Improved Reagent for Electrophilic Amination of Stabilized Carbanions

Article abstract of DOI:10.1021/ol035629w

(Equation presented) Enolate amination using O-di(p-methoxyphenyl) phosphinylhydroxylamine 2 is reported. Reagent 2 reacts efficiently with stabilized sodium or potassium enolates derived from malonates, phenylacetates, and phenylacetonitriles and is sufficiently soluble for use in solution at -78°C.

Full text of DOI:10.1021/ol035629w

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4187-4190
Improved Reagent for Electrophilic
Amination of Stabilized Carbanions
Jason A. Smulik and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
edVed@umich.edu
Received August 27, 2003
ABSTRACT
Enolate amination using O-di(p-methoxyphenyl)phosphinylhydroxylamine 2 is reported. Reagent 2 reacts efficiently with stabilized sodium or
potassium enolates derived from malonates, phenylacetates, and phenylacetonitriles and is sufficiently soluble for use in solution at −78 °C.
Direct amination of carbanions has been described using a
variety of hydroxylamines as electrophilic NH2+ equivalents,1
including O-diarylphosphinyl-,2 O-acyl,3 O-sulfonyl,4 and
O-dinitrophenyl derivatives,5 and a variety of O-alkyl hy-
droxylamines.6 The diphenylphosphinyl reagent 12a has the
most extensive track record for aminations2b,c and works
moderately well with a range of Grignard reagents and
somewhat better with increasingly stabilized enolates. How-
ever, the enolate aminations are less predictable for more
basic enolates, a pattern that has also been noted using O-2,4-
dinitrophenyl-hydroxylamine.5a
at the price of minimal solubility in nonpolar solvents, a
factor that may limit the reactivity of 1. A literature precedent
recommends stirring stabilized lithium enolates with a
suspension of 1 for 12 h at room temperature to achieve
aminations.2b These conditions would not be compatible with
potential applications of interest in our laboratory where the
need to conduct aminations -78 °C was anticipated.
Upon perusal of the literature, we noticed that Harger had
reported the di(p-dimethoxyphenyl)phosphinylhydroxylamine
2 in the same paper that first deduced the correct structure
of reagent 1.2a To our knowledge, 2 has not been used for
aminations, although one might expect improved solubility
in view of Harger’s isolation method (crystallization from
chloroform/ether or ethanol/ether) and from the lower melting
point compared to that of 1. In this report, we demonstrate
that reagent 2 is indeed more soluble and is sufficiently
reactive for use in electrophilic amination of stabilized
carbanions at -78 °C. We also provide comparisons with
O-(p-nitrobenzoyl)hydroxylamine 3, a reagent that has been
Compared to the other activated hydroxylamines, 1 has
the best reputation for stability, and the solid reagent may
be stored for extended periods. Unfortunately, improved
stability appears to reflect crystal lattice issues and comes
(1) Review: Erdik, E.; Ay, M. Chem. ReV. 1989, 89, 1947.
(2) (a) Harger, M. J. P. J. Chem. Soc., Perkin Trans. 1 1981, 3284. (b)
Boche, G.; Bernheim, M.; Schott, W. Tetrahedron Lett. 1982, 23, 5399.
(c) Colvin, E. W.; Kirby, G. W.; Wilson, A. C. Tetrahedron Lett. 1982,
23, 3835. (d) Boche, G. Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 4, p 2240. (e) Klo¨tzer,
W.; Stadlwieser, J.; Raneburger, J. Org. Synth. 1986, 64, 96.
(3) (a) Carpino, L. A. J. Am. Chem. Soc. 1960, 82, 3133. (b) Marmer,
W. N.; Maerker, G. J. Org. Chem. 1972, 37, 3520. (c) Boche, G.
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, 1995; Vol. 5, p 3270. (d) Shen, Y.; Friestad, G. K. J.
Org. Chem. 2002, 67, 6236.
(4) (a) Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis 1977, 1. (b)
Taylor, E. C.; Sun, J.-H. Synthesis 1980, 801.
(5) (a) Radhakrishna, A. S.; Loudon, G. M.; Miller, M. J. J. Org. Chem.
1979, 44, 4836. (b) Belletini, J. R.; Olson, E. R.; Teng, M.; Miller, M. J.
Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.,
Wiley: New York, 1995; Vol. 3, p 2189.
Figure 1. Electrophilic aminating reagents 1-3.
(6) Oguri, T.; Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1975, 23, 173.
10.1021/ol035629w CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/10/2003

recommended for amination of amide anions3d but has not
been tested for amination of enolates.
the Boc-protecting group with TFA afforded 2 in 50% yield
overall from the phosphinous acid 4. After workup, 2 was
easily isolated by precipitation of the crude solid from a
minimal amount of CH2Cl2 with hexane. This material has
a single phosphorus resonance in the 31P NMR spectrum and
is sufficiently pure for use with typical stabilized carbanions
as described below. Reagent 2 has been reported to decom-
pose at ambient temperature,2a but no appreciable decom-
position or loss of activity was found upon storing the dry
solid at -20 °C over several months. The electrophilic
amination of phenylacetonitrile using 2 was evaluated using
lithium, sodium, and potassium bases for anion generation
(Table 1). Boche had reported the same amination using LDA
Reagents 1 and 2 have been prepared from the corre-
sponding diarylphosphinic chlorides and hydroxylamine.2a,e
In our hands, preparation of 1 on gram scale using this
method gave inconsistent results in aminations as a result
of batch-dependent variations in purity. There were also
concerns with the literature procedure to prepare 2 because
the crystallization step involves ethanol or chloroform,2a
solvents that would have to be removed prior to amination
of increasingly basic enolates. We prefer an alternative
synthesis of 2 (Scheme 1) using N-protected hydroxylamine.
Scheme 1. Synthesis of 2
Table 1. Phenylacetonitrile Amination; 2 with Li, Na, and K
Bases
entry
base
conversion (%)
1
2
3
LiHMDS
NaHMDS
KOtBu
59
64
67
and 1 as the reagent and had obtained the aminonitrile in
37% yield (anion formation and addition of 1 at -78 °C;
amination at room temperature).2b Following a similar
procedure, reagent 2 gave better conversions and isolated
yields using all three bases examined (Table 1), with the
best result obtained with KOtBu (67%). Somewhat different
results were obtained in the electrophilic amination of ethyl
phenylacetate using 2 and various bases (Table 2; product
The method involves one more step than the Harger
synthesis, but it is straightforward and provides 2 in sufficient
purity for convenient use.7
Preparation of aminating reagent 2 was performed via the
known diarylphosphinous acid 48 (Scheme 1). Conversion
to the corresponding diarylphosphinic chloride 5 with thionyl
chloride, followed by HONHBoc/Et3N gave 6. Cleavage of
(7) O-(Di-p-methoxyphenyl)phosphinylhydroxylamine. In a flame-
dried flask equipped with magnetic stir bar and reflux condenser was
dissolved 1.0 g (3.81 mmol, 1.0 equiv) of di(p-methoxyphenyl)phosphinous
acid8 in 8.0 mL of benzene. The solution was cooled to 0 °C, and 0.42 mL
(5.72 mmol, 1.5 equiv) of SOCl2 was added dropwise via syringe. The
flask was then transferred to an 80 °C oil bath and stirred for 2 h. The
solution was concentrated (aspirator) to yield the diarylphosphinic chloride
as a yellow oil that was used in the next step. In a 100-mL round-bottom
flask equipped with a magnetic stir bar were dissolved 0.510 g (3.81 mmol,
1.0 equiv) of HONHBoc and 0.80 mL (5.72 mmol, 1.5 equiv) of Et3N in
CH2Cl2 (40 mL), and the mixture was cooled to 0 °C. To this solution was
added the di(p-methoxyphenyl)phosphinic acid chloride in CH2Cl2 (4.0 mL)
via syringe in one portion. The solution was allowed to warm to 23 °C.
After stirring for 8 h, CH2Cl2 (50 mL) and H2O (100 mL) were added, the
layers were separated, and the aqueous layer was extracted with CH2Cl2 (2
× 50 mL). The CH2Cl2 extract was dried (MgSO4), filtered, and concen-
trated, and the crude oil was purified by flash chromatography (1:1 EtOAc/
hexane) to give 1.05 g (70%) of 6 as a white solid. Analytical TLC: Rf
0.15 (1:1 ethyl acetate/hexanes). The white solid was dissolved in CH2Cl2
(4 mL), and TFA (4 mL) was added in one portion at 23 °C. After stirring
for 30 min, the solution was diluted with CH2Cl2 (30 mL) and H2O (30
mL) and solid NaHCO3 was added until gas evolution had ceased. The
aqueous layer was extracted with CH2Cl2 (3 × 50 mL), and the combined
organic layers were dried (MgSO4) and concentrated. The crude product
was dissolved in CH2Cl2 (4.0 mL), and hexane (50 mL) was slowly added
to yield 0.55 g (71%) of 2 as a finely divided white solid that was collected
by filtration (rt) and dried under vacuum (0.5 h). 31P NMR (162 MHz,
CDCl3) δ 39.6 ppm.
Table 2. Ethyl Phenyl acetate Amination with 2 versus Bases
entry
base
conversion (%)
1
2
3
4
5
LiHMDS
LDA
NaHMDS
KOtBu
P2-tBu
22
31
46
67
25
assay after conversion to the acetamide). Lithium enolates
gave significantly lower yields of the aminated product
(entries 1 and 2), but increased conversion was found for
sodium and potassium enolates (entries 3 and 4).9 Metal-
free enolate generation was also briefly examined using the
P2-tBu phosphazine base,10 but this procedure gave a low
yield in the amination (entry 4).
(8) Kanai, M.; Nakagawa, Y.; Tomioka, K. Tetrahedron 1999, 55, 3843.
4188
Org. Lett., Vol. 5, No. 22, 2003

Lower conversion in the phenylacetate lithium enolate
aminations implicates competing proton transfer from the
reagent 2 to quench the enolate. One possibility is internal
proton transfer in the complex 6, a scenario that is reminis-
and was also noted in the original report describing the
synthesis of 1 and 2.2a
To establish temperature and reactivity limits, the elec-
trophilic amination of ethyl phenylacetate/KOtBu using
reagent 2 was explored at -78 °C (Table 3). Reactions
Table 3. Ethyl Phenyl Acetate Amination with 2 at -78 °C
cent of the internal proton return phenomenon observed in
reactions of amine-containing lithium enolates with other
electrophiles.11 Simple intermolecular proton transfer is not
ruled out, but the internal pathway would be consistent with
the higher conversions observed for enolates containing the
less Lewis acidic sodium or potassium ions.
entry reagent time (h) conversion (%) additive concn (M)
1
2
3
4
5
6
7
2
2
2
2
2
2
1
2
6
2
6
2
4
6
35
76
44
55
57
70
27
none
none
DMF
DMF
CH2Cl2
CH2Cl2
none
0.01
0.01
0.05
0.05
0.05
0.05
0.01
The prospects for simple proton transfer from the reagent
2 to the ester enolate depend on the relative acidities in THF,
as well as on kinetic factors. Values for pKa’s in the range
of 22-2412 for phenylacetate ester or phenylacetonitrile
anions have been reported, but little is known about
O-substituted hydroxylamine pKa's in organic solvents. The
closest analogy (PhNHOBn; DMSO pKa ) 23.5)13 provides
some indication that proton transfer from 2 to the enolate
may be possible. Furthermore, prior studies using O-(2,4-
dinitrophenyl)hydroxylamine had found evidence for N-H
deprotonation by the lithium enolate of methyl phenylpro-
pionate,5a followed by self-amination of the reagent and
fragmentation to diimide.14 From 2, the analogous decom-
position process would lead to Ar2P(O)OH, a product that
was detected by ESMS in partly decomposed samples of 2
conducted at 0.10 M resulted in heterogeneous mixtures and
ca. 30% product formation after 2 h. When sufficient THF
was added to dissolve the reagent 2 (ca. 0.01 M), improved
conversions were found if sufficient time was allowed to
compensate for high dilution in the second-order amination
step (entries 1 and 2).
Other solvents were investigated to improve solubility.
Reagent 2 was found to be readily soluble in DMF, but
aminations conducted using 1.1 equiv of 2 with DMF as a
cosolvent in THF at -78 °C gave lower conversions even
though the conditions were homogeneous (entries 3 and 4).
On the other hand, addition of ca. 33% CH2Cl2 resulted in
good conversion and a faster reaction at 0.05 M. For
comparison, low-temperature electrophilic amination was
also attempted using reagent 1. Although reaction mixtures
remained heterogeneous (0.01 M) at -78 °C using 1, some
conversion to product was observed (Table 3, entry 7). These
findings suggest that there is little intrinsic reactivity dif-
ference between 1 and 2 and that the substantial differences
in % conversion reflect differences in the rate of self-
destruction compared to amination for reagent in solution
(2) or suspension (1).
Having established that 2 is suitable for low-temperature
aminations of the stabilized phenylacetate enolate, we
compared 2 with the original reagent 1 under simple room-
temperature amination conditions (Table 4; ca. 0.1 M,
heterogeneous conditions). Similar conditions had been used
by Boche et al., although the latter workers used LDA as
the base,2b whereas our experiments were conducted using
KOtBu or NaH. Table 4 summarizes representative amina-
tions of malonates, phenylacetates, and phenylacetonitriles
using reagents 2 (column 2) and 33d (column 3) and also
lists literature data obtained with reagent 1 (column 1).2b,c
Reagent 3 (O-(4-nitrobenzoyl)-hydroxylamine) proved to be
quite effective for amination of the more highly stabilized
enolates and is probably the reagent of choice for this purpose
(9) Representative Experimental Procedure. CAUTION! Although we
have not experienced, and are not aware of, detonations in the preparation
or use of reagents 1, 2, or 3, the related O-(mesitylsulfonyl)hydroxylamine
is explosive3a-c and detonation of O-dinitrophenylhydroxylamine in the
presence of KH has been reported.5a In view of this history, reagents 1-3
must be regarded as potential explosives, especially when the solid reagents
are mixed with strong base. Into a flame-dried 25-mL flask equipped with
a magnetic stir bar was dissolved 41 mg (0.25 mmol, 1.0 equiv) of ethyl
phenylacetate in THF (3.0 mL), and the mixture was cooled to -78 °C. A
freshly prepared solution of 31 mg (0.28 mmol, 1.1 equiv) of KOtBu in
THF (2.0 mL) was added dropwise via syringe, and the resulting solution
was allowed to stir for 15 min at -78 °C. Next, 81 mg (0.28 mmol, 1.1
equiv) of reagent 2 was added in one portion as a solid, and the mixture
was slowly allowed to reach 23 °C and stir overnight. To the solution was
added 71 µL (0.75 mmol, 3.0 equiv) of Ac2O and 210 µL (1.5 mmol, 6.0
equiv) of Et3N sequentially via syringe, and the mixture was allowed to
stir an additional 1 h at 23 °C. The solution was diluted with Et2O (20 mL)
and a saturated solution of ammonium chloride (30 mL). The layers were
separated, and the aqueous layer was extracted with Et2O (2 × 30 mL).
The combined organic layers were dried (MgSO4) and concentrated (rotary
evaporator), and the crude oil was purified by flash chromatography (1:1
ethyl acetate/hexanes) to give 37 mg of acetamide (67%) as a colorless oil.
Analytical TLC: Rf 0.20 (1:1 ethyl acetate/hexanes).
(10) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.;
Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz,
H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G.-Z.;
Peters, E.-M.; Peters, K.; von Schnering, H. G.; Walz, L. Liebigs Ann. 1996,
1055.
(11) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
(12) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (b) Kaufman,
M. J.; Streitwieser, A. J. Am. Chem. Soc. 1987, 109, 6092.
(13) Hughes, M. N.; Nicklin, H. G.; Shrimanker, K. J. Chem. Soc. (A)
1971, 3485. Bordwell, F. G.; Liu, W.-Z. J. Am. Chem. Soc. 1996, 118,
8777.
(14) Diimide formation was deduced from the formation of olefin
hydrogenation products; see ref 5a.
Org. Lett., Vol. 5, No. 22, 2003
4189

Overall, the results for 1 and 2 in Table 4 show an
advantage for 2 with the more basic anions. Highly stabilized
carbanions were aminated smoothly with either 1 or 2, and
clean conversion was observed using 1.1 equiv of reagent 2
for entries 2, 4, and 6. In these examples, it was experimen-
tally convenient to use NaH/THF (conditions A) to generate
the stabilized carbanions, while KOtBu was necessary for
entries 3 and 5.
Table 4. Scope and Comparison of Aminating Reagentsd
As the pKa of the substrate was increased, amination yields
decreased (Table 4, entries 3 and 5). Furthermore, attempts
to use reagent 3 for the amination of acetophenone enolate
were unsuccessful, while 2 gave 4% of the product (isolated
as the N-acetyl derivative). The pKa of acetophenone is 24.7
(DMSO),12a so this enolate may well be basic enough to
deprotonate 2, resulting in decomposition of the reagent.
The aminations using 2 are improved compared to
analogous literature results for 1.2b,c Although the solubility
difference between 1 and 2 is not large, it is sufficient to
show that the rate of amination at -78 °C is limited by
solubility for reagent 1.
In summary, electrophilic amination conducted using the
diarylphosphinylhydroxylamine 2 has been documented.
Reagent 2 was reliably prepared on gram scale from diethyl
phosphite via the diarylphosphinyl chloride 5. The best
results were obtained with highly stabilized sodium and
potassium enolates, but the more basic phenylacetate and
phenylacetonitrile anions also gave good yields.
a Isolated as the acetamide. b Sodium enolate.2c c Lithium enolate.2b
d Conditions A: NaH/THF, 15 min, 23 °C; 2 or 3, overnight, 23 °C.
Conditions B: KOtBu/THF, 15 min, -78 °C; 2 or 3, overnight, 23 °C.
Acknowledgment. This work was supported by the
National Institutes of Health (CA17918).
because of its ease of preparation and storage.3b However, 3
was not suitable for amination of the more highly basic
anions (entries 3 and 5).
OL035629W
4190
Org. Lett., Vol. 5, No. 22, 2003