An expedient stereoselective and chemoselective synthesis of bicyclic oxazolidinones from quinols and isocyanates

Article abstract of DOI:10.1039/c3ob00047h

A mild and efficient synthesis of bicyclic oxazolidinones from quinols and isocyanates, under DBU-mediated conditions at room temperature, is described. The aza-Michael addition to substituted cyclohexadienones is stereoselective and chemoselective. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob00047h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
An expedient stereoselective and chemoselective
synthesis of bicyclic oxazolidinones from quinols
Cite this: Org. Biomol. Chem., 2013, 11,
2939
and isocyanates†
Jinzhu Zhang,a,b Jing Wu,a,b Zhiwei Yin,a,b Haisu Zeng,a,b Kunal Khanna,a,b
Chunhua Huc and Shengping Zheng*a,b
Received 9th January 2013,
Accepted 9th March 2013
DOI: 10.1039/c3ob00047h
www.rsc.org/obc
A mild and efficient synthesis of bicyclic oxazolidinones from driving force of aromatization after
a [3,3]-sigmatropic
quinols and isocyanates, under DBU-mediated conditions at room rearrangement or an SNi′ reaction in the quinol system could
temperature, is described. The aza-Michael addition to substituted affect the reactivity. Therefore, we decided to explore the reac-
cyclohexadienones is stereoselective and chemoselective.
tion between quinols and isocyanates to see whether a [3,3]-
sigmatropic rearrangement or an aza-Michael addition ensues
after formation of the carbamate intermediates (Scheme 1). A
[3,3]-sigmatropic rearrangement or an SNi′ reaction would lead
to phenols as products, while the aza-Michael reaction would
afford bicyclic oxazolidinones. Oxazolidinones are an impor-
tant family of compounds widely used as chiral auxiliaries,11
ligands for metal catalysis,12 and antibiotics against methicil-
lin-resistant, vancomycin-resistant and penicillin-resistant
pathogens.13 Synthesis of oxazolidinones has been well-
documented in the literature.14 Many new methods have been
developed recently, such as IBX-mediated cyclization of
carbamates,15 Hofmann rearrangement of hydroxypropion-
amide,16 iron(II)-catalyzed nitrogen transfer of unsaturated
Quinols are important skeletons frequently found in bioactive
natural products.1 They are also useful synthetic building
blocks, serving as valuable intermediates in the total synthesis
of natural products.2 One of the main reaction sites on quinols
is the tertiary alcohol moiety. A well-known reaction involving
this site is cyclohexadienone–phenol rearrangement,3 which
leads to either hydroquinone or resorcinol products.4 Recently
new attention has been focused on asymmetric desymmetriza-
tion of the double bonds in quinol derivatives.5 Sorgi et al.
found that reaction between quinol and diketene in the pres-
ence of
a catalytic DMAP afforded a [3,3]-sigmatropic
rearrangement product arylacetone.6 On the other hand,
Harned and coworkers recently prepared bicyclic lactones via
an intramolecular Michael addition of quinol malonates.7 The
subtle difference between the starting materials (acetoacetates
vs. malonates) led to markedly different products, demonstrat-
ing rich reactivity in the cyclohexadienone setting in quinol
derivatives.
Thermal or acid-mediated migration of the acyloxy group
around the cyclohexadienone ring in quinol esters through a
[3,3]- or [1,3]-sigmatropic rearrangement has been known.8
Moreover, mercury-promoted and anionic [3,3]-sigmatropic
rearrangements for carbamates have also been reported.9
Although carbamates have been reported to undergo intra-
molecular Michael addition to unsaturated esters,10 the big
aDepartment of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10065,
USA. E-mail: szh0007@hunter.cuny.edu; Fax: +1 212-772-5332;
Tel: +1 212-396-6322
bThe Graduate Center, The City University of New York, 365 5th Avenue, New York,
NY 10016, USA
cDepartment of Chemistry, New York University, New York, NY 10003, USA
†Electronic supplementary information (ESI) available. CCDC 916845, 921685
and 916844. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3ob00047h
Scheme 1 Synthetic plan.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2939–2942 | 2939

View Article Online
Communication
Organic & Biomolecular Chemistry
alkoxycarbonyl azides,17 rhodium-18 and silver-catalyzed19 C–H
insertion of carbamates, and iron(II)-catalyzed aminobromina-
tion of allyl N-tosyloxy-carbamates.20 We reported herein our
findings on the one-step stereoselective and chemoselective
synthesis of bicyclic oxazolidinones from quinols.
Table 2 Substrate scope of the stereoselective cyclization
Under Sorgi’s conditions6 quinol 1a reacted with phenyl
isocyanate afforded 30% yield of a product which was charac-
terized as 3a,7a-dihydro-7a-methyl-3-phenyl-2,5(3H,4H)-benz-
oxazoledione (a bicyclic oxazolidinone) 2a, an aza-Michael
product from the carbamate intermediate. Under Harned’s
conditions7 (Cs2CO3, CH3CN), a messy mixture of products
was obtained. We next optimized the conditions for cyclization
and found that the reaction gave the best yield when DBU was
chosen as the base and methylene chloride as the solvent (see
Table 1).
Using a wide range of quinols, which are readily prepared
in one step from commercially available phenols,21 we explore
the generality of this reaction with phenyl isocyanate. Repre-
sentative results are shown in Table 2. For unsubstituted
quinols, stereoselective addition gave cis-fused bicyclic oxazo-
lidinones in good to excellent yields (2a–2i). The relative con-
figuration of cis ring fusion was confirmed by NOESY
spectroscopy data and further confirmed by X-ray crystallogra-
phy‡ (compounds 2n, 2q and 2x). For monosubstituted
quinols, the substrates cyclized chemoselectively to the unsub-
stituted conjugate double bonds (2j–2n). For bromo quinol
1m, surprisingly, our result was different from the cyclization
of quinol malonates reported by the Harned group.7 Harned
and coworkers obtained a cyclopropane product 4 which
resulted from cyclization from the more electron-deficient
bromo-substituted double bond in malonate 3 (Scheme 2).
While in our case, the nitrogen added to the unsubstituted
double bond, which was clearly indicated by one nonaromatic
alkenic proton and two methylene protons in the proton NMR
Table 1 Optimization of the reaction conditionsa
Entry
Base
Solvent
Yieldc (%)
1
2
3
4
5
6
7
8
9
DMAPb
Cs2CO3
Cs2CO3
NaH
CH2Cl2
CH3CN
CH2Cl2
THF
CH3CN
CH2Cl2
THF
31
Messy
Messy
Messy
62
88
69
DBUb
DBU
DBU
DBU
DBU
CHCl3
Toluene
70
56
a Unless otherwise noted, all reactions were performed with 1a
(0.3 mmol), PhNCO (0.36 mmol), base (15 mol%) in solvent (2 mL) at
room temperature for 3 h. b DMAP: 4 dimethylamino-pyridine; DBU:
1,8-diazabicycloundec-7-ene. c Isolated yields.
Scheme 2 Different modes of cyclization.
2940 | Org. Biomol. Chem., 2013, 11, 2939–2942
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Communication
of 2m. Furthermore, the structure of 2n was unambiguously
confirmed by X-ray crystallography. For reaction of bromo
Acknowledgements
quinols with alkyl isocyanates, only an intractable messy We are grateful to Professors Richard Franck, Randy Mootoo
mixture was obtained. Neither oxazolidinones nor aziridines and Klaus Grohmann for helpful discussions. We also thank
could be isolated. The mode of cyclization of bromo quinols Drs Cliff Soll and Matthew Devany for mass spectrometric and
is governed by a subtle stereoelectronic effect, as further NMR spectroscopic assistance respectively. Financial support
demonstrated in substrate 2o. Since a bromo substituent is from Hunter College, PSC-CUNY and the Bertha and Louis
similar in size to a methyl group, the inductive effect of the Weinstein Research Grant is gratefully acknowledged. C. H.
bromo group controlled the cyclization mode in 2o. The would like to acknowledge the support from the Molecular
stereochemistry of 2o was determined by comparison of its Design Institute at the Department of Chemistry of New York
coupling constant with that of 2q. For 3,5-disubstituted University.
quinol 1p, cyclization afforded 2p in good yield. For 2,6-disub-
stituted quinols 1q and 1r, an inseparable mixture of isomers
was obtained. All-cis isomers are the major products according
Notes and references
to nOe spectroscopy. For 2q, two recrystallizations afforded
the pure cis isomer, whose stereochemistry was confirmed by
X-ray crystallography (Fig. 1). It should be noted that the
stereochemistry of the alpha methyl to the carbonyl group in
2q is different from the Harned’s lactone cases.7 To
further explore the scope of this reaction, we next focused on
the generality of the addition partner isocyanates. Ethyl iso-
cyanate, butyl isocyanate, benzyl isocyanate, benzoyl isocya-
nate and tosyl isocyanate are all good partners to afford good
to excellent yields (2s–2w). Bicyclic 4-hydroxycyclohexenone
1x21a is also a good substrate for the aza-Michael addition,
which afforded tricyclic oxazolidinone 2x as the product
(Scheme 3).
‡Crystal data: 2n: C15H14BrNO3, M = 336.18, monoclinic, space group P21/c, a =
11.3435(10), b = 5.9481(5), c = 20.6935(18) Å, β = 103.5110(10)°, V = 1357.6(2) Å3,
T = 100(2) K, Z = 4, 25 544 reflections measured, 3362 independent reflections
(Rint = 0.0479); R1 = 0.0248 (I > 2σ(I)), 0.0338 (all data); wR(F2) = 0.0532 (I > 2σ(I)),
0.0564 (all data); CCDC number 916845. 2q: C16H17NO3, M = 271.31, monoclinic,
space group P21/c, a = 14.8275(13), b = 7.8956(7), c = 11.8515(11) Å, β = 94.9930
(10)°, V = 1382.2(2) Å3, T = 100(2) K, Z = 4, 26 236 reflections measured, 3432
independent reflections (Rint = 0.0326); R1 = 0.0354 (I > 2σ(I)), 0.0409 (all data);
wR(F2)
15H15NO4, M = 273.28, monoclinic, space group P21/n, a = 6.1123(4), b =
= 0.0897 (I > 2σ(I)), 0.0945 (all data); CCDC number 921685. 2x:
C
17.9740(12), c = 11.7487(8) Å, β = 96.0380(10)°, V = 1283.58(15) Å3, T = 100(2) K,
Z = 4, 26 919 reflections measured, 3196 independent reflections (Rint = 0.0302);
R1 = 0.0424 (I > 2σ(I)), 0.0483 (all data); wR(F2) = 0.1124 (I > 2σ(I)), 0.1176
(all data); CCDC number 916844.
In conclusion, we have developed a one-step stereoselective
and chemoselective synthesis of bicyclic oxazolidinones from
quinols in good to excellent yields. Starting from readily avail-
able phenols and isocyanates it affords oxazolidinones in an
effective two-step procedure. These highly functionalized het-
erocycles could be of interest to the pharmaceutical industry.
Synthesis of aminocyclitols and carbazoles from these oxazo-
lidinones is ongoing in our lab.
1 (a) M. Kaneda, T. Naid, T. Kitahara, S. Nakamura, T. Hirata
and T. Suga, J. Antibiot., 1988, 41, 602; (b) H. Kuwajima,
M. Takahashi, M. Ito, H. Wu, K. Takaishi and K. Inoue,
Phytochemistry, 1993, 33, 137; (c) N. Abe, O. Sugimoto,
K. Tanji and A. Hirota, J. Am. Chem. Soc., 2000, 122, 12606;
(d) S. Urban, J. W. Blunt and M. H. G. Munro, J. Nat. Prod.,
2002, 65, 1371; (e) A.-S. Lin, F.-R. Chang, C.-C. Wu,
C.-C. Liaw and Y.-C. Wu, Planta Med., 2005, 71, 867;
(f) G. Zappiaa, M. P. Menendezb, C. Sampaio de Andrade
Limac and B. Botta, Nat. Prod. Res., 2009, 23, 665.
2 (a) Z. You, A. H. Hoveyda and M. L. Snapper, Angew. Chem.,
Int. Ed., 2009, 48, 547; (b) T. A. Wenderski, S. Huang and
T. R. R. Pettus, J. Org. Chem., 2009, 74, 4104; (c) Q. Gu and
S.-L. You, Chem. Sci., 2011, 2, 1519; (d) P. D. Brown,
A. C. Willis, M. S. Sherburn and A. L. Lawrence, Org. Lett.,
2012, 14, 4537; (e) K. Zhao, G.-J. Cheng, H. Yang, H. Shang,
X. Zhang, Y.-D. Wu and Y. Tang, Org. Lett., 2012, 14, 4878.
3 (a) G. R. Clemo, R. D. Haworth and E. Walton, J. Chem.
Soc., 1930, 1110; (b) A. L. Wilds and C. Djerassi, J. Am.
Chem. Soc., 1946, 68, 1716; (c) B. Miller, Acc. Chem. Res.,
1975, 8, 245.
Fig. 1 Molecular structures of 2q and 2x with ellipsoids set at 50% probability
level.
4 (a) S. Goodwin and B. Witkop, J. Am. Chem. Soc., 1957, 79,
179; (b) E. Hecker and B. Meyer, Chem. Ber., 1964, 97, 1926;
(c) A. Planas, J. Tomás and J.-J. Bonet, Tetrahedron Lett.,
1987, 28, 471; (d) G. R. Tian, A. Mori, N. Kato and
H. Takeshita, Bull. Chem. Soc. Jpn., 1989, 62, 506;
(e) H. Uno, Y. Shiraishi, Y. Matsushima, A. Yayama and
H. Suzuki, Bull. Chem. Soc. Jpn., 1991, 64, 842; (f) H. Uno,
Scheme 3 Synthesis of tricyclic oxazolidinone.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 2939–2942 | 2941

View Article Online
Communication
Organic & Biomolecular Chemistry
A. Yamama and H. Suzuki, Chem. Lett., 1991, 1165; 12 (a) M. Murakata, H. Tsutsui and O. Hoshino, Org. Lett.,
(g) E. N. Pitsinos, V. I. Moutsos and O. Vageli, Tetrahedron
Lett., 2007, 48, 1523; (h) I. Kim, K. Kim and J. Choi, J. Org.
Chem., 2009, 74, 8492.
5 (a) N. T. Vo, R. D. M. Pace, F. O’Hara and M. J. Gaunt,
J. Am. Chem. Soc., 2008, 130, 404; (b) Q. Gu, Z.-Q. Rong,
C. Zheng and S.-L. You, J. Am. Chem. Soc., 2010, 132, 4056;
(c) R. Sunasee and D. L. J. Clive, Chem. Commun., 2010, 46,
701; (d) Cf. ref. 2c; (e) D. M. Rubush, M. A. Morges,
2001, 3, 299; (b) H. C. Ma, S. Wu, Q. S. Sun and Z. Q. Lei,
Lett. Org. Chem., 2010, 7, 212.
13 (a) D. J. Diekema and R. N. Jones, Lancet, 2001, 358, 1975;
(b) D. K. Hutchinson, Curr. Top. Med. Chem., 2003, 3, 1021;
(c) M. R. Barbachyn and C. W. Ford, Angew. Chem., Int. Ed.,
2003, 42, 2010–2023; (d) K. L. Leach, S. J. Brickner,
M. C. Noe and P. F. Miller, Ann. N. Y. Acad. Sci., 2011, 1222,
49.
B. J. Rose, D. H. Thamm and T. Rovis, J. Am. Chem. Soc., 14 N. Pandit, R. K. Singla and B. Shrivastava, Int. J. Med.
2012, 134, 13554; (f) W. Wu, X. Li, H. Huang, X. Yuan, Chem., 2012, 159285, DOI: 10.1155/2012/159285, 24 pages.
J. Lu, K. Zhu and J. Ye, Angew. Chem., Int. Ed., 2013, 52, 15 K. C. Nicolaou, P. S. Baran, Y.-L. Zhong and J. A. Vega,
1743. For a review, see: (g) C.-X. Zhou, W. Zhang and
S.-L. You, Angew. Chem., Int. Ed., 2012, 51, 12662.
6 K. L. Sorgi, L. Scott and C. A. Maryanoff, Tetrahedron Lett.,
1995, 36, 3597.
Angew. Chem., Int. Ed., 2000, 39, 2525.
16 C. Yu, Y. Jiang, B. Liu and L. Hu, Tetrahedron Lett., 2001,
42, 1449.
17 T. Bach, B. Sschlummer and K. Harms, Chem.–Eur. J., 2001,
7 R. Tello-Aburto, K. A. Kalstabakken, K. A. Volp and
A. M. Harned, Org. Biomol. Chem., 2011, 9, 7849.
8 (a) S. Harusawa, M. Miki, J.-I. Hirai and T. Kurihara, Chem.
7, 2581.
18 C. G. Espino and J. Du Bois, Angew. Chem., Int. Ed., 2001,
40, 598.
Pharm. Bull., 1985, 33, 899; (b) H. Suzuki, Y. Shiraishi, 19 Y. Cui and C. He, Angew. Chem., Int. Ed., 2004, 43, 4210.
K. Shimokawa and H. Uno, Chem. Lett., 1988, 127.
9 (a) Y. Endo, S. Hizatate and K. Shudo, Synlett, 1991, 649;
20 T. Kamon, D. Shigeoka, T. Tanaka and T. Yoshimitsu, Org.
Biomol. Chem., 2012, 10, 2363.
(b) L. E. Overman, C. B. Canpbell and F. M. Knoll, J. Am. 21 (a) M. C. Carreno, M. Gonzalez-Lopez and A. Urbano,
Chem. Soc., 1978, 100, 4822.
10 M. Hirama, T. Shigemoto, Y. Yamazaki and S. Ito, J. Am.
Chem. Soc., 1985, 107, 1797.
Angew. Chem., Int. Ed., 2006, 45, 2737; (b) F.-X. Felpin, Tetra-
hedron Lett., 2007, 48, 409; (c) T. Yakura, M. Omoto,
Y. Yamauchi, Y. Tian and A. Ozono, Tetrahedron, 2010, 66,
5833.
11 D. A. Evans, Aldrichimica Acta, 1982, 15, 23.
2942 | Org. Biomol. Chem., 2013, 11, 2939–2942
This journal is © The Royal Society of Chemistry 2013