An efficient synthesis of 1-methyl-4,5,6,7-tetrahydro-1 H-pyrrolo[2,3-c]pyridine and its N6-substituted analogues

Article abstract of DOI:10.1055/s-0032-1318346

An efficient synthesis of 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c] pyridine hydrochloride was achieved using simple sodium borohydride reduction of 6-benzyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-6-ium bromide as the key step followed by its debenzylation with hydrogen over palladium on carbon on a multigram scale. Similarly, a series of N⁶-substituted 1-methyl-1H-pyrrolo[2,3-c]pyridin-6-ium halides were synthesized and reduced with sodium borohydride, showing this method to be applicable for the synthesis of different N⁶-substituted 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2, 3-c]pyridines. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1318346

PAPER
▌919
paper
An Efficient Synthesis of 1-Methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine
and Its N6-Substituted Analogues
1-Methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridines
Maxim A. Nechayev,a,b Nikolay Yu. Gorobets,*c Sergiy M. Kovalenko,a Andrey A. Tolmachevb
a
National University of Pharmacy, Pushkinska str. 53, Kharkiv 61002, Ukraine
b
Enamine Ltd., Alexandra Matrosova Str. 23, Kyiv 01103, Ukraine
c
Laboratory for Physicochemical Processes, SSI ‘Institute for Single Crystals’ of NAS of Ukraine, Lenina Ave 60, Kharkiv 61001, Ukraine
Fax +38(57)3409343; E-mail: gorobets@isc.kharkov.com
Received: 08.11.2012; Accepted after revision: 12.02.2013
The most obvious route to compound 2 is the reduction of
Abstract: An efficient synthesis of 1-methyl-4,5,6,7-tetrahydro-
the corresponding pyrrolo[2,3-c]pyridine derivative 3.5 A
1H-pyrrolo[2,3-c]pyridine hydrochloride was achieved using sim-
literature survey revealed that the reduction of similar
ethyl 1H-pyrrolo[2,3-c]pyridine-2-carboxylate could be
ple sodium borohydride reduction of 6-benzyl-1-methyl-1H-pyrro-
lo[2,3-c]pyridin-6-ium bromide as the key step followed by its
debenzylation with hydrogen over palladium on carbon on a multi- accomplished using high-pressure hydrogenation over
gram scale. Similarly, a series of N6-substituted 1-methyl-1H-pyr-
rolo[2,3-c]pyridin-6-ium halides were synthesized and reduced
with sodium borohydride, showing this method to be applicable for
the synthesis of different N6-substituted 1-methyl-4,5,6,7-tetra-
hydro-1H-pyrrolo[2,3-c]pyridines.
platinum(IV) oxide6 or rhodium on alumina.7 Both meth-
ods include the use of substantial amounts of catalyst and
very long reaction times (up to 11 days). The starting
1-methyl-1H-pyrrolo[2,3-c]pyridine (3) can be obtained
by several methods,8 but because of the formation of regio-
isomers during the alkylation of 6-azaindole8a followed by
column chromatography8a,c or high dilution of the reaction
mixture8b these protocols are poorly scalable. We have re-
cently suggested a scalable method for the synthesis of
pyrrolo[2,3-c]pyridin-7-one (4).9 This method allows the
facile introduction of an alkyl substituent into the N1-po-
sition of the pyrrolo[2,3-c]pyridin-7-one core, and com-
pound 4 can be used as precursor for 6-azaindole 3
(Scheme 1).
Key words: heterocycles, cyclization, alkylation, reduction, hydro-
genation
Within modern trends in drug discovery, saturated hetero-
cycles have acquired additional value since the selection
of sp3-enriched low-molecular-weight molecules increas-
es the probability of finding a successful drug.1 In this
connection, heteroannulated piperidines of the common
formula 1 have found use as drugs, such as Clopidogrel2
and Ticlopidine,3 or have been suggested as drug candi-
dates, for example Carvotroline hydrochloride4 (Figure
1). In this work we aimed to develop a robust synthetic
route to isosteric 1-methyl-4,5,6,7-tetrahydro-1H-pyrro-
lo[2,3-c]pyridine building block 2 (Scheme 1) and use its
amino function for further modifications.
NH
N
NH
O
N
N
N
Me
Me
Me
4
2
3
Scheme 1 Planned synthesis of the building block 2
S
O
H
N
In contrast to our previous report, where the required ami-
doacetal 6 was obtained from pyrrole-2-carboxylic acid
by a standard amide coupling procedure followed by
methylation of the pyrrole nitrogen, we have now utilized
easily accessible 2,2,2-trichloro-1-(1-methyl-1H-pyrrol-
2-yl)ethanone10 (5) as an alternative starting material. The
use of 2-(trichloroacetyl)-1H-pyrrole (5) instead of the
corresponding pyrrole-2-carboxylic acid was more conve-
nient since the synthesis of amidoacetal 6 did not require
the application of any amide coupling reagents and the
methylation step was excluded (Scheme 2). Subsequent
acid-promoted intramolecular cyclization of amidoacetal
6 resulted in the formation of the required pyrrolo[2,3-
c]pyridin-7-one derivative 4 obtained in an increased total
yield of 88% over two steps (instead of 40% over three
steps using the previous procedure).
Het
OMe
N
R
Cl
1
Clopidogrel
S
H
N
N
HCl
Cl
N
N
F
Ticlopidine
Carvotroline hydrochloride
Figure 1 Heteroannulated piperidines as drugs or drug candidates
SYNTHESIS 2013, 45, 0919–0924
Advanced online publication: 27.02.2013
DOI: 10.1055/s-0032-1318346; Art ID: SS-2012-T0878-OP
© Georg Thieme Verlag Stuttgart · New York
Product 4 was transformed into 7-chloro-1-methyl-1H-
pyrrolo[2,3-c]pyridine (7) by heating in phosphoryl chlo-
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

920
M. A. Nechayev et al.
PAPER
Cl
CH(OMe)2
Cl
NH
O
N
N
Cl
c
a
d
b
NH
N
N
N
Cl
71%
N
91%
O
88%
(a,b)
Me
Me
Me
N
O
Me
5
6
4
7
3
Me
Scheme 2 Synthesis of 1-methyl-1H-pyrrolo[2,3-c]pyridine (3). Reagents and conditions: (a) (MeO)2CHCH2NH2 (1.3 equiv), 1,4-dioxane,
80 °C, 24 h; (b) TFA, r.t.,12 h; (c) POCl3 (3.0 equiv), 100 °C, 2 h; (d) H2, 10% Pd/C, Na2CO3, MeOH, r.t., atmospheric pressure, 12 h.
ride in 71% yield. Finally, the required pyrrolo[2,3-c]pyr- prolonged reaction time (72 h) and greater excess of iso-
idine 3 was obtained in 91% yield by hydrogenation of 7 propyl iodide were required to obtain salt 8d in 79% yield.
at atmospheric pressure in methanol using 10% palladium Generally, the reduction of quaternary salts 8a–f was car-
on carbon as the catalyst.
ried out by careful addition of the corresponding salt to a
suspension of sodium borohydride (2.2 equiv) in ethanol
at 15 °C, since the reaction was highly exothermic. The
isolated yields after an extraction workup are indicated in
Table 1. It should be noted that a Boc-protected amino
group (entry 5) survived under the conditions of both
transformations. The reduction of compound 8f derived
from 1-chloroacetone was accompanied by the transfor-
mation of the carbonyl function into a hydroxy group to
give alcohol derivative 9f.
Since we planned a multigram-scale synthesis of product
2, our first attempt was to apply a less expensive option,
10% palladium on carbon, as the catalyst for the following
high-pressure hydrogenation. When the hydrogenation of
3 was carried out in methanol at 50 °C and 50 bar hydro-
gen pressure for 24 hours the resulted conversion was
10%. Increasing the temperature and internal hydrogen
pressure (up to 70 °C, 70 bar) for a further 24 hours result-
ed in the formation of a range of byproducts in addition to
the starting material and only small amounts of the desired In summary, a seven-step synthesis of 1-methyl-4,5,6,7-
1
product (TLC and H NMR control). Consequently, we tetrahydro-1H-pyrrolo[2,3-c]pyridine
hydrochloride
switched to a different approach using preliminary pyri- (2·HCl) was developed avoiding high-pressure hydroge-
dine ring quaternization followed by its reduction nation and expensive catalysts. This practical synthetic se-
(Scheme 3). A quaternary bromide 8a was easily obtained quence was scaled up to 50 grams of the final product,
in 87% yield by simple heating with excess benzyl representing a 31% overall yield. Also a convenient strat-
bromide11 in dry toluene at 70 °C for 12 hours. Its reduc- egy to its N6-alkylated derivatives 9a–f was suggested.
tion by sodium borohydride yielded 6-benzyl-4,5,6,7-tet- Structures of all the products nicely fit the druglikeness
rahydro-1H-pyrrolo[2,3-c]pyridine (9a) in 94% yield. criteria including a relatively high sp3-fraction.12
The debenzylation of 9a proceeded under atmospheric
pressure at 50 °C in methanol using 10% palladium on
carbon as the catalyst to give the desired amine 2 isolated
as its hydrochloride salt in 67% yield after workup.
Solvents were purified according to standard procedures. All start-
ing materials were commercially available and were used without
additional purification. Melting points are uncorrected. Elemental
analysis was carried out on a EuroVector EA-3000 instrument. 1H
NMR spectra were recorded on a Bruker Avance DRX 500 (500
MHz) and Varian Unity plus 400 (400 MHz) spectrometers with
TMS as an internal standard. 13C NMR (126 MHz) spectra were
performed on a 500 MHz spectrometer. Copies of NMR spectra
were prepared using ACD/NMR Processor software (academic edi-
tion) and can be found in the Supporting Information. LC/MS spec-
tra were recorded using a chromatography/mass spectrometric
system that consists of high-performance liquid chromatograph
equipped with a diode-matrix and mass-selective detector. Ioniza-
tion method, chemical ionization under atmospheric pressure (AP-
CI). Ionization mode, simultaneous scanning of positive ions in the
mass range of 80–1000 m/z. According to HPLC MS and 1H NMR
spectral data, all synthesized compounds have purity >95%.
Encouraged by this result, we then utilized the same reac-
tion conditions for the synthesis of a series of N6-alkylated
tetrahydro-1H-pyrrolo[2,3-c]pyridines 9b–f (Table 1).
Thus for the synthesis of quaternary salts 8b–f we suc-
cessfully used different types of alkylating agents includ-
ing alkyl iodides (entries 2–4), alkyl bromides (entries 1,
5), and 1-chloroacetone (entry 6). The pyrrolo[2,3-c]pyri-
dinium salts, isolated as precipitates from toluene in most
cases, are white crystalline compounds obtained in very
good yields and >95% purity according to LC-MS, except
for 8f, which was obtained as viscous oil and used for the
next step immediately. In the case of isopropyl iodide a
Br–
N
N+
N
NH
·HCl
b
a
c, d
94%
67%
87%
N
N
N
N
Me
Me
Me
Me
2⋅HCl
3
8a
9a
Scheme 3 Synthesis of 1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine hydrochloride (2·HCl). Reagents and conditions: (a) BnBr (2.0
equiv), toluene, 70 °C, 12 h; (b) NaBH4 (2.2 equiv), EtOH, 15 °C, 0.5 h; (c) H2, 10% Pd/C, MeOH, 50 °C, atmospheric pressure, 18 h; (d) 10%
HCl–1,4-dioxane.
Synthesis 2013, 45, 919–924
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridines
921
Table 1 Synthesis of 6-Substituted 1-Methyl-1H-pyrrolo[2,3-c]pyridin-6-ium Halides 8a–f and Their Reduction to 6-Substituted 1-Methyl-
4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridines 9a–f
RX
toluene
N
N
R
N R
NaBH4
X–
70 °C, 12 h
N
N
N
Me
3
Me
8a–f
Me
9a–f
Entry
Product 8
Yield (%) of 8
Product 9
Yield (%) of 9
Br–
N
N+
N+
N+
N+
N+
N
1
87
94
N
Me
Me
9a
8a
I–
Me
N
N
N
N
N
N
Me
Et
2
77
85
74
71
58
Me
Me
8b
9b
I–
Et
N
N
3
84
Me
Me
8c
9c
I–
i-Pr
N
N
4b
79a
78a
i-Pr
Me
Me
8d
9d
Br–
O
O
N
N
N
Ot-Bu
N
Ot-Bu
5
H
H
Me
Me
8e
9e
Cl–
OH
O
N
N+
N
b
59c
N
6
–
Me
Me
9f
8f
a i-PrI (3.0 equiv) was used with a reaction time of 72 h.
b Hygroscopic oil, which was used immediately in the next step.
c NaBH4 (3.0 equiv) was used, the yield is given over two steps.
1-Methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (4)
1H NMR (400 MHz, DMSO-d6): δ = 10.85 (br s, 1 H, NH), 7.25 (d,
J = 2.5 Hz, 1 H, H2), 6.82 (d, J = 6.6 Hz, 1 H, H5), 6.39 (d, J = 6.6
Hz, 1 H, H4), 6.24 (d, J = 2.5 Hz, 1 H, H3), 4.05 (s, 3 H, CH3).
13C NMR (126 MHz, DMSO-d6): δ = 35.7, 101.3, 102.0, 123.2,
125.2, 131.8, 132.0, 156.3.
To a soln of 5 (344 g, 1.52 mol) in 1,4-dioxane (1.5 L) was added
2,2-dimethoxyethanamine (211 g, 2.00 mol) in one portion. The
soln was heated at 80 °C for 24 h (TLC monitoring). The solvent
was evaporated under reduced pressure and the oily residue was
carefully added to TFA (1.0 L) at such a rate that the reaction tem-
perature was maintained below 50 °C. The soln was stirred at r.t. for
12 h and then poured into ice-cold H2O (3.0 L) with intensive agi-
tation. The precipitate was filtered off, washed with H2O (2 × 400
mL), then resuspended in H2O (1 L) and neutralized with K2CO3 to
pH 8–9. The precipitate was filtered off, washed with H2O (2 × 400
mL) and dried to give the product as slightly brown solid; yield:
198 g (88%); HPLC purity >95%; mp 190–191 °C. The spectral
characteristics of the obtained material were identical with those re-
ported previously.9
LCMS: m/z = 149.0 [M + H]+.
Anal. Calcd for C8H8N2O: C, 64.85; H, 5.44; N, 18.91. Found: C,
64.84; H, 5.40; N, 18.90.
7-Chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine (7)
Compound 4 (180 g, 1.21 mol) was added portionwise to POCl3
(340 mL, 3.64 mol, 3.0 equiv). The mixture was heated at 100 °C
for 2 h and then poured into ice (3 kg). The soln was neutralized
with K2CO3 to pH 9–10 and extracted with EtOAc (2 × 300 mL).
The combined organic layers were filtered from polymeric residue,
IR (KBr): 3126, 2982, 2844, 1641, 1461, 1325 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 919–924

922
M. A. Nechayev et al.
PAPER
purified by flash chromatography (silica gel, EtOAc), and evaporat-
ed under reduced pressure to give the product as a slightly brown
solid; yield: 143 g (71%); HPLC purity >95%; mp 69–70 °C.
IR (KBr): 3428, 1601, 1501, 1328, 1115, 823 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 7.87 (d, J = 5.5 Hz, 1 H, H5),
7.63 (d, J = 2.9 Hz, 1 H, H2), 7.54 (d, J = 5.5 Hz, 1 H, H4), 6.57 (d,
J = 3.1 Hz, 1 H, H3), 4.12 (s, 3 H, CH3).
IR (KBr): 3400, 1642, 1486, 1167, 748, 712 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 10.05 (s, 1 H, H7), 8.54 (d,
J = 6.5 Hz, 1 H, H5), 8.34 (d, J = 2.1 Hz, 1 H, H2), 8.14 (d, J = 6.5
Hz, 1 H, H4), 7.62 (d, J = 6.8 Hz, 2 H, HAr), 7.40 (m, 3 H, HAr), 6.92
(d, J = 2.1 Hz, 1 H, H3), 5.92 (s, 2 H, CH2), 4.11 (s, 3 H, CH3).
13C NMR (126 MHz, DMSO-d6): δ = 143.8, 136.3, 135.9, 132.6,
131.9, 130.8, 129.5, 129.4, 128.9, 118.3, 103.4, 62.5, 34.6.
1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 5.2 Hz, 1 H, H5), 7.38
(d, J = 5.5 Hz, 1 H, H4), 7.13 (d, J = 3.1 Hz, 1 H, H2), 6.45 (d,
J = 2.9 Hz, 1 H, H3), 4.11 (s, 3 H, CH3).
13C NMR (126 MHz, DMSO-d6): δ = 137.4, 136.6, 133.5, 129.0,
115.8, 101.1, 36.7.
13C NMR (126 MHz, CDCl3): δ = 137.4, 136.5, 134.7, 134.1, 129.2,
115.2, 101.0, 36.6.
LCMS: m/z = 167.1 [M + H]+.
LCMS: m/z = 223.2 [M]+.
1,6-Dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium Iodide (8b)
White crystalline powder; yield: 6.4 g (77%); HPLC purity >95%;
mp 203–205 °C.
IR: 3446, 3055, 2988, 1644, 1486, 1185, 849, 595 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 9.52 (s, 1 H, H7), 8.33 (d,
J = 6.2 Hz, 1 H, H5), 8.28 (d, J = 2.6 Hz, 1 H, H2), 8.13 (d, J = 6.5
Hz, 1 H, H4), 6.94 (d, J = 2.6 Hz, 1 H, H3), 4.38 (s, 3 H, N+CH3),
4.06 (s, 3 H, NCH3).
Anal. Calcd for C8H7ClN2: C, 57.67; H, 4.23; N, 16.81. Found: C,
57.63; H, 4.20; N, 16.82.
13C NMR (126 MHz, DMSO-d6): δ = 143.1, 135.9, 132.8, 132.4,
131.2, 117.7, 103.2, 47.4, 34.6.
LCMS: m/z = 147.1 [M]+.
1-Methyl-1H-pyrrolo[2,3-c]pyridine (3)
To a soln of 7 (120 g, 0.72 mol) in MeOH (1.50 L), Na2CO3 (78.0
g, 0.94 mol, 1.3 equiv) and 10% Pd/C (20 g) were added. H2 was
bubbled through the mixture with vigorous stirring until no starting
material was observed (12 h, TLC control). The catalyst was filtered
off, washed with MeOH (2 × 150 mL) and the resulting soln was
evaporated under reduced pressure. The residue was diluted with
CHCl3 (300 mL) and filtered, and the inorganic material was
washed on the filter with additional CHCl3 (300 mL). The combined
filtrates were dried (MgSO4) and evaporated under reduced pres-
sure to give 3 as a yellowish liquid; yield: 86.6 g (91%); HPLC pu-
rity >95%.
6-Ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-6-ium Iodide (8c)
White crystalline powder; yield: 7.3 g (84%); HPLC purity >95%;
mp 195–197 °C.
IR (KBr): 3444, 3053, 1648, 1489, 1174, 815, 617 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 9.66 (s, 1 H, H7), 8.46 (d,
J = 6.5 Hz, 1 H, H5), 8.30 (d, J = 2.3 Hz, 1 H, H2), 8.14 (d, J = 6.5
Hz, 1 H, H4), 6.92 (d, J = 2.1 Hz, 1 H, H3), 4.53–4.80 (m, 2 H,
N+CH2CH3), 4.09 (s, 3 H, NCH3), 1.58 (t, J = 7.1 Hz, 3 H,
N+CH2CH3).
IR (KBr): 3390, 1606, 1506, 1253, 1030, 819 cm–1.
13C NMR (126 MHz, DMSO-d6): δ = 143.2, 136.1, 132.5, 131.7,
130.4, 118.0, 103.2, 55.7, 34.7, 17.4.
LCMS: m/z = 161.1 [M]+.
1H NMR (500 MHz, DMSO-d6): δ = 8.85 (s, 1 H, H7), 8.15 (d,
J = 5.2 Hz, 1 H, H5), 7.54 (d, J = 2.9 Hz, 1 H, H2), 7.52 (d, J = 5.5
Hz, 1 H, H4), 6.49 (d, J = 2.1 Hz, 1 H, H3), 3.90 (s, 3 H, CH3).
1H NMR (500 MHz, CDCl3): δ = 8.61 (s, 1 H, H7), 8.15 (d, J = 4.9
Hz, 1 H, H5), 7.37 (d, J = 5.2 Hz, 1 H, H4), 6.99 (d, J = 1.6 Hz, 1
H, H2), 6.33 (d, J = 2.1 Hz, 1 H, H3), 3.63 (s, 3 H, CH3).
13C NMR (126 MHz, DMSO-d6): δ = 138.3, 133.9, 133.8, 133.6,
132.7, 115.1, 100.1, 33.1.
6-Isopropyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-6-ium Iodide
(8d)
White crysalline powder; yield: 7.2 g (79%); HPLC purity >95%;
mp 223–225 °C.
IR (KBr): 3467, 3051, 1640, 1163, 824, 617 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 9.62 (s, 1 H, H7), 8.56 (d,
J = 6.0 Hz, 1 H, H5), 8.31 (d, J = 2.3 Hz, 1 H, H2), 8.16 (d, J = 6.8
Hz, 1 H, H4), 6.94 (d, J = 2.6 Hz, 1 H, H3), 4.93–5.19 [m, 1 H,
N+CH(CH3)2], 4.11 (s, 3 H, NCH3), 1.67 [d, J = 6.5 Hz, 6 H,
N+CH(CH)2].
13C NMR (126 MHz, CDCl3): δ = 138.3, 133.6, 133.0, 132.6, 132.4,
115.0, 100.3, 32.8.
LCMS: m/z = 133.1 [M + H]+.
Anal. Calcd for C8H8N2: C, 72.70; H, 6.10; N, 21.20. Found: C,
72.74; H, 6.13; N, 21.18.
13C NMR (126 MHz, DMSO-d6): δ = 143.4, 136.5, 132.7, 130.0,
128.8, 118.1, 103.2, 63.2, 34.7, 23.2.
LCMS: m/z = 175.2 [M]+.
6-Benzyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-6-ium Bromide
(8a); Typical Procedure
1-Methyl-1H-pyrrolo[2,3-c]pyridine (3, 80.0 g, 0.61 mol) was dis-
solved in anhyd toluene (1.50 L). BnBr (205 g, 1.20 mol, 2.0 equiv)
was added in one portion and the mixture was heated at 70 °C for
12 h under a reflux condenser. After cooling, the precipitate was fil-
tered off, washed with toluene (500 mL) and hexane (2 × 500 mL),
and dried under reduced pressure. This procedure is typical for the
synthesis of salts 8b–e on a 10.0-mmol scale. For the synthesis of
8d, i-PrI (3.0 equiv) was used and reaction time was 72 h. In the
case of 8f, after heating at 70 °C for 12 h, the solvent was decanted,
the residue was washed with toluene (50 mL) and hexane (50 mL).
The obtained brown viscous oil was dissolved in EtOH (30 mL) and
subjected directly to reduction with NaBH4 without characterization
and additional purification.
6-{2-[(tert-Butoxycarbonyl)amino]ethyl}-1-methyl-1H-pyrro-
lo[2,3-c]pyridin-6-ium Bromide (8e)
White crysalline powder; yield: 8.4 g (78%); HPLC purity >95%;
mp 169–171 °C.
IR (KBr): 3421, 3012, 2969, 1709, 1524, 1266, 1165 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 9.66 (s, 1 H, H7), 8.26–8.44
(m, 2 H, H2, H5), 8.13 (d, J = 6.2 Hz, 1 H, H4), 7.02–7.17 (m, 1 H,
NH), 6.93 (s, 1 H, H3), 4.67 (s, 2 H, N+CH2CH2NHBoc), 4.08 (s, 3
H, NCH3), 3.48–3.66 (m, 2 H, N+CH2CH2NHBoc), 1.17 [s, 9 H,
OC(CH3)3].
13C NMR (126 MHz, DMSO-d6): δ = 156.0, 143.4, 136.4, 132.5,
130.8, 117.7, 103.3, 78.5, 59.9, 41.3, 34.4, 28.4.
6-Benzyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-6-ium Bromide
(8a)
LCMS: m/z = 276.1 [M]+.
White crystalline solid; yield: 159.6 g (87%); HPLC purity >95%;
mp 72–74 °C.
Synthesis 2013, 45, 919–924
© Georg Thieme Verlag Stuttgart · New York

PAPER
1-Methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridines
923
6-Benzyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyri-
dine (9a); Typical Procedure
13C NMR (126 MHz, CDCl3): δ = 126.5, 120.3, 115.5, 105.7, 54.2,
46.8, 45.1, 32.9, 24.2, 18.6.
EtOH (1.0 L) was cooled to 15 °C and NaBH4 (41.6 g, 1.10 mol,
2.20 equiv) was added in one portion. To this suspension under vig-
orous stirring 8a (151 g, 0.50 mol) was added in such a rate that the
temperature was maintained at 15 °C. When the addition was com-
plete, the mixture was stirred at r.t. for 30 min and then evaporated
under reduced pressure. The residue was diluted with H2O (500 mL)
and K2CO3 (138 g, 1.0 mol) was added. The mixture was extracted
with EtOAc (2 × 300 mL), the combined extracts were combined
and evaporated. The residue was purified by flash chromatography
(silica gel, EtOAc–hexane–Et3N, 5:5:1) followed by evaporation
and drying in vacuo to give a yellowish powder; yield: 106 g (94%);
HPLC purity >95%; mp 69–71 °C.
LCMS: m/z = 179.2 [M + H]+.
Anal. Calcd for C11H18N2: C, 74.11; H, 10.18; N, 15.71. Found: C,
74.15; H, 10.16; N, 15.74.
tert-Butyl [2-(1-Methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-
c]pyridin-6-yl)ethyl]carbamate (9e)
White crystalline powder; yield: 2.67 g (58%); HPLC purity >95%;
mp 119–121 °C.
IR (KBr): 3376, 2930, 1683, 1543, 1178, 990, 721 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.51 (s, 1 H, H2), 5.95 (s, 1 H, H3),
5.14–5.37 (br s, 1 H, NH), 3.52 (s, 2 H, 7-CH2), 3.48 (s, 3 H, N-
CH3), 3.29–3.39 (br s, 2 H, NCH2CH2NHBoc), 2.67–2.79 (m, 4 H,
NCH2CH2NH-Boc, 5-CH2), 2.64 (s, 2 H, 4-CH2), 1.47 [s, 9 H,
OC(CH3)3].
13C NMR (126 MHz, CDCl3): δ = 156.1, 125.8, 120.6, 115.3, 105.7,
79.0, 56.6, 51.2, 49.4, 37.6, 32.9, 28.5, 23.5.
IR (KBr): 3421, 2798, 1500, 1308, 1130, 748, 699 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.44–7.53 (m, 2 H, HAr), 7.37–
7.44 (m, 2 H, HAr), 7.30–7.37 (m, 1 H, HAr), 6.54 (br s, 1 H, H2),
6.01 (d, J = 1.8 Hz, 1 H, H3), 3.82 (s, 2 H, NCH2Ph), 3.57 (br s, 2
H, 7-CH2), 3.47 (s, 3 H, NCH3), 2.81 (d, J = 5.2 Hz, 2 H, 5-CH2),
2.70 (br s, 2 H, 4-CH2).
13C NMR (126 MHz, CDCl3): δ = 138.9, 129.1, 128.4, 127.1, 126.1,
120.4, 115.3, 105.8, 62.5, 51.1, 49.7, 33.0, 23.5.
LCMS: m/z = 280.2 [M + H]+.
Anal. Calcd for C15H25N3O2: C, 64.49; H, 9.02; N, 15.04. Found: C,
64.47; H, 9.04; N, 15.00.
LCMS: m/z = 227.3 [M + H]+.
1-(1-Methyl-1,4,5,7-tetrahydro-6H-pyrrolo[2,3-c]pyridin-6-
yl)propan-2-ol (9f)
Yellowish oil; yield: 1.89 g (59%); HPLC purity >95%.
Anal. Calcd for C15H18N2: C, 79.61; H, 8.02; N, 12.38. Found: C,
79.63; H, 8.03; N, 12.34.
IR (KBr): 3407, 2928, 2365; 1636, 1501, 1311, 1057, 718 cm–1.
1,6-Dimethyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine
(9b)
1H NMR (500 MHz, CDCl3): δ = 6.54 (s, 1 H, H2), 5.98 (s, 1 H, H3),
3.99 [br s, 1 H, CH2CH(OH)Me], 3.72 (d, J = 13.5 Hz, 1 H, 7-CH2),
3.54 (d, J = 14.0 Hz, 1 H, 7-CH2), 3.50 (s, 3 H, N-CH3), 2.95 (d,
Yellowish oil; yield: 2.1 g (85%); HPLC purity >95%.
IR (KBr): 3368, 2936, 2777, 1645, 1498, 1306, 1060, 918, 700
cm–1.
J = 5.2 Hz,
1 H, 5-CH2), 2.58–2.78 [m, 4 H, 4-CH2,
CH2CH(OH)Me], 2.46 (t, J = 11.3 Hz, 1 H, 5-CH2), 1.23 (d, J = 5.7
Hz, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 125.8, 120.6, 115.3, 105.8, 65.2,
1H NMR (500 MHz, CDCl3): δ = 6.50 (d, J = 2.3 Hz, 1 H, H2), 5.97
(d, J = 2.6 Hz, 1 H, H3), 3.49 (s, 2 H, 7-CH2), 3.47 (s, 3 H, N1-CH3),
2.70 (s, 4 H, 4-CH2, 5-CH2), 2.55 (s, 3 H, N6-CH3).
62.9, 51.4, 49.8, 33.0, 23.5, 20.1.
LCMS: m/z = 195.1 [M + H]+.
13C NMR (126 MHz, CDCl3): δ = 126.0, 120.3, 114.8, 105.8, 53.3,
51.7, 46.1, 32.8, 23.7.
LCMS: m/z = 151.2 [M + H]+.
Anal. Calcd for C11H18N2O: C, 68.01; H, 9.34; N, 14.42. Found: C,
68.05; H, 9.31; N, 14.45.
Anal. Calcd for C9H14N2: C, 71.96; H, 9.39; N, 18.65. Found: C,
72.00; H, 9.36; N, 18.62.
1-Methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyridine Hydro-
chloride (2·HCl)
6-Ethyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyri-
dine (9c)
Yellowish oil; yield: 2.0 g (74%); HPLC purity >95%.
IR (KBr): 3368, 2932, 2803, 1498, 1311, 1064, 699 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.49 (d, J = 2.1 Hz, 1 H, H2), 5.94
(d, J = 2.1 Hz, 1 H, H3), 3.52 (s, 2 H, 7-CH2), 3.48 (s, 3 H, NCH3),
2.73 (d, J = 5.5 Hz, 2 H, 5-CH2), 2.55–2.71 (m, 4 H, 4-CH2,
NCH2CH3), 1.22 (t, J = 7.1 Hz, 3 H, NCH2CH3).
13C NMR (126 MHz, CDCl3): δ = 126.0, 120.3, 115.3, 105.7, 51.9,
51.1, 49.2, 32.9, 23.5, 12.7.
To a soln of 9a (106 g, 0.47 mol) in MeOH (700 mL), 10% Pd/C
(10.0 g) was added. The mixture was heated to 50 °C and H2 was
bubbled through the mixture under vigorous stirring until no start-
ing material was observed (18 h, TLC control). The mixture was fil-
tered and evaporated under reduced pressure. The residue was
dissolved in TBME (500 mL) and 10% HCl in 1,4-dioxane soln
(200 mL) was added portionwise under ice cooling. The precipitat-
ed product was filtered off, resuspended in i-PrOH (300 mL), fil-
tered, and washed with hexane (2 × 150 mL) to give a white
crystalline solid; yield: 54.5 g (67%); HPLC purity >95%; mp 198–
200 °C.
LCMS: m/z = 165.1 [M + H]+.
IR (KBr): 3435, 2944, 2790, 1601, 1501, 1451, 1439, 737 cm–1.
Anal. Calcd for C10H16N2: C, 73.13; H, 9.82; N, 17.06. Found: C,
73.16; H, 9.85; N, 17.02.
+
1H NMR (500 MHz, DMSO-d6): δ = 9.93 (br s, 1 H, NH2 ), 6.69 (d,
J = 1.8 Hz, 1 H, H2), 5.84 (d, J = 2.1 Hz, 1 H, H3), 4.14 (br s, 2 H,
7-CH2), 3.49 (s, 3 H, NCH3), 3.18 (br s, 2 H, 5-CH2), 2.70 (br s, 2
H, 4-CH2).
13C NMR (126 MHz, DMSO-d6): δ = 122.6, 120.3, 113.6, 105.9,
6-Isopropyl-1-methyl-4,5,6,7-tetrahydro-1H-pyrrolo[2,3-c]pyr-
idine (9d)
Yellowish oil; yield: 2.09 g (71%); HPLC purity >95%.
IR (KBr): 2964, 2909, 1639, 1497, 1308, 1174, 917, 697 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.49 (d, J = 2.1 Hz, 1 H, H2), 5.94
(d, J = 2.3 Hz, 1 H, H3), 3.61 (s, 2 H, 7-CH2), 3.48 (s, 3 H, NCH3),
2.91–3.08 [m, 1 H, NCH(CH3)2], 2.76 (d, J = 5.7 Hz, 2 H, 5-CH2),
2.64 (br s, 2 H, 4-CH2), 1.19 [d, J = 6.5 Hz, 6 H, NCH(CH3)2].
41.8, 33.4, 20.2.
LCMS: m/z = 137.2 [M + H]+.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 919–924

924
M. A. Nechayev et al.
PAPER
(6) Campbell, S. F.; Kobylecki, R. J. EP 186431, 1986; Chem.
Abstr. 1986, 105, 153548.
(7) Swinnen, D.; Bombrun, A. WO 2006008303, 2006; Chem.
Abstr. 2006, 144, 170972.
References
(1) (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem.
2009, 52, 6752. (b) Kingwell, K. Nat. Rev. Drug Discovery
2009, 8, 931.
(2) van der Meijden, M. W.; Leeman, M.; Gelens, E.; Noorduin,
W. L.; Meekes, H.; van Enckevort, W. J. P.; Kaptein, B.;
Vlieg, E.; Kellogg, R. M. Org. Process Res. Dev. 2009, 13,
1195.
(3) (a) Maffrand, J. P.; Eloy, F. Eur. J. Med. Chem. 1974, 9, 483.
(b) Satake, K.; Imai, T.; Kimura, M.; Morosawa, S.
Heterocycles 1981, 16, 1271. (c) Aillaud, I.; Haurena, C.;
Gall, E. L.; Martens, T.; Ricci, G. Molecules 2010, 15, 8144.
(4) Abou-Gharbia, M.; Patel, U. R.; Webb, M. B.; Moyer, J. A.;
Andree, T. H.; Muth, E. A. J. Med. Chem. 1987, 30, 1818.
(5) Other multistep approaches for the synthesis of 4,5,6,7-
tetrahydro-1H-pyrrolo[2,3-c]pyridine core apply
synthetically available pyrrole-2/3-carbaldehydes as starting
materials: (a) Rousseau, J.-F.; Dodd, R. H. J. Org. Chem.
1998, 63, 2731. (b) Bandini, M.; Melloni, A.; Piccinelli, F.;
Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem.
Soc. 2006, 128, 1424.
(8) (a) Mahadevan, I.; Rasmussen, M. Tetrahedron 1993, 49,
7337. (b) Van Baelen, G.; Hostyn, S.; Dhooghe, L.;
Tapolcsányi, P.; Mátyus, P.; Lemière, G.; Dommisse, R.;
Kaiser, M.; Brun, R.; Cos, P.; Maes, L.; Hajós, G.; Riedl, Z.;
Nagy, I.; Maes, B. U. W.; Pieters, L. Bioorg. Med. Chem.
2009, 17, 7209. (c) Huestis, M. P.; Fagnou, K. Org. Lett.
2009, 11, 1357.
(9) Nechayev, M. A.; Gorobets, N. Yu.; Borisov, A. V.;
Kovalenko, S. M.; Tolmachev, A. A. Mol. Divers. 2012, 16,
749.
(10) Jaramillo, D.; Liu, Q.; Aldrich-Wright, J.; Tor, Y. J. Org.
Chem. 2004, 69, 8151.
(11) It should be noted that application of benzyl chloride in such
procedure is not recommended since the resulting chloride
salt is highly hygroscopic.
(12) The sp3-fraction is the number of sp3-hybridized carbons
divided by the total carbon count; see ref. 1a for details.
Synthesis 2013, 45, 919–924
© Georg Thieme Verlag Stuttgart · New York