Efficient synthesis of highly functionalized dihydropyrido[2,3-d] pyrimidines by a double annulation strategy from α-alkenoyl-α- carbamoyl ketene-(S,S)-acetals

Article abstract of DOI:10.1021/jo0522106

A convenient and efficient synthesis of highly functionalized dihydropyrido[2,3-d]pyrimidines via a double [5 + 1] annulation strategy starting from easily available α-alkenoyl-α-carbamoyl ketene-(S,S)-acetals 1 and cheap reagents (NH₄OAc, DMF,

Full text of DOI:10.1021/jo0522106

Efficient Synthesis of Highly Functionalized
Dihydropyrido[2,3-d]pyrimidines by a Double Annulation Strategy
from r-Alkenoyl-r-carbamoyl Ketene-(S,S)-acetals
Lei Zhao, Fushun Liang,* Xihe Bi, Shaoguang Sun, and Qun Liu*
Department of Chemistry, Northeast Normal UniVersity, Changchun, 130024, China
liangfs112@nenu.edu.cn
ReceiVed October 24, 2005
A convenient and efficient synthesis of highly functionalized dihydropyrido[2,3-d]pyrimidines via a double
[5 + 1] annulation strategy starting from easily available R-alkenoyl-R-carbamoyl ketene-(S,S)-acetals 1
and cheap reagents (NH4OAc, DMF, and POCl3) has been developed. In the first step of the double
annulation route, 2-amino-3-carbamoyl-5,6-dihydro-4-pyridones 2 were created in high to excellent yields
by a formal [5C + 1N] annulation reaction of ketene-(S,S)-acetals 1 with ammonia (from ammonium
acetate). In the second step of the double annulation strategy, the highly functionalized dihydropyrido-
[2,3-d]pyrimidine derivatives, 7,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-ones 3 (when R1 ) aryl) and
7,8-dihydropyrido[2,3-d]pyrimidines 4 (when R1 ) H), were constructed, respectively, in fair to good
yields by reacting 2 with excessive Vilsmeier reagent (DMF/POCl3). A mechanism involved in the second
[5 + 1] annulation step, including a formal [5 + 1] annulation and accompanied chlorovinylation,
chloroformylation, amination, and aromatization reactions, is proposed.
Introduction
acetals,5 we found that the easily available R-alkenoyl ketene-
(S,S)-acetals,6 for example, R-alkenoyl-R-carbamoyl ketene-
(S,S)-acetals 1, showed promising structural features as novel
organic intermediates in annulation reactions7a and a series of
N-alkylated 2-alkylamino-3-carbamoyl-5,6-dihydro-4-pyridones
Pyrido[2,3-d]pyrimidines, as a kind of annulated uracils, have
received considerable attention due to their wide range of
biological activities.1 General methods for their synthesis involve
the annulation reactions starting from either suitably substituted
6-aminouracils2 or 2-amino-3-cyanopyridines3 and related sub-
strates.4 However, many of these methods suffer from drastic
reaction conditions and complex procedures, and use expensive
or not readily available starting materials.2-4 During the course
of our studies on the chemistry of functionalized ketene-(S,S)-
(2) (a) Ogura, H.; Sakaguchi, M. Chem. Lett. 1972, 657. (b) Anderson,
G. L. J. Heterocycl. Chem. 1985, 22, 1469. (c) Itoh, T.; Fujii, I.; Tomii,
Y.; Ishikawa, I.; Ogura, H.; Mizuno, Y.; Kawahara, N. J. Heterocycl. Chem.
1987, 24, 1453. (d) Bhuyan, P.; Boruah, R. C.; Sandhu, J. S. J. Org. Chem.
1990, 55, 568. (e) Youssif, S.; El-Bahaie, S.; Nabih, E. J. Chem. Res. (S)
1999, 112. (f) Koen, M. J.; Gready, J. E. J. Org. Chem. 1993, 58, 1104. (g)
Bhuyan, P.; Boruah, R. C.; Sandhu, J. S. J. Org. Chem. 1990, 55, 568. (h)
Devi, I.; Bhuyan, P. J. Synlett 2004, 283. (i) Spada, M. R.; Klein, R. S.;
Otter, B. A. J. Heterocycl. Chem. 1989, 26, 1851. (j) Ahluwalia, V. K.;
Kumar, R.; Khurana, K.; Batla, R. Tetrahedron 1990, 46, 3953. (k)
Ahluwalia, V. K.; Sharma, H. R.; Tyagi, R. Tetrahedron 1986, 42, 4045.
(l) Ahluwalia, V. K.; Aggarwal, R.; Alauddin, M.; Gill, G.; Khanduri, C.
H. Heterocycle 1990, 31, 129. (m) Wamhoff, H.; Muhr, J. Synthesis 1988,
919. (n) Srivastava, P.; Saxena, A. S.; Ram, V. J. Synthesis 2000, 541. (o)
Hughes, D. D.; Bagley, M. C. Synlett 2002, 1332.
(1) (a) Gangjee, A.; Vasudevan, A.; Queener, S. F.; Kisliuk, R. L J.
Med. Chem. 1995, 38, 1778. (b) Gangjee, A.; Adair, O.; Queener, S. F. J.
Med. Chem. 1999, 42, 2447. (c) Gangjee, A.; Adair, O.; Queener, S. F. J.
Med. Chem. 2003, 46, 5074. (d) DeGraw, J. I.; Christie, P. H.; Colwell, W.
T.; Sirotnak, F. M. J. Med. Chem. 1992, 35, 320. (e) Grivsky, E. M.; Lee,
S.; Sigel, C. W.; Duch, D. S.; Nichol, C. A. J. Med. Chem. 1980, 23, 327.
(f) Matsumoto, J.; Minami, S. J. Med. Chem. 1975, 18, 74. (g) Gangjee,
A.; Adair, O.; Queener, S. F. Bioorg. Med. Chem. 2001, 9, 2929.
10.1021/jo0522106 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/22/2005
1094
J. Org. Chem. 2006, 71, 1094-1098

Synthesis of Dihydropyrido[2,3-d]pyrimidines
TABLE 1. Reaction of 1a with NH4OAc under Different
Conditions
SCHEME 1
1a,
NH4OAc,
equiv
T,
°C
solvent
(mL)
time,
h
yield,
% (2a)
entry equiv
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
1.0
10.0
10.0
10.0
5.0
10.0
10.0
40 CH2Cl2 (5)
65 THF (5)
100 DMF (5)
100 DMSO (5)
100 DMSO (5)
75 DMSO (5)
20
20
10
5
4
6
no reaction
no reaction
63
80
92
84
TABLE 2. Synthesis of Dihydro-4-pyridones 2
sub-
entry strates 1
prod- time, yield,
were prepared via a formal [5C + 1N] annulation reaction under
mild conditions by reacting 1 with aliphatic primary amines.7b
To explore the synthetic potential of ketene-(S,S)-acetals 1, on
our ongoing research, a facile synthetic route to dihydropyrido-
[2,3-d]pyrimidines by a double [5 + 1] annulation strategy8 was
designed and succeeded. The double [5 + 1] annulation strategy
includes the following: (1) a formal [5C + 1N] annulation of
ketene-(S,S)-acetals 1 with ammonia to give 2-amino-3-car-
bamoyl-5,6-dihydro-4-pyridones 2 and (2) a second [5 + 1]
annulation of dihydro-4-pyridones 2 with the Vilsmeier reagent
(DMF/POCl3, as a one-carbon electrophile9) to provide the
pyrimidine framework of dihydropyrido[2,3-d]pyrimidines.
In the present research, it was found that, accompanying the
construction of the dihydropyrido[2,3-d]pyrimidines in the
second [5 + 1] annulation step, a series of reactions including
chlorovinylation, chloroformylation, amination, and aromatiza-
tion reactions occurred in the presence of excessive Vilsmeier
reagent, and as a result, the highly functionalized 7,8-dihydro-
pyrido[2,3-d]pyrimidin-4(3H)-ones 3 (when R1 ) aryl) and 7,8-
dihydropyrido[2,3-d]pyrimidines 4 (when R1 ) H) were created
in fair to good yields (Scheme 1). Herein, we wish to describe
our results for the short and efficient synthesis of dihydropyrido-
[2,3-d]pyrimidines 3 and 4 and present the proposed mechanism
involved.
R1
R2
ucts 2
h
%
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-ClC6H4 4-MeC6H4
4-ClC6H4 4-ClC6H4
4-ClC6H4 C6H5
4-ClC6H4 3,4-O2CH2C6H3
4-ClC6H4 4-FC6H4
4-ClC6H4 3-pyridyl
4-ClC6H4 2-thienyl
4-ClC6H4 2-furyl
2a
2b
2c
2d
2e
2f
2g
2h
2i
4.0
5.0
4.5
3.5
3.0
4.5
3.5
5.0
2.5
4.5
6.0
5.0
3.5
92
89
79
87
96
80
84
79
86
92
95
85
81
4-ClC6H4 t-C4H9
1j
1k
1l
H
H
H
H
4-MeC6H4
4-ClC6H4
C6H5
2j
2k
2l
1m
4-CH3OC6H4
2m
Synthesis of 2-Amino-3-carbamoyl-5,6-dihydro-4-pyri-
dones 2. In the preparation of dihydro-4-pyridones 2, the initial
experiments were carried out between 1a (R1 ) 4-ClC6H4, R2
) 4-MeC6H4) and NH4OAc (10.0 equiv) exploring different
solvents. In the experiments with CH2Cl2 or THF as the solvent,
however, no reaction was observed (monitored by TLC) either
at room temperature or under reflux conditions (Table 1, entries
1 and 2), whereas with DMF as the solvent and stirring at 100
°C for 10 h, a white solid was obtained in pure form in 63%
yield after pouring the reaction mixture into aqueous saturated
sodium chloride and collecting the filtrate (Table 1, entry 3).
The exclusive product was characterized as 2-amino-3-carbam-
oyl-5,6-dihydro-4-pyridone 2a on the basis of its spectra and
analytical data. The optimization of the reaction conditions,
including reaction temperature, solvents, and the feed ratio of
1a and NH4OAc, was investigated. After a series of optimization
experiments, DMSO was proved to be the best solvent and the
yield of pyridone 2a reached 92% when the reaction of 1a with
NH4OAc (10.0 equiv) was performed in DMSO at 100 °C for
4 h (Table 1, entry 5).
Results and Discussion
Synthesis of r-Alkenoyl-r-carbamoyl Ketene-(S,S)-acetals
1. The substrates, R-alkenoyl-R-carbamoyl ketene-(S,S)-acetals
1, as shown in Scheme 1, were prepared in excellent yields by
the Claisen-Schmidt condensation reactions of the correspond-
ing R-acetyl ketene-(S,S)-acetals with aldehydes as described
in our previous reports.7
(3) (a) Youssif S.; Assy, M. J. Chem. Res., Synop. 1996, 442; Youssif
S.; Assy, M. J. Chem. Res., Miniprint 1996, 2546. (b) Popp F. D.; Catala,
A. J. Org. Chem., 1961, 26, 2738. (c) Taylor E.; Cheng, C. J. Org. Chem.
1960, 25, 148. (d) Yoneda, F.; Sakuma, Y.; Mazumoto S.; Ito, R. J. Chem.
Soc., Perkin Trans. 1 1976, 1805.
(4) (a) Schell, P.; Richards, M. P.; Hanson, K.; Berk, S. C.; Makara, G.
M. J. Comb. Chem. 2005, 7, 96. (b) Mont, N.; Teixido´, J.; Borrell, J. I.;
Kappe, C. O. Tetrahedron Lett. 2003, 44, 5385.
(5) Reviews: (a) Dieter, R. K. Tetrahedron. 1986, 42, 3029. (b) Junjappa,
H.; Tla, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423. (c) Tla, H.; Junjappa,
H.; Barun, O. J. Organomet. Chem. 2001, 624, 34.
(6) (a) Bi, X.; Liu, Q.; Sun, S.; Liu, J.; Pan, W.; Zhao, L.; Dong, D.
Synlett 2005, 49. (b) Samuel, R.; Nair, S. K.; Asokan, C. V. Synlett 2000,
1804.
(7) (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem.
Soc. 2005, 127, 4578. (b) Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem.
Commun. 2005, 3580.
(8) (a) Grossman, R. B. Synlett 2001, 13. (b) Grossman, R. B.; Rasne,
R. M. Org. Lett. 2001, 3, 4027. (c) Ren, X.-F.; Konaklieva, M. I.; Shi, H.;
Dickey, S.; Lim, D. V.; Gonzalez, J.; Turos, E. J. Org. Chem. 1998, 63,
8898.
Under the optimized conditions, a range of reactions between
R-alkenoyl ketene-(S,S)-acetals 1 and NH4OAc (10.0 equiv)
were carried out by varying the substituents R1 and R2 of 1
(Table 2). It should be noted that in both cases for substituents
R1 ) aryl and hydrogen, the [5C + 1N] annulation reactions
of 1 with NH4OAc proceeded smoothly and the corresponding
pyridones 2 were formed in good to excellent yields (Table 2).
To our delight, the synthetic procedure of pyridones 2 was very
simple. In all the above experiments, pure pyridones 2 could
be obtained simply by recrystallization in diethyl ether without
using chromatographic separation.
Synthesis of Highly Functionalized Dihydropyrido[2,3-d]-
pyrimidines 3 and 4. With the readily available 2,3-dihydro-
6-amino-4-pyridones 2 at hand, our attention was then turned
to its reaction with the Vilsmeier reagent. As a result, a second
[5 + 1] annulation took place, in which 6-amino and carbamoyl
nitrogen groups of 2 acted as the 1,5-N,N-dinucleophiles and
(9) Tsuji, T.; Takenaka, K. J. Heterocycl. Chem. 1990, 27, 851.
J. Org. Chem, Vol. 71, No. 3, 2006 1095

Zhao et al.
the Vilsmeier reagent served as a one-carbon dielectrophile.9 It
was found in the initial experiment that complex products were
produced by reacting 2a with 1 equiv of POCl3 in DMF at
ambient temperature for 48 h. With the consideration that the
complex products in the above reaction may result from
insufficient amounts of Vilsmeier reagent toward a wide variety
of reactive sites in pyridones 2, large excessive amounts of
Vilsmeier reagent were then used to drive the reaction to
completion. To our delight, dihydropyrido[2,3-d]pyrimidines 3a
was successfully prepared in 42% isolated yield when the
reaction of pyridone 2a with excessive POCl3 (10.0 equiv) was
carried out in DMF at room temperature for 48 h. Meanwhile,
it was observed that prolonged reaction time, for example 72
h, would increase the yield of 3a up to 65%. As a result,
dihydropyrido[2,3-d]pyrimidines 3 (where R1 ) Ar, Table 3,
entries 1-9) and 4 (where R1 ) H, Table 3, entries 10-13)
were prepared in 43-73% isolated yields under the optimized
conditions as described above.
TABLE 3. Synthesis of Dihydropyrido[2,3-d]pyrimidines 3 and 4
sub-
strates 2
products
(3 or 4)
time,
h
yield,
%
entry
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
72
80
65
70
76
83
90
90
48
84
96
90
72
65
63
61
73
70
63
69
43
64
52
54
49
62
2j
2k
2l
4j
4k
4l
2m
4m
POCl3 is one of the most commonly used reagents and its
application in some types of reactions such as acylation,
halogenation, haloalkylation, haloformylation, dehydration, aro-
matization, and annulation has been reported.10-12 In the present
research, a similar mechanism for the formal [5C + 1N]
annulation related to the transformations from ketene-(S,S)-
acetals 1 to pyridones 2 has been previously discussed.7b On
the basis of the above experimental results, possible processes
for the formation of 3a-i and 4j-m are proposed, and depicted
in Schemes 2 and 3, respectively. For the formation of 3a-i
(corresponding to the starting materials 2a-i), the formylation
may occur first at the ring nitrogen of 2a-i to give intermediate
A in the presence of Vilsmeier reagent.13 Next, the amine group
at the 2-position of the N-formylated intermediate A reacts with
the Vilsmeier reagent to afford the aminomethylene ammonium
salt B.14 Followed by this, a nucleophilic attack of the amide
nitrogen at the positive carbon of the methylene moiety leads
to an intramolecular cyclization of B into C with elimination
of HCl. Then, 3a-i are constructed through a series of
transformations, including acid-catalyzed elimination of di-
methylamine (C to D), chlorovinylation (D to 5),10,14a and the
final formylation of 5.
In an effort to understand the mechanism of the formation
of dihydropyrido[2,3-d]pyrimidines 3 and 4, in an isolated
experiment, the reaction of 2a with Vilsmeier reagent (10.0
equiv) was quenched with aqueous NaOH after proceeding for
3 h. As a result, compound 5a was isolated in 30% yield. Under
the identical conditions, compound 5d was obtained from the
reaction of 2d with Vilsmeier reagent (10 equiv) in 22% yield
and its structure was established by the X-ray single-crystal
analysis (see the Supporting Information, Figure S1).
1
The comparison of H NMR, 13C NMR, and mass spectra
between 5d and 3d leads us to confirm the structure of product
1
3d without difficulty. In the H NMR spectrum of compound
5d, 6-H and 7-H display an AB coupling at δ 6.04 and 6.22,
respectively. As for 3d, the corresponding two peaks turn into
a singlet at δ 6.84 for 7-H and a new singlet at δ 10.26 for
6-formyl hydrogen. In mass spectroscopy, the mass difference
of the molecular ion peaks between 3d (470) and 5d (442) is
consistent with that of the formylation reaction. All the above
information indicated a formyl group was included to the
6-carbon atom of 3d. Similarly, it could be concluded that the
formyl group was oriented at the 6-carbon atom of 4 by
As to the formation of products 4j-m (Scheme 3), initially
2j-m undergo N-formylation to give intermediate E. Subse-
quently, the dehydration of the amide group of E gives rise to
corresponding carbonitrile F15 and the formation of amino-
methylene amonnium salt G is followed as described above.
Then, the nucleophilic attack of a dimethylamine at the carbon
atom of the protoned cyano group and subsequent nucleophilic
addition of the resulting imine nitrogen onto the positive carbon
1
comparing their H NMR and 13C NMR spectra with those of
dihydropyrido[2,3-d]pyrimidines 3. However, for the products
4, for example 4l, the two single peaks at 3.17 and 3.28 ppm in
1
the H NMR spectrum (and also the two single peaks at 36.0
and 42.1 ppm in 13C NMR spectrum) clearly indicated that a
dimethylamino group exists on the pyrimidine core and should
be located at the 4-position.
(10) (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.; Dong,
D. J. Org. Chem. 2003, 68, 9148. (b) Liu, Y.; Dong, D.; Liu, Q.; Qi, Y.;
Wang, Z. Org. Biomol. Chem. 2004, 2, 28. (c) Sun, S.; Liu, Y.; Liu, Q.;
Zhao, Y.; Dong, D. Synlett. 2004, 10, 1731. (d) Dong, D.; Liu, Y.; Zhao,
Y.; Qi, Y.; Wang, Z.; Liu, Q. Synthesis 2005, 85.
(11) Marson, C. M.; Giles, P. R. Synthesis Using Vilsmeier Reagents;
CRC Press: London, UK, 1994.
(12) (a) Pedras, M. S. C.; Zaharia, I. L. Org. Lett. 2001, 3, 1213. (b)
Lilienkampf, A.; Johansson, M. P.; Wahala, K. Org. Lett. 2003, 5, 3387.
(c) Pedras, M. S. C.; Jha, M. J. Org. Chem. 2005, 70, 1828. (d) Mahata, P.
K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org. Chem.
2003, 68, 3966.
(13) (a) Majo, V. J.; Perumal, P. T. J. Org. Chem. 1996, 61, 6523. (b)
Nagarajan, R.; Perumal, P. T. Synthesis 2004, 1269. (c) Hemanth Kumar,
K.; Selvi, S.; Perumal, P. T. J. Chem. Res. 2004, 218.
(14) (a) Thomas, A. D.; Asokan, C. V. Tetrahedron Lett. 2002, 43, 2273.
(b) Davis, C. S.; Kneval, A. M.; Jenkins, G. L. J. Org. Chem. 1962, 27,
1919.
(15) (a) Csuros, Z.; Soo´s, R.; Palinkas, J.; Bitter, I. Acta Chim. Acad.
Sci. Hung. 1970, 63, 215. (b) Okado, K.; Honna, K.; Yokoo, H. Jpn. Kokai
Tokyo Koho JP 0296557, 1990 (Chem. Abstr. 1990, 113, 131622).
The Vilsmeier reagent (halomethyleneiminium salt) formed
from the interaction of dialkyl formamides such as DMF with
1096 J. Org. Chem., Vol. 71, No. 3, 2006

Synthesis of Dihydropyrido[2,3-d]pyrimidines
SCHEME 2. Proposed Mechanism for the Formation of 3
SCHEME 3. Proposed Mechanism for the Formation of 4
7.29 (m, 4H), 7.55 (d, J ) 8.0, 2H), 7.81 (s,1H), 9.77 (s, 1H), 12.6
(s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 188.3, 167.4, 164.4,
138.9, 138.2, 137.6, 129.6 (2C), 129.11 (2C), 126.8 (2C), 126.1,
121.3 (2C), 88.5, 52.1, 43.8, 21.2. IR (KBr, cm-1) 3392, 1636,
1520, 490, 416. MS calcd m/z 355.1, found 356.3 [(M + 1)+]. Anal.
Calcd for C19H18ClN3O2: C, 64.13; H, 5.10; N, 11.81. Found: C,
64.24; H, 5.06; N, 11.72.
of the methylene take place. Thus, the annulation product H is
achieved. Intermediate H undergoes elimination of dimethyl-
amine, leading to aromatization. Finally, 4j-m are formed by
the reaction of I with excessive Vilsmeier reagent.
Conclusion
Synthesis of 3a-i and 4j-m. General procedure for the
preparation of 3 and 4 (with 3a as an example): The vilsmeier
reagent was prepared by adding POCl3 (10.0 mmol) dropwise to
ice cold dry DMF (5 mL) under stirring. The mixture was then
stirred for 10-15 min at 0 °C. To the above Vilsmeier reagent
was added 2a (1 mmol) as a solution in DMF (5 mL). Then the
mixture was allowed to warm to room temperature and then stirred
for 72 h. After the staring material was consumed (monitored by
TLC), the reaction mixture was poured into saturated sodium
chloride aqueous (50 mL). The mixture was extracted with
dichloromethane (3 × 20 mL), the combined organic phase was
washed with water (3 × 20 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (silica gel, petroleum ether:diethyl ether ) 2:1)
to give 3a (286 mg, 65%) as a yellow solid: mp 227-229 °C. 1H
NMR (500 MHz, DMSO-d6) δ 2.21(s, 3H), 6.57 (s, 1H), 7.06 (d,
J ) 8.0 Hz, 2H), 7.12 (d, J ) 8.0 Hz, 2H), 7.52 (d, J ) 7.5 Hz,
2H), 7.61 (d, J ) 7.5 Hz, 2H), 8.56 (s, 1H), 9.51(s, 1H), 10.14 (s,
1H).13C NMR (125 MHz, CDCl3) δ 187.1, 160.5, 156.3, 155.3,
151.4, 140.7, 138.8, 136.2, 134.0, 129.9 (2C), 129.5 (2C), 128.0
(2C), 127.6, 126.9 (2C), 102.2, 50.1, 21.1 (one of the signals was
not observed). IR (KBr, cm-1) 3446, 1359, 2341, 1684, 1489, 1601,
1443. MS calcd m/z 439.1, found 440.2 [(M + 1)+]. Anal. Calcd
The synthetic potential of R-alkenoyl ketene-(S,S)-acetals has
been further proven by the synthesis of highly functionalized
dihydropyrido[2,3-d]pyrimidines 3 and 4 via the double [5 +
1] annulation strategy. Some advantages, such as the readily
available substrates, cheap reagents, short steps, and mild
reaction conditions, make this novel double [5 + 1] annulation
strategy attractive and practical. Further study is currently
underway in our laboratory.
Experimental Section
Synthesis of 2a-m. General procedure for the preparation of
2a-m (with 2a as an example): To a solution of R-alkenoyl ketene-
(S,S)-acetal 1a (890 mg, 2.0 mmol) in DMSO (5 mL) was added
NH4OAc (1.54 g, 20.0 mmol) in one portion at room temperature.
The reaction mixture was stirred for 4 h at 100 °C and then poured
into saturated aqueous sodium chloride (50 mL). The precipitated
solid was collected by filtration, washed with water (3 × 30 mL),
and dried in vacuo to afford a white solid, which was purified by
recrystalization in diethyl ether solution to afford 2a (652 mg,
1
92%): mp 202-204 °C. H NMR (500 MHz, DMSO-d6) δ 2.29
(s, 3H), 2.65 (m, 2H), 4.69 (m, 1H), 7.01 (s, 1H), 7.21 (s, 2H),
J. Org. Chem, Vol. 71, No. 3, 2006 1097

Zhao et al.
for C22H15Cl2N3O3: C, 60.02; H, 3.43; N, 9.54. Found: C, 60.08;
H, 3.46; N, 9.40.
Supporting Information Available: Experimental details and
spectral data for compounds 1j-m, 2a-m, 3a-i, 4j-m, 5a, and
5d; CIF data for 5d. T This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the National
Natural Sciences Foundation of China (20272008) and the Key
Grant Project of Chinese Ministry of Education (10412) is
gratefully acknowledged.
JO0522106
1098 J. Org. Chem., Vol. 71, No. 3, 2006