Syntheses of aza-analogous iso-ergoline scaffolds using carbene mediated C-H insertion

Article abstract of DOI:10.1016/j.tet.2010.09.023

A novel direct, flexible, and robust approach to the iso-ergoline tetracyclic system in which a five or six-membered ring is established by intramolecular carbene C-H insertion is reported. The protocol involves a two step conversion of an aromatic aldehyde to the corresponding hydrazone and without purification further conversion to the diazo-compound followed by thermal carbene formation and C-H insertion α to a nitrogen.

Full text of DOI:10.1016/j.tet.2010.09.023

Tetrahedron 66 (2010) 9297e9303
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses of aza-analogous iso-ergoline scaffolds using carbene mediated
CeH insertion
,
Niels Krogsgaard-Larsen a, Mikael Begtrup a, Karla Frydenvang a, Jan Kehler b
*
a Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100, Denmark
b H. Lundbeck A/S, Department of Medicinal Chemistry, 9 Ottiliavej, DK-2500 Valby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2010
Received in revised form 19 August 2010
Accepted 6 September 2010
Available online 22 September 2010
A novel direct, flexible, and robust approach to the iso-ergoline tetracyclic system in which a five or six-
membered ring is established by intramolecular carbene CeH insertion is reported. The protocol involves
a two step conversion of an aromatic aldehyde to the corresponding hydrazone and without purification
further conversion to the diazo-compound followed by thermal carbene formation and CeH insertion
a
to a nitrogen.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
a partial agonist at the dopamine receptor and have been used in
the treatment of Parkinson’s disease.2 The semi-synthetic ergolines
of the lysergic acid type counts members like the hallucinogenic
LSD (4) but also Lisuride (5), which is a drug used in the treatment
of Parkinsons disease. The synthetic 7-aza isomeric ergolines
represented by compound 6 are potent neuroleptic dopaminergic
ligands.3 We therefore reasoned that the synthesis of the novel
10-aza-isoergoline ring system (7, Scheme 1) might give access to
pharmaceutically interesting compounds with modified physical
chemical-properties, since introduction of an additional nitrogen
atom into the ergoline ring system renders the indole part more
electron-rich. Moreover, it increases the polar surface area, while
decreasing lipophilicity and basicity.
The ergot alkaloids first isolated from the parasitic fungus
Claviceps, are found as metabolites in several fungi and plants in-
cluding penicillium and aspergillus. The ergot alkaloids are de-
rivatives of the ergoline ring system (1) (Fig. 1) and are divided in
three main groups, the clavine type derived from agroclavine (2)
(Fig. 1), the water-soluble lysergic acid type, and the water-in-
soluble lysergic acid type or peptide ergot alkaloids. The ergot al-
kaloids display a diverse spectrum of pharmacological properties,
which include central, peripheral, and neurohormonal activity due
to binding to adrenergic, dopaminergic, and serotonergic receptor
sites.1 For example, pergolide (3) from the clavine group act as
CH
3
O
N
S
N
CH
N
3
7
H
N
6
H
3
C
CH
3
R
8
CH
P r
H
CH
3
3
HN
CH
H
3
N
N
5
N
O
N
N
D
A
H
H
4
D
A
H
D
D
A
D
D
9
N
10
11
H
C
H
C
C
C
C
C
3
12
13
2
B
B
A
B
B
A
A
B
B
N
H
N
H
N
H
N
H
N
H
1
N
N
14
H
H
1
Agrodavine (2)
Pergolide (3)
LSD (4)
Lisuride (5)
Ergoline
Ergolines ( )
Novel 10-aza-
analogue (6)
analogue (7)
Fig. 1. Different ergolines and analogous structures.
In recent years, the insertion of carbenes into a carbone
hydrogen bond has attracted considerable interest because of its
potential for carbonecarbon bond formation. During the last
twenty years, one method of modifying the reactivity of the
* Corresponding author. E-mail address: jke@lundbeck.com (J. Kehler).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.023

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N. Krogsgaard-Larsen et al. / Tetrahedron 66 (2010) 9297e9303
Scheme 1. Synthesis of the novel tetracyclic scaffolds.
carbene, whilst still maintaining its reactivity toward carbone
hydrogen insertion, has been the application of transition metal
carbenes, especially rhodium.4 Thermally generated carbenes were
initially considered to be unselective in insertion reactions except
when intramolecular cyclisation was favored. In this paper CeH
insertion reactions using thermally generated carbenes are applied
successfully to intramolecular cyclisation reactions forming five-
membered and six-membered rings. Due to its similarity with the
bioactive ergolines and presence of the 4-piperazinoindole scaffold
in several neuroactive compounds,5 the novel, tetracyclic iso-
ergoline derived scaffold may give access to pharmaceutically in-
teresting compounds.
excellent yields (96%) of 1-tosyl-4-bromoindole 9.6 Benzylox-
ycarbonyl-protected piperazine was then introduced at the 4-po-
sition of the indole by cross-coupling using BuchwaldeHartwig
palladium catalysis conditions to give compound 10.7 All attempts
to perform the BuchwaldeHartwig coupling without tosyl pro-
tection failed. Good yields could be obtained in the Buch-
waldeHartwig coupling, however, strict control of reaction
temperature was required for minimisation of an undesired side
product resulting from detosylation of product 10 and subsequent
coupling with another molecule of substrate 9. The tosyl group was
easily and selectively removed under mild conditions by reduction
with magnesium to give the benzyloxycarbonyl protected
4-piperazinoindole 12.8 Cbz protection of commercially available
4-piperazinoindole 11 offered a simple one-pot synthesis of com-
pound 12, but due to the commercial price of compound 11, the
alternative route starting from less expensive 4-bromoindole 8 was
used. Formylation of the 3-position of piperazinoindole 12 was
accomplished using VilsmeiereHaack conditions to give the indole
aldehyde 14.9 Detosylation prior to formylation was essential, since
it was not possible to formylate the tosyl protected 10. Although
2. Results and discussion
The synthesis of the novel 10-aza-ergolines 7 and 23 is shown in
Scheme 1, notably using as a key synthetic-step an intramolecular
carbene mediated CeH insertion.
The synthesis starts from 4-bromoindole (8), which was first
protected by tosylation using phase-transfer conditions to give

N. Krogsgaard-Larsen et al. / Tetrahedron 66 (2010) 9297e9303
9299
both the 5- and 7-position in piperazinoindole 12 are activated
toward electrophilic attack the 3-formyl isomer 14 was the main
product.
An attempt to provide structural confirmation by X-ray crys-
tallography of compound 7 failed since a suitable crystal could not
be prepared. Instead, the aza-ergoline 7 was converted to the
n-propyl derivative 27 (Scheme 2), which after enantiomeric
separation by chiral HPLC afforded a suitable crystal X-ray crystal-
lography confirmed the structure of compound 27 (Fig. 3).
Highly reactive carbenes are generated in situ from a precursor,
most often a diazo compound.10 The synthetic protocols for the
preparation of diazo compounds are numerous, but a common
procedure involves conversion of a ketone or an aldehyde to the
corresponding tosylhydrazone, followed by deprotonation and
thermal elimination of sulfinate to yield the diazo compound.10 In
our case, the respective tosylhydrazone intermediates were pre-
pared by sonication in toluene of a mixture of either aldehyde 16 or
aldehyde 21 and tosylhydrazide.11 After drying (MgSO4) and fil-
tration, the corresponding tosylhydrazones were used directly
without further purification to form the diazo intermediates by
deprotonation using sodium hydride followed by heating using
microwave irradiation to 135 ꢀC. Further heating at 135 ꢀC led to the
in situ generation of the carbene by thermal decomposition of the
diazo compound. The carbene reacted selectively with CeH in-
sertion into the piperazine fragment. We observed that purification
of the intermediary hydrazones by recrystallisation did not im-
prove overall yields, therefore, the isolation and purification of in-
termediates was omitted. The tetracyclic compound 18 was
deprotected by exposure to microwave irradiation at 150 ꢀC for
4 min in a solution of KOH in DMSO and H2O.12 In the same fashion
the regioisomeric 5-formyl compound 20 could be converted to the
tetracyclic structure 22, however, CeH insertion leads to a five-
membered ring in this case. Moreover, the deprotected derivatives
23 and 26 turned out to be more unstable than 7, and decomposed
over time. Notably, the diprotected tetracyclic structures 22 and 18
could also be selective detosylated under similar conditions as
described for compound 10. The Cbz protection group could be
replaced with the Boc group without significant decrease in yields.
In this case Boc-protected 4-piperazinoindole (13), which is com-
mercially available, was used as starting material.
n-C3H7Br
i-Pr2NEt, DMSO, THF
60 °C, 18 h.
H
N
N
N
N
48 % Yield
N
H
N
H
19
27
Scheme 2. Synthesis of the n-propyl derivative 27 from compound 7.
Fig. 3. Perspective drawing (ORTEP)13 of the tetracyclic compound 27 determined by
X-ray crystallography. CCDC 783989.
The novel aza-ergoline 7 was characterized using 1H, 13C, 13C-
APT, COSY, HSQC, and HMBC. Notably, the normally symmetrical
signal from protons of unsubstituted piperazines was significantly
distorted reflecting the presence of a chiral centre and pronounced
conformational restriction of the molecule (Fig. 2).
3. Conclusion
In conclusion, the synthesis of a novel, tetracyclic iso-ergoline
analogue 7 has been developed. The key step is a quick, versatile
carbene mediated intramolecular CeH insertion alpha to a nitrogen
atom. No purification of the intermediates is needed, when the
tetracyclic structure is generated from aldehyde 16 or 17 as sub-
strates. The carbene mediated CeH insertion step is sufficiently
robust to tolerate microwave irradiation at elevated temperatures
(135 ꢀC in toluene for 10 min).
4. Experimental section
4.1. General methods
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
AV-500 at 500 MHz for H nuclei and 125 MHz for C nuclei. Micro-
wave-assisted reactions were performed using the following in-
struments: Emrys Optimizer (300 w), Emrys Synthesizer (300 w),
Biotage Initiater (400 w) and Biotage Advancer (300 w). The solvents
applied were deuterated chloroform (CDCl3), DMSO ((CD3)2SO),
methanol (CD3OD) or water (D2O). Tetramethylsilane (TMS) was
used as internal reference in the chloroform and DMSO. In case of
CD3OD and D2O the residual solvent peak was used as reference.
Multiplicities of 1H NMR signals are given as follows: s, singlet; br s,
broad singlet; m(s), multiplet that appears as a singlet; d, doublet; br
d, broad doublet; t, triplet; q, quartet; quin, quintet; se, sextet; h,
heptet; o, octet; n, nonet. The purification by chromatography were
performed either manually or using one of the following in-
struments: FlashMasterII (FM) from JonesChromatography with
Fig. 2. The aliphatic area of the HSQC spectrum of compound 7.

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N. Krogsgaard-Larsen et al. / Tetrahedron 66 (2010) 9297e9303
prepacked IST (international sorbent technology) columns, ISCO
Companion 4X (ISCO), Reactions and product mixtures were ana-
lyzed by thin layer chromatography (TLC) on silica gel precoated
0.25 mm silica gel plates and visualized under UV light or by use of
an analytical LCeMS system. LCeMS spectra were recorded on
either a Sciex API150ex or Sciex API300 apparatus. In-house HRMS
spectra were recorded on an Agilent/Bruker Daltonics LC-SPE-MS
apparatus.
DMSO (3 mL) and 20% KOH (1.5 mL) added. The mixture was heated
using microwave irradiation at 150 ꢀC for 4 min and then added
a large amount of EtOAc (300 mL). The organic phase was washed
with a combination of satd NH4Cl (75 mL) and satd NaHCO3
(75 mL), then twice with brine (150 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The pale light-brown solid was further
dried at 60 ꢀC in high vacuum to give 63 mg (60%) of an amorphous
solid. LCeMS: UV¼100% (tR¼0.29 min), ELS¼100% (tR¼0.35 min),
m/z¼214.1 (100%) (tR¼0.34 min, ESI, (MþHþ)). 1H NMR: (500 MHz,
4.2. Generalprocedureforformylationoftheindole(methodA)
CDCl3) d: 2.53e2.64 (3H, m), 2.77e2.91 (3H, m), 3.01e3.11 (2H, m),
3.2 (1H, br s), 3.65 (1H, dm, J¼12 Hz), 6.18 (1H, d, J¼8 Hz), 6.69 (1H,
Compound 12 (9.20 g, 27.4 mmol) was dissolved in DMF (30 mL),
purged with and placed under argon, and cooled to 0 ꢀC. POCl3
(2.80 mL, 30.0 mmol) was added dropwise under argon to the re-
action mixture over 15 min. The mixture was left at 0 ꢀC for 1.5 h and
then stirred at room temperature for another 1 h. Additional POCl3
(0.28 mL, 3.00 mmol) was added and the reaction mixture stirred at
room temperature for 1 h. To the reaction mixture was slowly added
water (12 mL) and the mixture stirred at room temperature for
45 min. The mixture was then carefully poured into a large sepa-
ration funnel and added a mixture of Et2O (400 mL), satd NaHCO3
(200 mL), and ice (handful) (Warning! Quenching of POCl3 can be
violent). The aqueous phase was extracted with Et2O (200 mL). The
combined organic phases were washed with brine/water (1:1)
(200 mL), brine (200 mL), dried over MgSO4, filtered, concentrated
in vacuo on Celite, and purified by flash chromatography (ISCO).
d, J¼8 Hz), 6.77 (1H, m), 6.88 (1H, t, J¼8 Hz), 10.49 (1H, s). 13C NMR:
(125 MHz, CDCl3) d: 27.7, 45.3, 46.7, 52.2, 56.8, 97.8, 101.9, 107.7,
115.4, 117.7, 122.9, 134.0, 142.4. HRMS: (MþHþ: C13H16N3) calcu-
lated: 214.1339, found: 214.1341, deviation: 0.9 ppm. TLC: Rf¼0.32
(EtOAc/MeOH: TEA, 3:2:1) (Excessive heating of TLC plate results in
a black spot).
4.4.2. 4-Bromo-1-(toluene-4-sulfonyl)-1H-indole (9). Compound 8
(14.8 g, 75.2 mmol), p-tosyl chloride (17.2 g, 90.2 mmol), and tet-
rabutylammonium hydrogensulfate (1.25 g, 3.69 mmol) were dis-
solved in toluene (90 mL) and 28% NaOH (90 mL) and water (30 mL)
added. The mixture was stirred for 10 min at room temperature
before the temperature was raised to 60 ꢀC for 2.5 h. The mixture
was stirred vigorously through the entire reaction period. The re-
action mixture was then diluted with toluene (400 mL) and water
(250 mL) and the phases were separated. The organic phase was
washed with water (250 mL), brine (250 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The brownish solid was crys-
tallised from EtOAc and a small amount of MeOH with heptane to
yield 23.4 g (89%) of slightly off white solid. LCeMS: UV¼100%
(tR¼1.84), ELS¼100% (tR¼1.90), m/z¼351.4 (95%)/349.1 (100%)
4.3. General procedure for formylation of the indole
(method B)
DMF (10 mL) was cooled to 0 ꢀC and dropwise added POCl3
(3.71 mL, 39.8 mmol). The mixture was then stirred at room tem-
perature for 30 min. In another flask 13 (10 g, 33.1 mmol) was dis-
solved in DMF (25 mL), cooled to 0 ꢀC, an argon atmosphere applied,
and dropwise added the solution containing the preformed for-
mamidinium chloride for 15 min. The mixture was stirred at 0 ꢀC for
2 h. To the mixture was added carefully 2 M NaOH (15 mL) and the
mixture stirred at room temperature for 30 min. The mixture was
transferred to a large separation funnel containing EtOAc (200 mL),
satd NaHCO3 (200 mL), and ice (handful) (Warning! Quenching of
POCl3 can be violent). After the gas production had ceased Et2O
(400 mL) was added. The aqueous phase was re-extracted with Et2O
(200 mL). The combined organic phases were washed twice with
brine/water (1:1) (200 mL), brine (200 mL), dried over MgSO4, fil-
tered, and purified by flash chromatography (ISCO).
(tR¼1.89 min, APPI, (MþHþ)). 1H NMR: (500 MHz, CDCl3)
d: 2.35
(3H, s), 6.72 (1H, d, J¼3.5 Hz), 7.17 (1H, t, J¼8 Hz), 7.24 (2H, t,
J¼9 Hz), 7.38 (1H, d, J¼7.5 Hz), 7.62 (1H, d, J¼3.5 Hz), 7.75 (2H, d,
J¼8 Hz), 7.94 (1H, d, J¼8.5 Hz). 13C NMR: (125 MHz, CDCl3)
d: 22.0,
109.2, 113.0, 115.4, 125.9, 126.6, 127.3, 130.4, 131.8, 135.4, 145.8. TLC:
Rf¼0.32 (EtOAc/heptane, 1:10).
4.4.3. Benzyl 4-[1-(toluene-4-sulfonyl)-1H-indol-4-yl]-piperazine-1-
carboxylate (10). Compound
9 (2.01 g, 5.74 mmol), benzyl
(1-piperazinyl)carboxylate (1.27 mL, 6.58 mmol), and sodium tert-
butylate (680 mg, 7.07 mmol) were suspended in toluene (20 mL)
and argon was bubbled through the suspension for 20 min. Pd(dba)2
(125 mg, 0.22 mmol) and 1-biphenyl-P(t-Bu)2 (117 mg, 0.39 mmol)
were added and suspension purged with argon for another 10 min
before the vial (35 mL capacity) was sealed and heated to 85 ꢀC for
18 h. The yellow/reddish suspension was filtered through a plug of
CeliteÒ. The vial was washed three times with EtOAc (20 mL), which
were afterward passed through the plug. The solution was con-
centrated in vacuo, dissolved in acetone, pre-adsorbed on CeliteÒ
(545 coarse) in vacuo and purified by flash chromatography (FM) to
yield 2.21 g (79%) of light brownish foam. LCeMS: UV¼100%
(tR¼1.88 min), ELS¼100% (tR¼1.94), m/z¼490.5 (tR¼1.92 min, APPI,
4.4. General procedure for magnesium assisted detosylation
of the indole (method C)
p-Tosylindole (2.50 mmol) was dissolved in dry THF (5 mL),
added dry MeOH (15 mL), cooled to 0 ꢀC, and added magnesium
powder (300 mg, 12.3 mmol). The mixture was removed from the
ice-bath and sonicated for 30 min. During the first 15 min the
mixture was removed several times from the sonification and
placed in an ice-bath for short periods of time due to a raise in the
temperature that caused reflux of the solvent. The mixture was
filtered through Celite and concentrated in vacuo (concentration
stopped before white gel formation). The reaction mixture was
transferred to a separation funnel containing 0.1 M HCl (100 mL)
and Et2O (100 mL). The aqueous phase was extracted three times
with Et2O (75 mL). The combined organic phases were washed with
satd NaHCO3 (150 mL), brine (150 mL), dried over MgSO4, filtered,
and purified by flash chromatography (FM).
(MþHþ)). 1H NMR: (500 MHz, CDCl3)
d: 2.33 (3H, s), 3.08 (4H, m),
3.70 (4H, m), 5.16 (2H, s), 6.65 (1H, d, J¼5 Hz), 6.70 (1H, d, J¼8 Hz),
7.20 (3H, m), 7.30e7.40 (5H, m), 7.54 (1H, d, J¼4 Hz), 7.67 (1H, d,
J¼9 Hz), 7.75 (2H, m). 13C NMR: (125 MHz, CDCl3)
d: 21.5, 44.1, 52.4,
67.3, 106.9, 108.4, 111.0, 124.3, 125.1, 125.4, 126.9, 128.0, 128.1, 128.5,
129.9, 135.2, 135.9, 136.6, 145.0, 145.7, 155.3. HRMS: (MþHþ:
C27H28N3O4S) calculated: 490.1795, found: 490.1803, deviation:
1.6 ppm. (MþNaþ: C27H27N3NaO4S) calculated: 512.1615, found:
512.1636, deviation: 4.1 ppm. TLC: Rf¼0.42 (EtOAc/heptane, 1:1).
4.4.1. 6,6a,7,8,9,10-Hexahydro-4H-pyrazino[1,2-a]pyrrolo[4,3,2-de]
quinoline (7). Compound 18 (245 mg, 0.49 mmol) was dissolved in
4.4.4. Benzyl 4-(1H-indol-4-yl)-piperazine-1-carboxylate (12).
Prepared using method C. Clear, colorless oil (658 mg, 80%).

N. Krogsgaard-Larsen et al. / Tetrahedron 66 (2010) 9297e9303
9301
Alternative method: 4-piperazin-1-yl-1H-indole dihydrochloride 11
(8.00 g, 29.2 mmol) was dissolved in THF (120 mL), added i-Pr2NEt
(16.5 mL, 94.7 mmol), purged with and placed under argon, and
cooled to 0 ꢀC. Cbz-Cl (4.6 mL, 32.2 mmol) was dropwise added for
15 min. The reaction mixture was left in an ice-bath for another
15 min before being removed and stirred at room temperature for
18 h. The reaction mixture was added Et2O (150 mL) and wash with
satd NaHCO3 (150 mL). The aqueous phase was re-extracted
with Et2O (150 mL) and the combined organic phases were washed
with brine (250 mL), dried over MgSO4, filtered, pre-adsorbed on
SiO2 in vacuo, and purified by flash chromatography (ISCO) to yield
9.23 g (94%) of clear, colorless oil. LCeMS: UV¼100% (tR¼1.14),
ELS¼100% (tR¼1.20), m/z¼336.6 (tR¼1.19 min, APPI, (MþHþ)). 1H
126.2,127.2,127.8,128.0,128.4,130.2,130.5,134.1,136.2,136.5,146.0,
147.3, 155.1, 187.4. HRMS: (MþHþ: C28H28N3O5S) calculated:
518.1744, found: 518.1728, deviation: 2.9 ppm. (MþNaþ:
C28H27N3NaO5S) calculated: 540.1564, found: 540.1556, deviation:
1.5 ppm TLC: Rf¼0.31 (EtOAc/heptane, 1:1).
4.4.8. tert-Butyl
4-(3-formyl-1-tosyl-1H-indol-4-yl)piperazine-1-
carboxylate (17). Compound 15 (1.29 g, 3.90 mmol), p-tosyl chlo-
ride (855 mg, 4.49 mmol), and benzyltriethylammonium chloride
(60 mg, 0.26 mmol) were dissolved in toluene (20 mL) and added
water (10 mL) and NaOH (28%) (10 mL). The mixture was stirred
vigorously for 45 min at room temperature. The mixture was then
diluted with EtOAc (100 mL) and poured into water (100 mL). The
organic phase was washed with brine (100 mL), dried over MgSO4,
filtered, pre-adsorbed on CeliteÒ (545 coarse) in vacuo, and purified
by flash chromatography (FM) to yield 1.62 g (86%) of clear oil/
white foam. LCeMS: UV¼99.4% (tR¼1.36 min), ELS¼100%
(tR¼1.41 min), m/z¼484.3 (79%), 428.2 (40%), 384.4 (100%)
NMR: (500 MHz, CDCl3)
d
: 3.18 (4H, br s), 3.74 (4H, br t, J¼5 Hz), 5.18
(2H, s), 6.50 (1H, m), 6.56 (1H, dm, J¼8 Hz), 7.06 (1H, dm, J¼8 Hz),
7.10 (1H, t, J¼8 Hz), 7.11 (1H, t, J¼3 Hz), 7.3e7.4 (5H, m), 8.33 (1H, s).
13C NMR: (125 MHz, CDCl3)
d: 44.2, 51.0, 67.2, 100.4, 106.5, 106.7,
121.2, 122.3, 123.1, 127.8, 128.0, 128.5, 136.5, 136.9, 145.1, 155.4.
HRMS: (Mþ: C20H21N3O2) calculated: 335.1628, found: 335.1631,
deviation: 0.9 ppm. (MþHþ: C20H22N3O2) calculated: 336.1707,
found: 336.1701, deviation: 1.8 ppm. (MþNaþ: C20H21N3NaO2)
calculated: 358.1526, found: 358.1532, deviation: 1.7 ppm. TLC:
Rf¼0.30 (EtOAc/heptane, 1:2).
(tR¼1.43 min, APPI, (MþHþ)). 1H NMR: (500 MHz, CDCl3)
d: 1.48
(9H, s), 2.38 (3H, s), 2.99 (4H, br s), 3.0e4.5 (4H, vbr s), 7.01 (1H, d,
J¼8 Hz), 7.26e7.35 (3H, m), 7.75 (1H, d, J¼9 Hz), 7.84 (2H, d, J¼8 Hz),
8.31 (1H, s), 10.61 (1H, s). 13C NMR: (125 MHz, CDCl3)
d: 21.8, 28.5,
43.5, 44.3, 52.6, 80.1, 109.8, 114.7, 122.1, 122.2, 126.3, 127.4, 130.37,
130.44, 134.4, 136.4, 146.2, 147.7, 154.8, 187.9. HRMS: (MþHþ:
C25H29N3O5S) calculated: 484.1901, found: 484.1896, deviation:
1.04 ppm. TLC: Rf¼0.37 (EtOAc/heptane, 1:1).
4.4.5. Benzyl 4-(3-formyl-1H-indol-4-yl)-piperazine-1-carboxylate
(14). Prepared using method A. Clear, colorless oil/foam (4.49 g,
12.36 mmol, 45%). LCeMS: UV¼99.1% (tR¼0.75), ELS¼100%
(tR¼0.80), m/z¼364.7 (100%) (tR¼0.80 min, APPI, (MþHþ)). 1H
4.4.9. Benzyl 4-(toluene-4-sulfonyl)-4,6,6a,7,9,10-hexahydro-4,8,10a-
triaza-acephenanthrylene-8-carboxylate (18). Compound 16 (540 mg,
1.04 mmol) and p-tosylhydrazide (200 mg, 1.07 mmol) were sus-
pended in toluene (15 mL). The mixture was subjected to sonication
for 3 h at room temperature. To the reaction mixture was added
MgSO4 and after 15 min filtered. The resulting solution was trans-
ferred to a microwave vial and toluene added to a total volume of
20 mL. NaH (60%) (44 mg, 1.10 mmol) was then added carefully and
the mixture purged with argon for 30 min until gas formation had
ceased. The vial was sealed and heated using microwave irradiation
for 12 min at 130 ꢀC. The resulting thick suspension was transferred
to a separation funnel with EtOAc (100 mL) and satd NaHCO3
(100 mL). The organic phase was washed with brine (100 mL), dried
over MgSO4, filtered, pre-adsorbed on CeliteÒ (545 coarse) in vacuo
and purified by flash chromatography (FM) to yield 285 mg (54%) of
white foam. LCeMS: UV¼100% (tR¼1.84 min), ELS¼100%
(tR¼1.90 min), m/z¼502.5 (100%) (tR¼1.88 min, APPI, (MþHþ)). 1H
NMR: (500 MHz, CDCl3) d: 2.9e3.2 (4H, br s), 3.3e4.2 (4H, vbr s),
5.18 (2H, s), 6.91 (1H, dd, J¼7 Hz, 2 Hz), 7.18e23 (2H, m), 7.3e7.4
(5H, m), 7.94 (1H, d, J¼3 Hz), 9.49 (1H, br s), 10.50 (1H, s). 13C
NMR: (125 MHz, CDCl3) d: 44.1, 52.3, 67.4, 108.8, 112.1, 119.1, 119.9,
124.2, 127.9, 128.2, 128.6, 131.9, 136.5, 138.4, 147.0, 155.5, 187.5.
HRMS: (MþHþ: C21H22N3O3) calculated: 364.1656, found:
364.1654, deviation: 0.6 ppm. (MþNaþ: C21H21N3NaO3) calcu-
lated: 386.1475, found: 386.1488, deviation: 3.4 ppm. TLC: Rf¼0.30
(EtOAc/heptane, 1:2).
4.4.6. Benzyl 4-(3-formyl-1H-indol-4-yl)-piperazine-1-carboxylate
(15). Prepared using method B. Clear, colorless oil/foam (36%).
LCeMS: UV¼99.5% (tR¼0.66 min), ELS¼100% (tR¼0.72 min),
m/z¼330.4 (100%), 274.4 (81%), 230.6 (52%) (tR¼0.74 min, APPI,
(MþHþ)). 1H NMR: (500 MHz, CDCl3)
d: 1.49 (9H, s), 2.9e3.2 (4H, br
s), 3.2e4.2 (4H, br s), 6.92 (1H, m), 7.18e7.24 (2H, m), 7.95 (1H, d,
J¼3 Hz), 9.75 (1H, br s), 10.51 (1H, s). 13C NMR: (125 MHz, CDCl3)
d:
NMR: (500 MHz, CDCl3) d: 2.33 (3H, s), 2.6e3.2 (6H, br m), 3.73 (1H,
28.5, 43.4, 44.4, 52.2, 80.2, 108.7, 111.9, 118.9, 119.9, 124.1, 132.2,
138.5, 147.0, 155.0, 187.5. HRMS: (MþHþ: C18H23N3O3) calculated:
330.1812, found: 330.1819, deviation: 2.20 ppm. TLC: Rf¼0.10
(EtOAc/heptane, 1:1).
br m), 4.15e4.35 (2H, br m), 5.15 (2H, s), 6.47 (1H, m), 7.06 (1H, br s),
7.19 (3H, m), 7.3e7.4 (6H, m), 7.74 (2H, d, J¼9 Hz). 13C NMR:
(125 MHz, CDCl3) d: 22.0, 27.0, 43.7, 46.4, 49.5, 55.6, 67.8, 104.3, 105.4,
115.5, 117.5, 120.3, 127.2, 128.4, 128.6, 129.0, 130.2, 134.5, 136.0, 136.9,
142.2, 145.1, 155.3. HRMS: (MþHþ: C28H28N3O4S) calculated:
502.1795, found: 502.1772, deviation: 4.6 ppm; (MþNaþ:
C28H27N3NaO4S) calculated: 524.1615, found: 524.1610, deviation:
1.0 ppm. TLC: Rf¼0.40 (EtOAc/heptane, 1:1).
4.4.7. Benzyl 4-[3-formyl-1-(toluene-4-sulfonyl)-1H-indol-4-yl]-pi-
perazine-1-carboxylate (16). Compound 14 (450 mg, 1.19 mmol),
p-tosyl chloride (300 mg,1.57 mmol), and benzyltriethylammonium
chloride (20 mg, 0.09 mmol) were dissolved in toluene (10 mL) and
water (5 mL) and NaOH (28%) (5 mL) added. The mixture was stirred
vigorously for 45 min at room temperature. The mixture was then
diluted with EtOAc (50 mL) and poured into water (50 mL). The
organic phase was washed with brine (50 mL), dried over MgSO4,
filtered, pre-adsorbed on CeliteÒ (545 coarse) in vacuo, and purified
by flash chromatography (FM) to yield 563 mg (92%) of clear col-
orless oil/white foam. LCeMS: UV¼98.9% (tR¼1.51), ELS¼100%
(tR¼1.57), m/z¼518.5 (100%) (tR¼1.56 min, APPI, (MþHþ)). 1H NMR:
4.4.10. tert-Butyl
4-tosyl-6a,7,9,10-tetrahydro-4H-pyrazino[1,2-a]
pyrrolo[4,3,2-de]quinoline-8(6H)-carboxylate (19). Compound 17
(498 mg, 1.03 mmol) and p-tosylhydrazide (200 mg, 1.07 mmol)
were suspended in toluene (15 mL). The reaction mixture was
subjected to sonication for 3 h at room temperature. To the reaction
mixture was added MgSO4 and after 15 min filtered. The resulting
solution was transferred to a microwave vial and toluene added to
a total volume of 20 mL. NaH (60%) (45 mg, 1.13 mmol) was then
added carefully and the mixture purged with argon for 30 min until
gas formation had ceased. The vial was sealed and heated using
microwave irradiation for 12 min at 130 ꢀC. The resulting thick
suspension was transferred to a separation funnel with EtOAc
(500 MHz, CDCl3) d: 2.36 (3H, s), 2.99 (4H, br s), 3.0e4.6 (4H, vbr s),
5.16 (2H, s), 6.99 (1H, d, J¼8 Hz), 7.25e7.38 (8H, m), 7.75 (1H, d,
J¼8 Hz), 7.84 (2H, d, J¼9 Hz), 8.31 (1H, s), 10.60 (1H, s). 13C NMR:
(125 MHz, CDCl3) d: 21.5, 43.8, 52.3, 67.1, 109.7, 114.6, 121.90, 121.93,

9302
N. Krogsgaard-Larsen et al. / Tetrahedron 66 (2010) 9297e9303
(100 mL) and satd NaHCO3 (100 mL) The organic phase was washed
with brine (100 mL), dried over MgSO4, filtered, pre-adsorbed on
CeliteÒ (545 coarse) in vacuo, and purified by flash chromatography
(FM) to yield 246 mg (51%) of white foam. LCeMS: UV¼97.5%
(tR¼1.81 min), ELS¼100% (tR¼1.87 min), m/z¼467.2 (5%), 412.4
(29%), 368.4 (100%) (tR¼1.87 min, APPI, (MþHþ)). 1H NMR:
ELS¼100% (tR¼1.25 min), m/z¼348.2 (100%) (tR¼1.24 min, APPI,
(MþHþ)). 1H NMR: (500 MHz, CDCl3)
d: 2.64 (1H, m), 2.94e3.08
(2H, m), 3.08e3.22 (2H, m), 3.44 (1H, m), 4.05e4.35 (3H, m), 5.17
(2H, s), 6.48 (1H, br s), 6.73 (1H, d, J¼8 Hz), 6.95 (1H, d, J¼8 Hz), 7.02
(1H, t, J¼3 Hz), 7.28e7.38 (5H, m), 8.23 (1H, br s). 13C NMR:
(125 MHz, CDCl3) d: 33.2, 43.8, 44.0, 46.8, 48.1, 48.3, 63.9, 67.8, 99.1,
(500 MHz, CDCl3)
d: 1.47 (9H, s), 2.31 (3H, s), 2.65 (1H, ddd, J¼16, 11,
101.7, 113.5, 117.2, 119.7, 123.7, 128.4, 128.6, 129.0, 137.1, 138.3, 143.1,
155.9. HRMS: (MþHþ: C21H21N3O2) calculated: 348.1707, found:
348.1698, deviation: 2.37 ppm. TLC: Rf¼0.37 (EtOAc/heptane, 1:1).
2 Hz), 2.72 (1H, dt, J¼12, 3 Hz), 2.65e2.88 (1H, m), 2.88e3.18 (3H,
m), 3.70 (1H, dm, J¼12 Hz), 4.00e4.38 (2H, br s), 6.47 (1H, d,
J¼8 Hz), 7.05 (1H, d, J¼1 Hz), 7.15e7.21 (3H, m), 7.36 (1H, d, J¼9 Hz),
7.74 (2H, d, J¼9 Hz). 13C NMR: (125 MHz, CDCl3)
d
: 21.6, 26.7, 28.5,
4.4.16. tert-Butyl 6a,7,9,10-tetrahydro-4H-pyrazino[1,2-a]pyrrolo[4,3,2-
de]quinoline-8(6H)-carboxy-late (25). Prepared using method C.
Clear, colorless oil (76%). LCeMS: UV¼97.9% (tR¼1.32 min),
ELS¼100% (tR¼1.37 min), m/z¼314.3 (10%), 258.5 (31%), 214.2
42.7, 43.7, 46.1, 48.7, 49.5, 55.3, 80.3, 103.9, 105.0, 115.4, 117.1, 120.0,
126.8, 129.8, 134.2, 135.6, 142.1, 144.7, 154.4. HRMS: (MþHþ:
C25H29N3O4S) calculated: 468.1952, found: 468.1939, deviation:
2.63 ppm. TLC: Rf¼0.41 (EtOAc/heptane, 1:1).
(100%) (tR¼1.39 min, APPI, (MþHþ)). 1H NMR: (500 MHz, CDCl3)
d:
1.53 (9H, s), 2.77e2.99 (3H, m), 3.00e3.27 (3H, m), 3.82 (1H, dm,
J¼12 Hz), 4.03e4.45 (2H, br m), 6.37 (1H, d, J¼8 Hz), 6.71 (1H, s),
6.82 (1H, d, J¼8 Hz), 7.11 (1H, t, J¼8 Hz), 8.10 (1H, br s). 13C NMR:
4.4.11. Benzyl 4-(5-formyl-1H-indol-4-yl)-piperazine-1-carboxylate
(20). Prepared using method A. Slight greenish oil/foam (1.34 g,
3.69 mmol, 13%). LCeMS: UV¼97.6% (tR¼1.29), ELS¼100%
(tR¼1.35), m/z¼364.8 (100%) (tR¼1.34 min, APPI, (MþHþ)). 1H
(125 MHz, CDCl3) d: 27.1, 28.5, 42.8, 43.9, 46.3, 48.9, 49.9, 56.1, 80.1,
99.3, 102.5, 108.6, 115.4, 118.0, 124.0, 134.4, 141.8, 154.7. HRMS:
(MþHþ: C18H23N3O2) calculated: 314.1863, found: 314.1855, de-
viation: 2.67 ppm. TLC: Rf¼0.48 (EtOAc/heptane, 1:1).
NMR: (500 MHz, CDCl3) d: 3.39 (4H, br s), 3.72 (4H, br s), 5.20 (2H,
s), 6.75 (1H, m), 7.19 (1H, d, J¼9 Hz), 7.21 (1H, t, J¼3 Hz), 7.31e7.42
(5H, m), 7.71 (1H, d, J¼9 Hz), 9.11 (1H, br s), 10.53 (1H, s). 13C NMR:
(125 MHz, CDCl3)
d: 44.7, 53.6, 67.5, 103.6, 108.6, 122.7, 122.8,
4.4.17. 3-(Toluene-4-sulfonyl)-3,6,6a,7,9,10-hexahydro-3,8,10a-triaza-
cyclopenta[c]fluorene-8-carboxylic acid benzyl ester (26). Prepared
using method C. Clear, colorless oil (73%). LCeMS: UV¼94%
(tR¼1.20 min), ELS¼100% (tR¼1.24 min), m/z¼348.2 (100%), 304.3
(24%), 257.7 (31%), 214.2 (57%) (tR¼1.24 min, APPI, (MþHþ)). 1H
123.3, 124.9, 128.0, 128.2, 128.6, 136.6, 141.3, 150.6, 155.5, 191.9.
HRMS: (MþHþ: C21H22N3O3) calculated: 364.1656, found:
364.1646, deviation: 2.7 ppm. (MþNaþ: C21H21N3NaO3) calculated:
386.1475, found: 386.1466, deviation: 2.3 ppm. TLC: Rf¼0.26
(EtOAc/heptane, 1:1).
NMR: (500 MHz, CDCl3) d: 2.64 (1H, m), 2.93e3.22 (4H, m), 3.44
(1H, m), 4.02e4.35 (3H, m), 5.17 (2H, s), 6.48 (1H, m), 6.73 (1H, d,
J¼8 Hz), 6.95 (1H, d, J¼8 Hz), 7.02 (1H, dd, J¼3 Hz, 3 Hz), 7.28e7.39
4.4.12. Benzyl 4-(5-formyl-1-tosyl-1H-indol-4-yl)piperazine-1-car-
boxylate (21). Compound 20 (1.34 g, 3.68 mmol), p-tosyl chloride
(813 mg, 4.26 mmol), and benzyltriethylammonium chloride
(60 mg, 0.26 mmol) were dissolved in toluene (20 mL) and water
(10 mL) and NaOH (28%) (10 mL) added. The mixture was stirred
vigorously for 45 min at room temperature. The mixture was then
diluted with EtOAc (100 mL) and poured into water (100 mL). The
organic phase was washed with brine (100 mL), dried over MgSO4,
filtered, pre-adsorbed on CeliteÒ (545 coarse) in vacuo, and purified
by flash chromatography (FM) to yield 1.70 g (89%) of yellow foam.
LCeMS: UV¼95% (tR¼1.78 min), ELS¼100% (tR¼1.83 min),
m/z¼518.5 (100%) (tR¼1.82 min, APPI, (MþHþ)). 1H NMR:
(5H, m). 13C NMR: (125 MHz, CDCl3)
d: 33.2, 43.8, 44.0, 46.8, 48.1,
48.3, 63.9, 67.8, 99.1, 101.7, 113.5, 117.2, 119.7, 123.7, 128.4, 128.6,
129.0, 137.1, 138.3, 143.1, 155.9. HRMS: (MþHþ: C21H21N3O2) cal-
culated: 348.1707, found: 348.1723, deviation: 4.79 ppm. TLC:
Rf¼0.37 (EtOAc/heptane, 1:2).
4.4.18. 8-Propyl-6,6a,7,8,9,10-hexahydro-4H-pyrazino[1,2-a]pyrrolo
[4,3,2-de]quinoline (27). Compound 7 (120 mg, 0.56 mmol) was
dissolved in THF (3 mL) and DMSO (3 mL). To the solution was
added i-Pr2NEt (120 mL, 0.69 mmol) and n-propylbromide (65 mL,
0.72 mmol). The reaction mixture was heated to 60 ꢀC and stirred
for 18 h. The mixture was transferred to a separation funnel con-
taining EtOAc (75 mL) and satd NaHCO3 (50 mL). The phases were
separated and the organic phase was washed with brine (50 mL),
dried over MgSO4, concentrated in vacuo, and purified using flash
chromatography (FM) to yield 69 mg of a pale white, glassy oil
(48%). The enantiomers were separated using an SFC system.
LCeMS: UV¼99.4% (tR¼0.35 min), ELS¼100% (tR¼0.37 min),
m/z¼255.9 (100%) (tR¼0.40 min, APPI, (MþHþ)). 1H NMR:
(500 MHz, CDCl3) d: 2.37 (3H, s), 3.30(4H, br s), 3.69 (4H, br s), 5.18
(2H, s), 6.86 (2H, d, J¼4 Hz), 7.25e7.29 (2H, m), 7.31e7.41 (5H, m),
7.61 (1H, d, J¼4 Hz), 7.76e7.83 (4H, m), 10.46 (1H, s). 13C NMR:
(125 MHz, CDCl3) d: 44.5, 53.5, 67.4, 108.2, 110.0, 125.8, 126.0, 126.2,
126.4, 127.1, 128.1, 128.2, 128.6, 130.2, 134.8, 136.6, 139.4, 145.7,
149.3, 155.3, 191.1. HRMS: (MþHþ: C28H28N3O5S) calculated:
518.1744, found: 518.1723, deviation: 4.1 ppm. (MꢁNaþ:
C28H27N3NaO5S) calculated: 540.1564, found: 540.1546, deviation:
3.3 ppm. TLC: Rf¼0.38 (EtOAc/heptane, 1:1).
(500 MHz, CDCl3)
d
: 0.88 (3H, t, J¼7 Hz), 1.49 (2H, se, J¼8 Hz), 1.94
(1H, t, J¼11 Hz), 2.15 (1H, dt, J¼12, 3 Hz), 2.29 (2H, t, J¼7 Hz), 2.67
(2H, m), 2.9e3.1 (4H, m), 3.70 (1H, dm, J¼12 Hz), 6.19 (1H, d,
J¼8 Hz), 6.69 (1H, d, J¼9 Hz), 6.78 (1H, m), 6.88 (1H, t, J¼8 Hz),10.50
4.4.13. 3,6,6a,7,9,10-Hexahydro-3,8,10a-triaza-cyclopenta[c]fluo-
rene-8-carboxylic acid benzyl ester (22). Prepared as described for
compound 18. HRMS: (MþHþ: C28H28N3O4S) calculated: 502.1795,
found: 502.1774, deviation: 4.2 ppm. (MþNaþ: C28H27N3NaO4S)
calculated: 524.1615, found: 524.1609, deviation: 1.1 ppm.
(1H, s). 13C NMR: (125 MHz, CDCl3)
d: 11.8, 19.5, 27.1, 45.9, 52.5, 56.1,
59.7, 59.8, 98.0, 102.0, 107.7, 115.5, 117.8, 122.9, 134.0, 142.0. HRMS:
(MþHþ: C16H22N3) calculated: 256.1808, found: 256.1812, de-
viation: ppm. TLC: Rf¼0.28 (EtOAc/heptane: TEA, 12:8:1). X-ray
crystallography: crystal data: C16H21N3, Mr¼255.36, orthorhombic,
space group P212121 (No. 19), a¼6.5007(3) Å, b¼11.8492(12) Å,
c¼17.645(2) Å, V¼1359.1(2) Å3, Z¼4, Dc¼1.248 Mg mꢁ3, F(000)¼
4.4.14. 6,6a,7,8,9,10-Hexahydro-3H-3,8,10a-triaza-cyclopenta[c]fluo-
rine (23). Prepared as described for compound 7. HRMS: (MþHþ:
C13H16N3) calculated: 214.1339, found: 214.1344, deviation:
2.3 ppm. Unstable compound that could not be characterized.
552,
m
(Mo K
a
)¼0.075 mmꢁ1, T¼122 (1) K, crystal dimensions¼
0.65ꢂ0.32ꢂ0.18 mm.
4.4.15. Benzyl 6a,7,9,10-tetrahydro-4H-pyrazino[1,2-a]pyrrolo[4,3,2-
de]quinoline-8(6H)-carboxylate (24). Prepared using method C.
Clear, colorless oil (78%) LCeMS: UV¼93.6% (tR¼1.20 min),
Data collection and processing: Diffraction data were collected
on an Enraf-Nonius KappaCCD diffractometer using graphite
monochromated Mo K
a
radiation (
l
¼0.71073 Å).14 The reflections

N. Krogsgaard-Larsen et al. / Tetrahedron 66 (2010) 9297e9303
9303
were measured in the range ꢁ8ꢃhꢃ8, ꢁ15ꢃkꢃ15, ꢁ22ꢃlꢃ22,
associated with this article can be found in online version at
doi:10.1016/j.tet.2010.09.023.
(2.88ꢀ< <27.58ꢀ). Data were reduced using the program
q
EvalCCD.15,16 A total of 19,804 reflections were averaged according
to the point group symmetry 222 resulting in 3142 unique re-
flections (Rint¼0.052 on Fo2). Absorption correction was applied
using the program NUMABS (Tmin¼0.930; Tmax¼0.973) as part of
the program maXus.17,18
References and notes
1. (a) Ninomiya, I.; Kiguchi, T. InThe Alkaloids: Chemistryand Pharmacology; Brossi, A.,
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Kofod, H., Eds.; Munksgaard: Copenhagen, 1984.
Structure solution and refinement. The structure was solved by the
direct method using the programme SHELXS9718e20 and refined
2. Lieberman, A. N.; Leibowitz, M.; Neophytides, A.; Kupersmith, M.; Mehl, S.;
Kleinberg, D.; Serby, M.; Goldstein, M. Lancet 1979, 314, 1129e1130.
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5. Neuroactive compounds build on the 4-piperazinoindole scaffold are found in,
e.g., WO-2008147812, WO-02102774: WO-00232863 WO-00236562.
6. Hodson, H. F.; Madge, D. J.; Slawin, A. N. Z.; Widdowson, D. A.; Williams, D. J.
Tetrahedron 1994, 50, 1899e1906.
using the programme SHELXL97.21 Full matrix least-squares re-
P
finement on F2 was performed, minimizing w(Fo2ꢁF2c)2, with an-
isotropic displacement parameters for the non-hydrogen atoms. The
positions of all hydrogen atoms were located on intermediate dif-
ference electron density maps and they were refined with fixed
isotropic displacement parameters. The refinement (235 parameters,
3142 reflections) converged at RF¼0.0292, wRF2¼0. 0730 for 2972
2(Fo2)þ(0.0372P)2þ0.2330P],
7. Nielsen, S. F.; Larsen, M.; Boesen, T.; Schønning, K.; Kromann, H. J. Med. Chem.
2005, 48, 2667e2677.
reflections with Fo>4
s
(Fo); w¼1/[
s
where P¼(Fo2þ2F2c)/3; S¼1.080. In the final difference Fourier map
maximum and minimum electron densities were 0.214 and
ꢁ0.143 e Åꢁ3, respectively. Absolute configuration could not be
identified based on the structure determination (Flack parame-
ter¼0.2(16)).22 Complex atomic scattering factors for neutral atoms
were as incorporated in SHELXL97.21,23 CCDC 783989.
8. Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997, 1017e1018.
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6823e6827.
10. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds. From Cyclopropanes to Ylides; John Wiley: New
York, NY, 1998.
11. Wenkert, E.; Moeller, P. D. R.; Piettre, S. R.; McPhail, A. T. J. Org. Chem. 1988, 53,
3178e3183.
12. (a) Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49, 2657e2662; (b) Chen,
G.-H.; Pam, P.; Chen, Y.; Meng, X.-B.; Li, Z.-J. Tetrahedron 2009, 65, 5922e5927.
13. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
Acknowledgements
14. COLLECT.B.V; Nonius Delft: The Netherlands, 1999.
The Drug Research Academy is gratefully acknowledged for
a Ph.D. grant. The research described was conducted at H. Lundbeck
A/S. We gratefully acknowledge the research facilities provided by
of H. Lundbeck A/S and The Faculty of Pharmaceutical sciences, The
University of Copenhagen. The technical assistance of Mr. F. Hansen,
Department of Chemistry, University of Copenhagen, with the
X-ray data collection is gratefully acknowledged.
15. Duisenberg, A. J. M. J. Appl. Crystallogr. 1992, 25, 92e96.
16. Duisenberg, A.J.M, EvalCCD, Ph.D. Thesis, University of Utrecht, The Nether-
lands, 1998.
17. Crystallographic Computing; Ahmed, F. R., Hall, S. R., Huber, C. P., Eds.; Munks-
gaard: Copenhagen, 1970; pp 255e270; Coppens, NUMABS, (included in the
program package MaXus).
18. Nonius maXus 1.2.1; Nonius BV, Delft: The Netherlands, 2003.
19. Sheldrick, G. M. SHELXS97. Program for the Solution of Crystal Structures; Uni-
€
€
versity of Gottingen: Gottingen, Germany, 1997.
20. Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467e473.
21. Sheldrick, G. M. SHELXL97. Program for Crystal Structure Refinement; University
Supplementary data
€
€
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