Lewis acid-promoted hetero Diels-Alder cycloaddition of α-acetoxynitroso dienophiles

Article abstract of DOI:10.1021/ol0491336

(Equation Presented) α-Acetoxynitroso compound 3 has been prepared as a new stable, isolable, and reactive dienophile in nitroso Diels-Alder reactions. The yield of the [4 + 2] cycloaddition of α-acetoxynitroso dienophile with 1,3-dienes could be enhanced in the presence of 20 mol % Lewis acid. An unexpected retro hetero-Michael reaction from 26 was observed, leading to the cleavage of the N-O bond of the cycloadduct. This tandem nitroso Diels-Alder/retro hetero-Michael sequence has been used with cyclic and acyclic 1,3-dienes.

Full text of DOI:10.1021/ol0491336

ORGANIC
LETTERS
2
004
Vol. 6, No. 14
449-2451
Lewis Acid-Promoted Hetero Diels−Alder
Cycloaddition of r-Acetoxynitroso
Dienophiles
2
G e´ raldine Calvet, Marion Dussaussois, Nicolas Blanchard, and
Cyrille Kouklovsky*
Laboratoire de Synth e` se des Substances Naturelles, Institut de Chimie Mol e´ culaire et
des Mat e´ riaux d’Orsay, Batiment 410, UniVersit e´ Paris Sud, 91400 Orsay-France
cykouklo@icmo.u-psud.fr
Received May 12, 2004
ABSTRACT
r-Acetoxynitroso compound 3 has been prepared as a new stable, isolable, and reactive dienophile in nitroso Diels−Alder reactions. The yield
of the [4 + 2] cycloaddition of r-acetoxynitroso dienophile with 1,3-dienes could be enhanced in the presence of 20 mol % Lewis acid. An
unexpected retro hetero-Michael reaction from 26 was observed, leading to the cleavage of the N−O bond of the cycloadduct. This tandem
nitroso Diels−Alder/retro hetero-Michael sequence has been used with cyclic and acyclic 1,3-dienes.
6
2e,g,h
The hetero Diels-Alder reaction is a powerful transforma-
tion, allowing rapid and stereoselective access to complex
heterocyclic structures. This particular class of nitroso Diels-
Swern conditions (Scheme 1, A). Ruthenium-,
iridium-
2
f
2c
, and copper-catalyzed hydrogen peroxide oxidations of
hydroxamic acids emerged recently as alternatives (Scheme
1
Alder cycloadditions affords the corresponding 3,6-dihydro-
1
,2-oxazine 1, a valuable building block in the context of
(
2) (a) Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126,
4
2
128-4129. (b) Ding, X.; Ukaji, Y.; Fujinami, S.; Inomata, K. Chem. Lett.
003, 32, 582-583. (c) Pulacchini, S.; Sibbons, K. F.; Shastri, K.; Motevalli,
total synthesis of natural or biologically active products. Until
very recently, this class of cycloadditions was resistant to
asymmetric catalysis despite an increasing number of reports
adressing this problem. In the case of acylnitroso dienophiles
2
M.; Watkinson, M.; Wan, H.; Whiting, A.; Lightfoot, A. P. Dalton Trans.
2003, 2043-2052. (d) Lightfoot, A. P.; Pritchard, R. G.; Wan, H.; Warren,
J. E.; Whiting, A. Chem. Commun. 2002, 2072-2073. (e) Flower, K. R.;
Lightfoot, A. P.; Wan, H.; Whiting, A. J. Chem. Soc., Perkin Trans. 1 2002,
2058-2064. (f) Iwasa, S.; Fakhruddin A.; Tsukamoto, Y.; Kameyama, M.;
Nishiyama, H. Tetrahedron Lett. 2002, 43, 6159-6161. (g) Iwasa, S.;
Tajima, K.; Tsushima, S.; Nishiyama, H. Tetrahedron Lett. 2001, 42, 5897-
2
(Scheme 1), these efforts have been hampered by the very
high reactivity of the nitroso moiety, as recently demonstrated
by time-resolved IR spectroscopy. Acylnitroso derivatives
3
5
899. (h) Flower, K. R.; Lightfoot A. P.; Wan, H.; Whiting, A. Chem.
2
are mostly obtained from hydroxamic acids by oxidation
Commun. 2001, 1812-1813. (i) Nakash, M.; Clyde-Watson, Z.; Feeder,
1
j,4
Dess-Martin periodinane,5 or under
N.; Davies, J. E.; Teat, S. J.; Sanders, J. K. M. J. Am. Chem. Soc. 2000,
with periodates,
1
22, 5286-5293. (j) Zhang, D.; S u¨ ling, C.; Miller, M. J. J. Org. Chem.
1998, 63, 885-888. (k) Meekel, A. A. P.; Resmini, M.; Pandit, U. K. Bioorg.
(1) (a) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317-1348. (b)
Med. Chem. 1996, 4, 1051-1057.
Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1-120. (c) Streith,
J.; Defoin, A. Synlett 1996, 189-200. (d) Kibayashi, C.; Aoyagi, S. Synlett
(3) Lifetime of 2 in organic solutions was estimated on the order of 1
ms before being trapped by 1,3-cyclohexadiene: Cohen, A. D.; Zeng, B.-
B.; King, S. B.; Toscano, J. P. J. Am. Chem. Soc. 2003, 125, 1444-1445.
(4) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc., Chem. Commun. 1973,
704-705. Emery, T.; Neilands, J. B. J. Am. Chem. Soc. 1960, 82, 4903-
4904.
1
995, 873-879. (e) Zuman, P.; Shah, B. Chem. ReV. 1994, 94, 1621-
1
641. (f) Streith, J.; Defoin, A. Synthesis 1994, 1107-1117. (g) Waldmann,
H. Synthesis 1994, 535-551. (h) Weinreb, S. M.; Staib, R. R. Tetrahedron
1
982, 38, 3087-3128. (i) Weinreb, S. M. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: New York, 1991; pp 401-512. (j) Kirby, G. W. Chem. Soc. ReV.
1
(5) Jenkins, N. E.; Ware, R. W., Jr.; Atkinson, R. N.; King, S. B. Synth.
Commun. 2000, 30, 947-953. See also ref 1a.
(6) Martin, S. F.; Hartmann, M.; Josey, J. A. Tetrahedron Lett. 1992,
33, 3583-3586.
977, 6, 1-24. For a recent theoretical study, see: Leach, A. G.; Houk, K.
N. J. Org. Chem. 2001, 66, 5192-5200.
1
0.1021/ol0491336 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/16/2004

Scheme 1. Literature Precedent Addressing the (Asymmetric)
Catalytic Nitroso Diels-Alder [4 + 2] Cycloaddition -
Table 1. [4 + 2] Cycloaddition of Heterodienophile 3 with
,3-Cyclohexadiene in the Presence of Various Lewis Acids
2a
c,h
1
entry
Lewis acid
5/6a
yield (three steps, %)b
1
, B). In the presence of a conjugated diene, the intermediate
1
2
3
4
none
Mg(OTf)2
CrCl3
2/98
2/98
2/98
2/98
14
41
41
41
acylnitroso 2 is efficiently trapped to afford the corresponding
hetero Diels-Alder adduct 1. However, the use of enan-
tiopure metal complexes as oxidizing agents did not induce
asymmetry, which tends to indicate that dissociation of the
acylnitroso 2 from the chiral metal complex occurs before
the [4 + 2] cycloaddition.2
Cu(OTf)2
a
1
Ratio determined by integration of the crude H NMR spectra and/or
b
by GC calibrated toward an internal standard (butylphthalate). Isolated
yield.
c,e
Less reactive nitroso dienophiles such as arylnitroso deri-
vatives could be better suited for a Lewis acid-mediated cata-
lysis in the nitroso Diels-Alder cycloaddition as pointed out
loxyiodo)benzenes are easily available,12 this procedure
constitutes an efficient synthesis of sterically and electroni-
cally tunable R-acyloxynitroso compounds.
1c
by Streith. Moreover, several complexes of arylnitroso with
7
metals have been reported in the literature. Disappointingly,
For these preliminary studies, we focused our attention
Lewis acids in general failed to affect the rate of the
arylnitroso cycloaddition with 1,3-cyclohexadiene, as el-
on the R-acetoxynitroso dienophile 3 (Scheme 2). Following
1
3
2c
2a
literature precedent, oxime 4 was prepared in three steps
egantly demonstrated by Whiting. Very recently, Yamamoto
from commercially available trishydroxy-methylnitromethane.
described the catalytic asymmetric nitroso Diels-Alder
reaction of 2-nitrosopyridine derivative in the presence of
When treated with (diacetoxyiodo)-benzene in CH
C, oxime 4 was smoothly transformed into the desired
dienophile 3 in 67% yield after chromatographic purifica-
2 2
Cl at 0
°
10 mol % of a chiral copper(I) complex. Excellent yields
and enantioselectivities up to 92% ee were observed. These
results prompted us to report our own studies in this field.
We decided to address the catalytic version of the nitroso
Diels-Alder [4 + 2] cycloaddition using R-acyloxynitroso
1
4
tion.
With a suitable preparation of 3 in hand, we next examined
the cycloaddition reaction of this dienophile with 1,3-
cyclohexadiene. The background reaction was investigated
first, in the absence of any Lewis acid promoter (Table 1,
entry 1). The crude reaction mixture was very clean,
consisting of only two products, the expected bicyclic
8
9
dienophiles (Scheme 2). The latter have elicited theoretical
Scheme 2. Synthesis of the R-Acetoxynitroso Dienophile 3
2j
15
oxazine 5 and the hydroxycarbamate 6, after acidic
hydrolysis, neutralization, and treatment with Boc O. To our
2
surprise, 5 was only a minor component of the crude reaction
mixture (5/6 > 2:98). This uncatalyzed reaction proved to
be unreproducible, as 6 was isolated in 0-19% yields in
five different runs. Screening of various achiral Lewis acids
revealed that Mg(OTf)
increase the yield of this sequence, allowing access to 6 in
1% isolated yield over three steps (74% average per step,
Table 1, entries 2-4).
The unexpected N-O bond cleavage leading to the
hydroxycarbamate 6 is very interesting from a synthetic point
2 2 3
, Cu(OTf) , and CrCl were able to
and pharmacological studies,10 but, to the best of our
knowledge, have never been used as dienophiles in [4 + 2]
cycloadditions. Conveniently, R-acyloxynitroso could be
synthesized by the reaction between hypervalent iodine
reagents and an oxime.11 Since a large variety of (diacy-
4
16,17
(
12) Merkushev, E. B.; Novikov, A. N.; Makarchenko, S. S.; Moskal’chuk,
(
7) Lee, J.; Chen, L.; West, A. H.; Richter-Addo, G. B. Chem. ReV. 2002,
A. S.; Glushkova, V. V.; Kogai, T. I.; Polyakova, L. G Russ. J. Org. Chem.
1975, 40, 6-1249.
1
1
02, 1019-1065. Cameron, M.; Gowenlock, B. G. Chem. Soc. ReV. 1990,
9, 355-379.
(13) Majewski, M.; Gleave, D. M.; Nowak, P. Can. J. Chem. 1995, 73,
1616-1626.
(
8) Iffland, D. C.; Criner, G. X. Chem. Ind. 1956, 176-177.
(9) Kresze, G.; Mayer, N. M.; Winkler, J. Liebigs Ann. Chem. 1971,
(14) This bright blue compound is stable at room temperature and can
be stored for several months without dimerization to the corresponding
colorless azodioxide derivative.
7
47, 172-190. Caragheorgheopol, A.; Caldararu, H.; Constantinescu, T.;
Em Sahini, V. J. Am. Chem. Soc. 1971, 93, 6766-6769. Just, G.; Dahl, K.
Tetrahedron 1968, 24, 5251-5269.
(15) Hall, A.; Bailey, P. D.; Rees, D. C.; Rosair, G. M.; Whightman, R.
H. J. Chem. Soc., Perkin Trans. 1 2000, 329-343.
(16) Other Lewis acids screened are TiCl4, Ti(Oi-Pr)4, FeCl3, AgBF4,
AgOAc, LiBr, BF3‚OEt2, MgCl2, ZnF2, ZnBr2, ZrCl4, SnCl4, Sn(OTf)2,
PdCl2, Sc(OTf)3, CeCl3, Yb(OTf)3, and Zn(OTf)2. All proved to be inferior
to the Lewis acids listed in Table 1: see Supporting Information.
(10) Rehse, K.; Herpel, M. Arch. Pharm. Pharm. Med. Chem. 1998, 331,
1
04-110.
(
11) This synthesis of R-acetoxynitroso derivatives capitalizes on a
fortuitous observation reported by Moriarty: Moriarty, R. M.; Prakash, O.;
Vavilikolanu, P. R. Synth. Commun. 1986, 16, 1247-1254.
2450
Org. Lett., Vol. 6, No. 14, 2004

Scheme 3. Postulated Mechanism for the Formation of
Compound 6
Scheme 4. Cycloaddition of 3 with Cyclic and Acyclic Dienes
a
b
(
E,E)/(E,Z) ) 65:35. Isolated as a 60:40 mixture.
a Lewis acid would lead to the more common N-binding
mode. Moreover, the presence of an ester moiety in the
R-position should favor the formation of a six-membered
chelate 21 (Scheme 5). Studies to clarifiy the role of the
of view since it avoids the use of toxic and expensive
18
19
reagents such as Mo(CO)
6
or Na(Hg) amalgam, which
are tradionally used to achieve the N-O bond scission of
the cycloadducts. The formation of 6 could be tentatively
explained (Scheme 3). Compounds 7 and 8 arise from the
Scheme 5. Postulated Lewis Acid Activation of
R-Acetoxynitroso Dienophile 3 in [4 + 2] Cycloaddition
[4 + 2] cycloaddition of R-acetoxynitroso 3 and 1,3-
cyclohexadiene and are thought to be in equilibrium. Acidic
hydrolysis of the acetonide moiety could lead to the 1,3-
diol 9, which could equilibrate to the corresponding enaminol
10. Retro hetero-Michael reaction of 10 followed by hy-
drolysis of the resulting imine and protection of the amino
moiety as a tert-butylcarbamate could then lead to the
observed product 6. Support for this mechanism comes from
the isolation of traces of compound 12, a byproduct of the
reaction. The stereochemistry of 12 has been determined by
Lewis acid in this nitroso Diels-Alder/retro hetero-Michael
sequence are in progress.
20
extensive multinuclear two-dimensional NMR experiments.
Furthermore, when the hydrolysis of the reaction mixture
7/8) was conducted with 20% aqueous NaOH solution,
In conclusion, we have disclosed the use of R-acetoxyni-
troso as a new class of heterodienophile for the nitroso
Diels-Alder reaction. The yield of this [4 + 2] cycloaddition
with electron-rich 1,3-dienes could be enhanced in the
presence of a catalytic amount of Lewis acid. An unexpected
N-O bond cleveage was observed during this study, leading
to synthetically useful amino alcohol derivatives. Extension
of this preliminary work to an asymmetric catalytic version
of the nitroso Diels-Alder is in progress in our laboratory.
(
hydroxycarbamate 6 was isolated in less than 3% yield,
which supported the fact that the N-O bond cleavage is
initiated by deprotection of the acetonide moiety of 7/8.
This nitroso Diels-Alder/retro hetero-Michael sequence
has been applied to cyclic and acyclic 1,3-dienes (13, 15,
17, and 19, Scheme 4). Clean conversion to the correspond-
ing hydroxycarbamates (14, 16, 18, and 20) was observed
in moderate yield over three steps.
Acknowledgment. We thank the Minist e` re de la Recher-
che et de l’Education for a grant (G.C.), the CNRS (UMR
8615), and the Universit e´ Paris-Sud for financial support.
We thank Dr. C. Meyer and Professor Dr. A. Vasella for
fruitful discussions.
R-Acetoxynitroso is expected to be less reactive than
1
acylnitroso 2. On the basis of the coordination chemistry
7
of C-nitroso compounds, we anticipate that the presence of
(
17) The solvent effect was also briefly investigated, and toluene turned
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 3, 5, 6, 12,
out to be superior to trifluorotoluene, nitromethane, acetonitrile, THF, and
CH2Cl2. DMF led only to decomposition products.
(
18) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F.
Tetrahedron Lett. 1990, 31, 3351-3354.
19) Keck, G. E.; Fleming, S.; Nickell, D.; Weider, P. Synth. Commun.
979, 9, 281-286.
20) See Supporting Information.
1
4, 16, 18, and 20. This material is available free of charge
(
via the Internet at http://pubs.acs.org.
1
(
OL0491336
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