Unprecedented base-promoted nucleophilic addition of diazoesters to nitrones

Article abstract of DOI:10.1016/j.tetlet.2013.07.044

A novel and efficient nucleophilic addition of metalated α-diazoacetates to a variety of nitrones is described. This approach provides a series of stable unprecedented β-alkylhydroxyamino-α- diazoesters with great synthetic potential.

Full text of DOI:10.1016/j.tetlet.2013.07.044

Tetrahedron Letters 54 (2013) 5103–5105
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Tetrahedron Letters
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Unprecedented base-promoted nucleophilic addition of diazoesters
to nitrones
⇑
⇑
Evelyn Lieou Kui, Alice Kanazawa , Jean-François Poisson, Sandrine Py
Département de Chimie Moléculaire (SERCO), UMR-5250, ICMG FR-2607, Université Joseph Fourier-CNRS, BP 53, 38041 Grenoble Cedex 09, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient nucleophilic addition of metalated
described. This approach provides a series of stable unprecedented b-alkylhydroxyamino-a-diazoesters
with great synthetic potential.
a-diazoacetates to a variety of nitrones is
Received 28 May 2013
Revised 1 July 2013
Accepted 8 July 2013
Available online 15 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
a-Diazoesters
Nitrones
Sugar-derived nitrones
Nucleophilic addition
Hydroxylamines
Nitrones represent one of the most useful and versatile nitro-
genated substrates in organic synthesis.1 Due to their dipolar struc-
ture they have been largely exploited in [3+2]-cycloaddition
reactions with alkenes.2 Also, due to their highly polarized C–N
double bond, nitrones show a pronounced electrophilic reactivity
compared to imines and hence are privileged substrates for nucle-
ophilic addition reactions. However, although a number of organo-
metallic additions to nitrones have been previously reported,1a–d to
the best of our knowledge, there has been no report on the direct
Inspired by the reported conditions for nucleophilic addition of
ethyl diazoacetate (EDA, 2a) to carbonyl compounds5,6 and
imines,5,7 we commenced our study with a brief screening of bases
to form hydroxylamine 3a from ethyl N-benzyl nitrone (1) (Ta-
ble 1). Although 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) cata-
lyzes the condensation of EDA with aldehydes and imines5 no
reaction was observed with nitrone 1, even after prolonged stirring
for several days (Table 1, entry 1). Using potassium hexamethyldi-
silazide (KHMDS) as base also failed (entry 2). Changing the base to
sodium hexamethyldisilazide (NaHMDS)7e gave the desired
hydroxylamine 3a in a modest 53% yield (entry 3). However, signif-
icant improvement was observed with lithium hexamethyldisilaz-
ide (LiHMDS) or lithium diisopropylamide (LDA)6,7e as bases,
affording the addition product in 93% and 94% yields respectively
(entries 4 and 5). We selected the conditions using LiHMDS as base
(commercially available solution), THF as solvent, at –78 °C for
1.5 h reaction time to study the scope of the nucleophilic addition.8
The addition of other commercial alkyl diazoesters to nitrone 1
was next tested using the previously optimized conditions
(Scheme 1). Pleasingly, with t-butyldiazoester (2b) and benzyl dia-
zoester (2c), hydroxylamines 3b and 3c were obtained in quantita-
tive yields.
nucleophilic addition of
a-diazoesters onto nitrones.
A wide array of transformations can be performed with
a
-diazo
carbonyl substrates.3 Particularly interesting reactions are those
involving decomposition of diazo moiety catalyzed by transition
metal complexes. Through metallocarbene species, a wide number
of reactions including C–H or X–H insertion processes, cyclopropa-
nations, cycloadditions, and Wolff rearrangement can be observed.
In connection with our ongoing research program devoted to
the development of new methodologies and synthetic applications
involving nitrones,4 we became interested in exploring the reactiv-
ity of nitrones with
a-diazo acetates, which are useful C-2 sub-
strates for the incorporation of diazo moiety. This approach
would provide densely functionalized hydroxylamines with great
potential in organic synthesis.
Encouraged by these preliminary results, we next extended the
addition of lithiated ethyl diazoacetate to a variety of nitrones.9 As
shown in Table 2 (entries 1–4), the reaction proceeded smoothly
with aliphatic aldonitrones, producing the corresponding hydrox-
ylamines in good to excellent yields. Interestingly, the reaction also
worked well with ketonitrone 8, furnishing the corresponding
⇑
Corresponding authors. Tel.: +33 4 76 51 48 03.
E-mail addresses: Alice.Kanazawa@ujf-grenoble.fr (A. Kanazawa), Sandrine.-
Py@ujf-grenoble.fr (S. Py).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.044

5104
E. Lieou Kui et al. / Tetrahedron Letters 54 (2013) 5103–5105
Table 1
O
Bn
Screening of bases in the reaction of EDA (2a) and ethyl N-benzyl nitrone (1)a
O
O
Bn
N
N
HO
Bn
O
O
N
O
O
Bn
O
N
Base
O
+
OEt
Et
OEt
OBn
Solvent, temperature
O
N2
2a
Et
N2
1
3a
20
21
Entry
Base
Solvent
T (°C)
Time
Yieldb (%)
Figure 1. Chiral N-benzyl nitrones 20 and 21.
1
2
3
4
5
DBU (10 mol %)
MeCN
THF
THF
THF
THF
rt
7 d
0c
KHMDS (1.5 equiv)
NaHMDS (1.5 equiv)
LiHMDS (1.5 equiv)
LDA (1.5 equiv)
–78
–78
–78
–78
1.5 h
1.5 h
1.5 h
1.5 h
0c
53c
93
94
Table 3
Addition of EDA onto chiral non racemic N-benzyl nitrones
a
b
c
Reactions were carried out with 1.0 equiv of 1 and 1.5 equiv of diazoester 2a.8
Isolated yield after column chromatography.
Starting nitrone was recovered.
Entry
1
Nitrone
Hydroxylamine
Yielda (%)
Drb (%)
75:25
HO
O
Bn
N
*
O
HO
Et
Bn
N2
OEt
Bn
O
N
O
O
20
92
O
Bn
N2
N
LiHMDS
+
OR
OR
THF, −78 °C
N2
Et
22
HO
2
1
2b, R = t-Bu
2c, R = Bn
3b, R = t-Bu (100%)
3c, R = Bn (100%)
N
*
O
O
OEt
Scheme 1. Addition of t-butyl and benzyl diazoesters to nitrone 1.
21
83
60:40
O
N2
OBn
O
Table 2
23
Addition of EDA to a variety of nitronesa
HO
R1
R3
N2
a
Isolated yield after column chromatography.
O
N
O
b
Diastereomeric ratio was determined by 1H NMR analysis of the crude reaction
O
R3
N
LiHMDS
mixture.
OEt
+
OEt
R2
R1 R2
N2
THF, −78 °C
Nitroneb
Hydroxylamine
Yieldc (%)
lithiated heteroaromatic nucleophiles to the same nitrone, which
showed a much higher diastereoselectivity (>90:10).14 No attempt
to improve the diastereoselectivity of these reactions was
undertaken.
Entry
1
2
3
4
5
6
7
8
4: R1 = Me2CHCH2, R2 = H, R3 = Bn
5: R1 = Me2CH, R2 = H, R3 = Bn
6: R1 = t-Bu, R2 = H, R3 = Bn
12
13
14
15
16
17
18
19
59
98
77
80
74
61d
46e
92
7: R1 = cyclohexyl, R2 = H, R3 = Bn
8: R1–R2: –(CH2)5–, R3 = Bn
We next turned our attention to sugar-derived cyclic nitrones.
This class of nitrones, and particularly five-membered cyclic nitro-
nes are useful building blocks for the synthesis of bioactive imino-
sugars.1e,15 The nucleophilic addition of lithiated ethyl
diazoacetate was performed on nitrones 24,4c,16 25,17,18 and
9: R1 = Ph, R2 = H, R3 = Bn
10: R1 = p-MeOC6H4, R2 = H, R3 = Bn
11: R1 = p-ClC6H4, R2 = H, R3 = Ph
a
b
c
For typical procedure see Ref. 8.
For the preparation of nitrones 4–11, see Ref. 9.
Isolated yield after column chromatography.
39% of 9 was recovered.
2619,20 (obtained respectively from
L-xylose, D-glucose, and D-man-
nose, Figure 2). Gratifyingly, the corresponding hydroxylamines 27,
28, and 29 were obtained in excellent chemical yields and with to-
tal diastereocontrol (Table 4). This result is in agreement with the
general trend observed in the nucleophilic addition to these cyclic
nitrones in which high diastereoselectivities are obtained through
an anti attack with respect to the C-3 alkoxy substituent.
In summary, we report an efficient, high yielding nucleophilic
addition of lithiated alkyl diazoesters with a variety of nitrones.
The selectivity observed with sugar-derived endocyclic nitrones
opens new perspectives for the synthesis of novel bioactive imino-
sugars. The study of the reactivity of these novel hydroxyamino
diazoesters through the formation of metallocarbenoids is ongoing
in our laboratory and will be reported in due course.
d
e
34% of 10 was recovered.
hydroxyamine 16 in 74% yield (entry 5). In the case of C-aromatic
N-benzyl nitrones, the isolated yields of compounds 17 and 18 are
slightly lower (entries 6 and 7). In these cases substantial amounts
of starting nitrones were recovered. With N-phenyl nitrone 11 (en-
try 8) the addition product was obtained in excellent yield (92%).
We also examined the diastereoselectivity of this nucleophilic
addition using chiral N-benzyl nitrones 20 (derived from
D-glycer-
aldehyde)10 and 21 (prepared from -glucose)11 (Fig. 1).
D
The reaction proceeded smoothly with nitrone 20 furnishing
the corresponding hydroxylamine 22 in 92% yield as a 75:25 mix-
ture of diastereomers (Table 3). It can be assumed that the major
product is the syn isomer based on the previously reported organo-
metallic additions to the same nitrone.12 The level of diastereose-
lectivity is consistent with that observed in the addition of the
lithium enolate of methyl acetate to nitrone 20.12e With nitrone
21, a 60:40 mixture of hydroxylamine 23 was obtained in 83%
yield. This result also matches with those observed in vinylation
reactions (low selectivities)13 but it contrasts with the addition of
O
O
O
N
O
N
N
BnO
BnO
BnO
O
O
O
BnO
OBn
BnO
25
Figure 2. Structures of sugar-derived nitrones 24, 25, and 26.
OBn
24
26

E. Lieou Kui et al. / Tetrahedron Letters 54 (2013) 5103–5105
5105
Table 4
Masson, G.; Philouze, C.; Py, S. Org. Biomol. Chem. 2005, 3, 2067–2069; (e)
Pillard, C.; Desvergnes, V.; Py, S. Tetrahedron Lett. 2007, 48, 6209–6213; (f)
Burchak, O. N.; Philouze, C.; Chavant, P. Y.; Py, S. Org. Lett. 2008, 10, 3021–3023;
(g) Xu, C.-P.; Huang, P.-Q.; Py, S. Org. Lett. 2012, 14, 2034–2037; (h) Gilles, P.;
Py, S. Org. Lett. 2012, 14, 1042–1045.
Addition of EDA onto cyclic sugar-derived nitrones
Entry
1
Nitrone
Hydroxylamine
Yielda (%)
Drb (%)
>99:1
5. For recent reviews on reactions involving
a-diazocarbonyl compounds as
OH
N2
nucleophiles, see: (a) Zhao, Y.; Wang, J. Synlett 2005, 2886–2892; (b) Zhang, Y.;
Wang, J. Chem. Commun. 2009, 5350–5361.
BnO
N
OEt
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Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem. 1990, 55, 4144–4153; (c)
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8. Typical procedure: To a solution of nitrone (1.0 equiv) and ethyl diazoacetate
(1.5 equiv) in THF at –78 °C, 1.5 equiv of LiHMDS (1 M in THF) was added
dropwise. After 1.5 h a saturated aqueous solution of NaHCO3 was added and
the resulting mixture was diluted with dichloromethane. The organic layer was
separated, washed with brine, dried (Na2SO4), and evaporated under reduced
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O
24
100
BnO
OBn
27
2
OH
N
N2
BnO
BnO
OEt
O
25
>99:1
BnO
OBn
28
100
92
3
OH
N2
O
N
OEt
O
O
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26
>99:1
O
O
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29
Isolated yield after column chromatography.
a
b
A single diastereomer was observed by 1H NMR analysis of the crude reaction
mixture.
Supplementary data
Supplementary data (complete characterization data for all new
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.044. These
data include MOL files and InChiKeys of the most important com-
pounds described in this article.
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