Improved methodology for the generation and trapping of α-lactams by weak nucleophiles

Full text of DOI:10.1021/jo991732g

J . Org. Chem. 2000, 65, 2591-2595
2591
Sch em e 1
Im p r oved Meth od ology for th e Gen er a tion
a n d Tr a p p in g of r-La cta m s by Wea k
Nu cleop h iles
Robert V. Hoffman,* Madhava M. Reddy, and
Francisco Cervantes-Lee†
of amine is needed. Without NaH, 2 equiv of amine are
required since one is converted to an ammonium salt
upon formation of the R-lactam and the other serves as
the nucleophile to trap it.
Department of Chemistry and Biochemistry,
New Mexico State University, North Horseshoe Drive,
Las Cruces, New Mexico 88003-8001
Received November 4, 1999
In tr od u ction
Earlier papers from this laboratory have described the
generation of R-lactams 2 from N-mesyloxyamides 1
derived from malonic esters and their reactions with
nucleophiles to produce a wide variety of R-substituted
esters and ureas 3, which themselves can be converted
to heterocycles (Scheme 1).1-3 Reaction of 1 with amines
is a very effective way to produce ureas since the amine
has the base strength required to produce the R-lactam
from 1 as well as the nucleophilicity needed to trap it.2
For weaker nucleophiles/bases such as hydrazines, hy-
drazides, and anilines, the reaction rate was quite slow.
In these cases successful reaction required slow (syringe
pump, 10-15 h) addition of a hindered tertiary amine
base such as Hunig’s base to a mixture of 1 and the
nucleophile. The tertiary amine was sufficiently basic to
convert 1 to the R-lactam 2 but, being protonated, did
not compete as a nucleophile.
When primary amines are utilized as nucleophiles,
sodium hydride can also be used to effect the base-
induced closure of the resulting urea 5 to hydantoin 6a
(eq 2).3 The overall transformation of 1a to 6a could also
be accomplished in one pot using an excess of NaH.
Likewise mesylate 1b was converted directly to hydan-
toin 6b using an excess of NaH (eq 3). The byproduct
of the NaH-induced ring closure is NaOEt which may
itself be sufficiently basic to promote hydantoin forma-
tion. This explains why ring closure is observed cases
such as the above where less than 2 equiv of NaH is
present. Ring closure is ensured by using 2 equiv of NaH.
This method was effective but requires fairly long
reaction times. Moreover, if the rate of addition was not
controlled accurately, reduced yields were observed be-
cause the tertiary amine could itself act as a competitive
nucleophile.4
We felt these difficulties could be minimized by em-
ploying a consumable, non-nucleophilic base in place of
an amine base. Sodium hydride appeared to be an
excellent choice since it is basic enough to form the
R-lactam but insufficiently soluble to function effectively
as a nucleophile. We are pleased to report that this
approach provides a much improved method to effect
this transformation. In addition the method can be
extended to phosphonoacetohydroxamates which yield
phosphonomethyl ureas. Finally, sonication was found
to enhance the rate of the heterogeneous reaction by 3-5
times.
When using less reactive nucleophile/base trapping
agents, it was found that NaH is quite advantageous in
promoting R-lactam formation. For example, treatment
of 1a with phenylhydrazine 7a gave no reaction after 30
h because phenylhydrazine is insufficiently basic to
promote R-lactam formation. In contrast, 1a was con-
verted to N-aminohydantoin 8a (78%) in 7 h upon
treatment with a mixture of phenylhydrazine 7a and
sodium hydride (eq 4). Acid hydrazides 7b and 7c can
also be used as the trapping agent to give N′-acyl-N-
aminohydantoins 8b and 8c in good yields.
Resu lts a n d Discu ssion
Treatment of N-mesyloxyamide 1a with benzylamine
or morpholine and suspended NaH produced the corre-
sponding ureas 4 and 5 in good yields (eq 1). Only 1 equiv
† To whom inquiries about the X-ray structure should be ad-
dressed: Department of Chemistry, University of Texas El Paso, 500
University Blvd., El Paso, TX 79968-0513.
(1) Hoffman, R. V.; Nayyar, N. K.; Chen, W., J . Org. Chem. 1995,
60, 4121.
Aromatic amines also gave good yields of products.
Reaction of 1a with indoline and sodium hydride gave
urea 9 which, being a tertiary amide, cannot close to a
hydantoin (eq 5). However, reaction of 1a with aniline
(2) Hoffman, R. V.; Nayyar, N. K., J . Org. Chem. 1995, 60, 5992.
(3) Hoffman, R. V.; Reddy, M. M.; Klumas, C. M.; Cervantes-Lee,
F., J . Org. Chem. 1998, 63, 9128-9130.
(4) Hoffman, R. V.; Nayyar, N. K.; Klinekole, B. W., J . Am. Chem.
Soc. 1992, 114, 6262.
10.1021/jo991732g CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/29/2000

2592 J . Org. Chem., Vol. 65, No. 8, 2000
Notes
Ch a r t 1
and NaH (1.2 equiv) gave a 1:1 mixture of urea 10 and
N-phenylhydantoin 11 (77%). Use of 2.2 equiv of NaH
gave only ring closed 11 (64%).
The success of this method suggested that other
electron-withdrawing groups which could acidify the
R-protons of an N-mesyloxy amide could be incorporated
into the resulting R-lactam, thus leading to a general
synthesis of N-substituted ureas. To this end, diethyl-
phosphonoacetic acid was converted to N-mesyloxy-
amides 12a ,b. Treatment of 12a with a variety of nitro-
gen nucleophiles 13a -h and sodium hydride in THF led
to the formation of diethyl phosphonomethylureas 14a -h
in good yields (Chart 1). Treatment of 12b with benzyl-
amine,13a , in the presence of sodium hydride, gave 15a
as well. This methodology can assemble relatively com-
plicated arrays in a straightforward manner and appears
to be extendible to other hydroxamic acids with acidified
R-hydrogens.
Our working hypothesis is that the nucleophiles are
converted at the NaH surface to strong soluble bases
(amide anions) which are the base species actually
involved in R-lactam formation. This hypothesis derives
from the observation that when 1a is simply stirred at
room temperature with sodium hydride in THF, it takes
32 h for complete decomposition of the starting material.
However, in the presence of sodium hydride and benzyl-
hydrazine, 1a is converted to 8a in 7 h. The hydrazine
apparently serves as a proton shuttle between 1a and
the sodium hydride surface. Further data are needed to
confirm this mechanistic hypothesis.
Ultrasonication of the reaction mixture was found to
give 3-5-fold increases in the rate of conversion to
products. For example, reaction of 1a with benzylamine
and NaH proceeded to completion in 3 h at 0 °C
(compared to 10 h at room temperature without sonica-
tion, cf. eq 1) and produced 5 in the same yield. Phos-
phonate 12b reacts readily with benzyl hydrazine 13f and
NaH at 0 °C in 2 h to give 15f (67%, eq 7). The analogous
reaction of 12a without sonication requires 10h at room
temperature for completion.
Sonication of a mixture of 1a and NaH led to the
disappearance of 1a in 5 h (compared to 32 h without
sonication) and yielded oxazolone 16 as the only product
in 83% yield (eq 8). The structure of 16 was ultimately
proven by X-ray crystallography.
This novel product is most likely formed by a vinylcy-
clopropane-like rearrangement of the intermediate R-lac-

Notes
J . Org. Chem., Vol. 65, No. 8, 2000 2593
suspension of NaH (0.095 g, 2.37 mmol) in THF (15 mL) at 0
°C. The mixture was stirred for 1 h at 0 °C and then at room
temperature. for 10 h. Removal of solvent gave a residue which
was taken up in EtOAc (50 mL), washed with water (2 × 10
mL), and dried (MgSO4). The solvent was evaporated and the
product purified by flash chromatography to afford 6a (78%) as
Sch em e 2
1
a solid: mp 148-149 °C. H NMR: δ 7.45-7.2 (m, 5H), 4.64 (s,
tam (Scheme 2). This type of rearrangement was postu-
lated for several R-lactams that were accessed photochem-
ically,5-7 but has not been observed previously for R-lac-
tams generated chemically. It is likely that these rear-
rangements have been missed in most solution phase
R-lactam studies because unsaturated R-lactams are
relatively rare and because nucleophiles are usually
present in the reaction mixture. The ability to produce
R-lactams in solution in the absence of nucleophiles
permits this reaction manifold to now be explored further.
In summary, sodium hydride can be used as an
effective consumable base for the generation and trapping
of R-lactams by weak nucleophiles. Only a slight excess
of the trapping nucleophile is required. Ultrasonication
can increase the rate of the reaction significantly. The
best general protocol appears to be reaction of an N-
mesyloxyamide, sodium hydride (1.1-2 equiv), and the
nucleophile (1.1 equiv) in THF with ultrasonication at
0 °C.
2H), 3.82 (s, 2H), 2.95 (s, 3H). 13C NMR: δ 169.5, 156.6, 136.1,
128.8, 128.6, 127.9, 51.7, 42.5, 29.6. IR (neat): 1770, 1715 cm-1
.
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.71. Found:
C, 64.55; H, 5.97; N, 13.59. Compound 6a could also be obtained
directly from 1a with NaH (2 equiv) and benzylamine (1.2 equiv).
1-Cycloh exyl-3-b en zyl-2,4-im id a zolid in ed ion e, 6b, was
prepared from 1b (0.7 g, 2.27 mmol), NaH (0.1 g, 2.5 mmol),
and benzylamine (0.26 g, 2.5 mmol) by the general procedure
above. After a reaction time of 10 h, 6b was obtained as a solid
in 65% yield after flash chromatography. mp 71-72 °C. 1H
NMR: δ 7.45-7.23 (m, 5H), 4.65 (s, 2H), 4.0-3.82 (m, 1H), 3.76
(s, 2H), 1.9-1.0 (m, 10H); 13C NMR: δ 170.4, 156.1, 136.6, 129.1,
128.2, 51.4, 46.3, 42.7, 31.0, 25.6; IR (KBr): 3080, 1768, 1714
cm-1. Anal. Calcd for C16H20N2O2: C, 70.55; H, 7.41; N, 10.29.
Found: C, 70.70; H, 7.19; N, 10.40.
1-Meth yl-3-(N-p h en yla m in o)-2,4-im id a zolid in ed ion e, 8a ,
was prepared from 1a (1.21 g, 5.05 mmol), NaH (0.22 g, 5.55
mmol), and phenylhydrazine 7a (0.60 g, 5.55 mmol). After a
reaction time of 7 h, 8a was obtained as an oil in 78% yield after
1
flash chromatography. H NMR: δ 7.25-7.0 (m, 2H), 6.97-6.7
(m, 3H), 6.46 (s, 1H), 3.90 (s, 2H), 2.96 (s, 3H). 13C NMR: δ 168.5,
155.5, 145.9, 129.6, 122.6, 114.6, 50.7, 30.6. IR (KBr): 3289,
3019,1787,1731,1605 cm-1. Anal. Calcd for C9H15N3O4: C, 47.14;
H, 6.60; N, 18.34. Found: C, 47.00; H, 6.70; N, 18.41. The data
are in agreement with data reported earlier for 8a .2
Exp er im en ta l Section
1-Meth yl-3-(N-ter t-bu toxyca r bon yla m in o)-2,4-im id a zo-
lid in e-d ion e, 8b, was prepared from 1a (1.05 g, 4.38 mmol),
NaH (0.193 g, 4.82 mmol), and tert-butyl carbazate 7b (0.608 g,
4.6 mmol). After a reaction time of 10 h, 8b was obtained as a
solid in 60% yield after purification by flash chromatography
(1:1 hexane:EtOAc). mp 160-61 °C. 1H NMR: δ 6.89 (s, 1H),
3.96 (s, 2H), 3.0 (s, 3H), 1.48 (s, 9H). 13C NMR: δ 167.4, 154.2,
Melting points are uncorrected. Chemical shifts are reported
in parts per million for chloroform-d solutions. Flash chroma-
tography was performed using Silica Gel 60 (230-400 mesh).
Ethylmalonyl chloride, N-methylhydroxylamine hydrochloride,
diethyl phosphonoacetic, and the amines and hydrazines used
in this study were all commercially available and were used
without further purification. N-Mesyloxyamides 1a 1 and 1b3
were prepared as reported earlier.
Gen er a l P r oced u r e for th e Rea ction of N-Mesyloxy
Ma lon a m id es 1a a n d 1b w ith Nu cleop h iles. A solution of
the N-mesyloxy malonamide (3.0 mmol) in THF (20 mL) was
added dropwise over 30 min to a suspension of NaH (3.3 mmol)
in THF (20 mL) at 0 °C. A solution of the amine or hydrazine
(3.3 mmol) in THF (20 mL) was then added dropwise. The
reaction was stirred at 0 °C for 1 h and then at room temperature
for 10-15 h. The solvent was removed by rotary evaporation,
and the residue was taken up in EtOAc (75 mL), washed with
1 M HCl (2 × 10 mL) and water (2 × 20 mL), and dried over
MgSO4. The solvent was removed under vacuum and the product
was purified by flash chromatography using hexane/EtOAc 3:2
unless otherwise specified.
153.4, 82.9, 50.2, 30.1, 27.9. IR (KBr) 3293, 2983,1790,1736 cm-1
.
Anal. Calcd for C9H15N3O4: C, 47.14; H, 6.60; N, 18.34. Found:
C, 47.00; H, 6.70; N, 18.41.
1-Me t h yl-3-(N -a llyloxyca r b on yla m in o)-2,4-im id a zo-
lid in ed ion e, 8c, was prepared from 1a (1.21 g, 5.06 mmol), NaH
(0.222 g, 5.56 mmol), and alloc hydrazide 7c (0.675 g, 5.8 mmol).
After a reaction time of 10 h, 8c was obtained as an oil in 73%
yield after purification by flash chromatography. 1H NMR: δ
7.65 (s, 1H), 6.05-5.8 (m, 1H), 5.42-5.2 (m, 2H), 4.65 (d, J )
5.0 Hz, 2H), 3.98 (s, 2H), 3.0 (s, 3H). 13C NMR: δ 168.1, 155.5,
132.3, 119.1, 67.8, 51.4, 30.2. IR (neat) 3271, 2942,1795,1736,
cm-1. M/S (m/e) 236.1 (M + Na+), 214.1 (M + H+), 170.1. Anal.
Calcd for C8H11N3O4: C, 45.05; H, 5.20; N, 19.72. Found: C,
44.96; H, 5.03; N, 19.57.
N-Meth yl-N-(car beth oxym eth yl)-N′-in dolin ylu r ea, 9, was
prepared from 1a (1.05 g, 4.38 mmol), NaH (0.193 g, 4.82 mmol),
and indoline (0.54 g, 4.5 mmol). After a reaction time of 15 h, 9
was obtained as an oil in 90% yield after purification by flash
chromatography. 1H NMR: δ 7.2-7.1 (m, 3H), 6.95-6.84 (m,
1H), 4.22 (q, J ) 7.1 Hz, 2H), 4.08 (s, 2H), 3.92 (t, J ) 8.1 Hz,
2H), 3.03 (t, J ) 8.1 Hz, 2H), 3.01 (s, 3H), 1.30 (t, J ) 7.1 Hz,
3H). 13C NMR: δ 170.2, 160.2, 144.5, 131.9, 127.5, 125.2, 122.0,
114.2, 61.4, 51.4, 50.8, 38.3, 28.5, 14.5. IR (neat) 2980, 1746,
1652 cm-1. Anal. Calcd for C14H18N2O3: C, 64.10; H, 6.91; N,
10.67. Found: C, 63.90; H, 6.84; N, 10.62.
N-Met h yl-N-(ca r b et h oxym et h yl)-N′-(4-oxocycloh exyl)-
u r ea , 4, was prepared from 1a (0.71 g, 2.96 mmol), NaH (0.13
g, 3.26 mmol), and morpholine (0.28 g, 3.26 mmol). After a
reaction time of 10 h, 4 was obtained as an oil in 73% yield after
flash chromatography: 1H NMR: δ 4.20 (q, J ) 7.0 Hz, 2H),
3.91 (s, 2H), 3.69 (t, J ) 4.9 Hz, 4H), 3.27 (t, J ) 4.9 Hz, 4H),
2.95 (s, 3H), 1.28 (t, J ) 7.0 Hz, 3H); 13C NMR: δ 169.9, 164.0,
66.5, 60.9, 51.3, 47.2, 38.0, 14.1; IR (neat) 2976, 1747, 1649 cm-1
.
These data are in agreement with data reported earlier for 4.1
N-(Ca r beth oxym eth yl)-N′-ben zylu r ea , 5, was prepared
from 1a (1.0 g, 4.17 mmol), NaH (0.20 g, 5.0 mmol), and
benzylamine (0.49 g, 4.6 mmol). After a reaction time of 15 h, 5
was obtained as an oil in 81% yield after flash chromatography.
1H NMR: δ 7.45-7.2 (m, 5H), 4.41 (s, 2H), 4.2 (q, J ) 7.2 Hz,
2H), 4.08 (s, 2H), 2.94 (s, 3H), 1.26 (t, J ) 7.2 Hz, 3H); IR (neat)
3386, 3080, 2934, 1713, 1644 cm-1. These data are in agreement
with data reported earlier for 5.1
N-Meth yl-N-(ca r beth oxym eth yl)-N′-p h en ylu r ea , 10, was
prepared from 1a (1.37 g, 5.71 mmol), NaH (0.25 g, 6.29 mmol),
and aniline (0.56 g, 6.0 mmol). After a reaction time of 15 h, 10
was obtained in 39% yield after flash chromatography, mp 68-
1
70 °C. H NMR: δ 7.4-6.98 (m, 5H), 6.85 (bs, 1H), 4.17 (q, J )
7.1 Hz, 2H), 4.08 (s, 2H), 3.03 (s, 3H), 1.25 (t, J ) 7.1 Hz, 3H).
13C NMR: δ 170.2, 155.8, 138.9, 128.7, 123.1, 120.1, 61.2, 50.6,
35.8, 14.1. IR (KBr) 3355, 3062, 2986, 1742, 1647 cm-1. Anal.
Calcd for C12H16N2O3: C, 60.99; H, 6.83; N, 11.86. Found: C,
61.00; H, 6.89; N, 12.01.
1-Meth yl-3-ben zyl-2,4-im id a zolid in ed ion e, 6a . Urea
5
(0.54 g, 2.15 mmol) in THF (10 mL) was added dropwise to a
(5) Goth, H.; Gagneux, A. R.; Eugster, C. H.; Schmid, H. Helv. Chim.
Acta 1967, 50, 137.
(6) Aurich, H. G. Leibigs Ann. Chem. 1970, 732, 195
(7) Rokach, J .; Hamel, P., Chem. Commun. 1979, 786.
1-Meth yl-3-p h en yl-2,4-im id a zolid in ed ion e, 11, was also
isolated from the above reaction mixture by flash chromatog-
raphy in 38% yield. mp 97-99 °C. 1H NMR: δ 7.5-7.34 (m, 5H),

2594 J . Org. Chem., Vol. 65, No. 8, 2000
Notes
3.96 (s, 2H), 3.00 (s, 3H). 13C NMR: δ 168.6, 155.7, 131.7, 129.0,
128.1, 125.9, 51.5, 29.8. IR (KBr) 3061, 2919, 1780, 1732 . M/S
(m/z): 191.1, 156.1. Anal. Calcd for C10H10N2O2: C, 63.14; H,5.26;
N, 14.73. Found: C, 62.96; H,5.53; N,14.73. Compound 11 was
obtained as the only product (64%) from the reaction of 1a , NaH
(2.2 equiv), and aniline (1.1 equiv).
N-Meth yl-N-m esyloxy d ieth ylp h osp h on oa ceta m id e, 12a .
Diethylphosphonoacetic acid was converted to diethylphospho-
noacetyl chloride using thionyl chloride by a standard proce-
dure:8 1H NMR: δ 4.23 (m, 4H), 3.53 (d, J ) 21 Hz, 2H), 1.38 (t,
J ) 7.2 Hz, 6H).
Triethylamine (4.74 g, 46.86 mmol) in methylene chloride (30
mL) was added to a solution of N-methylhydroxylamine hydro-
chloride (4.30 g, 51.55 mmol) in methylene chloride (120 mL),
and the mixture was stirred for 10 min in an ice bath. Diethyl
phosphonoacetyl chloride (7.57 g, 35.2 mmol) in methylene
chloride (18 mL) was added over a period of 25 min, and the
reaction was stirred for 2 h at 0 °C and then for 6 h at room
temperature. The reaction was washed with saturated NaCl (2
× 20 mL). The aqueous layer was extracted with ethyl acetate
(4 × 30 mL). The combined organic layers were dried (MgSO4),
filtered through a one inch silica pad, and evaporated. The crude
product was subjected to flash chromatography (8% MeOH in
ethyl acetate) to give N-methyl diethylphosphonoacetohydrox-
amic acid as an oil: 1H NMR δ 9.38 (br s, 1H), 4.19 (m, 4H),
3.28 (s, 3H), 3.23 (d, J ) 20 Hz, 2H), 1.36 (t, J ) 7 Hz, 6H); IR
(neat) 3172, 1650 cm-1. This material was carried on in the next
step without further purification or analysis.
a period of 30 min to a suspension of NaH (3.6 mmol) in THF
(20 mL) at 0 °C. A solution of amine or hydrazine in THF (20
mL) was added dropwise. The reaction was stirred at 0 °C for 1
h and then at room temperature for 15-20 h. The solvent was
evaporated, and the residue was taken into EtOAc (75 mL),
washed with water (2 mL), and dried over MgSO4. The solvent
was removed under vacuum, and the product was purified by
flash chromatography (8% MeOH in EtOAc).
N -(D ie t h y lp h o s p h o n o m e t h y l)-N -m e t h y l-N ′-b e n zy l-
u r ea , 14a was prepared from mesylate 12a (0.77 g, 2.54 mmol),
NaH (0.111 g, 2.79 mmol), and benzylamine 13a (0.333 g, 3.05
mmol) in THF (60 mL). The usual workup followed by flash
chromatography afforded 14a in 91% yield. 1H NMR: δ 7.3 (s,
5H), 5.63 (t, J ) 5.2 Hz, 1H), 4.39 (d, J ) 5.7 Hz, 2H), 4.2-4.08
(m, 4H), 3.71 (d, J ) 8.9 Hz, 2H), 3.0 (s, 3H), 1.29 (t, J ) 7.05
Hz, 6H); 13C NMR: δ158.7, 139.9, 128.8, 127.8, 127.4, 52.9, 45.7,
45.3, 43.5, 36.2, 16.7. IR (neat) 3338, 1638 cm-1. Anal. Calcd for
C14H23N2O4P: C, 53.48; H, 7.38; N, 8.92. Found: C, 53.32; H,
7.36; N, 9.00.
N -(D ie t h y lp h o s p h a n o m e t h y l)-N -m e t h y l-N ′,N ′-in d o -
lin ylu r ea , 14b, was prepared from mesylate 12a (0.77 g, 2.54
mmol), NaH (0.112 g, 2.8 mmol), and indoline 13b (0.32 g, 2.67
mmol) in THF (60 mL). The usual workup followed by flash
1
chromatography gave 14b in 79% yield. H NMR: δ 7.28-6.87
(m, 4H), 4.24-4.09 (m, 4H), 3.95-3.84 (m, 4H), 3.08 (s, 3H), 3.03
(t, J ) 8.1 Hz, 2H), 1.33 (t, J ) 7.1 Hz, 6H). 13C NMR: δ 159.9,
144.3, 131.8, 127.6, 125.2, 122.0, 113.9, 62.6, 50.8, 46.7, 43.5,
39.5, 28.4, 16.8. IR (neat) 2978, 1655 cm-1. Anal. Calcd for
C
15H23N2O4P‚ 1/2H2O: C, 53.73; H, 7.16; N, 8.36. Found: C,
Methanesulfonyl chloride (7.8 mmol) was added to a solution
of N-methyl diethylphosphonoacetohydroxamic acid (1.6 g, 7.1
mmol) and pyridine (1.23 g, 15.62 mmol) in methylene chloride
(10 mL). The mixture was stirred at 0 °C for 2 h, during which
time the color changed to orange. Water (2 mL) was added and
the stirring continued for 10 min. Additional methylene chloride
(30 mL) was added, and the mixture was washed with 2.5 M
HCl (15 mL). The aqueous layer was extracted with EtOAc (3
× 30 mL). The combined organic layers were dried (MgSO4) and
evaporated, and the crude product was purified by flash chro-
matography (hexanes/ EtOAc 2:8) to give mesylate 12a as an
54.18; H, 7.23; N, 8.35.
N-(Diet h ylp h osp h on om et h yl)-N-m et h yl-N′-(2-(m et h yl
3-p h en ylp r op a n oyl)u r ea , 14c, was prepared from mesylate
12a (0.89 g, 2.93 mmol), NaH (0.129 g, 3.22 mmol), and racemic
phenylalanine methyl ester (free base) 13c (0.63 g, 3.52 mmol)
in THF (60 mL). The usual workup followed by flash chroma-
tography gave 14c in 85% (0.97 g) yield as a yellow oil. 1H
NMR: δ 7.29-7.09 (m, 5H), 5.36 (bd, J ) 9.2 Hz, 1H), 4.68 (q,
J ) 6.2 Hz, 1H), 4.18-4.02 (m, 4H), 3.67 (s, 3H), 3.62 (d, J )
6.3 Hz, 2H), 3.10-3.04 (m, 2H), 2.92 (s, 3H), 1.34-1.19 (m, 6H).
13C NMR: δ 172.9, 157.3, 136.3, 129.1, 128.4, 127.0, 62.5, 54.8,
52.2, 45.3, 43.7, 38.1, 35.6, 16.4. IR (neat): 3328, 1743, 1651
cm-1. Anal. Calcd for C17H27N2O6P: C, 52.83; H, 7.05; N, 7.25.
Found: C, 52.76; H, 7.00; N, 6.55.
N-(Diet h ylp h osp h on om et h yl)-N-m et h yl-N′-(2-(m et h yl
3-h yd r oxyp r op a n oyl)u r ea , 14d was prepared from mesylate
12a 0.77 g, 2.54 mmol), NaH (0.111 g, 2.79 mmol), and racemic
serine methyl ester (free base) 13d (0.474 g, 3.05 mmol) in THF
(60 mL). The usual workup followed by flash chromatography
gave 14d as a mixture of rotamers in 70% yield. 1H NMR for
isomer 1: δ 8.1 (bd, 1H), 4.75-4.65 (m, 1H), 4.25-4.12 (m, 4H),
3.9 (m, 2H), 3.79 (s, 3H), 3.73 (d, J ) 7.7 Hz, 2H), 3.2 (bs, 1H),
3.06 (s, 3H), 1.4-1.30 (m, 6H). 1H NMR for isomer 2: δ 7.55
(bd, 1H), 4.6-4.5 (m, 1H), 4.25-4.12 (m, 4H), 3.9 (m, 2H), 3.77
(s, 3H), 3.57 (d, J ) 5.8 Hz, 2H), 3.2 (bs, 1H), 2.51 (s, 3H), 1.40-
1.30 (m, 6H). 13C NMR (mixture): δ 172.3, 171.0, 168.2, 167.9,
158.0, 65.3, 64.6, 64.1, 63.6, 62.7, 61.7, 56.8, 55.7, 55.2, 52.8,
46.7, 43.5, 36.9, 36.6, 36.2, 16.7. IR (neat): 3344, 1746, 1666
cm-1. Anal. Calcd for C11H23N2O7P: C, 40.48; H, 7.11; N, 8.59.
Found: C, 40.25; H, 6.94; N, 8.78.
1
oil in 70% yield, H NMR: δ 4.20 (m, 4H), 3.52 (s, 3H), 3.28 (s,
3H), 3.20 (d, J ) 21 Hz, 2H), 1.36 (t, J ) 7 Hz, 6H); IR 1691
cm-1. Anal. Calcd for C8H18NO7SP‚H2O: C, 29.90; H, 6.23; N,
4.36. Found: C, 29.32; H, 6.29; N, 3.93. This material is
somewhat unstable but can be stored for several months at -20
°C. Attempts to further purify 12a led to increased decomposi-
tion.
N-Ben zyl-N-m esyloxyd ieth ylp h osp h on oa ceta m id e, 12b ,
was prepared by the same route utilized for 12a . Dieth-
ylphosphonoacetyl chloride (11.0 g, 51.3 mmol) was reacted with
N-benzylhydroxylamine hydrochloride (8.8 g, 55.1 mmol) and
triethylamine (15 mL, 107 mmol) to give N-benzyl dieth-
ylphosphonoacetohydroxamic acid (oil) which was purified by
flash chromatography (8% MeOH in ethyl acetate) and used
directly in the next step. 1H NMR: δ 9.3 (br s, 1H), 7.31 (m,
5H), 4.82 (s, 2H), 4.12 (m, 4H), 3.21 (d, J ) 20 Hz, 2H), 1.29 (t,
J ) 7.1 Hz, 6H); IR 1635 cm-1
.
Methanesulfonyl chloride (3.09 g, 27 mmol) was added to a
solution of benzyl diethylphosphonoacetohydroxamic acid (7.4
g, 24.56 mmol) and pyridine (4.37 mL, 54.0 mmol) in dichlo-
romethane (20 mL). The mixture was stirred of 4 h at 0 °C and
water (4 mL) was added and stirring was continued for 10 min.
The reaction mixture was washed with 2.5 M HCl (3 × 20 mL),
dried and evaporated. The crude product was purified by column
chromatography (EtOAc) give N-benzyl-N-mesyloxy dieth-
ylphosphonoacetamide 12b in 52% yield, 1H NMR: δ 7.35 (s,
5H), 5.09 (s, 2H), 4.11 (m, 4 Hz), 3.18 (d, J ) 20 Hz, 2H), 3.13
N-(Dieth ylph osph on om eth yl)-N-m eth yl-N′-(allocam in o)-
u r ea , 14e, was prepared from mesylate 12a (0.606 g, 2.0 mmol),
NaH (0.088 g, 2.2 mmol), and alloc hydrazide 13e (0.28 g, 2.4
mmol) in THF (60 mL). The usual workup followed by flash
chromatography gave 14e in 57% yield as a mixture of rotomers.
1H NMR: δ 7.55 (bs, 1H), 7.1 (bs, 1H), 6.05-5.8 (m, 1H), 5.42-
5.2 (m, 2H), 4.65 (m, 2H), 4.3-4.1 (m, 4H), 3.75 (d, J ) 9.4 Hz)
and 3.62 (d, J ) 22.1 Hz, 2H total), 3.05 (s) and 2.5 (s, 3H total),
1.34 (t, J ) 7.0 Hz, 6H). 13C NMR: δ 167.9, 158.8, 157.6, 156.3,
132,6, 118.5, 66.8, 64.0, 63.6, 63.1, 60.7, 46.9, 43.8, 36.8, 36.5,
36.2, 16.7. IR (neat) 3231, 1738,1682 cm-1. Anal. Calcd for
(s, 3H), 1.30 (t, J ) 7 Hz, 6H); IR 1691 cm-1 13C NMR: δ 167.4,
;
134.3, 128.8, 128.4, 62.9, 62.8, 55.3, 37.7, 34.2, 32.9, 16.3. This
material could be stored for several months at -20 °C but was
insufficiently stable to obtain satisfactory elemental analysis.
Gen er a l P r oced u r e for t h e Syn t h esis of N-(Diet h -
ylp h osp h on om eth yl)-N-m eth ylu r ea s, 14. Diethylphosphano-
(N-mesyloxy)acetamide (3 mmol) in THF (20 mL) was added over
C
11H22N3O6P: C, 40.85; H, 6.86; N, 13.00. Found: C, 40.68; H,
6.78; N, 13.06.
N-(Diet h ylp h osp h on om et h yl)-N-m et h yl-N′-b en zyl-N′-
a m in ou r ea , 14f, was prepared from mesylate 12a (0.7 g, 2.3
mmol), NaH (0.133 g, 2.77 mmol), and benzyl hydrazine 13f (0.34
g, 2.77 mmol) in THF (60 mL). The usual workup and purifica-
(8) Vogel, A. Textbook of Practical Organic Chemistry, 4th ed.;
Longman: London, UK, 1978; p 498.
1
tion afforded 14f in 67% yield. H NMR: δ 7.34 (s, 5H), 4.46 (s,

Notes
J . Org. Chem., Vol. 65, No. 8, 2000 2595
2H), 4.21-4.07 (m, 4H), 3.87 (d, J ) 9.8 Hz, 2H), 3.65 (bs, 2H),
3.12 (s, 3H), 1.32 (t, J ) 7.2 Hz, 6H). 13C NMR: δ 164.8, 137.2,
129.2, 128.6, 127.9,62.5, 57.9, 48.0, 45.0, 39.5, 16.8. IR (neat):
3326, 1636 cm-1. Anal. Calcd for C14H24N3O4P‚1/2H2O: C, 49.76;
H, 7.31; N, 12.44. Found: C, 50.12; H, 7.42; N, 12.51.
N -(Die t h ylp h osp h a n om e t h yl)-N ,N ′-d ib e n zyl-N ′-a m i-
n ou r ea , 15f. Mesylate 12b (0.81 g, 2.13 mmol) in THF (20 mL)
was added dropwise to a suspension of NaH (0.094 g, 2.34 mmol)
in THF (20 mL) at 0 °C. After the addition was complete, 13f
(0.313 g, 2.56 mmol) in THF (20 mL) was added over a period of
20 min. The reaction was sonicated9 at 0 °C for 2 h. The solvent
was evaporated, and the residue was taken into ethyl acetate
(50 mL), washed with water (1 mL), dried (MgSO4), and
evaporated. The product was purified by flash chromatography
N-(Dieth ylp h osp h on om eth yl)-N-m eth yl-N′-(4-tr iflu or o-
m eth yl-2-p yr im id yla m in o)u r ea , 14g, was prepared from
mesylate 12a (0.77 g, 2.54 mmol), 2-hydrazino-4-(trifluorometh-
yl)pyrimidine 13g (0.475 g, 2.66 mmol), and NaH (0.111 g, 2.79
mmol) in THF (60 mL). The usual workup and purification
afforded 14g as a mixture of two rotamers in 68% yield. 1H NMR
for rotamer 1: δ 8.61-8.58 (m, 1H), 7.78 (d, J ) 11.0 Hz, 1H),
7.0 (m, 1H), 4.26-4.11 (m, 4H), 3.77 (d, J ) 9.5 Hz, 2H), 3.09 (s,
1
(hexanes/ethyl acetate 1:4) to afford 15f in 67% yield. H NMR:
δ 7.4-7.2 (m, 10H), 4.80 (s, 2H), 4.54 (s, 2H), 4.19-4.05 (m, 4H),
3.80 (d, J ) 9.8 Hz, 2H), 3.67 (bs, 2H), 1.31 (t, J ) 7.0 Hz, 6H).
13C NMR: δ 164.3, 137.7, 137.0, 129.0, 128.6, 128.1, 62.5, 58.1,
53.7, 44.9, 41.8, 16.8. IR (neat): 3472, 1645 cm-1. Anal. Calcd
for C20H28N3O4P: C, 59.23; H, 6.96; N, 10.37. Found: C, 58.92;
H, 7.02; N, 10.35.
1
3H), 2.3 (bs, 1H), 1.36-0.89 (m, 6H). H NMR for rotamer 2: δ
8.61-8.58 (m, 1H), 8.25 (bs, 1H), 7.0 (m, 1H), 4.26-4.11 (m, 4H),
3.67 (d, J ) 22.02 Hz, 2H), 2.58 (s, 3H), 2.3 (bs, 1H), 1.36-0.89
(m, 6H). 13C NMR (mixture): δ 167.5, 164.3, 163.1, 161.0, 159.0,
157.3, 156.6, 123.5, 117.9, 108.6, 64.0, 63.2, 61.3, 47.2, 44.0, 36.4,
16.7. 31P NMR: δ 22.15, 18.73. IR (neat): 3251, 1670 cm-1. Anal.
Calcd for C12H19N5O4F3P: C, 37.39; H, 4.97; N, 18.18. Found:
C, 37.50; H, 5.08; N, 18.48.
3-Meth yl-5-eth oxy-2-oxa zolon e, 16. Mesylate 1a (1.5 g, 6.27
mmol) in THF (20 mL) was added over a period of 30 min to a
suspension of NaH (0.3 g, 7.5 mmol) in THF (20 mL) at 0 °C.
The reaction was stirred at 0 °C for 1 h and then at room
temperature for 32 h. Solvent was removed under vacuo, and
the residue was taken into ethyl acetate (100 mL), washed with
sat. NaCl (1 × 15 mL), dried (MgSO4), and evaporated. The
product was purified by flash chromatography (hexanes:ethyl
N-(Diet h ylp h osp h on om et h yl)-N-m et h yl-N′-(2-t h ien yl-
ca r boxa m id o)u r ea , 14h , was prepared from mesylate 12a
(0.77 g, 2.54 mmol), NaH (0.111 g, 2.79 mmol), and 2-thiophen-
ecarboxylic hydrazide 13h (0.433 g, 3.05 mmol) in THF (60 mL).
The usual workup and purification afforded 14h as a mixture
of two rotamers in 30% yield. 1H NMR (mixture): δ 8.08 (bs,
1H), 7.72 (m, 1H), 7.51-7.41 (m, 1H), 7.07-6.96 (m, 2H), 4.26-
4.07 (m, 4H), 3.77-3.66 (m, 2H), 3.05 (s) and 2.52 (s, 3H total),
1.38-1.22 (m, 6H). 13C NMR (mixture): δ 166.8, 162.2, 160.5,
158.8, 136.7, 131.3, 129.7, 128.1, 64.1, 63.1, 60.8, 46.9, 43.7, 37.1,
36.1, 16.7. IR (CHCl3): 3251, 1641 cm-1. Anal. Calcd for
C12H20N3O5SP‚1/2H2O: C, 40.22; H, 5.86; N, 11.73. Found: C,
39.76; H, 5.81; N, 10.83.
N-(Diet h ylp h osp h on om et h yl)-N,N′-d ib en zylu r ea , 15a .
Mesylate 12b (0.7 g, 1.84 mmol) in THF (20 mL) was added
dropwise at 0 °C to a suspension of NaH (0.081 g, 2.02 mmol) in
THF (20 mL). After the addition is complete, 13a (0.235 g, 2.21
mmol) in THF (20 mL) was added over a period of 20 min. The
reaction was stirred at 0 °C for 1 h and then at room temperature
for 20 h. Solvent was evaporated, and the residue was taken
into ethyl acetate (50 mL), washed with water (1 mL), dried
(MgSO4), and evaporated. The product was purified by flash
chromatography to afford 15a in 74% yield. 1H NMR: δ 7.4-
7.15 (m, 10H), 5.87 (t, J ) 5.1 Hz, 1H), 4.62 (s, 2H), 4.41 (d, J )
5.5 Hz, 2H), 4.18-4.04 (m, 4H), 3.61 (d, J ) 8.8 Hz, 2H), 1.28
(t, J ) 7.0 Hz, 6H). 13C NMR: δ 159.0, 139.8, 137.4, 129.1, 128.8,
127.9, 127.4, 63.0, 51.5, 45.4, 44.7, 41.5, 16.7. IR (neat): 3352,
1636, 1541 cm-1. Anal. Calcd for C20H27N2O4P: C, 61.51; H, 6.97;
N, 7.18. Found: C, 61.42; H, 7.22; N, 7.10.
1
acetate 2:3) to give oxazolone 16 in 50% yield. mp 63-64 °C H
NMR: δ 5.6 (s, 1H), 4.0 (q, J ) 7.0 Hz, 2H), 3.16 (s, 3H), 1.37 (t,
J ) 7.0 Hz, 3H). 13C NMR: δ 151.9, 148.5, 91.5, 68.4, 30.7, 14.7.
IR (CHCl3): 1772, 1681 cm-1. M/S (m/z) 144.1, 116.1, 83.1, 44.0.
Anal. Calcd for C6H9NO3: C, 50.34; H, 6.29; N, 9.79. Found: C,
50.12; H, 6.09; N, 9.85.
If the same reaction mixture was sonicated at 0 °C, the
starting material disappeared in 5 h and 16 was produced in
83% yield after purification. Single crystals of 16 suitable for
X-ray structure determination were grown by allowing a solution
of 16 in dichloromethane to evaporate very slowly.
Ack n ow led gm en t. This work was supported in part
by Selectide Corp. and by the National Science Founda-
tion (CHE 9520431).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 12a , 12b, and 14h , 13C NMR spectra for 12b and
14h , and details of the X-ray structure determination data for
16. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O991732G
(9) The reaction flask was immersed in a Bransonic 220 Ultrasonic
bath (125 W) filled with ice-water and irradiated until the reaction
was complete.