One-pot two step synthesis of 5-cyano-dihydropyrimidinones using polyphosphate ester

Article abstract of DOI:10.1016/j.tetlet.2008.02.162

A combination of a modified Biginelli reaction and a polyphosphate ester (PPE)-promoted dehydration reaction provides 5-cyano-dihydropyrimidinones in good to excellent overall yields.

Full text of DOI:10.1016/j.tetlet.2008.02.162

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3009–3010
One-pot two step synthesis of 5-cyano-dihydropyrimidinones
using polyphosphate ester
Robert J. Schmidt *, Louis J. Lombardo, Sarah C. Traeger, David K. Williams
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543, United States
Received 19 December 2007; revised 22 February 2008; accepted 29 February 2008
Available online 4 March 2008
Abstract
A combination of a modified Biginelli reaction and a polyphosphate ester (PPE)-promoted dehydration reaction provides 5-cyano-
dihydropyrimidinones in good to excellent overall yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Substituted dihydropyrimidinones (DHPMs) have been
shown to serve as scaffolds for a variety of pharmacologi-
cally active molecules, including Ca2+ channel openers
(Verapamil) plus the cytotoxic agent monastrol (1) and
related analogs.1,2 Efforts to identify novel cytotoxic
agents, through a high throughput screen of the Bristol-
Myers Squibb compound collection, led to compound 2.
This compound was later found to induce a phenotype in
cells similar to the Eg5 inhibitor Monastrol.3 The original
synthesis of 2 described by Atwal et al.4–6 involved a four
step process utilizing a Knoevenagel condensation afford-
ing 2 in a 10% overall yield. To explore the SAR of this
potential series of cytotoxic agents, a general and high
yielding route was required. Herein, we describe the synthe-
sis of various 5-cyano-DHPMs, in good to excellent overall
yields, using a convergent, one-pot procedure.
The synthetic methodology used to generate DHPMs
has been well documented and has typically involved vari-
ations of the original Biginelli reaction.7–10 More recent
reports by Kappe and Falsone11,12 describe the synthesis
of these compounds via a one-pot condensation utilizing
PPE12 to generate 5-carboxylate DHPMs, however, 5-
cyano-dihydropyrimidinones 2 were not exemplified.13
Reports have shown that polyphosphate ester (PPE),
when used in an aprotic solvent such as THF, can serve
as a desiccant,12 and simple benzamides can be dehydrated
to their corresponding benzonitriles using this reagent.14
Our plan was to investigate whether PPE could serve as a
suitable reagent for forming 5-carboxamide-DHPMs. In
principle, PPE should be a strong enough desiccant to dehy-
drate the carboxamide to give the desired nitrile, while being
mild enough to use with functionally sensitive aldehydes.
After extensive optimization, we found that the two steps
could be carried out in a general and efficient one-pot pro-
cess to afford a variety of 5-cyano-DHPMs.15 As outlined in
Table 1, addition of 0.3 equiv of PPE to a reaction mixture
containing a 1:1:1.5 ratio of aldehyde/acetoacetamide/urea
in THF, at 75 °C for 1 h, was optimal for the formation of
5-carboxamide-DHPMs. Subsequent treatment of that
reaction mixture with an additional 2.3 equiv of PPE,
followed by heating at 85 °C for 1–3 h, afforded 5-cyano-
DHPMs in yields typically exceeding 70%.
OH
NO2
O
NC
Me
O
NH
NH
O
Me
N
H
S
N
H
1
2
*
Corresponding author. Tel.: +1 609 252 5337; fax: +1 609 252 6804.
E-mail address: robert.schmidt@bms.com (R. J. Schmidt).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.162

3010
R. J. Schmidt et al. / Tetrahedron Letters 49 (2008) 3009–3010
Table 1
A general two step, one-pot Biginelli reaction to generate 5-cyano-4-substituted dihydropyrimidinones
R
O
R
NC
Me
2.3 eq PPE
0.3 eq PPE
O
O
O
NH
H2N
NH
RCHO
+
+
NH2 H2N
NH2
N
H
O
Me
N
H
O
Entry
R
Yielda,b,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3-NO2-Phenyl
3-Cl-Phenyl
3-CF3-Phenyl
2-Thienyl
5-NO2-2-Thienyl
4-Br-2-Thienyl
4-Ph-2-Thienyl
3-Thienyl
5-meta-Cl-Phenyl-2-furanyl
5-meta-Cl-Phenyl-2-EtO2C-2-furanyl
6-Me-2-Pyridyl
t-Butyl
n-Butyl
94
78
70
72
91
68
91
51
38
27
70
34
97
77
Isopropyl
15
16
a
Methyl-benzyl ether
1-Methyl-1-pentyl
45
4
See Ref. 14 for general procedure.
b
c
Isolated yields after purification by SiO2 gel chromatography.
Characterized by 1H NMR, elemental analysis, and LC/MS.
5. Atwal, K. S.; O’Rielly, B. C.; Gougoutas, J.; Malley, M. Heterocycles
1987, 26, 1189–1192.
6. Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B.; Schwartz, J. J. Org.
Chem. 1989, 54, 5898–5907.
7. Kappe, C. O. Tetrahedron 1993, 49, 6937–6963.
8. Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem. 1998, 63, 3454–
3457.
A variety of substituted aromatic, aliphatic, and hetero-
aromatic aldehydes, with either electron-donating or elec-
tron-withdrawing groups, provided favorable results in
this reaction. For example, 5-cyano-dihydropyrimidinones
generated from 3-nitro and 4-phenyl-2-thienyl benzalde-
hyde afforded the corresponding products in greater than
90% yield. Aliphatic aldehydes were equally amenable to
these conditions with n-butyraldehyde providing the 5-
cyano-dihydropyrimidinone in 97% yield. Quaternary sub-
stitution at the 4-position of the DHPM could also be
achieved with ketones using this methodology, albeit in
significantly lower yields (compounds 15 and 16).
In summary, a new method for the preparation of
substituted 5-cyano-DHPMs was discovered that utilizes
a multicomponent coupling reaction promoted by PPE,
followed by a rapid and high yielding PPE-mediated dehy-
dration to afford the corresponding carbonitrile. The use of
PPE was well tolerated with a range of aldehydes and
ketones. In addition, this methodology is cost effective
and amenable to large-scale synthesis.
9. Yadav, J. S.; Subba, B. V.; Reddy, S.; Srinivas, R.; Venugopal, C.;
Ramalingam, T. Synthesis 2001, 9, 1341–1345.
10. Das, B.; Srinivas, K. Synthesis 2004, 13, 2091–2093.
11. Kappe, C. O.; Falsone, F. S. Synlett 1998, 7, 718–720.
12. Kappe, C. O.; Falsone, F. S. ARKIVOC 2001, ii, 122–134.
13. Kappe, C. O.; Roschger, P. J. Heterocycl. Chem. 1989, 26,
55–64.
14. Dixon, L. A. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L., Ed.; Wiley: Chichester, 1995; Vol. 6, pp 4166–4169.
Caution: PPE is stable refrigerated but decomposition occurs above
150 °C.
15. Typical procedure for the synthesis of 5-cyano-dihydropyrimidinones: A
mixture of 3-nitrobenzaldehyde (5.0 g, 33 mmol, 1.0 equiv), acetoac-
etamide (3.3 g, 33 mmol, 1.0 equiv), urea (3.0 g, 50 mmol, 1.5 equiv),
and polyphosphate ester (4.2 g, 10 mmol, 0.3 equiv) in THF (35 mL)
was heated in a sealed tube for 45 min at 75 °C. This mixture was
cooled to room temperature, additional polyphosphate ester (33 g,
76 mmol, 2.3 equiv) was added, and the heating was resumed at 85 °C
for 3 h. The reaction mixture was cooled to room temperature and
poured onto ice (800 g). The resulting precipitate was collected by
vacuum filtration and the solid washed with water followed by a small
amount of methanol and diethyl ether. The solid was then dried under
vacuum to yield 6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydro-
pyrimidine-5-carbonitrile as a light yellow solid (8.0 g; 94%) that was
used without further purification: 1H NMR (DMSO-d6, 400 MHz) d
9.70 (s, 1H), 8.21–8.23 (m, 1H), 8.16–8.17 (m, 1H), 7.98–8.00 (m, 1H),
7.80–7.81 (m, 1H), 7.74 (t, 1H, J = 7.9 Hz), 5.38 (s, 1H), 2.02 (s, 3H).
Anal. Calcd for C12H10N4O3: C, 55.81; H, 3.90; N, 21.69. Found: C,
55.79; H, 3.92; N, 21.52. MS: (MÀH)À 257.
References and notes
1. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052.
2. Bose, S.; Kumar, R.; Fatima, L. Synlett 2004, 2, 279–282.
3. Kimball, D., Lombardo, L., Rawlins, D., Xiao, H., Roussell, D. A
Method of Treating Proliferative Diseases Using Eg5 Inhibitors. PCT
Patent Application 2002/165240, 2002; Lombardo, L., Wu, L. Cyano-
Substituted Dihydropyrimidine Compounds and Their Use to Treat
Disease. U.S. Patents 6,809,102, 2004 and 6,900,214, 2005.
4. Atwal, K. S.; O’Reilly, B. C. Heterocycles 1987, 26, 1185–1188.