A diversity oriented four-component approach to tetrahydro-β- carbolines initiated by Sonogashira coupling

Article abstract of DOI:10.1039/b511861a

A consecutive four-component synthesis of highly-substituted tetrahydro-β-carbolines 6 can be achieved by a coupling-aminatio-aza- annulation-Pictet-Spengler (CAAPS) sequence creating five new a-bonds and four new Stereocenters in a one-pot fashion. The s

Full text of DOI:10.1039/b511861a

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A R T I C L E
A diversity oriented four-component approach to
tetrahydro-b-carbolines initiated by Sonogashira coupling
Alexei S. Karpov, Frank Rominger and Thomas J. J. M u¨ ller*
Organisch-Chemisches Institut der Ruprecht-Karls-Universit a¨ t Heidelberg, Im Neuenheimer
Feld 270, D-69120, Heidelberg, Germany. E-mail: Thomas_J.J.Mueller@urz.uni-heidelberg.de;
Fax: ++49(0)6221546579; Tel: ++49(0)6221546207
Received 23rd August 2005, Accepted 6th October 2005
First published as an Advance Article on the web 14th November 2005
A consecutive four-component synthesis of highly-substituted tetrahydro-b-carbolines 6 can be achieved by a
coupling-aminatio-aza-annulation-Pictet–Spengler (CAAPS) sequence creating five new r-bonds and four new
stereocenters in a one-pot fashion. The structures were unambiguously supported by X-ray structure analyses.
Introduction
Tetrahydro-b-carbolines not only constitute subunits in numer-
1
ous alkaloids but they are also templates for drug discovery
and have been used as scaffolds for combinatorial libraries.
2
They display a pronounced antitumor and antiviral activity and
some of them have been shown to efficiently inhibit monoamine
3
oxidase A and bind with nanomolar affinity to serotonin
4
receptors in the central nervous system. Hence, the development
of concise and modular syntheses of this class of heterocycles
is a highly rewarding methodological challenge for the rapidly
evolving field of diversity oriented synthesis.
In particular, multi-component reactions and sequential one-
pot processes address very fundamental principles of synthetic
5
efficiency and reaction design and are steadily gaining a
Scheme 1 One-pot syntheses of enaminones and heterocycles initiated
considerable and increasing academic, economic and ecological
interest. Additionally, the modular aspect of one-pot reactions
can be readily expanded into combinatorial and solid phase
by Sonogashira coupling of acid chlorides.
equivalents of 1,3-dicarbonyl compounds would only result in
an additional step in a reaction sequence, since ynones react with
binucleophiles as well giving rise to the same products. On the
other hand, it could be even more useful to take advantage of
the unique electronically amphoteric reactivity of b-enaminones
5,6
syntheses promising manifold opportunities for developing
novel lead structures of pharmaceuticals, catalysts and even
novel molecule based materials. Thus, the concept of integrat-
ing modern cross-coupling methodology, such as Sonogashira
7,8
coupling, and well-established Michael addition chemistry
into a one-pot consecutive process has been an ongoing focus in
4
trying to conserve all atoms in the final product, including
the enamino nitrogen atom. As a major consequence of our
modified Sonogashira conditions, the reaction medium after
9
our group.
10
Recently, we have demonstrated that Sonogashira coupling of
acid chlorides 1 and terminal alkynes 2 under extremely mild
conditions, i.e. using only one equivalent of triethylamine as
the first cross-coupling and the stoichiometric amine addition
steps is essentially neutral. Therefore, we decided to apply a,b-
unsaturated chlorides 9 as a fourth component, thus probing the
10
the base, furnishes ynones 3 that represent extremely versatile
18
compatibility of a subsequent aza-annulation reaction with the
11–14
building blocks in heterocyclic chemistry
due to their highly
conditions of the coupling–amination (CA) sequence (Scheme 2,
Table 1).
activated triple bond which lends itself to Michael addition.
Therefore, they can directly and without isolation be trans-
1
5
10,15
formed into b-enaminones 4, pyrimidines 5,
tetrahydro-b-
16
17
carbolins 6 and halofurans 7 in a one-pot fashion (Scheme 1).
In particular, the synthesis of tetrahydro-b-carbolines 6 most
clearly demonstrates the potential of this methodology for the
rapid construction of highly-substituted, complex heterocycles
where 5 new r-bonds and 4 new stereocenters can be installed in
a sequence of consecutive one-pot transformations. Here we
report details and mechanistic studies on the facile synthe-
sis of tetrahydro-b-carbolines 6 by a coupling-amination-aza-
annulation-Pictet–Spengler (CAAPS) sequence.
Scheme
2
One-pot four-component coupling-amination-aza-
annulation (CAA) sequence.
Results and discussion
Hence, after performing the CA reaction with acid chlorides
1, 1-hexyne (2a), and benzyl amine (8a) or homoveratryl amine
(8b), acryloyl chloride (9a) was added and after gentle heating
the intermediate enaminones were smoothly converted into 5-
acyl dihydropyrid-2-ones 10 that were isolated in moderate to
good yield as yellow or colorless oils. Interestingly, the use of
According to the basic principles of multi-component reactions
the products of consecutive transformations should preferen-
tially contain substantial fragments of all starting materials, thus
providing a high degree of atom-efficiency. As a consequence, the
use of b-enaminones 4 in the heterocyclic synthesis as synthetic
4
3 8 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5

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Table 1 One-pot four component coupling-amination-aza-annulation (CAA) sequence
Entry
Acid chloride 1
Amine 8
5-Acyl dihydropyrid-2-one 10
1
3
1
3
a
1
2
3
R = 2-thienyl (1a)
R = Bn (8a)
10a (R = 2-thienyl, R = Bn, 31%)
1
1
3
b
R = p-MeOC
6
H
4
(1b)
8a
10b (R = p-MeOC
6
H
4
3
, R = Bn, 63%)
2 6 3
3
1
c
1a
R = (MeO)
2
C
6
H
3
CH
2
CH
2
(8b)
10c (R = 2-thienyl, R = (MeO)
C
H
2 2
CH CH , 69%)
a
b
1
.2 Equiv of benzyl amine (8a) and 1.2 equiv of acryloyl chloride (9a) were used. 1.2 Equiv of benzyl amine (8a) and 1.5 equiv of acryloyl chloride
c
(
9a) were used. 1.2 Equiv of homoveratryl amine (8b) and 2.1 equiv of acryloyl chloride (9a) were used.
a slight excess of acryloyl chloride (9a) leads to the significant
increase of the yield (compare entries 1 and 2).
adding 1.0 equiv of DBU as a strong, non-nucleophilic base to
the reaction mixture in the second step (entries 10–11).
Interesting, however, is the excellent diastereoselectivity of the
The structure of the lactams 10 is unambiguously supported
1
2
1
6
by the spectroscopic data. Characteristically, in the H NMR
CAAPS sequence where the R , acyl-R , and R substituents are
spectra the resonances of two CH
2
groups are found at d 2.39–
exclusively placed in a syn–syn arrangement (Table 2, entries 1–
5, 7–11), whereas with a substituent R other than hydrogen,
7
2
.69 either as distinct singlets (10a, 10c) or as two multiplets
1
3
(
10b). Accordingly, in the C NMR spectra the carbon reso-
nances of dihydropyrid-2-one systems can be unambiguously
assigned at d 30.3–32.0 for the two CH groups, at d 118.2–119.5
and d 144.5–145.0 for two quaternary olefinic carbons, and at d
70.6–171.1 for the quaternary amide carbon. In addition, the
epimers are formed with moderate selectivity (entry 6, dr = 4.5 :
1). Most surprisingly, with (S)-(-)-tryptophan methyl ester (8d)
as a tryptamine derivative the only cyclization product isolated
in 45% yield is the tetrahydro-b-carboline 6h (entry 8, Fig. 1)
that is formed as a single diastereomer.
2
1
mass spectrometric and IR spectroscopic data corroborate the
suggested molecular structure of these aza-annulation products.
However, upon applying tryptamine (8c) or L-tryptophane
methylester (8d) as primary amines in the CAA sequence the
lactams 10 were not the final reaction products, but as a result of
19
a subsequent Pictet–Spengler reaction, only the indolo[2,3-a]
quinolizin-4-ones 6 were isolated in moderate to good yields as
colorless crystals (Scheme 3, Table 2).
1
2
n
6
7
Fig. 1 ORTEP plot of 6a (R = 2-thienyl, R = Bu, R = R = R =
H, hydrogen atoms were omitted for clarity).
The successful formation of the indolo[2,3-a] quinolizin-4-
one core and the relative stereochemistry is unambiguously
supported by numerous X-ray structure analyses (for 6a, 6b,
6c, 6e, 6f and 6h see Figs 1–6).†
Scheme
3
One-pot four-component coupling-amination-aza-
annulation-Pictet–Spengler (CAAPS) sequence.
† Crystal data for 6a–c,e–f,h,l. Data were collected on a Bruker Smart
CCD diffractometer for 6a, 6b, 6c, 6e, 6f, 6l, and on a Bruker APEX
diffractometer at for 6h. Mo K
the intensities were corrected for absorption effects using SADABS
a
radiation was used in all cases and
25
2
0
Thus, a Pictet–Spengler cyclization, i.e. an N-acyliminium
based on the laue symmetry of the reciprocal space. The structures
21
2
cyclization, terminates the CAA reaction in the sense of a four-
component coupling-aza-annulation-Pictet–Spengler (CAAPS)
sequence and generates a maximum of structural complexity
and diversity in a one-pot fashion.
The results show that the CAAPS sequence proceeds with
good yields for electron deficient (entry 2) and electron rich
entry 3) aromatic acid chlorides. Heteroaromatic (entries 1, 4–
0) and even aliphatic (entry 11) acid chlorides can be introduced
into the sequence. The substitution pattern on the alkyne 2
were solved by direct methods and refined against F with a full matrix
25
least square algorithm by using the SHELXTL software package.
Hydrogen atoms were refined isotropically for 6h and in several cases
where they were attached to heteroatoms, in all other cases they were
considered at calculated positions and refined using appropriate riding
models. In the case of 6c slight disorder had to be considered for the
last atom of the butyl chain, in 6f the thiophen rings occur in two
alternative orientations, additionally some electron density of severe
(
1
disordered solvent was found. 6a: C24
orthorhombic, space group Pna2
H
26
N
2
O
2
S × CH
2
Cl
2
, M = 491.45,
1
, a = 24.218(1), b = 14.582(1), c =
component is also highly flexible. In the case of phenylacetylene
14.204(1) A˚ , V = 5016.0(3) A˚
3
, T = 200(2) K, Z = 8, q = 1.302 g cm−3
,
calc
3
(
2b) the prolongation of heating is required to complete the
reaction. For example, after 3 h of reflux the desired product
d was obtained in only 27%, and 32% of an uncyclized aza-
annulation product was isolated. After 24 h of reflux, 41% of
d was obtained, while no traces of the aza-annulation product
were detected. This sluggish reaction is presumably caused by
the steric hindrance of the phenyl substituent.
It is worth mentioning that for the complete conversion of the
ynone to the b-enaminone, 2 equiv of the amine 8c were required,
due to a partial conversion to the hydrochloride (entries 1–9).
However, this amount can be reduced to 1.1 equiv simply by
crystal dimensions 0.34 × 0.34 × 0.18 mm , H = 21.96 deg, 31357
max
reflections measured, 6126 unique (Rint = 0.0396), 5352 observed (I > 2
−
1
r(I)), l = 0.37 mm , Tmin = 0.89, Tmax = 0.94, 578 parameters refined,
6
R
1
= 0.059 and wR2 = 0.153 for observed reflections, residual electron
−3
27 3 4
density −0.49 to 0.59 e A˚ . 6b: C26
H
N
O
, M = 445.5, monoclinic,
6
space group P2
1
/c, a = 11.762(1), b = 13.007(1), c = 14.732(1) A˚ , b =
◦
3
−3
9
7.724(1) , V = 2233.3(1) A˚ , T = 200(2) K, Z = 4, q = 1.325 g cm
,
3
crystal dimensions 0.40 × 0.34 × 0.11 mm , Hmax= 27.46 deg, 22678
reflections measured, 5107 unique (Rint = 0.0294), 3941 observed (I >
−1
2
r(I)), l = 0.09 mm , Tmin = 0.96, Tmax = 0.99, 298 parameters refined,
R1 = 0.041 and wR2 = 0.100 for observed reflections, residual electron
density −0.27 to 0.33 e A˚ − . 6c: C27
3
H
30
N
2
O
3
, M = 430.5, monoclinic,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1
4 3 8 3

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1
2
n
6
7
Fig. 2 ORTEP plot of 6b (R = p-O
2
NC
6
H
4
, R = Bu, R = R = R
=
H, hydrogen atoms were omitted for clarity).
1
In addition, in the H NMR spectra a single set of signals
corresponding to 1,2,3,6,7-H protons of quinolizin-4-one is
found in a range of d 1.96–5.52 (Fig. 7).
First, the equatorial proton 6-H appearing at d 4.76–5.25 can
a
be unambiguously assigned due to its characteristic downfield
shift by the deshielding of the adjacent amide carbonyl group.
Usually, it appears as a doublet of doublets of doublets with
2
3
coupling constants of J = 12.7–12.8 Hz, J = 4.6–4.8 Hz
◦
(
equatorial–axial, cf. dihedral angle from X-ray of 43–54 ) and
3
J = 1.3–1.8 Hz (equatorial–equatorial, cf. dihedral angle from
◦
X-ray of 65–75 ). For compound 6h where the ester group adopts
an equatorial position the resonance at d 5.52 can be assigned
to 6-H and gives rise to a doublet of doublets with coupling
a
3
3
constants of J = 6.8 Hz (axial–axial) and J = 2.7 Hz (axial–
equatorial). The other signals were readily assigned though
NOESY and COSY experiments. The resonances of 6-H
b
are
detected at d 2.91–3.41 as doublets of triplets with coupling
2
3
constants of J = 12.0–12.7 Hz and J = 3.4–4.7 Hz.
space group C2/c, a = 15.691(1), b = 16.534(1), c = 18.142(1) A˚ , b =
◦
3
−3
9
9.574(1) , V = 4641.2(1) A˚ , T = 298(2) K, Z = 8, q = 1.232 g cm
,
3
crystal dimensions 0.46 × 0.32 × 0.30 mm , Hmax = 27.47 deg, 23712
reflections measured, 5323 unique (Rint = 0.0371), 2835 observed (I >
−
1
2
r(I)), l = 0.08 mm , Tmin = 0.96, Tmax = 0.98, 300 parameters
refined, R1 = 0.049 and wR2 = 0.120 for observed reflections, residual
electron density −0.18 to 0.22 e A˚ . 6e: C25
−
3
H
N
O
S × CH OH, M =
28
2
2
3
4
52.61, monoclinic, space group P2
1
/n, a = 9.892(1), b = 10.392(1),
◦
3
c = 23.113(1) A˚ , b = 95.472(1) , V = 2365.2(1) A˚ , T = 200(2) K,
−
3
3
Z = 4, q = 1.271 g cm , crystal dimensions 0.46 × 0.28 × 0.08 mm ,
max = 27.45 deg, 23864 reflections measured, 5407 unique (Rint
.0363), 3937 observed (I > 2r(I)), l = 0.167 mm , Tmin = 0.94,
max = 0.99, 300 parameters refined, R1 = 0.041 and wR2 = 0.103 for
H
=
−
1
0
T
observed reflections, residual electron density −0.50 to 0.25 e A˚ . 6f:
−
3
C
25
H
28
N
2
O
2
S, M = 420.6, monoclinic, space group P2
1
/n, a = 8.624(1),
◦
3
b = 22.051(1), c = 13.223(1) A˚ , b = 100.164(1) , V = 2475.1(1) A˚ , T =
−
3
2
0
(
00(2) K, Z = 4, q = 1.129 g cm , crystal dimensions 0.50 × 0.26 ×
3
.22 mm , Hmax = 27.50 deg, 25612 reflections measured, 5688 unique
−
1
R
int = 0.0437), 3739 observed (I > 2r(I)), l = 0.15 mm , Tmin = 0.93,
T
max = 0.97, 324 parameters refined, R1 = 0.068 and wR2 = 0.191 for
observed reflections, residual electron density −0.58 to 0.65 e A˚ . 6h:
−
3
C
26
H
28
N
2
O
4
S × CH
2
Cl
2
, M = 549.5, monoclinic, space group P2
1
, a =
◦
◦
1
2.022(1), b = 14.950(1), c = 14.663(1) A˚ , a = 90.0 , b = 94.869(2) ,
◦
3
−3
c = 90.0 , V = 2625.9(4) A˚ , T = 100(2) K, Z = 4, q = 1.390 g cm
,
3
crystal dimensions 0.21 × 0.15 × 0.12 mm , Hmax = 26.37 deg, 23151
reflections measured, 10561 unique (Rint = 0.0423), 9120 observed (I >
−
1
2
r(I)), l = 0.36 mm , Tmin = 0.93, Tmax = 0.96, 877 parameters refined,
R1 = 0.050 and wR2 = 0.107 for observed reflections, residual electron
density −0.24 to 0.46 e A˚ . 6l: C18
−
3
H
N
O
, M = 312.4, monoclinic,
20
2
3
space group P2
1
/c, a = 11.526(1), b = 12.965(1), c = 10.742(1) A˚ , b =
◦
3
−3
9
4.770(1) , V = 1599.6(1) A˚ , T = 200(2) K, Z = 4, q = 1.297 g cm
,
3
crystal dimensions 0.42 × 0.22 × 0.16 mm , Hmax = 27.47 deg, 16235
reflections measured, 3648 unique (Rint = 0.0298), 3011 observed (I >
−
1
2
r(I)), l = 0.09 mm , Tmin = 0.96, Tmax = 0.99, 288 parameters refined,
R1 = 0.036 and wR2 = 0.089 for observed reflections, residual electron
density −0.24 to 0.19 e A˚ . CCDC reference numbers 281672 (6a),
−
3
2
2
81673 (6b), 281674 (6c), 281675 (6e), 281676 (6f), 235421 (6h), and
81677 (6l). For crystallographic data in CIF or other electronic format
see DOI: 10.1039/b511861a
4
3 8 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1

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Fig. 7 Numeration of quinolizinone core.
3
1
5.1 Hz and J = 5.6 Hz and a doublet of doublets with coupling
2
3
constants of J = 14.9 Hz and J = 4.2 Hz. For 6e the resonances
of 7-H give rise to a doublet of doublets of doublets at d 2.80 with
2
3
coupling constants of J = 15.6 Hz, J = 11.5 Hz (axial–axial)
3
and J = 6.9 Hz (axial–equatorial) and a doublet of doublets
2
3
at d 2.55 with coupling constants of J = 15.6 Hz and J =
5
.0 Hz (equatorial–axial). Accordingly, the resonances of 1-H,
which usually adopts an axial position, are found at d 3.16–4.90
appearing as doublets of doublets with coupling constants of J
1
2
n
6
3
Fig. 3 ORTEP plot of 6c (R = p-MeOC
6
H
4
, R = Bu, R = R =
7
R = H, hydrogen atoms were omitted for clarity).
=
13.1–13.5 Hz (axial–axial, cf. dihedral angle from X-ray of
◦
1
70–173 ) and 5.0–6.0 Hz (axial–equatorial, cf. dihedral angle
◦
from X-ray of 52–54 ) and can be unambiguously assigned by
1
1
the cross-peak of CH carbon and H proton in HMBC spectra,
since usually only one CH group is present in compounds.
Finally, 2-H resonances can be detected at d 1.88–2.62 and 3-H
resonances at d 2.31–2.93, which can be readily assigned from
the COSY experiments.
For compound 6g the most interesting information stems
from the coupling constant of 1-H and 12b-H resonances. The
resonance of 12b-H gives rise to a doublet at d 5.44 with
3
a coupling constant of J = 10.0 Hz (axial–axial coupling,
confirming a trans-relationship), the resonance of 1-H appears
3
as a doublet at d 3.60 with coupling constants of J = 12.0 Hz
3
1
2
n
7
(axial–axial), J = 10.0 Hz (axial–axial coupling, confirming a
Fig. 4 ORTEP plot of 6e (R = 2-thienyl, R = Bu, R = R = H,
3
6
trans-relationship) and J = 3.2 Hz (axial–equatorial) coupling.
R = CH
3
).
For alkynes bearing an electron withdrawing group this
sequence can be performed without the first cross-coupling step
in a three-component fashion (Scheme 4).
Scheme
4 One-pot three-component amination–aza-annulation-
Pictet–Spengler sequence (AAPS).
This time, since triethylammmonium hydrochloride is absent
from the reaction mixture, only 1.0 equiv of tryptamine 8c is
sufficient to complete the b-enaminone formation. Hence, this
one-pot three-component amination-aza-annulation-Pictet–
Spengler (AAPS) sequence provides additional flexibility in the
tetrahydro-b-carboline substitution pattern. The structure of
the major diastereomer is unambiguously supported by X-ray
structure analysis (for 6l see Fig. 8).†
1
2
n
6
Fig. 5 ORTEP plot of 6f (R = 2-thienyl, R = Bu, R = R = H,
7
R = CH
3
), major diastereomer.
1
2
n
Fig. 6 ORTEP plot of 6h (R = 2-thienyl, R = Bu, R = CO
2 3
CH ,
6
7
R = R = H).
The resonances of 7-H are identified in the region of d 2.66–
2
.93 and overlap with the butyl protons, but for 6d they are
Fig. 8 ORTEP plot of 6l (R
diastereomer.
2
= OEt, R
1
= R = R
6
= R = H), major
7
2
found as a doublet of triplets with coupling constants of J =
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1
4 3 8 5

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In order to rationalize the exclusive diastereoselectivity of
the CAAPS sequence two mechanistic pathways were proposed
Lewis and Brønsted acids to enhance the electrophilicity of the
acyliminium salt and to induce the Pictet–Spengler cyclization
(Scheme 6).
(
Scheme 5).
Scheme 6 CAAPS sequence for homoveratryl amine (8b).
By applying strong Brønsted acids such as CH
CF SO H or CF CO H the desired product 6m was obtained in
5, 66 or 70% yields, respectively, but with low diastereoselectiv-
ity (dr 1–1.4 : 1). After addition of weak Lewis acids such as BF
3
SO H,
3
3
3
3
2
5
3
,
trifluoroacetic anhydride or TMSCl, only the aza-annulation
product 10c was detected by TLC. Upon using stronger Lewis
acids such as TiCl
4
, SnCl
4
and POCl the formation of a black
3
tar was observed. Finally, TMSOTf was the superior Lewis acid
resulting in the formation of 6m in 65% with a dr of 1.6 : 1.
In order to compare our consecutive approach with the
stepwise splitting protocol, we synthesized the b-enaminone
15
4
a in 81% yield via the coupling–amination sequence and
subjected it to the aza-annulation–PS sequence with acryloyl
9a or methacryloyl 9c chlorides (Scheme 7).
Scheme 5 Plausible mechanistic pathways.
First, the addition of tryptamine to ynones results in the
formation of a (Z)-configured b-enaminone, which reacts with
an a,b-unsaturated acid chloride either via a cationic aza–Cope-
22
type rearrangement or via an aza–ene reaction. In the first
pathway a chair-like transition state is preferred, while in the
latter case the transition state has an envelope conformation
with an endo-electron withdrawing group lying over the fold
23
of the envelope. Both mechanisms rationalize the mutual syn-
6
orientation of the R and the carbonyl substituents. Finally, for
the resulting acyliminium species an intramolecular nucleophilic
attack by the indole can be expected to occur predominantly
anti with respect to the more bulky carbonyl group, leading
2
mainly to the syn diastereomer (with respect to R and carbonyl
substituents). Two diastereomers observed in the reaction with
7
methacryloyl chloride (R = CH
3
) were formed most probably
via epimerization.
Next, we turned our attention to the case of the homover-
atryamine 8b that gave rise to the aza-annulation product 10c
Scheme 7 CAAPS sequence as a splitting protocol.
(
Scheme 2, Table 1). We reasoned that the aromatic ring of the
homoveratryl amine carries activating substituents providing the
electronic character for the annulation to occur. However, it
seems as if the dimethoxyphenyl substituent is less nucleophilic
in comparison to indole. Therefore, we decided to test a range of
Indolo[2,3-a] quinolizin-4-ones 6a and 6f were obtained in
85% and 75% yields, respectively. The overall yields for this
splitting protocol lie in the same range as for the CAAPS
sequence. However, avoiding the isolation and purification of
4
3 8 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1

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the intermediate b-enaminone favors the application of the direct
CAAPS approach.
1.10–1.23 (m, 2 H), 1.28–1.40 (m, 2 H), 2.12–2.18 (m, 2 H), 2.57
(s, 4 H; dihydropyrid-2-one CH
6.94 (dd, J = 4.9 Hz, J = 3.8 Hz, 1 H), 7.09–7.28 (m, 6 H)
and 7.51 (dd, J = 4.9 Hz, J = 1.1 Hz, 1 H); d (CDCl , 75
MHz) 13.6 (CH ), 22.2 (CH ), 23.6 (CH ), 29.5 (CH ), 31.1
(CH ; dihydropyrid-2-one), 31.9 (CH ; dihydropyrid-2-one),
44.0 (CH ; benzyl), 119.2 (Cquat), 126.3 (CH), 127.2 (CH),
127.9 (CH), 128.7 (CH), 132.6 (CH), 133.9 (CH), 137.7 (Cquat),
144.5 (Cquat), 145.7 (Cquat), 171.1 (Cquat; amide) and 188.3 (Cquat
2
CH
2
), 4.89 (s, 2 H; PhCH
2
),
In conclusion, the four-component CAAPS sequence, where
five bonds and four stereocenters are formed in a one-pot
reaction, proceeds with reasonable yields and delivers, starting
from electronically diverse acid chlorides and aliphatic, aromatic
alkynes as well as (TMS)acetylene and a broad variety of
tetrahydro-b-carbolines 6. In addition, applying TMSOTf as
a Lewis acid the enaminone of homoveratrylamine (8b) can
be involved in a Pictet–Spengler cyclization again in a one-
pot fashion. This synthesis provides a rapid access to highly-
substituted subunits of numerous alkaloids. Further studies are
currently in progress.
C
3
3
2
2
2
2
2
2
;
+
+
+
ketone); m/z (EI ) 353 (M , 37%), 320 ((M − HS), 100) and
+
111 ((2-ThCO ), 32).
1
-Benzyl-6-butyl-5-(p-methoxybenzoyl)-3,4-dihydro-1H-pyridin-
-one (10b). Yellow oil; (Found: 377.1988. C24 requires
77.1991); mmax (thin film)(cm ) 2957, 2931, 1679, 1599, 1372,
257, 1143 and 1029; d (CDCl
2
3
1
3
7
3
7
7
H
27NO
3
−
1
Experimental
H
3
, 300 MHz) 0.80 (t, J = 7.4 Hz,
H), 1.14–1.27 (m, 2 H), 1.33–1.46 (m, 2 H), 2.15 (t, J =
All reactions were carried out in screw cap pressure vessels under
a nitrogen atmosphere. The solvents were dried according to
.7 Hz, 2 H), 2.49–2.57 (m, 2 H), 2.61–2.69 (m, 2 H), 3.83 (s,
24
H; CH
.19–7.39 (m, 5 H) and 7.61 (d, J = 8.8 Hz, 2 H); d
5 MHz) 13.7 (CH ), 22.3 (CH ), 23.6 (CH ), 29.4 (CH
CH ; dihydropyrid-2-one), 32.0 (CH ; dihydropyrid-2-one),
4.1 (CH ; benzyl), 55.5 (CH ; CH O), 113.8 (CH), 119.5 (Cquat),
3
O), 4.98 (s, 2 H; PhCH
2
), 6.84 (d, J = 8.8 Hz, 2 H),
(CDCl
), 31.1
standard procedures and were distilled prior to use. Column
chromatography: silica gel 60 M (mesh 230–400) Macherey–
Nagel. Thin layer chromatography (TLC): silica gel layered
aluminium foil (60 F254 Merck, Darmstadt). Melting points
C
3
,
3
2
2
2
(
2
2
4
1
1
1
3
2
3
3
(
uncorrected): Reichert–Jung Thermovar and B u¨ chi Melting
Point B-540. Pd(PPh Cl , CuI, acid chlorides 1, hexyne (2a),
26.5 (CH), 127.3 (CH), 128.8 (CH), 130.4 (Cquat), 131.2 (CH),
37.7 (Cquat), 144.7 (Cquat), 163.2 (Cquat), 171.1 (Cquat; amide) and
3
)
2
2
phenylacetylene (2b), (trimethylsilyl)acetylene (2c), amines 8
and a,b-unsaturated chlorides 9 were purchased from ACROS
+
+
+
95.5 (Cquat; ketone); m/z (EI ) 377 (M , 576), 360 (M − OH,
+
+
1
6), 334 (M − C
3
H
7
, 56) and 135 (p-CH
3
OC
6
H CO , 100).
4
or Merck and were used without further purification. H and
1
3
C NMR, DEPT-, NOESY-, COSY-, HMQC-, and HMBC
spectra were recorded on Bruker DRX 300 or Bruker DRX
00 spectrometers with CDCl or DMSO-d as solvents. The
assignments of quaternary C, CH, CH and CH were made
1
-[3,4-Dimethoxyphenylethyl]-6-butyl-5-(thiophene-2-carbonyl)-
,4-dihydro-1H-pyridin-2-one (10c). Colorless oil (∼90%
(product) 0.65 (neat diethyl ether); d (CDCl
50 MHz) 0.84 (t, J = 7.1 Hz, 3 H), 1.05–1.35 (m, 4 H),
.16–2.24 (m, 2 H), 2.39 (s, 4 H; dihydropyrid-2-one CH CH ),
.70–2.78 (m, 2 H), 3.72 (s, 3 H; CH O), 3.75 (s, 3 H; CH O),
.79–3.87 (m, 2 H), 6.64–6.70 (m, 3 H), 7.00 (dd, J = 4.9 Hz,
3
5
3
6
pure); R
f
H
3
,
2
3
2
2
2
3
on the basis of DEPT spectra. IR: Bruker Vector 22 FT-IR
spectrophotometer. MS: Jeol JMS-700 and Finnigan TSQ 700.
Elemental analyses were carried out in the microanalytical lab-
oratory of the Organisch-Chemisches-Institut der Universit a¨ t
Heidelberg.
2
2
3
3
J = 3.8 Hz, 1 H), 7.20 (dd, J = 3.8 Hz, J = 1.2 Hz, 1 H) and
(CDCl , 75 MHz) 13.3
), 28.7 (CH ), 30.3 (CH ), 31.4
; dihydropyrid-2-one), 36.8 (CH ; dihydropyrid-2-one),
), 55.4 (CH ; CH O), 55.5 (CH ; CH O), 110.9 (CH),
7
CH
CH
.54 (dd, J = 4.9 Hz, J = 1.2 Hz, 1 H); d
C
3
(
(
3
2
), 21.8 (CH
2
), 23.2 (CH
2
2
2
General procedure for the CAA sequence
2
In a screw cap pressure vessel 14 mg (0.02 mmol) of
42.1 (CH
2
3
3
3
3
Pd(PPh
3
)
2
Cl
2
, and 7 mg (0.04 mmol) of CuI were dissolved
111.8 (CH), 118.2 (Cquat), 120.5 (CH), 127.6 (CH), 130.5 (Cquat),
132.3 (CH), 133.6 (CH), 144.1 (Cquat), 145.0 (Cquat), 147.4 (Cquat),
148.5 (Cquat), 170.6 (Cquat; amide) and 188.0 (Cquat; ketone).
in 5 mL of degassed THF. Then 0.14 mL (1.00 mmol) of
triethylamine, as well as 1 mmol of acid chloride 1 and 0.12 mL
(
1.05 mmol) of hexyne 2a were successively added to the
solution. The reaction mixture was stirred for 2 h at room
temperature until the conversion was complete (monitored by
TLC). Afterwards 1.2 mmol of amine 8 were added and the
reaction mixture was heated at 70 C for 24 h. After complete
conversion of the ynone to the enaminone (TLC), acryloyl
General procedure for the CAAPS sequence
In a screw cap pressure vessel 14 mg (0.02 mmol) of
◦
Pd(PPh ) Cl , and 7 mg (0.04 mmol) of CuI were dissolved in
3
2
2
5
mL of degassed THF or toluene. Then 0.14 mL (1.00 mmol)
of triethylamine, as well as 1 mmol of acid chloride 1 and
1.05 mmol of alkyne 2 were successively added to the solution.
The reaction mixture was stirred for 2 h at room temperature
until the conversion was complete (monitored by TLC). After-
wards 2.0 mmol of amine 8c or 8d were added (for 6j and 6k
the amount of 8c was reduced to 1.1 mmol, adding 0.15 mL
chloride 9a (1.2–2.1 mmol) was added and the reaction mixture
was heated at 70 C for 3 h. After cooling to room temperature
the reaction mixture was diluted with methanol, stirred for
◦
1
0 min, evaporated and applied to column chromatography on
silica gel eluting with hexane–ethyl acetate 2 : 1 (10a,b) or ether
10c), to give the analytically pure 5-acyl dihydropyrid-2-ones
0 as oils (for experimental details, see Table 3).
(
1
(
1.00 mmol) of DBU at the same time) and the reaction mixture
◦
◦
was heated at 70 C (THF) or 100 C (toluene) for 10 h. After
complete conversion of ynone to enaminone (TLC), an a,b-
unsaturated acid chloride 9 (5.0 mmol) was added and the
1
-Benzyl-6-butyl-5-(thiophene-2-carbonyl)-3,4-dihydro-1H-
pyridin-2-one (10a). Colorless oil; (Found: 353.1470.
−
1
◦
C
2
7
21
H
23NO
2
S requires 353.1444); mmax (thin film)(cm ) 2957,
930, 1683, 1634, 1515, 1454, 1412, 1373, 1286, 1180, 843 and
29; d (CDCl ),
, 300 MHz) 0.73 (t, J = 7.2 Hz, 3 H; CH
reaction mixture was heated at 70 C for 3 h. After cooling to
r.t. the reaction mixture was diluted with methanol, stirred for
10 min, evaporated and applied to column chromatography on
H
3
3
Table 3 Experimental details for the CAA sequence
Acid chloride 1 Amine 8
Acryloyl chloride (9a)
Product (yield%)
1
1
1
47 mg (1.00 mmol) of 1a
71 mg (1.00 mmol) of 1b
47 mg (1.00 mmol) of 1a
0.13 mL (1.20 mmol) of 8a
0.13 mL (1.20 mmol) of 8a
0.20 mL (1.20 mmol) of 8b
0.10 mL (1.20 mmol)
0.12 mL (1.50 mmol)
0.17 mL (2.10 mmol)
110 mg (31%) of 10a
238 mg (63%) of 10b
295 mg (69%) of 10c
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1
4 3 8 7

View Article Online
Table 4 Experimental details for the CAAPS sequence
Acid chloride 1
Alkyne 2
Amine 8
a,b -Unsaturated chloride 9
Product (yield%)
a
1
1
1
1
1
1
47 mg (1.00 mmol) of 1a
0.12 mL (1.05 mmol) of 2a 320 mg (2.00 mmol) of 8c
0.12 mL (1.05 mmol) of 2a 320 mg (2.00 mmol) of 8c
0.12 mL (1.05 mmol) of 2a 320 mg (2.00 mmol) of 8c
0.11 mL (1.05 mmol) of 2b 320 mg (2.00 mmol) of 8c
0.12 mL (1.05 mmol) of 2a 320 mg (2.00 mmol) of 8c
0.12 mL (1.05 mmol) of 2a 320 mg (2.00 mmol) of 8c
0.41 mL (5.00 mmol) of 9a
0.41 mL (5.00 mmol) of 9a
0.41 mL (5.00 mmol) of 9a
0.41 mL (5.00 mmol) of 9a
0.48 mL (5.00 mmol) of 9b
0.48 mL (5.00 mmol) of 9c
210 mg (52%) of 6a
192 mg (43%) of 6b
254 mg (59%) of 6c
175 mg (41%) of 6d
210 mg (50%) of 6e
185 mg (44%) of 6f
and 40 mg (10%) of 6fꢀ
140 mg (32%) of 6g
210 mg (45%) of 6h
148 mg (30%) of 6i
206 mg (36%) of 6j
130 mg (36%) of 6k
a
86 mg (1.00 mmol) of 1c
a
71 mg (1.00 mmol) of 1b
a
47 mg (1.00 mmol) of 1a
a
47 mg (1.00 mmol) of 1a
a
47 mg (1.00 mmol) of 1a
a
c
1
1
1
3
1
47 mg (1.00 mmol) of 1a
0.14 mL (1.05 mmol) of 2c
320 mg (2.00 mmol) of 8c
0.41 mL (5.00 mmol) of 9a
b
d
47 mg (1.00 mmol) of 1a
0.12 mL (1.05 mmol) of 2a 510 mg (2.00 mmol) of 8d 0.80 mL (9.76 mmol) of 9a
a
47 mg (1.00 mmol) of 1a
179 mg (1.05 mmol) of 2d
320 mg (2.00 mmol) of 8c
0.41 mL (5.00 mmol) of 9a
0.41 mL (5.00 mmol) of 9a
0.41 mL (5.00 mmol) of 9a
a
e
18 mg (1.00 mmol)of 1d
0.12 mL (1.05 mmol) of 2a 175 mg (1.10 mmol) of 8c
a
e
07 mg (1.00 mmol) of 1e
0.12 mL (1.05 mmol) of 2a 175 mg (1.10 mmol) of 8c
silica gel, to give the analytically pure tetrahydro-b-carbolines 6
as solids (for experimental details, see Table 4).
(C=O), 1426, 1261, 1173, 1029, 843, 745, 593 and 505; d
(CDCl
H
3
, 500 MHz) 0.85 (t, J = 7.0 Hz, 3 H; Bu), 1.05–1.20 (m,
1
2
1
4
1
H), 1.24–1.40 (m, 3 H), 1.96–2.12 (m, 1 H), 2.20–2.40 (m,
rac-12b-Butyl-1-(thiophene-2-carbonyl)-2,3,6,7,12,12b-hexa-
H), 2.75–2.90 (m, 5 H), 2.98 (dt, J = 12.0 Hz, J = 4.0 Hz,
hydro-1H-indolo[2,3-a]
crystals; mp 250–251 C; R
quinolizin-4-one
(product) 0.37 (neat diethyl ether);
S requires C,
0.91; H, 6.45; N, 6.89%); mmax (KBr)(cm ) 2955, 2869, 1626
(CDCl , 500 MHz) 0.83 (t,
(6a). Colorless
H; 6-H), 3.74 (s, 3 H; CH
3
O), 3.93 (dd, J = 13.2 Hz, J =
◦
f
.9 Hz, 1 H; 1-H), 5.27 (ddd, J = 12.8 Hz, J = 4.8 Hz, J =
(
Found: C, 70.64; H, 6.44; N, 6.92. C24
H
26
−
N
1
2
O
2
.5 Hz, 1 H; 6-H), 6.74 (d, J = 9.0 Hz, 2 H), 7.04–7.17 (m, 3
7
H), 7.46–7.52 (m, 1 H), 7.66 (d, J = 9.0 Hz; 2 H) and 8.27 (s,
(
C=O), 1413, 1238 and 731; d
H
3
1
H; indole-NH); d
2
C
(CDCl
; 7-C), 21.5 (CH ; 2-C), 23.2 (CH
; 3-C), 35.7 (CH ; Bu), 39.8 (CH
; CH O), 62.0 (Cquat; 12b-C), 110.7 (Cquat), 111.0
3
, 125 MHz) 13.9 (CH
; Bu), 27.2 (CH
; 6-C), 52.6 (CH;
3
; Bu), 20.9
J = 7.4 Hz, 3 H; Bu), 1.02–1.11 (m, 1 H), 1.22–1.37 (m, 3 H),
(CH
2
2
2
; Bu),
2.10–2.23 (m, 2 H), 2.35–2.44 (m, 1 H; 2-H), 2.72–2.88 (m, 5 H),
2.98 (dt, J = 12.4 Hz, J = 3.8 Hz, 1 H; 6-H), 3.73 (dd, J =
13.4 Hz, J = 5.0 Hz, 1 H; 1-H), 5.22 (ddd, J = 12.8 Hz,
29.6 (CH
2
2
2
1-C), 55.3 (CH
3
3
(
(
CH), 113.7 (CH), 118.0 (CH), 119.3 (CH), 121.8 (CH), 125.9
J = 4.8 Hz, J = 1.5 Hz, 1 H; 6-H), 6.90 (dd, J = 4.9 Hz, J =
Cquat), 129.4 (Cquat), 130.3 (CH), 134.3 (Cquat), 135.7 (Cquat),
3
.7 Hz, 1 H), 7.03–7.09 (m, 2 H), 7.13–7.16 (m, 1 H), 7.38 (dd,
1
63.7 (Cquat), 169.6 (Cquat; amide) and 201.5 (Cquat; ketone); m/z
J = 3.7 Hz, J = 1.1 Hz, 1 H), 7.44–7.49 (m, 1 H), 7.54 (dd, J =
+
+
+
(
EI ) 430 (M , 13), 373 (32), 135 (4-MeOPhCO , 100).
4
(
2
.9 Hz, J = 1.1 Hz, 1 H) and 8.00 (s, 1 H; indole-NH); d
CDCl , 125 MHz) 13.9 (CH ; Bu), 20.1 (CH ; 7-C), 21.8 (CH
-C), 23.3 (CH ; Bu), 27.2 (CH ; Bu), 29.6 (CH ; 3-C), 35.9
; Bu), 40.0 (CH ; 6-C), 55.0 (CH; 1-C), 61.9 (Cquat; 12b-C),
C
3
3
2
2
;
rac-12b-Phenyl-1-(thiophene-2-carbonyl)-2,3,6,7,12,12b-hexa-
2
2
2
hydro-1H-indolo[2,3-a]
quinolizin-4-one
crystals; mp 315–316 C; (Found: C, 72.55; H, 5.26; N, 6.52.
S requires C, 73.21; H, 5.20; N, 6.57%); mmax
(6d). Colorless
(
CH
2
2
◦
1
1
1
10.0 (CH), 118.2 (CH), 119.5 (CH), 122.2 (CH), 126.0 (Cquat),
28.5 (CH), 132.5 (CH), 133.9 (Cquat), 135.2 (CH), 135.8 (Cquat),
C
26
H
22
N
2
O
2
−1
(
KBr)(cm ) 1651 (C=O), 1611, 1456, 1413, 1351, 1236, 1215,
43.9 (Cquat), 145.2 (Cquat), 169.6 (Cquat; amide) and 195.5 (Cquat
;
745 and 702; d
H
(DMSO-d
6
, 500 MHz) 1.80–1.90 (m, 1 H; 2-H),
+
+
ketone); m/z (FAB) 407 [(M + H) , 100] and 349 [(M + H) −
1
.92–1.99 (m, 1 H; 2-H), 2.26 (dd, J = 17.7 Hz, J = 5.4 Hz, 1
C
4
H
9
, 90].
H; 3-H), 2.41 (dd, J = 14.9 Hz, J = 4.2 Hz, 1 H; 7-H), 2.78
(
ddd, J = 17.7 Hz, J = 12.9 Hz, J = 6.8 Hz, 1 H; 3-H), 2.91 (dt,
rac-12b-Butyl-1-(4-nitrophenyl-1-carbonyl)-2,3,6,7,12,12b-
hexahydro-1H-indolo[2,3-a] quinolizin-4-one (6b). Yellow
J = 15.1 Hz, J = 5.6 Hz, 1 H; 7-H), 2.99 (dt, J = 12.1 Hz, J =
◦
4.4 Hz, 1 H; 6-H), 4.66 (dd, J = 12.7 Hz, J = 5.6 Hz, 1 H; 6-H),
crystals; mp 195–197 C; R
(
7
(
(
f
(product) 0.26 (neat diethyl ether);
requires C,
0.10; H, 6.11; N, 9.43%); mmax (KBr)(cm ) 2957, 2868, 1618
(CDCl , 500 MHz) 0.85
t, J = 7.1 Hz, 3 H; Bu), 1.01–1.18 (m, 1 H), 1.22–1.41 (m, 3
4
.81 (t, J = 3.6 Hz, 1 H; 1-H), 6.98–7.03 (m, 2 H), 7.10–7.18
Found: C, 69.79; H, 6.05; N, 9.41. C24
H
27
1
N
3
O
4
−
(m, 4 H), 7.27 (d, J = 7.6 Hz, 2 H), 7.38 (d, J = 7.6 Hz, 1 H),
7
1
.52 (d, J = 8.3 Hz, 1 H), 7.87 (dd, J = 4.9 Hz, J = 1.1 Hz,
H), 8.06 (dd, J = 3.9 Hz, J = 1.1 Hz, 1 H) and 11.76 (s, 1 H;
C=O), 1527, 1347, 1235 and 746; d
H
3
indole-NH); d
CH
6.7 (Cquat; 12b-C), 109.5 (Cquat), 111.4 (CH), 118.1 (CH), 119.0
C
(DMSO-d
6
, 125 MHz) 19.8 (CH ; 7-C), 21.8
2
H), 2.00 (ddd, J = 18.4 Hz, J = 9.0 Hz, J = 4.4 Hz, 1 H), 2.21
(
6
2
; 2-C), 28.9 (CH
2
; 3-C), 39.0 (CH ; 6-C), 47.2 (CH; 1-C),
2
(
(
(
1
5
1
dt, J = 18.4 Hz, J = 4.4 Hz, 1 H), 2.29–2.39 (m, 1 H), 2.65
dt, J = 18.0 Hz, J = 4.0 Hz, 1 H), 2.74–2.85 (m, 3 H), 2.90
ddd, J = 15.1 Hz, J = 3.3 Hz, J = 1.3 Hz, 1 H), 2.98 (dt, J =
(
(
(
(
CH), 121.8 (CH), 126.6 (Cquat), 126.9 (CH), 127.0 (CH), 127.8
CH), 128.3 (CH), 134.0 (CH), 135.8 (Cquat), 136.0 (CH), 136.1
2.4 Hz, J = 3.4 Hz, 1 H; 6-H), 3.92 (dd, J = 13.4 Hz, J =
.0 Hz, 1 H; 1-H), 5.24 (ddd, J = 12.7 Hz, J = 4.7 Hz, J =
.3 Hz, 1 H; 6-H), 7.03–7.08 (m, 3 H), 7.47–7.50 (m, 1 H), 7.68
C
quat), 141.3 (Cquat), 144.7 (Cquat), 171.7 (Cquat; amide) and 192.1
+ + +
Cquat; ketone); m/z (EI ) 426 (M , 100), 349 (M − Ph, 18) and
+
1
11 (2-ThCO , 70).
(
9
7
d, J = 9.0 Hz, 2 H), 7.83 (s, 1 H; indole-NH) and 8.05 (d, J =
.0 Hz, 2 H); d
-C), 21.1 (CH
; 3-C), 35.5 (CH
C
(CDCl
3
, 125 MHz) 14.0 (CH
3
; Bu), 21.0 (CH
; Bu), 27.0 (CH ; Bu), 29.3
; 6-C), 54.1 (CH; 1-C),
2
;
rac-12b-Butyl-2-methyl-1-(thiophene-2-carbonyl)-2,3,6,7,12,12b-
hexahydro-1H-indolo[2,3-a] quinolizin-4-one (6e). Colorless
2
; 2-C), 23.3 (CH
2
2
(
CH
2
2
; Bu), 40.1 (CH
2
◦
crystals; mp 301–302 C; R
f
(product) 0.32 (hexane–ethyl
S·
OH requires C, 70.40; H, 6.88; N, 6.46%); mmax
61.8 (Cquat; 12b-C), 110.1 (Cquat), 111.6 (CH), 118.2 (CH), 119.8
acetate; 1 : 1); (Found: C, 70.60; H, 6.68; N, 6.66. C25
.4 CH
H
28
N
2
O
2
(
(
2
CH), 122.4 (CH), 123.6 (CH), 125.9 (Cquat), 128.6 (CH), 133.4
0
3
C
quat), 135.6 (Cquat), 141.1 (Cquat), 150.1 (Cquat), 169.1 (Cquat) and
−
1
(KBr)(cm ) 2958, 1615 (C
(DMSO-d
, 500 MHz) 0.50 (t, J = 7.8 Hz, 3 H; Bu), 0.77 (d, J =
.9 Hz, 3 H; CH
=
O), 1415, 1233 and 742; dH
+
01.8 (Cquat; ketone); m/z (FAB) 446 [(M + H) , 100] and 388
+
6
[
(M + H) − C
4
H
9
, 75].
6
3
), 0.85 (dd, J = 14.7 Hz, J = 7.3 Hz, 1 H),
rac-12b-Phenyl-1-(thiophene-2-carbonyl)-2,3,6,7,12,12b-hexa-
0.94–1.04 (m, 1 H), 1.08–1.18 (m, 1 H), 1.24–1.34 (m, 1 H), 1.82
(dt, J = 12.8 Hz, J = 3.6 Hz, 1 H), 1.88–1.96 (m, 1 H; 2-H),
2.07–2.24 (m, 3 H), 2.55 (dd, J = 15.6 Hz, J = 5.0 Hz, 1 H; 7-H),
2.80 (ddd, J = 15.6 Hz, J = 11.5 Hz, J = 6.9 Hz, 1 H; 7-H), 3.41
(dt, J = 12.4 Hz, J = 5.0 Hz, 1 H; 6-H), 4.66 (d, J = 3.7 Hz,
hydro-1H-indolo[2,3-a]
crystals; mp 201–202 C; R
quinolizin-4-one
(product) 0.25 (neat diethyl ether);
requires C,
(6c). Colorless
◦
f
(
Found: C, 74.93; H, 7.01; N, 6.46. C27
H
30
1
N
2
O
3
−
7
5.32; H, 7.02; N, 6.51%); mmax (KBr)(cm ) 2957, 2868, 1600
4
3 8 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1

View Article Online
1
H; 1-H), 4.76 (dd, J = 13.7 Hz, J = 6.9 Hz, 1 H; 6-H), 6.97 (t,
J = 7.9 Hz, J = 1.2 Hz, 1 H), 7.06 (dt, J = 7.4 Hz, J = 1.2 Hz,
1 H), 7.15–7.19 (m, 2 H), 7.45 (d, J = 7.6 Hz, 1 H) and 7.74–7.77
J = 7.4 Hz, 1 H), 7.10 (t, J = 7.4 Hz, 1 H), 7.35–7.43 (m, 3 H),
8
.11 (dd, J = 5.0 Hz, J = 0.9 Hz, 1 H), 8.53 (dd, J = 3.7 Hz,
(m, 3 H); d
C
(CDCl
3
, 125 MHz) 21.2 (CH
2
), 26.4 (CH ; 2-C),
2
J = 0.9 Hz, 1 H) and 11.16 (s, 1 H; indole-NH); d
C
(DMSO-d
), 19.5 (CH
; 3-C), 27.0 (CH; 2-C), 35.5 (CH
6
,
31.9 (CH
2
), 40.7 (CH ; 6-C), 50.7 (CH; 1-C), 55.0 (CH; 12b-C),
2
75 MHz) 13.9 (CH
3
; Bu), 19.0 (CH
3
; CH
3
2
; 7-C),
111.3 (CH), 118.3 (CH), 119.9 (CH), 122.4 (CH), 126.5 (Cquat),
128.4 (CH), 132.0 (Cquat), 133.3 (CH), 135.8 (CH), 136.2 (Cquat),
21.9 (CH ; Bu), 26.2 (CH
2
2
2
;
Bu), 36.1 (CH
2
; Bu), 38.4 (CH
2
; 6-C), 48.8 (CH; 1-C), 63.0
142.2 (Cquat), 155.8 (Cquat), 168.3 (Cquat; amide) and 197.0 (Cquat;
+ + +
(
C
quat; 12b-C), 107.0 (Cquat), 110.9 (CH), 117.5 (CH), 118.4 (CH),
21.0 (CH), 126.8 (Cquat), 128.7 (CH), 134.4 (CH), 135.3 (Cquat),
36.5 (Cquat), 137.4 (CH), 147.3 (Cquat), 170.2 (Cquat; amide) and
ketone); m/z (EI ) 350 (M , 77), 239 (M − 2-ThCO, 100) and
+
1
1
1
1
111 (2-ThCO , 25).
(
+
+
(6S, 4S, 12bS)-12b-Butyl-4-oxo-1-(thiophene-2-carbonyl)-1,2,
92.7 (Cquat; ketone); m/z (EI ) 420 (M , 28), 363 (M − C
4
9
H ,
+
3,4,6,7,12,12b-octahydro-indolo-[2,3-a]quinolizin-6-carboxylic
00) and 111 (2-ThCO , 29).
◦
acid methyl ester (6h). Colorless crystals; mp 139–140 C; R
f
2
4
◦
rac-12b-Butyl-3-methyl-1-(thiophene-2-carbonyl)-2,3,6,7,12,12b-
hexahydro-1H-indolo[2,3-a] quinolizin-4-one major diastereomer
(product) 0.45 (neat ether); [a]
D
+178 (c 2.0, CH
2
Cl
2
); (Found:
C, 62.72; H, 5.77; N, 5.52; S, 6.32; Cl, 6.99. C26
H
28
N
2
O
4
S·0.5
6
f (syn–syn : syn–anti = 4.5 : 1). Colorless crystals; mp
CH
2
Cl
2
requires C, 62.72; H, 5.78; N, 5.36; S, 6.39; Cl, 7.18%);
◦
−1
209–210 C; R
f
(product) 0.35 (hexane–ethyl acetate; 2 : 1);
m
max (KBr)(cm ) 3428, 2955, 2931, 1739, 1650 (C=O), 1414,
(
Found: C, 71.11; H, 6.68; N, 6.67. C25
H
28
1
N
2
O
2
S requires C,
1239, 1060 and 741; d
H
(CDCl , 500 MHz) 0.60–0.70 (m, 1 H;
3
−
7
2
d
1.40; H, 6.71; N, 6.66%); mmax (KBr)(cm ) 3439, 3281, 2957,
Bu), 0.76 (t, J = 7.1 Hz, 3 H; Bu), 1.14–1.25 (m, 3 H; Bu), 2.24
(dt, J = 14.0 Hz, J = 4.0 Hz, 1 H; Bu), 2.31–2.37 (m, 2 H;
2-H), 2.61–2.66 (m, 1 H; Bu), 2.82–2.86 (m, 2 H; 3-H), 3.10 (dd,
J = 15.8 Hz, J = 6.9 Hz, 1 H; 7-H), 3.45 (dd, J = 15.8 Hz, J =
930, 1644 (C=O), 1462, 1414, 1351, 1301, 1237, 742 and 729;
(CDCl
, 500 MHz) 0.82 (t, J = 7.0 Hz, 3 H; Bu), 1.04–1.16
),
.84 (ddd, J = 14.1 Hz, J = 5.7 Hz, J = 4.4 Hz, 1 H; 2-H), 2.31
ddd, J = 14.5 Hz, J = 12.4 Hz, J = 4.2 Hz, 1 H), 2.62 (dt, J =
3.7 Hz, J = 9.8 Hz, 1 H; 2-H), 2.68–2.78 (m, 2 H), 2.81–2.88
H
3
(
1
m, 1 H), 1.22–1.36 (m, 3 H), 1.39 (d, J = 7.0 Hz, 3 H; CH
3
2.7 Hz, 1 H; 7-H), 3.67 (s, 3H; CO
2
CH
3
), 4.90 (t, J = 9.9 Hz,
(
1
1 H; 1-H), 5.29 (s, 1 H (CH
2
Cl
2
)), 5.52 (dd, J = 6.8 Hz, J =
2.7 Hz, 1 H; 6-H), 7.05–7.13 (m, 3 H), 7.18–7.19 (m, 1 H), 7.45
(dd, J = 6.3 Hz, J = 1.8 Hz, 1 H), 7.68 (dd, J = 4.9 Hz, J =
1.0 Hz, 1 H), 7.79 (dd, J = 3.8 Hz, J = 1.0 Hz, 1 H) and 8.16
(
m, 2 H), 2.96 (dt, J = 12.4 Hz, J = 3.7 Hz, 1 H; 6-H), 3.75 (dd,
J = 13.1 Hz, J = 6.0 Hz, 1 H; 1-H), 5.23 (ddd, J = 12.8 Hz,
J = 4.8 Hz, J = 1.6 Hz, 1 H; 6-H), 6.91 (dd, J = 4.9 Hz, J =
(s, 1 H; indole-NH); d
C
(CDCl
; 2-C), 23.0 (CH
; 3-C), 37.3 (CH ; Bu), 52.0 (CH; 1-C), 52.6 (CH
), 54.8 (CH; 6-C), 62.9 (Cquat; 12b-C), 107.6 (Cquat),
3
, 75 MHz) 13.9 (CH
3
; Bu), 22.5
3
.9 Hz, 1 H), 7.03–7.10 (m, 2 H), 7.14–7.16 (m, 1 H), 7.38 (dd,
(CH
30.0 (CH
CO CH
2
; 7-C), 22.7 (CH
2
2
; Bu), 25.5 (CH
2
; Bu),
J = 3.9 Hz, J = 1.0 Hz, 1 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.54
2
2
3
;
(
dd, J = 4.9 Hz, J = 1.0 Hz, 1 H) and 7.99 (s, 1 H; indole-NH);
2
3
d
C
(CDCl
CH ; 7-C), 23.3 (CH
3.9 (CH; 3-C), 35.4 (CH
3
, 125 MHz) 14.0 (CH
; Bu), 27.2 (CH
; Bu), 40.1 (CH
3
; Bu), 19.7 (CH
3
; CH
3
), 21.0
; 2-C),
111.3 (CH), 118.2 (CH), 119.6 (CH), 122.4 (CH), 125.2 (Cquat),
128.9 (CH), 133.9 (CH), 134.1 (Cquat), 135.9 (CH), 136.1 (Cquat),
144.4 (Cquat), 172.8 (Cquat; amide or ester), 172.9 (Cquat; amide
(
2
2
2
; Bu), 30.9 (CH
2
3
1
1
1
2
2
; 6-C), 53.9 (CH;
+
+
-C), 62.4 (Cquat; 12b-C), 111.0 (Cquat), 111.1 (CH), 118.1 (CH),
19.5 (CH), 122.1 (CH), 126.1 (Cquat), 128.4 (CH), 132.5 (CH),
34.5 (Cquat), 135.0 (Cquat), 135.1 (CH), 143.9 (Cquat), 173.0 (Cquat
or ester) and 197.9 (Cquat; ketone); m/z (EI ) 464 (M , 10), 407
+
+
(M − C
4
H , 100) and 111 (2-ThCO , 57).
9
;
+
+
rac-12b-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(thiophene-2-
amide) and 195.4 (Cquat; ketone); m/z (EI ) 420 (M , 5), 363
+
+
carbonyl)-2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a] quinolizin-
(
M − C
4
H
9
, 100) and 111 (2-ThCO , 43).
◦
4
0
5
-one (6i). Colorless crystals; mp 288–289 C; R
f
(product)
.45 (hexane–ethyl acetate; 2 : 1); (Found: C, 65.23; H, 6.87; N,
SSi requires C, 65.55; H, 6.93; N, 5.66%); mmax
ꢀ
Minor diastereomer 6f
.78. C27
H
34
−1
N
2
O
3
◦
Colorless crystals; mp 213–214 C; R
ethyl acetate; 2 : 1); (Found: C, 71.04; H, 6.92; N, 6.53.
S requires C, 71.40; H, 6.71; N, 6.66%); mmax
f
(product) 0.30 (hexane–
(KBr)(cm ) 2953, 2855, 1623 (C=O), 1412, 1253, 1103, 841
and 742; d (CDCl , 500 MHz) 0.01 (s, 3 H; TBS), 0.04 (s, 3 H;
H
3
C
25
H
28
N
2
O
2
1
TBS), 0.84 (s, 9 H; TBS), 2.00–2.10 (m, 1 H; 2-H), 2.65–2.87 (m,
−
(
KBr)(cm ) 2957, 2931, 1627 (C=O), 1463, 1414, 1350, 1237,
5 H), 2.95 (dt, J = 12.0 Hz, J = 4.2 Hz, 1 H; 6-H), 3.80–3.88
744 and 728; d (CDCl
H
3
, 300 MHz) 0.83 (t, J = 7.2 Hz, 3 H;
(m, 1 H; 1-H), 4.08 (d, J = 10.6 Hz, 1 H; TBSOCH
2
), 4.97
Bu), 0.86–0.92 (m, 1 H), 1.00–1.37 (m, 4 H), 1.42 (d, J = 6.0 Hz,
(d, J = 10.6 Hz, 1 H; TBSOCH ), 5.17 (dd, J = 12.8 Hz, J =
2
3
1
1
7
H; CH
3
), 2.08–2.32 (m, 3 H), 2.70–2.90 (m, 3 H), 3.02 (t, J =
3.3 Hz, 1 H; 6-H), 7.02–7.12 (m, 3 H), 7.17 (d, J = 7.8 Hz, 1 H),
7.45 (d, J = 7.5 Hz, 1 H), 7.58 (d, J = 3.5 Hz, 1 H), 7.65 (d, J
1.3 Hz, 1 H; 6-H), 3.77 (dd, J = 11.7 Hz, J = 3.7 Hz, 1 H;
-H), 5.22 (d, J = 12.1 Hz, 1 H; 6-H), 6.92–6.98 (m, 1 H), 6.96–
.12 (m, 2 H), 7.13–7.18 (m, 1 H), 7.40–7.50 (m, 2 H), 7.58 (d,
= 4.6 Hz, 1 H) and 7.95 (s, 1 H; indole-NH); d
C
(CDCl , 125
3
MHz) −5.8 (CH
21.2 (CH ), 23.7 (CH
; 6-C), 52.6 (CH; 1-C), 62.3 (Cquat; 12b-C), 65.0 (CH
), 110.6 (Cquat), 111.2 (CH), 118.4 (CH), 119.8 (CH),
3
; TBS), −5.7 (CH
3
; TBS), 18.2 (Cquat; tert-Bu),
J = 4.5 Hz, 1 H) and 7.95 (s, 1 H; indole-NH); d
MHz) 13.9 (CH ), 19.3 (CH ; CH ), 24.8 (CH ), 24.9 (CH
), 36.1 (CH), 37.8 (CH ), 40.0 (CH ; 6-C), 54.8
C
(CDCl
3
, 75
2
2
; 2-C), 25.8 (CH
3
; tert-Bu), 31.3 (CH ),
2
3
3
3
2
2
), 27.6
36.7 (CH
2
2
;
(
(
(
(
(
CH
2
), 30.8 (CH
2
2
2
TBSOCH
2
CH; 1-C), 62.0 (Cquat; 12b-C), 110.8 (Cquat), 111.0 (CH), 118.2
CH), 119.5 (CH), 122.1 (CH), 126.0 (Cquat), 128.5 (CH), 132.5
CH), 134.4 (Cquat), 135.0 (CH), 135.6 (Cquat), 143.6 (Cquat), 172.9
122.4 (CH), 126.0 (Cquat), 128.6 (CH), 132.8 (CH), 133.7 (Cquat),
135.3 (CH), 135.8 (Cquat), 143.6 (Cquat), 170.2 (Cquat; amide)
+
+
+
and 196.4 (Cquat; ketone); m/z (EI ) 494 (M , 4), 349 (M −
+
+
+
Cquat; amide) and 195.5 (Cquat; ketone); m/z (EI ) 420 (M , 11),
TBSOCH
2
, 100) and 111 (2-ThCO , 25).
+
+
3
63 (M − C
4
H
9
, 100) and 111 (2-ThCO , 80).
rac-1-(1-Benzenesulfonyl-1H-indole-3-carbonyl)-12b-butyl-
2,3,6,7,12,12b-hexahydro-1H-indolo[2,3-a] quinolizin-4-one (6j).
rac-1-(Thiophene-2-carbonyl)-2,3,6,7,12,12b-hexahydro-1H-
indolo[2,3-a] quinolizin-4-one (6g). Yellow crystals; mp 133–
◦
Colorless crystals; mp 286–288 C; (Found: C, 70.06; H, 5.65;
◦
1
5
34 C; R
f
(product) 0.48 (neat ethyl acetate); (Found: C,
S·CH Cl
N, 7.28; S, 5.58. C34
7.25; S, 5.53%); mmax (KBr)(cm ) 2960, 2932, 1844, 1619 (C=O),
1535, 1448, 1381, 1235, 1188, 1172, 748 and 732; d (CDCl
H
33
N
3
O
4
−
S requires C, 70.44; H, 5.74; N,
1
8.04; H, 4.66; N, 6.48; S, 7.31; Cl, 16.51. C20
requires C, 57.93; H, 4.63; N, 6.43; S, 7.37; Cl, 16.29%); mmax
H
18
N
2
O
2
2
2
H
3
,
−
1
(
7
(
1
KBr)(cm ) 3372, 1641 (C=O), 1413, 1251, 1235, 1061 and
53; d (CDCl , 500 MHz) 2.02–2.11 (m, 1 H; 2-H), 2.24–2.30
m, 1 H; 2-H), 2.55–2.90 (m, 5 H), 3.60 (ddd, J = 12.0 Hz, J =
0.0 Hz, J = 3.2 Hz, 1 H; 1-H), 5.13–5.19 (m, 1 H; 6-H), 5.29
s, 2 H (CH Cl
)), 5.44 (d, J = 10.0 Hz, 1 H; 12b-H), 7.06 (dt,
500 MHz) 0.83 (t, J = 7.4 Hz, 3 H; Bu), 1.03–1.12 (m, 1 H;
Bu), 1.24–1.40 (m, 3 H; Bu), 2.06–2.14 (m, 1 H; 2-H), 2.20–2.27
(m, 1 H; Bu), 2.37–2.47 (m, 1 H; 2-H), 2.71–2.93 (m, 5 H), 2.99
(dt, J = 12.0 Hz, J = 4.0 Hz, 1 H; 6-H), 3.67 (dd, J = 13.4 Hz,
J = 5.4 Hz, 1 H; 1-H), 5.25 (dd, J = 12.7 Hz, J = 4.4 Hz,
H
3
(
2
2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1
4 3 8 9

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1
1
H; 6-H), 6.97 (d, J = 8.0 Hz, 1 H), 7.02 (dt, J = 8.4 Hz, J =
.3 Hz, 1 H), 7.08 (dt, J = 7.0 Hz, J = 1.0 Hz, 1 H), 7.30–7.37
126.5 (Cquat), 132.5 (Cquat), 136.1 (Cquat), 168.5 (Cquat; amide) and
+
+
+
174.8 (Cquat; ester); m/z (EI ) 312 (M , 100), 256 (M − C
4
H ,
Et, 36).
9
+
+
(
m, 4 H), 7.48–7.53 (m, 2 H), 7.57 (dd, J = 8.7 Hz, J = 1.0 Hz,
100), 256 (M − CH
2
CH
2
CO, 80) and 239 (M − CO
2
2
H), 7.73 (dd, J = 7.0 Hz, J = 1.3 Hz, 1 H), 7.81 (s, 1 H;
PhSO
-indole-2-H), 7.92 (s, 1 H; indole-NH) and 8.31 (dd, J =
.4 Hz, J = 1.3 Hz, 1 H); d (CDCl , 75 MHz) 14.0 (CH ; Bu),
1.0 (CH ; 7-C), 21.7 (CH ; 2-C), 23.3 (CH ; Bu), 27.2 (CH
; 3-C), 36.0 (CH ; Bu), 40.0 (CH ; 6-C), 55.7
2
11b-Butyl-9,10-dimethoxy-1-(thiophene-2-carbonyl)-1,2,3,6,7,
11b-hexahydro-pyrido[2,1-a] isoquinolin-4-one (6m). In a screw
6
2
C
3
3
2
2
2
2
;
cap pressure vessel 14 mg (0.02 mmol) of Pd(PPh
3
)
2
2
Cl , and 7 mg
Bu), 29.6 (CH
2
2
2
(0.04 mmol) of CuI were dissolved in 5 mL of degassed toluene.
Then 0.14 mL (1.00 mmol) of triethylamine, 147 mg (1.00
mmol) of thiophene acid chloride 1a and 0.12 mL (1.05 mmol)
of hexyne 2a were added. The reaction mixture was stirred
for 3 h at room temperature until consumption of alkyne
(that was verified by TLC HE–EA 9 : 1). Afterwards 0.2 mL
(1.20 mmol) of homoveratryl amine 8b were added and the
(
(
(
(
(
(
CH; 1-C), 61.9 (Cquat; 12b-C), 111.0 (CH), 111.2 (Cquat), 113.0
CH), 118.4 (CH), 119.6 (CH), 120.8 (Cquat), 122.2 (CH), 122.7
CH), 125.0 (CH), 125.9 (CH), 126.1 (Cquat), 127.0 (CH), 127.3
C
C
C
quat), 129.7 (CH), 131.8 (CH), 134.3 (Cquat), 134.5 (CH), 134.6
quat), 135.7 (Cquat), 136.9 (Cquat), 169.7 (Cquat; amide) and 198.6
+
+
+
quat; ketone); m/z (EI ) 579 (M , 22), 522 (M − C
4
9
H , 64),
+
◦
2
84 (PhSO
2
Ind-3-CO , 100).
reaction mixture was heated at 100 C for 10 h. After complete
conversion of alkynone to enaminone (TLC hexane–ethyl
rac-12b-Butyl-1-isobutyryl-2,3,6,7,12,12b-hexahydro-1H-
acetate 4 : 1; for alkynone R
f
0.7, for enaminone R 0.2)
f
indolo[2,3-a] quinolizin-4-one (6k). Colorless crystals; mp
◦
acryloyl chloride 9a 0.17 mL (2.00 mmol) was added and the
1
C
3
(
(
0
1
4
2
2
3
7
94–196 C; (Found: C, 71.61; H, 7.89; N, 7.27; Cl, 1.61.
◦
reaction mixture was heated at 70 C for 3 h (TLC neat diethyl
23
H
30
N
2
O
2
·0.2 CH
.70%); mmax (KBr)(cm ) 3267, 2960, 2932, 2871, 1708, 1624
C=O), 1466, 1433, 1405 and 744; d
(CDCl , 500 MHz) 0.69
d, J = 6.7 Hz, 3 H; iso-Pr-CH ), 0.80 (t, J = 7.2 Hz, 3 H; Bu),
), 0.97–1.07 (m, 1 H; Bu),
2
Cl
2
−
requires C, 72.66; H, 7.99; N, 7.30; Cl,
ether; for the aza-annulation product 10c R
.30 mL (4.00 mmol) of CF CO H was added and the reaction
mixture was heated until the aza-annulation product was
consumed 10c (TLC in neat ethyl acetate; for 6m R 0.5, for
both diastereomers). The reaction mixture was quenched with
CO solution, extracted with CH Cl , dried, evaporated and
f
0.65). Afterwards
1
0
3
2
H
3
3
f
.94 (d, J = 7.0 Hz, 3 H; iso-Pr-CH
3
.20–1.32 (m, 3 H; Bu), 1.96 (ddd, J = 18.1 Hz, J = 9.0 Hz, J =
.7 Hz, 1 H; 2-H), 2.08 (dt, J = 14.2 Hz, J = 4.0 Hz, 1 H; Bu),
.13–2.21 (m, 1 H; 2-H), 2.28 (spt, J = 7.0 Hz, 1 H; iso-Pr-CH),
.60 (dt, J = 12.4 Hz, J = 3.4 Hz, 1 H; Bu), 2.66–2.76 (m,
H), 2.83 (ddd, J = 15.4 Hz, J = 3.4 Hz, J = 1.6 Hz, 1 H;
-H), 2.91 (dt, J = 12.4 Hz, J = 3.7 Hz, 1 H; 6-H), 3.16 (dd,
K
2
3
2
2
applied to column chromatography eluting with neat ethyl
acetate to give the analytically pure quinolizinone 6m as yellow
solid (300 mg, 70%).
1
◦
dr = 1.4 : 1 ( H NMR). Yellow solid; mp 67–68 C; R
f
(prod-
uct) 0.50 (neat ethyl acetate). (Found: 427.1788. C24
H
29NO S
4
J = 13.7 Hz, J = 5.0 Hz, 1 H; 1-H), 5.16 (ddd, J = 12.7 Hz,
J = 4.8 Hz, J = 1.5 Hz, 1 H; 6-H), 7.11 (dt, J = 8.0 Hz, J =
−
1
requires 427.1817); mmax (KBr)(cm ) 3440, 2955, 2934, 2870,
737, 1562, 1414, 1260, 1221 and 726; major diastereomer: d
CDCl
, 300 MHz) 0.84 (t, J = 7.3 Hz, 3 H; Bu), 1.04–1.14 (m, 1
H), 1.20–1.34 (m, 4 H), 1.80–2.15 (m, 3 H), 2.44–2.92 (m, 6 H),
1
H
1
.0 Hz, 1 H), 7.16 (dt, J = 7.7 Hz, J = 1.0 Hz, 1 H), 7.26 (d,
(
3
J = 8.0 Hz, 1 H), 7.49 (d, J = 7.7 Hz, 1 H) and 7.70 (s, 1 H;
indole-NH); d (CDCl , 125 MHz) 13.9 (CH ; Bu), 17.5 (CH
iso-Pr-CH ), 20.4 (CH ; 2-C), 20.9 (CH ; 7-C), 23.2 (CH ; Bu),
; Bu), 29.4 (CH ; 3-C), 35.4 (CH ; Bu), 39.9 (CH
C
3
3
3
;
3
6
.50 (s, 3 H; OCH
.42 (s, 1 H), 6.55 (s, 1 H), 6.80–6.85 (m, 1 H), 6.95–7.02 (m, 1
(CDCl , 300
3
), 3.76 (s, 3 H; OCH
3
), 5.04–5.14 (m, 1 H),
3
2
2
2
2
6
1
1
2
7
7.0 (CH
2
2
2
2
;
H) and 7.46–7.51 (m, 1 H). minor diastereomer: d
H
3
-C), 42.4 (CH; iso-Pr-CH), 56.8 (CH; 1-C), 61.4 (Cquat; 12b-C),
10.9 (CH), 111.1 (Cquat), 118.3 (CH), 119.7 (CH), 122.4 (CH),
26.2 (Cquat), 134.0 (Cquat), 135.8 (Cquat), 169.4 (Cquat; amide) and
MHz) 3.63 (s, 3 H; OCH
and 6.59 (s, 1 H); major diastereomer: d
3
), 3.75 (s, 3 H; OCH
(CDCl
), 26.6 (CH
), 54.8 (CH), 55.6 (CH
), 64.5 (Cquat; 12b-C), 109.8 (CH), 111.7 (CH),
3
), 6.46 (s, 1 H)
, 75 MHz) 13.9
C
3
(
(
5
CH
CH
5.8 (CH
3
2
; Bu), 20.2 (CH
2
), 23.2 (CH
2
2
), 28.9 (CH
2
), 30.0
),
+
+
+
18.3 (Cquat; ketone); m/z (EI ) 366 (M , 16), 309 (M − C
4
9
H ,
), 35.4 (CH
; OCH
2
), 39.6 (CH
2
3
; OCH
3
+
i
2) and 239 (M − C
4
H
9
− PrCO, 100).
3
3
rac-4-Oxo-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a] quinolizine-
-carboxylic acid ethyl ester (6l). In a screw cap pressure
vessel 0.2 mL (2.00 mmol) of ethyl propiolate 2e, and 320 mg
128.5 (Cquat), 128.6 (CH), 129.5 (Cquat), 132.0 (CH), 134.9 (CH),
1
145.6 (Cquat), 147.3 (Cquat), 169.6 (Cquat; amide) and 194.4 (Cquat
;
;
carbonyl); minor diastereomer: d
Bu), 19.9 (CH ), 23.3 (CH ), 27.3 (CH
37.2 (CH ), 43.6 (CH ), 51.0 (CH), 55.7 (CH
(CH ; OCH ), 62.7 (Cquat; 12b-C), 108.9 (CH), 111.5 (CH), 128.4
C
(CDCl
), 27.4 (CH
; OCH
3
, 75 MHz) 13.8 (CH
), 28.6 (CH
), 56.1
3
(
2.00 mmol) of tryptamine 8c were dissolved in 10 mL of
2
2
2
2
2
),
◦
THF. The reaction mixture was heated at 65 C for 3 h. After
2
2
3
3
complete conversion 0.18 mL (2.20 mmol) of acryloyl chloride
3
3
◦
9
6
a was added and the reaction mixture was heated at 70 C for
(Cquat), 129.0 (CH), 129.4 (Cquat), 132.1 (CH), 133.5 (CH), 144.0
(Cquat), 147.6 (Cquat), 169.4 (Cquat; amide) and 192.1 (Cquat; ketone);
h. After cooling to room temperature the reaction mixture
+
+
+
+
was diluted with methanol, stirred for 10 min, evaporated and
applied to column chromatography on silica gel eluting with
neat diethyl ether → neat ethyl acetate to give the analytically
pure quinolizinone 6l as colorless crystals (135 mg, 43%).
m/z (EI ) 427 (M , 6), 370 (M − C
4
H , 100), 111 (2-ThCO ,
9
66).
Splitting protocol
Crystallization was achieved from pentane–CH
2
Cl .
2
1
Syn : anti = 9 : 1 ( H NMR, minor diastereomer not listed).
(Z)-3-[2-(1H-Indol-3-yl)-ethylamino]-1-thiophen-2-yl-hepten-
one (4a). In a Schlenk flask a stirred mixture of 140 mg
◦
Colorless crystals; mp 186–187 C; R
f
(product) 0.50 (neat ethyl
acetate); (Found: C, 68.19; H, 6.41; N, 8.81. C18
H
20
N
2
O
3
requires
C, 69.21; H, 6.45; N, 8.97%); mmax (KBr)(cm ) 2930, 1723, 1619
C=O), 1467, 1444, 1327, 1299, 1160 and 739; d
(CDCl , 500
MHz) 1.40 (t, J = 7.1 Hz, 3 H; CO CH CH ), 2.02–2.12 (m, 1 H),
.22–2.28 (m, 1 H), 2.42–2.49 (m, 1 H), 2.65 (ddd, J = 17.6 Hz,
J = 4.9 Hz, J = 2.9 Hz, 1 H), 2.74 (d, J = 11.2 Hz, 1 H), 2.80–
.90 (m, 3 H), 4.39 (q, J = 7.1 Hz, 2 H; CO CH CH ), 5.10–5.15
m, 2 H), 7.11 (dt, J = 7.8 Hz, J = 1.0 Hz, 1 H), 7.18 (dt, J =
(0.20 mmol) of Pd(PPh
3
)
2
Cl , and 70 mg (0.40 mmol) of CuI
2
−
1
in 30.0 mL of THF was degassed for 5 min. Then 1.40 mL
(10.0 mmol) of triethylamine, 1.07 mL (10.0 mmol) of thiophene
acid chloride 1a and 1.2 mL (10.5 mmol) of hexyne 2a were
added. The reaction mixture was stirred for 2 h under nitrogen
at room temperature until the hexyne was completely consumed
(monitored by TLC). Then 1.92 g (12.0 mmol) of tryptamine 8c
and 30.0 mL of methanol were added. The reaction mixture was
heated to reflux temperature for 3 h until the conversion was
complete (monitored by TLC). The solvents were evaporated
and the residue was chromatographed on silica gel (hexane–
ethyl acetate, 2 : 1) to afford 2.86 g (81%) of the enaminone 4a
as a yellow oil.
(
H
3
2
2
3
2
2
2
2
3
(
8
7
1
4
1
.3 Hz, J = 1.0 Hz, 1 H), 7.31 (d, J = 8.3 Hz, 1 H), 7.49 (d, J =
.8 Hz, 1 H) and 8.50 (s, 1 H; indole-NH); d (CDCl , 125 MHz)
4.2 (CH ; CO CH CH ), 21.0 (CH ), 23.8 (CH ), 31.5 (CH
1.0 (CH ), 46.1 (CH), 55.3 (CH), 62.0 (CH ; CO CH CH
C
3
3
2
2
3
2
2
2
3
),
),
2
2
2
2
11.9 (Cquat), 111.2 (CH), 118.4 (CH), 119.8 (CH), 122.3 (CH),
4
3 9 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1

View Article Online
Yellow oil; R
CDCl
, 300 MHz) 0.99 (t, J = 7.2 Hz, 3 H; Bu), 1.36–1.48 (m,
H; Bu), 1.51–1.62 (m, 2 H; Bu), 2.26 (t, J = 7.6 Hz, 2 H;
Bu), 3.12 (t, J = 6.8 Hz, 2 H; tryptamine-CH ), 3.65 (q, J =
.6 Hz, 2 H; tryptamine-CH ), 5.68 (s, 1 H; olefinic), 7.06–7.11
m, 2 H), 7.18–7.26 (m, 2 H), 7.31–7.36 (m, 1 H), 7.43 (d, J =
f
(product) 0.50 (hexane–ethyl acetate; 2 : 1); d
H
7 For reviews, see e.g.: K. Sonogashira, in Metal-catalyzed Cross-
coupling Reactions, eds., F. Diederich and P. J. Stang, Wiley-VCH,
Weinheim, 1998, ch. 5; K. Sonogashira, J. Organomet. Chem., 2002,
(
2
3
6
53, 46; R. R. Tykwinski, Angew. Chem., 2003, 115, 1604; R. R.
2
Tykwinski, Angew. Chem., Int. Ed., 2003, 42, 1566.
6
(
5
1
1
4
2
8
For recent examples, see: M. Eckhardt and G. C. Fu, J. Am. Chem.
Soc., 2003, 125, 13642; A. Soheili, J. Albaneze-Walker, J. A. Murry,
P. G. Dormer and D. L. Hughes, Org. Lett., 2003, 5, 4191; J. Cheng,
Y. Sun, F. Wang, M. Guo, J. Xu, Y. Pan and Z. Zhang, J. Org. Chem.,
.1 Hz, 1 H), 7.63–7.67 (m, 2 H), 9.12 (s, 1 H; indole-2-H) and
1.40 (t, J = 5.5 Hz, 1 H; indole-NH); d (CDCl , 75 MHz):
3.5 (CH ; Bu), 22.4 (CH ), 25.9 (CH ), 29.7 (CH ), 31.8 (CH ),
3.3 (CH ), 90.5 (CH; olefinic), 111.0 (Cquat), 111.4 (CH), 117.8
C
3
2
004, 69, 5428.
A. S. Karpov, F. Rominger and T. J. J. M u¨ ller, J. Org. Chem., 2003,
8, 1503.
3
2
2
2
2
9
2
6
(
(
(
CH), 118.8 (CH), 121.4 (CH), 122.9 (CH), 126.6 (Cquat), 126.8
CH), 127.4 (CH), 129.1 (CH), 136.2 (Cquat), 147.0 (Cquat), 168.8
1
1
0 For the first report on the cross-coupling reaction of acid chlorides
and alkynes using only one equivalent of triethylamine, see: A. S.
Karpov and T. J. J. M u¨ ller, Org. Lett., 2003, 5, 3451.
1 For syntheses of pyrazoles, see e.g.: C. Moureu and R. Delange, Bull.
Soc. Chim. Fr., 1901, 25, 302; R. D. Miller and O. Reiser, J. Heterocycl.
Chem., 1993, 30, 755; D. B. Grotjahn, S. Van, D. Combs, D. A. Lev, C.
Schneider, M. Rideout, C. Meyer, G. Hernandez and L. Mejorado,
J. Org. Chem., 2002, 67, 9200.
Cquat; olefinic) and 180.3 (Cquat; ketone).
Synthesis of indolo[2,3-a]quinolizin-4-ones 6a or 6f via
aza-annulation-PS sequence
In a screw cap pressure vessel 353 mg (1.00 mmol) of enaminone
1
1
2 For syntheses of isoxazoles, see e.g.: K. Bowden and E. R. H. Jones,
J. Chem. Soc., 1946, 25, 953; R. M. Adlington, J. E. Baldwin, D.
Catterick, G. J. Pritchard and L. T. Tang, J. Chem. Soc.,Perkin Trans.
4
a was dissolved in 5 mL of degassed THF. Then a,b-unsaturated
chloride 9a or 9c (1.2 mmol) was added and the reaction
mixture was heated at 70 C for 3 h. After cooling to room
◦
1
, 2000, 303.
temperature the reaction mixture was diluted with 5 mL of
methanol, stirred for 10 min, evaporated and applied to column
chromatography on silica gel eluting with neat diethyl ether
3 For syntheses of pyrimidines, see e.g.: R. M. Adlington, J. E. Baldwin,
D. Catterick and G. J. Pritchard, Chem. Commun., 1997, 1757; M. C.
Bagley, D. D. Hughes, P. H. Taylor and X. Xiong, Synlett, 2003, 259;
M. C. Bagley, D. D. Hughes, H. M. Sabo, P. H. Taylor and X. Xiong,
Synlett, 2003, 1443.
(
compound 6a) or hexane–ethyl acetate 2 : 1 (compounds 6f)
to give 345 mg (85%) of compound 20a as colorless crystals or
12 mg (75%) of compound 6f (the ratio of diastereomers 4.5 : 1,
the diastereomers were separated by column chromatography)
crystallization was achieved from pentane–CH Cl ). For the
1
4 For syntheses of pyridines, see e.g.: F. Bohlmann and D. Rahtz, Chem.
Ber., 1957, 90, 2265; M. C. Bagley, C. Brace, J. W. Dale, M. Ohnesorge,
N. G. Philips, X. Xiong and J. Bower, J. Chem. Soc., Perkin Trans. 1,
2002, 1663; M. C. Bagley, J. W. Dale, M. Ohnesorge, N. G. Philips,
X. Xiong and J. Bower, J. Comb. Chem., 2003, 5, 41.
5 A. S. Karpov and T. J. J. M u¨ ller, Synthesis, 2003, 2815.
6 Preliminary communication: A. S. Karpov, T. Oeser and T. J. J.
M u¨ ller, Chem. Commun., 2004, 1502.
7 A. S. Karpov, E. Merkul, T. Oeser and T. J. J. M u¨ ller, Chem.
Commun., 2005, 2581.
18 For recent examples of aza-annulations, see e.g.: P. Benovsky, G. A.
Stephenson and J. R. Stille, J. Am. Chem. Soc., 1998, 120, 2493; K.
Paulvannan and T. Chen, J. Org. Chem., 2000, 65, 6160.
19 For a review, see e.g.: E. D. Cox and J. M. Cook, Chem. Rev., 1995,
95, 1797.
20 The aza-annulation-Pictet–Spengler reaction was reported last year
independently from our group: M. M. Abelman, J. K. Curtis and
D. R. James, Tetrahedron Lett., 2003, 44, 6527.
21 For a recent review on cyclization of N-acyliminium ions, see e.g.:
B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi and C. A.
Maryanoff, Chem. Rev., 2004, 104, 1431.
22 For mechanistic implications on the aza-annulation reaction, see:
N. S. Barta, A. Brode and J. R. Stille, J. Am. Chem. Soc., 1994, 116,
6201.
3
(
2
2
characterization, see the CAAPS sequence.
1
1
References and notes
1
1
2
For overviews, see e.g.: E. Breitmaier in Alkaloide, Teubner Studi-
enb u¨ cher, Stuttgart, 1997, p. 52; K. Stuart and R. Woo-Ming, Hete-
rocycles, 1975, 3, 223; B. T. Ho, W. M. McIsaac, K. E. Walker and V.
Estevez, J. Pharm. Sci., 1968, 57, 269; The Chemistry of Heterocyclic
Compounds, Part IV Supplement of Vol. 25, ed., J. E. Saxton, Wiley,
Chichester, 1994.
For reviews, see e.g.: S. Urban, S. J. H. Hickford, J. W. Blunt and
M. H. G. Munro, Curr. Org. Chem., 2000, 4, 765; J. B. Hudson,
Antiviral Res., 1989, 12, 55; D. J. McKenna and G. H. Towers,
J. Psychoact. Drugs, 1984, 16, 347.
3
4
B. T. Ho, J. Pharm. Sci., 1972, 61, 821.
J. E. Audia, D. A. Evrard, G. R. Murdoch, J. J. Droste, J. S. Nissen,
K. W. Schenk, P. Fludzinski, V. L. Lucaites, D. L. Nelson and M. L.
Cohen, J. Med. Chem., 1996, 39, 2773; B. E. Love and P. S. Raje,
J. Org. Chem., 1994, 59, 3219 and references therein; C. A. Busacca,
M. C. Eriksson, Y. Dong, A. S. Prokopowicz, A. M. Salvagno and
M. A. Tschantz, J. Org. Chem., 1999, 64, 4564 and references therein.
For recent reviews, see e.g.: L. Weber, K. Illgen and M. Almstetter,
Synlett, 1999, 366; I. Ugi, A. D o¨ mling and B. Werner, J. Heterocycl.
Chem., 2000, 37, 647.
23 I. Fleming, in Pericyclic Reactions, Oxford University Press, New
York, 2002, pp. 78 and 85.
5
6
24 Organikum, 14 edition, VEB Deutscher Verlag der Wissenschaften,
Berlin, 1993.
25 G. M. Sheldrick, Bruker Analytical X-ray-Division, Madison,
S. Kobayashi, Chem. Soc. Rev., 1999, 28, 1.
Wisconsin.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 3 8 2 – 4 3 9 1
4 3 9 1