Selective synthesis of substituted pyrrole-2-phosphine oxides and -phosphonates from 2H-azirines and enolates from acetyl acetates and malonates

Article abstract of DOI:10.1021/jo201932m

A simple and efficient selective synthesis of 1H-pyrrole-2-phosphine oxides 3 and -phosphonates 7 by addition of enolates derived from acetyl acetates to 2H-azirinylphosphine oxide 1 and -phosphonate 6 is reported. Nucleophilic addition of enolates derive

Full text of DOI:10.1021/jo201932m

Article
pubs.acs.org/joc
Selective Synthesis of Substituted Pyrrole-2-phosphine Oxides and
-phosphonates from 2H-Azirines and Enolates from Acetyl Acetates
and Malonates
Francisco Palacios,* Ana M. Ochoa de Retana, and Ander Velez del Burgo
́
́
́
Departamento de Quimica Organica I, Facultad de Farmacia, Centro de Investigaciones y Estudios Avanzados “Lucio Lascaray”,
́
Universidad del Pais Vasco, Apartado 450, 01080 Vitoria, Spain
S
* Supporting Information
ABSTRACT: A simple and efficient selective synthesis of 1H-pyrrole-2-phosphine oxides 3 and -phosphonates 7 by addition of
enolates derived from acetyl acetates to 2H-azirinylphosphine oxide 1 and -phosphonate 6 is reported. Nucleophilic addition of
enolates derived from diethyl malonate to 2H-azirines 1 and 6 led to the formation of functionalized 2-hydroxy-1H-pyrrole-5-
phosphine oxide 9 and -phosphonate 10, while vinylogous α-aminoalkylphosphine oxides 14 and -phosphonate 15 may be
obtained from azirines and the enolate derived from diethyl 2-phenylmalonate. Ring closure of vinylogous derivatives 14 and 15
in the presence of base led to the formation of 1,5-dihydro-3-pyrrolin-2-ones containing a phosphine oxide 17 or a phosphonate
group 18.
design and development of new methods of synthesis of
substituted pyrroles continues to be a challenge.11
INTRODUCTION
■
2H-Azirine ring systems represent an important class of
compounds because of their high reactivity.1 They can be
used as key intermediates in organic synthesis in the
preparation of heterocycles2a−e and acyclic functionalized
amino derivatives,2f−h since any of the three bonds of the
azirine ring can be cleaved, depending on the experimental
conditions used. On the other hand, pyrroles3 are important
heterocycles broadly used in material science4 and not only can
be found in naturally occurring and biologically important
molecules5 but also are important intermediates in the synthesis
of natural products;6 some of the recently isolated pyrroles have
been found to exhibit considerable cytotoxicity and function in
multidrug resistant (MDR) reversal7a and antimycobacterial
activity.7b In this context, 2-silyloxypyrroles I (Scheme 1, R =
The importance of azaheterocyclic phosphonates in
synthetic, agrochemical, and medicinal chemistry has been
well-documented12 because it is known that phosphorus
substituents regulate important biological functions13 and that
molecular modifications involving the introduction of organo-
phosphorus functionalities in simple synthons could be very
interesting because they can be useful substrates for the
preparation of biologically active compounds. However, very
little information is reported about the properties of
phosphonopyrroles12 III (Scheme 1) undoubtedly due to the
fact that there is no general method for their preparation. Only
a few examples have been reported for the synthesis of 2-
phosphonopyrroles (III) as shown in Scheme 2 involving either
the use of heterocyclic precursors such as the aromatization of
3-oxo-2-phosphonate pyrrolidines (IV)14 and the phosphor-
ylation of pyrroles (V)12a or the use of acyclic substrates such as
the [3 + 2] cycloaddition of iminomethylphosphonates (VI)
with acetylenic compounds15 or the ring-closing metathesis of
functionalized aminophosphorus derivatives (VII).16
Scheme 1
We describe new methods for the preparation of
phosphorus-substituted nitrogen heterocycles17 including N-
hydroxypyrrole derivatives17d from functionalized phosphine
oxides and phosphonates and the synthetic uses of amino-
phosphorus derivatives as starting materials for the synthesis of
SiR3) and α,β-unsaturated γ-butyrolactams or 1,5-dihydro-3-
pyrrolin-2-ones II (Scheme 1) demonstrated in the last years a
wide use as efficient donors in diastereoselective and in
enantioselective aldol reactions and related processes such as
Mannich and Michael reactions.8,9 For these reasons, although
many methods have been devised for their preparation10 the
Received: September 20, 2011
Published: October 14, 2011
© 2011 American Chemical Society
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Scheme 2
Table 1. Substituted Pyrroles 3 and 7
a
entry
compd
R
R1
R2
yield (%)
1
2
3
4
5
3a
3b
3c
7a
7b
Ph
CH3
CH3
C2H5
CH3
Ph
CH3
C2H5
CH3
CH3
CH3
60
60
75
60
95
Ph
Ph
OEt
OEt
a
Yield of isolated purified compounds 3 and 7 from azirines 1 or 6.
phosphine oxide group of this substituted pyrrole 3a resonated
at δP = 21.9 ppm, while singlets at δH = 1.89 (4JPH = 1.5 Hz)
1
and 2.42 ppm for both methyl groups in the H NMR were
observed. The formation of pyrrole 3a suggests the approach of
the enolate derived from acetyl acetate 2 to the CN double
bond of the azirine followed by ring-opening of the three
membered heterocycle 4, cyclization to the 5H-pyrrole 5, and
subsequent prototropic rearrangement to aromatic pyrrole 3.
Similarly, pyrrole-phosphine oxides 3b,c were obtained
(Scheme 2, Table 1, entries 2 and 3) when the reaction of
azirine 1a (R = Ph, R1 = CH3) was performed with the enolate
derived from ethyl 2-oxobutanoate 2b (R2 = C2H5) in the
presence of NaH in THF or by the reaction of azirine 1b (R =
Ph, R1 = C2H5) with the enolate derived from methyl 2-
oxobutanoate 2a (R2 = CH3). This process could also be
extended to 2H-azirines derived from phosphonates 6.
Treatment of 3-methyl- (6a) (R = OEt, R1 = CH3) and 3-
phenyl-2H-azirine (6b) (R = OEt, R1 = Ph) with the enolate
derived from methyl 2-oxobutanoate 2a gave 1H-pyrrol-2-yl
phosphonates 7a,b (Scheme 2, Table 1, entries 4 and 5).
Pyrrole derivatives3 have been also obtained by ring expansion
of 3-vinyl 2H-azirines23 or by reaction of azirines with dimethyl
acetylenedicarboxylate.24 However, our strategy describes, as far
as we know, the first synthesis of 1H-pyrrole-2-phosphonates
and -phosphine oxides from azirines.
Selective Addition of Enolates Derived from Diethyl
Malonates to 2H-Azirines. Reaction of enolates derived
from β-diesters to 2H-azirines was also studied in order to test
if these nucleophiles could give a new entry to substituted
phosphorylated pyrrole derivatives. For this reason, we
explored the reaction of 2H-azirinylphosphine oxides 1 and
-phosphonates 6 with the enolates derived from malonates.
Treatment of 3-methyl-2H-azirin-2-yldiphenylphosphine oxide
1a (R = Ph, R1 = CH3) and 3-ethyl-2H-azirin-2-ylphosphonate
6b (R = OEt, R1 = C2H5) with enolate derived from diethyl
malonate 8a (R3 = H) and NaH at 0 °C led exclusively to the
formation of 2-hydroxy-1H-pyrroles with a phosphine oxide 9
(R = Ph) (Scheme 4, Table 2, entries 1 and 2) or a
phosphonate in the 5 position 10 (R = OEt) (Scheme 4, Table
2, entry 3).
acyclic compounds18 and phosphorus-containing hetero-
cycles.19 Likewise, we reported the preparation of 2H-
azirinylphosphine oxides VIII (R = Ph) and -phosphonates
VIII (R = OEt, Scheme 2) through base-mediated Neber
reaction of β-ketoxime tosylates20 and their use for the
synthesis of aminophosphorus derivatives,21 and phosphory-
lated pyrazines,22a oxazoles,22b,c or aziridines.22d Continuing
with our interest in the chemistry of small strained nitrogen
heterocycles, we report here a new strategy for the preparation
of functionalized pyrroles (III) containing phosphorus
substituents such as a phosphine oxide (III, R = Ph) or a
phosphonate group (III, R = OEt) by the selective addition of
enolates derived from acetylacetates and malonates to
phosphorylated azirines VIII (Scheme 2).
RESULTS AND DISCUSSION
■
Selective Addition of Enolates Derived from Acetyla-
cetates to 2H-Azirines. Because of the strain of the three-
membered ring, the electrophilic character of the C−N double
bond is higher than in a normal imine, and azirines react with
nucleophiles at the N−C3 double bond to produce aziridines.1
Reaction of 2H-azirinylphosphine oxide 1a (R = Ph, R1 = CH3)
with methyl 2-oxobutanoate 2a (R2 = CH3) and NaH in THF
led to the formation of 4-methoxycarbonyl-3,5-dimethyl-1H-
pyrrol-2-ylphosphine oxide 3a (R = Ph, R1 = R2 = CH3;
Scheme 3, Table 1, entry 1). In the 31P NMR spectrum the
Scheme 3
The formation of these hydroxypyrrole derivatives 9 and 10
may be explained by nucleophilic addition of the enolate from
diethyl malonate to the imine bond of the azirines (Scheme 4)
followed by ring-opening of the aziridine intermediate 11 (R3 =
H) and [1,3] hydrogen rearrangement from the carbon to the
nitrogen atom with formation of intermediate 12, intra-
molecular cyclization of which may give 1,5-dihydro-3-
pyrrolin-2-one 13. The aromatization of these heterocycles 13
may give the corresponding pyrrole derivatives 9 and 10,
favored by the presence of an ethoxycarbonyl group in position
3. A procedure for the synthesis of 3-hydroxypyrrole-
phosphonates III (see Scheme 2, vide supra) by the
aromatization of 3-oxo-2-phosphonate pyrrolidines (IV) has
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Scheme 4
the formation of 1,5-dihydro-3-pyrrolin-2-ones or 1H-pyrrol-
2(5H)-ones with a phosphine oxide 17 (R = Ph) (Scheme 4,
Table 2, entries 7 and 8) or a phosphonate in the 5 position 18
(R = OEt) (Scheme 4, Table 2, entry 9). The formation of
these pyrrole derivatives 17 and 18 may be explained by
cyclocondensation of vinylogous derivatives 14 and 15 in the
presence of NaH, formation of N-protected 1,5-dihydro-3-
pyrrolin-2-ones 19, and deprotection of these heterocycles 19
(Scheme 4). This process describes the first synthesis of 1,5-
dihydro-3-pyrrolin-2-ones or 1H-pyrrol-2(5H)-ones 17 and 18
with a phosphorus-containing functional group.
Table 2. Heterocycles Obtained from Azirines and Enolates
Derived from Malonates
a
entry
compd
R
R1
yield (%)
b
1
2
3
4
5
6
7
8
9
9a
Ph
CH3
C2H5
C2H5
CH3
C2H5
CH3
CH3
C2H5
CH3
60
b
9b
Ph
72
b
10
OEt
Ph
65
b
14a
14b
15
50
b
Ph
60
b
OEt
Ph
45
c
17a
17b
18
83
c
Ph
70
c
OEt
94
CONCLUSION
a
b
■
Yield of isolated purified compounds 9, 10, 14, 15, 17, and 18. From
c
azirines 1 and 6. From vinylogous derivatives 14 and 15.
In conclusion, this account describes a simple, mild, and
convenient strategy for the selective synthesis of 1H-pyrroles 3
and 7 containing in the 2 position a phosphine oxide or a
phosphonate group by addition of enolates derived from β-keto
esters to 2H-azirinylphosphine oxide 1 and -phosphonate 6,
while the addition of enolates derived from diethyl malonate to
2H-azirines 1 and 6 led to the formation of functionalized 2-
hydroxy-1H-pyrrole-5-phosphine oxide 9 and -phosphonate 10.
However, vinylogous α-aminoalkylphosphine oxides 14 and
-phosphonate 15 may be obtained from azirines and the enolate
derived from diethyl 2-phenylmalonate. Vinylogous α-amino-
phosphorus derivatives are scarcely studied and prepared26 and
are isosteres of biologically active α-vinylglycines.27 Basic
cyclocondensation in the presence of a base (NaH) of these
substrates 14 and 15 gives 1,5-dihydro-3-pyrrolin-2-ones 17
and 18 with a phosphine oxide or a phosphonate group in 5
position. Substituted pyrroles are important building blocks in
organic synthesis,3−7 and in recent years, some specific pyrrole
derivatives such as oxypyrroles I or 1,5-dihydro-3-pyrrolin-2-
ones II (Scheme 1) gained great relevance in diastereoselective
and enantioselective preparative organic synthesis,8−11 while
phosphorus substituents regulate important biological func-
tions,13 and then molecular modifications involving the
introduction of organophosphorus functionalities in pyrrole
derivatives could be interesting because these new substituted
five membered heterocycles may be useful substrates for the
been reported.14 However, this process reported here describes,
as far as we know, the first the synthesis of 2-hydroxy-pyrroles
with a phosphine oxide 9 or a phosphonate in the 5 position
10.
However, a different behavior was observed by the reaction
of 2H-azirinylphosphine oxides 1 and - phosphonates 6 with
the enolate derived from a 2-substituted malonate. Treatment
of 2H-azirin-2-yldiphenylphosphine oxide 1a,b (R = Ph) and
2H-azirin-2-ylphosphonate 6a (R = OEt) with enolate derived
from diethyl 2-phenylmalonate 8b (R3 = Ph) and NaH at 0 °C
led exclusively to the formation of vinylogous α-amino-
alkylphosphine oxides 14 (R = Ph) (Scheme 4, Table 2,
entries 4 and 5) or -phosphonate 15 (R = OEt) (Scheme 4,
Table 2, entry 6). The selective nucleophilic addition of the
enolate of 2-phenyl diethyl malonate to the imine bond of the
azirines may explain the formation of adduct 11. Ring-opening
of the aziridine intermediate 11 with concomitant [1,5]
rearrangemnent of the carboxylate group to the nitrogen
atom may give the corresponding vinylogous α-amino-
alkylphosphine oxides 14 and -phosphonate 15.25 Vinylogous
α-aminophosphorus derivatives26 14 and 15 are isosteres of
biologically active α-vinylglycines.27
Thermal treatment of vinylogous α-aminoalkylphosphine
oxides 14 and -phosphonate 15 with NaH in reflux THF led to
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1
2
114.5 (d, JPC = 133.0 Hz), 128.4−133.5, 137.2 (d, JPC = 15.1 Hz),
preparation of biologically active compounds of interest in
medicinal chemistry.12
4
141.7 (d, JPC = 8.6 Hz), 168.8; 31P NMR (CD3OD) δ 22.5; IR
(NaCl) νmax 3155, 3082, 2958, 1698, 1169, 1127 cm−1; HRMS (ESI)
m/z calcd for C21H23NO3P [M+ + H] 368.1416, found 368.1418.
Methyl 5-Diethoxyphosphoryl-2,4-dimethyl-1H-pyrrole-3-
carboxylate (7a). Compound 7a was obtained as a yellow oil from
2H-azirine 6a using the general procedure (867 mg, 60%): Rf 0.30
EXPERIMENTAL SECTION
■
Solvents for extraction and chromatography were of technical grade.
All solvents used in reactions were freshly distilled. All other reagents
were recrystallized or distilled as necessary. All reactions were
performed under an atmosphere of dry nitrogen. Melting points are
uncorrected. IR-FT spectra were obtained as solids in KBr or as neat
oils in NaCl. Mass spectra (MS) were made by electron impact (EI) at
an ionizing voltage of 70 eV or by chemical ionization (CI) and high-
resolution mass spectra (HRMS) was measured by the EI method.1H
(300, 400 MHz), 13C (75, 100 MHz), and 31P NMR (120,160 MHz)
spectra were recorded on 300 or 400 MHz spectrometers, respectively,
in CDCl3, as specified below. Chemical shifts (δ H) are reported in
parts per million (ppm), relative to TMS as internal standard.
Chemical shifts (δC) are reported in parts per million (ppm), relative
to CDCl3, as internal standard in a broad band decoupled mode. The
abbreviations used are as follows: s, singlet; d, doublet; dd, double-
doublet; t, triplet; q, quartet; m, multiplet. Flash-column chromatog-
raphy was carried out using commercial grades of silica gel finer than
230 mesh. Analytical thin layer chromatography (TLC) was performed
on precoated silica gel 60 F254 plates, and spot visualization
wasaccomplished by UV light (254 nm) or KMnO4 solution. Azirines
1 and 6 were prepared according to literature procedure.20b
1
3
(ethyl acetate); H NMR (CD3OD) δ 1.23 (t, JHH = 7.0 Hz, 6H,
4
CH3), 2.30 (d, JPH = 1.8 Hz, 3H, CH3), 2.45 (s, 3H, CH3), 3.74 (s,
3H, OCH3), 3.91−4.06 (m, 4H, OCH2) 10.36 (s, 1H, NH); 13C NMR
(CD3OD) δ 11.9 (d, 4JPC = 3.0 Hz), 13.9 (d, 2JPC = 6.6 Hz), 16.2, 50.6
6
1
3
(d, JPC = 1.5 Hz), 62.1, 112.7 (d, JPC= 228.6 Hz), 113.1 (d, JPC
=
15.1 Hz), 132.0 (d, 2JPC= 17.1 Hz), 140.7 (d, 4JPC = 11.1 Hz) 166.0 (d,
4JPC = 2.5 Hz); 31P NMR (CD3OD) δ 11.7; IR (NaCl) νmax 3181,
3110, 2980, 2918, 1694, 1018 cm−1; HRMS (ESI) m/z calcd for
C12H21NO5P [M+ + H] 290.1157, found 290.1160.
Methyl 5-Diethoxyphosphoryl-2-methyl-4-phenyl-1H-pyr-
role-3-carboxylate (7b). Compound 7b was obtained as a white
solid from 2H-azirine 1b using the general procedure (1668 mg, 95%):
1
3
mp 157−158 °C; H NMR (CD3OD) δ 1.11 (t, JHH = 7.2 Hz, 6H,
CH3), 3.09 (d, 5JPH = 4.6 Hz, 3H, CH3), 3.60 (s, 3H OCH3), 3.83 (dq,
3JPH = 28.5 Hz, JHH = 7.2 Hz, 4H, OCH2), 7.33 (s, 5H, H-arom),
3
11.40 (s, 1H, NH); 13C NMR (CD3OD) δ 13.7, 15.9, 50.5, 62.1, 112.8
(d, 3JPC = 14.1 Hz), 113.6 (d, 1JPC = 228.6 Hz), 126.9−134.6, 135.5 (d,
2JPC = 16.6 Hz), 140.6 (d, 3JPC = 11.1 Hz) 165.4 (d, 4JPC = 2.5 Hz); 31
P
NMR (CD3OD) δ 10.3; IR (NaCl) νmax 3155, 3101, 2980, 1698,
1204, 1014 cm−1; HRMS (ESI) m/z calcd for NaC17H22NO5P [M+ +
Na] 374.1133, found 374.1137.
General Procedure for the Synthesis of Substituted Pyrrole
3 or 7. To a solution of NaH (5.5 mmol) in dry THF (15 mL) under
nitrogen atmosphere was added a solution of alkyl 2-oxobutanoate 2
(5.5 mmol). The mixture was stirred at room temperature for 1 h. A
solution of 2H-azirinylphosphine oxides 1 (R = Ph) or -phosphonates
6 (R = OEt) (5.0 mmol) in dry THF (6 mL) was added slowly under
nitrogen atmosphere. The mixture was stirred under reflux in THF for
2 or 5 h until TLC showed the disappearance of azirine. The NaH
remainder was neutralized with a saturated solution of NH4Cl, and the
solvent was evaporated under vacuum. The crude reaction was
dissolved with CH2Cl2 (25 mL) and washed with water (3 × 10 mL).
The organic layer was dried over anhydrous MgSO4 and filtered, and
the solvent was evaporated under vacuum. The crude product was
purified by chromatography using silica gel (hexane/ethyl acetate) to
yield the compounds 3 or 7 as white solid or as yellow oil.
General Procedure for the Synthesis of Substituted Pyrrole
9 and 10. To a solution of NaH (5.5 mmol) in dry THF (15 mL) at
0 °C under nitrogen atmosphere was added a solution of diethyl
malonate 8a (5.5 mmol). The mixture was stirred at the same
temperature for 1 h. A solution of 2H-azirinylphosphine oxides 1 (R =
Ph) or -phosphonates 6 (R = OEt2) (5 mmol) in dry THF (6 mL) was
slowly added at 0 °C under nitrogen atmosphere. The mixture was
stirred at room temperature for 2 or 5 h until TLC showed the
disappearance of azirine. The NaH remainder was neutralized with a
saturated solution of NH4Cl. The crude reaction was extracted with
CH2Cl2 (3 × 10 mL) and washed with water (3 × 10 mL). The
organic layer was dried over anhydrous MgSO4 and filtered, and the
solvent was evaporated under vacuum. The crude product was purified
by crystallization from CH2Cl2/hexane 1/1 or chromatography using
silica gel hexane/ethyl acetate 1/1 to yield the compound 9 or 10 as a
brown solid or as a colorless oil.
Methyl 5-Diphenylphosphoryl-2-hydroxy-4-methyl-1H-pyr-
role-3-carboxylate (9a). Compound 9a was obtained as a brown
solid from 2H-azirine 1a as described in the general procedure (1236
mg, 67%): mp 225−226 °C; 1H NMR (CD3OD) δ 1.32 (t, 3JHH = 7.2
Hz, 3H, CH3), 1.98 (d, JPH = 1.9 Hz, 3H, CH3) 4.30 (q, JHH = 7.2
Hz, 2H, OCH2), 7.41−7.70 (m, 10H, CH-arom), 9.60 (s, 1H, OH),
9.92 (s, 1H, NH); 13C NMR (CD3OD) δ 12.5, 14.4, 60.1, 95.1 (d, 3JPC
Methyl 5-Diphenylphosphoryl-2,4-dimethyl-1H-pyrrole-3-
carboxylate (3a). Compound 3a was obtained as a white solid
from 2H-azirine 1a using the general procedure (1059 mg, 60%): mp
236−237 °C; 1H NMR (CD3OD) δ 1.89 (d, 4JPH = 1.5 Hz, 3H, CH3),
2.42 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 7.36−7.69 (m, 10H, H-arom),
10.41 (s, 1H, NH); 13C NMR (CD3OD) δ 12.8, 13.9, 50.6, 113.3 (d,
1
3JPC = 11.1 Hz), 115.4 (d, JPC = 133.0 Hz), 128.4−133.2, 130.7 (d,
2JPC = 14.6 Hz), 141.0 (d, 4JPC = 8.1 Hz) 166.1; 31P NMR (CD3OD) δ
4
3
21.9; IR (NaCl) νmax 3154, 3081, 3037, 2958, 1698, 1438, 1169, 1125
cm−1; HRMS (ESI) m/z calcd for C20H21NO3P [M+ + H] 354.1254,
found 354.1253.
1
2
= 10.6 Hz), 108.7 (d, JPC = 136.5 Hz), 128.3 (d, JPC = 13.1 Hz),
Ethyl 5-Diphenylphosphoryl-2,4-dimethyl-1H-pyrrole-3-car-
boxylate (3b). Compound 3b was obtained as a white solid from
2H-azirine 1b using the general procedure (1101 mg, 60%): mp 241−
242 °C; 1H NMR (CD3OD) δ 1.27 (t, 3JHH = 7.2 Hz, 3H, CH3), 1.91
(s, 3H, CH3), 2.45 (s, 3H, CH3), 4.21 (q, 3JHH = 7.2 Hz, 2H, OCH2),
7.22−7.67 (m, 10H, CH-Arom), 10.44 (s, 1H, NH); 13C NMR
(CD3OD) δ 12.8, 14.2, 14.4, 59.3, 113.6 (d, 3JPC = 11.6 Hz), 115.4 (d,
128.5−133.3, 156.3 (d, JPC = 10.6 Hz), 168.4; 31P NMR (CD3OD) δ
4
20.9; IR (NaCl) νmax 3279, 3056, 2923, 2762, 1717, 1650, 1192, 1120
cm−1; HRMS (ESI) m/z calcd for NaC20H20NO4P [M+ + Na]
392.1028, found 392.1024.
Ethyl 5-Diphenylphosphoryl-4-ethyl-2-hydroxy-1H-pyrrole-
3-carboxylate 9b. Compound 9b was obtained as a brown solid
from 2H-azirine 1b as described in the general procedure (1379 mg,
72%) as a brown solid: mp 231−232 °C; H NMR (CD3OD) δ 0.71
(t, JHH = 6.6 Hz, 3H, CH3), 1.32, (t, JHH = 7.0 Hz, 3H, CH3), 2.35
2
1JPC = 133.0 Hz), 128.5−133.3, 130.7 (d, JPC = 14.6 Hz), 140.9 (d,
1
4JPC = 8.1 Hz), 165.9; 31P NMR (CD3OD) δ 21.9; IR (NaCl) νmax
3
3
3136, 3087, 3029, 2980, 1699, 1436, 1160, 1116 cm−1; HRMS (ESI)
m/z calcd for C21H23NO3P [M+ + H] 368.1416, found 368.1425.
Methyl 5-Diphenylphosphoryl-4-ethyl-2-methyl-1H-pyrrole-
3-carboxylate (3c). Compound 3c was obtained as a white solid
from 2H-azirine 1c using the general procedure (1376 mg, 75%): mp
245−246 °C; 1H NMR (CD3OD) δ 0.57 (t, 3JHH = 7.3 Hz, 3H, CH3),
3
3
(q, JHH = 6.6 Hz, 2H, CH2), 4.30 (q, JHH = 7.0 Hz, 2H, OCH2),
7.27−7.80 (m, CH-Arom), 9.64 (s, 1H, OH), 10.04 (s, 1H, NH); 13C
3
NMR (CD3OD) δ 14.2, 14.8, 19.8, 60.0, 94.0 (d, JPC = 10.6 Hz),
1
2
107.6 (d, JPC = 136.0 Hz), 128.4−132.0, 133.5, 134.9 (d, JPC = 13.6
Hz), 156.7 (d, 3JPC = 11.1 Hz), 168.1; 31P NMR (CD3OD) δ 21.4; IR
(NaCl) νmax 3292, 3136, 2980, 2900, 1654, 1200, 1120 cm−1; HRMS
(ESI) m/z calcd for C21H23NO4P [M+ + H] 384.1365, found
384.1366.
3
2.37 (q, JHH = 7.3 Hz, 2H, CH2), 2.49 (s, 3H, CH3), 3.77 (s, 3H,
OCH3), 7.40−7.68 (m, 10H, CH-arom), 11.21 (s, 1H, NH); 13C
3
NMR (CD3OD) δ 14.2, 14.6, 19.9, 50.5, 112.1 (d, JPC = 11.1 Hz),
9475
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Article
Ethyl 5-Diethoxyphosphoryl-4-ethyl-2-hydroxy-1H-pyrrole-
3-carboxylate (10). Compound 10 was obtained as a colorless oil
from 2H-azirine 6a as described in the general procedure (1037 mg,
65%): Rf 0.44 (ethyl acetate); 1H NMR (CD3OD) δ 1.08 (t, 3JHH = 7.3
phenylmalonate 8 (5 mmol). The mixture was stirred with reflux in
THF for 1−2 h until TLC showed the disappearance of compound 14
or 15. The NaH remainder was neutralized with a saturated solution of
NH4Cl, and the solvent was evaporated under vacuum. The crude
reaction was disolved with CH2Cl2 (25 mL) and washed with water (3
× 10 mL). The organic layer was dried over anhydrous MgSO4 and
filtered, and the solvent was evaporated under vacuum. The crude
product was purified by chromatography using silica-gel hexane/ethyl
acetate 1/1 to yield the compounds 17 or 18 as a colorless or a pale
yellow oil.
3
3
Hz, 3H, CH3), 1.27 (t, JHH = 7.0 Hz, 6H, CH3), 1.28 (t, JHH = 7.3
Hz, 3H, CH3), 2.67 (q, 3JHH = 7.3 Hz, 2H, CH2), 4.02 (dq, 3JPH = 23.8
3
3
Hz, JHH = 7.3 Hz, 4H, OCH2), 4.27 (q, JHH = 7.0 Hz, 2H, OCH2)
9.62 (s, 1H, OH), 9.89 (s, 1H, NH); 13C NMR (CD3OD) δ 14.5, 15.7,
2
1
16.4, 19.8, 60.3, 62.3, 94.1 (d, JPC = 14.1 Hz), 104.7 (d, JPC = 235.2
Hz), 135.7 (d, JPC = 16.6 Hz), 156.4 (d, JPC = 15.1 Hz), 168.5; 31P
NMR (CD3OD) δ 12.1; IR (NaCl) νmax 3279, 3074, 2980, 1721,
1663, 1232, 1014 cm−1; HRMS (ESI) m/z calcd for C13H23NO6P [M+
+ H] 320.1258, found 320.1253.
3
4
5-(Diphenylphosphoryl)-3-methyl-4-phenyl-1H-pyrrol-2-
(5H)-one (17a). Compound 17a was obtained as a colorless oil from
14a as described in the general procedure (1548 mg, 83%): Rf = 0.20
1
4
General Procedure for the Synthesis of α-Aminoalkylphos-
phine Oxides 14 and -phosphonate 15. To a solution of NaH
(5.5 mmol) in dry THF (15 mL) at 0 °C under nitrogen atmosphere
was added a solution of diethyl 2-phenylmalonate 8 (5.5 mmol). The
mixture was stirred at the same temperature for 1 h. A solution of 2H-
azirinylphosphine oxides 1 (R = Ph) or -phosphonates 6 (R = OEt) (5
mmol) in dry THF (6 mL) was added slowly at 0 °C under nitrogen
atmosphere. The mixture was stirred at room temperature for 2 or 5 h
until TLC showed the disappearance of azirine. The NaH remainder
was neutralized with a saturated solution of NH4Cl, and the solvent
was evaporated under vacuum. The crude reaction was dissolved with
CH2Cl2 (25 mL) and washed with water (3 × 10 mL). The organic
layer was dried over anhydrous MgSO4 and filtered, and the solvent
was evaporated under vacuum. The crude product was purified by
chromatography using silica gel (hexane/ethyl acetate) to yield the
compounds 14 or 15 as a white solid.
(ethyl acetate); H NMR (CD3OD) δ 2.19 (d, JPH = 2.2 Hz, 3H,
2
CH3), 5.19 (d, JPH = 14.2 Hz, 1H, CH-P), 6.41 (s, 1H, NH), 6.99−
7.92 (m, 15H, CH-Arom); 13C NMR (CD3OD) δ 14.8, 61.3 (d, 1JPC
=
2
3
72.0 Hz), 125.3−133.0, 134.3 (d, JPC = 6.0 Hz), 150.5 (d, JPC = 5.0
Hz), 172.9; 31P NMR (CD3OD) δ 29.9; IR (NaCl) νmax 3176, 3065,
1721, 1690, 1441, 1178 cm−1; HRMS (ESI) m/z calcd for
C23H21NO2P [M+ + H] 374.1310, found 374.1311.
5-(Diphenylphosphoryl)-3-ethyl-4-phenyl-1H-pyrrol-2-(5H)-
one (17b). Compound 17b was obtained as a pale yellow oil from
14b as described in the general procedure: (1355 mg, 70%): Rf 0.22
1
3
(ethyl acetate); H NMR (CD3OD) δ 1.16 (t, JHH = 7.5 Hz, 3H,
CH3), 2.62 (q, 3JHH = 7.5 Hz, 2H, CH2), 5.26 (d, 2JPH = 14.5 Hz, 1H,
CH-P), 6.91−7.86 (m, 15H, CH-Arom); 13C NMR (CD3OD) δ 13.7,
1
2
21,4, 58.7 (d, JPC = 72.5 Hz), 125.4−132.8, 133.8 (d, JPC = 5.5 Hz),
156.3 (d, JPC = 4.5 Hz), 173.2; 31P NMR (CD3OD) δ 30.1; IR
4
(NaCl) νmax 3176, 3065, 2967, 2932, 2869, 1677, 1432, 1196 cm−1
;
Ethyl 4-(Diphenylphosphoryl)-4-((ethoxycarbonyl)amino)-3-
methyl-2-phenylbut-2-enoate (14a). Compound 14a was ob-
tained as a white solid from 2H-azirine 1a as described in the general
HRMS (ESI) m/z calcd for C24H23NO2P [M++H] 388.1466, found
388.1474.
5-(diethoxyphosphoryl)-3-methyl-4-phenyl-1H-pyrrol-2-
(5H)-one 18. Compound 18 was obtained as a pale yellow oil from
15 as described in the general procedure (1.452 g, 94%): Rf 0.16 (ethyl
acetate); 1H NMR (CD3OD) δ 1.32 (t, 3JHH = 7.0 Hz, 6H, CH3), 2.28
(d, 4JPH = 2.4 Hz, 3H, CH3), 4.40 (q, 3JHH = 7.0 Hz, 4H, OCH2), 5.45
1
procedure (1227 mg, 50%): mp 93−94 °C; H NMR (CD3OD) δ
1.07−1.26 (m, 3JHH = 7.2 Hz, 6H, CH3), 2.27 (s, 3H, CH3), 3.97−4.21
3
2
(m, JHH = 7.2 Hz, 4H, OCH2), 5.58 (t, JPH = 9.2 Hz, 1H, CH-P),
6.30 (d, 3JHH = 3.8 Hz, 1H, NH), 6.81−7.91 (m, 15H, CH-Arom); 13
C
NMR (CD3OD) δ 13.8, 13.9, 17.1, 52.3 (d, 1JPC = 73.0 Hz), 60.5, 61.1,
2
(d, JPH = 18.6 Hz, 1H, CH-P), 7.25- 7.69 (m, 6H, H-Arom y NH);
127.4−132.6, 134.8, 135.8, 155.6 (d, JPC = 7.6 Hz), 167.9; 31P NMR
3
3
1
13C NMR (CD3OD) δ 14.5, 16.4 (d, JPC = 4.0 Hz), 58.5 (d, JPC
=
(CD3OD) δ 35.1; IR (NaCl) νmax 3203, 3056, 2976, 1708, 1534, 1249,
1196 cm−1; HRMS (ESI) m/z calcd for C28H31NO5P [M+ + H]
492.1934, found 492.1934.
4
2
152.1 Hz), 63.5, 128.1−129.4, 130.8 (d, JPC = 2.0 Hz), 133.9 (d, JPC
= 8.1 Hz), 148.0 (d, 3JPC = 7.6 Hz), 173.1 (d, 3JPC = 2.0 Hz); 31P NMR
(CD3OD) δ 18.1; IR (NaCl) νmax 3199, 3065, 2980, 1686, 1245, 1009,
729 cm−1; HRMS (ESI) m/z calcd for C15H21NO4P [M+ + H]
310.1203, found 310.1208.
Ethyl 3-((Diphenylphosphoryl)((ethoxycarbonyl)amino)-
methyl)-2-phenylpent-2-enoate (14b). Compound 14b was
obtained as a white solid from 2H-azirine 1b as described in the
general procedure (1515 mg, 60%): mp 122−123 °C; 1H NMR
(CD3OD) δ 1.08−1.22 (m, 3JHH = 7.0 Hz, 9H, CH3), 2.76 (dq, 4JPH
=
ASSOCIATED CONTENT
3
3
■
36.8 Hz, JHH = 7.0 Hz, 2H, CH2), 3.99−4.21 (m, JHH = 7.0 Hz, 4H,
2
S
* Supporting Information
OCH2), 5.57 (t, JPH = 9.5 Hz, 1H, CH-P), 6.18 (s, 1H, NH), 6.74−
7.95 (m, 15H, CH-Arom); 13C NMR (CD3OD) δ 13.8, 14.2, 14.8,
1H NMR and 13C NMR for compounds 3a−c, 7a,b, 9a,b, 10,
14a,b, 15, 17a,b, and 18. This material is available free of
charge via the Internet at http://pubs.acs.org/
1
23.9, 52.6 (d, JPC = 73.0 Hz), 60.4−61.5, 127.5−131.9, 135.1, 141.3,
2
155.6 (d, JPC = 9.1 Hz), 167.7; 31P NMR (CD3OD) δ 35.4; IR
(NaCl) νmax 3430, 3061, 2967, 2927, 1472, 1436, 1196, 1120 cm−1
;
HRMS (ESI) m/z calcd for C29H33NO5P [M+ + H] 506.2096, found
506.2106.
AUTHOR INFORMATION
■
Ethyl 4-(Diethoxyphosphoryl)-4-((ethoxycarbonyl)amino)-3-
methyl-2-phenylbut-2-enoate (15). Compound 15 was obtained
as a white solid from 2H-azirine 6a as described in the general
procedure (961 mg, 45%): mp 80−81 °C; 1H NMR (CD3OD) δ 1.22
(t, 3JHH = 7.1 Hz, 6H, CH3), 1.29 (t, 3JHH = 7.0 Hz, 6H, CH3), 2.11 (d,
Corresponding Author
*E-mail: francisco.palacios@ehu.es
ACKNOWLEDGMENTS
4JPH = 3.2 Hz, 3H, CH3), 3.88−4.31 (m, 8H, OCH2), 4.90 (dd, 2JPH
=
■
22.8 Hz, 3JHH = 9.1 Hz, 1H, CH-P), 5.66 (s, 1H, NH), 7.28−7.56 (m,
We thank the Direccio
́
́n del
3
5H, CH-Arom); 13C NMR (CD3OD) δ 14.0, 14.4, 16.0, 16.2 (d, JPC
Ministerio de Ciencia e Innovacio
CTQ2009-12156BQU) and the Universidad del Pais Vasco -
Departamento de Educacion Universidades e Investigacion of
Gobierno Vasco (UPV, GIU/09/57; IT-422-10) for support of
this work. A.V.d.B. thanks the Ministerio de Educacio
́
1
= 12.6 Hz), 50.8 (d, JPC = 150.6 Hz), 60.7−66.7, 127.7−129.5, 135.0
́
3
(d, 2JPC = 12.1 Hz), 135.7, 136.9, 155.3 (d, JPC = 11.1 Hz), 168.0 (d,
́
́
4JPC = 1.5 Hz); 31P NMR (CD3OD) δ 21.1; IR (NaCl) νmax 3244,
2985, 1708, 1530, 1499, 1218, 1022 cm−1; HRMS (ESI) m/z calcd for
́n
C20H31NO7P [M++H] 428.1838, found 428.1840.
(Madrid) for a predoctoral fellowship. We also thank SGIker
technical support for NMR spectra (MICINN, GV/EJ, and
European Social Found).
General Procedure for the Synthesis of Substituted Pyrroles
17 and 18. To a solution of NaH (5.5 mmol) in dry THF (15 mL)
under nitrogen atmosphere was added a solution of substituted
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Article
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