Synthesis of fluorinated pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d] pyrimidine nucleosides

Article abstract of DOI:10.1055/s-0029-1216640

With the purpose of synthesizing novel ADAs (adenosine deaminase) and IMPDH (inosine 5′-monophosphate dehydrogenase) inhibitors the reactions of 5-amino-1-tert-butyl-1-H-pyrrole-3-carbonitrile with fluorinated 1,3 - bielectrophiles were studied. An effici

Full text of DOI:10.1055/s-0029-1216640

PAPER
1851
Synthesis of Fluorinated Pyrrolo[2,3-b]pyridine and Pyrrolo[2,3-d]pyrimidine
Nucleosides
S
ynthesisof Fluor
i
inate
d
P
k
yrrolo[2,3-
b
t
]pyridi
o
ne
a
ndPyrro
r
lo[2,3-
d
]pyrim
O
idine
N
ucleosides. Iaroshenko,*a,b Yan Wang,c Dmitri V. Sevenard,d Dmitriy M. Volochnyuka,e
a
Enamine Ltd., 23 A. Matrosova St., 01103 Kyiv, Ukraine
Fax +380(44)5373253; E-mail: yaroshenko@enamine.net
b
c
d
e
National Taras Shevchenko University, 62 Volodymyrska St., 01033 Kyiv-33, Ukraine
Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstr.10, 78457 Konstanz, Germany
Hansa Fine Chemicals GmbH, BITZ, Fahrenheitstr. 1, 28359 Bremen, Germany
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02094 Kyiv-94, Ukraine
Received 24 October 2008; revised 22 January 2009
Dedicated Professor Andrei Tolmachev on the occasion of his 50th birthday
givamycin (3), and cadeguomycin (4) (Figure 1) were iso-
Abstract: With the purpose of synthesizing novel ADAs (adenos-
ine deaminase) and IMPDH (inosine 5¢-monophosphate dehydroge-
nase) inhibitors the reactions of 5-amino-1-tert-butyl-1-H-pyrrole-
3-carbonitrile with fluorinated 1,3--bielectrophiles were studied.
lated. Their frequent natural occurrence and unusual
biological properties have promoted ample studies to-
wards their synthesis and biological evaluation.2 Several
An efficient and convenient synthetical approach to fluorinated pyr- structurally related deazapurine nucleosides have been
synthesized, which have shown antitumor,3 anti-HIV,4
rolo[2,3-b]pyridines was developed. The tert-butyl protecting
and antiviral5 activity. Triciribine (TCN) successfully
group was successfully removed by treating the pyrrolopyridines or
-pyrimidines with 60% sulfuric acid and this was followed by direct
came through phase I clinical trials and it was advanced to
glycosylation of the products.
phase II studies as a potential antineoplastic agent.6 Con-
cerning the similar pyrrolopyridines the most significant
compound among them is 7-azaindolylcarboxy-endo-tro-
Key words: pyrrole, amine, fluorine, pyridine, annulation, electro-
philic aromatic substitution
panamide (DF 1012, 5) (Figure 1), which is the selected
candidate drug in a new class of non-narcotic antitussive
Nucleosides containing pyrrolo[2,3-b]pyridine and pyrro-
compounds and is actually under investigation in phase II
clinical trials.7
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 are
considered as 1,7-deaza- and 7-deazapurines, respective-
ly, and their biological activities are recognized to be
close to that of purine, over the last few decades a set of
drugs and bioactive molecules containing these two het-
erocyclic systems has appeared on the market.
A variety of C6 modified purines8 and their isosteres9 in-
cluding pyrrolopyridines10 and pyrrolopyrimidines11 are
ADA (adenosine deaminase) inhibitors. Some of them
have been synthesized and their pharmaceutical evalua-
tion is currently under investigation.
R1
O
NH2
R1
Me
R1
N
X
CO2H
R
NC
N
O
+
HN
N
R2
N
N
X
X
+
NH
O
N
+
N
H2N
RO
N
N
O
R2
N
N
R2
NH2
H
O
HO
t-Bu
N
H
N
R3
HO
7
8
9
HO
X = N, CH
R3 = H, OH
6
HO
OH
HO
OH
5 (DF 1012)
4
1 R = H
2 R = CN
3 R = CONH2
Scheme 1 Retrosynthetic analysis
Figure 1 Natural occurring and pharmacoactive pyrrolo[2,3-d]pyri-
midine and pyrrolo[2,3-b]pyridines
6-(Trifluoromethyl)-substituted purine analogues are
promising scaffolds for the elaboration of potential ADA
inhibitors.12 Through the electron-withdrawing trifluo-
romethyl group the hydration on position 6 is enabled to
form stable hydrates. The trifluoromethyl group is isoster-
ical close to the amino function,13 thus 6-hydroxy-6-(tri-
fluoromethyl)purines and their isosteres can be considered
as a putative adenosine deamination transition state mi-
metics. Coformycin and pentostatin and their derivatives
contain a tetrahedral carbon (C8) bearing a hydroxy
Recently, several naturally occurring nucleoside1 antitu-
mor antibiotics, possessing a pyrrolo[2,3-d]pyrimidine
framework, such as tubercidin (1), toyocamycin (2), san-
SYNTHESIS 2009, No. 11, pp 1851–1857
x
x.
x
x
.
2
0
0
9
Advanced online publication: 12.05.2009
DOI: 10.1055/s-0029-1216640; Art ID: P12008SS
© Georg Thieme Verlag Stuttgart · New York

1852
V. O. Iaroshenko et al.
PAPER
Table 1 Yields of Pyrrolo[2,3-b]pyridines 12a–ha
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 bielectro-
philic building blocks results in pyrrolo[2,3-b]pyridines
and pyrrolo[2,3-d]pyrimidines with the desired substitu-
tion pattern.
R1
R2
O
O
R1
N
NC
10 R1 = fluoroalkyl
11 R1 = CO2Me
NC
NH2
i
R2
N
N
t-Bu
8
t-Bu
12a–j
77–98%
This concept of building up heterocyclic systems has re-
cently gained wide popularity. Hence, it opens a wide
range of practical routes towards fluorinated purine ana-
logues and a number of fluorine containing small hetero-
cycles.15
Product
12a
12b
12c
R1
R2
Yieldb (%)
CF3
CF3
CF3
CF3
Me
Ph
80
84
78
82
81
83
84
82
80
77
Unsubstituted 1H-pyrrol-2-amine is hard to access and it
is not stable.16 For our current study the stable and easily
accessible 5-amino-1-tert-butyl-1H-pyrrole-3-carboni-
trile (8) was used. The tert-butyl protection group and the
electron-withdrawing cyano function maintain the stabili-
ty of this heterocycle. Furthermore, the tert-butyl and cy-
ano groups could easily be removed from the
pyrrolopyridine derivative.17
12d
12e
CF2H
Me
Ph
CF2Cl
12f
C2F5
Me
Et
12g
12h
12i
CF2CF2H
(CF2)3CF3
CO2Me
CO2Me
Further, a glycosylation reaction should be studied with
the purpose to couple ribose/2-deoxyribose derivatives
with the fluorinated nucleobase moiety 7.
Et
Me
Ph
In what follows, the design and synthesis of novel poten-
tial inhibitors of the ADAs and IMPDH enzyme families
are presented. The practical synthetic route to pyrrolo[2,3-
b]pyridines, starting from 5-amino-1-tert-butyl-1H-pyr-
role-3-carbonitrile (8) and a number of 1,3-CCC-bielec-
trophiles containing a fluoroalkyl group 10, 13, and 15
and acylpyruvates 11. Previously, methods giving rise to
pyrrolo[2,3-b]pyridines via annulation of the pyridine
ring to an aminopyrrole moiety have been reported.17,18
12j
a AcOH, reflux, inert atmosphere, 1 h.
b Yields refer to pure isolated products.
group. These naturally occurring ADA inhibitors possess
strong activity (coformycin, Ki = 1.0 × 10–11 M; pento-
statin, Ki = 2.5 × 10–12 M on calf intestine ADA), that is
attributed to the extremely tight-binding (nearly irrevers-
ible) interaction of these compounds with ADA, mimick-
ing the transition state of ADA activity.14
We began with a study of the reaction of the aminopyrrole
8 with polyfluoroalkyl-1,3-diketones 10 (Table 1). The
reaction yields pyrrolo[2,3-b]pyridines 12a–h bearing the
fluoroalkyl substituent in position 4 of the annulated pyri-
dine ring. Under the same conditions reaction of 8 with
acylpyruvates 11 delivers the esters 12i,j in 80% and 77%
yield, respectively. The cyclocondensation proceeds
regioselectively to provide the desired g-regioisomer; the
formation of the a-regioisomer was not observed (GC–
MS, 19F NMR).
Our primary interests are focused on the design and syn-
thesis of novel ligands for ADAs and IMPDH, which
CF3
F3C
NC
R
NC
13
O
O
i
NH2
N
N
N
t-Bu
R
t-Bu
14
The cyclic diketones 13 were no exception from the gen-
eral rule. They underwent pyridine ring annulation, lead-
8
a R = H 70%
b R = CF3CO 73%
ing
to
the
formation
of
linear
1,5,6,7-
Scheme 2 Reagents and conditions: (i) AcOH, reflux, inert at-
tetrahydrocyclopenta[b]pyrrolo[3,2-e]pyridine 14b and
mosphere, 1 h.
O
O
CF3
CF3
NC
NC
NC
CF3
15
MeO
NH2
N
N
i
ii
N
H
N
N
t-Bu
t-Bu
16
t-Bu
8
17
71%
68%
Scheme 3 Reagents and conditions: (i) anhyd DMF, inert atmosphere, 85 °C, 12 h; (ii) neat, inert atmosphere 180 °C, 5 h.
Synthesis 2009, No. 11, 1851–1857 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Pyrrolo[2,3-b]pyridine and Pyrrolo[2,3-d]pyrimidine Nucleosides
1853
5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinoline
14a Slow crystallization of compounds 12c and 12i (DMSO-
(Scheme 2). Cycloaddition takes place in boiling acetic d6, NMR tube) afforded stable diffraction-quality crystals.
acid under a nitrogen atmosphere for one hour. The reac- Single crystal X-ray investigation confirmed the pyrrolo-
tion is clean in the case of 10 and 11, if the initial diketone pyridine structure of molecules unambiguously (Figure 2
and pyrrolamine are analytically pure. An excess of elec- and Figure 3).
trophile was removed afterwards in vacuo and subsequent
purification was not required (12b, 12g). However, in the
case of cyclic diketones 13, examination of the reaction
mixture by 19F NMR, revealed a number of byproducts.
Attempts to isolate them failed. Pyrrolopyridines 12 and
14, could easily be purified by flash chromatography or
recrystallized from an appropriate solvent.
The application of 1,1,1-trifluoro-4-methoxybut-3-en-2-
one (15) for heterocyclizations was recently studied.19
Aminopyrrole 8 reacts smoothly with 15 to afford com-
pound 16, the product of initial attack of the b-position of
the vinyl function on the amino moiety of the aminohet-
Figure 2 Molecular structure of compound 12c
erocycle (Scheme 3). Reaction proceeds in dry N,N-di-
methylformamide at 85 °C under nitrogen.
This intermediate undergoes 6-exo-trig-cyclization under
harsh conditions (melting at 180 °C) yielding 1-tert-butyl-
4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-carbo-
nitrile (17). For a-substituted pyridines the coupling con-
stant (3JHH) between a- and b-protons is expected to be
about 8 Hz. In the case of 17 this coupling constant was
measured to be 4.7 Hz, which suggests strongly the g-CF3
structure of the pyridine formed.
CF3
N
N
CF3
NC
NC
F3C
N
i
CF3
Figure 3 Molecular structure of compound 12i
18
N
NH2
N
N
CF3
N
The inverse-electron-demand Diels–Alder reaction has
become a powerful tool for the assembly of fused pyrim-
idines.20 Aminopyrrole 8 react smoothly with 2,4,6-
tris(trifluoromethyl)-1,3,5-triazine (18) in acetic acid at 0
°C to deliver the pyrrolo[2,3-d]pyrimidine 19 (Scheme 4).
t-Bu
t-Bu
19
94%
8
Scheme 4 Reagents and conditions: (i) AcOH, 0 °C, 30 min then
r.t., 2 h.
CF3
X
CF3
CF3
X
NC
HO2C
i
X
– NH3
– CO2
N
N
R
N
R
N
N
R
N
H
H
t-Bu
20
12a, 17, 19
a X = CH, R = CF3 43%
b X = CH, R = H 39%
c X = N, R = CF3 44%
OMe
OAc
CF3
CF3
O
AcO
X
X
AcO
F3C
HO
22
F3C
N
N
N
N
O
20a, c
iii
ii
O
AcO
HO
OH
AcO
OAc
21
a X = CH 90%
b X = N 88%
a X = CH 84%
b X = N 87%
Scheme 5 Reagents and conditions: (i) H2SO4, 0 °C, 30 min then r.t, 2 h; (ii) BSA, TMS-OTf; (iii) MeOH, NH3, r.t., 12 h.
Synthesis 2009, No. 11, 1851–1857 © Thieme Stuttgart · New York

1854
V. O. Iaroshenko et al.
PAPER
Pyrrolo[2,3-b]pyridines 12 and 14; General Procedure
Finally, pyrrolopyridines 12a and 17 and pyrrolo[2,3-
d]pyrimidine 19 were transformed to the suitable for gly-
cosylation substrates 20 possessing a free N1 position.
This reaction was carried out in 60% sulfuric acid
(Scheme 5). The compounds 20 were obtained in moder-
ate yields (39–44%). The glycosylations were performed
by the silyl-Hilbert–Johnson reaction21 in dichloro-
methane, using O,N-bis(trimethylsilyl)acetamide (BSA)
for initial silylation of the heterocyclic moiety. As a cata-
lyst for the next glycosylation step, trimethylsilyl triflate
was used (Scheme 5). The deprotection of the products 21
into 22 was conducted by ammonia in methanol.
5-Amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (8, 0.33 g, 2 mmol)
and diketone 10 or 11 (12) or 13 (14) (2.2 mmol) were dissolved in
AcOH (20 mL) and heated under reflux under an inert atmosphere
for 1 h. Then this soln was evaporated under reduced pressure, treat-
ed with H2O, filtered, dried in air, and recrystallized from an appro-
priate solvent or subjected to column chromatography (silica gel).
1-tert-Butyl-4,6-bis(trifluoromethyl)-1H-pyrrolo[2,3-b]pyri-
dine-3-carbonitrile (12a)
Recrystallized (i-PrOH); colorless solid (0.54 g, 80%); mp 127–128
°C.
1H NMR (DMSO-d6): d = 1.76 (s, 9 H, CH3), 8.01 (s, 1 H, H2), 9.07
(s, 1 H, H5).
In summary, a convenient synthetic approach to the fluor-
inated pyrrolo[2,3-b]pyridine ring system was developed
based on commercially available 5-amino-1-tert-butyl-
1H-pyrrole-3-carbonitrile (8) and a series of 1,3-CCC flu-
orine containing bielectrophiles. The elaborated method
gives rise to pyrrolo[2,3-b]pyridines bearing the polyfluo-
roalkyl substituent at C4 of the annulated pyridine ring.
Attempts to synthesize N-glycosylated and N-alkylated
4-(polyfluoroalkyl)-1H-pyrrolo[2,3-b]pyridines are cur-
rently under investigation in our laboratory.
13C NMR (DMSO-d6): d = 28.2, 60.1, 82.0, 110.1, 113.4, 121.6 (q,
1
2
1JCF = 275 Hz), 121.9 (q, JCF = 275 Hz), 129.1 (q, JCF = 35 Hz),
140.0 (q, 2JCF = 35 Hz), 142.7, 146.4.
MS: m/z (%) = 335 (M+, 24), 274 (100), 57 (27).
1-tert-Butyl-6-methyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonitrile (12b)
Recrystallized (i-PrOH); colorless solid (0.47 g, 84%); mp 157–159
°C.
1H NMR (DMSO-d6): d = 1.79 (s, 9 H, CH3), 2.71 (s, 3 H, CH3),
7.61 (s, 1 H, H5), 8.70 (s, 1 H, H2).
13C NMR (DMSO-d6): d = 24.1, 28.3, 58.9, 80.5, 112.2, 113.6 (q,
3JCF = 5.6 Hz), 114.7, 123.2 (q, 1JCF = 275 Hz), 127.7 (q, 2JCF = 35
Hz), 138.3, 147.1, 153.2.
MS: m/z (%) = 281 (M+, 31), 226 (28), 225 (100), 156 (14), 57 (16),
41 (10).
All solvents were purified and dried by standard methods. NMR
spectra were recorded on Jeol JNM-LA 400, Varian VXR-300, or
Varian Mercury-400 spectrometers. 1H and 13C NMR spectra (300
and 100 MHz, respectively) were recorded using TMS as an internal
standard; 19F (282.2 MHz) NMR spectra with CFCl3 as an internal
standard. Mass spectra were obtained on a Hewlett-Packard HP GC/
MS 5890/5972 instrument (EI, 70 eV) by GC inlet or on a MX-1321
instrument (EI, 70 eV) by direct inlet. Column chromatography was
performed on silica gel (63–200 mesh, Merck). Silica gel Merck
60F254 plates were used for TLC. Satisfactory microanalysis ob-
tained C 0.33; H 0.45; N 0.25. Fluorinated 1,3-dicarbonyl com-
pounds were obtained using Claisen-type condensation of the
suitable carbonyl compound with the corresponding fluorinated
acid esters in the presence of NaOMe or LiH.22 For the preparation
of 21, synthetical routes described earlier have been used without
changing the reaction conditions.21
1-tert-Butyl-6-phenyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonitrile (12c)
Recrystallized (EtOH); colorless solid (0.54 g, 78%); mp 230–232
°C.
1H NMR (DMSO-d6): d = 1.87 (s, 9 H, CH3), 8.15 (br m, 3 H, CH),
7.50 (br m, 3 H, CH), 8.70 (s, 1 H, H2).
13C NMR (DMSO-d6): d = 28.4, 59.0, 81.2, 110.3 (q, 3JCF = 5.6 Hz),
1
113.2, 113.8, 122.4 (q, JCF = 275 Hz), 126.3, 128.4, 128.6 (q,
2JCF = 35 Hz), 129.0, 137.2, 138.9, 147.3, 150.9.
MS: m/z (%) = 342 (M+ + 1, 21), 343 (M+, 100), 57 (19).
X-ray Crystallography of 12c,i23
Crystallographic measurements were performed at r.t. on a Enraf-
Nonius CAD4 diffractometer operating in the w-2q scan mode (the
scanning rate ratio w/2q = 1.2). The structures were solved by direct
methods and refined by full-matrix least-squares technique in aniso-
tropic approximation using SHELXS97 and SHELXL9722 pro-
gram packages. Hydrogen atoms were placed at calculated position
and refined as ‘riding’ model.
1-tert-Butyl-4-(difluoromethyl)-6-methyl-1H-pyrrolo[2,3-b]py-
ridine-3-carbonitrile (12d)
Recrystallized (i-PrOH); colorless solid (0.43 g, 82%); mp 115–118
°C.
1H NMR (DMSO-d6): d = 1.75 (s, 9 H, CH3), 2.63 (s, 3 H, CH3),
1
7.37 (t, JHF = 54 Hz, 1 H, CF2H), 7.38 (s, 1 H, H5), 8.55 (s, 1 H,
H2).
Crystal data of 12c: monoclinic, P21/c, a = 15.689(3),
b = 5.8992(12), c = 18.760(4) Å, b = 108.31(3)°, V = 1648.3(6) Å3,
Z = 4, m(Mo-Ka) = 0.107 mm–1. 17282 reflections collected, 3106
unique reflections, (Rint = 0.0825), Mo-Ka radiation (l = 0.71073
Å), 226 parameters, R1 = 0.0486, wR2 = 0.0971, S = 1.080 [2447
reflections with I > 2s(I)].
13C NMR (DMSO-d6): d = 24.3, 28.5, 58.7, 80.8, 113.3 (t,
3
3
1JCF = 237 Hz), 113.6 (t, JCF = 3.6 Hz), 114.7 (t, JCF = 6.4 Hz),
115.6, 133.5 (t, 2JCF = 23 Hz), 137.0, 147.0, 153.0.
MS: m/z (%) = 263 (M+, 18), 208 (15), 207 (100), 156 (11).
1-tert-Butyl-4-(chlorodifluoromethyl)-6-phenyl-1H-pyrro-
lo[2,3-b]pyridine-3-carbonitrile (12e)
Recrystallized (EtOH); colorless solid (0.58 g, 81%); mp 251–253
°C.
Crystal data of 12i: triclinic, P1, a = 7.3838(15), b = 9.6733(19),
c = 9.982(2) Å, a = 77.66(3), b = 82.92(3), g = 85.55(3)°,
V = 690.2(2) Å3, Z = 2, m(Mo-Ka) = 0.089 mm–1; 8942 reflections
collected, 2567 unique reflections, (Rint = 0.0939), Mo-Ka radiation
(l = 0.71073 Å), 181 parameters, R1 = 0.0692, wR2 = 0.1654,
S = 1.096 [2194 reflections with I > 2s(I)].
1H NMR (DMSO-d6): d = 1.87 (s, 9 H, CH3), 7.53 (br m, 3 H), 8.07
(s, 1 H, H5), 8.18 (d, 3JHH = 7.8 Hz, 2 H), 8.70 (s, 1 H,).
Synthesis 2009, No. 11, 1851–1857 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Pyrrolo[2,3-b]pyridine and Pyrrolo[2,3-d]pyrimidine Nucleosides
1855
13C NMR (DMSO-d6): d = 28.9, 59.5, 81.9, 109.4 (t, 3JCF = 6.4 Hz),
112.8 (t, JCF = 2.4 Hz), 114.9, 124.6, (t, JCF = 290 Hz), 126.9,
129.0, 129.6, 135.2 (t, 2JCF = 29 Hz), 137.8, 139.7, 148.0, 151.3.
13C NMR (100.5 MHz, DMSO-d6): d = 28.5, 51.5, 58.7, 82.9,
114.3, 115.6, 118.3, 126.2, 128.6, 128.9, 130.5, 137.6, 140.0, 147.7,
150.3, 165.1.
3
1
MS: m/z (%) = 361 (M+ + 2, 13), 359 (M+, 36), 304 (23), 303 (100),
MS: m/z (%) = 333 (M+, 39), 278 (19), 277 (100), 246 (13), 219
269 (16), 268 (75), 57 (13).
(35), 218 (22).
1-tert-Butyl-6-methyl-4-(pentafluoroethyl)-1H-pyrrolo[2,3-
b]pyridine-3-carbonitrile (12f)
1-tert-Butyl-4-(trifluoromethyl)-5,6,7,8-tetrahydro-1H-pyrro-
lo[2,3-b]quinoline-3-carbonitrile (14a)
Colorless solid (0.55 g, 83%); mp 117–119 °C; Rf = 0.70 (EtOAc–
hexane, 1:3).
Colorless solid (0.45 g, 70%); mp 99–100 °C; Rf = 0.85 (EtOAc–
hexane, 1:4).
1H NMR (CDCl3): d = 1.78 (s, 9 H, CH3), 2.67 (s, 3 H, CH3), 7.24
1H NMR (CDCl3): d = 1.77 (s, 9 H, CH3), 1.78–1.91 (br m, 4 H,
(s, 1 H, H5), 7.94 (s, 1 H, H2).
CH2), 3.04–3.09 (br m, 4 H, CH2), 7.94 (s, 1 H, H2).
13C NMR (CDCl3): d = 24.6, 29.0, 59.3, 83.0, 111.5 (tq, 1JCF = 215
13C NMR (100.5 MHz, CDCl3): d = 22.2, 22.6, 25.8 (q, JCF = 4 Hz),
28.8, 33.8, 58.7, 82.4, 114.1, 116.0, 123.9, 121.6 (q, 1JCF = 270 Hz),
127.7 (q, 2JCF = 35 Hz), 136.5, 146.0, 153.7.
MS: m/z (%) = 321 (M+, 18), 266 (15), 265 (100), 264 (12), 237
(15), 196 (10).
2
3
Hz, JCF = 39 Hz), 113.9 (t, JCF = 2.0 Hz), 115.5, 115.8 (t,
1
2
3JCF = 8.0 Hz), 119.7 (qt, JCF = 285 Hz, JCF = 38 Hz), 129.1 (t,
2JCF = 25 Hz), 136.5, 147.9, 153.3.
MS: m/z (%) = 331 (M+, 35), 276 (27), 275 (100), 206 (52), 57 (19),
41 (10).
1-tert-Butyl-8-(2,2,2-trifluoroacetyl)-4-(trifluoromethyl)-
5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinoline-3-carbonitrile
(14b)
1-tert-Butyl-6-ethyl-4-(1,1,2,2-tetrafluoroethyl)-1H-pyrro-
lo[2,3-b]pyridine-3-carbonitrile (12g)
Colorless solid (0.55 g, 84%); mp 110–111 °C; Rf = 0.70 (EtOAc–
hexane, 1:4).
Colorless solid (0.61 g, 73%); mp 123–127 °C; Rf = 0.75 (EtOAc–
hexane, 1:4).
1H NMR (CDCl3): d = 1.35 (t, 3JHH = 7.8 Hz, 3 H, CH3), 1.50 (s, 9
H, CH3), 2.95 (d, 3JHH = 7.8 Hz, 2 H, CH2), 6.16 (t, 2JHH = 54 Hz, 1
H, CF2H), 7.24 (s, 1 H, H5), 7.93 (s, 1 H, H2).
1H NMR (CDCl3): d = 1.77 (s, 9 H, CH3), 1.79–1.88 (br m, 1 H,
CH), 2.04–2.09 (br m, 1 H, CH), 2.24–2.28 (br m, 0.58 H, CH), 2.70
(br s, 1.42 H, CH), 3.07 (br s, 2 H, CH), 4.63 (br s, 0.37 H, CH),
7.97–8.03 (br m, 1 H, CH).
13C NMR (CDCl3): d = 13.4, 29.0, 31.1, 59.0, 82.7, 110.0, 114.5 (t,
2
2JCF = 1.8 Hz), 114.9, 115.7, 130.1 (t, JCF = 26 Hz), 135.6, 147.7,
MS: m/z (%) = 417 (M+, 28), 362 (20), 361 (69), 265 (18), 264
158.2.
(100), 57 (21).
MS: m/z (%) = 327 (M+, 15), 272 (13), 271 (100), 270 (21), 220
(10), 57 (21), 41 (13).
(E)-1-tert-Butyl-5-[(4,4,4-trifluoro-3-oxobut-1-enyl)amino]-1H-
pyrrole-3-carbonitrile (16)
5-Amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (8, 0.66 g, 4 mmol)
and 15 (0.68 g, 4.4 mmol) were dissolved in anhyd DMF (10 mL)
and heated under an inert atmosphere at 85 °C for 12 h. The soln
was evaporated under reduced pressure, treated with H2O, and dried
under reduced pressure and the residue was subjected to column
chromatography (silica gel) to give a colorless solid (0.78 g, 68%);
mp 116–118 °C; Rf = 0.75 (hexane–EtOAc, 5:1).
1H NMR (CDCl3): d = 1.59 (s, 9 H, CH3), 5.68 (d, 3JHH = 8 Hz, 1 H),
6.20 (s, 1 H), 7.13 (s, 1 H), 7.29 (dd, 3JHH = 8 Hz, 3JHH = 4 Hz, 1 H),
11.80 (d, 3JHH = 4 Hz, 1 H, NH).
1-tert-Butyl-6-ethyl-4-(nonafluorobutyl)-1H-pyrrolo[2,3-b]py-
ridine-3-carbonitrile (12h)
Colorless solid (0.73 g, 82%); mp 61–63 °C; Rf = 0.65 (EtOAc–hex-
ane, 1:3).
1H NMR (CDCl3): d = 1.35 (t, 3JHH = 7.8 Hz, 3 H, CH3), 1.80 (s, 9
H, CH3), 2.95 (d, 3JHH = 7.8 Hz, 2 H, CH2), 7.23 (s, 1 H, H2), 7.96
(s, 1 H, H5).
13C NMR (CDCl3): d = 13.2, 28.8, 30.9, 58.9, 82.9, 114.5, 115.2,
129.0 (t, 2JCF = 25 Hz), 136.0, 147.6, 157.8.
MS: m/z (%) = 445 (M+, 20), 390 (27), 389 (100), 388 (17), 220
(27), 57 (11).
13C NMR (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 (M+ + 1, 11), 285 (M+, 56), 239 (22), 229 (77),
170 (11), 160 (90), 57 (100), 41 (37).
Methyl 1-tert-Butyl-3-cyano-6-methyl-1H-pyrrolo[2,3-b]pyri-
dine-4-carboxylate (12i)
Recrystallized (EtOH); colorless solid (0.43 g, 80%); mp 251–253
°C.
1H NMR (DMSO-d6): d = 1.75 (s, 9 H, CH3), 2.63 (s, 3 H, CH3),
3.93 (s, 3 H, CH3), 7.59 (s, 1 H, H5), 8.58 (s, 1 H, H2).
13C NMR (100.5 MHz, DMSO-d6): d = 24.1, 28.6, 51.7, 58.8, 82.7,
114.3, 116.2, 129.8, 138.7, 147.7, 152.7, 165.4.
MS: m/z (%) = 271 (M+, 41), 216 (19), 215 (100), 184 (30), 157
(63), 156 (25).
1-tert-Butyl-4-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-3-
carbonitrile (17)
1-tert-Butyl-5-[(4,4,4-trifluoro-3-oxobut-1-enyl)amino]-1H-pyr-
role-3-carbonitrile (16, 0.57 g, 2 mmol) in a 10-mL flask was melted
for 5 h under an inert atmosphere at 180 °C (temperature of the oil
bath), then the dark-green residue formed was subjected to column
chromatography (silica gel) to give a colorless solid (0.38 g, 71%);
mp 161–163 °C; Rf = 0.75 (hexane–EtOAc, 5:1).
1H NMR (CDCl3): d = 1.78 (s, 9 H, CH3), 7.41 (d, 3JHH = 4.7 Hz, 1
H), 7.99 (s, 1 H), 8.49 (d, 3JHH = 4.7 Hz, 1 H).
Methyl 1-tert-Butyl-3-cyano-6-phenyl-1H-pyrrolo[2,3-b]pyri-
dine-4-carboxylate (12j)
Recrystallized (EtOH); colorless solid (0.53 g, 77%); mp 275–278
°C.
3
13C NMR (CDCl3): d = 29.0, 59.3, 82.8, 113.8 (q, JCF = 4.7 Hz),
2
2
114.5, 115.7, 122.8 (q, JCF = 270 Hz), 129.8 (q, JCF = 35 Hz),
136.3, 143.7, 148.3.
1H NMR (DMSO-d6): d = 1.83 (s, 9 H, CH3), 3.98 (s, 3 H, CH3),
7.47–7.57 (br m, 3 H, CH), 8.16 (d, 3JHH = 7.8 Hz, 2 H, CH), 8.24
(s, 1 H, CH), 8.72 (s, 1 H, CH).
MS: m/z (%) = 267 (M+, 48), 212 (58), 211 (100), 192 (24), 57 (39),
56 (10), 41 (25).
Synthesis 2009, No. 11, 1851–1857 © Thieme Stuttgart · New York

1856
V. O. Iaroshenko et al.
PAPER
7-tert-Butyl-2,4-bis(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimi-
dine-5-carbonitrile (19)
1 H, CH), 7.53 (d, 3JHH = 3.5 Hz, 1 H), 7.87 (d, 3JHH = 3.5 Hz, 1 H),
8.01 (s, 1 H, H5).
To 5-amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (8, 0.33 g, 2
mmol) dissolved in AcOH (10 mL) at 0 °C, 2,4,6-tris(trifluoro-
methyl)-1,3,5-triazine (18, 0.64 g, 2.2 mmol) was added dropwise.
The mixture was stirred vigorously for 30 min and then kept at r.t.
for 2 h. Solvent was evaporated under reduced pressure. The brown
residue was recrystallized (EtOH–H2O) to give a colorless solid
(0.63 g, 94%); mp 133–135 °C.
13C NMR (DMSO-d6): d = 20.6, 20.9, 21.1, 63.1, 68.7, 73.3, 79.9,
1
89.3, 99.3, 110.1, 117.4, 121.6 (q, JCF = 275 Hz), 121.9 (q,
2
2
1JCF = 275 Hz), 129.1 (q, JCF = 35 Hz), 136.4, 140.0 (q, JCF = 35
Hz), 146.4, 170.0, 170.2, 170.3.
MS: m/z (%) = 512 (M+, 17), 511 (19), 488 (10), 479 (13), 477 (19),
399 (15), 387 (25), 325 (45), 301 (17), 293 (63), 281 (33), 207 (37),
189 (100), 158 (11), 157 (31), 123 (25), 101 (18).
1H NMR (DMSO-d6): d = 1.73 (s, 9 H, CH3), 8.21 (s, 1 H, H2).
13C NMR (DMSO-d6): d = 28.2, 60.1, 85.0, 113.4, 115.7, 119.5
(1JCF = 275 Hz), 121.3, (1JCF = 275 Hz), 1142.7, 143.3 (2JCF = 37
Hz), 146.4, 147.4 (2JCF = 37 Hz).
l-(2,3,5-Tri-O-acetyl-b-D-ribofuranosyl)-2,4-bis(trifluorometh-
yl)-7H-pyrrolo[2,3-d]pyrimidine (21b)
Colorless solid (0.90 g, 88%); mp 59–62 °C; Rf = 0.65 (EtOAc–hex-
ane, 1:3).
1H NMR (DMSO-d6): d = 2.00–2.05 (br s, 9 H, CH3), 3.52 (q,
3JHH = 6.2 Hz, 1 H, CH), 3.67 (m, 1 H, CH), 4.29 (q, 3JHH = 5.6 Hz,
1 H, CH), 4.75–4.82 (br m, 2 H, CH), 6.59 (d, 3JHH = 4.2 Hz, 1 H,
CH), 7.67 (d, 3JHH = 3.7 Hz, 1 H), 7.93 (d, 3JHH = 3.7 Hz, 1 H).
13C NMR (DMSO-d6): d = 20.6, 20.9, 21.1, 63.7, 67.9, 73.0, 79.0,
88.9, 99.9, 115.0, 119.4 (1JCF = 275 Hz), 121.3 (1JCF = 275 Hz),
142.0, 143.7 (2JCF = 37 Hz), 146.2, 147.0 (2JCF = 37 Hz), 170.5,
170.7, 170.9.
MS: m/z (%) = 336 (M+, 67), 279 (33), 57 (100).
Compounds 20; General Procedure
The corresponding pyrrolo[2,3-b]pyridine 12a, 17 or pyrrolo[2,3-
b]pyridine 19 (2 mmol) was dissolved in 60% H2SO4 (4 mL) at 0 °C,
and stirred for 30 min. The mixture was then kept at r.t. for 2 h. The
mixture was poured onto ice, the precipitate that formed was fil-
tered, dried in air, and recrystallized from an appropriate solvent.
4,6-Bis(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (20a)
Recrystallized (i-PrOH); colorless solid (0.22 g, 43%); mp 187–189
°C.
MS: m/z (%) = 513 (M+, 18), 501 (43), 470 (37), 461 (40), 419 (11),
387 (10), 357 (14), 303 (77), 278 (91), 205 (100), 194 (18), 134
(17), 112 (13), 97 (11).
3
1H NMR (DMSO-d6): d = 7.55 (d, JHH = 3.5 Hz, 1 H), 7.85 (d,
3JHH = 3.5 Hz, 1 H, CH), 7.91 (s, 1 H, H2), 12.08 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 100.0, 110.1, 117.4, 121.6 (q, 1JCF = 275
Deprotection of the Acylated Nucleosides; General Procedure
To a solution of the acylated nucleoside (1 mmol) in absolute
MeOH (5 mL) a sat. soln of NH3 in MeOH (20 mL) was added drop-
wise at 0 °C. The mixture was stirred for another 30 min and left for
12 h at r.t. The solvent was removed under reduced pressure, and the
formed material was kept for the next 24 h on a vacuum line. The
resultant yellow material was purified by column chromatography
on silica gel.
1
2
Hz), 121.9 (q, JCF = 275 Hz), 129.1 (q, JCF = 35 Hz), 140.0 (q,
2JCF = 35 Hz), 146.4.
MS: m/z (%) = 254 (M+, 100), 253 (11), 212 (35), 211 (87), 192
(49).
4-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (20b)
Recrystallized (i-PrOH); colorless solid (0.15 g, 39%); mp 180–181
°C.
l-(b-D-Ribofuranosyl)-4,6-bis(trifluoromethyl)-1H-pyrrolo[2,3-
b]pyridine (22a)
Colorless solid (0.32 g, 84%); mp 170–171 °C; Rf = 0.85 (EtOAc).
3
1H NMR (DMSO-d6): d = 7.35 (d, JHH = 3.5 Hz, 1 H), 7.44 (d,
3
3JHH = 4.7 Hz, 1 H, H5), 7.65 (d, JHH = 3.5 Hz, 1 H), 8.53 (d,
1H NMR (CDCl3): d = 3.58 (m, 1 H, CH), 3.64 (m, 1 H, CH), 4.11
(q, 3JHH = 4.5 Hz, 1 H, CH), 4.39 (br s, 1 H, CH), 4.63 (d, 3JHH = 4.5
Hz, 1 H, CH), 5.55 (br s, 3 H, OH), 6.44 (d, 3JHH = 4.9 Hz, 1 H, CH),
7.65 (d, 3JHH = 3.5 Hz, 1 H), 7.99 (d, 3JHH = 3.5 Hz, 1 H, CH), 8.11
(s, 1 H, H2).
13C NMR (DMSO-d6): d = 63.9, 65.0, 72.1, 88.8, 93.9, 99.0, 111.1,
117.0, 121.6 (q, 1JCF = 275 Hz), 121.7 (q, 1JCF = 275 Hz), 130.0 (q,
2JCF = 35 Hz), 136.4, 140.1 (q, 2JCF = 35 Hz), 146.7.
3JHH = 4.7 Hz, 1 H, H6), 12.03 (s, 1 H, NH).
3
13C NMR (DMSO-d6): d = 99.7, 113.0 (q, JCF = 4.7 Hz), 114.1,
2
2
122.0 (q, JCF = 270 Hz), 129.4 (q, JCF = 35 Hz), 136.9, 143.1,
148.3.
MS: m/z (%) = 186 (M+, 100), 185 (13).
2,4-Bis(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (20c)
Recrystallized (i-PrOH); colorless solid (0.22 g, 44%); mp 235–237
°C.
MS: m/z (%) = 386 (M+, 12), 380 (11), 356 (21), 309 (10), 299 (17),
233 (14), 219 (11), 218 (100), 201 (77), 179 (14), 156 (10), 67 (83).
3
1H NMR (DMSO-d6): d = 7.59 (d, JHH = 3.7 Hz, 1 H), 8.05 (d,
3JHH = 3.7 Hz, 1 H), 11.91 (s, 1 H, NH).
l-(b-D-Ribofuranosyl)-2,4-bis(trifluoromethyl)-7H-pyrrolo[2,3-
d]pyrimidine (22b)
Colorless solid (0.34 g, 87%); mp 167–168 °C; Rf = 0.70 (EtOAc).
13C NMR (DMSO-d6): d = 99.0, 115.0, 119.4 (1JCF = 275 Hz),
121.3 (1JCF = 275 Hz), 142.0, 143.7 (2JCF = 37 Hz), 146.2, 147.0
(2JCF = 37 Hz).
1H NMR (CDCl3): d = 3.47 (m, 1 H, CH), 3.61 (m, 1 H, CH), 4.14
(q, 3JHH = 4.5 Hz, 1 H, CH), 4.32 (br s, 1 H, CH), 4.67 (d, 3JHH = 4.5
Hz, 1 H, CH), 5.61 (br s, 3 H, OH), 6.48 (d, 3JHH = 4.2 Hz, 1 H, CH),
7.65 (d, 3JHH = 3.4 Hz, 1 H), 7.99 (d, 3JHH = 3.4 Hz, 1 H, CH).
13C NMR (DMSO-d6): d = 63.4, 67.0, 72.7, 78.5, 88.8, 99.3, 115.1,
119.6 (q, 1JCF = 275 Hz), 121.2 (q, 1JCF = 275 Hz), 141.2, 143.7 (q,
2JCF = 37 Hz), 144.4, 147.8 (q, 2JCF = 37 Hz).
MS: m/z (%) = 255 (M+, 100), 254 (52).
l-(2,3,5-Tri-O-acetyl-b-D-ribofuranosyl)-4,6-bis(trifluorometh-
yl)-1H-pyrrolo[2,3-b]pyridine (21a)
Colorless solid (0.92 g, 90%); mp 69–72 °C; Rf = 0.55 (EtOAc–hex-
ane, 1:3).
1H NMR (DMSO-d6): d = 1.99–2.05 (br s, 9 H, CH3), 3.48 (m, 1 H,
CH), 3.69 (m, 1 H, CH), 4.00 (q, 3JHH = 4.6 Hz, 1 H, CH), 4.39 (br
s, 1 H, CH), 4.64 (d, 3JHH = 4.6 Hz, 1 H, CH), 6.49 (d, 3JHH = 4.8 Hz,
MS: m/z (%) = 387 (M+, 100), 368 (17), 361 (30), 355 (48), 317
(67), 287 (58), 286 (34), 235 (100), 222 (12), 221 (19), 208 (31),
198 (17), 177 (10), 160 (10), 133 (13), 127 (17).
Synthesis 2009, No. 11, 1851–1857 © Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Pyrrolo[2,3-b]pyridine and Pyrrolo[2,3-d]pyrimidine Nucleosides
1857
(12) Erion, M. D.; Reddy, M. R. J. Am. Chem. Soc. 1998, 120,
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