Preparation of Hexahydrocarbazole Derivatives by Reductive Indolization

Article abstract of DOI:10.1002/ejoc.202001226

The reductive indolization is a two-step protocol performed in one flask: First, the acid-mediated Fischer indolization of a cyclic ketone with phenylhydrazine forms an iminium ion which is subsequently reduced by a hydrido borate reagent to the indoline as the final product. We utilized this new strategy for the preparation of hexahydrocarbazole derivatives with a side chain in the quaternary C4a-position. Starting materials were several N1- and aryl-substituted phenylhydrazines and a cyclic ketone with propanoic ester moiety, which is the product of the conjugated addition of cyclohexanone to ethyl acrylate. Furthermore, benzannulated congeners as well as a pyrido[4,3-b]indole derivative were accessed. The hexahydrocarbazole defines a molecular scaffold with two points of diversification. Therefore, several derivatives at N9 and at the C4a-side chain were prepared.

Full text of DOI:10.1002/ejoc.202001226

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Hexahydrocarbazoles
Preparation of Hexahydrocarbazole Derivatives by Reductive
Indolization
[
a]
[a]
[a]
[a]
Anna Dierks, Lukas Fliegel, Marc Schmidtmann, and Jens Christoffers*
Abstract: The reductive indolization is a two-step protocol per- cyclic ketone with propanoic ester moiety, which is the product
formed in one flask: First, the acid-mediated Fischer indolization of the conjugated addition of cyclohexanone to ethyl acrylate.
of a cyclic ketone with phenylhydrazine forms an iminium ion Furthermore, benzannulated congeners as well as a pyrido[4,3-b]-
which is subsequently reduced by a hydrido borate reagent to indole derivative were accessed. The hexahydrocarbazole de-
the indoline as the final product. We utilized this new strategy fines a molecular scaffold with two points of diversification.
for the preparation of hexahydrocarbazole derivatives with a Therefore, several derivatives at N9 and at the C4a-side chain
side chain in the quaternary C4a-position. Starting materials were prepared.
were several N1- and aryl-substituted phenylhydrazines and a
Introduction
thetic tetra- and hexahydrocarbazole derivatives. (+)-Aristotelin
1) can be isolated from several Aristotelia species (Elaeocarpa-
(
The carbazoles, as well as their tetrahydro[2] and hexahydro
[
1]
[
6]
ceae). (+)-Aspidospermidine (2) is the archetypical member of
[
3]
congeners, are an important class of heterocyclic compounds
and the core structural motif of numerous indole alkaloids.[4]
Furthermore, several synthetic pharmaceuticals carry this
[
7]
the Aspidosperma alkaloids.
Cebranopadol (3), a 2-oxa-
congener, is a novel opioid analgesic presently in clinical trials
for the therapy of a variety of different acute and chronic pain
[
5]
heterocycle. Figure 1 shows four naturally occurring and syn-
[
8]
states. Compound 4 shows remarkable antibiotic activity
against the multi-resistant MRSA and is therefore a valuable
[
9]
starting point for the development of new antibiotics. In this
compound, the five and six-membered rings are cis-annulated.
We have recently reported on a novel route to indolines
called “reductive indolization”, i.e. a Fischer indolization reaction
[
10]
under reductive conditions (Scheme 1). Oxoester 5 was con-
Figure 1. Four naturally occurring and synthetic tetra- and hexahydrocarb-
azole derivatives.
[
a] A. Dierks, L. Fliegel, Dr. M. Schmidtmann, Prof. Dr. J. Christoffers
Institut für Chemie, Carl von Ossietzky Universität Oldenburg,
2
6111 Oldenburg, Germany
E-mail: jens.christoffers@uol.de
http://www.uni-oldenburg.de/oc-christoffers/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202001226.
©
2020 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH · This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited.
Scheme 1. Reductive indolization of ꢀ-oxoester 5 (previous work) and δ-ox-
oester 9a (this publication).
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verted with phenylhydrazine under acidic conditions in the 13a. Therefore, we isolated compound 13a and converted it
presence of Et SiH as reducing agent furnishing the racemic with other reducing reagents. With NaBH , for example, only
3
4
hexahydrocarbazole derivative 6 exclusively as the diastereoiso- the ester moiety was reduced to the primary alcohol. With
mer with cis-annulated rings. After formation of the hydrazone NaBH(OAc)3,[17] however, we could successfully transform 3H-
and its tautomeric enamine 7, the reaction proceeded along indole derivative 13a to hexahydrocarbazole 10a (91 % yield,
the known mechanistic pathway: protonation at nitrogen, Scheme 2, lower arrow). After further, tedious experimentation
[
3,3]-sigmatropic rearrangement, nucleophilic addition of the finally a two-step, one flask protocol was developed depicted
aniline-NH to the iminium ion at the alicyclic ring followed by as conditions (d) in Table 1, which gave the target structure 10a
2
elimination of ammonia furnishing the iminium ion 8. Instead in 85 % yield together with minor amounts of the unwanted
of being deprotonated (since R ≠ H) forming the aromatic tetra- regioisomers 11 and 12 (together 10 %), which could be sepa-
hydrocarbazole, the cation 8 was reduced by the silane forming rated by column chromatography.
the hexahydrocarbazole derivative 6. The concept of “reductive
indolization” has been applied in the past for the synthesis of
[
11]
dihydroindole derivatives,
and very recently for Aspido-
[
12]
sperma alkaloids. It can be regarded as the reductive case of
an interrupted Fischer indolization, as introduced by Garg and
[
13]
co-workers.
We now report our efforts to extend the reduc-
tive indolization towards hexahydrocarbazole derivatives 10
with a C -side chain at the position 4a, thus, accessing the
3
carbon skeleton of compound 4 (Figure 1). Consequently, we
started our investigation with δ-oxoester 9a, which resulted
from the conjugated addition of cyclohexanone to ethyl acryl-
[
14]
ate.
Results and Discussion
The hunt for suitable reaction conditions furnishing target
structure 10a started with our previously established protocol
(
Scheme 2). However, when converting δ-oxoester 9a with
phenylhydrazine in the presence of Et SiH according to condi-
3
tions (a), a mixture of compounds 11, 12 (together 61 % yield)
[
15]
and 13a (23 %) were formed. While known compound 12 is
clearly a subsequent lactamization product of compound 11,
the latter is the resulting from the regioisomeric enamine. This
enamine is the kinetic, trisubstituted isomer, while the correct
enamine (leading to 3H-indol derivative 13a) is the thermody-
Scheme 2. Searching for appropriate reaction conditions; for conditions and
yields see Table 1.
Compound 10a was obtained as a single diastereoisomer. It
namic, tetrasubstituted isomer. Consequently, we raised the re- is furthermore a crystalline material suitable for single-crystal
[
18]
action temperature from 23 °C to 100 °C (together with a X-ray structure determination.
change of the solvent), and indeed, the correct regioisomer 13a representation of the molecular structure in the solid-state. The
became the main product when applying conditions (b). Actu- alicyclic A-ring is in chair-conformation with the C -side chain
Figure 2 shows an ORTEP-
3
ally, the target compound 10a (8 %) was only a minor compo- at C4a in the equatorial position. A- and B-ring are cis-annu-
nent in this mixture. We then screened changes of the solvent, lated. The bond angle C8a–N9–C9a of 106.0° clearly indicated
3
the temperature, and the stoichiometry and after some experi- that this nitrogen atom is sp -hybridized.
mentation, we were able to maximize the correct regiochemis-
After identification of suitable conditions, we went out to
try. Applying conditions (c) gave compound 13a (which is actu- check the scope of the reaction concerning the phenylhydra-
[
16]
ally literature known)
now in 74 % yield together with 10 % zine derivative (Scheme 3 and Table 2). Respective bromo-,
of lactam 12. Unfortunately, no traces of target compound 10a methoxy-, dimethyl- and fluoro-substituted phenylhydrazines
were detectable. From this observation, we concluded that were commercially available and gave products 10b–10e in 51–
Et SiH is not the appropriate reducing reagent for compound 71 % yields (Table 2, entries 2–5). Phenylhydrazines with an ad-
3
Table 1. Screening for suitable reaction conditions.
Conditions
Yield 11
Yield 12
Yield 13a
Yield 10a
(
(
(
(
a) 1.1 equiv. PhNHNH
b) 1.1 equiv. PhNHNH
2
, 1.1 equiv. Et
, 1.5 equiv. Et
, 2.0 equiv. Et
3
SiH, TFA, toluene (1:3), 23 °C, 16 h
41 %[a]
–
20 %
34 %
10 %
4 %
23 %
41 %
74 %[
–
–
8 %
–
2
3
SiH, TFA, AcOH (1:3), 100 °C, 16 h
SiH, AcOH, 100 °C, 16 h
b]
c) 1.1 equiv. PhNHNH
2
3
–
6 %[
a]
85 %
[b]
d) 1. 1.1 equiv. PhNHNH
2 3
, AcOH, 100 °C, 2.5 h; 2. 2.0 equiv. NaBH(OAc) , 23 °C, 1.5 h
[
a] Not completely separable mixture with compound 12. [b] Yield of isolated product.
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Table 2. Scope of the reductive indolization upon variation of the phenyl-
hydrazine derivative and the ring size of the δ-oxoester.
Entry
n
R
X[a]
Product
Yield[b]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
2
0
H
H
H
H
H
10a
10b
10c
10d
10e
10f
10g
10h
10i
85 %
61 %
51 %
68 %
71 %
73 %
78 %
6-Br
6-OMe
5,7-Me
6-F
H
H
H
H
2
H
Bn
allyl
H
[c]
37 %
0 %[
d]
H
[
[
a] Locants refer to compounds 10 (see Figure 2). [b] Isolated product.
c] Modified reaction times: 1. 5 h; 2. 16 h. [d] Product 10i was formed in
ca. 3 %, but could not be completely purified.
Figure 2. The ORTEP-representation of the molecular structure of compound
10a in the solid-state proves the constitution and relative cis-configuration.
ditional benzyl[19] or allyl[20] residue at N1 could be prepared
according to literature protocols. Conversion with δ-oxoester 9a
under standard conditions gave the respective N-substituted
hexahydrocarbazoles 10f and 10g in 73 % and 78 % yields, re-
spectively (entries 6 and 7). We then investigated the ring size
of the δ-oxoesters and prepared the cycloheptanone (com-
Scheme 4. Preparation of pyrido[4,3-b]indole derivative 10j from piperidone
9d.
[
21]
pound 9b)
and cyclopentanone derivatives (compound
[
22]
9
c)
according to literature protocols. Starting material 9b
yields remained unsatisfactory (Scheme 5). Moreover, com-
pound 10k (39 % yield, 56 % based on recovered starting mate-
rial) always contained a minor diastereoisomer. Upon attempts
to separate these isomers by chromatography, always a small
amount of 3H-indole derivative 13k (“di-dehydro-10k”) was
formed, presumably by oxidation. It is unclear whether the
main diastereoisomer of 10k is cis- or trans-configured. The
product 10l with two five-membered rings is of course only the
cis-isomer (yield 28 %).
gave product 10h in moderate yield (37 %, entry 8) when ap-
plying longer reaction times. In contrast, the cyclopenta[b]-
indole 10i was only obtained in trace amounts and could not
be fully purified when the cyclopentanone derivative 9c was
submitted to reaction with phenylhydrazine (entry 9).
Scheme 3. Investigating the scope of the reductive indolization, for ring size
n, residues R and X and yields see Table 2.
To pursue the preparation of a product with an additional
nitrogen function, we prepared the δ-oxoester 9d from N-
acetylpiperidone and ethyl acrylate. It was submitted to our
standard conditions for reductive indolization (Scheme 4). How-
ever, compound 10j was only obtained in unsatisfactory yield
(
32 %). At ambient temperature, compounds 9d and 10j
showed broad proton NMR spectra and partly doubled signal
Scheme 5. Conversion of benzannulated δ-oxoesters 9e and 9f; reagents and
1
3
conditions: (a) for 9e: 1. 1.5 equiv. PhNHNH , AcOH, 100 °C, 16 h; 2. 2.5 equiv.
sets in the C NMR spectra due to E/Z-isomerism along with
the amide C-N bond. At 100 °C, the proton NMR spectra con-
tained single signal sets.
2
NaBH(OAc)
3
, 23 °C, 3 h; (b) for 9f: 1. 1.2 equiv. PhNHNH
, 23 °C, 1.5 h.
2
, AcOH, 100 °C, 2.5 h;
2
. 2 equiv. NaBH(OAc)
3
Benzannulated δ-oxoesters, i.e. tetralone (9e) and indanone
The heterocyclic compound 10a defines a molecular scaffold
derivatives (9f), also underwent reductive indolization, though, holding two points for potential diversification: The nitrogen N-
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9
and the carboxylic acid in the side chain. Therefore, standard yield from BrosCl and pyridine. Conversion with a trimethoxy-
transformations of the amino and carboxylate groups, which phenyl isocyanate in boiling toluene gave urea 15 in 70 % yield.
are often found in the field of Medicinal Chemistry, were exem- Amidation of compound 10a with an aromatic carboxylic acid
plarily performed. Starting with the amino function of com- utilized HATU-DIPEA[17,23] as coupling reagent and gave 52 % of
pound 10a (Scheme 6), sulfonamide 14 was obtained in 75 % product 16 [61 % based on recovered starting material (brsm)].
Coupling of the aliphatic cyclohexane carboxylic acid with
HATU-DIPEA gave the amide 17 with superior result (65 % yield,
7
1 % brsm). And finally, reductive amination with trifluoro-
methylbenzaldehyde and isobutyraldehyde with NaCNBH in an
3
[
24]
acidic milieu
gave the tertiary amines 18 (60 %, 99 % brsm)
and 19 (67 %, 88 % brsm).
For the second diversifying strategy we first submitted com-
pound 10f to ester saponification with hydrochloric acid yield-
ing compound 20 in 95 % yield (Scheme 7). It was then coupled
with the HATU-DIPEA protocol with trifluoroethylamine to
furnish compound 21a with 86 % yield. With tert-butyl and
ethoxyethylamine, the amides 21b and 21c were obtained in
very good yield (97 % and 98 %, resp.). By application of
4
-bromo aniline, the compound 21d was formed also in good
yield (92 %). Furthermore, we intended to prepare the 4a-(2-
aminoethyl) derivative of the scaffold by Hofmann degradation
of the carboxylate function in compound 20. We relied on a
literature procedure applying the hypervalent iodine reagent
[
25]
PhI(OAc)2.
First of all, the parent unsubstituted amide 21e
was prepared in 93 % yield by activation of the acid 20 with
Boc O and conversion of the mixed anhydride with hartshorn
2
salt. The degradation proceeded with PhI(OAc) and the inter-
2
Scheme 6. Derivatization at nitrogen; reagents and conditions: (a) 1 equiv.
BrosCl (Bros = 4-BrC SO ), pyridine/CH Cl , 23 °C, 3 h; (b) 1.2 equiv. 3,4,5-
MeO) NCO, toluene, 100 °C, 3 h; (c) 1.5 equiv. 4-IC CO H, 1.5 equiv.
HATU, 1.5 equiv. DIPEA, CH , 23 °C, 17 h; (d) 1.1 equiv. CyCO H, 1.1 equiv.
HATU, 1.1 equiv. DIPEA, CH , 23 °C, 17 h; (e) 1 equiv. 4-CF CHO,
, EtOH, 23 °C, 4 h. (f) 1 equiv. iPrCHO,
, EtOH, 23 °C, 4 h. HATU = O-(7-azabenzo-
6
H
4
2
2
2
(
3
C
6
H
2
6
H
4
2
2
Cl
2
2
2
Cl
2
3
C
6
H
4
Scheme 7. Derivatization at the carboxylate function; reagents and condi-
0
0
.5 equiv. ZnCl
.5 equiv. ZnCl
2
, 1 equiv. NaCNBH
, 1 equiv. NaCNBH
3
tions: (a) HCl/H
1.5 equiv. RNH
2.8 equiv. (NH
PhI(OAc) , MeOH, 16 h.
2
O (conc.), 100 °C, 2 h; (b) 1.1 equiv. HATU, 1.1 equiv. DIPEA,
, CH Cl , 23 °C, 17 h; (c) 1.8 equiv. pyridine, 1.5 equiv. Boc O,
CO , 1,4-dioxane, 23 °C, 17 h; (d) 2.5 equiv. KOH, 1.0 equiv.
2
3
2
2
2
2
triazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate), DIPEA
=
4
)
2
3
ethyldiisopropylamine.
2
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mediate isocyanate was solvolyzed with MeOH to furnish the vent was removed in vacuo. The crude product was purified by
column chromatography (SiO , hexanes/MTBE, 3:1, R = 0.26) to
carbamate 22, however, the yield was moderate (44 %).
2
f
yield the title compound (767 mg, 3.87 mmol, 77 %) as a pale yellow
1
oil. H-NMR (300 MHz, CDCl ): δ = 3.40 (br s, 2H), 4.62 (s, 2H), 6.84
3
(
t, J = 7.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.26–7.39 (m, 7H) ppm.
Conclusion
[19]
All spectroscopic data are in accordance with the literature.
C H N (198.27 g mol ).
–
1
13 14 2
Hexahydrocarbazole derivatives 10a–10g are accessed by re-
ductive indolization, i.e. a two-step protocol performed con- 1-Allyl-1-phenylhydrazine.[20]
Phenylhydrazine
secutively in one flask consisting of acid-catalyzed 3H-indole 5.00 mmol) and allyl bromide (605 mg, 5.00 mmol) were added to
(420 mg, 5.00 mmol) in H O (5 mL). The result-
(541
mg,
formation with phenylhydrazine followed by reduction of the a solution of NaHCO
3
2
ing mixture was stirred at 100 °C for 3 h, subsequently cooled to
ambient temperature, and extracted with MTBE (3 × 15 mL). The
combined organic layers were dried (MgSO ), filtered and the sol-
vent was removed in vacuo. The crude product was purified by
column chromatography (SiO , hexanes/MTBE, 2:1, R = 0.26) to
yield the title compound (153 mg, 1.03 mmol, 21 %) as a pale yellow
oil. H-NMR (300 MHz, CDCl ): δ = 3.61 (br s, 2H), 4.04 (d, J = 5.9 Hz,
2
iminium-moiety with NaBH(OAc) . The starting material for this
3
transformation is δ-oxoester 9a resulting from the conjugated
addition of cyclohexanone to ethyl acrylate via the enamine.
Thus, the hexahydrocarbazoles 10a–10g carry a 2-(ethoxy-
carbonyl)ethyl side chain at their quaternary C4a-position. The
scope of the transformation was investigated by application of
phenylhydrazine derivatives with substituents at the phenyl
4
2
f
1
3
H), 5.25–5.31 (m, 2H), 5.89 (ddt, J = 17.5 Hz, J = 9.8 Hz, J = 5.9 Hz,
ring (Me, OMe, Br, F) as well as residues at the N1-position (allyl, 1H), 6.81 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 7.9 Hz, 2H), 7.24–7.29
benzyl). Yields of products 10a–10g range between 85 % and (m, 2H) ppm. All spectroscopic data are in accordance with the
[
20]
–1
5
1 %. Furthermore, δ-oxoesters 9b and 9c with cycloheptan- literature.
C
H
9
N
12
(148.21 g mol ).
2
one and cyclopentanone ring were investigated, however, the
yields of respective cyclohepta[b]indole 10h (37 %) are unsatis-
factory or in the case of cyclopenta[b]indole 10i almost zero. (2.0 equiv.) in toluene (1.3 L mol ) was heated to reflux under water
Conversion of 4-piperidone derived δ-oxoester 9d gave separation using a Dean–Stark trap for 3–5 h. Subsequently, all vola-
pyrido[4,3-b]indole derivative 10j also with unsatisfactory yield tile materials were removed under reduced pressure and the crude
General procedure A (GPA) for the preparation of δ-oxoesters
[14,21,22]
9.
A solution of cyclic ketone (1.0 equiv.) and pyrrolidine
–
1
–
1
enamine was dissolved in abs. THF (1.3 L mol ). Ethyl acrylate
1.3 equiv.) was added and the resulting mixture was heated to
(
(
32 %). The same drawback was observed for products 10k
39 %) and 10l (28 %) obtained from tetralone- and indanone
(
–
1
reflux for 16 h. Then H O (0.4 L mol ) was added and the mixture
2
derived δ-oxoesters 9e and 9f. Since the hexahydrocarbazoles
0 define a molecular scaffold with two points for diversifica-
was further heated to reflux for 2 h. Subsequently, all volatile
1
materials were removed under reduced pressure and the residue
tion, several derivatives at N9 (carboxamides, sulfonamides,
ureas, and N-alkyl derivatives) were prepared. Also, the
carboxylate function in the side chain was addressed by carbox-
–1
was diluted with H O (1 L mol ) and extracted with MTBE
2
–1
(
3 × 1 L mol ). The combined organic layers were washed
–1
–1
with hydrochloric acid (2 mol L , 1 × 2 L mol ) and brine
–
1
amide formation (five examples). The N-unsubstituted amide (1 × 2 L mol ), dried (MgSO ), filtered and the solvent was removed
4
2
1e at the C4a side chain was furthermore submitted to Hof- in vacuo. The crude product was purified by column chromatogra-
mann degradation.
phy to furnish δ-oxoesters 9a–9f.
Ethyl 3-(2-oxocyclohexyl)propanoate (9a).[14] According to GPA,
cyclohexanone (1.50 g, 15.3 mmol) was converted with pyrrolidine
(2.18 g, 30.6 mmol) and ethyl acrylate (1.99 g, 19.9 mmol) to yield
the title compound 9a (1.79 g, 9.03 mmol, 59 %) after chromatogra-
phy (SiO , hexanes/MTBE, 2:1, R = 0.30) as a colorless liquid.
Experimental Section
General. Preparative column chromatography was carried out us-
2
f
ing Merck SiO (35–70 μm, type 60 A) with hexanes (mixture of
1
2
H-NMR (300 MHz, CDCl ): δ = 1.24 (t, J = 7.1 Hz, 3H), 1.32–1.45 (m,
3
isomers, bp. 64–71 °C), tert-butyl methyl ether (MTBE), EtOAc,
1
2
H), 1.47–1.59 (m, 1H), 1.62–1.69 (m, 2H), 1.80–1.90 (m, 1H), 1.99–
CH Cl , and MeOH as eluents. TLC was performed on aluminum
2
2
.14 (m, 3H), 2.24–2.44 (m, 5H), 4.11 (q, J = 7.1 Hz, 2H) ppm. All
1
19
13
plates coated with SiO2 F254
.
H, F, and C NMR spectra
[14]
spectroscopic data are in accordance with the literature.
C H O (198.26 g mol ).
were recorded on Bruker Avance DRX 500 and 300 instruments.
Multiplicities of carbon signals were determined with DEPT experi-
ments. HRMS spectra of products were obtained with Waters Q-TOF
Premier (ESI, pos. mode) or Thermo Scientific DFS (EI) spectrome-
ters. IR spectra were recorded on a Bruker Tensor 27 spectrometer
–1
11 18 3
Ethyl 3-(2-oxocycloheptyl)propanoate (9b).[21] According to GPA,
cycloheptanone (1.00 g, 8.92 mmol) was converted with pyrrolidine
(1.27 g, 17.8 mmol) and ethyl acrylate (1.16 g, 11.6 mmol) to yield
the title compound 9b (1.07 g, 5.04 mmol, 57 %) after chromatogra-
[
19]
equipped with a diamond ATR unit. 1-Benzyl-1-phenylhydrazine
[20]
and 1-Allyl-1-phenylhydrazine are literature known and were pre- phy (SiO
, hexanes/EtOAc, 2:1, R
H-NMR (300 MHz, CDCl ): δ = 1.24 (t, J = 7.1 Hz, 3H), 1.30–1.43 (m,
3H), 1.54–2.65 (m, 12H), 4.11 (q, J = 7.1 Hz, 2H) ppm. All spectro-
= 0.48) as a colorless liquid.
2
f
1
pared accordingly. δ-Oxoesters 9a–9c and 9e were literature known
3
and prepared accordingly.[
commercially available.
14,21,22]
All other starting materials were
[
21]
scopic data are in accordance with the literature.
C H O
12 20 3
–
1
(212.29 g mol ).
1
5
-Benzyl-1-phenylhydrazine.[19] Phenylhydrazine (541 mg,
.00 mmol) and benzyl bromide (855 mg, 5.00 mmol) were added
to a solution of NaHCO (420 mg, 5.00 mmol) in H O (5 mL). The
Ethyl 3-(2-oxocyclopentyl)propanoate (9c).[22] According to GPA,
cyclopentanone (1.00 g, 11.9 mmol) was converted with pyrrolidine
(1.69 g, 23.8 mmol) and ethyl acrylate (1.55 g, 15.5 mmol) to yield
the title compound 9c (1.39 g, 7.57 mmol, 64 %) after chromatogra-
3
2
resulting mixture was stirred at 100 °C for 3 h, subsequently cooled
to ambient temperature, and extracted with MTBE (3 × 15 mL). The
combined organic layers were dried (MgSO ), filtered and the sol-
1
phy (SiO , hexanes/MTBE, 1:1, R = 0.39) as a colorless liquid. H-
4
2
f
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J = 7.5 Hz, J = 1.2 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H) ppm. 13C{ H}-
1
NMR (300 MHz, CDCl ): δ = 1.25 (t, J = 7.2 Hz, 3H), 1.48–2.33 (m,
3
9
H), 2.40 (t, J = 7.6 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H) ppm. All spectro- NMR (125 MHz, CDCl ): δ = 14.0 (CH ), 26.4 (CH ), 31.8 (CH ), 32.6
3
3
2
2
[22]
scopic data are in accordance with the literature.
C H O
(CH ), 46.2 (CH), 60.2 (CH ), 123.7 (CH), 126.3 (CH), 127.2 (CH), 134.6
2 2
1
0
16
3
–1
(184.24 g mol ).
(CH), 136.4 (C), 153.1 (C), 172.8 (C), 207.6 (C) ppm. IR (ATR): ν˜ = 2980
(
(
(
w), 2933 (w), 1729 (s), 1706 (vs), 1609 (m), 1589 (w), 1474 (w), 1464
m), 1436 (w), 1376 (w), 1326 (w), 1296 (w), 1275 (w), 1206 (w), 1177
w), 1146 (w), 1094 (w), 1069 (w), 1032 (w), 857 (w), 751 (m), 724
Ethyl 3-(1-acetyl-4-oxopiperidin-3-yl)propanoate (9d). Accord-
ing to GPA, N-acetyl-4-piperidone (988 mg, 7.00 mmol) was con-
verted with pyrrolidine (966 mg, 14.0 mmol) and ethyl acrylate
–
1
+
(w) cm . HR-MS (EI, 70 eV): calcd. 232.1094 (for C H O ), found
14 16 3
(911 mg, 9.10 mmol) to yield the title compound 9d (431 mg,
+
–1
2
32.1087 [M ]. C H O (232.28 g mol ). The compound was re-
14 16 3
1
.79 mmol, 26 %) after chromatography (SiO , EtOAc/MeOH, 10:1,
2
[26]
ported in literature, but insufficiently characterized.
Rf = 0.41) as a colorless liquid. NMR spectra showed partly doubled
signal sets due to E/Z-isomers (ratio 1:0.9) at the amide C–N-bond.
Conversion of δ-oxoester 9a with phenylhydrazine (Table 1,
1
conditions c). Et SiH (163 mg, 1.40 mmol) was added to a solution
H-NMR (500 MHz, CDCl ), major isomer: δ = 1.11–1.15 (m, 3H),
3
3
of δ-oxoester 9a (139 mg, 701 μmol) and phenylhydrazine (83 mg,
1.44–1.51 (m, 2H), 1.90–2.00 (m, 2H), 2.07 (s, 3H), 2.21–2.43 (m, 1H),
2.85 (dd, J = 13.0 Hz, J = 10.4 Hz, 1H), 3.10 (dd, J = 13.4 Hz, J =
10.5 Hz, 1H), 3.44 (dt, J = 13.8 Hz, J = 7.1 Hz, 1H), 3.83–3.92 (m, 2H),
3.97–4.02 (m, 2H), 4.37 (ddd, J = 13.0 Hz, J = 5.8 Hz, J = 1.5 Hz, 1H)
0
.77 mmol) in glacial acetic acid (3 mL), and the resulting mixture
was stirred at 100 °C for 16 h. Subsequently, the mixture was cooled
to ambient temperature, diluted with H O (5 mL), and extracted
2
with CH Cl (3 × 5 mL). The combined organic layers were washed
ppm; minor isomer: δ = 1.11–1.15 (m, 3H), 2.08 (s, 3H), 2.21–2.43
2
2
with sat. aq. NaHCO solution (1 × 5 mL), dried (MgSO ), filtered
(
m, 9H), 3.18 (ddd, J = 13.8 Hz, J = 9.1 Hz, J = 5.4 Hz, 1H), 3.97–4.02
m, 2H), 4.32 (dtd, J = 13.0 Hz, J = 5.7 Hz, J = 1.8 Hz, 1H) ppm.
3
4
and the solvent was removed in vacuo. The crude product was
(
1
3
1
purified by column chromatography (SiO , hexanes/EtOAc, 1:1) to
C{ H}-NMR (125 MHz, CDCl ), major isomer: δ = 13.90 (CH ), 21.0
2
3
3
yield in the first fraction the lactam 12 (16 mg, 71 μmol, 10 %,
(CH ), 21.9 (CH ), 22.1 (CH ), 45.3 (CH ), 45.4 (CH ), 48.6 (CH), 50.1
3 2 2 2 2
[
15b]
Rf = 0.57) as a light brown solid, mp. 120–123 °C; Lit.
126 °C.
(CH ), 60.1 (CH ), 168.9 (C), 172.59 (C), 207.7 (C) ppm; minor isomer:
2
2
Secondly, the tetrahydrocarbazole 13a (140 mg, 516 μmol, 74 %,
δ = 13.91 (CH ), 21.0 (CH ), 31.2 (2 CH ), 40.2 (CH ), 40.6 (CH ), 41.0
3
3
2
2
2
Rf = 0.28) was obtained as a yellow resin in another fraction.
(CH ), 49.0 (CH), 60.3 (CH ), 169.0 (C), 172.58 (C), 207.7 (C) ppm. IR
2
2
(
(
(
2
ATR): ν˜ = 2970 (w), 2937 (w), 2876 (w), 1724 (vs), 1644 (vs), 1424 2,3,3a,4,5,6-Hexahydro-6H-pyrido[3,2,1-jk]carbazole-6-one
[15b] 1
s), 1366 (m), 1312 (w), 1267 (m), 1234 (w), 1164 (m), 1139 (w), 1096
(12).
H-NMR (500 MHz, CDCl ): δ = 1.33–1.41 (m, 1H), 1.62 (qd,
3
–
1
w), 1029 (s), 854 (m), 600 (m) cm . HR-MS (EI, 70 eV): calcd.
J = 12.9 Hz, J = 4.5 Hz, 1H), 1.76–1.85 (m, 1H), 2.08–2.18 (m, 3H),
2.56 (dddt, J = 15.4 Hz, J = 9.4 Hz, J = 6.1 Hz, J = 3.5 Hz, 1H), 2.68–
2.83 (m, 4H), 7.24–7.31 (m, 2H), 7.38–7.40 (m, 1H), 8.42–8.44 (m, 1H)
ppm. 13C{ H}-NMR (125 MHz, CDCl ): δ = 20.1 (CH ), 22.5 (CH ), 28.7
+
+
41.1309 (for C H NO ), found 241.1307 [M ]. C H NO
12 19 4 12 19 4
–1
(241.29 g mol ).
1
3
2
2
Ethyl 3-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)propanoate
(
9e).[21]
(CH
2
), 29.5 (CH
2
), 32.5 (CH), 34.5 (CH ), 114.2 (C), 116.1 (CH), 117.8
2
A solution of 1-tetralone (1.02 g, 7.00 mmol), pyrrolidine
(
CH), 123.6 (CH), 123.9 (CH), 130.0 (C), 134.7 (C), 136.9 (C), 168.9 (C)
ppm. IR (ATR): ν˜ = 2942 (m), 2837 (m), 1699 (vs), 1632 (m), 1456
vs), 1440 (s), 1389 (vs), 1330 (m), 1310 (m), 1297 (m), 1246 (m),
(996 mg, 14.0 mmol), and pTosOH·H O (133 mg, 699 μmol) in tolu-
2
ene (9 mL) was heated to reflux under water separation using a
Dean–Stark trap for 24 h. Subsequently, all volatile materials were
removed under reduced pressure and the crude enamine was dis-
solved in abs. 1,4-dioxane (9 mL). Ethyl acrylate (911 mg, 9.10 mmol)
was added and the resulting mixture was heated to reflux for 16 h.
Then H O (3 mL) was added and the mixture was further refluxed
for 2 h. Subsequently, all volatile materials were removed under
reduced pressure and the residue was diluted with hydrochloric Ethyl 3-(2,3,4,4a-tetrahydro-1H-carbazol-4a-yl)propanoate
(
1
6
2
236 (m), 1176 (m), 1142 (m), 1129 (m), 1013 (m), 944 (m), 757 (vs),
–
1
82 (m), 582 (m), 567 (s), 560 (s) cm . HR-MS (EI, 70 eV): calcd.
+
+
25.1148 (for C15H15NO ), found 225.1145 [M ]. C15H15NO
–
1
(225.29 g mol ). The compound was reported in literature, but in-
2
[
15b]
sufficiently characterized.
–1
[16] 1
acid (2 mol L , 10 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine (1 × 10 mL), dried
(13a).
H-NMR (300 MHz, CDCl ): δ = 1.15 (t, J = 7.1 Hz, 3H),
3
1.15–1.25 (m, 1H), 1.42 (qt, J = 13.4 Hz, J = 4.4 Hz, 1H), 1.51–1.71
(
MgSO ), filtered and the solvent was removed in vacuo. The crude (m, 3H), 1.86 (qt, J = 13.6 Hz, J = 3.7 Hz, 1H), 2.10–2.24 (m, 2H),
4
product was purified by column chromatography (SiO , CH Cl , R =
0
an orange oil. H-NMR (300 MHz, CDCl ): δ = 1.24 (t, J = 7.1 Hz, 3H),
1
2.31–2.47 (m, 2H), 2.55 (td, J = 13.2 Hz, J = 5.7 Hz, 1H), 2.86–2.90
2
2
2
f
.34) to yield the title compound 9e (753 mg, 3.06 mmol, 44 %) as (m, 1H), 3.91–4.07 (m, 2H), 7.19 (t, J = 7.3 Hz, 1H), 7.27 (d, J =
1
6.4 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H) ppm. All
3
[
16]
.78–1.96 (m, 2H), 2.18–2.31 (m, 2H), 2.45–2.58 (m, 3H), 2.99–3.03 spectroscopic data are in accordance with the literature.
m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.29 (t, J =
–
1
(
C H21NO (271.36 g mol ).
17 2
7
.6 Hz, 1H), 7.45 (td, J = 7.5 Hz, J = 1.4 Hz, 1H), 8.00 (dd, J = 7.8 Hz,
General procedure B (GPB) for the preparation of hexahydro-
J = 1.1 Hz, 1H) ppm. All spectroscopic data are in accordance with
carbazole derivatives 10: A solution of δ-oxoester 9 (1.0 equiv.)
the literature.[ C H O (246.31 g mol ).
21]
–1
–1
15
18
3
and arylhydrazine (1.1–1.2 equiv.) in glacial acetic acid (2 L mol
Ethyl 3-(1-oxo-2,3-dihydro-1H-inden-2-yl)propanoate (9f).[26]
According to GPA, 1-indanone (925 mg, 7.00 mmol) was converted
with pyrrolidine (996 mg, 14.0 mmol) and ethyl acrylate (911 mg,
δ-oxoester) was stirred at 100 °C for 2.5 h and subsequently cooled
to ambient temperature. Then NaBH(OAc) (2.0 equiv.) was added
3
and the resulting mixture was further stirred at ambient tempera-
–
1
ture for 1.5 h. The mixture was diluted with H O (5 L mol ) and
2
9
2
.10 mmol) to yield the title compound 9f (404 mg, 1.74 mmol,
5 %) after chromatography (SiO , CH Cl , R = 0.23) as a pale yellow
–
1
extracted with CH Cl (3 × 5 L mol ). The combined organic layers
2
2
2
2
2
f
–1
1
were washed with sat. aq. NaHCO
3
solution (1 × 5 L mol ), dried
liquid. H-NMR (500 MHz, CDCl ): δ = 1.19 (t, J = 7.1 Hz, 3H), 1.79
3
(
MgSO ), filtered and the solvent was removed in vacuo. The crude
4
(dtd, J = 13.8 Hz, J = 8.5 Hz, J = 7.4 Hz, 1H), 2.16 (dtd, J = 13.8 Hz,
product was purified by column chromatography to furnish hexa-
hydrocarbazole derivatives 10.
J = 7.8 Hz, J = 5.8 Hz, 1H), 2.44 (t, J = 7.7 Hz, 2H), 2.63 (tdd, J =
8.2 Hz, J = 5.8 Hz, J = 4.1 Hz, 1H), 2.73 (dd, J = 17.1 Hz, J = 4.1 Hz,
1H), 3.29 (dd, J = 17.1 Hz, J = 7.9 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H),
7.29 (t, J = 7.4 Hz, 1H), 7.38 (dt, J = 7.7 Hz, J = 1.0 Hz, 1H), 7.51 (td,
Ethyl cis-3-(2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)propan-
oate (10a). According to GPB, δ-oxoester 9a (198 mg, 1.00 mmol)
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and phenylhydrazine (119 mg, 1.10 mmol) were converted with
32.7 (CH ), 32.9 (CH ), 46.8 (C), 55.8 (CH ), 60.2 (CH ), 63.7 (CH),
2 2 3 2
NaBH(OAc) (424 mg, 2.00 mmol) in AcOH (2 mL) to yield the title
109.8 (CH), 110.8 (CH), 111.7 (CH), 136.4 (C), 143.8 (C), 153.4 (C),
3
compound 10a (233 mg, 852 μmol, 85 %) after chromatography 173.9 (C) ppm. IR (ATR): ν˜ = 3353 (w), 2980 (w), 2927 (s), 2856 (m),
(
SiO , hexanes/CH Cl /MeOH, 1:1:0.03, R = 0.09) as a light brown
1727 (vs), 1597 (w), 1484 (s), 1447 (w), 1433 (m), 1373 (m), 1299 (w),
1251 (w), 1209 (m), 1174 (m), 1033 (s), 862 (w), 804 (m), 747 (w),
2
2
2
f
1
solid, mp. 60–62 °C. H-NMR (500 MHz, CDCl ): δ = 1.21 (t, J = 7.1 Hz,
3
1
3
–
1
H), 1.27–1.35 (m, 2H), 1.41–1.52 (m, 3H), 1.54–1.60 (m, 1H), 1.69–
.75 (m, 1H), 1.81–1.91 (m, 2H), 2.12 (ddd, J = 13.9 Hz, J = 10.5 Hz, C H NO ), found 303.1822 [M ]. C H NO (303.40 g mol ).
674 (w), 562 (w) cm . HR-MS (EI, 70 eV): calcd. 303.1829 (for
+
+
–1
18
25
3
18 25
3
J = 6.2 Hz, 1H), 2.20–2.31 (m, 2H), 3.44 (dd, J = 6.6 Hz, J = 5.2 Hz,
Ethyl cis-3-(5,7-dimethyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-
a-yl)propanoate (10d). According to GPB, δ-oxoester 9a (198 mg,
.00 mmol) and 3,5-dimethylphenylhydrazine (163 mg, 1.20 mmol)
were converted with NaBH(OAc)3 (424 mg, 2.00 mmol) in AcOH
2 mL) to yield the title compound 10d (205 mg, 680 μmol, 68 %)
after chromatography (SiO , hexanes/CH Cl /MeOH, 1:1:0.02, R =
1
6
H), 3.59 (br s, 1H), 4.07 (q, J = 7.1 Hz, 2H), 6.66 (d, J = 7.7 Hz, 1H),
.74 (td, J = 7.4 Hz, J = 0.9 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 7.03 (td,
4
1
1
3
1
J = 7.6 Hz, J = 1.3 Hz, 1H) ppm. C{ H}-NMR (125 MHz, CDCl ): δ =
3
1
3
1
4.2 (CH ), 21.2 (CH ), 21.4 (CH ), 29.0 (CH ), 30.0 (CH ), 32.88 (CH ),
3 2 2 2 2 2
(
2.93 (CH ), 46.4 (C), 60.2 (CH ), 63.4 (CH), 110.3 (CH), 118.6 (CH),
2
2
2
2
2
f
22.6 (CH), 127.3 (CH), 134.5 (C), 150.1 (C), 174.0 (C) ppm. IR (ATR):
1
0
7
1
1
2
1
.17) as a pale yellow oil. H-NMR (500 MHz, CDCl ): δ = 1.22 (t, J =
3
ν˜ = 3362 (w), 2927 (s), 2856 (m), 1729 (vs), 1607 (m), 1480 (m), 1462
.1 Hz, 3H), 1.38–1.47 (m, 3H), 1.55–1.72 (m, 4H), 1.79 (ddd, J =
3.8 Hz, J = 9.5 Hz, J = 4.5 Hz, 1H), 2.07 (ddd, J = 14.2 Hz, J =
1.5 Hz, J = 4.9 Hz, 1H), 2.11–2.23 (m, 2H), 2.21 (s, 3H), 2.25 (s, 3H),
.31 (ddd, J = 15.2 Hz, J = 11.5 Hz, J = 5.4 Hz, 1H), 3.45 (t, J = 4.5 Hz,
H), 4.09 (q, J = 7.1 Hz, 2H), 6.32 (s, 1H), 6.34 (s, 1H) ppm; a signal
(
(
7
s), 1452 (m), 1373 (w), 1303 (w), 1247 (w), 1174 (m), 1152 (m), 1019
–
1
m), 742 (vs), 677 (w), 603 (w), 554 (w), 534 (w) cm . HR-MS (EI,
0 eV): calcd. 273.1723 (for C17H23NO2+), found 273.1731 [M ].
+
–
1
C H NO (273.38 g mol ).
17
23
2
13
1
Reduction of tetrahydrocarbazole 13a with NaBH(OAc)3.
for the NH proton was not observed. C{ H}-NMR (125 MHz, CDCl ):
3
NaBH(OAc) (158 mg, 745 μmol) was added to a solution of tetrahy- δ = 14.2 (CH ), 18.6 (CH ), 20.57 (CH ), 20.62 (CH ), 21.2 (CH ), 27.3
3
3
3
2
2
3
drocarbazole 13a (100 mg, 369 μmol) in glacial acetic acid (1 mL)
(CH ), 30.9 (CH ), 31.1 (CH ), 33.3 (CH ), 47.6 (C), 60.2 (CH ), 61.5
2 2 2 2 2
and the resulting mixture was stirred at ambient temperature for (CH), 108.9 (CH), 122.6 (CH), 129.3 (C), 133.7 (C), 137.1 (C), 150.6 (C),
5
h. Subsequently, the mixture was diluted with H O (5 mL) and 174.1 (C) ppm. IR (ATR): ν˜ = 3362 (w), 2927 (m), 2857 (m), 1727 (vs),
2
extracted with CH Cl (3 × 5 mL). The combined organic layers were 1614 (m), 1587 (m), 1447 (m), 1373 (m), 1297 (m), 1259 (m), 1174
washed with sat. aq. NaHCO solution (1 × 5 mL), dried (MgSO ), (vs), 1160 (s), 1023 (m), 826 (s), 643 (m), 606 (m), 569 (m) cm . HR-
filtered and the solvent was removed in vacuo to yield the title MS (EI, 70 eV): calcd. 301.2036 (for C H NO ), found 301.2034
compound 10a (92 mg, 0.34 mmol, 91 %) as a light brown solid, [M ]. C H NO (301.43 g mol ).
2
2
–1
3
4
+
19
27
2
+
–1
19
27
2
mp. 60–62 °C.
Ethyl cis-3-(6-fluoro-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-
yl)propanoate (10e). According to GPB, δ-oxoester 9a (198 mg,
Ethyl cis-3-(6-bromo-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-
yl)propanoate (10b). According to GPB, δ-oxoester 9a (198 mg, 1.00 mmol) and 4-fluorophenylhydrazine (151 mg, 1.20 mmol) were
1
.00 mmol) and 4-bromophenylhydrazine (225 mg, 1.20 mmol)
converted with NaBH(OAc) (424 mg, 2.00 mmol) in AcOH (2 mL)
3
were converted with NaBH(OAc)3 (424 mg, 2.00 mmol) in AcOH
to yield the title compound 10e (208 mg, 714 μmol, 71 %) after
(
2 mL) to yield the title compound 10b (215 mg, 610 μmol, 61 %) chromatography (SiO , hexanes/CH Cl /MeOH, 1:1:0.03, R = 0.21)
2 2 2 f
1
after chromatography (SiO , hexanes/CH Cl /MeOH, 1:1:0.03, R =
0
CDCl ): δ = 1.23 (t, J = 7.1 Hz, 3H), 1.27–1.33 (m, 2H), 1.38–1.60 (m,
4
2
4
1
as a pale yellow solid, mp. 86–89 °C. H-NMR (500 MHz, CDCl ): δ =
2
2
2
f
3
1
.31) as a pale yellow solid, mp. 116–118 °C. H-NMR (500 MHz,
1.21 (t, J = 7.1 Hz, 3H), 1.25–1.33 (m, 2H), 1.39–1.50 (m, 3H), 1.53–
1.59 (m, 1H), 1.67–1.73 (m, 1H), 1.78–1.84 (m, 2H), 2.07–2.14 (m, 1H),
2.22–2.25 (m, 2H), 3.41 (br s, 1H), 3.44 (dd, J = 6.7 Hz, J = 5.1 Hz,
1H), 4.06 (q, J = 7.1 Hz, 2H), 6.53 (dd, J = 8.2 Hz, J = 4.3 Hz, 1H),
3
H), 1.69–1.75 (m, 1H), 1.78–1.87 (m, 2H), 2.07–2.13 (m, 1H), 2.22–
.25 (m, 2H), 3.45 (dd, J = 6.6 Hz, J = 5.3 Hz, 1H), 3.60 (br s, 1H),
.08 (q, J = 7.1 Hz, 2H), 6.51 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 2.0 Hz,
6.67–6.72 (m, 2H) ppm. 13C{ H}-NMR (125 MHz, CDCl ): δ = 14.1
1
3
1
3
1
H), 7.11 (dd, J = 8.2 Hz, J = 2.0 Hz, 1H) ppm. C{ H}-NMR (125 MHz, (CH ), 21.1 (CH ), 21.3 (CH ), 28.7 (CH ), 29.9 (CH ), 32.6 (CH ), 32.9
3
2
2
2
2
2
2
CDCl ): δ = 14.2 (CH ), 21.0 (CH ), 21.3 (CH ), 28.9 (CH ), 29.9 (CH ), (CH ), 46.8 (C), 60.3 (CH ), 63.8 (CH), 110.0 (d, J = 23.6 Hz, CH),
3
3
3
2
2
2
2
2
2
3
2
3
2.8 (CH ), 32.9 (CH ), 46.8 (C), 60.4 (CH ), 63.8 (CH), 110.2 (C), 111.6 110.4 (d, J = 8.1 Hz, CH), 113.2 (d, J = 23.2 Hz, CH), 136.4 (d, J =
2 2 2
1
(CH), 125.7 (CH), 130.1 (CH), 136.9 (C), 149.1 (C), 173.7 (C) ppm. IR
(ATR): ν˜ = 3346 (m), 2959 (w), 2925 (m), 2856 (w), 1729 (vs), 1596
(w), 1467 (m), 1447 (w), 1416 (w), 1376 (m), 1299 (w), 1209 (m),
6.9 Hz, C), 145.9 (C), 157.0 (d, J = 235.3 Hz, C), 173.7 (C) ppm.
19
1
F{ H}-NMR (470 MHz, CDCl ): δ = –126.00 ppm. IR (ATR): ν˜ = 3353
3
(m), 2989 (w), 2932 (m), 2857 (w), 1724 (vs), 1604 (w), 1479 (s), 1450
(m), 1417 (w), 1376 (m), 1296 (m), 1250 (m), 1206 (s), 1180 (m), 1046
(m), 1029 (m), 1016 (m), 1001 (m), 904 (m), 876 (m), 861 (m), 823
1
8
(
180 (m), 1147 (w), 1082 (w), 1047 (w), 1024 (w), 1013 (w), 996 (w),
76 (m), 860 (w), 834 (w), 824 (m), 773 (w), 739 (m), 706 (w), 629
m), 599 (s), 547 (m) cm . HR-MS (EI, 70 eV): calcd. 351.0828 (for
–
1
–1
(m), 810 (m), 744 (m), 663 (m), 562 (m), 504 (m) cm . HR-MS (EI,
+
+
–1
+
+
C H BrNO ), found 351.0819 [M ]. C H BrNO (352.27 g mol ). 70 eV): calcd. 291.1629 (for C17H22FNO2 ), found 291.1627 [M ].
17
22
2
17 22
2
–
1
C H FNO (291.37 g mol ).
17
22
2
Ethyl cis-3-(6-methoxy-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-
yl)propanoate (10c). According to GPB, δ-oxoester 9a (198 mg,
Ethyl cis-3-(9-benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-
yl)propanoate (10f). According to GPB, δ-oxoester 9a (198 mg,
1
.00 mmol) and 4-methoxyphenylhydrazine (170 mg, 1.23 mmol)
were converted with NaBH(OAc)3 (424 mg, 2.00 mmol) in AcOH
2 mL) to yield the title compound 10c (156 mg, 514 μmol, 51 %) 1.20 mmol) were converted with NaBH(OAc) (424 mg, 2.00 mmol)
[
19]
1.00 mmol) and 1-benzyl-1-phenylhydrazine
(238 mg,
(
3
after chromatography (SiO , hexanes/MTBE, 1:1, R = 0.24) as a pale in AcOH (2 mL) to yield the title compound 10f (266 mg, 732 μmol,
2
f
1
yellow oil. H-NMR (500 MHz, CDCl ): δ = 1.20 (t, J = 7.1 Hz, 3H),
73 %) after chromatography (SiO , hexanes/MTBE, 9:1, R = 0.28) as
3
2
f
1
1
.25–1.33 (m, 2H), 1.40–1.50 (m, 3H), 1.54–1.59 (m, 1H), 1.66–1.72 a colorless oil. H-NMR (500 MHz, CDCl ): δ = 1.25 (t, J = 7.1 Hz, 3H),
3
(
(
m, 1H), 1.79–1.87 (m, 2H), 2.07–2.13 (m, 1H), 2.23–2.27 (m, 2H), 3.29
1.29–1.41 (m, 2H), 1.46–1.60 (m, 3H), 1.61–1.72 (m, 2H), 1.82–1.87
br s, 1H), 3.42 (dd, J = 6.7 Hz, J = 5.0 Hz, 1H), 3.74 (s, 3H), 4.06 (q, (m, 1H), 1.94–1.99 (m, 1H), 2.12–2.35 (m, 3H), 3.28 (t, J = 5.0 Hz, 1H),
1
3
1
J = 7.1 Hz, 2H), 6.56–6.60 (m, 3H) ppm. C{ H}-NMR (125 MHz,
4.11 (q, J = 7.1 Hz, 2H), 4.15 (d, J = 15.7 Hz, 1H), 4.42 (d, J = 15.7 Hz,
CDCl ): δ = 14.1 (CH ), 21.3 (CH ), 21.4 (CH ), 28.8 (CH ), 29.9 (CH ), 1H), 6.43 (d, J = 7.8 Hz, 1H), 6.72 (t, J = 7.3 Hz, 1H), 6.99 (d, J =
3
3
2
2
2
2
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7
.2 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.1 Hz, 1H), 7.35 (t, (CH ), 51.1 (C), 60.1 (CH ), 68.5 (CH), 108.2 (CH), 117.7 (CH), 123.4
2 2
1
3
1
J = 7.5 Hz, 2H), 7.40 (d, J = 7.4 Hz, 2H) ppm. C{ H}-NMR (125 MHz, (CH), 127.5 (CH), 134.0 (C), 149.8 (C), 174.1 (C) ppm. IR (ATR): ν˜ =
CDCl ): δ = 14.2 (CH ), 21.0 (CH ), 21.4 (CH ), 24.0 (CH ), 30.2 (CH ), 3380 (w), 2980 (w), 2922 (m), 2853 (m), 1724 (s), 1606 (m), 1486 (m),
3
3
2
2
2
2
3
1.4 (CH ), 34.2 (CH ), 45.7 (C), 50.2 (CH ), 60.2 (CH ), 67.3 (CH),
1464 (m), 1456 (m), 1374 (w), 1314 (w), 1297 (w), 1254 (w), 1162
2
2
2
2
1
07.9 (CH), 117.6 (CH), 121.9 (CH), 126.8 (CH), 127.3 (2 CH), 127.4 (m), 1094 (w), 1020 (m), 910 (m), 860 (w), 730 (vs), 649 (w), 586 (w)
–
1
+
(
(
(
(
CH), 128.4 (2 CH), 135.2 (C), 139.0 (C), 151.2 (C), 173.9 (C) ppm. IR
cm . HR-MS (EI, 70 eV): calcd. 287.1880 (for C H NO ), found
18 25 2
+
–1
ATR): ν˜ = 2929 (m), 2855 (w), 1730 (vs), 1603 (m), 1494 (w), 1479 287.1875 [M ]. C H NO (287.40 g mol ).
18
25
2
s), 1452 (m), 1374 (w), 1353 (w), 1300 (w), 1266 (w), 1174 (m), 1156
Ethyl cis-3-(2-acetyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]-
indol-9b-yl)propanoate (10j). According to GPB, δ-oxoester 9d
–
1
w), 1026 (m), 734 (vs), 696 (s) cm . HR-MS (EI, 70 eV): calcd.
63.2193 (for C24H29NO2+), found 363.2192 [M ]. C24H29NO2
+
3
(
241 mg, 1.00 mmol) and phenylhydrazine (130 mg, 1.20 mmol)
were converted with NaBH(OAc)3 (424 mg, 2.00 mmol) in AcOH
2 mL) to yield the title compound 10j (100 mg, 316 μmol, 32 %)
after chromatography (SiO , EtOAc/MeOH, 10:0.4, R = 0.22) as a
–1
(363.50 g mol ).
Ethyl cis-3-(9-allyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
propanoate (10g). According to GPB, δ-oxoester 9a (117 mg,
5
(
2
f
90 μmol) and 1-allyl-1-phenylhydrazine[ (105 mg, 708 μmol)
20]
pale yellow oil. At ambient temperature, NMR spectra showed partly
doubled and broadened signal sets due to the amide moiety. At
were converted with NaBH(OAc)3 (250 mg, 1.18 mmol) in AcOH
1 mL) to yield the title compound 10g (144 mg, 459 μmol, 78 %)
after chromatography (SiO , hexanes/MTBE, 9:1, R = 0.30) as a color-
(
1
1
3
73 K, the H-NMR spectrum showed a single signal set. H-NMR
2
f
(500 MHz, [D ]DMSO, 373 K): δ = 1.16 (t, J = 7.1 Hz, 3H), 1.68–1.72
6
1
less oil. H-NMR (500 MHz, CDCl ): δ = 1.22 (t, J = 7.1 Hz, 3H), 1.34–
3
(m, 1H), 1.82–1.98 (m, 7H), 2.08–2.14 (m, 1H), 2.25–2.32 (m, 1H),
1
1
3
1
.39 (m, 2H), 1.42–1.56 (m, 3H), 1.62–1.65 (m, 2H), 1.69–1.74 (m, 1H),
.93 (ddd, J = 13.7 Hz, J = 10.5 Hz, J = 5.6 Hz, 1H), 2.16–2.31 (m,
H), 3.26 (t, J = 4.8 Hz, 1H), 3.59 (ddt, J = 16.1 Hz, J = 6.7 Hz, J =
.5 Hz, 1H), 3.85 (ddt, J = 16.1 Hz, J = 4.8 Hz, J = 1.8 Hz, 1H), 4.09
3
6
.40–3.65 (m, 5H), 4.02 (q, J = 7.1 Hz, 2H), 6.52 (d, J = 7.8 Hz, 1H),
.56 (t, J = 7.3 Hz, 1H), 6.93–7.01 (m, 2H) ppm. C{ H}-NMR
13
1
(125 MHz, CDCl ): δ = 14.1 (2 CH ), 21.2 (CH ), 21.3 (CH ), 26.4 (CH ),
3 3 3 3 2
2
4
8.0 (CH ), 29.55 (CH ), 29.58 (CH ), 30.3 (CH ), 31.1 (CH ), 37.5 (CH ),
2 2 2 2 2 2
(
q, J = 7.1 Hz, 2H), 5.17 (dq, J = 10.3 Hz, J = 1.6 Hz, 1H), 5.28 (dq,
J = 17.2 Hz, J = 1.6 Hz, 1H), 5.89 (dddd, J = 17.2 Hz, J = 10.3 Hz, J =
.7 Hz, J = 4.8 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 6.68 (td, J = 7.4 Hz,
J = 1.0 Hz, 1H), 6.94 (dd, J = 7.2 Hz, J = 1.3 Hz, 1H), 7.06 (td, J =
1.3 (CH ), 45.7 (CH ), 48.6 (C), 48.8 (C), 51.9 (CH ), 59.9 (CH), 60.1
2
2
2
(
(
(
CH), 60.3 (CH ), 60.5 (CH ), 109.4 (CH), 109.8 (CH), 118.8 (CH), 119.0
CH), 122.6 (CH), 123.4 (CH), 128.2 (CH), 128.6 (CH), 130.4 (C), 131.3
C), 150.1 (C), 150.5 (C), 169.4 (C), 169.7 (C), 173.2 (C), 173.4 (C) ppm.
2 2
6
1
3
1
7
.6 Hz, J = 1.4 Hz, 1H) ppm. C{ H}-NMR (125 MHz, CDCl ): δ = 14.2
3
IR (ATR): ν = 3312 (w), 2980 (w), 2927 (w), 2872 (w), 1727 (vs), 1629
(vs), 1607 (s), 1484 (m), 1466 (m), 1424 (m), 1367 (w), 1267 (w), 1179
(m), 1020 (m), 984 (w), 749 (s), 596 (w) cm . HR-MS (EI, 70 eV):
calcd. 316.1781 (for C H N O ), found 316.1776 [M ]. C H N O
˜
(CH ), 20.7 (CH ), 21.3 (CH ), 23.7 (CH ), 30.3 (CH ), 31.0 (CH ), 34.6
3 2 2 2 2 2
(CH ), 45.5 (C), 48.2 (CH ), 60.3 (CH ), 66.4 (CH), 107.8 (CH), 116.7
–1
2
2
2
(CH ), 117.5 (CH), 121.8 (CH), 127.4 (CH), 134.3 (CH), 135.4 (C), 150.7
+
+
2
18 24 2 3 18 24 2 3
(
(
(
C), 174.0 (C) ppm. IR (ATR): ν˜ = 3073 (w), 3049 (w), 2980 (w), 2929
m), 2856 (w), 1732 (vs), 1604 (m), 1477 (s), 1460 (m), 1373 (w), 1302
w), 1249 (w), 1176 (m), 1157 (m), 1024 (m), 917 (m), 754 (s), 739
–1
(316.40 g mol ).
Conversion of δ-oxoester 9e with phenylhydrazine and
NaBH(OAc) : A solution of δ-oxoester 9e (246 mg, 1.00 mmol) and
phenylhydrazine (162 mg, 1.50 mmol) in glacial acetic acid (2 mL)
was stirred at 100 °C for 16 h and subsequently cooled to ambient
temperature. Then NaBH(OAc) (530 mg, 2.50 mmol) was added and
the resulting mixture was further stirred at ambient temperature
for 3 h. The mixture was diluted with H O (10 mL) and extracted
with CH Cl (3 × 10 mL). The combined organic layers were washed
with sat. aq. NaHCO solution (10 mL), dried (MgSO ), filtered and
the solvent was removed in vacuo. The residue was purified by
column chromatography (SiO , hexanes/MTBE, 3:1, R = 0.29) to
yield in the first fraction the crude product 10k together with some
starting material 9e. Secondly, dihydrobenzocarbazole 13k (10 mg,
–1
+
(vs) cm . HR-MS (EI, 70 eV): calcd. 313.2036 (for C H NO ), found
3
2
0
27
2
+
–1
3
13.2028 [M ]. C H NO (313.44 g mol ).
20 27 2
Ethyl cis-3-(5a,6,7,8,9,10-hexahydro-5H-cyclohepta[b]indol-10a-
yl)propanoate (10h). A solution of δ-oxoester 9b (213 mg,
3
1
.00 mmol) and phenylhydrazine (162 mg, 1.50 mmol) in glacial
2
acetic acid (2 mL) was stirred at 100 °C for 5 h and subsequently
cooled to ambient temperature. Then NaBH(OAc) (424 mg,
2
2
3
3
4
2
.00 mmol) was added and the resulting mixture was further stirred
at ambient temperature for 16 h. The mixture was diluted with H O
2
2
f
(10 mL) and extracted with CH Cl (3 × 10 mL). The combined or-
2 2
ganic layers were washed with sat. aq. NaHCO solution (10 mL),
dried (MgSO ), filtered and the solvent was removed in vacuo. The
residue was purified by column chromatography (SiO , hexanes/
MTBE, 4:1 + 2 % NEt , R = 0.27) to yield the crude product together
with some starting material 9b. For further purification, this fraction
was diluted with MTBE (10 mL) and washed with half-concentrated
hydrochloric acid (10 mL). The aqueous layer was then neutralized
3
4
31 μmol, 3 %, R = 0.20) was obtained as a colorless oil in another
f
2
fraction. For further purification, the crude product 10k was diluted
with MTBE (10 mL) and washed with half-concentrated hydrochloric
acid (10 mL). The organic layer was dried (MgSO ), filtered and the
solvent was removed in vacuo to recover the starting material 9e
3
f
4
(74 mg, 0.30 mmol, 30 %). The aqueous layer was then neutralized
with sat. aq. NaHCO solution (50 mL) and extracted with MTBE (3 ×
3
with sat. aq. NaHCO solution (60 mL) and extracted with MTBE (3 ×
1
3
1
5 mL). The combined organic layers were dried (MgSO ), filtered
4
5 mL). The combined organic layers were dried (MgSO ), filtered
4
and the solvent was removed in vacuo to yield the title compound
0h (106 mg, 369 μmol, 37 %) as a pale yellow oil. 1H-NMR
500 MHz, CDCl ): δ = 1.20 (t, J = 7.2 Hz, 3H), 1.35–1.44 (m, 2H),
and the solvent was removed in vacuo to yield the title compound
0k (126 mg, 392 μmol, 39 %) as a colorless oil. The product was
isolated as a mixture of two diastereomers (dr = 81:19).
1
(
1
3
1
.48–1.59 (m, 4H), 1.69–1.80 (m, 3H), 1.86 (ddd, J = 13.6 Hz, J =
1
1.8 Hz, J = 4.9 Hz, 1H), 1.93–2.03 (m, 2H), 2.09 (ddd, J = 15.5 Hz, Ethyl 3-(6,6a,11,11a-tetrahydro-5H-benzo[a]carbazol-6a-yl)-
1
J = 11.6 Hz, J = 5.0 Hz, 1H), 2.32 (ddd, J = 15.5 Hz, J = 11.8 Hz, J =
propanoate (10k). H-NMR (500 MHz, CDCl ), major isomer: δ =
3
4
4
1
1
.6 Hz, 1H), 3.56 (dd, J = 8.9 Hz, J = 2.6 Hz, 1H), 3.66 (br s, 1H), 4.02–
.08 (m, 2H), 6.53 (d, J = 7.8 Hz, 1H), 6.67 (td, J = 7.4 Hz, J = 1.0 Hz,
1.22 (t, J = 7.1 Hz, 3H), 1.79 (ddd, J = 13.3 Hz, J = 10.2 Hz, J = 5.4 Hz,
1H), 2.07–2.11 (m, 2H), 2.19–2.31 (m, 2H), 2.48 (ddd, J = 16.3 Hz, J =
H), 6.89 (dd, J = 7.3 Hz, J = 1.2 Hz, 1H), 7.00 (td, J = 7.6 Hz, J = 10.0 Hz, J = 6.6 Hz, 1H), 2.59–2.64 (m, 2H), 4.05–4.12 (m, 2H), 4.60
.3 Hz, 1H) ppm. 13C{ H}-NMR (125 MHz, CDCl ): δ = 14.1 (CH ), 24.5 (s, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.77 (t, J = 7.4 Hz, 1H), 7.02 (t, J =
1
3
3
(
CH ), 25.7 (CH ), 29.6 (CH ), 30.9 (CH ), 33.9 (CH ), 36.8 (CH ), 37.2 7.6 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.12–
2 2 2 2 2 2
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European Journal of Organic Chemistry
7
1
3
1
.30 (m, 3H) ppm; minor isomer: δ = 1.13 (t, J = 7.1 Hz, 3H), 1.27–
.30 (m, 2H), 1.52–1.59 (m, 1H), 2.13–2.15 (m, 2H), 2.19–2.31 (m, 1H),
.03–3.06 (m, 2H), 3.92–3.96 (m, 2H), 4.58 (s, 1H), 6.86 (t, J = 7.4 Hz, (SiO , hexanes/MTBE, 3:1, R = 0.29) to yield the title compound 14
layer was dried (MgSO ), filtered and the solvent was removed in
vacuo. The crude product was purified by column chromatography
4
2
f
1
H), 6.89 (d, J = 7.7 Hz, 1H), 7.12–7.49 (m, 6H) ppm; signals for the (147 mg, 299 μmol, 75 %) as a colorless solid, mp. 116–118 °C. H-
1
3
1
NH protons were not observed. C{ H}-NMR (125 MHz, CDCl ), ma-
NMR (500 MHz, CDCl ): δ = 1.04–1.14 (m, 1H), 1.18 (t, J = 7.1 Hz,
3
3
jor isomer: δ = 14.2 (CH ), 27.0 (CH ), 29.8 (CH ), 33.2 (CH ), 36.0 3H), 1.20–1.28 (m, 2H), 1.36 (ddd, J = 13.8 Hz, J = 11.5 Hz, J = 5.2 Hz,
3
2
2
2
(
CH ), 48.1 (C), 60.3 (CH ), 65.3 (CH), 109.6 (CH), 118.8 (CH), 123.2
1H), 1.46–1.64 (m, 4H), 1.68 (ddd, J = 16.2 Hz, J = 11.4 Hz, J = 5.2 Hz,
1H), 1.85 (ddd, J = 16.2 Hz, J = 11.6 Hz, J = 5.1 Hz, 1H), 1.92–1.96
2
2
(CH), 126.7 (CH), 127.1 (CH), 127.8 (CH), 128.58 (CH), 128.62 (CH),
1
32.7 (C), 138.0 (C), 138.1 (C), 150.5 (C), 173.80 (C) ppm; minor iso- (m, 1H), 2.05–2.11 (m, 1H), 3.91 (dd, J = 8.1 Hz, J = 5.7 Hz, 1H), 4.00
mer: δ = 14.1 (CH ), 25.87 (CH ), 25.92 (CH ), 28.0 (CH ), 29.3 (CH ),
(q, J = 7.1 Hz, 2H), 6.97 (d, J = 7.1 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H),
3
2
2
2
2
4
1
1
7.2 (C), 60.1 (CH ), 70.4 (CH), 111.5 (CH), 119.6 (CH), 123.4 (CH), 7.22 (td, J = 7.8 Hz, J = 1.4 Hz, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.63 (d,
2
23.6 (CH), 125.8 (CH), 126.5 (CH), 127.6 (CH), 128.3 (CH), 136.0 (C), J = 8.1 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H) ppm. 13C{ H}-NMR (125 MHz,
1
36.2 (C), 136.6 (C), 151.2 (C), 173.82 (C) ppm. IR (ATR): ν˜ = 3369 CDCl ): δ = 14.2 (CH ), 19.9 (CH ), 20.0 (CH ), 28.6 (CH ), 29.2 (CH ),
3
3
2
2
2
2
(
(
w), 2980 (w), 2926 (w), 2852 (w), 1724 (vs), 1607 (m), 1484 (s), 1463
m), 1393 (w), 1374 (w), 1306 (w), 1252 (w), 1177 (m), 1156 (m),
29.8 (CH ), 36.9 (CH ), 46.5 (C), 60.4 (CH ), 68.5 (CH), 115.3 (CH),
2 2 2
123.5 (CH), 123.8 (CH), 128.0 (C), 128.2 (2 CH), 128.3 (CH), 132.3 (2
1
122 (w), 1093 (w), 1023 (m) 944 (w), 909 (m), 864 (w), 742 (vs), 670 CH), 136.0 (C), 137.9 (C), 140.4 (C), 172.7 (C) ppm. IR (ATR): ν˜ = 3086
–1
(w), 647 (w), 607 (w) cm . HR-MS (EI, 70 eV): calcd. 321.1723 (for
(w), 2934 (m), 2855 (w), 1727 (s), 1603 (w), 1573 (m), 1473 (m), 1459
(s), 1392 (m), 1347 (s), 1302 (w), 1279 (w), 1247 (w), 1160 (s), 1097
+
+
–1
C H NO ), found 321.1714 [M ]. C H NO (321.42 g mol ).
21
23
2
21 23
2
(
7
7
m), 1069 (m), 1009 (m), 979 (m), 846 (m), 833 (m), 760 (s), 733 (m),
Ethyl 3-(6,6a-dihydro-5H-benzo[a]carbazol-6a-yl)propanoate
–
1
12 (w), 701 (w), 616 (vs), 599 (s), 564 (vs), 550 (m) cm . HR-MS (EI,
1
(
13k). H-NMR (500 MHz, CDCl ): δ = 1.11 (t, J = 7.1 Hz, 3H), 1.63–
3
+
+
0 eV): calcd. 491.0760 (for C H BrNO S ), found 491.0770 [M ].
23
26
4
1
1
.70 (m, 1H), 1.75–1.83 (m, 2H), 2.17–2.20 (m, 2H), 2.51 (dd, J =
3.6 Hz, J = 5.0 Hz, 1H), 3.01 (dd, J = 17.8 Hz, J = 6.0 Hz, 1H), 3.36
–
1
C H BrNO S (492.43 g mol ).
23
26
4
Ethyl cis-3-[9-(3,4,5-trimethoxyphenyl)carbamoyl-2,3,4,4a,9,9a-
hexahydro-1H-carbazol-4a-yl]propanoate (15). 3,4,5-Trimethoxy-
phenyl isocyanate (100 mg, 478 μmol) was added to a solution of
hexahydrocarbazole 10a (109 mg, 399 μmol) in abs. toluene
(
ddd, J = 18.1 Hz, J = 12.6 Hz, J = 5.8 Hz, 1H), 3.88–3.98 (m, 2H),
.24 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.33–7.36 (m, 2H),
7
7
1
.38 (td, J = 7.6 Hz, J = 1.1 Hz, 1H), 7.42 (td, J = 7.5 Hz, J = 1.3 Hz,
H), 7.70 (d, J = 7.7 Hz, 1H), 8.12 (d, J = 7.5 Hz, 1H) ppm. 1 C{ H}-
3
1
(
0.4 mL) and the resulting mixture was stirred at 100 °C for 3 h.
Subsequently, the mixture was cooled to ambient temperature, di-
luted with CH Cl (10 mL) and washed with hydrochloric acid
NMR (125 MHz, CDCl ): δ = 14.0 (CH ), 25.8 (CH ), 27.9 (CH ), 28.8
3
3
2
2
(
(
(
CH ), 31.4 (CH ), 54.9 (C), 60.4 (CH ), 120.9 (CH), 122.1 (CH), 125.4
CH), 126.1 (CH), 126.9 (CH), 128.4 (CH), 129.0 (CH), 129.8 (C), 131.3
CH), 139.7 (C), 142.4 (C), 156.1 (C), 172.9 (C), 182.5 (C) ppm. IR (ATR):
2 2 2
2
2
–
1
(
1 mol L , 2 × 5 mL). The organic layer was dried (MgSO ), filtered
4
and the solvent was removed in vacuo. The crude product was
purified by column chromatography (SiO , hexanes/EtOAc, 1:1, R =
ν˜ = 3057 (w), 2980 (w), 2926 (w), 2857 (w), 1729 (s), 1574 (w), 1552
(m), 1453 (m), 1376 (w), 1352 (w), 1182 (w), 1157 (w), 1020 (w), 907
2
f
–
1
0.30) to yield the title compound 15 (136 mg, 282 μmol, 70 %) as
(m), 772 (m), 750 (s), 730 (s), 646 (w), 582 (w) cm . HR-MS (EI,
1
7
0 eV): calcd. 319.1567 (for C21H21NO2+), found 319.1571 [M ].
+
a colorless solid, mp. 162–164 °C. H-NMR (500 MHz, CDCl ): δ =
3
–
1
1.14–1.30 (m, 3H), 1.17 (t, J = 7.1 Hz, 3H), 1.50–1.63 (m, 3H), 1.71
C H NO (319.40 g mol ).
21
21
2
(ddd, J = 13.8 Hz, J = 10.1 Hz, J = 5.8 Hz, 1H), 1.93 (ddd, J = 13.8 Hz,
Ethyl cis-3-(4b,5,9b,10-tetrahydroindeno[1,2-b]indol-9b-yl)pro-
panoate (10l). According to GPB, δ-oxoester 9f (220 mg, 947 μmol)
and phenylhydrazine (123 mg, 1.14 mmol) were converted with
NaBH(OAc) (401 mg, 1.89 mmol) in AcOH (2 mL) to yield the title
compound 10l (82 mg, 0.27 mmol, 28 %) after chromatography
J = 10.3 Hz, J = 5.9 Hz, 1H), 2.03–2.10 (m, 1H), 2.19–2.25 (m, 3H),
3
6
.81 (s, 3H), 3.86 (s, 6H), 3.97–4.04 (m, 2H), 4.07 (dd, J = 9.3 Hz, J =
.2 Hz, 1H), 6.77–6.78 (m, 3H), 7.02 (t, J = 7.4 Hz, 1H), 7.09 (d, J =
3
7.0 Hz, 1H), 7.24 (td, J = 7.8 Hz, J = 1.6 Hz, 1H), 7.66 (d, J = 8.0 Hz,
13
1
1
H) ppm. C{ H}-NMR (125 MHz, CDCl ): δ = 14.1 (CH ), 21.4 (CH ),
3 3 2
1
(SiO , CH Cl /MeOH, 10:0.1, R = 0.45) as a colorless oil. H-NMR
2
2
2
f
21.9 (CH ), 28.5 (CH ), 29.1 (CH ), 30.1 (CH ), 37.4 (CH ), 46.1 (C),
2 2 2 2 2
(500 MHz, CDCl ): δ = 1.22 (t, J = 7.1 Hz, 3H), 2.17–2.29 (m, 3H),
3
56.1 (2 CH ), 60.5 (CH ), 60.9 (CH ), 67.0 (CH), 97.5 (2 CH), 115.6 (CH),
3 2 3
2
4
7
7
.43–2.50 (m, 1H), 3.25 (d, J = 16.2 Hz, 1H), 3.39 (d, J = 16.2 Hz, 1H),
.05–4.11 (m, 2H), 4.88 (s, 1H), 6.59 (d, J = 7.8 Hz, 1H), 6.75 (td, J =
.4 Hz, J = 0.8 Hz, 1H), 7.01 (td, J = 7.7 Hz, J = 1.2 Hz, 1H), 7.13–
.22 (m, 4H), 7.29 (d, J = 7.0 Hz, 1H) ppm; a signal for the NH proton
1
1
22.7 (CH), 123.4 (CH), 128.2 (CH), 134.0 (C), 134.6 (C), 135.6 (C),
41.7 (C), 152.1 (C), 153.3 (2 C), 173.6 (C) ppm. IR (ATR): ν˜ = 3303
(
(
w), 2929 (m), 2856 (w), 1732 (s), 1646 (vs), 1600 (vs), 1507 (vs), 1472
s), 1447 (s), 1414 (s), 1370 (m), 1349 (m), 1317 (m), 1234 (m), 1124
13
1
was not observed. C{ H}-NMR (125 MHz, CDCl ): δ = 14.2 (CH ),
–1
3
3
(vs), 1014 (m), 823 (m), 752 (vs), 734 (s), 664 (m) cm . HR-MS (EI,
70 eV): calcd. 482.2411 (for C27H34N O ), found 482.2412 [M ].
C H N O (482.58 g mol ).
3
1
1
0.3 (CH ), 35.2 (CH ), 45.5 (CH ), 56.7 (C), 60.3 (CH ), 72.2 (CH),
10.4 (CH), 119.3 (CH), 123.7 (CH), 123.8 (CH), 124.9 (CH), 127.1 (CH),
28.0 (CH), 128.2 (CH), 134.1 (C), 141.8 (C), 144.0 (C), 149.8 (C), 173.7
+
+
2
2
2
2
2 6
–1
27 34 2 6
Ethyl cis-3-[9-(4-iodobenzoyl)-2,3,4,4a,9,9a-hexahydro-1H-
carbazol-4a-yl]propanoate (16). 4-Iodobenzoic acid (149 mg,
(
(
(
C) ppm. IR (ATR): ν˜ = 3367 (w), 2980 (w), 2922 (w), 1724 (vs), 1607
m), 1483 (s), 1464 (s), 1447 (w), 1392 (w), 1376 (m), 1297 (w), 1253
w), 1163 (m), 1184 (m), 1100 (w), 1032 (m), 856 (w), 744 (vs), 582
600 μmol) was added to a solution of HATU (228 mg, 600 μmol)
and DIPEA (78 mg, 0.60 mmol) in CH Cl (2 mL) and the resulting
–1
+
2
2
(w) cm . HR-MS (EI, 70 eV): calcd. 307.1567 (for C H NO ), found
20 21 2
mixture was stirred at ambient temperature for 1 h. Hexahydrocar-
bazole 10a (109 mg, 399 μmol) was then added and the mixture
was further stirred at ambient temperature for 16 h. Subsequently,
the mixture was diluted with CH Cl (5 mL) and washed with water
+
–1
3
07.1568 [M ]. C H NO (307.39 g mol ).
20 21 2
Ethyl cis-3-[9-(4-bromophenyl)sulfonyl-2,3,4,4a,9,9a-hexahy-
dro-1H-carbazol-4a-yl]propanoate (14). Brosyl chloride (102 mg,
2
2
3
99 μmol) was added to a solution of hexahydrocarbazole 10a (5 mL), sat. aq. NaHCO solution (5 mL) and brine (5 mL). The or-
3
(
109 mg, 399 μmol) in pyridine (0.4 mL) and CH Cl (0.4 mL) and
ganic layer was dried (MgSO ), filtered and the solvent was removed
2
2
4
the resulting mixture was stirred at ambient temperature for 3 h.
Subsequently, the mixture was diluted with CH Cl (10 mL) and
in vacuo. The crude product was purified by column chromatogra-
phy (SiO , hexanes/MTBE/CH Cl , 3:1:1) to yield in the first fraction
2
2
2
2
2
washed with brine (1 × 5 mL) and water (1 × 5 mL). The organic
the title compound 16 (105 mg, 209 μmol, 52 %, R = 0.39) as a
f
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colorless oil. Secondly, starting material 10a (15 mg, 55 μmol, 14 %,
1.57–1.63 (m, 1H), 1.65–1.72 (m, 1H), 1.81–1.86 (m, 1H), 1.94–2.00
Rf = 0.31) was recovered in another fraction. H-NMR (500 MHz, (m, 1H), 2.20–2.35 (m, 3H), 3.27 (t, J = 5.0 Hz, 1H), 4.09 (q, J = 7.1 Hz,
D ]DMSO, 373 K): δ = 0.99–1.13 (m, 3H), 1.16 (t, J = 7.1 Hz, 3H), 2H), 4.20 (d, J = 16.2 Hz, 1H), 4.41 (d, J = 16.2 Hz, 1H), 6.35 (d, J =
1
[
6
1
9
9
4
1
1
3
2
.41–1.45 (m, 1H), 1.50–1.57 (m, 2H), 1.79 (ddd, J = 14.0 Hz, J = 7.8 Hz, 1H), 6.73 (td, J = 7.4 Hz, J = 1.0 Hz, 1H), 7.00 (dd, J = 7.3 Hz,
.9 Hz, J = 6.0 Hz, 1H), 1.86–1.91 (m, 2H), 2.13 (ddd, J = 15.8 Hz, J = J = 1.3 Hz, 1H), 7.03 (td, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.51 (d, J =
.9 Hz, J = 6.0 Hz, 1H), 2.18–2.26 (m, 2H), 4.01 (q, J = 7.1 Hz, 2H), 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H) ppm. 13C{ H}-NMR (125 MHz,
.08 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.5 Hz, CDCl ): δ = 14.2 (CH ), 21.0 (CH ), 21.4 (CH ), 24.1 (CH ), 30.2 (CH ),
H), 7.23 (d, J = 7.3 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.33–7.34 (m, 31.3 (CH ), 34.2 (CH ), 45.8 (C), 50.2 (CH ), 60.3 (CH ), 67.7 (CH),
1
3
3
2
2
2
2
2
2
2
2
1
3
1
H), 7.88 (d, J = 8.2 Hz, 2H) ppm. C{ H}-NMR (125 MHz, [D ]DMSO,
108.0 (CH), 118.2 (CH), 122.1 (CH), 124.2 (q, J = 271.8 Hz, C), 125.4
6
73 K): δ = 13.3 (CH ), 20.3 (CH ), 22.6 (CH ), 27.6 (CH ), 28.39 (CH ), (q, J = 3.7 Hz, 2 CH), 127.47 (CH), 127.49 (2 CH), 129.2 (q, J = 32.2 Hz,
3
2
2
2
2
8.40 (CH ), 35.9 (CH ), 45.5 (C), 59.2 (CH ), 66.4 (CH), 95.8 (C), 116.7 C), 135.3 (C), 143.4 (C), 150.9 (C), 173.9 (C) ppm. 19F{ H}-NMR
1
2
2
2
(
CH), 122.7 (CH), 123.3 (CH), 126.8 (CH), 128.1 (2 CH), 135.8 (C), 136.5 (470 MHz, CDCl ): δ = –62.40 ppm. IR (ATR): ν˜ = 2993 (w), 2919 (m),
3
(
C), 137.0 (2 CH), 140.6 (C), 166.8 (C), 171.8 (C) ppm. IR (ATR): ν˜ = 2850 (m), 1727 (vs), 1600 (m), 1476 (m), 1449 (m), 1323 (vs), 1313
2
1
1
983 (w), 2936 (m), 2856 (w), 1716 (s), 1637 (s), 1584 (m), 1473 (s),
459 (s), 1447 (m), 1393 (s), 1384 (vs), 1367 (m), 1272 (m), 1252 (m),
(s), 1202 (m), 1126 (m), 1106 (m), 1066 (s), 1017 (m), 856 (m), 843
–
1
(s), 829 (m), 764 (vs), 756 (s), 749 (s), 604 (m) cm . HR-MS (ESI, pos.
–
1
+
032 (m), 1007 (s), 829 (s), 763 (m), 753 (vs), 746 (s), 687 (m) cm . mode): calcd. 454.1964 (for C H F NNaO ), found 454.1972 [M +
25
28
–1
3
2
+
+
HR-MS (EI, 70 eV): calcd. 503.0952 (for C H INO ), found 503.0952 Na ]. C H F NO (431.50 g mol ).
2
4
26
3
25 28
3
2
+
–1
[M ]. C H INO (503.38 g mol ).
24 26 3
Ethyl cis-3-(9-isobutyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-
Ethyl cis-3-[9-(cyclohexylcarbonyl)-2,3,4,4a,9,9a-hexahydro-1H- yl)propanoate (19). Isobutyraldehyde (29 mg, 0.40 mmol) was
carbazol-4a-yl]propanoate (17). Cyclohexanecarboxylic acid added to a solution of hexahydrocarbazole 10a (109 mg, 399 μmol)
(56 mg, 0.44 mmol) was added to a solution of HATU (167 mg,
in EtOH (0.8 mL) and the resulting mixture was stirred at 0 °C for
4
39 μmol) and DIPEA (57 mg, 0.44 mmol) in CH Cl (2 mL) and 1 h. Then ZnCl2 (27 mg, 0.20 mmol) and NaCNBH3 (25 mg,
2 2
the resulting mixture was stirred at ambient temperature for 1 h.
Hexahydrocarbazole 10a (109 mg, 399 μmol) was then added and
the mixture was further stirred at ambient temperature for 16 h.
Subsequently, the mixture was diluted with CH Cl (5 mL) and
0.40 mmol) were added at 0 °C and the mixture was further stirred
at ambient temperature for 3 h. Subsequently, the mixture was di-
luted with water (5 mL) and extracted with MTBE (3 × 5 mL). The
combined organic layers were dried (MgSO ), filtered and the sol-
2
2
4
washed with water (5 mL), sat. aq. NaHCO solution (5 mL) and vent was removed in vacuo. The crude product was purified by
3
brine (5 mL). The organic layer was dried (MgSO ), filtered and the
column chromatography (SiO , hexanes/MTBE, 5:1) to yield in the
4
2
solvent was removed in vacuo. The crude product was purified by
column chromatography (SiO , hexanes/MTBE/CH Cl , 3:1:1) to yield
in the first fraction the title compound 17 (99 mg, 0.26 mmol, 65 %,
first fraction the title compound 19 (88 mg, 0.27 mmol, 67 %, R =
f
0.47) as a colorless oil. Secondly, starting material 10a (26 mg,
2
2
2
1
95 μmol, 24 %, R = 0.06) was recovered in another fraction. H-NMR
f
R = 0.35) as a colorless oil. Secondly, starting material 10a (10 mg, (500 MHz, CDCl ): δ = 0.98 (d, J = 6.6 Hz, 3H), 1.00 (d, J = 6.6 Hz,
f
3
1
3
8 μmol, 10 %, R = 0.30) was recovered in another fraction. H-NMR 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.28–1.32 (m, 2H), 1.43–1.58 (m, 4H),
f
(
500 MHz, [D ]DMSO, 323 K): δ = 0.95–1.03 (m, 2H), 1.11 (t, J = 1.70–1.76 (m, 1H), 1.82–1.91 (m, 2H), 1.93–2.01 (m, 1H), 2.14–2.23
6
7
1
.1 Hz, 3H), 1.20–1.35 (m, 3H), 1.37–1.51 (m, 4H), 1.53–1.60 (m, 2H),
.65–1.72 (m, 4H), 1.74–1.78 (m, 2H), 1.82–1.84 (m, 1H), 1.96–2.02 (q, J = 7.1 Hz, 2H), 6.45 (d, J = 7.8 Hz, 1H), 6.65 (t, J = 7.3 Hz, 1H),
(m, 3H), 2.78–2.85 (m, 2H), 3.22 (dd, J = 6.4 Hz, J = 4.8 Hz, 1H), 4.08
(
4
2
m, 2H), 2.17–2.27 (m, 2H), 2.59 (br s, 1H), 3.95 (q, J = 7.1 Hz, 2H),
6.93 (dd, J = 7.2 Hz, J = 0.8 Hz, 1H), 7.07 (td, J = 7.7 Hz, J = 1.2 Hz,
1H) ppm. 13C{ H}-NMR (125 MHz, CDCl ): δ = 14.1 (CH ), 20.7 (CH ),
1
.18–4.21 (m, 1H), 7.06 (td, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.18–7.21 (m,
3
3
3
1
3
1
H), 8.03 (br s, 1H) ppm. C{ H}-NMR (125 MHz, CDCl ): δ = 14.1
20.9 (CH ), 21.2 (CH ), 21.6 (CH ), 24.5 (CH ), 28.1 (CH), 30.1 (CH ),
3
3 2 2 2 2
(
(
(
(
(
(
CH ), 21.5 (CH ), 22.5 (CH ), 25.5 (CH ), 25.7 (CH ), 26.1 (CH ), 29.0 32.2 (CH ), 33.3 (CH ), 45.7 (C), 54.3 (CH ), 60.2 (CH ), 68.3 (CH),
3 2 2 2 2 2 2 2 2 2
CH ), 29.1 (CH ), 29.6 (CH ), 29.9 (CH ), 30.4 (CH ), 37.3 (CH ), 43.4 107.1 (CH), 116.7 (CH), 122.0 (CH), 127.4 (CH), 134.4 (C), 151.5 (C),
2
2
2
2
2
2
CH), 46.1 (C), 60.4 (CH ), 67.1 (CH), 119.0 (CH), 122.7 (CH), 123.5 174.0 (C) ppm. IR (ATR): ν˜ = 2927 (m), 2856 (w), 1732 (vs), 1604 (m),
2
CH), 128.0 (CH), 135.3 (C), 141.6 (C), 173.4 (C), 174.7 (C) ppm. IR
1479 (s), 1460 (m), 1450 (m), 1174 (m), 1157 (m), 1024 (m), 737 (vs)
–
1
+
ATR): ν˜ = 2926 (s), 2855 (m), 1732 (vs), 1652 (vs), 1597 (m), 1474 cm . HR-MS (EI, 70 eV): calcd. 329.2349 (for C H NO ), found
21
31
2
–
1
+
–1
s), 1460 (m), 1450 (m), 1403 (s), 1346 (m), 753 (vs), 737 (m) cm . 329.2348 [M ]. C H NO (329.48 g mol ).
21
31
2
+
HR-MS (ESI, pos. mode): calcd. 384.2533 (for C H NO ), found
3
2
4
34
3
cis-3-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
propanoic acid (20). A solution of hexahydrocarbazole 10f
(449 mg, 1.24 mmol) in conc. hydrochloric acid (4 mL) was heated
+
–1
84.2529 [M + H ]. C H NO (383.53 g mol ).
24 33 3
Ethyl cis-3-{9-[4-(trifluoromethyl)benzyl]-2,3,4,4a,9,9a-hexa-
hydro-1H-carbazol-4a-yl}propanoate (18). 4-(Trifluoromethyl)- to reflux for 2 h. Subsequently, the mixture was diluted with ice-
benzaldehyde (70 mg, 0.40 mmol) was added to a solution of hexa- water (15 mL) and extracted with MTBE (3 × 10 mL). The combined
hydrocarbazole 10a (109 mg, 399 μmol) in EtOH (0.8 mL) and the
organic layers were dried (MgSO ), filtered and the solvent was re-
4
resulting mixture was stirred at 0 °C for 1 h. Then ZnCl (27 mg, moved in vacuo to yield the title compound 20 (394 mg, 1.17 mmol,
2
1
0
.20 mmol) and NaCNBH (25 mg, 0.40 mmol) were added at 0 °C 95 %) as a colorless solid, mp. 100–104 °C. H-NMR (500 MHz,
3
and the mixture was further stirred at ambient temperature for 3 h.
CDCl ): δ = 1.26–1.39 (m, 2H), 1.44–1.69 (m, 6H), 1.81–1.86 (m, 1H),
3
Subsequently, the mixture was diluted with water (5 mL) and ex- 1.93 (ddd, J = 13.9 Hz, J = 10.8 Hz, J = 5.3 Hz, 1H), 2.17–2.24 (m,
tracted with MTBE (3 × 5 mL). The combined organic layers were 1H), 2.26–2.37 (m, 2H), 3.24 (t, J = 5.1 Hz, 1H), 4.12 (d, J = 15.7 Hz,
dried (MgSO ), filtered and the solvent was removed in vacuo. The 1H), 4.40 (d, J = 15.7 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 6.70 (t, J =
4
crude product was purified by column chromatography (SiO2,
hexanes/MTBE, 2:1) to yield in the first fraction the title compound
7.3 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 7.03 (td, J = 7.7 Hz, J = 1.0 Hz,
1H), 7.24–7.27 (m, 1H), 7.31–7.38 (m, 4H) ppm. 13C{ H}-NMR
(125 MHz, CDCl ): δ = 21.0 (CH ), 21.4 (CH ), 24.1 (CH ), 29.9 (CH ),
1
1
8 (103 mg, 239 μmol, 60 %, R = 0.50) as a colorless solid, mp. 92–
f
3
2
2
2
2
9
0
4 °C. Secondly, starting material 10a (43 mg, 0.16 mmol, 40 %, R = 31.3 (CH ), 34.1 (CH ), 45.6 (C), 50.2 (CH ), 67.3 (CH), 108.1 (CH),
f 2 2 2
1
.29) was recovered in another fraction. H-NMR (500 MHz, CDCl ): 117.7 (CH), 121.9 (CH), 126.9 (CH), 127.4 (2 CH), 127.5 (CH), 128.5 (2
3
δ = 1.23 (t, J = 7.1 Hz, 3H), 1.31–1.41 (m, 2H), 1.47–1.55 (m, 3H), CH), 134.9 (C), 138.9 (C), 151.2 (C), 179.8 (C) ppm. IR (ATR): ν˜ = 3023
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EurJOC
European Journal of Organic Chemistry
–
1
(
(
w), 2925 (m), 2850 (m), 1699 (vs), 1603 (m), 1476 (s), 1452 (m), 1433
(m), 1143 (w), 1027 (m), 731 (vs), 697 (s) cm . HR-MS (EI, 70 eV):
–
1
+
+
m), 1307 (m), 767 (m), 757 (m), 746 (s), 729 (vs), 696 (m) cm . HR- calcd. 390.2666 (for C H N O ), found 390.2666 [M ]. C H N O
26
34
2
26 34 2
+
–1
MS (EI, 70 eV): calcd. 335.1880 (for C H NO ), found 335.1876
(390.57 g mol ).
2
2
25
2
+
–1
[M ]. C H NO (335.45 g mol ).
22 25 2
cis-3-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-N-
(2-ethoxyethyl)propanamide (21c). According to GPC, hexahydro-
General procedure C (GPC) for the amide coupling of hexa-
hydrocarbazole derivative 20. Hexahydrocarbazole carboxylic carbazole carboxylic acid 20 (168 mg, 500 μmol) and 2-ethoxyethyl-
acid 20 (1.0 equiv.) was added to a solution of HATU (1.1 equiv.) amine (67 mg, 0.75 mmol) were converted with HATU (209 mg,
–
1
and DIPEA (1.1 equiv.) in CH Cl (5 L mol ) and the resulting mix- 550 μmol) and DIPEA (71 mg, 0.55 mmol) in CH Cl (2.5 mL) to
2
2
2
2
ture was stirred at ambient temperature for 1 h. Then the primary
amine (1.5 equiv.) was added and the mixture was further stirred
at ambient temperature for 16 h. Subsequently, the mixture was
yield the title compound 21c (199 mg, 489 μmol, 98 %) after chro-
matography (SiO , hexanes/MTBE, 1:4, R = 0.30) as a colorless oil.
2
f
1
H-NMR (500 MHz, CDCl ): δ = 1.19 (t, J = 7.0 Hz, 3H), 1.26–1.37 (m,
3
–
1
washed with water (1 × 5 L mol ), sat. aq. NaHCO solution (1 ×
2H), 1.45–1.55 (m, 3H), 1.59–1.69 (m, 2H), 1.77–1.82 (m, 1H), 1.94
(ddd, J = 13.4 Hz, J = 11.1 Hz, J = 4.9 Hz, 1H), 2.05 (ddd, J = 14.4 Hz,
3
–1
–1
5
L mol ) and brine (1 × 5 L mol ). The organic layer was dried
(
MgSO ), filtered and the solvent was removed in vacuo. The crude J = 11.0 Hz, J = 5.4 Hz, 1H), 2.13 (ddd, J = 14.4 Hz, J = 11.0 Hz, J =
4
product was purified by column chromatography to yield hexa-
hydrocarbazole carboxamides 21a–21d.
4.9 Hz, 1H), 2.23 (ddd, J = 13.4 Hz, J = 11.1 Hz, J = 5.4 Hz, 1H), 3.26
(t, J = 4.9 Hz, 1H), 3.37–3.40 (m, 2H), 3.44–3.50 (m, 4H), 4.12 (d, J =
1
7
5.7 Hz, 1H), 4.40 (d, J = 15.7 Hz, 1H), 5.72 (br s, 1H), 6.43 (d, J =
.8 Hz, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H), 7.03 (td,
cis-3-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-N-
(2,2,2-trifluoroethyl)propanamide (21a). According to GPC, hexa-
J = 7.7 Hz, J = 0.9 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.5 Hz,
hydrocarbazole carboxylic acid 20 (168 mg, 500 μmol) and 2,2,2-
trifluoroethylamine (74 mg, 0.75 mmol) were converted with HATU
H), 7.37 (t, J = 7.4 Hz, 2H) ppm. 13C{ H}-NMR (125 MHz, CDCl ): δ =
1
2
1
3
3
5.1 (CH ), 20.9 (CH ), 21.3 (CH ), 23.9 (CH ), 31.9 (CH ), 32.3 (CH ),
4.4 (CH ), 39.3 (CH ), 45.8 (C), 50.3 (CH ), 66.3 (CH ), 67.2 (CH), 69.0
3
2
2
2
2
2
(
(
209 mg, 550 μmol) and DIPEA (71 mg, 0.55 mmol) in CH Cl2
2.5 mL) to yield the title compound 21a (178 mg, 427 μmol, 86 %)
2
2
2
2
2
(
CH ), 108.2 (CH), 117.8 (CH), 122.0 (CH), 126.9 (CH), 127.4 (CH),
2
after chromatography (SiO , hexanes/MTBE/CH Cl , 3:1:1, R = 0.34)
2
2
2
f
1
27.5 (2 CH), 128.4 (2 CH), 135.5 (C), 138.8 (C), 151.1 (C), 173.0 (C)
ppm. IR (ATR): ν˜ = 3440 (w), 3312 (w), 3050 (w), 2929 (m), 2856 (m),
649 (m), 1603 (m), 1549 (m), 1522 (m), 1494 (m), 1479 (s), 1460
m), 1452 (m), 1377 (m), 1352 (m), 1264 (m), 1113 (s), 1027 (m), 731
1
as a colorless oil. H-NMR (500 MHz, CDCl ): δ = 1.28–1.38 (m, 2H),
3
1
.47–1.56 (m, 3H), 1.57–1.63 (m, 1H), 1.65–1.71 (m, 1H), 1.81–1.86
1
(m, 1H), 1.91–1.97 (m, 1H), 2.08–2.14 (m, 1H), 2.17–2.28 (m, 2H), 3.24
(t, J = 5.0 Hz, 1H), 3.77–3.88 (m, 2H), 4.12 (d, J = 15.6 Hz, 1H), 4.41
(d, J = 15.6 Hz, 1H), 5.77 (br s, 1H), 6.44 (d, J = 7.8 Hz, 1H), 6.70 (t,
(
(
–
1
vs), 697 (s) cm . HR-MS (EI, 70 eV): calcd. 406.2615 (for
+
+
–1
C H N O ), found 406.2612 [M ]. C H N O (406.57 g mol ).
26
34
2
2
26 34 2 2
J = 7.4 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 7.04 (td, J = 7.7 Hz, J =
1
3
1
1
.2 Hz, 1H), 7.25–7.29 (m, 1H), 7.32–7.39 (m, 4 H) ppm. C{ H}-NMR
cis-3-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-N-
(4-bromophenyl)propanamide (21d). According to GPC, hexa-
2.0 (CH ), 34.2 (CH ), 40.5 (q, J = 34.6 Hz, CH ), 45.8 (C), 50.0 (CH ), hydrocarbazole carboxylic acid 20 (168 mg, 500 μmol) and
7.3 (CH), 108.0 (CH), 117.6 (CH), 121.9 (CH), 124.0 (q, J = 278.4 Hz, 4-bromoaniline (129 mg, 0750 μmol) were converted with HATU
(209 mg, 550 μmol) and DIPEA (71 mg, 0.55 mmol) in CH Cl
C), 151.2 (C), 173.4 (C) ppm. F{ H}-NMR (470 MHz, CDCl ): δ = (2.5 mL) to yield the title compound 21d (225 mg, 460 μmol, 92 %)
(
3
6
125 MHz, CDCl ): δ = 20.8 (CH ), 21.2 (CH ), 24.0 (CH ), 31.9 (CH ),
3
2
2
2
2
2
2 2 2 2
1
C), 126.9 (CH), 127.4 (2 CH), 127.5 (CH), 128.4 (2 CH), 135.0 (C), 138.9
2
2
1
9
1
(
3
–
72.45 (s, CF ) ppm. IR (ATR): ν˜ = 3300 (w), 3063 (w), 3029 (w), 2932 after chromatography (SiO , hexanes/MTBE, 2:1, R = 0.35) as a color-
3
2
f
1
(
1
(
m), 2856 (w), 1663 (m), 1603 (m), 1549 (m), 1494 (m), 1479 (m),
460 (m), 1453 (m), 1396 (w), 1354 (w), 1266 (m), 1153 (vs), 1116
m), 1027 (m), 991 (m), 953 (w), 906 (w), 873 (w), 833 (m), 733 (vs),
less solid, mp. 72–79 °C. H-NMR (500 MHz, CDCl ): δ = 1.27–1.38
3
(m, 2H), 1.49–1.55 (m, 3H), 1.56–1.62 (m, 1H), 1.66–1.72 (m, 1H),
1.82–1.88 (m, 1H), 1.95–2.01 (m, 1H), 2.17–2.24 (m, 1H), 2.25–2.34
(m, 2H), 3.26 (t, J = 5.0 Hz, 1H), 4.11 (d, J = 15.6 Hz, 1H), 4.40 (d, J =
–
1
6
97 (s), 669 (m), 550 (m) cm . HR-MS (EI, 70 eV): calcd. 416.2070 (for
+
+
–1
C H F N O ), found 416.2072 [M ]. C H F N O (416.49 g mol ). 15.6 Hz, 1H), 6.44 (d, J = 7.8 Hz, 1H), 6.70 (t, J = 7.3 Hz, 1H), 6.97 (d,
24
27
3
2
24 27 3 2
J = 7.1 Hz, 1H), 7.02 (br s, 1H), 7.05 (t, J = 7.7 Hz, 1H), 7.23–7.27 (m,
cis-3-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-N-
tert-butyl)propanamide (21b). According to GPC, hexahydro-
carbazole carboxylic acid 20 (168 mg, 500 μmol) and tert-butyl-
H), 7.30–7.40 (m, 8H) ppm. 13C{ H}-NMR (125 MHz, CDCl ): δ = 20.9
1
1
3
(
(
CH ), 21.3 (CH ), 24.0 (CH ), 32.0 (CH ), 33.4 (CH ), 34.2 (CH ), 45.8
2 2 2 2 2 2
(
C), 50.0 (CH ), 67.4 (CH), 108.0 (CH), 116.6 (C), 117.6 (CH), 121.2 (2
2
amine (55 mg, 0.75 mmol) were converted with HATU (209 mg,
CH), 122.0 (CH), 127.0 (CH), 127.5 (2 CH), 127.6 (CH), 128.5 (2 CH),
31.9 (2 CH), 135.0 (C), 137.0 (C), 138.8 (C), 151.3 (C), 171.4 (C) ppm.
5
50 μmol) and DIPEA (71 mg, 0.55 mmol) in CH Cl (2.5 mL) to
2 2
1
yield the title compound 21b (190 mg, 486 μmol, 97 %) after chro-
matography (SiO , hexanes/MTBE, 2:1, R = 0.32) as a colorless oil.
IR (ATR): ν˜ = 3292 (w), 3180 (w), 3112 (w), 3053 (w), 3027 (w), 2927
2
f
(
(
(
m), 2853 (m), 1659 (s), 1602 (s), 1590 (s), 1534 (s), 1487 (s), 1478
s), 1452 (m), 1394 (s), 1351 (w), 1313 (m), 1243 (m), 1176 (w), 1144
w), 1112 (w), 1072 (m), 1026 (m), 1009 (m), 953 (w), 876 (w), 823
1
H-NMR (500 MHz, CDCl ): δ = 1.30 (s, 9H), 1.32–1.40 (m, 2H), 1.47–
3
1
2
.56 (m, 3H), 1.60–1.71 (m, 2H), 1.76–1.81 (m, 1H), 1.89–2.00 (m, 2H),
.03–2.09 (m, 1H), 2.20–2.26 (m, 1H), 3.26 (t, J = 4.8 Hz, 1H), 4.13 (d,
–
1
(s), 737 (vs), 696 (s), 536 (w), 506 (m) cm . HR-MS (EI, 70 eV): calcd.
J = 15.8 Hz, 1H), 4.40 (d, J = 15.8 Hz, 1H), 5.14 (s, 1H), 6.42 (d, J =
.8 Hz, 1H), 6.70 (td, J = 7.4 Hz, J = 0.9 Hz, 1H), 6.97 (dd, J = 7.2 Hz,
J = 1.0 Hz, 1H), 7.03 (td, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.25 (t, J =
+
+
4
88.1458 (for C28H29BrN O ), found 488.1463 [M ]. C28H29BrN O
2
2
7
–
1
(489.46 g mol ).
7
.2 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.38 (d, J = 7.5 Hz, 2H) ppm.
cis-3-(9-Benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)-
1
3
1
C{ H}-NMR (125 MHz, CDCl ): δ = 20.8 (CH ), 21.3 (CH ), 23.9 (CH ), propanamide (21e). Pyridine (214 mg, 2.70 mmol) and Boc O
3
2
2
2
2
2
5
1
1
2
8.7 (3 CH ), 31.6 (CH ), 33.1 (CH ), 34.6 (CH ), 45.8 (C), 50.2 (CH ), (491 mg, 2.25 mmol) were added to a solution of carboxylic acid
3 2 2 2 2
1.0 (C), 67.2 (CH), 107.9 (CH), 117.6 (CH), 121.9 (CH), 126.8 (CH),
27.3 (CH), 127.4 (2 CH), 128.4 (2 CH), 135.7 (C), 139.0 (C), 151.3 (C),
72.3 (C) ppm. IR (ATR): ν˜ = 3317 (w), 3050 (w), 3029 (w), 2966 (w),
930 (m), 2857 (w), 1647 (m), 1603 (m), 1544 (m), 1510 (m), 1494
20 (503 mg, 1.50 mmol) in 1,4-dioxane (3 mL) and the resulting
mixture was stirred at ambient temperature for 30 min. Then
(NH ) CO (404 mg, 4.20 mmol) was added and the resulting mix-
4
2
3
ture was stirred at ambient temperature for 16 h. Subsequently, the
(
m), 1479 (s), 1452 (s), 1392 (w), 1364 (m), 1317 (w), 1264 (m), 1224 mixture was diluted with H O (7 mL) and extracted with MTBE (3 ×
2
Eur. J. Org. Chem. 2020, 7164–7175
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7174
© 2020 The Authors. European Journal of Organic Chemistry
published by Wiley-VCH GmbH

Full Paper
doi.org/10.1002/ejoc.202001226
EurJOC
European Journal of Organic Chemistry
7
mL). The combined organic layers were dried (MgSO ), filtered
[1] A. W. Schmidt, K. R. Reddy, H.-J. Knölker, Chem. Rev. 2012, 112, 3193–
328.
4
3
and the solvent was removed in vacuo. The crude product was
purified by column chromatography (SiO , EtOAc, R = 0.35) to yield
the title compound 21e (464 mg, 1.39 mmol, 93 %) as a colorless
solid, mp. 44–52 °C. H-NMR (500 MHz, CDCl ): δ = 1.32–1.41 (m,
[
2] F. Tan, H.-G. Cheng, Chem. Commun. 2019, 55, 6151–6164.
2
f
[
3] Y. Wang, F. Xie, B. Lin, M. Cheng, Y. Liu, Chem. Eur. J. 2018, 24, 14302–
1
4315.
1
3
[
[
4] L. Li, Z. Chen, X. Zhang, Y. Jia, Chem. Rev. 2018, 118, 3752–3832.
5] S. Issa, A. Prandina, N. Bedel, P. Rongved, S. Yous, M. L. Borgne, Z. Bouaziz,
J. Enzyme Inhib. Med. Chem. 2019, 34, 1321–1346.
2
H), 1.48–1.59 (m, 3H), 1.61–1.72 (m, 2H), 1.81–1.86 (m, 1H), 1.95
(ddd, J = 12.9 Hz, J = 11.1 Hz, J = 4.7 Hz, 1H), 2.05–2.17 (m, 2H),
2
4
7
.19–2.28 (m, 1H), 3.28 (t, J = 4.9 Hz, 1H), 4.14 (d, J = 15.7 Hz, 1H),
.42 (d, J = 15.7 Hz, 1H), 5.54 (br s, 1H), 6.11 (br s, 1H), 6.45 (d, J =
.8 Hz, 1H), 6.72 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 7.05 (td,
[6] H.-J. Borschberg, Chimia 1991, 45, 329–341.
[7] J. M. Lopchuk, Prog. Heterocycl. Chem. 2011, 23, 1–25.
[8] a) S. Schunk, K. Linz, S. Frormann, C. Hinze, S. Oberbörsch, B. Sunder-
mann, S. Zemolka, W. Englberger, T. Germann, T. Christoph, B.-Y. Kögel,
W. Schröder, S. Harlfinger, D. Saunders, A. Kless, H. Schick, H. Sonnen-
schein, ACS Med. Chem. Lett. 2014, 5, 851–856; b) S. Schunk, K. Linz,
C. Hinze, S. Frormann, S. Oberbörsch, B. Sundermann, S. Zemolka, W.
Englberger, T. Germann, T. Christoph, B.-Y. Kögel, W. Schröder, S. Harlfin-
ger, D. Saunders, A. Kless, H. Schick, H. Sonnenschein, ACS Med. Chem.
Lett. 2014, 5, 857–862; c) D. Wachtendorf, M. Schmidtmann, J. Christof-
fers, Org. Lett. 2020, 22, 6420–6423.
[9] a) J. D. Podoll, Y. Liu, L. Chang, S. Walls, W. Wang, X. Wang, Proc. Natl.
Acad. Sci. USA 2013, 110, 15573–15578; b) P. M. Barbour, J. D. Podoll, L. J.
Marholz, X. Wang, Bioorg. Med. Chem. Lett. 2014, 24, 5602–5605; c) W.
He, B. M. Griffiths, W. Wang, X. Wang, Org. Biomol. Chem. 2017, 15, 4241–
J = 7.7 Hz, J = 1.1 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.35 (t, J = 7.6 Hz,
2
δ = 20.8 (CH ), 21.2 (CH ), 23.8 (CH ), 31.4 (CH ), 31.7 (CH ), 34.2
1
3
1
H), 7.40 (d, J = 7.4 Hz, 2H) ppm. C{ H}-NMR (125 MHz, CDCl ):
3
2
2
2
2
2
(CH ), 45.6 (C), 50.0 (CH ), 67.1 (CH), 107.9 (CH), 117.5 (CH), 121.8
2
2
(CH), 126.8 (CH), 127.28 (2 CH), 127.31 (CH), 128.3 (2 CH), 135.2 (C),
1
3
1
1
6
38.8 (C), 151.1 (C), 176.1 (C) ppm. IR (ATR): ν˜ = 3447 (w), 3329 (w),
186 (w), 3026 (w), 2926 (m), 2854 (m), 1660 (vs), 1602 (s), 1494 (m),
477 (s), 1452 (m), 1399 (w), 1350 (w), 1314 (w), 1262 (w), 1182 (w),
143 (w), 1113 (w), 1070 (w), 1026 (m), 950 (w), 874 (w), 734 (s),
–
1
96 (s), 569 (w) cm . HR-MS (EI, 70 eV): calcd. 334.2040 (for
+
+
–1
C H N O ), found 334.2035 [M ]. C H N O (334.46 g mol ).
22
26
2
22 26 2
4
245.
10] A. Dierks, M. Schmidtmann, J. Christoffers, Chem. Eur. J. 2019, 25, 5451–
462.
[
[
[
Methyl cis-[2-(9-benzyl-2,3,4,4a,9,9a-hexahydro-1H-carbazol-
a-yl)ethyl]carbamate (22). A solution of KOH (139 mg,
.48 mmol) in MeOH (2 mL) was added at 0 °C to a solution of
amide 21e (330 mg, 987 μmol) and PhI(OAc) (319 mg, 990 μmol)
5
4
2
11] J. P. Edwards, S. J. West, C. L. F. Pooley, K. B. Marschke, L. J. Farmer, T. K.
Jones, Bioorg. Med. Chem. Lett. 1998, 8, 745–750.
12] G. Martin, P. Angyal, O. Egyed, S. Varga, T. Soos, Org. Lett. 2020, 22, 4675–
4679.
2
in CH Cl (2 mL). The resulting mixture was stirred at 0 °C for 15 min
2
2
and for further 16 h at ambient temperature. Subsequently, the
reaction mixture was diluted with water (10 mL) and extracted with
CH Cl (3 × 10 mL). The combined organic layers were dried
[13] a) B. W. Boal, A. W. Schammel, N. K. Garg, Org. Lett. 2009, 11, 3458–3461;
b) A. W. Schammel, B. W. Boal, L. Zu, T. Mesganaw, N. K. Garg, Tetrahedron
2010, 66, 4687–4695; c) A. W. Schammel, G. Chiou, N. K. Garg, J. Org.
Chem. 2012, 77, 725–728; d) B. J. Simmons, M. Hoffmann, P. A. Cham-
pagne, E. Picazo, K. Yamakawa, L. A. Morrill, K. N. Houk, N. K. Garg, J. Am.
Chem. Soc. 2017, 139, 14833–14836; e) review: R. B. Susick, L. A. Morrill,
E. Picazo, N. K. Garg, Synlett 2017, 28, 1–11.
2
2
(
MgSO ), filtered and the solvent was removed in vacuo. The crude
4
product was purified by column chromatography (SiO hexanes/
2
MTBE, 1:1, R = 0.39) to yield the title compound 22 (157 mg,
f
1
4
31 μmol, 44 %) as a colorless oil. H-NMR (500 MHz, CDCl ): δ =
3
[
14] P. Schär, P. Renaud, Org. Lett. 2006, 8, 1569–1571.
1
.27–1.38 (m, 2H), 1.45–1.63 (m, 4H), 1.65–1.71 (m, 1H), 1.78–1.88
[
15] a) H. Fritz, O. Fischer, Tetrahedron 1964, 20, 1737–1753; b) H. T. Open-
shaw, R. Robinson, J. Chem. Soc. 1937, 941–946.
(m, 2H), 2.04–2.10 (m, 1H), 3.09–3.23 (m, 2H), 3.30 (br t, J = 4.5 Hz,
1
4
7
H), 3.64 (s, 3H), 4.13 (d, J = 15.7 Hz, 1H), 4.40 (d, J = 15.7 Hz, 1H),
.60 (br s, 1H), 6.42 (d, J = 7.8 Hz, 1H), 6.72 (t, J = 7.3 Hz, 1H), 7.01–
.05 (m, 2H), 7.27 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.38 (d,
[16] S. Gore, S. Baskaran, B. König, Org. Lett. 2012, 14, 4568–4571.
[17] L. Buschbeck, J. Christoffers, J. Org. Chem. 2018, 83, 4002–4014.
[18] Deposition Number 2027118 (for 10a) contains the supplementary crys-
tallographic data for this paper. These data are provided free of charge
by the joint Cambridge Crystallographic Data Centre and Fachinforma-
tionszentrum Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
13
1
J = 7.3 Hz, 2H) ppm. C{ H}-NMR (125 MHz, CDCl ): δ = 21.0 (CH ),
3
2
2
5
1
1.4 (CH ), 24.1 (CH ), 34.2 (CH ), 37.0 (CH ), 37.6 (CH ), 45.1 (C),
0.2 (CH ), 51.9 (CH ), 67.6 (CH), 108.1 (CH), 117.7 (CH), 121.9 (CH),
26.9 (CH), 127.3 (2 CH), 127.5 (CH), 128.4 (2 CH), 135.3 (C), 139.0
2 2 2 2 2
2
3
[
19] a) R. B. Perni, G. W. Gribble, Org. Prep. Proced. 1982, 14, 343–346; b) S.
Müller, M. J. Webber, B. List, J. Am. Chem. Soc. 2011, 133, 18534–18537.
20] a) M. M. Baum, E. H. Smith, J. Chem. Soc., Perkin Trans. 1 1993, 2513–
2519; b) J. Barluenga, I. Merino, S. Vina, F. Palacios, Synthesis 1990, 398–
400.
(C), 151.0 (C), 156.9 (C) ppm. IR (ATR): ν˜ = 3420 (w), 3339 (w), 3062
(w), 3026 (w), 2926 (m), 2854 (w), 1700 (s), 1603 (m), 1520 (m), 1494
(w), 1477 (s), 1452 (s), 1379 (w), 1354 (m), 1253 (s), 1190 (w), 1140
(m), 1113 (w), 1026 (m), 1001 (w), 946 (w), 777 (m), 733 (vs), 697 (s)
[
–1
+
cm . HR-MS (EI, 70 eV): calcd. 364.2145 (for C H N O ), found
[21] S. Muthusamy, S. A. Babu, C. Gunanathan, E. Suresh, P. Dastidar, Bull.
Chem. Soc. Jpn. 2002, 75, 801–811.
2
3 28 2 2
+
–1
3
64.2140 [M ]. C H N O (364.49 g mol ).
23 28 2 2
[
[
22] G. H. Lee, E. B. Choi, E. Lee, C. S. Pak, J. Org. Chem. 1994, 59, 1428–1443.
23] L. A. Carpino, H. Imazumi, A. El-Faham, F. J. Ferrer, C. Zhang, Y. Lee, B. M.
Foxman, P. Henklein, C. Hanay, C. Mügge, H. Wenschuh, J. Klose, M. Bey-
ermann, M. Bienert, Angew. Chem. Int. Ed. 2002, 41, 441–445; Angew.
Chem. 2002, 114, 457–461.
Acknowledgments
MTBE was obtained as a generous gift from Evonik Industries,
Marl, Germany.
[
[
24] M. Penning, J. Christoffers, Eur. J. Org. Chem. 2012, 2012, 1809–1818.
25] A. Dierks, J. Tönjes, M. Schmidtmann, J. Christoffers, Chem. Eur. J. 2019,
2
5, 14912–14920.
26] D. J. Bailey, N. S. Doggett, L. Y. Ng, T. Qazi, J. Med. Chem. 1976, 19, 438–
39.
[
4
Keywords: Cyclization · Nitrogen heterocycles · Reductive
indolization · Synthetic methods
Received: September 10, 2020
Eur. J. Org. Chem. 2020, 7164–7175
www.eurjoc.org
7175
© 2020 The Authors. European Journal of Organic Chemistry
published by Wiley-VCH GmbH