Studies on the Biginelli reaction: A mild and selective route to 3,4-dihydropyrimidin-2(1H)-ones via enamine intermediates

Article abstract of DOI:10.1016/j.tetlet.2005.10.124

L-Proline methyl ester hydrochloride was found to be an effective catalyst for assembling (±)-dihydropyrimidinones under mild conditions. Mechanistic insights into the useful selectivity elements of this amine-catalyzed process are also reported.

Full text of DOI:10.1016/j.tetlet.2005.10.124

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 55–56
Studies on the Biginelli reaction: a mild and selective route
to 3,4-dihydropyrimidin-2(1H)-ones via enamine intermediates
John Mabry and Bruce Ganem*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA
Received 15 August 2005; revised 25 October 2005; accepted 25 October 2005
Available online 9 November 2005
Abstract—L-Proline methyl ester hydrochloride was found to be an effective catalyst for assembling ( )-dihydropyrimidinones
under mild conditions. Mechanistic insights into the useful selectivity elements of this amine-catalyzed process are also reported.
Ó 2005 Elsevier Ltd. All rights reserved.
The synthesis of functionalized 3,4-dihydropyrimidin-2-
(1H)-ones (DHPMs, 1, Scheme 1) represents an excel-
lent example of the utility of one-pot multiple compo-
nent condensation reactions. Readily assembled as
racemates by the Biginelli reaction, DHPMs display a
range of useful pharmacological activity.1 The reaction
has traditionally been catalyzed by strong mineral acids,
but more recently has been performed using numerous
milder Lewis acid and heteropolyacid catalysts.2
methyl ester hydrochloride in promoting Biginelli
condensations.
Condensation of PhCHO, methyl acetoacetate, and urea
in the presence of L-proline (10 mol %, EtOH, reflux)
afforded DHPM 1a (Scheme 2), but as in the solvent-
free process,4 the product was racemic (30% yield).
Interestingly, condensations in MeOH as solvent formed
a previously-undetected heterocycle 2 at rt (30%, mix-
ture of racemic diastereomers).5 Intermediate 2 could
be converted to racemic 1a upon warming.
The currently-accepted mechanism of the Biginelli reac-
tion involves nucleophilic attack of the dicarbonyl com-
pound on a reactive N-acyliminium ion intermediate.
Recent mechanistic studies on L-proline catalysis3 led
us to test this amino acid in making DHPMs enantiose-
lectively. While our work was in progress, another group
developed a solvent-free synthesis of DHPMs in the
presence of L-proline, but observed no enantioselectiv-
ity.4 We investigated several additional chiral amines
as catalysts, and here report the usefulness of proline
Several other enantiomerically pure secondary amines
capable of forming enamines were investigated as Bigi-
nelli catalysts, including L-proline methyl ester, trans-
4-hydroxy-L-proline, L-prolinols 3–5, pyrrolidine 6,
aminoquinuclidine 7, and imidazolidinone 86 (Fig. 1).
However, in each case, 1a was obtained in low-to-mod-
est yield with no enantioselectivity.
Interestingly, the HCl salt of L-proline methyl ester
(10 mol %) afforded ( )-1a in nearly quantitative
yield. The requirement for secondary amine as its HCl
salt suggested a mechanism involving acid-promoted
X
X
O
H
R1
+
H2N
X = O or S
NH2
HN
R2
NH
R1
COR3
cat.
O
O
X
O
+
PhCHO
R2
R3
L-proline
MeOH
HN
R2
NH
R1
COR3
HN
NH
Ph
CO2Me
∆
+
CH3COCH2CO2Me
+
1 X = O or S
CH3
rt
Scheme 1.
CH3O
H2NCONH2
1a X= O, R1= Ph,
2
R2= Me, R3 = OMe
Keywords: Biginelli; Enamines; Dihydropyrimidinones.
Corresponding author. Tel.: +1 607 255 7360; fax: +1 607 255
6318; e-mail: bg18@cornell.edu
*
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.124

56
J. Mabry, B. Ganem / Tetrahedron Letters 47 (2006) 55–56
using pentane-2,4-dione as the b-dicarbonyl nucleophile.
R
R
OH
Me
Me
Consistent with the proposed mechanism, condensation
leading to 1j was very slow with ethyl benzoylacetate,
which is known to form enamines only sluggishly.9
N
H
6
N
H
O
3 R= H
4 R= Me
5 R= Ph
NMe
t-Bu
H
N
Ph
The formation of racemic DHPMs seems surprising in
retrospect, given the likely involvement of a chiral enam-
ine in the condensation. Interestingly, Biginelli reactions
involving chiral Ce and In acetoacetates were recently
reported to form DHPMs with only low eeꢀs.10 Taken
together, these data suggest that a highly enantioselec-
tive DHPM synthesis may also require asymmetric acti-
vation of the electrophilic acylimine component.
Nevertheless, the ability to differentiate dicarbonyl
nucleophiles using L-Pro-OMeÆHCl is a novel hallmark
of enamine-promoted Biginelli condensations, and
might serve as a useful selectivity element in complex
synthesis.11
Bn
N
H
N
Me
H
7
8
Figure 1.
Table 1. Biginelli condensations leading to DHPMs 1 catalyzed by
L-Pro-OMeÆHCla
R1CHO
Urea X = Product
(% yield)
O
O
R2
R3
Ph
R2 = Me, R3 = OMe
R2 = Me, R3 = OMe
R2 = Me, R3 = OMe
R2 = Me, R3 = OMe
R2 = Me, R3 = OMe
O
O
O
O
O
O
O
O
O
O
S
1a (99)
1b (82)
1c (86)
1d (68)
1e (69)
1f (70)
1g (63)
1h (66)
1i (33)
1j (10)b
4k (30)
3-OMeC6H5
4-OMeC6H5
4-NO2C6H5
4-BrC6H5
Acknowledgements
3-OMe-4-OH-C6H4 R2 = Me, R3 = OMe
n-C3H7
Ph
4-OMeC6H5
Ph
Ph
Ph
R2 = Me, R3 = OMe
R2, R3 = Me
This research was supported by a UNCFÆMerck Post-
doctoral Fellowship (to J.M.), support of the Cornell
NMR Facility has been provided by NSF and NIH.
R2, R3 = Me
R2 = Ph, R3 = OEt
R2 = Me, R3 = OMe
R2 = Me, R3 = OMe N-Me-urea 4l (58)
References and notes
a An ethanol solution of aldehyde (2.0 M) containing dicarbonyl
compound (1.0 equiv), urea (1.1–1.5 equiv) and L-Pro-OMeÆHCl
(10 mol %) was heated at reflux for 18 h. Crystalline product was
obtained either by crystallization upon cooling, or by removing the
ethanol in vacuo and triturating the residue with EtOH.
1. Review: Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
2. For a recent compilation of useful catalysts, see: Sun, Q.;
Wang, Y.; Ge, Z.; Cheng, T.; Li, R. Synthesis 2004, 1047.
3. List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5839.
b This reaction required 3 d at reflux; no 1j was formed after 18 h.
4. Yadav, J. S.; Kumar, S. P.; Kondaji, G.; Rao, R. S.;
Nagaiah, K. Chem. Lett. 2004, 33, 1168.
5. Spectral data on intermediate 2 (major diastereomer, mp
149–150 °C): 1H NMR (CDCl3): d 7.41–7.29 (m, 5H), 7.17
(s, N–H), 5.09–5.07 (m, N–H, one C–H), 3.56 (s, 3H), 3.49
(s, 1H), 3.34 (s, 3H), 2.89 (d, 1H), 1.56 (s, 3H); 13C NMR
(CDCl3): d 169.0, 155.3, 139.6, 129.0, 128.8, 127.9, 82.9,
56.4, 54.2, 52.1, 49.0, 23.1; IR (CH2Cl2) 3398, 3210, 2945,
enamine addition. Consistent with that hypothesis, the
pre-formed L-Pro-OMe enamine of methyl acetoacetate7
afforded ( )-1a in only 9% yield. However, upon addi-
tion of HCl (0.9 equiv), 1a was formed in 54% yield.
In further support of an enamine mechanism, triethyl-
amine hydrochloride, which cannot form enamines,
afforded 1a in 24% yield.8
1740, 1710, 1690 cmÀ1
.
6. Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 1172.
7. Prepared as described in Rao, R. B.; Singh, U. P.; Bhide,
G. V. Tetrahedron Lett. 1967, 719.
8. The synthesis of DHPMs using NH4Cl as catalyst has
recently been reported, under more forcing conditions:
Shaabani, A.; Basgir, A.; Teimouri, F. Tetrahedron Lett.
2003, 44, 857.
9. (a) Kloek, J. A.; Leschinsky, F. L. J. Org. Chem. 1978, 43,
1460; (b) McManis, J. S.; Ganem, B. J. Org. Chem. 1980,
45, 2041.
10. Munoz-Muniz, O.; Juaristi, E. ARKIVOC 2003, 9, 16.
11. Example: Franklin, A. S.; Ly, S. K.; Macklin, G. H.;
Overman, L. E.; Shaka, A. J. J. Org. Chem. 1999, 64, 1612.
While HCl salts of 2–8 were also more active catalysts
than the corresponding free bases, results were consis-
tently superior with L-Pro-OMeÆHCl (10 mol %), and
afforded access to a range of DHPMs (Table 1) under
significantly milder conditions than the standard Bigi-
nelli process.
Both aromatic and aliphatic aldehydes were trans-
formed into DHPMs using L-Pro-OMeÆHCl as catalyst.
Thioureas and N-substituted ureas also underwent suc-
cessful condensation. DHPMs could be synthesized