The first synthesis of [2-13C]phloroglucinol

Article abstract of DOI:10.1002/jlcr.1788

A fast and efficient synthesis of [2-¹³C]phloroglucinol in six steps from acyclic, non-aromatic precursors is presented, with regioselective placement of a ¹³C-atom in the aromatic ring. The ¹³C-label was introduced by rea

Full text of DOI:10.1002/jlcr.1788

Research Article
Received 15 January 2010,
Revised 23 March 2010,
Accepted 21 April 2010
Published online 18 June 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1788
The first synthesis of [2-13C]phloroglucinol
Ã
Laura J. Marshall,a Karl M. Cable,b and Nigel P. Bottinga
A fast and efficient synthesis of [2-13C]phloroglucinol in six steps from acyclic, non-aromatic precursors is presented, with
regioselective placement of a 13C-atom in the aromatic ring. The 13C-label was introduced by reaction of [13C]methyl iodide
with methyl 4-chloroformyl butyrate. Cyclization via an intramolecular Claisen condensation, followed by aromatization
gave [2-13C]resorcinol. Following subsequent methylation of the hydroxyl groups, the third hydroxyl group was introduced
using an iridium-catalysed C–H activation/borylation/oxidation procedure. Demethylation then yielded the desired
[2-13C]phloroglucinol.
Keywords: phloroglucinol; resorcinol; C–H activation
by Birch et al.3 during their biosynthetic studies on the
Introduction
incorporation of 14C-labelled acetic acid into griseofulvin.
We previously developed a synthetic route to [2-13C]resorcinol
Many natural products, such as polyketides, coumarins and
2a, where the phenol was constructed from acyclic precursors,
using [13C]methyl iodide as the source of isotopic label.4,5
Attempts were made to modify this approach for 13C-labelled
motif in these compounds arising via formal cyclization of three
flavonoids, contain monophenolic or polyphenolic moieties.1
The 1,3,5-trihydroxybenzene moiety is a common structural
acetate units.1 Phloroglucinol 1 (Figure 1) is a useful inter-
mediate in the synthesis of natural products of this type.1 New
phloroglucinol by including a suitable oxygen substituent in the
precursor, which would become the third hydroxyl group.
methodology for the preparation of isotopically labelled
versions of 1 is potentially valuable. This would allow the
synthesis of labelled versions of more complex phenolic
compounds for use in metabolic studies or as internal standards
for analyses using LC-MS and GC-MS assay techniques. There are
only a few examples of the synthesis of isotopically labelled
phloroglucinol in the literature.2,3
Pateschke et al.2 developed a route to [2,4,6-14C3]phlorogluci-
nol 1a via the diester 4, using diethyl [14C]malonate 3 (Scheme 1).
After reaction with sodium ethoxide (formed in situ from sodium
and ethanol) at 1351C for 4 h, phloroglucinol dicarboxylic acid
diethyl ester 4 was hydrolysed in refluxing potassium hydroxide
solution to yield the tri-labelled phloroglucinol 1a in 33% yield
over the two steps. [2,4,6-14C3]phloroglucinol was also obtained
However, despite considerable investigation, using a variety of
precursors and protecting group strategies, it was not possible
to retain the oxygen substituent and elimination usually
resulted in the synthesis of resorcinol derivatives.
A new synthetic route to [2-13C]phloroglucinol 1b has been
developed, which uses a modification of the iridium catalysed
C–H activation/borylation/oxidation procedure recently pub-
lished by Maleczka et al.6 Using this methodology, a hydroxyl
group can be inserted into the 3-position of [2-13C]resorcinol 2a
to give [2-13C]phloroglucinol 1b, the first single 13C-labelled
derivative of phloroglucinol to be reported.
Results and discussion
The synthesis of [2-13C]phloroglucinol 1b began with the
previously established route4 to [2-13C]resorcinol 2a, with some
modifications to improve the yields (Scheme 2). The isotopic
label was introduced at the first stage of the synthesis by the
treatment of methyl 4-chloroformylbutyrate 5 with the lithium
dimethylcuprate derived from [13C]methyl iodide. Purification by
column chromatography gave methyl 5-oxo-[6-13C]hexanoate 6
in 43% yield.
HO
OH
HO
OH
OH
1
2
Cyclization to [2-13C]cyclohexane-1,3-dione 7 was successful in
dry tetrahydrofuran, using carefully dried potassium tert-butoxide
Figure 1. Phloroglucinol 1 and Resorcinol 9.
HO 14C
14C 14C
OH
HO 14C
OH
H2
14C
b)
a)
14C 14C
EtO2C
aSchool of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, UK
bGSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
EtO2C
CO2Et
CO2Et
OH
OH
4
1a
3
*Correspondence to: Nigel P. Botting, School of Chemistry, University of St
Andrews, St Andrews, Fife KY16 9ST, UK.
E-mail: npb@st-andrews.ac.uk
Scheme 1. Patschke route to [2,4,6-14C3]phloroglucinol 1a6. Reagents and
conditions: (a) Na, EtOH, 1351C, 4 h (37%); (b) KOH (aq), 1301C (90%).
J. Label Compd. Radiopharm 2010, 53 601–604
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L. J. Marshall et al.
as base. Purification by column chromatography yielded the 18 h. Although the catalyst was found to be relatively air stable
desired product 7 in 69% yield, which was observed to be a as a solid (to the extent that a glove box was not required when
mixture of keto and enol tautomers under NMR conditions in handling the catalyst), it was necessary for the reaction to be
deuterated chloroform. It was possible from 1H-13C HSQC and carried out in degassed solvent under an argon atmosphere. The
HMBC experiments to distinguish between the two species and boronate intermediate 9 was recovered in 77% crude yield and
determine the 1H and 13C NMR data for each. The final stage in the was used in the oxidation step without further purification. It
route to [2-13C]resorcinol 2a involved the aromatization of was originally reported that oxidation using Oxones in a 50:50
[2-13C]cyclohexan-1,3-dione 7 by heating with a palladium on solution of acetone and water reaches completion after 5 min at
charcoal catalyst in xylene at 1381C. Efforts were made to optimize room temperature. However, we found that for our substrates,
the yield of this step by varying reaction temperature and time. an oxidation time of 30 min was required to ensure complete
The best yield was obtained by heating at reflux for 3 h. After oxidation. Formation of poly-hydroxylated species was not
purification by column chromatography, [2-13C]resorcinol 2a was observed although some starting material 8 remained. Purifica-
obtained in 88% yield, giving a yield of 26% over the three stages. tion by column chromatography gave the desired 3,5-
Methylation of the hydroxyl groups to give 1,3-dimethoxy- dimethoxy-[4-13C]phenol 10 in 59% yield.
[2-13C]benzene 8 was achieved by the treatment of [2-13C]re-
Finally, demethylation was required to complete the synthesis of
sorcinol 2a with methyl iodide in a suspension of caesium [2-13C]phloroglucinol 1b. A range of conditions was examined, and
carbonate in acetonitrile.7 The desired product 8 was isolated in it was found that treatment of 10 with boron tribromide solution
a 70% yield after purification.
(10 equivalents) in dichloromethane (ꢀ781C to rt) gave the
For the introduction of the third hydroxyl group, it was cleanest results and highest yields.9 After purification by column
desirable to find a method that gave the desired regioselectivity chromatography, [2-13C]phloroglucinol 1b was obtained in 81%
without polyhydroxylation taking place. This was accomplished yield (9% overall yield from 5 over th 6 steps). The 13C-atom was
by the use of an iridium-catalysed C–H activation/borylation/ clearly observed as an enhanced singlet at 93.9ppm in the 13C
oxidation procedure reported by Maleczka et al.6 However, the NMR spectrum. The quaternary carbon atoms were also present in
use of such electron-rich arenes had not been previously the 13C NMR spectrum (158.8 ppm), with C-1 and C-3 being
reported. Optimization studies were therefore undertaken and observed as a doublet with a large J value of 66 Hz due to coupling
conditions for the use of 1,3-dimethoxy-[2-13C]benzene 8 were with the adjacent 13C-atom. C-5 was observed as a doublet with a
established, where 77% conversion to boronate (9) was smaller J value of 3 Hz. The 1H NMR spectrum was also interesting,
achieved (Scheme 3).8 Under the same conditions, with H-2 being observed as a double triplet with a large J value of
1,3-bis(methoxymethyl)benzene gave 95% conversion to the 158 Hz due to coupling with the 13C-atom and a smaller J value of
corresponding boronate. The first stage in this reaction involved 1.8 Hz due to coupling with H-4 and H-6. H-4 and H-6 were
the treatment of the substrate with a borylating agent (B2Pin2) observed as a double doublet with J values of 4.6 and 1.8 Hz due to
in the presence of the catalyst [Ir(OMe)(COD)]2, ligand dtpby (di- coupling with the 13C-atom and H-2 proton, respectively.
tert-butyl-bipyridyl) and iso-hexane as the solvent. A reflux
temperature of 1101C was found to be optimal for the reaction.
Conversions were monitored by using HPLC, and it was found
Experimental
that the largest increase in conversion took place between 0 and
3 h, with a further smaller increase between 3 and 18 h and no
General
significant increase after 18 h. However, to obtain the highest NMR spectra were recorded on either a Bruker Avance 300 (1H
conversion possible, the reaction was allowed to proceed for 300 MHz and 13C 75.45 MHz) or a Bruker Avance II 400
13C
O
O
O
O
O
O
a)
b)
H313C
OCH3
Cl
OCH3
HO 13C
2a
5
6
7
H3CO 13C
OCH3
OH
d)
c)
8
Scheme 2. Synthesis of [2-13C]dimethylresorcinol 2a. Reagents and conditions: (a) Et2O, Li, 13CH3I, rt, 1 h, then CuI, 01C, 30 min, then ꢀ201C, 1 h, then rt, 18 h (43%); (b)
THF, KOtBu, reflux, 7 h, then HCl (69%); (c) Xylene, 10% Pd/C, reflux, 3 h, then HCl (88%); (d) Acetonitrile, Cs2CO3, CH3I, reflux, 6 h (70%);
H3CO 13C
OCH3
b)
H3CO 13C
OCH3
HO 13C
OH
H3CO 13C
OCH3
c)
a)
B
8
OH
10
OH
1b
O
O
9
Scheme 3. Synthesis of [2-13C]phlorogluciinol 1b. Reagents and conditions: (a) iso-Hexane, B2Pin2, dtbpy, [Ir(OMe)(COD)]2, 1101C, 18 h; (b) Acetone, aqueous Oxones, rt,
30 min (59% over two steps); (c) DCM, BBr3, ꢀ781C, 1 h, then rt, 18 h (81%).
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J. Label Compd. Radiopharm 2010, 53 601–604

L. J. Marshall et al.
(1H 400 MHz and 13C 100 MHz) spectrometer in the deuterated acetate, 1:4) to give 7 as a pale yellow solid (1.13 g, 69%). mp
solvent stated. 13C NMR spectra were recorded using the 106–106.51C (Lit (unlabelled)11 1051C); m/z (CI1) 114 [(M1H)1,
PENDANT or DEPTQ sequence and internal deuterium lock. 100%]; Keto and enol tautomers were observed in the H NMR
1
Chemical shifts (d) in ppm are given relative to tetramethylsi- spectrum. Data for keto form: dH (400 MHz, CDCl3) 3.36 (2H, d, J
lane, coupling constants (J) are given in Hz. Low-resolution (LR) 130.1 Hz, 13CH2-2), 2.36 (4H, dt, J 6.5, 1.8 Hz, CH2-4,6), 1.88–2.00
and high-resolution (HR) electrospray mass spectral analyses (2H, m, CH2-5); dC (100 MHz, CDCl3) 204.0 (d, J 36 Hz, C = O), 58.4
were recorded on a Micromass GC-T spectrometer (time- (enhanced, 13CH2-2), 32.1 (CH2-4,6), 18.4 (CH2-5); Data for enol
of-flight). Major fragments are given as percentages of the base form: dH (400 MHz, CDCl3) 8.69 (1H, s, OH), 5.54 (1H, d, J 161.0 Hz,
peak intensity. Melting points were recorded in open capillaries 13CH-2), 2.55 (2H, t, J 6.5 Hz, CH2-6), 2.36 (2H, dt, J 6.5, 1.8 Hz,
using an Electrothermal 9100 melting point apparatus and are CH2-4), 1.88–2.00 (2H, m, CH2-5); dC (100 MHz, CDCl3) 188.2
uncorrected. Analytical TLC was carried out on Merck 5785 (C = O), 104.3 (enhanced, 13CH-2), 39.9 (CH2-6), 32.1 (CH2-4), 21.0
Kieselgel 60F254 fluorescent plates. The components were (CH2-5).
observed under ultraviolet light (254 nm). Flash chromatography
was performed according to the procedure of Still et al.10 using
silica gel of 35–70 mm particle size. Dried solvents were obtained
dry using the MBRAUN solvent purification system MB SPS-800.
All chemicals and reagents were used as delivered from Sigma-
Aldrich, Acros, Strem or Alfa-Aesar unless otherwise indicated.
All reactions involving moisture-sensitive reagents were per-
formed in oven-dried glassware under positive pressure of
argon. Potassium tert-butoxide was dried by heating to 1001C in
a vacuum tube for around 2 h and then stored in a dessicator.
[2-13C]Resorcinol (2a)
To a flask containing [2-13C]cyclohexane-1,3-dione 7 (0.288 g,
2.55 mmol) and xylene (50 ml), palladium on carbon was added
(10%, 1.44 g). The mixture was heated at reflux for 3 h, then the
palladium catalyst filtered off through a bed of celite. The
reaction mixture was extracted with aqueous sodium hydroxide
(20%, 4 ꢁ 100 ml). The combined aqueous layers were cooled to
01C, acidified to pH 2 with concentrated HCl and extracted with
diethyl ether (3 ꢁ 100 ml) and ethyl acetate (3 ꢁ 100 ml). The
solvents were then removed at reduced pressure to give an
orange oil. Purification was performed by using column
chromatography (silica gel, diethyl ether/petroleum ether, 2:1)
to give 2a as a white solid (248 mg, 88%). mp 108–1091C (Lit
(unlabelled)12 109–1111C); m/z (CI1) 112 [(M1H)1, 100%]; dH
(400 MHz, acetone-d6) 8.21 (2H, d, J 5.1 Hz, OH), 6.98 (1H, dt, J
8.1, 1.2 Hz, CH-5), 6.36 (1H, dt, J 157, 2.3 Hz, 13CH-2), 6.29–6.37
(2H, m, CH-4,6); dC (75.45 MHz, acetone-d6) 159.9 (d, J 67 Hz,
C-OH), 130.7 (CH-5), 109.0 (CH-4,6), 103.5 (enhanced, 13CH-2).
Methyl 5-oxo-[6-13C]hexanoate (6)
To dry diethyl ether (300 ml) under an argon atmosphere,
lithium pieces were added (2.04 g, 294 mmol). [13C]Methyl iodide
(10 g, 70.5 mmol) was added and the reaction mixture stirred at
room temperature for 1 h. After this time, the reaction mixture
was cooled to 01C and copper iodide (13.4 g, 70.5 mmol) added.
After stirring for 30 min at 01C, the resulting lithium dimethyl-
cuprate was cooled to ꢀ201C. Pre-cooled methyl 4-chlorofor-
mylbutyrate
5 (7 ml, 8.33 g, 50.6 mmol) was then added
1,3-Dimethoxy-[2-13C]benzene (8)
dropwise with vigorous stirring. The temperature was main-
tained at ꢀ201C for 1 h, and the reaction mixture was stirred at
room temperature overnight. The reaction was quenched with
saturated ammonium chloride solution (90 ml) and filtered to
remove the copper residue. The filtrate was extracted with
diethyl ether (3 ꢁ 40 ml), washed with brine (40 ml), and dried
(MgSO4). The solvents were removed at reduced pressure to
give the crude product. Purification was performed by using
column chromatography (silica gel, petroleum ether/ethyl
acetate, 9:1) to give 6 as a colourless oil (3.17 g, 43%). m/z
(ES1) 168 [(M1Na)1, 45%]; dH (400 MHz, CDCl3) 3.63 (3H, s,
OCH3), 1.85 (2H, quintet, J 7.2 Hz, CH2-3), 2.48 (2H, t, J 7.2 Hz,
CH2-4), 2.31 (2H, t, J 7.2 Hz, CH2-2), 2.11 (3H, d, J 127 Hz, 13CH3);
dC (100 MHz, CDCl3) 207.9 (d, J 41.2 Hz, COCH3), 173.5 (COOMe),
51.5 (OCH3), 42.4 (CH2-4), 32.9 (CH2-2), 29.9 (enhanced, 13CH3),
18.8 (CH2-3).
To a solution of [2-13C]resorcinol 2a (0.24 g, 2.16 mmol) and
caesium carbonate (1.41 g, 4.32 mmol) in acetonitrile (100 ml),
methyl iodide was added (0.68 ml, 1.53 g, 10.8 mmol). The
mixture was heated at reflux for 6 h, after which time the
solvents were removed at reduced pressure. The residue was
dissolved in diethyl ether (2 ꢁ 200 ml), washed with water
(3 ꢁ 60 ml) and the combined organic layers dried (MgSO4). The
solvents were removed at reduced pressure to give the crude
product. Purification was performed by using column chromato-
graphy (silica gel, petroleum ether/ethyl acetate, 4:1) to give 8 as a
colourless oil (0.21 g, 70%). m/z (CI1) 140 [(M1H)1, 100%], 139
[(M)1, 15]; HRMS (CI1) [Found: (M1H)1, 140.0790, 13C12C7H11O2
requires 140.0793]; dH (400 MHz, CDCl3) 7.11 (1H, dt, J 8.2,
1.3 Hz, CH-5), 6.40–6.46 (2H, m, CH-4,6), 6.39 (1H, dt, J 158.2,
2.4 Hz, 13CH-2), 3.70 (3H, s, CH3); dC (100 MHz, CDCl3) 161.0
(d, J 70 Hz, C-1,3), 129.7 (d, J 5 Hz, CH-5), 106.1 (d, J 3Hz, CH-4,6),
100.5 (enhanced, 13CH-2), 55.3 (d, J 4 Hz, CH3).
[2-13C]Cyclohexan-1,3-dione (7)
To a solution of methyl 5-oxo-[6-13C]hexanoate
14.5 mmol) in dry tetrahydrofuran (280 ml) was added potassium
6 (2.1 g,
3,5-Dimethoxy-[4-13C]phenol (10) via 3,5-dimethoxy-
[4-13C]phenylboronic acid pinacol ester (9)
tert-butoxide (6.5 g, 57.9 mmol). The mixture was heated at
reflux for 7 h, after which time the solvents were removed at A solution of degassed 1,3-dimethoxy-[2-13C]benzene 8 (100 mg,
reduced pressure. The residue was dissolved in water (120 ml) 0.72 mmol) in iso-hexane (5 ml) was transferred into an air-free
and acidified to pH 1 with conc. HCl. The aqueous layer was flask containing B2Pin2 (183 mg, 0.72 mmol), [Ir(OMe)(COD)]2
extracted with ethyl acetate (6 ꢁ 120 ml). The organic layer was (4.8 mg, 1 mol%) and dtbpy (3.9 mg, 2 mol%). The flask was
then dried (MgSO4) and the solvents removed at reduced sealed and the reaction mixture stirred at 1001C for 18 h. The iso-
pressure to give an orange solid. Purification was performed by hexane was then removed at reduced pressure to give the
using column chromatography (silica gel, petroleum ether/ethyl intermediate borolane 9 (77% conversion) as an orange oil
J. Label Compd. Radiopharm 2010, 53 601–604
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L. J. Marshall et al.
which was used without further purification. Analysis for crude as an off-white solid (44 mg, 81%). m.p. 215–215.51C (Lit
intermediate: m/z (CI1) 266 [(M1H)1, 100%], 265 [(M)1, 30]; (unlabelled)14 2161C); m/z (CI1) 128 [(M1H)1, 100%], 127
HRMS (CI1) [Found: (M1H)1, 266.1657, 13C12C13H22O4B requires [(M)1, 25]; HRMS (CI1) [Found: (M1H)1, 128.0435, 13C12C5H7O3
266.1645]; dH (300 MHz, CDCl3) 6.96 (2H, dd, J 6.9, 3.2 Hz, CH-2,6), requires 128.0429]; dH (300 MHz, DMSO-d6) 8.93 (3H, t, J 2.4 Hz,
6.58 (1H, dt, J 210, 3.2 Hz, 13CH-4), 3.82 (6H, s, CH3), 1.35 (12H, s, OH), 5.63 (2H, dd, J 4.6, 1.8 Hz, CH-4,6), 5.63 (1H, dt, J 158.0,
CH3); dC (100 MHz, CDCl3)y 157.1 (C-3,5), 111.3 (CH-2,6), 104.4 1.8 Hz, 13CH-2); dC (100 MHz, DMSO- d6) 93.9 (enhanced, 13CH-2
(enhanced, 13CH-4), 83.9 (CO(CH3)2), 55.5 (CH3), 24.8 (CH3).y and CH-4,6), 158.8 (d, J 66 Hz, C-1,3), 158.8 (d, J 3 Hz, C-5).
Observed by HSQC and/or HMBC, correlates with data from
unlabelled compound previously synthesized during optimiza- Conclusion
tion studies.
An efficient route for the synthesis of [2-13C]phloroglucinol 1b
Acetone (2.3 ml) was added to the crude borolane 9 and the
via [2-13C]resorcinol 2a has been developed starting from
mixture stirred to produce a homogeneous solution. An
[13C]methyl iodide. The third hydroxyl group was introduced
using an iridium-catalysed C–H activation/borylation/oxidation
procedure. This route allows the regioselective placement of
one 13C-atom within the aromatic ring, starting from acyclic,
non-aromatic precursors.
aqueous solution of Oxones (531 mg, 0.864 mmol, in 2.3 ml of
H2O) was then added dropwise over 2–4 min and the reaction
mixture allowed to stir vigorously for 30 min. After this time, the
reaction was quenched by the addition of saturated sodium
sulphite solution (10 ml). The aqueous phase was extracted with
diethyl ether. The organic solvents were removed at reduced
pressure and the crude material dissolved in dichloromethane
and passed through a plug of silica gel. The solvents were then
removed at reduced pressure once more to give the crude
product, which contained traces of starting material (77%
conversion). Purification was performed by using column
chromatography (silica gel, petroleum ether/ethyl acetate, 2:1)
to give the desired product 10 as an off-white solid (66 mg,
59%). m.p. 40–40.51C (Lit (unlabelled)13 401C); m/z (CI1) 156 [(M
1H)1, 100%]; HRMS (CI1) [Found: (M1H)1, 156.0745,
13C12C7H11O3 requires 156.0742]; dH (400 MHz, CDCl3) 5.98 (1H,
t, J 160.0, 2.2 Hz, 13CH-4), 5.97 (2H, d, J 4.7, 2.2 Hz, CH-2,6), 3.68
(6H, s, CH3); dC (100 MHz, CDCl3) 161.6 (d, J 71 Hz, C-3,5), 157.7 (d,
J 4 Hz, C-OH), 94.2 (d, J 3 Hz, CH-2,6), 92.9 (enhanced, 13CH-4),
55.3 (d, J 4 Hz, CH3).
Acknowledgements
We are grateful to GlaxoSmithKline for funding and the BBSRC
for a studentship.
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To
0.426 mmol) in dichloromethane (6 ml) at ꢀ781C under an
argon atmosphere, boron tribromide solution was added (1 M in
dichloromethane, 5 ml, 5 mmol). The reaction mixture was
stirred at ꢀ781C for 1 h, then allowed to warm to room
temperature. After stirring overnight at room temperature, the
solution was cooled to 01C and water (3 ml) added. The solvents
were then removed at reduced pressure and the aqueous phase
extracted with ethyl acetate (3 ꢁ 15 ml). The organic layers were
combined, dried (MgSO4), and the solvents were removed at
reduced pressure to give the crude product as a light brown
solid. Purification was performed by using column chromato-
graphy (silica gel, petroleum ether/ethyl acetate, 1:1) to give 1b
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J. Label Compd. Radiopharm 2010, 53 601–604