Conjugate addition to 1-phosphono-2-aza-1,3-butadienes: Synthesis of phosphonylated γ-lactams

Article abstract of DOI:10.1021/jo0488661

(Chemical Equation Presented). Several 1-phosphono-2-aza-1,3-butadienes, 1 and 13-20, were evaluated in the reaction with different enolate-type nucleophiles to induce addition at the 1- or the 4-position of the azadiene. 1-Phosphono-2-azadienes 1 react w

Full text of DOI:10.1021/jo0488661

Conjugate Addition to 1-Phosphono-2-aza-1,3-butadienes:
Synthesis of Phosphonylated γ-Lactams
Bart Vanderhoydonck and Christian V. Stevens*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University,
Coupure links 653, B-9000 Ghent, Belgium
Chris.Stevens@UGent.be
Received July 5, 2004
Several 1-phosphono-2-aza-1,3-butadienes, 1 and 13-20, were evaluated in the reaction with
different enolate-type nucleophiles to induce addition at the 1- or the 4-position of the azadiene.
1-Phosphono-2-azadienes 1 react with sodium malonate at the 1-position, leading to the formation
of bisenamines 12 after elimination of the phosphonate moiety. On the contrary, sodium malonate
adds at the 4-position of 1-aryl-1-phosphono-2-azadienes 14-19 when the azadienes bear a
halogenated phenyl substituent, and the resulting addition products 21-26 are easily transformed
into the corresponding phosphonylated γ-lactams 35-40. The regioselectivity of the addition is
explained by reversal of polarization of the azadiene due to the electron-withdrawing character of
the halogenated phenyl substituents.
Introduction
represent an interesting class of such electron-poor
2-azadienes and may be useful intermediates for the
synthesis of cyclic as well as acyclic R-aminophosphonate
derivatives.1 R-Aminophosphonates are promising bio-
active compounds5,6 since they mimic the transition states
during peptide hydrolysis6 and can be considered as
surrogates for R-amino acids.7 In fact, several R-amino-
phosphonic acids are reported to act as enzyme inhibi-
tors,8 antibacterial agents,9 or neurotransmitters10 and
have been used as haptens for the generation of catalytic
monoclonal antibodies.11 Also, some aminoalkylbisphos-
phonic acid derivatives have gained importance as anti-
inflammatory agents and can be used for the treatment
of disorders in calcium metabolism.12 Nevertheless, the
Being key intermediates in organic synthesis for the
construction of both heterocyclic systems and acyclic
polyfunctionalized compounds, substituted 2-aza-1,3-
butadienes have proven to be an important class of
compounds.1 Although the synthesis and reactivity of
2-azadienes is well established, they mainly focus on
electron-rich1,2 and electronically neutral 2-azadienes.1,3
Probably owing to the lack of general methods for their
synthesis, electron-poor 2-azadienes have received much
less attention.1,4 Phosphonylated 2-aza-1,3-butadienes
* To whom correspondence should be addressed. Phone: +32(0)9/
264 59 57. Fax: +32(0)9/264 62 43.
(1) For reviews, see: (a) Jayakumar, S.; Ishar, M. P. S.; Mahajan,
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Curr. Chem. 1997, 189, 1. (c) Ghosez, L. Stereocontrolled Organic
Synthesis; Blackwell: Oxford, 1994; p 193. (d) Barluenga, J.; Toma´s,
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10.1021/jo0488661 CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/02/2004
J. Org. Chem. 2005, 70, 191-198
191

Vanderhoydonck and Stevens
SCHEME 1. Retrosynthetic Analysis of Novel Amino Phosphonates from 1-Phosphono-2-azadienes 1 and 2
synthesis of phosphonylated 2-azadienes and its modifi-
cation toward new R-aminophosphonates have been
rarely reported in the literature.13-15
ics.17 Various phosphono â-lactams have also been pre-
pared; however, these derivatives did not possess prom-
ising antibacterial properties.18 On the other hand, 1,3-
butadiene phosphonates 5 react with ketone19a and alde-
hyde19b enolates via 1,6-addition, leading to the corre-
sponding alkenyl or cyclohexadienyl phosphonates 6 and
7, respectively (Scheme 1). More recently, a diastereose-
lective addition of lithiated Scho¨llkopf’s bislactim ether
to 1,3-butadiene phosphonates was reported.20 To the best
of our knowledge, no Michael additions of this type have
been applied to phosphonylated 2-azadienes, nor to
2-azadienes bearing another electron-withdrawing group
at the 1-position. So, considering this reaction pattern,
1-phosphono-2-aza-1,3-butadienes 1 and 2 could lead to
a new entry toward cyclic and/or acyclic R-aminophos-
phonates 8 and 9 (Scheme 1).
Moreover, reduction of the imine functionality of acyclic
R-aminophosphonates 9 and subsequent ring closure
would lead to new phosphonylated γ-lactams. Despite
some promising exceptions,21,22 γ-lactams generally ex-
hibit only low antibacterial activity when compared with
their â-lactam analogues.23 Further, certain γ-lactam
derivatives show antiviral activity against HIV-124 or act
as cholesterol absorption inhibitors.25 Phosphonylated
γ-lactams are quite rarely reported in the literature,26
In connection with our interest in the synthesis of
heterocyclic aminophosphonates, we recently evaluated
the synthesis of 2-phosphonoaziridines 3 from 1-phospho-
no-2-azadienes 1 and 2.13 It was shown that nonaromatic
1-phosphono-2-azadienes 1 act as imines toward diazo
compounds (Scheme 1). Hence, 1-phosphono-2-azadienes
1 could be useful compounds for the construction of
phosphono â-lactams 4 using appropriate nucleophiles
(Scheme 1). A lot of attention is still directed toward the
synthesis of â-lactams because of their importance in the
field of elastase inhibitors16 and monobactam antibiot-
(8) (a) Cristau, H.-J.; Coulombeau, A.; Genevois-Borella, A.; Pirat,
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192 J. Org. Chem., Vol. 70, No. 1, 2005

Conjugate Addition to 1-Phosphono-2-aza-1,3-dienes
SCHEME 2. Addition of Sodium Malonate to
1-Phosphono-2-azadienes 1a-c
although the presence of a phosphonate functionality
could render these compounds interesting properties
associated with R-amino phosphonates.5,6
Results and Discussion
Addition of Sodium Malonate to 1-Phosphono-2-
aza-1,3-dienes. To evaluate the preparation of phospho-
nylated â-lactams 4, 1-phosphono-2-azadienes 1 were
prepared according to a procedure recently reported by
our group.13 Different nucleophiles allowing the synthesis
of the corresponding â-lactams via nucleophilic addition
at the imine functionality were applied. Adding 1-phospho-
no-2-azadiene 1a to the lithium enolate of methyl esters
led to mixtures containing neither addition product nor
the â-lactam 4 after workup (Scheme 2). Since â-lactams
can be formed employing imines as electrophiles in
Reformatsky reactions with R-halo esters,27 1-phosphono-
2-azadiene 1a was treated with the zinc enolate of methyl
2-bromoacetate (Scheme 2). However, the reaction did not
furnish the expected â-lactam 4, but a complex reaction
mixture was formed.
Guided by the findings by Pudovik et al. concerning
the nature of nucleophiles for successful addition to 1,3-
butadiene phosphonates 5,19c the less basic carbanion of
methyl malonate was evaluated for addition to 1-phospho-
no-2-azadiene 1a. The azadiene was added to 1.2 equiv
of sodium malonate, which was prepared using sodium
hydride as base. After workup, a liquid was isolated
which could be purified by flash chromatography; how-
ever, elucidation of the structure did not confirm the
formation of the corresponding phosphono â-lactam 4. In
fact, the addition of sodium malonate to 1-phosphono-2-
azadiene 1a was followed by an intramolecular proton
shift, after which the phosphonate moiety was elimi-
nated, furnishing bisenamine 12a (Scheme 2). The reac-
tion was accelerated when performed in refluxing THF
(3 h instead of 24 h at room temperature) and was also
successfully employed for the preparation of bisenamines
12b and 12c (Scheme 2). Although all the crude reaction
mixtures mainly contain the corresponding bisenamines
1
12 (>80%, estimated by H NMR), the isolated yields of
pure compounds were rather poor, possibly due to the
instability of the enamine functionality. To avoid the
intramolecular proton shift and direct the reaction
toward ring closure, sodium 2-methylmalonate was ap-
plied as nucleophile. Unfortunately, at room temperature
or in refluxing THF, only complex reaction mixtures were
obtained after workup.
(22) For some examples, see: (a) Kar, G. K.; Roy, B. C.; Adhikari,
S. D.; Ray, J. K.; Brahma, N. K. Bioorg. Med. Chem. 1998, 6, 2397. (b)
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Foster, B. J.; Hatfield, L. D.; Hobbs, J. N., Jr.; Hornback, W. J.;
Hunden, D. C.; Jones, N. D.; Kinnick, M. D.; Morin, J. M., Jr.; Munroe,
J. E.; Swartzendruber, J. K.; Vogt, D. G. Tetrahedron 1989, 45, 1905.
(c) Jungheim, L. N.; Sigmund, S. K. J. Org. Chem. 1987, 52, 4007.
(23) For some examples, see: (a) Crossley, M. J.; Crumbie, R. L.;
Fung, Y. M.; Potter, J. J.; Pegler, M. A. Tetrahedron Lett. 1987, 28,
2883. (b) Boyd, D. B.; Elzey, T. K.; Hatfield, L. D.; Kinnick, M. D.;
Morin, J. M., Jr. Tetrahedron Lett. 1986, 27, 3453. (c) Boyd, D. B.;
Foster, B. J.; Hatfield, L. D.; Hornback, W. J.; Jones, N. D.; Munroe,
J. E.; Swartzendruber, J. K. Tetrahedron Lett. 1986, 27, 3457. (d)
Baldwin, J. E.; Lowe, C.; Schofield, C. J. Tetrahedron Lett. 1986, 27,
3461.
(24) Hungate, R. W.; Chen, J. L.; Starbuck, K. E.; Vacca, J. P.;
McDaniel, S. L.; Levin, R. B.; Dorsey, B. D.; Guare, J. P.; Holloway,
M. K.; Whitter, W.; Darke, P. L.; Zugay, J. A.; Schleif, W. A.; Emini,
E. A.; Quintero, J. C.; Lin, J. H.; Chen, I.-W.; Anderson, P. S.; Huff, J.
R. Bioorg. Med. Chem. 1994, 2, 859.
(25) Dugar, S.; Kirkup, M. P.; Clader, J. W.; Lin, S.-I.; Rizvi, R.;
Snow, M. E.; Davis, H. R., Jr.; McCombie, S. W. Bioorg. Med. Chem.
Lett. 1995, 5, 2947.
Addition of Sodium Malonate to 1-Aryl-1-phospho-
no-2-aza-1,3-dienes. Considering the lack of reactivity
of 1-aryl-1-phosphono-2-aza-1,3-dienes 2 toward diazo
compounds,13a enolate nucleophiles were not expected to
add to the imine functionality of these derivatives.
However, prompted by the reports of Darling and co-
workers about 1,6-additions to 1,3-butadiene phospho-
nates 5,19a,b 1-aryl-1-phosphono-2-azadienes 2 were thought
to be susceptible to this type of Michael addition (Scheme
1). Since sodium malonate was an appropriate nucleo-
phile for the addition to 1-phosphono-2-azadienes 1, this
enolate was chosen for an initial evaluation of the 1,6-
addition. So, 1-phenyl-1-phosphono-2-azadiene 13 was
added to 3 equiv of sodium malonate in THF, and the
solution was heated to reflux temperature. Monitoring
the reaction for 48 h by TLC clearly showed that no
reaction took place and that the starting material was
recovered (Scheme 3).
(26) (a) Olive, G.; Le Moigne, F.; Mercier, A.; Tordo, P. Synth.
Commun. 2000, 30, 619. (b) Uryupin, A. B.; Rakhov, I. A.; Kolesova,
V. A.; Petrovskii, P. V.; Mastryukova, T. A.; Kabachnik, M. I. Izv. Akad.
Nauk, Ser. Khim. 1995, 2250; Chem. Abstr. 1996, 124, 317320m. (c)
Yamaguchi, M.; Tsukamoto, Y.; Hayashi, A.; Minami, T. Tetrahedron
Lett. 1990, 31, 2423. (d) Mikroyannidis, J. A. Phosphorus Sulfur Relat.
Elem. 1982, 12, 249. (e) Du, Y.; Wiemer, D. F. J. Org. Chem. 2002, 67,
5709 and references therein.
Next, 1-(4-bromophenyl)-1-phosphono-2-azadiene 14a
was subjected to the same reaction conditions. The
presence of a bromine atom at the para-position of the
phenyl ring was presumed to increase the polarization
of the azadiene system, promoting attack at C-4 of the
diene system. Indeed, after 48 h of reflux, a mixture was
recovered containing addition product, i.e., imine 21a,
(27) (a) Ross, N. A.; MacGregor, R. R.; Bartsch, R. A. Tetrahedron
2004, 60, 2035. (b) For a review, see: Hart, D. J.; Ha, D. Chem. Rev.
1989, 89, 1447.
J. Org. Chem, Vol. 70, No. 1, 2005 193

Vanderhoydonck and Stevens
TABLE 1. Addition of Dimethyl Malonate and Malononitrile to 1-Aryl-1-phosphono-2-azadienes 13-20
azadiene
product 21-29,
azadiene 13-20
13-20
R1
X, Y, Z
R3, R4
R3, R4 ) CO2Me
yielda (%)
in crude mixturec (%)
13
CH3
X ) H, Y ) H, Z ) H
X ) H, Y ) Br, Z ) H
X ) Br, Y ) H, Z ) H
X ) Cl, Y ) H, Z ) H
X ) H, Y ) F, Z ) H
X ) F, Y ) H, Z ) H
X ) H, Y ) H, Z ) F
X ) H, Y ) OMe, Z ) H
X ) H, Y ) Br, Z ) H
X ) H, Y ) Br, Z ) H
X ) H, Y ) Br, Z ) H
X ) H, Y ) Br, Z ) H
X ) H, Y ) Br, Z ) H
X ) Cl, Y ) H, Z ) H
no reaction
21a, 50 (69)
22, 51 (91)
23, 45 (89)
24, 49 (67)
25, 47 (82)
26, 44 (90)
no reaction
21b, 9b
no reaction
no reaction
no reaction
28, 53 (81)
29, 50 (79)
100
9
14a
15
CH3
R3, R4 ) CO2Me
R3, R4 ) CO2Me
R3, R4 ) CO2Me
R3, R4 ) CO2Me
R3, R4 ) CO2Me
R3, R4 ) CO2Me
R3, R4 ) CO2Me
R3, R4 ) CO2Me
R3, R4 ) CO2Me
R3 ) CO2Me, R4 ) C(O)Me
R3 ) CO2Me, R4 ) P(O)(OEt)2
R3, R4 ) CN
CH3
6
16
CH3
7
17
CH3
6
18
CH3
5
19
CH3
1
20
CH3
100
91b
100
100
100
<1
<1
14b
14c
14a
14a
14a
16
CH2CH3
(CH2)5
CH3
CH3
CH3
CH3
R3, R4 ) CN
a The crude yield is give in parentheses. b The amounts of addition product 21b and azadiene 14b were estimated from the 31P NMR
spectrum. c Estimated from the 31P NMR spectra of the crude reaction mixtures.
SCHEME 3. Addition of Dimethyl Malonate and
Malononitrile to 1-Aryl-1-phosphono-2-azadienes
13-20 (See Table 1)
14a-19 can be considered as electron-withdrawing func-
tionalities and, consequently, induce attack at the 4-posi-
tion of the diene system. All the imines were purified by
flash chromatography and isolated in moderate yield
(Table 1).
The dependence of the 1,6-addition on steric hindrance
was examined by reacting 1-phosphono-2-azadienes 14b
and 14c with sodium malonate (Scheme 3, Table 1). The
addition is shown to be rather sensitive to steric hin-
drance, since after 4 days of reflux, azadiene 14b gives
rise to the formation of only 9% of addition product 21b.
Further, azadiene 14c appears to be completely unreac-
tive toward nucleophilic addition under these reaction
conditions. Keeping the nature of sodium malonate in
mind, some other nucleophiles were also evaluated for
the addition to 1-(4-bromophenyl)-1-phosphono-2-azadi-
ene 14a. Triethyl phosphonoacetate and methyl aceto-
acetate were both deprotonated with sodium hydride in
THF, after which azadiene 14a was added. After 48 h of
reflux, only starting material was isolated. Taking into
account the sensitivity of the addition reaction to steric
hindrance, the unsuccessful addition of triethyl phospho-
noacetate could be explained by the larger dimensions
of this nucleophile compared to dimethyl malonate. The
reason for the observed unreactivity of acetoacetate
toward azadienes 14a is not clear. On the contrary,
malononitrile cleanly adds to both 1-phosphono-2-azadi-
ene 14a and 16 when deprotonated with sodium hydride.
The addition was complete after 24 h of reflux, and the
crude reaction mixtures only contained traces of starting
material (Table 1). In contrast to the imines 21a-26,
addition products 28 and 29 are rather unstable, espe-
cially when dried over magnesium sulfate after workup.
Utilizing potassium carbonate as drying agent gave
better results so that the imines could be isolated.
and 9% of the starting material 14a. Prolonged heating
(96 h) of the reaction mixture did not drive the reaction
to completion, and moreover, no formation of ring-closed
compound 27 was observed (Scheme 3). In an attempt to
prepare cyclic imine 27, addition product 21a was puri-
fied (by means of flash chromatography) and treated with
base. After 24 h of reflux, sodium hydride as well as LDA
gave rise to the formation of a mixture of the acyclic imine
21a, 1-phosphono-2-azadiene 14a, and dimethyl mal-
onate (Scheme 3).
To extend the reaction toward different derivatives and
to confirm the necessity of an electron-withdrawing
halogen atom on the phenyl substituent, several 1-aryl-
1-phosphono-2-azadienes 15-20 were prepared13a and
employed in the addition reaction (Scheme 3, Table 1).
The reactions with azadienes bearing a halogenated
phenyl substituent all result in a mixture of the corre-
sponding imine 22-26 and a small amount of starting
material (Table 1). On the other hand, reaction of sodium
malonate with 1-(4-methoxyphenyl)-1-phosphono-2-aza-
diene 20 led to the recovery of starting material. This
observation is in accordance with the decreased polariza-
tion of the azadiene due to the electron-donating nature
of the methoxy group. Although also halogen atoms are
mesomeric donating functionalities, they are considered
as mainly electron-withdrawing when positioned on an
aromatic ring. Indeed, the addition of sodium malonate
to azadiene 19, possessing a fluorine atom in the meta-
position, was also successful. Hence, it was reasoned that
the halogenated aromatic substituents on azadienes
Preparation of Phosphonylated γ-Lactams from
1-Aryl-1-phosphono-2-aza-1,3-dienes. With imines
21a-25 in hand, it was decided to explore the synthesis
of phosphonylated γ-lactams 35-40 (Scheme 4). There-
fore, imines 21a-25 were reduced to the corresponding
amines 30-34 using sodium cyanoborohydride in the
presence of 1 equiv of glacial acetic acid. Subsequently,
amines 30-34 were heated in refluxing toluene to induce
ring closure to the corresponding γ-lactams 35-39
(Scheme 4). Reduction of imine 21a with molecular
194 J. Org. Chem., Vol. 70, No. 1, 2005

Conjugate Addition to 1-Phosphono-2-aza-1,3-dienes
acquired at 68 and 109 MHz, respectively. The relative
proportions between two diastereoisomers were measured by
SCHEME 4. Synthesis of Phosphonylated
γ-Lactams 35-40 from the Corresponding Imines
21a-25
1
integration of the H peaks. Chemical shifts (δ) are reported
in parts per million from the peak for TMS as an internal
reference. Coupling constants (J) are given in hertz. IR spectra
were recorded with an FT-IR spectrometer. Low-resolution
mass spectra (MS) were obtained at 70 eV or using ES (4000
V). All solvents were dried extensively over sodium/benzophe-
none ketyl (THF, toluene) or used as such (absolute ethanol).
The 1,6-addition experiments were performed under an inert
nitrogen atmosphere.
General Procedure for the Preparation of Bisen-
amines 12a-c. In a flask of 25 mL, sodium hydride (1.2 mmol)
was added to anhydrous THF (5 mL). The suspension was
placed under a dry nitrogen atmosphere, and dimethyl mal-
onate (1.2 mmol), dissolved in 5 mL of anhydrous THF, was
added using a syringe. After 15 min of stirring at room
temperature, the corresponding azadiene 1a-c (2 mmol),
dissolved in 5 mL of THF, was added to the reaction mixture
using a syringe. Subsequently, the reaction mixture was
heated to reflux temperature and stirred for 3 h. Silica was
added to the reaction mixture, and the solvent was removed
under reduced pressure. Purification by flash chromatography
afforded bisenamines 12a-c as white solids (yield 26-31%).
Data for dimethyl 2-{[(2-methyl-1-propenyl)amino]-
methylene}malonate (12a): 1H NMR (CDCl3) δ 1.74 (3H,
d, J ) 2.0 Hz, CH3), 1.75 (3H, s, CH3), 3.73 (3H, d, J ) 1.3 Hz,
OCH3), 3.82 (3H, d, J ) 1.6 Hz, OCH3), 6.03 (1H, dd, J ) 10.9
Hz, J ) 1.3 Hz, CH), 8.02 (1H, d, J ) 13.7 Hz, J ) 1.1 Hz,
CH), 10.83 (1H, m, NH); 13C NMR (CDCl3) δ 16.4, 21.9, 50.8,
51.1, 89.8, 118.6, 122.7, 154.4, 165.7, 169.3; IR (KBr) 3427,
1673, 1630, 1596 cm-1; MS m/z 213 [M+]; mp 105 °C; Rf(EtOAc/
PET, 8/2) ) 0.28. Anal. Calcd for C10H15NO4: C, 56.33, H, 7.09.
Found: C, 56.40, H, 7.17.
Data for dimethyl 2-{[(2-ethyl-1-butenyl)amino]meth-
ylene}malonate (12b): 1H NMR (CDCl3) δ 1.04 (3H, t, J )
7.4 Hz, CH3), 1.08 (3H, t, J ) 7.7 Hz, CH3), 2.08 (2H, qd, J )
7.2 Hz, J ) 1.0 Hz, CH2), 2.16 (2H, q, J ) 7.5 Hz, CH2), 3.74
(3H, s, OCH3), 3.83 (3H, s, OCH3), 5.98 (1H, d, J ) 10.9 Hz,
CH), 8.05 (1H, d, J ) 13.5 Hz, CH), 10.88 (1H, m, NH); 13C
NMR (CDCl3) δ 12.1, 12.6, 22.5, 26.6, 51.2, 51.5, 90.2, 121.8,
130.3, 154.9, 166.1, 169.6; IR (KBr) 3436, 1672, 1635, 1595
cm-1; MS m/z 241 [M+]; mp 53 °C; Rf(EtOAc/PET, 8/2) ) 0.22.
Anal. Calcd for C12H19NO4: C, 59.73, H, 7.94. Found: C, 59.75,
H, 7.91.
hydrogen in the presence of a catalytic amount (0.1 equiv)
of palladium on carbon immediately leads to the isolation
of γ-lactam 40. As a result, nonhalogenated phosphono
γ-lactam 40 can be prepared despite the fact that the
addition of sodium malonate to 1-phenyl-1-phosphono-
2-azadiene 13 was not successful (Table 1).
Since the separation of imines 21a-25 from 1-phospho-
no-2-azadienes 14-19 by flash chromatography leads to
some loss of product, the γ-lactam synthesis was per-
formed starting from the crude mixtures obtained after
the addition reaction. The presence of minor amounts of
the starting azadienes did not negatively influence the
reduction of the imines 21a-25 nor the ring closure of
amines 30-34. Following this procedure, γ-lactams 35-
40 were prepared as equimolar mixtures of both diaste-
reoisomers and obtained in good yield after purification
by means of flash chromatography (Scheme 4). Several
attempts were made to separate both diastereoisomers
of the γ-lactams 35-40, but unfortunately all efforts
failed.
Conclusion
Data for dimethyl 2-{[(cyclohexylidenemethyl)amino]-
methylene}malonate (12c): 1H NMR (CDCl3) δ 1.58 (6H,
s, CH2), 2.10 (2H, s, CH2), 2.21 (2H, s, CH2), 3.73 (3H, s, OCH3),
3.83 (3H, s, OCH3), 6.00 (1H, d, J ) 11.2 Hz, CH), 8.04 (1H, d,
J ) 13.9 Hz, CH), 10.88 (1H, m, NH); 13C NMR (CDCl3) δ 26.4,
26.9, 27.6, 28.1, 33.2, 51.2, 51.5, 90.0, 120.0, 127.1, 154.8, 166.0,
169.7; IR (KBr) 3435, 1677, 1629, 1596 cm-1; MS m/z 253 [M+];
mp ) 129 °C; Rf(EtOAc/PET, 8/2) ) 0.29. Anal. Calcd for
C13H19NO4: C, 61.64, H, 7.56. Found: C, 61.48, H, 7.67.
General Procedure for the Preparation of Imines
21a-26, 28, and 29. In a flask of 50 mL, sodium hydride (6
mmol) was dissolved in anhydrous THF (10 mL). The suspen-
sion was placed under a dry nitrogen atmosphere, and di-
methyl malonate (6 mmol) (or malononitrile (4 mmol) for the
preparation of imines 26-29), dissolved in 10 mL of anhydrous
THF, was added using a syringe. After 15 min of stirring at
room temperature, the corresponding azadiene 13-19 (2
mmol), dissolved in 10 mL of THF, was added to the reaction
mixture using a syringe. Subsequently, the reaction mixture
was heated to reflux temperature and stirred for 48 h. The
reaction mixture was poured into 20 mL of aqueous sodium
bicarbonate (0.1 M) and extracted with diethyl ether (3 × 20
mL). The combined organic fractions were dried over magne-
sium sulfate (potassium carbonate was used for the synthesis
of 28 and 29). Next, the magnesium sulfate was filtered off,
and the solvent was evaporated under reduced pressure,
affording the crude reaction product as a yellow oil. Purifica-
The study of the reactivity of 1-phosphono-2-aza-1,3-
butadienes 1 and 13-20 toward enolate nucleophiles
consolidates the concept that these 2-azadienes are
interesting compounds for the synthesis of new cyclic and
acyclic R-aminophosphonates. On one hand, non-aromatic-
substituted 1-phosphono-2-azadienes 1 act as activated
imines toward sodium malonate and diazo compounds,13
leading to the formation of bisenamines 12 and aziri-
dines, respectively. However, the synthesis of phospho-
nylated â-lactams 4 is obstructed by an intramolecular
proton shift and the leaving group capacity of the
phosphonate moiety. On the other hand, the polarization
of 1-phosphono-2-azadienes is reversed when substituted
with a halogenated phenyl group activating the 4-position
of the diene system. These halogenated substrates allow
a not yet reported Michael-type addition of malonates to
1-phosphono-2-azadienes. Finally, this reaction pattern
offers a new entry to rarely reported phosphonylated
γ-lactams 35-40 from 1-phosphono-2-azadienes 14a-18.
Experimental Section
General Methods. Flash chromatography was performed
on silica gel (0.035-0.070 mm). 1H NMR spectra were recorded
at 270 MHz. 13C NMR and 31P NMR experiments were
J. Org. Chem, Vol. 70, No. 1, 2005 195

Vanderhoydonck and Stevens
1
tion by flash chromatography yielded imine 21a-26 (or 28 or
29 when malononitrile was used) in moderate yield (yield 49-
56%).
malonate (25): H NMR (CDCl3) δ 1.23 (3H, t, J ) 7.1 Hz,
P(O)OCH2CH3), 1.26 (3H, t, J ) 7.0 Hz, P(O)OCH2CH3), 1.31
(3H, s, CH3), 1.32 (3H, s, CH3), 3.57 (3H, s, OCH3), 3.72 (3H,
s, OCH3), 3.83 (1H, s, CH), 4.03 (4H, m, P(O)OCH2CH3), 5.07
(1H, d, JHP ) 18.4 Hz, CHP), 7.03 (1H, t, J ) 9.1 Hz, CH),
7.14 (1H, t, J ) 7.4 Hz, CH), 7.24 (1H, m, CH), 7.73 (1H, tt, J
) 7.4 Hz, J ) 2.0 Hz, CH), 7.85 (1H, d, JHP ) 4.4 Hz, HCdN);
13C NMR (CDCl3) δ 16.4, 16.5, 23.2, 24.0, 41.9, 52.2, 52.4, 58.2,
Data for dimethyl 2-((2E)-2-{[(E)-(4-bromophenyl)(di-
ethoxyphosphoryl)methyl]imino}-1,1-dimethylethyl)malo-
1
nate (21a): H NMR (CDCl3) δ 1.23 (3H, t, J ) 6.9 Hz, P(O)-
OCH2CH3), 1.25 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 1.31 (3H,
s, CH3), 1.32 (3H, s, CH3), 3.61 (3H, s, OCH3), 3.72 (3H, s,
OCH3), 3.82 (1H, s, CH), 4.00 (4H, m, P(O)OCH2CH3), 4.63
63.0 (d, JCP ) 6.9 Hz), 63.2 (d, JCP ) 6.9 Hz), 64.2 (d, JCP
)
152.3 Hz), 115.1 (dd, J ) 21.9 Hz, J ) 2.3 Hz), 123.7 (dd, J )
13.3 Hz, J ) 7.5 Hz), 124.1 (t, J ) 3.5 Hz), 129.1 (dd, J ) 8.6
Hz, J ) 2.9 Hz), 130.5 (t, J ) 3.5 Hz), 159.9 (dd, JCF ) 246.3
Hz, JCP ) 6.3 Hz), 168.5, 168.7, 173.6 (d, JCP ) 15.0 Hz); 31P
NMR (CDCl3) δ 19.85 (d, JPF ) 5.9 Hz); IR (neat) 1759, 1736
cm-1; MS m/z 446 [M + H+]; Rf(EtOAc/PET, 4/6) ) 0.13. Anal.
Calcd. for C20H29FNO7P: C, 53.93, H, 6.56. Found: C, 54.26,
H, 6.69.
(1H, d, JHP ) 18.5 Hz, CHP), 7.36 (2H, dd, J ) 8.6 Hz, JHP
2.1 Hz, CH), 7.46 (2H, d, J ) 8.3 Hz, CH), 7.82 (1H, d, JHP
)
)
4.9 Hz, HCdN); 13C NMR (CDCl3) δ 16.3, 16.4, 23.2, 23.9, 41.7,
52.1, 52.2, 58.1, 62.9 (d, JCP ) 7.3 Hz), 63.0 (d, JCP ) 8.6 Hz),
71.6 (d, JCP ) 151.3 Hz), 121.5 (d, JCP ) 4.9 Hz), 130.0 (2C, d,
JCP ) 6.1 Hz), 131.2 (2C, d, JCP ) 2.4 Hz), 135.4 (d, JCP ) 7.3
Hz), 168.4, 168.5, 173.1 (d, JCP ) 14.7 Hz); 31P NMR (CDCl3)
δ 19.40; IR (neat) 1756, 1738, 1733 cm-1; MS m/z 508/506 [M
+ H+]; Rf(EtOAc/PET, 1/1) ) 0.24. Anal. Calcd for C20H29-
BrNO7P: C, 47.44, H, 5.77. Found: C, 47.66, H, 5.62.
Data for dimethyl 2-((2E)-2-{[(E)-(diethoxyphospho-
ryl)(3-fluorophenyl)methyl]imino}-1,1-dimethylethyl)-
1
malonate (26): H NMR (CDCl3) δ 1.23 (3H, t, J ) 7.0 Hz,
Data for dimethyl 2-((2E)-2-{[(E)-(2-bromophenyl)(di-
ethoxyphosphoryl)methyl]imino}-1,1-dimethylethyl)malo-
P(O)OCH2CH3), 1.26 (3H, t, J ) 7.1 Hz, P(O)OCH2CH3), 1.32
(3H, s, CH3), 1.34 (3H, s, CH3), 3.62 (3H, s, OCH3), 3.73 (3H,
s, OCH3), 3.86 (1H, s, CH), 4.05 (4H, m, P(O)OCH2CH3), 4.67
(1H, d, JHP ) 18.4 Hz, CHP), 6.96 (1H, t, J ) 8.0 Hz, CH),
7.29 (3H, m, CH), 7.82 (1H, d, JHP ) 4.7 Hz, HCdN); 13C NMR
(CDCl3) δ 16.4, 16.5, 23.1, 24.2, 41.8, 52.2, 52.4, 58.1, 63.1 (d,
JCP ) 8.1 Hz), 63.2 (d, JCP ) 6.9 Hz), 71.9 (d, JCP ) 151.1 Hz),
114.5 (dd, J ) 21.3 Hz, J ) 2.9 Hz), 115.3 (dd, J ) 23.1 Hz, J
) 5.8 Hz), 124.0 (dd, J ) 5.8 Hz, J ) 2.3 Hz), 129.6 (dd, J )
1
nate (22): H NMR (CDCl3) δ 1.22 (3H, t, J ) 7.1 Hz, P(O)-
OCH2CH3), 1.28 (3H, t, J ) 7.1 Hz, P(O)OCH2CH3), 1.31 (6H,
s, CH3), 3.57 (3H, s, OCH3), 3.71 (3H, s, OCH3), 3.81 (1H, s,
CH), 4.02 (4H, m, P(O)OCH2CH3), 5.27 (1H, d, JHP ) 18.7 Hz,
CHP), 7.12 (1H, tt, J ) 7.7 Hz, J ) 1.8 Hz, CH), 7.32 (1H, t,
J ) 7.6 Hz, CH), 7.54 (1H, d, J ) 8.0 Hz, CH), 7.83 (2H, m,
CH, HCdN); 13C NMR (CDCl3) δ 16.36 (d, JCP ) 4.6 Hz), 16.42
(d, JCP ) 4.6 Hz), 23.2, 23.7, 41.8, 52.0, 52.2, 57.9, 62.9 (d, JCP
) 8.1 Hz), 63.1 (d, JCP ) 6.9 Hz), 70.4 (d, JCP ) 154.6 Hz),
123.8 (d, JCP ) 8.1 Hz), 127.3 (d, JCP ) 2.3 Hz), 129.0 (d, JCP
) 2.3 Hz), 131.4 (d, JCP ) 4.6 Hz), 132.6, 135.5 (d, JCP ) 6.9
Hz), 168.3, 168.5, 173.3 (d, JCP ) 15.0 Hz); 31P NMR (CDCl3)
δ 19.97; IR (neat) 1758, 1735 cm-1; MS m/z 508/506 [M + H+];
Rf(EtOAc/PET, 1/1) ) 0.21. Anal. Calcd for C20H29BrNO7P: C,
47.44, H, 5.77. Found: C, 47.64, H, 5.66.
8.1 Hz, J ) 3.5 Hz), 138.8 (t, J ) 7.5 Hz), 162.7 (dd, JCF
)
245.7 Hz, JCP ) 3.5 Hz), 168.6, 168.7, 173.2 (d, JCP ) 15.0 Hz);
31P NMR (CDCl3) δ 19.68 (d, JPF ) 2.2 Hz); IR (neat) 1758,
1735 cm-1; MS m/z 446 [M + H+]; Rf(EtOAc/PET, 1/1) ) 0.22.
Anal. Calcd for C20H29FNO7P: C, 53.93, H, 6.56. Found: C,
54.23 H, 6.70.
Data for diethyl (4-bromophenyl){[(E)-3,3-dicyano-2,2-
dimethylpropylidene]amino}methylphosphonate (28):
1H NMR (CDCl3) δ 1.24 (3H, t, J ) 7.0 Hz, P(O)OCH2CH3),
1.25 (3H, t, J ) 7.0 Hz, P(O)OCH2CH3), 1.41 (3H, s, CH3), 1.44
(3H, s, CH3), 4.01 (4H, m, P(O)OCH2CH3), 4.26 (1H, s, CH),
4.72 (1H, d, JHP ) 19.3 Hz, CHP), 7.42 (2H, dd, J ) 8.5 Hz,
JHP ) 2.2 Hz, CH), 7.50 (2H, d, J ) 8.3 Hz, CH), 7.69 (1H, d,
JHP ) 4.9 Hz, HCdN); 13C NMR (CDCl3) δ 16.4, 16.5, 22.7,
23.1, 31.4, 43.5, 63.3 (d, JCP ) 4.6 Hz), 63.4 (d, JCP ) 6.9 Hz),
71.3 (d, JCP ) 150.0 Hz), 112.02, 112.06, 122.2 (d, JCP ) 4.6
Hz), 129.9 (2C, d, JCP ) 5.8 Hz), 131.7 (2C, d, JCP ) 2.3 Hz),
134.1 (d, JCP ) 8.1 Hz), 167.9 (d, JCP ) 15.0 Hz); 31P NMR
(CDCl3) δ 18.56; IR (neat) 2253, 2213, 1665 cm-1; MS m/z 440/
442 [M + H+]; Rf(EtOAc/PET, 7/3) ) 0.31. Anal. Calcd for
C18H23BrN3O3P: C, 49.10, H, 5.27. Found: C, 48.97, H, 5.39.
Data for diethyl (2-chlorophenyl){[(E)-3,3-dicyano-2,2-
dimethylpropylidene]amino}methylphosphonate (29):
1H NMR (CDCl3) δ 1.22 (3H, t, J ) 7.1 Hz, P(O)OCH2CH3),
1.28 (3H, t, J ) 7.0 Hz, P(O)OCH2CH3), 1.40 (3H, s, CH3), 1.44
(3H, s, CH3), 4.04 (4H, m, P(O)OCH2CH3), 4.27 (1H, s, CH),
5.37 (1H, d, JHP ) 19.5 Hz, CHP), 7.24 (1H, tt, J ) 7.4 Hz, J
) 1.9 Hz, CH), 7.32 (1H, d, J ) 7.7 Hz, CH), 7.38 (1H, d, J )
8.5 Hz, CH), 7.74 (1H, d, JHP ) 4.7 Hz, HCdN), 7.90 (1H, dt,
J ) 7.7 Hz, J ) 2.0 Hz, CH); 13C NMR (CDCl3) δ 16.4 (d, JCP
) 4.6 Hz), 16.5 (d, JCP ) 5.8 Hz), 22.8, 23.0, 31.4, 43.5, 63.3
(d, JCP ) 6.9 Hz), 63.5 (d, JCP ) 6.9 Hz), 67.2 (d, JCP ) 153.4
Hz), 112.1 (2C), 127.2, 129.3, 129.5, 131.1 (d, JCP ) 4.6 Hz),
132.8 (d, JCP ) 8.1 Hz), 133.3 (d, JCP ) 6.9 Hz), 168.3 (d, JCP
) 13.8 Hz); 31P NMR (CDCl3) δ 18.98; IR (neat) 2254, 2200,
1668 cm-1; MS m/z 398/396 [M + H+]; Rf(EtOAc/PET, 6/4) )
0.38. Anal. Calcd for C18H23ClN3O3P: C, 54.62, H, 5.86.
Found: C, 54.83, H, 5.75.
Data for dimethyl 2-((2E)-2-{[(E)-(2-chlorophenyl)(di-
ethoxyphosphoryl)methyl]imino}-1,1-dimethylethyl)malo-
1
nate (23): H NMR (CDCl3) δ 1.22 (3H, t, J ) 7.1 Hz, P(O)-
OCH2CH3), 1.27 (3H, t, J ) 7.1 Hz, P(O)OCH2CH3), 1.31 (6H,
s, CH3), 3.57 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.82 (1H, s,
CH), 4.05 (4H, m, P(O)OCH2CH3), 5.28 (1H, d, JHP ) 18.7 Hz,
CHP), 7.20 (1H, t, J ) 7.4 Hz, CH), 7.28 (1H, m, CH), 7.31
(1H, d, J ) 8.0 Hz, CH), 7.83 (2H, m, CH, HCdN); 13C NMR
(CDCl3) δ 16.4 (d, JCP ) 3.5 Hz), 16.5 (d, JCP ) 3.5 Hz), 23.2,
23.9, 41.8, 52.1, 52.3, 58.0, 63.0 (d, JCP ) 6.9 Hz), 63.1 (d, JCP
) 6.9 Hz), 67.9 (d, JCP ) 154.6 Hz), 126.8 (d, JCP ) 3.5 Hz),
128.7 (d, JCP ) 3.5 Hz), 129.3, 131.1 (d, JCP ) 4.6 Hz), 133.3
(d, JCP ) 8.1 Hz), 133.9 (d, JCP ) 6.9 Hz), 168.5, 168.7, 173.5
(d, JCP ) 15.0 Hz); 31P NMR (CDCl3) δ 19.94; IR (neat) 1758,
1735 cm-1; MS m/z 464/462 [M + H+]; Rf(EtOAc/PET, 1/1) )
0.24. Anal. Calcd for C20H29ClNO7P: C, 52.01, H, 6.33.
Found: C, 52.35, H, 6.40.
Data for dimethyl 2-((2E)-2-{[(E)-(diethoxyphospho-
ryl)(4-fluorophenyl)methyl]imino}-1,1-dimethylethyl)-
1
malonate (24): H NMR (CDCl3) δ 1.22 (3H, t, J ) 7.1 Hz,
P(O)OCH2CH3), 1.24 (3H, t, J ) 6.8 Hz, P(O)OCH2CH3), 1.32
(6H, s, CH3), 3.59 (3H, s, OCH3), 3.72 (3H, s, OCH3), 3.83 (1H,
s, CH), 3.99 (2H, quintet, J ) 7.4 Hz, P(O)OCH2CH3), 4.00
(2H, quintet, J ) 7.3 Hz, P(O)OCH2CH3), 4.65 (1H, d, JHP
)
17.8 Hz, CHP), 7.02 (2H, t, J ) 8.6 Hz, CH), 7.45 (2H, m, CH),
7.81 (1H, d, JHP ) 4.6 Hz, HCdN); 13C NMR (CDCl3) δ 16.3,
16.4, 23.3, 23.9, 41.7, 52.1, 52.3, 58.1, 62.9 (d, JCP ) 7.3 Hz),
63.0 (d, JCP ) 7.4 Hz), 71.5 (d, JCP ) 153.8 Hz), 115.1 (2C, dd,
JCF ) 21.9 Hz, JCP ) 2.4 Hz), 129.9 (2C, t, J ) 7.3 Hz), 131.9
(t, JCP ) 3.7 Hz), 162.3 (dd, JCF ) 246.6 Hz, JCP ) 3.7 Hz),
168.5, 168.6, 172.8 (d, JCP ) 15.9 Hz; 31P NMR (CDCl3) δ 19.87
(d, JPF ) 5.4 Hz); IR (neat) 1756, 1738, 1732 cm-1; MS m/z
446 [M + H+]; Rf(EtOAc/PET, 1/1) ) 0.17. Anal. Calcd for
C20H29FNO7P: C, 53.93, H, 6.56. Found: C, 53.58, H, 6.71.
General Procedure for the Preparation of Amines 30-
34. In a flask of 25 mL, imine 21a-25 (2 mmol) and glacial
acetic acid (2.2 mmol) were dissolved in 10 mL of anhydrous
methanol. The reaction mixture was stirred at room temper-
ature, and sodium cyanoborohydride (2.1 mmol) was added
Data for dimethyl 2-((2E)-2-{[(E)-(diethoxyphospho-
ryl)(2-fluorophenyl)methyl]imino}-1,1-dimethylethyl)-
196 J. Org. Chem., Vol. 70, No. 1, 2005

Conjugate Addition to 1-Phosphono-2-aza-1,3-dienes
portionwise. The reaction mixture was protected from moisture
by a calcium chloride tube and stirred for 12 h. To the reaction
mixture were added 10 mL of aqueous sodium bicarbonate (0.1
M) and 20 mL of diethyl ether. The organic phase was
separated from the water phase and washed with 2 × 10 mL
of aqueous sodium bicarbonate (0.1 M). The organic fraction
was dried over magnesium sulfate. Next, the magnesium
sulfate was filtered off, and the solvent was evaporated under
reduced pressure, affording the crude reaction product as a
yellow oil with high purity (>98%). Purification by flash
chromatography yielded amine 30-34 in good yield (77-95%).
CH2), 2.48 (1H, d, J ) 12.5 Hz, CH2), 3.65 (3H, s, OCH3), 3.70
(1H, s, CH), 3.71 (3H, s, OCH3), 3.88 (2H, m, P(O)OCH2CH3),
3.91 (1H, d, JHP ) 20.8 Hz, CHP), 4.12 (2H, quintet, J ) 7.2
Hz, P(O)OCH2CH3), 7.03 (2H, t, J ) 8.6 Hz, CH), 7.35 (2H, m,
CH); 13C NMR (CDCl3) δ 16.3 (d, JCP ) 4.9 Hz), 16.5 (d, JCP
)
4.9 Hz), 23.6, 23.8, 37.6, 51.98, 52.04, 56.6, 57.5 (d, JCP ) 17.1
Hz), 61.2 (d, JCP ) 152.6 Hz), 62.7 (d, JCP ) 7.3 Hz), 63.0 (d,
JCP ) 7.3 Hz3), 115.3 (2C, d, JCF ) 23.2 Hz), 130.1 (2C, t, J )
7.3 Hz), 132.1 (t, J ) 3.0 Hz), 162.4 (dd, JCF ) 246.0 Hz, JCP
) 3.1 Hz), 168.9, 169.0; 31P NMR (CDCl3) δ 23.32 (d, JPF ) 4.0
Hz); IR (neat) 3318, 1755, 1732 cm-1; MS m/z 448 [M + H+];
Rf(EtOAc/PET, 1/1) ) 0.16. Anal. Calcd for C20H31FNO7P: C,
53.69, H, 6.98. Found: C, 53.91, H, 7.89.
Data for dimethyl 2-(2-{[(diethoxyphosphoryl)(2-fluo-
rophenyl)methyl]amino}-1,1-dimethylethyl)malonate (34):
1H NMR (CDCl3) δ 1.04 (3H, s, CH3), 1.08 (3H, s, CH3), 1.11
(3H, t, J ) 7.1 Hz, P(O)OCH2CH3), 1.34 (3H, t, J ) 7.0 Hz,
P(O)OCH2CH3), 2.01 (1H, br s, NH), 2.42 (1H, d, J ) 12.4 Hz,
CH2), 2.51 (1H, d, J ) 12.6 Hz, CH2), 3.66 (3H, s, OCH3), 3.71
(3H, s, OCH3), 3.73 (1H, s, CH), 3.82 (1H, m, P(O)OCH2CH3),
3.95 (1H, m, P(O)OCH2CH3), 4.21 (2H, quintet, J ) 7.0 Hz,
P(O)OCH2CH3), 4.37 (1H, d, JHP ) 22.0 Hz, CHP), 7.04 (1H, t,
J ) 9.0 Hz, CH), 7.17 (1H, t, J ) 7.1 Hz, CH), 7.27 (1H, m,
CH), 7.51 (1H, tt, J ) 7.4 Hz, J ) 1.9 Hz, CH); 13C NMR
(CDCl3) δ 16.2 (d, JCP ) 5.8 Hz), 16.5 (d, JCP ) 5.8 Hz), 23.6,
23.7, 37.8, 52.00, 52.03, 53.8 (d, JCP ) 156.9 Hz), 56.5, 57.7 (d,
JCP ) 16.1 Hz), 62.7 (d, JCP ) 6.9 Hz), 63.2 (d, JCP ) 6.9 Hz),
115.3 (d, JCP ) 20.8 Hz), 123.9 (d, J ) 13.8 Hz), 124.4, 129.2
(d, J ) 3.5 Hz), 129.3 (d, J ) 2.3 Hz), 161.0 (dd, JCF ) 245.7
Hz, JCP ) 6.9 Hz), 169.0 (2C); 31P NMR (CDCl3) δ 23.09 (d,
JPF ) 5.9 Hz); IR (neat) 3311, 1755, 1733 cm-1; MS m/z 448
[M + H+]; Rf(EtOAc/PET, 1/1) ) 0.26. Anal. Calcd for C20H31-
FNO7P: C, 53.69, H, 6.98. Found: C, 53.71, H, 6.99.
General Procedure for the Preparation of γ-Lactams
35-39. In a flask of 25 mL, amine 30-34 (1 mmol) was
dissolved in 10 mL of anhydrous toluene and was heated under
reflux. The reaction mixture was protected from moisture by
a calcium chloride tube on top of the condenser. The reaction
was followed by 31P NMR, taking samples out of the reaction
mixture. When ring closure was observed to be complete (the
required reaction time is mentioned with the spectral data for
each derivative), the solvent was evaporated under reduced
pressure, affording the crude γ-lactam 35-39 as a yellow oil.
Purification by flash chromatography yielded the pure lactam
in moderate yield (51-68%).
Data for methyl 1-[(4-bromophenyl)(diethoxyphos-
phoryl)methyl]-4,4-dimethyl-2-oxo-3-pyrrolidinecarbox-
ylate (35): synthesized according to the general procedure
applying 2 days of reflux; 1H NMR (CDCl3) δ 0.99 (6H, s, 2 ×
CH3), 1.10 (3H, s, CH3), 1.17 (3H, t, J ) 7.2 Hz, P(O)OCH2CH3),
1.19 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 1.27 (3H, s, CH3), 1.34
(3H, t, J ) 7.3 Hz, P(O)OCH2CH3), 1.37 (3H, t, J ) 7.3 Hz,
P(O)OCH2CH3), 2.96 (1H, d, J ) 9.9 Hz, CH2), 3.06 (1H, s,
CH), 3.08 (2H, m, CH, CH2), 3.53 (1H, d, J ) 9.6 Hz, CH2),
3.63 (3H, s, OCH3), 3.70 (1H, d, J ) 9.9 Hz, CH2), 3.74 (3H, s,
OCH3), 4.03 (4H, m, 2 × P(O)OCH2CH3), 4.20 (4H, m, 2 × P(O)-
OCH2CH3), 5.70 (1H, d, JHP ) 21.1 Hz, CHP), 5.73 (1H, d, JHP
) 21.1 Hz, CHP), 7.50 (8H, d, J ) 2.6 Hz, 8 × CH); 13C NMR
(CDCl3) δ 16.1, 16.2 (d, JCP ) 3.7 Hz), 16.4 (d, JCP ) 2.4 Hz),
16.5 (d, JCP ) 2.4 Hz), 22.4, 22.7, 27.8, 28.5, 36.9, 37.2, 51.0
(d, JCP ) 159.9 Hz), 51.1 (d, JCP ) 159.9 Hz), 52.0 (2C), 56.4,
56.7, 59.7, 59.8, 62.7 (d, JCP ) 7.4 Hz), 63.0 (d, JCP ) 6.1 Hz),
63.1 (d, JCP ) 7.4 Hz), 63.2 (d, JCP ) 6.1 Hz), 122.8, 122.9,
131.2 (d, JCP ) 3.6 Hz), 131.4 (2C, d, JCP ) 8.5 Hz), 131.5 (2C,
d, JCP ) 8.6 Hz), 131.8 (d, JCP ) 3.6 Hz), 131.9 (2C), 132.0
(2C), 168.7, 168.9, 169.7 (d, JCP ) 6.1 Hz), 170.2 (d, JCP ) 6.1
Hz); 31P NMR (CDCl3) δ 18.65, 19.32; IR (neat) 1738, 1732,
1704, 1694 cm-1; MS m/z 478/476 [M + H+]; Rf(EtOAc/PET,
1/1) ) 0.17. Anal. Calcd for C19H27BrNO6P: C, 47.91, H, 5.71.
Found: C, 47.83, H, 5.79.
Data for dimethyl 2-(2-{[(4-bromophenyl)(diethoxy-
phosphoryl)methyl]amino}-1,1-dimethylethyl)malonate
1
(30): H NMR (CDCl3) δ 1.04 (3H, s, CH3), 1.07 (3H, s, CH3),
1.16 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 1.30 (3H, t, J ) 7.1
Hz, P(O)OCH2CH3), 1.71 (1H, br s, NH), 2.42 (1H, d, J ) 10.9
Hz, CH2), 2.48 (1H, d, J ) 10.7 Hz, CH2), 3.65 (3H, s, OCH3),
3.69 (1H, s, CH), 3.71 (3H, s, OCH3), 3.89 (1H, d, JHP ) 19.8
Hz, CHP), 3.90 (2H, m, P(O)OCH2CH3), 4.12 (2H, quintet, J
) 7.3 Hz, P(O)OCH2CH3), 7.26 (2H, dd, J ) 8.6 Hz, JHP ) 2.3
Hz, CH), 7.47 (2H, d, J ) 8.3 Hz, CH); 13C NMR (CDCl3) δ
16.3 (d, JCP ) 6.1 Hz), 16.5 (d, JCP ) 6.1 Hz), 23.6, 23.7, 37.5,
51.9, 52.0, 56.5, 57.5 (d, JCP ) 15.9 Hz), 61.3 (d, JCP ) 152.6
Hz), 62.7 (d, JCP ) 6.1 Hz), 63.0 (d, JCP ) 7.3 Hz), 121.7 (d,
JCP ) 3.6 Hz), 130.1 (2C, d, JCP ) 6.1 Hz), 131.5 (2C), 135.5
(d, JCP ) 2.5 Hz), 168.8, 168.9; 31P NMR (CDCl3) δ 22.75; IR
(neat) 3318, 1755, 1732 cm-1; MS m/z 510/508 [M + H+]; Rf-
(EtOAc/PET, 1/1) ) 0.22. Anal. Calcd for C20H31BrNO7P: C,
47.25, H, 6.15. Found: C, 47.43, H, 6.08.
Data for dimethyl 2-(2-{[(2-bromophenyl)(diethoxy-
phosphoryl)methyl]amino}-1,1-dimethylethyl)malonate
1
(31): H NMR (CDCl3) δ 1.03 (3H, s, CH3), 1.07 (3H, s, CH3),
1.08 (3H, t, J ) 7.0 Hz, P(O)OCH2CH3), 1.36 (3H, t, J ) 7.1
Hz, P(O)OCH2CH3), 1.72 (1H, br s, NH), 2.39 (1H, d, J ) 12.4
Hz, CH2), 2.46 (1H, d, J ) 12.6 Hz, CH2), 3.65 (3H, s, OCH3),
3.72 (3H, s, OCH3), 3.73 (1H, s, CH), 3.74 (1H, m, P(O)OCH2-
CH3), 3.89 (1H, m, P(O)OCH2CH3), 4.23 (2H, m, P(O)OCH2-
CH3), 4.62 (1H, d, JHP ) 22.3 Hz, CHP), 7.15 (1H, tt, J ) 7.1
Hz, J ) 1.6 Hz, CH), 7.35 (1H, t, J ) 7.3 Hz, CH), 7.57 (2H,
m, CH); 13C NMR (CDCl3) δ 16.2 (d, JCP ) 5.8 Hz), 16.5 (d,
JCP ) 6.9 Hz), 23.6, 23.7, 37.7, 51.98, 52.04, 56.4, 57.3 (d, JCP
) 16.1 Hz), 59.8 (d, JCP ) 154.6 Hz), 62.8 (d, JCP ) 6.9 Hz,
63.2 (d, JCP ) 6.9 Hz), 125.3 (d, JCP ) 9.2 Hz), 127.8 (d, JCP
)
3.5 Hz), 129.2 (d, JCP ) 2.3 Hz), 129.4 (d, JCP ) 3.5 Hz), 132.8,
136.3, 168.9, 169.0; 31P NMR (CDCl3) δ 23.21; IR (neat) 3312,
1755, 1733 cm-1; MS m/z 510/508 [M + H+]; Rf(EtOAc/PET,
1/1) ) 0.30. Anal. Calcd for C20H31BrNO7P: C, 47.25, H, 6.15.
Found: C, 47.28, H, 6.13.
Data for dimethyl 2-(2-{[(2-chlorophenyl)(diethoxy-
phosphoryl)methyl]amino}-1,1-dimethylethyl)malonate
1
(32): H NMR (CDCl3) δ 1.04 (3H, s, CH3), 1.08 (3H, s, CH3),
1.09 (3H, t, J ) 7.0 Hz, P(O)OCH2CH3), 1.36 (3H, t, J ) 7.0
Hz, P(O)OCH2CH3), 2.08 (1H, br s, NH), 2.40 (1H, d, J ) 12.6
Hz, CH2), 2.47 (1H, d, J ) 12.4 Hz, CH2), 3.66 (3H, s, OCH3),
3.72 (3H, s, OCH3), 3.73 (1H, s, CH), 3.76 (1H, m, P(O)OCH2-
CH3), 3.91 (1H, m, P(O)OCH2CH3), 4.24 (2H, m, P(O)OCH2-
CH3), 4.63 (1H, d, JHP ) 22.3 Hz, CHP), 7.23 (1H, t, J ) 7.5
Hz, CH), 7.31 (1H, m, CH), 7.37 (1H, d, J ) 7.8 Hz, CH), 7.60
(1H, d, J ) 7.7 Hz, CH); 13C NMR (CDCl3) δ 16.2 (d, JCP ) 5.8
Hz), 16.6 (d, JCP ) 5.8 Hz), 23.6, 23.7, 37.8, 52.06, 52.09, 56.5,
57.1 (d, JCP ) 155.8 Hz), 57.5 (d, JCP ) 16.1 Hz), 62.8 (d, JCP
) 6.9 Hz), 63.3 (d, JCP ) 6.9 Hz), 127.2 (d, JCP ) 2.3 Hz), 128.9
(d, JCP ) 2.3 Hz), 129.3 (d, JCP ) 3.5 Hz), 129.5, 134.5, 134.6,
169.0 (2C); 31P NMR (CDCl3) δ 23.22; IR (neat) 3311, 1755,
1732 cm-1; MS m/z 466/464 [M + H+]; Rf(EtOAc/PET, 1/1) )
0.33. Anal. Calcd for C20H31ClNO7P: C, 51.78, H, 6.74.
Found: C, 51.79, H, 6.71.
Data for dimethyl 2-(2-{[(diethoxyphosphoryl)(4-fluo-
rophenyl)methyl]amino}-1,1-dimethylethyl)malonate (33):
1H NMR (CDCl3) δ 1.04 (3H, s, CH3), 1.07 (3H, s, CH3), 1.14
(3H, t, J ) 7.1 Hz, P(O)OCH2CH3), 1.31 (3H, t, J ) 7.1 Hz,
P(O)OCH2CH3), 1.72 (1H, br s, NH), 2.41 (1H, d, J ) 12.2 Hz,
Data for methyl 1-[(2-bromophenyl)(diethoxyphos-
phoryl)methyl]-4,4-dimethyl-2-oxo-3-pyrrolidinecarbox-
J. Org. Chem, Vol. 70, No. 1, 2005 197

Vanderhoydonck and Stevens
ylate (36): synthesized according to the general procedure
applying 6 days of reflux; 1H NMR (CDCl3) δ 0.99 (3H, s, CH3),
1.05 (3H, s, CH3), 1.09 (3H, s, CH3), 1.17 (6H, t, J ) 7.1 Hz, 2
× P(O)OCH2CH3), 1.27 (3H, s, CH3), 1.38 (3H, t, J ) 7.1 Hz,
P(O)OCH2CH3), 1.39 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 2.74
(1H, d, J ) 9.6 Hz, CH2), 2.92 (1H, d, J ) 9.2 Hz, CH2), 3.08
(1H, d, J ) 2.6 Hz, CH), 3.11 (1H, s, CH), 3.52 (1H, d, J ) 9.2
Hz, CH2), 3.64 (3H, s, OCH3), 3.65 (1H, d, J ) 9.6 Hz, CH2),
3.74 (3H, s, OCH3), 4.07 (4H, m, 2 × P(O)OCH2CH3), 4.26 (4H,
m, 2 × P(O)OCH2CH3), 6.11 (1H, d, JHP ) 20.5 Hz, CHP), 6.17
(1H, d, JHP ) 20.5 Hz, CHP), 7.22 (2H, td, J ) 7.5 Hz, J ) 1.5
Hz, 2 × CH), 7.35 (2H, t, J ) 7.6 Hz, 2 × CH), 7.65 (2H, t, J
) 7.0 Hz, 2 × CH), 8.06 (2H, t, J ) 7.6 Hz, 2 × CH); 13C NMR
(CDCl3) δ 16.1 (2C, d, JCP ) 3.6 Hz), 16.5 (2C, d, JCP ) 4.9
Hz), 22.5, 22.8, 28.0, 28.5, 37.0, 37.1, 51.4 (d, JCP ) 161.1 Hz),
51.4 (d, JCP ) 161.1 Hz), 51.9 (2C), 56.7 (2C), 59.7, 60.1, 62.9
(d, JCP ) 7.3 Hz), 63.0 (d, JCP ) 6.1 Hz), 63.2 (2C, d, JCP ) 7.3
Hz), 125.7 (d, JCP ) 14.6 Hz), 126.0 (d, JCP ) 14.6 Hz), 127.3,
IR (neat) 1739, 1733, 1703, 1695 cm-1; MS m/z 416 [M + H+];
Rf(EtOAc/PET, 1/1) ) 0.14. Anal. Calcd for C19H27FNO6P: C,
54.94, H, 6.55. Found: C, 55.15, H, 6.49.
Data for methyl 1-[(diethoxyphosphoryl)(2-fluorophen-
yl)methyl]-4,4-dimethyl-2-oxo-3-pyrrolidinecarboxylate
(39): synthesized according to the general procedure applying
3 days of reflux; 1H NMR (CDCl3) δ 0.99 (3H, s, CH3), 1.01
(3H, s, CH3), 1.10 (3H, s, CH3), 1.16 (3H, t, J ) 7.0 Hz, P(O)-
OCH2CH3), 1.17 (3H, t, J ) 7.0 Hz, P(O)OCH2CH3), 1.27 (3H,
s, CH3), 1.37 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 1.39 (3H, t, J
) 6.9 Hz, P(O)OCH2CH3), 2.90 (1H, d, J ) 9.6 Hz, CH2), 3.06
(1H, d, J ) 9.4 Hz, CH2), 3.07 (1H, d, J ) 2.5 Hz, CH), 3.08
(1H, s, CH), 3.59 (1H, d, J ) 9.4 Hz, CH2), 3.62 (3H, s, OCH3),
3.70 (1H, d, J ) 9.6 Hz, CH2), 3.74 (3H, s, OCH3), 4.04 (4H,
m, 2 × P(O)OCH2CH3), 4.24 (4H, m, 2 × P(O)OCH2CH3), 6.09
(1H, d, JHP ) 20.9 Hz, CHP), 6.10 (1H, d, JHP ) 20.6 Hz, CHP),
7.10 (1H, tt, J ) 8.2 Hz, J ) 1.4 Hz, CH), 7.13 (1H, tt, J ) 8.0
Hz, J ) 1.6 Hz, CH), 7.17 (2H, t, J ) 7.7 Hz, 2 × CH), 7.35
(1H, t, J ) 6.9 Hz, CH), 7.37 (1H, t, J ) 7.4 Hz, CH), 7.89
(1H, t, J ) 7.9 Hz, CH), 7.92 (1H, t, J ) 7.7 Hz, CH); 13C NMR
(CDCl3) δ 16.2 (d, JCP ) 2.3 Hz), 16.3 (d, JCP ) 2.3 Hz), 16.5,
16.6, 22.5, 22.8, 27.9, 28.5, 37.0, 37.3, 44.72 (d, JCP ) 162.7
Hz), 44.74 (d, JCP ) 163.8 Hz), 52.1 (2C), 56.8, 56.9, 59.8, 60.1,
63.0 (d, JCP ) 8.1 Hz), 63.1 (d, JCP ) 6.9 Hz), 63.3 (2C, d, JCP
) 6.9 Hz), 116.0 (2C, J ) 21.9 Hz), 119.6 (d, JCP ) 15.0 Hz,
JCF ) 4.6 Hz), 121.0 (d, JCP ) 14.4 Hz, JCF ) 5.2 Hz), 124.1 (d,
J ) 3.5 Hz), 124.2 (d, J ) 3.5 Hz), 130.7, 130.8, 131.4 (d, J )
3.5 Hz), 131.5 (d, J ) 2.3 Hz), 160.9 (dd, JCF ) 249.8 Hz, JCP
) 6.3 Hz), 161.0 (dd, JCF ) 249.8 Hz, JCP ) 6.3 Hz), 168.9
(2C), 169.5 (d, JCP ) 4.6 Hz), 169.9 (d, JCP ) 4.6 Hz); 31P NMR
(CDCl3) δ 19.10 (d, JPF ) 3.7 Hz), 19.69 (d, JPF ) 4.5 Hz); IR
(neat) 1739, 1704, 1699 cm-1; MS m/z 416 [M + H+]; Rf(EtOAc/
PET, 4/6) ) 0.10. Anal. Calcd for C19H27FNO6P: C, 54.94, H,
6.55. Found: C, 54.98, H, 6.52.
127.4, 130.3 (2C), 131.7 (d, JCP ) 6.1 Hz), 131.8 (2C, d, JCP
)
3.6 Hz), 132.0 (d, JCP ) 6.1 Hz), 133.6 (2C), 168.7, 168.8, 169.0
(d, JCP ) 2.4 Hz), 169.2 (d, JCP ) 3.7 Hz); 31P NMR (CDCl3) δ
19.07, 19.58; IR (neat) 1739, 1704, 1699 cm-1; MS m/z 478/
476 [M + H+]; Rf(EtOAc/PET, 1/1) ) 0.16. Anal. Calcd for
C19H27BrNO6P: C, 47.91, H, 5.71. Found: C, 47.79, H, 5.80.
Data for methyl 1-[(2-chlorophenyl)(diethoxyphos-
phoryl)methyl]-4,4-dimethyl-2-oxo-3-pyrrolidinecarbox-
ylate (37): synthesized according to the general procedure
applying 9 days of reflux; 1H NMR (CDCl3) δ 0.98 (3H, s, CH3),
1.03 (3H, s, CH3), 1.09 (3H, s, CH3), 1.17 (6H, t, J ) 6.9 Hz, 2
× P(O)OCH2CH3), 1.27 (3H, s, CH3), 1.38 (3H, t, J ) 7.1 Hz,
P(O)OCH2CH3), 1.39 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 2.74
(1H, d, J ) 9.6 Hz, CH2), 2.92 (1H, d, J ) 9.2 Hz, CH2), 3.07
(1H, d, J ) 2.6 Hz, CH), 3.10 (1H, s, CH), 3.52 (1H, d, J ) 9.2
Hz, CH2), 3.64 (3H, s, OCH3), 3.65 (1H, d, J ) 9.6 Hz, CH2),
3.74 (3H, s, OCH3), 4.05 (4H, m, 2 × P(O)OCH2CH3), 4.25 (4H,
m, 2 × P(O)OCH2CH3), 6.16 (1H, d, JHP ) 20.8 Hz, CHP), 6.20
(1H, d, JHP ) 20.5 Hz, CHP), 7.31 (4H, m, 4 × CH), 7.45 (2H,
m, 2 × CH), 8.05 (2H, m, 2 × CH); 13C NMR (CDCl3) δ 16.1 (d,
JCP ) 2.4 Hz), 16.2 (d, JCP ) 2.5 Hz), 16.4, 16.5, 22.4, 22.7,
General Procedure for the Preparation of γ-Lactam
40. Imine 21a (1 mmol) was dissolved in 10 mL of anhydrous
ethanol together with 10 mol % palladium on carbon, and the
reaction mixture was brought under a hydrogen atmosphere
for 3 days. After filtration over Celite and evaporation of the
solvent under reduced pressure, the crude γ-lactam 40 was
isolated as a yellow oil. Purification by flash chromatography
yielded the pure lactam in 52% yield.
27.9, 28.5, 36.9, 37.1, 48.6 (d, JCP ) 161.1 Hz), 48.7 (d, JCP
)
162.3 Hz), 51.7 (2C), 56.7 (2C), 59.8, 60.1, 62.8 (d, JCP ) 7.3
Hz), 62.9 (d, JCP ) 7.3 Hz), 63.1 (d, JCP ) 7.3 Hz), 63.2 (d, JCP
) 7.3 Hz), 126.7, 126.8, 130.2 (6C), 131.5 (d, JCP ) 3.6 Hz),
131.7 (d, JCP ) 3.7 Hz), 135.2 (d, JCP ) 13.5 Hz), 135.5 (d, JCP
) 13.4 Hz), 168.7, 168.8, 169.0 (d, JCP ) 3.7 Hz), 169.3 (d, JCP
) 3.6 Hz); 31P NMR (CDCl3) δ 18.97, 19.52; IR (neat) 1739,
1703, 1700 cm-1; MS m/z 434/432 [M + H+]; Rf(EtOAc/PET,
1/1) ) 0.11. Anal. Calcd for C19H27ClNO6P: C, 52.84, H, 6.30.
Found: C, 52.80, H, 6.35.
Data for methyl 1-[(diethoxyphosphoryl)(phenyl)-
methyl]-4,4-dimethyl-2-oxo-3-pyrrolidinecarboxylate (40):
1H NMR (CDCl3) δ 0.98 (6H, s, 2 × CH3), 1.10 (3H, s, CH3),
1.13 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 1.16 (3H, t, J ) 6.9
Hz, P(O)OCH2CH3), 1.27 (3H, s, CH3), 1.35 (3H, t, J ) 6.9 Hz,
P(O)OCH2CH3), 1.37 (3H, t, J ) 7.3 Hz, P(O)OCH2CH3), 3.00
(1H, d, J ) 9.6 Hz, CH2), 3.06 (1H, s, CH), 3.08 (1H, d, J ) 2.6
Hz, CH), 3.09 (1H, d, J ) 9.6 Hz, CH2), 3.56 (1H, d, J ) 9.6
Hz, CH2), 3.62 (3H, s, OCH3), 3.73 (1H, d, J ) 9.6 Hz, CH2),
3.74 (3H, s, OCH3), 4.02 (4H, m, 2 × P(O)OCH2CH3), 4.21 (4H,
m, 2 × P(O)OCH2CH3), 5.75 (1H, d, JHP ) 21.1 Hz, CHP), 5.78
(1H, d, JHP ) 20.8 Hz, CHP), 7.36 (6H, m, 6 × CH), 7.61 (4H,
m, 4 × CH); 13C NMR (CDCl3) δ 16.1, 16.2 (d, JCP ) 4.8 Hz),
16.4, 16.5, 22.4, 22.8, 27.7, 28.5, 36.9, 37.2, 51.7 (d, JCP ) 158.7
Hz), 51.9 (d, JCP ) 158.7 Hz), 51.97, 52.00, 56.6, 56.8, 59.8,
60.0, 62.6 (d, JCP ) 7.3 Hz), 62.97 (d, JCP ) 6.1 Hz), 63.04 (d,
JCP ) 6.1 Hz), 63.2 (d, JCP ) 7.3 Hz), 128.7 (6C, t, J ) 8.5 Hz),
129.8 (4C, J ) 7.9 Hz), 132.0 (d, JCP ) 3.7 Hz), 132.6 (d, JCP
) 3.7 Hz), 168.8, 169.0, 169.7 (d, JCP ) 6.1 Hz), 170.2 (d, JCP
) 4.9 Hz); 31P NMR (CDCl3) δ 19.35, 19.97; IR (neat) 1738,
1694 cm-1; MS m/z 398 [M + H+]; Rf(EtOAc/PET, 1/1) ) 0.20.
Anal. Calcd for C19H28NO6P: C, 57.42, H, 7.10. Found: C,
57.25, H, 7.19.
Data for methyl 1-[(diethoxyphosphoryl)(4-fluorophen-
yl)methyl]-4,4-dimethyl-2-oxo-3-pyrrolidinecarboxylate
(38): synthesized according to the general procedure applying
2 days of reflux; 1H NMR (CDCl3) δ 0.98 (3H, s, CH3), 0.99
(3H, s, CH3), 1.10 (3H, s, CH3), 1.15 (3H, t, J ) 6.9 Hz, P(O)-
OCH2CH3), 1.17 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 1.27 (3H,
s, CH3), 1.35 (3H, t, J ) 6.9 Hz, P(O)OCH2CH3), 1.38 (3H, t, J
) 6.9 Hz, P(O)OCH2CH3), 2.97 (1H, d, J ) 9.6 Hz, CH2), 3.06
(1H, s, CH), 3.08 (2H, m, CH, CH2), 3.54 (1H, d, J ) 9.2 Hz,
CH2), 3.63 (3H, s, OCH3), 3.72 (1H, d, J ) 9.9 Hz, CH2), 3.74
(3H, s, OCH3), 4.02 (4H, m, 2 × P(O)OCH2CH3), 4.21 (4H, m,
2 × P(O)OCH2CH3), 5.73 (1H, d, JHP ) 21.4 Hz, CHP), 5.76
(1H, d, JHP ) 21.4 Hz, CHP), 7.06 (2H, t, J ) 8.6 Hz, 2 × CH),
7.07 (2H, t, J ) 8.6 Hz, 2 × CH), 7.61 (4H, m, 4 × CH); 13C
NMR (CDCl3) δ 16.1, 16.2 (d, JCP ) 4.9 Hz), 16.4 (d, JCP ) 2.4
Hz), 16.5 (d, JCP ) 2.4 Hz), 22.4, 22.8, 27.8, 28.5, 36.9, 37.2,
50.9 (d, JCP ) 159.9 Hz), 51.1 (d, JCP ) 161.1 Hz), 52.0 (2C),
Acknowledgment. This work was supported by the
Belgian IWT (Instituut voor de Aanmoediging van
Innovatie door Wetenschap en Technologie in Vlaan-
deren, Institute for the Promotion of Innovation by
Science and Technology in Flanders).
56.5, 56.7, 59.8, 60.0, 62.7 (d, JCP ) 7.4 Hz), 63.1 (2C, d, JCP
)
7.3 Hz), 63.3 (d, JCP ) 7.4 Hz), 115.7 (2C, d, JCF ) 21.9 Hz),
115.8 (2C, d, JCF ) 22.0 Hz), 128.0 (d, J ) 3.7 Hz), 128.6 (d, J
) 3.7 Hz), 131.6 (2C, d, J ) 8.5 Hz), 131.9 (2C, d, J ) 7.3 Hz),
162.7 (2C, d, JCF ) 245.4 Hz), 168.8, 169.0, 169.8 (d, JCP ) 4.9
Hz), 170.3 (d, JCP ) 6.1 Hz); 31P NMR (CDCl3) δ 19.08, 19.73;
JO0488661
198 J. Org. Chem., Vol. 70, No. 1, 2005