Reactions of conjugate phosphinyl- and phosphonyl-nitroso alkenes with enamines. Preparation of N-hydroxypyrrole derivatives

Article abstract of DOI:10.1021/jo900489j

The synthesis of highly functionalized N-hydroxypyrrole derivatives by the formal [3+2] cycloaddition reaction of enamines and nitroso alkenes derived from phosphine oxides and phosphonates is reported. Intermediate phosphorylated nitrones, whose formatio

Full text of DOI:10.1021/jo900489j

Reactions of Conjugate Phosphinyl- and Phosphonyl-Nitroso
Alkenes with Enamines. Preparation of N-Hydroxypyrrole
Derivatives†
Jesu´s M. de los Santos, Roberto Ignacio, Domitila Aparicio, and Francisco Palacios*
Departamento de Qu´ımica Orga´nica I, Facultad de Farmacia, UniVersidad del Pa´ıs Vasco,
Apartado 450, 01080 Vitoria, Spain
Jose´ M. Ezpeleta‡
Departamento de F´ısica Aplicada II, Facultad de Farmacia, UniVersidad del Pa´ıs Vasco,
Apartado 450, 01080 Vitoria, Spain
francisco.palacios@ehu.es
ReceiVed March 5, 2009
The synthesis of highly functionalized N-hydroxypyrrole derivatives by the formal [3+2] cycloaddition
reaction of enamines and nitroso alkenes derived from phosphine oxides and phosphonates is reported.
Intermediate phosphorylated nitrones, whose formation can be explained by a conjugate addition of
enamines to phosphorylated nitroso alkenes and formation of the five-membered heterocycles, are isolated.
CHART 1. Reactivity Pattern of Nitroso Alkenes I
Introduction
The chemistry of nitroso compounds has been intensively
studied in the past decades, especially due to their applications
in the fields of asymmetric synthesis and cycloaddition pro-
cesses.1 Likewise, nitroso alkenes are functionalized nitroso
derivatives, and the presence of an adjacent double bond in
conjugation with the nitroso moiety introduces new reactivity
centers in these substrates and then increases the synthetic value
of these compounds, especially as heterodienes in Diels-Alder
reactions.2 After pioneering work by Gilchrist’s group,3 cy-
cloaddition reactions in which a nitroso alkene I participates as
the 4π-electron component in hetero-Diels-Alder reactions4
with alkenes,3a,b,5 and enol ethers,6 for the construction of six-
membered heterocycles II have been described (see Chart 1).
However, to the best of our knowledge, not many examples of
(4) Selected reviews: (a) Gilchrist, T. L.; Wood, J. E. ComprehensiVe
Heterocyclic Chemistry II; Boulton, A. J., Ed.; Pergamon: Oxford, UK, 1996;
Vol. 6, pp 279-299. (b) Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997,
189, 1–120.
(5) (a) Gilchrist, T. L.; Roberts, T. G. J. Chem. Soc., Chem. Commun. 1978,
847–849. (b) Iskander, G. M.; Gulta, V. S. J. Chem. Soc., Perkin Trans. 1 1982,
1891–1895. (c) Dennmark, S. E.; Dappen, M. S.; Sternberg, J. A. J. Org. Chem.
1984, 49, 4741–4743.
(6) (a) Gilchrist, T. L.; Iskanderl, G. M.; Yagoub, A. K. J. Chem. Soc.,
Chem. Commun. 1981, 696–698. (b) Hippeli, C.; Reissig, H.-U. Synthesis
1987, 77–79. (c) Gallos, J. K.; Sarli, V. C.; Varvogli, A. C.; Papadoyanni,
C. Z.; Papaspyrou, S. D.; Argyropoulos, N. G. Tetrahedron Lett. 2003, 44,
3905–3909. (d) Arnold, T.; Reissig, H.-U. Synlett 1990, 514–516. (e) Reissig,
H.-U.; Hippeli, C.; Arnold, T. Chem. Ber. 1990, 123, 2403–2411. (f) Arnold,
T.; Orschel, B.; Reissig, H.-U. Angew. Chem., Int. Ed. 1992, 31, 1033–1035.
(g) Zimmer, R.; Reissig, H.-U. Angew. Chem., Int. Ed. 1988, 27, 1518–1519.
(h) Zimmer, R.; Reissig, H.-U. Liebigs Ann. Chem. 1991, 553–562. (i) Orschel,
B.; Scherer, S.; Reissig, H.-U. Synthesis 2002, 11, 1553–1563.
† Dedicated to Prof. Josep Font on the occasion of his 70th Birthday.
‡ Contact this author regarding the X-ray crystal structure determination.
(1) For recent reviews see: (a) Yamamoto, Y.; Yamamoto, H. Eur. J. Org.
Chem. 2006, 2031–2043. (b) Yamamoto, H.; Nimiyama, N. Chem. Commun.
2005, 3514–3525. (c) Gowenlock, B. G.; Richter-Addo, G. B. Chem. ReV. 2004,
104, 3315–3340. (d) Adam, W.; Krebs, O. Chem. ReV. 2003, 103, 4131–4146.
(2) For an excellent review see: Gilchrist, T. L. Chem. Soc. ReV. 1983, 12,
53–73.
(3) (a) Faragher, R.; Gilchrist, T. L. J. Chem. Soc., Chem. Commun. 1976,
581–582. (b) Faragher, R.; Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1979,
249–257. (c) Gilchrist, T. L.; Roberts, T. G. J. Chem. Soc., Perkin Trans. 1
1983, 1283–1292. (d) Davies, D. E.; Gilchrist, T. L.; Roberts, T. G. J. Chem.
Soc., Perkin Trans. 1 1983, 1275–1281.
3444 J. Org. Chem. 2009, 74, 3444–3448
10.1021/jo900489j CCC: $40.75 2009 American Chemical Society
Published on Web 04/03/2009

Preparation of N-Hydroxypyrrole DeriVatiVes
CHART 2. Retrosynthetic Pathway for the Preparation of
N-Hydroxypyrrole Derivatives IV
the hetero-Diels-Alder reaction of nitroso alkenes with enam-
ines7 have been reported. Jorgensen and co-workers8 recently
reported the first catalyzed hetero-Diels-Alder reaction of
nitroso alkenes and carbonyl derivatives using pyrrolidine as
the organocatalyst, and this hetero-Diels-Alder reaction in-
volves enamine intermediates formed by condensation of the
carbonyl compounds with pyrrolidine.
We have previously described the generation of phosphinyl
I (R2 ) POPh2) and phosphonyl nitroso-alkenes I (R2
)
SCHEME 1. Addition of Enamines 3 to Highly Reactive
Phosphorylated Nitroso Alkenes 1 and 2
PO(OEt)2) and the conjugate addition of some nucleophiles, such
as amines and amino-esters, for the preparation of R-amino
phosphonate derivatives III (see Chart 1).9 In this context, we
are interested in the preparation of three-,10 five-,11 and six-
membered12 nitrogen-containing heterocycles, as well as the
synthesis of new amino phosphorus derivatives13 and their
synthetic use for the construction not only of the carbon-carbon
double bond14 but also of the carbon-nitrogen double bond.15
It is known that phosphorus substituents regulate important
biological functions,16 and the introduction of organophosphorus
functionalities in simple synthons may afford the development
of new strategies for the preparation of phosphorylated azahet-
erocycles.17 For this reason, we wish to describe herein a further
and efficient strategy of the regioselective preparation of highly
functionalized N-hydroxypyrroles with a phosphine oxide (IV,
R ) Ph) or phosphonate group at the 3-position (IV, R ) OEt),
generated through treatment of phosphinyl and phosphonyl-
nitroso alkenes I with enamines V (Chart 2).
(7) (a) Tahdi, A.; Titouani, S. L.; Soufiaoui, M. Tetrahedron 1998, 54, 65–
70. (b) Henning, R.; Lerch, U.; Urbach, H. Synthesis 1989, 265–268.
(8) Wabnitz, T. C.; Saaby, S.; Jorgensen, K. A. Org. Biomol. Chem. 2004,
2, 828–834.
(9) de los Santos, J. M.; Ignacio, R.; Aparicio, D.; Palacios, F. J. Org. Chem.
2007, 72, 5202–5206.
(10) (a) Palacios, F.; Ochoa de Retana, A. M.; Alonso, J. M. J. Org. Chem.
2006, 71, 6141–6148. (b) Palacios, F.; Aparicio, D.; Ochoa de Retana, A. M.;
de los Santos, J. M.; Gil, J. I.; Alonso, J. M. J. Org. Chem. 2002, 67, 7283–
7288.
(11) (a) de los Santos, J. M.; Aparicio, D.; Lo´pez, Y.; Palacios, F. J. Org.
Chem. 2008, 73, 550–557. (b) Palacios, F.; Alonso, C.; Legido, M.; Rubiales,
G.; Villegas, M. Tetrahedron Lett. 2006, 47, 7815–7818. (c) Palacios, F.;
Aparicio, D.; Vicario, J. Eur. J. Org. Chem. 2005, 2843–2850. (d) Palacios, F.;
Ochoa de Retana, A. M.; Gil, J. I.; Alonso, J. M. Tetrahedron 2004, 60, 8937–
8947.
(12) (a) Vicario, J.; Aparicio, D.; Palacios, F. J. Org. Chem. 2009, 74, 452–
456. (b) Aparicio, D.; Attanasi, O. A.; Filippone, P.; Ignacio, R.; Lillini, S.;
Mantellini, F.; Palacios, F.; de los Santos, J. M. J. Org. Chem. 2006, 71, 5897–
5905. (c) Palacios, F.; Herra´n, E.; Alonso, C.; Rubiales, G.; Lecea, B.; Ayerbe,
M.; Coss´ıo, F. P. J. Org. Chem. 2006, 71, 6020–6030. (d) Palacios, F.; Ochoa
de Retana, A. M.; Gil, J. I.; Lo´pez de Munain, R. Org. Lett. 2002, 4, 2405–
2408.
Results and Discussion
The reaction of 1,2-oxazabuta-1,3-dienes 1 and 2 with
enamines 3 was explored. Thus, the addition of enamine 3a
i
(R1 ) Pr, R2 ) H) to the highly reactive 4-phosphonyl-
heterodiene 1 (R ) OEt), generated in situ from R-bro-
mooximes,9 in CH2Cl2 at room temperature was performed. The
highly colored 4-phosphonyl-1,2-oxazabuta-1,3-diene 1 disap-
peared very fast, showing the end of the reaction with the
formation, rather than of the expected six-membered 1,2-oxazine
4, the hydroxypyrrole-3-phosphonate 5a in good yield (89%)
as a sole product and in a regioselective fashion (Scheme 1,
Table 1, entry 1).
The process was extended to the reaction of 4-phosphonyl-
1,2-oxazabuta-1,3-diene 1 with other enamines derived from
aldehydes 3b-d and from ketones 3e-g in CH2Cl2 at room
temperature to give hydroxypyrrole-3-phosphonates 5 in good
yield (Scheme 1, Table 1, entries 2-4 and 5-7, respectively).
It was necessary to obtain evidence for structure 5a, because it
is known that nitroso alkenes mainly react with dienophiles
according to [4+2]-cycloaddition processes (vide supra). In the
latter case, compound 4 could be expected and produced instead
of the N-hydroxypyrrole 5. The choice between structures 5 and
4 was based upon the 2D NMR and mass spectral data. Namely,
the HMBC spectrum showed a cross signal between the vinylic
proton (H-5) with the signal downfield corresponding to the
carbon (C-2) of 5a. This cross signal unambiguously confirms
the presence of the N-hydroxypyrrole 5a and not the oxazine
ring 4 (four bonds distance between H-6 and C-3 in the
oxazine ring). Also two cross signals were observed between
the vinylic proton (H-5) with the quaternary carbons C-3 and
C-4 of the N-hydroxypyrrole 5a. Moreover, the high resolution
(13) For a recent review of ꢀ-aminophosphonates see: Palacios, F.; Alonso,
C.; de los Santos, J. M. Chem. ReV. 2005, 105, 899–931.
(14) (a) Palacios, F.; Ochoa de Retana, A. M.; Oyarzabal, J.; Pascual, S.;
Ferna´ndez de Troconiz, G. J. Org. Chem. 2008, 73, 4568–4574. (b) Palacios,
F.; Vicario, J. Org. Lett. 2006, 8, 5405–5408. (c) Palacios, F.; Aparicio, D.;
Lo´pez, Y.; de los Santos, J. M.; Ezpeleta, J. M. Tetrahedron 2006, 62, 1095–
1101. (d) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J. J.
Org. Chem. 2004, 69, 8767–8774. (e) Palacios, F.; Ochoa de Retana, A. M.;
Pascual, S. Org. Lett. 2003, 4, 769–772.
(15) (a) Palacios, F.; Vicario, J.; Maliszewska, A.; Aparicio, D. J. Org. Chem.
2007, 72, 2682–2685. (b) Palacios, F.; Aparicio, D.; Vicario, J. J. Org. Chem.
2006, 71, 7690–7696. (c) Coss´ıo, F. P.; Alonso, C.; Lecea, B.; Ayerbe, M.;
Rubiales, G.; Palacios, F. J. Org. Chem. 2006, 71, 2839–2847. (d) Palacios, F.;
Herra´n, E.; Alonso, C.; Rubiales, G. Tetrahedron 2006, 62, 7661–7666. (e)
Palacios, F.; Alonso, C.; Amezua, P.; Rubiales, G. J. Org. Chem. 2002, 67,
1941–1944.
(16) For reviews see: (a) Engel, R. In Handbook of Organophosphorus
Chemistry; M. Dekker, Inc.: New York, 1992. (b) Kafarski, P.; Lejezak, B.
Phosphorus Sulfur 1991, 63, 193–215. (c) Hoagland, R. E. In Biologically ActiVe
Natural Products; Culter, H. G., Ed.; ACS Symposium Series 380; American
Chemical Society: Washington DC, 1988; p 182. (d) Toy, A. D. F.; Walsh, E. N.
In Phosphorus Chemistry in EVeryday LiVing; American Chemical Society:
Washington DC, 1987; p 333.
(17) For an excellent review see: Moonen, K.; Laureyn, I.; Stevens, C. V.
Chem. ReV. 2004, 104, 6177–6215.
J. Org. Chem. Vol. 74, No. 9, 2009 3445

Santos et al.
TABLE 1. N-Hydroxypyrrole Phosphonates 5 Obtained through
Addition of Enamines 3 to Nitroso Alkene 1
TABLE 2. N-Hydroxypyrrole Phosphine Oxides 8 Obtained
through Addition of Enamines 3 to Nitroso Alkene 2
a After chromatography. b Yields of pure compounds 5 are based on
1,2-oxazabuta-1,3-diene 1. c Yields of compounds 5 based on isolated
nitrones 7.
a After chromatography. b Yields of pure compounds 8 are based on
1,2-oxazabuta-1,3-diene 2. c Yield of compound 8 based on isolated
nitrone 7c.
mass spectra for compound 5a showed an ion peak for the
fragment [M+ - OH] typical loss corresponding to these
structures. The X-ray diffraction analysis finally determined the
structure of N-hydroxypyrrole 5g. The corresponding ORTEP
drawing for compound 5g is shown in the Supporting Informa-
tion.
TABLE 3. Isolated Phosphorylated Nitrones 7
A plausible mechanism for the formation of the N-hydroxy-
pyrroles 5 can be explained through initial conjugate addition
of enamine 3 at the terminal carbon atom of heterodiene 1 to
give adduct 6, which promptly affords nitrone 7 by ring closure
(formally a [3+2] dipolar cycloaddition). Elimination of the
pyrrolidine residue in nitrones 7 leads to substituted N-
hydroxypyrroles 5 isolable by flash chromatography. The
electron-withdrawing phosphonate group (PO(OEt)2) on the
terminal carbon atom of nitroso alkene 1 may enhance the elec-
trophilic character of this atom and may also favor the initial
Michael addition of the enamines on this carbon atom to obtain
the five-membered heterocycles 5. Nitroso alkenes have been
shown to add themselves to the CdN double bond of some
1,2-oxazines,18 1,3-diazabuta-1,3-dienes,19 and imines,20 as well
as to the CdC double bond attached to a pyrimidinone ring,21
with the formation of unusual [3+2] cycloadducts. However,
as far as we know, this process represents the first example of
a formal [3+2] cycloaddition reaction of nitroso alkenes to
electron-rich olefins such as enamines, for the preparation of
pyrrole derivatives. In fact, a theoretical study with the DFT
method at the B3LYP/G-316* level of the reaction of nitroso
alkenes with enamines suggests a polar [4+2] Diels-Alder
reaction characterized by a nucleophilic attack of the enamine
at the conjugate position of the nitroso alkene with concomitant
six-membered-ring closure.22
entry
product
R
R1
R2
yield (%)a
1
2
3
7a
7b
7c
OEt
OEt
Ph
Pr
H
H
H
85
87
83
Ph
iPr
a Yield of isolated nitrones after flash chromatography.
bromooximes,9 with enamines 3a-g to give hydroxypyrrole-
3-phosphine oxides 8 in good yields (Scheme 1, Table 2). The
scope of the process is not limited to enamines derived from
aldehydes 3a,b,d (Scheme 1, Table 2, entries 1-3), given that
enamines derived from ketones 3e,g (Scheme 1, Table 2, entries
4,5) also led to the regioselective formation of hydroxypyrrole-
3-phosphine oxides 8. NMR data and mass spectrometry are
consistent with the assigned structure of compounds 8, and the
X-ray diffraction analysis finally determined the structure of
N-hydroxypyrrole 8a. The corresponding ORTEP drawing for
compound 8a is shown in the Supporting Information.
Further evidence for the mechanism of formation of N-
hydroxypyrroles derived from phosphonates 5 and phosphine
oxides 8 is confirmed by the isolation of nitrone intermediates
7. The nitrones 7 showed a tendency to aromatize and readily
occurred in the reaction media to afford the corresponding
N-hydroxypyrroles 5 and 8. However, in some cases, when the
process was performed at 0 °C, nitrones 7a,b derived from
phosphonates (R ) OEt) and 7c derived from phosphine oxides
(R ) Ph) proved to be stable enough for the reaction conditions
and even for flash chromatography and it was possible to isolate
them and characterize them on the basis of analytical and
spectral data (Scheme 1, Table 3). Thus, the mass spectrum of
compound 7a, for example, analyzed as C16H31N2O4P, exhibited
an intense molecular ion M + 1 peak (m/z 347). The 31P NMR
spectrum of 7a showed only an absorption at δ 23.1 ppm
indicating that the formation of the pentagonal heterocycle takes
place in a diastereoselective fashion, while the 1H NMR
The strategy was extended to 4-phosphinyl-1,2-oxazabuta-
1,3-dienes 2 (R ) Ph), prepared also through base treatment of
(18) (a) Zimmer, R.; Collas, M.; Czerwonka, R.; Hain, U.; Reissig, H.-U.
Synthesis 2008, 237–244. (b) Mackay, D.; Watson, K. N. J. Chem. Soc., Chem.
Commun. 1982, 775–776.
(19) (a) Sharma, A. K.; Mazumdar, S. N.; Mahajan, M. P. J. Chem. Soc.,
Perkin Trans. 1 1997, 3065–3070. (b) Sharma, A. K.; Hundal, G.; Obrai, S.;
Mahajan, M. P. J. Chem. Soc., Perkin Trans. 1 1999, 615–619.
(20) (a) Marwaha, A.; Bharatam, P. V.; Mahajan, M. P. Tetrahedron Lett.
2005, 46, 8253–8256. (b) Marwaha, A.; Singh, P.; Mahajan, M. P. Tetrahedron
2006, 62, 5474–5486.
(21) Sharma, A. K.; Mahajan, M. P. Heterocycles 1995, 40, 787–800.
(22) Domingo, L. R.; Picher, M. T.; Arroyo, P. Eur. J. Org. Chem. 2006,
2570–2580.
3446 J. Org. Chem. Vol. 74, No. 9, 2009

Preparation of N-Hydroxypyrrole DeriVatiVes
spectrum showed absorptions at δ 4.89 ppm as a doublet with
coupling constant 3JHH ) 10.4 Hz for H-5, and H-3 exhibited a
Experimental Section
General Methods. Reagent and solvent purification, workup
procedures, and analyses were performed in general as describe in
the Supporting Information.
3
doublet of doublet at 2.56 (2JPH ) 27.8 and JHH ) 4.3 Hz).
This lower coupling constant value than that corresponding to
H-5 indicates that H-3 and H-4 protons are syn related. The
13C NMR spectra were also in agreement with the nitrone
structure assigned above to 7a. Compounds 7 can be transformed
into pyrroles 5 and 8 by thermal treatment in the absence of
solvent (1-2 h).
To the best of our knowledge, this novel strategy is the first
example of the preparation of N-hydroxypyrrole derivatives
through reaction of enamines to phosphorylated nitroso alkenes
to be reported.23 Pyrroles are important heterocycles broadly
used in material science24 and can be found in naturally
occurring and biologically important molecules.25 Some of the
recently isolated pyrrole containing marine natural products have
been found to exhibit considerable cytotoxicity and function as
multidrug resistant (MDR) reversal agents.26 Among them,
N-hydroxypyrrole containing antibiotic chromoxymycin27 has
shown antitumor activity, and the cyclic depsipeptide hormao-
mycin,28 with an interesting spectrum of biological activities,
has a unique structure with a side chain terminated with a residue
of N-hydroxypyrrole-2-carboxylic acid.
General Procedure for the Addition of Enamines to Phos-
phorylated Nitroso Alkenes 1 and 2. To a stirred solution of
R-bromooxime9 (1.0 mmol) in CH2Cl2 (5 mL) was added triethy-
lamine (1.2 mmol). Then the corresponding enamine 3a-i (1.2
mmol) was added at once at room temperature and under a nitrogen
atmosphere. The reaction was allowed to stir at room temperature
for 15-30 min. The solvent was removed by rotary evaporation
and the residue was stirred with diethyl ether. The triethylamine
hydrobromic salt was filtered through a sintered glass vacuum
filtration funnel. The solid was washed twice with ether and the
filtrate was concentrated to dryness in vacuum to get stable nitrones
7 or N-hydroxypyrroles 5 and 8. N-Hydroxypyrroles 5c,d and 8a
derived from stable nitrones 7a,b,c, respectively, were obtained
through heating nitrones 7 at 60 °C in the absence of solvent.
Diethyl 1-hydroxy-4-isopropyl-2-methyl-1H-pyrrol-3-ylphos-
phonate (5a): 5a (245 mg, 89%) was obtained as a brown oil from
1-bromo-2-hydroxyiminopropyl phosphonic acid diethyl ester9 (287
mg, 1.0 mmol), Et3N (168 µL, 1.2 mmol), and (E)-1-(3-methylbut-
1-enyl)pyrrolidine 3a (167 mg, 1.2 mmol) as described in the
general procedure at room temperature. The crude product was
purified by flash chromatography (SiO2, AcOEt/pentane 50:50). IR
(NaCl) νmax 3423, 2961, 1214, 1031, 963 cm-1; 1H NMR (300 MHz,
CDCl3) δ 11.16 (br s, 1H), 6.53 (d, 4JPH ) 6.0 Hz, 1H), 4.02-3.92
3
(m, 4H), 3.00 (m, 1H), 1.98 (s, 3H), 1.29 (t, JHH ) 7.2 Hz, 6H),
Conclusion
3
1.13 (d, JPH ) 6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 133.6
2
2
3
In conclusion, the first synthesis of functionalized N-hydroxy-
pyrroles containing a phosphine oxide or phosphonate group at
the C-3 position of the heterocyclic system by means of a [3+2]
formal cycloaddition reaction of phosphorylated nitroso alkenes
and enamines is described. In contrast, a theoretical study with
the DFT method at the B3LYP/G-316* level of the reaction of
nitroso alkenes with enamines suggests a polar [4+2] Diels-Alder
reaction with concomitant six-membered-ring closure. Interme-
diate phosphorylated nitrones have been isolated. Their forma-
tion can be explained by a conjugate addition of enamines to
phosphorylated nitroso alkenes and formation of the five-
membered heterocycles. It also should be emphasized that the
use of these very reactive phosphorylated heterodienes opens a
novel route to other functionalized cyclic and acyclic phosphorus
compounds due to the marked ability of nitroso alkenes to add
nucleophiles. These N-hydroxypyrrole derivatives may be important
synthons in organic synthesis for the preparation of biologically
active compounds of interest to medicinal chemistry.25-28
(d, JPC ) 26.0 Hz), 129.8 (d, JPC ) 12.5 Hz), 114.1 (d, JPC
)
13.5 Hz), 94.7 (d, 1JPC ) 218.4 Hz), 61.3 (d, 2JPC ) 5.6 Hz), 25.5,
24.5, 16.1 (d, 3JPC ) 7.0 Hz), 9.2; 31P NMR (120 MHz, CDCl3) δ
21.9; MS (EI) m/z 275 (M+, 10), 258 (100), 202 (40); HRMS (EI)
m/z calcd for C12H22NO4P [M+] 275.1286, found [M+] 275.1263.
(2S*,3R*,4R*)-4-(Diethoxyphosphoryl)-5-methyl-3-propyl-2-
(pyrrolidin-1-yl)-3,4-dihydro-2H-pyrrole 1-oxide (7a): 7a (294
mg, 85%) was obtained as a colorless oil from 1-bromo-2-
hydroxyiminopropyl phosphonic acid diethyl ester9 (287 mg, 1.0
mmol), Et3N (168 µL, 1.2 mmol), and (E)-1(pent-1-enyl)pyrrolidine
3c (167 mg, 1.2 mmol) as described in the general procedure, when
the process was performed at 0 °C. The crude product was purified
by flash chromatography (SiO2, AcOEt/pentane 20:80). IR (NaCl)
ν
max 2959, 1626, 1447, 1235, 1050, 957 cm-1; 1H NMR (400 MHz,
CDCl3) δ 4.18-4.04 (m, 4H), 3.89 (d, JHH ) 10.4 Hz, 1H),
3
3.09-2.95 (m, 4H), 2.77-2.64 (m, 1H), 2.56 (dd, 2JPH ) 27.8 Hz,
3JHH ) 4.3 Hz, 1H), 2.16 (d, JPH ) 2.8 Hz, 3H), 1.82-1.76 (m,
4
4H), 1.49-1.26 (m, 10H), 0.91 (t, JHH ) 7.0 Hz, 3H); 13C NMR
3
2
3
(75 MHz, CDCl3) δ 160.3 (d, JPC ) 8.5 Hz), 93.5 (d, JPC ) 3.4
2
2
Hz), 63.0 (d, JPC ) 6.5 Hz), 62.4 (d, JPC ) 7.0 Hz), 47.2, 43.2
1
2
3
(d, JPC ) 131.7 Hz), 38.5 (d, JPC ) 4.0 Hz), 36.2 (d, JPC ) 6.0
3
3
Hz), 24.9, 21.7, 18.9, 16.3 (d, JPC ) 5.5 Hz), 16.3 (d, JPC ) 5.5
Hz), 14.2; 31P NMR (120 MHz, CDCl3) δ 23.1; MS (CI) m/z 347
(M+ + 1, 100).
(23) A synthesis of N-hydroxypyrroles has been described through reaction
of enolates with R-halooximes: Haelters, J. P.; Corbel, B.; Sturtz, G. Phosphorus,
Sulfur, Silicon 1989, 44, 53–74.
(24) (a) Butler, M. S. J. Nat. Prod. 2004, 67, 2141–2153. (b) Joule, J. A.;
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Diethyl 1-hydroxy-2-methyl-4-propyl-1H-pyrrol-3-ylphospho-
nate (5c): 5c (226 mg, 82%) was obtained as a colorless oil by
heating intermediate phosphorylated nitrone 7a for 2 h as described
in the general procedure. The crude product was purified by flash
chromatography (SiO2, AcOEt/pentane 40:60). IR (NaCl) νmax 3126,
2955, 1442, 1208, 1025, 963 cm-1; 1H NMR (300 MHz, CDCl3) δ
11.07 (br s, 1H), 6.46 (d, 4JPH ) 6.0 Hz, 1H), 4.07-3.96 (m, 4H),
4
2.44-2.31 (m, 2H), 1.86 (d, JPH ) 1.8 Hz, 3H), 1.56-1.48 (m,
2H), 1.32 (t, 3JHH ) 7.2 Hz, 6H), 0.94 (t, 3JHH ) 7.5 Hz, 3H); 13
C
2
NMR (75 MHz, CDCl3) δ 133.8 (d, JPC ) 26.0 Hz), 122.1 (d,
2JPC ) 12.0 Hz), 115.9 (d, JPC ) 13.1 Hz), 95.3 (d, JPC ) 218.3
3
1
2
3
Hz), 61.4 (d, JPC ) 6.0 Hz), 28.6, 23.6, 16.2 (d, JPC ) 7.1 Hz),
14.1, 9.1; 31P NMR (120 MHz, CDCl3) δ 22.8; HRMS (EI) m/z
calcd for C12H22NO4P [M+] 275.1286, found [M+] 275.1282.
(28) Zlatopolskiy, B. D.; Kroll, H.-P.; Melotto, E.; de Meijere, A. Eur. J.
Org. Chem. 2004, 4492–4502.
J. Org. Chem. Vol. 74, No. 9, 2009 3447

Santos et al.
4-Benzyl-3-(diphenylphosphoryl)-2-methyl-1H-pyrrol-1-ol (8b):
8b (341 mg, 88%) was obtained as a colorless solid from 1-bromo-
1-(diphenylphosphinoyl) propan-2-one oxime9 (351 mg, 1.0 mmol),
Et3N (168 µL, 1.2 mmol), and (E)-1-(3-phenylprop-1-enyl)pyrro-
lidine 3b (224 mg, 1.2 mmol) as described in the general procedure
at room temperature. The crude product was purified by flash
chromatography (SiO2, AcOEt/pentane 50:50). Mp 131-134 °C;
IR (KBr) νmax 3412, 2921, 1488, 1436, 1157, 1134 cm-1; 1H NMR
(300 MHz, CDCl3) δ 12.56 (br s, 1H), 7.71-6.80 (m, 15H), 6.23
Acknowledgment. This work was financially supported by
the Universidad del Pa´ıs Vasco-Departamento de Educacio´n,
Universidades e Investigacio´n del Gobierno Vasco (GIU- 07/
114; IT-277-07) and Direccio´n General de Investigacio´n del
Ministerio de Ciencia y Tecnolog´ıa (MCYT, Madrid DGI,
CTQ2006-09323).
Supporting Information Available: Full characterization
data and procedures for the synthesis of all new compounds,
ORTEP diagrams, and X-ray crystallographic data for com-
pounds 5g and 8a. This material is available free of charge via
the Internet at http://pubs.acs.org.
4
(d, 4JPH ) 4.5 Hz, 1H), 3.02 (s, 2H), 1.41 (d, JPH ) 0.9 Hz, 3H);
2
13C NMR (75 MHz, CDCl3) δ 140.2, 134.6 (d, JPC ) 19.6 Hz),
134.2, 132.8, 131.7, 131.7, 131.6, 131.6, 128.8, 128.6, 128.5, 128.0,
2
3
125.7, 121.2 (d, JPC ) 10.0 Hz), 118.4 (d, JPC ) 10.0 Hz), 99.5
(d, JPC ) 128.2 Hz), 32.6, 9.6; 31P NMR (120 MHz, CDCl3) δ
1
25.0; HRMS (EI) m/z calcd for C24H22NO2P [M+] 387.1388, found
[M+] 387.1412.
JO900489J
3448 J. Org. Chem. Vol. 74, No. 9, 2009