Pyrrolo[2,3-d]pyrimidine-core-extended π-systems: Synthesis of 2,4,7-triarylpyrrolo[2,3- d ]pyrimidines

Article abstract of DOI:10.1055/s-0030-1260931

A simple and facile synthesis of novel fluorescent pyrrolo[2,3-d] pyrimidines with various aryl and heteroaryl assemblies in positions 2, 4, and 7 of the heterocycle by combination of the Suzuki cross-coupling and copper(I) iodide N-arylation reactions of chloropyrrolo[2,3-d]pyrimidines with arylboronic acids and haloarenes is described. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260931

LETTER
1705
Pyrrolo[2,3-d]pyrimidine-Core-Extended p-Systems:
Synthesis of 2,4,7-Triarylpyrrolo[2,3-d]pyrimidines
Synthesis of
2
i
r
g
i
d
]p
t
yrimid
aines s Tumkevicius,* Jelena Dodonova
Vilnius University, Faculty of Chemistry, Department of Organic Chemistry, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: sigitas.tumkevicius@chf.vu.lt
Received 11 March 2011
ing on the amount of arylboronic acid and reaction
conditions proceeded to give 4-aryl-2-chloro- (1) or 2,4-
diarylpyrrolo[2,3-d]pyrimidines (4, R = R¢)7, respective-
ly. However, attempts to synthesize 2,4-diarylpyrrolopy-
Abstract: A simple and facile synthesis of novel fluorescent pyrro-
lo[2,3-d]pyrimidines with various aryl and heteroaryl assemblies in
positions 2, 4, and 7 of the heterocycle by combination of the Suzuki
cross-coupling and copper(I) iodide N-arylation reactions of chlo-
ropyrrolo[2,3-d]pyrimidines with arylboronic acids and haloarenes rimidines by the Suzuki coupling of 1 with arylboronic
is described.
acids failed. Otherwise, we observed that Boc group at the
position 7 of pyrrolo[2,3-d]pyrimidine increases reactivi-
ty of 2-chlorine group of pyrrolo[2,3-d]pyrimidine in the
Suzuki coupling.7 Therefore, for the synthesis of pyrro-
lo[2,3-d]pyrimidines 4 with different aryl groups in posi-
Key words: pyrrolo[2,3-d]pyrimidine, oligoarylenes, Suzuki cou-
pling, N-arylation, fluorescence
tions
2
and
4
from 4-aryl-2-chloropyrrolo[2,3-
The introduction of a heteroaryl moiety into extended p-
systems often brings about a number of interesting prop-
erties that are useful in the development of advanced elec-
tronic and photonic materials.1 Owing to the light-
emitting,2 self-assembling,3 and complex-forming4 prop-
erties with metal ions or organic molecules such materials
are of interest in biological, chemical, and materials sci-
ence. Although the parent pyrrolo[2,3-d]pyrimidine is
known to possess fluorescence properties5 and some de-
rivatives were demonstrated to be suitable for probing the
structure of DNA,6 exploitation of this heteroaromatic
core in functional p-systems is insufficient. Only recently,
pyrrolo[2,3-d]pyrimidine-core-based oligoarylenes have
been synthesized and elucidated as blue-light emitters.7
To develop more efficient fluorescent materials we report
herein on the sequential assembly of p-systems, such as
aryl groups, onto the pyrrolo[2,3-d]pyrimidine core as a
useful method for the construction of more p-extended tri-
arylpyrrolo[2,3-d]pyrimidines bearing various aryl
branches in positions 2, 4, and 7 of the heterocycle. Intro-
duction of different aryl functionalities at various posi-
tions of pyrrolo[2,3-d]pyrimidine was not only
synthetically challenging but is also important for tuning
of structure and photophysical properties of the pyrro-
lo[2,3-d]pyrimidine derivatives as well as for construction
of biologically active pyrrolo[2,3-d]pyrimidine deriva-
tives. Arylpyrrolo[2,3-d]pyrimidines were found to dis-
play a wide range of biological activities, such as
antimicrobial,8a inhibition of protein kinases8b–e and dihy-
drofolate reductase,8f antagonist effects to receptors,8g and
cytostatic effects.8h
d]pyrimidines (1) we have developed a protocol consist-
ing of N(7) protection with Boc group, Suzuki coupling,
and N(7)-deprotection reactions (Scheme 1). Synthesis of
N(7)-Boc derivatives 2 was carried out by the reaction of
1 with Boc2O in CH2Cl2 in the presence of DMAP and
DIPEA.9 The Suzuki coupling of 2 with arylboronic acids
using Pd(OAc)2/P(2-biphenyl)Cy2/K3PO4 as a catalyst
system proceeded at reflux in dry 1,4-dioxane.10 Depro-
tection of N(7) of 3 to give compounds 4 in good yields
R
R
N
i
N
N
N
Cl
N
Cl
N
R
H
Boc
1a,b
2a (61%)
2b (80%)
Suzuki
coupling
ii
R
iii
N
N
N
H
N
N
N
Boc
R'
R'
4a–c (73–80%)
3a–c (69–79%)
Earlier we found that the Suzuki coupling of 2,4-dichloro-
pyrrolo[2,3-d]pyrimidine with arylboronic acids depend-
2a R = H; 2b R = OMe; 3a, 4a R = H, R' = OEt;
3b, 4b R = H, R' = Ph; 3c, 4c R = OMe, R' = OEt
Scheme 1 Reagents and conditions: i) Boc2O, DMAP, DIPEA,
CH2Cl2; ii) R¢C6H4B(OH)2, Pd(OAc)2, P(2-biPh)Cy2, K3PO4, 1,4-
dioxane, reflux; iii) HCl, Me2CO, reflux.
SYNLETT 2011, No. 12, pp 1705–1708
Advanced online publication: 05.07.2011
DOI: 10.1055/s-0030-1260931; Art ID: D08111ST
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

1706
S. Tumkevicius, J. Dodonova
LETTER
was achieved by reflux 3 with concentrated hydrochloric
R
acid in acetone11 or trifluoracetic acid in CH2Cl2.
R
Products 4a–c thus obtained and pyrrolo[2,3-d]pyri-
midines 4d,e, prepared directly by the Suzuki coupling of
2,4-dichloro[2,3-d]pyrimidine with arylboronic acids as
described previously,7 were subjected to N-arylation
(Scheme 2). The catalyst system CuI/trans-1,2-diami-
nocyclohexane/K3PO4 was used as the catalyst system of
choice.12 Employing other ligands and bases in the reac-
tion gave worse results. For example, the reaction of 4e
with iodobenzene using CuI/1,10-phenanthroline/Cs2CO3
as a catalyst system furnished the target compound 5h in
only 49% yield, while using CuI/trans-1,2-diaminocyclo-
hexane/K3PO4 as a catalyst system, compound 5h was ob-
tained in 85% yield (Table 1, entry 8).
N
i
N
N
N
N
N
H
R'
R'
4a–e
5a–k
R''
Scheme 2 Reagents and conditions: i) 4-R¢¢C6H4I(Br), CuI, ( )-
trans-1,2-diaminocyclohexane, K3PO4, 1,4-dioxane, reflux.
The synthesized 2,4,7-triarylpyrrolo[2,3-d]pyrimidines
were subjected to optical absorption and fluorescence
studies. The compounds in dilute THF solution exhibited
strong absorption with their absorption maxima posi-
tioned in the range of 256–342 nm. The pyrrolo[2,3-d]pyr-
imidine derivatives in THF solution were found to exhibit
fluorescence with emission maxima located in the range
of 403–540 nm and fluorescence quantum yields ranging
from 2% to 40%. The fluorescence lifetimes estimated in
THF solutions span the range from 2.6 ns to 12.2 ns.
To achieve full conversion of compounds 4 in the N-ary-
lation reaction an amount of CuI ranging from 3–10 mol%
was used.13 The reaction proceeded at reflux temperature
of dioxane and worked well with aryl iodides and bro-
mides bearing electron-donating or electron-withdrawing
groups. The yields of 2,4,7-triarylpyrrolo[2,3-d]pyri-
midines varied from good to excellent (Table 1). Lower
yields of compounds 5i–k (Table 1, entries 9–11) were
obtained, presumably because of their more complex pu-
rification by column chromatography.
Table 1 Preparation of Compounds 5
Entry
Compd 5
R
R¢
R¢¢
CuI (mol%)
Reaction time (h) Yield (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
H
OEt
Ph
Ph
OEt
H
CN
3
10
5
6
25
11
90
95
93
99
92
72
82
H
CN
H
OMe
H
OMe
H
5
9.5
OMe
NPh2
CN
5
12
22
12
H
H
6
5g
H
H
5
8
9
5h
5i
H
5
7
7
10
19
22
85
51
57
N
N
N
N
N
N
N
N
OMe
CN
10
5j
11
5k
NPh2
8
29
59
Synlett 2011, No. 12, 1705–1708 © Thieme Stuttgart · New York

LETTER
Synthesis of 2,4,7-Triarylpyrrolo[2,3-d]pyrimidines
d]pyrimidines 2 – Compound 2a
1707
In summary, we have developed a simple synthetic strat-
egy that permits the assembly of aromatic p-systems onto
a pyrrolo[2,3-d]pyrimidine core in a programmable and
diversity-oriented format. A more detailed study of the
photophysical properties of the synthesized compounds in
various solvents and in a solid state and further variations
of oligoarylene branches at the pyrrolo[2,3-d]pyrimidine
framework are currently being carried out, and the results
will be reported in due course.
To a solution of compound 1a7 (0.42 g, 1.83 mmol) in anhyd
CH2Cl2 (5 mL) DIPEA (0.48 mL, 2.75 mmol), DMAP (0.07
g, 0.57 mmol), and di(tert-butyl)dicarbonate (0.6 g, 2.75
mmol) were added. The reaction mixture was refluxed for 80
min, CH2Cl2 was evaporated under reduced pressure, and the
residue was purified by column chromatography (eluent:
CHCl3) to give compound 2a (0.37g, 61%); mp 76–77 °C.
1H NMR (300 MHz, CDCl3): d = 1.74 (s, 9 H, CMe3), 6.89
(d, J = 4.2 Hz, 1 H, 5-H), 7.58–7.61 [m, 3 H, 3¢,4¢,5¢-H (Ph)],
7.74 (d, J = 4.2 Hz, 1 H, 6-H), 8.06–8.09 [m, 2 H, 2¢,6¢-H
(Ph)]. 13C NMR (75 MHz, CDCl3): d = 28.3, 86.0, 104.1,
116.9, 128.0, 129.2, 129.3, 131.2, 136.6, 147.3, 154.4,
156.2, 160.6. HRMS: m/z calcd for C17H16ClN3O2 [M + H]+:
330.1004; found: 330.1000.
Acknowledgment
Research Council of Lithuania is greatly acknowledged for financi-
al support (project No. MIP-65/2010).
(10) Representative Procedure for the Preparation of 2,4-
Diaryl-7-(tert-butoxycarbonyl)-7H-pyrrolo[2,3-d]-
pyrimidines 3a–c – Compound 3a
References and Notes
A solution of compound 2a (0.07 g, 0.21 mmol) in anhyd
1,4-dioxane (5 mL) was degassed with argon, and Pd(OAc)2
(2.0 mol%) and dicyclohexyl(2-biphenyl)phoshine (4.0
mol%) were added with stirring under argon. The mixture
was stirred for 10 min, then 4-ethoxyphenylboronic acid
(0.042 g, 0.25 mmol) and anhyd K3PO4 (0.11 g, 0.52 mmol)
were added. The reaction mixture was refluxed for 4 h. Then
the solvent was evaporated under reduced pressure, and H2O
(5 mL) was added to dissolve inorganic salts. The obtained
solution was extracted with CHCl3 (3 × 25 mL), the
combined organic layers were dried with Na2SO4, filtered,
and evaporated under reduced pressure to dryness. The
resulting solid was purified by column chromatography
(eluent: CHCl3) to give compound 3a (0.07 g, 79%); mp
141–141.9 °C. 1H NMR (300 MHz, CDCl3): d = 1.49 (t,
J = 6.9 Hz, 3 H, Me), 1.81 (s, 9 H, CMe3), 4.16 (q, J = 6.9
Hz, 2 H, OCH2), 6.88 (d, J = 4.2 Hz, 1 H, 5-H), 7.05 [dm,
J = 9.0 Hz, 2 H, 3¢,5¢-H (EtOC6H4)], 7.58–7.61 [m, 3 H,
3¢,4¢,5¢-H (Ph)], 7.75 (d, J = 4.2 Hz, 1 H, 6-H), 8.20 [dm,
J = 7.9 Hz, 2 H, 2¢,6¢-H (Ph)], 8.68 [dm, J = 9.0 Hz, 2 H,
2¢,6¢-H (EtOC6H4)]. 13C NMR (75 MHz, CDCl3): d = 15.1,
28.5, 63.7, 84.9, 104.4, 114.5, 115.9, 127.1, 129.0, 129.3,
130.1, 130.4, 131.4, 138.4, 148.6, 154.3, 158.2, 159.9,
161.1. HRMS: m/z calcd for C25H25N3O3 [M + H]+:
416.1969; found: 416.1962.
(1) (a) Hughes, G.; Bryce, M. R. J. Mater. Chem. 2005, 15, 94.
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Yang, C.; Wang, Q.; Zhang, Z.; Zou, T.; Qin, J.; Ma, D.
Angew. Chem. Int. Ed. 2008, 47, 8104.
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C. W.; Wong, K. T.; Liao, Y. L.; Lee, G. H.; Peng, S. M.
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2954.
(4) (a) Bunzli, J.-C. G.; Piguet, C. Chem. Soc. Rev. 2005, 34,
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(5) Seela, F.; Steker, H. Liebigs Ann. Chem. 1984, 1719.
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Pearson, W. H.; Mackie, H.; Randolph, J. B.; Somers, R. L.
Tetrahedron Lett. 2004, 45, 2457.
(11) Representative Procedure for the Preparation of 2,4-
Diaryl-7H-pyrrolo[2,3-d]pyrimidines 4a–c – Compound
4a
(7) Tumkevicius, S.; Dodonova, J.; Kazlauskas, K.; Masevicius,
V.; Skardziute, L.; Jursenas, S. Tetrahedron Lett. 2010, 51,
3902.
To a solution of compound 3a (0.1 g, 0.24 mmol) in a
mixture of acetone (9 mL) and H2O (2 mL) concd HCl (0.06
mL, 1.94 mmol) was added. The reaction mixture was
refluxed with stirring for 7 d, then cooled to r.t., the
precipitate was filtered off to give compound 4a (0.06g,
80%); mp 275–276 °C. 1H NMR (300 MHz, DMSO-d6):
d = 1.39 (t, J = 6.9 Hz, 3 H, Me), 4.13 (q, J = 6.9 Hz, 2 H,
OCH2), 6.90 (dd, J3 = 3.5 Hz, J4 = 1.8 Hz, 1 H, 5-H), 7.08
[dm, J = 9.0 Hz, 2 H, 3¢,5¢-H (EtOC6H4)], 7.59–7.65 [m, 4 H,
6-H, 3¢,4¢,5¢-H (Ph)], 8.31 [dm, J = 7.9 Hz, 2 H, 2¢,6¢-H
(Ph)], 8.49 [dm, J = 9.0 Hz, 2 H, 2¢,6¢-H (EtOC6H4)], 12.21
(s, 1 H, NH). 13C NMR (75 MHz, DMSO-d6): d = 15.4, 63.9,
100.9, 113.4, 114.9, 128.4, 129.3, 129.6, 129.7, 130.8,
131.7, 138.9, 154.5, 156.1, 157.0, 160.6. HRMS: m/z calcd
for C20H17N3O [M + H]+: 316.1444; found: 316.1446.
(12) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727.
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A. Acta Pharm. 2009, 59, 145. (b) Wiesner, J. B.; Ugarkar,
B. G.; Castellino, A. J.; Barankiewicz, J.; Dumas, D. P.;
Gruber, H. E.; Foster, A. C.; Erion, M. D. J. Pharm. Exp.
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N.; Munschauer, R.; Rafferty, P. Bioorg. Med. Chem. Lett.
2002, 12, 1683. (d) Altmann, E.; Missbach, M.; Green, J.;
Susa, M.; Wagenknecht, H.; Widler, L. Bioorg. Med. Chem.
Lett. 2001, 11, 853. (e) Widler, L.; Green, J.; Missbach, M.;
Susa, M.; Altmann, E. Bioorg. Med. Chem. Lett. 2001, 11,
849. (f) Gibson, C. L.; Huggan, J. K.; Kennedy, A.; Kiefer,
L.; Lee, J. K.; Suckling, C. J.; Clements, C.; Harvey, A. L.;
Hunter, W. N.; Tulloch, L. B. Org. Biomol. Chem. 2009, 7,
1829. (g) Hess, S.; Muller, C. E.; Frobenius, W.; Reith, U.;
Klotz, K.-N.; Eger, K. J. Med. Chem. 2000, 43, 4636.
(h) Naus, P.; Pohl, R.; Votruba, I.; Dzubak, P.; Haiduch, M.;
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Cihlar, T.; Hocek, M. J. Med. Chem. 2010, 53, 460.
(9) Representative Procedure for the Preparation of 4-Aryl-
7-(tert-butoxycarbonyl)-2-chloro-7H-pyrrolo[2,3-
(13) Representative Procedure for the Preparation of 2,4,7-
triaryl-7H-pirolo[2,3-d]pirimidines(5) – Compound 5a
A solution of compound 4a (0.06 g, 0.19 mmol) in anhyd
1,4-dioxane (3 mL) was degassed with argon, and CuI (1
mol%) and anhyd K3PO4 (0.07 g, 0.33 mmol) were added.
Synlett 2011, No. 12, 1705–1708 © Thieme Stuttgart · New York

1708
S. Tumkevicius, J. Dodonova
LETTER
The mixture was stirred for 10 min, then 4-iodobenzonitrile
(0.04 g, 0.17 mmol) and trans-1,2-diaminocyclohexane (10
mol%) were added. The reaction mixture was refluxed with
stirring and after 1 h and 2 h, respectively, an additional
amount of 1 mol% CuI was added. The total amount of CuI
used in the reaction was 3 mol%, and total reflux time was 6
h. Then EtOAc (5 mL) was added to the reaction mixture,
and the solution was filtered through a layer of silica gel. The
solvents were removed under reduced pressure and the
residue purified by column chromatography (eluent:
mp 206.3–206.8 °C (from 2-PrOH–EtOAc). 1H NMR (300
MHz, CDCl3): d = 1.51 (t, J = 6.9 Hz, 3 H, Me), 4.17 (q,
J = 6.9 Hz, 2 H, OCH2), 7.04–7.09 [m, 3 H, 5-H, 3¢,5¢-H (4-
EtOPh)], 7.61–7.62 [m, 4 H, 6-H, 3¢,4¢,5¢-H (Ph)], 7.93 [dm,
J = 9.0 Hz, 2 H, 3¢,5¢-H (N7-Ph)], 8.21 [dm, J = 9.0 Hz, 2 H,
2¢,6¢-H (N7-Ph)], 8.30 [m, J = 7.9 Hz, 2 H, 2¢,6¢-H (Ph)], 8.10
[dm, J = 9.0 Hz, 2 H, 2¢,6¢-H (4-EtOPh)]. 13C NMR (75
MHz, CDCl3): d = 15.1, 63.8, 104.2, 109.7, 114.6, 114.9,
118.8, 123.6, 126.9, 129.1, 129.3, 129.9, 130.5, 131.1,
133.7, 138.5, 141.8, 153.3, 158.5, 159.1, 161.1. HRMS: m/z
calcd for C27H20N4O [M + H]+: 417.1710; found: 417.1710.
hexane–EtOAc = 27:1) to give compound 5a (0.071g, 90%;
Synlett 2011, No. 12, 1705–1708 © Thieme Stuttgart · New York

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