Couto et al.
JOCNote
SCHEME 5
Apparently, because of its higher nucleophilicity and basicity,
it is the oxygen atom, and not the nitrogen, of the amide that
promotes the cyclization step to render the iminolactone C.19
Finally, a hydrolysis step during workup renders the final
compounds 8.
In summary, the new reactivity of the iodine(III) reagent
PIFA has been developed and extended to a straightforward
preparation of furo[3,4-d]pyrimidine-2,5-dione derivatives.
The present strategy is based on a preliminary preparation of
a series of 5-carboxamidodihydropyrymidinones by a Bigi-
nelli multicomponent reaction followed by an unprecedented
PIFA-mediated intramolecular metal-free allylic oxycarbonyla-
tion reaction promoted by the hypervalent iodine reagent that
avoids an additional functionalization step of the allylic position.
and 6g, and also from the fact that a bulkier R2 substituent
(as in 6f) negatively affects the success of the reaction. On the
other hand, the behavior of 6d with respect to 6e informs that
the presence of deactivated N-aryl groups also has a negative
influence on the success of the cyclization. It has been found
as well that unsubstituted carboxamide 6h equally produced
the expected heterocycle, although in a highly diminished
yield (23%).16 In conclusion, the N-phenyl group appears to
be the optimal substituent over other activated and deacti-
vated arylic candidates and, therefore, on the basis of these
results, the series of furo-DHPMs 8b,c was extended to
derivatives 8d,e.
The high dependence of the efficiency of the reaction on
the nature of the aryl substituent (R1) is probably the major
informative observation that led us to suggest a plausible mech-
anism as depicted in Scheme 5. Considering the known ability of
PIFA to oxidize amides into nitrenium ions,17 we propose inter-
mediate A as thestarting point at which the electronic and steric
influence of R1 in the course of the reaction results is evident.
Thus, in view of the transformation of 6d into 8c, this assump-
tion explains the diminished efficiency encountered in the
preparation of such compounds from 6e,g since, respectively,
deactivated N-aryl groups (as in 6e) cannot stabilize the
positive charge that is being developed in intermediate A,
and, on the other hand, hindered arylamides (as in 6g) hamper
the approach of the iodine(III) reagent to the amide. There-
fore, N-phenyl-substituted substrates appear to be the best
selection to accomplish the projected transformation. Then,
the ring closure step, which takes place after PhI release, can
be explained by a 1,5-hydride shift giving rise to intermediate
B, in which the allylic position results activated toward the
intramolecular nucleophilic attack of the amide group.18
Experimental Section
Representative Procedure for the Synthesis of Dihydropyrimi-
dine 6a. A mixture of 3-ketoamide 2 (1 mmol), aldehyde
3(1 mmol), urea 4 (1.5 mmol) and chloroacetic acid (15 mol %)
was heated in an oil bath (90 °C) for 7-10 h in the absence of
solvents. The progress of the reaction was monitored by TLC.
When the reaction was completed, the flask was removed from
the oil bath and allowed to stand at room temperature. Then, the
mixture was poured into water and extracted with CH2Cl2. The
organic extracts were dried with Na2SO4 (anh), solvent was
evaporated under reduced pressure, and the resulting residue
was purified by column chromatography (hexanes/EtOAc, 3/7)
followed by crystallization from hexanes (65% yield): mp
1
182-185 °C (hexanes); IR (film) υ 3237, 1682, 1672, 1432; H
NMR (300 MHz, DMSO-d6) 2.02 (s, 3H), 3.67 (s, 3H), 5.37
(s, 1H), 6.80-6.85 (m, 2H), 6.96-6.99 (m, 1H), 7.20-7.23 (m,
3H), 7.52-7.55 (m, 3H), 8.68 (br s, 1H), 9.54 (br s, 1H); 13C
NMR (300 MHz, DMSO-d6) 17.5, 55.4, 55.5, 105.8, 112.6,
112.7, 118.7, 120.1, 123.5, 128.9, 130.1, 138.9, 139.7, 149.3,
153.1, 159.7, 165.8; MS [M þ 1] m/z 338 (100), 337 (15), 245
(61), 244 (39); HRMS calcd for C19H19N3O3 Hþ 338.1517,
3
found 338.1505.
Typical Procedure for the PIFA-Mediated Cyclization Reaction.
Synthesis of furoDHPMs 8a-f. A solution of PIFA (1.33 mmol)
in CH2Cl2 (10 mL) was added to another solution of DHPM 6
(1.0 mmol) in CH2Cl2 (5 mL). The new solution was heated to
reflux for 5-7 h, and when the reaction was completed, the
mixture was cooled to room temperature then washed with 10%
aq Na2CO3 (1 ꢀ 10 mL) and brine (1 ꢀ 10 mL). The organic phase
was dried on Na2SO4 and filtered, and the solvent was removed
under reduced pressure. The resulting residue was purified as
indicated for each individual compound.
Synthesis of 4-(3-Methoxyphenyl)-1-methyl-4,7-dihydro-1H,3H-
furo[3,4-d]pyrimidine-2,5-dione (8a). According to the typical pro-
cedure furoDHPM 8a was obtained from DHPM 6b in 18% yield
as a yellowish solid after purification by column chromatography
(hexanes/EtOAc, 3/7) followed by crystallization from hexanes: mp
126-129 °C(hexanes);IR(film) υ1751, 1315; 1H NMR (300 MHz,
CDCl3) 3.13 (s, 3H), 3.78 (s, 3H), 4.76 (s, 2H), 5.37 (s, 1H), 5.80
(s, 1H), 6.72-6.81 (m, 3H), 7.24-7.29 (m, 1H); 13C NMR
(300 MHz, CDCl3) 29.9, 53.7, 55.3, 64.6, 99.2, 112.1, 113.9,
118.3, 130.0, 142.4, 151.4, 158.7, 160.3, 169.6; MS [M þ 1] m/z
275 (100), 274 (21), 273 (52), 167 (23); HRMS calcd for
(16) A Hofmann rearrangement leading to a 5-aminoDHPM was not
observed either.
(17) Aryl groups were selected, over other possibilities, on the basis of
their known ability to stabilize oxidized amides (acylnitrenium ions). See, for
example: (a) Falvey, D. E. In Reactive Intermediate Chemistry; Moss, R. A.,
Platz, M., Jones, M., Jr., Eds.; John Wiley & Sons: Hoboken, NJ, 2004; pp
593-650 and references cited therein. (b) Malamidou-Xenikaki, E.; Spyroudis, S.;
Tsanakopoulou, M.; Hadjipavlou-Litina, D. J. Org. Chem. 2009, 74, 7315–7321.
(c) Kikugawa, Y. Heterocycles 2009, 78, 571–607.
(18) Metal-catalyzed C-H activation processes accomplished as a result
of the generation of stabilized deficient intermediates followed by a 1,5-
hydride shift are known. See, for example: (a) Tobisu, M.; Chatani, N.
Angew. Chem., Int. Ed. 2006, 45, 1683–1684. (b) Tobisu, M.; Nakai, H.;
Chatani, N. J. Org. Chem. 2009, 74, 5471.
(19) This particular behavior, in the context of I(III)-mediated hetero-
cyclic synthesis, was first reported by Kita’s group. (a) Tamura, Y.; Yakura, T.;
Haruta, J.-I.; Kita, Y. J. Org. Chem. 1987, 52 (2), 3927–3930. Later, the
preferential formation of lactams over lactones was reached by subtle modifica-
tion of the amide functional group by Knappp’s and Ciufolini’s groups: (b)
Knapp, S.; Levorse., A. T. J. Org. Chem. 1988, 53, 4006–4014. (c) Braun, N. A.;
Ousmer, M.; Bray, J. D.; Bouchu, B.; Peters, K.; Peters, E.-M.; Ciufolini, M. A.
J. Org. Chem. 2000, 65, 4397–4408.
C14H14N2O4 Hþ 275.1032, found 275.1028.
3
Synthesis of 4-(3-Methoxyphenyl)-1,3-dimethyl-4,7-dihydro-
1H,3H-furo[3,4-d]pyrimidine-2,5-dione (8b). According to the
typical procedure furoDHPM 8b was obtained from DHPM 6c
in 65% yield as a yellowish solid after purification by column
chromatography (hexanes/EtOAc, 1/1) followed by crystalliza-
tion from hexanes: mp 205-210 °C (hexanes); IR (film) υ 1712,
1
1328; H NMR (300 MHz, CDCl3) 2.90 (s, 3H), 3.17 (s, 3H),
7956 J. Org. Chem. Vol. 75, No. 22, 2010