Synthesis of 2-phosphonopyrroles via a one-pot RCM/oxidation sequence

Article abstract of DOI:10.1021/jo060160e

A four-step synthesis of 2-phosphonopyrroles is presented starting from suitable aldehydes. The key step in the synthesis involves a one-pot ring-closing metathesis/oxidation sequence of a functionalized α-aminoalkenyl phosphonate. Notwithstanding the pre

Full text of DOI:10.1021/jo060160e

example was presented in which a BOC-protected 3-oxo-2-
phosphonopyrrolidine was converted to the corresponding
3-hydroxy-2-phosphonopyrrole by treatment with trifluoroacetic
acid.7 On the other hand, addition of enolates and enamines to
phosphonoazoalkenes8 or addition of cyano methylphosphonate
anion to azoalkenes9 was shown to lead to 3-phosphonopyrroles.
Finally, only one example of a meta-mediated ring closure
between an alkyne and a C-N double bond using Pd has been
reported.10 However, since the discovery and development of
practical useful ruthenium-based metathesis catalysts in the past
decennium,11 ring-closing metathesis (RCM) has found wide
application in the synthesis of complex (hetero)cyclic com-
pounds.12 Furthermore, an increasing interest exists in combining
ring-closing metathesis with a second reaction step in order to
obtain complex, highly functionalized molecules in a one-pot
reaction.13 The use of RCM to form heteroaromatic compounds,
however, has only recently appeared in the literature.14 In this
paper, we present the synthesis of N-benzyl-2-phosphono-3-
pyrrolines via RCM starting from functionalized R-aminoalkenyl
phosphonates and their in situ conversion to the corresponding
2-phosphonopyrroles by tetrachloroquinone (TCQ).
Synthesis of 2-Phosphonopyrroles via a One-Pot
RCM/Oxidation Sequence
Kristof Moonen, Nicolai Dieltiens, and Christian V. Stevens*
Research Group SynBioC, Department of Organic Chemistry,
Faculty of Bioscience Engineering, Ghent UniVersity,
Coupure links 653, B-9000 Ghent, Belgium
chris.steVens@ugent.be
ReceiVed January 24, 2006
R,â-Unsaturated N-allylaldimines 1 are phosphonylated with
complete regioselectivity15 using a modified Pudovik reaction
(4) (a) Ivonin, S. P.; Tolmachev, A. A.; Terikovska, T. E.; Anischchenko,
A. A.; Chaikovskaya, A. A., Pinchuk, A. M. Heteroatom Chem. 2003, 14,
258. (b) Quin, L. D.; Marsi, B. G. J. Am. Chem. Soc. 1985, 107, 3389. (c)
Griffin, C. E.; Peller, R. P.; Peters, J. A. J. Org. Chem. 1965, 30, 91.
(5) (a) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am. Chem. Soc.
2005, 127, 9263. (b) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. Tetrahedron
Lett. 2005, 46, 2563. (c) Berre´e, F.; Marchand, E. Morel, G. Tetrahedron
Lett. 1992, 33, 6155.
(6) (a) Huang, W.-S.; Zhang, Y.-X.; Yuan, C. J. Chem. Soc., Perkin
Trans. 1 1996, 1893. (b) Ngwe, H.; Kinoshita, H.; Inomata, K. Bull. Chem.
Soc. Jpn. 1994, 67, 3320. (c) Yuan, C.; Huang, W. Synthesis 1993, 473.
(7) Davis, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523.
(8) (a) Palacios, F.; Aparicio, D.; de los Santos, J. Tetrahedron 1999,
55, 13767. (b) Haelters, J.-P.; Corbel, B.; Sturtz, G. Phosphorus, Sulfur,
Silicon Relat. Elem. 1989, 44, 53.
A four-step synthesis of 2-phosphonopyrroles is presented
starting from suitable aldehydes. The key step in the synthesis
involves a one-pot ring-closing metathesis/oxidation sequence
of a functionalized R-aminoalkenyl phosphonate. Notwith-
standing the presence of a nucleophilic nitrogen atom and
high substitution patterns in the substrate, the results of the
RCM reaction are excellent using mild reaction conditions.
Furthermore, a synergism is observed between the RCM
catalyst and the oxidizing agent, causing higher oxidation
rates and allowing reaction for substrates that normally fail
to ring close under standard RCM conditions.
(9) Attanasi, O. A.; De Crescentini, L.; Foresti, E.; Gatti, G.; Giorgi, R.;
Perrulli, F. R.; Santeusanio, S. J. Chem. Soc., Perkin Trans. 1 1997, 1829.
(10) Palacios, F.; Aparicio, D.; de los Santos, J. M.; Vicario, J.
Tetrahedron 2001, 57, 1961.
(11) For reviews concerning recent developments in design of ruthenium
metathesis catalysts, see: (a) Dragutan, I.; Dragutan, V.; Filip, P. ArkiVoc,
2005, x, 105. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013.
(12) (a) Nicolau, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490. (b) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004,
104, 2127. (c) Phillips, A. J.; Abell, A. D. Aldrichim. Acta 1999, 32, 75.
(d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. For a recent
review on the use of RCM for the synthesis of nitrogen-containing
heterocycles, see: (e) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104,
2199.
(13) (a) van Otterlo, W. A. L.; Coyanis, E.; Mabel, E.; Panayides, J.-L.;
de Koning, C. B.; Fernandes, M. A. Synlett 2005, 501. (b) van Otterlo, W.
A. L.; Morgans, G. L.; Madeley, L. G.; Kuzvidza, S.; Moleele, S. S.;
Thornton, N.; de Koning, C. B. Tetrahedron 2005, 61, 7746. (c) Schmidt,
B. J. Org. Chem. 2004, 69, 7672. (d) Lee, H.-Y.; Kim, H. Y.; Tae, H.;
Kim, B. G.; Lee, J. Org. Lett. 2003, 5, 3439. (e) Grigg, R.; Hodgson, A.;
Morris, J.; Sridharan, V. Tetrahedron Lett. 2003, 44, 1023. (f) Kinderman,
S. S.; Van Maarseven, J. H.; Schoenmaker, H. E.; Hiemstra, H.; Rutjes, F.
P. J. T. Org. Lett. 2001, 3, 2045. (g) Evans, P.; Grigg, R.; Ramzan, M. I.;
Sridharan, V.; York, M. Tetrahedron Lett. 1999, 40, 3021.
Phosphonylated azaheterocycles are an important class of
compounds with high biological potential as conformationally
restricted bioisosteres of amino acids.1 During our research2 in
this area, we became interested in phosphonopyrroles as the
well-known biological properties of pyrroles3 may be enhanced
by the presence of a phosphonate group. Only a limited amount
of research on the synthesis of these compounds has been
performed. 2-Phosphonopyrroles can be obtained through direct
phosphorylation of a pyrrole nucleus, but only in low to
moderate yields.4 Nitrile ylides containing an electron-with-
drawing phosphonate group have been reacted with alkynes5
or alkenes containing a suitable leaving group6 to yield
2-phosphonopyrroles via a 1,3-dipolar cycloaddition. One
(1) The topic of nonaromatic phosphonylated azaheterocycles has been
reviewed recently: Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. ReV.
2004, 104, 6177.
(2) (a) Moonen, K.; Stevens, C. V. Synthesis 2005, 3603. (b) Vander-
hoydonck, B.; Stevens, C. V. J. Org. Chem. 2005, 70, 191.
(3) The Synthesis, ReactiVity, and Physical Properties of Substituted
Pyrroles; Alan Jones, R., Ed.; Pyrroles; John Wiley & Sons:New York,
1992; Vol. 48, Part 2, p 640.
(14) (a) Donohoe, T. J.; Orr, A. J.; Gosby, K.; Bingham, M. Eur. J.
Org. Chem. 2005, 1969 (and references therein). (b) Evanno, L.; Nay, B.;
Bodo, B. Synth. Commun. 2005, 35, 1559.
(15) We reported recently that regioselectivity in phosphite additions to
R,â-unsaturated imines is very dependent on the type of reagent used:
Moonen, K.; Van Meenen, E.; Verwe´e, A.; Stevens, C. V. Angew. Chem.,
Int. Ed. 2005, 44, 7407.
10.1021/jo060160e CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/11/2006
4006
J. Org. Chem. 2006, 71, 4006-4009

amides, carbamates, sulfonamides...).12b,c,e Failure of RCM
reactions with substrates containing a nucleophilic nitrogen atom
adjacent to the metathesized alkene is often attributed to
poisoning of the catalyst or to disfavored conformation of the
substrate.17 The poisoning of the catalyst was possibly avoided
in our case because of the presence of the electron-withdrawing
phosphonate group, which reduced the nucleophilic properties
of the amine.
SCHEME 1
Furthermore, in case of R1 phenyl, styrene is formed during
the ring-closing reaction, which unlike ethene does not boil off
from the reaction mixture. Liberation of ethene from the reaction
mixture is often indicated as the driving force in RCM reactions.
A closer look to the crude 1H NMR spectrum revealed, however,
the presence of stilbene, which could also be obtained as
colorless crystals from the reaction mixture. Stilbene is probably
formed together with ethene via cross-metathesis of styrene in
a second catalytic cycle (Scheme 2) and is easily removed during
the subsequent chromatographic purification. It should be noted
that two active species of the catalyst are present in the reaction
mixture: carbene 9, which is presented as the propagating
species in the general Chauvin mechanism,18 and Grubbs’
carbene 8, which is regenerated during the catalytic cycle in
this case. While substituted double bounds are often not well
tolerated by ruthenium-based catalysts,19 R1 (Ph or Me) and R2
groups are very well tolerated in our case, even under very mild
conditions. However, when phosphonate 3g (R3 ) Me) was
selected as a substrate in the RCM reaction, no reaction occurred
at all and the starting material was recovered, even under reflux
in CH2Cl2 or benzene. When switching to refluxing in chlo-
robenzene as a solvent, 31P NMR showed the disappearance of
the starting material and the simultaneous appearance of a signal
at 10.4 ppm. Upon workup, this signal proved to be the
corresponding enaminophosphonate resulting from the migration
of the double bond toward the phosphonate. These observations
indicated that the RCM reaction is most likely initiated via the
least hindered double bond and that the following intramolecular
conversions are less dependent on the steric bulk of the olefin.
When two substituted double bonds are present in the molecule,
the initiation seems to be delayed to such a large extent that no
reaction is possible anymore.19
TABLE 1. Synthesis of Phosphonates 2-5
R1
R2
R3
2a (%)
3b (%)
4a (%)
5b (%)
a
b
c
d
e
f
Ph
Ph
H
Me
Bn
isoamyl
Ph
H
H
H
H
H
H
Me
95
90
27
88c
80c
44
74
61
50
50
54c
35c
92
86
44
58
62
70
54d
75
84
72
70
75
71
Me
Ph
Me
Me
Ph
CH2CH2Ph
H
g
a Yield after acid/base extraction. b Yield after column chromatography.
c Mixture of E and Z isomers. d Spontaneous oxidation to pyrrole 5e using
air was observed during workup.
(Scheme 1).16 The R-aminoalkenyl phosphonates are obtained
in high yield and purity after a simple acid/base extraction (Table
1). Benzylation was performed using 1.5 equiv of benzyl
bromide in acetone and an excess of K2CO3 as a base. Complete
conversion usually occurs in 16-20 h at reflux temperature,
giving clean mixtures of N-benzylated phosphonates 3 and
benzyl bromide. The reaction speed can be increased by adding
catalytic amounts of sodium iodide (5-10 h) or by using
microwave heating. Opposite to phosphonates 2, N-benzylami-
noalkenyl phosphonates 3 could not be isolated using an acid/
base extraction, probably indicating decreased base character-
istics of the substrate. The phosphonates 3 could be obtained
in pure form via column chromatography; however, considerable
product losses resulted.
The obtained aminoalkenyl phosphonates 3 were treated with
Grubbs’ second-generation catalyst 6, and the reaction was easily
monitored using 31P NMR. Pyrrolines 4 were formed very
smoothly at room temperature in dichloromethane as a single
reaction product (δ31P ) 24.58-24.91 ppm). Most examples
of azaheterocyclic ring formation via RCM presented in the
literature deal with non-nucleophilic nitrogen groups (e.g.,
After complete conversion of the starting amino phosphonates
3 (3-5 h at room temperature),20 the phosphonopyrrolines 4
could be obtained in pure form as a colorless oil via an acid/
base extraction of the reaction mixture, which illustrated the
basic properties of the pyrroline. Pyrroline 4f could not be
isolated. Instead, 1-benzyl-3-(2-phenylethyl)-1H-pyrrole was
formed due to aromatization through elimination of the phos-
phonate group during workup. This side reaction was not
observed in any of the other cases.
To obtain phosphonopyrroles 5, the use of tetrachloroquinone
(TCQ) has already proven effective in combination with catalyst
(17) (a) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871. (b) Le
Flohic, A.; Meyer, C.; Cossy, J.; Desmurs, J.-R. Tetrahedron Lett. 2003,
44, 8577. (c) Briot, A.; Bujard, M.; Gouverneur, V.; Nolan, S. P.;
Mioskowski, C. Org. Lett. 2000, 2, 1517. (d) Fu¨rstner, A.; Thiel, O. R.;
Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204.
(e) Campagne, J.-M.; Ghosez, L. Tetrahedron Lett. 1998, 39, 6175. (f)
Rutjes, F. P.; Schoemaker, H. E. Tetrahedron Lett. 1997, 38, 677. (g) Shon,
Y.-S.; Lee, T. R. Tetrahedron Lett. 1997, 38, 1283.
(18) He´risson, J.-L.; Chauvin, Y. Macromol. Chem. 1971, 141, 161.
(19) Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912 and references
therein.
(20) In case of phosphonate 3e, complete conversion to pyrroline 4e
needed 3 h at reflux temperature. Complete conversion to pyrrole 5e was
obtained after 5 h at reflux followed by 12 h at room temperature.
(16) Van Meenen, E.; Moonen, K.; Acke, D.; Stevens, C. V. ArkiVoc
2006, i, 31.
J. Org. Chem, Vol. 71, No. 10, 2006 4007

SCHEME 2
6.21 When phosphonates 3 are treated with catalyst 6 and 1 equiv
of TCQ, the expected pyrroles 5 are formed as a single reaction
product (δ31P ) 13-15 ppm) after stirring for up to 16 h at
room temperature. By monitoring the reaction using 31P NMR,
a minor decrease of the RCM reaction rate was observed by
the action of TCQ. When catalyst 6 was allowed to react for 2
h with the substrate (giving approximately 60% conversion to
the pyrroline) before the addition of TCQ, the pyrroles were
obtained after 5-7 h at room temperature.20
SCHEME 3
A mechanism for this ring-closing metathesis with in situ
oxidative aromatization has already been proposed before.21 No
ruthenium is really required for the oxidation,22 as pure 4b and
4c are also converted to the corresponding pyrroles 5b,c by
stirring with TCQ at room temperature for 22 h. However, this
is considerably slower than in the presence of catalyst 6. Two
reaction pathways may be considered to explain these results:
(a) hydrogen atoms are transferred in the process of oxidative
addition and reductive elimination which involves hydride
complexes or (b) hydrogen donor and acceptor are brought
together by simultaneous coordination to the central metal of
the catalyst, followed by direct transfer of the hydrogen atoms
from the pyrroline to the TCQ.23 In light of the mild reaction
conditions in combination with the fact that no pyrrole formation
is observed in the absence of TCQ, the assumption that
hydrogens are transferred via pathway (b) seems to be reason-
able.
When the reaction was monitored using 31P NMR, decreasing
reaction rates were observed in connection to reaction time, and
a maximum conversion of only 30% was reached. This kind of
behavior suggests catalyst inhibition by the pyrroline 10a,d
rather than by the starting material 2a,d (Scheme 3). When TCQ
was added together with catalyst 6, the formed pyrroline was
oxidized immediately in the reaction mixture, and 100%
conversion to the pyrrole 11a,d took place at reflux temperature
in dichloromethane in 23 h or in benzene in 7 h. The reaction
mixture was much less clean than in the case of the N-benzyl
substrates 3, and pyrroles 11 could only be obtained in low
yields after a laborious chromatographic purification. Neverthe-
less, the reaction sequence clearly illustrates the synergism
between ruthenium mediated ring-closing metathesis and oxida-
tion by TCQ. Furthermore, the failure of RCM reactions with
substrates containing a NH functionality should be attributed
to its nucleophilic properties rather than to the need of a proper
conformation for ring closure.
With these excellent RCM results in hand, we tried to ring
close phosphonates 3a and 3d possessing a free NH group.
(21) Dieltiens, N.; Stevens, C. V.; Allaert, B.; Verpoort, F. ArkiVoc 2005,
i, 92.
(22) (a) Dieltiens, N.; Stevens, C. V.; De Vos, D.; Allaert, B.; Drozdzak,
R.; Verpoort, F. Tetrahedron Lett. 2004, 45, 8995. (b) Cren, S.; Wilson,
C.; Thomas, N. R. Org. Lett. 2005, 7, 3521.
In conclusion, we have presented an interesting pathway
toward functionalized 2-phosphonopyrroles and pyrrolines.
Phenyl-substituted alkenes can be used in the RCM reaction,
giving rise to the formation of styrene and stilbene as side
products. The nucleophilic nitrogen atom in the substrates 3 is
very well tolerated by the catalyst. Furthermore, an opportunistic
(23) Nishiguchi, T.; Kurooka, A.; Fukuzumi, K. J. Org. Chem. 1974,
39, 2403.
(24) % conversion to the pyrrole was observed using 31P NMR. Yields
reported are isolated yields (after column chromatography). Pyrrole 10d
could only be obtained in 90% purity.
(25) Takabe, K.; Fujiwara, H.; Katagiri, T.; Tanaka, J. Tetrahedron Lett.
1975, 1237.
4008 J. Org. Chem., Vol. 71, No. 10, 2006

aqueous layer was washed twice with 2 mL of dichloromethane,
neutralized until slightly alkaline, and extracted twice with 4 mL
of dichloromethane. The combined organic phases were dried using
MgSO4. The corresponding pyrrolines 4 were obtained as clear,
colorless oils after filtration and evaporation of the solvent.
Dimethyl 1-Benzyl-2,5-dihydro-1H-pyrrol-2-ylphosphonate
(4a). 1H NMR δ (300 MHz, ppm): 3.29-3.43 (1H, multiplet); 3.65
(1H, d, JAB ) 13.5 Hz); 3.71-3.80 (1H, multiplet); 3.80 (3H, d,
JH-P ) 10.2 Hz); 3.83 (3H, d, JH-P ) 10.2 Hz); 4.09-4.16 (1H,
multiplet); 5.74-5.92 (1H, multiplet); 5.87-5.92 (1H, multiplet);
7.22-7.38 (5H, multiplet). 13C NMR δ (75 MHz, ppm): 53.1 (d,
JC-P ) 8.1 Hz); 53.7 (d, JC-P ) 6.9 Hz); 60.1 (d, JC-P ) 5.8 Hz);
60.53 (d, JC-P ) 8.1 Hz); 68.4 (d, JC-P ) 176.5 Hz); 124.0 (d,
JC-P ) 5.8 Hz); 127.0; 128.3; 128.6; 130.2 (d, JC-P ) 12.7 Hz);
139.2. 31P NMR δ (121 MHz, ppm): 24.58. IR νmax (cm-1): 1246
(PdO); 1058, 1031 (P-O). MS m/z: 268 (100, [M + H]+, 158
(18, [M + H - PO(OMe)2]+). Yield: 44%.
Synthesis of 2-Phosphonopyrroles 5. To an oven-dried round-
bottom flask was added 0.39 mmol of aminoalkenyl phosphonate
3 together with 4 mL of dry dichloromethane. The solution was
stirred under a nitrogen atmosphere, and 16.4 mg (5 mol %) of
Grubbs’ second-generation catalyst 6 was added. The reaction
mixture was then stirred for 2 h at room temperature, giving
approximately 60% conversion to the pyrroline. Then 94.8 mg (0.39
mmol) of TCQ was added, and stirring was continued for 3-5 h
at room temperature. The course of the reaction was conveniently
monitored via 31P NMR spectra of samples directly from the
reaction mixture. In case of phosphonate 3e, complete conversion
to pyrrole 5e was only obtained after 5 h at reflux. When complete
conversion was obtained, the solvent was removed under reduced
pressure. The pyrroles 5 were obtained in pure form as brownish
oils using column chromatography on silica gel with a hexane/
ethyl acetate mixture as a mobile phase.
synergism exists between catalyst 6 and oxidant TCQ, which
allows the conversion of NH containing substrates to the
corresponding pyrroles. To the best of our knowledge, this is
the first example of RCM using the second-generation Grubbs’
catalyst on secondary free amines without the need to convert
them to a hydrochloride salt. We are currently planning to
broaden the scope of this reaction to include substrates suitable
for enyne metathesis.
Experimental Section
Synthesis N-Benzyl R-Aminoalkenyl Phosphonates 3. To a
round-bottom flask was added 3.1 mmol of R-aminoalkenyl
phosphonate 2 together with 3 g of K2CO3, 0.23 g (1.5 mmol) of
NaI, and 4 mL of acetone. Then, 0.79 g (4.65 mmol) of benzyl
bromide was added, and the mixture was refluxed for 5-10 h. The
course of the reaction was conveniently monitored via 31P NMR
spectra directly from the reaction mixture. After complete conver-
sion of the starting material, the solids were removed by filtration
and the solvent by evaporation under reduced pressure. The
corresponding N-benzyl R-aminoalkenyl phosphonate 3 was ob-
tained in pure form as a pale yellow oil after column chromatog-
raphy over silica gel using a hexane/ethyl acetate mixture as a
mobile phase.
Dimethyl (2E)-1-(Allyl(benzyl)amino)-3-phenylprop-2-enylphos-
1
phonate (3a). H NMR δ (300 MHz, ppm): 3.10 (1H, dd, JAB
)
14.0 Hz, J ) 7.7 Hz); 3.51 (1H, d, JAB ) 13.8 Hz); 3.63-3.68
(1H, multiplet); 3.68 (3H, d, JH-P ) 10.5 Hz); 3.85 (3H, d, JH-P
)
10.7 Hz); 3.85 (1H, dd, JH-P ) 24.2 Hz, J ) 9.1 Hz); 4.22 (dd,
JAB ) 13.8 Hz, J ) 1.9 Hz); 5.19-5.29 (2H, multiplet); 5.79-
5.93 (1H, multiplet); 6.37 (1H, ddd, Jtrans ) 16.7 Hz, J ) 9.1 Hz,
JH-P ) 6.3 Hz); 6.60 (1H, Jtrans ) 15.7 Hz, JH-P ) 3.03 Hz); 7.20-
7.45 (10H, multiplet). 13C NMR δ (75 MHz, ppm): 52.7 (d, JC-P
) 6.9 Hz); 53.7 (d, JC-P ) 6.9 Hz); 54.3 (d, JC-P ) 6.9 Hz); 55.2
(d, JC-P ) 8.4 Hz); 59.5 (d, JC-P ) 160.4 Hz); 117.7; 119.8; 126.7;
127.1; 128.1; 128.3; 128.5; 128.7; 128.8; 129.0; 136.3; 136.4; 137.0
(d, JC-P ) 6.9 Hz); 139.4. 31P NMR δ (121 MHz, ppm): 27.11. IR
νmax (cm-1): 1642, 1601 (CdC); 1243 (PdO); 1039 (br, P-O).
MS m/z: 262 (13); 372 ([M + H]+, 100). Chromatography: Hex/
EtOAc (3/4) Rf ) 0.26. Yield: 61%.
Synthesis of 2-Phosphono-3-pyrrolines 4. To an oven-dried
round-bottom flask was added 0.34 mmol of aminoalkenyl phos-
phonate 3 together with 4 mL of dry dichloromethane. The solution
was stirred under a nitrogen atmosphere, and 14.4 mg (5 mol %)
of Grubbs’ second-generation catalyst 6 was added. The reaction
mixture was then stirred for 3-5 h at room temperature, depending
on the derivative used. The course of the reaction was conveniently
monitored via 31P NMR spectra of samples directly from the
reaction mixture. Only in the case of phosphonate 3e did complete
conversion to pyrroline 4e require 3 h at reflux temperature. The
reaction mixture was then poured into a separatory funnel containing
5 mL of 1 N HCl(aq). After vigorous shaking and phase separation,
the organic layer was removed from the funnel. The remaining
Dimethyl 1-Benzyl-1H-pyrrol-2-ylphosphonate (5a). 1H NMR
δ (300 MHz, ppm): 3.60 (6H, d, JH-P ) 11.6 Hz); 5.36 (2H, s);
6.22-6.26 (1H, multiplet); 6.86-6.89 (1H, multiplet); 6.90-6.94
(1H, multiplet); 7.10-7.34 (5H, multiplet). 13C NMR δ (75 MHz,
ppm): 52.4; 52.8 (d, JC-P ) 4.6 Hz); 109.1 (d, JC-P ) 13.8 Hz);
117.6 (d, JC-P ) 227.3 Hz); 122.5 (d, JC-P ) 17.3 Hz); 127.2;
127.7; 128.7; 129.0 (d, JC-P ) 11.5 Hz); 137.9. 31P NMR δ (121
MHz, ppm): 13.63. IR νmax (cm-1): 1250 (PdO); 1029 (br, P-O).
MS m/z: 266 (100, [M + H]+). Chromatography: Hex/EtOAc (2/
3) Rf ) 0.26. Yield: 75%.
Acknowledgment. We thank the Fund for Scientific Re-
search Flanders (FWO Vlaanderen) and Ghent University (BOF)
for financial support.
Supporting Information Available: Spectral data of com-
pounds 2b-g, 3b-g, 4b-e, 5b-f, and 11a,d are reported together
with copies of their 13C spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO060160E
J. Org. Chem, Vol. 71, No. 10, 2006 4009