Addition of functional vinylzinc reagents to nitrones: Synthesis of (E)-N-allylhydroxylamines and their rearrangement into (E)-O-allylhydroxylamines

Article abstract of DOI:10.1039/b104427n

The vinylzinc reagents derived from hydrozirconation of alkynes and transmetallation add readily to nitrones to yield pure (E)-N-allylhydroxylamines; some of these rearrange into O-allylhydroxylamines.

Full text of DOI:10.1039/b104427n

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Addition of functional vinylzinc reagents to nitrones: synthesis of
(E)-N-allylhydroxylamines and their rearrangement into
(E)-O-allylhydroxylamines
Shashi Urvish Pandya, Corinne Garçon, Pierre Y. Chavant, Sandrine Py and Yannick Vallée*
LEDSS, UMR 5616, Université J. Fourier, BP53, F-38041 Grenoble CEDEX 9, France.
E-mail: Yannick.Vallee@ujf-grenoble.fr
Received (in Cambridge, UK) 18th May 2001, Accepted 26th July 2001
First published as an Advance Article on the web 4th September 2001
The vinylzinc reagents derived from hydrozirconation of
alkynes and transmetallation add readily to nitrones to yield
pure (E)-N-allylhydroxylamines; some of these rearrange
into O-allylhydroxylamines.
For our study, we needed adducts from g-functionalized, pure
E, vinylmetallic species. Thus, we decided to prepare these
reagents according to Wipf’s procedure:10 hydrozirconation of
alkynes followed by transmetallation to the (E)-vinylzinc
species. We found that the resultant organometallic reagents
add readily onto nitrones, under mild conditions, to give
secondary N-hydroxylamines in good yields† (Scheme 1, Table
1).
In the course of our studies on nitrones,1 we became interested
in obtaining (E)-allylic N-hydroxylamines by the addition of
organometallic reagents onto nitrones.
In the past, addition of organolithium or organomagnesium
reagents onto CNN bonds2 was studied to a much lesser extent
than the corresponding addition onto carbonyl functions, the
major reason being that imines are less prone to nucleophilic
addition and more prone to deprotonation. In recent years, there
has been a renewed interest in the addition of organometallics
onto CNN double bonds because of both the availability of more
selective organotransition reagents, and the use of more reactive
CNN species. Among the latter, nitrones appear to be an
interesting choice as precursors. They are reactive, readily
available and stable. Indeed, recent work has dealt with the
addition of alkyl,3 allyl4 and alkynyl3,5 lithium, magnesium and
zinc reagents onto nitrones.
Comparatively fewer examples of the addition of vinylic
organometallics to CNN bonds have been described. Imines do,
however, react readily with vinylzinc compounds.6 It has also
been shown that vinylmagnesium bromide adds to tosyl
imines.7 Furthermore, it was demonstrated8 that vinylmagne-
sium bromide adds rapidly to nitrones. These results were
extended to diastereoselective additions onto chiral nitrones9
but the results were limited to the simplest ethenyl organo-
metallic reagent.
As expected, only the E configuration was observed in the
double bond of all the products. Also, excellent conversions
were obtained for the addition of the vinylzinc species derived
from hex-1-yne onto a variety of nitrones 2. Steric hindrance in
the nitrone (entry g, 39% conversion) is a limitation. The more
hindered vinylzinc reagent derived from hex-3-yne led to
incomplete conversion (entry h), and the formation of N-
benzyl-N-(1-phenylpropyl)hydroxylamine (10%), resulting
from ethylzinc addition, accompanied the allylic product 3h.
Addition onto the chiral nitrone 2d led to moderate diaster-
eoselectivity at 0 °C. Functionalized alkynes can also be used in
this protocol. The pivalate-protected but-3-yn-1-ol led readily to
3i and 3j. In other examples however, the w-cyanoalkyne (entry
k), the O-protected propynol11 (entries l, m, n, o) and the
Scheme 1 Reagents and conditions: (a) Cp2ZrHCl, CH2Cl2, rt, 1 h; vacuum;
Et2Zn, CH2Cl2, 265 to 0 °C; (b) CH2Cl2, 0 °C, 6 h.
Table 1 Preparation of N-allylhydroxylamines
Alkyne 1
Nitrone 2
Conv. of
2 (%)a
Isolated
yield (%)
Entry
R1
R2
R3
R4
a
b
c
n-Bu
n-Bu
n-Bu
H
H
H
PhCH2
p-CF3PhCH2
p-CF3PhCH2
Ph
Ph
Me
> 95
> 95
> 95
62
70
58
d
n-Bu
H
PhCH2
> 95
83
de 72%
62c
50c
29c
30
58
60b
5b
e
f
g
h
i
j
k
l
m
n
o
p
q
n-Bu
n-Bu
n-Bu
Et
PivO-(CH2)2-
PivO-(CH2)2-
NC-(CH2)3-
TMSO-CH2-
TMSO-CH2-
MeO-CH2-
MeO-CH2-
(EtO)2CH-
Ph
H
H
H
Et
H
H
H
H
H
H
H
H
H
Ph
p-Tolyl
t-Bu
p-MeO-Ph
> 95
> 95
39
Ph
Ph
Ph
Ph
i-Pr
Ph
Ph
p-MeO-Ph
Ph
p-MeO-Ph
Ph
Ph
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
Ph
PhCH2
Ph
PhCH2
PhCH2
40
> 95
> 95
75
90
> 95
50
> 95
46
90
32b
30c
35b
40c
16
0d
a Estimated from NMR of the crude product. b A significant amount of alkynyl adduct was also isolated, see text. c Isolated as the isomeric form 4, see text.
d Only alkynyl adduct, 50% yield.
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Chem. Commun., 2001, 1806–1807
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DOI: 10.1039/b104427n

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currently studying an asymmetric version of this reaction by
adding chiral zinc ligands to the reaction mixture.
Notes and references
† Typical experimental procedure: to a suspension of zirconocene hydro-
chloride (1.2 mmol) in CH2Cl2 (2 mL) under an N2 atmosphere at 20 °C was
added hex-1-yne (1.8 mmol) using standard Schlenk procedures. The
reaction was stirred at 20 °C until a homogeneous solution was formed. All
volatiles were then removed under reduced pressure at 20 °C, to give a
yellow vinylchlorozirconocene reagent. To the resultant solid was added
CH2Cl2 (2 mL) and the mixture was cooled to 265 °C. Diethylzinc (1.2
mmol, as a 1.1 M solution in toluene), was added dropwise (over 10 min) at
265 °C and allowed to stir for 15 min at 265 °C. The vessel was then
immersed in an ice bath and a solution of (N-benzylidene)benzylamine N-
oxide (1 mmol) in CH2Cl2 (2 mL) was added dropwise. After 6 h stirring at
0 °C, the reaction was quenched with saturated NaHCO3 solution (2 mL),
and extracted with ethyl acetate. The combined organic extracts were
washed with brine, dried over Na2SO4, and filtered through a pad of silica.
Removal of the solvents under reduced pressure and purification by
chromatography (silica, cyclohexane–ethyl acetate 90+10) yielded the pure
adduct 3.
Scheme 2 Rearrangement of N-allylhydroxylamines 3.
phenylacetylene (entry q) all yielded substoichiometric
amounts of vinylzinc reagent, presumably due to a less efficient
hydrozirconation step. In these runs, the conversions of nitrones
2 were incomplete, and the expected products 3 were contami-
nated with N-propargylhydroxylamines,‡ derived from the
addition of the alkyne 1 onto the nitrone 2.§
‡ The IUPAC name for propargyl is prop-2-ynyl.
§ We found that a mixture of alkyne 1, nitrone 2 and diethylzinc in
CH2Cl2 or toluene at rt leads quantitatively to N-propargylhydroxylamine
adducts, and we are currently studying this reaction. A similar addition of
species generated from the reaction of dialkylzinc with terminal alkynes
onto aromatic aldehydes has been described previously.14
All the vinyl adducts freshly obtained from this procedure
were the expected (E)-N-allylhydroxylamines 3. Surprisingly
however, we observed that on standing (at room temperature),
some of the samples (neat or in CDCl3 solutions) isomerized
slowly, with allylic transposition, to yield (E)-O-allylhydrox-
ylamines 4 (Scheme 2). This process occurs particularly readily
for N-arylhydroxylamines. In these cases, the rearrangement
was complete within 24 h at 20 °C and consequently, the
rearranged adducts were isolated after completion of this step
(entries e, f, m, o). This rearrangement also occurred in the case
of N-tert-butylhydroxylamine 3g. The structure of 4o was
confirmed by its reduction to the (E)-allylic alcohol 5 (Zn,
AcOH–MeOH 1+9, 40 °C, 2 h, quant.).
To our knowledge, this rearrangement has not been pre-
viously described, although it can be related with several
observations, involving allylic N–O bonds, including the
Meisenheimer rearrangement of tertiary amine N-oxides.12
We observed qualitatively that the rate of this rearrangement
depends strongly on the nitrogen atom substitution: Aryl > t-Bu
> > Bn. Several observations hint at a radical mechanism. First,
the reaction seems to be initiated by air: in an early experiment,
we observed a 50+50 mixture of 3o and 4o 2 h after working-up
the reaction. We repeated the experiment, using for the
hydrolytic work-up freshly distilled solvents and freshly boiled
water phases, and handling the crude materials with simple
anaerobic precautions: the amount of isomer 4o was then
reduced to less than 3% (NMR) of the crude material.
Thereafter, exposure to air induced the rearrangement. EPR of
the crude materials during isomerization showed a strong
signal, with a fine structure consistent with the aminoxyl radical
derived from 3. Obviously, this radical could be the active
species, undergoing a Meisenheimer [2,3] rearrangement. We
are currently investigating the mechanism, scope, and limita-
tions of this new reaction.
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It is important to note that the above isomerization amounted
only to traces if the R3 substituent on the nitrogen atom was a
benzyl group: as seen in Table 1, the N-benzyl-N-allylhydrox-
ylamines 3 can be isolated in good yields. They can be readily
reduced to provide the corresponding (E)-N-benzyl-N-allyl-
amines.
In conclusion, we have shown that the sequence: terminal
alkyne hydrozirconation, Zr to Zn exchange and addition to
nitrones, is a good method to stereoselectively synthesize (E)-
N-allylhydroxylamines, under mild conditions and in good
yields. It is noteworthy that this reaction occurs with no need for
an external activating agent such as amino-alcohols.13 We are
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Synthesis, 1999, 1453.
Chem. Commun., 2001, 1806–1807
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