Letter Cite This: Org. Lett. 2018, 20, 1884−1887
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Base-Mediated Fragmentation of Bicyclic Dihydro-3,6-oxazines: Transformation of Nitroso Diels−Alder Cycloadducts Rémy Campagne,‡ Friederike Schak̈ el,†,‡ Régis Guillot, Valérie Alezra,* and Cyrille Kouklovsky* Institut de Chimie Moléculaire et des Matériaux d’Orsay, UMR CNRS No. 8182, Univ. Paris-Sud, Université Paris-Saclay, F-91405 Orsay, France S Supporting Information *
ABSTRACT: Nitroso Diels−Alder cycloadditions of benzene oxide with various acyl-nitroso derivatives are described. Treatment of these cycloadducts with methyllithium results in a fast fragmentation reaction, leading to highly functionalized cyclic amino alcohols. The mechanism of the reaction and the role of the epoxide in the fragmentation process are investigated. The reaction proceeds via the formation of an unsaturated imine, which tautomerizes to an enamine if no neighboring epoxide is present.
H
formations and possess interesting synthetic potential. Therefore, 1 was synthesized in three steps according to the literature procedure (Scheme 1): bromination of 1,4-cyclohexadiene gave
eterocyclic structures bearing heteroatom−heteroatom bonds are valuable synthetic intermediates that have been widely used in the synthesis of natural products. A particular focus has been made on nitrogen−oxygen bond-containing compounds that are obtained via heterocycloaddition processes or other strategies, especially 3,6-dihydro-2H-oxazines, which are obtained via nitroso Diels−Alder cycloadditions.1 In most cases, cleavage of the nitrogen−oxygen bond is undertaken just after cycloaddition to unmask the amino and hydroxyl (or carbonyl) functions (Figure 1). Although reductive cleavage is mostly
Scheme 1. Synthesis of Benzene Oxide 1 and Its Cycloadditions with Acyl-Nitroso Derivatives
dibromide 2, which was oxidized with m-CPBA to give the stable epoxide 3. Treatment of 3 with DBU at room temperature afforded target diene 1. However, the volatility of 1 prevented any isolation or purification; therefore, crude 1 was treated with various acyl-nitroso derivatives (prepared in situ by periodate oxidation of N-acyl hydroxylamines). The results are summarized in Scheme 1. Cycloadducts 4a−d were obtained in good overall yields as single diastereomers. The relative configurations of 4a were determined by X-ray diffraction and proved to be anti, with the dienophile attacking from the face opposite the epoxide.8 Our initial goal was to study the regioselectivity of the addition of organometallic reagents onto the epoxide function. Thus, cycloadduct 4a was treated with excess methyllithium in THF at 0 °C. A fast reaction occurred, leading to the formation of two products, 5a and 6 (together with decomposition products), which were not identified as products from addition of the epoxide (Scheme 2). With both compounds being crystalline, the
Figure 1. General methods for N−O bond cleavage in 3,6-dihydro-2Hoxazines.
employed,2 many alternative methods based on fragmentation3 or elimination4 reactions have also been developed for substrates that are sensitive toward reductive conditions.5 Herein, we report a new base-mediated fragmentation of nitroso Diels−Alder cycloadducts of benzene oxide. Benzene oxide 1 was first described by Vogel and co-workers who synthesized it in three steps from 1,4-cyclohexadiene.6 Its reactivity as a diene in Diels−Alder reactions was later investigated with N-phenylmaleimide.7 Although 1 has been less used than other benzene 1,2-diol derivatives as functionalized cyclohexadiene for cycloaddition reactions, we anticipated that its reaction with heterodienophiles could lead to highly functionalized products that could undergo selective trans© 2018 American Chemical Society
Received: February 5, 2018 Published: March 9, 2018 1884
DOI: 10.1021/acs.orglett.8b00426 Org. Lett. 2018, 20, 1884−1887
Letter
Organic Letters
submitted to the same reaction conditions. Methyl carbamate 4b gave a clean reaction, with side product 6 being obtained in trace amounts. However, a mixture of 1,2- and 1,4-addition products 5b and 7b was obtained.10 The best results were observed with the Boc-protected substrate 4c, which gave the 1,2-addition compound 5c in high yield and excellent selectivity (Table 1).
Scheme 2. Outcome of the Methylithium Reaction with Cycloadduct 4a
Table 1. Product Distribution in the Fragmentation Reaction of Carbamate-Protected Cycloadducts 4b,c structures and stereochemistry of 5a and 6 were assigned on the basis of X-ray diffraction data: 5a arises from N−O bond cleavage and addition of a second equivalent of methyllithium onto a transient imine, whereas compound 6 is an acyclic conjugated oxime, in which the addition of another equivalent of methyllithium also occurred. This intriguing result prompted us to investigate the mechanism of the reaction and explain the formation of both products. The postulated mechanism for the formation of compound 5a is depicted in Scheme 3: coordination of methyllithium to the
a
entry
R
yield (%)
5/7
dr 5a
dr 7a
1 2
CO2Me (4b) Boc (4c)
64 80
2/1 4/1
99/1 93/7
99/1 99/1
Determined by 1H NMR analysis of the crude product.
Having given the best yields and selectivities, the Bocprotected cycloadduct was selected for screening of reaction conditions. As methyllithium was used in the process both as base and as nucleophile, other organometallic reagents were screened. However, Grignard reagents or cuprates were not basic enough to ensure deprotonation of 4c; even a mixture of methyllithium and methyl Grignard reagent (1 equiv of MeLi with 1.5 equiv of MeMgBr) gave only unreacted starting material. Thus, the use of strongly basic organometallic reagents, such as organolithium derivatives, was necessary to ensure fragmentation reaction. The outcome of addition of other organolithium reagents was next examined (Table 2). Although the addition of n-
Scheme 3. Postulated Mechanism for the Formation of Compound 5a
acetyl group assists deprotonation of the neighboring carbon at the bridgehead position; a β-elimination then occurs, which results in the cleavage of the N−O bond, and formation of an Nacylimine, which undergoes addition of a second equivalent of methyllithium. Attack of the nucleophile occurs anti to the epoxide ring, giving a single diastereomer. It is noteworthy that the epoxide function is preserved throughout the reaction.9 The formation of conjugated oxime 6 was difficult to rationalize, however; the absence of the acetyl group in 6 suggests base-mediated deacylation of 5a as the first step; therefore, a mechanism was proposed in which epoxide opening to an enolate, followed by β-elimination, leads to an oxime and an aldehyde, with the latter undergoing further addition of methyllithium (Scheme 4). The low yield of 5a, together with the formation of side products, such as 6, proved that the acetyl function was not appropriate for the fragmentation reaction. Therefore, compounds 4b,c bearing carbamate protecting groups were
Table 2. Scope of the Fragmentation Reaction with Different Organolithium Reagents
entry
R
temp (°C)
yield (%)
5/7
dr 5c
1 2 3 4
Me nBu tBu Ph
0 −78 −78 −78 to 0
80 64 0a 0b
4/1 1/4
99/1 99/1
a
Decomposition. bStarting material was recovered. cDetermined by 1H NMR analysis of the crude product.
Scheme 4. Postulated Mechanism for the Formation of Compound 6
butyllithium requires lower temperature, it gave a good yield of fragmentation products; however, the 1,2/1,4 selectivity was reversed, with the 1,4-addition compound 7e being the major product. Phenyllithium was not basic enough to promote deprotonation, whereas t-butyllithium induced decomposition of the substrate. An important feature for this reaction is the presence of the epoxide, which remains intact in the fragmentation process. It was important to assign the importance of the epoxide ring in the 1885
DOI: 10.1021/acs.orglett.8b00426 Org. Lett. 2018, 20, 1884−1887
Letter
Organic Letters
Further studies concerning the scope and the selectivity of this reaction are currently in progress in our laboratory.
reaction. Therefore, a series of experiments were undertaken with substrates lacking the epoxide function. First, the cycloadduct 8, obtained by nitroso Diels−Alder cycloaddition of 1,3cyclohexadiene, was treated under standard conditions (MeLi, THF, 0 °C). The major product was the enamide 9, arising from tautomerization of the intermediate imine (Scheme 5). Formation of enamide 9 proved that deprotonation and elimination occurred; however, fast tautomerization to the enamide prevented further addition of methyllithium.11,12
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00426. Experimental procedures, analytical data, and NMR spectra for all new compounds; X-ray data for compounds 4a, 4c, 5a, 5c, 6, and 13 (PDF)
Scheme 5. Fragmentation Reaction of Cycloadduct 8
Accession Codes
CCDC 1812746−1812751 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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A second experiment was performed using the acetonide of cis3,5-cylohexadiene-1,2 diol 12, which is widely used as a diene for various Diels−Alder reactions as well as a building block for total synthesis.13,14 Acetonide 12 was prepared in four steps from 1,4cyclohexadiene via a slight modification of the literature protocol:15 dibromination, dihydroxylation, diol protection, and elimination gave the crude acetonide 12, which was not isolated, but immediately engaged in a nitroso Diels−Alder reaction with Boc-nitroso to give cycloadduct 13 as a single diastereomer. The stereochemistry of 13 was determined via Xray diffraction and proved to be anti. When 13 was submitted to the standard conditions for the fragmentation reaction, a fast reaction occurred to a mixture of compounds, 14 and 15, which are products of the fragmentation process, followed by 1,2- or 1,4-addition of methyllithium, as well as enamide 16, which is obtained through tautomerization of the intermediate imine (Scheme 6).
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Cyrille Kouklovsky: 0000-0001-5399-9469 Present Address †
Institute for Organic Chemistry, Leibniz Universitat Hannover, Schneiderberg 1B, 30167 Hannover, Germany. Author Contributions ‡
R.C. and F.S. contributed equally.
Notes
The authors declare no competing financial interest.
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Scheme 6. Synthesis and Nitroso Diels−Alder Cycloaddition of Benzene-1,2-diol Acetonide 12 and Its Fragmentation Reaction
ACKNOWLEDGMENTS This research was supported by CNRS and Université Paris-Sud. We thank the Erasmus program for a grant to F.S.
These two experiments show that the imine−enamine equilibrium is key for the overall process and the formation of the final amine product. Although, in all cases, deprotonation and fragmentation to the imine occurred, the presence of the epoxide in 4 prevents enamine formation. The latter process is partially (but not totally) inhibited for acetonide 13, whereas the absence of any function strongly favors the formation of the enamine. In conclusion, we have developed a new method for the transformation of cycloadducts bearing N−O bonds, leading to highly functionalized cyclohexene derivatives in a highly selective fashion. This reactions proceeds through regioselective metalation, elimination, and organometallic addition and leads to valuable synthetic tools for the synthesis of cyclitol derivatives.
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DOI: 10.1021/acs.orglett.8b00426 Org. Lett. 2018, 20, 1884−1887
