Efficient Arndt-Eistert synthesis of selective 5-HT7 receptor antagonist SB-269970

Article abstract of DOI:10.1080/00397910902737155

This contribution describes a novel Arndt-Eistert approach for the efficient synthesis of the potent and selective 5-HT7-antagonist, (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970), from D-proline. The synthesis was ca

Full text of DOI:10.1080/00397910902737155

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Efficient Arndt–Eistert
Synthesis of Selective 5-HT7
Receptor Antagonist SB-269970
Christina Schjøth-Eskesen a & Henrik Helligsø Jensen
a
a Department of Chemistry , Aarhus University ,
Aarhus, Denmark
Published online: 12 Aug 2009.
To cite this article: Christina Schjøth-Eskesen & Henrik Helligsø Jensen (2009)
Efficient Arndt–Eistert Synthesis of Selective 5-HT7 Receptor Antagonist SB-269970,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:18, 3243-3253, DOI: 10.1080/00397910902737155
To link to this article: http://dx.doi.org/10.1080/00397910902737155
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Synthetic Communications1, 39: 3243–3253, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902737155
Efficient Arndt–Eistert Synthesis of Selective
5-HT7 Receptor Antagonist SB-269970
Christina Schjøth-Eskesen and Henrik Helligsø Jensen
Department of Chemistry, Aarhus University, Aarhus, Denmark
Abstract: This contribution describes a novel Arndt–Eistert approach for the
efficient synthesis of the potent and selective 5-HT7-antagonist, (R)-3-(2-(2-
(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970), from
D-proline. The synthesis was carried out in 10 steps with an overall yield of 23%.
Keywords: Arndt–Eistert homologation, D-proline, selective 5-HT7 receptor
antagonist
Development of selective antagonists against human receptors is a widely
used strategy in medicinal chemistry to obtain a desired pharmacological
response. Drug targets such as the human serotonin (5-HT) receptor,[1] of
which seven distinct types are currently known, are still not fully under-
stood and continue to attract attention among neurophysiologists and
medicinal chemists. Recently, Lovell and coworkers[2] reported that
SB-269970 (9) was a highly potent and selective antagonist against the
human 5-HT7 receptor,[3] and since then, numerous important scientific
contributions have found SB-269970 to have an effect on anxiety and
to act as an antidepressant.[4–6]
Although certain steps in the original synthesis of SB-269970 (9) have
been published,[2] no full protocol is currently available in the scientific or
patent literature.[7] We here report an efficient, novel, and complete
synthesis of homochiral SB-269970 with full experimental details in the
Received December 3, 2008.
Address correspondence to Henrik Helligsø Jensen, Department of Chemistry,
Aarhus University, Langelandsgade 140, DK 8000 Aarhus C, Denmark. E-mail:
hhj@chem.au.dk
3243

3244
C. Schjøth-Eskesen and H. H. Jensen
hope that this will lead to further investigations of the physiological
effects exerted by this promising drug on the human 5-HT7 receptor.
We set out to prepare SB-269970 (9) using an Arndt–Eistert route
from commercially available D-proline. Because of the well-known
ring-opening reaction associated with Wolff rearrangement of proline
sulfonamides,[8] we decided to introduce a tert-butyl carbamate (Boc)
as a temporary nitrogen protecting group and prepare the sulfonamide
function late in the synthetic sequence. D-Proline was Boc-protected
and reacted with isobutyl chloroformate in the presence of triethylamine
to give 2, in 82% and 91% yields (Scheme 1). The mixed anhydride (2) was
treated with diazomethane to give diazoketone (3) (89%),[9] which subse-
quently underwent silver benzoate–promoted Wolff rearrangement[10]
in methanol to give methyl ester 4 in 85% yield.[9] The ester function
was next reduced with lithium borohydride in tetrahydrofuran (THF)
to give primary alcohol 5 in 82% yield (Scheme 2).[11]
We noticed some discrepancies in the literature, such as specific
optical rotation values for this known Boc-homoprolinol (5). Despite it
being well accepted that Arndt–Eistert synthesis leads to complete
retention of stereochemistry,[10,12] partial erosion of stereochemical purity
could in principle have occurred prior to the Wolff rearrangement step,
and a rigorous investigation of the enantiofidelity up to this point was
accordingly undertaken. The high-performance liquid chromatography
(HPLC) traces of racemic Boc-homoprolinol [(ꢀ)5] made through the
same synthetic sequence and that of (R)-5 prepared from D-proline led
us to the conclusion that no racemization had occurred.
Scheme 1. Synthesis of Boc-homoprolinol from proline.

Receptor Antagonist SB-269970
3245
Scheme 2. Synthesis of SB 269970-HCl salt from Boc-homoprolinol.
The primary alcohol (5) underwent reaction with methanesulfonyl
chloride in pyridine followed by substitution with 4-methyl piperidine
in acetonitrile to give tertiary amine 6 in an overall yield of 65%.[2] The
carbamate protecting group was removed by treatment by trifluoroacetic
acid treatment, and the amine function reacted with the appropriate
benzyl-protected arylsulfonyl chloride (7, Scheme 3). This gave sulfona-
mide 8 in near quantitative yield over two steps. The benzyl group was
finally removed by hydrogenolysis at 1 bar over a Pd-C catalyst to give
SB 269970 (9).[2]
3-Benzyloxy benzenesulfonyl chloride (7) was made according to a
slight modification of a protocol by Pandya and coworkers.[13] First,
3-bromophenol (10, Scheme 3) was reacted with benzyl bromide in
acetone in the presence of potassium carbonate to give 3-benzyloxy
bromobenzene (11) in quantitative yield. This was then added to magne-
sium turnings in THF to give the corresponding Grignard reagent. For
this particular bromide, it was essential for reaction success to heat the
solution for only 15 min and not the full hour as suggested by Pandya
et al.[13] Further reaction with sulfur dioxide and later oxidation by
sulfuryl chloride gave the arylsulfonyl chloride (12, Scheme 3).
Scheme 3. Synthesis of sulfonyl chloride 12.

3246
C. Schjøth-Eskesen and H. H. Jensen
In conclusion, we have demonstrated that the 5-HT7 receptor
antagonist SB 269970 (9) could be prepared efficiently in enantiopure
form from D-proline using an Arndt–Eistert approach. The synthetic
sequence gave an overall yield of 23% over 10 steps and can be used
for gram-scale preparation of SB 269970 for antidepressive and
anti-anxiety tests in animal models.
EXPERIMENTAL
All glassware used for reactions under nitrogen was dried in the oven
(ꢁ120ꢂC). Anhydrous solvents were dried by standard procedures.[14]
Thin-layer chromatography (TLC) was performed on silica-coated
aluminium sheets (Merck 60 F254). They were visualized in ultraviolet
(UV) light or by staining with ninhydrin, KMnO4, or anisaldehyde.
Flash chromatography was done using Fluka silica gel 60
(230–400 mesh) as stationary phase.
NMR spectra were recorded on a Varian Mercury 400 spectrometer.
Optical rotation was measured at 293 K on a PE-314 polarimeter with
the unit deg ꢃ cm2=g, and concentrations were reported in g=100 mL.
Melting points were measured on a Buchi B-540 instrument and are
¨
uncorrected. Mass spectra (MS) were recorded at a Micromass LC-TOF
instrument using electrospray ionization (ESI). D-Proline ([a]D 74.4 (c 4.0,
H2O), [a]D 75.4 (c 1.0, CH3OH)) was purchased from FluoroChem
and used without purification. 3-Bromophenol was purchased from
Sigma-Aldrich.
(R)-(1-tert-Butoxycarbonyl)proline (1)
Di-tert-butyl dicarbonate (20.9 g, 0.096 mol) was added to a solution of
D-proline (10.0 g, 0.087 mol) in THF (60 mL) and a 2 M solution of
aqueous sodium hydroxide (60 mL). The reaction mixture was stirred
at room temperature overnight. The THF was then evaporated, and
the resulting mixture was washed with diethyl ether. The aqueous phase
was acidified to pH ꢁ2–3 by addition of an aqueous solution of 1%
hydrochloric acid and extracted with CH2Cl2 (3 ꢄ 50 mL). The combined
organic extracts were dried over MgSO4 and concentrated under reduced
pressure to give the Boc-protected proline (15.3 g, 82%) as white crystals.
Further purification was not necessary. Mp 132.6–135.2ꢂC; lit.
133–134ꢂC.[15] Rf 0.67 (EtOAc=CH3COOH 95:5). [a]D 46.6 (c 1.0,
CH3OH); lit. [a]D 63.6 (c 1.0, acetic acid).[15] 1H NMR (CDCl3,
400 MHz) d 9.56 (bs, 0.5H), 4.38–4.32 (m, 0.5H), 4.28–4.21 (m, 0.5H),

Receptor Antagonist SB-269970
3247
3.61–3.30 (m, 2H), 2.38–2.21 (m, 1H), 2.12–1.83 (m, 3H), 1.48, 1.42 (9H,
appearing as two singlets). 13C NMR (CDCl3, 100 MHz) d 179.1, 176.1,
156.3, 154.3, 81.4, 80.6, 59.4, 59.2, 47.2, 46.6, 31.0, 29.0, 28.6, 28.5, 24.5,
23.9. Double signals in H and C NMR are seen because of the presence of
rotamers. HRMS(ES): calcd. for C10H17NO4Na 238.1055; found 238.1051.
(R)-2-Isobutoxycarbonyloxycarbonyl-pyrrolidine-1-carboxylic
Acid tert-Butyl Ester (2)
Triethylamine (9.8 mL, 0.072 mol) and isobutylchloroformate (3.3 mL,
0.026 mol) were added to a solution of Boc-proline (1) (5.0 g,
0.024 mol) in dry CH2Cl2 (40 mL) at 0ꢂC. The reaction mixture was
stirred under nitrogen at 0ꢂC for 2 h before dilution with CH2Cl2. The
organic layer was washed twice with a 1% hydrochloric acid, three times
with saturated aqueous NaHCO3, dried over MgSO4, and concentrated
to give anhydride 2 (6.7 g, 91%) as a colorless oil. No further purification
1
was necessary. Rf 0.59 (petrol=EtOAc 5:1). [a]D 37.9 (c 1.0, CHCl3). H
NMR (CDCl3, 400 MHz) d 4.41–4.35 (m, 0.5H), 4.31–4.26 (m, 0.5H),
4.08–4.01 (m, 2H), 3.61–3.35 (m, 2H), 2.35–2.23 (m, 1H), 2.18–1.85
(m, 4H), 1.45, 1.43 (9H, appearing as two singlets), 0.96 (d, 6H, J
6.8 Hz). 13C NMR (CDCl3, 100 MHz) d 168.0, 153.6, 149.2, 80.9, 76.0,
59.3, 46.6, 30.8, 29.7, 28.3, 23.9, 18.9. Double signals in 1H NMR are seen
because of the presence of rotamers.
(R)-tert-Butyl 2-(2-diazoacetyl)pyrrolidine-1-carboxylate (3)
Caution: This reaction was carried out behind a blast shield in a darkened
fume hood using Clearfit1 glassware. Diazald (21.4 g) in diethylether
(140 mL) was added via an addition funnel over 30 min to a magnetically
stirred, oil bath–heated (70ꢂC), 250-mL, round-bottomed flask contain-
ing potassium hydroxide (KOH) (6 g, 0.11 mol), H2O (20 mL), and
diethylene glycol monoethyl ether (35 mL). The evaporating yellow
ethereal diazomethane solution was condensed and put into a receiving,
ice bath–cooled (0ꢂC), 250-mL, round-bottomed flask containing anhy-
dride 2 (3.33 g, 10.6 mmol) in dry diethylether (55 mL). After the addition
of the 140-mL Diazald in diethylether, diethylether (30 mL) was added
via the addition funnel to drive out the remaining diazomethane, which
could be seen by the distillate turning colorless. The receiving flask was
then allowed to warm to room temperature and left to stir for another
3 h. The reaction mixture was then flushed with nitrogen for 30 min
and afterward heated to 43ꢂC for 30 min to concentrate the reaction

3248
C. Schjøth-Eskesen and H. H. Jensen
mixture, which was then transferred to a regular round-bottomed flask
and evaporated to dryness under reduced pressure. The material was
purified by flash chromatography (petrol=EtOAc 3:1) to give diazoke-
tone 3 (2.25 g, 89%) as a yellow oil. Rf 0.38 (petrol=EtOAc 2:1). [a]D
119.3 (c 1.0, CHCl3). Lit. [a]D ꢅ118 (c 1.0, CH3OH) for antipode.[9]
NMR data was in accordance with those previously reported for the
antipode.[9] HRMS(ES): calcd. for C11H17N3O3Na 262.1168; found:
262.1168.
(R)-1-tert-Butoxycarbonyl-2-carbomethoxymethylpyrrolidine (4)
A solution of silver benzoate (210 mg, 0.92 mmol) in Et3N (4 mL,
28 mmol) was added to a stirred solution of diazoketone 3 (2.20 g,
9.2 mmol) in CH3OH (37 mL, 0.92 mol) at 0ꢂC. The reaction mixture
was stirred overnight in the dark under an atmosphere of nitrogen and
allowed to reach room temperature. The solvent was then evaporated
under reduced pressure, and the residue was taken up in ethyl acetate,
washed with saturated aqueous NaHCO3 and brine, and dried over
MgSO4. Filtration and concentration gave a black oil, which was purified
by flash chromatography (petrol=EtOAc 10:1) to give methylester 4
(1.90 g, 85%) as a colorless oil. Rf 0.6 (petrol=EtOAc 3:1). [a]D 32.1
(c 1.0, CHCl3). [a]D 39.8 (c 1.0, CH3OH). Lit. ꢅ43.2 (c 1.0, CH3OH)
for antipode.[9] NMR spectra were identical with those previously repor-
ted for the antipode.[9] HRMS(ES): calcd. for C12H21NO4Na 266.1368;
found:266.1360.
(R)-tert-Butyl 2-(2-Hydroxyethyl)pyrrolidine-1-carboxylate (5)
Lithium borohydride (440 mg, 20 mmol) was added to a stirred solution
of methylester 4 (1.63 g, 6.7 mmol) in dry THF (18 mL). The reaction
mixture was stirred at 50ꢂC under nitrogen for 3 h before cooling to
ambient temperature and was diluted with H2O and ethyl acetate. The
aqueous layer was acidified to pH ꢁ2–3 by addition of 3% hydrochloric
acid. The organic phase was then washed twice with saturated aqueous
NaHCO3, dried over MgSO4, and concentrated under reduced pressure.
The product was purified by flash chromatography (petrol=EtOAc 3:1) to
give 5 (1.18 g, 82%) as a colorless oil. Rf 0.26 (petrol=EtOAc 2:1). [a]D
ꢅ16.5 (c 1.0, benzene); [a]D 6.9 (c 1.0, CHCl3); lit. [a]D ꢅ57.6 (c 1.0,
benzene) for antipode.[16] [a]D ꢅ13.8 (c 1.1, CHCl3) for antipode.[17] 1
H
NMR (CDCl3, 400 MHz) d 4.15–4.08 (m, 1H), 3.63–3.52 (m, 2H),
3.42–3.25 (m, 3H), 2.04–1.82 (m, 3H), 1.72–1.56 (m, 2H), 1.46 (s, 9H).

Receptor Antagonist SB-269970
3249
13C NMR (CDCl3, 100 MHz) d 156.6, 79.9, 59.2, 53.6, 46.5, 38.5, 31.3,
28.5, 23.6. The NMR data were largely in accordance with previously
reported data for the antipode.[18] HRMS(ES): calcd. for C11H21NO3Na:
238.1419; found:238.1423.
To prove that no racemization had occurred, HPLC analysis of
primary alcohol (R)5 and (ꢀ)5 was carried out as follows: 10 mL of
sample [5 or (ꢀ)5, 5 mg=mL in iPrOH=hexane] was analyzed (k 202.2 nm)
on an AD28 HPLC column (eluent: iPrOH=hexane 5:95, flow: 1 mL=min).
t[(R)5] 14.6 min. only; t[(ꢀ)5] 10.4 and 15.1 min.
(R)-2-[2-(4-Methyl-piperidine-1-yl)-ethyl]-pyrrolidine-1-carboxylic
acid tert-Butyl Ester (6)
Alcohol 5 (1.00 g, 4.6 mmol) was dissolved in dry pyridine (20 mL).
Methanesulfonyl chloride (0.50 mL, 6.0 mmol) was added to the solution
at 0ꢂC, and the reaction mixture was stirred under nitrogen and at 0ꢂC
for 2 h before being diluted with CH2Cl2 and washed with H2O. The
organic layer was separated, dried over MgSO4, filtered, and concen-
trated to give the crude mesylate. This was dissolved in dry acetonitrile
(5 mL) containing 4-methylpiperidine (1.1 mL, 9.2 mmol). The mixture
was stirred at room temperature and overnight and then heated to
50ꢂC for 90 min to obtain full conversion. The acetonitrile was evapo-
rated under reduced pressure, and the residue was dissolved in CH2Cl2
and washed twice with saturated aqueous NaHCO3. The organic layer
was dried over MgSO4, and removal of the solvent gave a yellow oil,
which was purified by flash chromatography (petrol=EtOAc=Et3N
49.5:49.5:1) to give amine 6 (0.90 g, 65%) as a colorless oil. Rf 0.49 (pet-
rol=EtOAc=Et3N 49.5:49.5:1). [a]D 30.5 (c 1.0, CHCl3). 1H NMR (CDCl3,
400 MHz) d 3.85–3.72 (m, 1H), 3.46–3.28 (m, 2H), 2.95–2.87 (m, 2H),
2.40–2.25 (m, 2H), 2.10–1.55 (m, 10H), 1.44 (s, 9H), 1.39–1.15 (m, 3H),
0.89 (d, 3H, J 6.4 Hz). 13C NMR (CDCl3, 100 MHz) d 154.8, 79.2,
56.2, 55.9, 54.3, 46.4, 34.3, 32.1, 31.6, 30.9, 28.7, 23.9, 22.0. HRMS(ES):
calcd. for C17H32N2O2Na 319.2364; found 319.2354.
(R)-1-(2-(1-(3-(Benzyloxy)phenylsulfonyl)pyrrolidin-2-yl)ethyl)-4-
methylpiperidine (8)
Boc-protected tertiary amine 6 (560 mg, 1.89 mmol) was dissolved in
CH2Cl2=trifluoroacetic acid (1:1, 10 mL) and stirred under nitrogen and
at ambient temperature for 30 min. The solvents were evaporated under
reduced pressure, and the remaining salt was dissolved in aqueous NaOH
(2 M, 10 mL) at 0ꢂC. To this solution was added freshly prepared

3250
C. Schjøth-Eskesen and H. H. Jensen
3-(benzyloxy)benzene-1-sulfonyl chloride (7) (1.01 g, 3.6 mmol) in diethy-
lether (12 mL). The biphasic mixture was vigorously stirred at 0ꢂC and
during the night allowed to warm to room temperature. The mixture
was diluted with CH2Cl2 and made acidic by adding an aqueous
solution of 3% hydrochloric acid. The water phase was removed,
and the organic phase was washed three times with a sodium carbo-
nate solution. It was dried over MgSO4, and the solvent was
removed. The residue was dissolved in CH2Cl2 and was again washed
with sodium carbonate three times and dried. Removal of the solvent
gave the title compound (806 mg, 96%) as a light pink oil without
the need for further purification. Rf 0.67 (petrol=EtOAc=Et3N
65.3:32.7:2). [a]D 68.8 (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz)
d 7.45–7.31 (m, 8H), 7.21–7.15 (m, 1H), 5.13 (s, 2H), 3.66–3.57 (m,
1H), 3.38–3.31 (m, 1H), 3.15–3.06 (m, 1H), 3.01–2.86 (m, 2H),
2.49–2.30 (m, 2H), 2.11–1.85 (m, 3H), 1.81–1.18 (m, 10H), 0.91
(d, 3H, J 6.0 Hz). 13C NMR (CDCl3, 100 MHz) d 159.0, 138.9,
136.4, 130.3, 128.9, 128.4, 127.7, 120.2, 120.0, 113.5, 70.5, 59.2,
55.8, 54.2, 49.1, 34.4, 33.7, 31.1, 24.2, 22.1. HRMS(ES): calcd. for
1
C25H34N2O3SH 443.2368; found 443.2363. The H NMR data were
similar with those previously reported.[2]
(R)-3-(2-(2-(4-Methylpiperidin-1-yl)ethyl)pyrrolidin-1-ylsulfonyl)phenol
Hydrochloric Salt (SB 269970) (9)
A solution of sulfonamide 8 (1.00 g, 2.3 mmol) in ethanol (30 mL) and
concentrated hydrochloric acid (1.0 mL) was hydrogenated over
palladium on charcoal (10%, 180 mg) at room temperature for 72 h.
During the course of the reaction, more palladium catalyst was added
twice. The reaction mixture was filtered through celite with methanol
and concentrated. The residue was dissolved in hot methanol and filtered.
Removal of the solvent gave a solid, which was purified by flash chroma-
tography (CHCl3=CH3OH 9:1) to give SB 269970 (0.69 g, 79%) as a fine
white powder. Rf 0.38 (CHCl3=CH3OH 9:1). [a]D 35.2 (c 1.0, DMSO). 1H
NMR (DMSO-d6, 400 MHz) d 10.3 (s, 1H), 10.1 (b s, 1H), 7.47 (t, 1H, J
7.6 Hz), 7.32–7.24 (m, 2H), 7.14 (dd, 1H, J 1.6 Hz, J 8.4 Hz), 3.77–3.67
(m, 1H), 3.54–3.40 (m, 2H), 3.35–3.29 (m, 1H), 3.26–2.81 (m, 6H),
2.14–1.88 (m, 4H), 1.70–1.41 (m, 6H), 0.96 (d, 3H, J 6.0 Hz). 13C
NMR (DMSO-d6, 100 MHz) d 158.4, 137.7, 130.8, 120.6, 118.0, 114.2,
58.2, 53.5, 52.1, 48.8, 30.9, 30.5, 29.7, 28.4, 23.7, 21.4. 1H NMR data were
similar to those previously reported.[2] HRMS(ES) calcd. for
C18H28N2O3SH 353.1899; found 353.1893.

Receptor Antagonist SB-269970
3251
1-(Benzyloxy)-3-bromobenzene (11)
K2CO3 (16 g, 116 mmol) and benzyl bromide (7.55 mL, 63.6 mmol)
were added to a solution of 3-bromophenol (10.0 g, 57.8 mmol) in
dry acetone (60 mL). The reaction mixture was refluxed for 2 h before
the solvent was evaporated, and the residue was dissolved in CH2Cl2
and H2O. The aqueous phase was further extracted three times with
CH2Cl2, the combined organic layers were dried over MgSO4, filtered,
and concentrated to give a solid. The product was recrystallized from
petrol, and the mother liquor was purified by flash chromatography
(petrol ! petrol=CH2Cl2 95:5) to give the desired product (combined
yield: 16.9 g, 96%). Mp. 60.9–61.5 (petrol); lit.: 61–62ꢂC.[18] Rf 0.41
(petrol=CH2Cl2 95:5). 1H NMR (CDCl3, 400 MHz) d 7.44–7.32
(m, 5H), 7.17–7.09 (m, 3H), 6.93–6.90 (m, 1H), 5.05 (s, 2H). 13C
NMR (CDCl3, 100 MHz) d 159.8, 136.6, 130.8, 128.9, 128.4, 127.7,
124.3, 123.0, 118.4, 114.1, 70.4. NMR data were similar to those
previously reported.[19]
3-(Benzyloxy)benzene-1-sulfonyl Chloride (7)
Magnesium turnings (896 mg, 37 mmol) in dry THF (10 mL) were
activated with addition of dibromoethane (0.5 mL) before benzylated
bromophenol (11) (4.85 g, 18.4 mmol) in dry THF (20 mL) was added
at such a rate that the solution was kept at a gentle reflux. The
reaction mixture was further refluxed for 15 min before it was cooled
to ꢅ40ꢂC. Sulfur dioxide was bobbled through the solution for 5 min,
and the solution was additionally stirred for 15 min at ꢅ40ꢂC before
SO2Cl2 (1.5 mL, 18.4 mmol) was added and the cold bath was
removed. The solution was allowed to reach ambient temperature
and stirred for an additional 15 min. The reaction mixture was then
poured into an ice water=Et2O mixture. The layers were separated,
and the aqueous phase was extracted three times with Et2O.
The combined ethereal layers were then washed with aqueous
saturated NaHCO3 solution until pH ꢁ7, dried over MgSO4, and
concentrated. Flash column chromatography on silica (petrol=
CH2Cl2 5:1) afforded sulfonyl chloride 7 (3.89 g, 75%) as light yellow
1
crystals. Rf 0.25 (petrol=CH2Cl2 5:1). H NMR (CDCl3, 400 MHz) d
7.68–7.29 (m, 9H), 5.15 (s, 2H). 13C NMR (CDCl3, 100 MHz) d
159.4, 145.5, 135.7, 130.9, 129.0, 128.8, 127.9, 122.7, 119.6, 112.6,
71.0. HRMS(ES): calcd. for C13H1135ClO3SNa 305.0015; found
305.0013.

3252
C. Schjøth-Eskesen and H. H. Jensen
ACKNOWLEDGMENTS
We thank the Department of Chemistry, Aarhus University, and
Dr. O. Wiborg for financial support. We also acknowledge OChem
Graduate School, Aarhus University, for support.
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1. Nichols, D. E.; Nichols, C. D. Serotonin receptors. Chem. Rev. 2008, 108,
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