C- and N-cyanoacetylation of 6-aminopyrimidines with cyanoacetic acid and acetic anhydride

Article abstract of DOI:10.1016/j.tetlet.2008.07.084

A series of 6-aminopyrimidines are cyanoacetylated with a mixture of cyanoacetic acid and acetic anhydride. When pyrimidin-4(3H)-ones are used as substrates, the substitution occurs at C-5, however, when the substrates are substituted pyrimidines at the C-2 and C-4, the cyanoacetylation takes place at the exocyclic amino group.

Full text of DOI:10.1016/j.tetlet.2008.07.084

Tetrahedron Letters 49 (2008) 5672–5675
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
C- and N-cyanoacetylation of 6-aminopyrimidines with
cyanoacetic acid and acetic anhydride
Jairo Quiroga a, , Jorge Trilleras , Jaime Gálvez , Braulio Insuasty , Rodrigo Abonía ,
a
a
a
a
*
b,
b
b
*
Manuel Nogueras , Justo Cobo , Antonio Marchal
Grupo de Investigación de Compuestos Heterocíclicos, Department of Chemistry, Universidad del Valle A. A. 25360 Cali, Colombia
Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
a
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 6-aminopyrimidines are cyanoacetylated with a mixture of cyanoacetic acid and acetic anhy-
dride. When pyrimidin-4(3H)-ones are used as substrates, the substitution occurs at C-5, however, when
the substrates are substituted pyrimidines at the C-2 and C-4, the cyanoacetylation takes place at the
exocyclic amino group.
Received 6 June 2008
Revised 14 July 2008
Accepted 15 July 2008
Available online 19 July 2008
Ó 2008 Published by Elsevier Ltd.
Keywords:
Cyanoacetylation
6
3
-Aminopyrimidines
-Pyrimidinyl-3-oxopropanenitriles
Simple nitrogenated heteroaromatic compounds have received
cyanide,3 or from an alkyl carboxylate using acetonitrile in the
presence of a strong base, like sodium amide. The cyanoacetylat-
4
much attention in the literature over the years. These compounds
can be considered as potential building blocks in synthesis and are
found in a wide variety of pharmacologically and biologically ac-
tive compounds. The pyrimidine is a widespread heterocyclic moi-
ety, which is present in numerous natural products as well as
ing reagent (acetic anhydride and cyanoacetic acid under heating)
5
has been used in the synthesis of 6-aminouracils via urea, by N-
6
acetylation and C-acetylation of enamines. Other activation proce-
dures, such as conversion to cyanoacetyl chloride, have also been
described, although this reagent is typical for its tendency to
1
synthetic pharmacophores with biological activities. Substituted
7
pyrimidines, particularly with amino-groups at 2 and 4 positions,
are known pharmacophores in several structure-based drug design
approaches in medicinal chemistry.2
Heterocycles containing a cyanoacetyl group are relatively
unexplored, most of reported preparations to get them involved
nucleophilic displacement of halide in haloacetyl derivatives by
self-polymerize (particularly when heated). Generation of the
cyanoacetylation reagent from cyanoacetic acid and acetic anhy-
dride has somehow been forgotten, and instead other less conve-
nient reagents such as pyrazole derivative have been used.8
The systems containing 3-oxopropanenitrile moiety are used
as a building block in various reactions such as cyclizations9 or
O
N
Ar
O
O
Ar
H C
3
R
X
CN
Ar
H
CN
Ar
H C
H
CN
R
N
O
N
H C
3
R
N
H
O
N
3
N
N
R
Ph
N
N
NH2
N
Ph
H C
3
X
NH2
X = O, S; R = H, CH
-, 4-CH OC
3
6 5
R = C H -, Indol-3-yl-
Ar = C
6
H
5
3
6
H
4
-, 4-ClC
6
H
4
-
Scheme 1.
*
Corresponding authors. Fax: +57 2 33392440 (J.Q.); fax: +34 618907111 (M.N.).
E-mail addresses: jaiquir@univalle.edu.co (J. Quiroga), mmontiel@ujaen.es (M. Nogueras).
0
040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.07.084

J. Quiroga et al. / Tetrahedron Letters 49 (2008) 5672–5675
5673
we have reported synthesis of dihydropyrido[2,3-d]pyrimidines
O
O
O
starting from readily available aminopyrimidin-4-ones, benzoyl-
R
O
R
O
CN
N
N
12
acetonitrile and benzaldehydes (Scheme 1).
To demonstrate the generality of cyanoacetic acid-acetic anhy-
dride reagent in order to get cyanoacetylation, we have investi-
gated its scope on diverse 6-aminopyrimidines to develop a route
to functionalize the C-5 position at pyrimidines. So, to render the
cyanoacetylation the pyrimidines, were poured onto a solution of
the cyano-acetylating reagent and heated to 85 °C for 5 min, 3-oxo-
propanenitrile pyrimidine derivatives were isolated as solid prod-
N
CH3
NH2
N
CH3
NH2
NCCH CO H, Ac O
2
2
2
1a,b
2a,b
50 - 85 ºC for 5 min.
O
O
N
O
R
R
CN
N
N
13
ucts by simple filtration.
R'X
N
NH2
R'X
NH2
Two main different behaviours were observed depending on the
pyrimidine frame, so when pyrimidin-4(3H)-ones are used as sub-
strates, substitution does indeed occur at C-5 to provide 5-cyano-
acetylpyrimidine derivatives (Scheme 2, Table 1, entries 2–4).
Interestingly, various substrates such as pyrimidines substituted
at the N-1, C-2 and N-3 position reacted efficiently with cyanoacet-
ylating reagent in good yields.
However, when the substrates used were formal aromatic
pyrimidines, no ring substitution occurs. Instead, acetylation
occurred at the exocyclic amino group giving N-acetylated pyrim-
idines (Scheme 3, Table 1, entries 5a–d).
In C-cyanoacetylated compounds, the exocyclic carbonyl group
is nearly coplanar with the ring, with a deviation of carbonyl atom
O from the mean plane of the ring; this is probably associated both
with the polarization of the molecular–electronic structure and
with an intramolecular N–HÁ Á ÁO hydrogen bond, which is
3
a-e
4
a-e
; 3a : R = R’ = H, X = S; 3b: R = H , R’ = CH
S; 3c: R = R’ = CH , X = S; 3d: R = H , R’ = CH , X = O; 3e: R = R’
H, X = NH
1
a-b: R = H, CH
3
3
, X =
3
3
=
Scheme 2.
synthesis of the other heterocyclic systems which have exciting
biological properties.
Recently, we have reported synthesis of pyrazolopyridines
derivatives in the reaction of aminopyrazoles with 3-oxopro-
panenitrile derivatives or with its precursors, and aldehydes. Also
5
a,7,10
1
1
Table 1
Cyanoacetylated 6-aminopyrimidines with cyanoacetic acid and acetic anhydride to yield 3-pyrimidinyl-3-oxopropanenitrile derivatives
Entry
Pyrimidine
Product
Mp (°C)
%
Recrystallization solvent
DMF/ethanol (5/3)
O
O
O
CN
2
a
213–215
95
HN
HN
O
N
NH
2
O
N
NH
2
CH
3
CH
3
O
O
O
H
3
C
H
3
C
CN
N
N
2
b
260–262 (260)a (250–251)b
87 (99)a (95)b
DMF
O
N
NH
2
O
N
NH2
CH
3
CH3
O
O
O
CN
HN
HN
4
4
a
>300
68
70
DMF/ethanol (5/3)
DMF/ethanol (5/3)
DMF
S
H
N
H
NH
2
S
H
N
H
NH
2
O
O
O
CN
b
HN
HN
283–285
3
C
3
C
S
N
O
NH
2
S
N
O
NH
2
O
H
3
C
S
H
3
C
S
CN
CN
4
4
c
N
N
246–248
272–274
60
60
H
H
3
C
H C
3
N
O
NH
2
N
O
NH2
O
d
HN
HN
DMF
3
C
H C
3
O
N
NH
2
O
N
NH2
(continued on next page)

5
674
J. Quiroga et al. / Tetrahedron Letters 49 (2008) 5672–5675
Table 1 (continued)
Entry
Pyrimidine
Product
Mp (°C)
%
Recrystallization solvent
Ethanol
O
O
N
O
CN
4
e
>300
75
HN
HN
2
H
H
2
N
N
N
NH
2
H N
NH2
CH
3
CH
3
O
O
5
5
a
N
O
O
209–211
200–202
80
74
Ethanol
Ethanol
H
H
3
C
CN
CN
3
C
O
O
N
O
N
O
O
N
O
NH
2
H
CH
N
3
CH
N
3
b
3
C
H
3
C
N
O
N
H
N
O
NH
2
CH
3
CH
3
5
5
c
N
N
O
O
156–158
256–258
60
70
Ethanol
Ethanol
N
N
H
H
3
C
C
CN
CN
H
H
3
C
C
S
S
N
N
H
S
S
N
NH
2
2
Cl
Cl
d
3
3
N
N
H
N
NH
a,b
Mp and yield reported in the literature.7,15
R
N
R
N
NCCH CO H, Ac O
2
2
2
N
O
N
5
0 - 85 ºC for 5 min.
H
3
C
CN
H C
3
X
N
H
X
NH2
5
a-d
6a-d
5
a,c : R = OCH
3
3
, X = O, S; 5b: R = OCH on position 4 and 6, X =
NH ; 5d: R = Cl, X = S
2
Scheme 3.
1
3
charge-assisted as a consequence of the polarization. This behav-
logical activities. This work is currently in progress and the results
will be reported in due course.
1
iour is observed in H NMR spectra, two signals to exocyclic NH
were observed as a result of the difference between these two
2
1
4
protons.
Acknowledgements
The structure of all new compounds was determined on the ba-
sis of their analytical, 1D and 2D-NMR spectra and HR-MS, which
agree with the proposed structures. Single crystal X-ray diffraction
analysis of compounds 2b, 4c, 5c and 5d was used to corroborate
the postulated structures. The crystal structure of compound 2b
shows the formation of a hydrogen-bond.13
In summary, cyanoacetylation by combination of cyanoacetic
acid and acetic anhydride is presented as a convenient method
for preparation of cyanoacetylated pyrimidines. We have
demonstrated a simple and efficient approach to obtained 3-(pyr-
imidin-5-yl)-3-oxopropane-nitrile derivative and N-(pyrimidin-
The authors thank ‘Servicios Técnicos de Investigación of Uni-
versidad de Jaén’ and the staff for data collection, and the Conse-
jería de Innovación, Ciencia y Empresa (Junta de Andalucía,
Spain), the Universidad de Jaén, Universidad del Valle and COL-
CIENCIAS for financial support. J.T. thanks COLCIENCIAS for sup-
porting a research visit to the Universidad de Jaén.
References and notes
1. (a) Choudhury, A.; Chen, H.; Nilsen, C. N.; Sorgi, K. L. Tetrahedron Lett. 2008, 49,
102–105; (b) Brndvang, M.; Gundersen, L. L. Tetrahedron Lett. 2007, 48, 3057–
4
yl)-2-cyano-acetamide in a regioselective fashion depending on
3059; (c) Peng, Z.-H.; Journet, Michel; Humphrey, G. Org. Lett. 2006, 8,
395–398; (d) Girreser, U.; Heber, D.; Schutt, M. Tetrahedron 2004, 60, 11511–
11517.
the nature of the pyrimidine precursor. The activated methylene
group in the obtained compounds (see Table 1) can take part in
numerous reactions providing access to more complex molecules.
Thus, new derivatives may be used as intermediates to construct
novel heterocyclic compounds that incorporate pyrimidines
moieties into a molecule, and may potentially have enhanced bio-
2. (a) Baudet, N.; Knochel, P. Org. Lett. 2006, 8, 3737–3740; (b) Baraldi, P. G.;
Bovero, A.; Fruttarolo, F.; Romagnolo, R.; Tabrizi, M. A.; Preti, D.; Varani, K.;
Borea, P. A.; Moorman, A. R. Bioorg. Med. Chem. 2003, 11, 4161–4169.
3.
Hayashi, H.; Ohmoto, S.; Somei, M. Heterocycles 1997, 45, 1647–1650.
4. Eby, C. J.; Hauser, C. R. J. Am. Chem. Soc. 1957, 79, 723–725.

J. Quiroga et al. / Tetrahedron Letters 49 (2008) 5672–5675
5675
5
.
(a) Abdel-Motaleb, R. M.; Abdel-Salam Makhloof, Abdel -Monein.; Ibrahim, H.
M.; Elnagdi, M. H. J. Heterocycl. Chem. 2007, 44, 109–114; (b) Isobe, Y.; Tobe, M.;
Inoue, Y.; Isobe, Y.; Tsichiya, M.; Hayashi, H. Bioorg. Med. Chem. 2003, 11, 4933–
13. Trilleras, J.; Low, J. N.; Cobo, J.; Marchal, A.; Glidewell, C. Acta Crystallogr., Sect. C
2008, 64, 149–154.
14. General procedure for the reaction of pyrimidines with the cyanoacetylating
4
940; (c) Papesch, V.; Schroeder, E. J. Org. Chem. 1951, 1879–1890; (d) Muller,
reagent: The pyrimidines were added to a solution of cyanoacetic acid
T.; Augustin, M.; Werchan, H. G. Z. Chem. 1989, 29, 281–283.
Kappe, T.; Stelze, H. P.; Ziegler, E. Monatsh. Chem. 1983, 114, 953.
Slätt, J.; Romero, I.; Bergman, J. Synthesis 2004, 16, 2760–2765.
Slätt, J.; Janosik, T.; Wahlström, N.; Bermang, J. J. Heterocycl. Chem. 2005, 42,
(50 mmol) in acetic anhydride (50 ml) at 50 °C. The mixture was heated to
85 °C for 5 min, whereupon the products started to crystallize. After a further
5 min, the mixture was allowed to cool to ambient temperature, and the
resulting solid products were collected by filtration, washed with methanol,
dried in air and recrystallized. Data for 3-(6-amino-1,2,3,4-tetrahydro-1,3-
6.
7.
8.
1
41–145.
9
.
(a) Lim, H. N.; Song, Y. S.; Lee, K. J. Synthesis 2007, 21, 3376–3384; (b)
Ryabukhin, S. V.; Volochnyuk, D. M.; Plaskon, A. S.; Naumchik, V. S.; Tolmachev,
A. A. Synthesis 2007, 8, 1214–1224; (c) Vildan Burgaz, E.; Yılmaz, M.; Tarık
Pekela, A.; ktemera, A. O. Tetrahedron 2007, 63, 7229–7239.
dimethyl-2,4-dioxopyrimidin-5-yl)-3-oxopropanenitrile (entry 2b): Yellow solid,
1
yield 87%, mp 260–262 °C. H NMR (400 MHz DMSO-d
6
) d: 3.13 (s, 3H, N
); 7.67 (s, 1H, CH-5); 8.51 (s, 1H,
). C NMR (100 MHz DMSO-d ) d: 27.6 (N –CH ); 29.7
1
–
CH
NH
(N
3
); 3.30 (s, 3H, N
); 10.66 (s, 1H, NH
–CH ); 33.2 (CH
3
–CH ) 4.36 (s, 2H, CH
2
3
2
13
2
6
3
3
1
0. (a) Zhu, S.-L.; Ji, S.-J.; Su, X.-M.; Sun, C.; Liu, Y. Tetrahedron Lett. 2008, 49, 1777–
781; (b) Radwan, M. A. A.; Ragab, E. A.; Sabrya, N. M.; El-Shenawy, S. M.
1
3
2
); 89.3 (C-5); 116.5 (CN); 149.3 (C-2); 158.1 (C-6); 161.2
À1
1
(C-4); 186.5 (C@O). IR (KBr) cm 3451–3162 (NH st); 2247 (CN st) 1715, 1654,
Bioorg. Med. Chem. 2007, 15, 3832–3841; (c) Sun, C.; Ji, S.-J. ; Liu, Y. Tetrahedron
Lett. 2007, 48, 8987–8989; (d) Zhuang, B.-R. ; Hsu, G.-J. ; Sung, K. Bioorg. Med.
Chem. 2006, 14, 3399–3404; (e) Berghot, M. A.; Moawad, E. B. Eur. J. Pharm. Sci.
1603 (C@O st). HR-MS calcd for C
Calcd for C : C, 48.65; H, 4.54; N, 25.21. Found: C, 48.92; H, 4.98; N,
25.61. Data for N-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-cyanoacetamide
9 10 4 3
H N O 222.0742, found 222.0753. Anal.
9 10 4 3
H N O
1
2
003, 20, 173–179.
(entry 5d): Yellow solid, yield 70%, mp 256–258 °C.
DMSO-d ) d: 2.48 (s, 3H, S–CH ) overlap with DMSO-d
CH ); 7.67 (s, 1H, H-5); 11.44 (s, 1H, NH). C NMR (100 MHz DMSO-d
(CH ); 27.3 (CH ); 104.0 (C-5); 115.0 (CN); 158.2 (C-6); 160.5 (C-4); 164.0
(C@O); 172.0 (C-2). IR (KBr) cm 3313 (NH st); 2262 (CN st); 1720 (C@O st);
1321–1261 (SCH d). HR-MS calcd for C ClN OS 242.0024, found 242.0029.
ClN OS: C, 39.59; H, 2.91; N, 23.09. Found: C, 39.76; H,
H
NMR (400 MHz
signal; 4.02 (s, 2H,
) d: 13.5
1
1. (a) Quiroga, J.; Trilleras, J.; Sánchez, A. I.; Insuasty, B.; Abonía, R.; Nogueras, M.;
Cobo, J. Lett. Org. Chem., submitted for publication.; (b) Low, J. N.;
Cobo, J.; Sánchez, A.; Trilleras, J.; Glidewell, C. Acta Crystallogr., Sect. C 2007,
6
3
6
13
2
6
3
2
À1
63, 287–291; (c) Quiroga, J.; Cruz, S.; Insuasty, B.; Abonía, R.; Nogueras, M.;
Sánchez, A.; Cobo, J.; Low, J. N. J. Heterocycl. Chem. 2001, 38, 53–60; (d)
Quiroga, J.; Cruz, S.; Insuasty, B.; Abonía, R. Heterocycl. Commun. 2000, 6, 275–
3
H
8 7
4
Anal. Calcd for C
3.33; N, 22.99.
H
8 7
4
2
82.
1
2. Quiroga, J.; Cisneros, C.; Insuasty, B.; Abonía, R.; Nogueras, M.; Sánchez, A.
15. Smirnova, N. M.; Cherdantseva, N. M.; Burova, O. A.; Nesterov, V. M.; Safonova,
Tetrahedron Lett. 2001, 42, 5625–5627.
T. S. Chem. Heterocycl. Compd. 1990, 811–815.