An Enantio- and Diastereoselective Mannich/Pictet–Spengler Sequence To Form Spiro[piperidine-pyridoindoles] and Application to Library Synthesis

Article abstract of DOI:10.1002/ejoc.201601508

A new tandem strategy based on a Mannich/Pictet–Spengler sequence has been developed and applied to the synthesis of a new small library (14 examples) of privileged compounds based on the spiro[piperidine-pyridoindole] core. The sequence proceeds by a diastereoselective Pictet–Spengler cyclization after condensation of several tryptamine derivatives with three novel piperidin-4-ones containing the fluorinated substituents F, CF₃and SF₅. The piperidin-4-ones were synthesized from readily available starting materials by an enantioselective multi-component organocatalytic Mannich reaction.

Full text of DOI:10.1002/ejoc.201601508

A Journal of
Accepted Article
Title: An Enantio- and Diastereoselective Mannich-Pictet−Spengler
Sequence to Form Spiro[piperidine-pyridoindoles] and Application
to Library Synthesis
Authors: Alejandra Riesco-Dominguez, Nick van der Zwaluw, Daniel
Blanco-Ania, and Floris P. J. T. Rutjes
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using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601508
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601508
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10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
An Enantio- and Diastereoselective Mannich-Pictet−Spengler
Sequence to Form Spiro[piperidine-pyridoindoles] and
Application to Library Synthesis
Alejandra Riesco-Domínguez,[a] Nick van der Zwaluw,[a] Daniel Blanco-Ania[a] and Floris P. J. T.
Rutjes*[a]
Abstract:
A
new tandem strategy based on
a
Mannich
Figure 1. Natural and synthetic active compounds containing the spiro-
piperidine moiety
Pictet−Spengler sequence has been developed and additionally
applied to the synthesis of a new small library (fourteen examples) of
privileged compounds based on the spiro[piperidine-pyridoindole]
core. The sequence proceeds via
a
diastereoselective
In this regard, substituents at the 2- and 6-positions of the
piperidine ring could be vital to modulate biological activity.[4]
Furthermore, it is well documented that the presence of fluorine
atoms can greatly enhance the drug-likeness of small molecules.
Due to properties such as electronegativity, atom size and
lipophilicity, the introduction of fluorine into small molecules can
effectively alter their biological activity and bioavailability in
comparison to the non-fluorinated counterparts.[5,6]
Inspired by previous piperidinone syntheses from our group[7] and
in conjunction with current work on spirocyclic compound libraries
in the framework of the European Lead Factory,[8] we herewith
report an enantio- and diastereoselective reaction sequence for
the synthesis of spiro 2,6-diarylpiperidine-pyridoindole structures
(7) and their utilization to the synthesis of a focused compound
library also containing a variety of fluorine functionalities.
Pictet−Spengler cyclization, after condensation of several tryptamine
derivatives with three novel piperidin-4-ones containing the
fluorinated substituents F, CF3 and SF5. The piperidin-4-ones were
synthesized from readily available starting materials via an
enantioselective multicomponent organocatalytic Mannich reaction.
Introduction
Spirocyclic compounds have been increasingly exploited as lead
compounds in early phases of drug discovery due to their unique
properties, such as the intrinsic three-dimensionality, the
conformational restriction enhancing binding to a target and the
structural patentability.[1] Over the past few years, various
examples of natural compounds and synthetic drugs containing
spiro-fused heterocycles have been discovered possessing
relevant biological activities (Figure 1).[2] In particular, nitrogen-
containing spiro heterocycles have been identified to play a key
role in biological and pharmaceutical processes,[3] rendering this
framework an attractive building block for further research.
Examples include iboluteine, an iboga-type indole alkaloid
isolated from Apocynaceae family, fluspirilene, an antipsychotic
drug used for the treatment of schizophrenia, and fenspiride
hydrochloride, an antitussive drug.
Results and Discussion
From
a retrosynthetic point of view, the spiro[piperidine-
pyridoindole] core of compounds 7 could be generated from
piperidin-4-one 4 and substituted indole derivatives through a
diastereoselective Pictet−Spengler reaction (Scheme 1). The
enantiopure piperidin-4-one 4 could itself be diastereoselectively
obtained from β-amino ketone
3 via an intramolecular
organocatalyzed Mannich reaction. Lastly, amino ketone 3 should
be accessible through an enantioselective organocatalyzed three-
component Mannich reaction of commercially available p-
anisidine, 3,4-dimethoxybenzaldehyde and acetone.
O
F
N
Et
O
NH
N
H
MeO
N
O
N
iboluteine
O
NH2
NH
F
R
R
N
N
fluspirilene
H
HCl
.
O
NH2 HCl
HN
fenspiride hydrochloride
N
H
O
Ar
PictetSpengler
reaction
Mannich
reaction
Ar1
N
H
Ar
Ar1
N
H
Ar
7
3
4
[a]
A. Riesco-Domínguez, N. van der Zwaluw, Dr. D. Blanco-Ania, Prof.
dr. F. P. J. T. Rutjes
Institute for Molecules and Materials, Radboud University
Heyendaalseweg 135, 6525 AJ Nijmegen, the Netherlands
f.rutjes@science.ru.nl
Scheme 1. Retrosynthesis of the spiro[piperidine-4,1′-pyrido[3,4-b]indole
framework
www.soc.science.ru.nl
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10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
The forward synthesis commenced with the preparation of
protected β-amino ketone 1, as previously reported by our
group.[7] Compound 1 was obtained in 61% yield and >99% ee
5 depending on the temperature. In this manner, we observed that
at low temperatures the formation of 4A was favored, whereas at
room temperature imines 5 and 6 were the major compounds in
through
a
multi-component
L-proline-catalyzed Mannich
the reaction mixture. The presence of
5
and 6, 4-
reaction.[7,9] We selected compound 1 for the synthesis of this
library due to the high relevance of the 3,4-dimethoxyphenyl
group in nature and active drugs.[10] From compound 1, two
possible synthetic routes for the synthesis of 2,6-disubstituted
piperidin-4-ones were envisioned (Scheme 2). Early efforts were
focused on the synthesis of p-methoxyphenyl (PMP)-protected
piperidinones 2 in a one-pot procedure via a Mannich cyclization.
fluorobenzaldehyde and 3,4-dimethoxybenzaldehyde confirmed
the existence of the equilibrium between compounds 4A, 5 and 6
(Scheme 3).
Table 1. Conditions for the synthesis of 4A
Entry
Reagent (equiv)
Et3N (1)
Solvent
Et3N/1,2-DCE
THF
t (°C)
21−60
21–70
40
Ratio 5/4A
3.3:1
2:1
1
2
3
4
5
6
O
1) H5IO6, H2SO4
PMP
O
NH2.HCl
Ar
RCHO
O
HN
KOt-Bu (0.2)
Et3N (0.5)
1:1 H2O/MeCN
2) HCl/AcOEt
46%
Ar
R
N
Ar
1,2-DCE
1,2-DCE
CH2Cl2
3.3:1
1.7:1
0.3:1
0:1
PMP
2
1
3
CSA (1.2)
60
ee >99%
ArCHO
L
-proline
TFA (1.2)
21
Et3N, Na2SO4
EtOH, 21 °C
220 min
Et3N
ArCHO
R
L-proline (0.2)
MeCN
21
O
O
O
O
Table 1
O
N
N
H
Ar
Ar = C6H33,4-(OMe)2
Ar1 = C6H44-F
Ar
Ar1
N
H
Ar
Ar1
N
Ar
Ar1
N
Ar
R
5
4A C

4A
: R = F (75%)
4B: R = CF3 (38%)
4C
5
4A
6
Scheme 3. Equilibrium between 4a and imines 5 and 6
: R = SF5 (28%)
Scheme 2. Synthetic route for the piperidin-4-one synthesis
Following the optimization of the two-step synthesis of 4A, a one-
pot procedure was investigated in order to obtain the cyclized
product directly from 3. Thus, amine hydrochloride 3 was treated
with Et3N and anhydrous Na2SO4 in the presence of catalytic
This approach involved a challenging scaffold synthesis owing to
the high level of steric hindrance as a result of the three
contiguous substituents.[11] In our efforts to synthesize product 2,
protected amine 1 was reacted with several aldehydes, in the
presence of various catalysts and under a range of temperatures
(see Supporting Information). Unfortunately, none of these
conditions led to the desired N-protected piperidin-4-one 2. Due
to these difficulties, we then chose to synthesize the unprotected
scaffold with reduced steric hindrance (4, Scheme 2). To this end,
the deprotection of N-PMP amine 1 was carried out employing
H5IO6 under acidic conditions to afford the corresponding product
3 in 46% yield.[12] Subsequently, the free amino ketone 3 was
treated with triethylamine and 4-fluorobenzaldehyde to afford
amounts of L-proline, to afford the cyclized product 4A in 75%
yield. In the same way, two additional cis-2,6-diarylpiperidin-4-
ones 4B and 4C, containing –CF3 and –SF5 groups, were
synthesized in 38 and 28% yield, respectively.[13] A clarification of
the mechanism for this diastereoselective cyclization via an
intramolecular Mannich reaction is depicted in Scheme 4. Firstly,
the iminium ion species formed by reaction of amine 3 and the
corresponding aldehyde is positioned in the chair conformation
with the lowest energy, in which the two hydrogens are placed in
pseudo-axial positions. Secondly, the enamine, formed by L-
proline and the ketone, attacks the iminium ion giving the final
piperidin-4-one with a cis-configuration, having the two bulky aryl
groups in equatorial positions. The cis-stereochemistry of the
products was confirmed by NOESY studies.
1
imine 5 (R = F). H NMR data of the reaction showed not only
imine formation, but also a side product, which could not be
characterized, and the cyclized product 4A. Several reaction
conditions were investigated to obtain full conversion of imine 5
into the desired product 4A (Table 1). The conditions previously
reported by us[7] for these types of cyclizations were unsuccessful
(entry 4). After further investigation, we were pleased to find that
full conversion to the cyclized product 4A could be achieved when
O
O
H
H
O
H
N
O
H
N
N
H
H
Ar1
Ar1
Ar1
HN
Ar
Ar
Ar
H
using L-proline as the catalyst.
Scheme 4. Mechanism for the diastereoselective cyclization
In addition, 1H NMR analysis of the reaction crudes showed a slow
equilibrium between imine 5 and cyclized product 4A under
certain conditions, which yielded different ratios between 4A and
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10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
With the core scaffolds 4A−C in hand, we focused on the
development of a new library of spiro compounds based on
derivatization of the ketone via the classic Pictet−Spengler
reaction.[14] Initially, 3-methoxy-, 3,4-dimethoxy-, and 3-
fluorophenethylamine were selected as test substrates (Scheme
5).[15]
washing step with NH4OH (25% in water) was performed in
order to remove residual triethylammonium salts.
To explain the diastereoselectivity we propose a rationale
that is in accordance with the known reactivity of
cyclohexanones towards nucleophiles.[17]
Table 2. Scope of the Pictet−Spengler cyclization
Ar2
NH2
R1
R2
R
O
R
H2N
N
HN
TFA
or
HN
4A C

N
H
N
R2
H
Ti(OiPr)4
N
H
Ar
TfOH
Ar1
N
Ar
R1
Ar1
Method A or B
N
H
Ar
N
Ar
H
H
X
3780%
R1 = OMe, R2 = H
4AC
X
R
1 = F, R2 = H
R1 = OMe, R2 = OMe
Scheme 5. Reaction with 2-phenylethyl amines
X =
F
(4A)
4B
7Aa
d

CF3
SF5 (4C)
(
)
7Bad
Ar = C6H33,4-(OMe) 2
X = CF3
7Ca
d

Test reactions without catalyst showed difficulties to reach
full conversion to the corresponding imines. However, after
thorough investigation (see: Supporting Information), the
reaction was carried out in the presence of Ti(OiPr)4, which
led to complete imine formation. When performing the
subsequent Pictet−Spengler reaction using both TFA and
TfOH as promoters, however, no cyclized product was
observed in any of these cases.
X = SF5
X = F
HN
HN
N
HN
N
H
N
H
H
Ar1
Ar1
Ar1
N
H
Ar
N
H
Ar
N
Ar
H
7Aa
7Ba
7Ca
(A)
(A)
(A)
47%
52%
41%
OMe
OMe
OMe
Due to these preliminary results, the more reactive
tryptamine was chosen as the model substrate to start with
HN
HN
HN
N
H
N
H
N
H
(Table 2). The reactions of 4A−C with tryptamine were
Ar1
Ar1
Ar1
N
H
7Ab
Ar
N
H
7Bb
Ar
N
H
Ar
carried out in dichloromethane in the presence of molecular
sieves 4Å, which smoothly afforded the imine intermediate.
Addition of TFA at 0 °C then led to the diastereoselective
7Cb
(B)
56%
(B)
(B)
74%
77%
OH
OH
OH
formation of compounds 7Aa−Ca in moderate yields (Table
HN
HN
HN
2, method A).
N
H
N
H
N
H
Ar1
Ar1
Ar1
N
H
Ar
N
H
Ar
N
H
Ar
Further screening of reaction conditions (Table 7, Supporting
Information) led us to conclude that optimal conversion to the
imine could be achieved by reaction of the selected amine
with Ti(OiPr)4 (1.3 equiv), in the presence of Et3N (1.2 equiv,
only for substrates delivered as hydrochloric salt) in THF at
room temperature. As previously stated, addition of TFA at 0
°C then successfully delivered the desired Pictet−Spengler
cyclization products. It is important to note that in all cases
initially a mixture of the piperidin-4-one and imine was
formed, that could not be driven to full conversion into the
7Ac
80%
7Bc
74%
7Cc
(B)
76%
(B)
(B)
F
F
F
HN
HN
HN
N
H
N
H
N
H
Ar1
Ar1
Ar1
N
H
Ar
N
H
Ar
N
H
Ar
7Ad
74%
7Bd
37%
7Cd
(B)
52%
(B)
(B)
[a] Method A: reaction carried out in CH2Cl2 and in the presence of molecular
sieves, followed by addition of TFA. Method B: Ti(OiPr)4 (1.3 equiv) in THF
followed by addition of TFA. [b] Yield given based on recovered starting material
(BORSM) for compounds 7Ab−Cd.
imine. Following these conditions, compounds 7Ab−Cd, with
an average yield of 67%, were synthesized. It is worth noting
that TfOH was used as the acid in the synthesis of
compounds 7Ad−Cd. In these instances, the use of TFA in
The cyclization presumably proceeds through a chairlike
transition state, in which the indole ring exclusively attacks
from the equatorial direction, which is the least hindered side
(Scheme 6). 2D NMR studies (NOESY) confirmed the
different amounts (2.2, 4.0 and 7.0 equiv) was not sufficient
for the cyclization to take place.[16] The resulting molecules,
containing three N-H groups, are difficult to purify through
standard silica gel column chromatography. For this reason,
isolation was performed by inactivation of the silica with Et3N.
Moreover, after column chromatography, an additional
stereochemistry of products 7Aa−Cd.
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10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
H
An enantio- and diastereoselective route for the synthesis of a
new class of spiro piperidine structures via a Mannich and
Pictet−Spengler reaction sequence has been developed. Three
new cis-2,6-disubstituted piperidin-4-one analogues containing
fluorine functionalities have been synthesized and incorporated
into the synthetic route. Finally, this methodology has been
implemented to the synthesis of a compound library consisting of
a total of 14 examples all being single stereoisomers. Currently
the biological properties of these compounds are being evaluated
in various assays.
H
N
H
Ar1
HN
Ar
N
H
O
H
H
H
Ar1
HN
Ar
N
H
H
HN
Ar1
HN
Ar
Scheme 6. Rationale for the diastereoselectivity of the Pictet−Spengler
cyclization
To extend this library of compounds and to further expand
the scope of the synthetic strategy, we synthesized
compound 12 from indole-2-carbaldehyde, and compound
13 using a smaller pyrrole-based heterocycle (Scheme 8).
Firstly, the Pictet−Spengler precursors
were synthesized from commercially available indole-2-
carbaldehyde and pyrrole-2-carbaldehyde via Henry
reaction with nitromethane,[18] followed by reduction of the
nitro alkenes and 10, using LiAlH4 in Et2O for the synthesis
of
and a mixture of NaBH4/NiCl2 for the synthesis of 11 [19]
9 and 11 (Scheme 7)
Experimental Section
a
General information: Reagents were obtained from commercial suppliers
and were used without purification. Standard syringe techniques were
applied for the transfer of dry solvents and air- or moisture-sensitive
reagents. Reactions were followed, and RF values were obtained, using
thin layer chromatography (TLC) on silica gel-coated plates (Merck 60
F254) with the indicated solvent mixture. Detection was performed with UV
light, and/or by charring at ca. 150 °C after dipping into a solution of either
2% anisaldehyde in ethanol/H2SO4, (NH4)6Mo7O24·4H2O (25 g/L) or
ninhydrin. IR spectra were recorded on an IR-ATR Bruker TENSOR 27
spectrometer. High-resolution mass spectra were recorded on a JEOL
AccuTOF (ESI) or a MAT900 (EI, CI, and ESI). Optical rotations were
determined with a Perkin Elmer 241 polarimeter. NMR spectra were
recorded at 298 K on a Varian Inova 400 (400 MHz), Bruker Avance III 400
MHz or Bruker Avance III 500 MHz spectrometer in the solvent indicated.
Chemical shifts are given in parts per million (ppm) with respect to
tetramethylsilane (0.00 ppm), or CHD2OD (3.31 ppm) as internal standard
for 1H NMR; and CDCl3 (77.16 ppm), or CD3OD (49.00 ppm) as internal
8
9
.
H2N
MeNO2
NaOH
O
H
NO2
LiAlH4
THF
N
N
MeOH
N
H
H
H
85%
70%
8
9
H2N
MeNO2, NaOAc
MeNH2.HCl
O
NO2
1) NaBH4, MeOH
N
N
H
H
MeOH
2) NiCl2.6H2O
NaBH4
N
H
H
35%
10
11
standard for 13C NMR. Coupling constants are reported as
J values in hertz
Scheme 7. Henry reaction and subsequent reduction for the synthesis of
amines and 11
(Hz). 1H NMR data are reported as follows: chemical shift (ppm),
multiplicity (s = singlet, d = doublet, dd = doublet of doublets, dt = doublet
of triplets, ddd = doublet of doublet of doublets, t = triplet, m = multiplet, b
= broad), coupling constants (Hz), and integration. Compounds were fully
characterized by 1H and 13C spectra and 2D gDQCOSY, gHSQC, gHMBC
and NOESY spectra. Column or flash chromatography was carried out
using ACROS silica gel (0.035–0.070 mm, and 60 Å pore diameter).
9
Finally, precursors
9 and 11 were subjected to the previously
optimized conditions in the presence of piperidin-4-one 4A to
completely diastereoselectively afford the corresponding
Pictet−Spengler products 12 and 13, in 52% yield in both
cases (Scheme 8).
(4S)-4-(3,4-Dimethoxyphenyl)-4-[(4-methoxyphenyl)amino]butan-2-
one 1.
3,4-Dimethoxybenzaldehyde (10.5 g, 63.2 mmol), 4-anisidine (7.78 g, 63.2
mmol) and L-proline (1.5 g, 12.64 mmol) were added to a mixture of DMSO
H
N
NH2
(45 mL) and acetone (180 mL). The resulting reaction mixture was stirred
for 23 h. The reaction mixture was quenched with 100 mL potassium
phosphate buffer (0.5 M, pH 7, 100 mL). Subsequently, a total of 150 mL
of potassium phosphate buffer (0.5 M, pH 7) was added in portions. The
reaction mixture was cooled to 0 °C and the product started to precipitate.
After stirring for 20 min, the suspension was filtered off and the residue
was washed with water (0 °C, 50 mL). The product was dried in vacuo.
The product was obtained as an off-white powder (19 g). The product was
recrystallized from EtOAc and obtained as white crystals (12.7 g, 38.5
mmol). 1H NMR [400 MHz, δ (ppm), CDCl3]: 6.91–6.86 (m, 2 H), 6.83–6.77
HN
52%
N
H
Ar1
N
H
Ar
i
4A
1) , Ti(O Pr)4
21 °C, 6 h
9
12
2) TFA (2.2 equiv)
021 °C, 6 h
H
N
NH2
HN
(m, 1 H), 6.72–6.66 (m, 2 H), 6.55–6.48 (m, 2 H), 4.69 (t,
J = 6.5 Hz, 1 H),
N
H
3.84 (s, 6 H), 3.69 (s, 3 H), 2.88 (d,
J
= 6.5 Hz, 2 H), 2.10 (s, 3 H). 13C
52%
Ar1
N
H
Ar
NMR [101 MHz, δ (ppm), CDCl3]: 207.5, 152.5, 149.3, 148.2, 141.1, 135.5,
118.3, 115.5, 114.8, 111.3, 109.6, 56.0, 55.9, 55.7, 55.3, 51.5, 30.9. FTIR
[ꢀ̅
(cm−1)]: 3385, 1708, 1510, 1253, 1235, 1139, 1027, 821. HRMS [ESI
(m/z)] calcd for C38H46N2O8Na (M + Na)+: 352.15248, found: 352.15248.
11
13
Scheme 8. Synthesis of spiro compounds 12 and 13
HPLC: ee >99%, Chiralpak AD-H (250 × 4.6 mm), flow: 1.0 mL/min,
heptane/propan-2-ol 80:20, retention time:
1: 18.7 min, ent-(1): 15.7 min.
Mp: 147–151 °C. [α]D20 +2.4 (
c
0.41, CHCl3). Yield: 61%.
Conclusions
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10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
(4S)-4-Amino-4-(3,4-dimethoxyphenyl)butan-2-one hydrochloride 3.
According to the general procedure, the reaction of amino ketone
Aqueous H2SO4 (1 M, 12.1 mL, 12.1 mmol) and H5IO6 (2.87 g, 12.6 mmol)
hydrochloride
orange solid. 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.66–7.56 (m, 4 H),
7.03–6.97 (m, 2 H), 6.85 (d, = 8.1 Hz, 1 H), 4.14 (dd; = 8.6, 7.0 Hz; 1
H), 4.03 (dd; = 11.0, 3.6 Hz; 1 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 2.68–2.53
(m, 4 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 207.5, 149.4, 148.9, 146.7
(q, = 1.2 Hz), 135.2, 130.3 (q, = 32.5 Hz), 127.1 (2×), 125.9 (q, = 3.7
Hz, 2×), 122.7 ( F3, indirect observation), 118.8, 111.3, 109.7, 61.1, 60.8,
56.1, 50.6, 50.3. HRMS [ESI (m/z)] calcd for (C20H21F3NO3 + H)+
3 (2.5 g, 9.63 mmol) afforded 4B (1.4 g, 3.70 mmol) as an
were added to
a
solution of (4
S)-4-(3,4-dimethoxyphenyl)-4-(4-
methoxyphenylamino)-butan-2-one (1) (4 g, 12.1 mmol) in MeCN/H2O
J
J
(120 mL, 1:1). The mixture was stirred for 1.5 h at room temperature. The
mixture was washed with CH2Cl2 (3 × 60 mL) and the resulting aqueous
phase was diluted with CH2Cl2 (60 mL). The pH of the aqueous layer was
brought to 9 via addition of 5 M aqueous KOH under vigorous stirring. The
layers were separated and the aqueous layer was extracted with CH2Cl2
(3 × 60 mL). The combined organic layers were dried over Na2SO4 and
HCl/EtOAc (9.5 mL) was added. The resulting mixture was concentrated
until the product precipitated. The product was isolated by filtration and
J
J
J
J
C
=
380.14735, found 380.14778 (|Δ| = 1.13 ppm).
RF: 0.60 (heptane/EtOAc,
1:1). Yield: 38%.
dried in vacuo to afford
NMR [400 MHz, δ (ppm), CD3OD]: 7.03 (d,
2 H), 4.64 (t, = 6.8 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s, 3 H), 3.20 (d,
Hz, 2 H), 2.20 (s, 3 H). 13C NMR [101 MHz, δ (ppm), CD3OD]: 207.5, 151.2,
150.9, 130.3, 121.1, 113.1, 112.1, 56.7, 56.5, 52.2, 47.6, 30.1. FTIR
(cm−1)]: 3395, 2936, 1709, 1515, 1264, 1143, 1018. HRMS [ESI (m/z)]
calcd for (C12H18NO3 + H)+ = 224.12867, found 224.13151 (|Δ| = 12.69
ppm). Yield: 46%.
3
(1.44 g, 5.54 mmol) as a pale yellow solid. 1H
= 1.8 Hz, 1 H), 7.00–6.96 (m,
= 6.8
(2S,6R)-2-(3,4-Dimethoxyphenyl)-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]piperidin-4-one 4C.
J
J
J
According to the general procedure, the reaction of amino ketone
hydrochloride (2.2 g, 8.61 mmol) afforded 4C (1.07 g, 2.45 mmol) as a
yellow solid. 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.79–7.74 (m, 2 H),
7.61–7.56 (m, 2 H), 7.03–6.96 (m, 2 H), 6.86 (d, = 7.9 Hz, 1 H), 4.17–
4.12 (dd; = 8.3, 6.5 Hz, 1 H), 4.04 (dd; = 11.0, 3.3 Hz; 1 H), 3.92 (s, 3
3
[ꢀ̅
J
J
J
H), 3.88 (s, 3 H), 2.69–2.50 (m, 4 H). 13C NMR [101 MHz, δ (ppm), CDCl3]:
207.2, 153.7 (indirect observation), 149.4, 148.9, 146.6–146.5 (m), 135.1,
127.1 (2×), 126.7–126.5 (2×), 118.8, 111.3, 109.7, 61.1, 60.5, 56.1, 50.6,
(3S)-4-(3,4-Dimethoxyphenyl)-4-[(E)-(4-
fluorobenzylidene)amino]butan-2-one 5.
Triethylamine (0.44 mL, 3.18 mmol) and 4-fluorobenzaldehyde (0.34 mL,
50.2. FTIR [ꢀ̅
(cm−1)]: 1714, 1517, 829. HRMS [ESI (m/z)] calcd for
(C19H21F5NO3S + H)+ = 438.11623, found 438.11611 (|Δ| = 0.27 ppm). RF
0.60 (heptane/EtOAc, 1:1). Yield: 28%.
3.18 mmol) were added to a solution of
3 (1.65 g, 6.36 mmol) in dry 1,2-
:
dichloroethane (115 mL). The mixture was concentrated in vacuo. Dry 1,2-
dichloroethane (110 mL) was added to the residue and the mixture was
concentrated again in vacuo. Dry 1,2-dichloroethane (110 mL) and
triethylamine (0.44 mL, 3.18 mmol) were added to the resulting mixture
General procedure for the synthesis of compounds 7Aa−Ca
A mixture of piperidin-4-one 4A−C (1.00 equiv) and tryptamine (1.00 equiv
and was concentrated in vacuo. The mixture was dissolved in dry 1,2-
for the synthesis of 7Aa and 7Ca and 1.60 equiv for the synthesis of 7Ba
)
dichloroethane (113 mL) and triethylamine (0.44 mL, 3.18 mmol) and 4-
fluorobenzaldehyde (0.03 mL, 0.32 mmol) were added. The resulting
mixture was concentrated in vacuo to afford the crude imine. 1H NMR [400
MHz, δ (ppm), CD3OD]: 8.33 (s, 1 H), 7.77–7.70 (m, 2 H), 7.10–7.04 (m, 2
dissolved in CH2Cl2 was stirred at 21 °C under inert atmosphere for the
time indicated in each case. Then, the solution was cool down to 0 °C, TFA
(2.2 equiv) was added and the reaction mixture was warmed up to 21 °C
and stirred for the time indicated in each case. The reaction was quenched
with a saturated NaHCO3 solution and the aqueous layer was extracted
with CH2Cl2 (three times). The combined organic layers were washed with
brine, dried over Na2SO4, filtered off and concentrated in vacuo.
H), 6.98–6.93 (m, 2 H), 6.85–6.82 (m, 1 H), 4.85 (dd;
J
= 8.9, 4.2 Hz; 1 H),
3.90 (s, 3 H), 3.86 (s, 3 H), 3.21 (dd;
16.3, 4.2 Hz; 1 H), 2.11 (s, 3 H).
J
= 16.3, 8.9 Hz; 1 H), 2.89 (dd;
J =
General procedure for the syntheses of compounds 4A–C.
A mixture of (1.00 equiv), triethylamine (1.00 equiv), the corresponding
aldehyde (1.00 equiv), -proline (0.20 equiv) and anhydrous Na2SO4 (0.28
3
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-fluorophenyl)-2′,3′,4′,9′-
tetrahydrospiro[piperidine-4,1′-pyrido[3,4-b]indole] 7Aa.
L
equiv) in EtOH was stirred at room temperature under inert atmosphere
for 3–4 h. Then, the mixture was quenched with NH4Cl (75 mL) and the
aqueous layer was extracted with EtOAc (3 × 200 mL). The organic layers
were combined and extracted with a solution 0.1 M HCl (3 × 200 mL). The
combined extracted aqueous layers were washed with EtOAc and they
were neutralized with 1.0 M aqueous sodium hydroxide to pH 7–8. The
aqueous layer was extracted with EtOAc (3 × 200 mL), saturated brine
solution was added and the organic layers were dried with anhydrous
Na2SO4, filtered off and concentrated under reduced pressure to afford
According to the general procedure, the reaction of piperidin-4-one 4A
(51.5 mg, 0.16 mmol) was stirred overnight in 2.5 mL of CH2Cl2 for the
imine formation. TFA (27 µl, 0.34 mmol) in CH2Cl2 (0.14 mL) was added
and the reaction was stirred for 48 h. The crude mixture was purified by
column chromatography (heptane/EtOAc 4:1 → EtOAc) and ion exchange
column chromatography (ISOLUTE SCX-2) to afford compound 7Aa (38.5
mg, 0.08 mmol) as a yellow solid. 1H NMR [500 MHz, δ (ppm), CDCl3):
7.86 (bs, 1 H), 7.49–7.44 (m, 3 H), 7.29 (d,
= 8.1, 7.1, 1.3 Hz; 1 H), 7.10–7.06 (m, 1 H), 7.06–6.98 (m, 4 H), 6.83 (d,
= 8.2 Hz, 1 H), 4.50–4.43 (m, 1 H), 4.40 (dd;
(s, 3 H), 3.86 (s, 3 H), 3.26 (t, = 5.7 Hz, 2 H), 2.75 (t,
2.08–1.93 (m, 4 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 162.1 (d,
244.7 Hz), 149.1, 148.4, 140.5, 139.4, 137.3, 135.6, 128.4 (d, = 7.9 Hz,
2×), 127.6, 121.9, 119.5, 119.0, 118.3, 115.4 (d, = 21.1 Hz, 2×), 111.3,
110.9, 110.2, 108.9, 56.6, 56.3, 56.1, 56.1, 53.3, 45.1, 45.1, 39.4, 23.3.
FTIR
(cm‒1)]: 3364, 2933, 2835, 1603, 1507, 1223, 1136, 1025, 804.
HRMS [ESI (m/z)] calcd for (C29H30FN3O2 + H)+ = 472.23985, found
472.24003 (|Δ| = 0.4 ppm). F: 0.43 (EtOAc). Yield: 52%.
J
= 8.0 Hz, 1 H), 7.13 (ddd;
J
J
compounds 4A–C.
J
= 10.9, 3.1 Hz; 1 H), 3.92
= 5.7 Hz, 2 H),
(2S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-fluorophenyl)piperidin-4-one
4A.
According to the general procedure, the reaction of amino ketone
J
J
J
=
J
hydrochloride
orange solid. 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.48–7.41 (m, 2 H),
7.08–7.02 (m, 2 H), 7.02–6.96 (m, 2 H), 6.85 (d, = 8.1 Hz, 1 H), 4.05 (dd;
= 10.2, 4.5 Hz; 1 H), 4.01 (dd; = 10.9, 3.7 Hz; 1 H), 3.92 (s, 3 H), 3.88
(s, 3 H), 2.66–2.50 (m, 4 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 208.1,
162.4 (d, = 246.2 Hz), 149.3, 148.8, 138.6 (d, = 3.1 Hz), 135.4, 128.3
(d, = 8.1 Hz, 2×), 118.8, 115.7 (d, = 21.3 Hz, 2×), 111.3, 109.7, 61.1,
60.6, 56.1, 56.1, 50.7, 50.6. FTIR
(cm−1)]: 3305, 1710, 1509, 1264, 1232.
HRMS [ESI (m/z)] calcd for (C19H20FNO3 + H)+ = 330.15055, found
330.15190 (|Δ| = 4.11 ppm). F: 0.50 (heptane/EtOAc, 1:1). Yield: 75%.
3 (2.5 g, 9.63 mmol) afforded 4A (2.4 g, 7.28 mmol) as an
J
J
[ꢀ̅
J
J
R
J
J
J
J
[ꢀ̅
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-[4-(trifluoromethyl)phenyl]-
2′,3′,4′,9′-tetrahydrospiro-[piperidine-4,1′-pyrido[3,4-b]indole] 7Ba.
R
According to the general procedure, the reaction of piperidin-4-one 4B
(100 mg, 0.26 mmol) was stirred for 5 h, in the presence of molecular
sieves 4 Å, in CH2Cl2 (5 mL) for the imine formation. TFA (44 µl, 0.57
mmol) in CH2Cl2 (0.25 mL) was added and the reaction was stirred for 24
(2S,6R)-2-(3,4-Dimethoxyphenyl)-6-[4-
(trifluoromethyl)phenyl]piperidin-4-one 4B.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
h. The crude was purified by two columns of chromatography
(heptane/EtOAc 3:1 → EtOAc/MeOH 10:1) and (heptane/EtOAc 2:3 →
EtOAc/MeOH 10:1) to afford compound 7Ba (56.6 mg, 0.11 mmol). 1H
NMR [400 MHz, δ (ppm), CDCl3]: 7.84 (bs, 1 H), 7.67–7.55 (m, 4 H), 7.47
108.9, 108.7, 95.1, 56.6, 56.3, 56.1 (2×), 55.9, 53.2, 45.1, 45.0, 39.4, 23.3.
FTIR
HRMS [ESI (m/z)] calcd for (C30H32FN3O3 + H)+ = 502.25093, found
[ꢀ̅
(cm‒1)]: 3366, 2931, 2835, 1628, 1507, 1223, 1153, 1025, 764.
502.25059 (|Δ| = 0.7 ppm).
RF: 0.30 (heptane/EtOAc/Et3N, 4:4:1). Yield
(d,
1.3 Hz; 1 H), 7.10–7.01 (m, 3 H), 6.84 (d,
10.5, 3.5 Hz; 1 H), 4.42 (dd; = 10.4, 3.4 Hz; 1 H), 3.92 (s, 3 H), 3.87 (s,
3 H), 3.34–3.20 (m, 2 H), 2.75 (t,
= 5.7 Hz, 2 H), 2.08–1.90 (m, 4 H). 13
NMR [101 MHz, δ (ppm), CDCl3]: 149.1, 149.0 (q, = 1.0 Hz), 148.4,
139.2, 137.3, 135.6, 129.6 (q, = 32.3 Hz), 127.5, 127.2 (2×), 125.6 (q,
= 3.7 Hz, 2×), 124.3 (q, = 272.2 Hz, F3), 122.0, 119.6, 118.9, 118.4,
111.3, 110.9, 110.1, 109.0, 56.6, 56.4, 56.1 (2×), 53.2, 45.2, 45.0, 39.4,
23.3. FTIR
(cm‒1)]: 3367, 2931, 2838, 1618, 1516, 1261, 1118, 1017,
806. HRMS [ESI (m/z)] calcd for (C30H30F3N3O2 + H)+ = 522.23708, found
522.23684 (|Δ| = 0.5 ppm). F: 0.22 (heptane/EtOAc, 2:3). Yield: 41%.
J
= 7.7 Hz, 1 H), 7.27 (dt;
J
= 8.0, 0.9 Hz; 1 H), 7.13 (ddd;
J = 8.1, 7.1,
(BORSM): 74%.
J
= 8.1 Hz, 1 H), 4.54 (dd;
J =
J
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-7′-methoxy-6-[4-
(trifluoromethyl)phenyl]-2′,3′,4′,9′-tetrahydro-spiro[piperidine-4,1′-
pyrido[3,4-b]indole] 7Bb.
According to the general procedure, the reaction of piperidin-4-one 4B (50
mg, 0.132 mmol) afforded 7Bb (56.0 mg, 0.102 mmol). 1H NMR [500 MHz,
J
C
J
J
J
J
C
δ (ppm), CDCl3]: 7.69 (bs, 1 H), 7.64–7.55 (m, 4 H), 7.34 (d,
H), 7.06–7.01 (m, 2 H), 6.84 (d, = 8.2 Hz, 1 H), 6.80 (d, = 2.2 Hz, 1 H),
6.75 (dd; = 8.6, 2.2 Hz; 1 H), 4.53 (dd; = 11.1, 2.3 Hz; 1 H), 4.41 (dd;
= 10.3, 3.5 Hz; 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.81 (s, 3 H), 3.28–3.22
(m, 2 H), 2.71 (t,
= 5.6 Hz, 2 H), 2.05–1.89 (m, 4 H), 1.62 (bs, 2 H). 13
NMR [101 MHz, δ (ppm), CDCl3]: 156.4, 149.1, 149.0, 148.4, 138.1, 137.3,
136.4, 129.6 (q, = 32.3 Hz), 127.2 (2×), 125.5 (q, = 3.7 Hz, 2×), 124.3
(q, = 272.0 Hz, F3), 122.0, 118.9, 118.8, 111.3, 110.2, 108.8, 108.7,
J = 8.6 Hz, 1
[ꢀ̅
J
J
J
J
J
R
J
C
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]-2′,3′,4′,9′-tetrahydro-spiro[piperidine-4,1′-
pyrido[3,4-b]indole] 7Ca.
According to the general procedure, the reaction of piperidin-4-one 4C (40
mg, 0.09 mmol) was stirred for 5 h, in the presence of molecular sieves 4
Å, in CH2Cl2 (1.5 mL) for the imine formation. TFA (20 µl, 0.20 mmol) was
added and the reaction was stirred overnight. The crude was purified by
column chromatography (heptane/EtOAc 4:1→ EtOAc) to afford
compound 7Ca (24.4 mg, 0.042 mmol). 1H NMR [400 MHz, δ (ppm),
J
J
J
C
95.2, 56.6, 56.4, 56.1 (2×), 55.9, 53.2, 45.1, 44.9, 39.4, 23.3. FTIR [ꢀ̅
(cm‒
1)]: 3369, 2926, 2835, 1619, 1515, 1260, 1097, 1066, 797. HRMS [ESI
(m/z)] calcd for (C31H32F3N3O3 + H)+ = 552.24737, found 552.24740 (|Δ| =
0.1 ppm). RF: 0.32 (heptane/EtOAc/Et3N, 4:4:1). Yield: 77%.
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-7′-methoxy-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]-2′,3′,4′,9′-tetrahydrospiro[piperidine-4,1′-pyrido[3,4-
b]indole] 7Cb.
CDCl3]: 7.89 (s, 1 H), 7.75–7.69 (m, 2 H), 7.62–7.57 (m, 2 H), 7.48 (d,
7.7 Hz, 1 H), 7.27 (d, = 7.4 Hz, 1 H), 7.14 (t, = 7.5 Hz, 1 H), 7.11–7.01
(m, 3 H), 6.85 (d, = 8.1 Hz, 1 H), 4.55 (dd; = 10.3, 2.9 Hz; 1 H), 4.43
(dd; = 10.6, 2.7 Hz; 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.37–3.17 (m, 2 H),
2.76 (t,
= 5.5 Hz, 2 H), 2.12–1.91 (m, 4 H), 1.86 (bs, 1 H). 13C NMR [101
MHz, δ (ppm), CDCl3]: 152.9 (quint, = 17.1 Hz), 149.1, 148.8, 148.4,
139.1, 137.1, 135.6, 127.5, 127.1 (2×), 126.3 (quint, = 4.6 Hz, 2×), 122.0,
119.5, 118.9, 118.4, 111.3, 110.9, 110.1, 109.0, 56.3 (2×), 56.1, 56.1, 53.2,
45.1, 44.8, 39.4, 23.2. FTIR
(cm‒1)]: 3373, 2934, 2838, 1592, 1515,
1232, 1138, 1027, 840. HRMS [ESI (m/z)] calcd for (C29H31F5N3O2S + H)+
J =
J
J
According to the general procedure, the reaction of piperidin-4-one 4C (50
mg, 0.114 mmol) afforded 7Cb (18.1 mg, 0.030 mmol). In this case, after
following the general procedure, the crude was purified by a second
column chromatography (heptane/EtOAc 2:1 → EtOAc/MeOH 10:1) and
an ion exchange column chromatography (ISOLUTE SCX-2). The dried
product was dissolved again in CH2Cl2 (5 mL) and washed with aqueous
NH4OH (5 mL). The combined aqueous layers were extracted with CH2Cl2
(3 × 5 mL) and organic layers were washed with brine, dried over Na2SO4,
filtered off and dried in vacuo. 1H NMR [400 MHz, δ (ppm), CDCl3]: 7.73–
J
J
J
J
J
J
[ꢀ̅
= 580.20571, found 580.20471 (|Δ| = 1.73 ppm). RF: 0.34 (heptane/EtOAc,
2:3). Yield: 47%.
7.70 (m, 2 H), 7.68 (bs, 1 H), 7.61–7.57 (m, 2 H), 7.34 (d,
7.04 (d, = 2.0 Hz, 1 H), 7.02 (dd; = 8.2, 2.0 Hz; 1 H), 6.84 (d,
Hz, 1 H), 6.79 (d, = 2.2 Hz, 1 H), 6.75 (dd; = 8.6, 2.2 Hz; 1 H), 4.53 (dd;
= 11.1, 2.2 Hz; 1 H), 4.41 (dd; = 10.4, 3.5 Hz; 1 H), 3.92 (s, 3 H), 3.87
(s, 3 H), 3.81 (s, 3 H), 3.28–3.21 (m, 2 H), 2.71 (t, = 5.7 Hz, 2 H), 2.04–
1.87 (m, 4 H), 1.62 (bs, 2 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 156.5,
152.9 (quint, = 17.6 Hz), 149.1, 148.8, 148.5, 137.9, 137.1, 136.4, 127.1
(2×), 126.3 (quint, = 4.4 Hz, 2×), 122.0, 118.9, 118.9, 111.3, 110.1, 108.9,
108.8, 95.2, 56.3 (2×), 56.1, 56.1, 55.9, 53.2, 45.1, 44.8, 39.4, 23.3. FTIR
(cm‒1)]: 3371, 2938, 2837, 1629, 1516, 1262, 1154, 1027, 823, 729.
HRMS [ESI (m/z)] calcd for (C30H32F5N3O3S + H)+ =610.21561, found
J
= 8.6 Hz, 1 H),
J
J
J
= 8.2
J
J
General procedure for the synthesis of compounds 7Ab−Cb
A solution of Ti(OiPr)4 (1.30 equiv) in dry THF (0.5 mL) was added to a
J
J
J
mixture of piperidin-4-one 4A−C (1.00 equiv) and 6-methoxytryptamine
J
(1.20 equiv) in dry THF (2 mL) at 21 °C under argon atmosphere. After 6
h, TFA (2.20 equiv) dissolved in dry THF (0.5 mL) was added at 0 °C; the
reaction was warmed up to 21 °C and stirred for 19−24 h. The reaction
was quenched with a saturated NaHCO3 solution and diluted with EtOAc.
The layers were separated and the aqueous phase was extracted with
EtOAc (3×). The combined organic layers were washed with brine, dried
over Na2SO4, filtered off and concentrated in vacuo. The crude was
purified by column chromatography (heptane/EtOAc 2:1 → EtOAc/MeOH
10:1). The dried product was dissolved in CH2Cl2 (5 mL) and washed with
aqueous NH4OH (5 mL). The aqueous phase was extracted with CH2Cl2
(3 × 5 mL) and the combined organic layers were washed with brine, dried
J
[ꢀ̅
610.21628 (|Δ| = 1.1 ppm).
(BORSM): 56%.
RF: 0.28 (heptane/EtOAc/Et3N, 4:4:1). Yield
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-fluorophenyl)-2′,3′,4′,9′-
tetrahydrospiro[piperidine-4,1′-pyrido[3,4-b]indol]-6′-ol 7Ac.
Et3N (25 µL, 0.182 mmol) dissolved in dry THF (0.25 mL) and Ti(OiPr)4 (58
µL, 0.197 mmol) dissolved in dry THF (0.25 mL) were added to a mixture
of 4A (50 mg, 0.152 mmol) and 5-hydroxytryptamine hydrochloride (38.7
mg, 0.182 mmol) dissolved in dry THF (0.5 mL). After 30 min, additional
Et3N (25 µL, 0.182 mmol) and THF (16.5 mL) were added. After 4.5 h, TFA
(52 µL, 0.668 mmol) dissolved in dry THF (0.5 mL) was added at 0 °C and
the reaction was warmed up to 21 °C and stirred for 21 h. The reaction
was quenched with an aqueous saturated NaHCO3 solution and diluted
with EtOAc. The organic and aqueous phases were separated and the
aqueous phase was extracted with EtOAc (4×). The combined organic
layers were washed with brine, dried with Na2SO4, filtered and dried in
vacuo. The crude was dissolved in dry THF (2 mL) and 5-
hydroxytryptamine hydrochloride (15.5 mg, 0.073 mmol), Et3N (10 µL,
0.073 mmol) in dry THF (0.5 mL) and Ti(OiPr)4 (23.2 µL, 0.079 mmol) were
added. After 3 h, TFA (10.4 µL, 0.134 mmol) was added at 0 °C; the
over Na2SO4, filtered off and dried in vacuo to afford compounds 7Ab−Cb.
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-fluorophenyl)-7′-methoxy-
2′,3′,4′,9′-tetrahydrospiro-[piperidine-4,1′-pyrido[3,4-b]indole] 7Ab.
According to the general procedure, the reaction of piperidin-4-one 4A (50
mg, 0.152 mmol) afforded 7Ab (41.5 mg, 0.083 mmol). 1H NMR [400 MHz,
δ (ppm), CDCl3]: 7.79 (bs, 1 H), 7.48–7.44 (m, 2 H), 7.33 (d,
H), 7.05 (d, = 1.9 Hz, 1 H), 7.03–6.98 (m, 3 H), 6.82 (d, = 8.3 Hz, 1 H),
6.80 (d, = 2.2 Hz, 1 H), 6.74 (dd; = 8.6, 2.2 Hz; 1 H), 4.44 (dd; = 9.1,
4.9 Hz; 1 H), 4.39 (dd; = 11.0, 2.9 Hz; 1 H), 3.91 (s, 3 H), 3.86 (s, 3 H),
3.81 (s, 3 H), 3.24 (t, = 5.7 Hz, 2 H), 2.70 (t, = 5.7 Hz, 2 H), 2.06–1.92
(m, 4 H), 1.72 (bs, 2 H). 13C NMR [126 MHz, δ (ppm), CDCl3]: 162.1 (d,
= 245.0 Hz), 156.4, 149.1, 148.3, 140.5, 138.2, 137.3, 136.4, 128.4 (d,
7.9 Hz, 2×), 122.0, 118.9, 118.8, 115.4 (d,
J = 8.6 Hz, 1
J
J
J
J
J
J
J
J
J
J
=
J
= 21.2 Hz, 2×), 111.2, 110.1,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
reaction mixture was warmed up to 21 °C and stirred for 20.5 h. The
reaction was quenched with an aqueous saturated NaHCO3 solution and
diluted with EtOAc. The organic and aqueous phases were separated and
the aqueous phase was extracted with EtOAc (4×). The combined organic
layers were washed with brine, dried with Na2SO4, filtered and dried in
vacuo. The crude was purified by column chromatography (EtOAc →
EtOAc/MeOH 10:1). The dried product was dissolved in CH2Cl2 (5 mL) and
washed with aqueous NH4OH (2 × 5 mL). The combined aqueous layers
were extracted with CH2Cl2 (3 × 10 mL) and the combined organic layers
were washed with brine, dried over Na2SO4, filtered off and dried in vacuo
to afford 7Ac (37.0 mg, 0.076 mmol) as a yellow solid. 1H NMR [500 MHz,
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]-2′,3′,4′,9′-tetrahydro-spiro[piperidine-4,1′-
pyrido[3,4-b]indol]-6′-ol 7Cc.
Et3N (19 µL, 0.137 mmol) dissolved in dry THF (0.5 mL) and Ti(OiPr)4 (44
µL, 0.149 mmol) dissolved in dry THF (0.5 mL) were added to a mixture of
4A (50 mg, 0.114 mmol) and 5-hydroxytryptamine hydrochloride (29.2 mg,
0.137 mmol) in dry THF (2 mL). After 6 h, TFA (19 µL, 0.251 mmol)
dissolved in dry THF (0.5 mL) was added at 0 °C and the reaction mixture
was warmed up to 21 °C and stirred for 20 h. The reaction was quenched
with NaHCO3 and diluted with EtOAc. The organic layer was separated
and the aqueous phase was extracted with EtOAc (4×). The combined
organic layers were washed with brine, dried over Na2SO4, filtered off and
dried in vacuo. The crude was purified by column chromatography
(heptane/EtOAc 1:1 → EtOAc/MeOH 10:1) and the dried product was
dissolved in CH2Cl2 (5 mL) and washed with aqueous NH4OH (5 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 5 mL) and the combined
organic layers were washed with brine, dried over Na2SO4, filtered off and
δ (ppm), CDCl3]: 7.81 (bs, 1 H), 7.45 (m, 2 H), 7.09 (d,
7.05 (d, = 2.0 Hz, 1 H), 7.03–6.96 (m, 3 H), 6.84 (d, = 2.4 Hz, 1 H), 6.81
(d, = 8.2 Hz, 1 H), 6.67 (dd; = 8.6, 2.4 Hz; 1 H), 4.44 (dd; = 10.4, 3.6
Hz; 1 H), 4.39 (dd; = 11.1, 2.6 Hz; 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.22
(t, = 5.7 Hz, 2 H), 2.63 (t,
= 5.7 Hz, 2 H), 2.10–1.93 (m, 4 H). 13C NMR
[101 MHz, δ (ppm), CDCl3]: 162.1 (d, = 245.2 Hz), 149.6, 149.1, 148.4,
= 2.9 Hz), 137.1, 130.9, 128.5 (d, = 7.9 Hz, 2×), 128.3,
= 21.2 Hz, 2×), 111.5, 111.5, 111.3, 110.2, 108.4, 103.4,
(cm‒1)]: 3367,
2931, 2838, 1591, 1515, 1261, 1118, 1016, 800. HRMS [ESI (m/z)] calcd
J = 8.6 Hz, 1 H),
J
J
J
J
J
J
J
J
J
140.6, 140.2 (d,
119.0, 115.4 (d,
J
J
J
dried in vacuo to afford 7Cc (32.4 mg, 0.054 mmol) as a purple solid. 1
NMR [500 MHz, δ (ppm), CDCl3]: 7.81 (bs, 1 H), 7.71–7.66 (m, 2 H), 7.59–
7.54 (m, 2 H), 7.08 (d, = 8.6 Hz, 1 H), 7.04 (d, = 1.9 Hz, 1 H), 7.01 (dd;
= 8.2, 1.9 Hz, 1 H), 6.84 (d, = 2.4 Hz, 1 H), 6.82 (d, = 8.3 Hz, 1 H),
= 8.6, 2.4 Hz; 1 H), 4.54–4.50 (m, 1 H), 4.41 (dd; = 11.2, 2.2
= 5.6
Hz, 2 H), 2.13–1.90 (m, 5 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 153.0
(quint, = 16.9 Hz), 149.6, 149.2, 148.5, 148.3, 140.2, 136.7, 130.9, 128.2,
127.2 (2×), 126.3 (quint, = 4.2 Hz, 2×), 119.1, 111.7, 111.5, 111.3, 110.2,
108.4, 103.5, 56.5, 56.4, 56.1, 56.1, 53.3, 44.6, 44.3, 39.3, 23.1. FTIR
H
56.7, 56.4, 56.1, 56.1, 53.4, 44.8 (2×), 39.3, 23.2. FTIR [ꢀ̅
J
J
J
J
J
for (C29H30FN3O3 + H)+ = 488.23454, found 488.23494 (|Δ| = 0.8 ppm). RF
0.32 (EtOAc/Et3N, 8:1). Yield (BORSM): 80%.
:
6.67 (dd;
J
J
Hz; 1 H), 3.87 (s, 3 H), 3.85 (s, 3 H), 3.29–3.16 (m, 2 H), 2.62 (t,
J
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-[4-(trifluoromethyl)phenyl]-
2′,3′,4′,9′-tetrahydrospiro-[piperidine-4,1′-pyrido[3,4-b]indol]-6′-ol
7Bc.
J
J
Et3N (22 µL, 0.158 mmol) dissolved in dry THF (0.50 mL) and Ti(OiPr)4 (50
µL, 0.171 mmol) dissolved in dry THF (0.50 mL) were added to a mixture
of 4B (50 mg, 0.132 mmol) and 5-hydroxytryptamine hydrochloride (33.6
mg, 0.158 mmol) dissolved in dry THF (2 mL). After 7 h, TFA (22 µL, 0.290
mmol) dissolved in dry THF (0.5 mL) was added at 0 °C and the reaction
was warmed up to 21 °C and stirred for 23 h. The reaction was quenched
with an aqueous saturated NaHCO3 solution and diluted with EtOAc. The
organic and aqueous phases were separated and the aqueous phase was
extracted with EtOAc (4 h). The combined organic layers were washed
with brine, dried with Na2SO4, filtered and dried in vacuo. The crude was
dissolved in dry THF (1.5 mL) and 5-Hydroxytryptamine hydrochloride
(33.6 mg, 0.158 mmol), Et3N (22 µL, 0.158 mmol) in dry THF (0.5 mL) and
Ti(OiPr)4 (50 µL, 0.171 mmol) were added. After 7 h, TFA (22 µL, 0.290
mmol) dissolved in dry THF (0.5 mL) was added at 0 °C; the reaction
mixture was warmed up to 21 °C and stirred for 24.5 h. The reaction was
quenched with an aqueous saturated NaHCO3 solution and diluted with
EtOAc. The organic and aqueous phases were separated and the aqueous
phase was extracted with EtOAc (3×). The combined organic layers were
washed with brine, dried with Na2SO4, filtered and dried in vacuo. The
crude was purified via column chromatography (heptane/EtOAc 1:1 →
EtOAc/MeOH 10:1). The dried product was dissolved in CH2Cl2 (5 mL) and
washed with aqueous NH4OH (5 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 5 mL) and the combined organic layers were washed with
brine, dried over Na2SO4, filtered off and dried in vacuo to afford 7Bc (27.5
mg, 0.051 mmol) as a purple solid. 1H NMR [400 MHz, δ (ppm), CDCl3]:
[ꢀ̅
(cm‒1)]: 3367, 2961, 2839, 1592, 1516, 1260, 103, 799. HRMS [ESI (m/z)]
calcd for (C29H30F5N3O3S + H)+ = 596.20116, found 596.20063 (|Δ| = 0.9
ppm).
RF: 0.37 (EtOAc/Et3N, 8:1). Yield (BORSM): 76%.
General procedure for the synthesis of compounds 7Ad−Cd
A solution of Et3N (1.20 equiv) in dry THF (0.5 mL) and a solution of
Ti(OiPr)4 (1.30 equiv) in dry THF (0.5 mL) were added to a mixture of
piperidin-4-one 4A
(1.20 equiv) in dry THF (2 mL) at 21 °C under argon atmosphere. After 4−7
h, TfOH (3.00 equiv for 7Ad 7Bd and 3.50 equiv for 7Cd) dissolved in dry
−C (1.00 equiv) and 5-fluorotryptamine hydrochloride
−
THF (0.5 mL) was added at 0 °C; the reaction was warmed up to 21 °C
and stirred for 22−25 h. The reaction was quenched with a saturated
NaHCO3 solution and diluted with EtOAc. The layers were separated and
the aqueous phase was extracted with EtOAc (3×). The combined organic
layers were washed with brine, dried over Na2SO4, filtered off and
concentrated in vacuo. The crude was purified by column chromatography
(heptane/EtOAc 2:1 → EtOAc/MeOH 10:1) and the dried product was
dissolved in CH2Cl2 (5 mL) and washed with aqueous NH4OH (5 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 5 mL) and the combined
organic layers were washed with brine, dried over Na2SO4, filtered off and
dried in vacuo to afford compounds 7Ad−Cd.
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6′-fluoro-6-(4-fluorophenyl)-
2′,3′,4′,9′-tetrahydrospiro-[piperidine-4,1′-pyrido[3,4-b]indole] 7Ad.
According to the general procedure, the reaction of piperidin-4-one 4A (50
mg, 0.152 mmol) afforded 7Ad (46.1 mg, 0.094 mmol) as a yellow solid.
1H NMR [500 MHz, δ (ppm), CDCl3]: 7.93 (bs, 1 H), 7.50–7.43 (m, 2 H),
7.70 (bs, 1 H), 7.62–7.55 (m, 4 H), 7.10 (d,
1.8 Hz, 1 H), 7.02 (dd; = 8.2, 1.9 Hz; 1 H), 6.86 (d,
(d, = 8.2 Hz, 1 H), 6.68 (dd; = 8.6, 2.4 Hz; 1 H), 4.53 (dd;
Hz; 1 H), 4.41 (dd; = 10.7, 3.0 Hz; 1 H), 3.90 (s, 3 H), 3.86 (s, 3 H), 3.34–
3.16 (m, 2 H), 2.66 (t,
= 5.7 Hz, 2 H), 2.19–1.91 (m, 5 H). 13C NMR [101
MHz, δ (ppm), CDCl3]: 149.6, 149.1, 148.5, 148.3, 140.3, 136.7, 130.9,
129.6 (q, = 32.4 Hz), 128.2, 127.3 (2×), 125.6 (q, = 3.7 Hz, 2×), 124.3
(q, = 272.0 Hz, F3), 119.1, 111.7, 111.5, 111.3, 110.2, 108.3, 103.5,
56.7, 56.6, 56.1, 56.0, 53.4, 44.5, 44.3, 39.3, 23.1. FTIR
(cm‒1)]: 3364,
J
= 8.6 Hz, 1 H), 7.04 (d,
= 2.4 Hz, 1 H), 6.83
= 10.7, 3.0
J =
J
J
J
J
J
J
J
7.20–7.16 (m, 1 H), 7.10 (dd;
H), 7.02–6.98 (m, 3 H), 6.86 (td;
1 H), 4.46–4.43 (m, 1 H), 4.40 (dd;
3.86 (s, 3 H), 3.25 (t, = 5.8 Hz, 2 H), 2.69 (t,
J
= 9.4, 2.5 Hz; 1 H), 7.04 (d,
= 9.2, 2.5 Hz; 1 H), 6.82 (d,
= 10.8, 3.1 Hz; 1 H), 3.91 (s, 3 H),
= 5.8 Hz, 2 H), 2.09–1.93
13C NMR [126 MHz, δ (ppm), CDCl3]: 162.1 (d,
= 234.3 Hz), 149.1, 148.4, 141.4, 140.4, 137.1,
= 9.8 Hz), 119.0, 115.4 (d,
= 9.4 Hz), 111.2, 110.1, 109.9 (d, = 26.0 Hz),
= 4.3 Hz), 103.4 (d, = 23.2 Hz), 56.6, 56.3, 56.1, 56.1, 53.3,
J
= 2.0 Hz, 1
J
J
= 8.2 Hz,
J
J
J
J
C
J
J
[ꢀ̅
(m, 4 H), 1.72 (bs, 2 H)
.
J
3305, 2931, 2836, 1591, 1509, 1223, 1140, 1024, 800. HRMS [ESI (m/z)]
calcd for (C30H30F3N3O3 + H)+ = 538.23216, found 538.23175 (|Δ| = 0.8
= 245.2 Hz), 157.9 (d,
J
132.1, 128.4 (d,
21.1 Hz, 2×), 111.4 (d,
109.1 (d,
J
= 7.9 Hz, 2×), 127.9 (d,
J
J =
ppm). RF: 0.32 (EtOAc/Et3N, 8:1). Yield (BORSM): 74%.
J
J
J
J
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
45.0, 45.0, 39.3, 23.2. FTIR
1225, 1139, 1025, 798. HRMS [ESI (m/z)] calcd for (C29H29F2N3O2 + H)+ =
490.23155, found 490.23061 (|Δ| 0.9 ppm). RF 0.37
[
ꢀ
̅
(cm‒1)]: 3362, 2930, 2838, 1601, 1508,
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6-(4-fluorophenyl)-2',3',4',5'-
tetrahydrospiro[piperidine-4,1'-pyrido[4,3-b]indole] 12
According to the general procedure, the reaction of piperidin-4-one 4A (15
mg, 0.05 mmol) afforded 12 (12 mg, 0.03 mmol). 1H NMR [400 MHz, δ
(ppm), CDCl3]: 7.88–7.75 (m, 2 H) 7.51−7.47 (m, 2 H), 7.31–7.27 (m, 1 H),
7.14–7.09 (m, 2 H), 7.08–7.03 (m, 2 H), 7.03–6.95 (m, 2 H), 6.85−6.80 (m,
=
:
(heptane/EtOAc/Et3N, 4:4:1). Yield (BORSM): 74%.
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6′-fluoro-6-(4-
(trifluoromethyl)phenyl)-2′,3′,4′,9′-tetrahydro-spiro[piperidine-4,1′-
pyrido[3,4-b]indole] 7Bd.
According to the general procedure, the reaction of piperidin-4-one 4B (50
1 H), 4.47–4.41 (m, 1 H), 4.40 (dd;
J
= 12.2, 2.2 Hz; 1 H), 3.90 (s, 3 H),
3.85 (s, 3 H), 3.26 (t,
J
= 5.6 Hz, 2 H), 2.74 (t, J = 5.6 Hz, 2 H), 2.60–2.39
(m, 2 H), 1.92–1.82 (m, 2 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 162.0
mg, 0.132 mmol) afforded 7Bd (21.9 mg, 0.041 mmol) as a yellow solid.
In this case, after following the general procedure, the crude was purified
for a second time by an ion exchange column (ISOLUTE SCX-2); the dried
product was dissolved in CH2Cl2 (5 mL) and washed with aqueous NH4OH
(5 mL). The aqueous phase was extracted with CH2Cl2 (3 × 5 mL) and the
combined organic layers were washed with brine, dried over Na2SO4,
filtered off and dried in vacuo. 1H NMR [500 MHz, δ (ppm), CDCl3]: 7.94
(indirect observation), 149.0, 148.2, 140.0 (indirect observation), 137.9
(indirect observation), 132.5, 131.1, 128.5 (d,
119.5, 119.4, 119.0, 116.4, 115.2 (d, = 21.1 Hz, 2×), 111.3, 110.9, 110.4,
56.9, 56.6, 56.1 (2×), 54.2, 44.8, 44.6, 38.7, 24.8. FTIR
(cm‒1)]: 3366,
J = 7.8 Hz, 2×), 125.1, 121.2,
J
[ꢀ̅
2957, 2856, 1602, 1508, 1229, 1156, 1026, 763. HRMS [ESI (m/z)] calcd
for (C29H31F1N3O2 + H)+ = 472.24003, found 472.24094 (|Δ| = 1.92 ppm).
R
F: 0.35 (EtOAc/Et3N, 8:1). Yield: 52%.
(bs, 1 H), 7.65–7.55 (m, 4 H), 7.20–7.15 (m, 1 H), 7.10 (dd;
Hz; 1 H), 7.08–7.04 (m, 1 H), 7.06–7.00 (m, 1 H), 6.86 (td; = 9.2, 2.6 Hz;
1 H), 6.83 (d, = 8.3 Hz, 1 H), 4.57–4.52 (m, 1 H), 4.45–4.41 (m, 1 H),
3.91 (s, 3 H), 3.86 (s, 3 H), 3.29–3.22 (m, 2 H), 2.70 (t, = 5.5 Hz, 2 H),
2.09–1.92 (m, 4 H), 1.80 (bs, 2 H). 13C NMR [101 MHz, δ (ppm), CDCl3]:
157.9 (d, = 234.3 Hz), 149.2, 148.5, 148.4, 141.1, 136.8, 132.1, 129.7
(q, = 32.6 Hz), 127.9 (d, = 9.6 Hz), 127.3 (2×), 125.6 (q, = 3.4 Hz,
2×), 124.3 (q, = 271.5 Hz, F3), 119.0, 111.4 (d, = 9.6 Hz), 111.3,
110.2, 110.0 (d, = 26.0 Hz), 109.1 (d, = 4.5 Hz), 103.4 (d, = 23.2 Hz),
56.6, 56.5, 56.1, 56.1, 53.2, 44.6, 44.4, 39.3, 23.1. FTIR
(cm‒1)]: 3362,
2935, 2837, 1586, 1514, 1261, 1017, 799. HRMS [ESI (m/z)] calcd for
J = 9.4, 2.4
J
(2S,4S,6R)-2-(3,4-dimethoxyphenyl)-6-(4-fluorophenyl)-1',5',6',7'-
tetrahydrospiro[piperidine-4,4'-pyrrolo[3,2-c]pyridine] 13.
According to the general procedure, the reaction of piperidin-4-one 4A (40
mg, 0.12 mmol) afforded 13 (22 mg, 0.062 mmol). 1H NMR [400 MHz, δ
(ppm), CDCl3]: 7.79 (bs, 1 H), 7.49–7.39 (m, 2 H), 7.06–6.95 (m, 4 H), 6.82
J
J
J
J
J
J
(d,
(dd;
3.86 (s, 3 H), 3.20 (t,
(m, 4 H), 1.68 (bs, 1 H). 13C NMR [101 MHz, δ (ppm), CDCl3]: 162.0 (d,
= 244.4 Hz), 149.0, 148.1, 141.1 (d, = 3.0 Hz), 138.0, 128.4 (d, = 7.9
Hz, 2×), 124.8, 118.9, 116.0, 115.1 (d, = 21.1 Hz, 2×), 111.2, 110.9,
J
= 8.2 Hz, 1 H), 6.60 (t,
= 11.3, 3.5 Hz; 1 H), 4.29 (dd;
= 5.8 Hz, 2 H), 2.58 (t,
J
= 2.7 Hz, 1 H), 6.06 (t,
= 11.6, 2.9 Hz; 1 H), 3.90 (s, 3 H),
= 5.8 Hz, 2 H), 2.07–1.79
J = 2.7 Hz, 1 H), 4.33
J
C
J
J
J
J
J
J
J
J
[ꢀ̅
J
J
J
(C30H29F4N3O2 + H)+ = 540.22734, found 540.22741 (|Δ| = 0.1 ppm). RF
:
J
110.2, 104.5, 56.8, 56.5, 56.1 (2×), 53.5, 46.4, 46.3, 38.9, 24.3. FTIR [ꢀ̅
0.41 (heptane/EtOAc/Et3N, 4:4:1). Yield (BORSM): 37%.
(cm‒1)]: 3379, 2930, 2836, 1604, 1508, 1227, 1156, 1026, 765. HRMS [ESI
(m/z)] calcd for (C25H29F1N3O2 + H)+ = 422.22438, found 422.22591 (|Δ| =
(2S,4S,6R)-2-(3,4-Dimethoxyphenyl)-6′-fluoro-6-[4-(pentafluoro-λ6-
sulfanyl)phenyl]-2′,3′,4′,9′-tetrahydrospiro[piperidine-4,1′-pyrido[3,4-
b]indole] 7Cd.
3.63 ppm).
RF: 0.45 (EtOAc/Et3N, 8:1). Yield: 52%.
According to the general procedure, the reaction of piperidin-4-one 4C (50
Supporting information: Full experimental details for the preparation of
the compounds described herein, characterization of new compounds and
copies of 1H and 13C NMR spectra are described in the Supporting
Information.
mg, 0.114 mmol) afforded 7Cd (27.6 mg, 0.046 mmol) as a yellow solid.
1H NMR [500 MHz, δ (ppm), CDCl3]: 8.02 (bs, 1 H), 7.71 (d,
H), 7.58 (d, = 8.4 Hz, 2 H), 7.20–7.15 (m, 1 H), 7.10 (dd;
1 H), 7.04 (d, = 2.0 Hz, 1 H), 7.02 (dd; = 8.2, 2.0 Hz; 1 H), 6.87 (td;
9.1, 2.6 Hz; 1 H), 6.83 (d, = 8.2 Hz, 1 H), 4.54 (dd; = 7.6, 6.1 Hz; 1 H),
4.42 (dd; = 11.0, 2.2 Hz; 1 H), 3.91 (s, 3 H), 3.86 (s, 3 H), 3.31–3.20 (m,
2 H), 2.69 (t,
= 5.7 Hz, 2 H), 2.13–1.96 (m, 4 H). 13C NMR [101 MHz, δ
(ppm), CDCl3]: 157.9 (d, = 234.4 Hz), 153.0 (quint, = 16.9 Hz), 149.2,
148.5, 148.4, 141.0, 136.8, 132.1, 127.9 (d, = 9.6 Hz), 127.2 (2×), 126.3
(quint, = 4.5 Hz, 2×), 119.0, 111.4 (d, = 9.8 Hz), 111.3, 110.1, 110.0 (d,
= 26.6 Hz), 109.2 (d, = 4.5 Hz), 103.4 (d, = 23.4 Hz), 56.4, 56.3, 56.1
(2×), 53.2, 44.9, 44.6, 39.3, 23.2. FTIR
(cm‒1)]: 3367, 2962, 2839, 1588,
1515, 1260, 1022, 795. HRMS [ESI (m/z)] calcd for (C29H29F6N3O2S + H)+
598.19536, found 598.19629 (|Δ| 1.6 ppm). RF 0.25
(heptane/EtOAc/Et3N, 4:4:1). Yield (BORSM): 52%.
J
= 8.8 Hz, 2
J
J = 9.5, 2.5 Hz;
J
J
J =
J
J
J
Acknowledgements
J
J
J
This work has been supported by the FP7 Marie Curie Actions of
the European Commission via the ITN ECHONET Network
(MCITN-2012-316379).
J
J
J
J
J
J
[ꢀ̅
Keywords: Enantioselective Mannich reaction •
Diastereoselective Pictet−Spengler reaction • Spiro piperidines •
Tetrahydro--carbolines
=
=
:
General procedure for the synthesis of compounds 12 and 13
Ti(OiPr)4 was added to a mixture of piperidin-4-one 4A (1.00 equiv) and
the amine (1.20 equiv; 2-(1 -indol-2-yl)ethan-1-amine for 12 and 2-(1
[1]
a) G. Müller, T. Berkenbosch, J. Benningshof, D. Stumpfe, J. Bajorath,
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B. Singh, Bioorg. Med. Chem. Lett. 2014, 24, 3673−3682; b) R. Rios,
Chem. Soc. Rev. 2012, 41, 1060−1074.
H
H-
pyrrol-2-yl)ethan-1-amine for 13) in dry THF (3 mL) at 21 °C under argon
atmosphere. After 6 h, TFA (2.20 equiv) was added at 0 °C; the reaction
was warmed up to 21 °C and stirred overnight. The reaction was quenched
with a saturated NaHCO3 solution (3 mL) and diluted with EtOAc. The
layers were separated and the aqueous phase was extracted with EtOAc
(4 × 6 mL). The combined organic layers were washed with brine, dried
over Na2SO4, filtered off and concentrated in vacuo. The crude was
purified by column chromatography (heptane/EtOAc 2:1 → EtOAc); the
dried product was dissolved in CH2Cl2 (5 mL) and washed with aqueous
NH4OH (5 mL). The aqueous phase was extracted with CH2Cl2 (3 × 5 mL)
and the combined organic layers were washed with brine, dried over
[2]
For Iboluteine, see: a) B. Q. Tang, W. J. Wang, X. J. Huang, G. Q. Li, L.
Wang, R. W. Jiang, T. T. Yang, L. Shi, X. Q. Zhang, W. C. Ye, J. Nat.
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Paganelli, F. Persi-Paoli, Tetrahedron 2001, 57, 1631−1637. For
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L. H. Hellberg, Synth. Commun. 1994, 24, 1483−1487.
[3]
C. M. Marson, Chem. Soc. Rev. 2011, 40, 5514−5533.
Na2SO4, filtered off and dried in vacuo to afford compounds 12 and 13
.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
[4]
a) P. Nithya, F. R. N. Khan, S. M. Roopan, U. Shankar, J. S. Jin, Chem.
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a) D. O'Hagan, Chem. Soc. Rev. 2008, 37, 308−319; b) E. P. Gillis, K. J.
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K. Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881−1886; d) For
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[12] J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg, P. L. Alsters,
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[13] The reactions for the syntheses of compounds 4B and 4C were not
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10.1002/ejoc.201601508
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
Key Topic* Tetrahydro--carbolines,
Spiro Heterocycles
Alejandra Riesco-Domínguez, Nick van
der Zwaluw, Daniel Blanco-Ania] and
Floris P. J. T. Rutjes*
Page No. – Page No.
An enantio- and diastereoselective Mannich-Pictet−Spengler sequence has been
developed for the synthesis of a new small library (14 compounds) of fluorinated
spiro tetrahydro--carbolines.
Title An Enantio- and Diastereoselective
Mannich-Pictet−Spengler Sequence to
form Spiro[piperidine-pyridoindoles] and
application to Library Synthesis
*one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.