Synthesis of Chiral Selenazolines from N-Acyloxazolidinones via a Selenative Rearrangement of Chiral Cyclic Skeletons

Article abstract of DOI:10.1021/acs.orglett.8b02520

A synthetic route to chiral selenazolines from readily available N-acyloxazolidinones via a selenative rearrangement of a chiral cyclic skeleton is reported. The reaction proceeds in the presence of elemental selenium, a hydrochlorosilane, and an amine. A

Full text of DOI:10.1021/acs.orglett.8b02520

Letter
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Synthesis of Chiral Selenazolines from N‑Acyloxazolidinones via a
Selenative Rearrangement of Chiral Cyclic Skeletons
Fumitoshi Shibahara,* Tomoki Fukunaga, Saki Kubota, Akihito Yoshida, and Toshiaki Murai*
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan
S
* Supporting Information
ABSTRACT: A synthetic route to chiral selenazolines from
readily available N-acyloxazolidinones via a selenative
rearrangement of a chiral cyclic skeleton is reported. The
reaction proceeds in the presence of elemental selenium, a
hydrochlorosilane, and an amine. Although the stability of the
obtained selenazoline products is relatively low, a wide range of selenazolines was successfully prepared.
xazolines and thiazolines are widely found in a variety of
compounds such as natural products,1 biologically active
hydrochlorosilanes, and amines. The reaction did not involve
racemization on their chiral center.
O
compounds,2 and chiral ligands,3 where they play important
roles in their functionality. Consequently, the synthesis of such
compounds has attracted significant attention for more than a
century.4 In contrast, the corresponding selenium isologues,
i.e., selenazolines, which also play specific roles in vivo,5 have
seldomly been studied, owing to the synthetic difficulties
associated with their formation and the instability of the
selenated starting materials and products.6 Recently, we have
developed a new route to selenium-containing compounds
from carbonyl species via the formal reductive activation of
stable elemental selenium with a hydrochlorosilane as the
terminal reductant.7 During the course of our studies, we
conducted the reaction with N-acyloxazolidinones and,
unexpectedly, obtained selenazoline products (Figure 1,
In order to gain insight into the chemoselectivity of such
selenation reactions between amide carbonyl and cyclic
carbamoyl carbonyl moieties, we conducted a reaction between
N-benzoyloxazolidinone (1a), trichlorosilane, and dibenzyl-
amine at 115 °C for 15 h, which generated the corresponding
selenazoline 3a as the major product in moderate yield,
although the crude reaction mixture contained a series of
unidentified decomposition byproducts (Table 1, entry 1). In
a
Table 1. Optimization of the Reaction Conditions
c
entry
amine
silane
temp (°C)
solvent
yield (%)
1
2
3
4
5
6
7
HNBn2
HSiCl3
HSiCl3
HSiCl3
HSiCl3
HSiCl3
HSiCl3
HSiMeCl2
HSiMeCl2
115
115
115
115
115
140
140
160
toluene
toluene
toluene
toluene
49
trace
trace
25
45
44
DMAP
DABCO
NEt3
NEt3
NEt3
toluene
mesitylene
mesitylene
mesitylene
52
56
b
8
NEt3
a
Unless noted otherwise, reactions were conducted for 15 h in a
b
c
screw-capped test tube. Reaction time: 3 h. Isolated yields.
Figure 1. Previously reported synthetic routes to oxazolines and the
synthesis of selenazolines in this work.
the reaction mixture, simple selenated compounds such as 2a
were not detected. Subsequently, we tested various amines in
order to optimize the reaction conditions. Amines are essential
for this reaction, given that 3a was not obtained in their
absence (entry 2). Nucleophilic amines were not effective, and
the use of N,N-dimethyl-4-aminopyridine (DMAP) or 1,4-
bottom). A similar transformation of N-acyloxazolidinones
with lithium iodide and an amine had previously been reported
for the synthesis of chiral oxazolines (Figure 1, top), but
reports on the application to the synthesis of chiral
selenazolines as well as thiazolines do not exist.8 Herein, we
report a new route to chiral selenazolines via the reaction
between chiral N-acyloxazolidinones, elemental selenium,
Received: August 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02520
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Organic Letters
Letter
diazabicyclo[2.2.2]octane (DABCO) did not afford the desired
selenazoline in satisfactory yield (entries 3 and 4). On the
other hand, the use of triethylamine furnished the selenazoline
in moderate yield, which is comparable to that from the
reaction with dibenzylamine (entry 5). In the interest of an
easier separation of the products and amines, a more volatile
triethylamine was selected for the further optimization of the
reaction conditions. Although more complex mixtures were
obtained at higher temperatures, the product yield was not
affected (entry 6). The use of the less reactive methyldi-
chlorosilane resulted in the suppression of the side reactions
and increased the yield of 3a (entry 7). Meanwhile, we
detected a time-dependent spontaneous decomposition of the
selenated intermediates and selenazoline product under those
reaction conditions, probably due to their highly labile nature.
We thus conducted the reaction at 160 °C in order to shorten
the reaction time and increase the yield to 56% in only 3 h
(entry 8). Notably, this reaction mixture was cleaner than
those obtained from longer reaction times, although we did
detect trace amounts of several compounds that retain the
oxazolidinone skeleton. In addition, a racemization was not
observed at the chiral center of the aminoalcohol moiety of the
oxazolidinone under these reaction conditions in the reaction
with enantiopure substrates (R)- and (S)-1a.9 Addition of LiI,
which is a key additive for previous oxazoline synthesis,8 did
not affect the reaction efficiency at all.
(entries 1−6), although the yield significantly decreased when
a 2-pyridyl group was introduced at that position (entry 7).
Alkyl substituents also withstood the reaction conditions to
furnish the corresponding products (3i−m; entries 8−12),
although the isolated yield of highly volatile 3i was relatively
low. In addition, the stability of the corresponding 2-tert-
butylselenazoline 3k was comparatively low and significant
decomposition was observed even upon storage under argon
after isolation (entry 10). On the other hand, the yields of 2-
(1-arylethyl)selenazolidinones 3l and 3m were good, probably
due to their comparatively high stability (entries 11 and 12).
Nevertheless, complete epimerization at the α-position of the
amide carbonyl moiety on the substrate was observed; the
reaction of the isolated diastereomers furnished the corre-
sponding products in the same 1:1 diastereomer mixture
(Scheme 1A and 1B). In contrast, no epimerization of
Scheme 1. Reactions of the Individual Diastereomers of 1l
With these reaction conditions in hand, we subsequently
investigated the substrate scope (Figure 2). Substrates with
functionalized phenyl groups or electron-rich heterocycles on
the acyl moiety were well tolerated under these conditions
(R*,R*)- and (R*,S*)-1l occurred under the standard
conditions in the absence of elemental selenium (Scheme
1C). This result clearly suggests that such an epimerization
occurs after the selenation. Generally, the selenocarbonyl
moiety has the higher acidity of the α-position compared to
that of the conventional “oxo”carbonyl group on account of the
difficulties associated with the hybridization of the atomic
orbitals on the selenium atom. Regarding the substituents on
the amino alcohol moiety in the oxazolidinone, a benzyl-
substituted aliphatic group at the 4-position afforded the
corresponding product in a yield comparable to that of 1a
(entry 13). On the other hand, 4,4-disubsituted 1o did not
afford 3o (entry 14), and an aromatic substituent at the 4-
position decreased the yield of 3p (entry 15). Finally,
substituents at the 5-position critically influence the efficiency
of the reaction, and the corresponding selenazolines were not
detected (entries 16 and 17). In short, the stability trend of the
selenazolines is mainly due to the bulkiness of the substituent
on the 2-position, and tertiary substituents and aryl groups
bearing a relatively bulky substituent at the ortho-position10
significantly give a negative impact for the stability as well as
yields of the products.
To compare the reaction behavior between the present
selenation and the analogous thionation, we conducted the
same experiment using elemental sulfur (Scheme 2). The
reaction afforded the corresponding thiazoline in moderate
yield, although significant amounts of N-thioacyloxazolidinone
2a′ and eliminated oxazolidinthione 4a′ were also generated.
We also performed reactions using Woollins’ or Lawesson’s
Figure 2. Investigation of substrate scope of the reaction. Reactions
were conducted in a screw-capped test tube. All yields refer to isolated
yields. Yields in parentheses were determined by 1H NMR using
(CH2Cl)2 as the internal standard.
B
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Scheme 2. Reaction between 1a, NEt3, HSiMeCl2, and
Elemental Sulfur
Scheme 4. Further Control Experiments and Related
Reactions
reagents instead of selenium and sulfur, but 3a and 3a′ were
obtained in only trace amounts (Scheme 3).
PMP = p‐MeOC6H
Scheme 3. Reaction with Woollins’ and Lawesson’s
Reagents
decomposed at 160 °C. Oxazolidiselone 4 was previously
synthesized by Silks and co-workers,11 but in that case, the
compounds were treated below room temperature. These
results indicate that the ready selenation of the oxazolidinone
moiety is followed by a rearrangement under harsh conditions
that may be assisted by attack of amines added or in situ
generated nucleophilic species to make ease of ring opening as
well. Moreover, 6 is unstable under these high-temperature
reaction conditions and readily decomposes even if it is
generated during the present selenazoline reaction. A similar
rearrangement was observed for thionolactone 7, even though
the reaction needed a nucleophilic amine such as DMAP,
probably due to the low reactivity of the C−O bond in the
thionocarboxy ester moiety (Scheme 4B). The different
product distributions obtained from the selenazoline- and
thiazoline-forming reactions under the respective reaction
conditions (vide supra) probably reflect the reactivity of the
intermediates, where the selenated intermediates are much
more reactive toward the rearrangement from 4 to 6 by C−O
bond cleavage (Scheme 2) and the low-energy barrier of
successive recyclizations from 2 to 3 (Table 1, entry 7).
Moreover, the reaction of N-benzoyl-δ-lactam (9) furnished
selenated and debenzolylated δ-selenolactam (11) in moderate
yield (Scheme 4C). Usually, the selenation and thionation of
lactam moieties proceed faster than at chainlike amide
moieties.7a Moreover, the pKa value of selenoamides is
significantly lower than that of the corresponding “oxo”amides
(vide supra), which also renders the selenolactam moiety a
good leaving group. This result suggests that the elimination of
the oxazolidiselone moiety occurs readily to give 4 after the
initial selenation at the carbamoyl carbonyl group, followed by
successive rapid rearrangement and/or direct decomposition
reactions.
To gain insight into the reaction pathway, we subsequently
conducted several control experiments and related reactions.
Considering their similarities, thioacyl substrate 2a′ was used
for the control experiments, given that 2a could not be
isolated. Initially, attempts to initiate the reaction by simple
heating failed, and 2a′ was recovered quantitatively (Table 2,
Table 2. Control Experiments for the Corresponding
Thiazoline Synthesis
a
entry
additives
3a′ (%)
4′ (%)
5 (%)
2a′ (%)
1
2
3
4
5
>95
>95
60
56
10
HSiMeCl2
NEt3
HSiMeCl2, NEt3
S8, HSiMeCl2, NEt3
S8, HSiMeCl2, NEt3
12
10
35
35
15
22
32
39
b
6
a
b
4.4 equiv for 2a’. 2a′′ was used as the substrate instead of 2a′.
entry 1). While addition of HSiMeCl2 did not affect the
distribution of the products (entry 2), NEt3 promoted the
reaction, although 3a′ was obtained in low yield (entry 3).
Again, addition of HSiMeCl2 under these reaction conditions
did not influence the product distribution (entry 4), whereas
further addition of elemental sulfur (under otherwise identical
conditions) significantly improved the yield of 3a to a value
comparable to that of 1a (entry 5). A similar result was
obtained from the reaction of 2a′′ under identical conditions
(entry 6). These results suggest that the formation of the
thiazoline proceeds via the 2-fold thionation of 1a.
Furthermore, a reaction of free oxazolidinone 5 was carried
out under the standard selenation conditions at 80 °C, which
did not afford the corresponding oxazolidiselone 4 but
selenazolidinone 6 in moderate yield (Scheme 4A), which
Based on these results, we would like to propose a plausible
reaction pathway (Scheme 5). Initially, the selenation12 should
occur randomly at the amide or carbamoyl moiety to give I or
I′; a further selenation should furnish diselenated intermediate
II. Moreover, once generated, I′ would readily decompose
under these conditions via formation of 6, and both reactions
may exist in competition. The moderate yield obtained in most
cases should thus probably originate from the selectivity of
those initial selenation processes. The contribution regarding
C
DOI: 10.1021/acs.orglett.8b02520
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ORCID
Scheme 5. Probable Reaction Pathway
Fumitoshi Shibahara: 0000-0003-2889-140X
Toshiaki Murai: 0000-0003-4945-0996
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from JSPS KAKENHI
Grant Nos. 16K05769 and 18H04245 in the context of
“Precisely Designed Catalysts with Customized Scaffolding”.
We also thank Prof. Makoto Yamashita and Dr. Jun-ichi Ito
(Nagoya University) for helpful discussions and suggestions on
the synthesis of metal complexes described in the Supporting
Information.
the orbital hybridization on the selenium atom from resonance
forms II′ and II′′ should be higher than that of II, and in
particular, the rearrangement to III should readily occur from
II′′, probably assisted by the amine or in situ generated
nucleophilic species on the ring-opening process.13 The
carbamoyl C−N bond should thus be weakened by the effect
of the orbital hybridization described above, leading to a
formal decarboxylation (elimination of OCSe species) to
give intermediate IV, though the highly nucleophilic selenium
atom may remain on the intermediate at this stage. Successive
intramolecular SN2-type cyclizations should then afford the
corresponding selenazoline 3. On the other hand, as shown in
Scheme 3, the reaction does not proceed when phosphorus-
based chalcogenation reagents are used, which suggests that
the silane and the amine also play an important role in several
steps of the reaction pathway, particularly as a Lewis acid and/
or nucleophilic catalyst on the rearrangement and formal
decarboxylation step.
In conclusion, we have developed a new route to chiral
selenazolines that proceeds via a selenative rearrangement of
chiral N-acyloxazolidinones. The steric information on the
position α to nitrogen was totally retained under the reaction
conditions, which was confirmed by a racemization test with an
enantiopure substrate. Although the product yields are still
modest, mainly owing to their instability, a wide variety of
chiral selenazolines could be prepared by this method. Further
applications of these chiral selenazolines, particularly in the
preparation of the chiral metal complexes10 and in asymmetric
catalysis, are currently in progress in our group.
REFERENCES
■
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02520.
Attempts of synthesis of several bidentate and pincer-
type ligands and complexes, brief estimations of
stabilities of II and III by DFT calculations,
1
experimental details, and copies of H and 13C NMR
of novel compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(8) May, A. E.; Willoughby, P. H.; Hoye, T. R. J. Org. Chem. 2008,
73, 3292.
(9) For details, see Figure S1 in the Supporting Information.
* E-mail: fshiba@gifu-u.ac.jp.
* E-mail: mtoshi@gifu-u.ac.jp.
D
DOI: 10.1021/acs.orglett.8b02520
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Organic Letters
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(10) For the further preliminary examples of other compounds
toward chiral ligand as well as preparing metal complexes, see
Schemes S1−4, and descriptions in the Supporting Information.
Those compounds are not fully characterized owing to productivity
and stability so far.
(11) Ollivault-Shiflett, M.; Kimball, D. B.; Silks, L. A. J. Org. Chem.
2004, 69, 5150.
(12) For the proposed reaction pathway of the selenation of
carbonyl group, see ref 7a.
(13) In addition, III is more stable by ca. 16 kcal/mol than the
corresponding II as estimated by density functional theory (DFT)
calculations at the B3LYP//6-31G(d, p) level (Figure S2); thus, the
equilibrium of the rearrangement is highly biased to III. Gaussian 09
(rev.D.01) was used for the DFT calculations; full details of the
citation of the Gaussian package are in the Supporting Information.
E
DOI: 10.1021/acs.orglett.8b02520
Org. Lett. XXXX, XXX, XXX−XXX