First practical and efficient synthesis of 3-phosphorylated β-carboline derivatives using the Pictet-Spengler reaction

Article abstract of DOI:10.1002/ejoc.201403418

We report here the first practical and efficient synthesis of the diethyl 1,2,3,4-tetrahydro-β-carboline-3-phosphonates 3 and 4 as well as diethyl 9H-β-carboline-3-phosphonates 5 and 6. The target compounds were prepared in good yields by application of t

Full text of DOI:10.1002/ejoc.201403418

Job/Unit: O43418
/KAP1
Date: 05-01-15 15:30:37
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201403418
First Practical and Efficient Synthesis of 3-Phosphorylated β-Carboline
Derivatives Using the Pictet–Spengler Reaction
José Luis Viveros-Ceballos,[a] Francisco J. Sayago,[b] Carlos Cativiela,*[b] and
Mario Ordóñez*[a]
Keywords: Synthetic methods / Drug design / Phosphorylation / Nitrogen heterocycles
We report here the first practical and efficient synthesis of
the diethyl 1,2,3,4-tetrahydro-β-carboline-3-phosphonates 3
and 4 as well as diethyl 9H-β-carboline-3-phosphonates 5
and 6. The target compounds were prepared in good yields
by application of the Pictet–Spengler reaction of easily ob-
tainable phosphotryptophan diethyl ester 7. The procedure
is based on simple preparation of racemic 7 followed by a
Pictet–Spengler reaction with several aldehydes and sub-
sequent oxidation chemistry.
eration of 1 and 2 analogues such as diethyl 1,2,3,4-tetra-
hydro-β-carboline-3-phosphonates 3, and 4 and diethyl 9H-
β-carboline-3-phosphonates 5 and 6 from phosphotrypto-
phan diethyl ester 7, using the Pictet–Spengler reaction, to
the best of our knowledge, has not yet been described in
the literature, despite their great potential in medicinal
chemistry and organic synthesis, as reflected by the α-
aminophosphonic acids and their derivatives.[9,10] Given the
potential of these agents, it is of great importance that new
methods be developed for their preparation.[11]
Introduction
Tetrahydro-β-carbolines (THβCs) and β-carbolines (βCs)
are a class of pharmacophores present in a large number of
natural indole alkaloids found in numerous plants, foods,
beverages and animals; expression of potent biological ac-
tivity is a common feature.[1] Specifically, the 1,2,3,4-tetra-
hydro-β-carboline-3-carboxylic acid 1 and 9H-β-carboline-
3-carboxylic acid 2 have been used as key templates in the
preparation of many naturally occurring and more complex
synthetic compounds, that demonstrate a variety of impor-
tant and potent pharmacological activities. It has been re-
ported that compounds incorporating the 1,2,3,4-tetra-
hydro-β-carboline-3-carboxylic acid 1 and 9H-β-carboline-
3-carboxylic acid 2 scaffolds display a wide spectrum of
pharmacological capabilities including the expression of
anticancer,[2] antithrombotic,[3] and antimalarial activities[4]
as well as an affinity for binding the benzodiazepine recep-
tor (Figure 1) and modulating its downstream pathways.[5]
Additionally, in the area of organic synthesis, 1 has been
used for the preparation of catalysts.[6] Due to the relevant
properties displayed by 1 and 2 and their related derivatives,
much effort have been dedicated to the preparation of these
compounds; predominant approaches involve the use of
tryptophan in Pictet–Spengler reactions.[7,8] However, gen-
Figure 1. Structure of 1,2,3,4-tetrahydro-β-carboline-3-carboxylic
acid 1, 9H-β-carboline-3-carboxylic acid 2, and their 3-phosphor-
ylated analogues 3–6.
[a] Universidad Autónoma del Estado de Morelos, Centro de
Investigaciones Químicas,
62209 Cuernavaca, Morelos, Mexico
Considering the high value of these non-coded com-
pounds in connection with our current research interest in
the synthesis of novel conformationally restricted α-amino-
phosphonic acids,[12] we now report herein the first conve-
nient synthesis of diethyl 1,2,3,4-tetrahydro-β-carboline-3-
phosphonates 3 and 4 as well as diethyl 9H-β-carboline-3-
phosphonates 5 and 6 from phosphotryptophan diethyl
ester 7 using the Pictet–Spengler reaction.
E-mail: palacios@uaem.mx
http://www.ciq.uaem.mx/laboratorio-de-acidos-
aminofosfonicos-y-fosfonopeptidos/
[b] Universidad de Zaragoza – CSIC, Departamento de Química
Orgánica, ISQCH,
50009 Zaragoza, Spain
E-mail: cativiela@unizar.es
http://www.unizar.es/aminoacidosypeptidos/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403418.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. L. Viveros-Ceballos, F. J. Sayago, C. Cativiela, M. Ordóñez
FULL PAPER
meric ratio (Table 1, Entry 3). Compound 7 was also found
to react with acetaldehyde, and the diethyl cis- and trans-1-
Results and Discussion
For the synthesis of target compound 3 (R = H) we
envisaged that this could be obtained from 7 using an iden-
tical Pictet–Spengler protocol previously applied to the syn-
thesis of compound 1 and its derivatives. The synthetic
route is outlined in Scheme 1. The key phosphotryptophan
diethyl ester intermediate 7 was obtained essentially accord-
ing to the literature method,[13] starting from indole-3-acetic
acid 8 with 49% overall yield. With compound 7 in hand,
we initially carried out the Pictet–Spengler reaction with
aqueous formaldehyde solution (1.8 equiv.) and 2 n HCl in
an EtOH/H2O mixture as solvent at room temperature, af-
fording target compound 3 in 50% yield along with
hydroxymethyl derivative 8 in 18% yield. After several
attempts, we found that reaction of 7 with aqueous form-
aldehyde (1.0 equiv.) and 2 n HCl in EtOH/H2O at room
methyl-1,2,3,4-tetrahydro-β-carboline-3-phosphonate
4d
(78:22) mixture was obtained in 68% yield (Table 1, Entry
4). The reaction with isobutyraldehyde gave the mixture of
cis- and trans-isomers 4e (68:32) in 83% yield (Table 1,
Entry 5). However, in the reaction of 7 with ethyl glyoxalate
it was not possible to isolate corresponding 1,2,3,4-tetra-
hydro-β-carboline 4f; during reaction workup it appears
that 4f was oxidized to give directly β-carboline-3-
phosphonate 6f. Finally, the Pictet–Spengler reaction of
phosphotryptophan diethyl ester 7 with acetone and cyclo-
hexanone, provided cyclized products 4g and 4h in 75 and
69% yield, respectively (Table 1, Entries 7 and 8). The cis-
and trans-1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines
4a–e were separated by flash column chromatography and
characterized using IR, NMR and MS.
temperature, afforded compound
(Scheme 1).
3
in 85% yield
Table 1. Synthesis of the 1,2,3,4-tetrahydro-β-carbolines 4a–h by
Pictet–Spengler reaction.
Entry
Compound; R
RЈ
cis/trans Yield [%]
1
2
3
4
5
6
7
8
4a. C6H5
H
H
H
H
H
H
Me
75:25
62:38
94:06
78:22
68:32
–
–
–
86
81
72
68
83
–
4b; 4-BrC6H4
4c; 4-MeOC6H4
4d; Me
4e; iPr
4f; CO2Et
4g; Me
[a]
75
69
4h; –(CH2)5–
[a] The isolated product was the β-carboline 6f.
Scheme 1. Synthetic route employed for the preparation of target
compound 3.
The cis- and trans-stereochemistry for each 1,2,3,4-tetra-
hydro-β-carboline 4 listed in Table 1, was determined un-
1
With these results, the next step was to explore the scope equivocally by analyzing the correlation spots in its H-1H
of the Pictet–Spengler reaction of phosphotryptophan di- NOESY spectra as depicted in Figure 2. For cis-4a–e, there
ethyl ester 7 with several aromatic and aliphatic aldehydes. is a clear correlation signal (NOE) between H-3 and H-1,
The goal was to identify conditions enabling Pictet–Speng- indicating that H-3 and H-1 are located on the same side of
ler synthesis of diethyl 1,2,3,4-tetrahydro-β-carboline-3- the piperidine ring; for trans-4a–e this correlation is absent.
phosphonates 4. We first carried out the reaction of com- However, for the trans products one additional correlation
pound 7 with benzaldehyde, and, after several attempts, we signal (NOE) between H-1 and the CH3 group at C-1 was
were pleased to see that the Pictet–Spengler reaction in the observed for 4d. A similar correlation between H-1 and the
presence of catalytic trifluoroacetic acid (TFA) in CH2Cl2 HC(CH3)2 at C-1 for 4e was also observed. These data indi-
with molecular sieves (4 Å) at room temperature, proceeded cate that the methyl (for 4d) or isopropyl group (for 4e)
smoothly to afford the cis- and trans-isomers 4a (75:25) and H-3 are, in both cases, located on the same side of the
mixture in 86% yield (Table 1, Entry 1). After successfully piperidine ring.
optimizing the reaction conditions, we conducted a broader
Having generated 1,2,3,4-tetrahydro-β-carboline 3 and
investigation of this reaction using various aldehydes and the cis- and trans-1,3-disubstituted derivatives 4a–f now in
ketones, the results of which are summarized in Table 1. hand, we next attempted to produce diethyl 9H-β-carb-
Thus, the reaction of 7 with 4-bromobenzaldehyde, gave de- oline-3-phosphonates 5 and 6a–f. Our studies showed that
sired product 4b as a mixture of cis- and trans-isomers 3 and 4a–f can be readily converted into compounds 5 and
(62:38) in 81% yield (Table 1, Entry 2). Alternatively, the 6a–f, respectively, by employing trichloroisocyanuric acid
reaction of 7 with 4-methoxybenzaldehyde gave cis- and (TCCA) as an effective oxidizing agent[14] in the presence
trans-isomers 4c in 72% yield and with a 94:6 diastereoiso- of triethylamine (TEA) and with dimethylformamide
2
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Synthesis of 3-Phosphorylated β-Carbolines
alized by exposure to UV light (254 nm), iodine vapours or sub-
mersion in solutions of phosphomolybdic acid in ethanol or nin-
hydrin (ninhydrin/ethanol/acetic acid/ethylene glycol/dimethyl
ether). Column chromatography was performed using 60 Å (0.04–
0.063 mm) silica gel from Macherey–Nagel. Melting points were
determined with a Gallenkamp apparatus. IR spectra were re-
corded with a Nicolet Avatar 360 FTIR spectrophotometer; νmax is
given for the main absorption bands. 1H, 13C and 31P NMR spectra
were recorded with a Bruker AV-400 instrument at room tempera-
ture except when another temperature is specified; the residual sol-
vent signal was used as the internal standard; chemical shifts (δ)
are expressed in parts per million and coupling constants (J) in
Hertz. High-resolution mass spectra were obtained with a Bruker
Microtof-Q spectrometer.
Figure 2. Determination of cis- and trans-stereochemistry of 4a–e
by NOESY.
(DMF) as solvent, according to the synthetic route outlined
in Table 2. Thus, 1,2,3,4-tetrahydro-β-carbolines 3 and 4a–f,
obtained as described above, were subjected without further
purification to TCCA and TEA in DMF at –10 °C, to
afford 9H-β-carboline-3-phosphonates 5 and 6a–f in mod-
erate to good yields. The results are summarized in the
Table 2.
Diethyl 1-Amino-2-(indol-3-yl)ethylphosphonate (7): Oxalyl chloride
(3.98 g, 2.7 mL, 31.4 mmol) was added dropwise over 5 min to a
stirred solution of indole-3-acetic acid (5.0 g, 28.54 mmol) in dry
dichloromethane (106 mL) at 0 °C under an argon atmosphere. The
mixture was stirred at 0 °C for 5 min and then DMF (104 mg,
0.11 mL, 1.42 mmol) was added in one portion. The solution was
warmed at room temperature and then stirred until the mixture no
longer effervesced. The mixture was concentrated under reduced
pressure to leave the corresponding acid chloride as a yellow oil,
which was used straight away. The acyl chloride was dissolved in
THF (18 mL) and cooled to 0 °C, and triethyl phosphite (4.72 g,
4.95 mL, 28.4 mmol) was added dropwise under anhydrous condi-
tions. When the addition was complete, the reaction was warmed
at 70 °C and stirred for 15 min. The solvent was evaporated under
reduced pressure yielding the α-ketophosphonate, which was used
without additional purification in the following step. The crude α-
ketophosphonate was added to a solution of hydroxylamine hydro-
chloride (2.37 g, 34.1 mmol) in dry pyridine (5.1 mL) and EtOH
(8.5 mL), and the mixture was stirred at room temperature for 12 h.
After evaporation of solvent under reduced pressure, the crude resi-
due was dissolved in dichloromethane (40 mL), washed with 3 n
HCl (2ϫ 10 mL) and water (10 mL). The organic layer was dried
with anhydrous sodium sulfate and evaporated under reduced pres-
sure to obtain the crude oxime, which was added under argon to a
suspension of zinc (7.42 g, 113.50 mmol) in formic acid (29 mL).
The reaction was stirred overnight, and the suspension was filtered.
The filtrate was evaporated and the crude product was purified by
column chromatographic using an AcOEt/MeOH (95:5) mixture as
Table 2. Synthesis of 9H-β-carboline-3-phosphonates 5 and 6a–f.
Entry
Compound; R
Yield [%]
1
2
3
4
5
6
7
5; H
83a
63
76
57
19
39
84
6a. C6H5
6b; 4-BrC6H4
6c; 4-MeOC6H4
6d; Me
6e; iPr
6f; CO2Et
[a] 1. HCHO (1.0 equiv.), 2 n HCl, EtOH/H2O, room temp.
Conclusions
eluent, affording 7 (4.13 g, 49% yield) as a yellow oil. IR (neat): ν
˜
1
= 3246, 1221, 1052, 1026 cm–1. H NMR (400 MHz, CDCl3): δ =
In summary, we have established the conditions and pro-
cedure for the first practical and efficient synthesis of di-
ethyl 1,2,3,4-tetrahydro-β-carboline-3-phosphonates 3 and
4 as well as diethyl 9H-β-carboline-3-phosphonates 5 and
6. Target compounds were prepared in good yields by appli-
cation of Pictet–Spengler reactions with readily obtainable
phosphotryptophan diethyl ester 7 and several aldehydes
and ketones. This contribution represents the first Pictet–
Spengler reaction using α-aminophosphonates as key inter-
mediates in the preparation of novel cyclic α-amino-
phosphonates.
1.36 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.36 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 1.42 (br. s, 2 H, NH2), 2.86 (ddd, J = 15.0, 11.6,
8.3 Hz, 1 H, CH2CH), 3.35–3.44 (m, 2 H, CH2CH, CH-P), 4.15–
4.26 (m, 4 H, OCH2CH3), 7.07–7.13 (m, 2 H, Harom), 7.19 (ddd, J
= 8.2, 7.1, 1.1 Hz, 1 H, Harom), 7.37 (ddd, J = 8.2, 0.8, 0.8 Hz, 1
H, Harom), 7.60 (dd, J = 7.9, 1.1 Hz, 1 H, Harom), 8.62 (br. s, 1 H,
indole-NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.7 (d, J =
5.6 Hz, CH3CH2O), 27.9 (CH2CH), 49.3 (d, J = 154.9 Hz, CH-P),
62.4 (d, J = 7.1 Hz, OCH2CH3), 62.5 (d, J = 7.2 Hz, OCH2CH3),
111.4 (Ar), 111.5 (d, J = 17.3 Hz, Ar), 118.7 (Ar), 119.5 (Ar), 122.2
(Ar), 123.3 (Ar), 127.3 (Ar), 136.6 (Ar) ppm. 31P NMR (162 MHz,
CDCl3): δ = 28.63 ppm. HRMS (ESI): calculated for C14H22N2O3P
[M + H]+, m/z 297.1368; found for [M + H]+, m/z 297.1356.
Diethyl 1,2,3,4-Tetrahydro-β-carboline-3-phosphonate (3): Formal-
dehyde (55 mg, 51 μL, 0.68 mmol, 37% aqueous solution) was
added dropwise to a solution of the α-aminophosphonate 7
(200 mg, 0.67 mmol) and 2 n HCl (0.34 mL, 0.68 mmol) in EtOH/
H2O (1.0:0.1 mL). The reaction mixture was stirred for 3 h at room
Experimental Section
General: All reagents were used as received from commercial
suppliers without further purification. Thin-layer chromatography
(TLC) was performed with Macherey–Nagel Polygram® SIL G/
UV254 precoated silica gel polyester plates. The products were visu- temperature, was concentrated under reduced pressure, diluted with
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J. L. Viveros-Ceballos, F. J. Sayago, C. Cativiela, M. Ordóñez
a mixture of phosphotryptophan ethyl ester (7; 200 mg,
0.67 mmol), benzaldehyde (72 mg, 0.07 mL, 0.67 mmol), dry
CH2Cl2 (7 mL) and TFA (0.07 mL, 0.91 mmol) was reacted in the
presence of activated molecular sieves (4 Å, 70 mg) to give cis- and
trans-isomers 4a in a 75:25 ratio (calculated from the crude reaction
mixture).
FULL PAPER
CH2Cl2 (20 mL) and neutralized with satd. NaHCO3 solution
(20 mL). The layers were separated, and the aqueous phase was
further extracted with CH2Cl2 (2ϫ 10 mL). The organic extracts
were combined and dried with anhydrous magnesium sulfate, fil-
tered and evaporated under reduced pressure. The residue was puri-
fied by column chromatography with CH2Cl2:iPrOH (85:15) as elu-
ent to give 3 (170 mg, 85%) as a yellow oil. IR (neat): ν = 3232,
˜
cis-4a: White solid (160 mg, 62%); m.p. 188–190 °C. IR (nujol): ν
1
˜
1259, 1054, 1028 cm–1. H NMR (400 MHz, CDCl3): δ = 1.37 (t,
= 3223, 1228, 1025, 963 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.39 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.39 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 2.08 (br. s, 1 H, NH), 3.03–3.18 (m, 2 H, 4-H), 3.53
(ddd, J = 15.3, 10.8, 4.7 Hz, 1 H, 3-H), 4.16–4.31 (m, 4 H,
OCH2CH3), 5.15 (s, 1 H, 1-H), 7.09–7.15 (m, 2 H, Harom), 7.16–
7.20 (m, 1 H, Harom), 7.30–7.38 (m, 5 H, Harom), 7.52–7.57 (m, 1
H, Harom), 7.73 (br. s, 1 H, indole-NH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.6 (d, J = 5.6 Hz, CH3CH2O), 23.1 (C-4), 51.9 (d,
J = 159.7 Hz, C-3), 59.2 (d, J = 18.5 Hz, C-1), 62.6 (d, J = 6.6 Hz,
OCH2CH3), 62.7 (d, J = 6.4 Hz, OCH2CH3), 108.5 (d, J = 17.1 Hz,
Ar), 111.0 (Ar), 118.2 (Ar), 119.6 (Ar), 121.9 (Ar), 127.1 (d, J =
2.6 Hz, Ar), 128.5 (Ar), 128.6 (Ar), 128.9 (Ar), 134.6 (d, J = 2.5 Hz,
Ar), 136.0 (Ar), 141.0 (Ar) ppm. 31P NMR (162 MHz, CDCl3): δ
= 26.34 ppm. HRMS (ESI): calculated for C21H26N2O3P [M +
H]+, m/z 385.1681; found for [M + H]+, m/z 385.1675.
J = 7.1 Hz, 3 H, CH3CH2O), 1.39 (t, J = 7.1 Hz, 3 H, CH3CH2O),
1.92 (br. s, 1 H, NH), 2.88–3.05 (m, 2 H, 4-H), 3.31 (ddd, J = 17.1,
10.5, 5.3 Hz, 1 H, 3-H), 4.03 (d, J = 16.0 Hz, 1 H, 1-H), 4.08 (d, J
= 16.0 Hz, 1 H, 1-H), 4.19–4.29 (m, 4 H, OCH2CH3), 7.09 (ddd, J
= 7.7, 7.7, 1.1 Hz, 1 H, Harom), 7.14 (ddd, J = 7.7, 7.7, 1.3 Hz, 1
H, Harom), 7.30 (dd, J = 7.7, 1.1 Hz, 1 H, Harom), 7.47 (dd, J = 7.7,
1.3 Hz, 1 H, Harom), 8.14 (br. s, 1 H, indole-NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.7 (d, J = 5.6 Hz, CH3CH2O), 22.9 (C-
4), 43.5 (d, J = 18.4 Hz, C-1), 51.3 (d, J = 161.6 Hz, C-3), 62.6 (d,
J = 6.8 Hz, OCH2CH3), 62.7 (d, J = 6.8 Hz, OCH2CH3), 107.4 (d,
J = 16.1 Hz, Ar), 110.9 (Ar), 117.9 (Ar), 119.6 (Ar), 121.8 (Ar),
127.3 (d, J = 2.6 Hz, Ar), 132.4 (d, J = 2.5 Hz, Ar), 135.9 (Ar) ppm.
31P NMR (162 MHz, CDCl3): δ = 26.70 ppm. HRMS (ESI): calcu-
lated for C15H22N2O3P [M + H]+, m/z 309.1368; found for [M +
H]+, m/z 309.1356.
Diethyl
9-Hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-3-phos-
trans-4a: Pale yellow solid (62 mg, 24%); m.p. 168–170 °C. IR
(nujol): ν = 3187, 1226, 1030, 964 cm–1. 1H NMR (400 MHz,
phonate (9): Under the reaction conditions described for the prepa-
ration of 3, when the formaldehyde (1.8 equiv.) was used,
hydroxymethyl derivative 9 (39 mg, 18%) was obtained as a yellow
˜
CDCl3): δ = 1.12 (t, J = 7.0 Hz, 3 H, CH3CH2O), 1.15 (t, J =
7.0 Hz, 3 H, CH3CH2O), 2.06 (br. s, 1 H, NH), 2.87–3.00 (m, 2 H,
4-H), 3.25 (ddd, J = 16.5, 9.5, 5.9 Hz, 1 H, 3-H), 3.85–4.06 (m, 4
H, OCH2CH3), 5.14 (s, 1 H, 1-H), 7.01–7.11 (m, 4 H, Harom), 7.14–
7.21 (m, 4 H, Harom), 7.46 (dd, J = 7.4, 1.1 Hz, 1 H, Harom), 8.12
(br. s, 1 H, indole-NH) ppm. 13C NMR (100 MHz, CDCl3): δ =
16.4 (d, J = 5.8 Hz, CH3CH2O), 16.5 (d, J = 5.9 Hz, CH3CH2O),
22.7 (C-4), 45.7 (d, J = 159.5 Hz, C-3), 55.3 (d, J = 16.2 Hz, C-1),
62.3 (d, J = 6.6 Hz, OCH2CH3), 62.7 (d, J = 6.8 Hz, OCH2CH3),
109.0 (d, J = 14.8 Hz, Ar), 111.1 (Ar), 118.3 (Ar), 119.6 (Ar), 122.1
(Ar), 127.0 (d, J = 2.3 Hz, Ar), 127.9 (Ar), 128.5 (Ar), 128.6 (Ar),
133.1 (d, J = 2.5 Hz, Ar), 136.1 (Ar), 141.7 (Ar) ppm. 31P NMR
(162 MHz, CDCl3): δ = 27.08 ppm. HRMS (ESI): calculated for
C21H26N2O3P [M + H]+, m/z 385.1681; found for [M + H]+, m/z
385.1664.
oil. IR (neat): ν = 3232, 1267, 1027 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 1.27 (t, J = 7.0 Hz, 3 H, CH3CH2O), 1.29 (t, J =
7.1 Hz, 3 H, CH3CH2O), 2.48–2.59 (m, 1 H, 4-H), 2.67–2.76 (m, 1
H, 4-H), 2.89 (ddd, J = 17.0, 11.4, 4.2 Hz, 1 H, 3-H), 3.92 (d, J =
16.3 Hz, 1 H, 1-H), 4.00–4.09 (m, 4 H, OCH2CH3), 4.12 (d, J =
16.3 Hz, 1 H, 1-H), 5.40 (d, J = 11.5 Hz, 1 H, NCH2O), 5.44 (d, J
= 11.5 Hz, 1 H, NCH2O), 7.09 (ddd, J = 8.1, 7.1, 0.5 Hz, 1 H,
Harom), 7.17 (ddd, J = 7.7, 7.1, 0.8 Hz, 1 H, Harom), 7.35 (dd, J =
7.7, 0.5 Hz, 1 H, Harom), 7.43 (dd, J = 8.1, 0.8 Hz, 1 H, Harom) ppm.
13C NMR (100 MHz, CDCl3): δ = 16.5 (d, J = 5.6 Hz, CH3CH2O),
16.6 (d, J = 5.7 Hz, CH3CH2O), 22.4 (C-4), 42.4 (d, J = 18.7 Hz,
C-1), 50.8 (d, J = 161.9 Hz, C-3), 62.6 (d, J = 6.9 Hz, OCH2CH3),
63.1 (d, J = 6.9 Hz, OCH2CH3), 66.5 (NCH2O), 107.7 (d, J =
16.4 Hz, Ar), 109.4 (Ar), 118.1 (Ar), 119.9 (Ar), 121.8 (Ar), 127.4
(d, J = 2.7 Hz, Ar), 133.2 (d, J = 2.6 Hz, Ar), 136.1 (Ar) ppm. 31P
NMR (162 MHz, CDCl3): δ = 27.01 ppm. HRMS (ESI): calculated
for C16H24N2O4P [M + H]+, m/z 339.1474; found for [M + H]+,
m/z 339.1472.
Diethyl cis- and trans-[1-(4-Bromophenyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indol-3-yl]phosphonate 4b: According to the general
procedure, a mixture of phosphotryptophan ethyl ester (7; 200 mg,
0.67 mmol), 4-bromobenzaldehyde (125 mg, 0.67 mmol), dry
CH2Cl2 (7 mL) and TFA (0.07 mL, 0.91 mmol) was reacted in the
presence of activated molecular sieves (4 Å, 70 mg) to give cis- and
trans-isomers 4b in a 62:38 ratio (calculated from the crude reaction
mixture).
General Procedure for the Preparation of Diethyl 1,2,3,4-Tetrahydro-
β-carboline-3-phosphonates 4a–h: To a stirred solution of phospho-
tryptophan ethyl ester (7; 200 mg, 0.67 mmol), a carbonyl com-
pound (aldehyde or ketone, 0.67 mmol) and activated molecular
sieves (4 Å, about 100 mg/mmol) in dry CH2Cl2 (7 mL), TFA
(0.07 mL, 0.91 mmol) were added. The reaction mixture was stirred
at room temperature and the progress was monitored by TLC
(CH2Cl2:iPrOH, 8:2). Upon completion of the reaction (3–4 h), the
volatiles were removed under reduced pressure and the crude mate-
rial was diluted with CH2Cl2 (20 mL), washed with satd. NaHCO3
solution, and the aqueous phase was further extracted with CH2Cl2
(2ϫ 10 mL). The organic extracts were combined and dried with
anhydrous MgSO4, filtered and the solvent was evaporated. The
residue was purified by column chromatography with CH2Cl2:
iPrOH (95:5) as eluent to provide pure cis- and trans-isomers 4a–e
as well as cyclization products 4g and 4h.
cis-4b: White solid (154 mg, 49%); m.p. 221–223 °C. IR (nujol): ν
˜
= 3193, 1226, 1024, 965 cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.38 (t, J = 7.1 Hz, 6 H, CH3CH2O), 2.10 (br. s, 1 H, NH), 2.97–
3.18 (m, 2 H, 4-H), 3.52 (ddd, J = 15.1, 10.6, 4.9 Hz, 1 H, 3-H),
4.15–4.29 (m, 4 H, OCH2CH3), 5.14 (s, 1 H, 1-H), 7.08–7.17 (m, 2
H, Harom), 7.18–7.25 (m, 3 H, Harom), 7.47 (d, J = 8.4 Hz, 2 H,
Harom), 7.53 (dd, J = 5.8, 3.1 Hz, 1 H, Harom), 7.58 (br. s, 1 H,
indole-NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.7 (d, J =
5.7 Hz, CH3CH2O), 23.1 (C-4), 51.9 (d, J = 159.7 Hz, C-3), 58.7
(d, J = 18.6 Hz, C-1), 62.8 (d, J = 6.8 Hz, OCH2CH3), 62.9 (d, J
= 6.6 Hz, OCH2CH3), 108.9 (d, J = 17.1 Hz, Ar), 111.1 (Ar), 118.4
(Ar), 119.8 (Ar), 122.2 (Ar), 122.6 (Ar), 127.1 (d, J = 2.5 Hz, Ar),
130.4 (Ar), 132.1 (Ar), 134.0 (d, J = 2.4 Hz, Ar), 136.1 (Ar), 140.0
(Ar) ppm. 31P NMR (121 MHz, CDCl3): δ = 26.04 ppm. HRMS
Diethyl cis- and trans-(1-Phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indol-3-yl)phosphonate (4a): According to the general procedure,
4
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43418
/KAP1
Date: 05-01-15 15:30:37
Pages: 9
Synthesis of 3-Phosphorylated β-Carbolines
(ESI): calculated for C21H25BrN2O3P [M + H]+, m/z 463.0786; (d, J = 2.3 Hz, Ar), 129.8 (Ar), 133.4 (d, J = 2.4 Hz, Ar), 133.8
found for [M + H]+, m/z 463.0784.
(Ar), 136.0 (Ar), 159.4 (Ar) ppm. 31P NMR (162 MHz, CDCl3): δ
= 27.26 ppm. HRMS (ESI): calculated for C22H28N2O4P [M +
H]+, m/z 415.1787; found for [M + H]+, m/z 415.1776.
trans-4b: White solid (101 mg, 32%); m.p. 206–208 °C. IR (nujol):
1
ν = 3165, 1242, 1021, 954 cm–1. H NMR (400 MHz, CDCl ): δ =
˜
3
Diethyl cis- and trans-(1-Methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indol-3-yl)phosphonate (4d): According to the general procedure,
1.24 (t, J = 7.0 Hz, 3 H, CH3CH2O), 1.25 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 2.16 (br. s, 1 H, NH), 2.94–3.06 (m, 2 H, 4-H), 3.25
(ddd, J = 17.1, 9.2, 6.3 Hz, 1 H, 3-H), 3.96–4.16 (m, 4 H,
OCH2CH3), 5.16 (s, 1 H, 1-H), 7.04 (d, J = 8.4 Hz, 2 H, Harom),
7.13 (ddd, J = 7.7, 7.7, 1.3 Hz, 1 H, Harom), 7.18 (ddd, J = 7.7, 7.7,
1.3 Hz, 1 H, Harom), 7.28 (dd, J = 7.7, 1.3 Hz, 1 H, Harom), 7.37
(d, J = 8.4 Hz, 2 H, Harom), 7.54 (dd, J = 7.7, 1.3 Hz, 1 H, Harom),
8.34 (br. s, 1 H, indole-NH) ppm. 13C NMR (75 MHz, CDCl3): δ
= 16.4 (d, J = 5.8 Hz, CH3CH2O), 16.5 (d, J = 5.9 Hz, CH3CH2O),
22.7 (C-4), 45.7 (d, J = 160.3 Hz, C-3), 54.6 (d, J = 16.4 Hz, C-1),
62.3 (d, J = 6.8 Hz, OCH2CH3), 62.8 (d, J = 6.8 Hz, OCH2CH3),
109.0 (d, J = 14.7 Hz, Ar), 111.1 (Ar), 118.4 (Ar), 119.7 (Ar), 121.9
(Ar), 122.3 (Ar), 126.9 (d, J = 2.3 Hz, Ar), 130.3 (Ar), 131.5 (Ar),
132.5 (d, J = 2.5 Hz, Ar), 136.1 (Ar), 140.7 (Ar) ppm. 31P NMR
(162 MHz, CDCl3): δ = 26.78 ppm. HRMS (ESI): calculated for
C21H25BrN2O3P [M + H]+, m/z 463.0786; found for [M + H]+, m/z
463.0776.
a
mixture of phosphotryptophan ethyl ester (7; 200 mg,
0.67 mmol), acetaldehyde (31 mg, 0.04 mL, 0.70 mmol), dry
CH2Cl2 (7 mL) and TFA (0.07 mL, 0.91 mmol) was reacted in the
presence of activated molecular sieves (4 Å, 70 mg) to give cis- and
trans-isomers 4d in a 78:22 ratio (calculated from the crude reaction
mixture).
cis-4d: Brown oil (98 mg, 45%). IR (neat): ν = 3254, 1228, 1027,
˜
1
966 cm–1. H NMR (400 MHz, CDCl3): δ = 1.39 (t, J = 7.1 Hz, 3
H, CH3CH2O), 1.39 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.48 (d, J =
6.7 Hz, 3 H, CH3CH), 1.76 (br. s, 1 H, NH), 2.89–3.01 (m, 2 H, 4-
H), 3.39 (ddd, J = 17.1, 9.7, 6.3 Hz, 1 H, 3-H), 4.17–4.31 (m, 5 H,
1-H, OCH2CH3), 7.10 (ddd, J = 7.8, 7.8, 1.0 Hz, 1 H, Harom), 7.15
(ddd, J = 7.8, 7.8, 1.0 Hz, 1 H, Harom), 7.33 (dd, J = 7.8, 1.0 Hz,
1 H, Harom), 7.48 (dd, J = 7.8, 1.0 Hz, 1 H, Harom), 8.24 (br. s, 1
H, indole-NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.5 (d, J
= 5.6 Hz, CH3CH2O), 16.6 (d, J = 5.5 Hz, CH3CH2O), 20.3
(CH3CH), 23.2 (C-4), 49.3 (d, J = 18.3 Hz, C-1), 51.6 (d, J =
161.6 Hz, C-3), 62.5 (d, J = 6.8 Hz, OCH2CH3), 62.7 (d, J =
6.8 Hz, OCH2CH3), 107.2 (d, J = 16.9 Hz, Ar), 110.9 (Ar), 118.0
(Ar), 119.5 (Ar), 121.7 (Ar), 127.2 (d, J = 2.9 Hz, Ar), 135.7 (Ar),
136.7 (d, J = 2.6 Hz, Ar) ppm. 31P NMR (162 MHz, CDCl3): δ =
26.66 ppm. HRMS (ESI): calculated for C16H24N2O3P [M + H]+,
m/z 323.1525; found for [M + H]+, m/z 323.1512.
Diethyl cis- and trans-[1-(4-Methoxyphenyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indol-3-yl]phosphonate (4c): According to the general
procedure, a mixture of phosphotryptophan ethyl ester (7; 200 mg,
0.67 mmol), p-anisaldehyde (92 mg, 0.08 mL, 0.67 mmol), dry
CH2Cl2 (7 mL) and TFA (0.07 mL, 0.91 mmol) was reacted in the
presence of activated molecular sieves (4 Å, 70 mg) to give cis- and
trans-isomers 4c in a 94:06 ratio (calculated from the crude reaction
mixture).
trans-4d: Brown oil (49 mg, 23%). IR (neat): ν = 3252, 1230, 1028,
˜
cis-4c: White solid (180 mg, 64%); m.p. 184–186 °C. IR (nujol): ν
˜
1
966 cm–1. H NMR (400 MHz, CDCl3): δ = 1.36 (t, J = 7.1 Hz, 3
= 3227, 1248, 1028, 966 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.40 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.40 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 2.05 (br. s, 1 H, NH), 3.02–3.18 (m, 2 H, 4-H), 3.55
(ddd, J = 15.5, 10.7, 5.0 Hz, 1 H, 3-H), 3.81 (s, 3 H, CH3O), 4.19–
4.31 (m, 4 H, OCH2CH3), 5.13 (s, 1 H, 1-H), 6.89 (d, J = 8.6 Hz,
2 H, Harom), 7.10–7.17 (m, 2 H, Harom), 7.19–7.24 (m, 1 H, Harom),
7.27 (d, J = 8.6 Hz, 2 H, Harom), 7.55 (dd, J = 5.9, 3.1 Hz, 1 H,
H, CH3CH2O), 1.37 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.46 (d, J =
6.9 Hz, 3 H, CH3CH), 2.02 (br. s, 1 H, NH), 2.86–3.04 (m, 2 H, 4-
H), 3.50 (ddd, J = 17.6, 10.4, 4.8 Hz, 1 H, 3-H), 4.16–4.26 (m, 4
H, OCH2CH3), 4.29 (q, J = 6.9 Hz, 1 H, 1-H), 7.10 (ddd, J = 7.7,
7.7, 1.1 Hz, 1 H, Harom), 7.15 (ddd, J = 7.7, 7.7, 1.1 Hz, 1 H,
Harom), 7.31 (dd, J = 7.7, 1.1 Hz, 1 H, Harom), 7.48 (dd, J = 7.7,
1.1 Hz, 1 H, Harom), 7.90 (br. s, 1 H, indole-NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.7 (d, J = 5.2 Hz, CH3CH2O), 21.5
(CH3CH), 23.0 (C-4), 46.3 (d, J = 160.4 Hz, C-3), 46.9 (d, J =
16.1 Hz, C-1), 62.4 (d, J = 6.8 Hz, OCH2CH3), 62.8 (d, J = 6.8 Hz,
OCH2CH3), 107.0 (d, J = 15.0 Hz, Ar), 110.9 (Ar), 118.2 (Ar),
119.7 (Ar), 121.9 (Ar), 127.2 (d, J = 2.4 Hz, Ar), 135.8 (Ar), 136.8
(Ar) ppm. 31P NMR (162 MHz, CDCl3): δ = 27.28 ppm. HRMS
(ESI): calculated for C16H24N2O3P [M + H]+, m/z 323.1525; found
for [M + H]+, m/z 323.1515.
H
arom), 7.63 (br. s, 1 H, indole-NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 16.6 (d, J = 5.6 Hz, CH3CH2O), 23.1 (C-4), 51.9 (d,
J = 159.6 Hz, C-3), 55.3 (CH3O), 58.5 (d, J = 18.5 Hz, C-1), 62.6
(d, J = 6.7 Hz, OCH2CH3), 62.7 (d, J = 6.6 Hz, OCH2CH3), 108.5
(d, J = 17.2 Hz, Ar), 111.0 (Ar), 114.2 (Ar), 118.1 (Ar), 119.5 (Ar),
121.8 (Ar), 127.1 (d, J = 2.6 Hz, Ar), 129.8 (Ar), 133.0 (Ar), 135.0
(d, J = 2.5 Hz, Ar), 136.0 (Ar), 159.7 (Ar) ppm. 31P NMR
(162 MHz, CDCl3): δ = 26.42 ppm. HRMS (ESI): calculated for
C22H28N2O4P [M + H]+, m/z 415.1787; found for [M + H]+, m/z
415.1782.
Diethyl cis- and trans-(1-Isopropyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-
b]indol-3-yl)phosphonate (4e): According to the general procedure, a
mixture of phosphotryptophan ethyl ester (7; 200 mg, 0.67 mmol),
isobutyraldehyde (49 mg, 62 μL, 0.68 mmol), dry CH2Cl2 (7 mL)
and TFA (0.07 mL, 0.91 mmol) was reacted in the presence of acti-
vated molecular sieves (4 Å, 70 mg) to give cis- and trans-isomers
4e in a 68:32 ratio (calculated from the crude reaction mixture).
trans-4c: Yellow solid (22 mg, 8%); m.p. 179–181 °C. IR (neat): ν
˜
= 3227, 1245, 1029, 967 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.23 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.26 (t, J = 7.1 Hz, 3 H,
CH3CH2O), 1.84 (br. s, 1 H, NH), 2.98–3.12 (m, 2 H, 4-H), 3.38
(ddd, J = 16.3, 9.5, 5.7 Hz, 1 H, 3-H), 3.77 (s, 3 H, CH3O), 4.01–
4.16 (m, 4 H, OCH2CH3), 5.24 (s, 1 H, 1-H), 6.81 (d, J = 8.7 Hz,
2 H, Harom), 7.11 (d, J = 8.7 Hz, 2 H, Harom), 7.13 (ddd, J = 7.7, cis-4e: Pale yellow oil (131 mg, 55%). IR (nujol): ν = 3219, 1247,
˜
7.7, 1.1 Hz, 1 H, Harom), 7.18 (ddd, J = 7.7, 7.7, 1.1 Hz, 1 H,
Harom), 7.28 (dd, J = 7.7, 1.1 Hz, 1 H, Harom), 7.55 (dd, J = 7.7,
1034, 968 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.84 [d, J =
6.9 Hz, 3 H, (CH3)2CH], 1.13 [d, J = 6.8 Hz, 3 H, (CH3)2CH], 1.39
1.1 Hz, 1 H, Harom), 7.82 (br. s, 1 H, indole-NH) ppm. 13C NMR (t, J = 7.1 Hz, 6 H, CH3CH2O), 1.65 (br. s, 1 H, NH), 2.20–2.30
(75 MHz, CDCl3): δ = 16.5 (d, J = 6.7 Hz, CH3CH2O), 16.6 (d, J
[m, 1 H, CH(CH3)2], 2.85–3.00 (m, 2 H, 4-H), 3.33 (ddd, J = 15.3,
= 6.2 Hz, CH3CH2O), 22.7 (C-4), 45.7 (d, J = 159.2 Hz, C-3), 54.8 10.2, 5.4 Hz, 1 H, 3-H), 4.10 (d, J = 1.8 Hz, 1 H, 1-H), 4.18–4.35
(d, J = 16.0 Hz, C-1), 55.4 (CH3O), 62.3 (d, J = 6.6 Hz, (m, 4 H, OCH2CH3), 7.10 (ddd, J = 7.6, 7.6, 1.1 Hz, 1 H, Harom),
OCH2CH3), 62.7 (d, J = 6.8 Hz, OCH2CH3), 109.1 (d, J = 14.8 Hz,
Ar), 111.0 (Ar), 113.9 (Ar), 118.4 (Ar), 119.7 (Ar), 122.2 (Ar), 127.1
7.15 (ddd, J = 7.6, 7.6, 1.1 Hz, 1 H, Harom), 7.34 (dd, J = 7.6,
1.1 Hz, 1 H, Harom), 7.49 (dd, J = 7.6, 1.1 Hz, 1 H, Harom), 8.18
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O43418
/KAP1
Date: 05-01-15 15:30:37
Pages: 9
J. L. Viveros-Ceballos, F. J. Sayago, C. Cativiela, M. Ordóñez
FULL PAPER
(br. s, 1 H, indole-NH) ppm. 13C NMR (100 MHz, CDCl3): δ = H, CH3CH2O), 1.49–2.01 (m, 10 H, NH, CH2), 2.85–2.99 (m, 2 H,
16.4 [(CH3)2CH], 16.6 (d, J = 5.7 Hz, CH3CH2O), 16.7 (d, J = 4-H), 3.40 (ddd, J = 19.3, 10.7, 5.3 Hz, 1 H, 3-H), 4.20–4.30 (m, 2
5.6 Hz, CH3CH2O), 19.2 [(CH3)2CH], 23.3 (C-4), 31.7 [CH(CH3) H, OCH2CH3), 4.30–4.40 (m, 2 H, OCH2CH3), 7.09 (ddd, J = 7.5,
2], 51.5 (d, J = 160.5 Hz, C-3), 58.6 (d, J = 17.4 Hz, C-1), 62.7 (d,
J = 6.7 Hz, OCH2CH3), 62.9 (d, J = 6.7 Hz, OCH2CH3), 109.0 (d,
J = 17.1 Hz, Ar), 110.9 (Ar), 118.0 (Ar), 119.5 (Ar), 121.7 (Ar),
127.3 (d, J = 2.8 Hz, Ar), 135.2 (d, J = 2.4 Hz, Ar), 136.0 (Ar) ppm.
31P NMR (162 MHz, CDCl3): δ = 26.82 ppm. HRMS (ESI): calcu-
lated for C18H28N2O3P [M + H]+, m/z 351.1838; found for [M +
H]+, m/z 351.1830.
7.5, 1.1 Hz, 1 H, Harom), 7.15 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H,
arom), 7.33 (dd, J = 7.5, 1.1 Hz, 1 H, Harom), 7.48 (dd, J = 7.5,
H
1.1 Hz, 1 H, Harom), 8.20 (br. s, 1 H, indole-NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.7 (d, J = 5.9 Hz, CH3CH2O), 16.8 (d,
J = 5.8 Hz, CH3CH2O), 21.2 (CH2), 21.5 (CH2), 23.5 (d, J =
1.7 Hz, C-4), 26.0 (CH2), 34.9 (CH2), 38.6 (CH2), 47.0 (d, J =
163.0 Hz, C-3), 53.1 (d, J = 16.7 Hz, C-1), 62.1 (d, J = 7.0 Hz,
OCH2CH3), 63.4 (d, J = 6.7 Hz, OCH2CH3), 106.7 (d, J = 16.8 Hz,
Ar), 110.9 (Ar), 118.2 (Ar), 119.5 (Ar), 121.7 (Ar), 127.3 (d, J =
3.1 Hz, Ar), 135.5 (Ar), 141.0 (d, J = 2.9 Hz, Ar) ppm. 31P NMR
(162 MHz, CDCl3): δ = 27.52 ppm. HRMS (ESI): calculated for
C20H30N2O3P [M + H]+, m/z 377.1994; found for [M + H]+, m/z
377.1979.
trans-4e: Brown solid (66 mg, 28%); m.p. 148–150 °C. IR (nujol):
1
ν = 3219, 1227, 1027, 965 cm–1. H NMR (400 MHz, CDCl ): δ =
˜
3
1.03 [d, J = 6.7 Hz, 3 H, (CH3)2CH], 1.13 [d, J = 6.7 Hz, 3 H,
(CH3)2CH], 1.35 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.37 (t, J =
7.1 Hz, 3 H, CH3CH2O), 1.93 (br. s, 1 H, NH), 2.04 [dhept, J =
6.8, 6.7 Hz, 1 H, CH(CH3)2], 2.86–3.04 (m, 2 H, 4-H), 3.52 (ddd,
J = 17.9, 10.1, 5.2 Hz, 1 H, 3-H), 3.73 (d, J = 6.8 Hz, 1 H, 1-H),
4.15–4.29 (m, 4 H, OCH2CH3), 7.09 (ddd, J = 7.8, 7.8, 1.2 Hz, 1
General Procedure for the Preparation of Diethyl β-Carboline-3-
phosphonates 5 and 6a–f: To a stirred solution of crude 1,2,3,4-
H, Harom), 7.15 (ddd, J = 7.8, 7.8, 1.2 Hz, 1 H, Harom), 7.32 (dd, J tetrahydro-β-carboline-3-phosphonate 3 and 4a–f, obtained as de-
= 7.8, 1.2 Hz, 1 H, Harom), 7.49 (dd, J = 7.8, 1.2 Hz, 1 H, Harom), scribed above, and TEA (136 mg, 0.19 mL, 1.34 mmol) in dry
8.05 (br. s, 1 H, indole-NH) ppm. 13C NMR (100 MHz, CDCl3): δ
DMF (4 mL) at –10 °C under an argon atmosphere, a solution of
= 16.6 (d, J = 6.0 Hz, CH3CH2O), 16.7 (d, J = 5.8 Hz, CH3CH2O), trichloroisocyanuric acid (TCCA, 157 mg, 0.67 mmol) in dry DMF
19.5 [(CH3)2CH], 20.5 [(CH3)2CH], 22.9 (C-4), 33.1 [CH(CH3)2],
47.6 (d, J = 159.3 Hz, C-3), 57.2 (d, J = 15.1 Hz, C-1), 62.2 (d, J
= 6.9 Hz, OCH2CH3), 62.9 (d, J = 6.7 Hz, OCH2CH3), 107.9 (d, J
= 14.8 Hz, Ar), 110.8 (Ar), 118.1 (Ar), 119.5 (Ar), 121.8 (Ar), 127.1
(1 mL) was slowly added. The mixture was stirred at 0 °C for 2 h
and the progress was monitored by TLC (CH2Cl2:iPrOH, 95:5).
Upon completion of the reaction (2–3 h), the reaction mixture was
diluted with AcOEt and washed with satd. solution of NaCl. The
(d, J = 2.4 Hz, Ar), 135.3 (d, J = 2.5 Hz, Ar), 135.7 (Ar) ppm. 31P organic layer was dried with anhydrous MgSO4, filtered and the
NMR (162 MHz, CDCl3): δ = 27.70 ppm. HRMS (ESI): calculated
for C18H28N2O3P [M + H]+, m/z 351.1838; found for [M + H]+,
m/z 351.1830.
solvent was evaporated. The residue was purified by column
chromatography with CH2Cl2:iPrOH (97:3) as eluent to provide
oxidation products 5 and 6a–f, respectively.
Diethyl (1,1-Dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-3- Diethyl 9H-Pyrido[3,4-b]indol-3-ylphosphonate (5): According to
yl)phosphonate (4g): According to the general procedure, a mixture
of phosphotryptophan ethyl ester (7; 200 mg, 0.67 mmol), acetone
the general procedure, a mixture of the crude 3, TEA (136 mg,
0.19 mL, 1.34 mmol), dry DMF (4 mL) and a solution of trichloro-
(40 mg, 0.05 mL, 0.68 mmol), dry CH2Cl2 (7 mL) and TFA isocyanuric acid (TCCA, 157 mg, 0.67 mmol) was reacted to afford
(0.07 mL, 0.91 mmol) was reacted in the presence of activated mo-
5 (171 mg, 83%) as a yellow oil. IR (neat): ν = 1249, 1025,
˜
1
lecular sieves (4 Å, 70 mg), affording 4g as a white solid (171 mg,
968 cm–1. H NMR (400 MHz, CDCl3): δ = 1.31 (t, J = 7.1 Hz, 6
75%); m.p. 156–158 °C. IR (nujol): ν = 3251, 1220, 1027, 955 cm–1.
H, CH3CH2O), 4.15–4.31 (m, 4 H, OCH2CH3), 7.29 (ddd, J = 8.0,
7.1, 0.9 Hz, 1 H, Harom), 7.53 (ddd, J = 8.3, 7.1, 1.2 Hz, 1 H,
˜
1H NMR (400 MHz, CDCl3): δ = 1.40 (t, J = 7.0 Hz, 3 H,
CH3CH2O), 1.40 (t, J = 7.0 Hz, 3 H, CH3CH2O), 1.45 (s, 3 H, Harom), 7.64 (dd, J = 8.3, 0.9 Hz, 1 H, Harom), 8.08 (dd, J = 8.0,
CH3), 1.51 (s, 3 H, CH3), 1.62 (br. s, 1 H, NH), 2.84–3.01 (m, 2 H, 1.2 Hz, 1 H, Harom), 8.71 (d, J = 7.5 Hz, 1 H, Harom), 9.11 (s, 1 H,
4-H), 3.49 (ddd, J = 18.9, 11.4, 4.5 Hz, 1 H, 3-H), 4.18–4.38 (m, 4 Harom), 10.78 (br. s, 1 H, indole-NH) ppm. 13C NMR (100 MHz,
H, OCH2CH3), 7.09 (ddd, J = 7.6, 7.6, 1.0 Hz, 1 H, Harom), 7.15
(ddd, J = 7.6, 7.6, 1.0 Hz, 1 H, Harom), 7.33 (dd, J = 7.6, 1.0 Hz,
1 H, Harom), 7.47 (dd, J = 7.6, 1.0 Hz, 1 H, Harom), 8.26 (br. s, 1
H, indole-NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.7 (d, J
CDCl3): δ = 16.5 (d, J = 6.2 Hz, CH3CH2O), 62.9 (d, J = 5.7 Hz,
OCH2CH3), 112.5 (Ar), 120.7 (Ar), 121.1 (d, J = 27.6 Hz, Ar),
121.2 (d, J = 2.4 Hz, Ar), 121.9 (Ar), 127.8 (d, J = 15.1 Hz, Ar),
128.9 (Ar), 135.5 (d, J = 25.4 Hz, Ar), 137.3 (d, J = 3.5 Hz, Ar),
= 5.8 Hz, CH3CH2O), 23.6 (C-4), 28.3 (CH3), 29.6 (CH3), 47.6 (d, 138.1 (d, J = 234.0 Hz, Ar), 141.1 (Ar) ppm. 31P NMR (162 MHz,
J = 162.1 Hz, C-3), 51.4 (d, J = 17.3 Hz, C-1), 62.4 (d, J = 6.8 Hz, CDCl3): δ = 14.90 ppm. HRMS (ESI): calculated for C15H18N2O3P
OCH2CH3), 63.0 (d, J = 6.7 Hz, OCH2CH3), 106.2 (d, J = 16.8 Hz,
Ar), 110.9 (Ar), 118.3 (Ar), 119.5 (Ar), 121.8 (Ar), 127.2 (d, J =
3.0 Hz, Ar), 135.7 (Ar), 140.3 (d, J = 2.8 Hz, Ar) ppm. 31P NMR
(162 MHz, CDCl3): δ = 27.08 ppm. HRMS (ESI): calculated for
C17H26N2O3P [M + H]+, m/z 337.1681; found for [M + H]+, m/z
337.1680.
[M + H]+, m/z 305.1055; found for [M + H]+, m/z 305.1056.
Diethyl (1-Phenyl-9H-pyrido[3,4-b]indol-3-yl)phosphonate (6a):
According to the general procedure, a mixture of the crude 4a,
TEA (136 mg, 0.19 mL, 1.34 mmol), dry DMF (4 mL) and a solu-
tion of trichloroisocyanuric acid (TCCA, 157 mg, 0.67 mmol) was
reacted to afford 6a as a colourless oil (163 mg, 63%). IR (KBr):
1
Diethyl (2Ј,3Ј,4Ј,9Ј-Tetrahydrospiro[cyclohexane-1,1Ј-pyrido[3,4-b]-
indol]-3Ј-yl)phosphonate (4h): According to the general procedure, a
mixture of phosphotryptophan ethyl ester (7; 200 mg, 0.67 mmol),
cyclohexanone (66 mg, 0.07 mL, 0.67 mmol), dry CH2Cl2 (7 mL)
and TFA (0.07 mL, 0.91 mmol) was reacted in the presence of acti-
vated molecular sieves (4 Å, 70 mg), affording 4h as a white solid
ν = 1242, 1026, 966 cm–1. H NMR (400 MHz, CDCl ): δ = 1.34
˜
3
(t, J = 7.1 Hz, 6 H, CH3CH2O), 4.17–4.33 (m, 4 H, OCH2CH3),
7.32 (ddd, J = 7.9, 7.2, 1.0 Hz, 1 H, Harom), 7.37 (tt, J = 7.4, 1.3 Hz,
1 H, Harom), 7.46 (dd, J = 7.4, 7.1 Hz, 2 H, Harom), 7.53 (ddd, J =
8.2, 7.2, 1.1 Hz, 1 H, Harom), 7.64 (dd, J = 8.2, 1.0 Hz, 1 H, Harom),
7.94 (dd, J = 7.1, 1.3 Hz, 2 H, Harom), 8.11 (dd, J = 7.9, 1.1 Hz, 1
(176 mg, 69%); m.p. 175–177 °C. IR (nujol): ν = 3248, 1220, 1028, H, Harom), 8.63 (d, J = 7.2 Hz, 1 H, Harom), 9.63 (br. s, 1 H, indole-
˜
966 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.24–1.36 (m, 1 H,
CH2), 1.40 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.41 (t, J = 7.1 Hz, 3
NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.6 (d, J = 6.3 Hz,
CH3CH2O), 63.0 (d, J = 5.9 Hz, OCH2CH3), 112.3 (Ar), 120.2 (d,
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43418
/KAP1
Date: 05-01-15 15:30:37
Pages: 9
Synthesis of 3-Phosphorylated β-Carbolines
J = 27.8 Hz, Ar), 121.0 (Ar), 121.8 (d, J = 2.5 Hz, Ar), 121.9 (Ar), 234.0 Hz, Ar), 140.7 (Ar), 144.2 (d, J = 25.3 Hz, Ar) ppm. 31P
128.5 (Ar), 128.8 (Ar), 128.9 (Ar), 129.0 (Ar), 129.1 (Ar), 134.5 (d, NMR (162 MHz, CDCl3): δ = 15.22 ppm. HRMS (ESI): calculated
J = 3.6 Hz, Ar), 137.9 (Ar), 139.4 (d, J = 232.7 Hz, Ar), 140.7 (Ar), for C16H20N2O3P [M + H]+, m/z 319.1212; found for [M + H]+,
144.0 (d, J = 25.2 Hz, Ar) ppm. 31P NMR (162 MHz, CDCl3): δ =
14.04 ppm. HRMS (ESI): calculated for C21H22N2O3P [M + H]+,
m/z 381.1368; found for [M + H]+, m/z 381.1372.
m/z 319.1204.
Diethyl (1-Isopropyl-9H-pyrido[3,4-b]indol-3-yl)phosphonate (6e):
According to the general procedure, a mixture of the crude 4e, TEA
(136 mg, 0.19 mL, 1.34 mmol), dry DMF (4 mL) and a solution of
trichloroisocyanuric acid (TCCA, 157 mg, 0.67 mmol) was reacted
Diethyl [1-(4-Bromophenyl)-9H-pyrido[3,4-b]indol-3-yl]phosphonate
(6b): According to the general procedure, a mixture of the crude
4b, TEA (136 mg, 0.19 mL, 1.34 mmol), dry DMF (4 mL) and a
solution of trichloroisocyanuric acid (TCCA, 157 mg, 0.67 mmol)
to afford 6e as a white solid (91 mg, 39%); m.p. 179–181 °C. IR
(nujol): ν = 1230, 1037, 965 cm–1. H NMR (400 MHz, CDCl ): δ
1
˜
3
= 1.37 (t, J = 7.1 Hz, 6 H, CH3CH2O), 1.41 [d, J = 6.8 Hz, 6 H,
(CH3)2CH], 3.72 [hept, J = 6.8 Hz, 1 H, CH(CH3)2], 4.23–4.40 (m,
4 H, OCH2CH3), 7.28 (ddd, J = 7.9, 7.2, 0.9 Hz, 1 H, Harom), 7.52
(ddd, J = 8.2, 7.2, 0.9 Hz, 1 H, Harom), 7.69 (dd, J = 8.2, 0.9 Hz,
1 H, Harom), 8.04 (dd, J = 7.9, 0.9 Hz, 1 H, Harom), 8.61 (d, J =
7.3 Hz, 1 H, Harom), 10.53 (br. s, 1 H, indole-NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.5 (d, J = 6.3 Hz, CH3CH2O), 21.5
[(CH3)2CH], 31.9 [CH(CH3)2], 63.2 (d, J = 6.0 Hz, OCH2CH3),
112.4 (Ar), 119.5 (d, J = 28.1 Hz, Ar), 120.4 (Ar), 121.5 (Ar), 121.9
(d, J = 2.6 Hz, Ar), 127.3 (d, J = 15.4 Hz, Ar), 128.3 (Ar), 134.7
(d, J = 3.6 Hz, Ar), 137.7 (d, J = 231.8 Hz, Ar), 140.6 (Ar), 152.1
(d, J = 24.2 Hz, Ar) ppm. 31P NMR (162 MHz, CDCl3): δ =
14.36 ppm. HRMS (ESI): calculated for C18H24N2O3P [M + H]+,
m/z 347.1525; found for [M + H]+, m/z 347.1539.
was reacted to afford 6b as a white solid (236 mg, 76%); m.p. 206–
1
208 °C. IR (nujol): ν = 1213, 1024, 945 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 1.36 (t, J = 7.1 Hz, 6 H, CH3CH2O), 4.18–4.34 (m, 4
H, OCH2CH3), 7.33 (ddd, J = 8.0, 7.2, 0.9 Hz, 1 H, Harom), 7.46
(d, J = 8.6 Hz, 2 H, Harom), 7.54 (ddd, J = 8.2, 7.2, 1.1 Hz, 1 H,
H
arom), 7.66 (dd, J = 8.2, 0.9 Hz, 1 H, Harom), 7.72 (d, J = 8.6 Hz,
2 H, Harom), 8.09 (dd, J = 8.0, 1.1 Hz, 1 H, Harom), 8.54 (d, J =
7.1 Hz, 1 H, Harom), 9.79 (br. s, 1 H, indole-NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.6 (d, J = 6.3 Hz, CH3CH2O), 63.1 (d,
J = 6.0 Hz, OCH2CH3), 112.4 (Ar), 120.0 (d, J = 27.6 Hz, Ar),
121.1 (Ar), 121.8 (d, J = 2.4 Hz, Ar), 121.9 (Ar), 123.3 (Ar), 129.0
(Ar), 129.2 (d, J = 14.9 Hz, Ar), 129.9 (Ar), 132.0 (Ar), 134.3 (d,
J = 3.6 Hz, Ar), 136.6 (Ar), 139.4 (d, J = 233.9 Hz, Ar), 140.9 (Ar),
142.6 (d, J = 25.4 Hz, Ar) ppm. 31P NMR (162 MHz, CDCl3): δ =
13.71 ppm. HRMS (ESI): calculated for C21H21BrN2O3P [M +
H]+, m/z 459.0473; found for [M + H]+, m/z 459.0467.
Ethyl 3-(Diethoxyphosphoryl)-9H-pyrido[3,4-b]indole-1-carboxylate
(6f): To a stirred solution of phosphotryptophan ethyl ester (7;
200 mg, 0.67 mmol) was added ethyl glyoxylate (70 mg, 0.14 mL,
0.68 mmol, 50% solution in toluene), activated molecular sieves
(4 Å, 70 mg) in dry CH2Cl2 (7 mL), and TFA (0.07 mL,
0.91 mmol). The reaction mixture was stirred at room temperature
and the progress was monitored by TLC (CH2Cl2:iPrOH, 8:2).
Upon completion of the reaction (4 h), volatiles were removed un-
der reduced pressure and the crude material was diluted with
CH2Cl2 (20 mL), washed with satd. NaHCO3, and the aqueous
phase further extracted with CH2Cl2 (2ϫ 10 mL). The organic ex-
tracts were combined and dried with anhydrous MgSO4, filtered
and the solvent was evaporated to obtain 4f, which due to its pro-
pensity to oxidize, was used without isolation in the following step.
According to the general procedure, a mixture of the crude 4f, TEA
(136 mg, 0.19 mL, 1.34 mmol), dry DMF (4 mL) and a solution of
trichloroisocyanuric acid (TCCA, 157 mg, 0.67 mmol) was reacted
to afford 6f as a yellow solid (213 mg, 84%); m.p. 157–159 °C. IR
Diethyl [1-(4-Methoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl]phosphon-
ate (6c): According to the general procedure, a mixture of the crude
4c, TEA (136 mg, 0.19 mL, 1.34 mmol), dry DMF (4 mL) and a
solution of trichloroisocyanuric acid (TCCA, 157 mg, 0.67 mmol)
was reacted to afford 6c as a pale yellow solid (157 mg, 57%); m.p.
148–150 °C. IR (nujol): ν = 1245, 1021, 946 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 1.33 (t, J = 7.1 Hz, 6 H, CH3CH2O), 3.67
(s, 3 H, CH3O), 4.16–4.33 (m, 4 H, OCH2CH3), 6.84 (d, J = 8.8 Hz,
2 H, Harom), 7.30 (ddd, J = 7.9, 7.2, 0.9 Hz, 1 H, Harom), 7.52 (ddd,
J = 8.3, 7.2, 1.1 Hz, 1 H, Harom), 7.69 (dd, J = 8.3, 0.9 Hz, 1 H,
Harom), 7.83 (d, J = 8.8 Hz, 2 H, Harom), 8.07 (dd, J = 7.9, 1.1 Hz,
1 H, Harom), 8.55 (d, J = 7.3 Hz, 1 H, Harom), 9.89 (br. s, 1 H,
indole-NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.5 (d, J =
6.3 Hz, CH3CH2O), 55.3 (CH3O), 62.9 (d, J = 5.9 Hz, OCH2CH3),
112.4 (Ar), 114.1 (Ar), 119.6 (d, J = 27.9 Hz, Ar), 120.8 (Ar), 121.7
(Ar), 121.8 (d, J = 2.5 Hz, Ar), 128.6 (Ar), 128.7 (d, J = 15.2 Hz,
Ar), 129.7 (Ar), 130.3 (Ar), 134.3 (d, J = 3.6 Hz, Ar), 138.9 (d, J
= 232.9 Hz, Ar), 140.8 (Ar), 143.9 (d, J = 25.2 Hz, Ar), 160.2
(Ar) ppm. 31P NMR (162 MHz, CDCl3): δ = 14.27 ppm. HRMS
(ESI): calculated for C22H24N2O4P [M + H]+, m/z 411.1474; found
for [M + H]+, m/z 411.1484.
(nujol): ν = 1703, 1228, 1031, 974 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 1.39 [t, J = 7.1 Hz, 6 H, (CH3CH2O)2P(O)], 1.46 [t, J
=
7.1 Hz,
3
H, CH3CH2OC(O)], 4.24–4.40 [m,
4
H,
P(O)(OCH2CH3)2], 4.53 [q, J = 7.1 Hz, 2 H, C(O)OCH2CH3], 7.36
(ddd, J = 7.9, 6.4, 1.8 Hz, 1 H, Harom), 7.58–7.64 (m, 2 H, Harom),
8.14 (dd, J = 7.9, 0.8 Hz, 1 H, Harom), 8.82 (d, J = 6.5 Hz, 1 H,
Harom), 10.20 (br. s, 1 H, indole-NH) ppm. 13C NMR (100 MHz,
Diethyl (1-Methyl-9H-pyrido[3,4-b]indol-3-yl)phosphonate (6d):
According to the general procedure, a mixture of the crude 4d,
TEA (136 mg, 0.19 mL, 1.34 mmol), dry DMF (4 mL) and a solu-
tion of trichloroisocyanuric acid (TCCA, 157 mg, 0.67 mmol) was
CDCl3):
δ = 14.4 [CH3CH2OC(O)], 16.5 [d, J = 6.2 Hz,
(CH3CH2O)2P(O)], 62.0 [C(O)OCH2CH3], 63.3 [d, J = 6.1 Hz,
P(O)(OCH2CH3)2], 112.3 (Ar), 121.0 (d, J = 2.4 Hz, Ar), 121.5
(Ar), 122.2 (Ar), 123.6 (d, J = 28.1 Hz, Ar), 129.9 (Ar), 130.8 (d,
J = 14.0 Hz, Ar), 131.0 (d, J = 25.2 Hz, Ar), 137.5 (d, J = 3.3 Hz,
reacted to afford 6d as a yellow oil (41 mg, 19%). IR (nujol): ν =
˜
1
1236, 1042, 969 cm–1. H NMR (400 MHz, CDCl3): δ = 1.34 (t, J
Ar), 139.8 (d, J = 234.1 Hz, Ar), 140.8 (Ar), 166.6 (C=O) ppm. 31
P
= 7.1 Hz, 6 H, CH3CH2O), 2.81 (s, 3 H, CH3), 4.16–4.32 (m, 4 H,
OCH2CH3), 7.27 (ddd, J = 8.0, 7.2, 0.9 Hz, 1 H, Harom), 7.50 (ddd,
J = 8.3, 7.2, 1.1 Hz, 1 H, Harom), 7.62 (dd, J = 8.3, 0.9 Hz, 1 H,
Harom), 8.02 (dd, J = 8.0, 1.1 Hz, 1 H, Harom), 8.54 (d, J = 7.7 Hz,
1 H, Harom), 10.44 (br. s, 1 H, indole-NH) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.5 (d, J = 6.3 Hz, CH3CH2O), 20.6
(CH3), 62.8 (d, J = 5.8 Hz, OCH2CH3), 112.4 (Ar), 119.6 (d, J =
27.6 Hz, Ar), 120.6 (Ar), 121.8 (Ar), 121.9 (Ar), 126.8 (d, J =
NMR (162 MHz, CDCl3): δ = 12.53 ppm. HRMS (ESI): calculated
for C18H22N2O5P [M + H]+, m/z 377.1266; found for [M + H]+,
m/z 377.1253.
Acknowledgments
The authors are thankful for financial support by the Mexican
15.7 Hz, Ar), 128.5 (Ar), 136.1 (d, J = 3.6 Hz, Ar), 137.6 (d, J = Consejo Nacional de Ciencia y Tecnología (CONACYT) for finan-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43418
/KAP1
Date: 05-01-15 15:30:37
Pages: 9
J. L. Viveros-Ceballos, F. J. Sayago, C. Cativiela, M. Ordóñez
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Received: November 1, 2014
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43418
/KAP1
Date: 05-01-15 15:30:37
Pages: 9
Synthesis of 3-Phosphorylated β-Carbolines
Carbolinephosphonates
J. L. Viveros-Ceballos, F. J. Sayago,
C. Cativiela,* M. Ordóñez* .............. 1–9
First Practical and Efficient Synthesis of 3-
Phosphorylated β-Carboline Derivatives
Using the Pictet–Spengler Reaction
We report the first practical and efficient
synthesis of diethyl 1,2,3,4-tetrahydro-β-
carboline-3-phosphonates and diethyl 9H-
β-carboline-3-phosphonate derivatives. The
target compounds were prepared in good
yields using Pictet–Spengler reactions of
phosphotryptophan diethyl ester with
several aldehydes followed by oxidation
chemistry.
Keywords: Synthetic methods
/ Drug
design / Phosphorylation / Nitrogen hetero-
cycles
Eur. J. Org. Chem. 0000, 0–0
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