Oxime derivatives as α-electrophiles. from α-tetralone oximes to tetracyclic frameworks

Article abstract of DOI:10.1021/ol2012204

When subjected to the conditions of a Semmler-Wolff/Schroeter aromatization, the oximes of 4-benzyl-substituted tetralones undergo an electrophilic aromatic substitution reaction to form tetracyclic frameworks.

Full text of DOI:10.1021/ol2012204

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3266–3269
Oxime Derivatives as r-Electrophiles.
From r-Tetralone Oximes to Tetracyclic
Frameworks
ꢀ
Beatrice Quiclet-Sire,* Nina Tolle, Syeda Nahid Zafar, and Samir Z. Zard*
€
ꢁ
Laboratoire de Synthese Organique, CNRS UMR 7652 Ecole Polytechnique, 91128
Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received May 8, 2011
ABSTRACT
When subjected to the conditions of a SemmlerÀWolff/Schroeter aromatization, the oximes of 4-benzyl-substituted tetralones undergo an
electrophilic aromatic substitution reaction to form tetracyclic frameworks.
Various synthetic applications for oximes have been
reported since their first application to the identifica-
tion of ketones and aldehydes in the late 19th century.1
The Beckmann rearrangement of ketoximes is a classi-
cal textbook reaction, which has found widespread
utility.2 Oximes are known to react as O or N nucleo-
philes,3 and their use as CdN electrophiles has been
reported.4 Additionally, their CÀH acidity is often
sufficient for R-alkylation-reactions, and coordination
of transition metal atoms can lead to a β-CÀH activa-
tion through cyclopalladation reactions for example.5
A lesser known reaction is the aromatization under
acidic conditions of oximes derived from R,β-unsatu-
rated cyclohexanones, first described by Semmler and
Wolff and later extended to oximes of R-tetralones by
Schroeter and his collaborators.6
A few years ago, we devised a concise route to
R-tetralones7 based on the radical xanthate transfer
technology8 and applied it to the total synthesis of
a number of natural products such as norpar-
vulenone, O-methyl asparvenone, and shinanolone.9
We also found that R-tetralones 3, obtained by the
(6) (a) Semmler, W. Ber. Dtsch. Chem. Ges. 1892, 25, 3352. (b) Wolff,
L. Justus Liebigs Ann. Chem. 1902, 322, 351. (c) Schroeter, G.; Gluschke,
€
A.; Gotzky, S.; Huang, J.; Irmisch, G.; Laves, E.; Schrader, O.; Stier, G.
Ber. Dtsch. Chem. Ges. 1930, 63, 1308.
(7) Liard, A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z. Tetrahedron
Lett. 1997, 38, 1759.
(8) For reviews of the xanthate transfer chemistry, see: (a) Zard, S. Z.
Angew. Chem., Int. Ed. 1997, 36, 672. (b) Zard, S. Z. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim,
2001; Vol. 1, p 90. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.;Eur. J. 2006,
12, 6002. (d) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264,
201. (e) Zard, S. Z. Aust. J. Chem. 2006, 59, 663. (f) Zard, S. Z. Org.
Biomol. Chem. 2007, 5, 205. (g) Quiclet-Sire, B.; Zard, S. Z. Pure Appl.
Chem. 2011, 83, 519.
(9) (a) Cordero Vargas, A.; Quiclet-Sire, B.; Zard, S. Z Org. Lett.
2003, 5, 3717. (b) Cordero Vargas, A.; Quiclet-Sire, B.; Zard, S. Z.
Tetrahedron Lett. 2004, 45, 7355. (c) Cordero-Vargas, A.; Quiclet-Sire,
B.; Zard, S. Z. Org. Biomol. Chem. 2005, 3, 4432. (d) Cordero-Vargas,
A.; Quiclet-Sire, B.; Zard, S. Z. Bioorg. Med. Chem. 2006, 14, 6165. (e)
Petit, L.; Zard, S. Z. Chem. Commun. 2010, 46, 5148.
(1) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988.
(2) (a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1888, 19, 988. For
reviews see:(b) Donaruma, L. G.; Held, W. Z. Org. React. 1960, 11, 1. (c)
Gawley, R. E. Org. React. 1988, 35, 14.
(3) Smith, P. A. S.; Robertson, J. E. J. Am. Chem. Soc. 1962, 84, 1197.
(4) (a) Yoshida, M.; Uchiyama, K.; Narasaka, K. Heterocycles 2000,
52, 681. (b) Hoch, J. Compt. Rend. 1934, 198, 1865. (c) Campbell, K. N.;
McKenna, J. F. J. Org. Chem. 1939, 4, 198. (d) Rodriques, K. E.; Basha,
A.; Summers, J. B.; Brooks, D. W. Tetrahedron Lett. 1988, 29, 3455.
(5) Dunina, V. V.; Zalevskaya, O. A.; Potapov, V. M. Russ. Chem.
Rev. 1988, 57, 250.
r
10.1021/ol2012204
Published on Web 05/26/2011
2011 American Chemical Society

additionÀcyclization of an S-phenacyl xanthates 1 to
vinyl acetate or vinyl pivalate, underwent facile aroma-
tization upon heating with acid to give the correspond-
ing naphthols 4 (Scheme 1).10
Table 1. Synthesis of R-Tetralone Oximes 7aÀm
Scheme 1. Unexpected Formation of a Tetracyclic Product
entry
yield 5 [%]
yield 6 [%]
yield 7 [%]
a
b
c
d
e
f
83
87
86
72
55
62
48
48
50
48
42
32
51
53
51
54
57
95
94
94
76
78
87
83
81
98
98
92
96
88
69
a
To complement this very effective synthesis of naphthols
(and naphthalenes, more generally), we contemplated
applying the SemmlerÀWolff/Schroeter reaction to obtain
R-naphthylamines. We therefore prepared R-tetralone
6a by addition of xanthate 1a to allylbenzene, and the
resulting adduct 5a was ring closed by exposure to stoi-
chiometric amounts of lauroyl peroxide. The correspond-
ing oxime 7a was then heated to 80 °C for 40 min in neat
acetic anhydride to form the O-acetate 8a, followed by
addition of a mixture of acetic and methanesulfonic acid
and heating to 130 °C for 30 min. We were surprised to
find after purification of the crude mixture that the major
product was not the expected N-acetyl naphthylamide
9a (32%) but tetracyclic compound 10a, isolated in
52% yield.
In order to explore the scope of this new transforma-
tion, we prepared variously substituted R-tetralone
oximes 7bÀm by the same three-step sequence outlined
in Scheme 1 for the parent substrate 7a. The structures
and yields are summarized in Table 1. Exposure of these
oximes to the combination of acetic anhydride and
acetic acid/methanesulfonic acid under the same con-
ditions previously used for 7a furnished the corre-
sponding tetracyclic ketones 10bÀm after workup in
addition to variable amounts of the N-acetyl-naphthy-
lamines 9 resulting from the normal Schroeter reaction
(Table 2).
g
h
i
96
a
a
a
j
k
l
89
85
87
m
a One pot procedure from 1/14 to 6.
In most cases, the yield of the tetracyclic ketone was of
the order of 40À50%, and it was shown for several
examples that the corresponding N-acyl-naphthylamine
constituted most of the material balance. The presence
of electron-donating methoxy groups caused significant
erosion in the yield (entries b, dÀe). The effect was most
noticeable when the methoxy group was attached to the
pendent aromatic ring (entries cÀe). Furthermore, the
reactions were not clean for these cases. Numerous side
products were observed, which appeared to result from
FriedelÀCrafts acylation of both the starting material
and the tetracyclic ketone and N-acetyl-naphthylamine
products. Indeed, the products of the electrophilic aro-
matic substitution reaction of 7c could be characterized
as the monoacetylated tetracycles 10ci (R3 = H, R5 =
acetyl) and 10cii (R5 = H, R3 = acetyl) in a ratio of 7:3.
Furthermore, model experiments showed that the treat-
ment of (3,4-dimethoxyphenyl)acetic acid or 4-allyl-1,2-
dimethoxybenzene under the reaction conditions re-
sulted in complete conversion into the mono-, di-, and
ꢀ
(10) Cordero-Vargas, A.; Perez-Martin, I.; Quiclet-Sire, B.; Zard,
S. Z. Org. Biomol. Chem. 2004, 2, 3018.
Org. Lett., Vol. 13, No. 12, 2011
3267

the SemmlerÀWolff/Schroeter reaction. However, the
presence of a pendant aromatic ring opens up another
reaction pathway involving a FriedelÀCrafts reaction and
leading to acetylimine 13. Hydrolysis during a basic work-
up would finally give rise to ketone 10.
Table 2. Influence of the Electronic Nature of the Aromatic
Rings on the Ratio of the Products 9 and 10, Respectively
Scheme 2. Proposed Mechanism of the Electrophilic Aromatic
Substitution Reaction
Evidence for such a pathway was obtained by mod-
ifying the workup procedure to avoid as much as
possible the hydrolysis of intermediate 13j. Thus, by
diluting the crude reaction mixture with methanol, a
very brief treatment with aqueous sodium bicarbonate
followed by separation of the organic layer, drying,
evaporation, and rapid chromatography furnished
N-acetylimide 13j in 34% yield.
The use of unsubstituted oximes as precursors of R-
electrophiles in a CÀC-bond formation process is unpre-
cedented as far as we can tell. The closest analogy is in a
very recent report by the group of Miyata, where reaction
of a cyclic N-alkoxy enamine with trialkyl- or triaryl-
aluminum reagentsresults inR-alkylationorR-arylation.11
Tetracyclic frameworks such as those present in 10 are
very rare. Two syntheses, depicted in Scheme 3, have been
reported so far. Both rely on intramolecular FriedelÀ-
Crafts reactions. The first, by Roberts and co-workers,12
involves generation of the requisite intermediate cation by
a hydride transfer from tetralin 16 and furnishes 2,3:6,7-
dibenzobicyclo[3.3.1]nona-2,6-diene 17. The second, by
Stetter and Reischl, hinges on a more classical double
a Complex mixture of byproducts. b Two acetylated products: 10ci
(R3 = H, R5 = acetyl): 10cii (R5 = H, R3 = acetyl) = 7:3. c After
reacetylation of the crude product.
triacetylated compounds along with noncharacterized
degradation products.
A plausible mechanism accounting for the formation of
tetracyclic derivatives 10 is displayed in Scheme 2 for the
case of 10j. The combination of acetic anhydride and
methanesulfonic acid is sufficiently powerful to further
acetylate oxime acetate 8 to give intermediate 11, which is
in equilibrium with enamide 12. This reaction is almost
certainly reversible and may not be complete. Enamide 12
normally would evolve into N-acetyl naphthylamide 9 by
(11) Miyoshi, T.; Miyakawa, T.; Ueda, M.; Miyata, O. Angew.
Chem., Int. Ed. 2011, 50, 928.
(12) Roberts, R. M.; Anderson, G. P.; Khalaf, A. A.; Low, C.-E.
J. Org. Chem. 1971, 36, 3342.
(13) (a) Stetter, H.; Reischl, A. Chem. Ber. 1960, 93, 791. (b)
Makosza, M. Roczniki Chemii 1967, 41, 1037.
3268
Org. Lett., Vol. 13, No. 12, 2011

intramolecular FriedelÀCrafts reaction to generate the
central bicyclic scaffold in diketone 21.13
Despite the modest yields, due mostly to the existence
of the competing normal Schroeter reaction, the pre-
sent approach is short, convergent, and flexible. It
allows a rapid entry to variously susbstituted tetra-
cyclic ketones not readily accessible otherwise. But
perhaps more importantly, this work brings to the
fore an aspect of oxime reactivity hitherto unappreci-
ated, and this could have more far reaching synthetic
consequences.
Scheme 3. Synthetic Routes to Symmetric Tetracycles 3 and 7
Acknowledgment. We dedicate this paper with re-
spect and admiration to Professor Andrew S. Kende
(University of Rochester). We thank Ecole Polytech-
nique and SFERE for financial support to N.T. and
S.N.Z.
Supporting Information Available. Experimental pro-
cedures, full spectroscopic data and copies of 1H and 13
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 13, No. 12, 2011
3269