Selective N1-Alkylation of 3,4-Dihydropyrimidin-2(1H)-ones Using Mitsunobu-Type Conditions

Abstract

The regioselective N1-alkylation of 3,4-dihydropyrimidin-2(1H)-ones via Mitsunobu reaction is reported. Using the highly reactive Mitsunobu coupling reagent combination N,N,N′,N′-tetramethylazodicarboxamide/tributylphosphine (TMAD-TBP) and a set of primary alcohols a small library of N1-alkylated dihydropyrimidones is obtained in good to excellent yields.

Mitsunobu reaction - selective alkylations - amides - dihydropyrimidones - Biginelli condensation

References

<A NAME="RG23802ST-1">1</A> Kappe CO. Acc. Chem. Res.  2000,  33:  879 

See for example:

<A NAME="RG23802ST-2A">2a</A> Mayer TU. Kapoor TM. Haggarty SJ. King RW. Schreiber SL. Science  1999,  286:  971 

<A NAME="RG23802ST-2B">2b</A> Sidler DR. Barta N. Li W. Hu E. Matty L. Ikemoto N. Campbell JS. Chartrain M. Gbewonyo K. Boyd R. Corley EG. Ball RG. Larsen RD. Reider PJ. Can. J. Chem.  2002,  80:  646 

<A NAME="RG23802ST-2C">2c</A> Rovnyak GC. Atwal KS. Hedberg A. Kimball SD. Moreland S. Gougoutas JZ. O’Reilly BC. Schwartz J. Malley MF. J. Med. Chem.  1992,  35:  3254 

<A NAME="RG23802ST-3">3</A> For a recent review, see: Kappe CO. Eur. J. Med. Chem.  2000,  35:  1043 

<A NAME="RG23802ST-4A">4a</A> Biginelli P. Gazz. Chim. Ital.  1893,  23:  360 

<A NAME="RG23802ST-4B">4b</A> Review: Kappe CO. Tetrahedron  1993,  49:  6937 

<A NAME="RG23802ST-5">5</A>

Note that the successful use of N,N′-disubstituted and N-aryl-ureas in the Biginelli condensation is not well documented in the literature. In our own hands, these building blocks often produced mixtures of various unidentified products along with only small amounts of the desired dihydropyrimidones. See also: Kappe, C. O.; Stadler, A. Org. Synth. 2003, 63, in press.

<A NAME="RG23802ST-6">6</A> Stadler A. Kappe CO. J. Comb. Chem.  2001,  3:  624 ; and references cited therein

<A NAME="RG23802ST-7A">7a</A> Khanina EL. Andaburskaya MB. Duburs G. Zolotoyabko RM. Latv. PSR Zinat. Akad. Vestis, Kim. Ser.  1978,  197 ; Chem. Abstr. 1978, 89, 43319r

<A NAME="RG23802ST-7B">7b</A> Cho H. Takeuchi Y. Ueda M. Mizuno A. Tetrahedron Lett.  1988,  29:  5405 

For reviews on the Mitsunobu reaction, see:

<A NAME="RG23802ST-8A">8a</A> Mitsunobu O. Synthesis  1981,  1 

<A NAME="RG23802ST-8B">8b</A> Hughes DL. Org. React.  1992,  42:  335 

<A NAME="RG23802ST-8C">8c</A> Hughes DL. Org. Prep. Proced. Int.  1996,  28:  127 

<A NAME="RG23802ST-9">9</A> Tsunoda T. Yamamiya Y. Ito S. Tetrahedron Lett.  1993,  34:  1639 

<A NAME="RG23802ST-10">10</A> Tsunoda T. Otsuka J. Yamamiya Y. Ito S. Chem. Lett.  1994,  539 

In general, examples found in the literature are limited to relatively acidic sulfonamides or trifluoroacetamides. For some recent examples involving amides, see:

<A NAME="RG23802ST-11A">11a</A> Kozai S. Takaoka S. Maruyama T. Tetrahedron Lett.  2002,  43:  2633 

<A NAME="RG23802ST-11B">11b</A> Evans PA. Manangan T. Tetrahedron Lett.  2001,  42:  6637 

<A NAME="RG23802ST-11C">11c</A> Bombrun A. Casi G. Tetrahedron Lett.  2002,  43:  2187 

<A NAME="RG23802ST-11D">11d</A> Reichwein JF. Liskamp RMJ. Tetrahedron Lett.  1998,  39:  1243 

<A NAME="RG23802ST-12">12</A> Note that the use of high-temperature microwave chemistry was unsuccessful here. For microwave-assisted Mitsunobu alkylations, see: Steinreiber A. Stadler A. Mayer SF. Faber K. Kappe CO. Tetrahedron Lett.  2001,  42:  6283 

<A NAME="RG23802ST-13">13</A> ¹H NMR spectroscopy (characteristic 3-5 Hz coupling between C4-H and N3-H) readily allows one to distinguish between N1-, N3- and O-alklyated DHPMs. For details and the selective preparation of N3-alkylated DHPMs, see: Kappe CO. Roschger P. J. Heterocycl. Chem.  1989,  26:  55 

<A NAME="RG23802ST-14">14</A>

Typical Experimental Procedure (Outlined for Entry 5): In a dry 5 mL reaction vial the appropriate DHPM (R¹ = EtO, R² = Ph, R³ = Me; 26 mg, 0.10 mmol) was dissolved in anhyd dioxane (0.5 mL) at 70 °C. After cooling to r.t. benzyl alcohol (54 mg, 0.50 mmol, 52 µL), TBP (51 mg, 0.25 mmol, 62 µL) and TMAD (43 mg, 0.25 mmol) were added. The vial was sealed, flushed with argon and the reaction mixture shaken for 15 h at r.t. The white precipitate that was formed was filtered off, and the crude reaction mixture separated by silica gel flash chromatography (DCM:EtOAc 1:1) providing 21.2 mg (61%) of N1-alkylated DHPM as colorless crystals, mp 155 °C (lit. [6] 155-156 °C). ¹H NMR (DMSO-d ₆): δ = 1.09 (t, J = 7.1 Hz, 3 H), 2.36 (s, 3 H), 4.02 (q, J = 7.1 Hz, 2 H), 4.84 and 5.09 (2 d, J = 16.6 Hz, 2 H), 5.24 (d, J = 3.2 Hz, 1 H), 7.06 (d, J = 7.0 Hz, 2 H), 7.22-7.35 (m, 8 H), 8.16 (d, J = 3.3 Hz, 1 H). MS (APCI): m/z (%) = 351(28) [M⁺].

<A NAME="RG23802ST-15A">15a</A> Zaragoza F. Stephensen H. J. Org. Chem.  2001,  66:  2518 

<A NAME="RG23802ST-15B">15b</A> Tsunoda T. Ozaki F. Ito S. Tetrahedron Lett.  1994,  35:  5081 

<A NAME="RG23802ST-15C">15c</A> Tsunoda T. Nagino C. Oguri M. Ito S. Tetrahedron Lett.  1996,  37:  2459