Synthesis of fused 3-aminoazepinones via trapping of a new class of cyclic seven-membered allenamides with furan

Article abstract of DOI:10.1021/ol501529z

Novel tricyclic tetrahydroazepinones were synthesized via an in situ Diels-Alder reaction of furan with cyclic allenamides. These reactive intermediates are the first examples of cyclic seven-membered allenamides and were prepared starting from N-(2-chlor

Full text of DOI:10.1021/ol501529z

Letter
pubs.acs.org/OrgLett
Synthesis of Fused 3‑Aminoazepinones via Trapping of a New Class
of Cyclic Seven-Membered Allenamides with Furan
Ben Schurgers,† Ben Brigou,‡ Zofia Urbanczyk-Lipkowska,§ Dirk Tourwe,† Steven Ballet,†
́
Frank De Proft,‡ Guy Van Lommen,∥ and Guido Verniest*,†
†Research Group of Organic Chem‡istry, Department of Chemistry and Department of Bio-engineering Sciences, Faculty of Science
and Bio-engineering Sciences and Department of General Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels,
Belgium
§Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka Str 44/52, 01-224 Warsaw, Poland
∥Department of Medicinal Chemistry, Galapagos NV, Generaal De Wittelaan L11-A3 B-2800 Mechelen, Belgium
S
* Supporting Information
ABSTRACT: Novel tricyclic tetrahydroazepinones were
synthesized via an in situ Diels−Alder reaction of furan with
cyclic allenamides. These reactive intermediates are the first
examples of cyclic seven-membered allenamides and were
prepared starting from N-(2-chloroallyl)-2-allylglycine deriva-
tives via ring-closing metathesis followed by dehydrochlorina-
tion. The trapping of the intermediate cycloallene with furan
occurred endo- and regioselectively and provided a convenient
entry into new building blocks for medicinal chemistry. The diastereoselectivity of the cycloaddition was confirmed using
quantum chemical computations.
llenamides have emerged in recent years as versatile and
polyvalent building blocks in organic synthesis.1 Since
because of their high ring strain.24 The combination of an
allene and an amide group in a cyclic system has to our
knowledge been described only for unconjugated systems.25 In
the present study, the generation of a new class of seven-
membered cyclic N-allenamides as starting material for new
azepane derivatives was evaluated.
A
their discovery by Dickinson in 1967,2 acyclic allenamides have
gained attention as a more stable form of allenamines, which
are prone to hydrolysis, polymerization, and isomerization.1
Allenamides are attractive building blocks for the preparation of
bioactive compounds and have been used in the synthesis of a
variety of heterocycles such as pyrroles,3 imidazolidines,4
bicyclic guanidines,5 furans,6 benzazepines,7 and cephams.8 In
addition, by introduction of chiral or directing substituents at
the N-atom, regio- and stereoselective transformations have
been described.9,10 Regarding the use of the cumulene bond of
allenamides as substrate for cycloaddition reactions, thermal [2
+ 2]-cycloadditions,11 Pauson−Khand-type [2 + 2 + 1]-
cycloadditions,12 and [4 + 3]-cycloadditions after epoxidation
of the allenamide have been described.13 Allenamides are
generally prepared via base-induced isomerization of prop-
argylamides,2,14−16 aminocyclization,17,18 copper-catalyzed N-
allenylation of amides,19 and elimination reactions.20,21
Because of our interest in new 3-amino-1,3,4,7-tetrahydro-
2H-azepin-2-ones bearing fused (carbo- or heteroaromatic)
rings for use in peptidomimetic chemistry,26 a synthetic route
toward related new nonplanar 3-aminoazepinones was
envisaged by making use of cycloaddition reactions with
seven-membered cyclic allenamides. Indeed, the synthesis of
new nonplanar heterocyclic core structures with a considerable
number of tetrahedral centers is of upcoming importance in
medicinal chemistry.27 In order to evaluate the possible
formation of seven-membered allenamides via dehydrohaloge-
nation,20,21 a model study to efficiently synthesize the
corresponding halogenated tetrahydroazepinones 4 (Scheme
1) was performed. N-Protected racemic allylglycine derivatives
1a were synthesized via a Claisen rearrangement of O-allyl-N-
Cbz-glycinate28 or by allylation of N-benzophenonimine-O-
ethylglycinate followed by imine hydrolysis, protection of the
nitrogen with Boc2O, and hydrolysis of the ethyl ester.29 While
the amidation of pentenoic acid 1a with secondary amines is
well described and proceeded uneventfully to give amide 5,30
the coupling of the corresponding amino acid derivatives 1b
In contrast to allenamides in which only the amide moiety is
part of a heterocyclic ring system, analogous derivatives
characterized by a cyclic N-allene system in small- to
medium-sized rings have not been studied to date.22 It is
however known that allenes can be accommodated in small-
and medium-sized ring systems, as demonstrated by various
experiments where generated 1,2-cyclohexadienes are trapped
or dimerized in situ.23 The nine-membered and higher ring
homologues are stable and can be isolated, while smaller ring
systems are unstable at room temperature and spontaneously
dimerize or decompose in the absence of trapping agents
Received: May 28, 2014
© XXXX American Chemical Society
A
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Letter
the temperature to 25 °C, the starting compound was
completely consumed within 30 min. Because no intermediate
allenamide could be detected in the complex mixture at
different stages during the reaction, high reactivity and rapid
dimerization can be suggested. In the following experiments,
the dehydrohalogenation reaction was performed in furan as a
solvent. Although normal demand Diels−Alder reactions of
allenamides with furans are quite rare, successful regioselective
intramolecular examples have been described recently.34
Scheme 1
We were pleased to observe the clean formation of only two
cycloadducts in a 3:2 ratio after treatment of 4d with 4 equiv of
t-BuOK in furan at room temperature during 18 h.35 The
possibility of a formation of the cycloadducts 7a via initial
cycloaddition of furan to 4d followed by dehydrochlorination
was excluded since no reaction occurred when 4d was treated
with furan when no t-BuOK was present, even at elevated
temperatures. It should be noted that also the nonhalogenated
azepinone 4c did not give cycloadducts when treated with
furan, with or without t-BuOK, and only starting material was
recovered. X-ray analysis revealed unambiguously the relative
stereochemistry of the obtained major and minor cycloadducts
7a and 7a′ (see Supporting Information). The selectivity in
formation of both regioisomers 7 and 7′ via a normal electron-
demand [4 + 2]-cycloaddition of allenes 6 (Scheme 2) with the
with secondary amines 2 proved to be more difficult. After
screening a wide variety of coupling reagents, including DCC,
EDC, DIC, PyBOP, TBTU, PyBrop EDC/HOAt, and DIC/
HOAt, the best results to give 3a−i were obtained by using
HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo-
[4,5-b]pyridinium-3-oxide hexafluorophosphate) in CH2Cl2.
Having in hand a variety of diene substrates 3a−i and 5,
ring-closing metathesis, to give tetrahydroazepinones 4, was
investigated. Because of the ease of synthesis, first metathesis
experiments were performed using 4-pentenamide 5 as a
substrate. However, in no case could the envisaged ring
structure be obtained in good yields, and mainly starting
material and decomposition products were observed. It is
known that the introduction of extra substituents in the
aliphatic part increases the viability for ring closure during
RCM.31 Therefore, further studies were evaluated on α-amino
acid derivatives 3a−i. Unfortunately, metathesis reactions of 2-
bromoallylated derivative 3a using Grubbs’ II catalyst or the
related Umicore catalyst M2 did not result in acceptable yields
of the corresponding brominated tetrahydroazepinone 4a.32
However, when the same reactions were performed using
nonhalogenated33 or 2-chlorinated substrates, compounds 4
were obtained in good yields (Scheme 1). 6-Chloro-3-amino-
1,3,4,7-tetrahydro-2H-azepinones 4d−i are a new class of easily
available chlorinated azepinone derivatives that can be used as
building blocks for further transformations.
The obtained chlorinated tetrahydroazepinone 4d was
subjected to deprotonation reactions with t-BuOK in order to
effect a dehydrochlorination. While no reaction was observed at
0 °C or below, even after 1 h, the reaction at room temperature
gave rise to a complex reaction mixture. HPLC and LC−MS
analysis of the obtained mixture revealed the presence of three
major compounds (almost equimolar), of which the molar mass
corresponded to dimeric compounds, probably formed via [2 +
2]-cycloaddition of an intermediate allene. Unfortunately, the
isolation and separation of the obtained dimers were not
successful via preparative HPLC. It is known that reactive
allenes can dimerize easily to form a mixture of regioisomeric
cyclobutane derivatives.23b To further study the plausible
formation of intermediate allenamides, the deprotonation
reaction was performed in deuterated THF and followed by
NMR at different temperatures. Also in this case, it was
observed that no reaction occurred at 0 °C, while after raising
a
Scheme 2.
a
Notes: (a) Ratio determined by HPLC. (b) Isolated yield after
preparative HPLC. (c) Isolated yield of 7a−e after column
chromatography.
electron-rich furan corresponds well with the difference in the
electron-rich N−CC bond and the more electron poor C
C−CH2 bond in 6. It should be noted that in addition to the
novelty of the cyclic allene structure, the observed regiose-
lectivity is another example of the very few reported normal
Diels−Alder reactions with allenamides. In a first reaction of an
intermolecular36 and one recent intramolecular example,34 an
analogous regioselectivity is described. Next to the above-
described regioselectivity, the formation of only one racemic
diastereomer of both regioisomers is remarkable. In theory, two
diastereomers can be formed upon dehydrochlorination of 4d
because of the axial chirality of the allene group. When taking
diastereomer 6aisomer 1 (Scheme 3) into account, four different
approaches of furan can be considered (Figure 1). The
structures depicted in Figure 1 are drawn according to DFT
calculations (vide infra) performed on two related substrates 6x
(R1 = Moc, R2 = Me) and 6y (R1 = Cbz, R2 = Bn). For both
substrates 6x and 6y the allene C5−C6−C7 bending angle and
B
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To evaluate the scope of this transformation, derivatives 4d−
i were treated with t-BuOK in furan, and the major isomer was
separated from the minor regioisomer (ratio M:m varied from
2:1 to 96:4) via column chromatography (Scheme 2). In
addition, an N-acetylated analogue 4k was obtained via
treatment of 4e with TFA, followed by reaction with acetic
anhydride, and was treated with t-BuOK in furan to give 7e. It
was observed that the dehydrochlorination−cycloaddition
tandem reaction did not proceed in the case of unprotected
amines. In this case only side products and starting material
were found in the reaction mixture. We suggest that the
presence of an electron-withdrawing group on the amine is
necessary to prevent it from attacking the reactive allenamide.
In an attempt to reduce the amount of furan used, reactions
were performed using 1 equiv of furan in THF. In this case only
dimers were found in the reaction mixture. Also the use of 2,3-
and 2,5-dimethylfuran and N-Boc-pyrrole did not result in
cycloaddition under these reaction conditions. In order to
elaborate the obtained stable tricyclic compounds 7 further into
additional derivatives for medicinal chemistry, hydrogenation
reactions were evaluated (Scheme 4).
Scheme 3
the H−C5−C6−C7 twist angle correspond well with literature
values (see Supporting Information).24 While approaches A
and D (Figure 1) are not plausible because of steric hindrance,
both an endo- and exo-cycloaddition (approaches B and C,
respectively) seem probable. One might even suggest the exo-
approach to be more favored because of steric reasons.
However, it was surprising to observe only the endo adduct
7a (via B) in which Ha and Hb adopt a trans configuration. An
analogous stereochemical consideration can be made for the
minor regioisomer (see Supporting Information). Despite the
assumed higher steric hindrance, related endo-selectivity was
observed by Hsung in an intramolecular acyclic allene furan
cycloaddition.15
Although no explanation of this selectivity was reported,
DFT calculations by Houk and Tolbert of the reaction of furan
with 1,2-cyclohexadiene at the BLYP/6-31G* level37 revealed
that also in this case the endo-approach is kinetically favored.
Because of the observed trans relationship of Ha and Hb in 7a
and the cis relationship of Ha and Hc in 7a′, a furan
cycloaddition using the other diastereomer of 6aisomer 2
(Scheme 3) is unlikely. Indeed, in order to obtain the observed
stereochemistry, a highly hindered approach of the furan ring
(related to approach A, but with inversed stereochemistry at C3,
Figure 1) would be necessary. This suggests the selective
formation of one diastereomer 6aisomer 1 from the reaction of 4d
with t-BuOK. In all, not only is the tandem dechlorination/
cycloaddition reaction regioselective (major:minor ratio of 3:2)
and completely endo-selective, the observed stereochemistry
also suggests a diastereoselective dechlorination. This combi-
nation is unprecedented, and the stereochemical pathways were
rationalized by computational analysis (DFT) on the two
model substrates 6x and 6y. Calculations were performed at the
B3LYP/6-311G** level. We were pleased to find that our
model was able to correctly predict the experimental outcome
of the cycloaddition. The major product (approach B, Figure 1)
is both kinetically and thermodynamically favored. The
calculated energy difference of transition state B from the
other transition states C, D, and A (4.80, 8.26, and 38.00 kcal/
mol, respectively, for 6y, Figure 1) corresponds with the
observed selectivity (a more detailed description of the
computational analysis is included in the Supporting
Information).
Scheme 4
The reaction of 7c and 7d under H2 atmosphere (2−4 bar)
over catalytic amounts of Pd−C resulted in a simultaneous
reduction of the Z-double bond and N-deprotection to give 8a
and 8b. The reaction of the obtained amines 8 with aldehydes
followed by treatment with NaCNBH3 in methanol at pH 4−5
yielded new derivatives 9a, 9b, and 9c. It is clear that the
enamide functionality remained intact even after hydrogenation
and reductive amination protocols.
In conclusion, we were able to synthesize a novel class of
tricyclic tetrahydro-aminoazepinones via an in situ Diels−Alder
reaction of furan with cyclic allenamides. The reactive
allenamide intermediates were prepared from substituted N-
(2-chloroallyl)-2-allylglycinamide derivatives via ring-closing
metathesis followed by dehydrochlorination by t-BuOK. The
intermediate allenamides reacted in situ with furan in a
regioselective (reaction at the terminal CC bond of the
allenamide), a diastereoselective (furan addition at the opposite
Figure 1. Four possible approaches in the Diels−Alder reaction of furan with 6y (R1 = Cbz, R2 = Bn). Substituents on 6y are omitted for clarity.
C
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face of the 3-aminosubstituent), and an endo-selective manner,
suggesting a diastereoselective allenamide formation. The
obtained cycloadducts were hydrogenated and derivatized
into novel tricyclic heterocycles of interest as new core
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and 45.64 kcal/mol) as well as thermodynamically favored as
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reported in due time.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectroscopic data (1H and 13C NMR spectra) for all new
compounds, LC−MS data of crude mixtures, and X-ray data
(CIF) for compounds 7a and 7a′. Additional computational
data regarding 6x and 6y. This material is available free of
charge via the Internet at http://pubs.acs.org.
(26) (a) Van Rompaey, K.; Van Den Eynde, I.; De Kimpe, N.;
Tourwe,
Van den Eynde, I.; De Wachter, R.; Kosson, P.; Misicka, A.; Lipkowski,
A.; Chung, N. N.; Schiller, P. W.; Tourwe, D. Tetrahedron 2006, 63,
1459. (c) Buysse, K.; Farard, J.; Nikolaou, A.; Vaucquelin, G.;
Pedersen, D. S.; Tourwe, D.; Ballet, S. Org. Lett. 2011, 13, 6468.
́
D. Tetrahedron 2003, 59, 4421. (b) Pulka, K.; Feytens, D.;
́
AUTHOR INFORMATION
■
Corresponding Author
́
(27) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752.
*E-mail: gvernies@vub.ac.be.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are indebted to the agency for Innovation by
Science and Technology (IWT) and Galapagos NV for
financial support. G.V. thanks Umicore for the generous gift
of M2 catalyst.
(31) Reaction conditions: reflux in CH2Cl2 [0.01 M], catalyst loading
of 0.1 mol %. For further discussion concerning the effects of tether
substituents in RCM, see: Gardiner, J.; Aitken, S. G.; McNabb, S. B.;
Zaman, S.; Abell, A. D. J. Organomet. Chem. 2006, 691, 5487.
(32) Reaction conditions: reflux in CH2Cl2 or PhMe [0.01 M],
catalyst loading of 0.05−0.5 mol %. This led to only starting material
and decomposition products. For examples of RCM reactions using
vinyl halides, see: (a) Matteis, V. D.; van Delft, F. L.; de Gelder, R.;
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A.; Koblan, K. S.; Salvatore, C. A.; Mosser, S. D.; Johnston, V. K.;
Wong, B. K.; Miller-Stein, C. M.; Hershey, J. C.; Graham, S. L.; Vacca,
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