Tetraarylphosphonium Salt-Catalyzed Synthesis of Oxazolidinones from Isocyanates and Epoxides

Article abstract of DOI:10.1021/acs.orglett.7b02722

Preparation of a range of oxazolidinones, including enantioenriched N-aryl-substituted oxazolidinones, in which tetraarylphosphonium salts (TAPS) catalyze the [3 + 2] coupling reaction of isocyanates and epoxides effectively, is described. The key finding is a Br?nsted acid/halide ion bifunctional catalyst that can accelerate epoxide ring opening with high regioselectivity. Mechanistic studies disclosed that the ylide generated from TAPS, along with the formation of halohydrins, plays a crucial role in the reaction with isocyanates.

Full text of DOI:10.1021/acs.orglett.7b02722

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Tetraarylphosphonium Salt-Catalyzed Synthesis of Oxazolidinones
from Isocyanates and Epoxides
Yasunori Toda,* Shuto Gomyou,† Shoya Tanaka,† Yutaka Komiyama,† Ayaka Kikuchi,
and Hiroyuki Suga*
Department of Materials Chemistry, Faculty of Engineering, Shinshu University, 4-17-1 Wakasato, Nagano 380-8553, Japan
S
* Supporting Information
ABSTRACT: Preparation of a range of oxazolidinones, including enantioenriched N-aryl-substituted oxazolidinones, in which
tetraarylphosphonium salts (TAPS) catalyze the [3 + 2] coupling reaction of isocyanates and epoxides effectively, is described.
The key finding is a Brønsted acid/halide ion bifunctional catalyst that can accelerate epoxide ring opening with high
regioselectivity. Mechanistic studies disclosed that the ylide generated from TAPS, along with the formation of halohydrins, plays
a crucial role in the reaction with isocyanates.
xazolidinones represent an important class of nitrogen
Oand oxygen containing heterocyclic compounds, many of
which exhibit great utility, not only as valuable intermediates in
organic synthesis but also in their own right.1 In particular, N-
aryl-substituted oxazolidinones have gained increasing attention
from medicinal chemists and pharmacologists due to the potent
biological activity of the oxazolidinones.2 Thus, the develop-
ment of a facile, practical, and robust access to a diverse array of
those derivatives, in order to expeditiously generate chemical
libraries for drug discovery, has been intensively pursued.
There are a large number of strategies that have been used
for the synthesis of an oxazolidinone core.3−6 One of the most
straightforward and atom-economical methods is the [3 + 2]
coupling reaction of isocyanates and epoxides, which enables
modular and flexible production of lead analogues by switching
one or both substrates. In 1958, Speranza and Peppel
demonstrated the catalytic transformation by using quaternary
ammonium salts.7 In other reports, several metal salts have
been shown to catalyze the reaction, but undesirable conditions
(e.g., excessive high temperature, high catalyst loadings, large
excess of epoxides, or slow addition of isocyanates) were often
required to afford the products.8 Although these problems have
some recent modernized solutions using metal complexes,
chemical yields tend to drastically decrease when electron-
deficient or aliphatic isocyanates are employed.9
for the initiation of ring opening of epoxides by the synergistic
effect of a Brønsted acid and a nucleophilic halide ion. We hence
reasoned that TAPS catalysis could be applicable to the
addition of other heterocumulenes to epoxides as well as
carbon dioxide. However, this remains a formidable challenge
since no effective organocatalysis has been reported for the
synthesis of oxazolidinones via the [3 + 2] coupling reaction to
date. Herein, we describe TAPS catalysis that allows the
coupling between isocyanates and epoxides (Figure 1). This
approach would not only grant efficient entry to oxazolidinone
synthesis but also empower bifunctional TAPS as the premier
organocatalytic entities for epoxide activation and functional-
ization. Moreover, the present study shows that the ylide10b
Meanwhile, over the past two decades, organocatalysts have
made remarkable progress, enabling various transformations
without the use of costly and/or toxic metals. We have recently
developed a tetraarylphosphonium salt (TAPS) prepared from
an ortho-halogenated cresol and triphenylphosphine in only one
step, which was proven to facilitate the reaction of carbon
dioxide with terminal epoxides.10a In the reaction presented, an
ortho-hydroxy group on TAPS has been found to be important
Figure 1. Strategy for [3 + 2] coupling reaction of isocyanates and
epoxides by organocatalysis.
Received: September 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02722
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
derived from TAPS exhibits a specific character as a Brønsted
base, delivering intermediates to products wherein TAPS could
be regenerated.
Scheme 1. Substrate Scope
At the outset of our study, we selected isocyanate 3a as the
representative electron-deficient aryl isocyanate for screening of
reaction conditions. The initial experiments were performed
using epoxide 2a and 1.2 equiv of 3a in chlorobenzene at 120
°C for 6 h (Table 1). To our delight, 15 mol % of TAPS 1a
a
Table 1. Optimization of Reaction Conditions
b
entry
1 (mol %)
conditions
4a (%)
1
2
3
4
5
6
7
1a (15)
none
PhCl (0.3 M), 120 °C, 6 h
PhCl (0.3 M), 120 °C, 6 h
PhCl (0.3 M), 120 °C, 6 h
PhCl (0.3 M), 120 °C, 6 h
PhCl (0.3 M), 100 °C, 6 h
1,4-dioxane (0.3 M), 100 °C, 6 h
DMA (0.3 M), 100 °C, 6 h
PhCl (1.0 M), 100 °C, 6 h
PhCl (1.0 M), 100 °C, 24 h
>98
0
1a (2)
1b (2)
1b (2)
1b (2)
1b (2)
1b (2)
1b (2)
45
52
35
28
16
c
8
c
81
9
>98 (94)
a
Unless otherwise noted, all reactions were carried out on a 0.20 mmol
b
scale using epoxide 2a and 1.2 equiv of isocyanate 3a. Determined by
1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal
c
standard (isolated yield is shown in parentheses). 0.60 mmol scale.
(counterion X− = Br−) afforded oxazolidinone 4a in
quantitative yield, while no reaction was observed in the
absence of a catalyst (Table 1, entries 1 and 2). An attempt to
lower the catalyst loading of 1a (2 mol %) resulted in low yield,
but TAPS 1b, bearing an iodide ion (X− = I−), afforded an over
50% yield of 4a (Table 1, entries 3 and 4). To establish a
procedure under mild reaction conditions, the temperature,
solvent, and concentration were further screened (Table 1,
entries 5−8). As a result, good conversion was achieved with a
higher concentration of substrates in chlorobenzene, and finally
4a was obtained in 94% isolated yield by prolonging the period
of a reaction (Table 1, entry 9).
The scope of substrates is summarized in Scheme 1. First, a
series of aryl isocyanates 3 was examined to probe the
generality of the TAPS-catalyzed coupling reaction. For
reactions involving 2a, phenyl and p-methoxyphenyl isocya-
nates (3b and 3c) showed higher reactivity than 3a (6 h for 4b
and 4c vs 24 h for 4a). On the other hand, 5 mol % of 1b was
required when p-chlorophenyl isocyanate (3d) was employed
(4d: 80%). For reactions involving epichlorohydrin (2b), a
similar tendency was observed: higher yields were obtained
with use of 3b and 3c while 3d gave a lower yield (4e: 88% and
4f: 93% vs 4g: 72%). In contrast, ortho-halogenated aryl
isocyanate 3e was accommodated efficiently, affording the
corresponding oxazolidinones 4h in 97% yield. Only 0.5 mol %
of 1b was able to catalyze the coupling with 3e and 3f (4h: 94%
and 4i: 80%), while aryl isocyanate with dihalogen substituents
3g was challenging presumably due to the decomposition of 3g
(4j: 78%). Steric effects of 3 were also investigated (3h vs 3i),
but there was no significant difference between the meta- and
ortho-position (4k: 93% vs 4l: 91%). In addition, isocyanate 3j
having an ester group furnished 4m in good yield. Next, a
a
Unless otherwise noted, all reactions were carried out on a 0.60 mmol
scale using 2 mol % of 1b, epoxide 2 and 1.2 equiv of isocyanate 3 in
PhCl (1.0 M) at 100 °C. 5 mol %. 3 mol %. 120 °C.
b
c
d
variety of terminal epoxides 2 were screened to couple with 3b.
Glycidol derivatives 2c−g afforded 4n−r in high yields except
for 4o. Epoxides 2d−g bearing amino and alkyl groups were
also applicable to give 4s−u in good to high yields. Styrene
oxide (2k) underwent the [3 + 2] reaction; however, a
regioisomer of 4v was apparently observed. Moreover,
enantiopure epoxides (S)-2a and (S)-2l were submitted to
the optimized reaction conditions to provide the optically active
oxazolidinones, and (S)-4b and (S)-4w were obtained with high
enantiomeric excesses without stereochemical erosion.11 Cyclo-
hexene oxide was challenging; thus, only 5% of the
1
corresponding product was observed by H NMR analysis.
To expand the applicability of our methodology, other
isocyanates 5 were tested (Scheme 2a). Delightfully, TAPS
catalysis tolerated isocyanates 5a−d, whereas aliphatic iso-
cyanates led to poor yields in most previous reports.9a,c
Furthermore, the reaction 2b with 3h was performed on gram
scale in the presence of 1 mol % of TAPS 1b, affording 4k in
excellent yield (Scheme 2b). Toloxatone (4x)12 was synthe-
sized in three steps from commercially available 2d and 3h. For
the enantioenriched product (S)-4w, para-selective iodination
B
DOI: 10.1021/acs.orglett.7b02722
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthetic Application
Figure 2. (a) 1H NMR experiments. (b) Effect of catalysts on the ring
opening of epoxides.
faster conversion of 2i into 11, which mostly correlated to the
chemical yields of 4i (Figure 2b). On the basis of the results
above, the iodohydrin formation seemed to attain equilibrium
after 1 h. As shown in Scheme 3a, a moderate amount of syn-D-
of the N-aryl ring produced (S)-4y without loss of
enantioselectivity (Scheme 2c).13
In order to evaluate the TAPS catalysis established, we
conducted control experiments by using several catalysts 7−9
(Table 2). In the case of previously reported TAPS-catalyzed
Scheme 3. Mechanistic Studies
Table 2. Evaluation of TAPS Catalysis for [3 + 2] Coupling
Reaction of Isocyanates and Epoxides
11 was epimerized to anti-D-11 during the course of the
reaction, while trans-D-2i maintained the stereochemistry at the
β-carbon. This observation evidently disclosed halide ion
substitution on alkyl halides started occurring. Next, iodohydrin
11 was reacted with isocyanate 3b to gain insight into the
second step (Scheme 3b). It should be noted that ylide 10
advantageously produced carbamate 12 in comparison with
other Brønsted bases.15 We confirmed that treatment of this
carbamate 12 with 1 equiv of ylide 10 leads to formation of the
oxazolidinone 4t and regeneration of TAPS 1b (Scheme 3c).
Importantly, although the cyclization proceeded insufficiently at
25 °C, elevated temperature facilely enabled the process to
yield both 4t and 1b. Supported by these experiments, we
propose the mechanism of TAPS-catalyzed formal [3 + 2]
cycloaddition in Figure 1. The catalysis involves a three-step
sequence: (i) halohydrin formation; (ii) carbamate formation;
(iii) oxazolidinone formation. It is strongly suggested that the
ring-closing step determines the rate of the whole trans-
formation, where a less acidic N−H proton needs to be
released. The pivotal factor of a successful coupling between 2
and 3 would be a rapid halohydrin addition to 3, which
prevents decomposition of 3, generating carbamate intermedi-
ate 12 as a resting state of the overall process.
CO2 fixation, it has been revealed that the epoxide-adduct 7a
was formed in situ that could activate epoxides to afford cyclic
carbonates.10a Interestingly, only a 31% yield of 4r (R1 = allyl)
was obtained in the reaction of 2g with 3b using 7a, which
strongly suggested that the adduct 7a was not an active species
in the present reaction (Table 2, entry 2). Furthermore,
compared with TAPS 8a (ortho-OH), the use of 8b (meta-
OH), 8c (para-OH), and 9 led to decreased yields of 4r (Table
2, entries 3−6). The effect of catalysts was also investigated for
epoxide 2i (R1 = nBu), and as expected, 1b marked the highest
yield with similar tendency (Table 2, entries 7−12).14 This
result motivated us to scrutinize the mechanism of the [3 + 2]
coupling reaction. First, we conducted 1H NMR experiments in
CDCl3 at 25 °C to monitor the behavior of the catalysts
(Figure 2a; see Supporting Information (SI)). When TAPS 1b
was mixed with a stoichiometric amount of epoxide 2i, the Ar−
H protons on the cresol moiety significantly shifted upfield. It
should be emphasized that iodohydrin 11 was observed within
10 min upon the addition of 2i. At the period of 60 min, the
aromatic protons gave sharp signals, indicating the generation
of the corresponding ylide 10. We postulated that the
difference of catalytic ability might be attributed to the epoxide
ring-opening step, and attempted the same experiments for
catalysts 8a−c and 9 as well. Indeed, TAPS 1b showed much
In summary, we have demonstrated a TAPS-catalyzed [3 +
2] coupling reaction of isocyanates and epoxides for the
synthesis of oxazolidinones. This method was found to be
robust for a series of isocyanates and applicable to various
C
DOI: 10.1021/acs.orglett.7b02722
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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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.7b02722.
Experimental procedures; spectroscopic data for all new
compounds (PDF)
Crystallographic data for (S)-4y (CIF)
(7) Speranza, G. P.; Peppel, W. J. J. Org. Chem. 1958, 23, 1922.
(8) Selected examples of metal salts catalysis. Lithium halides:
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J. E.; Kauffman, W. J. Tetrahedron Lett. 1971, 12, 809. (d) Aroua, L.;
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Commun. 2014, 50, 15187. (c) Wang, P.; Qin, J.; Yuan, D.; Wang, Y.;
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(10) (a) Toda, Y.; Komiyama, Y.; Kikuchi, A.; Suga, H. ACS Catal.
2016, 6, 6906. (b) Toda, Y.; Sakamoto, T.; Komiyama, Y.; Kikuchi, A.;
Suga, H. ACS Catal. 2017, 7, 6150.
(11) The result of the reaction using enantiopure styrene oxide (S)-
2k is shown in SI.
(12) Berlin, I.; Zimmer, R.; Thiede, H.-M.; Payan, C.; Hergueta, T.;
Robin, L.; Puech, A. J. Br. J. Clin. Pharmacol. 1990, 30, 805.
(13) This transformation can be an alternative method instead of
handling p-iodophenyl isocyanate, and several coupling reactions
would be applicable to (S)-4y for the synthesis of bioactive
compounds. (a) Gregory, W. A.; Brittelli, D. R.; Wang, C.-L. J.;
Kezar, H. S.; III; Carlson, R. K.; Park, C.-H.; Corless, P. F.; Miller, S. J.;
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A.; Frost, C. G. Eur. J. Org. Chem. 2016, 2016, 1305.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ytoda@shinshu-u.ac.jp (Y.T.).
*E-mail: sugahio@shinshu-u.ac.jp (H.S.).
ORCID
Yasunori Toda: 0000-0001-9725-9438
Author Contributions
†S.G., S.T., and Y.K. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by the Japan Society for the
Promotion of Science (JSPS) through a Grant-in-Aid for Young
Scientists (B) (Grant No. JP17K14483). We gratefully
acknowledge the alumni association “Wakasatokai” of Faculty
of Engineering, Shinshu University.
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