tert-butyl (phenylsulfonyl)alkyl-N-hydroxycarbamates: The first class of N-(Boc) nitrone equivalents

Article abstract of DOI:10.1021/ol051766c

(Chemical Equation Presented) tert-Butyl (phenylsulfonyl)alkyl-N- hydroxycarbamates 1 have been easily prepared from aldehydes and tert-butyl N-hydroxycarbamate in a methanol-water mixture using sodium benzenesulfinate and formic acid. These sulfones 1 behave as N-(Boc)-protected nitrones 4 in the reaction with organometallics to give N-(Boc)hydroxylamines. Some chemical transformations showing their interest as building blocks in organic synthesis are described.

Full text of DOI:10.1021/ol051766c

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5147-5150
tert-Butyl (Phenylsulfonyl)alkyl-
N-hydroxycarbamates: The First Class
of N-(Boc) Nitrone Equivalents
Xavier Guinchard, Yannick Valle´e, and Jean-Noe1l Denis*
Laboratoire d’Etudes Dynamiques et Structurales de la Se´lectiVite´ (LEDSS),
UJF-CNRS, Institut de Chimie Mole´culaire de Grenoble, UniVersite´ Joseph Fourier,
Grenoble 1, BP 53, 38041 Grenoble Cedex 9, France
jean-noel.denis@ujf-grenoble.fr
Received July 26, 2005
ABSTRACT
tert-Butyl (phenylsulfonyl)alkyl-N-hydroxycarbamates 1 have been easily prepared from aldehydes and tert-butyl N-hydroxycarbamate in a
methanol water mixture using sodium benzenesulfinate and formic acid. These sulfones 1 behave as N-(Boc)-protected nitrones 4 in the
−
reaction with organometallics to give N-(Boc)hydroxylamines. Some chemical transformations showing their interest as building blocks in
organic synthesis are described.
Nucleophilic addition reaction to the carbon-nitrogen double
bond represents a viable and powerful procedure1 to prepare
an exceptionally large range of amino derivatives. Reactivity
of imines strongly depends on the nature of the substituent
directly linked to the nitrogen atom. Imines bearing N-alkyl
or N-aryl groups are easily prepared and stored, but their
reactivity toward nucleophiles is not particularly significant
in most cases.1-3 This lack of reactivity requires the use of
strong organometallic reagents. The basicity of such reagents
often promotes enolization in the N-alkylimines rather than
the expected addition.3 This side reaction is partially sup-
pressed by using imines bearing an electron-withdrawing
group. N-Acyl and N-tosyl groups increase the efficiency of
the addition reaction to imines.4 However, their preparation
is difficult,4b,e,i they are unstable,4a,e,f and/or the removal of
the acyl moiety is frequently difficult requiring harsh
conditions.5 To overcome these synthetic limitations, many
research groups have used N-carbamoylimines,4h,i,6 N-sulfi-
nylimines,7 or N-acyliminium ions.1a,3,8 The electrophilicity
of the imine moiety is therefore enhanced, and a range of
(4) (a) Trost, B. M.; Marrs, C. J. Org. Chem. 1991, 56, 6468-6470. (b)
Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131-134. (c) Sisko, J.;
Weinreb, S. M. J. Org. Chem. 1990, 55, 393. (d) Murry, J. A.; Frantz, D.
E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem.
Soc. 2001, 123, 9696-9697. (e) Chemla, F.; Hebbe, V.; Normant, J.-F.
Synthesis 2000, 75-77. (f) Mecozzi, T.; Petrini, M. Tetrahedron Lett. 2000,
41, 2709-2712. (g) Mecozzi, T.; Petrini, M. Synlett 2000, 73-74. (h)
Ballini, R.; Petrini, M. Tetrahedron Lett. 1999, 40, 4449-4452. (i) Lee, K.
Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2003, 44, 1231-1234.
(5) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(6) (a) Giri, N.; Petrini, M.; Profeta, R. J. Org. Chem. 2004, 69, 7303-
7308. (b) Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, R. Org. Biomol.
Chem. 2003, 1, 4275-4281. (c) Kanazawa, A. M.; Denis, J.-N.; Greene,
A. E. J. Org. Chem. 1994, 59, 1238-1240. (d) Mecozzi, T.; Petrini, M. J.
Org. Chem. 1999, 64, 8970-8972. (e) Petrini, M.; Profeta, R.; Righi, P. J.
Org. Chem. 2002, 67, 4530-4535. (f) Marcantoni, E.; Mecozzi, T.; Petrini,
M. J. Org. Chem. 2002, 67, 2989-2994. (g) Banphavichit, V.; Chaleaw-
lertumpon, S.; Bhanthumnavin, W.; Vilaivan, T. Synth. Commun. 2004,
34, 3147-3160. (h) Mecozzi, T.; Petrini, M.; Profeta, R. J. Org. Chem.
2001, 66, 8264-8267. (i) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem.
Soc. 2002, 124, 12964-12965. (j) Klepacz, A.; Zwierzak, A. Tetrahedron
Lett. 2002, 43, 1079-1080. See also 3.
(1) (a) ComprehensiVe Organic Synthesis; Heathcock, C. H., Ed.;
Pergamon: Oxford, 1991; Vol. 2. (b) Block, R. Chem. ReV. 1998, 98, 1407-
1438. (c) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069-1094.
(2) (a) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42, 1364-
1367. (b) Badorrey, R.; Cativiela, C.; Diaz-de-Villegas, M. D.; Diez, R.;
Galvez, J. A. Eur. J. Org. Chem. 2002, 3763-3767.
(7) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002,
35, 984-995. (b) Viso, A.; Fernandez de la Pradilla, R.; Lopez-Rodriguez,
M. L.; Garcia, A.; Alonso, M. J. Org. Chem. 2004, 69, 1542-1547 and
references therein.
(3) Zhang, J.; Wei, C.; Li, C.-J. Tetrahedron Lett. 2002, 43, 5731-5733.
10.1021/ol051766c CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/12/2005

new nucleophilic addition reactions are allowed. At the same
time, interest in the chemistry of nitrones has grown,9 due
to their enhanced electrophilicity, high stability, and easy
accessibility. During the last years, numerous original nucleo-
philic addition reactions to these powerful tools have been
developed as methods for accessing N-hydroxylamines that
can be further transformed into important nitrogen-containing
compounds. The great majority of the nitrones used in such
reactions bear a benzyl group on the nitrogen atom, which
must be further eliminated in most of the cases by catalytic
hydrogenolysis. These nitrogen-deprotection reactions cannot
be achieved in the presence of hydrogen-sensitive groups
such as carbon-carbon double or triple bonds.10
The N-(tert-butoxycarbonyl) [N-(Boc)] group is an easily
cleavable protecting group allowing preparation of hydrogen-
sensitive amine compounds. We therefore searched for a
method to prepare the unknown N-(Boc) nitrones. However,
all attempts using literature methods11 for the preparation of
classical nitrones failed. During this work, we found that
tert-butyl (phenylsulfonyl)alkyl-N-hydroxycarbamates 1 be-
have as N-(Boc)-protected nitrones in reactions with orga-
nometallic compounds. Herein, we report their preparation
and their reaction with 1-alkynyllithiums and Grignard
reagents.
crystalline solids, which can be stored at room tempera-
ture during several weeks. Alternatively, these compounds
can be prepared by reaction of tert-butyl N-hydroxycar-
bamate with an appropriate aldehyde and phenylsulfinic acid
in CH2Cl2 at room temperature in the presence of
MgSO4.6f
We then attempted to prepare N-(Boc) nitrones 4 from
these sulfones 1 by a base-assisted elimination of phenylsulfi-
nate group.6c When sulfone 1d was treated with K2CO3 in
THF (rt or reflux), with 1 or 2 equiv of n-BuLi in THF at
-78 °C, with NaH in CH2Cl2, or with DBU in THF, all of
1
the starting material was consumed. In the H NMR spec-
tra, we observed the presence of a triplet at 6.7 ppm, which
could correspond to the HCdN proton of the expected
nitrone 4d. However, all attempts to isolate the nitrone failed.
We then decided to prove its existence as a synthetic
intermediate by trapping it with a suitable dipolarophile.
Indeed, reaction of sulfone 1d with dimethyl acetylenedi-
carboxylate in the presence of K2CO3 in THF at reflux led
to the isolation of the 1,3-dipolar cycloadduct 3 (Scheme 1)
in 65% yield.
Scheme 1
Compounds 1 are prepared from aldehydes 2, tert-bu-
tyl N-hydroxycarbamate, and sodium benzenesulfinate in
MeOH/H2O in the presence of formic acid (Table 1).6f,12
Table 1. Yields of Pure Isolated Sulfones 1
The formation of this product proves undoubtedly that
sulfone 1d can suffer a base-assisted elimination of the
phenylsulfonyl group to provide the N-(Boc) nitrone 4d in
the reaction mixture.
We then showed that sulfones 1 are able to react with 2
equiv of alkynyllithiums 5 in THF to give the corresponding
propargylic N-hydroxylamines 6 with good yields (Table 2).
These results show that this reaction can be carried out in
the presence of extra functional groups such as ether, double
bond, trimethylsilyl, and diethyl acetal.
With these results in hands, we could propose the fol-
lowing mechanism: the organometallic reagent initially acts
as a base, converting the starting sulfone 1 into the N-(Boc)
nitrone 4, which then reacts with a second equiv of the
organometallic 5 to afford the addition product.
The major interest in preparing N-(Boc)-protected com-
pounds is that this protecting group is more efficiently
removed than alkyl, acyl, and tosyl groups. Moreover, the
a Reaction carried out in THF/H2O. b Yield obtained with 1 equiv of
aldehyde. c Reaction carried out with PhSO2H. d dr (50/50).
These derivatives are isolated by simple filtration of the
reaction mixture with good yields. Sulfones 1 are stable
(10) We partially solved this problem by using methoxy-substituted
benzylnitrones as electrophilic reagents followed by a sequential protection-
deprotection sequence. See: Dagoneau, C.; Denis, J.-N.; Valle´e, Y. Synlett
1999, 602-604.
(11) Merino, P. In Science of Synthesis; Padwa, A., Ed.; Georg Thieme
Verlag: Stuttgart, 2004; Vol. 27, Chapter 13, pp 511-580.
(12) Rawson, G.; Engberts, J. B. F. N. Tetrahedron 1970, 26, 5653-
5664.
(8) (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817-
3856. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431-1628.
(9) (a) Merino, P. C. R. Chimie 2005, 8. (b) Lombardo, M.; Trombini,
C. Synthesis 2000, 759-774. (c) Merino, P.; Franco, S.; Merchan, F. L.;
Tejero, T. Synlett 2000, 442-454.
5148
Org. Lett., Vol. 7, No. 23, 2005

However, if necessary, the reduction of the N-O bond in
compound 6g was achieved with SmI2 in THF in the presence
of H2O.16 Depending on the conditions, it has been possible
to obtain selectively either compound 9 or 10, in 73% and
57% yield, respectively (Scheme 4).
Table 2. Yields of Pure Isolated Products 6a-s
Scheme 4
We then examined the reactivity of tert-butyl (phenylsul-
fonyl)alkyl-N-hydroxycarbamates 1 toward Grignard reagents
such as vinyl- and allylmagnesium bromides. These reactions
have been successfully applied to sulfones 1d and 1g used
as models. We observed that the effects of the solvent and
the temperature were dramatic in these reactions. Indeed,
when the reaction of 2 equiv of vinylmagnesium bromide
was performed with 1 equiv of the sulfone 1d into THF,
CH2Cl2, or toluene, at either 0 °C or lower, product 13a was
obtained with low yields (17-50%). In all cases, it was
contamined by the byproduct 11. The best result was obtained
by using toluene as the solvent, at room temperature for 45
min, with 3 equiv of Grignard reagent, leading to product
13a in 83% yield (Scheme 5) with no traces of byproduct
a 3 equiv of alkynyllithium was used. b dr (50/50).
chemistry of nitrones provides an oxygen atom which could
be useful for further transformations. For example, the
N-hydroxyamino compound 6e can be transformed into 2,3-
dihydroisoxazole 7 by palladium-mediated cyclization13 in
85% yield as shown in Scheme 2.
Scheme 5
Scheme 2
Moreover, treatment of the protected coupound 6g by a
8% methanolic solution of HCl14 afforded quantitatively the
propargylic primary N-hydroxylamine 8 (Scheme 3). Until
11. These conditions have been successfully applied to the
sulfone 1g, leading to product 13b with 71% yield.
Scheme 3
(13) Stoner, E. J.; Roden, B. A.; Chemburkar, S. Tetrahedron Lett. 1997,
38, 4981-4984. For another synthesis of isoxazolines, see: Aschwanden,
P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2, 2331-2333.
(14) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1997, 8, 2381-2401.
(15) (a) Fassler, R.; Franz, D. E.; Oetiker, J.; Carreira, E. M. Angew.
Chem., Int. Ed. 2002, 41, 3054-3056. (b) Knight, D.; Leese, M. P.
Tetrahedron Lett. 2001, 42, 2593-2595.
(16) Masson, G.; Cividino, P.; Py, S.; Valle´e, Y. Angew. Chem., Int.
Ed. 2003, 42, 2265-2268.
now, only rare reactions have allowed direct access to
primary propargylic N-hydroxylamines.15
Org. Lett., Vol. 7, No. 23, 2005
5149

Allylation reaction has been carried out under the same
conditions (Scheme 6). The homoallylic N-hydroxylamine
N-(Boc)-protected propargylic, allylic, and homoallylic hy-
droxylamines 6, 13, and 14 in good yields. We showed that
these compounds are powerful building blocks in organic
synthesis by reporting their transformations into 2,3-dihy-
droisoxazole 7, primary N-hydroxylamine 8, N-(Boc)-pro-
pargylic amine 9, and N-(Boc)-R,â-ethylenic amine 10. We
are currently studying the reactivity of sulfones 1 toward
other reagents.
Scheme 6
Acknowledgment. We thank the “Association de la
Recherche contre le Cancer” (ARC) for financial support.
This research was supported by a grant from the “Ministe`re
de la Jeunesse, de l’Education Nationale et de la Recherche”
to X.G.
14 was obtained in 50% yield. It was contamined by the
side product 12 (25% yield).
In summary, we have developed the first synthesis of tert-
butyl (phenylsulfonyl)alkyl-N-hydroxycarbamates 1. We
have demonstrated that these compounds are suitable precur-
sors of N-(Boc) nitrones by means of a 1,3-dipolar cycload-
dition. We then have studied their reactions with alkynyl-
lithiums 5, vinyl- and allylmagnesium bromides, affording
Supporting Information Available: Experimental pro-
cedures and full characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051766C
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Org. Lett., Vol. 7, No. 23, 2005