A one-pot synthesis of 4-aryl-2-methyl-1,2,3,4-tetrahydro-γ-carbolines from 5-aryloxazolidines and indoles via a Mannich/Friedel-Crafts sequence

Article abstract of DOI:10.1016/j.tetlet.2014.09.058

Benzaldehydes react smoothly with the nonstabilized azomethine ylide derived from sarcosine and formaldehyde to form 5-aryloxazolidines, which undergo ring-opening to give 2-(indol-3-ylmethylamino)-1-arylethanols in 69-79% yields on reaction with indoles in acetic acid. Their subsequent acid-catalyzed cyclization into 4-aryl-2-methyl-1,2,3,4-tetrahydro-γ-carbolines was performed in polyphosphoric acid in moderate yields. The latter can also be prepared directly from 5-aryloxazolidines and indoles in polyphosphoric acid.

Full text of DOI:10.1016/j.tetlet.2014.09.058

Accepted Manuscript
A one-pot synthesis of 1-aryl-3-methyl-1,2,3,4-tetrahydro-γ-carbolines from 5-
aryloxazolidines and indoles via a Mannich/Friedel–Crafts sequence
Vladimir S. Moshkin, Vyacheslav Y. Sosnovskikh
PII:
S0040-4039(14)01559-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.09.058
TETL 45152
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 June 2014
28 August 2014
11 September 2014
Please cite this article as: Moshkin, V.S., Sosnovskikh, V.Y., A one-pot synthesis of 1-aryl-3-methyl-1,2,3,4-
tetrahydro-γ-carbolines from 5-aryloxazolidines and indoles via a Mannich/Friedel–Crafts sequence, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.09.058
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Graphical abstract
________________________________________________________________________________
A one-pot synthesis of 1-aryl-3-methyl-1,2,3,4-tetrahydro-γ-carbolines from 5-aryloxazolidines and indoles via a
Mannich/Friedel–Crafts sequence
Vladimir S. Moshkin*, Vyacheslav Y. Sosnovskikh
________________________________________________________________________________________________________________________
∗ Corresponding author. Fax: +7 343 261 59 78;
e-mail: mvslc@mail.ru

A one-pot synthesis of 1-aryl-3-methyl-1,2,3,4-tetrahydro-γ-carbolines from 5-
aryloxazolidines and indoles via a Mannich/Friedel–Crafts sequence
Vladimir S. Moshkin*, Vyacheslav Y. Sosnovskikh
Department of Chemistry, Institute of Natural Sciences, Ural Federal University, 620000 Ekaterinburg,
Russian Federation
A B S T R A C T
Benzaldehydes react smoothly with the nonstabilized azomethine ylide derived from sarcosine and
formaldehyde to form 5-aryloxazolidines, which undergo ring-opening to give 2-(indol-3-
ylmethylamino)-1-arylethanols in 69–79% yields on reaction with indoles in acetic acid. Their
subsequent acid-catalyzed cyclization into 2-methyl-4-aryl-1,2,3,4-tetrahydro-γ-carbolines was
performed in polyphosphoric acid in moderate yields. The latter can also be prepared directly from
5-aryloxazolidines and indoles in polyphosphoric acid.
Keywords: 5-Aryloxazolidines; Indoles; 1,2,3,4-Tetrahydro-γ-carbolines; Phenylethanolamines;
Benzaldehydes; Nonstabilized azomethine ylides.
Derivatives of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, also known as 1,2,3,4-tetrahydro-γ-
carboline, constitute the skeleton of a number of physiologically active natural products and such
well-known drugs as Diazoline, Dimebon, and their analogues.1 Tetrahydro-γ-carbolines have
attracted strong interest in medicinal chemistry due to their useful biological properties and methods
for their synthesis and pharmacological data on these heterocycles have been reviewed.1,2 Because
of the important applications of γ-carboline derivatives, various synthetic methodologies have been
developed for the production of these compounds, however, novel methods for annelation of the
piperidine fragment to the indole molecule are still required in organic chemistry.
In particular, there are a limited number of syntheses of 1-aryl-1,2,3,4-tetrahydro-γ-carbolines,
which afford moderate yields only. Generally, these compounds are synthesized by the Friedel–
Crafts reaction starting from 2-(indol-3-ylmethylamino)-1-arylethanols3 (products of sodium
borohydride reduction of imines prepared from indole-3-carboxaldehyde and ethanolamines4) and
2

N-(indol-3-ylmethyl)ephedrines5 (products of the Mannich reaction of ephedrines with
formaldehyde and indoles) in concentrated sulfuric acid. The parent 4-phenyl-2,3,4,5-tetrahydro-
1H-pyrido[4,3-b]indole has been synthesized by the addition of β-nitrostyrene to a lithiated 1-
diethoxymethylindole, followed by reduction of the corresponding 1-diethoxymethyl-2-(2-nitro-1-
phenylethyl)indole and Pictet–Spengler recyclization.6 Alternatively, this compound can be
obtained by the involvement of the corresponding indol-3-ylmethylaminoethanol in the Friedel–
Crafts cyclization.3 Information on the synthesis of 1,2,3,4-tetrahydro-γ-carbolines from
oxazolidines and indoles is absent from the literature. Nevertheless, N-alkyl-1,3-oxazolidines react
with indole and N-methylindole in the presence of MeSiCl3 to form the expected Mannich bases.7
In connection with our interest in the chemistry of 5-aryloxazolidines 1, which are easily
obtained from aromatic aldehydes and nonstabilized azomethine ylides,8 we have developed
convenient methods for the preparation of 1,2,3,4-tetrahydroisoquinolin-4-ols 2, N-benzyl-β-
hydroxy-β-phenethylamines 3, 4-aryl-1,2,3,4-tetrahydroisoquinolines 4 and 2-alkylamino-1-
arylethanols 5.9 Taking into account these results, we envisaged that the ring-opening of 5-
aryloxazolidines 1 by slightly nucleophilic indoles would produce the corresponding Mannich
bases, which could be converted into the target 1-aryl-1,2,3,4-tetrahydro-γ-carbolines 6 with the
assistance of an acidic catalyst to generate a second electrophilic center. To the best of our
knowledge, no such approach has been reported previously and we now describe the first use of the
oxazolidine system in the one-pot synthesis of 1,2,3,4-tetrahydro-γ-carbolines (Scheme 1).
3

Scheme 1. One-pot syntheses of phenethylamine derivatives.
The starting 5-aryloxazolidines 1a–c, prepared from aromatic aldehydes, sarcosine, and
formaldehyde, were used in the subsequent step without any purification. While p-
bromobenzaldehyde reacted cleanly under the usual conditions (1.5 equiv. of sarcosine, benzene or
toluene, azeotropic removal of water), unsubstituted benzaldehyde and m-anisaldehyde did not react
completely, even using a substantial excess of formaldehyde and sarcosine (up to 2.5 equiv). We
have improved the published procedure8,9 for the preparation of 5-aryloxazolidines 1a,c via the two-
stage addition of a mixture of sarcosine and formaldehyde (first 1.0 equiv of sarcosine and after 2
hours of boiling, a further 0.7 equiv).10
4

Scheme 2. Synthesis of compounds 7.
Next, it was found that 3-methyl-5-phenyloxazolidine (1a) reacted with indole in acetic acid at
70 °C to give liquid Mannich base 7a after column chromatographic purification (Scheme 2). The
first attempt to simplify this process by obtaining the hydrochloride of free base 7a was not
successful due to its low stability. Alternatively, treatment of 7a with a solution of anhydrous oxalic
acid, a weaker acid, in dry Et2O, allowed us to isolate analytically pure solid hydrogen oxalate 7a in
76% yield without any chromatography.10 With optimum conditions for the preparation of Mannich
base 7a in hand, the reactions of oxazolidines 1b,c as well as N-methylindole, were investigated. As
can be seen from Table 1, we obtained products 7a–d in high yields (69–79%).11 An important
feature of the present reaction is that oxazolidine 1c, prepared from m-anisaldehyde, reacted
smoothly with indole to give amino alcohol 7d, whereas its intramolecular recyclization into 6-
methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol (2, R = 6-MeO) via iminium cation A, which
can act as an internal electrophile, did not occur.9a Thus, compounds 2, 5, and 7 could be
synthesized from the same starting material simply by modifying the reaction conditions.
Apparently, the high yield of the Mannich bases 7 might be due to the electron-rich character of the
indole ring.
5

Table 1. The compounds prepared from 5-aryloxazolidines 1 and indoles (yields based on
the starting benzaldehyde).
Tetrahydro-γ-
Amino alcohol 7·(CO2H)2
carboline 6
d
–
a From 7a; free base mp 89–93 °C.
b As the free base, mp 132–135 °C.
c As a hydrogen oxalate salt, mp 179–183 °C.
d Inseparable mixture of products.
As mentioned above, the Mannich reaction between indoles and N-alkyloxazolidines has been
reported,7 but the preparation of a 1,2,3,4-tetrahydro-γ-carboline via this reaction does not appear to
have been described. In connection with this, we attempted to develop optimized conditions for a
double electrophilic substitution in a one-pot process from 5-aryloxazolidines 1a–c and indoles. The
development of a one-pot synthesis is attractive since it would obviate the isolation and purification
of the intermediate Mannich bases. We found that when 5-aryloxazolidines 1a,b and indole were
heated in polyphosphoric acid (PPA) at 90 °C for 1.5 hours, tetrahydro-γ-carbolines 6a,b were
6

obtained in 30% and 34% yields, respectively. Under the same conditions, N-methylindole gave the
expected product 6c as a low melting product, which could not be purified by crystallization, and
therefore was chromatographed on an SiO2 column and characterized after conversion into its
hydrogen oxalate salt 6c in 38% yield (Scheme 3). Methods for the cyclization other than by
treatment with PPA turned out to be less successful (with catalysts such as trifluoroacetic acid,
trifluoroacetic acid in toluene, and p-toluenesulfonic acid in toluene or dichloromethane).
Scheme 3. Synthesis of compounds 6.
Finally, the cyclization of amino alcohol 7a to give 2-methyl-4-phenyl-2,3,4,5-tetrahydro-1H-
pyrido[4,3-b]indole (6a) was performed in PPA using the above conditions, and the resulting
product was isolated after recrystallization from methanol as colorless crystals in 54% yield. All our
attempts to cyclize the amino alcohol 7d or oxazolidine 1c led to inseparable mixtures of products,
probably due to the presence of two nucleophilic aromatic rings, which are able to react with
cationic intermediates.
The structures of products 6a–c and 7a–d were established by elemental analysis and IR, 1H, and
13C NMR spectroscopy. Despite their simplicity, these compounds were not previously described. It
is known that cationic cyclizations such as 7 → 6 occur via spiro intermediate B, which can lead to
1
the possibility of the formation of β-carboline 6' along with γ-carboline 6 (Scheme 4).5,12,13 The H
7

NMR spectra of known isomers 6' show significant shielding of the aromatic indole protons (δ
6.53–7.40), being likely due to the mutual influence of two benzene rings.14 On the other hand, the
1H NMR chemical shifts of the corresponding protons in γ-carbolines 6a–c are not shielded because
of the greater distance between the rings. Indeed, compound 6 (R = R′ = H) had similar proton
signals in the δ 6.95–7.50 region as was described earlier.6 It should be noted that the melting point
observed here for 6a (mp 89–93 °C) differed significantly from that reported for isomeric 3-methyl-
1-phenyl-1,2,3,4-tetrahydro-β-carboline (mp 216–218 °C).15
Scheme 4. 1H NMR signals of the indole protons.
In conclusion, we have developed a novel and simple method for preparing pharmaceutically
valuable
1-aryl-1,2,3,4-tetrahydro-γ-carbolines
starting from
commercially available
benzaldehydes, in a one-pot procedure without purification of the intermediate products. The
successful synthesis of these compounds from indoles and oxazolidines suggests that further
investigation of other electron-rich heterocycles and arenes might be profitable in this context.
Acknowledgment
This work was financially supported by the Russian Science Foundation (Grant 14-13-00388)
and carried out under the terms of the Ural Federal University development program with the
financial support of young scientists.
References and notes
1. (a) Alekseyev, R. S.; Kurkin, A. V.; Yurovskaya, M. A. Chem. Heterocycl. Compd. 2011, 46, 1169; (b)
Smirnova, O. B.; Golovko, T. V.; Granik, V. G. Pharm. Chem. J. 2011, 44, 654; (c) Cao, L.; Choi, S.;
8

Moon, Y.; Tamilarasu, N.; Qi, H.; Lennox, W. J.; Hwang, S. WO Patent 2006058088; Chem. Abstr.
2006, 145, 27846.
2. (a) Ivachtchenko, A. V.; Mitkin, O. D.; Kadieva, M. G.; Tkachenko, S. E. Russ. Chem. Rev. 2010, 79,
285; (b) Alekseyev, R. S.; Kurkin, A. V.; Yurovskaya, M. A. Chem. Heterocycl. Compd. 2010, 46, 777.
3. Abou-Gharbia, M.; Patel, U. R.; Webb, M. B.; Moyer, J. A.; Andree, T. H.; Muth, E. A. J. Med. Chem.
1987, 30, 1818.
4. Walker, G. N.; Moore, M. A. J. Org. Chem. 1961, 26, 432.
5. Decker, M.; Faust, R.; Wedig, M.; Nieger, M.; Holzgrabe, U.; Lehmann, J. Heterocycles 2001, 55,
1455.
6. Kraxner, J.; Gmeiner, P. Synthesis 2000, 1081.
7. (a) Fairhurst, R.; Heaney, H.; Papageorgiou, G.; Wilkins, R. F.; Eyley, S. C. Tetrahedron Lett. 1989, 30,
1433; (b) Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron 1997, 53, 14381.
8. Nyerges, M.; Fejes, I.; Virányi, A.; Groundwater, P. W.; Töke, L. Synthesis 2001, 1479.
9. (a) Moshkin, V. S.; Sosnovskikh, V. Y. Tetrahedron Lett. 2013, 54, 2455; (b) Moshkin, V. S.;
Sosnovskikh, V. Y. Tetrahedron Lett. 2013, 54, 2699; (c) Moshkin, V. S.; Sosnovskikh, V. Y.
Tetrahedron Lett. 2013, 54, 5869.
10. General procedure for the preparation of 5-aryloxazolidines 1. A mixture of the corresponding
aromatic aldehyde (10.0 mmol), finely ground sarcosine (0.89 g, 10 mmol), and paraformaldehyde (0.39
g, 13 mmol of formaldehyde) was refluxed in dry benzene (17 mL), with magnetic stirring and removal
of the formed H2O by means of a Dean-Stark trap. After 2 h, a second portion of sarcosine (0.62 g, 7
mmol), and paraformaldehyde (0.30 g, 10 mmol of formaldehyde) was added. Refluxing was continued
for an additional 3–5 h. The resulting solution was evaporated in vacuo to give oily 5-aryl-3-
methyloxazolidines 1, which were used without additional purification.
General procedure for the preparation of amino alcohols 7a–d. To a solution of indole or N-
methylindole (1.0 mmol) in oxazolidine 1 (1.0 mmol) was added AcOH (1.5 mL). The resulting solution
was concentrated in vacuo on a rotary evaporator at 70 °C for 30 min, then H2O (5 mL) and conc. NH3
(0.5 mL) were added. The product was extracted with Et2O (2×7 mL), dried over Na2SO4, and the Et2O
removed in vacuo to give crude compound 7, which was dissolved in dry Et2O (5 mL) and converted
into the hydrogen oxalate salt by treatment with a solution of anhydrous oxalic acid (0.09 g, 1.0 mmol)
in dry Et2O (5 mL). The filtered and washed salt was dried in vacuo on a rotary evaporator at 50 °C for
90 min (stored without moisture).
General procedure for the preparation of tetrahydro-γ-carbolines 6a–c. To a solution of indole or N-
methylindole (1.0 mmol) in oxazolidine 1 (1.0 mmol) was added warm PPA (1.3 mL) and the resulting
mixture was heated to 90 °C for 90 min with stirring (interval 10–15 min) using a spatula. H2O was
added to the residue at room temperature, followed by addition of excess concentrated aqueous NaOH
solution with cooling. The mixture was extracted with CH2Cl2 (2×7 mL) using a magnetic stirrer, dried
over Na2SO4, and evaporated to give the crude γ-carboline 6.
9

11. 2-{[(1H-Indol-3-yl)methyl](methyl)amino}-1-(3-methoxyphenyl)ethanol hydrogen oxalate (7d). Light
pink powder, yield 69%, mp 68–72 °C (with slow decomposition). IR (ATR): 3304, 3114, 3052, 2963,
2838, 1715, 1600, 1487, 1456, 1432, 1339, 1239, 1191, 1155, 1068, 1035, 919, 870, 743, 694 cm–1; 1H
NMR (400 MHz, DMSO-d6) δ 2.82 (s, 3H, MeN), 3.10–3.20 (m, 2H, СH2), 3.73 (s, 3H, MeO), 4.51 (d,
J = 13.6 Hz, 1H, CHH), 4.58 (d, J = 13.6 Hz, 1H, CHH), 5.03–5.09 (m, 1H, СH), 6.81 (ddd, J = 8.1,
2.3, 0.8 Hz, 1H, H-4'), 6.89–6.93 (m, 2H, H-2', H-6'), 7.05 (td, J = 7.4, 0.9 Hz, 1H, H-5/6), 7.12 (td, J =
7.5, 1.0 Hz, 1H, H-6/5), 7.23 (t, J = 8.1 Hz, 1H, H-5'), 7.42 (d, J = 8.0 Hz, 1H, H-4/7), 7.60 (d, J = 2.4
Hz, 1H, H-2), 7.74 (d, J = 7.9 Hz, 1H, H-7/4), 11.51 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) δ
50.7, 55.1, 60.0, 65.0, 67.1, 102.5, 111.5, 112.0, 113.2, 118.0, 118.5, 119.7, 121.7, 127.6, 129.2, 129.5,
136.1, 143.6, 159.3, 164.4. Anal. Calcd for C19H22N2O2⋅(CO2H)2⋅H2O: C, 60.28; H, 6.26; N, 6.69.
Found: C, 60.42; H, 6.13; N, 6.55.
2-Methyl-4-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (6a). The crude product 6a was dissolved
in warm toluene (3.5 mL) and diluted with hexane (13 mL). The mixture was cooled to 0 °C and
filtered. The mother liquid was evaporated in vacuo and the residue was recrystallized from MeOH (by
cooling in a fridge). Colourless crystals, yield 54% (from 7a), 30% (from 1a) mp 89–93 °C (MeOH). IR
(ATR): 3392, 3145, 3055, 3027, 2965, 2937, 2870, 2845, 2784, 2743, 1622, 1598, 1492, 1451, 1349,
1326, 1307, 1237, 1225, 1159, 1148, 1121, 1098, 1075, 1052, 1031, 1008, 974, 736, 697 cm–1; 1H NMR
(400 MHz, DMSO-d6) δ 2.40 (s, 3H, MeN), 2.62 (dd, J = 11.3, 6.2 Hz, 1H, 3-CHH), 2.98 (dd, J = 11.3,
5.2 Hz, 1H, 3-CHH), 3.58 (d, J = 13.6 Hz, 1H, 1-CHH), 3.67 (d, J = 13.6 Hz, 1H, 1-CHH), 4.25 (t, J =
5.5 Hz, 1H, H-4), 6.94 (t, J = 7.4 Hz, 1H, H-7/8), 7.00 (t, J = 7.5 Hz, 1H, H-8/7), 7.19–7.25 (m, 4H, H-
6/9, Ph), 7.27–7.32 (m, 2H Ph), 7.38 (d, J = 7.7 Hz, 1H, H-9/6), 10.56 (s, 1H, NH); 13C NMR (101
MHz, DMSO-d6) δ 40.9, 45.6, 51.7, 61.7, 108.8, 111.3, 117.6, 118.6, 120.8, 125.4, 126.8, 128.47,
128.54, 134.2, 136.5, 143.1. Anal. Calcd for C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.23; H,
6.76; N, 10.69.
4-(4-Bromophenyl)-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrogen oxalate (6c). The
crude product was chromatographed on an SiO2 column (CH2Cl2/MeOH, 100:3). The low melting free
base obtained was dissolved in dry acetone and converted into the hydrogen oxalate salt by treatment
with a solution of oxalic acid (0.09 g, 1.0 mmol) in dry acetone, then diluted with dry Et2O. After
filtration and washing with Et2O, the salt was dried in vacuo on a rotary evaporator at 50 °C for 90 min.
Light yellow powder, yield 38%, mp 179–183 °C. IR (ATR): 2960, 2879, 2697, 2590, 1717, 1605,
1487, 1472, 1425, 1404, 1354, 1324, 1252, 1184, 1137, 1087, 1014, 956, 818, 752, 700 cm–1; 1H NMR
(400 MHz, DMSO-d6) δ 2.84 (s, 3H, MeN), 3.23 (s, 3H, MeN), 3.33 (dd, J = 11.3, 8.5 Hz, 1H, 3-CHH),
3.72 (dd, J = 11.3, 5.4 Hz, 1H, 3-CHH), 4.36 (d, J = 14.0 Hz, 1H, 1-CHH), 4.44 (d, J = 14.0 Hz, 1H, 1-
CHH), 4.75 (br t, J = 6.0 Hz, 1H, H-4), 7.09 (t, J = 7.3 Hz, 1H, H-7/8), 7.15–7.24 (m, 3H, H-2′, H-6′, H-
8/7), 7.39 (d, J = 8.1 Hz, 1H, H-6/9), 7.53 (d, J = 7.8 Hz, 1H, H-9/6), 7.57 (d, J = 7.8 Hz, 2H, H-3′, H-
5′); 13C NMR (101 MHz, DMSO-d6) δ 30.2, 37.1, 42.5, 50.2, 57.9, 104.9, 109.6, 117.9, 119.4, 120.7,
121.8, 124.1, 130.5, 131.8, 132.6, 137.3, 139.3, 163.8. Anal. Calcd for C19H19BrN2⋅(CO2H)2⋅0.5H2O: C,
10

55.52; H, 4.88; N, 6.17. Found: C, 55.35; H, 4.84; N, 6.12.
12. Jackson, A. H.; Naidoo, B; Smith, P. Tetrahedron 1968, 24, 6119.
13. Curness, K.; Dyke, S. Heterocycles 1979, 12, 1133.
14. Lehmann, J.; Jiang, N.; Behncke, A. Arch. Pharm. 1993, 326, 813.
15. Ames, A. F.; Ames, D. E.; Coyne, C. R.; Grey, T. F.; Lockhart, I. M.; Ralph, R. S. J. Chem. Soc. 1959,
3388.
11