Easy and efficient generation of reactive anions with free and supported ylides as neutral Bronsted bases

Article abstract of DOI:10.1016/S0040-4020(99)01039-X

The tris(dimethylamino)-C-dimethylphosphorus ylide 5 and the tris(dimethylamino)phosphorus ylide C-bound to Merrifield's resin 6 are used as strong non-nucleophilic bases in N-alkylation reactions of β-amino phosphine oxides and α-amino acid derivatives,

Full text of DOI:10.1016/S0040-4020(99)01039-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 663–669
Easy and Efficient Generation of Reactive Anions with Free and
Supported Ylides as Neutral Brønsted Bases
a,*
a
a
b
Francisco Palacios, Domitila Aparicio, Jes u´ s M. de los Santos, Antoine Baceiredo and
b
Guy Bertrand
a
Departamento de Qu ´ı mica Org a´ nica, Facultad de Farmacia, Universidad del Pa ´ı s Vasco, Apartado 450, 01080 Vitoria, Spain
b
Laboratoire d’H e´ t e´ rochimie Fondamentale et Appliqu e´ e, Universit e´ Paul Sabatier, 118, Route de Narbonne,
3
1062 Toulouse C e´ dex 04, France
Received 13 September 1999; revised 8 November 1999; accepted 25 November 1999
Abstract—The tris(dimethylamino)-C-dimethylphosphorus ylide 5 and the tris(dimethylamino)phosphorus ylide C-bound to Merrifield’s
resin 6 are used as strong non-nucleophilic bases in N-alkylation reactions of b-amino phosphine oxides and a-amino acid derivatives, and in
the C-alkylation reaction of enamines and benzophenone imines derived from glycine ethyl ester. Base-catalyzed aldol-type condensation
(Henry) reaction of nitroethane with aldehydes and olefination reactions of phosphine oxides and phosphonates are also described. ᭧ 2000
Elsevier Science Ltd. All rights reserved.
3
e
An important tool in organic synthesis is the generation of
anions under mild reaction conditions that can in turn par-
ticipate in interesting and useful transformations. Classic
methods involve the use of ionic bases such as alkali
metal hydroxides, alkoxides, hydrides or metalorganic
reagents. However, their use is limited in some cases
because their elimination is not easy and in most cases
needs work-up. The nucleophilic attack of the base to the
substrate may also take place as a side reaction. Therefore,
there is a need for new classes of strong non-ionic and non-
nucleophilic bases.
effects of the conjugate porphyrin anion, but their high
molecular weight and cost are drawbacks for their extensive
use. Phosphorus ylides, isosteric analogues of phosphazenes
by substitution of the nitrogen atom for the carbon atom, are
more basic than the corresponding phosphazenes, but this
property has seldom been used in organic and organo-
4
metallic chemistry. Simple ylides such as P-tris(dimethyl-
amino)-C-dimethylphosphorus ylide 5 can be conveniently
used as strong non-nucleophilic bases for alkylation of
nitrogen heterocycles. Here we report some applications
of 5 for regioselective N- and C-alkylation of acyclic
compounds and for olefination reactions. The use in organic
synthesis of a supported version 6 of this type of base, with
potential applications in combinatorial chemistry, is also
presented (Fig. 1).
5,6
Proazaphosphatranes 1 have recently been described as
1
a
strong non-ionic bases. They have been used for the
1
b
1c
acylation and silylation of alcohols, for the dehydro-
1
d
1e
halogenation of alkyl halides and to deprotonate nitriles
or b-dicarbonyl compounds. Proton sponges, related to
,8-bis(dimethylamino)-naphthalene (DMAN) 2, and new
1
f
2a
1
Results and Discussion
ones, derived from the replacement of one or both dimethyl-
amino groups by phosphazene groups 3 are also strong
2
b
N-Alkylation reactions
bases. These phosphazene-substituted proton sponges 3
are stronger than DMAN 2, but are of no practical value,
since the free bases cannot be prepared. In the late 1980s,
In order to explore the basic and non-nucleophilic behavior
of ylide 5, we first tested selective N-functionalization reac-
tions of b-amino phosphine oxides 7. Amines, derived
from phosphine oxides and especially aminophosphonates,
polyaminophosphazenes such as 4 (namely P tBu) were
7
4
3
reported as excellent strong uncharged bases. They have
found applications for the deprotonation of compounds of
3
d
phosphorus analogs of amino acids, are useful intermediates8
very low acidity or for measuring the kinetic isotope
not only in organic synthesis but also in medicinal chemistry.
The selective N-functionalization reactions of b-amino
phosphine oxide 7 can be performed with phosphorus
ylide 5 as non-ionic base instead of organometallic reagents
Keywords: basicity; carbanions; phosphorus ylides; solid-phase synthesis;
supported ylides.
9
or sodium hydride. Indeed, addition of an excess (2 equiv.)
*
Corresponding author. Tel.: ϩ34-945-013103; fax: ϩ34-945-130756;
e-mail: qoppagaf@vf.ehu.es
of a freshly prepared THF solution of the phosphorus ylide 5
0
040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01039-X

6
64
F. Palacios et al. / Tetrahedron 56 (2000) 663–669
Figure 1.
Scheme 1.
1
2,13
to a THF solution of 7, followed by addition of the alkyl-
ating reagent (MeI) led to formation of N-functionalized
b-amino phosphine oxide 8 in excellent yield (87%) after
elimination of the phosphonium salt 5H ,I by addition of
ether to the reaction mixture and simple filtration
increased in the presence of bases.
However, the ambi-
13
dent nucleophilic reactivity of activated metallo enamines
has the problem of site reactivity and they can react with
electrophilic compounds not only at the nitrogen atom but
also at the b carbon of the enamine. The regioselective
C-alkylation reaction of secondary b-enamine derived
from phosphine oxide 11 was performed by treatment
with ylide 5 in THF, followed by addition of methyl iodide,
but the C-a-methyl-b-enamine 12 was isolated, as a mixture
of both Z and E isomers (Scheme 2). Compounds 12 were
characterized on the basis of their spectroscopic data. Thus,
the P NMR spectrum of the mixture 12Z/E showed two
different absorptions at d 36.3 and 39.5 in an approximate
isomer ratio 1:1 as evidenced by the relative peaks areas for
each isomer, in which the high-field chemical shift corre-
ϩ
Ϫ
(Scheme 1).
14
This process can also be extended to a-amino acid deriva-
tives. The selective alkylation processes at the N atom
versus the Ca atom for amino acid derivatives have been
1
0
widely studied. Good results were also obtained for the
31
selective N-alkylation reaction of N-protected glycine alkyl
1
1
ester 9. Addition of a slight excess of ylide 5 to a THF
solution of N-Boc-a-amino ester 9, followed by treatment
with allyl bromide, led to the N-alkylated compound 10 in a
regioselective fashion, but in moderate yield (61%)
P
1
sponded to the E-isomer. Further examination of the H and
(Scheme 1).
C-Alkylation reactions
Ylide 5 can also be efficiently used for C-alkylation
reactions and carbon–carbon bond formation reactions.
Enamines are excellent reagents for carbon–carbon bond
1
2
formation
and their nucleophilic character can be
Scheme 2.

F. Palacios et al. / Tetrahedron 56 (2000) 663–669
665
Scheme 3.
Scheme 4.
Scheme 5.
1
3
C NMR spectra was consistent with the b-enamine
reaction is a known method for the construction of carbon–
carbon bonds, which leads to formation of 2-nitroalcohols,
which are versatile synthetic intermediates in the prepara-
1
3
18
structure. In the C NMR spectrum, the methyl group of
3
the E-isomer resonates at dC 13.9 ( J ˆ3.0 Hz). Con-
PC
versely, the Z-isomer showed clearly different absorption
tion of 2-aminoalcohols, of particular significance in the
3
19
for the methyl group at dC 21.3 ( J ˆ12.1 Hz). Similar
synthesis of biologically active compounds and amino
PC
3
20
coupling constants ( J ) had been previously observed in
sugars. Ylide 5 is also able to promote the nitroaldol
PC
1
5
14
E- and Z-b-hydrazino or b-enamino phosphine oxides or
phosphonates.
reaction between p-tolualdehyde 15a and nitroethane.
Treatment of a nitroethane solution of ylide 5 at 0ЊC with
p-tolualdehyde 15a gave nitroalcohols 16a as a mixture of
syn and anti derivatives (2:1 ratio), obtained in excellent
yield (90%) but with low stereoselectivity (Scheme 4).
Nitroalcohol 16a was characterized by its spectroscopic
This process can also be extended to a-amino acid deriva-
tives. a-Amino acid derivatives can be alkylated in a regio-
selective fashion in the presence of ylide 5 not only at the N
atom as has been described in Scheme 1, but also at the Ca
1
data. The H NMR spectrum showed well-resolved doublets
16
atom when imines derived from amino acids are used.
for the methine proton (H ) and the proton absorption of
1
Treatment of benzophenone–imine derivative of glycine
the anti-isomer was shifted to a lower field dH 5.19
1
7
3
alkyl ester 13 with a freshly prepared THF solution of
the base 5, followed by addition of methyl iodide led to
formation of C-a-functionalized imine 14a (RˆMe) in a
selective fashion and in good yield (80%). This compound
( J ˆ4.1 Hz) relative to that of the syn-isomer dH 4.87
HH
3
( J ˆ9.2 Hz), which is consistent with previously reported
HH
18c
13
syn- and anti-2-nitroalcohols. Likewise in C NMR this
latter isomer showed a downfield shift absorption for the
methine carbon (C ) d 88.3 relative to that observed for
14a was characterized on the basis of its spectroscopic data,
1
C
having spectroscopic, analytical and physical properties in
the anti-isomer d 87.4.
C
1
7
full agreement with the literature. In the same way, the
selective C-alkylation of the benzophenone–imine deriva-
tive 13 was performed using allyl bromide affording imine
Olefination reactions
1
4b (RˆCH CHyCH ) in 67% yield. The use of phase-
The reaction of an a-phosphorus-stabilized anion with a
carbonyl derivative is undoubtedly one of the most useful
methods for selectively constructing carbon–carbon double
bonds. Phosphorus ylide 5 may also be useful as a strong
base in carbon–carbon double bond formation reactions by
the Horner–Wittig reaction of phosphine oxide anions and
by the Horner–Wadsworth–Emmons reaction of phos-
phonate anions for two carbon homologation of hydrazones.
2
2
transfer conditions employed for the alkylation of the a
1
0,16d–g
anion of glycine derivatives
employing ylide 5 as a strong non-nucleophilic base
Scheme 3).
could be replaced by
21
(
Another carbon–carbon bond formation reaction was
explored. Base-catalyzed aldol-type condensation (Henry)

6
66
F. Palacios et al. / Tetrahedron 56 (2000) 663–669
Scheme 6. (i) 13, THF, 0ЊC, 1 h, MeI, THF, 0ЊC to rt, 5 h, 84%; (ii) 15b, nitroethane, 0ЊC, 0.5 h, 70%; (iii) 17b, THF, 0ЊC, 1 h, 15b, THF, 0ЊC to reflux, 36 h,
5%.
6
1
5
Treatment of b-hydrazones derived from phosphonate 17a
those obtained with ylide 5 in solution, simple filtration of
the reaction mixture and evaporation of the solvent afforded
compounds 14a, 16b and 18b in good yields, while the resin
6 could be regenerated by washing with acetonitrile and
simple deprotonation.
with ylide 5 followed by addition of p-tolualdehyde 15a led
to the formation of a,b-unsaturated hydrazone 18a in good
3
yield (Scheme 5). Vicinal JHHˆ16.5 Hz between the
vinylic protons of 18a were consistent with the E configura-
1
5
tion of the carbon–carbon double bond. Similarly, treat-
15
ment of b-hydrazones derived from phosphine oxide 17b
with ylide 5 followed by addition of p-nitrobenzaldehyde
5b gave a,b-unsaturated hydrazone 18b (Scheme 5).
These results were very similar to that obtained when
In conclusion, ylide 5 and supported ylide 6 are versatile and
efficient non-nucleophilic strong bases, which can be
used for selective N- and C-alkylation reactions and for
olefination reaction under mild reaction conditions. It is of
particular interest that in each case the phosphonium salt
1
1
5
methyllithium or LDA was used as base.
ϩ
Ϫ
5
H ,X (XˆBr or I) can be precipitated from the reaction
Supported ylides
mixture by addition of ether and easily eliminated by simple
filtration. In all of the reactions mentioned above, no trace of
adducts resulting from nucleophilic behavior of 5 was
observed. Moreover, supported ylide 6 could be a valuable
intermediate not only for solid-phase synthesis but also for
combinatorial chemistry.
Polymer supported phosphorus ylides have recently been
used in combinatorial synthesis with aldehydes (Wittig
22
23
reaction) for the preparation of small organic molecules.
24
Therefore, in order to make the use of ylides as strong non-
nucleophilic bases more attractive, we investigated their use
5
in solid-phase synthesis of supported ylide 6.
Experimental
The reactivity of ylide attached to Merrifield’s resin 6
was first tested for C-alkylation reaction of a-amino acid
derivatives. The selective C-alkylation reaction of the
benzophenone–imine derivative of glycine alkyl ester 13
was accomplished using supported ylide 6 at 0ЊC in THF,
followed by addition of methyl iodide. The C-a-functiona-
lized imine 14a was obtained in excellent yield (84%)
General
Chemicals were purchased from Aldrich Chemical
Company. Solvents for extraction and chromatography
were technical grade. All solvents used in reactions were
freshly distilled from appropriate drying agents before use.
All other reagents were recrystallized or distilled as neces-
sary. All reactions were performed under an atmosphere of
dry nitrogen. Analytical TLC was performed with Merck
silica gel 60 F254 plates. Visualization was accomplished
(Scheme 6).
Henry reaction was also explored. Supported ylide 6
promoted the nitroaldol reaction between p-nitrobenzalde-
hyde 15b and nitroethane giving nitroalcohols 16b (70%) as
a mixture (1.3:1 ratio) of syn and anti derivatives
by UV light and KMnO solution. Flash chromatography
4
was carried out using Merck silica gel 60 (230–400 mesh
ASTM). Melting points were determined with an Electro-
thermal IA9100 Digital Melting Point Apparatus and are
(
Scheme 6). Finally, the resin 6 may also be useful as a
strong base in carbon–carbon double bond formation
1
13
31
reactions and was used for homologation of hydrazones.
uncorrected. H (300 MHz), C (75 MHz) and P NMR
15
Treatment of b-hydrazono phosphine oxide 17b with
ylide 6 followed by addition of p-nitrobenzaldehyde 15b
led to the formation of a,b-unsaturated hydrazone 18b
(120 MHz) spectra were recorded on a Varian VXR
300 MHz spectrometer using CDCl solutions with TMS
3
1
13
as an internal reference for H and C NMR spectra and
phosphoric acid (85%) for P NMR spectra. Coupling
3
1
(Scheme 6). Although these results were comparable to

F. Palacios et al. / Tetrahedron 56 (2000) 663–669
667
constants (J) are reported in Hertz. Low-resolution mass
spectra (MS) were obtained at 50–70 eV by electron impact
Anal. Calcd for C H NO (243.30): C, 59.24; H, 8.70; N,
12 21 4
5.76. Found: C, 59.42; H, 8.67; N, 5.73.
(
EIMS) on a Hewlett Packard 5971 spectrometer. Data are
reported in the form m/z (intensity relative to baseˆ100).
Infrared spectra (IR) were recorded on a Nicolet IRFT
Magna 550 spectrometer for neat oils. Peaks are reported
in cm . Elemental analyses were performed in a LECO
CHNS-932 apparatus. Ylides 5 and 6, b-amino 7 and
b-enanimo phosphine oxide 11, amino acid derivatives
9
phine oxide 17b were synthesized according to literature
procedures.
General procedure for the preparation of Z- and E-2-(N-
t-butylamino)-1-methylprop-1-enylphosphine oxide (12).
To a freshly prepared Ϫ78ЊC solution of ylide 5 (656 mg,
3.2 mmol) in THF (20 mL) was added a solution of b-enam-
inophosphine oxide 11 (470 mg, 1.5 mmol) in THF
(10 mL). The mixture was allowed to stir at this temperature
for 1 h and a solution of methyl iodide (112 mL, 1.8 mmol)
in THF (5 mL) was then added at the same temperature.
After the mixture was allowed to warm to room tempera-
ture, the reaction mixture was stirred and heated at reflux for
48 h. The solution was separated from the phosphonium
salts by addition of ether (50 mL) and filtration. After
evaporation of the solvent, the residue was purified by
flash chromatography eluting with 1:2 AcOEt/hexanes to
yield compound 12 (280 mg, 57%) as a pale yellow oil;
Ϫ1
5
7
1
4
11
17
15
and 13 and b-hydrazono phosphonate 17a and phos-
1
5
General procedure for the preparation of 2-(N-methyl-
N-p-tolylamino)butyldiphenylphosphine oxide (8). To a
freshly prepared Ϫ78ЊC solution of ylide 5 (656 mg,
3
.2 mmol) in THF (20 mL) was added a solution of
b-aminophosphine oxide 7 (545 mg, 1.5 mmol) in THF
10 mL). The mixture was allowed to stir at this temperature
1
(
H NMR (300 MHz) 7.86–7.45 (m, 10 H, Ph), 2.23 (d,
3
for 1 h and a solution of methyl iodide (112 mL, 1.8 mmol)
in THF (5 mL) was then added at the same temperature.
After the mixture was allowed to warm to room tempera-
ture, the reaction mixture was stirred and heated at reflux for
J ˆ13.0 Hz, 3 H, CH ), 2.01 (s, 3 H, CH ), 1.52 (s, 9 H,
PH
3
3
13
t-Bu); C NMR (75 MHz) 173.2 (C–N), 133.2–127.3 (Ph),
1
84.2 (d, J ˆ121.4 Hz, C–P), 72.1 (C), 34.0 (d,
PC
2
3
J ˆ12.0 Hz, CH ), 28.1 (3 CH ), 21.3 (d, J ˆ12.1 Hz,
PC
3
3
PC
31
3
2
4 h. The solution was separated from the phosphonium
Z-CH ), 13.9 (d, J ˆ3.0 Hz, E-CH );
P NMR
Ϫ1
3
PC
3
salts by addition of ether (50 mL) and filtration. After
evaporation of the solvent, the residue was purified by
flash chromatography eluting with 1:1 AcOEt/hexanes to
(120 MHz) 39.5 and 36.3; IR (NaCl) 3267 cm (NH),
Ϫ1 Ϫ1
1567 cm
(C–N), 1170 cm
(PyO); EIMS m/z 327
ϩ
ϩ
ϩ
(M , 27), 312 [(M ϪMe), 64], 201 (Ph PO , 100). Anal.
2
1
yield compound 8 (492 mg, 87%) as a pale yellow oil; H
Calcd for C H NOP: C, 73.37; H, 8.00; N, 4.28. Found: C,
20
26
73.13; H, 8.03; N, 4.26.
3
General procedure for the preparation of ethyl
N-(diphenylmethylene)alaninate (14a). Procedure A: to
a freshly prepared Ϫ78ЊC solution of ylide 5 (461 mg,
2.25 mmol) in THF (15 mL) was added a solution of
a-iminoester 13 (534 mg, 2 mmol) in THF (10 mL). The
mixture was allowed to stir at this temperature for 1 h and
a solution of methyl iodide (137 mL, 2.2 mmol) in THF
(2 mL) was then added at the same temperature. After the
mixture was allowed to warm to room temperature, the
reaction mixture was stirred and heated at reflux for 12 h.
The solution was separated from the phosphonium salts by
addition of ether (50 mL) and filtration. After evaporation of
the solvent, the residue was purified by flash chromato-
graphy eluting with 1:6 AcOEt/hexanes to yield compound
14a (450 mg, 80%) as a pale yellow oil. Procedure B: to a
freshly prepared 0ЊC suspension of solid-supported ylide 6
(2.25 g) in THF (20 mL) was added a solution of a-imino-
ester 13 (534 mg, 2 mmol) in THF (8 mL). The mixture was
allowed to stir at this temperature for 1 h and a solution of
methyl iodide (137 mL, 2.2 mmol) in THF (2 mL) was then
added at the same temperature. After the mixture was
allowed to warm to room temperature, the reaction mixture
was stirred for 5 h. Filtration and evaporation of the solvent
under vacuum led to compound 14a (472 mg, 84%) as a pale
yellow oil. The product obtained had spectroscopic/
analytical/physical properties in full agreement with the
CH ), 1.77 (m, 1 H, CH ), 1.49 (m, 1 H, CH ), 0.71 (t,
3
2
2
3
13
JHHˆ7.3 Hz, 3 H, CH ); C NMR (75 MHz,) 148.0–
3
1
12.1 (Ph), 55.1 (CH N), 50.0 (CH), 32.2 (d,
3
1
J ˆ69.5 Hz, CH P), 26.6 (CH ), 19.6 (CH ), 10.7
PC
2
2
3
3
1
Ϫ1
(
(
(
CH ); P NMR (120 MHz) 31.7; IR (NaCl) 1162 cm
3
ϩ ϩ
PyO); EIMS m/z 377 (M , 26), 348 [(M ϪEt), 66], 201
ϩ
Ph PO , 100). Anal. Calcd for C H NOP (377.47): C,
2
24 28
7
3
6.37; H, 7.48; N, 3.71. Found: C, 76.07; H, 7.50; N,
.72.
General procedure for the synthesis of ethyl N-allyl-N-t-
butoxycarbonylglycinate (10). To a freshly prepared
Ϫ78ЊC solution of ylide 5 (656 mg, 3.2 mmol) in THF
(
20 mL) was added a solution of N-Boc glycine ester 9
(305 mg, 1.5 mmol) in THF (10 mL). The mixture was
allowed to stir at this temperature for 1 h and a solution of
allyl bromide (130 mL, 1.5 mmol) in THF (5 mL) was then
added at the same temperature. After the mixture was
allowed to warm to room temperature, the reaction mixture
was stirred and heated at reflux for 48 h. The solution was
separated from the phosphonium salts by addition of ether
(
50 mL) and filtration. After evaporation of the solvent, the
residue was purified by flash chromatography eluting with
:4 AcOEt/hexanes to yield compound 10 (222 mg, 61%) as
1
1
a pale yellow oil; H NMR (300 MHz) 5.71 (m, 1 H, CH),
.13 (m, 2 H, CH y), 4.23 (m, 2 H, OCH ), 3.79 (m, 2 H,
17
5
literature data.
2
2
CH ), 3.21 (s, 2 H, CH N), 1.38 (s, 9 H, tBu), 1.24 (t,
2
2
3
13
JHHˆ7.0 Hz, 3 H, CH ); C NMR (75 MHz) 169.8
Synthesis of ethyl N-(diphenylmethylene)-2-allylglyci-
nate (14b). To a freshly prepared Ϫ78ЊC solution of ylide
5 (461 mg, 2.25 mmol) in THF (15 mL) was added a solu-
tion of a-iminoester 13 (534 mg, 2 mmol) in THF (10 mL).
The mixture was allowed to stir at this temperature for 1 h
3
(
CyO), 167.7 (CyO), 131.6 (CH), 117.8 (CH y), 76.9
2
(
1
(
C), 60.8 (OCH ), 55.6 (CH ), 46.0 (CH ), 28.2 (3 CH ),
2
2
2
3
Ϫ1
Ϫ1
4.0 (CH ); IR (NaCl) 1750 cm
(CyO), 1721 cm
3
ϩ
ϩ
CyO); EIMS m/z 142 [(M ϪBoc), 17], 57 (t-Bu , 100).

6
68
F. Palacios et al. / Tetrahedron 56 (2000) 663–669
and a solution of allyl bromide (173 mL, 2 mmol) in THF
5 mL) was then added at the same temperature. After the
mixture was allowed to warm to room temperature, the
reaction mixture was stirred and heated at reflux for 48 h.
The solution was separated from the phosphonium salts by
addition of ether (50 mL) and filtration. After evaporation of
the solvent, the residue was purified by flash chromato-
(10 mL). The mixture was allowed to stir at this temperature
for 1 h and a solution of p-tolualdehyde 15a (236 mL,
2 mmol) in THF (5 mL) was then added at the same
temperature. After the mixture was allowed to warm to
room temperature, the reaction mixture was stirred and
heated at reflux for 48 h. The solution was separated from
the phosphonium salts by addition of ether (50 mL) and
filtration. After evaporation of the solvent, the residue was
(
graphy eluting with 1:6 AcOEt/hexanes to yield compound
1
1
4b (411 mg, 67%) as a pale yellow oil; H NMR
purified by flash chromatography eluting with 1:10 Et O/
2
(
5
2
300 MHz) 7.81–7.10 (m, 10 H, Ph), 5.62 (m, 1 H, CH),
hexanes to yield compound 18a (303 mg, 75%) as a pale
yellow oil. The product obtained had spectroscopic/
analytical/physical properties in full agreement with the
.07 (m, 2 H, CH ), 4.10 (m, 2 H, OCH ), 3.21 (m, 1 H, CH),
2 2
3 13
.60 (m, 2 H, CH ), 1.18 (t, J ˆ7.0 Hz, 3 H, CH );
C
2
HH
3
15
NMR (75 MHz) 196.6 (CyO), 137.6 (CH), 134.3–127.1 (Ph
literature data.
and yC), 117.5 (CH ), 65.3 (CH), 60.8 (OCH ), 38.1 (CH ),
2
2
2
Ϫ1
Ϫ1
1
4.2 (CH ); IR (NaCl) 1739 cm
(CyO), 1660 cm
Synthesis of syn- and anti-E-p-nitrophenylbuten-3-one
N,N-dimethylhydrazone (18b). Procedure A: to a freshly
prepared Ϫ78ЊC solution of ylide 5 (461 mg, 2.25 mmol) in
THF (15 mL) was added a solution of b-hydrazophosphine
oxide 17b (600 mg, 2 mmol) in THF (10 mL). The mixture
was allowed to stir at this temperature for 1 h and a solution
of p-nitrobenzaldehyde 15b (308 mg, 2 mmol) in THF
(5 mL) was then added at the same temperature. After the
mixture was allowed to warm to room temperature, the
reaction mixture was stirred and heated at reflux for 36 h.
The solution was separated from the phosphonium salts by
addition of ether (50 mL) and filtration. After evaporation of
the solvent, the residue was purified by flash chromato-
3
ϩ
ϩ
(CyN); EIMS m/z 307 (M , 23), 266 [(M ϪAllyl), 100].
Anal. Calcd for C H NO (307.39): C, 78.15; H, 6.89; N,
2
0
21
2
4.56. Found: C, 77.95; H, 6.86; N, 4.57.
General procedure for the preparation of syn- and anti-
-nitro-1-p-tolylpropan-1-ol (16a). To a 0ЊC solution of
p-tolualdehyde 15a (414 mL, 3.51 mmol) in nitroethane
2
(
15 mL) was added a freshly prepared solution of ylide 5
(62 mg, 0.3 mmol) in nitroethane (5 mL). After the mixture
was allowed to warm to room temperature, the reaction
mixture was stirred for 12 h. The solution was separated
from the phosphonium salts by addition of ether (50 mL)
and filtration. After evaporation of the solvent, the residue
was purified by flash chromatography eluting with 1:10
AcOEt/hexanes to yield a mixture of syn and anti nitro-
alcohols (2:1 ratio) 16a (616 mg, 90%) as a pale yellow
graphy eluting with 1:10 Et O/hexanes to yield compound
2
18b (326 mg, 70%) as a red oil. Procedure B: to a freshly
prepared 0ЊC suspension of solid-supported ylide 6 (2.25 g)
in THF (20 mL) was added a solution of b-hydrazono-
phosphine oxide 17b (600 mg, 2 mmol) in THF (8 mL).
The mixture was allowed to stir at this temperature for 1 h
and a solution of p-nitrobenzaldehyde 15b (308 mg,
2 mmol) in THF (2 mL) was then added at the same
temperature. After the mixture was allowed to warm to
room temperature, the reaction mixture was stirred and
heated at reflux for 36 h. Filtration and evaporation of the
solvent under vacuum led to compound 18b (303 mg, 65%)
as a red oil. The product obtained had spectroscopic/
analytical/physical properties in full agreement with the
1
oil; H NMR (300 MHz) 7.26–6.87 (m, 4 H, syn- and
3
anti-Ph), 5.19 (d, J ˆ4.1 Hz, 1 H, anti-CH), 4.87 (d,
HH
3
JHHˆ9.2 Hz, 1 H, syn-CH), 4.64 (m, 2 H, syn- and anti-
CH), 3.18 (s, 2 H, syn- and anti-OH), 2.27 (s, 3 H, syn-CH ),
3
3
2
.26 (s, 3H, anti-CH ), 1.41 (d, J ˆ6.7 Hz, 3 H, anti-
3
HH
3
13
CH ), 1.20 (d, J ˆ6.9 Hz, 3 H, syn-CH ); C NMR
3
HH
3
(75 MHz) 138.4, 137.7, 135.9, 135.5, 129.2, 128.9, 126.7,
1
25.8 (syn- and anti-Ph), 88.3 (syn-CH), 87.4 (anti-CH),
7
5.6 (syn-CH), 73.8 (anti-CH), 20.8 (CH ), 16.0 (syn-
3
Ϫ1
CH ), 12.4 (anti-CH ); IR (NaCl) 3357 cm
(OH)
3
3
Ϫ1
ϩ
15
1
554 cm
(NO2); EIMS m/z 195 (M , 3), 148
literature data.
ϩ
ϩ
[(M ϪHNO ), 16], 121 [(M ϪEtϪNO ), 100]. Anal.
2
2
Calcd for C H NO (195.22): C, 61.53; H, 6.71; N, 7.17.
1
0
13
3
Found: C, 61.29; H, 6.73; N, 7.19.
Acknowledgements
General procedure for the synthesis of syn- and anti-2-
nitro-1-(p-nitrophenyl)propan-1-ol (16b). To a freshly
prepared 0ЊC suspension of solid-supported ylide 6 (0.2 g)
in nitroethane (8 mL) was added a solution of p-nitro-
benzaldehyde 15b (308 mg, 2 mmol) in nitroethane
The present work has been supported by the Direcci o´ n
General de Ense n˜ anza Superior e Investigaci o´ n Cient ´ı fica
(Madrid DGESIC, PB96-0252) and by the Comunidad de
Trabajo de los Pirineos (Departamento de Industria y
Educaci o´ n, Universidades e Investigaci o´ n del Gobierno
Vasco, Vitoria, IT96-1). J. M. de los Santos thanks the
Consejer ´ı a de Educaci o´ n del Gobierno Vasco for a
postdoctoral fellowship.
(
3
2 mL). The mixture was allowed to stir at 0ЊC for
0 min. Filtration and evaporation of the solvent under
vacuum led to compound 16b (316 mg, 70%) as a pale
yellow oil. The product obtained had spectroscopic/
analytical/physical properties in full agreement with the
2
5
literature data.
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