Oxazolidinone-promoted, torquoselective Nazarov cyclizations

Article abstract of DOI:10.1021/ol300316a

Oxazolidinones are powerful promoters of the Nazarov reaction, enabling the cyclization of conventionally resistant substrates to be achieved under mild conditions. They exert excellent regio-and torquoselective control in both the conventional Nazarov reaction giving cyclopentenones and in the "interrupted" Nazarov reaction, giving more highly substituted multistereocenter containing products.

Full text of DOI:10.1021/ol300316a

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1732–1735
Oxazolidinone-Promoted,
Torquoselective Nazarov Cyclizations
Daniel J. Kerr,† Michael Miletic,† Jason H. Chaplin,† Jonathan M. White,‡ and
Bernard L. Flynn*,†
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences,
Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia, and
Bio21 Institute, School of Chemistry, University of Melbourne, Parkville, Victoria 3010,
Australia
bernard.flynn@monash.edu
Received February 9, 2012
ABSTRACT
Oxazolidinones are powerful promoters of the Nazarov reaction, enabling the cyclization of conventionally resistant substrates to be achieved
under mild conditions. They exert excellent regio- and torquoselective control in both the conventional Nazarov reaction giving cyclopentenones
and in the “interrupted” Nazarov reaction, giving more highly substituted multistereocenter containing products.
Nazarov cyclization of divinyl and aryl vinyl ketones 1
offers access to a diverse array of cyclopentanoids 4,
including cyclopentenones, indenones, and other ring
fused arrangements (Scheme 1).1 This scope is further
enhanced by the ability to trap the oxyallyl cation inter-
mediate 3 with nucleophiles (Nu) and dipolarophiles,
giving more elaborate cyclopentanoid products 5 and
6.2 The breadth of available cyclopentyl structures acces-
sible by Nazarov cyclization and the capacity to use this
reaction in multibond and multistereocenter form-
ing reaction cascades provide significant impetus for
the development of enantioselective (torquoselective)
versions of this reaction.3 While chiral acid catalysis is
effective for activated substrates bearing strong electron
donors, e.g., 1 (X = OR), most substrates require high
Scheme 1. Nazarov Reaction
† Monash University.
‡ University of Melbourne.
(1) For reviews of the Nazarov reactions, see: (a) Denmark, S. E. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Chapter 5.6.3, pp 751. (b) Tius, M. Eur. J.
Org. Chem. 2005, 2193. (c) Pellissier, H. Tetrahedron 2005, 61, 6479. (d)
Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577. (e) Vaidya, T.;
Eisenberg, R.; Frontier, A. J. ChemCatChem 2011, 3, 1531. (f) Shimada,
N.; Stewart, C; Tius, M. A. Tetrahedron 2011, 67, 5851.
(2) For a recent review, see: (a) Grant, T. N.; Rieder, C. J.; West,
F. G. Chem. Commun. 2009, 5676. For an alternative approach to
trapping 3 based on WagnerꢀMeervein rearrangements, see: (b) Huang,
J.; Lebuf, D.; Frontier, A. J. J. Am. Chem. Soc. 2011, 133, 6307. (c)
Lebuf, D.; Huang, J.; Gandon, V.; Frontier, A. J. Angew. Chem., Int. Ed.
2011, 50, 10981.
acid concentrations and are not conducive to catalysis.4
Accordingly, we have sought a chiral activating group X,
which can promote the cyclization of even the most
(4) (a) Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett. 2003, 5, 4931.
(b) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J.
Angew. Chem., Int. Ed. 2007, 46, 2097. (c) Cao, P.; Deng, C.; Zhou,
Y.-Y.; Sun, X.-L.; Zheng, J.-C.; Xie, Z.; Tang, Y. Angew. Chem., Int. Ed.
2010, 49, 4463.
(3) For reviews on asymmetric Nazarov cyclizations, see refs 1e and
1f.
r
10.1021/ol300316a
Published on Web 03/28/2012
2012 American Chemical Society

Table 1. Synthesis of Nazarov Precursors 10 and Their Cyclization to Cyclopentanoids 11
a See the Supporting Information for details of these couplings. b PMP = 4-methoxyphenyl. c Yield is for major diastereomer (isolated),
diastereomeric ratio (dr) determined using H NMR of the crude reaction mixture; a dr >20:1 indicates no other diastereomer was observable by
1
1H NMR. d Reaction conditions: MeSO3H (2ꢀ10 equiv) in CH2Cl2, 1,2-dichloroethane, or toluene at rt or heating, depending on substrate; see the
Supporting Information for details. e Cyclized using 2 equiv of TfOH in CH2Cl2 at 40 °C.
resistant substrates 1, torquoselectively, and that can
control the regiochemical placement of the double bond
in 4a/b and nucleophiles (Nu) in 5.5 In previous work, we
explored the use of the Evans’ oxazolidinones linked
(5) For asymmetric Nazarov cyclization of allenyl vinyl ethers using
chiral auxiliaries, see: (a) Berger, G. O.; Tius, M. A. J. Org. Chem. 2007,
72, 647. (b) See also ref 1f and references cited therein.
(6) (a) Kerr, D. J.; Metje, C.; Flynn, B. L. Chem. Commun. 2003,
1380. (b) Kerr, D. J.; Flynn, B. L. J. Org. Chem. 2010, 75, 7073.
Org. Lett., Vol. 14, No. 7, 2012
1733

through a carbonyl group (X = A) in the torquoselective
Nazarov cyclizations of 1 to 4a (Scheme 1).6 While this
group had a significant influence of the regiochemical
placement of the double bond, favoring 4a over 4b, only
quite modest diastereomeric ratios (dr) could be achieved
(dr = 3:1). In this work, we describe the preparation of
Nazarov substrates 1 bearing a related auxiliary, wherein
the carbonyl linker has been exluded (X = B). These
auxiliaries promote the Nazarov cyclization of a broad
range of substrates, giving excellent torquo- and regio-
selective access to 4a and 5.
Synthesis of Aryl Vinyl and Divinyl Ketones. The dearth
of effective methods for the efficient stereoselective synthe-
sis to divinyl and aryl vinyl ketones 1 is a limitation of the
Nazarov reaction. In this work, we have developed ready
access to a series of oxazolidinone substituted Nazarov
substrates 10aꢀm from ynamides 7 using several different
palladium-mediated coupling techniques (Table 1 and
Scheme 2).7,8
the alkyne. This could be addressed by exchanging the
phenyloxazolidinone for the isopropyloxazolidinone 7d,
which undergoes more regioselective syn-hydrostannyla-
tion 7d f 8d, giving a higher yield of 10e (83%) in
reductive coupling with 9a (entry 5, Table 1).10 Accord-
ingly, the isopropyloxazolidinone was used in the prep-
aration of all other Nazarov precursors 10 (R2 = aryl) by
reductive coupling.
Reaction of 7c with HBr (from TMSBr and MeOH) in
dichloromethane gave alkenyl bromide 12 (100%), which
was used in carbonylative couplings to form 10jꢀl
(Scheme 2).11 Initial attempts to couple 12 to boronic acids
under standard carbonylative SuzukiꢀMiyaura reaction
conditions failed.12 In a systematic investigation of reaction
conditions, we developed a carbonylative SuzukiꢀMiyaura
coupling that could be performed at room temperature
under just 1 atm of CO(g) using organotrifluoroboronate
salts, CsF, and Pd(dppf)Cl2 in THF.13,14 Under these
conditions, ketones 10j (95%) and10k (72%) were obtained
in good yield. A carbonylative Stille coupling of 12 to 15
gave 10l (84%).15,16
Nazarov Cyclization. Nazarov cyclizations 10 f 11 were
achieved using MeSO3H in nonpolar solvents (dichloro-
methane, 1,2-dichoroethane, or toluene) (Table 1).17 While
cyclization of divinyl ketones could be achieved using
catalytic quantities of acid (<10 mol %), this gave a cis/
trans-mixture of isomers. Excess MeSO3H was employed to
ensure complete epimerization of the oxazolidinone to give
exclusively the trans-isomer. Much to our satisfaction, the
cyclization of divinyl ketones 10aꢀf,l produced only one
double-bond regioisomer 11aꢀf,l, favoring placement of
the double bond distal to the auxiliary. X-ray crystal
structure analysis of 11c and 11d (entries 3 and 4, Table 1)
confirmed the β-stereochemistry of the R2 substituent, and
Scheme 2. Carbonylative Coupling Approaches to 10jꢀl
A one-pot reductive coupling protocol was used in the
preparation of the majority of Nazarov precursors 10
(Table 1).6 This involves initial palladium-mediated syn-
hydrostannylation of ynamides 7 f 8, followedby addition
of an acid chloride 9 and copper(I) thiophenecarboxy-
late (CuTC) cocatalyst to facilitate a Stille-type cross-
coupling 8 þ 9 f 10 (Table 1).9 This protocol proved very
effective in providing direct access to Nazarov substrates
10aꢀi,m (43ꢀ95%), giving good yields in most cases
(entries 1ꢀ9 and 13, Table 1). The modest yield obtained
for 10d (51%) was attributed to poor regioselectivity in
the hydrostannylation of 7c.10 This arises as a result of the
capacity of the group R2 = Ph in 7c to compete with
the oxazolidinone in directing the tin to the R-carbon of
(11) For an alternative hydrobromination of ynamides using MgBr2
in CH2Cl2, see: (a) Rodriguez, D.; Martinez-Esperon, M. F.; Castedo,
L.; Saa, C. Synlett 2007, 1963. (b) Mulder, J. A.; Kurtz, K. C. M.; Hsung,
R. P.; Coverdale, H.; Frederick, M. O.; Shen, L.; Zificsak, C. A. Org.
Lett. 2003, 5, 1547.
(12) See, for example: Couve-Bonnaire, S.; Carpentier, J.-F.;
Mortreux, A.; Castanet, Y. Tetrahedron 2003, 59, 2793.
(13) For carbonylative SuzukiꢀMiyaura couplings using BF3 salts
under more forcing conditions, see: Wu, X.-F.; Neumann, H.; Beller, M.
Adv. Synth. Catal. 2011, 353, 788 and references cited therein.
(14) A fuller account of the scope and limitations of this reaction will
be reported elsewhere.
(15) Compound 15 was formed by syn-hydrostannylation of the cor-
responding arylalkyne; see: Xu, G.; Loftus, T. L.; Wargo, H.; Turpin,
J. A.; Buckheit, R. W., Jr.; Cushman, M. J. Org. Chem. 2001, 66, 5958.
(16) Cu(I) salts facilitate carbonylative Stille reactions: Mazzola,
R. D., Jr.; Giese, S.; Benson, C. L.; West, F. G. J. Org. Chem. 2010,
69, 220.
(17) Cyclization of the resistant substrate 11i required 2 equiv of
TfOH in CH2Cl2 at 40 °C.
(18) See the Supporting Information.
(7) Ynamides 7aꢀd were prepared from the corresponding bro-
moalkynes and the oxazolidinones using standard methods: Zhang,
X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kurtz, K. C. M.; Oppenheimer,
J.; Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R.
J. Org. Chem. 2006, 71, 4170. See also the Supporting Information.
(8) For reviews on the synthetic application of ynamides, see: (a) De
Korver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.;
Hsung, R. P. Chem. Rev. 2010, 110, 5064. (b) Evano, G.; Coste, A.;
Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840.
(9) For previous reports on the hydrostannylation of ynamides, see:
Buissonneaud, D.; Cintrat, J.-C. Tetrahedron Lett. 2006, 47, 3139.
(10) The ratio of regioisomers in the hydrostannylation of 7c and 7d is
3:1 and 6:1, respectively; see the Supporting Information.
1
(19) Evidence for H-bonding in TS-I comes from H NMR of 11f,
which is very similar in structure to TS-I. The enolic OH in 11f appears as
a sharp singlet at 8.55 ppm, indicative of intramolecular H-bonding.
(20) (a) Denmark, S. E.; Habermas, K. L.; Hite, G. A. Helv. Chim.
Acta 1988, 71, 168. (b) Koltunov, K. Yu.; Walspurger, S.; Sommer, J.
Tetrahedron Lett. 2005, 46, 8391. (b) Malona, J. A.; Colbourne, J. M.;
Frontier, A. J. Org. Lett. 2006, 8, 5661. (c) Vaidya, T.; Manbeck, G. F.;
Chen, S.; Frontier, A. J. J. Am. Chem. Soc. 2011, 133, 3300. (d) Malona,
J. A.; Colbourne, J. M.; Frontier, A. J. Org. Lett. 2006, 8, 5661. (e)
Vaidya, T.; Manbeck, G. F.; Chen, S.; Frontier, A. J. J. Am. Chem. Soc.
2011, 133, 3300.
1734
Org. Lett., Vol. 14, No. 7, 2012

we have tentatively assigned all other Nazarov products this
stereochemistry.18 This observed sense of induction can be
rationalized by evoking the transition-state structure TS-I/
II (Figure 1). A combination of intramolecular H-bonding
and overlap between nitrogen electron-lone-pair and catio-
nic π-system in TS-I direct R1 toward R2, sterically favoring
TS-I over TS-II.19
in similar trapping reactions have been frustrated by
competitive proton elimination.21
Auxiliary Cleavage. The oxazolidinone auxiliary was
cleaved from a sample set of Nazarov cyclization prod-
ucts 11 using either lithium naphthalenide (LiNp) or
SmI2, giving the products (16ꢀ20) in good yield and
enantiomeric excess (Scheme 3).22 Oxazolidinones can
also be ring-cleaved to produce an NH2 groups, but we
have not yet evaluated this for products 11.23
Scheme 3. Auxiliary Cleavage
Figure 1. Proposed transition state of Nazarov cyclization.
This new, oxazolidinone-mediated Nazarov reaction
accommodates a large variety of substrate classes, includ-
ing sterically hindered and aryl fused substrates, which
generally require high acid concentrations in order to
cyclize and are unsuitable for chiral catalysis. Cyclization
of the sterically hindered substrate 10f to 11f proceeded
smoothly with good induction, enabling two stereocen-
ters to be generated torquoselectively (99%, dr >20:1)
(entry 6, Table 1). While the cyclization of aryl vinyl
ketones 10gꢀk required moderate heating (40ꢀ80 °C) in
some cases, all products 11gꢀk were obtained in good
yield (76ꢀ97%) and in excellent diastereoselectivity
(dr >20:1) (entries 7ꢀ11, Table 1). These are much milder
conditions then are generally required to cyclize aryl vinyl
ketones.20 In fact, all previous attempts to cyclize furan-2-
yl vinyl ketones have failed.20a,b,c Thus, the efficient
formation of 11i (79%) and 11k (82%), the latter at room
temperature, indicate that the oxazolidinone is a powerful
promoter of Nazarov cyclization.17 Both intra- and inter-
molecular trapping reactions were attempted and both
proceed in good yield with excellent regio- and stereo-
chemical control, 10m f 11m (85%, dr >20:1) and 10b þ
N-methylindole f 11n (93%, dr = 18:1). This is notable,
as previous attempts to use related substrates 1 (Ra = Me)
In summary, the stereoselective syn-hydrostannylation
and syn-hydrobromination of readily accessible ynamides
7 provides concise access to a range of aryl vinyl and
divinyl ketones 10througha variety of different palladium-
mediated coupling techniques. In the course of these
studies, a new carbonylative SuzukiꢀMiyaura cou-
pling, which operates at room temperature and 1 atm of
CO(g) (balloon), has been developed. Oxazolidinones
have emerged as highly effective multifunctional auxili-
aries in Nazarov cyclization, enabling access to a broad
range of cyclopentanoid structures. In addition to afford-
ing high levels of torquoselective control in the Nazarov
cyclization, the oxazolidinones also exerts excellent re-
giochemical control in the placement of the double-bond
in 4 and of the nucleophile in 5. As an activating group,
the oxazolidinone auxiliary has enabled the cyclization of
conventionally resistant substrates to be achieved, tor-
quoselectively. Finally, this auxiliary can be conveniently
cleaved using reductants, such as LiNp or SmI2.
(21) Rieder, R. J.; Fradette, C. J.; West, F. G. Heterocycles 2010, 80,
1413.
Supporting Information Available. X-ray crystal struc-
ture data for 11c and 11d, preparative procedures and
spectroscopic data for all compounds, and chiral HPLC
traces for 16ꢀ20. This material is available free of charge
via the Internet at http://pubs.acs.org.
(22) The enantiomeric excesses are based on a combination of chiral
HPLC and 1H NMR of the oxazolidinone substituted substrates. Note
that the enantiomeric excesses are not a reflection of the level of
induction in cases 17, 19, and 20 since the major diastereomer was
further purified by chromatography prior to auxiliary cleavage.
(23) (a) Huang, J.; Hsung, R. P. J Am. Chem. Soc. 2005, 127, 50. (b)
Lucet, D.; Sabelle, S.; Kostelitz, O.; Le Gall, T.; Mioskowski, C. Eur. J.
Org. Chem. 1999, 2583.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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