Efficient one-pot synthesis of 6-arylpyrrolo[3,2- d ]pyrimidines from 6-arylethynyl-5-nitropyrimidines

Article abstract of DOI:10.1055/s-0029-1219544

A highly concise one-pot synthesis of 6-arylpyrrolo[3,2-d]pyrimidines via conjugative addition reaction of secondary amines to 6-arylethynyl-5- nitropyrimidines and subsequent reduction is described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219544

LETTER
1107
Efficient One-Pot Synthesis of 6-Arylpyrrolo[3,2-d]pyrimidines from
6-Arylethynyl-5-nitropyrimidines
E
fficient
n
S
ynthesis of
g
6-Arylpyrro
a
lo[3,2-
d
]pyrimidi
C
ne
s
ikotiene,* Erika Pudziuvelyte, Algirdas Brukstus
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University, Naugarduko 24, 03225 Vilnius, Lithuania
Fax +370(5)2330987; E-mail: inga.cikotiene@chf.vu.lt
Received 14 January 2010
Our initial studies were aimed at finding optimal condi-
tions for the amine-mediated reductive cyclization of the
6-arylethynyl-5-nitropyrimidines. Our investigation be-
gan with 4-amino-5-nitro-6-phenylethynylpyrimidine
(1a), the corresponding amine (1 equiv) in different sol-
vents under the reductive conditions (Table 1). The best
results were obtained using secondary amines, such as di-
ethylamine, pyrrolidine, or piperidine in methanol and
performing reduction by hydrogen in the presence of 10%
palladium on charcoal (entries 4, 6, 7).
Abstract: A highly concise one-pot synthesis of 6-arylpyrrolo[3,2-
d]pyrimidines via conjugative addition reaction of secondary
amines to 6-arylethynyl-5-nitropyrimidines and subsequent reduc-
tion is described.
Key words: pyrrolo[3,2-d]pyrimidines, 6-arylethynyl-5-nitropyrimi-
dines, enamines, cyclization
The pyrrolo[3,2-d]pyrimidine heterosystem is an impor-
tant class of compounds, possessing notable biological ac-
tivities, in particular purine nucleoside phosphorylase1
and thymidylate synthase2 inhibitory, neuropeptide Y5
receptor3 and A1, A2-adenoside receptor4 antagonistic
properties. A literature survey revealed that 5-aminopy-
rimidines with suitable substituents are the most often
used starting compound for this purpose.5 Also there are
only few examples of straightforward synthesis of pyrro-
lo[3,2-d]pyrimidines from 5-nitropyrimidines6 and 4-
alkynylpyrimidines.7 The latter method includes classic
formation of the pyrrole ring from the neighboring amino
group and alkynyl moiety. Normally, the addition of het-
eroatomic nucleophiles to triple bonds requires high acti-
vation energy, so use of harsh reaction conditions, strong
bases, or transition-metal catalysts are in practice.8
NH2
NH2
NO2
NO2
i
N
N
H
R1
N
R1
N
R2
Ph
Ph
N
ii
R3
iii
NH2
NH2
NO2
NO2
H
N
N
H
R1
N
R1
N
S
Ph
HN
Ph
R2
R2
Previous work in our group showed that the triple bond of
some 6-arylethynylpyrimidines is electron-deficient,
therefore it is extremely reactive towards nucleophilic re-
agents, and for that reason the formation of addition prod-
ucts as well as various pyrimidine condensed derivatives
are favorable.9 Moreover, we showed that primary and
secondary amines and thiols take part in a regio- and ste-
reoselective addition reaction to the triple bond of 5-nitro-
6-phenylethynylpyrimidines to form the corresponding
syn addition (in the case of secondary amines) or anti ad-
dition (in the case of primary amines or thiols) products
(Scheme 1).10
Scheme 1 Our previous work. Reagents and conditions: i) secon-
dary amine (1 equiv), CH2Cl2, r.t., 20 min; ii) primary amine (1
equiv), CH2Cl2, r.t., 48 h; iii) R2SNa (1 equiv), MeOH, r.t., 30 min.
Other solvents (dichloromethane, ethylacetate) under the
same reductive conditions were also investigated and
proved to be far less effective (entries 1–3, 10, 11). More-
over, using of primary amines (benzylamine, propyl-
amine) resulted in longer reaction times (entries 3, 8, 9).
The latter three results can be explained by much more
slower reaction of starting compound 1a with primary
amines and also by stabilization of intermediate enamines
(2, 3) by intramolecular hydrogen bond between NH moi-
ety and nitrogen of the pyrimidine ring.
As the latter reaction of starting compounds with second-
ary amines were fast and high-yielding, we decide to
study the possibility of straightforward one-pot synthesis
of the pyrrolo[3,2-d]pyrimidine framework from 6-aryl-
ethynyl-5-nitropyrimidines via reductive cyclization of
intermediate enamines.
N
Ph
N
NH2
N
N
NH2
Ph
N
N
5a
SYNLETT 2010, No. 7, pp 1107–1109
x
x.
x
x.
2
0
1
0
Advanced online publication: 23.02.2010
DOI: 10.1055/s-0029-1219544; Art ID: G02410ST
Figure 1 Structure of dimeric side-product 5a
© Georg Thieme Verlag Stuttgart · New York

1108
I. Cikotiene et al.
LETTER
the room temperature. Upon reduction, the intermediate 3
rapidly cyclized via intramolecular 1,5-electrocyclic reac-
tion to give the target pyrrolo[3,2-d]pyrimidine (4a). It
should be noted, that we did not find any evidence about
the reduction of intermediate enamines C=C bond.
Table 1 Reaction Conditions for Nucleophilic Reductive Cycliza-
tion of 4-Amino-5-nitro-6-phenylethynylpyrimidine (2a)
Entry Solvent
Amine
Reductant
Time
(h)
Yield of
4a (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
MeOHb
MeOH
MeOH
MeOH
MeOH
Et2NH
H2, Pd/C
H2, Pd/C
24
24
60
2
35a
33a
20a
98
30c
90
94
85
81
78
41
30
58
(CH2)4NH
Table 2 Synthesis of 2,4-Disubstituted 6-Arylpyrrolo[3,2-d]pyrim-
idines 4a–p by the Presented Method11,12
PhCH2NH2 H2, Pd/C
R2
R3
R2
R3
Et2NH
H2, Pd/C
N
N
N
1) Et2NH,
2) H2, Pd/C, MeOH
H
NO2
Et2NH
NH2NH2·H2O
H2, Pd/C
1
N
N
N
Ar
R1
N
(CH2)4NH
(CH2)5NH
PrNH2
2
R1
Ar
H2, Pd/C
2
1
4
Entry Starting R1
compound
NR2R3
Ar
Ph
Product Yield
(%)
H2, Pd/C
10
12
15
48
48
3
PhCH2NH2 H2, Pd/C
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
H
H
H
H
NH2
NH2
NH2
NH2
4a
98
80
83
79
82
85
78
84a
86a
88
90
92
91
88
10 THF
11 EtAc
12 EtAc
13 DMF
Et2NH
Et2NH
Et2NH
Et2NH
H2, Pd/C
H2, Pd/C
SnCl2
4-MeC6H4 4b
4-EtC6H4
4-FC6H4
Ph
4c
4d
4e
SnCl2
SCH3 NH2
SCH3 NH2
SCH3 NH2
a Incomplete reduction of 2a was observed by TLC.
b Reaction was performed at reflux temperature.
c Formation of dimeric side product 5a was observed.
4-MeC6H4 4f
1g
1h
1k
4-EtC6H4
4g
4h
4k
4l
Changing the reductant into hydrazine hydrate in boiling
methanol (either in the presence of Pd/C or without the
catalyst), resulted in formation of side dimeric product 5a
(Table 1, entry 5, Figure 1). Using tin(II) chloride in ethyl
acetate or dimethylformamide at room temperature also
decreased the yield of final 4-amino-6-phenylpyrrolo[3,2-
d]pyrimidine (4a, Table 1, entries 12, 13). It is noteworthy
that better yields of final product were achieved when the
H
NHCH2C6H5 Ph
SCH3 NHCH2C6H5 Ph
10 1l
11 1m
12 1n
H
N(CH2)4
Ph
Ph
SCH3 N(CH2)4
4m
H
H
H
N(CH2)4
N(CH2)5
N(CH2)4O
4-MeC6H4 4n
starting material was refluxed with an equivalent of sec- 13 1o
Ph
Ph
4o
ondary amine in methanol for 10–15 minutes, and after
the formation of enamine 2 was complete (observed by
TLC as deep-red spot), the nitro group was subsequently
reduced in the same flask by hydrogen, using 10% Pd/C at
14 1p
4p
a Reductive N-debenzylation of final compounds was not observed.
NH2
NH2
NH2
NH2
NO2
NO2
[H]
N
R1R2NH
N
N
H
H
N
N
N
R1
R1
Ph
Ph
N
Ph
N
R2
R2
1a
2
3
[H]
NH2
NH2
NH2
N
H
N
N
Ph
N
Ph
N
6
4a
Scheme 2 Study on the one-pot preparation of pyrrolo[3,2-d]pyrimidine framework
Synlett 2010, No. 7, 1107–1109 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of 6-Arylpyrrolo[3,2-d]pyrimidines
1109
Hutchison, T. L.; Kezar, H. D.; Morris, P. E.; Schramm,
L. T.; Tyler, P. C. J. Org. Chem. 2001, 66, 5723.
(7) (a) Rodriguez, A. L.; Koradin, C.; Dohle, N.; Knochel, P.
Angew. Chem. Int. Ed. 2000, 39, 2488. (b) Susvilo, I.;
Brukstus, A.; Tumkevicius, S. Synlett 2003, 1151.
(c) Cikotiene, I.; Pudziuvelyte, E.; Brukstus, A.
Also, it is important to start the reduction of the nitro
group only after the complete formation of enamine 2.
Otherwise, the formation of 2,5-diamino-6-phenylethy-
nylpyrimidine (6) stops the reaction in the first step, be-
cause of inactivation of the triple bond by electron-
donating 5-amino group (Scheme 2).
J. Heterocycl. Chem. 2008, 45, 1615.
(8) (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675.
(b) Beller, M.; Riermeier, T. H. In Transition Metals for
Organic Synthesis; Wiley-VCH: Weinheim, 1998.
(c) Teles, J. H.; Brode, S.; Chabanas, M. Angew. Chem.
1998, 110, 1478. (d) Koradin, C.; Dohle, W.; Rodriguez,
A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571.
(9) (a) Cikotiene, I.; Morkunas, M.; Motiejaitis, D.; Rudys, S.;
Brukstus, A. Synlett 2008, 1693. (b) Cikotiene, I.; Kairys,
V.; Buksnaitiene, R.; Morkunas, M.; Motiejaitis, D.; Rudys,
S.; Brukstus, A.; Fernandes, M. X. Tetrahedron 2009, 65,
5752. (c) Cikotiene, I.; Morkunas, M. Synlett 2009, 284.
(d) Cikotiene, I.; Morkunas, M.; Rudys, S.; Buksnaitiene, R.;
Brukstus, A. Synlett 2008, 2799.
So, according to the present methodology, we have pre-
pared various 2,4-disubstituted 6-arylpyrrolo[3,2-d]py-
rimidines 4a–p via consequent conjugative addition of
secondary amine to 6-arylethynyl-5-nitropyrimidines 1a–
p and reductive cyclization reaction of intermediate
enamines. The results are summarized in Table 2.
In conclusion, we have developed a novel, simple, and
high-yielding synthetic method of pyrrolo[3,2-d]pyrimi-
dine framework via one-pot reaction of 2,4-disubstituted
6-arylethynyl-5-nitropyrimidines with secondary amines
followed by reductive cyclization. We believe that the
present methodology extends promise for the convenient
synthetic protocol for the preparation of pyrrolo[3,2-d]py-
rimidine derivatives of biological interest.
(10) Cikotiene, I.; Pudziuvelyte, E.; Brukstus, A.; Tumkevicius,
S. Tetrahedron 2007, 63, 8145.
(11) Typical Procedure for the Preparation of 2,4-
Disubstituted 6-Arylpyrrolo[3,2-d]pyrimidines 4a–o
To a solution of the corresponding 6-arylethynyl-5-nitro-
pyrimidine 1a–p (0.3 mmol) in MeOH (5 mL) freshly
distilled Et2NH (21,9 mg, 0.3 mmol) was added. The
resulting reaction mixture was refluxed for 15 min, then
deeply red solution was cooled to r.t., 10% Pd/C (0.33 mg,
0.03 mmol) was added, and the resulted mixture was stirred
under H2 atmosphere for 2 h. After the completion of the
reaction, the catalyst was filtered off, the mother liquid was
evaporated under reduced pressure, the residue washed with
H2O, filtered, and recrystallized to give compounds 4a–p.
4-Amino-6-phenylpyrrolo[3,2-d]pyrimidine (4a)
Yield 98%; mp 226–227 °C (from DMF–H2O). IR (KBr):
Acknowledgment
We thank Lithuanian State Science and Studies Foundation for the
financial support (Reg. No. T-09027; Grant No. T-67/09).
References and Notes
(1) (a) Farutin, V.; Masterson, L.; Andricopulo, A. D.; Cheng,
J.; Riley, B.; Hakimi, R.; Frazer, J. W.; Cordes, E. H. J. Med.
Chem. 1999, 42, 2422. (b) Evans, G. B.; Furneaux, R. H.;
Gainsford, G. J.; Hanson, J. C.; Kicska, G. A.; Sauve, A. A.;
Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2003, 46, 155.
(2) (a) Gangjee, A.; Li, W.; Yang, J.; Kisliuk, R. L. J. Med.
Chem. 2008, 51, 68. (b) Bavetsias, V.; Jackman, A. L. Curr.
Med. Chem. 1998, 5, 265.
(3) Norman, M. H.; Chen, N.; Chen, Z.; Fotsch, C.; Hale, C.;
Han, N.; Hurt, R.; Jenkins, T.; Kincaid, J.; Liu, L.; Lu, Y.;
Moreno, O.; Santora, V. J.; Sonnenberg, J. D.; Karbon, W.
J. Med. Chem. 1994, 37, 1526; and ref. 16-19 therein.
(4) (a) Fredholm, B. B.; Zerman, A. P.; Jacobson, K. A.; Koltz,
K.-N.; Luiden, J. Pharmacol. Rev. 2001, 53, 527.
n
max = 3444, 3441, 3396 (NH, NH2) cm–1. 1H NMR (300
MHz, DMSO-d6): d = 6.81 (br s, 2 H, NH2), 6.86 (s, 1 H,
C7H), 7.38 (t, J = 7.5 Hz, 1 H, ArH), 7.51 (t, J = 7.5 Hz, 2
H, ArH), 7.87 (d, J = 7.5 Hz, 2 H, ArH), 8.11 (s, 1 H, C2H),
11.64 (br s, 1 H, NH) ppm. 13C NMR (75 Hz, DMSO-d6):
d = 98.6, 114.7, 125.1, 128.3, 129.0, 131.1, 131.4, 139.4,
150.2, 150.7 ppm. Anal. Calcd for C12H10N4: C, 68.56; H,
4.79; N, 26.65. Found: C, 68.37; H, 4.51; N, 26.88.
4-Amino-2-methylthio-6-phenylpyrrolo[3,2-d]pyrimi-
dine (4e)
(b) Grahner, B.; Winiwarter, S.; Lanzner, W.; Muller, C. E.
J. Med. Chem. 2000, 43, 4288. (c) Stefanachi, A.; Nicolotti,
O.; Leonetti, F.; Cellamare, S.; Campagna, F.; Loza, M. I.;
Brea, J. M.; Mazza, F.; Gavuzzo, E.; Carotti, A. Bioorg.
Med. Chem. 2008, 16, 9780.
Yield 82%; mp 235–237 °C (from DMF–H2O). IR (KBr):
n
max = 3446, 3443, 3398 (NH, NH2) cm–1. 1H NMR (300
MHz, DMSO-d6): d = 2.45 (s, 3 H, SCH3), 6.77 (s, 1 H,
C7H), 7.14 (br s, 2 H, NH2), 7.36 (t, J = 7.5 Hz, 1 H, ArH),
7.49 (t, J = 7.5 Hz, 2 H, ArH), 7.91 (d, J = 7.5 Hz, 2 H, ArH),
12.19 (br s, 1 H, NH) ppm. 13C NMR (75 Hz, DMSO-d6):
d = 13.4, 98.8, 112.9, 125.2, 127.4, 128.1, 131.5, 139.5,
148.8, 150.3, 160.6 ppm. Anal. Calcd for C13H12N4S: C,
60.91; H, 4.72; N, 21.86. Found: C, 60.77; H, 4.66; N, 21.99.
4-Morpholino-6-phenylpyrrolo[3,2-d]pyrimidine (4p)
Yield 88%; mp >230 °C (dec.; from MeOH). IR (KBr):
(5) (a) Pfleiderer, M. Chem. Ber. 1957, 90, 738. (b) Kawahara,
N.; Nakajima, T.; Itoh, T.; Ogura, H. Chem. Pharm. Bull.
1985, 33, 4740. (c) Sizova, O. S.; Glushkov, R. G. Pharm.
Chem. J. 1984, 18, 420. (d) Brahta, M.; Daves, G. D.
J. Chem. Soc., Perkin Trans. 1 1992, 1883. (e) Majumdar,
K. C.; Das, U.; Jana, N. K. J. Org. Chem. 1998, 63, 3550.
(f) De Jong, R. L.; Davidso, J. G.; Dozeman, G. J.; Fiore,
P. J.; Giri, P.; Kelly, M. E.; Puls, T. P.; Seamans, R. E. Org.
Process Res. Dev. 2001, 5, 216. (g) Majumdar, K. C.;
Mondal, S. Tetrahedron 2009, 65, 9604. (h) Song, J. J.;
Tan, Z.; Reeves, J. T.; Fandrick, D. R.; Lee, H.; Yee, N. K.;
Senanayake, C. H. Tetrahedron Lett. 2009, 50, 3952.
(6) (a) Cupps, T. L.; Wise, D. S.; Townsend, L. B. J. Org. Chem.
1983, 48, 1060. (b) Cupps, T. L.; Wise, D. S.; Townsend,
L. B. Tetrahedron Lett. 1982, 23, 4759. (c) Otmar, M.;
Masojidkova, M.; Budesinsky, M.; Holy, A. Tetrahedron
1998, 54, 2931. (d) Evans, G. B.; Furneaux, R. H.;
n
max = 3341 (NH) cm–1. 1H NMR (300 MHz, CDCl3):
d = 3.87 (br s, 8 H, morpholino), 6.86 (s, 1 H, C7H), 7.41–
7.48 (m, 3 H, ArH), 7.72 (d, J = 7.2 Hz, 2 H, ArH), 8.52 (s,
1 H, C2H), 9.23 (br s, 1 H, NH) ppm. 13C NMR (75 Hz,
CDCl3): d = 46.8, 66.6, 100.9, 116.4, 125.9, 129.1, 129.2,
131.2, 142.1, 150.8, 150.9, 151.4 ppm. Anal. Calcd for
C16H16N4O: C, 68.55; H, 5.75; N, 19.99. Found: C, 68.50; H,
5.66; N, 20.08.
(12) Compounds 4b–d,f–o and 5a were also fully characterized
by IR, 1H NMR, 13C NMR spectroscopic and
microanalytical data.
Synlett 2010, No. 7, 1107–1109 © Thieme Stuttgart · New York

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