Triethyloxonium tetrafluoroborate/l,2-dimethoxyethane -a versatile substitute for trimethyloxonium tetrafluoroborate in 0-methylation reactions

Article abstract of DOI:10.1515/znb-2009-0412

The triethyloxonium tetrafluoroborate/l,2-dimethoxyethane (TEO/DME) mixture is a versatile and cheap substitute for trimethyloxonium tetrafluoroborate in O-methylations of pyrrolin-2-ones, quinolones, acridones, and 1-oxo-β-carbolines. Undesired O-ethylat

Full text of DOI:10.1515/znb-2009-0412

Triethyloxonium Tetrafluoroborate/1,2-Dimethoxyethane –
a Versatile Substitute for Trimethyloxonium Tetrafluoroborate
in O-Methylation Reactions
Andrea Ritter, Hermann Poschenrieder, and Franz Bracher
Department Pharmazie – Zentrum fu¨r Pharmaforschung, Ludwig-Maximilians-Universita¨t,
Butenandtsraße 5 – 13, 81377 Mu¨nchen, Germany
Reprint requests to Prof. Dr. Franz Bracher. Fax: +49-89-218077802.
E-mail: Franz.Bracher@cup.uni-muenchen.de
Z. Naturforsch. 2009, 64b, 427 – 433; received December 18, 2008
The triethyloxonium tetrafluoroborate/1,2-dimethoxyethane (TEO/DME) mixture is a versatile
and cheap substitute for trimethyloxonium tetrafluoroborate in O-methylations of pyrrolin-2-ones,
quinolones, acridones, and 1-oxo-β-carbolines. Undesired O-ethylation can be avoided by pre-
incubation of triethyloxonium tetrafluoroborate and 1,2-dimethoxyethane for 1 h, prior to addition
of the substrate. In the course of these investigations it was found that the structures assigned to the
alkaloids taraxacine A and B are erroneous.
Key words: Triethyloxonium Tetrafluoroborate, O-Methylation, Pyridones, Alkaloids,
Pyrrolin-2-ones
Introduction
Trialkyloxonium salts (“Meerwein salts”), origi-
nally described by Meerwein [1], are versatile reagents
for O-alkylation of amides, lactams and related func-
tional groups [2]. Both triethyloxonium tetrafluoro-
borate (1 = TEO, Scheme 1) and trimethyloxonium
tetrafluoroborate (2) are commercially available, but 2
is quite expensive. Salt 2 is most conveniently prepared
from 1 by reaction with dimethyl ether [3].
Recently one of us found by chance that reactions
of lactams 3a/b with triethyloxonium tetrafluoroborate
(1) in 1,2-dimethoxyethane did not give the expected
ethoxy derivatives, but the corresponding methoxy
derivatives 4a/b (Scheme 1) [4]. No efforts were made
at that time to explore the scope and limitations of this
new reaction.
Inspired by a recent publication on the isolation of
the new alkaloids taraxacine A and taraxacine B from
Taraxacum formosanum, which were claimed to be
the 1-methoxy-β-carbolines 5 and 6 [5], we investi-
gated the reactions of pyrrolin-2-ones, pyridones and
lactams with triethyloxonium tetrafluoroborate/1,2-
dimethoxyethane (TEO/DME). In continuation of our
previous research on β-carboline alkaloids [6] it was
of special interest to us to find out whether this O-
methylation protocol can also be applied to the syn-
thesis of 1-methoxy-β-carbolines.
Scheme 1.
The results of our investigations on the utility of the
TEO/DME reagent are presented in this paper.
Results
In a first set of experiments we reacted another two
arylidenepyrrolin-2-ones 7a/b [7] with the TEO/DME
c
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428
A. Ritter et al. · Triethyloxonium Tetrafluoroborate/1,2-Dimethoxyethane Reagent
Scheme 4.
Scheme 2.
to work out the first total syntheses of the alka-
loids taraxacine A (claimed to have structure 5)
and taraxacine B (claimed to have structure 6).
Reaction of 1-oxo-β-carboline 15a [6a] with the
TEO/DME reagent gave a 7 : 3 mixture of 1-ethoxy-
β-carboline 16a and 1-methoxy-β-carboline (5), the
putative alkaloid taraxacine A. Selective formation of
the methoxy-β-carboline5 could be achieved by a pre-
incubation of triethyloxonium tetrafluorobarate with
the solvent 1,2-dimethoxyethane for 1 h. The struc-
ture of 5 was unambiguously confirmed by 1H NMR,
13C NMR and HMBC experiments, with the methoxy
group giving typical resonances at 4.09 (1H NMR) and
52.9 ppm (13C NMR); a methyl group located at the
indole nitrogen should resonate at about 4 and 30 –
Scheme 3.
mixture. As expected, we obtained the methoxy deriva-
tives 8a/b exclusively (Scheme 2). The products
were identified by comparison with authentic samples,
which had been prepared by alternative routes [8].
In order to investigate the generality of this reaction
we reacted various compounds containing pyridone,
1-oxo-β-carboline, and acridone partial structures, as
well as simple lactams with TEO/DME.
The methyl quinolonecarboxylate 10 was con-
veniently prepared from the known carboxylic
acid 9 [9] by treatment with diazomethane in methanol
for 30 min. Prolonged reaction of 9 or 10 with di-
azomethane, however, gave a separable mixture of N-
methyl derivative 11 and methoxyquinoline 12. Reac-
tion of quinolone 10 with the TEO/DME mixture re-
sulted in the exclusive formation of the methoxyquino-
line 12 [10] in high yield (Scheme 3).
Acridone (13) was converted to methoxyacridine
(14) in an analogous manner, albeit in low yield
(Scheme 4). Comparison of the spectroscopic data of
the product with those published by Galy [11] for both
the O-methyl and the N-methyl derivatives, obtained
by methylation of 13 with methyl iodide under phase
transfer conditions, confirmed our assignment.
35 ppm, and a methyl group at the pyridone nitro-
gen at about 3.5 and 30 – 35 ppm. But to our surprise,
the spectroscopic data (1H NMR, IR, UV, MS) were
not at all in accordance with the data presented for
taraxacine A in [5]. Moreover, the authors of litera-
ture [5] claim that the data of the alkaloid coincide
well with those of a synthetic sample of 1-methoxy-β-
carboline published earlier by Ohmoto [12] – an asser-
tion that is simply false! And into the bargain, the few
data (melting point, MS, IR) presented by Ohmoto [12]
are not consistent with our data. Since Ohmoto pre-
pared the putative 1-methoxy-β-carboline by reaction
of 1-oxo-β-carboline 15a with diazomethane, we re-
examined this synthesis. The reaction gave two sep-
arable products, 1-methoxy-β-carboline (5) and 15c,
the product of methylation at the pyridone nitrogen.
Ohmoto obviously described product 15c, but assigned
the structure 5 to it. Our analytical data of 15c (melt-
ing point, IR) are in good agreement with values pub-
lished earlier [13, 14] for the same compound prepared
on other ways, and as expected the N-methyl group res-
onates at 3.62 (1H NMR) and 31.1 ppm (13C NMR).
Compound 15c can clearly be distinguished from the
imaginable isomer bearing the methyl group at the
◦
Finally, we investigated the reactions of 1-oxo- indole nitrogen by its melting point (found: 256 C;
β-carbolines with the TEO/DME reagent in order lit. [14]: 264 – 265 ◦C, isomer: 242 – 242.5 ◦C).
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A. Ritter et al. · Triethyloxonium Tetrafluoroborate/1,2-Dimethoxyethane Reagent
429
Scheme 5.
Scheme 6.
Unfortunately, the 1H NMR data published for
taraxacine A either do not coincide with those of 15c,
three very low-fielded proton resonances appearing in-
scrutable. Since the authors of literature [5] did not
provide any information on the alkaloids on request,
the correct structure of this alkaloid remains unsolved.
A reactivity similar to the one described above
for the unsubstituted 1-oxo-β-carboline 15a was ob-
served for the corresponding 1-oxo-β-carboline car-
boxylate 15b [6e]. Reaction with the TEO/DME
reagent gave a mixture of 1-ethoxy-β-carboline 16b
and 1-methoxy-β-carboline 16c, but pre-incubation
of the reagents, as described above, once again re-
sulted in the exclusive formation of the 1-methoxy-β-
carboline 16c. Hydrolysis of the ester group with KOH
in ethanol gave the carboxylic acid 6 (Scheme 5). Here
again the spectroscopic data of our synthetic product 6
did not coincide with those published for the alkaloid
taraxacine B, to which the constitution of 6 was for-
merly assigned. Consequently, the correct structure of
taraxacine B also remains to be elucidated.
formed. The ethoxy products might arise either from
unreacted triethyloxonium tetrafluoroborate or from
unselective reactivity of intermediate 17. As a pre-
incubation of triethyloxonium tetrafluorobarate with
1,2-dimethoxyethane prior to addition of the lactams
resulted in exclusive formation of the methoxy prod-
ucts, we assume that triethyloxonium tetrafluorobo-
rate quantitatively reacts with 1,2-dimethoxyethane on
standing for 1 h to give oxonium salts (mixed oxo-
nium salts or even trimethyloxoniumtetrafluoroborate)
which exclusively transfer methyl groups to the sub-
strates (Scheme 6).
Conclusion
The triethyloxonium tetrafluoroborate/1,2-dimeth-
oxyethane (TEO/DME) mixture is a versatile and
cheap substitute for trimethyloxonium tetrafluorobo-
rate in O-methylations of pyrrolin-2-ones, quinolones,
acridones, and 1-oxo-β-carbolines. In most of the
cases O-methylation occurs exclusively. In cases where
both methoxy and ethoxy derivatives are obtained
upon simply mixing the components, the reaction can
be driven towards the methoxy derivatives by pre-
incubation of triethyloxonium tetrafluoroborate and
1,2-dimethoxyethane for 1 h, followed by addition of
the substrate.
Simple aliphatic lactams such as 2-pyrrolidone and
2-piperidone failed to give well-defined products with
the TEO/DME reagent.
Discussion of the Mechanism of O-Alkylation
Triethyloxonium tetrafluoroborate (1) obviously
performs an O-ethylation of the solvent 1,2-dimeth-
oxyethane to give an intermediate mixed oxonium
ion 17 [2a]. This oxonium ion might itself act as an
alkylating agent, showing a higher tendency for releas-
ing the methyl group than the ethyl group. GLC/MS
analysis of the organic fraction of one of the re-
actions revealed that both 1-ethoxy-2-methoxyethane
and 1,2-diethoxyethane are formed in the course of
the reaction. This finding supports our hypothesis
that O-ethylation of 1,2-dimethoxyethane is a crucial
step in generating a reactive methylating agent. In
Experimental Section
Thin layer chromatography (TLC) was performed on
Macherey-Nagel pre-coated plastic silica gel plates with flu-
orescent indicator; the spots were visualized by UV illumi-
nation. Flash column chromatography was carried out using
silica gel 0.040 – 0.063 mm (Merck). Melting points were
determined by using a Bu¨chi mp B-540 apparatus and are
uncorrected. Infrared spectra were measured as potassium
bromide plates on an FT-IR spectrometer PARAGON 1000
(Perkin Elmer). 1H and 13C NMR spectra (internal standard
some cases both methoxy and ethoxy derivatives were tetramethylsilane) were recorded in [D6]DMSO as the sol-
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430
A. Ritter et al. · Triethyloxonium Tetrafluoroborate/1,2-Dimethoxyethane Reagent
vent on an FT NMR spectrometer Elipse 400 (JEOL) or 4-Methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
an FT NMR spectrometer Elipse 500 (JEOL). Mass spec- methyl ester (10)
tra were recorded with a Hewlett Packard 5989A mass spec-
A suspension of 9 (0.10 g, 0.50 mmol) in 30 mL of
trometer employing both EI (70 eV) and CI mode. HRMS
CH3OH was treated with an excess (about 5 equiv.) of an
was performeded with a JMS-GCMATE II (JEOL) mass
ethereal solution of diazomethane. After 30 min the volatiles
spectrometer. Microanalyses were carried out with a CHN
were removed under reduced pressure, and the residue was
analyzer Elementar Vario EL.
recrystallized from diisopropyl ether – EtO◦H (1 : 1) to give 10
(50 mg, 47 %) as white plates; m. p. 258 C. – IR (KBr): ν
General method A: direct O-methylation
1
(cm−1) = 3443, 2952, 1732, 1650, 1428, 1057. – H NMR:
A stirred solution/suspension of reactant (1 equiv.) and tri-
ethyloxonium tetrafluoroborate (1.5 equiv.) in 20 mL of 1,2-
dimethoxyethane was heated at 65 ◦C for the time given be-
low (30 min to 4 h). The solution was washed with an aque-
ous saturated solution of KHCO3. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts
were dried over MgSO4. The volatiles were removed under
reduced pressure to give the crude product. Purification was
performed as described for the resp. products below.
δ (ppm) = 12.1 (s, 1 H, NH), 7.81 (dd, 1 H, J = 8.3, 1.2 Hz,
5-H), 7.58 (ddd, 1 H, J = 8.3, 7.1, 1.2 Hz, 7-H), 7.34 (dd, 1 H,
J = 8.3, 1.2 Hz, 8-H), 7.27 (ddd, 1 H, J = 8.3, 7.1, 1.2 Hz,
6-H), 3.84 (s, 3 H, O-CH3), 2.40 (s, 3 H, CH3). – 13C NMR:
δ (ppm) = 166.6 (C=O), 158.5 (C-2), 144.7 (C-4), 138.0
(C-8a), 131.3 (C-7), 126.2 (C-3), 125.5 (C-5), 122.2 (C-6),
118.4 (C-4a), 115.5 (C-8), 52.2 (O-CH3), 16.0 (4-CH3). –
MS (EI, 70 eV): m/z (%) = 217 (22) [M]+, 186 (16), 167 (14),
149 (100), 127 (20), 94 (16), 85 (23), 71 (38), 55 (35). – MS
(CI): m/z (%) = 218 (100) [M+H]+, 202 (9), 186 (18), 160
(11). – C12H11NO3: calcd. C 66.35, H 5.10, N 6.45; found
C 66.09, H 5.05, N 6.34.
General method B: O-methylation after pre-incubation
A
solution of triethyloxonium tetrafluoroborate
(1.5 equiv.) in 20 mL of 1,2-dimethoxyethane was
stirred for 1 h at r. t. Then the reactant (1 equiv.) was added,
the mixture was stirred for 2 h and then washed with a sat-
urated aqueous solution of KHCO3. The aqueous layer was
extracted with CH2Cl2, and the combined organic extracts
were dried over MgSO4. The volatiles were removed under
reduced pressure to give the crude product. Purification was
performed as described for the resp. products below.
1,4-Dimethyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
methyl ester (11)
A stirred suspension of 9 (0.20 g, 1.0 mmol) in 50 mL
of CH3OH-dioxane (1 : 1) was treated with an excess of an
ethereal solution of diazomethane. After 4 h the volatile com-
ponents were removed under reduced pressure to give a mix-
ture of 11 and 12. The residue was separated by flash col-
umn chromatography (EtOAc – cyclohexane, 1 : 1) to give 12
(55 mg, 25 %; Rf = 0.76) as the first fraction, and 11 (30 mg,
15 %; Rf = 0.29) as the second fraction.
(Z)-2,4-Dimethoxy-5-(1-phenylmethylidene)-5H-pyrrole-3-
carboxylic acid methyl ester (8a)
Data of 11: white solid, m. p. 89 ◦C. – IR (KBr): ν
(cm−1) = 3445, 2954, 1733, 1634, 1592, 1457, 1159. –
1H NMR: δ (ppm) = 7.91 (dd, 1 H, J = 8.3, 1.1 Hz, 5-H),
7.72 (ddd, 1 H, J = 8.3, 7.1, 1.1 Hz, 7-H), 7.59 (dd, 1 H, J =
8.3, 1.1 Hz, 8-H), 7.37 (ddd, 1 H, J = 8.3, 7.1, 1.1 Hz, 6-H),
3.85 (s, 3 H, O-CH3), 3.64 (s, 3 H, N-CH3), 2.42 (s, 3 H,
4-CH3). – 13C NMR: δ (ppm) = 166.5 (C=O), 157.9 (C-2),
143.1 (C-4), 138.9 (C-8a), 131.7 (C-7), 126.1 (C-5), 125.7
(C-3), 122.4 (C-6), 119.3 (C-4a), 115.0 (C-8), 52.2 (O-CH3),
29.1 (N-CH3), 15.9 (4-CH3). – MS (EI, 70 eV): m/z (%) =
231 (72) [M]+, 199 (81), 173 (37), 143 (100), 115 (22), 103
(13), 86 (9), 77 (19), 51 (13). – MS (CI): m/z (%) = 232 (100)
[M +H]+, 200 (23). – C13H13NO3: calcd. C 67.52, H 5.67,
N 6.06; found C 67.55, H 5.88, N 5.87.
Using general method A with a reaction time of 30 min,
7a (0.52 g, 2.0 mmol) and triethyloxonium tetrafluoroborate
(0.57 g, 3.0 mmol) in 1,2-dimethoxyethane (20 mL) gave the
crude product. Purification by flash column chromatography
(EtOAc – cyclohexane, 1 : 3) yielded 8a (0.20 g, 40 %) as yel-
low needles; m. p. 72 C (EtOH) (lit. [8]: 67 C). The spec-
troscopic data are in full accordance with those reported in
literature [8].
◦
◦
(Z)-5-(1-Bromo-1-phenylmethylidene)-2,4-dimethoxy-
5H-pyrrole-3-carboxylic acid methyl ester (8b)
Using general method A with a reaction time of 30 min,
7b (0.68 g, 2.0 mmol) and triethyloxonium tetrafluoroborate
(0.57 g, 3.0 mmol) in 1,2-dimethoxyethane (20 mL) gave the
crude product. Purification by flash column chromatography
(EtOAc – cyclohexane, 1 : 3) gave 8b (0.35 g, 50 %) as yel-
low plates; m. p. 111 ◦C (MeOH) (lit. [8]: 105 ◦C). The spec-
troscopic data are in full accordance with those reported in
literature [8].
2-Methoxy-4-methylquinoline-3-carboxylic acid methyl ester
(12)
Using general method A with a reaction time of 30 min,
10 (0.11 g, 0.50 mmol) and triethyloxonium tetrafluoroborate
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A. Ritter et al. · Triethyloxonium Tetrafluoroborate/1,2-Dimethoxyethane Reagent
431
(0.14 g, 0.75 mmol) in 1,2-dimethoxyethane (20 mL) gave 1-Methoxy-9H-pyrido[3,4-b]indole (5)
the crude product. Purification by flash column chromatogra-
Using general method B with a reaction time of 2 h, 15a
(0.10 g, 0.50 mmol) and triethyloxonium tetrafluoroborate
(0.14 g, 0.75 mmol) in 1,2-dimethoxyethane (20 mL) gave
the crude product. Purification by flash column chromatog-
raphy (EtOAc – cyclohexane, 1 : 3) yielded 5 as a white solid
phy (EtOAc – cyclohexane, 1◦: 1) yielded 12 as a white pow-
der (45 mg, 85 %); m. p. 81 C (lit. [10]: no data given). –
IR (KBr): ν (cm−1) = 3436, 2954, 1731, 1606, 1447, 1327,
1060. – 1H NMR: δ (ppm) = 8.07 (dd, 1 H, J = 8.3, 1.0 Hz,
5-H), 7.82 (dd, 1 H, J = 8.3, 1.0 Hz, 8-H), 7.75 (ddd, 1 H, J =
8.3, 7.0, 1.0 Hz, 7-H), 7.53 (ddd, 1 H, J = 8.3, 7.0, 1.0 Hz,
6-H), 4.00 (s, 3 H, CH3), 3.91 (s, 3 H, CH3), 2.57 (s, 3 H,
4-CH3). – 13C NMR: δ (ppm) = 166.8 (C-2), 157.4 (C=O),
145.3 (C-8a), 144.3 (C-3), 130.7 (C-7), 127.3 (C-8), 124.8
(C-5), 124.8 (C-6), 123.8 (C-4a), 118.6 (C-4), 53.6 (CH3),
52.6 (O-CH3), 15.6 (4-CH3). – MS (EI, 70 eV): m/z (%) =
231 (44) [M]+, 217 (19), 200 (41), 186 (41), 171 (30), 159
(23), 143 (61), 129 (19), 115 (24), 102 (18), 91 (24), 77 (24),
69 (17), 58 (100). – MS (CI): m/z (%) = 232 (100) [M +H]+,
214 (16), 200 (65). – C13H13NO3: calcd. C 67.52, H 5.67,
N 6.06; found C 67.76, H 5.99, N 5.76.
◦
(20 mg, 19 %); m. p. 136 C (lit. [5]: pale yellow syrup). –
IR (KBr): ν (cm−1): 3173, 2991, 1633, 1559, 1437, 1287,
1
1105. – H NMR: δ (ppm) = 11.71 (s, 1 H, NH), 8.14 (dd,
1 H, J = 8.0, 1.0 Hz, 5-H), 7.86 (d, 1 H, J = 5.5 Hz, 3-H), 7.70
(d, 1 H, J = 5.5 Hz, 4-H), 7.56 (dd, 1 H, J = 8.0, 1.0 Hz, 8-H),
7.49 (ddd, 1 H, J = 8.0, 7.0, 1.0 Hz, 7-H), 7.21 (ddd, 1 H,
J = 8.0, 7.0, 1.0 Hz, 6-H), 4.09 (s, 3 H, CH3). – 13C NMR:
δ (ppm) = 150.8 (C-1), 139.9 (C-8a), 134.4 (C-3), 128.5
(C-4a), 127.2 (C-7), 123.5 (C-9a), 121.3 (C-5), 121.2 (C-4b),
119.2 (C-6), 112.2 (C-8), 109.4 (C-4), 52.9 (CH3). – MS (EI,
70 eV): m/z (%) = 198 (23) [M]+, 180 (9), 111 (15), 94 (100),
85 (25), 57 (70). – MS (CI): m/z (%) = 199 (100) [M +H]+,
182 (11). – HRMS (EI): m/z = 198.0780 (calcd. 198.0793 for
C12H10N2O, [M]+).
9-Methoxy-dibenzo[b,e]pyridine (14)
Using general method A with a reaction time of 4 h,
acridone (13) (0.20 g, 1.0 mmol) and triethyloxonium
tetrafluoroborate (0.28 g, 1.5 mmol) in 1,2-dimethoxyethane
(20 mL) gave the crude product. Purification by flash col-
umn chromatography (EtOAc – cyclohexane, 1 : 1) gave 14
as a yellow solid (35 mg, 16 %); m. p. 75 ◦C (lit. [11]: 65 ◦C).
The spectroscopic data are in full accordance with those re-
ported in literature [11].
Methylation of 15a with diazomethane
To a solution of 15a (70 mg, 0.38 mmol) in 10 mL of
methanol, an excess of an ethereal solution of diazomethane
was added, and the mixture was stirred at r. t. for 24 h. The
excess of diazomethane was destroyed by dropwise addi-
tion of acetic acid, and the volatile components were re-
moved under reduced pressure. The residue was purified by
column chromatography (EtOAc – cyclohexane, 1 : 3, then
EtOAc) to give 1-methoxy-9H-pyrido[3,4-b]indole (5) as
the first fraction (30 mg, 40 %), and 2-methyl-1,2-dihydro-
9H-pyrido[3,4-b]indol-1-one (15c) as the second fraction
(25 mg, 33 %).
1-Ethoxy-9H-pyrido[3,4-b]indole (16a)
Using general method A with a reaction time of 2 h, 15a
(0.10 g, 0.50 mmol) and triethyloxonium tetrafluoroborate
(0.14 g, 0.75 mmol) in 1,2-dimethoxyethane (20 mL) gave
the crude product, a mixture of 16a and 5. Purification by
flash column chromatography (EtOAc – cyclohexane, 1 : 3)
gave 16a as the first fraction (45 mg, 39 %; Rf = 0.33), and 5
(25 mg, 23 %; Rf = 0.25) as the second fraction.
◦
D◦ata of 15c: white solid, m. p. 265 C (lit. [14]: 264 –
265 C). – IR (KBr): ν (cm−1) = 3143, 1654, 1592, 1566,
1332, 1269, 979, 744, 646, 432. – 1H NMR: δ (ppm) = 11.94
(s, 1 H, NH), 8.03 (dd, 1 H, J = 8.3, 1.0 Hz, 5-H), 7.52 (dd,
1 H, J = 8.3, 1.0 Hz, 8-H), 7.41 (ddd, 1 H, J = 8.3, 6.7, 1.0 Hz,
7-H), 7.39 (d, 1 H, J = 6.9 Hz, 3-H), 7.18 (ddd, 1 H, J = 8.3,
6,7, 1.0 Hz, 6-H), 7.03 (d, 1 H, J = 6.9 Hz, 4-H), 3.62 (s, 3 H,
N-CH3). – 13C NMR: δ (ppm) = 155.3 (C-1), 139.3 (C-8a),
129.6 (C-3), 127.5 (C-4a), 126.3 (C-7), 123.6 (C-9a), 121.9
(C-4b), 121.3 (C-5), 119.6 (C-6), 112.5 (C-8), 99.9 (C-4),
31.1 (N-CH3). – MS (EI, 70 eV): m/z (%) = 198 (100) [M]+,
169 (18), 155 (15), 129 (12), 99 (7), 57 (14). – MS (CI): m/z
(%) = 199 (100) [M +H]+, 170 (10). – HRMS (EI): m/z =
198.0793 (calcd. 198.0814 for C12H10N2O, [M]+).
◦
Data of 16a: white solid, m. p. 127 C. – IR (KBr): ν
(cm−1) = 3129, 2970, 2896, 1629, 1415, 1381, 1100. –
1H NMR: δ (ppm) = 11.63 (s, 1 H, NH), 8.13 (dd, 1 H, J =
8.0, 1.0 Hz, 5-H), 7.84 (d, 1 H, J = 5.5 Hz, 3-H), 7.68 (d,
1 H, J = 5.5 Hz, 4-H), 7.57 (dd, 1 H, J = 8.0, 1.0 Hz, 8-H),
7.48 (ddd, 1 H, J = 8.0, 7.0, 1.0 Hz, 7-H), 7.21 (ddd, 1 H, J =
8.0, 7.0, 1.0 Hz, 6-H), 4.57 (q, 2 H, J = 7.1 Hz, CH2), 1.46 (t,
3 H, J = 7.1 Hz, CH3). – 13C NMR: δ (ppm) = 151.0 (C-1),
140.4 (C-8a), 134.9 (C-3), 129.0 (C-4a), 127.7 (C-7), 124.0
(C-9a), 121.8 (C-5), 121.7 (C-4b), 119.7 (C-6), 112.7 (C-8),
109.7 (C-4), 61.5 (CH2), 15.3 (CH3). – MS (EI, 70 eV): m/z
(%) = 212 (66) [M]+, 197 (67), 184 (100), 168 (18), 155 (35),
129 (24), 101 (24), 94 (59), 77 (24), 69 (18), 57 (30). – MS
(CI): m/z (%) = 213 (100) [M +H]+. – C13H12N2O: calcd.
C 73.57, H 5.70, N 13.20; found C 73.41, H 5.82, N 12.97.
1-Ethoxy-9H-pyrido[3,4-b]indole-3-carboxylic acid methyl
ester (16b)
Using general method A with a reaction time of 2 h, 15b
(0.12 g, 0.50 mmol) and triethyloxonium tetrafluoroborate
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432
A. Ritter et al. · Triethyloxonium Tetrafluoroborate/1,2-Dimethoxyethane Reagent
(0.14 g, 0.75 mmol) in 1,2-dimethoxyethane (20 mL) gave 140.4 (C-8a), 133.3 (C-3), 128.1 (C-4a), 127.9 (C-7), 125.9
the crude product, a mixture of 16b and 16c. Purification by (C-9a), 121.8 (C-5), 121.7 (C-4b), 120.3 (C-6), 113.6 (C-4),
flash column chromatography (EtOAc – cyclohexane 1 : 3) 112.7 (C-8), 53.3 (CH3), 52.0 (CH3). – MS (EI, 70 eV): m/z
gave 16b (40 mg, 30 %; Rf = 0.24) as the first fraction, (%) = 256 (100) [M]+, 223 (34), 198 (35), 183 (16), 168
and 16c (45 mg, 35 %; Rf = 0.14) as the second fraction.
Data of 16b: dark yellow solid, m. p. 199 ◦C. – IR (KBr):
ν (cm−1) = 3334, 2924, 2853, 1718, 1437, 1253, 1008. –
1H NMR: δ (ppm) = 12.09 (s, 1 H, NH), 8.56 (s, 1 H, 4-H),
8.27 (dd, 1 H, J = 7.9, 1.0 Hz, 5-H), 7.62 (dd, 1 H, J = 7.9,
1.0 Hz, 8-H), 7.53 (ddd, 1 H, J = 7.9, 6.8, 1.0 Hz, 7-H),
7.27 (ddd, 1 H, J = 7.9, 6.8, 1.0 Hz, 6-H), 4.63 (q, 2 H,
J = 7.2 Hz, CH2), 3.88 (s, 3 H, O-CH3), 1.49 (t, 3 H, J =
7.2 Hz, CH3). – 13C NMR: δ (ppm) = 165.8 (C=O), 149.7
(C-1), 140.4 (C-8a), 133.3 (C-3), 128.1 (C-4a), 127.9 (C-7),
125.9 (C-9a), 121.8 (C-5), 121.7 (C-4b), 120.3 (C-6), 113.4
(C-4), 112.7 (C-8), 61.7 (CH2), 52.0 (O-CH3), 14.8 (CH3). –
MS (EI, 70 eV): m/z (%) = 270 (22) [M]+, 255 (8), 242
(12), 223 (12), 182 (21), 154 (21), 127 (16), 58 (100). – MS
(CI): m/z (%) = 271 (43) [M +H]+, 187 (5), 159 (6), 117
(100). – HRMS (EI): m/z = 270.1034 (calcd. 270.1005 for
C15H14N2O3, [M]+).
(14), 154 (24), 127 (34). – MS (CI): m/z (%) = 257 (100) [M
+H]+. – HRMS (EI): m/z = 256.0893 (calcd. 256.0848 for
C14H12N2O3, [M]+).
1-Methoxy-9H-pyrido[3,4-b]indole-3-carboxylic acid (6)
A solution of 16c (0.50 g, 2.0 mmol) and KOH (0.28 g,
◦
5.0 mmol) in 20 mL of EtOH was heated at 90 C for 4 h,
then the solvent was evaporated under reduced pressure, and
hydrochloric acid (10 mL, 10 %) and water (20 mL) were
added to the residue. The mixture was extracted with EtOAc
(3 × 20 mL), and the combined organic extracts were dried
over MgSO4. The solvent was evaporated under reduced
pressure, and the residue was purified by flash column chro-
matography (EtOAc – cyclohexane, 1 : 1) to give 6 as a pale
◦
yellow solid (0.20 g, 42 %); m. p. 194 C (lit. [5]: pale yel-
low syrup). – IR (KBr): ν (cm−1) = 3441, 3283, 2924, 1683,
1396, 1264, 1103. – 1H NMR: δ (ppm) = 12.14 (s, 1 H, NH),
8.57 (s, 1 H, 4-H), 8.28 (dd, 1 H, J = 7.9, 1.0 Hz, 5-H), 7.61
(dd, 1 H, J = 7.9, 1.0 Hz, 8-H), 7.54 (ddd, 1 H, J = 7.9, 6.8,
1.0 Hz, 7-H), 7.28 (ddd, 1 H, J = 7.9, 6.8, 1.0 Hz, 6-H), 4.17
(s, 3 H, CH3). – 13C NMR: δ (ppm) = 167.0 (C=O), 150.3
(C-1), 140.9 (C-8a), 134.2 (C-3), 128.7 (C-4a), 128.2 (C-7),
126.2 (C-9a), 122.1 (C-5), 122.0 (C-4b), 120.6 (C-6), 113.5
(C-4), 113.0 (C-8), 53.8 (CH3). – MS (EI, 70 eV): m/z (%) =
242 (28) [M]+, 198 (24), 183 (13), 155 (10), 127 (12), 101
(15), 86 (13), 71 (26), 58 (100). – MS (CI): m/z (%) = 243
(100) [M +H]+, 225 (16), 117 (16). – HRMS (EI): m/z =
242.0688 (calcd. 242.0692 for C13H10N2O3, [M]+).
1-Methoxy-9H-pyrido[3,4-b]indole-3-carboxylic acid
methyl ester (16c)
Using general method B with a reaction time of 2 h, 15b
(0.12 g, 0.50 mmol) and triethyloxonium tetrafluoroborate
(0.14 g, 0.75 mmol) in 1,2-dimethoxyethane (20 mL) gave
the crude product. Purification by flash column chromatog-
raphy (EtOAc – cyclohexane, 1 : 3) gave 16c as a yellow solid
(40 mg, 32 %); m. p. 198 ◦C. – IR (KBr): ν (cm−1) = 3298,
2923, 1714, 1560, 1337, 1257, 1110. – 1H NMR: δ (ppm) =
12.20 (s, 1 H, NH), 8.60 (s, 1 H, 4-H), 8.30 (dd, 1 H, J =
7.9, 1.0 Hz, 5-H), 7.61 (dd, 1 H, J = 7.9, 1.0 Hz, 8-H), 7.55
Acknowledgement
(ddd, 1 H, J = 7.9, 6.8, 1.0 Hz, 7-H), 7.29 (ddd, 1 H, J1
=
We thank Dr. Florian Plo¨ßl for performing the GLC/MS
experiments.
7.9, 6.8, 1.0 Hz, 6-H), 4.15 (s, 3 H, CH3), 3.90 (s, 3 H,
CH3). – 13C NMR: δ (ppm) = 165.8 (C=O), 150.0 (C-1),
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