Direct synthesis of polyfunctionalized unsaturated δ-lactones and δ-lactams from α-alkenoyl α-carboxyl/carbamoyl ketene S,S-acetals under Vilsmeier conditions

Article abstract of DOI:10.1021/jo900663z

(Chemical Equation Presented) An efficient method for direct synthesis of polyfunctionalized unsaturated δ-lactones 2 and δ-lactams 4 has been developed from the reaction of the easily available α-alkenoyl α-carboxyl/carbamoyl ketene S,S-acetals 1/3 and V

Full text of DOI:10.1021/jo900663z

heterocyclic scaffolds, especially those with polyfunctional
groups, is an important task for further studies.
Direct Synthesis of Polyfunctionalized
Unsaturated δ-Lactones and δ-Lactams from
r-Alkenoyl r-Carboxyl/Carbamoyl Ketene
S,S-Acetals under Vilsmeier Conditions
Functionalized ketene S,S-acetals are versatile intermediates
in organic synthesis.3,4 During the course of our studies in this
context,5-9 we found that the readily available R-alkenoyl ketene
S,S-acetals showed fascinating structural features as novel
intermediates for their dense substitution patterns and flexible
alkylthio functionality able to play multiple roles. A number of
annulation strategies based on them have been developed in
our group for the synthesis of various carbo- and heterocyclic
compounds, such as the [5 + 1] annulations for phenols6a and
pyrrolizidines,6e the domino reaction for fused tetraheterocyclic
compounds,7 and the three-component [4 + 2] cycloaddition
for cyclohexanones.8 In addition, tetronic acid,9a tetramic acid,9b
and thiophene derivatives9c were synthesized with R-alkenoyl
R-carboxyl/carbamoyl ketene S,S-acetals as starting materials
through intramolecular oxa/aza/thia-anti-Michael addition reac-
tions, respectively. However, in comparison, the direct intramo-
lecular oxa/aza-Michael addition of either R-alkenoyl R-carboxyl
or R-alkenoyl R-carbamoyl ketene S,S-acetals leading to the
correspondingsix-memberedheterocycleshasnotbeenestablished9,10
due to decarboxylation of the former under both basic and acidic
conditions9a,10a and competition of the aza/thia-anti-Michael
additions of the latter under basic conditions.9b,c Very recently,
as an alternative route, a one-pot synthesis of functionalized
unsaturated δ-lactones via reduction-lactonizations of R-alk-
enoyl R-carboxyl ketene S,S-acetals has been reported by us.11
As part of a continuing interest in solving the problems in the
synthesis of the corresponding six-membered heterocycles
starting directly from the easily available R-alkenoyl R-carboxyl
Jun Liu,† Mang Wang,*,†,‡ Feng Han,† Yingjie Liu,† and
Qun Liu*,†
Department of Chemistry, Northeast Normal UniVersity,
Changchun, 130024, China, and State Key Laboratory of
Fine Chemicals, Dalian UniVersity of Technology,
Dalian, 116012, China
wangm452@nenu.edu.cn
ReceiVed March 30, 2009
An efficient method for direct synthesis of polyfunctionalized
unsaturated δ-lactones 2 and δ-lactams 4 has been developed
from the reaction of the easily available R-alkenoyl R-car-
boxyl/carbamoyl ketene S,S-acetals 1/3 and Vilsmeier re-
agents (DMF/POCl3 or DMF/PBr3) via a cyclization followed
by a halovinylation or haloformylation sequence.
(3) For reviews, see: (a) Dieter, R. K. Tetrahedron 1986, 42, 3029. (b)
Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423.
(4) For selected recent reports, see: (a) Joseph, B. K.; Verghese, B.;
Sudarsanakumar, C.; Deepa, S.; Viswam, D.; Chandran, P.; Asokan, C. V. Chem.
Commun. 2002, 736. (b) Panda, K.; Suresh, J. R.; Ila, H.; Junjappa, H. J. Org.
Chem. 2003, 68, 3498. (c) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa,
H. J. Org. Chem. 2005, 70, 10030. (d) Rao, H. S. P.; Sivakumar, S. J. Org.
Chem. 2006, 71, 8715. (e) Yu, H.; Yu, Z. Angew. Chem., Int. Ed. 2009, 48,
2929.
(5) (a) Yin, Y.; Wang, M.; Liu, Q.; Hu, J.; Sun, S.; Kang, J. Tetrahedron
Lett. 2005, 46, 4399. (b) Fu, Z.; Wang, M.; Ma, Y.; Liu, Q.; Liu, J. J. Org.
Chem. 2008, 73, 7625. (c) Yuan, H.-J.; Wang, M.; Liu, Y.-J.; Liu, Q. AdV. Synth.
Catal. 2009, 351, 112.
(6) For [5 + 1] annulations, see: (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. (c) Bi, X.; Dong, D.; Li, Y.; Liu, Q.;
Zhang, Q. J. Org. Chem. 2005, 70, 10886. (d) Hu, J.; Zhang, Q.; Yuan, H.; Liu,
Q. J. Org. Chem. 2008, 73, 2442. (e) Tan, J.; Xu, X.; Zhang, L.; Li, Y.; Liu, Q.
Angew. Chem., Int. Ed. 2009, 48, 2868. (f) Zhang, L.; Liang, F.; Cheng, X.;
Liu, Q. J. Org. Chem. 2009, 74, 899.
The core structures of δ-lactones and δ-lactams exist in a
large number of natural and unnatural pharmaceutically and
biologically important compounds.1 General methods for their
synthesis involve cyclization of appropriately substituted open
chain precursors.2 However, many of these methods are limited
in their use by a relatively narrow scope of substrates, harsh
reaction conditions, multiple steps, or the use of not easily
available starting materials. Therefore, the development of an
efficient synthetic approach for the construction of these
† Northeast Normal University.
‡ Dalian University of Technology.
(1) (a) Haynes, L. J. Q. ReV. Chem. Soc. 1948, 2, 46. (b) Davies-Coleman,
M. T.; Rivett, D. E. A. In Progress in the Chemistry of Organic Natural Products;
Zechmeister, L., Ed.; Springer-Verlag: New York, 1989; Vol. 55, p 1. (c) Nangia,
A.; Prasuna, G.; Rao, P. B. Tetrahedron 1997, 53, 14507. (d) De Lucca, G. V.
Bioorg. Med. Chem. Lett. 1997, 7, 501.
(2) For selective examples on the synthesis of δ-lactones, see: (a) Pa`mies,
O.; Ba¨ckvall, J.-E. J. Org. Chem. 2002, 67, 1261. (b) Andreana, P. R.; McLellan,
J. S.; Chen, Y.; Wang, P. G. Org. Lett. 2002, 4, 3875. (c) Dong, C.; Alper, H.
J. Org. Chem. 2004, 69, 5011. (d) Baza´n-Tejeda, B.; Bluet, G.; Broustal, G.;
Campagne, J.-M. Chem.sEur. J. 2006, 12, 8358. For selective examples on the
synthesis of δ-lactams, see: (e) Sainte, F.; Serckx-Poncin, B.; Hesbain-Frisque,
A.; Ghosez, L. J. Am. Chem. Soc. 1982, 104, 1428. (f) Padwa, A.; Heidelbaugh,
T. M.; Kuethe, J. T. J. Org. Chem. 2000, 65, 2368. (g) Yamamoto, Y.; Takagishi,
H.; Itoh, K. Org. Lett. 2001, 3, 2117. (h) Gibson, K. R.; Hitzel, L.; Mortishire-
Smith, R. J.; Gerhard, U.; Jelley, R. A.; Reeve, A. J.; Rowley, M.; Nadin, A.;
Owens, A. P. J. Org. Chem. 2002, 67, 9354. (i) Godineau, E.; Landais, Y. J. Am.
Chem. Soc. 2007, 129, 12662.
(7) For the domino reaction, see: Liang, F.; Zhang, J.; Tan, J.; Liu, Q. AdV.
Synth. Catal. 2006, 348, 1986.
(8) For the multicomponent reaction, see: Ma, Y.; Wang, M.; Li, D.;
Bekturhun, B.; Liu, J.; Liu, Q. J. Org. Chem. 2009, 74, 3166.
(9) For intramolecular anti-Michael additions, see: (a) Bi, X. H.; Liu, Q.;
Sun, S. G.; Liu, J.; Pan, W.; Zhao, L.; Dong, D. W. Synlett 2005, 49. (b) Li, Y.;
Liang, F.; Bi, X.; Liu, Q. J. Org. Chem. 2006, 71, 8006. (c) Bi, X.; Zhang, J.;
Liu, Q.; Tan, J.; Li, B. AdV. Synth. Catal. 2007, 349, 2301.
(10) (a) Choi, E. B.; Youn, I. K.; Pak, C. S. Synthesis 1991, 15. For a one-
pot synthesis of substituted pyridine-2,4(1H,3H)-diones from the reaction of
acyl(carbamoyl)ketene S,S-acetals with N,N-dimethylformamide dimethyl acetal,
see: (b) Li, Y.; Li, W.; Zhang, R.; Zhou, Y.; Dong, D. Synthesis 2008, 3411.
For synthesis of dihydropyranones from the reaction of R-acetyl ketene S,S-
acetals with aldehydes, see: (c) Ouyang, Y.; Huang, J.; Pan, W.; Liang, Y.; Yang,
Y.; Dong, D. W. Eur. J. Org. Chem. 2009, 2003.
(11) For reduction-lactonization, see: Liu, J.; Wang, M.; Li, B.; Liu, Q.;
Zhao, Y. J. Org. Chem. 2007, 72, 4401.
5090 J. Org. Chem. 2009, 74, 5090–5092
10.1021/jo900663z CCC: $40.75  2009 American Chemical Society
Published on Web 05/21/2009

TABLE 1. Optimization of Reaction Conditions of 1a under
Vilsmeier Conditionsa
TABLE 2. Cyclizations of r-Alkenoyl r-Carboxyl Ketene
S,S-Acetals 1 under Vilsmeier Conditionsa
yield of 2a (%)b
entry
1
R
2
X
time (h)
yield (%)b
entry
1a: POCl3
T (°C)
time (h)
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
5.0
5.5
5.5
10
4.0
3.5
3.5
4.0
5.0
6.0
83
76
80
54
84
86
83
80
78
82
1
2
3
4
5
6
7
1:1
1:2
1:2
1:2
1:2
1:3
1:4
60
60
70
90
100
70
9.0
7.0
5.0
4.5
4.0
4.5
4.0
50
79
82
80
81
83
81
2-ClC6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
3,4-CH2O2C6H3
2-thienyl
t-Bu
70
a 1a (1.0 mmol), DMF (5.0 mL). b Isolated yields.
1a
C6H5
2j
a 1 (1.0 mmol), POCl3 or PBr3 (3.0 mmol), DMF (5.0 mL), 70 °C.
and R-alkenoyl R-carbamoyl ketene S,S-acetals, the Vilsmeier
reagent (VR) mediated cyclization reactions of R-alkenoyl
R-carboxyl/carbamoyl ketene S,S-acetals were studied.12 In this
paper, we wish to report the results.
b Isolated yields.
SCHEME 1. Proposed Mechanism for the Formation of 2
R-Alkenoyl R-carboxyl ketene S,S-acetals 1 were prepared
in excellent yields by the aldol condensation of R-acetyl ketene
S,S-acetals with aldehydes (including aliphatic and aromatic
aldehydes) under basic conditions according to the reported
procedure.11 In the present research, the reaction of (E)-2-(1,3-
dithiolan-2-ylidene)-3-oxo-5-phenylpent-4-enoic acid 1a with
Vilsmeier reagent was initially performed. As described in Table
1, entry 1, treatment of 1a (1.0 mmol) with POCl3 (1.0 mmol)
in DMF (5.0 mL) at 60 °C for 9.0 h, a colorless semisolid was
isolated after workup and column chromatography of the
resulting mixture. The product was characterized as an unsatur-
ated δ-lactone, 4-chloro-3-(1,3-dithiolan-2-ylidene)-6-phenyl-
3,6-dihydro-2H-pyran-2-one 2a (50% isolated yield), on the
basis of the spectral and analytical data. Then the optimization
of the reaction conditions with respect to the molar ratio of 1a
to POCl3 and the reaction temperatures was investigated. It was
found that a higher temperature and excess of POCl3 resulted
in a high yield of 2a in shorter reaction times (Table 1, entries
2-7). In comparison, the reaction performed at 70 °C with a
1:3 molar ratio of 1a to POCl3 was chosen as the optimal
condition in terms of yields and reaction time (Table 1, entry
6).
a heteroaromatic substituent (Table 2, entry 8), and an aliphatic
substituent (Table 2, entry 9) at the ꢀ-position of the alkenoyl
moiety of 1 can give the desired δ-lactones 2 in high yield in
general. In the case of 1d, with a strong electron-withdrawing
group (4-nitrophenyl), longer reaction time was required and
the yield of 2d was moderate (Table 2, entry 4). In addition,
PBr3/DMF was proven to be effective for this procedure as well.
The corresponding δ-lactone 2j was afforded in 82% yield
(Table 2, entry 10).
On the basis of the above results and related studies,10-14
a
Under the optimal conditions, a range of reactions of
R-alkenoyl R-carboxyl ketene S,S-acetals 1b-i was carried out
and the results are summarized in Table 2. It is clear that,
according to the experimental results (Table 2), this protocol
provides an efficient approach for the synthesis of polyfunc-
tionalized unsaturated δ-lactones 2 starting directly from R-alk-
enoyl R-carboxyl ketene S,S-acetals 1. The substrates 1 bearing
an aromatic substituent (Table 2, electroneutral, entry 1;
electron-deficient, entries 2-4; or electron-rich, entries 5-7),
plausible mechanism for the formation of unsaturated δ-lactones
2 is presented in Scheme 1. The first step of the reaction may
involve the formation of an unstable intramolecular Michael
adduct, δ-lactone I.10a Formation of δ-lactone I results in the
release of acyl structure, which leads to halogenated δ-lactones
2 by halovinylation of I under Vilsmeier conditions (I f II f
III f 2).13,14 In the above mechanism, the Vilsmeier reagent
plays a significant role, probably at the stage of the haloviny-
lation (I f II f III f 2), which is the driving force to move
the equilibrium (1 f I) toward more stable δ-lactones 2.
Encouraged by the successful synthesis of unsaturated δ-lac-
tones 2 and with an aim to provide more information about the
scope and mechanism of this protocol, the reactions of R-alk-
enoyl R-carbamoyl ketene S,S-acetals 3 under Vilsmeier condi-
(12) Vilsmeier reagents are commercially available and have found extensive
applications in organic synthesis, see: (a) Meth-Cohn, O.; Stanforth, S. P. In
ComprehensiVe Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New
York, 1991; Vol. 2, p 777. (b) Marson, C. M. Tetrahedron 1992, 48, 3659. For
selected examples, see: (c) Meth-Cohn, O.; Taylor, D. L. Tetrahedron 1995,
51, 12869. (d) Amaresh, R. R.; Perumal, P. T. Tetrahedron 1999, 55, 8083. (e)
Smeets, S.; Asokan, C. V.; Motmans, F.; Dehaen, W. J. Org. Chem. 2000, 65,
5882. (f) Gangadasu, B.; Narender, P.; Kumar, S. B.; Ravinder, M.; Rao, B. A.;
Ramesh, Ch.; Raju, B. C.; Rao, V. J. Tetrahedron 2006, 62, 8398. (g) Xiang,
D.; Yang, Y.; Zhang, R.; Liang, Y.; Pan, W.; Huang, J.; Dong, D. J. Org. Chem.
2007, 72, 8593. (h) Xiang, D.; Wang, K.; Liang, Y.; Zhou, G.; Dong, D. Org.
Lett. 2008, 10, 345. (i) Wang, K.; Xiang, D.; Liu, J.; Pan, W.; Dong, D. Org.
Lett. 2008, 10, 1691.
(13) (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.; Dong, D.
J. Org. Chem. 2003, 68, 9148. (b) Chen, L.; Zhao, Y.-L.; Liu, Q.; Cheng, C.;
Piao, C.-R. J. Org. Chem. 2007, 72, 9259. (c) Zhao, L.; Liang, F.; Bi, X.; Sun,
S.; Liu, Q. J. Org. Chem. 2006, 71, 1094.
(14) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu, Q.
Org. Lett. 2007, 9, 2421.
J. Org. Chem. Vol. 74, No. 14, 2009 5091

TABLE 3. Reactions of r-Alkenoyl r-Carbamoyl Ketene
S,S-Acetals 3 under Vilsmeier Conditionsa
involving the Vilsmeier reagent-induced cyclization followed
by a halovinylation or haloformylation is proposed. This
synthetic protocol is associated with readily available starting
materials, a wide range of products, and easy control of the
reaction conditions. The potential utilization and extension of
the scope of the methodology are currently under investigation.
Experimental Section
entry
3
R
Ar
C6H5
4-ClC6H4
4-MeOC6H4 4c
4-MeOC6H4 4d
4
time (h) yield (%)b
Typical Procedure for the Synthesis of Unsaturated δ-Lac-
tones 2 (2a as an example). To a solution of R-alkenoyl R-carboxyl
ketene dithioacetal 1a (292 mg, 1.0 mmol) in DMF (5.0 mL) was
added POCl3 (0.27 mL, 3.0 mmol) in one portion at room
temperature. The reaction mixture was then heated to 70 °C with
stirring for about 5 h. After completion of the reaction as indicated
by TLC, the reaction mixture was quenched with saturated aqueous
NaHCO3 (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were washed with saturated aqueous
NaCl (3 × 20 mL), dried over MgSO4, filtered, and concentrated
in vacuo. The crude product was purified by flash silica gel
chromatography with petroleum ether/ether (8/1, v/v) as eluent to
give 2a (257 mg, 83%) as a colorless semisolid.
4-Chloro-3-(1,3-dithiolan-2-ylidene)-6-phenyl-3,6-dihydro-2H-
pyran-2-one (2a): colorless semisolid; 1H NMR (500 MHz, CDCl3)
δ 3.37-3.39 (m, 2H), 3.47-3.49 (m, 2H), 5.83 (d, J ) 4.0 Hz,
1H), 6.06 (d, J ) 4.0 Hz, 1H), 7.35-7.39 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 167.1, 164.4, 137.8, 129.0, 128.9 (2C), 128.8, 126.9
(2C), 122.8, 109.0, 78.1, 38.7, 37.7; IR (KBr) 3060, 2924, 2854,
1693, 1464, 1213, 1154, 890 cm-1; MS (ESI) m/z 311 [(M + 1)]+.
Anal. Calcd for C14H11ClO2S2: C, 54.10; H, 3.57. Found: C, 53.96;
H, 3.50.
4-Chloro-5-(1,3-dithiolan-2-ylidene)-6-oxo-1,2-diphenyl-1,2,5,6-
tetrahydropyridine-3-carbaldehyde (4a): yellow crystal, mp 72-74
ꢁC; 1H NMR (500 MHz, CDCl3) δ 3.31-3.36 (m, 1H), 3.44-3.54
(m, 3H), 5.83 (s, 1H), 7.07 (d, J ) 8.5 Hz, 2H), 7.20-7.31 (m,
8H), 10.13 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 187.6, 172.5,
163.3, 142.9, 140.9, 139.3, 129.5, 128.7 (2C), 128.6 (2C), 127.8,
126.8, 126.0 (2C), 125.9 (2C), 114.0, 61.0, 38.0, 37.4; IR (KBr)
3050, 2856, 2411, 1694, 1539, 1465, 1387, 1239, 1003 cm-1; MS
(ESI) m/z 414 [(M + 1)]+. Anal. Calcd for C21H16ClNO2S2: C,
60.93; H, 3.90, N, 3.38. Found: C, 60.78; H, 3.86; N, 3.34.
1
2
3
4
5
3a C6H5
3b C6H5
3c C6H5
3d 4-ClC6H4
3e 4-MeOC6H4 4-MeOC6H4 4e
4a
4b
4.5
5.0
4.0
5.0
3.5
82
76
72
70
80
a 3 (1.0 mmol), POCl3 (3.0 mmol), DMF (5.0 mL), 70 °C. b Isolated
yields.
tions were examined. At first, the substrates R-alkenoyl R-car-
bamoyl ketene dithioacetals 3 were prepared in excellent yields
either by condensation of the corresponding 2-(1,3-dithiolan-
2-ylidene)-3-oxobutanamides with aldehydes or by amination
of the corresponding R-alkenoyl R-carboxyl ketene S,S-acetals
1.9b Then, the reaction of (E)-2-(1,3-dithiolan-2-ylidene)-3-oxo-
N,5-diphenylpent-4-enamide 3a with POCl3 (3.0 equiv) in DMF
at 70 °C was performed. To our delight, the reaction proceeded
smoothly and afforded unsaturated δ-lactam 4a in 82% yield
within 4.5 h (Table 3, entry 1). Interestingly, in contrast with
the reaction of 1 with Vilsmeier reagents, the reaction of 3a
under identical conditions gave 4-chloro-5-formyl unsaturated
δ-lactam. The tolerance of the selected substrates 3 to this
reaction was subsequently explored. The experimental results
are presented in Table 3. Clearly, all the reactions of 3b-e with
POCl3 (3.0 equiv) in 5.0 mL of DMF at 70 °C could afford the
corresponding 4-chloro-5-formyl unsaturated δ-lactams 4b-e
in high yields (Table 3, entries 2-5). It is worth noting that,
similar to the mechanism for the formation of 4-chloro-
unsaturated δ-lactones 2, a tandem cyclization-chloroformylation
process would be involved for the formation of 4-chloro-5-
formyl-unsaturated δ-lactams 4. In comparison, the extra step,
the formylation of the corresponding 4-chloro-unsaturated
δ-lactam intermediate, may be due to the 4-chloro unsaturated
δ-lactam being more reactive toward Vilsmeier reagents than
the corresponding 4-chloro-unsaturated δ-lactones 2.13,15
In summary, a convenient and efficient method for the
synthesis of polyfunctionalized unsaturated δ-lactones 2 and
δ-lactams 4 has been developed. This strategy allows the direct
application of R-alkenoyl R-carboxyl/carbamoyl ketene dithio-
acetals 1 and 3 under Vilsmeier conditions. A mechanism
Acknowledgment. Financial support of this research by
NNSFC-20872015, the State Key Laboratory of Fine Chemicals,
NENU-STC08007/07007, and NENU-20070308 are greatly
acknowledged.
Supporting Information Available: Experimental details,
spectral and analytical data for compounds 2 and 4, and copies
1
of H NMR and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) In our research, the corresponding 4-chloro-unsaturated δ-lactams were
not obtained under the reaction conditions used.
JO900663Z
5092 J. Org. Chem. Vol. 74, No. 14, 2009