Efficient methodology for alkylation of vinylnitroso compounds with carbon nucleophiles

Article abstract of DOI:10.1016/j.tetlet.2010.02.050

A diverse array of nitrosoalkenes derived from both acyclic and cyclic ketones, as well as aldehydes, via the Denmark protocol using α-chloro-O-TBS-oximes can be trapped efficiently in situ by a wide variety of potassium ester enolates to afford conjugate addition products in good yields.

Full text of DOI:10.1016/j.tetlet.2010.02.050

Tetrahedron Letters 51 (2010) 2032–2035
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient methodology for alkylation of vinylnitroso compounds
with carbon nucleophiles
*
Puhui Li, Max M. Majireck, Jason A. Witek, Steven M. Weinreb
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A diverse array of nitrosoalkenes derived from both acyclic and cyclic ketones, as well as aldehydes, via
Received 21 January 2010
Accepted 8 February 2010
Available online 14 February 2010
the Denmark protocol using
a-chloro-O-TBS-oximes can be trapped efficiently in situ by a wide variety of
potassium ester enolates to afford conjugate addition products in good yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Conjugate additions
Oximes
Nitrosoalkenes
Vinylnitroso compounds are highly reactive, generally unstable
species which have found only sporadic use in organic synthesis.1
There are presently two procedures most commonly used to gener-
ate nitrosoalkenes (Scheme 1). The most widely applied method
a wide variety of ester enolates. It should be noted that vinylnitr-
oso compounds derived from cyclic ketones6 as well as aldehydes4a
are still relatively rare and therefore we have opted to explore
reactions involving such systems to probe the scope of the
methodology.
involves base-promoted 1,4-elimination of an
a-halo oxime 1 to
produce the vinylnitroso species 3. These transient intermediates
are known to undergo rapid conjugate additions with a variety of
hetero and carbon nucleophiles in a Michael-type reaction to
produce adducts 4 in good yields. When forming the vinylnitroso
species via this process it is common to utilize at least 2 equiv of
a nucleophile, one of which acts as the base for the initial elimina-
tion step. Such a procedure, however, is inefficient when using
valuable nucleophiles.
We have developed a general experimental procedure to effect
this transformation as shown in Scheme 2 and have explored the
scope and limitations of this methodology. Thus, an ester deriva-
tive 5 (1.2 equiv) is first converted into its potassium enolate with
potassium hexamethyldisilazide in THF at À78 °C. The addition of
an
a-chloro-O-TBS-oxime 6 (1.0 equiv) to the enolate solution is
followed by slow addition of tetrabutylammonium fluoride solu-
tion in THF (1.2 equiv). The mixture is then slowly warmed to
0 °C, and after 2 h the reaction is worked up to yield alkylation
product 7. A number of examples of this process along with chro-
matographically isolated yields of oxime products 7 are listed in
A second, less widely used method for nitrosoalkene generation
developed by Denmark, et al. relies on the treatment of an O-silyl-
a
-halo oxime 2 with a fluoride source to form 3.2 Several scattered
examples have appeared describing the production of vinylnitroso
compounds via this procedure in the presence of a nitrogen or
oxygen heteronucleophile to afford the corresponding conjugate
addition products.3 In addition, two reports exist of the generation
and intermolecular trapping of carbon nucleophiles starting from
HO
N
Cl
silyl-a
-halo oximes like 2.4 Recently we have used the Denmark
base
HO
O
N
procedure to effect the first examples of intramolecular conjugate
N
Nuc-
1
additions of enolates to vinylnitroso compounds.5
Nuc
F-
In view of our interest in exploring the potential of nitrosoalk-
enes as enolonium ion equivalents in organic synthesis,7 we have
studied effecting intermolecular conjugate additions of a number
of vinylnitroso compounds formed by the Denmark strategy with
R3SiO
N
4
3
Cl
2
* Corresponding author. Tel.: +1 814 863 0189; fax: +1 814 865 3292.
E-mail address: smw@chem.psu.edu (S.M. Weinreb).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.050

P. Li et al. / Tetrahedron Letters 51 (2010) 2032–2035
2033
occasionally oxime mixtures are formed (see Table 1). We were
pleased to find that in general the alkylation procedure works well
with a variety of a-chloro-O-TBS-oxime substrates including those
derived from cyclic ketones and aldehydes. Moreover, it was
gratifying to see that with the aldehyde-derived nitrosoalkene in
entries n and o it is possible to produce adjacent quaternary carbon
centers.
OH
R4
N
X
Y
R1O2C
X
1) KHMDS, THF, -78 °C
2)
R1O2C
Y
Cl
R2
R3
N OTBS
R2 R3
5
then TBAF
-78-0 °C
7
R4
6
One interesting observation which was made is that with some
Scheme 2.
ester and
used for the enolization can affect the product yield. For example,
using ethyl -nitroacetate (entry d) KHMDS gave the desired
a-chloro silyl oxime combinations, the nature of the base
Table 1. In most cases a single oxime geometric isomer is formed,
assumed to have the more stable (E)-configuration, although
a
Table 1
Intermolecular Michael additions of carbon nucleophiles to nitrosoalkenes
Entry
Ester derivative
Nitrosoalkene precursor
Product
Yield
95%a
EtO2C
EtO2C
EtO2C
EtO2C
CO2Et
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OH
OH
OH
OH
OH
N
N
N
N
N
N
N
EtO2C
EtO2C
N
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
a
CO2Et
Me
EtO2C
b
c
d
e
f
84%
EtO2C
Me
CO2Et
NO2
EtO2C
Et
69%
EtO2C
Et
NO2
57%b,c
71%c
95%c
79%c
EtO2C
O
Me
O
EtO2C
Me
EtO2C
MeO2C
SO2Ph
Ph
OH
PhO2S
N
MeO2C
MeO2C
MeO2C
OH
Ph
N
g
EtO2C
EtO2C
CO2Et
CO2Et
OTBS
OTBS
OH
N
N
N
EtO2C
EtO2C
h
i
85%d,e
Cl
Cl
OH
OH
N
N
EtO2C
Me
72%
EtO2C
Me
EtO2C
CO2Et
OTBS
N
EtO2C
j
Et
73%
Cl
EtO2C
Et
MeO2C
MeO2C
SO2Ph
Ph
OTBS
OTBS
OH
N
N
N
PhO2S
k
l
82%c
Cl
Cl
MeO2C
OH
N
Ph
55%c,d
MeO2C
(continued on next page)

2034
P. Li et al. / Tetrahedron Letters 51 (2010) 2032–2035
Table 1 (continued)
Entry
Ester derivative
Nitrosoalkene precursor
Product
Yield
EtO2C
CO2Et
OTBS
EtO2C
CO2Et
H
N
Cl
m
n
64%d,e
H
N
OH
EtO2C
CO2Et
Me
OTBS
Me
EtO2C
N
CO2Et
H
Cl
74%
H
N
OH
EtO2C
CO2Et
OTBS
Et
EtO2C
N
CO2Et
H
Cl
Et
o
69%d
H
N
OH
MeO2C
Ph
OTBS
MeO2C
Ph
H
N
Cl
p
q
63%
88%
H
N
OH
EtO2C
EtO2C
CO2Et
OTBS
N
OH
EtO2C
N
N
Me
Cl
Ph
EtO2C
Ph
Ph
Me
CO2Et
OTBS
N
OH
EtO2C
r
s
71%
75%
Et
Cl
Ph
EtO2C
Et
MeO2C
EtO2C
Ph
OTBS
N
OH
Ph
N
Cl
Ph
MeO2C
Ph
CO2Et
OTBS
N
OH
N
t
51%f
69%
Ph
Ph
H
Ph
H
Cl
Cl
EtO2C
CO2Et
EtO2C
EtO2C
CO2Et
OTBS
H
OH
N
N
N
Me
Ph
H
u
EtO2C
CO2Et
Me
CO2Et
OTBS
H
OH
N
Et
68%d,g
Ph
Ph
H
v
Cl
EtO2C
CO2Et
Et
MeO2C
EtO2C
Ph
OTBS
H
OH
N
N
N
w
75%c,d
Ph
Ph
Ph
H
Cl
Cl
MeO2C
Ph
CO2Et
OTBS
H
OH
N
x
67%d
Ph
H
EtO2C
CO2Et
a
Use of LiHMDS and NaHMDS gave yields of 91% and 94%, respectively.
No desired product was formed when using LiHMDS or NaHMDS.
An accurate stereochemical assignment could not be made since the products exist as a complex mixture of E/Z-isomers and/or diastereomers which were not separable
b
c
by column chromatography.
d
2 equiv of KHMDS and 2 equiv of ester derivative were used.
The deprotonation step was performed at 0 °C to prevent freezing of the reaction mixture.
Use of LiHMDS and NaHMDS gave 34% and 51%, respectively.
E/Z ratio could not be determined.
e
f
g

P. Li et al. / Tetrahedron Letters 51 (2010) 2032–2035
2035
be trapped in situ with a wide range of potassium ester enolates
to give Michael-type adducts in good yields. We are currently
exploring some extensions of the methodology and applications
to the synthesis of complex molecules.
OH
O
OTBS
N
N
N
Me
Cl
Me
Me
General procedure for intermolecular Michael additions of carbon
nucleophiles to in situ-generated nitrosoalkenes. To a À78 °C solution
of ester derivative 5 (0.46 mmol) in THF (1 mL) was added KHMDS
8
9
10
Scheme 3.
(917 lL, 0.5 M in PhMe, 0.46 mmol). The resulting solution was
then stirred for 45 min at that temperature. The O-TBS-oxime 6
dissolved in THF (0.38 mmol in 0.3 mL of THF) was added slowly
over 1 min, followed by the dropwise addition of TBAF (458 lL,
H2N
O
1) KHMDS, THF, -78 °C
OTBS
N
CN
1.0 M in THF, 0.46 mmol) over 3 min. The resulting solution was
immediately transferred to a 0 °C ice bath and stirred for an addi-
tional 2 h. The reaction mixture was diluted with conc. aqueous
NH4Cl and EtOAc. The organic layer was separated and the aqueous
layer was extracted with EtOAc. The combined organic layers were
dried over MgSO4 and concentrated in vacuo to give a residue,
which was purified by flash column chromatography on silica gel
eluting with a mixture of ethyl acetate and hexanes. Isolated yields
of conjugate addition products 7 are shown in Table 1.
2)
Cl
12
PhO2S
N
PhO2S
11
then TBAF
-78-0 °C
13 (54%)
Scheme 4.
alkylation product in 57% yield, whereas with NaHMDS and
LiHMDS none of the product was formed. With diethyl malonate
and the aldehyde-derived substrate in entry t, KHMDS and NaH-
MDS gave similar product yields but LiHMDS gave a substantially
reduced yield. On the other hand, using diethyl malonate and the
cyclic ketone-derived silyl oxime substrate in entry a, the yield of
alkylation product is only slightly dependant upon the base: 95%
with KHMDS, 94% with NaHMDS, and 91% with LiHMDS. In a few
of the examples in the table (entries h, l, m, o, v, w, x) it was found
that there was a significant improvement in product yield if the
amount of the ester potassium enolate is increased to 2 equiv.
To our surprise, it was observed that enolates of 1,3-diketones
and simple ketone enolates do not add to vinylnitroso compounds
under these conditions. At present we cannot rationalize this fail-
ure since there a number of examples in the literature of such Mi-
chael reactions of nitrosoalkenes generated from base elimination
Acknowledgment
We are grateful to the National Institutes of Health (9R56GM-
087733) for financial support of this research.
References and notes
1. For reviews of vinylnitroso compounds and lead references see: (a) Gilchrist, T.
L. Chem. Soc. Rev. 1983, 11, 53; (b) Lyapkalo, I. M.; Ioffe, S. L. Russ. Chem. Rev.
1998, 67, 467.
2. (a) Denmark, S. E.; Dappen, M. S. J. Org. Chem. 1984, 49, 798; (b) Denmark, S. E.;
Dappen, M. S.; Sternberg, J. A. J. Org. Chem. 1984, 49, 4741; (c) Denmark, S. E.;
Dappen, M. S.; Sear, N. L.; Jacobs, R. T. J. Am. Chem. Soc. 1990, 112, 3466.
3. (a) Hassner, A.; Murthy, K. Tetrahedron Lett. 1987, 28, 683; (b) Padwa, A.;
Chiacchio, U.; Dean, D. C.; Schoffsatll, A. M.; Hassner, A.; Murthy, K. S. K.
Tetrahedron Lett. 1988, 29, 4169; (c) Hassner, A.; Maurya, R.; Mesko, E.
Tetrahedron Lett. 1988, 29, 5313; (d) Hassner, A.; Murthy, K. S. K.; Padwa, A.;
Bullock, W. H.; Stull, P. D. J. Org. Chem. 1988, 53, 5063; (e) Hassner, A.; Murthy, K.
S. K.; Padwa, A.; Chiacchio, U.; Dean, D. C.; Schoffstall, A. M. J. Org. Chem. 1989,
54, 5277; (f) Hassner, A.; Maurya, R.; Friedman, O.; Gottlieb, H. E.; Padwa, A.;
Austin, D. J. Org. Chem. 1993, 58, 4539; (g) Trewartha, G.; Burrows, J. N.; Barrett,
A. G. M. Tetrahedron Lett. 2005, 46, 3553.
of simple
enolates to the more highly substituted nitrosoalkene 9 formed
from -chloro-O-TBS-oxime only led to the tautomerized
,b-unsaturated oxime 10 in varying yields (Scheme 3).
Finally, the potassium anion from -phenylsulfonylacetonitrile
(11) reacts with the nitrosoalkene from -chloro-O-TBS-oxime 12
a
-halo oximes.1,8 In addition, all attempts to add ester
a
8
a
a
4. (a) Hassner, A.; Maurya, R. Tetrahedron Lett. 1989, 30, 5803; (b) Kaiser, A.;
Wiegrebe, W. Monatsh. Chem. 1998, 129, 937.
a
5. Korboukh, I.; Kumar, P.; Weinreb, S. M. J. Am. Chem. Soc. 2007, 129, 10342.
6. See for example: (a) Ohno, M.; Torimitsu, S.; Naruse, N.; Okamoto, M.; Sakai, I.
Bull. Chem. Soc. Jpn. 1966, 39, 1129; (b) Trost, B. M.; Barrett, D. Tetrahedron 1996,
52, 6903; (c) Corey, E. J.; Melvin, L. S., Jr.; Haslanger, M. F. Tetrahedron Lett. 1975,
3117.
7. For some other examples of enolonium ion equivalents see: Fuchs, P. L. J. Org.
Chem. 1976, 41, 2935; Wender, P. A.; Erhardt, J. M.; Letendre, L. J. J. Am. Chem.
Soc. 1981, 103, 2114. and references cited therein.
but produces adduct 13 where the oxime hydroxyl group has
cyclized onto the initially formed cyano sulfone (Scheme 4). The
moderate yield of 13 is probably due to its instability on silica
gel chromatography.
In conclusion, we have described a general procedure whereby
vinylnitroso compounds formed via the Denmark protocol from a
diverse array of
a-chloro-O-TBS-ketoximes and -aldoximes can
8. Oppolzer, W.; Battig, K.; Hudlicky, T. Tetrahedron 1981, 37, 4359.