Facile synthesis of fluorinated pyrrolo[2,3-b]pyridines

Article abstract of DOI:10.1055/s-0028-1087530

With the purpose to synthesize novel ADAs (adenosine deaminase) and IMPDH (inosine 5′-monophosphate dehydrogenase) inhibitors the reaction of 5-amino-1-tert-butyl-1H-pyrrolo-3-carbonitrile with fluorinated 1,3-biselectrophiles was studied. An efficient an

Full text of DOI:10.1055/s-0028-1087530

456
LETTER
Facile Synthesis of Fluorinated Pyrrolo[2,3-b]pyridines
S
ynthesisof Fluor
l
inate
d
P
r
yrrolo[2
i
,3-
b
]p
c
s
h Groth,* Viktor O. Iaroshenko, Yan Wang, Thomas Wesch
Fachbereich Chemie und Konstanz Research School Chemical Biology, Universität Konstanz, Fach M-720, Universitätsstr. 10,
78457 Konstanz, Germany
Fax +49(7531)884155; E-mail: Ulrich.groth@uni-konstanz.de
Received 9 September 2008
similar pyrrolopyridines the most significant compound
Abstract: With the purpose to synthesize novel ADAs (adenosine
among them is 7-azaindolylcarboxy-endo-tropanamide
deaminase) and IMPDH (inosine 5¢-monophosphate dehydroge-
(DF 1012, 5, Figure 1), which is the selected candidate
drug in a new class of non-narcotic antitussive compounds
nase) inhibitors the reaction of 5-amino-1-tert-butyl-1H-pyrrolo-3-
carbonitrile with fluorinated 1,3-biselectrophiles was studied. An
efficient and convenient synthetical approach to obtain fluorinated and is actually under investigation in phase II clinical tri-
als.7
pyrrolo[2,3-b]pyridines was developed. tert-Butyl protecting group
was successfully cleaved by treating of synthesized pyrrolo-
It became apparent that a variety of C-6-modified purines8
pyridines with concentrated sulfuric acid.
and their isosteres9 including pyrrolopyridines10 and
Key words: pyrrol, amine, fluorine, pyridine, annulation, electro-
philic aromatic substitution
pyrrolopyrimidines11 were recognized as ADA (adeno-
sine deaminase) inhibitors. Some of them have been syn-
thesized and their pharmaceutical evaluation is currently
under investigation.
Nucleosides containing pyrrolo[2,3-b]pyridine and pyrro-
6-(Trifluoromethyl)-substituted purine analogues are sus-
pected to be a promising scaffold for the elaboration of
potential ADA inhibitors.12 Through the electron-with-
drawing CF3 group the hydration on the position 6 is en-
abled to form stable hydrates. The CF3 group is
isosterically similar to the amino function,13 thus 6-hy-
droxy 6-(trifluoromethyl)purines and their isosteres can
be considered as a putative adenosine deamination transi-
tion-state mimetic. Coformycin and pentostatin and their
derivatives contain a tetrahedral carbon (C-8) bearing a
hydroxy group. These naturally occurring ADA inhibitors
possess a strong activity (coformycin, Ki = 1.0·10–11 M;
pentostatin, Ki = 2.5·10–12 M on calf intestine ADA) that
is attributed to the extremely tight-binding (nearly irre-
versible) interaction of those compounds with ADA,
mimicking the transition state of ADA activity.14
lo[2,3-d]pyrimidine ring systems as a nucleobase play a
significant role in modern medical chemistry. Since pyr-
rolo[2,3-b]pyridines and pyrrolo[2,3-d]pyrimidines were
considered as 1,7-deaza and 7-deazapurines, respectively,
and their biological activities were recognized to be close
to purine one; in the last decades a set of drugs and bioac-
tive molecules containing those two heterocyclic systems
appeared on the market.
Recently, several naturally occurring nucleoside antineo-
plastics,1 possessing a pyrrolo[2,3-d]pyrimidine frame-
work, such as tubercidin (1), toyocamycin (2), sangiva-
mycin (3), and cadeguomycin (4, Figure 1) were isolated.
Their frequent natural occurrence and unusual biological
properties have promoted ample studies toward their syn-
thesis and biological evaluation.2 Several structurally re-
lated deazapurine nucleosides have been synthesized,
which have shown antitumor,3 anti-HIV,4 and antiviral5
activities. Triciribine (TCN) came successfully through
phase I clinical trial, and it was advanced to phase II stud-
ies as a potential antineoplastic agent.6 Concerning the
It was shown that the 6-chloro-substituted purine base15 is
dehalogenated by inosine 5¢-monophosphate dehydroge-
nase (IMPDH) and a covalent bond is formed at C-6 with
Cys 331.
O
NH2
Me
CO2H
R
N
O
HN
N
NH
N
H2N
RO
N
N
N
O
O
N
H
N
HO
HO
OH
HO
OH
1 R = H
5 (DF 1012)
4
2 R = CN
3 R = CONH2
Figure 1 Natural occurring and pharmacoactive pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridines
SYNLETT 2009, No. 3, pp 0456–0460
x
x.
x
x.
2
0
0
8
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087530; Art ID: G27908ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Facile Synthesis of Fluorinated Pyrrolo[2,3-b]pyridines
457
Hence, purines and their analogues bearing polyfluoro- We have started our attempts with the study of the reac-
alkyl substituents in the positions 2 and 6 should also be tion of the previously mentioned aminopyrrol 8 with poly-
considered as potential IMPDH inhibitors, due to the pos- fluoroalkyl-1,3-diketones 10 (Scheme 2). The studied
sible formation of the covalent binding with the Cys 331 reaction yields pyrrolo[2,3-b]pyridines 1120 (Table 1)
rest of the active side of the enzyme. We are suspecting bearing the fluoroalkyl substituent in the position 4 of the
that the highly electrophilic C-6 (C-2) atom bearing an annulated pyridine ring. The cyclocondensation proceeds
electron-withdrawing polyfluoroalkyl group will attack regioselectively to provide the desired g-regioisomer; a
the mercapto function of Cys 331. The stable adduct re- formation of the a-RF regioisomer was not observed (13C
sults in an irreversible enzyme inhibition.
NMR, 19F NMR).
Our primary interests are focused on the design and syn-
thesis of novel ligands for ADA and IMPDH, which
would be based on the polyfluoroalkyl containing purines
and purine isosteres. The retrosynthetic analysis
(Scheme 1) is based on the chemical properties of elec-
tron-enriched aminoheterocycles. The heteroannulation
of aminopyrroles and polyfluoro-substituted 1,3-CCC/
1,3-CNC-biselectrophiles results in the pyrrolo[2,3-b]py-
ridines and pyrrolo[2,3-d]pyrimidine with the desired
substitution pattern.
RF
N
RF
NC
NC
i
O
+
N
N
R
O
R
NH2
8
10
11a–h 81–98%
Scheme 2 Reagents and conditions: (i) AcOH, reflux under inert
atmosphere, 1 h.
Table 1 Yields of Pyrrolo[2,3-b]pyridines 11a–i
R1
Product
11a
RF
R
Yield (%)a
R1
R1
X
NC
CF3
CF3
Me
Ph
Me
Ph
Me
Et
89
94
88
81
90
98
84
89
R2
+
N
N
X
X
O
11b
11c
CF3
+
R2
N
N
N
R2
NH2
H
HO
t-Bu
CF3
HO
R3
6
7
8
9
11d
11e
CF2H
CF2Cl
C2F5
X = N, C
3 = H, OH
R
Scheme 1 Retrosynthetic analyses
11f
This concept of building up heterocyclic systems has re- 11g
CF2CF2H
CF3CF2CF2CF2
cently gained a wide popularity. Hence, it opens a wide
range of practical routes towards fluorinated purine ana-
11h
Et
logues, and a number of small fluorine-containing hetero- a Yields refer to pure isolated products.
cycles.16
The unsubstituted 1H-pyrrol-2-amine is hardly accessible
and not stable.17 For our current study the stable and easily
accessible 5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile
was used. The tert-butyl protection group and the elec-
tron-withdrawing cyano function maintain the stability of
this heterocycle. Furthermore, the tert-butyl and cyano
groups could easily be removed from the pyrrolopyridine
derivate.18
The cyclic diketones 12 were no exception to the general
rule. They have proved to be suitable for the reaction of
pyridine ring annulation, which led to the formation of lin-
ear 1,5,6,7-tetrahydrocyclopenta[b]pyrrolo[3,2-e]pyridine
and 5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinolines 13
(Scheme 3). Various solvents were tested as reaction me-
dia, the best results have been obtained using acetic acid.
Cycloaddition takes place in boiling acetic acid under in-
ert atmosphere of nitrogen for one hour.21 The studied in-
teraction proceeds quite clean to deliver no byproducts, if
the initial diketone and pyrrolamine were analytically
pure. An excess of electrophile was removed afterwards
in vacuo, and the subsequent purification was not de-
manded (11b,g). However, in the case of cyclic diketones
12, during the examination of the reaction mixture by 19F
NMR, a number of byproducts were detected. Attempts to
isolate them failed. Formed pyrrolopyridines 11 and 13
could easily be purified by flash chromatography or
recrystallized from the appropriate solvent.
Further, a glycosylation reaction should be studied with
the purpose to couple ribose/2-deoxyribose rests with the
fluorinated nucleobase moiety 7.
In the following, the design and synthesis of novel poten-
tial inhibitors of the ADA and IMPDH enzymes family
are presented. The practical synthetic route to pyrrolo[2,3-
b]pyridines, starting from the 5-amino-1-tert-butyl-1H-
pyrrole-3-carbonitrile (8) and a number of 1,3-CCC-bis-
electrophiles containing a fluoroalkyl group (10, 12, 14).
Previously, methods giving rise to pyrrolo[2,3-b]py-
ridines via annulation of pyridine ring to aminopyrrole
moiety have been reported.18,19
Synlett 2009, No. 3, 456–460 © Thieme Stuttgart · New York

458
U. Groth et al.
LETTER
RF
RF
CF3
CF3
NC
CF3
N
NC
NC
HO2C
i
O
i
ii
(CH2)n
(CH2)n
+
N
N
N
N
O
N
R
R
N
NH2
N
N
R
H
H
R
t-Bu
R
t-Bu
13a,b
8
12a,b
11a–c, 16
17 20–43%
a: RF = CF3, R = H, n = 2
b: RF = CF3, R = CF3CO, n = 2
c: RF = CF2CF2H, R = H, n = 1
61%
55%
64%
Scheme 5 Reagents and conditions: (i) concd H2SO4 100 °C, 8 h,
(ii) concd HCl, reflux, 8 h.
Scheme 3 Reagents and conditions: (i) AcOH, reflux under inert at-
mosphere, 1 h.
polyfluoroalkyl substituent by the C-4 atom of the annu-
lated pyridine ring. The reactions described demonstrate
the practical use of the evaluated method, which also al-
lows one to build up libraries of scaffolds 17. The pyrrolo-
pyridines of type 17 are considered as potent
pharmacophor. The attempts to synthesize N-glycosylat-
ed and N-alkylated 4-(polyfluoroalkyl)-1H-pyrrolo[2,3-
b]pyridines are currently under investigation in our labo-
ratory.
The application of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one
(14) for the heterocyclization has recently been studied.22
Aminopyrrole 8 reacts smoothly with 14 to afford com-
pound 15,23 the product of initial attack of b-position of
vinyl function on the amino moiety of the aminohetero-
cycle (Scheme 4). Reaction proceeds in absolute DMF by
85 °C under inert atmosphere.
This intermediate undergoes 6-exo-trig cyclization under
the harsh conditions (melting at 180 °C) yielding 1-tert-
butyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3
carbonitrile (16).24 For the a-substituted pyridines the
coupling constant (3JHH) between a- and b-protons is ex-
pected to be about 8 Hz. In the case of 16 this coupling
constant was measured to be 4.7 Hz, which strongly sug-
gests the g-CF3 substitution of the formed pyridine.
Acknowledgment
V.I. thanks the DAAD, Euler program, for a fellowship and the part-
nership program between the University of Konstanz and the NTSU
Kiew for having the opportunity, to perform his doctoral studies in
Konstanz. T.W. thanks the Konstanz research school chemical bio-
logy (KoRS-CB) for scientific encouragement and its academic
training. We thank Dmitri Sevenard, Hansa Fine Chemicals GmbH,
for providing valuable starting materials. We are grateful to the
Bayer AG, the Merck KGaA, and the Wacker AG for generous gifts
of reagents.
Slow crystallization of compound 11c from DMSO af-
forded stable diffraction-quality crystals. Single-crystal
X-ray investigation confirmed the pyrrolopyridine struc-
ture of molecule 11c unambiguously.25
References and Notes
Finally, pyrrolopyridines 11a and 13 were transformed to
the substrates 17 suitable for glycosylation possessing the
free first position. This reaction was carried out in a two-
step procedure. During the first step the tert-butyl-protect-
ed pyrrolopyridine carbonitrile was treated with concen-
trated sulfuric acid for a period of eight hours at 100 °C.
Lower temperatures resulted quantitatively in the tert-
butyl-protected carboxylic acid. The decarboxylation was
carried out under reflux in concentrated hydrochloric acid.
The compounds 17 were obtained in moderate yields
(Scheme 5).
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In summary, a convenient synthetic approach to the
fluorinated pyrrolo[2,3-b]pyridine ring system was devel-
oped based on the commercially available 5-amino-1-tert-
butyl-1H-pyrrole-3-carbonitrile (8) and the series of 1,3-
CCC fluorine-containing biselectrophiles. The elaborated
method gives rise to pyrrolo[2,3-b]pyridine bearing the
(3) (a) Nekhai, S.; Bhat, U. G.; Ammosova, T.; Radhakrishnan,
S. K.; Jerebtsova, M.; Niu, X.; Foster, A.; Layden, T. J.;
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O
CF3
NC
NC
CF3
NC
i
CF3
ii
O
+
N
N
N
N
NH2
N
H
OMe
t-Bu
t-Bu
t-Bu
8
14
15 68%
16 71%
Scheme 4 Reagents and conditions: (i) in absolute DMF under inert atmosphere, 85 °C, 12 h; (ii) without solvent, under inert atmosphere
180 °C, 5 h.
Synlett 2009, No. 3, 456–460 © Thieme Stuttgart · New York

LETTER
147, 420059. (c) Fujiwara, Y.; Hosokawa, Y.; Watanabe,
Facile Synthesis of Fluorinated Pyrrolo[2,3-b]pyridines
459
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pyrrolo[2,3-b]pyridine-3-carbonitrile (11e)
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Colorless solid (0.65g, 90%); mp 234 °C (from EtOH). 1H
NMR (400 MHz, DMSO-d6): d = 1.87 (9 H, s, CH3), 7.53
(3 H, br m), 8.07 (1 H, s), 8.18 (2 H, d, 3JCH = 7.8 Hz), 8.70
(1 H, s). 13C NMR (100.5 MHz, DMSO-d6): d = 28.9, 59.5,
81.9, 109.4 (t, 3JCF = 6.4 Hz), 112.8 (t, 3JCF = 2.4 Hz), 114.9,
124.6, (t, 1JCF = 290 Hz), 126.9, 129.0, 129.6, 135.2 (t,
2JCF = 30 Hz), 137.8, 139.7, 148.0, 151.3. MS: m/z (%) =
361(13) [M+ + 2], 359(36) [M+], 304(23), 303(100), 269(16),
268(75), 57(13). Anal. Calcd for C19H16ClF2N3: C, 63.42; H,
4.48; Cl, 9.85; F, 10.56; N, 11.68. Found: C, 63.50; H, 4.53;
N, 11.75.
(21) The General Procedure for Synthesis of Pyrrolo[2,3-
b]pyridines 11 and 13
5-Amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (0.33 g, 2
mmol) and diketone 10 (or 12, 2.2 mmol) were dissolved in
AcOH (20 mL) and heated under reflux in the inert
atmosphere during 1 h. Then this solution was evaporated
under reduced pressure, treated with H2O, filtrated, and dried
on the air and recrystallized from an appropriate solvent, or
was subjected to column chromatography over SiO2.
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(4,4,4-trifluoro-3-oxobut-1-enylamino)-1H-pyrrole-3-
carbonitrile (15)
5-Amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (0.66 g,
4 mmol) and 14 (0.68 g, 4.4 mmol) were dissolved in abs.
DMF (10 mL) and heated under inert atmosphere at 85 °C
for 12 h. The solution was evaporated under reduced
pressure, treated with H2O, and dried under reduced
pressure. Afterwards, the residue was subjected to column
chromatography over SiO2.
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Colorless solid (0.78 g, 68%); mp 116–118 °C; Rf = 0.75
(hexane–EtOAc, 5:1). 1H NMR (400 MHz, CDCl3): d = 1.59
(9 H, s, CH3), 5.68 (1 H, d, 3JHH = 8 Hz), 6.20 (1 H, s.), 7.13
(1 H, s), 7.29 (1 H, dd, 3JHH = 8 Hz, 3JHH = 4 Hz), 11.80
(1 H, d, 3JHH = 4 Hz, NH). 13C NMR (100.5 MHz, CDCl3):
d = 29.9, 58.1, 90.7, 91.0, 103.7, 119.8 (d, 1JCF = 285 Hz),
117.7, 131.0, 140.7, 153.3, 180.2 (q, 2JCF = 33 Hz). MS:
m/z (%) = 286(11) [M+ + 1], 285(56) [M+], 239(22), 229(77),
170(11), 160(90), 57(100), 41(37). Anal. Calcd for
C13H14F3N3O: C, 54.73; H, 4.95; F, 19.98; N, 14.73; O, 5.61.
Found: C, 54.80; H, 4.98; N, 14.78.
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(24) Procedure for the Synthesis of 1-tert-Butyl-4-(trifluoro-
methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (16)
1-tert-Butyl-5-(4,4,4-trifluoro-3-oxobut-1-enylamino)-1H-
pyrrole-3-carbonitrile (15, 0.57 g, 2 mmol) in a 10 mL flask
was melted for 5 h under inert atmosphere at 180 °C
(temperature of the oil bath), then the dark-green residue
formed was subjected to column chromatography over SiO2.
Colorless solid (0.38 g, 71%); mp 161–163 °C. Rf = 0.75
(hexane–EtOAc, 5:1). 1H NMR (400 MHz, CDCl3): d = 1.78
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U. Groth et al.
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(9 H, s, CH3), 7.41 (1 H, d, 3JHH = 4.7 Hz, H), 7.99 (1 H, s),
8.49 (1 H, d, 3JHH = 4.7 Hz). 13C NMR (100.5 MHz, CDCl3):
d = 29.0, 59.3, 82.8, 113.8 (q, 3JCF = 4.7 Hz), 114.5, 115.7,
122.8 (q, 2JCF = 270 Hz), 129.8 (q, 2JCF = 35 Hz), 136.3,
143.7, 148.3. MS: m/z (%) = 267(48) [M+], 212(58),
211(100), 192(24), 57(39), 56(10), 41(25). Anal. Calcd for
C13H12F3N3: C, 58.42; H, 4.53; F, 21.33; N, 15.72. Found: C,
58.50; H, 4.59; N, 15.71.
(25) Crystallographic data (excluding structure factors) for the
structure11c reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 683574 and can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336033;
email: deposit@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/
data_request/cif.
Synlett 2009, No. 3, 456–460 © Thieme Stuttgart · New York

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