Regioselective alkylation reactions of enamines derived from phosphane oxides - Synthesis of phosphorus substituted enamino esters, δ-amino-phosphonates, pyridone derivatives and pyrroles

Article abstract of DOI:10.1002/1099-0690(200109)2001:17<3357::AID-EJOC3357>3.0.CO;2-J

α-Substituted (2-iminoalkyl)phosphane oxides were obtained from the azaenolates of imines or enamines and alkyl halides. The functionalized imines or enamines thus obtained were used for the synthesis of δ-amino esters, δ-amino phosphonates and heterocycl

Full text of DOI:10.1002/1099-0690(200109)2001:17<3357::AID-EJOC3357>3.0.CO;2-J

FULL PAPER
Regioselective Alkylation Reactions of Enamines Derived from Phosphane
Oxides ؊ Synthesis of Phosphorus Substituted Enamino Esters,
δ-Amino-phosphonates, Pyridone Derivatives and Pyrroles
[a]
[a]
[a]
[a]
´
´
Francisco Palacios,* Domitila Aparicio, Jesus Garcıa, Javier Vicario, and
[b]
´
´
Jose Marıa Ezpeleta
Keywords: Enamines / Alkylation / Nitrogen heterocycles / Phosphane oxides
α-Substituted (2-iminoalkyl)phosphane oxides were obtained
from the azaenolates of imines or enamines and alkyl hal-
phonates and heterocycles such as 3,4-dihydropyridin-2-
ones, 2-pyridones and pyrroles containing a phosphinyl sub-
ides. The functionalized imines or enamines thus obtained stituent.
were used for the synthesis of δ-amino esters, δ-amino phos-
Introduction
tuted (2-iminoalkyl)phosphane oxides (II) from N-
metalated β-posphinylenamines (I) (Scheme 1). These α-
functionalized β-imines (II) are a versatile tool for the
formation of δ-amino esters (IIIa; E ϭ CO2R) or δ-amino
phosphonates [IIIb; E ϭ PO(OR)2] and for the construction
of phosphorus-containing five and six-membered hetero-
cycles such as pyrroles (IV) and 2-pyridone derivatives (V).
Enamines have attracted a great deal of attention in re-
cent years because of their range of applications,[1] and en-
amines stabilized through conjugation with an electron-
withdrawing group have also been extensively used as ver-
satile key intermediates in organic synthesis.[2,3] In particu-
lar, metaloenamines,[4] carbanions derived from enamines
or enolizable imines, are useful substrates for the regio- and
stereoselective carbonϪcarbon bond formation reaction
with alkylating agents.[5] We are interested in the design of
new nitrogen-containing acyclic and cyclic derivatives bear-
ing a phosphane oxide moiety. This substituent could regu-
late important biological functions and increase the biolo-
gical activity of these compounds, in a similar way to that
reported for other pharmaceuticals,[6] and has recently been
used for the design of organic solids.[7] In this context, we
have described the synthesis of three-,[8] five-[9] and six-
membered[10] phosphorus-substituted nitrogen heterocycles
from enamines and imines derived from phosphazenes or
phosphane oxides. β-Functionalized enamines derived from
phosphane oxides and phosphonates are also used as syn-
thetic intermediates in the synthesis of acyclic derivatives
such as α,β-unsaturated imines[11a] allylamines,[11b,11c] 1-az-
adienes derived from γ-amino esters,[11d] and β-amino-func-
tionalized compounds,[11e] as well as of phosphorus-con-
taining heterocycles.[12] Continuing with our interest in the
chemistry of new phosphorus-substituted compounds, we
report here an easy and regioselective synthesis of α-substi-
Scheme 1
Results and Discussion
Reaction of N-metalated β-Phosphinylenamines with Alkyl
Halides
[a]
´
´
Departamento de Quımica Organica I, Facultad de Farmacia,
´
Universidad del Paıs Vasco
Apartado 450, 01080 Vitoria, Spain
N-metalated enamines have recently been prepared from
aziridines,[13] although they used to be obtained by treat-
ment of primary or secondary enamines or enolizable im-
ines with bases. Simple imines will deprotonate regioselec-
tively on the less substituted side, forming an azaenolate,[4,5]
which can then be alkylated. But in our case, the presence
[b]
´
Departamento de Fısica Aplicada, Facultad de Farmacia,
´
Universidad del Paıs Vasco
Apartado 450, 01080 Vitoria, Spain
Fax: (internat.) ϩ34-945/130-756
E-mail: qoppagaf@vf.ehu.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
Eur. J. Org. Chem. 2001, 3357Ϫ3365
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0917Ϫ3357 $ 17.50ϩ.50/0
3357

´
F. Palacios, D. Aparicio, J. Garcıa, J. Vicario, J. M. Ezpeleta
FULL PAPER
of an excellent anion stabilizing group such as phosphane ine 3a (see Table 1, entry 2) was obtained in moderate to
oxide could control the deprotonation at the internal car- good yields, and in a regioselective fashion, when ethyl
bon. Enamines and imines derived from phosphane oxides bromide was used. Compounds 3 were characterized on the
1/1Ј were easily prepared by addition of achiral and chiral basis of their spectroscopic data. Thus, the 31P NMR spec-
amines to allenes.[11c] In the case of N-aliphatic derivatives, trum of compound 3a showed an absorption at δP ϭ 30.9.
these compounds were obtained as mixures of E- and Z- Likewise, the 1H and 13C NMR spectra gave a multiplet for
enamines, while in the case of N-aromatic compounds, they the methine proton at δH ϭ 3.44 and a well resolved doub-
were obtained as mixtures of β-imino (major) and β-enam- let at δC ϭ 55.0 with a coupling constant of 1JPC ϭ 62.9 Hz
ino (minor) phosphane oxides. The deprotonation of func- for the carbon atom directly bonded to the phosphinyl moi-
tionalized enamines and/or imines 1/1Ј with methyllithium ety.
in THF (N-aromatic enamines/imines were metalated at 0
The scope of the reaction was not limited to simple alkyl
°C whereas N-aliphatic enamines were metalated at lower halides (ethyl bromide), given that functionalized alkyl hal-
temperatures) gave the azaenolates 2, which were then al- ides such as allyl or propargyl halides, ethyl 3-bromopro-
kylated with alkyl halides (Scheme 2). Mixtures of β-imino pionate or diethyl (2-bromoethyl)phosphonate also reacted
and β-enamino phosphane oxides could be used without with aza-enolates 2 to give the α,α-difunctionalized imines
separation for this metalation as the reaction with both en- 3 (see Table 1, entries 3Ϫ11), while the use of ethyl bro-
amino or imino derivatives gave lithium enamides (lithium moacetate afforded the E isomer of the tautomeric β-en-
azaenolates). After aqueous workup, the α-substituted im- amine 3Ј (see Table 1, entry 1). This methodology, used for
the preparation of α-functionalized β-imines 3, can also be
extended to chiral β-phosphinylenamines when chiral N-(α-
methylbenzyl)enamine derivatives were used (see Table 1,
entries 6Ϫ8).
Reaction of N-metalated β-Phosphinylenamines with Ethyl
Chloroformate: N- vs. Cα-Acylation
The acylation of enamines gives access to a wide variety
of acyclic and cyclic derivatives.[2b] Enamines are ambident
nucleophilic reagents (N vs. Cα) and the course of the acyl-
ation reaction is often critically dependent upon the type of
enamine used, on the substituent present in the two re-
agents and on the experimental conditions.[14] The regiose-
lective Cα-acylation of N-tolyl-functionalized phosphane
oxides (R1 ϭ p-CH3-Ph) 1/1Ј was accomplished using
methyllithium as the base followed by the addition of ethyl
chloroformate, at 0 °C, and the (α-phosphinyl-β-enamino)-
ester 4 was obtained as a mixture of the Z- and E-isomers
(see Table 1, entry 12). However, when the acylation reac-
Scheme 2. Reaction of N-metalated β-phosphinyl enamines with
alkyl halides
Table 1. α-Functionalized imines and enamines 3Ϫ5 obtained
Entry
Compound
R1
R2
Yield (%)[a]
M.p. (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
3Ј
3a
3b
3c
3d
3e
3f
3g
3h
3i
p-CH3-Ph
p-CH3ϪPh
p-CH3ϪPh
p-CH3ϪPh
CH2ϪCO2Et
Et
CH2ϪCHϭCH2
CH2ϪCH2ϪPO(OEt)2
CH2ϪCϵCH
CH2ϪCH2ϪCO2Et
CH2ϪCH2ϪPO(OEt)2
CH2ϪCϵCH
CH2ϪCH2ϪCO2Et
CH2ϪCH2ϪPO(OEt)2
CH2ϪCϵCH
-
-
-
-
-
79
82
81
73
176Ϫ177
174Ϫ175
121Ϫ122
132Ϫ133
119Ϫ120
Oil
p-CH3ϪPh
81[b]
84[b]
78[b]
84
(S)-PhϪCHϪCH3
(S)-PhϪCHϪCH3
(S)-PhϪCHϪCH3
Ph2CH
Ph2CH
Ph2CH
p-CH3ϪPh
p-CH3ϪPh
(S)-PhϪCHϪCH3
(R)-PhϪCHϪCH3
(Ϯ)-PhϪCHϪCH3
Oil
Oil
84
68
106Ϫ107
124Ϫ125
113Ϫ114
122Ϫ123
115Ϫ116
122Ϫ123
122Ϫ123
106Ϫ107
3j
91
4
83[c]
69
5a
5b
5c
5d
74
74
74
[a]
[b]
[c]
Yield obtained from enamines and/or imines 1/1Ј. Ϫ Obtained as a 1:1 mixture of (S,R) and (S,S) diastereoisomers. Ϫ Obtained
as a 1:1 mixture of Z and E isomers.
3358
Eur. J. Org. Chem. 2001, 3357Ϫ3365

Regioselective Alkylation Reactions of Enamines Derived from Phosphane Oxides
FULL PAPER
tion of achiral (R1 ϭ p-CH3-Ph, rac-PhϪCHϪCH3) and tionalized primary amines derived from δ-amino esters 10
chiral [R1 ϭ (R)-, (S)-PhϪCHϪCH3] compounds 1/1Ј was and phosphonates 11 (Table 2, entries 7,8). δ-Amino phos-
carried out at low temperature (Ϫ78 °C), only the (E)-N- phonates are constituents of phosphapeptide antibiotics
acylated β-enaminophosphane oxides 5aϪd were isolated such as Plumbeomicin[18a] or Rhizocticin[18b] and have
(see Table 1, entries 13Ϫ16). Compounds 5 were character-
ized on the basis of their spectroscopic data and a crystal
structure determination for 5b. Acid hydrolysis of 5a led to
the formation of ethyl N-tolylcarbamate 6 and β-ketophos-
Table 2. Secondary and primary amines 8, 9, 10, 11 and pyridone
derivatives 13, 14 obtained
Entry Compound R1
R2 Yield (%) M.p. (°C)
phane oxide 7 (see Scheme 3).
1
2
3
4
5
6
7
8
9
10
11
12
13
8a
(S)-PhϪCHϪCH3
Ph2CH
p-CH3ϪPh
(S)-PhϪCHϪCH3
Ph2CH
p-CH3ϪPh
H
H
p-CH3ϪPh
p-CH3OϪPh
(S)-PhϪCHϪCH3
Ph2CH
H
H
H
H
H
H
H
H
H
86,[a] 81[b] Oil
8b
91,[a] 84[b] Oil
8c
62,[b] 64[c] 104Ϫ105
9a
87[a]
Oil
9b
85,[a] 80[b] Oil
9c
77,[a] 70[b] 108Ϫ109
10
89[d]
85[e]
83[b]
Oil
Oil
146Ϫ147
159Ϫ160
11
13a
13b
13c
13d
14
CH3 78[b]
H
H
80,[a] 79[b] 142Ϫ143
81,[a] 77[b] 101Ϫ102
p-CH3OϪPh
CH3 69[f]
162Ϫ163
[a]
[b]
Yield obtained from imines 3. Ϫ
Yield obtained from en-
[c]
amines and/or imines 1/1Ј. Ϫ Yield obtained from dihydropyri-
done 13a. Ϫ
Yield obtained by deprotection of imine 9b. Ϫ Yield obtained
from dihydropyridone 13b.
[d]
[e]
Yield obtained by deprotection of imine 8b. Ϫ
Scheme 3. Reaction of N-metalated β-phosphinyl enamines with
ethyl chloroformate
[f]
Reduction of Functionalized Imines 3c,e,f,h,i: Synthesis of
the δ-Amino Esters 8,10 and δ-Amino Phosphonates 9,11
A variety of reducing agents, such as hydrogen in the
presence of metal catalysts,[15,16] and simple or modified hy-
drides,[15,17] have been developed for the conversion of im-
ine group into amines. In our case, reduction of the imino
CϭN double bond of functionalized imines 3c,e,f,h,i was
achieved when these derivatives were treated with sodium
cyanoborohydride in the presence of a Lewis acid such as
zinc chloride. Reduction of the previously prepared achiral
and chiral imines 3 with NaBH3CN/ZnCl2 in EtOH at re-
flux for 12Ϫ24 hours led to the formation of the δ-amino
esters 8a,b (E ϭ CO2Et, Table 2, entries 1, 2) or δ-amino
phosphonates 9aϪc [E ϭ PO(OEt)2, Table 2, entries 4Ϫ6]
(see Scheme 4) containing a phosphane oxide group in the
γ-position. They were obtained as mixtures of two diastere-
omers. From a preparative point of view, it is of interest
that the synthesis of the δ-amino esters 8 and phosphonates
9 does not require the isolation and purification of the im-
ines 3, and the former can be obtained in one pot from the
phosphane oxides 1/1Ј after alkylation, evaporation of the
solvent and reduction with the hydride (Table 2, entries
1Ϫ3,5,6). Spectroscopic data support the structure of com-
pounds 8 and 9. The 13C NMR spectra of products 8 and
9 show the presence of a new signal at δ ϭ 48Ϫ50 belonging
to the CϪN bond and the absence of the typical signal for
the CϭN group (in the range of δ ϭ 150Ϫ170). The select-
ive removal of the benzhydryl group of N-substituted
δ-amino esters 8b and phosphonates 9b was achieved by
Scheme 4. Cyclization and reduction of α-substituted (2-iminoalk-
catalytic hydrogenation [Pd(OH)2/C], affording func- yl)phosphane oxides
Eur. J. Org. Chem. 2001, 3357Ϫ3365
3359

´
F. Palacios, D. Aparicio, J. Garcıa, J. Vicario, J. M. Ezpeleta
FULL PAPER
proved to be potent antagonists of N-methyl--aspartic acid carbonϪcarbon, carbonϪoxygen or carbonϪnitrogen
(NMDA) displaying anticonvulsant activity.[18cϪ18h]
bonds from allenes[22] or propargyl derivatives.[23] Similarly,
electrophile-mediated cyclization is an efficient route to ni-
trogen-containing heterocycles,[24] and palladium-mediated
cyclizations are particularly attractive in this sense espe-
cially when allene[25] or propargyl[26] systems are used as the
π-components. For this reason, we envisaged that achiral
and chiral propargylic-substituted β-imines derived from
the phosphane oxides 3d,g,j could be used for the synthesis
of phosphinylated pyrroles by Pd0- and PdII-catalyzed re-
gioselective heterocyclization reactions. Thus, treating the
β-imines derived from the phosphane oxides 3d,g,j with
bromobenzene, catalytic amounts of Pd(PPh3)4 and K2CO3
in DMF at 60 °C, and aqueous workup (Scheme 5, method
A), led to the formation of the achiral and chiral pyrroles
15aϪc (R2 ϭ Ph) in moderate yields and in a regioselective
fashion (see Table 3, entries 1Ϫ3). The spectroscopic data
and mass spectrometry were in agreement with the pro-
Cyclization of Imines 3e,3h: Synthesis of the
Phosphinylated 2-Pyridone Derivatives 13 and 14
The imines derived from ethyl 3-bromopropionate (3e
and 3h) can be used for the construction of six-membered
heterocycles containing a phosphinyl substituent in the 5-
position of the heterocyclic system. Thus, the compounds
3e and 3h (E ϭ CO2Et) were cyclocondensed with methylli-
thium as the base to give the achiral and chiral 5-phosphin-
ylated 3,4-dihydropyridin-2-ones 13c and 13d in excellent
yields (Table 2, entries 11,12). Likewise, the phosphinylated
3,4-dihydropyridin-2-ones 13a؊d were directly prepared
from the phosphane oxides 1/1Ј, a base (methyllithium) and
ethyl bromopropionate (Table 2, entries 9Ϫ12). Com-
pounds 13 were characterized on the basis of their spectro-
scopic data. Thus, the 31P NMR of compound 13a showed
1
posed structure for pyrroles 15. In the H NMR spectrum
1
an absorption at δP ϭ 31.5, while the H NMR spectrum
of pyrrole 15a the signal for the methine proton appears at
showed multiplet signals for the CH2 groups (δH ϭ 2.14,
δH ϭ 2.56) and the 13C NMR spectrum gave three well-
resolved doublets at δC ϭ 23.8 (3JPC ϭ 11.2 Hz) for one
methylene carbon, at δC ϭ 31.2 (2JPC ϭ 7.5 Hz) for two
methylene carbons, and at δC ϭ 105.4 (1JPC ϭ 109.5 Hz)
for the carbon atom directly bonded to the phosphinyl moi-
ety of 13a. As far as we know, this strategy leads to the
first examples of 3,4-dihydropyridin-2-ones 13 containing
phosphinyl substituents in the ring system. The formation
of heterocycles 13 can be explained by a cyclization reaction
of the aza-enolates 12 derived from imines 3 (E ϭ CO2Et)
followed by the loss of ethanol (Scheme 4).
Reduction of the previously prepared 3,4-dihydropyridin-
2-one 13a (R1 ϭ p-CH3ϪPh) with NaBH3CN/ZnCl2 in re-
fluxing EtOH led to the formation of the δ-amino ester 8c
(E ϭ CO2Et, R1 ϭ p-CH3ϪPh, Table 2, entry 3) containing
a phosphane oxide group in the γ-position, while the oxida-
tion of the phosphinylated 3,4-dihydropyridin-2-one 13b
(R1 ϭ p-CH3OϪPh) with cerium(IV) ammonium nitrate
(CAN) in acetonitrile gave 2-pyridone (14) (see Scheme 4,
Table 2, entry 13). A solid-phase approach to 3,4-dihy-
dropyridin-2-ones has been reported recently.[19a] These het-
erocycles are potential calcium channel modulators[19b] and
have been used for the synthesis of peptides[19c] and
alkaloids,[19dϪ19f] while the pyridin-2-one substructure is
found in many biologically active natural and synthetic
compounds that possess medicinal properties.[20,21] During
the preparation of this manuscript, a synthesis of 2-pyri-
dones with a phosphane oxide substituent for the design of
organic solids was reported.[7]
δ
H ϭ 5.70 with a coupling constant of 3JPH ϭ 3.8 Hz, while
the 13C NMR spectrum of this compound shows a signal at
δC ϭ 107.9 (1JPC ϭ 128.9 Hz) for the carbon atom directly
bonded to the phosphinyl moiety (C-3), as well as doublets
at δC ϭ 110.4 (2JPC ϭ 13.1 Hz) and at δC ϭ 137.1 (2JPC
ϭ
16.6 Hz) and a singlet at δC ϭ 138.4, for the heterocyclic
carbon atoms C-4, C-2 and C-5, respectively. The formation
of these heterocycles may be supposed to proceed by gen-
eration of the σ-vinylpalladium complexes 17 via an intram-
olecular regioselective trans addition of the enamino NH to
the palladium-allyl system 16.[25] The reductive elimination
of Pd0 and isomerization would afford the pyrroles 15
(Scheme 5).
This process can be extended to the preparation of pyr-
roles 15d,e,f (R2 ϭ H) by treating the β-imines derived from
phosphane oxides 3d,j,g with catalytic amounts of
Pd(OAc)2 and K2CO3 in DMF at 60 °C and aqueous
workup (Scheme 5, method B; Table 3, entries 4Ϫ6). Al-
ternatively, the phosphinylated pyrroles 15 were prepared in
a one-pot reaction from β-enamines and/or imines 1/1Ј and
propargyl bromide, when the crude adducts 3d,j were dir-
ectly treated with bromobenzene, without their prior isola-
tion, catalytic amounts of Pd(PPh3)4 and K2CO3 in DMF
(R2 ϭ Ph) or catalytic amounts of Pd(OAc)2 and K2CO3 in
DMF (R2 ϭ H) and aqueous workup (Table 3, entries
1,2,4). Pyrrole ring systems are important in organic chem-
istry because they constitute the skeleton of natural prod-
ucts such as alkaloids, and some antibiotics and poly-
mers.[27]
In conclusion, the synthesis described in this paper pro-
vides an efficient and easy access to α-functionalized β-im-
ines substituted with a phosphane oxide group, making use
of readily available starting materials. These functionalized
imines can serve as intermediates in the synthesis of acyclic
Palladium-Catalyzed Cyclization Reaction of the α-
Propargyl β-Imino Phosphane Oxides 3d,g,j: Synthesis of
the Phosphinylated Pyrroles 15 and 18
The palladium-catalyzed allylation of carbon, oxygen or compounds such as δ-amino esters and δ-amino phosphon-
nitrogen nucleophiles is widely recognized as one of the ates, as well as of new nitrogen heterocycle compounds such
most powerful synthetic tools for the construction of as 5-phosphinylated-3,4-dihydropyridin-2-ones or 2-pyri-
3360
Eur. J. Org. Chem. 2001, 3357Ϫ3365

Regioselective Alkylation Reactions of Enamines Derived from Phosphane Oxides
FULL PAPER
(EIMS) on a Hewlett Packard 5971 or 5973 spectrometer, or by
chemical ionization (CI) on a Hewlett Packard 1100MSD. Data
are reported in the form m/z (intensity relative to base ϭ 100).
Infrared spectra (IR) were recorded on a Nicolet IRFT Magna 550
spectrometer, and were obtained as solids in KBr or as neat oils.
Peaks are reported in cmϪ1. Elemental analyses were performed in
a LECO CHNS-932 apparatus. [α]2D0 measurements were taken on
a PerkinϪElmer 341 polarimeter using a Na/HaI lamp. Enamines
and/or imines 1/1Ј were synthesized according to literature proced-
ures.[11c]
General Procedure for the Alkylation of Imines and/or Enamines 1/
1Ј Derived from Phosphane Oxides: To a solution of aromatic en-
amine/imine 1/1Ј at Ϫ78 °C or a solution of aliphatic enamine 1 at
0 °C (both 5 mmol) in THF (15 mL) was added a 1.6  methylli-
thium solution in diethyl ether (5 mmol). The mixture was allowed
to stir at this temperature for 1 h. A solution of alkyl halide
(6 mmol) in THF (5 mL) was then added at the same temperature.
After the mixture was allowed to warm to room temp., the reaction
mixture was stirred at this temperature until TLC indicated the
disappearance of the enamine and/or imine 1/1Ј. The mixture was
then diluted with water (50 mL) and extracted with CH2Cl2 (3 ϫ
25 mL). The combined organic layers were washed with water,
dried over MgSO4 and concentrated under vacuum. The crude res-
idue was purified by flash column chromatography eluting with
AcOEt/hexanes (3:1).
Scheme 5. Palladium-catalyzed cyclization reaction of α-propargyl
(2-iminoalkyl)phosphane oxides
Ethyl 3-(Diphenylphosphinyl)-4-(p-tolylamino)pent-3-enoate (3Ј):
Synthesized according to the general procedure with ethyl bro-
moacetate (0.67 mL, 6 mmol), affording 1.71 g (79%) of 3Ј as a
white solid. M.p.: 176Ϫ177 °C. Ϫ 1H NMR: δ ϭ 7.63Ϫ7.15 (m, 14
Table 3. Pyrroles obtained
Entry Compound R1
R2 Yield (%) M.p. (°C)
2
1
2
3
4
5
6
15a
15b
15c
15d
15e
15f
p-CH3ϪPh
Ph 70,[a] 65[b] 131Ϫ132
Ph 76,[a] 72[b] 142Ϫ143
H), 3.92 (m, 1 H), 3.77 (m, 1 H), 3.37 (d, JHH ϭ 17.0 Hz, 1 H),
2
2.77 (d, JHH ϭ 17.0 Hz, 1 H), 2.30 (s, 3 H), 1.67 (s, 1 H), 1.43 (s,
Ph2CH
(S)-PhϪCHϪCH3 Ph 74[a]
105Ϫ106
3 H), 1.11Ϫ1.02 (m, 3 H). Ϫ 13C NMR: δ ϭ 170.0, 154.8 (d, 2JPC ϭ
p-CH3ϪPh
Ph2CH
(S)-PhϪCHϪCH3
H
H
H
69,[a] 63[b] 153Ϫ154
1
17.6 Hz), 138.6Ϫ128.2 (m), 103.8 (d, JPC ϭ 126.4 Hz), 60.4, 41.1,
73[a]
78[a]
165Ϫ166
121Ϫ122
31
˜
21.2, 15.3, 14.0. Ϫ P NMR: δ ϭ 24.6. Ϫ IR (KBr): ν ϭ 2992,
1739, 1616 cmϪ1. Ϫ MS: m/z (%) ϭ 433 (24) [Mϩ]. Ϫ C26H28NO3P
(433.48): calcd. C 72.04, H 6.51, N 3.23; found C 71.97, H 6.48,
N 3.19.
[a]
[a]
Yield obtained from propargyl imines 3. Ϫ
Yield obtained
from enamines and/or imines 1/1Ј.
[2-(Diphenylphosphinyl)-1-methylbutylidene]-p-tolylamine (3a): Syn-
thesized according to the general procedure with ethyl iodide
(0.48 mL, 6 mmol), affording 1.53 g (82%) of 3a as a white solid.
M.p.: 174Ϫ175 °C. Ϫ 1H NMR: δ ϭ 7.91Ϫ6.04 (m, 14 H), 3.44
(m, 1 H), 2.20 (s, 3 H), 1.78 (s, 3 H), 1.76 (m, 2 H), 0.96 (t, 3JHH ϭ
7.5 Hz, 3 H). Ϫ 13C NMR: δ ϭ 168.9, 147.8Ϫ118.7 (m), 55.0 (d,
dones as well as 3-phosphinylated-pyrroles, in a stepwise
fashion or in a one-pot reaction.
Experimental Section
3
1JPC ϭ 62.9 Hz), 20.7, 19.2, 18.2, 12.7 (d, JPC ϭ 5.1 Hz). Ϫ 31P
NMR: δ ϭ 30.9. Ϫ IR (KBr): ν ϭ 2959, 1634, 1450 cmϪ1. Ϫ MS:
˜
General: Chemicals were purchased from Aldrich. Solvents for ex-
traction and chromatography were technical grade. All solvents
used in reactions were freshly distilled from appropriate drying
m/z (%) ϭ 375 (60) [Mϩ]. Ϫ C24H26NOP (375.45): calcd. C 76.78,
H 6.98, N 3.73; found C 76.69, H 6.93, N 3.78.
agents before use. All other reagents were recrystallized or distilled General Procedure for the C- and N-acylation of Enamines and/or
as necessary. All reactions were performed under an atmosphere of Imines 1/1Ј Derived from Phosphane Oxides: A 1.6  methyllithium
dry nitrogen. Analytical TLC was performed with Merck silica gel solution in diethyl ether (5 mmol) was added to a solution of en-
60 F254 plates. Visualization was accomplished by UV light. Flash
chromatography was carried out using Merck silica gel 60
amine and/or imine 1/1Јderived from phosphane oxide (5 mmol) in
THF (15 mL) at 0 °C (for C-acylation) or Ϫ78 °C (for N-acylation).
(230Ϫ400 mesh ASTM). Melting points were determined with an The mixture was allowed to stir at this temperature for 1 h. A solu-
Electrothermal IA9100 Digital Melting Point Apparatus and are tion of ethyl chloroformate 0.57 mL (6 mmol) in THF (5 mL) was
uncorrected. 1H (300 MHz), 13C (75 MHz) and 31P NMR then added at the same temperature. After the mixture was allowed
(120 MHz) spectra were recorded on a Varian VXR 300 MHz spec-
trometer using CDCl3 solutions with TMS as an internal reference
to warm to room temp., the reaction mixture was stirred until TLC
indicated the disappearance of the enamine and/or imine 1/1Ј. The
mixture was then diluted with water (50 mL) and extracted with
CH2Cl2 (3 ϫ 25 mL). The combined organic layers were washed
with water, dried over MgSO4 and concentrated under vacuum.
The crude residue was purified by flash column chromatography
1
(δ ϭ 0.00) for H and 13C NMR spectra and 85% phosphoric acid
(δ ϭ 0.0) for 31P NMR spectra. Chemical shifts (δ) are reported in
ppm. Coupling constants (J) are reported in Hertz. Low-resolution
mass spectra (MS) were obtained at 50Ϫ70 eV by electron impact
Eur. J. Org. Chem. 2001, 3357Ϫ3365
3361

´
F. Palacios, D. Aparicio, J. Garcıa, J. Vicario, J. M. Ezpeleta
FULL PAPER
eluting with AcOEt/hexanes (1:4) in the case of C-acylation or pre-
and 4.75 (s, 1 H), 4.02Ϫ3.74 (m, 5 H), 3.07Ϫ2.98 (m, 1 H), 2.51
cipitated from diethyl ether and recrystallized from hexanes/dichlo- and 2.16 (m, 1 H), 2.16Ϫ1.90 (m, 2 H), 1.65Ϫ1.53 (m, 2 H),
romethane in the case of N-acylation.
1.23Ϫ1.05 (m, 9 H). Ϫ 13C NMR: δ ϭ 144.5Ϫ126.4 (m), 64.5, 63.5,
1
3
61.6, 61.4, 50.1, 49.5, 43.0 and 44.9 (2 dd, JPC ϭ 69.5 Hz, JPC
ϭ
Ethyl 2-(Diphenylphosphinyl)-3-p-tolylaminobut-2-enoate (4): Syn-
thesized according to the general procedure with the corresponding
enamine/imine 1/1Ј (5 mmol), affording 1.74 g (83%) of a mixture
of isomers 4 (E/Z ϭ 1:1) as a white solid. M.p.: 122Ϫ123 °C. Ϫ
1H NMR: δ ϭ 12.50 (s, 1 H), 7.86Ϫ6.99 (m, 14 H), 3.81Ϫ3.69 (m,
2 H), 2.48 (s, 3 H), 2.34 and 2.33 (s, 3 H), 0.76 and 0.61 (2 t,
14.1 Hz and 1JPC ϭ 67.5 Hz, 3JPC ϭ 12.1 Hz), 25.1 and 24.8 (2 dd,
3
1
3
1JPC ϭ 139.0 Hz, JPC ϭ 8.1 Hz and JPC ϭ 139.0 Hz, JPC
ϭ
7.1 Hz), 19.3, 19.1, 17.2, 17.1, 16.3, 16.1. Ϫ 31P NMR: δ ϭ 31.4,
28.9, 30.7, 30.1. Ϫ IR (film): ν ϭ 2985, 1699, 1435 cmϪ1. Ϫ MS:
˜
m/z (%) ϭ 590 (100) [Mϩ ϩ 1]. Ϫ C34H41NO4P2 (589.65): calcd. C
69.26, H 7.01, N 2.38; found C 69.20, H 6.97, N 2.42.
3
3JHH ϭ 7.3 Hz and JHH ϭ 7.3 Hz, 3 H). Ϫ 13C NMR: δ ϭ 173.0
2
2
and 171.2 (2 d, JPC ϭ 4.0 Hz and JPC ϭ 13.6 Hz), 169.9 and
The δ-amino esters 8a؊c and δ-amino phosphonates 9b,c can also
be obtained in a one-pot reaction: To a solution of aromatic en-
amine/imine 1/1Ј at Ϫ78 °C or a solution of aliphatic enamine 1 at
0 °C (each 5 mmol) in THF (15 mL) was added a 1.6  methylli-
thium solution in diethyl ether (5 mmol). The mixture was allowed
to stir at this temperature for 1 h. A solution of alkyl halide
(6 mmol) in THF (5 mL) was then added at the same temperature.
After the mixture was allowed to warm to room temp., it was
stirred for 12 h. The resulting solution was then concentrated under
vacuum, diluted with EtOH (15 mL) and a previously prepared so-
lution of NaBH3CN and ZnCl2 in EtOH (10 mL) was then added.
The mixture was stirred and refluxed for 24 h. and then was con-
centrated under vacuum, washed with NaOH (0.1 , 50 mL) and
extracted with CH2Cl2 (3 ϫ 25 mL). The combined organic layers
were washed with water, dried over MgSO4 and concentrated under
vacuum. The crude residue was purified by flash column chromato-
graphy eluting with AcOEt/hexanes (4:1 or 1:4) to afford 1.88 g
(81%) of 8a, 2.20 g (84%) of 8b, 1.39 g (62%) of 8c, 2.51 g (85%)
of 9b or 1.79 g (70%) of 9c.
167.4 (2 d, 2JPC ϭ 11.1 Hz and 2JPC ϭ 12.1 Hz), 137.6Ϫ126.0 (m),
1
1
85.6 and 81.2 (2 d, JPC ϭ 123.7 Hz and JPC ϭ 112.3 Hz), 59.3,
3
3
58.8, 20.9, 20.2 and 19.3 (d, JPC ϭ 8.0 Hz and JPC ϭ 3.5 Hz),
31
˜
13.8, 13.3. Ϫ P NMR: δ ϭ 42.2, 31.0. Ϫ IR (KBr): ν ϭ 2924,
1690, 1608 cmϪ1. Ϫ MS: m/z (%) ϭ 419 (46) [Mϩ]. Ϫ C25H26NO3P
(419.46): calcd. C 71.59, H 6.25, N 3.34; found C 71.50, H 6.20,
N 3.38.
Ethyl [2-(Diphenylphosphinyl)-1-methylvinyl]-p-tolylcarbamate (5a):
Synthesized according to the general procedure with the corres-
ponding enamine/imine 1/1Ј (5 mmol), affording 1.44 g (69%) of 5a
1
as a white solid. M.p.: 115Ϫ116 °C. Ϫ H NMR: δ ϭ 7.71Ϫ6.92
2
3
(m, 14 H), 6.00 (d, JPH ϭ 19.2 Hz, 1 H), 4.11 (q, JHH ϭ 7.2 Hz,
4
3
2 H), 2.27 (s, 3 H), 2.12 (d, JPH ϭ 1.5 Hz, 3 H), 1.13 (t, JHH
ϭ
7.2 Hz, 3 H). Ϫ 13C NMR: δ ϭ 155.1 (d, JPC ϭ 10.6 Hz), 153.2,
136.9Ϫ126.6 (m), 111.2 (d, 1JPC ϭ 108.3 Hz), 61.4, 20.2 (d, 3JPC ϭ
4.0 Hz), 19.6, 13.5. Ϫ 31P NMR: δ ϭ 22.4. Ϫ IR (KBr): ν˜ ϭ 2919,
1705, 1620 cmϪ1. Ϫ MS: m/z (%) ϭ 419 (44) [Mϩ]. Ϫ C25H26NO3P
(419.46): calcd. C 71.59, H 6.25, N 3.34; found C 71.67, H 6.21,
N 3.30
2
General Procedure for the Synthesis of the Primary δ-Amino esters
10 and the Primary δ-Amino Phosphonates 11: A solution of δ-
amino ester 8b or δ-amino phosphonate 9b (5 mmol) and Pd(OH)2/
C 20% (0.35 g, 0.5 mmol) in EtOH (15 mL) was stirred under a
hydrogen atmosphere (80 psi) until TLC indicated the disappear-
ance of the starting material (3Ϫ4 days). The mixture was then
filtered through celite, washed with a 10% aqueous solution of cit-
ric acid (50 mL) and extracted with AcOEt (3 ϫ 25 mL). The com-
bined organic layers were washed with water, dried over MgSO4
and concentrated under vacuum.
General Procedure for the Synthesis of δ-Amino Esters 8 and δ-Am-
ino Phosphonates 9: To a suspension of ZnCl2 (0.68 g, 5 mmol) in
EtOH (10 mL) was added NaBH3CN (0.63 g, 10 mmol). After
10 min. stirring a solution of δ-imino ester or δ-iminophosphonate
3 (5 mmol) in EtOH (10 mL) was added. The reaction mixture was
stirred and refluxed until TLC indicated the disappearance of the
imine 3 (12Ϫ24 h). The mixture was then concentrated under va-
cuum, washed with NaOH (0.1 , 50 mL) and extracted with
CH2Cl2 (3 ϫ 25 mL). The combined organic layers were washed
with water, dried over MgSO4 and concentrated under vacuum.
The crude residue was purified by flash column chromatography
eluting with AcOEt/hexanes (4:1).
Ethyl 5-Amino-4-(diphenylphosphinyl)hexanoate (10): Synthesized
according to the general procedure with a mixture of δ-amino es-
ters 8b (2.56 g, 5 mmol), affording 1.60 g (89%) of a mixture of
diastereoisomers 10 (de ϭ 50%) as a pale yellow oil. Rf ϭ 0.09
Ethyl 5-(Benzhydrylamino)-4-(diphenylphosphinyl)hexanoate (8b):
Synthesized according to the general procedure with δ-iminoester
3h (2.62 g, 5 mmol), affording 2.39 g (91%) of a mixture of diaster-
eoisomers 8b (de ϭ 50%) as a pale yellow oil. Rf ϭ 0.08 (AcOEt).
1
(AcOEt). Ϫ H NMR: δ ϭ 7.82Ϫ7.11 (m, 10 H), 5.92 and 5.81 (s,
2 H), 4.08Ϫ3.87 (m, 2 H), 2.47Ϫ1.43 (m, 6 H), 1.35Ϫ1.10 (m, 3
3
3
H), 1.01 and 0.98 (2 d, JHH ϭ 6.4 Hz and JHH ϭ 6.4 Hz, 3 H).
1H NMR: δ ϭ 7.80Ϫ7.00 (m, 20 H), 4.84 and 4.76 (s, 1 H),
Ϫ
13C NMR: δ ϭ 173.7, 171.3, 133.2Ϫ126.0 (m), 60.3, 48.3, 47.4,
39.5 and 37.3 (2 d, JPC ϭ 71.0 Hz and JPC ϭ 71.0 Hz), 31.5 and
Ϫ
1
1
4.04Ϫ3.89 (m, 3 H), 3.05Ϫ2.94 (m, 1 H), 2.76 and 2.49 (m, 1 H),
2.22Ϫ2.00 (m, 4 H), 1.17Ϫ1.09 (m, 6 H). Ϫ 13C NMR: δ ϭ 172.7
and 172.4, 144.2Ϫ126.1 (m), 64.0, 63.3, 59.8, 49.5, 49.1, 41.3 and
38.8 (2 d, 1JPC ϭ 69.5 Hz and 1JPC ϭ 68.9 Hz), 32.9 and 32.3 (2 d,
3
3
30.6 (2 d, JPC ϭ 12.1 Hz and JPC ϭ 11.9), 23.8 and 23.4 (2 d,
3JPC ϭ 16.3 Hz and JPC ϭ 11.9), 21.4, 21.3, 14.1. Ϫ 31P NMR:
3
δ ϭ 32.7, 32.3. Ϫ IR (film): ν ϭ 3051, 1725, 1672 cmϪ1. Ϫ MS: m/
˜
z (%) ϭ 360 (100) [Mϩ ϩ 1]. Ϫ C20H26NO3P (359.40): calcd. C
3
3JPC ϭ 8.6 Hz and JPC ϭ 7.6 Hz), 19.1, 17.8, 18.9 and 17.8 (2 d,
3
3JPC ϭ 10.9 Hz and JPC ϭ 8.9 Hz), 13.8. Ϫ 31P NMR: δ ϭ 35.9
66.84, H 7.29, N 3.90; found C 66.75, H 7.33, N 3.87.
and 33.0. Ϫ IR (film): ν ϭ 2979, 1733, 1447 cmϪ1. Ϫ MS: m/z
˜
Diethyl [4-Amino-3-(diphenylphosphinyl)pentyl]phosphonate (11):
Synthesized according to the general procedure with the mixture
of δ-amino phosphonates 9b (2.95 g, 5 mmol), affording 1.80 g
(%) ϭ 526 (100) [Mϩ ϩ 1]. Ϫ C33H36NO3P (525.63): calcd. C 75.41,
H 6.90, N 2.66; found C 75.35, H 6.84, N 2.67.
Diethyl
[4-(Benzhydrylamino)-3-(diphenylphosphinyl)pentyl]phos-
(85%) of a mixture of diastereoisomers 11 (de ϭ 50%) as a pale
1
phonate (9b): Synthesized according to the general procedure with yellow oil. Rf ϭ 0.05 (AcOEt). Ϫ H NMR: δ ϭ 7.79Ϫ7.10 (m, 12
δ-iminophosphonate 3i (2.94 g, 5 mmol), affording 2.50 g (85%) of H), 4.05Ϫ3.82 (m, 4 H), 2.42Ϫ2.15 (m, 1 H), 2.17Ϫ1.42 (m, 5 H),
a mixture of diastereoisomers 9b (de ϭ 50%) as a pale yellow oil.
1.27Ϫ1.08 (m, 9 H). Ϫ 13C NMR: δ ϭ 132.3Ϫ126.0 (m), 61.7, 61.6,
1
1
3
1
Rf ϭ 0.10 (AcOEt). Ϫ H NMR: δ ϭ 7.81Ϫ7.00 (m, 20 H), 4.82 56.3 and 55.7 (2 dd, JPC ϭ 55.4 Hz, JPC ϭ 10.6 Hz and JPC
ϭ
3362 Eur. J. Org. Chem. 2001, 3357Ϫ3365

Regioselective Alkylation Reactions of Enamines Derived from Phosphane Oxides
FULL PAPER
3
55.4 Hz, JPC ϭ 11.0 Hz), 47.3, 47.2, 29.7, 29.6, 23.9 and 22.8 (2 a saturated solution of NaCl (100 mL) and water (100 mL). The
1
3
1
3
dd, JPC ϭ 142.5 Hz, JPC ϭ 8.5 Hz and JPC ϭ 142.6 Hz, JPC
ϭ
combined organic layers were dried over MgSO4 and concentrated
6.9 Hz), 20.1, 20.0, 16.4, 16.3. Ϫ 31P NMR: δ ϭ 31.5, 30.1, 31.4, under vacuum. The crude residue was purified by crystallization
29.1. Ϫ IR (film): ν˜ ϭ 2984, 1693, 1486 cmϪ1. Ϫ MS: m/z (%) ϭ from diethyl ether, affording 1.48 g (69%) of 14 as a white solid.
424 (100) [Mϩ ϩ 1]. Ϫ C21H31NO4P2 (423.43): calcd. C 59.57, H M.p.: 162Ϫ163 °C. Ϫ 1H NMR: δ ϭ 7.64Ϫ6.95 (m, 14 H), 6.86
7.38, N 3.31; found C 59.49, H 7.34, N 3.29.
(dd, 3JPH ϭ 10.8 Hz, 3JHH ϭ 9.5 Hz, 1 H), 6.32 (dd, 4JPH ϭ 2.6 Hz
3
3JHH ϭ 9.5 Hz, 1 H), 3.78 (s, 3 H), 2.82 (q, JHH ϭ 7.2 Hz, 2 H),
General Procedure for the Synthesis of the N-aryl Dihydropyridones
13a and 13b: To a Ϫ78 °C solution of aromatic enamine/imine 1/
1Ј(5 mmol) in THF (15 mL) was added a 1.6  methyllithium solu-
tion in diethyl ether. The mixture was allowed to stir at this temper-
ature for 1 h. and a solution of ethyl 3-bromopropionate (0.48 mL,
6 mmol) in THF (5 mL) was then added. After the mixture was
allowed to warm to room temp., the reaction mixture was stirred
until TLC indicated the disappearance of the aromatic imine/en-
3
2
0.64 (t, JHH ϭ 7.2 Hz, 3 H). Ϫ 13C NMR: δ ϭ 162.0 (d, JPC
ϭ
2
15.1 Hz),159.7, 142.0 (d, JPC ϭ 12.1 Hz), 133.4Ϫ114.1 (m), 117.0
(d, JPC ϭ 12.0 Hz), 107.4 (d, JPC ϭ 114.2 Hz), 55.5, 25.7, 13.1.
3
1
31
Ϫ1
˜
P NMR: δ ϭ 30.2. Ϫ IR (KBr): ν ϭ 3012, 1694, 1629 cm .
Ϫ
Ϫ MS: m/z (%) ϭ 430 (100) [Mϩ ϩ 1]. Ϫ C26H24NO3P (429.45):
calcd. C 72.72, H 5.63, N 3.26; found C 72.81, H 5.60, N 3.28.
General Procedure for the Synthesis of Pyrroles 15. Procedure A: A
amine 1/1Ј. The mixture was then diluted with water (50 mL) and solution of K2CO3 (3.46 g, 25 mmol), phenyl bromide (1.05 mL,
extracted with CH2Cl2 (3 ϫ 25 mL). The combined organic layers
were washed with water, dried over MgSO4 and concentrated under
vacuum. The crude residue was purified by crystallization from di-
ethyl ether.
10 mmol), Pd(PPh3)4 (0.115 g, 0.1 mmol) and imine 3d,g,j (5 mmol)
in DMF (20 mL) was stirred at 60 °C until TLC indicated the dis-
appearance of the starting material (6Ϫ12 h). The mixture was di-
luted with water (50 mL) and extracted with AcOEt (3 ϫ 25 mL).
The combined organic layers were washed with water (50 mL),
dried over MgSO4 and concentrated under vacuum. The crude res-
idue was purified by flash column chromatography eluting with
AcOEt/hexanes (3:1).
5-(Diphenylphosphinyl)-6-methyl-1-p-tolyl-3,4-dihydro-1H-pyridin-
2-one (13a). Synthesized according to the general procedure
withthe corresponding enamine/imine 1/1Ј (5 mmol), affording
1.66 g (83%) of 13a as a white solid. M.p.: 146Ϫ147 °C. Ϫ 1H
NMR: δ ϭ 7.85Ϫ7.03 (m, 14 H), 2.56 (m, 2 H), 2.30 (s, 3 H), 2.14 Procedure B: A solution of K2CO3 (3.46 g, 25 mmol), Pd(OAc)2
2
(m, 2 H), 1.86 (s, 3 H). Ϫ 13C NMR: δ ϭ 170.2, 150.9 (d, JPC
ϭ
(0.023 g, 0.1 mmol) and the imine 3d,g,j (5 mmol) in DMF (20 mL)
1
15.5 Hz), 132.8Ϫ128.5 (m), 105.4 (d, JPC ϭ 109.5 Hz), 31.2 (d, was stirred at 60 °C until TLC indicated the disappearance of the
3
3
2JPC ϭ 7.5 Hz), 23.8 (d, JPC ϭ 11.2 Hz), 21.0, 19.8 (d, JPC
ϭ
starting material (6Ϫ12 h). The mixture was then diluted with
5.0 Hz). Ϫ 31P NMR: δ ϭ 31.5. Ϫ IR (KBr): ν ϭ 3061, 1694, 1620 water (50 mL) and extracted with AcOEt (3 ϫ 25 mL). The com-
˜
cmϪ1. Ϫ MS: m/z (%) ϭ 401 (80) [Mϩ]. Ϫ C25H24NO2P: calcd. C
bined organic layers were washed with water (50 mL), dried over
MgSO4 and concentrated under vacuum. The crude residue was
purified by flash column chromatography eluting with AcOEt/hex-
anes (1:3).
74.80, H 6.03, N 3.49; found C 73.75, H 5.99, N 3.47.
General Procedure for the Synthesis of N-alkyl Dihydropyridones
13c and 13d: To a solution of imine 3e or 3h (5 mmol) in THF
(15 mL) at 0 °C was added a 1.6  methyllithium solution in diethyl
5-Benzyl-3-(diphenylphosphinyl)-2-methyl-1-p-tolyl-1H-pyrrole
ether (5 mmol). The mixture was allowed to stir at this temperature (15a): The general procedure A was followed using imine 3d (1.93 g,
for 1 h. After the mixture was allowed to warm to room temp. it 5 mmol), affording 1.61 g (70%) of 15a as a white solid. M.p.:
was stirred until TLC indicated the disappearance of 3e or 3h. The
131Ϫ132 °C. Ϫ 1H NMR: δ ϭ 7.75Ϫ6.74 (m, 19 H), 5.70 (d,
mixture was then diluted with water (50 mL) and extracted with 3JPH ϭ 3.8 Hz, 1 H), 3.57 (s, 2 H), 2.31 (s, 3 H), 1.95 (s, 3 H). Ϫ
CH2Cl2 (3 ϫ 25 mL). The combined organic layers were washed
13C NMR: δ ϭ 138.4, 137.1 (d, 2JPC ϭ 16.6 Hz), 135.7Ϫ127.8 (m),
2
1
with water, dried over MgSO4 and concentrated under vacuum.
110.4 (d, JPC ϭ 13.1 Hz), 107.9 (d, JPC ϭ 128.9 Hz), 32.7, 21.1,
The crude residue was purified by crystallization from diethyl ether. 14.0. Ϫ 31P NMR: δ ϭ 24.6. Ϫ IR (KBr): ν˜ ϭ 2919, 1507 cmϪ1
.
Ϫ MS: m/z (%) ϭ 461 (100) [Mϩ]. Ϫ C31H28NOP (461.54): calcd.
5-(Diphenylphosphinyl)-6-methyl-1-[1-(S)-phenylethyl]-3,4-dihydro-
1H-pyridin-2-one (13c): Synthesized according to the general pro-
C 80.67, H 6.11, N 3.03; found C 80.74, H 6.08, N 3.07.
cedure with imine 3e (2.31 g, 5 mmol), affording 1.65 g (80%) of 3-(Diphenylphosphinyl)-2,5-dimethyl-1-p-tolyl-1H-pyrrole (15d): The
13c as a white solid. M.p.: 142Ϫ143 °C. Ϫ [α]2D0 ϭ Ϫ13.1 (c ϭ 1.09,
general procedure B was followed using imine 3d (1.93 g, 5 mmol),
affording 1.32 g (69%) of 15d as a white solid. M.p.: 153Ϫ154 °C.
Ϫ H NMR: δ ϭ 7.73Ϫ6.97 (m, 14 H), 5.56 (d, JPH ϭ 3.7 Hz, 1
H), 2.34 (s, 3 H), 1.99 (s, 3 H), 1.77 (s, 3 H). Ϫ 13C NMR: δ ϭ
138.4, 137.0 (d, 2JPC ϭ 17.1 Hz), 135.5Ϫ127.7 (m), 110.3 (d, 2JPC ϭ
1
3
CH2Cl2). Ϫ H NMR: δ ϭ 7.74Ϫ7.09 (m, 15 H), 5.45 (q, JHH
ϭ
1
3
6.6 Hz, 1 H), 2.45 (m, 2 H), 2.05 (m, 2 H), 1.95 (s, 3 H), 1.91 (d
2
3JHH ϭ 6.6 Hz, 3 H). Ϫ 13C NMR: δ ϭ 170.3, 151.5 (d, JPC
ϭ
1
16.1 Hz), 133.2Ϫ126.1 (m), 109.1 (d, JPC ϭ 108.8 Hz), 60.3, 32.0
(d, JPC ϭ 7.2 Hz), 23.2 (d, JPC ϭ 11.1 Hz), 19.8, 13.7. Ϫ 31P 12.9 Hz), 107.7 (d, 1JPC ϭ 138.4 Hz), 21.1, 12.7, 12.6. Ϫ 31P NMR:
NMR: δ ϭ 30.9. Ϫ IR (KBr): ν˜ ϭ 3033, 1700, 1632 cmϪ1. Ϫ MS: δ ϭ 24.7. Ϫ IR (KBr): ν˜ ϭ 3017, 1519 cmϪ1. Ϫ MS: m/z (%) ϭ
m/z (%) ϭ 416 (100) [Mϩ ϩ 1]. Ϫ C26H26NO2P (415.47): calcd. C 385 (75) [Mϩ]. Ϫ C25H24NOP (385.44): calcd. C 77.90, H 6.28, N
2
3
75.16, H 6.31, N 3.37; found C 73.25, H 6.29, N 3.34.
3.63; found C 80.01, H 6.30, N 3.64.
Procedure for the Synthesis of 5-(Diphenylphosphinyl)-6-ethyl-1-(4-
X-ray Crystallography for 5b: Single-crystal X-ray diffraction ex-
methoxyphenyl)-1H-pyridin-2-one (14): A solution of ceric ammo- periments were carried out on a EnrafϪNonius CAD-4 diffracto-
nium nitrate (CAN) (8.22 g, 15 mmol) in water (50 mL) was added
to a solution of N-aryl dihydropyridone 13b (2.16 g, 5 mmol) in
meter using graphite-monochromated Mo-Kα radiation (λ ϭ 0.7173
A). A prismatic crystal of dimensions 0.21 ϫ 0.16 ϫ 0.11 mm was
˚
acetonitrile (30 mL) at 0 °C. The mixture was allowed to stir at used for data collection. Crystal data: orthorhombic (space group
˚
this temperature for 1 h. and water (300 mL) was then added. The
P212121), a ϭ 8.659(2), b ϭ 10.673(2), c ϭ 25.455(11) A, V ϭ
mixture was extracted with AcOEt (3 ϫ 50 mL) and the organic 2352.5(12) A ,ρcalcd. ϭ 1.224 g·cmϪ3. Data collection was per-
3
˚
layer was sequentially washed with a 20% aqueous solution of
formed at 293 K, with 2θmax ϭ 50° and θϪ2θ scans. The total num-
Na2SO3 (3 ϫ 50 mL), a saturated solution of KHCO3 (100 mL), ber of measured reflections was 4660, of which 4139 were inde-
Eur. J. Org. Chem. 2001, 3357Ϫ3365
3363

´
F. Palacios, D. Aparicio, J. Garcıa, J. Vicario, J. M. Ezpeleta
FULL PAPER
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squares against |F|2; all reflections were considered (SHELXL-
97[30]). The total number of parameters was 284, and all H atoms
were generated using geometrical criteria and refined isotropically.
Final values for R indices: Rw(all) ϭ 0.1269, Rw(obs) ϭ 0.1083,
R(all) ϭ 0.0736 and R(obs) ϭ 0.0391. Residual electron density:
min. ϭ Ϫ0.204 and max ϭ 0.268.
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´
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icio, J. Garcıa, Tetrahedron 1998, 54, 1647Ϫ1656. Ϫ [10d] F. Pal-
´
Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-152699. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK [Fax: (internat.) ϩ44-1223/336-033; E-mail:
deposit@ccdc.cam.ac.uk].
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´
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´
´
´
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´
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Acknowledgments
This work was supported by The University of the Basque Country
(UPV-170.123-G11/99), the Direccion General de Ensen˜anza Su-
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´
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´
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´
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