Novel intramolecular reactivity of oximes: Synthesis of cyclic and spiro-fused imines

Article abstract of DOI:10.1021/ol0630043

(Chemical Equation Presented) Under conventional heat (135-145°C) or microwave irradiation and 1 equiv of acetic anhydride, ortho-substituted aryl-oximes undergo a novel sp³ C-H activated cyclization to produce the corresponding isoindoles, and

Full text of DOI:10.1021/ol0630043

ORGANIC
LETTERS
2007
Vol. 9, No. 6
981-983
Novel Intramolecular Reactivity of
Oximes: Synthesis of Cyclic and
Spiro-Fused Imines
Ce´cile G. Savarin,* Christiane Grise´, Jerry A. Murry, Robert A. Reamer, and
David L. Hughes
Department of Process Research, Merck Research Laboratories, Merck & Co.,
P.O. Box 2000, Rahway, New Jersey 07065
cecilesaVarin@gmail.com
Received December 12, 2006
ABSTRACT
Under conventional heat (135
novel sp3
H activated cyclization to produce the corresponding isoindoles, and aliphatic oximes afford the corresponding dihydropyrroles.
The cyclization occurs with various substrates in good yield (46 82%) leading to unique spiro-fused and cyclic imines. An initial mechanistic
investigation suggests the reaction occurs via a nitrenium or vinyl nitrene intermediate.
−145 °C) or microwave irradiation and 1 equiv of acetic anhydride, ortho-substituted aryl-oximes undergo a
C−
−
Oximes are useful functional groups which can be easily
prepared from the corresponding ketones.1 They are known
to undergo a number of transformations including Beckmann
rearrangement to afford the corresponding amides,2 Neber
rearrangement to afford amino ketones,3 reductions to the
corresponding amine,4 reductive coupling with a carbonyl
moiety to provide amino alcohols, and enamide formation.5
In addition, Narasaka and co-workers recently described the
palladium- and copper-catalyzed cyclization of olefinic oxime
derivatives to the corresponding dihydropyrroles.6 We were
recently interested in taking advantage of the reaction of
oximes in the presence of acetic acid, acetic anhydride, and
iron to afford the corresponding enamides.7 Specifically, we
required the preparation of acyl enamides from aryl-oximes
having an aliphatic ortho substituent. As we started to
investigate this transformation, we discovered the formation
of a novel byproduct, a spiro-fused imine in which the
nitrogen had formally inserted into the sp3 C-H bond of
the ortho aliphatic substituent (Scheme 1). Given the novelty
of this transformation, we pursued a more detailed study of
this reaction and have now developed a procedure which
provides the C-H insertion product with good yield and
selectivity. In this communication, we wish to report our
results regarding this intriguing cyclization, including its
(1) (a) Bousquet, E. W.; Carothers, W. H.; McEwen, W. L. Organic
Synthesis; Wiley and Sons: New York, 1943; Coll. Vol. II, pp 313-315.
(b) Holmes, A. B.; Smith, A. L.; Williams, S. F.; Hughes, L. R.; Lidert, Z.;
Swithenbank, C. J. Org. Chem. 1991, 56, 1393.
(2) (a) Beckmann, E. Ber. 1886, 19, 988. (b) Donaruma, L. G.; Heldt,
W. Z. Org. React. 1960, 11, 1. (c) For cationic cyclization of oximes:
Gawley, B.; Termine, E. J.; Onan, K. D. J. Chem. Soc., Chem. Commun.
1981, 581.
(3) (a) Verstappen, M. M. H.; Ariaans, G. J. A.; Zwanenburg, B. J. Am.
Chem. Soc. 1996, 118, 35, 8491. (b) Ooi, T.; Takahashi, M.; Doda, K.;
Maruoka, K. J. Am. Chem. Soc. 2002, 124 (26), 7640. (c) Garst, M. E.;
Cox, D. D.; Harper, R. W.; Kemp, D. S. J. Org. Chem. 1975, 40 (8), 1169.
(d) House, H. O.; Berkowitz, W. F. J. Am. Chem. Soc. 1963, 85, 307. (e)
Cram, D. J.; Hatch, M. J. J. Am. Chem. Soc. 1953, 75, 33.
(4) (a) Harrison, J. R.; Moody, C. J.; Pitts, M. R. Synlett 2000, 11, 1601
and references herein. (b) Cho, B. T. Aldrichimica Acta 2002, 35, 1, 3.
(5) Marco-Contelles, J.; Gallego, P.; Rodrigeux-Fernandez, M.; Khiar,
N.; Destabel, C.; Bernabe´, M.; Martinez-Grau, A.; Chiara, J. L. J. Org.
Chem. 1997, 62, 7397 and references herein.
(6) (a) Narasaka, K. Pure Appl. Chem. 2003, 75 (1), 19 and references
cited herein. (b) No metal used: Kitamura, M.; Yoshida, M.; Kikuchi, T.;
Narasaka, K. Synthesis 2003, 15, 2415. (c) Nishimura, T.; Nishiguchi, Y.;
Maeda, Y.; Uemura, S. J. Org. Chem. 2004, 69 (16), 5342.
(7) (a) Barton, D. H. R.; Boar, R. B.; McGhie, J. F.; Robinson, M. J.
Chem. Soc., Perkin I 1975, 1241. (b) Laso, N. M.; Quiclet-Sire, B.; Zard,
S. Z. Tetrahedron Lett. 1996, 37 (10), 1605. (c) Burk, M. J.; Casy, G.;
Johnson, N. B. J. Org. Chem. 1998, 63, 6084. (d) Zhang, X.; Zhu, G. J.
Org. Chem. 1998, 63, 9590. (e) Zhu, G.; Casalnuovo, A. L.; Zhang, X. J.
Org. Chem. 1998, 63, 8100.
10.1021/ol0630043 CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/24/2007

Scheme 1
Table 1. Cyclization of Oximes
scope and limitations, as well as preliminary mechanistic
insights of this novel reaction.
As we were exploring the reactivity of oxime 1a, we
initially observed that treating this compound with acetic
anhydride, iron, and acetic acid at 70 °C for 17 h provided
two main products: the expected enamide 2a and a new
cyclized product 3a. In the presence of iron, varying AcOH
and Ac2O gave different ratios of enamide 2a to spiro-imine
3a. In the absence of iron, 40% of the desired spiro-imine
was isolated with a 4:1 ratio of spiro to enamide while
reacting the oxime in neat Ac2O/pyridine.7a However, when
the reaction was carried out with 3 equiv of acetic anhydride
in refluxing toluene, only the acetate oxime was detected.
In refluxing xylenes (135 °C), the cyclization proceeded in
58% assay yield and no enamide or Beckmann products were
observed. Moreover, no cyclization occurred when the oxime
was heated without additives at 135 °C. These experiments
demonstrate that both acetic anhydride and high temperatures
are necessary for this cyclization to occur.
A survey of the relevant literature revealed a single
example by Lansbury and co-workers8 who reported that
7-alkyl-1-indanone oximes undergo C-H bond insertion
when treated with polyphosphoric acid at 130 °C.9 The
authors speculated that a very strained system prevented the
Beckmann rearrangement from occurring which led to the
observed product via an alternate pathway. Interestingly,
subjecting compound 1a under these conditions provided
only the Beckmann product (Scheme 2). In addition, the use
Scheme 2
b
a Conventional heat at 135 °C. Microwave at 240 °C.
The optimization of the reaction conditions with oxime
1a was undertaken as well as investigation of the scope and
limitations. Various high-boiling solvents (dimethylacetamide
(DMAC), xylenes, dichlorobenzene) worked equally well with
no observable rate difference. We then examined the effect
of the activating anhydrides in the best two solvents. Although
yields were moderate, the reaction was promoted with
phthalic, benzoic, and succinic anhydrides. Acetic anhydride
in DMAC or xylene was the most efficient protocol.
A full equivalent of acetic anhydride is needed for the
reaction to proceed to completion: 0.5 equiv only afforded
of trifluoroacetic anhydride in toluene at 70 °C also only
led to the Beckmann product. However, treating oxime 1b
with 1 equiv of Ac2O cleanly afforded the spiro-imine. This
reaction constitutes an interesting complement to the known
metal-catalyzed C-H amination reactions.10
(8) (a) Lansbury, P. T.; Mancuso, N. R. J. Am. Chem. Soc. 1966, 88 (6),
1205. (b) Lansbury, P. T.; Colson, J. G.; Mancuso, N. R. J. Am. Chem.
Soc. 1964, 86, 5225.
(9) Mittel and co-workers failed in trying to carry out such a cyclization
in refluxing acetic and sulfuric acid: Mittell, I. Ber. 1931, 64B, 71.
(10) (a) For a review: Davies, H. M. L.; Long, M. S. Angew. Chem.,
Int. Ed. 2005, 44, 3518 and references herein. (b) Wehn, P. M.; Du Bois,
J. Org. Lett. 2005, 7 (21), 4685. (c) Espino, C. G.; Fiori, K. W.; Kim, M.;
Du Bois, J. J. Am. Chem. Soc. 2004, 126 (47), 15378. (d) Fiori, K. W.;
Fleming, J. J.; Du Bois, J. Angew. Chem., Int. Ed. 2004, 43 (33), 4349.
982
Org. Lett., Vol. 9, No. 6, 2007

Scheme 3
Scheme 4
32% yield of product. We also observed that as the number
of equivalents of acetic anhydride was increased beyond 2.0
the yield decreased.11
A screen of bases (pyridine, potassium carbonate, Hunig’s
base, KO-t-Bu, imidazole, DBU) and acids (acetic acid and
camphorsulfonic acid) at temperatures between 70 and
135 °C did not lead to improved reaction conditions. High
temperatures were still required for the reaction to proceed
as well as long reaction time.
The cyclization was studied under microwave conditions
using the same solvent and amount of acetic anhydride. This
modification allowed for a more concentrated media (1 mmol
in 3 mL). Under microwave irradiation (240 °C), the cycliza-
tion was complete in 30 min with a clean reaction profile
and good yield (78%). Therefore, the cyclized product can
be obtained in 1-2 days by thermal treatment or in 0.5 h
using microwaves.
With the optimized protocol, the scope of the reaction was
studied by cyclizing various oximes. These oximes are
readily obtained from their corresponding ketone using
known protocols (Table 1).1 Oximes 1a-c with a cyclohexyl
or a cyclopentyl group in ortho positions were cyclized in
efficient yields. However, no desired product was isolated
in the case of the trifluorooxime 1d.12
as samarium diiodide, AIBN, and triethylborane did not
provide the desired cyclized product. Moreover, the use of
a BHT additive in the cyclization did not affect the yield of
cyclization.
The O-acylated oxime intermediate was detected by
HPLC/MS and by NMR, and it was also possible to isolate
this product after treatment with Ac2O. When this isolated
oxime-acetate was heated alone or in the presence of acetic
anhydride, no cyclized product was observed. However,
when the oxime-acetate was heated in the presence of acetic
acid, the spiro compound was observed. From these experi-
ments, we concluded that the oxime-acetate is an intermediate
on the reaction pathway and acetic acid generated from the
acetate formation was essential to the cyclization. Moreover,
the enamide was not an intermediate on the reaction
pathway: no cyclized product was generated when the
enamide was treated with acetic anhydride and acetic acid.
A possible mechanism could involve the formation of a
nitrenium ion or a vinyl nitrene,13 which then inserts into
the proximal C-H bond (Scheme 4).
Of interest, aliphatic oximes 1e and 1f efficiently cyclized
to the corresponding dihydropyrrole. For substrate 1e, no
enamide or Beckmann rearrangement products were observed
while reacting the substrate with 1 equiv of Ac2O. However,
when 1e was submitted to TFAA or neat PPA, only
formation of the Beckmann product was observed with no
trace of dihydropyrrole (Scheme 3).
In summary, a novel reactivity of oximes was uncovered
and investigated. With 1 equiv of acetic anhydride at 135 °C
or under microwave irradiation, ortho-substituted aryl-oximes
undergo a novel sp3 C-H activated cyclization to produce
the corresponding isoindoles in good yields. Moreover, the
obtained products are highly attractive building blocks. The
proposed mechanism involves C-H insertion of the nitre-
nium ion derived from the oxime-acetate intermediate.
Further work to better understand the course of the reaction
as well as the use as key intermediates for the synthesis of
biologically active compounds is presently underway.
One of the possible mechanisms for this cyclization could
involve a radical pathway. However, radical promoters such
(11) The formation of two other side products was also observed. Treating
pure isolated spiro with acetic anhydride at 135 °C also led to these side
products which were identified as the acylated products of the spiro, which
gives further option to functionalize the spiro imine.
(12) In the case of the formation of unsubstituted isoindole (using, for
instance, ethanone, 1-(2-methylphenyl), or oxime), only oxidized products
were obtained. The desired products are reported to be relatively unstable
and easily oxidized. Veber, D. F.; Lwowski, W. J. Am. Chem. Soc. 1964,
86, 4152.
Acknowledgment. We thank Vicky Vydra and Thomas
Novak from Merck Research Laboratories for their help
performing the high-resolution mass spectrometry analysis
and X-ray analysis.
(13) (a) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003, 103, 2905. (b) Kasturi,
T. R.; Jayaram, S. K.; Pragnacharyulu, P. V. P.; Sattigeri, J.; Reddy, G.
M.; Kumar, K. A. Tetrahedron 1993, 49 (1), 113. (c) Kasturi, T. R.; Kumar,
K. A.; Pragnacharyulu, P. V. P. Tetrahedron 1993, 49 (1), 125. (d) Kasturi,
T. R.; Kumar, K. A.; Pragnacharyulu, P. V. P.; Sridevi, G. Tetrahedron
1993, 49 (1), 135.
Supporting Information Available: Experimental details
and characterization for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0630043
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