Application of chlorotrimethylsilane in Pictet-Spengler reaction

Article abstract of DOI:10.1007/s00706-012-0804-7

Chlorotrimethylsilane has been found to be an efficient condensing agent in the Pictet-Spengler reaction, affording an extremely straightforward synthetic route to tetrahydro-β-carboline derivatives and their analogs. The applicability of the method has b

Full text of DOI:10.1007/s00706-012-0804-7

Monatsh Chem (2012) 143:1507–1517
DOI 10.1007/s00706-012-0804-7
ORIGINAL PAPER
Application of chlorotrimethylsilane in Pictet–Spengler reaction
•
Sergey V. Ryabukhin Dmitriy M. Panov
•
•
•
Andrey S. Plaskon Andrey A. Tolmachev
Radomyr V. Smaliy
Received: 30 September 2011 / Accepted: 4 June 2012 / Published online: 18 July 2012
Ó Springer-Verlag 2012
Abstract Chlorotrimethylsilane has been found to be an
efficient condensing agent in the Pictet–Spengler reaction,
affording an extremely straightforward synthetic route to
tetrahydro-b-carboline derivatives and their analogs. The
applicability of the method has been studied, and a repre-
sentative library of structurally diverse products has been
created.
no expensive reagents or special conditions for generating
mostly heterocyclic pharmacophores. Among these, the
most promising are those involving diverse and readily
available starting materials, as they enable wide variation
of the pharmacophore environment. As a vivid example,
the long-known Pictet–Spengler reaction [1–3] may be
mentioned (Scheme 1); it is extensively applied for syn-
thesis of the tetrahydro-b-carboline ring system occurring
in many natural and synthetic compounds and providing
diverse biological activity [4–10].
Keywords Mannich reaction ꢀ Tetrahydro-b-carboline ꢀ
Carbonyl compounds ꢀ Cyclizations ꢀ Heterocycles
Recent efforts have been mainly focused on the enantio-
selective [11] and solid-phase [12] versions of this reaction as
well as on the search for new condensing agents [13]. At the
same time, the conditions of this acid-catalyzed reaction still
remain to be understood better, since they differ significantly
even for similar substrates; For instance, the catalysts are
represented by acids of various strength, both mineral and
organic, with the latter sometimes used in large amount as a
solvent. Moreover, the temperature regime varies to a great
extent, from boiling in xylene to room temperature, and the
reaction time can also be different.
Introduction
The current interest of synthetic and especially pharma-
ceutical chemists lies in facile one-step reactions requiring
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0804-7) contains supplementary
material, which is available to authorized users.
The present study addresses optimization of the con-
densing agent and especially unification of the synthetic
procedure for the Pictet–Spengler reaction aiming at its pre-
parative convenience for a wide diversity of carbonyl and
amine components, and high yields of target products.
Indeed, halosilanes are known to be condensing agents in
Mannich-type reactions [14, 15] (which include the Pictet–
S. V. Ryabukhin (&)
The Institute of High Technologies, Kyiv National Taras
Shevchenko University, 4 Glushkov str., Kyiv 03187, Ukraine
e-mail: s.v.ryabukhin@gmail.com
S. V. Ryabukhin ꢀ D. M. Panov ꢀ A. S. Plaskon ꢀ
A. A. Tolmachev
Kyiv National Taras Shevchenko University, 62 Volodymyrska
Street, Kyiv 01033, Ukraine
D. M. Panov ꢀ A. S. Plaskon ꢀ A. A. Tolmachev ꢀ R. V. Smaliy
Enamine Ltd., 23 Alexandra Matrosova Street, Kyiv 01103,
Ukraine
NH2
H+
NH
R'
O
R
C
+
H
- H2O
N
R
R'
N
H
H
R. V. Smaliy
Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, Murmanska 5, Kyiv 02094, Ukraine
Scheme 1
123

1508
S. V. Ryabukhin et al.
Spengler reaction [16] as a particular case), and, as we found
previously, Me3SiCl is also effective in some other conden-
sations of carbonyl compounds [17], e.g., the Knoevenagel
[18], Biginelli [19], and Friedlaender [20] reactions. More-
over, silylation of free functionalities (often used to protect
them from undesired reactions) should be especially advan-
tageous, since it enables the Pictet–Spengler reaction to be
performed with polyfunctional substrates.
proceed typically with formation of an additional c-lactam
ring by condensation of the carboxylic group with free NH
fragment. It should be noted that, in the case of dicarbox-
ylic acid 4o, decarboxylation of the final product was
observed under the reaction conditions (entries 14, 15, 22,
27).
In case of using amines 1b and 1c only one of two possible
diastereomers formed, which is in accordance with previous
results obtained using halosilanes as condensing agents [16].
The relative configuration of the products 5be, 5bg, and 5ce
was assigned by comparing the nuclear magnetic resonance
(NMR) spectra with the literature data. For other compounds
which are obtained as single diastereomers, analogous
stereochemistry should be expected. An additional confir-
mation can be obtained from analysis of the coupling
constants of the ABX system according to the Karplus–
Conroy relationship (Table 2) [42]. In particular, the cou-
pling constant values are consistent with the conformations
shown in Fig. 1 (equatorial position of both substituents):
JAX & 8 Hz corresponds to the dihedral angle *160°
(axial–axial coupling), whereas JBX & 5 Hz is consistent
with the value *30° (axial–equatorial coupling). In case of
the opposite orientation of the C-3 or C-4 substituent, both
the JAX and JBX values would be close to *5 Hz.
According to the liquid chromatography/mass spec-
trometry (LC/MS) data, the conversion degree is never
below 80 % and the reaction proceeds almost quantita-
tively in most cases. Comparative analysis of the
elaborated methodology with previous reported methods is
shown in Table 3. The isolated yields of target compounds
are mainly limited by their high water solubility and
extractability with organic solvents (for instance, trypto-
phan derivatives are extremely water soluble).
Results and discussion
As amine components, we have studied classical unsub-
stituted tryptamine (1a), b-phenyltryptamine (1b, one of
many substituted tryptamines easily obtainable by con-
densation of indole with arylaldehyde and nitroalkane
followed by nitro group reduction) [16], tryptophan (1c),
and b-hetarylethylamines 2a [21] and 3a containing
p-excessive heterocyclic residues. The carbonyl components
4 successfully used in the reaction concerned (Table 1) can
be conventionally divided into three groups: simple aliphatic
(cyclic and acyclic) and carboaromatic aldehydes and
ketones 4a–4f (entries 1–6, 16–18, 25, 26, 29, 31–33), their
bare and electron-donor (acceptor) substituted heterocyclic
counterparts 4g–4j (entries 7–10, 19), and bi- and trifunc-
tional oxo compounds 4k–4q (entries 11–15, 20–24, 27, 28,
30) containing the second carbonyl, carboxyl, phenolic,
hydroxyl and amino groups (Table 1).
It has been found that chlorotrimethylsilane is indeed an
efficient condensing agent in the Pictet–Spengler reaction.
In the series of experiments using various solvents, tem-
peratures, acid scavengers, and reagent molar ratios, the
optimum (in conversion and further purification) and most
general reaction conditions are as follows: Pyridine is used
as solvent and HCl as scavenger, and the synthesis is car-
ried out at 100 °C using 1:5 amine/Me3SiCl molar ratio.
The molar ratio is in accordance with our previous obser-
vations [41] which suggest the following estimate for the
chlorotrimethylsilane amount: two equivalents per each of
evolving water plus one equivalent per every functional
group of substrate reactive to Me3SiCl plus an excess
equivalent to maximize the chemical conversion and
remove water traces from the starting materials and the
solvent. Larger amounts of Me3SiCl have no noticeable
effect on the conversion degree and complicate product
isolation. As a result, we have elaborated a general and
preparatively facile procedure for synthesis and isolation of
compounds 5–7 (Table 1; Schemes 2, 3).
The LC/MS analysis of the reaction mixtures has revealed
that the condensation occurs successfully not only with car-
bonyl components presented in Table 1 but also with a great
number of other oxo compounds including polyfunctional
reagents (pyruvic acid, methylglyoxal, glyoxylic acid,
2-oxosuccinic acid, 3,5-dimethylisoxazole-4-carbaldehyde,
and 4-piperidone). However, the general procedure for
product isolation suggested by us does not afford the desired
compounds in pure form due, as a rule, to the above-men-
tioned high water solubility or difficulties with complete
removalof residualpyridine hydrochloride. Atthesame time,
these products may be isolated using some appropriate
purification methods, e.g., chromatography.
Among bifunctional carbonyl components, dimedone
(4q) exhibits a peculiar behavior in the Pictet–Spengler
reaction: it reacts exclusively as a monoketone (entry 24);
the second oxo group does not enter into the condensation
even with fourfold excess of amine components (no trace
of bis-condensed products was detected in reaction mix-
tures by LC/MS analysis).
The reaction goes to completion within 4–12 h
(Table 1) depending on the reactivity of the carbonyl
component. The least reactive are acetophenones and other
alkylarylketones, in contrast to highly reactive isatin (4k)
and aldehydes. In case of 4-oxoacids 4n, 4o the reactions
123

Application of chlorotrimethylsilane in Pictet–Spengler reaction
1509
Table 1 Synthesis of a diverse library of tetrahydro-b-carbolines
R2
R1
NH2
R1
R2
R4
NH
R3
O
+
R4
N
N
R3
H
H
5aa-5ao, 5bc-5be, 5bg, 5bk-5bl,
5bo-5bq, 5cd, 5ce, 5cn, 5cp
1a-1c
4a-4q
Amine
Carbonyl compound
Product
Reaction time/h
4
M.p. (lit. m.p.)/°C
262 (dec.) (263–264 [22])
Yield/%
82
1
2
NH2
Me
O
NH
HCl
Me
4a
HN 5aa
1a
N
H
1a
4
117 (118–120 [23, 24])
83
Me
NH
O
Me 4b
Me
N
5abH
Me
3
4
1a
1a
8
8
92 (110–113 [25])
132 (132 [26])
83
88
Me
NH
Me
O
Me
4c
Me
N
5ac
H
NH
O
4d
N
5ad H
5
6
1a
1a
4
248 (dec.) (254 [27])
273 (267–269 [28])
92
87
O
NH
HCl
4e
Ph
5ae
N
H
10
O
HCl
NH
Me
Me
4f
Ph
5af HN
7
8
1a
1a
6
6
147 (146–147 [29])
94
91
S
NH
4g O
N
H
5ag
S
141
N
O
NH
Ph
4h
S
N
H
N
S
5ah
Ph
123

1510
S. V. Ryabukhin et al.
Table 1 continued
Amine
Carbonyl compound
Product
Reaction time/h
6
M.p. (lit. m.p.)/°C
Yield/%
92
9
1a
233
N
NH
HCl
N
O
Me
4i
N
H
N
N
5ai
Me
10
11
12
1a
1a
1a
10
230
78
86
93
O
HCl
NH
N
Me
4j
N
H
N
5aj
6
202 (dec.)
O
NH
O
O
NH
N
4k HN
H
5ak
8
[300
O
HO2C
NH
4l
N
H
5al
CO2H
13
1a
8
194 (189–191 [30])
88
OH
O
NH
N
H
OH
4m
5am
14
15
16
1a
1a
10
10
8
257 (259–260 [31])
242 (245–247 [32])
276 (dec.)
76
81
89
O
O
N
Me
4nCO H
2
N
H
5an
O
O
N
4oCO H
HO2C
2
N
H
5ao
4c
NH2
Ph
Ph
HCl
NH
Me
1b
Me
N
5bc
N
H
H
17
1b
4d
8
154 (185–187 [33])
90
Ph
NH
N
5bd H
123

Application of chlorotrimethylsilane in Pictet–Spengler reaction
1511
Table 1 continued
Amine
Carbonyl compound
Product
Reaction time/h
6
M.p. (lit. m.p.)/°C
Yield/%
82
18
19
1b
4e
268 (dec.) [34]a
Ph
HCl
NH
Ph
5be
N
H
1b
1b
4g
4k
6
6
168 [35]a
87
75
Ph
NH
N
H
S
5bg
20
21
231 [36]a
Ph
NH
O
NH
N
H
5bk
1b
4l
8
[300
85
Ph
NH
N
H
5bl
CO2H
22
23
1b
1b
4o
12
273 [37]a
76
71
Ph
O
N
N
H
5bo
8
125
Ph
O
Me
N
4p
NH
N
5bp H
N
24
1b
12
202 (dec.)
73
O
Ph
NH
Me
Me
4qOH
N
H
5bq
OH
25
26
4d
4e
10
196 (dec.) (192 [38])
78
76
NH2
CO2H
CO2H
NH
1c
N
N
5cd H
H
1c
8
210 (254 [39])
CO2H
NH
Ph
5ce
N
H
123

1512
S. V. Ryabukhin et al.
Table 1 continued
Amine
Carbonyl compound
Product
Reaction time/h
12
M.p. (lit. m.p.)/°C
Yield/%
84
27
28
1c
4n
216
CO2H
N
O
N
H
5cn
1c
4p
10
230 (dec.) [40]a
72
CO2H
NH
N
5cp H
N
29
30
4d
4k
8
6
255 (dec.)
81
71
Me
N
Me
N
HCl
NH
Ph
Ph
NH2
2a
Me
Me
6ad
2a
202
Me
N
Ph
NH
O
Me
N
6ak
H
31
32
4b
4d
4f
6
8
124
143
128
76
82
77
NH2
N
N
N
NH
3a
N
Me
Me
7ab
3a
3a
N
NH
N
7ad
33
10
N
N
NH
Me
Ph
7af
a
Reference to NMR data
Under the general conditions chosen by us, the reaction
cannot be carried out with furan carbonyl derivatives (since
extensive tarring of the reaction mixture occurs), b-dike-
tones (a complex product mixture is typically formed),
a-halo oxo compounds (alkylation of pyridine as a side-
reaction), and tetralone (due to its low reactivity, the
conversion degree is about 10 %). As already mentioned,
the only limitation to the use of other carbonyl components
is that the corresponding reaction products are highly water
soluble. Unfortunately, it is also impossible to react
amines much less C-nucleophilic than tryptamine [such as
2-(1,3-benzodioxol-5-yl)ethylamine, 2-(2-methyl-1,3-thia-
zol-4-yl)ethylamine, and histidine].
The possible mechanism of Me3SiCl-mediated Pictet–
Spengler reaction is shown in Scheme 4. Under the opti-
mized reaction conditions, Me3SiCl reacts with amine to
give monosilylated compound B and is likely to coordinate
to the carbonyl group of the aldehyde to give electrophilic
intermediate A [49–51]. The reaction of A and B is likely
to give intermediate C containing Me3Si- and Me3SiO-
fragments in a position favorable for elimination of stable
(Me3Si)2O. After elimination, the formed intermediate D is
123

Application of chlorotrimethylsilane in Pictet–Spengler reaction
1513
H
NH2
N
R4
R3
R4
H
A
H
X
O
Ph
+
H
B
R3
Me
Me
H
N
Me
Me
B
N
COOH
N
N
NH
H
Ar
Ph
NH
H
Ar
Ph
H
X
H
A
6ad, 6ak
2a
4a-4q
5be, 5bg, 5bk, 5bl
5ce
Scheme 2
R4
H
N
R3
H
A
R4
R3
NH2
H
B
X
N
Ph
N
N
H
O
H
O
+
B
N
N
COOH
N
N
H
N
H
A
H
O
H
X
H3C
5cn
3a
4a-4q
7ab, 7ad, 7af
5bo
Scheme 3
Fig. 1 Expected stereochemistry for compounds 5 according to
Karplus–Conroy relationship
Table 2 Coupling constants for ABX systems in appropriate
compounds
Table 3 Comparative analysis of the elaborated methodology
Compound
J
AX/Hz
JBX/Hz
Reagent
Yield/%
Solvent
T/°C
Time/h
Ref.
5be
5bg
5bk
5bl
8.1
7.9
7.9
7.8
7.8
8.2
8.1
4.9
5.1
5.1
5.2
5.1
4.9
5.0
Me3SiCl
I2
92
90
88
93
82
Py
100
rt
4
–
MeCN
CH2Cl2
CH2Cl2
–
3.5
[43]
[44]
[45]
[29]
TFA
rt
24
5bo
5ce
5cn
Yb(OTf)3
120
80
1 (MW)
12
SO2
NH
SO2
rearranged to the final product 5. According to ab initio
calculations, the syn-conformation of Si–N–C–OSi may be
stabilized via a Si–OSi coordination bond [d(Si–O) =
0.27 nm].
TFA
H2SO4
HCl
75
77
94
87
H2O
H2O
–
rt
36
[30]
[46]
[47]
[48]
70
100
60
14
0.05 (MW)
8
HCl
MeOH
In conclusion, it has been found that application of
chlorotrimethylsilane in Pictet–Spengler cyclocondensa-
tion enables convenient unification of the synthetic
methodology. The method suggested is appropriate for the
reaction with commonly used and well-studied starting
compounds as well as with more complex polyfunctional
substrates, thus offering much synthetic promise for the
creation of product and building-block libraries.
Kieselgel Merck 60 (230–400 mesh) as stationary phase.
Melting points were measured on a Bu¨chi melting point
apparatus. NMR spectra were recorded on Bruker 170
1
Avance 500 (500.1 MHz for H and 125.7 MHz for 13C)
and Varian Unity Plus 400 spectrometers (400.4 MHz for
1H) using tetramethylsilane (TMS) as internal standard.
Mass spectra were recorded on an Agilent 1100 LCMSD
SL instrument (CI) and Agilent 5890 Series II 5972 GCMS
instrument (EI). The parameters of chromatography–mass
analysis were as follows: Column: Zorbax SB-C18,
1.8 lm, 4.6 mm 9 15 mm; eluent A: acetonitrile–water
with 0.1 % of trifluoroacetic acid (TFA) (95:5); eluent B:
water with 0.1 % of TFA; flow rate: 3 cm3/s; volume of
injected sample: 1 mm3. Ultraviolet (UV) detectors were
operated at 215, 254, and 265 nm. The ionization method
was chemical ionization under atmospheric pressure (APCI)
Experimental
All chemicals were obtained from commercially available
sources and used without further purification (Aldrich,
Fluka, Enamine Ltd.). All solvents were purified by stan-
dard methods. All procedures were carried out under open
atmosphere with no precautions taken to exclude ambient
moisture. Column chromatography was performed using
123

1514
S. V. Ryabukhin et al.
Scheme 4
R4
-
Cl
Cl
R4
Me3SiCl
R2
+
R3
O
SiMe3
SiMe3
R4
O
R4
O
R3
O
R3
R3
Me3Si Cl
4
A
R2
R2
N
R1
R1
R1
SiMe3
A
SiMe3
N
H
NH2
Me3SiCl
Py
O
SiMe3
-HCl
R4
N
SiMe3
R3
N
N
H
SiMe3
1
B
C
Me3SiCl
H2O
-2(Me3Si)2O
R2
R2
R1
NH
R3
R4
R1
NH
R4
-HCl
N+
H
NH
R3
Cl
D
5
2,3,4,9-Tetrahydro-1-(2-phenylthiazol-4-yl)-1H-pyrido-
[3,4-b]indole (5ah, C20H17N3S)
with simultaneous scanning of positive and negative ions in
the mass range of m/z = 80–1,000. According to high-
performance liquid chromatography (HPLC) MS data, all
synthesized compounds had purity [95 %. A BRANSON
2510E-MT ultrasonic bath was used. Elemental analyses
were carried out on a Vario MICRO Cube (Elementar)
elemental microanalyzer.
1
Yield 91 %; m.p.: 141 °C; H NMR (400 MHz, DMSO-
d6): d = 2.65 (m, 2H), 3.00 (m, 1H), 3.10 (m, 1H), 5.36 (s,
1H), 6.93 (t, 1H, JH,H = 7.1 Hz), 7.03 (t, 1H,
3
3
3JH,H = 7.1 Hz), 7.28 (d, 1H, JH,H = 7.1 Hz), 7.40 (s,
3
1H), 7.48 (d, 1H, JH,H = 7.1 Hz), 7.50 (m, 3H), 7.99 (m,
2H), 10.57 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 22.4, 41.2, 53.1, 108.4, 111.7, 117.1, 118.1, 118.8,
121.2, 126.7, 127.2, 129.7, 130.7, 133.6, 134.1, 136.4,
158.7, 167.5 ppm; MS (APCI): m/z = 332 ([M ? 1]?).
General procedure for the synthesis of 5, 6, and 7
The corresponding amine (2 mmol) and carbonyl com-
pound (2 mmol) were placed in a 15-cm3 screw-cap vial
and dissolved in 2–4 cm3 pyridine. Chlorotrimethylsilane
(1.086 g, 10 mmol) was added portion-wise to the solution.
The tube was thoroughly sealed and heated on a water bath
for 4 h. After cooling, the flask was opened (Caution! HCl
overpressure inside) and 1.012 g triethylamine (10 mmol)
was added portion-wise to the solution. Water (8 cm3) was
added to the solution, the suspension formed was sonicated
at 20 °C for 2 h, and the precipitate formed was filtered and
washed with 2 cm3 i-PrOH or Et2O. The products were
isolated as follows: the precipitate formed was filtered and
washed with 2 cm3 i-PrOH or Et2O. If no precipitate formed
after addition of water, the emulsion was separated and the
upper layer of hexamethyldisiloxane was carefully removed
by pipette or syringe, and the aqueous layer was extracted
with 2–5 cm3 CH2Cl2. The organic layer was separated by
syringe and evaporated under reduced pressure. The prod-
uct formed was dried in vacuo at 60 °C for 2 h.
2,3,4,9-Tetrahydro-1-(1-methyl-1H-pyrazol-4-yl)-1H-
pyrido[3,4-b]indole hydrochloride (5ai, C15H17ClN4)
1
Yield 92 %; m.p.: 233 °C; H NMR (500 MHz, DMSO-
d6): d = 2.99 (m, 2H), 3.20 (m, 2H), 3.84 (s, 3H), 5.76 (s,
1H), 7.02 (t, 1H, JH,H = 7.6 Hz), 7.10 (t, 1H,
3
3
3JH,H = 7.6 Hz), 7.30 (d, 1H, JH,H = 7.6 Hz), 7.49 (d,
1H, 3JH,H = 7.6 Hz), 7.52 (s, 1H), 7.75 (s, 1H), 9.70 (br s,
2H), 10.91 (s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 19.1, 39.1, 47.8, 47.9, 106.9, 112.0, 116.6, 118.5,
119.3, 122.1, 126.4, 130.4, 132.1, 136.8, 139.6 ppm; MS
(APCI): m/z = 253 ([M ? 1]?).
2,3,4,9-Tetrahydro-1-methyl-1-(2-pyridinyl)-1H-pyrido-
[3,4-b]indole hydrochloride (5aj, C17H18ClN3)
1
Yield 78 %; m.p.: 230 °C; H NMR (500 MHz, DMSO-
d6): d = 2.05 (s, 3H), 2.96 (m, 1H), 3.03 (m, 2H), 3.51 (m,
1H), 7.01 (t, 1H, JH,H = 7.7 Hz), 7.07 (t, 1H,
3
3
3JH,H = 7.7 Hz), 7.19 (t, 1H, JH,H = 7.7 Hz), 7.39 (m,
123

Application of chlorotrimethylsilane in Pictet–Spengler reaction
1515
3
1H), 7.47 (d, 1H, JH,H = 7.7 Hz), 7.50 (m, 1H), 7.52 (d,
1H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 41.0,
51.8, 57.1, 111.3, 111.7, 118.7, 119.1, 121.0, 126.6, 126.7,
128.6, 128.7, 129.2, 129.8, 130.9, 136.3, 136.7, 144.5,
147.8, 167.9 ppm; MS (APCI): m/z = 187 ([M ? 1]?).
1H, 3JH,H = 7.7 Hz), 7.91 (m, 1H), 10.00 (br s, 2H), 11.60
(s, 1H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 18.6,
25.8, 26.0, 61.7, 106.9, 112.1, 118.9, 119.6, 122.6, 122.8,
124.4, 126.1, 131.8, 137.1, 138.5, 149.5, 157.9 ppm; MS
(APCI): m/z = 264 ([M ? 1]?).
20,30,40,90-Tetrahydro-1-methyl-40-phenylspiro[piperidine-
4,10-[1H]pyrido[3,4-b]indole] (5bp, C22H25N3)
1
20,30,40,90-Tetrahydrospiro[3H-indole-3,10-[1H]pyrido[3,4-
b]indol]-2(1H)-one (5ak, C18H15N3O)
Yield 71 %; m.p.: 125 °C; H NMR (500 MHz, DMSO-
d6): d = 1.55 (m, 1H), 1.75 (m, 1H), 2.14 (m, 1H), 2.20 (s,
3H), 2.26 (m, 2H), 2.60 (m, 2H), 2.75 (m, 1H), 3.11 (m,
Yield 86 %; m.p.: 202 °C (decomp.); 1H NMR (500 MHz,
DMSO-d6): d = 2.75 (m, 1H), 2.79 (m, 1H), 3.09 (m, 1H),
3.58 (m, 1H), 6.90–6.99 (m, 3H), 7.02 (t, 1H,
3
2H), 4.08 (m, 1H), 6.61 (d, 1H, JH,H = 7.6 Hz), 6.68 (t,
3
3
1H, JH,H = 7.6 Hz), 7.15 (t, 1H, JH,H = 7.6 Hz), 7.19
(m, 3H), 7.27 (m, 3H), 10.89 (s, 1H) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 35.8, 36.0, 41.4, 46.7, 48.7,
50.1, 50.96, 51.02, 109.7, 111.4, 118.4, 118.8, 120.7,
126.4, 126.8, 128.5, 128.6, 136.2, 142.9, 144.9 ppm; MS
(APCI): m/z = 332 ([M ? 1]?).
3JH,H = 7.0 Hz), 7.09 (d, 1H, JH,H = 7.0 Hz), 7.17 (d,
3
1H, 3JH,H = 7.6 Hz), 7.26 (t, 1H, 3JH,H = 7.6 Hz), 7.46 (d,
1H, 3JH,H = 7.6 Hz), 10.42 (s, 1H), 10.46 (s, 1H) ppm; 13
C
NMR (125 MHz, DMSO-d6): d = 20.4, 39.3, 61.2, 110.1,
110.9, 111.8, 118.5, 119.2, 122.2, 122.5, 126.1, 126.6,
129.75, 129.77, 130.7, 136.9, 143.2, 176.1 ppm; MS
(APCI): m/z = 290 ([M ? 1]?).
20,30,40,90-Tetrahydro-5,5-dimethyl-40-phenylspiro[cyclo-
hexane-1,10-[1H]pyrido[3,4-b]indol]-3-one
(5bq, C24H26N2O)
4-(2,3,4,9-Tetrahydro-1H-pyrido[3,4-b]indole-1-yl)ben-
zoic acid (5al, C18H16N2O2)
Yield 73 %; m.p.: 202 °C (decomp.); 1H NMR (500 MHz,
DMSO-d6): d = 0.92 (s, 3H), 0.95 (s, 3H), 1.98 (s, 2H),
1
Yield 93 %; m.p.: [300 °C; H NMR (400 MHz, DMSO-
3
2.12 (s, 2H), 3.64 (dd, 1H, JH,H = 8.0 Hz, JH,H
2
d6): d = 2.75 (m, 2H), 3.00 (m, 1H), 3.05 (m, 1H), 5.17 (s,
1H), 6.95 (m, 2H), 7.22 (d, 1H, JH,H = 7.8 Hz), 7.40 (m,
=
3
13.2 Hz), 3.75 (dd, 1H, 3JH,H = 5.1 Hz, 2JH,H = 13.2 Hz),
3
3
4.49 (dd, 1H, JH,H = 5.1 Hz, JH,H = 8.0 Hz, 1H), 5.00
3
3H), 7.91 (d, 2H, JH,H = 7.7 Hz), 10.24 (s, 1H) ppm; 13C
3
NMR (125 MHz, DMSO-d6): d = 22.4, 41.5, 56.6, 108.8,
111.6, 118.1, 118.8, 121.2, 127.3, 129.1, 129.7, 131.1,
134.9, 136.5, 147.7, 168.0 ppm; MS (APCI): m/z = 293
([M ? 1]?).
(s, 1H), 6.88 (t, 1H, JH,H = 7.5 Hz), 7.01 (t, 1H,
3JH,H = 7.5 Hz), 7.17 (m, 2H), 7.25 (m, 2H), 7.33 (m,
2H), 7.36 (s, 1H), 10.99 (s, 1H) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 28.39, 28.42, 32.7, 40.6, 41.2, 42.6, 48.0,
50.6, 94.1, 111.9, 116.0, 118.8, 119.0, 121.5, 122.6, 126.7,
127.1, 128.4, 128.7, 136.8, 143.9, 163.6 ppm; MS (APCI):
m/z = 359 ([M ? 1]?).
2,3,4,9-Tetrahydro-1,1-dimethyl-4-phenyl-1H-pyrido[3,4-
b]indole hydrochloride (5bc, C19H21ClN2)
1
Yield 89 %; m.p.: 276 °C (decomp.); H NMR (500 MHz,
DMSO-d6): d = 1.82 (s, 3H), 1.85 (s, 3H), 3.20 (dd, 1H,
2,3,5,6,11,11b-Hexahydro-11b-methyl-3-oxo-1H-indolizi-
no[8,7-b]indole-5-carboxylic acid (5cn, C16H16N2O3)
2
3
3JH,H = 8.1 Hz, JH,H = 13.1 Hz), 3.60 (dd, 1H, JH,H
=
2
3
1
5.0 Hz, JH,H = 13.1 Hz), 4.52 (dd, 1H, JH,H = 5.0 Hz,
3JH,H = 8.1 Hz), 6.50 (d, 1H, 3JH,H = 7.7 Hz), 6.79 (t, 1H,
3JH,H = 7.7 Hz), 7.02 (t, 1H, 3JH,H = 7.7 Hz), 7.20 (m, 2H),
7.28 (m, 4H), 10.00 (br s, 2H), 11.30 (s, 1H) ppm; 13C NMR
(DMSO-d6, 125 MHz, ppm): d = 26.2, 29.8, 42.1, 52.2,
108.4, 111.6, 118.4, 119.2, 120.8, 124.3, 126.6, 126.7,
128.57, 128.62, 132.8, 136.4, 143.8; MS (APCI): m/z
= 277 ([M ? 1]?).
Yield 84 %; m.p.: 216 °C; H NMR (500 MHz, DMSO-
d6): d = 1.75 (s, 3H), 2.45 (m, 1H), 2.51 (m, 1H), 2.78 (dd,
1H, JH,H = 8.1 Hz, JH,H = 14.8 Hz), 3.02 (m, 2H), 3.25
3
2
3
(dd, 1H, JH,H = 5.0 Hz, JH,H = 14.8 Hz), 4.58 (dd, 1H,
2
3
3JH,H = 5.0 Hz, JH,H = 8.1 Hz), 7.27 (m, 2H), 7.45 (m,
3
1H), 8.23 (d, 1H, JH,H = 7.8 Hz), 11.02 (s, 1H) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 22.0, 22.8, 31.0, 32.0,
52.0, 53.4, 111.2, 116.0, 119.6, 124.6, 125.6, 128.7, 134.9,
135.1, 167.9, 170.9 ppm; MS (APCI): m/z = 285
([M ? 1]?).
4-(2,3,4,9-Tetrahydro-4-phenyl-1H-pyrido[3,4-b]indole-1-
yl)benzoic acid (5bl, C24H20N2O2)
1
Yield 85 %; m.p.: [300 °C; H NMR (400 MHz, DMSO-
20,30,40,90-Tetrahydro-1-methylspiro[piperidine-4,10-
[1H]pyrido[3,4-b]indole]-30-carboxylic acid
(5cp, C17H21N3O2)
3
2
d6): d = 2.81 (dd, 1H, JH,H = 7.8 Hz, JH,H = 12.1 Hz),
3.34 (dd, 1H, JH,H = 5.2 Hz, JH,H = 12.1 Hz), 4.27 (dd,
3
2
3
3
1H, JH,H = 5.2 Hz, JH,H = 7.8 Hz), 5.32 (m, 1H), 6.62
(d, 1H, 3JH,H = 7.8 Hz), 6.90 (t, 1H, 3JH,H = 7.8 Hz), 7.20
Yield 72 %; m.p.: 230 °C (decomp.); 1H NMR (400 MHz,
DMSO-d6): d = 1.55 (m, 1H), 1.95 (m, 1H), 2.05 (m, 1H),
2.65 (m, 5H), 2.95 (m, 2H), 3.04 (m, 3H), 3.71 (dd, 1H,
3
(t, 1H, JH,H = 7.8 Hz), 7.20–7.30 (m, 6H), 7.45 (d, 2H,
3
3
3
3JH,H = 7.6 Hz), 7.94 (d, 2H, JH,H = 7.6 Hz), 10.51 (s,
3JH,H = 4.9 Hz, JH,H = 8.0 Hz), 6.92 (t, 1H, JH,H
=
123

1516
S. V. Ryabukhin et al.
3
7.6 Hz), 7.04 (t, 1H, JH,H = 7.6 Hz), 7.29 (d, 1H,
1,2,3,4-Tetrahydro-1-methyl-1-phenylpyrido[40,30:4,5]imi-
dazo[1,2-a]pyridine (7af, C17H17N3)
3
3JH,H = 7.6 Hz), 7.39 (d, 1H, JH,H = 7.6 Hz), 10.96 (s,
1H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 25.3,
35.6, 36.1, 46.8, 48.4, 49.8, 50.8, 51.1, 107.9, 111.5, 118.4,
120.1, 126.6, 132.2, 136.5, 140.7, 173.0 ppm; MS (APCI):
m/z = 300 ([M ? 1]?).
Yield 77 %; m.p.: 128 °C; H NMR (500 MHz, DMSO-
1
d6): d = 1.81 (s, 3H), 2.71–2.78 (m, 3H), 2.99 (m, 1H),
6.71 (t, 1H, JH,H = 6.7 Hz), 7.12 (m, 3H), 7.24 (m, 1H),
3
3
7.29 (m, 2H), 7.53 (d, 1H, JH,H = 8.8 Hz), 7.71 (d, 1H,
3JH,H = 6.7 Hz) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 24.9, 27.2, 39.7, 57.0, 111.9, 117.0, 123.5, 124.1,
125.3, 127.1, 127.5, 128.8, 142.2, 144.1, 145.2 ppm; MS
(APCI): m/z = 264 ([M ? 1]?).
20,50,60,70-Tetrahydro-10,30-dimethyl-20-phenylspiro[cyclo-
hexane-1,40-[4H]pyrrolo[3,4-c]pyridine] hydrochloride
(6ad, C20H27ClN2)
Yield 81 %; m.p.: 255 °C (decomp.); 1H NMR (400 MHz,
DMSO-d6): d = 1.35 (m, 1H), 1.61 (m, 2H), 1.77 (m, 3H),
1.83 (s, 3H), 1.93 (m, 2H), 2.00 (s, 3H), 2.15 (m, 2H), 2.75
Acknowledgments The authors thank Mr. Vitaliy V. Polovinko for
NMR measurements and Mrs. Olga V. Manoylenko for chromato-
graphic separations.
3
(m, 2H), 3.25 (m, 2H), 7.21 (d, 2H, JH,H = 7.6 Hz), 7.52
(m, 3H), 8.98 (br s, 2H) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 10.8, 12.8, 19.2, 20.6, 24.7, 34.0, 38.5,
58.7, 110.5, 117.9, 121.5, 122.0, 128.5, 128.8, 129.9,
138.2 ppm; MS (APCI): m/z = 295 ([M ? 1]?).
References
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20,50,60,70-Tetrahydro-10,30-dimethyl-20-phenylspiro[3H-
indole-3,40-[4H]pyrrolo[3,4-c]pyridin]-2(1H)-one
(6ak, C22H21N3O)
1
Yield 71 %; m.p.: 202 °C; H NMR (500 MHz, DMSO-
d6): d = 1.27 (s, 3H), 1.87 (s, 3H), 2.55 (m, 2H), 2.99 (m,
1H), 3.52 (m, 1H), 6.80 (d, 1H, JH,H = 7.6 Hz), 6.89 (t,
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3
3
1H, JH,H = 7.6 Hz), 7.34 (m, 4H), 7.37 (t, 1H,
3JH,H = 7.6 Hz), 7.45 (m, 2H), 10.23 (s, 1H) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 10.5, 10.9, 22.4, 40.6,
60.9, 109.6, 114.6, 115.0, 121.3, 121.6, 122.1, 125.0,
128.0, 128.5, 128.7, 129.7, 135.1, 138.5, 142.3, 179.8 ppm;
MS (APCI): m/z = 344 ([M ? 1]?).
1,2,3,4-Tetrahydro-1-isopropylpyrido[40,30:4,5]imidazo-
[1,2-a]pyridine (7ab, C13H17N3)
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Tetrahedron 64:1654
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1
Yield 76 %; m.p.: 124 °C; H NMR (400 MHz, DMSO-
3
d6): d = 0.67 (d, 3H, JH,H = 6.3 Hz), 1.01 (d, 3H,
3JH,H = 6.3 Hz), 2.38 (m, 1H), 2.63 (m, 2H), 2.86 (m,
3
1H), 3.13 (m, 1H), 4.05 (d, 1H, JH,H = 4.6 Hz), 6.77 (t,
1H, 3JH,H = 6.8 Hz), 7.13 (t, 1H, 3JH,H = 8.9 Hz), 7.44 (d,
3
3
1H, JH,H = 8.9 Hz), 8.27 (d, 1H, JH,H = 6.8 Hz) ppm;
13C NMR (DMSO-d6, 125 MHz, ppm): d = 21.8, 22.4,
24.4, 25.7, 37.8, 57.2, 112.3, 118.0, 124.1, 126.4, 139.8,
140.1, 144.8; MS (APCI): m/z = 216 ([M ? 1]?).
30,40-Dihydrospiro[cyclohexane-1,10(20H)-pyrido-
[40,30:4,5]imidazo[1,2-a]pyridine] (7ad, C15H19N3)
Yield 82 %; m.p.: 143 °C; 1H NMR (500 MHz, DMSO-d6):
d = 1.45–1.81 (m, 8H), 2.06 (m, 2H), 2.62 (m, 2H), 2.92 (m,
20. Ryabukhin SV, Volochnyuk DM, Plaskon AS, Naumchik VS,
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3
2H), 6.80 (t, 1H, JH,H = 8.7 Hz), 7.12 (t, 1H,
3JH,H = 8.7 Hz), 7.43 (d, 1H, 3JH,H = 8.7 Hz), 8.45 (d, 1H,
3JH,H = 8.7 Hz) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 20.7, 24.6, 25.7, 31.1, 38.7, 55.5, 112.2, 117.2, 123.9,
126.0, 140.4, 140.5, 144.5 ppm; MS (APCI): m/z = 242
([M ? 1]?).
123

Application of chlorotrimethylsilane in Pictet–Spengler reaction
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123