Intermediates in the synthesis of nitrogen heterocycles: Addition of acylated camphorsultams to nitroalkenes

Article abstract of DOI:10.1016/j.tetlet.2003.09.029

Reaction of acylated camphorsultam 7 with nitroalkenes in the presence of TiCl₄ and Et₃N gave addition products in good yields (>70%) and with excellent stereocontrol. Addition of propionylated camphorsultam 15 to nitrostyrene gave t

Full text of DOI:10.1016/j.tetlet.2003.09.029

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8153–8156
Intermediates in the synthesis of nitrogen heterocycles:
addition of acylated camphorsultams to nitroalkenes
Joanna E. Clare,a Christine L. Willis,a,* Josephine Yuen,a Kenneth W. M. Lawrie,b
Jonathan P. H. Charmantc and Anob Kantachac
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK
bGlaxoSmithKline, Gunnel’s Wood Road, Stevenage, Herts, SG1 2NY, UK
cStructural Chemistry Laboratory, School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK
Received 6 August 2003; accepted 1 September 2003
Abstract—Reaction of acylated camphorsultam 7 with nitroalkenes in the presence of TiCl4 and Et3N gave addition products in
good yields (>70%) and with excellent stereocontrol. Addition of propionylated camphorsultam 15 to nitrostyrene gave the
addition product 16 in which two new asymmetric centres were created, the stereochemical outcome of the reaction was confirmed
by X-ray cystallography.
© 2003 Elsevier Ltd. All rights reserved.
Nitro containing compounds are particularly versatile
intermediates in organic synthesis. They facilitate car-
bon–carbon bond forming reactions and the nitro
group may be readily transformed into a wide range of
functionalities including reduction to amines and via a
Nef reaction to carbonyl compounds.1 In a previous
paper we have shown that reaction of nitromethane
with (1S,2R)-N-[(E)-crotonyl]bornane-10,2-sultam 1 in
the presence of DBU in THF and DMPU gave a 3:1
mixture of diastereomers 2 and 3 in 90% yield. The
major product 2 was purified by crystallisation from
methanol (Scheme 1) and the structure confirmed by
X-ray crystallography.2 Hydrolytic cleavage of the aux-
iliary gave (S)-3-methyl-4-nitrobutanoic acid 4, a valu-
able building block for the synthesis of cis- and
trans-3-hydroxy-5-methylpiperidin-2-ones 5 and 6 in
good yields using biotransformations to create the
asymmetric centre at C-3 with complete stereocontrol.
In order to improve this approach to the synthesis of
hydroxypiperidinones, a more efficient method for the
preparation of 4 is required.
ture precedent we found for the proposed reaction of 7
with (E)-nitropropene was by Brenner and Seebach
being addition of acyloxazolidinone 8 to nitropropene
in the presence of titanium tetrachloride and diiso-
propylethylamine giving a 9:1 mixture of diastereomers
9a and 10a from which the major product 9a was
isolated in 36% yield (Scheme 2).4 Although the yield
was disappointing, the diastereoselectivity was a signifi-
cant improvement on the 3:1 mixture of 2 and 3 which
we had obtained from the conjugate addition of
nitromethane to the chiral crotonate 1,2 and so we were
encouraged to proceed.
We have shown previously that aldol products are
formed in good yield by reaction of acylated sultam 7
with a variety of aldehydes mediated by titanium tetra-
chloride and an amine base (e.g. diisopropylethyl-
amine).5 Thus, we anticipated that reaction of 7 with
nitropropene under similar conditions would give a
good yield of 2/3. We now report the results of our
investigations on the reactions of (E)-nitroalkenes with
camphorsultams 7 and 15.
An attractive option was to consider a different discon-
nection of 2 in a retro-Michael mode giving the
acylated sultam 7 and (E)-1-nitroprop-1-ene (Scheme
1). Nitroalkenes are among the most powerful Michael
acceptors and indeed such reactions have been carried
out using acylated chiral auxiliaries.3 The nearest litera-
Results and Discussion
(E)-Nitropropene6 and acylcamphorsultam
7 were
treated with TiCl4 and Et3N in CH2Cl2 at −78°C. The
reaction mixture was quenched with aqueous NH4Cl at
−78°C and following a standard extraction protocol a
* Corresponding author.
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doi:10.1016/j.tetlet.2003.09.029

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J. E. Clare et al. / Tetrahedron Letters 44 (2003) 8153–8156
Scheme 1.
Scheme 2.
1
9:1 mixture of products was apparent by H and 13C
none 8 although the stereoselectivity in each case was
similar (Scheme 2). However, as well as changing the
auxiliary, a further difference between the two experi-
ments was the work-up procedure. Brenner and
Seebach4 reported that, following the reaction, the
organic phase containing the crude product was washed
sequentially with acid, base and then again with acid.
Thus we repeated the reaction of acylated sultam 7 with
nitropropene and worked-up the reaction under these
conditions. No nitronate 11 was observed in the 1H
NMR spectrum of the crude material but, in this case,
the addition products 2 and 3 were isolated in only 67%
yield following flash chromatography compared with a
90% yield on working up the reaction mixture simply
with aqueous NH4Cl prior to flash chromatography.
For further comparison, we treated acyloxazolidinone 8
NMR spectroscopy (Scheme 3).7 The H NMR spec-
1
trum revealed the presence of a doublet (J 7.5 Hz) at l
6.22, characteristic of the nitronate intermediate 11. A
minor amount (ca 10%) of the 3%R-nitronate 12 was
apparent in the spectrum and only a trace of the nitro
derivative 2 in which the 4%-protons resonate in the
region l 4.0–4.5 ppm. The crude product was purified
by flash chromatography giving 2 and 3 in a pleasing
90% yield and the major diastereomer was further
purified by crystallisation.8
From this result it is apparent that reaction of nitro-
propene with acylated sultam 7 gave a significantly
higher yield of addition product 2 (Scheme 3) compared
with the analogous reaction with acylated oxazolidi-

J. E. Clare et al. / Tetrahedron Letters 44 (2003) 8153–8156
8155
Scheme 3.
and nitropropene with TiCl4 and iPr2EtN and worked
up the reaction either by quenching with aqueous
NH4Cl or using the more elaborate acid/base/acid wash
giving 9a in 52% and 33% yield respectively after flash
chromatography. Thus it is apparent that the work-up
procedure does indeed have a significant effect on the
yield of isolated addition products. In the examples
reported above, higher yields of products were obtained
by a simple work-up with aqueous NH4Cl followed by
purification by flash chromatography on silica.
lowing crystallisation from methanol, the analytically
pure product 2 was isolated in 85% yield.
If these reactions are to be valuable in the stereocon-
trolled synthesis of substituted piperidin-2-ones other
than the cis- and trans-3-hydroxy-5-methylpiperidin-2-
ones 5 and 6, then the diastereoselective addition of
acylated sultam 7 to a range of nitroalkenes must be
achieved. Treatment of 7 with nitrostyrene under the
standard conditions gave the diastereomer 13 as the
sole product in 73% yield whilst with (E)-1-nitro-3-
methylprop-1-ene the isopropyl derivative 14 was iso-
lated in 80% yield, again as a single diastereomer
(Scheme 4). In each case, the reactions were worked up
using aqueous ammonium fluoride. Finally we found
that reaction of propionyl sultam 15 and nitrostyrene
with TiCl4 and Et3N gave 16 with the creation of 2 new
Since 2 is crystalline, ideally we required a work-up
procedure for the reaction of acylated sultam 7 and
nitropropene with TiCl4 and Et3N which avoided the
necessity of using silica to breakdown the nitronate 11.
This was achieved by quenching the reaction mixture
with aqueous ammonium fluoride4 at −78°C and, fol-
Scheme 4.

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J. E. Clare et al. / Tetrahedron Letters 44 (2003) 8153–8156
3. (a) Mulzer, J.; Zuhse, R.; Schmiechen, R. Angew. Chem.
Int. Ed. Engl. 1992, 31, 870–872; (b) Aslanian, R.; Lee, G.;
Iyer, R. V.; Shih, N.-Y.; Piwinski, J. J.; Draper, R. W.;
McPhail, A. T. Tetrahedron: Asymmetry 2000, 11, 3867–
3871; (c) Palomo, C.; Aizpurua, J. M.; Oiarbide, M.;
Garcia, J. M.; Gonzalez, A.; Odriozola, I.; Linden, S. A.
Tetrahedron Lett. 2001, 42, 4829–4831; (d) Rimkus, A.;
Sewaid, N. Org. Lett. 2002, 4, 3289–3291. For reviews see:
(e) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877–1894; (f) Barrett, A. G. M. Chem. Soc.
Rev. 1991, 20, 95–127.
4. Brenner, M.; Seebach, D. Helv. Chim. Acta 1999, 82,
2365–2379.
5. LeSann, C.; Simpson, T. J.; Smith, D. I.; Watts, P.; Willis,
C. L. Tetrahedron Lett. 1999, 40, 4093–4096.
Figure 1. X-Ray structure of 16.
6. Nitroalcohols were prepared by the method of Lucet, D.;
Sabelle, S.; Kostelitz, O.; LeGal, T.; Mioskowski, C. Eur.
J. Org. Chem. 1999, 2583–2591; nitroalkenes were pre-
pared according to the method of Denmark, S. E.;
Schuter, E. J. Org. Chem. 1995, 60, 1013–1019.
7. General procedure for conjugate addition: sultam (1
equiv.) in CH2Cl2 (0.3 M) was cooled to −78°C under N2.
TiCl4 (1.0M in CH2Cl2, 2 equiv.) was added and the yellow
solution stirred for 10 minutes. Triethylamine (1.2 equiv.)
was added dropwise to give a dark red suspension and the
mixture stirred for 30 minutes. The nitroalkene (2 equiv.)
was taken up in CH2Cl2 (3 M) then added dropwise to the
reaction mixture. After stirring for 4.5 hours at −78°C the
reaction was quenched and worked up by one of the
following methods.
asymmetric centres in >98% de and 70% yield (based
upon recovered starting material, 60% isolated yield).
The product 16 was crystallised from toluene and X-ray
crystallography confirmed the stereochemical outcome
of the reaction (Fig. 1).9
In conclusion, we have shown that the titanium tetra-
chloride promoted reaction of acylated camphor sul-
tams with nitroalkenes in the presence of base gives
good yields of addition products and the creation of
new asymmetric centres with excellent stereocontrol.
We have also demonstrated that the work-up procedure
has a significant effect on the yields of the isolated
products.
Workup A: The reaction mixture was quenched at −78°C
with saturated aqueous NH4Cl. The organic layer was
separated and the aqueous layer extracted with CH2Cl2.
The combined organic fractions were washed with water
and brine, dried over MgSO4 and concentrated in vacuo to
yield the crude nitronate. Purification by column chro-
matography eluting with increasing percentage of EtOAc
in light petroleum gave the addition product.
Acknowledgements
We are grateful to the EPSRC and GSK for funding to
J.E.C.
Workup B: The reaction mixture was quenched at −78°C
with aqueous 20% NH4F. The organic layer was separated
and the aqueous layer extracted with CH2Cl2. The com-
bined organic layers were washed with water and brine,
dried over MgSO4 and concentrated in vacuo to yield the
crude product. Recrystallisation from methanol gave the
addition product.
References
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