chemical shift (in ppm on the
δ
scale relative to
δ
TMS
= 0), integration,
multiplicity, coupling constant and interpretation. Electron ionisation (EI) mass spectra were obtained
on a MS50TC mass spectrometer (Kratos, Manchester, UK). Analytical Reverse Phase HPLC (RP-HPLC)
®
was conducted on a Waters 600 (100
µ
L) system (Waters, Elstree, UK) using a 717plus autosampler
®
and 996 PDA detector (190 to 800 nm) equipped with a Phenomenex Luna C18(2) 5
µm column
(
(
i.d. 4.6 mm, length 300 mm). A binary solvent system was used A = water (0.1% TFA), B = MeCN
´
1
˝
0.1% TFA) at a flow rate of 1.00 mL
¨
min ; and the column was maintained at 30
˘
1 C. The elution
program was a linear gradient from 0 min (95A:5B) to 30 min (5A:95B), isocratic from 30 min to
5 min (5A:95B), before recovery of the initial conditions over 5 min and equilibration over 10 min,
3
giving a total run time of 50 min. Melting points were determined on an Electrothermal Melting Point
apparatus (Gallenkamp, Loughborough, UK) and are uncorrected. Optical rotations were performed
on a POLAAR 20 polarimeter (Optical Activity, Ramsey, UK).
3
.2. General Procedure for Batch Reaction Conditions in ACS-Grade Methanol
A solution of the starting material (~10 mmol) and pTsOH (10 mol %) in MeOH (1.0 mL per mmol
starting material) was stirred for 10 min, then a solution of NBS (100 mol %; recrystallized from H O)
2
in MeOH (0.1 M) was added dropwise over 20 min from a foiled reaction flask. The reaction mixture
was stirred for a further 5 min and then concentrated in vacuo. The resultant residue was purified
using column chromatography (CH Cl , or 1% MeOH in CH Cl ).
2
2
2
2
3
.3. Characterization of Products
1
2
-Bromo-4-methylphenol (10) [23]: 10.1 mmol; 1.73 g (92%); Rt = 24.3 min; H-NMR
.30 (1H, br s, ArH), 7.04 (1H, br d, J = 8.2 Hz, ArH), 6.94 (1H, d, J = 8.2 Hz, ArH), 5.43 (1H, s, OH), 2.30
(126 MHz, CDCl ) 150.0 (C), 132.2 (CH), 131.4 (C), 129.8 (CH), 115.8 (CH),
δ (500 MHz, CDCl3)
7
(
3H, s, OCH3); 13C-NMR
δ
3
81
+
79
+
1
09.9 (C), 20.2 (CH ); m/z (EI) 188 ( BrM , 52%), 186 ( BrM , 54), 107 (100), 77 (35).
3
˝
˝
1
2
,6-Dibromo-4-methylphenol (11) [24]: Rt = 27.6 min; mp 47–49 C, lit [24] 49–51 C; H-NMR
δ
(500 MHz,
13
CDCl ) 7.26 (2H, br s, ArH), 5.70 (1H, s, OH), 2.25 (3H, s, OCH ); C-NMR
δ (126 MHz, CDCl ) 147.1
3
3
3
81
81
+
81 79
+
(C), 132.4 (2
ˆ
CH and C), 109.4 (2
ˆ
C), 20.0 (CH ); m/z (EI) 268 ( Br BrM , 46%), 266 ( Br BrM ,
3
79
79
+
1
00), 264 ( Br BrM , 48), 187 (39),185 (41).
1
2
7
(
1
-Bromo-4-fluorophenol (
.21 (1H, ddd, J = 7.7, 2.5 and 0.7 Hz ArH), 7.00–6.93 (2H, m, 2
2) [23]: 10.3 mmol; 1.70 g (86%); Rt = 23.1 min; H-NMR δ (500 MHz, CDCl3)
ˆ
ArH), 5.32 (1H, s, OH); 13C-NMR
126 MHz, CDCl ) 156.4 (d, J = 242 Hz, C), 148.9 (d, J = 3 Hz, CH), 118.7 (d, J = 26 Hz, C),
16.3 (d, J = 8 Hz, CH), 116.0 (d, J = 23 Hz, CH), 109.5 (d, J = 10 Hz, C); F-NMR
δ
1
4
2
3
CF
CF
CF
3
2
3
19
δ
(471 MHz,
CF
CF
CF
81
+
79
+
CDCl3)
´
121.97 (td, J = 7.7 and 5.4 Hz); m/z (EI) 192 ( BrM , 98%), 190 ( BrM , 100), 82 (43), 83 (27).
3
-Bromo-4-hydroxy-5-methoxybenzaldehyde (12) [25]: 9.09 mmol; 1.89 g (90%); Rt = 21.4 min; mp
˝
˝
1
1
60–162 C, lit [25] 162–164 C, EtOH; H-NMR
δ (500 MHz, DMSO-d ) 10.72 (1H, s, OH), 9.79 (1H,
6
13
s, CHO), 7.73 (1H, d, J = 1.8 Hz, ArH), 7.43 (1H, d, J = 1.8 Hz, ArH), 3.92 (3H, s, OCH3); C-NMR
δ
(
(
126 MHz, DMSO-d ) 190.9 (CH), 150.3 (C), 149.1 (C), 129.4 (C), 129.2 (CH), 110.1 (CH), 109.7 (C), 56.8
6
81
+
79
+
CH ); m/z (EI) 232 ( BrM , 94%), 231 (86) 230 ( BrM , 100), 229 (95).
3

Molecules 2016, 21, 88
6 of 8
˝ ˝
-Bromo-2-naphthol (13) [23]: 9.05 mmol; 1.98 g (98%); Rt = 26.4 min; mp 80–82 C, lit [23] 82–83 C;
1
1
H-NMR
δ (500 MHz, CDCl ) 8.06 (1H, br d, J = 8.4 Hz, ArH), 7.81 (1H, br d, J = 8.1 Hz, ArH), 7.77 (1H,
3
d, J = 8.8 Hz, ArH), 7.60 (1H, ddd, J = 8.4, 6.9 and 1.2 Hz, ArH), 7.42 (1H, ddd, J = 8.1, 6.9 and 1.0 Hz,
ArH), 7.30 (1H, d, J = 8.8 Hz, ArH), 5.94 (1H, s, OH); 13C-NMR
δ
(126 MHz, CDCl ) 150.6 (C), 132.3 (C),
3
1
(81
29.7 (C), 129.4 (CH), 128.2 (CH), 127.9 (CH), 125.3 (CH), 124.2 (CH), 117.2 (CH), 106.2 (C); m/z (EI) 224
BrM , 98%), 222 ( BrM , 100), 115 (26), 114 (36).
+
79
+
1
2
-Bromo-4-tert-butylphenol (14) [26]: 10.1 mmol; 2.07 g (90%); Rt = 27.6 min; H-NMR
δ
(500 MHz,
CDCl ) 7.48 (1H, d, J = 2.3 Hz, ArH), 7.27 (1H, dd, J = 8.5 and 2.3 Hz, ArH), 6.99 (1H, d, J = 8.5 Hz, ArH),
3
13
5
1
7
.39 (1H, s, OH), 1.32 (9H, s, C(CH ) ); C-NMR δ (126 MHz, CDCl ) 149.9 (C), 145.1 (C), 128.8 (CH),
26.3 (CH), 115.6 (CH), 109.9 (C), 34.2 (C), 31.4 (3
4), 215 (100), 213 (86), 134 (87).
3 3 3
81
+
79
+
ˆ
CH ); m/z (EI) 230 ( BrM , 76%), 228 ( BrM ,
3
1
˝
3
9
-Bromo-[1,1 -biphenyl]-4-ol (
4
) [27]: 10.0 mmol; 2.22 g (89%); Rt = 24.2 min; mp 92–94 C, lit [27
˝
4–95 C; H-NMR δ (500 MHz, CDCl ) 7.70 (1H, d, J = 2.2 Hz), 7.56–7.48 (2H, m), 7.46 (1H, dd, J = 8.4
]
1
3
13
and 2.2, Hz), 7.44–7.39 (2H, m), 7.37–7.29 (1H, m), 7.09 (1H, d, J = 8.4 Hz), 5.52 (1H, s, OH); C-NMR
δ
(
1
8
126 MHz, CDCl ) 151.7 (C), 139.5 (C), 135.4 (C), 130.5 (CH), 128.9 (2
ˆ
CH), 128.0 (CH), 127.3 (CH),
3
81
+
79
+
26.8 (2
ˆ
CH), 116.3 (CH), 110.7 (C); m/z (EI) 250 ( BrM , 100%), 248 ( BrM , 100), 139 (38), 86 (58),
4 (99).
1
1
1
1
3
-Bromo-3 -fluoro-6 -methoxy-[1,1 -biphenyl]-4-ol (15): 3.49 mmol; 0.93 g (90%); Rt = 28.3 min; H-NMR
δ
(500 MHz, CDCl ) 7.67 (1H, d, J = 2.1 Hz, ArH), 7.41 (1H, dd, J = 8.4 and 2.1 Hz, ArH), 7.09 (1H, d,
3
J = 8.4 Hz, ArH), 7.03 (1H, ddd, J = 9.2, 3.1 and 0.7 Hz, ArH), 7.03–6.98 (1H, m, ArH), 6.91 (1H, ddd,
1
3
J = 8.7, 4.5 and 0.7 Hz, ArH), 5.57 (1H, s, OH), 3.81 (3H, s, OCH ); C-NMR
δ
(126 MHz, CDCl ) 157.1
3
3
1
4
4
(
(
1
8
d, J = 239 Hz, C), 152.5 (d, J = 2 Hz, C), 151.6 (C), 132.7 (CH), 131.3 (d, J = 2 Hz, C), 130.3
CH), 130.1 (d, J = 8 Hz, C), 117.1 (d, J = 24 Hz, CH), 115.6 (CH), 114.4 (d, J = 23 Hz, CH),
CF
CF
CF
2
3
2
CF
CF
CF
3
19
12.3 (d, J = 8 Hz, CH), 109.9 (C), 56.2 (CH ); F-NMR
δ
(471 MHz, CDCl3)
´
123.79 (ddd, J = 9.2,
CF
3
81
+
79
+
79
+
.3 and 4.5 Hz); m/z (EI) 298 ( BrM , 89%), 296 ( BrM , 90), 203 (20) 202 (100); HRMS (EI) BrM
79
found 295.9839, C H O BrF requires 295.9843.
13
10
2
Methyl (S)-2-tert-butoxycarbonylamino-3-(3-bromo-4-hydroxyphenyl)propanoate (ent-
6
): 5.00 mmol; 1.68 g
˝
α] = 59.0 (c 1, CHCl ); mp 117–119 C; H-NMR δ (500 MHz, CDCl , 323 K)
D 3 3
1
(
89%); Rt = 25.3 min; [
.24 (1H, d, J = 2.0 Hz, ArH), 6.97 (1H, dd, J = 8.3 and 2.0 Hz, ArH), 6.90 (1H, d, J = 8.3 Hz, ArH), 5.50
1H, br s, OH), 5.01 (1H, br s, NH), 4.51 (1H, br s, -CH), 3.71 (3H, s, OCH ), 3.04 (1H, dd, J = 14.0
and 5.8 Hz, CH H Ar), 2.97—2.88 (1H, m, CH H Ar), 1.43 (9H, s, C(CH ) ); C-NMR
7
(
α
3
13
δ
(126 MHz,
A
B
A
B
3 3
CDCl , 323 K) 172.2 (C), 155.2 (C), 151.8 (C), 133.0 (CH), 130.1 (CH), 129.8 (C), 116.3 (CH), 110.2 (C),
3
+
8
1
3
0.3 (C), 54.7 (CH), 52.3 (CH ), 37.5 (CH ), 28.4 (3
00%), 396 ([79BrM + Na] , 99), 374 (14) 342 (10), 340 (11); HRMS (ESI+, MeOH) [M + Na] found
96.0434, C H O N BrNa requires 396.0417.
ˆ
CH ); m/z (ESI+, MeOH) 398 ([81BrM + Na] ,
3
2
3
+
+
79
15
20
5
4
. Conclusions
In assessing the use of methanol as a carrier solvent for the mono ortho-bromination of phenols
by NBS under flow conditions, the “dark reaction” clearly indicated that UV-vis irradiation was
not a prerequisite for success. Thus batch reaction conditions were optimized to allow a range of
NBS-mediated mono ortho-bromination reactions to be carried out in ACS-grade methanol on gram
scale without UV-vis irradiation in reaction times of 25 min. The highly selective product distributions
achieved meant that the desired products of these reactions were readily purified in excellent yields
(
86%–98%), thus providing an extremely facile route to high value medicinal chemistry building blocks.
With an efficient route to the synthesis of the mono ortho-brominated derivative of Boc-D-Tyr-OMe in
hand, the synthesis of the intriguing anti-cancer natural product, bisebromoamide, may now be tackled.

Molecules 2016, 21, 88
7 of 8
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/21/1/88/s1,
1
13
Figure S1: Choice of wavelength for reaction monitoring, Figure S2: H- and C-NMR spectra for compounds 15
and ent-6.
Acknowledgments: We thank Cancer Research UK (Grant Reference C21383/A6950), EPSRC and BBSRC
(
studentship to SKB, BBS/S/H/2005/13535) for funding. We thank Alessio De Simone for the preparation
1
1
1
of 3 -fluoro-6 -methoxy-[1,1 -biphenyl]-4-ol starting material.
Author Contributions: H.J.J., S.K.B. and A.H. designed and performed the experiments described in the
introduction; D.G. and B.W.H.S. designed and performed the flow experiments; D.G. designed and performed the
experiments in ACS-grade methanol; A.N.H. and D.G. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
Daum, S.; Erdmann, F.; Fischer, G.; Féaux-de-Lacroix, B.; Hessamian-Alinejad, A.; Houben, S.; Frank, W.;
Braun, M. Aryl indanyl ketones: Efficient inhibitors of the human peptidyl prolyl cis/trans isomerase Pin1.
Angew. Chem. Int. Ed. 2006, 45, 7454–7458. [CrossRef] [PubMed]
2
.
Crosignani, S.; Prêtre, A.; Jorand-Lebrun, C.; Fraboulet, G.; Seenisamy, J.; Augustine, J.K.; Missotten, M.;
Humbert, Y.; Cleva, C.; Abla, N.; et al. Discovery of potent, selective, and orally bioavailable
alkynylphenoxyacetic acid CRTH2 (DP2) receptor antagonists for the treatment of allergic inflammatory
diseases. J. Med. Chem. 2011, 54, 7299–7317. [CrossRef] [PubMed]
3
.
Teruya, T.; Sasaki, H.; Fukazawa, H.; Suenaga, K. Bisebromoamide, a potent cytotoxic peptide from the
marine cyanobacterium Lyngbya sp.: Isolation, stereostructure, and biological activity. Org. Lett. 2009, 11,
5
062–5065. [CrossRef] [PubMed]
4.
5.
6.
7.
Gao, X.G.; Liu, Y.Q.; Kwong, S.Q.; Xu, Z.S.; Ye, T. Total synthesis and stereochemical reassignment of
bisebromoamide. Org. Lett. 2010, 12, 3018–3021. [CrossRef] [PubMed]
Li, W.H.; Yu, S.Y.; Jin, M.Z.; Xia, H.G.; Ma, D.W. Total synthesis and cytotoxicity of bisebromoamide and its
analogues. Tetrahedron Lett. 2011, 52, 2124–2127. [CrossRef]
Boys, S.K. Tyrosine Derivatives and Their Anti-Cancer Applications. Ph.D. Thesis, The University of
Edinburgh, Edinburgh, UK, 2012.
Johnston, H.J. Development of Novel Analogues of the Anti-Proliferative Marine Natural Product
Bisebromoamide: Synthesis and Structure Activity Relationship Studies. Ph.D. Thesis, The University
of Edinburgh, Edinburgh, UK, 2014.
8
9
1
1
1
.
Johnston, H.J.; McWhinnie, F.S.; Landi, F.; Hulme, A.N. Flexible, phase-transfer catalyzed approaches to
4
-substituted prolines. Org. Lett. 2014, 16, 4778–4781. [CrossRef] [PubMed]
.
Johnston, H.J.; Hulme, A.N. A facile, inexpensive and scalable route to thiol-protected α-methyl cysteine.
Synlett 2013, 24, 591–594.
0. Zhou, C.-Y.; Li, J.; Peddibhotla, S.; Romo, D. Mild arming and derivatization of natural products via an
In(OTf) -catalyzed arene iodination. Org. Lett. 2010, 12, 2104–2107. [CrossRef] [PubMed]
3
1. Chhattise, P.K.; Ramaswamy, A.V.; Waghmode, S.B. Regioselective, photochemical bromination of aromatic
compounds using N-bromosuccinimide. Tetrahedron Lett. 2008, 49, 189–194. [CrossRef]
2. Bovonsombat, P.; Khanthapura, P.; Krause, M.M.; Leykajarakul, J. Facile syntheses of 3-halo and mixed
3,5-dihalo analogues of N-acetyl-L-tyrosine via sulfonic acid-catalysed regioselective monohalogenation.
Tetrahedron Lett. 2008, 49, 7008–7011. [CrossRef]
1
3. Bovonsombat, P.; Ali, R.; Khan, C.; Leykajarakul, J.; Pla-on, K.; Aphimanchindakul, S.; Pungcharoenpong, N.;
Timsuea, N.; Arunrat, A.; Punpongjareorn, N. Facile p-toluenesulfonic acid-promoted para-selective
monobromination and chlorination of phenol and analogues. Tetrahedron 2010, 66, 6928–6935. [CrossRef]
4. Verner, E.; Katz, B.A.; Spencer, J.R.; Allen, D.; Hataye, J.; Hruzewicz, W.; Hui, H.C.; Kolesnikov, A.; Li, Y.;
Luong, C.; et al. Development of serine protease inhibitors displaying a multicentered short (<2.3 Å) hydrogen
1
bond binding mode: Inhibitors of urokinase-type plasminogen activator and factor Xa. J. Med. Chem. 2001
,
4
4, 2753–2771.
1
5. Hartman, R.L.; McMullen, J.P.; Jensen, K.F. Deciding whether to go with the flow: Evaluating the merits of
flow reactors for synthesis. Angew. Chem. Int. Ed. 2011, 50, 7502–7519. [CrossRef] [PubMed]
6. Lévesque, F.; Seeberger, P.H. Highly efficient continuous flow reactions using singlet oxygen as a “green”
reagent. Org. Lett. 2011, 13, 5008–5011. [CrossRef] [PubMed]
1

Molecules 2016, 21, 88
8 of 8
1
1
7. Knowles, J.P.; Elliott, L.D.; Booker-Milburn, K.I. Flow photochemistry: Old light through new windows.
Beilstein J. Org. Chem. 2012, 8, 2025–2052. [CrossRef] [PubMed]
8. Wojcik, F.; O’Brien, A.G.; Götze, S.; Seeberger, P.H.; Hartmann, L. Synthesis of carbohydrate-functionalised
sequence-defined oligo(amidoamine)s by photochemical thiol-ene coupling in a continuous flow reactor.
Chem. Eur. J. 2013, 19, 3090–3098. [CrossRef] [PubMed]
1
2
2
9. McQuade, D.T.; Seeberger, P.H. Applying flow chemistry: Methods, materials, and multistep synthesis.
J. Org. Chem. 2013, 78, 6384–6389. [CrossRef] [PubMed]
0. Bovonsombat, P.; McNelis, E. Ring halogenations of polyalkylbenzenes with N-halosuccinimide and acid
catalysts. Synthesis 1993, 237–241. [CrossRef]
1. Mahajan, T.; Kumar, L.; Dwivedi, K.; Agarwal, D.D. Efficient and facile chlorination of industrially-important
aromatic compounds using NaCl/p-TsOH/NCS in aqueous media. Ind. Eng. Chem. Res. 2012, 51, 3881–3886.
[CrossRef]
2
2
2
2
2. Stock, R.I.; Nandi, L.G.; Nicoleti, C.R.; Schramm, A.D.S.; Meller, S.L.; Heying, R.S.; Coimbra, D.F.;
Andriani, K.F.; Caramori, G.F.; Bortoluzzi, A.J.; et al. Synthesis and solvatochromism of substituted
4
-(nitrostyryl)phenolate dyes. J. Org. Chem. 2015, 80, 7971–7983. [CrossRef] [PubMed]
3. Mangas-Sánchez, J.; Busto, E.; Gotor-Fernández, V.; Gotor, V. Straightforward synthesis of enantiopure
,3-dihydrobenzofurans by a sequential stereoselective biotransformation and chemical intramolecular
2
cyclization. Org. Lett. 2010, 12, 3498–3501. [CrossRef] [PubMed]
4. Adimurthy, S.; Ramachandraiah, G.; Bedekar, A.V.; Ghosh, S.; Ranu, B.C.; Ghosh, P.K. Eco-friendly and
versatile brominating reagent prepared from a liquid bromine precursor. Green Chem. 2006, 8, 916–922.
[CrossRef]
5. Huang, G.-J.; Bhaskar-Reddy, M.V.; Kuo, P.-C.; Huang, C.-H.; Shih, H.-C.; Lee, E.J.; Yang, M.-L.; Leu, Y.-L.;
Wu, T.-S. A Concise synthesis of viscolin, and its anti-inflammatory effects through the suppression of iNOS,
COX-2, ERK phosphorylation and proinflammatory cytokines expressions. Eur. J. Med. Chem. 2012, 48,
3
71–378. [CrossRef] [PubMed]
6. Podgoršek, A.; Stavber, S.; Zupan, M.; Iskra, J. Environmentally benign electrophilic and radical bromination
on water”: H O -HBr system versus N-bromosuccinimide. Tetrahedron 2009, 65, 4429–4439. [CrossRef]
2
2
“
2
2
7. Schmidt, B.; Holter, F. Suzuki-Miyaura cross coupling reactions with phenoldiazonium salts.
Org. Biomol. Chem. 2011, 9, 4914–4920. [CrossRef] [PubMed]
Sample Availability: Samples of the compounds are available from the authors.
©
2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons by Attribution
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/).