A method for the preparation of [13C6]-labelled 2-substituted naphthalenes

Article abstract of DOI:10.1002/jlcr.1798

A reliable route is described for the preparation of various 2-substituted derivatives of [1,2,3,4,4a,8a-¹³C₆]-naphthalene via the bromide 10. The approach is used to prepare [naphthalene-1,2,3,4,4a,8a- ¹³C₆]-2-

Full text of DOI:10.1002/jlcr.1798

Note
Received 26 March 2010,
Revised 16 May 2010,
Accepted 22 May 2010
Published online 30 July 2010 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1798
A method for the preparation of [13C6]-
labelled 2-substituted naphthalenes
Ã
George J. Ellames and John M. Herbert
A reliable route is described for the preparation of various 2-substituted derivatives of [1,2,3,4,4a,8a-13C6]-naphthalene via
the bromide 10. The approach is used to prepare [naphthalene-1,2,3,4,4a,8a-13C6]-2-(2-bromoethyl)naphthalene (1), a key
intermediate in the synthesis of labelled SR57746A, Xaliproden (2).
Keywords: 13C; [13C6]-naphthalene; [13C6]-2-bromonaphthalene; [13C6]-SR57746A; benzannulation; 7-bromo-1-[4a; 5; 6; 7; 8;
8a-13C6]tetralone
anhydride.5 In our case, Friedel-Crafts acylation of [13C6]-
bromobenzene with succinic anhydride, followed by Huang-
Introduction
A variety of routes to a number of singly and multiply 13C-labelled
arenes,1 and specifically to naphthalenes with defined labelling
patterns,2,3 have been described in the literature in recent years.
Many of the methods described are somewhat limited in scope,2
but there is one convenient and reliable approach that appears
consistently in the literature, involving annulation of a second ring
onto an existing benzene framework, and has been used for the
generation of both singly and multiply labelled naphthalenes.1,3 In
this paper, we report the adaptation of this sequence to the
synthesis of 2-substituted [13C6]-naphthalenes, exemplified by
[naphthalene-1,2,3,4,4a,8a-13C6]-2-(2-bromoethyl)naphthalene (1),
which was required for the synthesis of the neurotropic and
neuroprotective agent Xaliproden,4 in labelled form ([naphthalene-
1,2,3,4,4a,8a-13C6]-SR57746A, 2). As 2 was to be used in human
comparative bioavailability studies, it was necessary to develop a
route which was robust, and where it would be possible to ensure
that any side-products could be removed efficiently. Indeed, the
choice of labelling pattern was made following the examination of
potential routes to the alternative labelled form 3, which were
abandoned in view of difficulties encountered in separating side-
products generated during the introduction of a trifluoromethyl
group onto a labelled arene precursor.4
Minlon reduction of the keto acid (4), gave [benzene-13C6]-4-(4-
bromophenyl)butanoic acid (5). It was necessary to ensure
that the formation of the hydrazone derived from 5 was
complete before heating the reaction mixture, in order to
avoid formation of the pyrazinone 6; to this end, it was desirable
to stir the mixture for an extended period at room temperature
and then at 901C before refluxing. Polyphosphoric acid-
promoted intramolecular Friedel-Crafts acylation was carried
out on this intermediate to give 7-bromo-1-tetralone (7).6 This in
turn was reduced with sodium borohydride, and the inter-
mediate alcohol dehydrated by heating in toluene with
p-toluenesulfonic acid to give the dihydronaphthalene 8,7 from
which the fully aromatic system was obtained by dehydrogena-
tion with DDQ in dioxane. [1,2,3,4,4a,8a-13C6]-2-Bromonaphtha-
lene (9) was thereby prepared by benzannulation of
[13C6]-bromobenzene in an overall yield of 25%. Efficient
lithium/halogen exchange occurred on treatment of 9 with
tert-butyllithium, the lithiated species being quenched in the
present case with ethylene oxide8 to give 10, accompanied by a
small quantity of the parent naphthalene, 11. Final conversion of
10 into 1 was conveniently carried out using hydrobromic acid
at reflux.8
CF3
CF3
*
*
*
*
*
*
*
*
*
N
*
*
*
*
*
*
*
*
N
Br
*
1
2
3
Results and discussion
Isotope Chemistry and Metabolite Synthesis Department, Sanofi-Aventis,
Willowburn Avenue, Alnwick, Northumberland NE66 2JH, UK
The preparation of bromide 1 is outlined in Scheme 1.
Generation of naphthalenes with one or two labels in the ring
that is being built up is well precedented,1 and a very
similar sequence to that illustrated has been used to prepare
1,4-dilabelled 1-tetralone from 1,4-dilabelled succinic
*Correspondence to: John M. Herbert, Isotope Chemistry and Metabolite
Synthesis Department, Sanofi-Aventis, Willowburn Avenue, Alnwick, North-
umberland NE66 2JH, UK.
E-mail: john.herbert@sanofi-aventis.com
J. Label Compd. Radiopharm 2010, 53 801–803
Copyright r 2010 John Wiley & Sons, Ltd.

G. J. Ellames and J. M. Herbert
O
O
Br
COOH
Br
COOH
HN
*
*
N2H4.OH2, DEG
Br
*
*
*
*
O
O
*
*
*
*
*
*
*
*
*
*
*
*
RT, then 180oC
(80%)
N
AlCl3, RT (90%)
5
O
*
*
*
*
*
4
PPA, 90oC
(78%)
*
Br
O
1. NaBH4
EtOH-THF, RT
6
Br
Br
Br
*
*
*
DDQ, dioxane
reflux (61%)
*
*
*
*
*
*
*
*
*
*
*
*
*
2. TsOH, toluene
70-75oC (70%)
*
*
9
8
7
*
*
*
*
*
*
1. t-BuLi, Et2O, RT
2. ethylene oxide (90%)
11
*
*
*
*
48% aq. HBr
reflux (85%)
*
*
*
*
*
*
*
OH
Br
*
10
Scheme 1. Preparation of 1 from [13C6]-bromobenzene.
1
In principle, a range of 2-substituted labelled naphthalenes added to 2 M hydrochloric acid (1400 ml) and extracted four
should be available from intermediate 10 and, given the times with ethyl acetate. The combined extracts were washed
commercial availability of [13C2]- and [13C4]-succinic acids, the with brine, dried (MgSO4), and evaporated. The residue was
approach is also applicable to the preparation of 2-substituted purified by chromatography on silica gel (400 g) in hexane: ethyl
naphthalenes with a range of substitution patterns.
acetate (3:1) containing glacial acetic acid (0.5%), followed by
azeotropic removal of traces of acetic acid using toluene, to give
5 (14.567 g, 84%) as a white solid, dH(CDCl3) 1.96 (2H, m), 2.38
(2H, dd), 2.62 (2H, m), 6.92 (2H, dm), 7.54 (2H, dm); m/z 248, 250
(M1), 188, 190 (100%, M-CH3COOH), 175, 177 (C7H6Br1); HRMS
248.0145 (calc. for C143C6H11BrO2 248.0156).
Experimental
All NMR spectra were recorded using a Jeol GSX-270 instrument,
unless otherwise indicated. Low- and high-resolution (electron
impact) mass spectra were recorded using a VG Autospec
magnetic sector instrument at the University of York. Reagents
were obtained commercially; in particular, [13C6]bromobenzene
(99 atom %) was purchased from Isotec Ltd. and Cambridge
Isotope Laboratories.
[4a,5,6,7,8,8a-13C6]-7-Bromo-3,4-dihydro-2H-naphthalen-1-
one (7)
A mixture of 5 (14.567 g, 58 mmol.) and 85% polyphosphoric
acid (84 g) was heated at 901C for 90 min, and then diluted with
water. The mixture was extracted three times with ethyl acetate,
and the combined extracts were washed with aqueous sodium
hydrogencarbonate and dried (MgSO4). Solvent was removed
under reduced pressure and the residue was purified by column
chromatography on silica gel in with hexane: ethyl acetate (95:5)
to give 7 (10.498 g, 78%) as a white solid, m.p. 69–711C.
dH(CDCl3) 2.13 (2H, tt), 2.66 (2H, t), 2.93 (2H, br), 7.17 (1H, dm,
1JCH ca. 160 Hz), 7.56 (1H, dm, 1JCH ca. 165 Hz), 8.18 (1H, dm, 1JCH
ca. 165 Hz); dC(CDCl3) 120.6 (ddd), 129.7 (ddd), 130.85 (ddd),
134.05 (ddd, C4a), 136.1 (ddd), 143.1 (ddd, C8a); m/z 230, 232
(100%, M1), 202, 204 (M-CO), 174, 176 (202-C2H2); HRMS
230.0036 (calc. for C143C6H9BrO = 230.0038).
[benzene-13C6]-4-(4-Bromophenyl)-4-oxobutanoic Acid (4)
Aluminium (III) chloride (21.559 g, 0.162 mol) was added to a
stirred suspension of succinic anhydride (7.729 g, 77 mmol) in
[13C6]-bromobenzene (12.639 g, 77 mmol). The mixture was
stirred at room temperature for 18 h, then poured onto a
mixture of ice and concentrated hydrochloric acid (500 ml). The
resulting suspension was stirred for 45 min, filtered, and the
solid washed with water and air-dried to give 4 (18.304 g, 90%)
as a white solid. dH(CDCl3) 2.84 (2H, t), 3.28 (2H, t), 7.44 (2H, dm),
8.04 (2H, dm); m/z 262, 264 (M1), 245, 247 (M-.OH), 189, 191
(100%); HRMS 261.9938 (calc. for C143C6H9BrO3 261.9948).
[4a,5,6,7,8,8a-13C6]-7-Bromo-1,2-dihydronaphthalene (8)
[benzene-13C6]-4-(4-Bromophenyl)butanoic Acid (5)
Sodium borohydride (1.201 g, 32 mmol) was added to
7
4 (18.304 g, 70 mmol.) was redissolved in diethylene glycol
(180 ml) at 601C, potassium hydroxide (9.853 g) in water (15 ml)
was added, and the deep yellow solution was stirred for a
further 30 min while cooling to room temperature. A nitrogen
atmosphere was established and hydrazine hydrate (5.9 ml,
0.105 mol) was added. The mixture was stirred for 12 h, then
heated at 901C for 30 min, and then at 1801C for 9 h, cooled, and
(10.498 g, 45 mmol.) in ethanol: tetrahydrofuran (1:1, 120 ml) at
room temperature. After stirring for 1 h, volatile materials were
removed under reduced pressure and 1 M hydrochloric acid
(100 ml) was added to the residue. The mixture was extracted
three times with ether and the combined extracts were washed
with aqueous sodium hydrogencarbonate, dried (MgSO4), and
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J. Label Compd. Radiopharm 2010, 53 801–803

G. J. Ellames and J. M. Herbert
concentrated to dryness. The residue was redissolved in toluene white solid. m.p. 641C; dH(CDCl3) 3.04 (2H, m), 3.95 (2H, td),
(200 ml), 4-toluenesulfonic acid (1.071 g, 6 mmol.) was added, 7.0–8.2 (7H, m); m/z 178 (M1), 147 (100%).
and the mixture was stirred for 75 min at 70–751C. On cooling,
[naphthalene-4a,5,6,7,8,8a-13C6]-2-(2-Bromoethyl)naphtha-
the mixture was washed with aqueous sodium hydrogencarbo-
lene (1)
nate and diluted with hexane to 1000 ml. The solution was
filtered through silica gel and eluted further with hexane. The
filtrates were evaporated to give 8 (6.666 g, 70%) as a pale
yellow oil. dH(CDCl3) 2.33 (2H, m), 2.76 (2H, m), 6.10 (1H, m), 6.40
(1H, m), 6.6–7.6 (3H, m); dC(CDCl3) 120.6 (ddd), 129.9 (ddd), 130.5
(ddd), 134.05 (ddd), 136.1 (ddd), 143.1 (ddd); m/z 214, 216 (M1),
135 (100%); HRMS 214.0090 (calc. for C143C6H9Br = 214.0089).
A suspension of 10 (1.913 g, 11 mmol.) in 48% hydrobromic acid
(27 ml) was stirred at reflux for 18.5 h, cooled, and extracted
three times with toluene. The combined extracts were washed
with aqueous sodium hydrogencarbonate, evaporated, and the
residue redissolved in hexane (25 ml) and filtered through silica
gel (100 g), washing with additional hexane until all of the
product had been eluted. Evaporation of the eluate gave 1
(2.187 g, 82.5%) as a white solid. m.p. 61–621C. dH(CDCl3) 3.33
[1,2,3,4,4a,8a-13C6]-2-Bromonaphthalene (9)
(2H, m), 3.66 (2H, td), 7.0-8.2 (7H, m); m/z 240, 242 (M1), 147
(100%); HRMS 240.0247 (calc. for C163C6H Br = 240.0245).
79
DDQ (21.450 g, 94 mmol.) was added to a stirred solution of 8
(6.666 g, 31 mmol.) in dioxane (100 ml) and the resulting deep
green suspension was heated at 1001C for 75 min. After cooling,
the mixture was diluted with 2 M aqueous sodium hydroxide,
hexane, and methyl tert-butyl ether. The phases were separated
and the organic phase was washed five times with 2 M aqueous
sodium hydroxide, water, and dried (MgSO4). Solvent was
evaporated and the residue was chromatographed on silica gel
in hexane to give 9 (4.029 g, 61%) as a white solid, m.p. 56–571C.
dH(CDCl3) 7.2–8.4 (m); m/z 212, 214 (M1), 133 (100%); HRMS
211.9933 (calc. for C143C6H7Br 211.9932).
11
Acknowledgements
The authors wish to thank Dr S. .J. Byard for NMR spectra and
Dr T. Dransfield (University of York) for high-resolution mass
spectra.
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1
(2H, dm, 1JCH 163 Hz), 7.47 (2H, ddd), 7.84 (2H, dm, JCH 157 Hz),
7.84 (2H, m); m/z 134, 84, 49 (100%); HRMS 134.0830 (calc. for
C143C6H8 = 134.0827). Further elution gave 10 (2.280 g, 67%) as a
J. Label Compd. Radiopharm 2010, 53 801–803
Copyright r 2010 John Wiley & Sons, Ltd.
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