A re-investigation of the Fries rearrangement of 3-chlorophenyl acetate and synthesis of 2-azido-1-(4-(benzyloxy)-2-chlorophenyl)ethanone from 4-bromo-3-chlorophenol

Article abstract of DOI:10.1016/j.tetlet.2017.11.016

The Fries rearrangement of 3-chlorophenyl acetate provided the expected 4-chloro-2-hydroxy-acetophenone as the major product and 2,4-diacetyl resorcinol and 2-chloro-4-hydroxy-acetophenone as minor products. 4-Benzyloxy-2-chloroacetophenone was prepared by a Heck reaction and then elaborated to 4-benzyloxy-2-chlorophenacyl azide.

Full text of DOI:10.1016/j.tetlet.2017.11.016

Accepted Manuscript
A re-investigation of the Fries rearrangement of 3-chlorophenyl acetate and
synthesis of 2-azido-1-(4-(benzyloxy)-2-chlorophenyl)ethanone from 4-bro-
mo-3-chlorophenol
Panayiotis A. Procopiou, Diane M. Coe, George Procopiou
PII:
S0040-4039(17)31410-7
https://doi.org/10.1016/j.tetlet.2017.11.016
TETL 49459
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 September 2017
2 November 2017
7 November 2017
Please cite this article as: Procopiou, P.A., Coe, D.M., Procopiou, G., A re-investigation of the Fries rearrangement
of 3-chlorophenyl acetate and synthesis of 2-azido-1-(4-(benzyloxy)-2-chlorophenyl)ethanone from 4-bromo-3-
chlorophenol, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.016
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A re-investigation of the Fries rearrangement of 3-chlorophenyl acetate and synthesis of
2-azido-1-(4-(benzyloxy)-2-chlorophenyl)ethanone from 4-bromo-3-chlorophenol
Panayiotis A. Procopiou,* Diane M. Coe, George Procopiou
Respiratory Therapeutic Area, GlaxoSmithKline Medicines Research Centre, Gunnels Wood
Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom
 Corresponding author. Tel.: +44 1438 790496; fax: +44 1438 768302
 E-mail address: pan.a.procopiou@gsk.com (P.A. Procopiou)
Keywords: Fries rearrangement, 3-chlorophenyl acetate, 2-chloro-4-hydroxy-acetophenone,
4-benzyloxy-2-chlorophenacyl azide, Heck reaction

Abstract
The Fries rearrangement of 3-chlorophenyl acetate provided the expected 4-chloro-2-
hydroxy-acetophenone as the major product and 2,4-diacetyl resorcinol and 2-chloro-4-
hydroxy-acetophenone as minor products. 4-Benzyloxy-2-chloroacetophenone was prepared
by a Heck reaction and then elaborated to 4-benzyloxy-2-chlorophenacyl azide.
Phenacyl azides are highly functionalised compounds used as versatile starting materials in
medicinal chemistry. For example the azide moiety of these compounds undergoes click
chemistry (azide-acetylene cycloaddition)1 to produce triazoles,2-4 is reduced to diazo
compounds,5 oxidised to nitro ketones6 or azidoesters,7 and undergoes photolysis.8 The
ketone group can undergo condensation with ester enolates9 or aldehydes,10 forms
heterocycles, such as pyrroles,11 imidazoles,12 and oxazoles.13 In addition there is a huge
interest in enantioselective reduction of the keto group of phenacyl azides to form 2-azido-1-
arylethanols using either enantioselective reducing agents14 or biotransformations.15,16 The
azido group of such compounds can then be reduced to provide enantiomerically pure
phenethanolamines, useful intermediates for the synthesis of for example β2 agonists.17-19
Phenacyl azides are readily formed from the corresponding bromides, which in turn are
prepared by the bromination of acetophenones. We were interested in using the phenacyl
azide 1, or a protected form of it, in one of our medicinal chemistry programmes.
Figure 1. Retrosynthesis of 1

At the time this work was initiated the precursor acetophenone 2 was not commercially
available. However, there was one report for its preparation,20 where 3-chlorophenyl acetate
3 underwent a Fries rearrangement to provide two regioisomeric acetophenones. The
products were separated by steam distillation, which provided 4-chloro-2-
hydroxyacetophenone 4 in 50-60% yield depending on the reaction temperature, and the
regioisomer 2-chloro-4-hydroxyacetophenone 2 as the minor product. Even though this
procedure gave a mixture, it was decided to use it and isolate enough quantities of 2 for our
studies. Our synthesis started from 3-chlorophenol 5, which was converted into the acetate
ester 3, before being added slowly to AlCl3 at 150 °C for 1 h in the absence of any solvent as
reported previously20 (Scheme 1). The reaction gave a mixture, which was separated by
column chromatography on silica to provide the major product 4-chloro-2-
hydroxyacetophenone 4 (62%), 2-chloro-4-hydroxyacetophenone 2 (8%), 3-chlorophenol 5
and a new product 6. This new product was found to be a mixture by NMR and GCMS (CI;
CH4) tR=4.80 min, 43.1%, m/z 129, 131 (3:1) (M+H)+, tR=6.06 min, 54.5%, m/z 195 (M+H)+
and tR=6.15 min, 2.4%, m/z 225, 227 (3:1) (M+H)+. The first peak to elute had the mass-ion
1
of 3-chlorophenol, whereas the second peak did not contain chlorine (no Cl isotope). H, 13C
NMR, HSQC, HMBC and NOE spectra were recorded, and from the observed correlations
(Fig. 2) and the mass-ion, the structure of 6 was assigned as 1,1'-(2,4-dihydroxy-1,3-
phenylene)diethanone, which was previously prepared by the Friedel-Crafts acylation of
resorcinol as independently reported by two groups.21,22 The trace impurity (m/z 225, 227) in
our mixture was not identified.

Scheme 1. Reagents and conditions: i) Ac2O (1.02 equiv.), H2SO4 (cat.), 17 h, 20 °C, 99%;
ii) AlCl3 (1.5 equiv.), 150 °C, 1 h, 4 (62%), 2 (8%), 6 (6%), 5 (6%).
Figure 2. Observed correlations for 6. Red arrows HMBC, blue arrows NOE
A proposed mechanism for the formation of diketone 6 is outlined in Scheme 2. Presumably
3 is acting as the acetyl source, either trans-acetylating 4 to form 7 and releasing 3-
chlorophenol 5, followed by a second Fries rearrangement to provide the chloro-diketone 8 or
alternatively, direct Friedel-Crafts acylation of 4 with 3 to provide 8 and 5. This might
explain the presence of 3-chlorophenol in the reaction mixture. The formation of 6 might
arise from 8 following work-up and substitution of chloride via a SNAr reaction. It is
conceivable that the minor Fries rearrangement product 2 could also undergo
acylation/rearrangement/SNAr reaction to provide another regioisomer of 6. Irrespective of
the exact mechanism we have not detected any other regioisomer of 6.

Scheme 2. Proposed mechanism for the formation of 6
Having failed to isolate substantial quantities of acetophenone 2 using the published method
we next investigated Heck chemistry starting from the commercially available 4-bromo-3-
chlorophenol 9 as outlined in Scheme 3. Thus, treatment of 9 with benzyl bromide in the
presence of potassium carbonate gave benzyl ether 10, which was then reacted with ethyl
vinyl ether in the presence of Pd(OAc)2 and tri(o-tolyl)phosphine to provide the protected
acetophenone 11. Treatment of 11 with trimethylphenylammonium tribromide in THF at
room temperature gave the phenacyl bromide 12, together with 4-bromo-1-butanol (arising
from cleavage of THF by the brominating agent). Reaction of 12 with sodium azide in DMF
at room temperature afforded the required phenacyl azide 13.23
Scheme 3. Reagents and conditions: i) BnBr (1 equiv.), K2CO3 (1.06 equiv.), DMF (1
mL/mmol), 20 °C, 24 h, 99%; ii) (a) ethyl vinyl ether (1 mL/mmol), Pd(OAc)2 (0.02 equiv.),
P(o-MeC6H4)3 (0.1 equiv.), Et3N (2 equiv.), DMF (1 mL/mmol), 100 °C, 5 h, 47%, (b) 2M
–
HCl-EtOAc (1:1; 5 mL/mmol), 20 °C, 15 h; iii) PhN+Me3 Br3 (1 equiv.), THF (3.5
mL/mmol), 20 °C, 1.5 h; iv) NaN3 (2 equiv.), DMF 0.5 mL/mmol), 20 °C, 2 h, 77% (over
two steps).
In conclusion, the reaction of 3-chlorophenyl acetate 3 with AlCl3 at 150°C provided mainly
the Fries rearrangement product 4 together with a small quantity of 2 and a mixture of the
unexpected diketone 6 and chlorophenol 5. The phenacyl azide 13 was prepared from 4-
bromo-3-chlorophenol 9 via a sequence of protection, Heck reaction, bromination and azide
displacement.

Acknowledgement
We thank Stephen Richards for the 2D-NMR analysis of compound 6.
Declaration
The authors are/were GSK employees, have given approval to the manuscript, and have no
competing financial interests.
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23. Characterisation data:
4-Chloro-2-hydroxyacetophenone (4): LCMS (System A) tR=2.63 min, 97%; (System B)
1
tR=7.55 min, ES–ve m/z 169, 171 (M–H)–; H NMR (CDCl3, 400 MHz) 12.4 (1H, s), 7.66
(1H, d, J 8 Hz), 7.00 (1H, d, J 2 Hz), 6.88 (1H, dd, J 8, 2 Hz), 2.62 (3H, s); 13C NMR
(CDCl3, 101 MHz) 203.4 (CO), 162.7 (C-2), 141.4 (C-4), 131.7 (C-6), 119.2 (C-5), 118.1 (C-
3), 118.0 (C-1), 26.2 (CH3); NOE observed from OH (12.4 ppm) to the doublet J 2 Hz at 7.00
ppm (3-H); HMBC correlations observed from 2-OH to C1 (118.0 ppm) and CO (203.4 ppm)
and from CH3 (2.62 ppm) to CO and C1.
2-Chloro-4-hydroxyacetophenone (2): LCMS (System B) tR=5.82 min, 100%, ES+ve m/z
171, 173 (M+H)+, ES–ve m/z 169, 171 (M–H)–; 1H NMR (CDCl3, 400 MHz) 7.65 (1H, d, J 9

13
Hz), 7.12 (1H, br), 6.95 (1H, d, J 2 Hz), 6.81 (1H, dd, J 9, 2 Hz), 2.66 (3H, s); C NMR
(CDCl3, 101 MHz) 201.4, 159.7, 134.2, 132.5, 131.0, 118.0, 114.3, 30.6.
1
3-Chlorophenol (5) H NMR (CDCl3, 400 MHz) 7.14 (1H, t, J 8 Hz), 6.90 (1H, ddd, J 8, 2,
1.5 Hz), 6.84 (1H, t, J 2 Hz), 6.72 (1H, ddd, J 8, 2, 1.5 Hz), 5.50 (1H, s); 13C NMR (CDCl3,
101 MHz) 156.4, 134.8, 130.4, 121.0, 115.9, 114.5; LCMS (System A) tR=2.95 min, ES–ve
m/z 127, 129 (M–H)–.
1
1,1'-(2,4-Dihydroxy-1,3-phenylene)diethanone (6): H NMR (CDCl3, 400 MHz) 14.8 (1H,
13
s), 14.2 (1H, s), 7.82 (1H, d, J 9 Hz), 6.40 (1H, d, J 9 Hz), 2.80 (3H, s), 2.60 (3H, s); C
NMR (CDCl3, 101 MHz) 205.7, 203.1, 170.8, 168.2, 137.9, 112.0, 109.8, 109.5, 33.5, 26.2;
LCMS (System A) tR=3.14 min; ES+ve m/z 195 (M+H)+; ES–ve m/z 193 (M–H)–.
1
4-(Benzyloxy)-1-bromo-2-chlorobenzene (10): H NMR (CDCl3, 400 MHz) 7.49 (1H, d, J
13
9 Hz), 7.44-7.33 (5H, m) 7.11 (1H, d, J 3 Hz), 6.77 (1H, dd, J 9, 3 Hz), 5.04 (2H, s); C
NMR (CDCl3, 101 MHz) 158.8, 136.4, 135.3, 134.3, 129.1, 128.7, 127.9, 117.2, 115.6,
113.6, 70.9; LCMS (System A) tR=4.01 min, 98%, ES–ve m/z 295, 297, 299 (M–H)–. Found:
C, 52.53; H, 3.40. C13H10BrClO requires C, 52.47; H, 3.39%.
1
1-(4-(Benzyloxy)-2-chlorophenyl)ethanone (11): H NMR (CDCl3, 400 MHz) 7.67 (1H, d,
J 8 Hz), 7.45-7.30 (5H, m), 7.02 (1H, d, J 2 Hz), 6.91 (1H, dd, J 8, 2 Hz), 5.10 (2H, s), 2.64
(3H, s); 13C NMR (CDCl3, 101 MHz) 197.9, 161.1, 135.5, 133.6, 131.8, 130.7, 128.4, 128.1,
127.2, 116.7, 113.2, 70.2, 30.4; LCMS (System A) tR=3.45 min, 100%, ES+ve m/z 261, 263
(M+H)+. Found: C, 68.54; H, 4.96; Cl, 13.52. C15H13ClO requires C, 69.10; H, 5.03; Cl,
13.60%.
1
1-(4-(Benzyloxy)-2-chlorophenyl)-2-bromoethanone (12): H NMR (CDCl3, 400 MHz)
7.68 (1H, d, J 9 Hz), 7.43-7.35 (5H, m), 7.04 (1H, d, J 2.5 Hz), 6.93 (1H, dd, J 9, 2.5 Hz),
5.11 (2H, s), 4.54 (2H, s); LCMS (System A) tR=3.87 min, ES–ve m/z 383, 385, 387 (M–H)–.

1
2-Azido-1-(4-(benzyloxy)-2-chlorophenyl) ethanone (13): H NMR (CDCl3, 400 MHz)
7.73 (1H, d, J 9 Hz), 7.42-7.35 (5H, m), 7.04 (1H, d, J 2.5 Hz), 6.94 (1H, dd, J 9, 2.5 Hz),
5.11 (2H, s), 4.53 (2H, s); LCMS (System A) tR=3.58 min, ES+ve m/z 302, 304 (M+H)+.
LCMS analysis was conducted on either a Supelcosil LCABZ+PLUS column (System A) (33
mm  4.6 mm id) eluting with 0.1% formic acid and 0.01 M ammonium acetate in water
(solvent A), and 0.05% formic acid and 5% water in acetonitrile (solvent B), using the
following elution gradient 0.00.7 min 0% B, 0.74.2 min 100% B, 4.2–5.3 min 0% B, 5.3–
5.5 min 0% B at a flow rate of 3 mL min1 or was performed on a Monolithic C18 column
(System B) (50 mm  4.6 mm) eluting with 0.1% formic acid in water (solvent A) and
acetonitrile containing 0.1% formic acid (solvent B) using the following elution gradient:
0.0–3.0 min 5% to 50% B, 3.0 to 5.0 min 50–80% B, 5.0–6.5 min 80 to 95% B, 6.5–8.0 min
held at 95% B, 8.0–8.2 min 95 to 5% B, 8.2–10 min 5% B at a flow rate of 0.5 mL/min,
detecting with a UV detector between 220–400 nm. The mass spectra were recorded on a
Waters ZQ spectrometer using electrospray positive and negative mode (ES+ve and ES–ve).

 A re-examination of the Fries rearrangement of 3-chlorophenyl acetate
 Synthesis of 4-benzyloxy-2-chlorophenacyl azide
 2,4-diacetyl resorcinol