Synthesis of Oxazolidin-2-ones by Tandem Cyclization of Propargylic Alcohols and Phenyl Isocyanate Promoted by Silver Catalysts as π-Lewis Acids

Article abstract of DOI:10.1055/s-0035-1560263

Highly Z-selective syntheses of oxazolidin-2-ones from propargylic alcohols containing internal alkynes and phenyl isocyanate were achieved by using a combination of silver acetate and N,N-dimethylaminopyridine. The catalytic system was applied to proparg

Full text of DOI:10.1055/s-0035-1560263

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2447–2450
letter
2447
K. Sekine et al.
Letter
Synlett
Synthesis of Oxazolidin-2-ones by Tandem Cyclization of Propar-
gylic Alcohols and Phenyl Isocyanate Promoted by Silver Catalysts
as π-Lewis Acids
Kohei Sekine
O
O
Takanori Mawatari
10 mol% AgOAc
30 mol% DMAP
Ph
OH
O
N
Ph
Tohru Yamada*
O
N
R1
R2
R1
R2
(Z)
R1
R2
Ph
Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
yamada@chem.keio.ac.jp
R3
R3
N
C O
R3
Ag+
49–99% yield
17 examples
R
R
1 = R2 = Me
1 = R2 = Ph
R3 = aryl, alkyl
Received: 06.07.2015
Accepted after revision: 08.08.2015
Published online: 09.09.2015
applied to substrates containing an internal alkyne group
under mild conditions; and (c) the corresponding exo-alke-
nyl cyclic compounds were obtained with Z-selectivity with
respect to the geometry of the C=C double bond.
DOI: 10.1055/s-0035-1560263; Art ID: st-2015-u0506-l
Abstract Highly Z-selective syntheses of oxazolidin-2-ones from prop-
argylic alcohols containing internal alkynes and phenyl isocyanate were
achieved by using a combination of silver acetate and N,N-dimethylami-
nopyridine. The catalytic system was applied to propargylic alcohols
containing alkyl-substituted alkyne groups. By considering the results
in the presence and absence of an electron-withdrawing group on the
aromatics, it was shown that the silver catalyst effectively activates the
C≡C triple bond by acting as a π-Lewis acid to produce the correspond-
ing oxazolidinones with high Z-selectivities.
Because of the advantages of silver catalysts as π-Lewis
acids, we examined the silver-catalyzed Z-selective synthe-
sis of oxazolidinones from propargylic alcohols and isocya-
nates. The cyclization reaction is a practical method for the
synthesis of oxazolidinones. Bases or group 11 metals have
been reported to promote the cyclization of the O-propar-
gylic carbamates.4 Base-, copper-, or ruthenium-catalyzed
tandem cyclizations of propargylic alcohols and isocya-
nates have also been reported.5 Some reaction conditions
can be applied to internal alkyne derivatives, but the range
of substituents at terminal positions of the alkynes was in-
adequate. For example, DBU or N-heterocyclic carbenes cat-
alyzed the highly Z-selective domino cyclization of propar-
gylic alcohol and isocyanates, but substitutions at the ter-
minal position were limited to aromatic groups.5d,e In this
communication, we report a Z-selective tandem cyclization
of propargylic alcohols and isocyanates promoted by a
combination of silver catalysts and bases (Scheme 1).
Key words silver, catalysis, cyclizations, oxazolidinones, tandem reac-
tions, isocyanates
Silver catalysts are widely used in organic reactions as
Lewis acids1 despite having several disadvantages, for ex-
ample, their frequent sensitivity to light and their poor sol-
ubility in organic solvents. Because several silver-catalyzed
cyclization reactions of alkyne or allene derivatives have re-
cently been reported,2 we decided to examine silver-cata-
lyzed or -mediated methodologies. Our group has reported
that combinations of silver salts and bases promote the cas-
cade carboxylation and cyclization of propargylic amines,
propargylic alcohols, and ketone-containing alkynes with
carbon dioxide.3 In these reactions, the silver catalysts ef-
fectively activate the C≡C triple bond from the opposite side
to the nucleophile. As a result of this anti-addition, Z-alke-
nyl heterocyclic compounds are formed stereoselectively.
The features of silver catalysts in these reactions can be
summarized as follows: (a) barely soluble but air- and
moisture-stable silver salts, such as silver acetate, were
used in common organic solvents under homogeneous con-
ditions with the addition of organic bases, for example, 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU) or 7-methyl-1,5,7-triaza-
bicyclo[4.4.0]dec-5-ene; (b) the silver catalyst system was
O
R
O
N
Ag+/base
O
(Z)
R3
R1
R2
R
R
OH
O
N
N
C O
(Z)-3
R1
R2
R1
R2
O
R3
R3
Ag+
R3 = aryl, alkyl
R
O
N
1
2
(E)
R1
R2
R3
(E)-3
Scheme 1 Silver-catalyzed one-pot synthesis of (Z)-oxazolidinones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2447–2450

2448
K. Sekine et al.
Letter
Synlett
As the first series of screenings, the propargylic alcohol
1a was used as a model substrate to evaluate several condi-
tions (Table 1). As already reported,5d DBU promoted the re-
action of the propargylic alcohol 1a and phenyl isocyanate
to afford the oxazolidinone 3a in 92% yield with a Z/E ratio
of 86:14 (Table 1, entry 1). In the presence of N,N-dimethyl-
4-aminopyridine (DMAP), the corresponding oxazolidinone
3a was not obtained at all, and the corresponding carba-
mate 2a was obtained in 78% yield (entry 2). We assumed
that DMAP, a weaker base, promoted the nucleophilic addi-
tion of the alcohol to phenyl isocyanate but was ineffective
in the cyclization step. Because of the background cycliza-
tion by DBU, we screened various silver salts by using
DMAP as the base (entries 3–5). As expected, a mixture of
silver nitrate or silver acetate with DMAP in dichlorometh-
ane formed a clear solution after stirring for 15 minutes. In
the cases of silver nitrate or silver tosylate, the correspond-
ing oxazolidinone 3a was produced in low yield together
with the intermediate 2a (entries 3 and 4, respectively). On
the other hand, silver acetate efficiently promoted the cy-
clization to give the oxazolidinone 3a in 78% yield with a
Z/E ratio of 98:2 (entry 5).6 We postulated that the silver
catalysts effectively activate the C≡C triple bond as a π-Lew-
is acid to promote the cyclization through anti-addition,
giving the Z-isomer selectively, unlike DBU (entry 1). Sever-
al solvents were investigated in attempts to improve the
yield of the oxazolidinone 3a (entries 6–9). In toluene and
chlorobenzene, the oxazolidinone 3a was obtained in more
than 80% yield, but the carbamate 2a was also formed. Fi-
nally, 1,2-dichlorobenzene turned out to be the most suit-
able solvent for promoting the cyclization, and it produced
the oxazolidinone 3a in 94% yield with a high Z-selectivity
(Z/E = 97:3).
The optimized conditions were successfully applied to
various substrates (Table 2). First, substitutions on the aro-
matics were examined. The reactions of substrates 1b
(4-Me), 1c (3-Me), and 1d (2-Me) gave the corresponding
oxazolidinones 3b–d with a high Z-selectivity regardless of
the position of the methyl group (Table 2, entries 2–4). In
the case of propargylic alcohol 1e containing a methoxy
group at the para-position, although the corresponding car-
bamate 2e still remained after 15 hours, the product 3e was
obtained in 73% yield with a high Z-selectivity (entry 5).
The fluorine-substituted propargylic alcohol 1f was trans-
formed into the oxazolidinone 3f in three hours (entry 6).
The silver catalyst system could also be applied to the alkyl-
substituted internal alkynes 1g–k. Propargylic alcohols 1g,
1h, and 1i were converted into the corresponding (Z)-alke-
nyl oxazolidinones in 71, 49, and 71% yield, respectively
(entries 7–9). In addition, alkynes substituted with a long
octyl chain or with a cyclohexyl group were converted into
the corresponding oxazolidinones 3j and 3k, respectively
(entries 10 and 11). Next, we examined alkynes terminated
with heterocyclic groups. Propargylic alcohols 1l and 1m
with a 2-thienyl and a 2-pyridyl group, respectively, were
good substrates, giving oxazolidinones 3l and 3m in moder-
Table 1 Screening of Catalysts and Solventsa
10 mol% cat.
base
O
O
Ph
OH
(1.5 equiv)
Ph
Ph
N
C O
O
N
Ph
+
O
N
H
solvent
40 °C, 12 h
(Z)
Ph
Ph
1a
2a
3a
Entry
Catalyst
Base (mol%)
Solvent
Yieldb (%) of 2a
Yieldb (%) of 3a
Z/Ec
86:14
1
2
3
4
5
6
7
8
9
none
DBU (20)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
6
92
0
d
–
DMAP (30)
DMAP (30)
DMAP (30)
DMAP (30)
DMAP (30)
DMAP (30)
DMAP (30)
DMAP (30)
78
–
–
d
AgNO3
AgOTs
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
90
<1e
7
91
96:4
98:2
96:4
97:3
96:4
97:3
21
78
82
83
88
94
toluene
PhCl
14
15
o-xylene
trace
trace
1,2-Cl2C6H4
a Reaction conditions: 1a (0.40 mmol), PhNCO (1.5 equiv), solvent (2 mL), 40 °C, 12 h.
b Isolated yield.
c Determined by GC.
d Not analyzed.
e GC yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2447–2450

2449
K. Sekine et al.
Letter
Synlett
ate yields and a high Z-selectivity (entries 12 and 13). The
reaction of the secondary propargylic alcohol 1n with phe-
nyl isocyanate gave the corresponding oxazolidinone 3n in
80% yield (entry 14). As mentioned above, the (Z)-oxazolid-
inone derivatives were selectively produced in accordance
with our previous study on silver-catalyzed cyclization of
alkyne derivatives.3
in propargylic alcohol 1p was protected as the acetal, the
reaction proceeded to give the oxazolidinone 3q in 93%
yield with a high Z-selectivity. The deprotection of oxazo-
lidinone 3q gave the oxazolidinone (Z)-3p (Z/E = 97:3). (Z)-
3p was then exposed to the reaction conditions and the Z/E
ratio was determined after 0.5, 1, 3, and 48 hours. No isom-
erization at all was observed under these conditions, elimi-
nating the possibility of isomerization of (Z)-3p to (E)-3p.
Table 2 The Application of the Optimized Conditions to Various Prop-
argylic Alcoholsa
OH
O
10 mol% AgOAc
30 mol% DMAP
1.5 equiv PhNCO
Ph
O
O
N
AgOAc (10 mol%)
OH
DMAP (30 mol%)
(Z)
1,2-Cl2C6H4
40 ºC, 18 h
Ph
Ph
R1
R2
+
O
N
O
N
C O
1,2-Cl2C6H4, 40 °C
(Z)
R3
(1.5 equiv)
R1
R2
R3
O
O
O
1q
3q
93% yield (Z/E = 97:3)
1
3
Entry Product R1
R2
R3
Time
(h)
Yieldb Z/Ec
(%) of 3
O
Ph
O
N
cat. PPTS
1
2
3a
3b
3c
3d
3e
3f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Ph
4-Tol
9
9
94
84
92
88
73
89
71
49
71
67
67
62
70
80
99
93
98:2
99:1
(Z)
H2O–acetone
reflux, 1.5 h
O
3
3-Tol
12
7
98:2
4d
5
2-Tol
97:3
3p
95% yield (Z/E = 97:3)
4-MeOC6H4
4-FC6H4
Me
15
3
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
50:50
40:60
Scheme 2 Reactions for the carbonyl-protected substrate
6
7e
8
3g
3h
3i
12
20
49
12
12
7
Comparative experiments were conducted using the
substrates 1b and 1p (Table 3). In the absence of silver salts,
substrate 1b, containing an electron-donating group, was
not converted at all into the oxazolidinone 3b. In contrast,
oxazolidinone 3p was formed in 43% yield with a Z/E ratio
of 30:70 in the absence of the silver catalyst (Table 3, entry
1). These results suggested that the substrate 1p itself is
more reactive in the cyclization step to produce the E-iso-
mer as the major product, which might explain the poor se-
Bu
9
(CH2)2Ph
(CH2)7Me
Cy
10e
11e
12
13
14
15
16
3j
3k
3l
2-thienyl
2-pyridyl
Ph
3m
3n
3o
3p
12
16
3
Me
Me
Me
Me
4-F3CC6H4
4-AcC6H4
7
Table 3 Reactions in the Absence of Silver Catalysts
a Reaction conditions: 1 (0.40 mmol), PhNCO (1.5 equiv), AgOAc (10 mol%),
DMAP (30 mol%), 1,2-Cl2C6H4 (2 mL), 40 °C.
b Isolated yield.
OH
10 mol% Lewis acid
30 mol% DMAP
O
c Determined by GC.
Ph
d AgOAc (15 mol%) and DMAP (45 mol%) were used.
e DMAP (50 mol%) was used.
1.5 equiv PhCNO
O
N
1,2-Cl2C6H4, 40 °C
(Z)
R
R
1
3
In contrast to the previous results, when we used the al-
cohols 1o and 1p, which have electron-withdrawing trifluo-
romethyl and acetyl groups, respectively, attached to the
aromatic moiety, we obtained E-isomers in similar quanti-
ties to the Z-isomers (entries 15 and 16). On the basis of a
previous report,3 we assumed that (Z)-3p was formed ini-
tially with high selectivity and that it subsequently isomer-
ized to (E)-3p as a result of the presence of the electron-
withdrawing group and/or the silver catalyst. We prepared
the oxazolidinone (Z)-3p selectively through protection of
the carbonyl group in the propargylic alcohol 1p and subse-
quent deprotection (Scheme 2). When the carbonyl group
R = 4-Me (3b)b
R = 4-Ac (3p)c
Entrya
Lewis acid
–
Yieldd (%)
Z/Ee
Yieldd (%)
Z/Ee
f
1
2
0
–
43
93
30:70
40:60
AgOAc
84
99:1
a Reaction conditions: 1 (0.40 mmol), PhNCO (1.5 equiv), AgOAc (10
mol%), DMAP (30 mol%), 1,2-Cl2C6H4 (2 mL), 40 °C.
b 9 h.
c 7 h.
d Isolated yield
e Determined by GC.
f Not analyzed.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2447–2450

2450
K. Sekine et al.
Letter
Synlett
lectivity toward the Z-isomers (entry 2). Moreover, the sil-
ver catalyst is assumed to promote a different reaction
pathway, for example, by acting as a Lewis acid to an elec-
tron-withdrawing group.7 In other words, for substrates
1a–n and 1q, which were transformed into the correspond-
ing (Z)-oxazolidinones with a high selectivity, the silver cat-
alyst plays a crucial role as a π-Lewis acid in efficiently pro-
moting the cyclization through anti-addition and produc-
ing the corresponding oxazolidinones with a high Z-
selectivity.
In summary, the highly Z-selective oxazolidinone syn-
theses from propargylic alcohols containing internal
alkynes and phenyl isocyanate were achieved by the combi-
nation of AgOAc and DMAP. The catalytic system was ap-
plied to propargylic alcohols bearing alkyl-substituted
alkynes. Considering the results with or without an elec-
tron-withdrawing group on the aromatics, it was found that
the silver catalyst effectively activated the C–C triple bond
as a -Lewis acid to produce the corresponding oxazolidi-
nones with high Z-selectivities.
J. Org. Chem. 2014, 7413. (n) Gronnier, C.; Faudot dit Bel, P.;
Henrion, G.; Kramer, S.; Gagosz, F. Org. Lett. 2014, 16, 2092.
(o) Meng, X.; Liao, P.; Liu, J.; Bi, X. Chem. Commun. 2014, 50,
11837. (p) Sheng, J.; Fan, C.; Ding, Y.; Fan, X.; Wu, J. Chem.
Commun. 2014, 50, 4188. (q) Yang, L.; Ma, Y.; Song, F.; You, J.
Chem. Commun. 2014, 50, 3024.
(3) (a) Yamada, W.; Sugawara, Y.; Cheng, H.-M.; Ikeno, T.; Yamada,
T. Eur. J. Org. Chem. 2007, 2604. (b) Yoshida, S.; Fukui, K.;
Kikuchi, S.; Yamada, T. Chem. Lett. 2009, 38, 786. (c) Yoshida, S.;
Fukui, K.; Kikuchi, S.; Yamada, T. J. Am. Chem. Soc. 2010, 132,
4072. (d) Kikuchi, S.; Yoshida, S.; Sugawara, Y.; Yamada, W.;
Cheng, H.-M.; Fukui, K.; Sekine, K.; Iwakura, I.; Ikeno, T.;
Yamada, T. Bull. Chem. Soc. Jpn. 2011, 84, 698. (e) Kikuchi, S.;
Sekine, K.; Ishida, T.; Yamada, T. Angew. Chem. Int. Ed. 2012, 51,
6989. (f) Ishida, T.; Kikuchi, S.; Tsubo, T.; Yamada, T. Org. Lett.
2013, 15, 848. (g) Ishida, T.; Kikuchi, S.; Yamada, T. Org. Lett.
2013, 15, 3710. (h) Sekine, K.; Takayanagi, A.; Kikuchi, S.;
Yamada, T. Chem. Commun. 2013, 49, 11320. (i) Ishida, T.;
Kobayashi, R.; Yamada, T. Org. Lett. 2014, 16, 2430. (j) Ugajin, R.;
Kikuchi, S.; Yamada, T. Synlett 2014, 25, 1178.
(4) (a) Kimura, M.; Kure, S.; Yoshida, Z.; Tanaka, S.; Fugami, K.;
Tamaru, Y. Tetrahedron Lett. 1990, 31, 4887. (b) Tamaru, Y.;
Kimura, M.; Tanaka, S.; Kure, S.; Yoshida, Z. Bull. Chem. Soc. Jpn.
1994, 67, 2838. (c) Ritter, S.; Horino, Y.; Lex, J.; Schmalz, H.-G.
Synlett 2006, 3309. (d) Ramesh, R.; Chandrasekaran, Y.; Megha,
R.; Chandrasekaran, S. Tetrahedron 2007, 63, 9153.
Supporting Information
(5) (a) Shachat, N.; Bagnell, J. J. Jr. J. Org. Chem. 1963, 28, 991.
(b) Stoffel, P. J.; Speziale, A. J. J. Org. Chem. 1963, 28, 2814.
(c) Ohe, K.; Ishihara, T.; Chatani, N.; Kawasaki, Y.; Murai, S.
J. Org. Chem. 1991, 56, 2267. (d) Kim, W. S.; Yoon, E. Y.; Jo, K. A.;
Kang, E. J. Bull. Korean Chem. Soc. 2011, 32, 3158. (e) Jo, K. A.;
Maheswara, M.; Yoon, E.; Lee, Y. Y.; Yun, H.; Kang, E. J. J. Org.
Chem. 2012, 77, 2924. (f) Alamsetti, S. K.; Persson, A. K.; Jiang,
T.; Bäckvall, J. E. Angew. Chem. Int. Ed. 2013, 52, 13745. (g) Li, D.
Y.; Chen, H. J.; Liu, P. N. Adv. Synth. Catal. 2015, 357, 1193.
(6) (4Z)-4-Benzylidene-5,5-dimethyl-3-phenyl-1,3-oxazolidin-
2-one; Typical Procedure
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560263.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
References and Notes
(1) (a) Silver in Organic Chemistry; Harmata, M., Ed.; Wiley-VHC:
Weinheim, 2010. (b) Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev.
2008, 108, 3149. (c) Álvarez-Corral, M.; Muñoz-Dorado, M.;
Rodríguez-García, I. Chem. Rev. 2008, 108, 3174. (d) Naodovic,
M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132. (e) Yamamoto, Y.
Chem. Rev. 2008, 108, 3199.
A mixture of AgOAc (6.7 mg, 10 mol%) and DMAP (14.7 mg, 30
mol%) in 1,2-Cl2C6H4 (0.5 mL) was stirred for 15 min under N2, A
solution of the propargylic alcohol 1a (64.1 mg, 0.4 mmol) in
1,2-Cl2C6H4 (0.75 mL) was added, followed by a solution of
PhNCO (65 μL, 1.5 equiv) in 1,2-Cl2C6H4 (0.75 mL), and the
mixture was stirred at 40 °C for 9 h. The reaction was quenched
with H2O, and the mixture was extracted with EtOAc (3 ×). The
organic layers were combined, washed with brine, and dried
(Na2SO4). The E/Z ratio was measured by GC analysis of the
crude mixture. The solvent was then removed under reduced
pressure, and the residue was purified by column chromatogra-
phy (silica gel, hexane–EtOAc) to give oxazolidinone 3a as color-
less solid; yield: 105.4 mg (94%); 1H NMR (400 MHz, CDCl3):
δ = 1.73 (s, 6 H), 5.63 (s, 1 H), 6.66 (d, J = 7.3 Hz, 2 H), 6.82–6.92
(m, 3 H), 6.98–7.06 (m, 5 H).
(2) For selected examples, see: (a) Sai, M.; Matsubara, S. Org. Lett.
2011, 13, 4676. (b) Wang, Y.; Zhu, L.; Zhang, Y.; Hong, R. Angew.
Chem. Int. Ed. 2011, 50, 2787. (c) Zhang, X.; Zhou, Y.; Wang, H.;
Guo, D.; Ye, D.; Xu, Y.; Jiang, H.; Liu, H. Green Chem. 2011, 13,
397. (d) Wang, Y.; Zheng, K.; Hong, R. J. Am. Chem. Soc. 2012,
134, 4096. (e) Chioua, M.; Soriano, E.; Infantes, L.; Jimeno, M. L.;
Marco-Contelles, J.; Samadi, A. Eur. J. Org. Chem. 2013, 35.
(f) Gao, M.; He, C.; Chen, H.; Bai, R.; Cheng, B.; Lei, A. Angew.
Chem. Int. Ed. 2013, 52, 6958. (g) Hu, Y.; Yi, R.; Wu, F.; Wan, B.
J. Org. Chem. 2013, 78, 7714. (h) Brioche, J.; Meyer, C.; Cossy, J.
Org. Lett. 2013, 15, 1626. (i) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.; Bi,
X. Angew. Chem. Int. Ed. 2013, 52, 6953. (j) Liu, J.; Xie, X.; Liu, Y.
Chem. Commun. 2013, 49, 11794. (k) Verma, K. A. K.;
Choudhary, D.; Saunthwal, R. K.; Rustagi, V.; Patel, M.; Tiwari, R.
J. Org. Chem. 2013, 78, 6657. (l) Wong, V. H. L.; Hor, T. S. A.; Hii,
K. K. Chem. Commun. 2013, 49, 9272. (m) Breman, A. C.; Ruiz-
Olalla, A.; van Maarseveen, J. H.; Ingemann, S.; Hiemstra, H. Eur.
(7) It is also possible that isomerization of the vinylsilver interme-
diate produced the (E)-oxazolidinone, but the detail remains
unclear.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2447–2450