Synthesis of the 7-azaindole (1H-pyrrolo[2,3-b]pyridine) analogous to cannabimimetic JHW 200

Article abstract of DOI:10.1080/00397910600767504

Cannabinoid agonists have been suggested to have potential therapeutic uses. The synthesis of a new cannabimimetic analogue of JHW 200 possessing a 7-azaindole unit instead of an indole moiety is described. The approach used for indole derivatives failed, and a new strategy that involves the reaction of a nitrile and 1-naphtyl magnesium bromide was studied. Copyright Taylor & Francis Group, LLC.

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Synthesis of the 7‐Azaindole
(1H‐Pyrrolo[2,3‐b]pyridine) Analogous to
Cannabimimetic JHW 200
Sébastien Gluszok a , Laurence Goossens a , Patrick Depreux a , Didier Barbry
b & Jean‐Pierre Hénichart a
a Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille,
Lille, France
b Laboratoire de Chimie Organique, Université des Sciences et Technologies
de Lille, Villeneuve d'Ascq, France
Version of record first published: 16 Feb 2007.
To cite this article: Sébastien Gluszok, Laurence Goossens, Patrick Depreux, Didier Barbry & Jean‐Pierre
Hénichart (2006): Synthesis of the 7‐Azaindole (1H‐Pyrrolo[2,3‐b]pyridine) Analogous to Cannabimimetic
JHW 200, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 36:19, 2797-2805
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Synthetic Communicationsw, 36: 2797–2805, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600767504
Synthesis of the 7-Azaindole
(1H-Pyrrolo[2,3-b]pyridine) Analogous
to Cannabimimetic JHW 200
´
Sebastien Gluszok, Laurence Goossens, and Patrick Depreux
Institut de Chimie Pharmaceutique Albert Lespagnol, Universite de Lille,
´
Lille, France
Didier Barbry
Laboratoire de Chimie Organique, Universite des Sciences et
Technologies de Lille, Villeneuve d’Ascq, France
´
´
Jean-Pierre Henichart
´
Institut de Chimie Pharmaceutique Albert Lespagnol, Universite de Lille,
Lille, France
Abstract: Cannabinoid agonists have been suggested to have potential therapeutic
uses. The synthesis of a new cannabimimetic analogue of JHW 200 possessing a
7-azaindole unit instead of an indole moiety is described. The approach used for
indole derivatives failed, and a new strategy that involves the reaction of a nitrile
and 1-naphtyl magnesium bromide was studied.
Keywords: Amino-alkyl-indole, 7-azaindole, cannabimimetic, Grignard condensation
INTRODUCTION
For thousands of years, preparations of the plant Cannabis sativa have been used
not only for recreational purposes but also in traditional medicinal chemistry.[1]
Following the identification of D9-tetrahydrocannabinol[2] (D9-THC) (1) (Fig. 1),
Received in the U.K. August 16, 2005
Address correspondence to Patrick Depreux, Institut de Chimie Pharmaceutique
´
Albert Lespagnol, Universite de Lille, EA 2692, 3, rue du Professeur Laguesse,
B.P. 83, F 59006 Lille, France. E-mail: patrick.depreux@univ-lille2.fr
2797

Figure 1. Structure of compounds.

7-Azaindole (1H-Pyrrolo[2,3-b]pyridine)
2799
one of the most psychoactive components of marijuana, a large range of new
structures binding to cannabinoid receptors have been reported.[3–5] The canna-
binoid ligands may be useful agents to treat some disorders such as chronic
inflammatory disease,[5] obesity[6] (the CB1 antagonist SR 141716 is actually
under clinical trials), Parkinson’s disease,[7] and cancer.[8]
Among the nonclassical cannabinoids, we particularly are interested in
the class of amino-alkyl-indoles (AAI). This class of compounds was
reported in 1992,[9] and one of the most studied compound is WIN 55212-2
(2). Less rigid analogues of (2), JHW compounds,[5] were then considered
for their ability to bind to cannabinoid receptors. In our research to find
new cannabinoid agonists, JHW 200[5] (3) (CB1 Ki ¼ 42 nM) was used as
a reference compound.
On the other hand, azaindoles have been the subject of investigations in
medicinal chemistry because they are considered indole bioisosters.[10–12]
They are potential pharmaceuticals agents.[10] For example, DF 1012 (5)
(7-azaindolylcarboxy-endo-tropanamide),[13] an antitussive candidate drug,
is actually under investigation in phase II clinical trials. Moreover, recent
reports show great interest in replacing the indole ring with a 7-azaindole
unit in isogranulatimide[11] and staurosporine analogues[12] designed to
increase the interactions with the target enzyme(s).
In this article, we report the synthesis of f1-(2-morpholin-4-yl-ethyl)-1H-
pyrrolo[2,3-b]pyridin-3-ylg-naphthalen-1-yl-methanone (4), an analogue of
the cannabimimetic JHW 200 (3) possessing a 7-azaindole moiety instead
of the indole moiety.
RESULTS AND DISCUSSION
To access AAI, Eisenstat et al.[14] proposed two main approaches: in the first
one, the indole anion (obtained from ethyl-magnesium bromide and indole)
reacts with an excess of 1-napthoyl chloride. This strategy was not efficient
(a, Scheme 1) with 7-azaindole (6). The AAI have also been prepared
another way, using Friedel–Crafts acylation of indole. Moreover, Zang
et al.[15] reported good yields in the reaction of 7-azaindole with a large
range of acyl chlorides, but in our hands 7-azaindole (6) and its 1-alkyl
derivative (7) do not react with 1-naphtoyl chloride (b, Scheme 1). This
1-alkyl derivative (7) resulted from the reaction of N-(2-chloroethyl)morpho-
line hydrochloride with the 7-azaindole anion obtained from compound (6)
and sodium hydride. The lack of reactivity of the 3-position of the
7-azaindole compared to the same position of the indole, implied in these
two procedures, is probably due to the withdrawing effect of the pyridyl
nitrogen atom.
The Suzuki coupling often offers a good method to obtain aryl ketones.
Unfortunately, the palladium-catalyzed coupling of 1-naphtylboronic acid
with 7-azaindol-3-carboxylic acyl chloride (8)[13–16] (c[17], Scheme 1) or

2800
S. Gluszok et al.
Scheme 1. Strategies used to obtain compound (4): Reagents and conditions: (a)
1) EtMgBr 2) 1-Napthoyl chloride, ether, rt, 1 h. (b) AlCl3 (3 equiv.), CH2Cl2, rt,
1 h. (c) 1-Naphthylboronic acid, Cs2CO3, Pd(PPh3)4, toluene, 1008C, 16 h.
(d) 1-Naphthylboronic acid, pivalic anhydride, Pd(OAc)2, diphenyl(ferrocenyl)phos-
phane (DPPF), THF, 608C, 16 h. (e) THF, reflux, 2 h, 45%. (f) Pyridinium dichro-
mate, CH2Cl2. (g) THF, reflux, 2 h, 45%. (h) H2SO4 (1M), reflux, 2 h, 85%. (i) 1)
NaH, DMF, 08C, 30 min, 2) N-(2-chloroethyl)morpholine hydrochloride, DMF,
608C, 6 h, 85%.
7-azaindol-3-carboxylic acid (9)[13–16] (d[18], Scheme 1) does not yield the
desired compound.
We then investigated a Grignard approach to (14). Reactions of acyl
chlorides or carboxylic esters with organometallic reagents led to poor
yields of ketones, due to the difficulty of stopping the ketone from being
converted into the tertiary alcohol. We have used two other pathways to
obtain the compound (14). Addition of 1-naphtyl magnesium bromide on
3-formyl-7-azaindole (10) (obtained in 50% yield from 7-azaindole
according the Robinson’s procedure[16]) led to the secondary alcohol (11) in
45% yield. Attempts to oxidate the secondary alcohol (11) (f, Scheme 1)
via pyridinium dichromate were unsuccessful, whereas 3-acetyl-7-azaindole
was obtained in good yield from 3-(2-hydroxyethyl)-7-azaindole.[19] The
use of different solvents, glacial acetic acid, or other oxidation methods
(Swernoxydation) did not improve this result.
Lastly, the reaction of 1-naphtyl magnesium bromide with 3-cyano-7-
azaindole (12) afforded the corresponding imine (13) with fairly good yield

7-Azaindole (1H-Pyrrolo[2,3-b]pyridine)
2801
(45%). 3-Cyano-7-azaindole (12) can be obtained from 3-formyl-7-azaindole
(10) according to Robinson’s method in two steps[16] with poor yields. Alter-
natively, (12) was prepared in four steps from succinonitrile.[13] The imine
(13) was easily hydrolyzed with diluted sulfuric acid into the corresponding
ketone (14). Compound (14) was then alkylated as described for (7). N-Alky-
lation of the 7-azaindole anion was performed in an aprotic solvent (DMF) and
at low temperature to avoid N-alkylation on the pyridine ring. Literature[10]
showed that 7-azaindole is alkylated on the pyridyl nitrogen atom ring by
heating. The analysis of the crude alkylation product of (14) showed the
presence of another product (10%): this nonisolated product might be
the 7-alkylated compound, as obtained and characterized in the alkylation
crude of 3-formyl-7-azaindole (10) (Scheme 2) beside the main 1-alkylated
compound.
In conclusion, the synthesis of an analogue of JHW 200 with a 7-azaindole
moiety is described. The preparation of others analogues with a 5-azaindole
moiety are in progress. Biological properties of these compounds, especially
their ability to bind to cannabinoid receptors, will be evaluated.
EXPERIMENTAL
Apparatus and Procedures
1H and 13C NMR spectra were recorded on a AC-300 Bruker instrument.
Column chromatography was performed on Merck silica gel
(0.040–0.063 mm). IR spectra were recorded on a Brucker Vector 22
Scheme 2. Mechanism of the N-alkylation of the 3-formyl-7-azaindole (10):
Reagents and conditions: (a) 1) NaH, DMF, 08C, 30 min, 2) N-(2-chloroethyl)morpho-
line hydrochloride, DMF, 608C, 6 h.

2802
S. Gluszok et al.
instrument. APCIþ (atmospheric pressure chemical ionization) mass spectra
were obtained on a LC-MS system Thermo Electron Surveyor MSQ.
4-[2-(1H-Pyrrolo[2,3-b]pyridin-1-yl)ethyl]morpholine (7). A solution of
7-azaindole (6) (1 g, 8.5 mmol) in DMF (7 mL) was added under nitrogen
to a cooled (08C) suspension of sodium hydride (1.24 g, 31 mmol; 60% in
mineral oil) in anhydrous DMF (7 mL). The resulting mixture was stirred
for 30 min. N-(2-Chloroethyl)morpholine hydrochloride (2.15 g, 11.5 mmol)
was added, and the resulting solution was stirred at 508C for 6 h. After
cooling at room temperature, 4 mL of water were added; the mixture was
filtered and the residue washed with DMF. The solution was concentrated,
and the product was purified by column chromatography [CHCl3/EtOH: 8/
1
2 (v/v)] to give (7) as a yellow oil (1.27 g, 65%). H NMR (300 MHz,
CDCl3) d 2.48 (m, 4H), 2.73 (t, 2H, J ¼ 6.7 Hz), 3.62 (m, 4H), 4.40 (t, 2H,
J ¼ 6.7 Hz), 6.40 (d, 1H, J ¼ 3.6 Hz), 7.00 (dd, 1H, J ¼ 8.0, 4.9 Hz), 7.25
(d, 1H, J ¼ 3.6 Hz), 7.85 (dd, 1H, J ¼ 8.0, 1.5 Hz), 8.28 (dd, 1H, J ¼ 4.9,
1.5 Hz). 13C NMR (50 MHz, CDCl3) d 41.6, 53.6, 58.2, 66.9, 99.4, 115.6,
120.5, 128.4, 128.7, 142.6, 147.4; LC/MS m/z 232 (MHþ, 95%).
[1-(2-Morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl](1-naphthyl)methanol
(11). A solution of 1-bromonaphthalene (1.41 g, 6.8 mmol) in THF (2 mL) was
slowly added to a stirred suspension of magnesium (0.16 g, 6.8 mmol) in
anhydrous THF (5 mL). After refluxing 2 h, the mixture was cooled to room
temperature and a solution of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (10)
(0.2 g, 1.3 mmol) in hot THF (5 mL) was slowly added and refluxed for 2 h.
Water (2 mL) was added; the precipitate was filtered and washed with THF.
The solution was concentrated; water (10 mL) and Et2O (10 mL) were
added. The precipitate was collected by filtration, washed with Et2O, and
dried to give (11) as a white solid (0.16 g, 45%), mp 1278C. 1H NMR
(300 MHz, DMSO-d6) d 5.9 (d, 1H, J ¼ 4.4 Hz), 6.65 (d, 1H, J ¼ 4.4 Hz),
6.95 (dd, 1H, J ¼ 7.7, 4.6 Hz), 7.20 (d, 1H, J ¼ 2.2 Hz), 7.4 (m, 2H), 7.55
(t, 1H, J ¼ 7.4 Hz), 7.82 (d, 2H, J ¼ 8.0 Hz), 7.9 (d, 2H, J ¼ 7.7 Hz),
8.15 (dd, 1H, J ¼ 4.4, 1.4 Hz), 8.2 (d, 1H, J ¼ 7.4 Hz), 11.45 (bs, 1H). 13C
NMR (50 MHz, DMSO-d6) d 66.3, 115.0, 117.7, 118.2, 123.8, 124.2, 125.3,
125.6, 127.4, 128.4, 130.3, 133.4, 140.3, 142.4, 148.7; LC/MS m/z 275
(MHþ, 98%).
1-(2-Morpholinoethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (15) and
7-(morpholinoethyl)-7H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (16). These
compounds were obtained according to the same chemical procedure
described for compound (7) using compound (10) as the starting material.
The crude product was purified by column chromatography [CHCl3/EtOH:
8/2 (v/v)] to afford two isomers.
1-(2-Morpholinoethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (15)
1
as an oil (0.36 g, 69%): H NMR (300 MHz, CDCl3) d 2.46 (m, 4H), 2.76

7-Azaindole (1H-Pyrrolo[2,3-b]pyridine)
2803
(t, 2H, J ¼ 6.2 Hz), 3.62 (m, 4H), 4.4 (t, 2H, J ¼ 6.2 Hz), 7.19 (dd, 1H,
J ¼ 8.1, 4.7 Hz), 7.95 (s, 1H), 8.33 (dd, 1H, J ¼ 4.7, 1.6 Hz), 8.46 (dd, 1H,
J ¼ 8.1, 1.6 Hz), 9.90 (s, 1H). 13C NMR (50 MHz, CDCl3) d 42.0, 53.6,
57.8, 66.9, 116.2, 117.5, 118.8, 130.4, 138.9, 144.8, 148.4, 184.6; LC/MS
m/z 260 (MHþ, 98%).
7-(Morpholinomethyl)-7H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (16) as an
1
oil (0.054 g; 10%): H NMR (300 MHz, CDCl3) d 2.49 (m, 4H), 2.95 (t, 2H,
J ¼ 6.0 Hz), 3.62 (m, 4H), 4.81 (t, 2H, J ¼ 6 Hz), 7.16 (dd, 1H, J ¼ 7.6,
6.4 Hz), 7.87 (d, 1H, J ¼ 6.4 Hz), 8.38 (s, 1H), 8.81 (d, 1H, J ¼ 7.6 Hz), 9.97
(s, 1H). 13C NMR (50 MHz, CDCl3) d 50.7, 53.6, 57.1, 66.8, 113.4, 119.2,
126.8, 132.7, 134.5, 151.4, 155.8, 184.8; LC/MS m/z 260 (MHþ, 97%).
1-Naphthyl(1H-pyrrolo[2,3-b]pyridin-3-yl)methanimine (13). This compound
was obtained according to the same chemical procedure described for
compound (11) using compound (12) as the starting material. The crude
product obtained from 1-bromonaphtalene and 1H-pyrrolo[2,3-b] pyridine-
3-carbonitrile (12) was treated after evaporation of THF by a diluted
solution of hydrochloric acid. The acidic aqueous layer was washed with
Et2O (3 ꢀ 15 mL) and treated by a solution of sodium hydroxide until it
reached pH 9. The precipitate was collected by filtration, washed with
1
water, and dried to give (13) as a white solid (0.17 g, 45%), mp 138 8C. H
NMR (300 MHz, DMSO-d6) d 3.40 (bs, 1H), 7.15 (m, 2H), 7.50 (m, 4H),
7.80 (d, 1H, J ¼ 7.7 Hz), 7.90 (d, 1H, J ¼ 8 Hz), 8.05 (d, 1H, J ¼ 7.7 Hz),
8.30 (d, 1H, J ¼ 4.4 Hz), 8.50 (d, 1H, J ¼ 7.4 Hz), 10.9 (bs, 1H). 13C NMR
(50 MHz, DMSO-d6) d 114.9, 117.1, 124.6, 125.2, 125.4, 126.2, 126.6,
128.3, 128.6, 129.9, 130.1, 132.6, 133.2, 139.0, 143.7, 150.1, 170.7; LC/
MS m/z 272 (MHþ, 96%).
Naphthalen-1-yl-(1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (14). A mixture
of the imine (13) (0.16 g, 0.59 mmol) in diluted sulfuric acid 1 M solution
(15 mL) was refluxed for 2 h. The solution was cooled at room temperature,
diluted with water (10 mL), and filtered. A concentrated solution of sodium
hydroxide was added until precipitation. The precipitate is collected by fil-
tration, washed with water, and dried to give (14) as a white solid (0.072 g,
1
45%), mp 1258C. H NMR (300 MHz, DMSO-d6) d 7.30 (m, 1H), 7.55
(m, 3H), 7.75 (m, 1H), 7.85 (m, 1H), 8.05 (m, 3H), 8.35 (m, 1H), 8.55
(m, 1H), 12.65 (bs, 1H). 13C NMR (50 MHz, DMSO-d6): d 115.8, 118.4,
124.9, 125.2, 126.2, 126.3, 126.9, 128.3, 129.8, 130.1, 133.4, 136.8, 137.6,
144.7, 149.3, 191.4; LC/MS m/z 273 (MHþ, 98%).
[1-(2-Morpholinoethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl](1-naphthyl)meth-
anone (4). This compound was obtained according to the same chemical
procedure described for compound (7) using compound (14) as the starting
material. The crude product obtained from (14) was treated after evaporation
of THF by a diluted solution of hydrochloric acid. The acidic aqueous layer

2804
S. Gluszok et al.
was washed three times with CHCl3 and treated with a solution of sodium
hydroxide until it reached pH 9. The precipitate was extracted with ether;
the organic layers were dried and concentrated to afford a brown oil, which
was purified by column chromatography [CHCl3/EtOAc: 5/5 (v/v)] to give
(4) as a yellow oil (0.085 g, 85%). IR (neat): 2960, 1630, 1695, 1115 cm21
.
1H NMR (300 MHz, CDCl3) d 2.35 (m, 4H), 2.70 (t, 2H, J ¼ 6.1 Hz), 3.45
(m, 4H), 4.35 (t, 2H, J ¼ 6.1 Hz), 7.35 (m, 1H), 7.45 (m, 3H), 7.65
(m, 2H), 7.9 (m, 2H), 8.15 (m, 1H), 8.4 (m, 1H), 8.7 (m, 1H). 13C NMR
(50 MHz, CDCl3) d 41.6, 53.4, 57.7, 66.8, 115.7, 118.8, 119.3, 124.4,
125.7, 126.0, 126.4, 126.9, 128.3, 130.4, 130.7, 131.1, 133.8, 138.2, 138.8,
144.5, 148.3, 192.0; LC/MS m/z 386 (MHþ, 100%).
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