Michael addition of N-heteroaromatics to vinylphosphonates and synthesis of phosphoryl pyrrolizones by cyclization of michael adducts

Article abstract of DOI:10.1055/s-0032-1317894

Novel phosphonate compounds were synthesized via Michael addition of N-heteroaromatic compounds to aryl- and alkyl-substituted vinylphosphonates using scandium triflate as the catalyst. Intramolecular cyclization reaction of the Michael adducts obtained gives novel (dimethoxyphosphoryl)pyrrolizin-3-ones in high yields as a single diastereomer. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0032-1317894

PAPER
▌193
paper
Michael Addition of N-Heteroaromatics to Vinylphosphonates and Synthesis
of Phosphoryl Pyrrolizones by Cyclization of Michael Adducts
Michael Addition to Vinylphosphonates and Phosphonylpyrrolizones
Dilek Isik Tasgin, Canan Unaleroglu*
Hacettepe University, Department of Chemistry, 06800 Ankara, Turkey
Fax +90(312)2992163; E-mail: canan@hacettepe.edu.tr
Received: 19.10.2012; Received after revision: 22.11.2012
tion of N-2b,7b,8a,9 or C-substituted10,11 pyrrole derivatives.
Abstract: Novel phosphonate compounds were synthesized via
Base-catalyzed condensation11c and intramolecular cycli-
Michael addition of N-heteroaromatic compounds to aryl- and
zation of C-alkylpyrrole derivatives in the presence of so-
alkyl-substituted vinylphosphonates using scandium triflate as the
catalyst. Intramolecular cyclization reaction of the Michael adducts
dium carbonate11d and sodium hydride10 are effective
obtained gives novel (dimethoxyphosphoryl)pyrrolizin-3-ones in methods for the synthesis of pyrrolizine ring structures.
high yields as a single diastereomer.
Flash vacuum pyrolysis is also an applicable method for
the cyclization of both N-alkyl-9b and C-alkyl-
Key words: phosphonates, pyrrolizinones, Michael addition, metal
triflates, heteroaromatic compounds
substituted11a,b pyrrole derivatives to pyrrolizine ring
structures. The intramolecular Wittig reaction of N-sub-
stituted phosphorus ylides has been used for the synthesis
of functionalized 1H-pyrrolizine derivatives.2b,8a,9a Aryl-
substituted pyrrolizine derivatives have been synthesized
by the intramolecular cyclization of N-alkylpyrrole deriv-
atives in the presence of boron tribromide.7b
Phosphonates1 and pyrrolizines2 have attracted interest
because of their biologically important properties. Deriv-
atives of phosphonates are active as insecticides, herbi-
cides, fungicides, plant growth regulators, and drugs and
they are also effective transition-state-analogue inhibitors
for a variety of enzymes.3 Many synthetic methods for
phosphonate analogues utilize C–C,4 C–P,5 and C–N6
bond-formation processes. Among these, Michael addi-
tion appears to be more successful, since vinylphospho-
nates containing electron-withdrawing groups at the α-
position are potential Michael acceptors.4c The Michael
addition reactions of N-heteroaromatics, e.g. imidazole
and pyridine to bis(phosphono)ethylenes,4f nitroalkanes to
ethyl 2-(diethoxyphosphoryl)acrylate,4g,h indole to dicy-
clohexylammonium 2-(diethoxyphosphoryl)acrylate,4i vi-
nylidene bisphosphonates and vinylphosphonates4j have
been studied. However, to the best of our knowledge, di-
rect addition of pyrrole to vinylphosphonates has not yet
been reported.
In our previous studies we reported that the metal triflates
are suitable catalysts for the addition reactions of pyrrole
to α,β-unsaturated systems.12 We obtained ester- and cya-
no-functionalized pyrrole addition products in high yields
with metal triflates. Among the obtained products, the es-
ter-functionalized dimethyl 2-[phenyl(1H-pyrrolyl)meth-
yl]malonate, methyl 2-cyano-3-phenyl-3-(1H-pyrrol-2-
yl)propanoate and their substituted derivatives gave pyr-
rolizin-3-one structures via intramolecular cyclization re-
actions.10,12b
These results and the above-mentioned importance of
phosphonate analogues encouraged us to search the cata-
lytic addition reaction of N-heteroaromatics to vinylphos-
phonates with metal triflates. The obtained products were
used in intramolecular cyclization reactions (Scheme 1).
Pyrrolizin-3-ones are mainly isolated from plants, insects,
animals, marine organisms, and microbes.7 The biological
activity of pyrrolizines has been attributed to their unique
bridgehead nitrogen skeleton.8 They are used as anti-
inflammatory and analgesic drugs and as aromatase and
tumor inhibitors. Current methods for the construction of
the pyrrolizine skeleton involve intramolecular cycliza-
The Knoevenagel condensation was used for the synthesis
of vinylphosphonates 3a–p from the corresponding alde-
hydes 1a–p and trimethyl phosphonoacetate (2) in toluene
in the presence of acetic acid and piperidine.13 The con-
densation products 3a–p were obtained in 10–86% yields
(Table 1). The configurational assignment for the com-
pounds 3a–p were based on the values of the vicinal cou-
O
R
O
O
OMe
P
OMe
R
NaH
THF
P
N
catalyst
r.t.
R
OMe
Ar
OMe
+
Ar H
OMe
O
OMe
O
P
OMe
OMe
O
Scheme 1
SYNTHESIS 2013, 45, 0193–0198
Advanced online publication: 07.12.2012
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0
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8
8
1
1
4
3
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1
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DOI: 10.1055/s-0032-1317894; Art ID: SS-2012-T0827-OP
© Georg Thieme Verlag Stuttgart · New York

194
D. I. Tasgin, C. Unaleroglu
PAPER
3
pling constant JH,P of the olefinic proton and the ferent N-heteroaromatics to 3a. The results are
phosphorus atom. Nickson reported 3JH,P values of diethyl summarized in Table 2. The addition of pyrrole to substi-
E- and Z-(3,3,3-trifluoroprop-1-enyl)phosphonate as 21 tuted vinylphosphonates 3b–j gave the addition products
Hz for 3Jcis,H,P and 43 Hz for 3Jtrans,H,P 14 In our case, 3JH,P 4b–j in 40–98% yields (entries 2–10). The electron-with-
.
values of the major isomers are in the range of 22.6–26.8 drawing 4-trifluoromethyl substituent did not affect the
Hz, except in the case of 3l where 3JH,P for the major iso- performance of the reaction and 4b was obtained in 98%
mer is 44.0 Hz. According to these values, the configura- yield (entry 2). On the other hand, electron-donating 4-
tions of 3a–k,m–p are assigned as mainly E, and of 3l as methoxy and 4-hydroxy substituents lowered the yield
mainly Z.
and gave the addition products 4d and 4h in 84% and 85%
yields, respectively (entries 4 and 8); 4-methyl, 4-fluoro,
4-chloro, 4-bromo, and 4-cyano substituents gave the
products 4c,e,f,g,i in 62–92% yields (entries 3, 5–7, and
9). The 4-nitro-substituted addition product 4j was ob-
tained with the lowest yield of 40% (entry 10). Sterically
hindered 2,4,6-trimethyl-substituted vinylphosphonate 3k
did not give the addition product 4k (entry 11). Next, we
performed the addition reaction of pyrrole to pyrrol-2-yl-,
2-furyl-, and 2-thienyl-substituted vinylphosphonates
3l–n. Attempts at the addition of pyrrole to these vi-
nylphosphonates were disappointing under the optimized
conditions. We recovered the starting material in all cases
and no addition product was observed. Hereafter to obtain
the addition products 4l–n, the catalytic activities of the
hydrochloric acid, trifluoroacetic acid, Montmorillonite
K-10, and Montmorillonite KSF were investigated. Only
trifluoroacetic acid catalyzed the addition reaction of pyr-
role to 3l and the addition product 4l was obtained in 45%
yield (entry 12). The addition reactions of pyrrole to 2-fu-
ryl- and 2-thienyl-substituted vinylphosphonates 3m,n
were catalyzed by Montmorillonite K-10 in 25% and 30%
yields (entries 13 and 14). However, the addition products
4m and 4n could not be obtained as pure compounds as
they have the same Rf values as the starting materials
3m,n. To test the applicability of this reaction for alkyl-
substituted vinylphosphonates, cyclohexyl- and isobutyl-
substituted vinylphosphonates were selected as α,β-unsat-
urated systems. The addition of pyrrole to 3o and 3p
yielded the corresponding products 4o and 4p with 69%
and 77% yields, respectively (entries 15 and 16). N-Sub-
stituted pyrroles and indole were examined to determine
whether these molecules are viable on the Michael addi-
tions to 3a. When 1-methyl-1H-pyrrole was employed, a
sharp decrease was observed in the yield of the addition
product 4q (entry 17). With 1-phenyl-1H-pyrrole, no ad-
dition product was observed even after 96 hours (entry
18). These results showed that substituents on the pyrrole
nitrogen complicated the reaction. On the indole side, the
addition product 4s was obtained with 99% yield (entry
19). The addition products 4a–j,m–s were obtained as a
mixture of diastereomers. The ratio of diastereomers was
identified by NMR spectroscopy.
Table 1 Knoevenagel Reactions of Trimethyl Phosphonoacetate
with Aldehydes
O
O
OMe
O
OMe
P
P
piperidine, AcOH
toluene, reflux
R
OMe
OMe
3a–p
+
OMe
OMe
R
H
O
O
1a–p
2
Entry
R
Product
Yielda (%) Ratio E/Z
1
2
Ph
3a
3b
3c
3d
3e
3f
55
40
65
35
50
45
50
86
36
30
20
77
70
50
15
10
95:5
4-F3CC6H4
4-MeC6H4
89:11
95:5
3
4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-HOC6H4
4-NCC6H4
4-O2NC6H4
2,4,6-Me3C6H2
pyrrol-2-yl
2-furyl
88:12
87:13
92:8
5
6
7
3g
3h
3i
93:7
8
86:14
89:11
87:13
75:25
31:69
93:7
9
10
11
12
13
14
15
16
3j
3k
3l
3m
3n
3o
3p
2-thienyl
Cy
91:9
93:7
i-Bu
83:17
a Isolated yields after column chromatography.
After obtaining the Michael acceptors 3a–p, we next in-
vestigated the optimum conditions using different metal
triflates in different solvents in a model system; the reac-
tion of pyrrole with the mixture of (E)- and (Z)-3a (Sup-
porting Information, Table S1). The best result (98%
yield) was obtained with 10 mol% scandium triflate in tol-
uene at room temperature with 55:45 diastereomeric ratio.
The same diastereomeric ratios were obtained when addi-
tions of pyrrole to (E)- and (Z)-3a were performed sepa-
rately, indicating that E- and Z-isomers have no impact on
the diastereoselectivity. With the optimized conditions in
hand, we performed the addition reaction of pyrrole to vi-
nylphosphonates 3b–p and the addition reactions of dif-
We then carried out several experiments to determine
whether the diastereoselectivity is kinetically or thermo-
dynamically controlled. The effect of temperature on the
ratio of diastereomers was investigated by performing the
addition reaction of pyrrole to 3g at different tempera-
tures. The products were obtained with 40:60, 48:52, and
49:51 ratios at –70 °C, room temperature, and 100 °C, re-
Synthesis 2013, 45, 193–198
© Georg Thieme Verlag Stuttgart · New York

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Michael Addition to Vinylphosphonates and Phosphonylpyrrolizones
195
Table 2 Addition Reaction of N-Heteroaromatics to Vinylphosphonates
O
R
O
P
OMe
OMe
OMe
OMe
P
R
Sc(OTf)3, toluene
r.t.
Ar
+
Ar
H
O
OMe
O
OMe
3a–p
4a–s
Entry
R
Ar
Product
Yielda (%)
dr
1
2
Ph
pyrrol-2-yl
4a
4b
4c
4d
4e
4f
98
98
92
84
62
78
86
85
72
40
-
55:45
61:39
51:49
55:45
65:35
53:47
51:49
56:44
54:46
52:48
-
4-F3CC6H4
4-MeC6H4
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
pyrrol-2-yl
3
4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-HOC6H4
4-NCC6H4
4-O2NC6H4
2,4,6-Me3C6H2
pyrrol-2-yl
2-furyl
5
6
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
4j
4k
4lb
45
25
30
69
77
58
–
-
4mc
4nc
81:19
66:34
61:39
67:33
57:43
–
2-thienyl
Cy
4o
4p
4q
4r
4s
i-Bu
Ph
1-methylpyrrol-2-yl
1-phenylpyrrol-2-yl
indol-3-yl
Ph
Ph
99
60:40
a Isolated yields after column chromatography.
b Reaction was performed with 10% TFA in excess pyrrole.
c Reactions were performed with 0.093 g Montmorillonite K-10 in excess pyrrole and the products could not be purified for further reactions.
spectively. These results indicated that temperature of sodium hydride lowered the yield of the cyclization
change has no clear effect on diastereoselectivity and for- product 5a (entries 2–7). When the intramolecular cycli-
mation of the addition product is thermodynamically con- zation reactions of 4b–j,l–p were performed under opti-
trolled.
mum conditions [NaH (1.5 equiv), THF, r.t.], the 4-
(trifluoromethyl)-, 4-methyl-, 4-methoxy-, 4-fluoro-, 4-
chloro-, 4-bromo-, and 4-cyanophenyl-, pyrrol-2-yl-, 2-
furyl-, 2-thienyl-, cyclohexyl-, and isobutyl-substituted
cyclization products 5b–g,i,l–p were obtained in high
yields (74–99%) and as single diastereomers (entries 8–
13, 15, 17–21). 4-Hydroxy and 4-nitro substituents on the
phenyl ring lowered the yield of the cyclization products
5h and 5j to 44% and 45%, respectively (entries 14 and
16). The configuration of the phosphorylpyrrolizones 5a–
j,l–p could be assigned from their 3JH,H values. In our pre-
vious study, we demonstrated that 3-oxo-1-phenyl-2,3-di-
hydro-1H-pyrrolizine-2-carbonitrile derivatives had trans
The obtained addition products 4a–j,l–p appear to be suit-
able compounds for the synthesis of dimethoxyphospho-
ryl-substituted pyrrolizin-3-ones through intramolecular
cyclization of the pyrrole nitrogen. We next turned our at-
tention to the intramolecular cyclization of the addition
products 4a–j,l–p with sodium hydride. The intramolecu-
lar cyclization reaction of 4a was performed as a model
reaction with 1.5 equivalents of sodium hydride in tetra-
hydrofuran at room temperature. The cyclization product
5a was obtained as single diastereomer with 81% yield
(Table 3, entry 1). Performing the reaction in different sol-
vents, at different temperatures and with various amounts
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 193–198

196
D. I. Tasgin, C. Unaleroglu
PAPER
(Scheme 2). The methyl group at C2 in dimethyl 1-(4-bro-
mophenyl)-2-methyl-3-oxo-2,3-dihydro-1H-pyrrolizin-
2-ylphosphonate (6) indicated that epimerization took
place under the applied reaction conditions. Consequent-
ly, after epimerization the thermodynamically more stable
trans products 5a–j,l–p are formed. The structures and
diastereomeric ratios of both the addition and the cycliza-
Table 3 Intramolecular Cyclization Reaction of 4a–j,l–p
R
O
P
OMe
OMe
R
N
NaH
OMe
N
H
O
P
O
OMe
OMe
O
4a–j,l–p
R
5a–j,l–p
1
tion products were identified by H, 13C, and 31P NMR
spectroscopic techniques.
Entry
Product Solvent Temp Ratio 4a– Yielda
(°C)
j,l–p/NaH (%)
Br
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5a
5a
5a
5a
5a
5a
5b
5c
THF
r.t.
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:2
81
57
49
55
33
78
39
99
98
98
74
88
99
44
87
45
99
92
96
99
65
Br
toluene r.t.
CH2Cl2 r.t.
O
NaH, THF
N
OMe
OMe
3
P
MeI, 0 °C to r.t.
O
P
OMe
OMe
N
4
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
0
50
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
O
H
O
OMe
5
6
4g
6
Scheme 2
7
1:1
8
4-F3CC6H4
4-MeC6H4
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
Commercially available reagents and solvents were used without
further purification. H NMR (400 MHz), 13C NMR (100 MHz),
1
9
and 31P NMR (162 MHz) spectra were recorded using TMS or
H3PO4 as an internal reference with a Bruker 400 FT NMR spec-
trometer. Peaks that represent both the major and minor diastereo-
mers are indicated by *. Square brackets indicate peaks arising from
the minor diastereomer, where applicable. Infrared spectra were re-
corded by ATR (Nicolet İS10). HRMS were recorded on a Agilent
(1200/6210) TOF LC/MS spectrometer. Melting points were re-
corded on Gallenkamp melting-point apparatus. Reactions were
monitored by TLC using precoated silica plates (Kieselgel 60,
F254, E. Merck), visualized with UV light. Flash column chroma-
tography was performed by using silica gel (0.05–0.63 mm, 230–
400 mesh ASTM, E. Merck).
10
11
12
13
14
15
16
17
18
19
20
21
4-MeOC6H4 5d
4-FC6H4
5e
5f
4-ClC6H4
4-BrC6H4
4-HOC6H4
4-NCC6H4
5g
5h
5i
4-O2NC6H4 5j
In this experimental section procedures are given for the formation
of 3a–p, 4a–j,l–q,s, 5a–j,l–p, and 6, however, physical and spectro-
scopic data are only given for one example. Physical and spectro-
scopic data for compounds 3a15 and 3f16 correspond to those given
in the literature. Compounds 3b–e,g–p, 4a–j,l–q,s, 5a–j,l–p, and 6
are novel and their physical and spectroscopic data are given in the
Supporting Information.
pyrrol-2-yl
2-furyl
2-thienyl
Cy
5l
5m
5n
5o
5p
Methyl 3-Aryl-2-(dimethoxyphosphoryl)acrylates 3a–p; Gener-
al Procedure
i-Bu
a Isolated yields after column chromatography.
Triethyl phosphonoacetate (2, 2.08 mmol) and aldehyde 1a–p (2.35
mmol) were dissolved in toluene (10 mL) and piperidine (0.062
mmol) and AcOH (0.033 mmol) were added to this soln. The result-
ing mixture was refluxed under a Dean–Stark trap for 8 h (TLC
monitoring). After the completion of the reaction, the solvent was
removed under reduced pressure and the residue was purified by
flash column chromatography (silica gel, EtOAc–hexane, 1:1).
configuration if the vicinal coupling constant of the hy-
drogens was in the range 4.8–6.4 Hz and cis configuration
if the vicinal coupling constant was in the range of 8.2–8.8
Hz.10 In this work, the vicinal coupling constants of the
hydrogens of 5a–j,l–p are between 4.0–4.4 Hz. As the
vicinal coupling constants of 5a–j,l–p are in good agree-
Methyl (E/Z)-2-(Dimethoxyphosphoryl)-3-phenylacrylate (3a)15
Colorless viscous oil; yield: 309 mg (55%); ratio E/Z 95:5; Rf = 0.20
(EtOAc–hexane, 1:1).
ment with the coupling constants previously correlated IR (ATR): 3007, 2956, 2854, 1743, 1613, 1566, 1436, 1255, 1211,
1006, 861, 746 cm–1.
with trans configurations, the novel phosphorylpyrroli-
1H NMR (400 MHz, CDCl3): δ = 3.60 (s, 3 H, OCH3, Z), 3.63 (s, 3
H, OCH3, Z), 3.82 (s, 3 H, OCH3, E), 3.84 (s, 3 H, OCH3, E), 3.87
(s, 3 H, OCH3, E), 3.91 (s, 3 H, OCH3, Z), 7.37–7.45 (m, 8 H, ArH,
E and Z), 7.61–7.65 (m, 2 H, ArH, Z), 7.70 (d, 3JP,H = 24.2 Hz, 1 H,
CH=C, E), 8.28 (d, 3JP,H = 44.1 Hz, 1 H, CH=C, Z).
zones 5a–j,l–p are also assigned as trans. An experiment
was designed to understand why only the trans diastereo-
isomer is formed in all cases. In this experiment, the reac-
tion of 4g with sodium hydride in the presence of
iodomethane in tetrahydrofuran was investigated
Synthesis 2013, 45, 193–198
© Georg Thieme Verlag Stuttgart · New York

PAPER
Michael Addition to Vinylphosphonates and Phosphonylpyrrolizones
197
13C NMR (100 MHz, CDCl3): δ = 52.4 (E and Z), 52.9 (E and Z),
53.0 (E and Z), 122.6 (d, 1JP,C = 180.0 Hz, E and Z), 128.5 (E and
Z), 128.9 (E and Z), 130.4 (E and Z), 133.2 (d, 3JP,C = 19.8 Hz, E and
Z), 149.0 (d, JP,C = 6.2 Hz, E and Z), 166.5 (d, JP,C = 12.6 Hz, E
and Z).
6.50 (br s, 1 H, Hpyrrole), 6.60 (br s, 1 H, Hpyrrole), 10.49 (br s, 1 H,
NH), 10.55 (br s, 1 H, NH).
1
13C NMR (100 MHz, DMSO-d6): δ = 37.1, 50.7 (d, JP,C = 129.2
2
2
2
2
Hz), 52.5, 52.9 (d, JP,C = 6.7 Hz), 53.2 (d, JP,C = 6.4 Hz), 104.7,
106.4, 107.3, 107.4, 116.9, 117.5, 132.0, 132.2, 168.5 (d, 2JP,C = 4.3
Hz).
31P NMR (162 MHz, CDCl3): δ = 14.7 (Z), 17.1 (E).
HRMS (ESI): m/z [M + H]+ calcd for C12H16O5P: 271.0735; found:
31P NMR (162 MHz, DMSO-d6): δ = 24.1.
271.0705.
HRMS (ESI): m/z [M + H]+ calcd for C14H20N2O5P: 327.1109;
found: 327.1116.
Methyl 2-(Dimethoxyphosphoryl)-3-phenyl-3-(1H-pyrrol-2-
yl)propanoate (4a); Typical Procedure
Dimethyl 3-Oxo-1-phenyl-2,3-dihydro-1H-pyrrolizin-2-ylphos-
phonate (5a); Typical Procedure
To a soln of methyl (E/Z)-2-(dimethoxyphosphoryl)-3-phenylacry-
late (3a, 0.093 mmol) in toluene (2 mL) at r.t. was added Sc(OTf)3
(0.0093 mmol, 10 mol%) and the mixture was stirred for 0.5 h. Pyr-
role (0.93 mmol) was added to the mixture instantly via syringe
pump. The resulting mixture was stirred at r.t. for 48 h (TLC moni-
toring). Metal triflate was removed from the reaction medium by
subjecting the mixture to a short flash column chromatography (sil-
ica gel, EtOAc). The eluent was removed under reduced pressure
and the residue was purified by flash column chromatography (sili-
ca gel, EtOAc–hexane, 1:1 or 4:1) to give a light brown powder;
yield: 31 mg (98%); dr 55:45; mp 173.8–174.8 °C; Rf = 0.13
(EtOAc–hexane, 1:1).
Methyl 2-(dimethoxyphosphoryl)-3-phenyl-3-(1H-pyrrol-2-yl)pro-
panoate (4a, 0.074 mmol) was dissolved in THF (2 mL) and NaH
(0.111 mmol) was added to the soln at 0 °C. The resultant mixture
was stirred at r.t. for 2 h (TLC monitoring). After completion of the
reaction pH 7 phosphate buffer (5 mL) was added to the mixture and
the product was extracted with EtOAc (3 × 10 mL) and dried
(MgSO4). The solvent was removed under reduced pressure and the
residue was purified by flash column chromatography (silica gel,
EtOAc–hexane, 1:1) to give a light yellow powder; yield: 18 mg
(81%); mp 71.2–72.1 °C; Rf = 0.27 (EtOAc–hexane, 1:1).
IR (ATR): 2952, 2925, 2893, 2838, 1751, 1593, 1558, 1499, 1479,
1389, 1286, 1251, 1192, 1026, 888, 829, 810, 687, 601 cm–1.
IR (ATR): 3260, 3007, 2948, 2849, 1731, 1570, 1495, 1439, 1264,
1234, 1209, 1030, 805, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.45 (dd, JH,H = 4.0 Hz,
3
1H NMR (400 MHz, CDCl3): δ = 3.33–3.42 (m, 12 H, 4 OCH3)*,
2JP,H = 24.8 Hz, 1 H, CH), 3.75 (d, 3JP,H = 10.5 Hz, 3 H, OCH3), 3.78
3
3.56 (s, 3 H, OCH3), [3.65 (d, JP,H = 11.1 Hz, 3 H, OCH3)], 3.75
3
3
(d, JP,H = 10.4 Hz, 3 H, OCH3), 4.79 (dd, JH,H = 4.0 Hz,
(dd, 3JH,H = 6.2 Hz, 2JP,H = 21.3 Hz, 1 H, CH), [3.77 (dd, 3JH,H = 5.2
Hz, 2JP,H = 21.7 Hz, 1 H, CH)], 4.57–4.73 (m, 2 H, 2 CH)*, [5.80 (br
s, 1 H, Hpyrrole)], 5.97–6.08 (m, 3 H, 3 Hpyrrole)*, 6.60 (br s, 2 H, 2
3JP,H = 16.8 Hz, 1 H, CH), 5.90–5.91 (m, 1 H, Hpyrrole), 6.46 (t,
3JH,H = 3.2 Hz, 1 H, Hpyrrole), 7.05 (d, JH,H = 3.2 Hz, 1 H, Hpyrrole),
3
7.15–7.28 (m, 5 H, ArH).
Hpyrrole)*, 7.12–7.25 (m, 10 H, ArH)*, 8.66 (br s, 1 H, NH), [9.17 (br
13C NMR (100 MHz, CDCl3): δ = 40.1 (d, 2JP,C = 1.4 Hz), 52.3 (d,
s, 1 H, NH)].
2JP,C = 6.7 Hz), 53.1 (d, JP,C = 6.5 Hz), 54.6 (d, JP,C = 137.5 Hz),
105.3, 110.8, 118.9, 126.2, 126.8, 128.0, 139.5 (d, 3JP,C = 7.0 Hz),
140.0 (d, 3JP,C = 4.0 Hz), 164.5 (d, 2JP,C = 3.7 Hz).
2
1
13C NMR (100 MHz, CDCl3): δ = 43.2 (d, 2JP,C = 2.6 Hz), [43.8 (d,
1
1
2JP,C = 3.0 Hz)], 51.2 (d, JP,C = 131.5 Hz), [52.2 (d, JP,C = 132.3
2
Hz)], 52.4, [52.8], 53.0 (d, JP,C = 6.6 Hz), [53.2], 53.3, [53.6 (d,
31P NMR (162 MHz, CDCl3): δ = 22.4.
HRMS (ESI): m/z [M + H]+ calcd for C15H17NO4P: 306.0890;
2JP,C = 7.1 Hz)], 106.7, [107.5], 108.1, [108.4], [117.3], 117.7,
[127.1], 127.2, 127.9*, 128.3*, 128.5*, 130.1, [130.7 (d, 3JP,C = 8.3
Hz)], 140.3 (d, 3JP,C = 4.0 Hz), [140.5], [168.0 (d, 2JP,C = 4.8 Hz)],
169.3 (d, 2JP,C = 4.4 Hz).
found: 306.0885.
Dimethyl 1-(4-Bromophenyl)-2-methyl-3-oxo-2,3-dihydro-1H-
pyrrolizin-2-ylphosphonate (6)
31P NMR (162 MHz, CDCl3): δ = 23.5, [25.5].
HRMS (ESI): m/z [M + H]+ calcd for C16H21NO5P: 338.1152;
Methyl 3-(4-bromophenyl)-2-(dimethoxyphosphoryl)-3-(1H-pyr-
rol-2-yl)propanoate (4g, 0.074 mmol) was dissolved in THF (2 mL)
and MeI (0.081 mmol) was added. Then NaH (0.111 mmol) was
added to this soln at 0 °C. The resultant mixture was stirred at r.t.
for 1 h (TLC monitoring). After completion of the reaction, pH 7
phosphate buffer (5 mL) was added to the mixture and the product
was extracted with EtOAc (3 × 10 mL) and dried (MgSO4). The sol-
vent was removed under reduced pressure and the residue was puri-
fied by flash column chromatography (silica gel, EtOAc–hexane,
1:1) to give a light yellow viscous oil; yield: 14 mg (60%); Rf = 0.57
(EtOAc–hexane, 2:1).
found: 338.1127.
Methyl 2-(Dimethoxyphosphoryl)-3-(1H-pyrrol-2-yl)propano-
ates 4l–n; General Procedure
Vinylphosphonate 3l–n (0.093 mmol) was dissolved in excess pyr-
role (3.72 mmol) and catalyst [TFA (0.0093 mmol) or Montmoril-
lonite K-10 (0.093 g)] was added to the mixture at r.t.. The resulting
mixture was stirred at r.t. for 48 h (TLC monitoring). The catalyst
was removed from the reaction medium by subjecting the mixture
to short flash column chromatography (silica gel, EtOAc). The elu-
ent was removed under reduced pressure and the residue was puri-
fied by flash column chromatography (silica gel, EtOAc–hexane,
4:1).
IR (ATR): 2954, 2923, 2890, 1752, 1595, 1557, 1493, 1477, 1387,
1285, 1190, 1023, 889, 687, cm–1.
3
1H NMR (400 MHz, CDCl3): δ = 1.81 (d, JP,H = 15.6 Hz, 3 H,
Methyl 2-(Dimethoxyphosphoryl)-3,3-di(1H-pyrrol-2-yl)pro-
panoate (4l)
Light yellow powder; yield: 14 mg (45%); mp 168.5–169.7 °C;
Rf = 0.44 (EtOAc).
CH3), 3.25 (d, 3JP,H = 11.1 Hz, 3 H, OCH3), 3.63 (d, 3JP,H = 9.0 Hz,
3
3 H, OCH3), 4.37 (d, JP,H = 17.1 Hz, 1 H, CH), 5.97 (br s, 1 H,
H
pyrrole), 6.55 (t, 3JH,H = 3.1 Hz, 1 H, Hpyrrole), 7.14 (d, 3JH,H = 3.1 Hz,
1 H, Hpyrrole), 7.33 (d, 3JH,H = 8.4 Hz, 2 H, ArH), 7.45 (d, 3JH,H = 8.4
IR (ATR): 3255, 2968, 2836, 1737, 1638, 1520, 1443, 1358, 1226,
1120, 1025 cm–1.
Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 20.2 (d, 3JP,C = 4.9 Hz), 50.7, 52.5
1H NMR (400 MHz, DMSO-d6): δ = 3.21 (d, 3JP,H = 10.8 Hz, 3 H,
2
2
1
(d, JP,C = 7.2 Hz), 54.1 (d, JP,C = 7.0 Hz), 58.6 (d, JP,C = 137.7
Hz), 106.0, 112.2, 119.5, 122.0, 129.6, 131.8, 135.4 (d, 3JP,C = 5.4
Hz), 138.5 (d, 3JP,C = 2.0 Hz), 169.5 (d, 2JP,C = 3.1 Hz).
OCH3), 3.43 (s, 3 H, OCH3), 3.47 (d, 3JP,H = 10.8 Hz, 3 H, OCH3),
3
2
4.03 (dd, JH,H = 12.4 Hz, JP,H = 19.6, 1 H, CH), 4.63 (dd,
3JH,H = 10.0 Hz, 3JP,H = 12.0, 1 H, CH), 5.80 (br s, 1 H, Hpyrrole), 5.84
(br s, 1 H, Hpyrrole), 5.89 (br s, 1 H, Hpyrrole), 5.96 (br s, 1 H, Hpyrrole),
31P NMR (162 MHz, CDCl3): δ = 22.6.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 193–198

198
D. I. Tasgin, C. Unaleroglu
PAPER
Phosphorus, Sulfur Silicon Relat. Elem. 2002, 177, 137.
HRMS (ESI): m/z [M + H]+ calcd for C16H18BrNO4P: 398.0151;
found: 398.0154.
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Acknowledgment
The authors thank Hacettepe University for financial support (BAP
project 011D10601006).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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© Georg Thieme Verlag Stuttgart · New York