2-Diethoxyphosphoryl-4-nitroalkanoates - Versatile intermediates in the synthesis of α-alkylidene-γ-lactones and lactams

Article abstract of DOI:10.1055/s-2004-835656

Michael addition of various nitroalkanes 7a-f to ethyl (2- diethoxyphosphoryl)acrylate (6) gave 2-diethoxyphosphoryl-4-nitroalkanoates 8a-f. Transformation of the nitro functionality into hydroxy or amino group and cyclization yielded 3-(diethoxyphosphory

Full text of DOI:10.1055/s-2004-835656

LETTER
2685
2-Diethoxyphosphoryl-4-nitroalkanoates – Versatile Intermediates in the
Synthesis of a-Alkylidene-g-lactones and Lactams
Versatile
I
nterm
d
e
diates in th
y
e
Synthesis
o
t
f
a-Alk
a
ylidene-g-lactone
B
s
and Lactam
s
łaszczyk, Henryk Krawczyk, Tomasz Janecki*
Institute of Organic Chemistry, Technical University of Łódz, Zeromskiego 116, 90-924 Łódz, Poland
Fax +48(42)6365530; E-mail: tjanecki@p.lodz.pl
Received 30 July 2004
COOR
R1
Y
R2
Abstract: Michael addition of various nitroalkanes 7a–f to ethyl (2-
a
R1
diethoxyphosphoryl)acrylate (6) gave 2-diethoxyphosphoryl-4-ni-
troalkanoates 8a–f. Transformation of the nitro functionality into
hydroxy or amino group and cyclization yielded 3-(diethoxyphos-
phoryl)tetrahydro-2-furanones 11a–e or 3-(diethoxyphosphor-
yl)pyrrolidin-2-ones 14a–e, respectively. These compounds were
then used in Horner–Wadsworth–Emmons olefinations of alde-
hydes to give 3-alkylidenedihydrofuran-2-ones 12a–e or 17a–c and
3-methylidenepyrrolidin-2-ones 15a–e.
COOR
+
NO2
R2
3
2
1
NO2
R2
COOR
R1
R2
b
R1
O
X
XH
5
4
Key words: Michael addition, nitroalkanoates, Wittig type olefina-
tion, a-alkylidenelactones, a-methylidenelactams
X = O, NH, Y = Br, OAc
Scheme 1 (a) Base; (b) Nef reaction and reduction of carbonyl
group (X = O) or reduction of nitro group (X = NH).
a-Alkylidene-g-lactone and lactam framework can be
found in many natural compounds exhibiting wide and
usually strong biological activity.1 As a consequence,
many synthetic routes for the construction of this skeleton
have been developed.1–4
presence of NaH as a base (Scheme 2). Initially, we used
equimolar amounts of nitroalkane and acrylate
(6:7:NaH = 1:1:1.1). However, yields of nitroalkanoates 8
were only moderate (40–50%) under these conditions. We
found out that yield can be improved significantly when
two-fold excess of nitroalkane (6:7:NaH = 1:2:1.1) was
used. Crude products were purified by column chroma-
tography to give alkanoates 8a–f11 as mixtures of dia-
stereoisomers with close to a 3:2 ratio (Table 1).
One of very attractive but little explored approaches em-
ploys functionalized nitroalkanes for the construction of
lactone or lactam ring. This method utilizes 2-alkylidene-
4-nitroalkanoates 3 which can be prepared in base-pro-
moted SN2¢ reaction of nitroalkanes 1 with acrylates 2 eas-
ily accessible from Baylis–Hillman adducts5 (Scheme 1).
Transformation of 3 into 4-hydroxy- or 4-aminoal-
kanoates 4 can be accomplished via Nef reaction followed
by reduction of the carbonyl group or simple reduction of
nitro group, respectively. Depicted reaction sequence has
been successfully used in the preparation of g-lactones 5
(X = O)6,7 and, very recently, g-lactams 5 (X = NH).8
These syntheses, although convenient, are however re-
stricted to a-arylmethylidene-g-lactones,6 a-methylidene-
g-lactones7 or a-arylmethylidene-g-lactams.8
O
(EtO)2P
O
(EtO)2P
COOEt
R1
a
+
COOEt
NO2
R1
NO2
6
8a–f
7a–f
Scheme 2 Reagents and conditions: (a) NaH, THF, r.t., 24 h.
In this communication we report that nitroalkanoate ap-
proach combined with Horner–Wadsworth–Emmons
technique for the construction of alkylidene bond9 estab-
lishes a novel, general and convenient method for the
synthesis of a-alkylidene-g-lactones 12 or 17 and a-meth-
ylidene-g-lactams 15.
4-Nitroalkanoates 8a–e were then used in two indepen-
dent synthetic protocols for the preparation of 3-alky-
lidenedihydrofuran-2-ones 12a–e or 17a–c and 3-
methylidenepyrrolidin-2-ones 15a–e.
In the first protocol nitro functionality was converted into
carbonyl group (Nef reaction) using mild oxidative condi-
tions to give 2-diethoxyphosphoryl-4-oxoalkanoates 9a–
e, usually in excellent yields (Scheme 3, Table 1).
Chemoselective reduction of the carbonyl group in al-
kanoates 9 using NaBH4 gave 4-hydroxyalkanoates 10a–
e which, after acidic work up, lactonized spontaneously to
2-Diethoxyphosphoryl-4-nitroalkanoates 8a–f, which are
the key intermediates in our method, were readily ob-
tained in Michael addition of nitroalkanes 7a–f to ethyl
(2-diethoxyphosphoryl)acrylate (6)10 in THF, in the
3-(diethoxyphosphoryl)tetrahydrofuran-2-ones
11a–e.
SYNLETT 2004, No. 15, pp 2685–2688
0
7
.1
2
.2
0
0
4
Advanced online publication: 08.11.2004
DOI: 10.1055/s-2004-835656; Art ID: G29904ST
© Georg Thieme Verlag Stuttgart · New York
These compounds were obtained as mixtures of dia-
stereoisomers with close to a 1:1 ratio. Finally, furanones

2686
E. Błaszczyk et al.
LETTER
O
O
O
P(OEt)2
(EtO)2P
(EtO)2P
COOEt
COOEt
c
b
R1
a
R1
O
O
R1
R1
O
O
O
OH
10a–e
8a–e
12a–e
11a–e
d
9a–e
O
O
P(OEt)2
(EtO)2P
COOEt
+
e
R1
R1
O
O
N
R1
R1
N
O
H
N
OH
16a–e
NH2
13a–e
H
15a–e
14a–e
Scheme 3 Reagents and conditions: (a) 1. MeONa/MeOH, r.t., 0.5 h; 2. conc. H2SO4, MeOH, –60 °C, 2 h; (b) 1. NaBH4, MeOH, NaOH, H2O,
r.t, 20 h; 2. 1 N HCl(aq); (c) K2CO3, 36% formalin, 0–5 °C, 15 min; (d) NH4HCO2, 10% Pd/C, MeOH–THF, 0 °C to r.t., 24 h; (e) 1. NaH, THF;
2. (CH2O)n, reflux, 1 h.
11a–e treated with formalin in the presence of K2CO3 at along with various amounts (6–26%) of 1-hydroxymeth-
0–5 °C (Villieras procedure)12 yielded expected 3-meth- yl-3-methylidenepyrrolidin-2-ones 16a–e as by-products.
ylidenedihydrofuran-2-ones 12a–e.13 All obtained com- Purification and separation of these mixtures using col-
pounds were purified by column chromatography on umn chromatography on silica gel afforded pure pyrrolid-
silica gel; yields are given in Table 1.
inones 15a–e14 in good to moderate yields (Table 1).
The second protocol starts with palladium-catalyzed am- Unfortunately, neither of these protocols proved effective
monium formate reduction of nitro group in 4-nitroal- toward nitroalkanoate 8f. In both cases complex mixtures
kanoates 8a–e to give, after spontaneous lactamization, 3- of products, difficult to identify, were obtained.
(diethoxyphosphoryl)pyrrolidin-2-ones 14a–e as mix-
tures of diastereoisomers with close to a 3:2 ratio
Extension of our method on the synthesis of 3-alkylidene-
dihydrofuran-2-ones was fully successful. Aliphatic as
(Scheme 3, Table 1). Disappointingly, application of the
well as aromatic aldehydes reacted efficiently with
Villieras procedure to pyrrolidinones 14a–e was unsuc-
sodium derivatives of furanone 11d in boiling benzene to
cessful with substrates recovered after standard work-up.
give, after standard work-up and purification by column
chromatography, 3-alkylidenedihydrofuran-2-ones 17a–c
(Scheme 4). Compounds 17a,b were obtained as mixtures
of E- and Z-isomers, whereas compound 17c was formed
However, we were pleased to observe that olefination of
formaldehyde using 14a–e can be effectively accom-
plished when sodium hydride with paraformaldehyde in
boiling THF was used. Under these conditions expected
as a single E-isomer (Table 2).
3-methylidenepyrrolidin-2-ones 15a–e were formed
Table 1 Synthesis of 3-Methylidenedihydrofuran-2-ones 12 and 3-Methylidenepyrrolidin-2-ones 15
Yield (%)a,b
Ratioc
R1
8
9
11
12
67
67
76
56
48
14
88
84
69
60
70
15
58
63
60
76
40
15:16
a
b
c
H
95
95
98
68
85
95
96
92
83
62
70
72
72
83
70
93:7
Me
n-Bu
Ph
74:26
86:14
82:18
94:6
d
e
OMe
OMe
f
p-NO2C6H4
40
–
–
–
–
–
–
a Yield of isolated, purified product.
b All new compounds were characterized by IR, 1H NMR, 13C NMR, and 31P NMR spectroscopy and gave satisfactory elemental analyses.
c Ratio determined from 1H NMR of the crude product.
Synlett 2004, No. 15, 2685–2688 © Thieme Stuttgart · New York

LETTER
Synthesis of a-Alkylidene-g-lactones and Lactams
2687
(10) (a) Prepared in 73% yield by modified literature
Configurational assignments were made using diagnostic
deshielding effect of the carbonyl group exerted on the
cis-oriented vinyl proton,15 e.g., in 17a vinyl protons with
chemical shift d = 6.51 ppm and d = 5.90 ppm were attrib-
uted to (E)-17a and (Z)-17a, respectively. Disappointing-
ly, reaction of the sodium salt of pyrrolidinone 14d with
isobutyraldehyde in boiling benzene gave (E)-3-(2¢-meth-
ylpropylidene)-5-benzylpyrrolidin-2-one in low, 6% yield
after purification by column chromatography. In the
similar reaction performed with benzaldehyde we were
unable to isolate a pure product.
procedure.10b A mixture of 36% formaline (28 mL, 0,30
mol), piperidine (1 mL) and MeOH (450 mL) was refluxed
for 0.5 h. To this mixture was added triethyl phosphono-
acetate (30.0 g 0.13 mol) in one portion at 25 °C and the
mixture was heated at reflux for 70 h. After 20 h and 48 h
additional portions of piperidine (0.5 mL) were added.
Progress of the reaction was monitored by 31P NMR. The
solution was cooled and concentrated by rotatory
evaporation, the residue was extracted with CCl4 (3 × 100
mL), combined extracts were dried (MgSO4), evaporated
and 85% H3PO4 (3 mL) was added to the residue which was
distilled in high vacuum (85–87 °C/0.4 Torr) to give pure
ethyl 2-(diethoxyphosphory)lacrylate (6, 22.4 g; 73%).
(b) Semmelhack, M. F.; Tomesh, J. C.; Czarny, M.;
R2
Boettger, S. J. Org. Chem. 1978, 43, 1259.
a
11d
(11) General Procedure for the Preparation of Ethyl 2-
diethoxyphosphoryl-4-nitroalkanoates 8a–f. Asolutionof
nitroalkane 7 (17.0 mmol) in THF (10 mL) was added to a
stirred suspension of NaH (0.213 g; 8.9 mmol) in THF (40
mL) under argon atmosphere at 0–4 °C. The reaction
mixture was stirred for 40 min at r.t., cooled to 0–4 °C, and
a solution of ethyl 2-diethoxyphosphorylacrylate (6) (2.000
g; 8.5 mmol) in THF (10 mL) was added. The mixture was
then stirred for 24 h at r.t., THF was evaporated off at r.t. and
the residue was quenched with H2O (15 mL) and extracted
with CH2Cl2 (4 × 20 mL). The organic extracts were dried
(MgSO4) and evaporated at r.t., to give a crude product,
which was purified by column chromatography (silica gel,
eluent CHCl3–acetone = 90:10 for 8a–c, CHCl3–
O
O
Ph
17a–c
Scheme 4 Reagents and conditions: (a) 1. NaH, benzene, r.t., 0.5 h;
2. R2CHO, benzene, reflux, 4 h.
Table 2 Synthesis of 3-Alkylidenedihydrofuran-2-ones 17a–c
17
a
R2
E:Za
Yield (%)b,c
i-Pr
30:70
85:15
>99:1
78
90
82
b
Ph
acetone = 95:5 for 8d,e and EtOAc–hexane = 95:5 for 8f).
Spectroscopic data for ethyl 2-diethoxyphosphoryl-5-(3,4-
dimethoxyphenyl)-4-nitropentanoate (8e); dr 65:35. IR
(film): 1732, 1552, 1260 cm–1. 1H NMR (250 MHz, CDCl3):
d = 1.28 (t, 3JHH = 7.0 Hz, 3 H, major + minor), 1.31 (t,
3JHH = 7.0 Hz, 3 H, major), 1.32 (td, 3JHH = 7.2 Hz,
c
1-naphtyl
a Taken from 1H NMR of the crude product.
b Yield of isolated, purified product based on 11d.
c All new compounds were characterized by IR, 1H NMR, and 13
NMR spectroscopy and gave satisfactory elemental analyses.
C
4JPH = 0.5 Hz, 3 H, minor), 1.33 (td, 3JHH = 7.5 Hz, 4JPH = 0.5
Hz, 3 H, major), 1.34 (td, 3JHH = 7.0 Hz, 4JPH = 0.5 Hz, 3 H,
minor), 2.28–2.75 (m, 2 H, major + minor), 2.84 (m, 1 H,
major + minor), 3.02 (dd, 2JHH = 14.5 Hz, 3JHH = 7.2 Hz, 1 H,
minor), 3.03 (dd, 2JHH = 14.5, 3JHH = 5.5 Hz, 1 H, major),
3.22 (dd, 2JHH = 14.5 Hz, 3JHH = 8.8 Hz, 1 H, major), 3.23
(dd, 2JHH = 14.5 Hz, 3JHH = 7.5 Hz, 1 H, minor), 3.85 (s, 3 H,
major + minor), 3.86 (s, 3 H, major + minor), 4.02–4.28 (m,
4 H, major + minor), 4.67–4.81 (m, 1 H, major), 4.90–5.03
In summary, we have developed a novel, facile and
general approach to 3-alkylidenedihydrofuran-2-ones 12
or 17 and 3-methylidenepyrrolidin-2-ones 15 starting
from common intermediates – 2-diethoxyphosphoryl-4-
nitroalkanoates 8.
(m, 1 H, minor), 6.62–6.82 (m, 3 H, major + minor). 13
C
Acknowledgment
NMR (62.9 MHz, CDCl3): d = 13.82 (s), 16.07 (d, 3JPC = 6.0
Hz), 30.04 (d, 2JPC = 4.5 Hz), 30.26 (d, 2JPC = 3.5 Hz), 39.46
(s), 39.60 (s), 41.77 (d, 1JPC = 130.2 Hz), 42.06 (d,
This work was supported by the Polish State Committee for
Scientific Research (KBN, Project No 4 T09A 135 24).
1JPC = 130.6 Hz), 55.67 (s), 55.70 (s), 61.76 (s), 61.82 (s),
62.99 (d, 2JPC = 6.5 Hz), 87.39 (d, 3JPC = 8.4 Hz), 87.67 (d,
3JPC = 15.0 Hz), 111.26 (s), 111.73 (s), 111.81 (s), 120.88
(s), 121.02 (s), 127.10 (s), 148.28 (s), 148.93 (s), 167.58 (d,
2JPC = 5.7 Hz), 167.73 (d, 2JPC = 6.3 Hz). 31P NMR (101
MHz, CDCl3): d = 20.46 (major), 21.12 (minor). Anal. Calcd
for C19H30NO9P: C, 51.00; H, 6.76; N, 3.13; P, 6.92. Found:
C, 51.12; H, 6.69; N, 3.20; P, 6.80.
References
(1) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl.
1985, 24, 94.
(2) Paquette, L. A.; Mendez-Andino, J. Tetrahedron Lett. 1999,
40, 4301; and references cited therein.
(3) Steurer, S.; Podlech, J. Eur. J. Org. Chem. 2002, 899; and
references cited therein.
(4) Kang, S.-K.; Kim, K.-J.; Hong, Y.-T. Angew. Chem. Int. Ed.
2002, 1584; and references cited therein.
(5) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996,
52, 8001.
(6) Bauchet, R.; Le Rouille, E.; Foucaud, A. Bull. Soc. Chim. Fr.
1991, 128, 267.
(7) Ballini, R.; Bosica, G.; Livi, D. Synthesis 2001, 1519.
(8) Basavaiah, D.; Rao, J. S. Tetrahedron Lett. 2004, 45, 1621.
(9) Janecki, T.; Błaszczyk, E. Synthesis 2001, 403.
(12) Villieras, J.; Rambaud, M. Synthesis 1984, 406.
(13) General Procedure for the Preparation of 3-
Methylidenedihydrofuran-2-ones 12a–e. A mixture of 3-
(diethoxyphosphoryl)tetrahydrofuran-2-one 11 (1.0 mmol),
K2CO3 (0.415 g; 3.0 mmol) and 36% formaline (0.54 mL;
7.0 mmol) was stirred at 0–4 °C for 15 min. The mixture was
extracted with Et2O (4 × 15 mL), dried (MgSO4) and
evaporated. Residue was purified by column chromato-
graphy (silica gel, eluent CHCl3) to give 12. Spectroscopic
data for 5-(3,4-dimethoxyphenylmethyl)-3-methylidene-
dihydrofuran-2-one (12e). IR (film): 1772, 1664 cm–1.
Synlett 2004, No. 15, 2685–2688 © Thieme Stuttgart · New York

2688
E. Błaszczyk et al.
LETTER
1H NMR (250 MHz, CDCl3): d = 2.59 (ddt, 2JHH = 17.0 Hz,
3JHH = 6.0 Hz, 4JHH = 2.8 Hz, 1 H), 2.81 (dd, 2JHH = 14.3 Hz,
3JHH = 6.0 Hz, 1 H), 2.89 (ddt, 2JHH = 17.0 Hz, 3JHH = 7.8 Hz,
4JHH = 2.8 Hz, 1 H), 2.95 (dd, 2JHH = 14.3 Hz, 3JHH = 6.0 Hz,
1 H), 3.79 (s, 3 H), 3.80 (s, 3 H), 4.69 (dq, 3JHH = 7.8 Hz,
3JHH = 6.0 Hz, 1 H), 5.49 (t, 4JHH = 2.8 Hz, 1 H), 6.10 (t,
4JHH = 2.8 Hz, 1 H), 6.65–6.78 (m, 3 H). 13C NMR (62.9
MHz, CDCl3): d = 32.50 (s), 41.27 (s), 55.90 (s), 55.92 (s),
77.21 (s), 111.32 (s), 112.74 (s), 121.68 (s), 127.89 (s),
148.14 (s), 149.02 (s), 121.98 (s), 134.37 (s), 170.13 (s).
Anal. Calcd for C14H16O4: C, 67.73; H, 6.50. Found: C,
67.88; H, 6.41.
residue was extracted with CH2Cl2 (3 × 15 mL). Combined
organic extracts were washed with H2O (5 mL), dried
(MgSO4) and evaporated to give crude 15, which were
purified by column chromatography (silica gel, eluent
CHCl3). Spectroscopic data for 5-(3,4-dimethoxyphenyl-
methyl)-3-methylidenepyrrolidin-2-one (15e). IR (film):
3100, 1684, 1662 cm–1. 1H NMR (250 MHz, CDCl3): d =
2.45 (ddt, 2JHH = 17.0 Hz, 3JHH = 4.0 Hz, 4JHH = 2.2 Hz, 1 H),
2.73 (ddt, 2JHH = 17.0 Hz, 3JHH = 7.5 Hz, 4JHH = 2.2 Hz, 1 H),
2.82 (dd, 2JHH = 13.8 Hz, 3JHH = 7.6 Hz, 1 H), 3.15 (dd,
2JHH = 13.8 Hz, 3JHH = 3.4 Hz, 1 H), 3.86 (s, 3 H), 3.87 (s, 3
H), 4.02–4.20 (m, 1 H), 5.18 (t, 4JHH = 2.2 Hz, 1 H), 5.83 (t,
4JHH = 2.2 Hz, 1 H), 6.53–6.57 (m, 3 H). 13C NMR (62.9
MHz, CDCl3): d = 28.13 (s), 37.41 (s), 55.81 (s), 58.20 (s),
115.92 (s), 111.14 (s), 112.69 (s), 121.72 (s), 128.17 (s),
147.89 (s), 148.93 (s), 135.58 (s), 163.89 (s). Anal. Calcd for
C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 67.09; H,
6.57, N, 5.83.
(14) General Procedure for the Preparation of 3-
Methylidenepyrrolidin-2-ones 15a–e. A solution of 3-
(diethoxyphosphoryl)pyrrolidin-2-one 14 (1.00 mmol) in
THF (7.0 mL) was added to a suspension of NaH (0.025 g;
1.05 mmol) in THF (3 mL) and the reaction mixture was
stirred at r.t. for 30 min. Next, paraformaldehyde (0.033 g,
1.10 mmol) was added in one portion, the mixture was
refluxed for 1 h and cooled to 0–4 °C. Then H2O (3 mL) was
added, THF was evaporated under reduced pressure and the
(15) Macomber, R. S. A. Complete Introduction to Modern NMR
Spectroscopy; John Wiley and Sons: New York, 1998, 416.
Synlett 2004, No. 15, 2685–2688 © Thieme Stuttgart · New York