Novel, versatile three-step synthesis of 1,2,3,4,10,10a-hexahydro- pyrazino[1,2- a ]indoles by intramolecular carbene-mediated C-H insertion

Article abstract of DOI:10.1055/s-0030-1258967

A new convenient three-step synthesis of the privileged CNS scaffold 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles has been developed. The method makes use of an intramolecular carbene-mediated C-H insertion in phenylpiperazine-derived tosyl-hydrazones m

Full text of DOI:10.1055/s-0030-1258967

PAPER
4287
Novel, Versatile Three-Step Synthesis of 1,2,3,4,10,10a-Hexahydro-
pyrazino[1,2-a]indoles by Intramolecular Carbene-Mediated C–H Insertion
S
ynthese
s
of Hexa
i
hydrop
e
yrazinoindo
l
les s Krogsgaard-Larsen,a Mikael Begtrup,a Matthias M. Herth,a Jan Kehler*b
a
Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken,
2100 Copenhagen, Denmark
b
H. Lundbeck A/S, Department of Medicinal Chemistry, 9 Ottiliavej, 2500 Valby, Denmark
Fax +45 36438237; E-mail: jke@lundbeck.com
Received 31 August 2010; revised 22 September 2010
text, the hexahydropyrazinoindoles could be considered
as tricyclic indoline-based phenylpiperazine derivatives.
Indeed, hexahydropyrazinoindole fulfills the definition of
a privileged scaffold since its derivatives have been prov-
Abstract: A new convenient three-step synthesis of the privileged
CNS scaffold 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles has
been developed. The method makes use of an intramolecular car-
bene-mediated C–H insertion in phenylpiperazine-derived tosyl-
hydrazones made from 2-fluorobenzaldehydes. Notably, the en to provide ligands for several diverse targets like, for
example, 5-HT2C receptor agonists,4 nicotinic receptor
piperazine can be replaced with other cyclic nitrogen bases and the
ligands,5 antiviral agents,6 serotonin ligands,7 fibrinogen
methodology is successfully extended to pyrrolidine, piperidine,
azepane, morpholine, and homopiperazine.
receptor antagonists,8 and Gly-T-1 inhibitors for treating
neurological and neuropsychiatric disorders.9
Key words: 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles, C–H
insertion, phenylpiperazine, carbene, cyclization
The currently published methods for the syntheses of
1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole are rela-
tively long and tedious using between 6–10 chemical
The classical archetype pharmacophoric motif of a com-
steps starting from indoles or indole-2-carboxylic es-
pound acting in the central nervous system (CNS) is the
ters.4a,b During our exploration of the thermal carbene-
combination of a phenyl group and an aliphatic amine,
mediated C–H insertion,10 it became evident that tricyclic
since 80% of currently marketed CNS drugs contain a
phenylpiperazine derivatives could be synthesized in
phenyl group and 60% contain an amine.1 The term ‘priv-
three steps from readily available starting materials. Due
ileged structure’ was introduced in medicinal chemistry in
to the larger number of commercially available substrates,
the late 1980s by Evans and co-workers to define scaf-
this protocol represents a more general approach than
folds, which were capable of providing useful ligands for
what has previously been described. In this paper, we
diverse receptors, and clever modification of such struc-
wish to describe a short and convenient three-step synthe-
tures could be a viable alternative for design of new recep-
sis of hexahydropyrazinoindoles 5 (Scheme 1).
tor ligands.2 In this context, the 1,2,3,4,10,10a-
hexahydropyrazino[1,2-a]indole (1) (Figure 1) makes up
a rigid template, which is ideally placed within the CNS
drugability space.1b,c
The Boc-protected 2-piperazinobenzaldehydes with sub-
stituents in the phenyl ring of 3a–j were readily synthe-
sized from the corresponding commercially available 2-
fluorobenzaldehydes 2a–j (Scheme 1). In our hands,
DMSO became the solvent of choice for the preparation
of the piperazinobenzaldehydes 3a–i. Even though short
reaction times for the SNAr have been reported in the lit-
erature, it was not possible to reproduce the literature con-
ditions.11–13 Mostly, the use of DMF has been reported as
the preferred solvent for the nucleophilic substitution, but
DMSO was reported as an alternative12,14 and became our
preferred solvent, since 2-N,N-dimethylaminobenzalde-
hyde was formed as a side product, when DMF was used
as solvent. One limitation to the SNAr reaction was found
with the 3-substituted 2-fluorobenzaldehydes, which were
poor substrates for the SNAr possibly due to steric hin-
drance, and only the 3-chloro analogue was successfully
synthesized, albeit in low yields.12 As expected, another
limitation to this SNAr was the presence of electron-donat-
ing groups (EDGs) para to the fluorine leaving group.
Weak electron donors, such as a methyl group, had a sig-
nificant effect on the yields, and stronger electron-donat-
ing groups such as a methoxy group significantly
inhibited the SNAr reaction in agreement with literature
H
N
N
1
Figure 1 The structure of 1,2,3,4,10,10a-hexahydropyrazino[1,2-
a]indole (1)
The hexahydropyrazinoindole can also be considered a
privileged scaffold derived from two other privileged
scaffolds, namely the arylpiperazine and the indole by for-
mal ring-closure and hydrogenation.3 Thus, in this con-
SYNTHESIS 2010, No. 24, pp 4287–4299
x
x.
x
x
.
2
0
1
0
Advanced online publication: 09.11.2010
DOI: 10.1055/s-0030-1258967; Art ID: Z22010SS
© Georg Thieme Verlag Stuttgart · New York

4288
N. Krogsgaard-Larsen et al.
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reports.12 The piperazinobenzaldehydes 3a–j were used as
substrates for the key step, the carbene-mediated intramo-
lecular C–H insertion forming the Boc-protected tricyclic
phenylpiperazines 4a–j (Table 1). The details of the reac-
tion are described in Scheme 2.
O
O
N
N
F
3
a
O
4
6
3
4
O
R
5
6
O
O
O
O
R
5
2a–j
3a–j
N
N
N
N
b
a
O
S
O
O
NH
O
O
N
H
N
N
N
c
N
3a
6
6
b
6
9
9
7
7
8
O
R
8
O
R
O
O
O
O
5a–j
4a–j
N
N
N
N
compounds 2 and 3
compounds 4 and 5
N
N
a: H
f: 4-Br
a: H
f: 7-Br
b: 4-Me
c: 5-Me
d: 4-Cl
e: 6-Cl
g: 5-Br
b: 7-Me
c: 8-Me
d: 7-Cl
e: 9-Cl
g: 8-Br
h: 4-OMe
i: 6-OMe
j: 5-NO2
h: 7-OMe
i: 9-OMe
j: 8-NO2
N2
Scheme 1 Synthesis of hexahydropyrazinoindoles 5. Reagents and
conditions: (a) Boc-piperazine, K2CO3, DMSO, 95 °C, 4 d; (b) 1. p-
TsNHNH2, toluene, microwave irradiation, 135 °C, 12 min, 2. NaH
(60%), toluene, microwave irradiation, 135 °C, 12 min; (c) Et2O,
MeOH, 2 M HCl in Et2O, r.t., 18 h.
4a
7
8
Scheme 2 The intermediates of the carbene-mediated C–H inser-
tion. Reagents and conditions: (a) p-TsNHNH2, toluene, microwave
irradiation, 135 °C, 12 min; (b) NaH (60%), toluene, microwave irra-
diation, 135 °C, 12 min.
Table 1 Compounds 3–5 Prepared
Entry
R
Yield (%) of 3
R
Yield (%) of 4
Yield (%) of 5
O
O
O
O
H
N
N
N
N
N
N
6
3
6
7
O
9
9
7
4
6
8
R
8
5
R
R
a
b
c
d
e
f
H
48
40
39
76
67
56
35
76
87
80
H
58
58
62
67
35
45
65
61
52
52
90
93
77
97
91
80
84
91
89
94
4-Me
5-Me
4-Cl
7-Me
8-Me
7-Cl
6-Cl
9-Cl
4-Br
7-Br
g
h
i
5-Br
8-Br
4-OMe
6-OMe
5-NO2
7-OMe
9-OMe
8-NO2
j
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

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Syntheses of Hexahydropyrazinoindoles
4289
The insertion of a carbene into a carbon–hydrogen bond Notably, the piperazine moiety can be replaced with other
has attracted considerable interest because of its potential cyclic nitrogen bases and the scope of the methodology
in forming carbon–carbon bonds.15,16 Carbenes being neu- was successfully extended to pyrrolidine, piperidine,
tral electrophilic species with only six valence electrons, azepane, morpholine, and homopiperazine. All steps in
exist either as a free carbene or bound to a transition state the reaction sequence, that is, the SNAr reactions, hydra-
metal as a metallocarbenoid. The highly reactive carbenes zone formations, diazo generations, and cyclization reac-
are generated in situ from a precursor, most often a diazo tions gave comparable high yields leading to the products
compound.17 The synthetic protocols for preparation of shown in Scheme 3, namely 2,3,9,9a-tetrahydro-1H-pyr-
diazo compounds are numerous, but a common procedure rolo[1,2-a]indole (11a),19 6,7,8,9,9a,10-hexahydropyri-
involves conversion of a ketone or an aldehyde into the do[1,2-a]indole (11b),20 7,8,9,10,10a,11-hexahydro-6H-
corresponding tosylhydrazone, followed by deprotonation azepino[1,2-a]indole (11c), 3,4,10,10a-tetrahydro-1H-
and thermal elimination of the sulfinate to yield the diazo [1,4]oxazino[4,3-a]indole (11d).
compound.17,18 The hydrazone 6 was easily formed in
high yield. On small scale, the hydrazones were conve-
X
niently synthesized under microwave conditions. When
conversion of larger portions of substrate is required, son-
n
F
a
N
O
ication is an effective and mild synthetic alternative. This
O
latter approach does not have the volume restrictions of
the standard laboratory microwave reactors and is com-
patible with more heat sensitive functional groups. The
downside of the sonication method is the longer reaction
times.
9a: X = CH2, n = 0 (76%)
2a
9b: X = CH2, n = 1 (84%)
9c: X = CH2, n = 2 (68%)
9d: X = O, n = 1 (78%)
Thorough drying was conducted to avoid side reactions
b
after in situ generation of the diazo compound and car-
bene. Removal of water could be conducted either by
treatment of the reaction mixture with MgSO4 (in the
cases with homogeneous reaction mixtures) or simply by
azeotropic evaporation in a rotavapor. The crude hydra-
zone could normally be used without further purification.
X
X
N
n
n
c
N
O
S
O
NH
N
The reaction sequence in Scheme 2 is conveniently per-
formed in one-pot with thermal in situ generation of the
characteristic red-orange solution of the diazo compound
7 at 135 °C and sustained heating promoted the thermal
generation of the carbene 8, which immediately perform
the intramolecular C–H insertion. Conversion of the hy-
drazone to form the intermediate diazo compounds 7
could be accomplished using various bases, for example,
potassium tert-butoxide or sodium hydroxide under
phase-transfer conditions. Whereas no significant differ-
ences in yield were detected, the use of sodium hydride
appeared to produce fewer by-products and was for this
reason selected as the preferred base for the deprotona-
tion. After the addition of sodium hydride to a solution of
the hydrazone, the reaction mixture was purged with ar-
gon until the hydrogen formation had ceased, and the re-
action mixture was subjected to heating using microwave
irradiation for the C–H insertion to reach completion. A
limitation to this carbene-mediated C–H insertion was ob-
served, when a strong electron-withdrawing group was
situated para to the benzylic carbene center. Thus, with a
nitro group placed in this position, the carbene was not
able to react in a C–H insertion reaction, and only uniden-
tified side products were formed. The Boc-protection
group could be removed in high yield by standard proce-
dures such as treatment with anhydrous hydrochloric acid
in a mixture of methanol–diethyl ether, and the hexahy-
dropyrazinoindoles were isolated as the hydrochloride
salts.
10a: X = CH2, n = 0 (56%)
10b: X = CH2, n = 1 (65%)
10c: X = CH2, n = 2 (86%)
10d: X = O, n = 1 (61%)
11a: X = CH2, n = 0 (81%)
11b: X = CH2, n = 1 (75%)
11c: X = CH2, n = 2 (78%)
11d: X = O, n = 1 (58%)
Scheme 3 Formation of products 11a–d. Reagents and conditions:
(a) cyclic amine, K2CO3, DMSO, 95 °C, 4 d; (b) p-TsNHNH2, tolu-
ene, microwave irradiation, 135 °C, 10 min; (c) NaH (60%), toluene,
microwave irradiation, 135 °C, 12 min.
The carbene-mediated C–H insertion into homopipera-
zine 13 (Scheme 4) proceeded without complications and
in good yield. The methodology was completely analo-
gous to the previously identified protocols described in
Schemes 1 and 3. The main issues in this case were
whether regioselectivity could be achieved and the two
isomers could be separated. NMR studies showed no sig-
nificant regioselectivity, which was probably the result of
both insertion kinetics and the temperature at which the
reaction was performed. However, the separation of the
two Boc-protected compounds was remarkably straight-
forward and could be achieved by reverse phase column
chromatography. A surprisingly large difference in the Rf
value of the two regioisomers 14 and 15 may be due to
different molecular conformations and consequently a
differentiated interaction with solid phase during chroma-
tography under the given conditions.
Simple thermally generated carbenes without significant
stabilization such as methylene, dichlorocarbene, and the
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N. Krogsgaard-Larsen et al.
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O
N
O
N
O
O
F
b
a
O
N
N
O
S
O
65%
NH
O
N
2a
12
13
c
14: 34%
15: 31%
O
O
N
O
H
O
N
NH
N
d
d
N
N
+
N
N
84%
85%
16
14
15
17
Scheme 4 Carbene-mediated C–H insertion into homopiperazine 13. Reagents and conditions: (a) Boc-piperazine, K2CO3, DMSO, 95 °C, 4
d; (b) p-TsNHNH2, toluene, microwave irradiation, 135 °C, 10 min; (c) NaH (60%), toluene, microwave irradiation, 135 °C, 12 min; (d) 2 M
HCl in Et2O, Et2O, MeOH, r.t., 18 h.
benzylcarbenes are normally not considered regioselec-
tive towards insertion.15–17 However, in this paper, we
have confirmed that C–H insertion reactions using ther-
X
X
mally generated carbenes have potential for synthetically
meaningful transformations, when applied to intramolec-
ular cyclization reactions forming five-membered rings.
N
N
O
S
O
a
N2
NH
N
When the carbene is stabilized as a metallocarbenoid, the
selectivity of C–H insertions has been reported to in-
crease.15,16 During the last thirty years, the reactivity of
carbenes has been successfully modified while still main-
taining their reactivity toward C–H insertion by applica-
tion of transition metal carbenes, such as rhodium.15,16
Dirhodium catalysts were found to be especially effective
and the first such reaction involving dirhodium tetraace-
tate was reported in 1981 by Teyssié.21
18: X = CH2
19: X = O
10b: X = CH2
10d: X = O
thermal
conditions
b
catalytic
c
conditions
X
N
X
We were therefore interested in investigating whether our
cyclization methodology could be modified to use a metal
carbene, especially with the aim of being able to obtain
some stereoselectivity in the cyclization reaction. As a
model substrate for investigation and optimization of the
catalytic C–H insertion, the piperidine derivative 18 and
morpholine derivative 19 (Scheme 5) were chosen. The
reason for choosing these two derivatives was to investi-
gate whether a second hetero atom had any influence on
the C–H insertion potential due to its inductively destabi-
lizing effect of the C–H insertion transition state, which is
observed when intermolecular C–H insertion into mor-
pholine is attempted.
N
N
X
20: X = CH2
21: X = O
11b: X = CH2
11d: X = O
Scheme 5 Formation of dimeric products in the attempted catalytic
C–H insertion reaction. Reagents and conditions: (a) BnNEt3Cl,
NaOH (14%), toluene–CH2Cl2, 70 °C, 3 h; (b) microwave irradiation,
135 °C, 10 min; (c) Rh2(OAc)4, toluene, –78 °C.
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Syntheses of Hexahydropyrazinoindoles
4291
Boc-Protected 1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]in-
doles 4a–j; General Procedure
In situ generation and in situ purification of the diazo in-
termediates 18 and 19 were achieved under highly basic
phase-transfer conditions22followed by phase separation
and drying/dehydration of the organic phase using sodium
sulfate. The standard method for generating the transient
metal carbenes is by metal-induced extrusion of nitrogen
from diazo compounds.15To our surprise, all catalytic
conditions tested resulted in the formation of the dimers
20 and 21 as the main products (E/Z ratio 4:1) and, nota-
bly, no C–H insertion was observed. Dimer formation is a
very common side reaction (Scheme 5) when applying
carbene chemistry,23 but the dimer being the main, or in
most cases the sole, product was unexpected.
To a solution of 2-piperazinebenzaldehyde 3a–i (1 g, 1 equiv) in tol-
uene (10 mL) was added tosylhydrazide (1.05 equiv). The mixture
was sonicated at r.t. for 3 h. In the cases where the mixtures were
homogeneous, they were dried (MgSO4) and filtered after 10 min
into a 20 mL microwave vial. In the cases where the mixtures were
heterogeneous, the H2O was removed by azeotropic evaporation
with toluene. In both cases toluene was added until a total volume
of 20 mL, followed by the addition of NaH (1.08 equiv) (vigorous
bubbling) and the mixture was purged with argon for 20 min (until
bubbling ceased). The vial was sealed and heated using microwave
irradiation at 135 °C for 10 min. EtOAc (100 mL) was added to the
mixture and washed with sat. aq NaHCO3 (75 mL), brine (75 mL),
dried (MgSO4), and concentrated in vacuo. the residue was purified
by flash chromatography (heptane–EtOAc) (Tables 1 and 3).
In conclusion, the synthesis of a series of novel, tricyclic
indoline based phenyl piperazines was successfully ac-
complished. The synthesis utilized a versatile carbene me-
diated intramolecular C–H insertion a to nitrogen and
turned out to be a fast and robust reaction. The methodol-
ogy offers a simple and more general approach to the syn-
thesis of tricyclic derivatives of compound 1 due to the
commercial availability of substrates. However, the limi-
tations of the SNAr reaction and carbene–mediated C–H
insertion in addition to absence of stereoselectivity make
this novel method complementary to the existing meth-
ods.
1,2,3,4,10,10a-Hexahydropyrazino[1,2-a]indoles 5a–j; General
Procedure
To the protected tricycle 4a–j (500 mg, 1 equiv) in MeOH (2.5 mL)
were added Et2O (5 mL) and 2 M HCl in Et2O (5 mL) [if the reagent
formed a thick gum, an additional amount of MeOH (2.5 mL) was
added]. The mixture was stirred at r.t. for 2 d and then concentrated
in vacuo.
Isolation of the HCl Salt: The solid was suspended/dissolved in a
very small amount of MeOH and then triturated with Et2O. The sus-
pension was filtered, the solid washed with a small amount of Et2O,
and dried in a vacuum oven.
Isolation of the Free Base: The solid was dissolved in aq 1 M HCl
(75 mL) and washed with Et2O (2 × 75 mL). The aqueous phase was
basified with concd NaOH and extracted with CH2Cl2 (2 × 75 mL).
The combined organic phases were washed with brine (75 mL),
dried (MgSO4), filtered, and concentrated in vacuo (Tables 1
and 4).
Microwave-assisted reactions were performed using the following
instruments: Emrys Optimizer (300 W), Emrys Synthesizer (300
W), Biotage Initiater (400 W), and Biotage Advancer (300 W). 1H
NMR and 13C NMR spectra were recorded on a Bruker Avance AV-
500 operating at 500 MHz for 1H NMR and 125 MHz for 13C NMR.
The solvents applied were CDCl3 or DMSO-d6. TMS was used as
internal reference in CDCl3 or DMSO-d6. Multiplicities of 1H NMR
signals are given as follows: s, singlet; br s, broad singlet; s(m),
multiplet that appears as a singlet; d, doublet; br d, broad doublet; t,
triplet; q, quartet; quint, quintet; v br = very broad. High-resolution
mass spectrometry (HRMS) analyses were performed on an Agi-
lent/Bruker Daltonics LC-SPE-MS spectrometer. Elemental analy-
ses were performed on a Flash EA1112 from Thermo Fischer
Scientific. Chromatography was either performed manually on sili-
ca gel columns (Kieselgel 40, 0.040–0.063 mm) or by using the fol-
lowing instruments: FlashMasterII from JonesChromatography
with prepacked IST columns, ISCO Companion 4X or ISCO
CompanionXL. Preparative LC-MS was performed on a Sciex
API150ex from Applied Biosystems. Analytical LC-MS were per-
formed on either a Sciex API150ex or a API300 from Applied Bio-
systems. Reactions and product mixtures were analyzed by TLC on
silica gel precoated Merck 60 F254 0.25 mm silica gel plates and vi-
sualized under UV light.
Hydrazones 10a–d and 13; General Procedure
To a solution of the 2-amino-substituted benzaldehyde 9a–d or 12
(1 g, 1 equiv) in toluene (10 mL) was added tosyl hydrazide (1.05
equiv). The mixture was sonicated at r.t. for 3 h or heated using mi-
crowave irradiation at 135 °C for 10 min. In the case of a clear so-
lution, the mixture was filtered and concentrated in vacuo, however,
if the mixture had turned into a mash it was transferred into a sepa-
ratory funnel containing EtOAc (100 mL) and sat. aq NaHCO3 (75
mL). The organic phase was washed with brine (75 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The solid obtained
was crystallized by dissolving in EtOAc–MeOH and diluting with
heptane (Table 5).
C–H Insertion with Hydrazones 10a–d and 13 as Substrates;
Formation of 11a–d, 14, and 15; General Procedure
The hydrazone 10a–d or 13 (500 mg, 1 equiv) was dissolved in tol-
uene (20 mL) and NaH (1.08 equiv) was added carefully to the so-
lution (vigorous bubbling). The mixture was purged with argon for
20 min until H2 formation had ceased. The vial was sealed and heat-
ed using microwave irradiation at 135 °C for 10 min. To the mixture
was added EtOAc (75 mL) and the organic layer was washed with
sat. aq NaHCO3 (75 mL), brine (75 mL), dried (MgSO4), and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (heptane–EtOAc) (Table 5).
Substituted 2-Piperazinobenzaldehydes 3a–j, 9a–d, and 12;
General Procedure
Aldehyde 2a–i (2 g, 1 equiv), tert-butyl piperazine-1-carboxylate
(1.2 equiv), and K2CO3 (1.3 equiv) were suspended in DMSO (12
mL). The mixture was heated to 95 °C in a sealed vessel for 4 d. The
mixture was poured into a separatory funnel containing EtOAc (100
mL) and Et2O (100 mL) and the organic phase was washed with
phosphate buffer pH 7 (2 × 100 mL), brine–H2O (1:1, 2 × 100 mL)
and brine (100 mL), dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by flash chromatography (heptane–
EtOAc) (Tables 1 and 2).
Carbene-Mediated Dimerization of the Hydrazones 10b,d;
General Procedure
To a solution of hydrazone 10b,d (500 mg, 1 equiv) in toluene (20
mL) and CH2Cl2 (5 mL) were added BnNEt3Cl (5 mol%) and aq
NaOH (14%, 20 mL). The mixture was heated to 70 °C for 3 h. The
organic phase was separated, dried (Na2SO4), and filtered. The or-
ganic phase was slowly added (3 h) to a suspension of Rh2(OAc)4
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

4292
N. Krogsgaard-Larsen et al.
PAPER
Table 2 Spectral Data of Compounds 3
Entry Product 1H NMR (500 MHz, CDCl3): 13C NMR (125 MHz,
HRMS: m/z
LC-MS
TLC
(R)
d, J (Hz)
CDCl3): d, J (Hz)
(M + H+)
O
O
N
N
3
O
6
4
5
R
3a
H
1.49 (9 H, s), 3.04 (4 H, br s),
3.63 (4 H, m), 7.11 (1 H, d,
J = 8), 7.16 (1 H, t, J = 8), 7.54
(1 H, dt, J = 8, 1.5), 7.83 (1 H,
dd, J = 8, 1.5), 10.35 (1 H, s)
–
–
UV = 98.6% (tR = 1.55 Rf = 0.27
min), ELS = 100%
(tR = 1.60 min),
m/z = 291.2
heptane–EtOAc
(3:2)
3b
3c
4-Me
5-Me
1.49 (9 H, s), 2.39 (3 H, s), 3.02 22.1, 28.4, 43.2 (br), 44.2
(4 H, m), 3.63 (4 H, m), 6.89 (1 (br), 53.6, 79.9, 119.6, 123.9, calcd: 305.1860; min), ELS = 100%
H, s), 6.96 (1 H, d, J = 8), 7.72 126.3, 130.5, 146.2, 154.6, found: 305.1866
(1 H, d, J = 8), 10.27 (1 H, s) 155.3, 190.5
C17H25N2O3
UV = 99.3% (tR = 1.55 Rf = 0.21
heptane–EtOAc
(4:1)
(tR = 1.60 min),
m/z = 305.2
1.50 (9 H, s), 2.35 (3 H, s), 3.00 20.5, 28.4, 43.3 (br), 44.2
(4 H, m), 3.63 (4 H, m), 7.03 (1 (br), 53.9, 79.9, 119.3, 128.7, calcd: 305.1860; min), ELS = 100%
C17H25N2O3
UV = 100% (tR = 1.57 Rf = 0.23
heptane–EtOAc
(4:1)
H, d, J = 8), 7.36 (1 H, dd,
J = 9, 1.5), 7.64 (1 H, d,
J = 1.5), 10.37 (1 H, s)
130.0, 132.8, 135.8, 153.3, found: 305.1869
154.7, 191.3
(tR = 1.62 min),
m/z = 305.3
3d
4-Cl
1.49 (9 H, s), 3.04 (4 H, m),
3.63 (4 H, m), 7.07 (1 H, d,
J = 1.5), 7.12 (1 H, dd, J = 8, 126.9, 131.7, 141.1, 154.5, found: 325.1319
28.3, 43.0 (br), 44.0 (br),
53.5, 80.0, 119.5, 123.1,
C16H22ClN2O3
calcd: 325.1313; min), ELS = 100%
UV = 99.8% (tR = 1.65 Rf = 0.24
heptane–EtOAc
(4:1)
(tR = 1.70 min),
m/z = 325.5
1.5), 7.75 (1 H, d, J = 9), 10.24 155.8, 189.5
(1 H, s)
3e
3f
6-Cl
4-Br
1.49 (9 H, s), 3.02 (4 H, m),
3.63 (4 H, m), 7.00 (1 H, d,
J = 9), 7.12 (1 H, d, J = 8), 7.40 125.7, 134.1, 137.0, 154.5, found: 325.1321
28.2, 43.0 (br), 44.1 (br),
53.1 (br), 79.7, 117.7, 124.5, calcd: 325.1313; min), ELS = 100%
C16H22ClN2O3
UV = 99.1% (tR = 1.58 Rf = 0.19
heptane–EtOAc
(4:1)
(tR = 1.64 min),
m/z = 325.4
(1 H, t, J = 8), 10.38 (1 H, s)
155.4, 189.0
1.49 (9 H, s), 3.01 (4 H, m),
3.63 (4 H, m), 7.00 (1 H, d,
J = 9), 7.62 (1 H, dd, J = 9,
2.5), 7.92 (1 H, d, J = 2.5),
10.26 (1 H, s)
28.8, 43.4 (br), 44.5 (br),
54.1 (br), 80.4, 116.5, 121.6, calcd: 369.0808; min), ELS = 100%
130.4, 132.8, 137.9, 154.5, found: 369.0822
154.9, 189.7
C16H22BrN2O3
UV = 100% (tR = 1.72 Rf = 0.33
heptane–EtOAc
(5:2)
(tR = 1.77 min),
m/z = 369.2
3g
3h
5-Br
1.49 (9 H, s), 3.04 (4 H, m),
3.63 (4 H, m), 7.23 (1 H, d,
J = 2), 7.29 (1 H, dd, J = 9, 2), 127.7, 130.4, 132.2, 155.0, found: 369.0821
7.67 (1 H, d, J = 9), 10.24 (1 H, 156.2, 190.2
s)
28.8, 43.5 (br), 44.4 (br),
54.0, 80.5, 123.0, 126.6,
C16H22BrN2O3
calcd: 369.0815; min), ELS = 100%
UV = 100% (tR = 1.70 Rf = 0.36
heptane–EtOAc
(5:2)
(tR = 1.75 min),
m/z = 371.1
4-OMe 1.47 (9 H, s), 3.01 (4 H, m),
3.61 (4 H, m), 3.84 (3 H, s),
28.5, 43.3 (br), 44.3 (br),
53.6, 55.6, 80.1, 105.0,
C17H25N2O4
calcd: 321.1809; min), ELS = 100%
UV = 100% (tR = 1.44 Rf = 0.42
heptane–EtOAc
(1:1)
6.51 (1 H, d, J = 2), 6.64 (1 H, 108.1, 122.5, 133.4, 154.8, found: 321.1804
dd, J = 9, 2), 7.78 (1 H, d,
J = 9), 10.13 (1 H, s)
(tR = 1.49 min),
m/z = 321.2
157.3, 165.3, 189.5
3i
3j
6-OMe 1.46 (9 H, s), 3.00 (4 H, m),
3.61 (4 H, m), 3.88 (3 H, s),
28.5, 43.4 (br), 44.4 (br),
53.2 (br), 56.1, 79.9, 105.1, calcd: 321.1809; min), ELS = 100%
C17H25N2O4
UV = 97.7% (tR = 1.33 Rf = 0.37
heptane–EtOAc
(1:1)
6.62 (2 H, d, J = 8), 7.42 (1 H, 111.1, 117.5, 135.6, 154.9, found: 321.1809
t, J = 8), 10.36 (1 H, s)
(tR = 1.38 min),
m/z = 321.2
155.4, 162.9, 189.1
5-NO2 1.47 (9 H, s), 3.25 (4 H, m),
3.66 (4 H, m), 7.08 (1 H, d,
28.5, 43.0 (br), 43.9 (br),
52.9, 80.6, 118.6, 126.4,
C16H22N3O5
calcd: 336.1554; min), ELS = 100%
UV = 98.3% (tR = 1.41 Rf = 0.40
heptane–EtOAc
(1:1)
J = 9), 8.29 (1 H, dd, J = 9, 2), 128.9, 129.5, 141.4, 154.6, found: 336.1545
8.60 (1 H, d, J = 2), 10.09 (1 H, 157.9, 188.3
(tR = 1.47 min),
m/z = 335.2
s)
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

PAPER
Syntheses of Hexahydropyrazinoindoles
4293
(2 mol%) in toluene (10 mL) at –78 °C under N2 using a syringe
pump. After stirring for 30 min at –78 °C, the mixture was allowed
to warm up to r.t. and filtered through a small plug of Celite and
concentrated in vacuo. The residue was purified by flash chroma-
tography (heptane–EtOAc) (Table 5).
Table 3 Spectral Data of Compounds 4
Entry Product 1H NMR
(R) (500 MHz, CDCl3): d, J (Hz)
13C NMR
(125 MHz, CDCl3): d
HRMS:
LC-MS
TLC
m/z (M + H+)
O
O
N
N
6
9
7
8
R
4a
4b
H
1.48 (9 H, s), 2.58 (1 H, dd, J = 15, 28.5, 32.4, 42.1 (br), 43.2
9), 2.74–3.05 (4 H, m), 3.38 (1 H, (br), 44.1, 47.2 (br), 48.2
m), 3.52 (1 H, br d, J = 11), 3.95– (br), 62.6, 80.0, 106.3, 118.3, found: 275.1763
4.33 (2 H, m), 6.46 (1 H, d, J = 8), 124.9, 127.5, 128.8, 150.5,
C16H23N2O2
calcd: 275.1754; (tR = 1.53 min),
UV = 100%
Rf = 0.32
heptane–EtOAc
(3:1)
ELS = 100%
(tR = 1.58 min),
m/z = 274.5
6.68 (1 H, t, J = 7), 7.05–7.12 (2
154.8
H, m)
7-Me
1.48 (9 H, s), 2.28 (3 H, s), 2.53 (1 21.8, 28.5, 32.1, 42.1 (br),
C17H25N2O2
UV = 95.2%
Rf = 0.36
H, dd, J = 15, 9), 2.70–3.09 (3 H, 43.2 (br), 44.2, 47.2 (br),
v br m), 2.93 (1 H, dd, J = 15, 8), 48.2 (br), 62.8, 80.0, 107.4, found: 289.1905
3.36 (1 H, m), 3.50 (1 H, m), 3.95– 118.9, 124.6, 126.0, 137.4,
calcd: 289.1911; (tR = 1.70 min),
heptane–EtOAc
(3:1)
ELS = 100%
(tR = 1.76 min),
m/z = 289.3
4.35 (2 H, v br m), 6.29 (1 H, s),
6.50 (1 H, d, J = 7), 6.97 (1 H, d,
J = 7)
150.7, 154.9
4c
4d
4e
8-Me
7-Cl
9-Cl
1.48 (9 H, s), 2.24 (3 H, s), 2.55 (1 20.9, 28.5, 32.5, 42.0 (br),
H, dd, J = 15, 9), 2.70–3.09 (3 H, 43.1 (br), 44.5, 47.0 (br),
m), 2.93 (1 H, dd, J = 15, 8), 3.32 48.1 (br), 63.0, 80.0, 106.3, found: 289.1900
(1 H, m), 3.49 (1 H, m), 3.95–4.30 125.9, 127.6, 129.2, 148.4,
(2 H, m), 6.38 (1 H, d, J = 8), 6.88 154.9
C17H25N2O2
calcd: 289.1911; (tR = 1.64 min),
UV = 97.7%
Rf = 0.36
heptane–EtOAc
(3:1)
ELS = 100%
(tR = 1.70 min),
m/z = 289.2
(1 H, d, J = 8), 6.93 (1 H, s)
1.48 (9 H, s), 2.53 (1 H, dd, J = 15, 28.5, 31.9, 42.0 (br), 43.1
9), 2.66–3.06 (3 H, v br m), 2.95 (1 (br), 43.9, 47.1 (br), 48.1
C16H22ClN2O2
calcd: 309.1364; (tR = 1.78 min),
UV = 99.4%
Rf = 0.34
heptane–EtOAc
(3:1)
H, dd, J = 15, 8), 3.46 (2 H, m),
(br), 62.7, 80.2, 106.7, 117.7, found: 309.1351 ELS = 100%
3.95–4.35 (2 H, v br m), 6.40 [1 H, 125.5, 127.3, 133.3, 151.7,
s(m)], 6.62 (1 H, dd, J = 8, 1), 6.96 154.8
(1 H, d, J = 8)
(tR = 1.84 min),
m/z = 308.3
1.48 (9 H, s), 2.60 (1 H, dd, J = 16, 28.4, 31.6, 41.9 (br), 43.1
9), 2.68–3.03 (3 H, v br m), 3.07 (1 (br), 44.0, 47.1 (br), 48.1
C16H22ClN2O2
calcd: 309.1364; (tR = 1.80 min),
UV = 97.8%
Rf = 0.34
heptane–EtOAc
(3:1)
H, dd, J = 16, 8), 3.48 (2 H, m),
(br), 61.7, 80.1, 104.3, 118.1, found: 309.1353 ELS = 100%
3.95–4.35 (2 H, m), 6.31 (1 H, d, 126.8, 129.0, 130.9, 151.7,
J = 8), 6.64 (1 H, d, J = 8), 7.00 (1 154.7
H, t, J = 8)
(tR = 1.86 min),
m/z = 308.5
4f
7-Br
8-Br
1.48 (9 H, s), 2.57 (1 H, dd, J = 11, 28.8, 32.6, 42.2 (br), 43.4
4), 2,65–3.04 (3 H, v br m), 2.97 (1 (br), 44.5, 47.3 (br), 48.3
H, dd, J = 11, 3), 3.36–3.52 (2 H, (br), 62.9, 80.5, 107.9, 110.1, found: 359.0863
m), 3.95–4.35 (2 H, v br m), 6.31 128.3, 130.5, 131.6, 150.0,
C16H22BrN2O2
calcd: 353.0859; (tR = 1.82 min),
UV = 99.7%
Rf = 0.30
heptane–EtOAc
(4:1)
ELS = 100%
(tR = 1.88 min),
m/z = 354.3
(1 H, d, J = 9), 7.16 (2 H, m)
155.1
4g
1.48 (9 H, s), 2.51 (1 H, dd, J = 15, 28.5, 32.0, 42.0 (br), 43.1
C16H22BrN2O2
UV = 99.7%
Rf = 0.33
9), 2.66–3.03 (3 H, m), 2.94 (1 H, (br), 43.9, 47.1 (br), 48.2
calcd: 353.0859; (tR = 1.83 min),
heptane–EtOAc
(4:1)
dd, J = 15, 8), 3.45 (2 H, m), 3.92– (br), 62.6, 80.2, 109.5, 120.7, found: 353.0861
4.32 (2 H, m), 6.55 [1 H, br s(m)], 121.3, 126.0, 127.9, 151.9,
6.77 (1 H, dd, J = 7.5, 1.5), 6.91 (1 154.8
ELS = 100%
(tR = 1.89 min),
m/z = 352.6
H, dm, J = 7.5)
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

4294
N. Krogsgaard-Larsen et al.
PAPER
Table 3 Spectral Data of Compounds 4 (continued)
Entry Product 1H NMR
13C NMR
(125 MHz, CDCl3): d
HRMS:
LC-MS
TLC
(R)
(500 MHz, CDCl3): d, J (Hz)
m/z (M + H+)
O
O
N
N
6
9
7
8
R
4h
4i
7-OMe 1.48 (9 H, s), 2.51 (1 H, dd, J = 15, 28.8, 32.0, 42.5 (br), 43.5
C17H25N2O3
calcd: 305.1860; (tR = 1.60 min),
UV = 99.0%
Rf = 0.33
heptane–EtOAc
(5:2)
9), 2.71–3.03 (3 H, m), 2.92 (1 H, (br), 44.5, 47.5 (br), 48.6
dd, J = 15, 8), 3.41 (1 H, m), 3.47 (br), 55.8, 63.4, 80.4, 94.6, found: 305.1866
(1 H, m), 6.06 (1 H, d, J = 2.5), 102.3, 121.5, 125.3, 152.2,
6.20 (1 H, dd, J = 8, 2.5), 6.97 (1 155.2, 160.6
H, d, J = 8)
ELS = 100%
(tR = 1.65 min),
m/z = 305.3
9-OMe 1.48 (9 H, s), 2.50 (1 H, dd, J = 15, 27.6, 28.5, 41.2 (br), 42.4
C17H25N2O3
calcd: 305.1860; (tR = 1.60 min),
UV = 99.6%
Rf = 0.38
heptane–EtOAc
(5:2)
9), 2.71–3.02 (3 H, v br m), 2.99 (1 (br), 43.4, 46.2 (br), 47.3
H, dd, J = 15, 8), 3.43 (1 H, m),
(br), 54.4, 61.6, 79.1, 99.4, found: 305.1868 ELS = 100%
3.51 (1 H, m), 6.16 (1 H, d, J = 8), 100.9, 133.8, 128.1, 151.2,
(tR = 1.66 min),
6.30 (1 H, d, J = 8), 7.06 (1 H, t,
J = 8)
154.0, 155.6
m/z = 305.3
4j
8-NO2 1.41 (9 H, s), 2.56 (1H, dd, J = 16, 28.2, 31.0, 42.0 (br), 43.1*, Anal. Calcd for
UV = 99.2%
Rf = 0.44
8), 2.70 [1 H, br s(m)], 2.83 [1 H, 47.6 (br), 48.6 (br), 61.2,
br s(m)], 3.02 (2 H, m), 3.53 (1 H, 80.3, 103.4, 120.8, 126.4,
C16H21N3O4: C,
60.17; H, 6.63; N, ELS = 100%
13.16. (tR = 1.55 min),
(tR = 1.49 min),
heptane–EtOAc
(1:1)
dm, J = 7), 3.67 (1 H, m), 3.95–
128.5, 138.2, 154.3, 155.2
4.30 (2 H, m), 6.22 (1 H, d, J = 9), * merged with the second
Found: C, 60.26; m/z = 264.1
7.76 [1 H, s(m)], 7.91 (1 H, dd,
broad piperazine peak
H, 6.70; N, 13.08
J = 9, 1.5)
Table 4 Spectral Data of Compounds 5
Entry Product 1H NMR (500 MHz, CDCl3):
13C NMR
(125 MHz, CDCl3): d
HRMS:
LC-MS
TLC
(R)
d, J (Hz)
m/z (M + H+)
H
N
N
6
7
9
8
R
5a
5b
H
1.69 [1 H, br s], 2.55 (1 H, dd, J = 15,
10), 2.77 (1 H, t, J = 11), 2.87 (2 H, m), 64.5, 106.2, 118.1,
2.91–3.01 (2 H, m), 3.07 (1 H, dd, 125.1, 127.8, 129.3,
J = 12, 3), 3.40 (1 H, m), 3.53 (1 H, m), 151.5
6.43 (1 H, d, J = 8), 6.64 (1 H, t, J = 7.5),
7.07 (2 H, m)
33.3, 45.0, 46.0, 50.6,
C11H15N2
calcd: 175.1230; (tR = 0.59 min)
found: 175.1236
UV = 100%
Rf = 0.34
EtOAc–
MeOH–Et3N
(3:2:1)
ELSD = 100%
(tR = 0.65 min),
m/z = 175.3
7-Me
2.29 (3 H, s), 2.56 (1 H, dd, J = 15, 8),
2.94 (1 H, t, J = 12), 3.04 (2 H, m), 3.39 46.5, 60.0, 107.9, 119.8, calcd: 189.1386; (tR = 0.82 min)
21.7, 32.4, 41.8, 42.2,
C12H17N2
UV = 98.3%
Rf = 0.32
EtOAc–
(3 H, m), 3.68 (1 H, dd, J = 13, 3), 3.88 124.9, 125.0, 137.8,
found: 189.1383
ELSD = 100%
(tR = 0.88 min),
m/z = 189.4
MeOH–Et3N
(3:2:1)
(1 H, m), 6.31 (1 H, s), 6.55 (1 H, d,
J = 7.5), 6.99 (1 H, d, J = 7.5), 8.1–8.6
(1 H, br s)
149.5
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

PAPER
Syntheses of Hexahydropyrazinoindoles
4295
Table 4 Spectral Data of Compounds 5 (continued)
Entry Product 1H NMR (500 MHz, CDCl3):
13C NMR
(125 MHz, CDCl3): d
HRMS:
LC-MS
TLC
(R)
d, J (Hz)
m/z (M + H+)
H
N
N
6
7
9
8
R
5c
8-Me
2.26 (3 H, s), 2.68 (1 H, dd, J = 15.5, 6), 20.3, 32.3, 41.6, 41.7,
3.01 (1 H, t, J = 12), 3.12 (2 H, m), 3.30 45.2, 59.6, 108.8, 126.8, calcd: 189.1386; (tR = 0.83 min)
C12H17N2
UV = 100%
Rf = 0.33
EtOAc–
(1 H, dt, J = 13.5, 3), 3.41 (2 H, m), 3.81 128.4, 129.8, 130.6,
(1 H, m), 3.89 (1 H, dd, 14.5, 2.5), 6.70 146.6
(1 H, d, J = 8), 7.07 (1 H, d, J = 8), 7.14
(1 H, s)
found: 189.1385
ELSD = 100%
(tR = 0.89 min),
m/z = 189.3
MeOH–Et3N
(3:2:1)
5d
5e
5f
7-Cl
9-Cl
7-Br
8-Br
1.79 [1 H, br s], 2.48 (1 H, dd, J = 15, 9), 32.3, 44.5, 45.3, 50.2,
2.72 (1 H, t, J = 11), 2.77–2.98 (4 H, m), 64.0, 106.1, 117.1,
3.03 (1 H, dd, J = 12, 3), 3.45 (2 H, m), 125.2, 127.4, 133.2,
C11H14ClN2
calcd: 209.0840; (tR = 0.92 min)
found: 209.0832
UV = 100%
Rf = 0.33
EtOAc–
MeOH–Et3N
(3:2:1)
ELSD = 100%
(tR = 0.98 min),
m/z = 208.8
6.35 (1 H, d, J = 1.5), 6.57 (1 H, dd,
J = 7.5, 1.5), 6.93 (1 H, d, J = 7.5)
152.3
1.84 [1 H, br s], 2.56 (1 H, dd, J = 15.5, 32.1, 44.6, 45.5, 50.3,
9 Hz), 2.74 (1 H, t, J = 11), 2.82 (1 H, 63.1, 103.9, 117.6,
m), 2.88–3.00 (2 H, m), 3.00–3.09 (2 H, 126.9, 129.0, 130.9,
C11H14ClN2
calcd: 209.0840; (tR = 0.91 min)
found: 209.0831
UV = 99.1%
Rf = 0.35
EtOAc–
MeOH–Et3N
(3:2:1)
ELSD = 100%
(tR = 0.97 min),
m/z = 208.8
m), 3.49 (2 H, m), 6.27 (1 H, d, J = 8),
6.59 (1 H, d, J = 8), 6.98 (1 H, t, J = 8)
152.3
1.79 [1 H, br s], 2.52 (1 H, dd, J = 15, 9), 32.7, 44.5, 45.5, 50.1,
2.73 (1 H, t, J = 11), 2.79–3.00 (4 H, m), 63.9, 107.0, 109.0,
3.04 (1 H, dd, J = 12, 2.5), 3.44 (2 H, m), 127.7, 130.0, 131.3,
6.27 (1 H, d, J = 8), 7.13 (1 H, d, J = 8), 150.2
7.14 (1 H, s)
C11H14BrN2
calcd: 253.0335; (tR = 0.97 min)
found: 253.0325
UV = 100%
Rf = 0.32
EtOAc–
MeOH–Et3N
(3:2:1)
ELSD = 100%
(tR = 1.03 min),
m/z = 255.3
5g
1.85 [1 H, br s], 2.46 (1 H, dd, J = 15, 9), 32.3, 44.5, 45.3, 50.2,
C11H14BrN2
calcd: 253.0335; (tR = 0.97 min)
UV = 100%
Rf = 0.34
EtOAc–
2.71 (1 H, t, J = 11), 2.81 (1 H, dt,
63.9, 108.9, 120.0,
J = 12, 3), 2.88 (2 H, m), 2.95 (1 H, dm, 121.1, 125.7, 128.0,
J = 12), 3.03 (1 H, dd, J = 12, 3), 3.44 (2 152.5
H, m), 6.49 [1 H, s(m)], 6.71 (1 H, dd,
found: 253.0325
ELS = 100%
(tR = 1.03 min),
m/z = 255.4
MeOH–Et3N
(3:2:1)
J = 8, 1.5), 6.88 (1 H, d, J = 8)
5h
7-OMe 2.26 [1 H, br s], 2.49 (1 H, ddd, J = 15, 32.5, 44.8, 45.7, 50.4,
C12H17N2O
UV = 96.4%
Rf = 0.35
EtOAc–
9, 0.5), 2.77 (1 H, dd, J = 12, 11), 2.83– 55.8, 64.7, 94.1, 101.8, calcd: 205.1335; (tR = 0.76 min)
2.94 (3 H, m), 3.00 (1 H, m), 3.07 (1 H, 121.6, 125.1, 152.7,
dd, J = 12, 3), 3.41–3.57 (2 H, m), 3.76 160.6
(3 H, s), 6.03 (1 H, d, J = 2), 6.17 (1 H,
found: 205.1334
ELS = 100%
(tR = 0.82 min),
m/z = 205.2
MeOH–Et3N
(3:2:1)
dd, J = 8, 2), 6.95 (1 H, d, J = 8)
5i
5j
9-OMe 2.12 [1H, br s], 2.46 (1 H, dd, J = 15, 9), 30.2, 45.0, 46.1, 50.5,
C12H17N2O
UV = 98.7%
Rf = 0.38
EtOAc–
MeOH–Et3N
(3:2:1)
2.77 (1 H, dd, J = 12, 11), 2.81–3.00 (4 55.7, 64.3, 100.3, 101.7, calcd: 205.1335; (tR = 0.76 min)
H, m), 3.05 (1 H, dd, J = 12, 3), 3.45 (1 115.0, 129.2, 153.1,
H, m), 3.52 (1 H, m), 6.13 (1 H, d, J = 8), 156.8
6.27 (1 H, d, J = 8), 7.04 (1 H, t, J = 8)
found: 205.1330
ELS = 100%
(tR = 0.82 min),
m/z = 205.3
8-NO2 2.58 (1 H, dd, J = 16, 8), 2.64 (1 H, t,
32.8, 45.3, 45.6, 51.5,
C11H14N3O2
calcd: 220.1081; (tR = 0.57 min)
ELS = 100%
UV = 97.7%
Rf = 0.29
EtOAc–
MeOH–Et3N
(3:2:1)
J = 12), 2.75 (1 H, dt, J = 12, 3.5), 3.01 63.6, 104.8, 122.1,
(1 H, dm, J = 13), 3.04–3.14 (3 H, m),
3.70 (1 H, dd, J = 13, 2.5), 3.77 (1 H, m),
6.35 (1 H, d, J = 9), 7.78 [1 H, s(m)],
7.94 (1 H, dd, J = 9, 4)
128.0, 130.7, 139.4, 157 found: 220.1071
(tR = 0.63 min),
m/z = 220.2
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

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PAPER
Table 5 Spectral Data of Compounds 9–17, 20, and 21
Entry Product
1H NMR (500 MHz, CDCl3): 13C NMR
d, J (Hz)
HRMS:
LC-MS
TLC
–
(125 MHz, CDCl3): d m/z (M + H+)
9a
1.93–2.00 (4 H, m), 3.31–3.37 26.0, 52.7, 114.6,
(4 H, m), 6.79 (1 H, t, J = 8), 116.4, 123.0, 133.1,
6.82 (1 H, d, J = 9), 7.36 (1 H, 134.2, 150.0, 190.1
m), 7.69 (1 H, dd, J = 8, 2),
known compound UV = 100%
(tR = 0.72 min),
N
ELS = no signal,
m/z = 176.5
O
10.08 (1 H, s)
9b
1.61 (2 H, m), 1.76 (4 H, m), 24.4, 26.6, 56.0,
C12H16NO
calcd: 190.1226; (tR = 0.51 min),
UV = 100%
Rf = 0.63
heptane–
EtOAc
(3:1)
3.05 (4 H, m), 7.06 (1 H, t,
J = 8), 7.09 (1 H, d, J = 8),
119.4, 122.3, 129.0,
129.6, 135.2, 157.4,
found: 190.1226
C13H18NO
ELS = no signal,
m/z = 190.2
N
7.49 (1 H, dt, J = 8, 2), 7.80 (1 192.0
H, dd, J = 8, 2), 10.31 (1 H, s)
O
9c
1.66 [4 H, br s(m)], 1.79 [4 H, 27.8, 28.7, 56.0,
UV = 99.4%
Rf = 0.52
heptane–
EtOAc
(2:1)
br s(m)], 3.38 (4 H, m), 6.91
(1 H, t, J = 7), 7.06 (1 H, d,
J = 9), 7.40 (1 H, t, J = 8),
7.72 (1 H, d, J = 8), 10.19 (1
H, s)
118.6, 119.6, 126.7,
130.6, 134.3, 156.2,
191.3
calcd: 204.1383; (tR = 0.63 min),
found: 204.1383
ELS = no signal,
m/z = 204.5
N
O
9d
3.08 (4 H, m), 3.89 (4 H, m), 54.0, 66.8, 118.7,
7.11 (1 H, d, J = 8), 7.14 (1 H, 122.8, 128.5, 130.1,
t, J = 8), 7.54 (1 H, tm, J = 8), 135.0, 155.2, 190.9
7.81 (1 H, dd, J = 8, 1), 10.33
C11H14NO2
calcd: 192.1019; (tR = 0.81 min),
found: 192.1007
UV = 99.6%
Rf = 0.35
heptane–
EtOAc
(3:1)
O
N
ELS = no signal,
m/z = 192.2
(1 H, s)
O
10a
1.84 (4 H, m), 2.39 (3 H, s),
3.09 (4 H, m), 6.80 (2 H, m), 115.6, 119.6, 122.5,
7.21 (1 H, tm, J = 8), 7.29 (2 128.0, 128.7, 129.7,
H, d, J = 8), 7.58 (1 H, dt,
J = 8), 7.88 (2 H, d, J = 8),
8.16 (1 H, s), 8.39 (1 H, v br s)
21.7, 25.3, 52.8,
C18H22N3O2S
calcd: 344.1427; tained due to
found: 344.1428
could not be ob-
Rf = 0.39
heptane–
EtOAc
(1:1)
precipitation
130.8, 135.5, 144.1,
149.8
N
O
S
O
NH
N
10b
10c
10d
1.52 (2 H, m), 1.63 (4 H, m), 21.7, 24.1, 26.3, 54.8, C19H24N3O2S
2.38 (3 H, s), 2.79 (4 H, m), 119.3, 123.1, 127.0,
could not be ob-
calcd: 358.1584; tained due to
Rf = 0.35
heptane–
EtOAc
(2:1)
7.00 (2 H, m), 7.27 (3 H, m), 127.4, 128.0, 129.7,
7.72 (1 H, d, J = 8), 7.88 (2 H, 131.1, 135.6, 144.1,
d, J = 8), 8.15 (1 H, br s), 8.2– 147.3, 153.6
8.7 (1 H, v br s)
found: 358.1581
precipitation
N
O
S
O
NH
N
1.64 [8 H, s(m)], 2.39 (3 H, s), 21.7, 27.2, 29.1, 56.8, C20H26N3O2S
could not be ob-
Rf = 0.38
heptane–
EtOAc
(2:1)
3.04 (4 H, m), 6.95 (1 H, t,
J = 8), 7.04 (1 H, d, J = 8),
120.8, 122.4, 127.0,
127.5, 128.0, 129.7,
calcd: 372.1740; tained due to
found: 372.1739
precipitation
7.26 (1 H, tm, J = 8), 7.29 (2 131.0, 135.6, 144.1,
H, d, J = 8), 7.68 (1 H, d,
J = 8), 7.89 (2 H, d, J = 8),
8.19 (1 H, s), 8.36 (1 H, v br s)
148.1, 155.3
N
O
S
O
NH
N
2.40 (3 H, s), 2.84 (4 H, m),
3.78 (4 H, m), 7.03 (1 H, d,
J = 8), 7.06 (1 H, t, J = 8),
21.7, 53.5, 67.1,
119.2, 123.9, 127.3,
127.6, 128.0, 129.8,
C18H21N3O3S
calcd: 360.1376; tained due to
found: 360.1372 precipitation
could not be ob-
Rf = 0.25
heptane–
EtOAc
(1:1)
O
N
7.30 (2 H, d, J = 8), 7.34 (1 H, 131.3, 135.5, 144.3,
tm, J = 8), 7.75 (1 H, d, J = 8), 146.7, 152.2
7.89 (2 H, d, J = 8), 8.22 (1 H,
O
S
O
NH
s), 8.53 (1 H, br s)
N
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

PAPER
Syntheses of Hexahydropyrazinoindoles
4297
Table 5 Spectral Data of Compounds 9–17, 20, and 21 (continued)
Entry Product
1H NMR (500 MHz, CDCl3): 13C NMR
d, J (Hz)
(125 MHz, CDCl3): d m/z (M + H+)
HRMS:
LC-MS
TLC
11a
1.29–1.41 (1 H, m), 1.80–1.95 25.9, 31.4, 34.0, 52.4, C11H14N
UV = 100%
not deter-
mined
(highly li-
pophilic)
(3 H, m), 2.98 (1 H, dd, J = 11, 65.4, 111.1, 119.3,
2), 3.17–3.26 (2 H, m), 3.42– 124.9, 127.6, 130.0,
3.49 (1 H, m), 3.92–3.99 (1 H, 154.8
m), 6.62 (1 H, d, J = 8), 6.78
calcd: 160.1121; (tR = 0.29 min),
found: 160.1120
ELS = no signal,
m/z = 160.0
N
(1 H, dm, J = 8), 7.10 (1 H, d,
J = 8), 7.12 (1 H, t, J = 8)
11b
1.37–1.47 (1 H, m), 1.50–1.67 24.6, 24.8, 30.8, 35.7, C12H16N
UV = 97.8%
not deter-
mined
(highly li-
pophilic)
(2 H, m), 1.69–1.75 (1 H, m), 45.3, 65.4, 105.9,
1.83–1.92 (2 H, m), 2.58 (1 H, 117.6, 124.6, 127.3,
dd, J = 15, 11), 2.64 (1 H, dt, 129.5, 1151.9
J = 7, 3), 2.97 (1 H, dd, J = 15,
calcd: 174.1277; (tR = 0.57 min),
found: 174.1275
ELS = no signal,
m/z = 174.2
N
8), 3.17–3.26 (1 H, m), 3.61–
3.67 (1 H, m), 6.45 (1 H, d,
J = 8), 6.65 (1 H, t, J = 8),
7.04–7.10 (2 H, m)
11c
1.49 (1 H, m), 1.60 (1 H, m), 27.27, 27.30, 28.4,
1.72 (2 H, m), 1.83 (2 H, m), 37.3, 37.8, 48.4, 64.3, calcd: 188.1434; (tR = 0.58 min),
C13H18N
UV = 100%
not deter-
mined
1.94 (2 H, m), 2.69 (1 H, dd,
J = 16, 8), 3.07 (1 H, ddd,
J = 13, 7, 4), 3.26 (1 H, dd,
J = 16, 10), 3.47 (1 H, ddd,
J = 12, 9, 5), 3.85 (1 H, dq,
J = 9, 3), 6.35 (1 H, d, J = 8),
6.60 (1 H, t, J = 7), 7.02 (1 H,
d, J = 7), 7.08 (1 H, t, J = 8)
105.8, 116.5, 123.9,
127.5, 128.7, 152
found: 188.1435
ELS = no signal,
m/z = 188.1
(highly li-
pophilic)
N
11d
2.55 (1 H, dd, J = 15, 8), 3.00 31.5, 45.2, 62.3, 65.9, C11H13NO
UV = 99.3%
Rf = 0.56
heptane–
EtOAc
(3:1)
O
(1 H, dd, J = 15, 8), 3.19 (1 H, 70.6, 106,6, 118.4,
dt, J = 13, 4), 3.47–3.56 (2 H, 125.4, 128.0, 129.2,
m), 3.61–3.72 (2 H, m), 3.90 150.9
(2 H, dt, J = 10, 4), 6.50 (1 H,
calcd: 176.1070; (tR = 1.21 min),
found: 176.1067
ELS = no signal,
m/z = 176.1
N
d, J = 8), 6.72 (1 H, t, J = 8),
7.10–7.16 (2 H, m)
12
–
–
C17H25N2O3
calcd: 305.1860; (tR = 1.29 min),
found: 305.1867
UV = 99.2%
–
O
O
ELS = 100%
(tR = 1.35 min)
m/z = 305.3
N
N
O
13
DMSO-d6, 80 °C: 1.43 (9 H,
s), 1.81 (2 H, m), 2.37 (3 H, s), 47.1, 55.0, 55.7, 78.3, calcd: 473.2217; tained due to
20.4, 27.6, 27.8, 44.9, C24H32N4O4S
could not be ob-
Rf = 0.35
heptane–
EtOAc
(1:1)
O
N
2.98 (2 H, m), 3.03 (2 H, m), 120.8, 122.5, 126.0,
3.46 (2 H, m), 3.51 (2 H, m), 126.7, 127.2, 129.0,
7.01 (1 H, t, J = 8), 7.12 (1 H, 130.2, 136.3, 142.8,
d, J = 8), 7.29 (1 H, tm, J = 8), 145.8, 153.2, 154.2
7.38 (2 H, d, J = 8), 7.54 (1 H,
found: 473.2207
precipitation
O
N
O
N
S
O
d, J = 8), 7.76 (2 H, d, J = 8),
8.27 (1 H, s), 11.07 (1 H, v br
NH
s)
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

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PAPER
Table 5 Spectral Data of Compounds 9–17, 20, and 21 (continued)
Entry Product
1H NMR (500 MHz, CDCl3): 13C NMR
d, J (Hz)
HRMS:
LC-MS
TLC
(125 MHz, CDCl3): d m/z (M + H+)
14
1.49 (9 H, s), 1.95 (2 H, m),
2.61 (1 H, dd, J = 16, 8), 2.91 33.2, 45.7, 46.1, 46.3, calcd: 289.1991; (tR = 1.52 min),
26.3, 26.9, 28.5, 33.1, C17H24N2O2
UV = 100%
Rf = 0.45
heptane–
O
(1.5 H, m), 3.00 (0.5 H, dd,
J = 13, 10), 3.17 (2 H, m),
3.71 (2 H, m), 3.78–3.95 (1.5 106.5, 117.4, 124.56,
H, m), 4.16 (0.5 H, dm,
46.4, 53.7, 54.0, 65.9, found: 289.1906
66.1, 79.6, 106.3,
ELS = only slight- EtOAc
O
ly detectable and
therefore analyti-
cally unsuitable,
m/z = 289.2
(2:1)
N
124.63, 127.5, 127.6,
128.1, 128.3, 151.5,
N
J = 14), 6.43 (1 H, d, J = 8),
6.64 (1 H, t, J = 7), 7.06 (2 H, 151.7, 155.3, 155.5
m)
15
1.47 (9 H, s), 1.94 (1 H, m),
2.07 (1 H, m), 2.71 (1 H, dd,
J = 16, 10), 2.89 (1 H, m),
3.20 (1 H, m), 3.38–3.77 (6 H, 79.7, 106.9, 107.1,
m), 6.43 (1 H, d, J = 8), 6.67 117.8, 118.0, 124.1,
(1 H, m), 7.01–7.12 (2 H, m) 124.2, 127.5, 127.6,
128.6, 128.8, 152.7,
28.6, 35.6, 36.1, 36.8, C17H24N2O2
36.9, 44.9, 45.8, 46.1, calcd: 289.1911; (tR = 1.49 min),
46.6, 48.4, 64.9, 65.1, found: 289.1903
UV = 100%
Rf = 0.41
heptane–
O
O
ELS = only slight- EtOAc
N
N
ly detectable and
therefore analyti-
cally unsuitable,
m/z = 289.3
(2:1)
155.4
16
1.85 (1 H, m), 2.04 (2 H, m), 30.0, 34.2, 47.1, 48.8, C12H16N2
UV = 100%
Rf = 0.24
EtOAc–
MeOH–
Et3N
NH
2.64 (1 H, dd, J = 16, 9), 2.79 57.0, 67.1, 106.0,
(2 H, m), 3.16 (4 H, m), 3.52 116.9, 124.0, 127.5,
(1 H, ddd, J = 13, 8, 5), 3.88 (1 128.3, 152.5
H, dq, J = 9, 2), 6.37 (1 H, d,
calcd: 189.1386; (tR = 0.48 min)
found: 189.1385
ELSD = 100%
(tR = 0.54 min),
m/z = 189.3
N
(8:4:1)
J = 8), 6.61 (1 H, t, J = 7),
7.01 (1 H, d, J = 7), 7.07 (1 H,
t, J = 8)
17
1.85 (1 H, m), 1.97 (1 H, m), 37.1, 39.4, 48.0, 48.2, C12H16N2
2.20 (1 H, br s), 2.69 (1 H, dd, 50.8, 64.2, 106.2,
J = 16, 9), 2.82 (1 H, ddd, 117.1, 123.9, 127.5,
J = 14, 11, 4), 3.00 (2 H, m), 128.7, 152.7
3.09–3.28 (3 H, m), 3.55 (1 H,
m), 3.90 (1 H, dq, J = 9, 4),
6.36 (1 H, d, J = 8), 6.62 (1 H,
t, J = 7), 7.01 (1 H, d, J = 7),
7.06 (1 H, t, J = 8)
UV = 100%
calcd: 189.1386; (tR = 0.47 min),
Rf = 0.24
EtOAc–
MeOH–
Et3N
H
N
found: 189.1391
ELSD = 100%
(tR = 0.53 min),
m/z = 189.3
(8:4:1)
N
20
3.04 [2 H (cis), m], 3.14 [8 H 52.6 (t), 53.2 (cis),
C22H27N2O2
UV = 99.2%
Rf = 0.33
heptane–
(trans), m], 3.87–3.98 [10 H
(cis/trans), m], 6.76 [2 H
67.8 (cis/trans), 118.1 calcd: 351.2067; (trans = 64.9%,
(trans), 119.1 (cis),
O
found: 351.2067
cis = 22.8%),(trans: EtOAc
tR = 2.05 min, cis: (3:1)
tR = 2.10 min)
ELS = 100%
(trans/cis = 100%)
(trans: tR = 2.11
(trans), s], 6.84 [2 H (trans), t, 122.6 (trans), 123.9
N
J = 7], 7.03 [2 H (trans), d,
J = 8], 7.10 [0.5 H (cis), d,
J = 8], 7.16 [0.5 H (cis), t,
(cis), 125.9 (cis),
126.8 (trans), 127.0
(cis), 128.5 (trans),
N
O
J = 7], 7.18–7.28 [4 H (trans), 128.7 (cis), 130.2
m], 7.32 [0.5 H (cis), t, J = 8], (trans), 131.1 (trans),
7.49 [0.5 H (cis), s], 7.67 [0.5 132.6 (cis), 151.1
min, cis: tR = 2.16
min); trans/cis:
H (cis), d, J = 8]
(cis), 151.5 (trans)
m/z = 351.3
21
1.63–1.72 [5 H (cis/trans), m], 24.9 (c/t), 27.1 (cis/
C24H31N2
UV = 99.6%
Rf = 0.60
heptane–
1.78–1.90 [10 H (cis/trans),
trans), 53.8 (trans), 54.4 calcd: 347.2482; (trans = 72.1%,
m], 3.03 [2 H (cis), m], 3.12 [8 (cis), 118.3 (trans),
found: 347.2476
cis = 23.2%),(trans: EtOAc
tR = 2.27 min, cis: (10:1)
tR = 2.46 min)
H (trans), m], 6.78 [2 H
119.1 (cis), 121.7
(trans), s], 6.83 [2 H (trans), t, (trans), 123.0 (cis),
N
J = 8], 7.07 [2 H (trans), d,
J = 8], 7.12 [0.5 H (cis), d,
J = 8], 7.14 [0.5 H (cis), t,
J = 8], 7.23 [2 H (trans), dt,
J = 15, 2], 7.31 [0.5 H (cis), dt, 131.5 (trans), 132.9
J = 15, 2], 7.37 [2 H (trans), (cis), 152.7 (cis), 153.1
125.7 (cis), 126.5
(trans), 126.8 (cis),
128.1 (trans), 128.3
(cis), 130.0 (trans),
ELS = 100%
(trans: 89.0%,
cis: 11.0%) (trans:
tR = 2.33 min, cis:
tR = 2.52 min)
trans: m/z = 346.9,
cis: m/z = 346.9
N
dd, J = 8, 1], 7.53 [0.5 H (cis), (trans)
s], 7.76 [0.5 H (cis), dm, J = 8]
Synthesis 2010, No. 24, 4287–4299 © Thieme Stuttgart · New York

PAPER
Syntheses of Hexahydropyrazinoindoles
4299
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Acknowledgment
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
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