Efficient synthesis of functionalized 2-carbamoylpyran-4-ones by ring-transformation of 5-alkylidene-2,5-dihydropyrrol-2-ones

Article abstract of DOI:10.1055/s-2004-835652

Functionalized 2-carbamoylpyran-4-ones were prepared by acid-mediated ring-transformations of readily available 5-alkylidene-3-arylamino-2,5- dihydropyrrol-2-ones.

Full text of DOI:10.1055/s-2004-835652

LETTER
2779
Efficient Synthesis of Functionalized 2-Carbamoylpyran-4-ones by Ring-
Transformation of 5-Alkylidene-2,5-dihydropyrrol-2-ones
Efficient
S
o
ynthesis of
F
a
unctionali
c
ed 2-Carba
h
m
oylpyran-
i
a
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt Universität Greifswald, Soldmannstrasse 16, 17487 Greifswald, Germany
b
Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
E-mail: peter.langer@uni-greifswald.de
Received 29 July 2004
Abstract: Functionalized 2-carbamoylpyran-4-ones were prepared
by acid-mediated ring-transformations of readily available 5-alkyl-
idene-3-arylamino-2,5-dihydropyrrol-2-ones.
1) 2 LDA
2) 2a–e
R
Cl
N
O
+
O
Key words: cyclizations, dianions, domino reactions, heterocycles,
pyran-4-ones, rearrangements
R N
Cl
R
N
THF
O
2a–e
1a
O
NHR
3a–e
The pyran-4-one core structure is of pharmacological
relevance and occurs in a variety of natural products.1 A
classical and prominent approach to pyran-4-ones relies
on the acid-mediated cyclization of 1,3,5-tricarbonyl
compounds.2 The biosynthesis of many natural pyran-4-
ones follows this pathway.2 We have recently reported3 a
new synthesis of 5-alkylidene-2,5-dihydropyrrol-2-ones
by cyclization of 1,3-dicarbonyl dianions with oxalic
acid-bis(imidoyl)chlorides which can be regarded as aza-
analogues of oxalyl chloride.4 Herein, we wish to report a
new and convenient synthesis of functionalized 2-car-
bamoylpyran-4-ones from readily available 5-alkylidene-
3-arylamino-2,5-dihydropyrrol-2-ones. Our methodology
relies on an efficient acid-mediated ring-transformation.
O
O
RN
NHR
A
Scheme 1 Mechanism of the formation of 3a–e
mediate C. Cleavage of the pyrrolidinone ring gave the
enolized triketide D. Subsequently, the final product was
formed by acid-mediated recyclization and extrusion of
water. The reaction of 5-alkylidene-3-arylamino-2,5-di-
hydropyrrol-2-ones 3b–e with hydrochloric acid afforded
the carbamoylpyran-4-ones 4b–e in 61–95% yield
(Table 1). The structure of 4a–e was studied by spectro-
scopic methods and was independently confirmed by a
crystal structure analysis of 4d. All carbamoylpyran-4-
ones 4a–e exhibit a strong UV-activity.
Our starting point was the cyclization of the dianion of 2-
acetyltetralone (1a) with oxalic acid-bis(imidoyl) dichlo-
rides 2a–e (Scheme 1). These reactions afforded the E-
configured 5-alkylidene-3-arylamino-2,5-dihydropyrrol-
2-ones 3a–e.5 The synthesis of 3d has been reported earli-
er by us.3a The formation of 3a–e proceeds by regioselec-
tive cyclization to give intermediate A and subsequent
Dimroth-rearrangement. The structure and the configura-
tion of compounds 3 were elucidated by spectroscopic
methods (NOESY measurements).
Table 1 Synthesis of Pyran-4-ones 4a–e
3, 4
a
R
Yield of 3 (%)a
Yield of 4 (%)a
C6H5
45
51
85
55
84
75
95
85
61
92
Treatment of a THF-solution of 5-alkylidene-3-arylami-
no-2,5-dihydropyrrol-2-one 3a with an aqueous solution
of HCl afforded the unexpected carbamoylpyran-4-one
4a6 in 75% yield (Scheme 2). During the optimization of
this reaction the following parameters proved important:
a) the choice and the concentration of the acid (HCl,
10%), b) the solvent (THF) and c) the reaction time. The
formation of 4a can be explained as follows: The enamine
group of 3a was hydrolyzed to give intermediate A. The
latter was protonated (intermediate B) and subsequently
underwent a conjugate addition of water to give inter-
b
o-MeC6H4
o-(MeO)C6H4
p-(MeO)C6H4
1-Naph
c
d
e
a Isolated yields.
The cyclization of the dianion of 2-acetyl-1-decalone
with 2d afforded the known3a 5-alkylidene-2,5-dihydro-
pyrrol-2-one 3f. Treatment of the latter with hydrochloric
acid gave the carbamoylpyran-4-one 4f in 77% yield
(Scheme 3).
SYNLETT 2004, No. 15, pp 2779–2781
0
7
.1
2
.2
0
0
4
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835652; Art ID: D21304ST
© Georg Thieme Verlag Stuttgart · New York

2780
J. T. Anders et al.
LETTER
O
O
R
N
THF, H2O
HCl (10%)
O
1) 2.3 LDA
O
O H+
2) 2a–d
H
1c
R
R
N
N
20 °C
1 h
RNH2
N
O
THF
Cl
N
R
R
_
O
NHR
3a–e
O
OH
A
+
3g–j
R
N
Cl
2a–d
H+
HCl, THF
O
O
O
NHR
4g–j
OH
OH
OH
+
H2O
Scheme 4 Synthesis of 4g–j
Table 2 Synthesis of Pyran-4-ones 4g–j
R
N
N
R
O
OH
O
C
B
3, 4
R
Yield of 3 (%) a
Yield of 4 (%)a
g
h
i
C6H5
80
58
61
42
79
89
75
61
o-MeC6H4
o-(MeO)C6H4
p-(MeO)C6H4
j
OH
_
O
H2O
a Isolated yields.
HO
O
O
O
O
NHR
NHR
We have recently reported the synthesis of 5-alkylidene-
2,5-dihydropyrrol-2-one 3k by cyclization of dilithiated
benzoylacetone (1d) with 2a.3a Treatment of 3k with hy-
drochloric acid afforded the carbamoylpyran-4-one 4k
(Scheme 5).
D
4a–e
Scheme 2 Mechanism of the formation of 4a–e
O
O
H
H
O
O
R
N
Ph
N
H
Ph
O
O
1) 2.3 LDA
2) 2d
1d
1) 2.3 LDA
H
Ph
1b
H
2) 2a
N
H
O
N
Cl
N
Ph
O
THF
N
Cl
R
R
THF
+
Ph
+
3f (42%)
Ph
N
Cl
3k (54%)
R
N
Cl
2a
2d
R = p-(MeO)C6H4
H
HCl, THF
Ph
HCl, THF
H
O
O
O
O
O
O
NHPh
NHR
4f (77%)
4k (30%)
Scheme 3 Synthesis of 4f
Scheme 5 Synthesis of 4k
The reaction of the dianion of 2-acetyl-6-methylcyclohex-
an-1-one (1c) with oxalic acid-bis(imidoyl) dichlorides
2a–d afforded the 5-alkylidene-2,5-dihydropyrrol-2-ones
3g–j. Treatment of these compounds with hydrochloric
acid resulted in formation of the carbamoylpyran-4-ones
4g–j in 61–89% yield (Scheme 4, Table 2).
Our preliminary studies related to the preparative scope of
the new ring-transformation show that 1,3-diketone-
rather than b-ketoester-derived 5-alkylidene-2,5-di-
hydropyrrol-2-ones have to be employed. The best yields
were observed for the synthesis of bicyclic or tricyclic
carbamoylpyran-4-ones.
Synlett 2004, No. 15, 2779–2781 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of Functionalized 2-Carbamoylpyran-4-ones
2781
7.51 (m, 5 H, Ar), 7.69 (s, 1 H, 4-H), 7.87 (s, NH), 8.06–8.09
(dd, 1 H, Ar). 13C NMR: d = 24.79 (CH2), 28.79 (CH2),
55.97 (CH3), 56.21 (CH3), 100.27 (CH), 109.00 (C), 110.59,
112.26, 116.59, 121.01, 121.52, 122.98, 123.99, 126.53,
127.08, 127.48, 128.25 (CH), 129.57 (C), 132.68 (CH),
134.16, 135.26, 139.36, 143.17, 148.90, 152.43, 152.65 (C),
161.69 (CO), 187.82 (CO). IR (KBr): 3369.6 (m), 3345.8
(m), 1701.5 (s), 1631.0 (s), 1596.6 (s), 1558.0 (s), 1536.0 (s),
1490.6 (s), 1461.5 (s), 1346-3 (s), 1296.7 (s), 1243.0 (s),
1210.1 (m), 1122.0 (s), 1027.3 (s), 927.68 (s), 738.4 (s)
cm–1. UV/Vis: lmax (lg e) = 248.9 (5.17), 271.6 (5.21), 433.2
(5.39). MS (EI, 70 eV): m/z (%) = 453.3 (27.4) [M+ + 1],
452.2 (100.0) [M+], 423.2 (46.1), 330.1 (15.8), 302.1 (74.4),
274.1 (5.0), 141.1 (31.8), 114.4 (36.2), 77.4 (24.9). The
exact molecular mass m/z = 452.1736 2 mD ([M]+) of
C28H24O4N2 was confirmed by HRMS (EI, 70 eV). Anal.
Calcd for C28H24O4N2: C, 74.30; 5.35. Found: C, 73.99; H,
5.02.
Acknowledgment
Financial support from the Konrad-Adenauer-Stiftung (scholarship
for J. T. A.), the government of Vietnam (scholarship for V. T. H.
N.) and the Deutsche Forschungsgemeinschaft is gratefully ack-
nowledged.
References
(1) Römpp Lexikon Naturstoffe; Fugmann, B.; Lane-Fugmann,
S.; Steglich, W., Eds.; Thieme: Stuttgart, 1997.
(2) (a) Feist, H. Justus Liebigs Ann. Chem. 1890, 257, 258.
(b) Feist, H. Chem. Ber. 1895, 28, 1823. (c) Lehmann, K.;
Grabow, J. Chem. Ber. 1935, 68, 704. (d) Heyns, C.;
Vogelsang, F. Chem. Ber. 1954, 87, 1440. (e) Hauser, C.
R.; Harris, T. M. J. Am. Chem. Soc. 1958, 80, 6360.
(f) Yamamoto, M.; Sugiyama, N. Bull. Chem. Soc. Jpn.
1975, 48, 508. (g) Review: Harris, T. M.; Harris, C. M.
Tetrahedron 1977, 33, 2159. (h) Griffin, D. A.; Leeper, F.
J.; Staunton, J. J. Chem. Soc., Perkin Trans. 1 1984, 1035.
(i) Yamamoto, M.; Iwasa, S.; Takatsuki, K.; Yamada, K. J.
Org. Chem. 1986, 51, 346. (j) Yamaguchi, M.; Shibato, K.;
Nakashima, H.; Minami, T. Tetrahedron 1988, 44, 4767.
(3) (a) Langer, P.; Döring, M. Synlett 2001, 1437. (b) Anders,
J. T.; Görls, H.; Langer, P. Eur. J. Org. Chem. 2004, 1897.
(4) For a review of cyclizations of oxalic acid-bis(imidoyl)
dichlorides, see: Langer, P.; Döring, M. Eur. J. Org. Chem.
2002, 221.
(5) General Procedure for the Synthesis of 5-Alkylidene-3-
arylamino-2,5-dihydropyrrol-2-ones (3):3 A THF solution
of LDA was prepared by addition of n-BuLi (3.05 mL, 4.4
mmol, 1.5 M solution in n-hexane) to a THF solution (40
mL) of diisopropylamine (0.45 g, 0.62 mL, 4.4 mmol) at
0 °C. To the LDA solution was added the dicarbonyl
compound 1 (2.0 mmol) at 0 °C. The solution was stirred at
0 °C for 60 min and was subsequently cooled to –78 °C and
transferred to a THF solution (40 mL) of the oxalic acid-
bis(arylimidoyl)dichloride 2 (2.0 mmol) at –78 °C. The
solution was allowed to warm to 20 °C within 12 h. To the
solution was added an aq solution of NH4Cl (100 mL, 1 M).
The organic layer and the aqueous layer were separated and
the latter was extracted with Et2O (4 × 150 mL). The
combined organic layers were dried (MgSO4), filtered and
the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel, pentane–Et2O = 10:1
→ 1:1) to give the 3-arylamino-2,5-dihydropyrrol-2-ones 3
as yellow to red crystals. Compound 3c: Starting with a THF
solution (40 mL) of LDA (6.9 mmol, 2.3 equiv), 2-
(6) General Procedure for the Synthesis of
Carbamoylpyran-4-ones (4): The 3-arylamino-2,5-
dihydropyrrol-2-one (3) was dissolved in THF (25 mL) at
20 °C. To this solution, an aq solution of HCl (15 mL, 1 M)
was added under vigorous stirring. After stirring for 24 h at
20 °C, the pale yellow solution was poured into H2O (150
mL). The organic and the aqueous layer were separated and
the latter was extracted with Et2O (3 × 100 mL). The
combined organic layers were dried (MgSO4), filtered and
the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel) to give 4 as colorless
or yellow solids. Compound 4c: Starting with a THF
solution (50 mL) of 3c (120 mg) and an aq solution of HCl
(40 mL, 10%), 4c was isolated by chromatography (silica
gel, n-hexane–EtOAc = 5:1 → 3:1) as a colorless solid (68
mg, 85%). 1H NMR: d = 2.87 (t, 2 H, CH2), 2.97 (t, 2 H,
CH2), 4.03 (s, 3 H, CH3), 6.96–7.06 (m, 1 H, Ar), 7.13–7.18
(m, 1 H, Ar), 7.24 (s, 1 H, CHCO), 7.31 (d, 1 H, Ar), 7.41–
7.46 (m, 1 H, Ar), 7.44 (d, 2 H, Ar), 7.85 (d, 1 H, Ar), 8.51
(d, 1 H, Ar), 9.37 (s, 1 H, NH). 13C NMR: d = 18.90 (CH2),
26.94 (CH2), 56.26 (CH3O), 110.32 (CH), 115.63 (CH),
119.93 (CH), 121.69 (CH), 122.52 (C), 122.96 (CH), 125.23
(CH), 126.62 (C), 127.26 (CH), 127.57 (C, 128.85 (CH),
131.66 (CH), 139.39 (C), 148.31 (C), 154.14 (C), 156.44
(C), 157.18 (CO), 178.56 (CO). IR (KBr): 3407.8 (m),
2941.6 (w), 1765.1 (m), 1693.8 (s, 1651.0 (s), 1603.0 (s),
1536.0 (s), 1462.6 (s), 1417.0 (s), 1333.3 (m), 1252.9 (s),
1159.5 (m), 1121.8 (m), 1024.5 (m), 758.5 (m), 632.9 (m),
542.6 (w) cm–1. UV/Vis: lmax (lg e) = 213.2 (5.4), 219.4
(5.39), 252.1 (5.14), 290.5 (5.18), 311.7 (5.24). MS (EI, 70
eV): m/z (%) = 348.7 (2.2) [M+ + 1], 347.6 (18.9) [M+],
346.7 (88.2), 345.7 (100.0), 196.8 (20.3), 170.8 (20.3), 140.9
(29.3), 114.3 (20.6), 91.9 (7.9), 28.0 (6.4). The exact
molecular mass m/z = 347.1158 2 mD ([M]+) of C21H17O4N
was confirmed by HRMS (EI, 70 eV). Anal. Calcd for
C21H17O4N: C, 69.15; H, 4.94. Found: C, 69.50; H, 5.16.
acetyltetralone (3.0 mmol, 0.57 g) and a THF solution (40
mL) of oxalic acid-bis(o-methoxyphenyl)imidoyl chloride
(3.0 mmol, 1.01 g), 3c was isolated after chromatography (n-
hexane–EtOAc = 25:1 → 20:1) as a yellow solid (1.15 g,
85%). 1H NMR: d = 2.89 (m, 2 H, CH2), 2.96 (m, 2 H, CH2),
3.90 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 6.91–6.94 (m, 1 H,
Ar), 6.99–7.05 (m, 3 H, Ar), 7.17–7.26 (m, 2 H, Ar), 7.32–
Synlett 2004, No. 15, 2779–2781 © Thieme Stuttgart · New York