Synthesis of stable 2H-pyran-5-carboxylates via a catalyzed propargyl-claisen rearrangement/oxa-6π electrocyclization strategy

Article abstract of DOI:10.1021/ol061856x

(Chemical Equation Presented) The application of easily accessed propargyl vinyl ethers for the synthesis of monocyclic 2H-pyrans was achieved. Under the reaction conditions, highly substituted heterocycles were obtained in moderate to excellent yields. T

Full text of DOI:10.1021/ol061856x

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4795-4797
Synthesis of Stable
2H-Pyran-5-carboxylates via a Catalyzed
Propargyl-Claisen Rearrangement/
Oxa-6
π Electrocyclization Strategy
Helge Menz and Stefan F. Kirsch*
Department Chemie, Technische UniVersita¨t Mu¨nchen, Lichtenbergstrasse 4,
85747 Garching, Germany
stefan.kirsch@ch.tum.de
Received July 27, 2006
ABSTRACT
The application of easily accessed propargyl vinyl ethers for the synthesis of monocyclic 2H-pyrans was achieved. Under the reaction conditions,
highly substituted heterocycles were obtained in moderate to excellent yields. The one-pot sequence proceeds via a Ag(I)-catalyzed propargyl-
Claisen rearrangement, followed by a base-catalyzed isomerization, and 6
pyrans.
π-oxaelectrocyclization, leading to the formation of stable 2H-
The synthesis of stable 2H-pyrans is an ongoing challenge
in organic synthesis.1 Since 2H-pyrans undergo a reversible
electrocyclic ring-opening to 1-oxatrienes,2 classical strategies
toward monocyclic 2H-pyrans generally afford an equilibrat-
ing mixture.3 Typically, the substrate-dependent equilibrium
is dominated by 1-oxatrienes,3d,g while the 2H-pyran form
is favored only in a few cases due to increased steric
interactions.4,5 Although there are numerous applications of
1-oxatrienes,6,7 the synthetic utility of monocyclic 2H-pyrans
is somewhat limited.8,9
Recently, we reported that acceptor substituted propargyl
vinyl ethers 1 can be transformed into highly substituted
furans by a gold(I)-catalyzed propargyl-Claisen rearrange-
ment/heterocyclization cascade.10 In this reaction, the catalyst
promotes a 5-exo-dig heterocyclization of the ketone (or its
tautomeric enol form) onto the allene (Scheme 1). On the
(4) (a) Takanishi, K.; Urabe, H.; Kuwajima, I. Tetrahedron Lett. 1987,
28, 2281. (b) Adams, R. D.; Chen, L. J. Am. Chem. Soc. 1994, 116, 4467.
(c) Quing, F.-L.; Gao, W.-Z. Tetrahedron Lett. 2000, 41, 7727. (d) Fan,
M.; Yan, Z.; Liu, W.; Liang, Y. J. Org. Chem. 2005, 70, 8204.
(5) For synthetic routes to bicyclic 2H-pyrans, see inter alia: (a) Shishido,
K.; Shitara, E.; Fukumoto, K. J. Am. Chem. Soc. 1985, 107, 5810. (b) Tsuda,
T.; Kiyoi, T.; Miyane, T.; Saegusa, T. J. Am. Chem. Soc. 1988, 110, 8570.
(6) For selected references on electrocyclic ring-closures involving
1-oxatrienes, see: (a) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N. Eur.
J. Org. Chem. 2005, 23 and references cited herein. (b) Shishido, K.; Hiroya,
K.; Fukumoto, K.; Kametani, T. Tetrahedron Lett. 1986, 27, 971. (c)
Stevenson, R.; Weber, J. V. J. Nat. Prod. 1988, 51, 1215. (d) Kurdyumov,
A. V.; Hsung, R. P.; Ihlen, K.; Wang, J. Org. Lett. 2003, 5, 3935. (e)
Pujanauski, B. G.; Prasad, B. A. B.; Sarpong, R. J. Am. Chem. Soc. 2006,
128, 6786.
(7) For leading references on electrocyclic ring-closures involving
1-azatrienes, see: (a) Maynard, D. F.; Okamura, W. H. J. Org. Chem. 1995,
60, 1763. (b) Tanaka, K.; Mori, H.; Katsumura, S. J. Org. Chem. 2001, 66,
3099.
(8) (a) Balaban, T.-S.; Balaban, A. T. Tetrahedron Lett. 1987, 28, 1341.
(b) Moorhoff, C. M. Tetrahedron 1997, 53, 2241. (c) Moorhoff, C. M.;
Winkler, D. New J. Chem. 1998, 1485.
(1) For general reviews, see: (a) Kuthan, J.; Sebek, P.; Boehm, S. AdV.
Heterocycl. Chem. 1995, 62, 19. (b) Hepworth, J. D. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Boulton, A. J.,
McKillop, A., Eds.; Pergamon: Oxford, UK, 1984; Vol. 3, p 737.
(2) (a) Kluge, A. F.; Lillya, C. P. J. Am. Chem. Soc. 1971, 93, 4458. (b)
Kluge, A. F.; Lillya, C. P. J. Org. Chem. 1971, 36, 1977. (c) Zhu, Y.;
Ganapathy, S.; Liu, R. S. H. J. Org. Chem. 1992, 57, 1110.
(3) For references pertinent to the stabilizing effect of substitution on
the kinetic stability of monocyclic 2H-pyrans, see: (a) Duperrier, A.; Dreux,
J. Tetrahedron Lett. 1970, 11, 3127. (b) Marvell, E. N.; Gosink, T.;
Churchley, P.; Li, T. H. J. Org. Chem. 1972, 37, 2989. (c) Marvell, E. N.;
Chadwick, T.; Caple, G.; Gosink, T.; Zimmer, G. J. Org. Chem. 1972, 37,
2992. (d) Gosink, T. A. J. Org. Chem. 1974, 39, 1942. (e) de Groot, A.;
Jansen, B. J. M. Tetrahedron Lett. 1975, 16, 3407. (f) Roedik, A.; Neukam,
T. Liebigs Ann. Chem. 1975, 240. (g) Moorhoff, C. M. Synthesis 1997,
685. (h) Kouno, R.; Tsubota, T.; Okauchi, T.; Minami, T. J. Org. Chem.
2000, 65, 4326.
10.1021/ol061856x CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/15/2006

ketones, which then should undergo base-catalyzed isomer-
ization, and the sequence concludes with a 6π-electron
electrocyclic ring-closure of 4 to give the 2H-pyrans 3. The
overall process can be considered formally an equivalent of
a propargyl-Claisen rearrangement/6-endo-trig cyclization
domino reaction.
Scheme 1. Synthesis of Furans and 2H-Pyrans from Propargyl
Vinyl Ethers
To realize the isomerization step, preliminary studies have
been carried out on allenic ketone 2a, which was prepared
by treatment of propargyl vinyl ether 1a with 5 mol % of
AgSbF6 in CH2Cl2. Initial results indicated that KOtBu (10
mol %, 30 min, 15%), EtN(iPr)2 (10 mol %, 30 min, 17%),
NEt3 (10 mol %, 30 min, 50%), DBU (5 mol %, 30 min,
100%), and DMAP (50 mol %, 12 h, 100%) all afford highly
substituted 2H-pyran 3a. Among these bases, however, DBU
is the most efficient catalyst based on reaction time. When
the reaction was performed in the absence of DBU or in the
presence of a catalytic amount of protic acid, no isomeriza-
tion product 3a was obtained at all. We were pleased to find
that the substitution pattern favors the exclusive formation
of the cyclic 2H-pyran 3a. The corresponding 1-oxatriene
basis of these results, we became interested in the possibility
of constructing 2H-pyrans by a preferential 6-endo-trig
cyclization of allenes. We report herein that highly substituted
2H-pyrans, which only occasionally undergo ring-opening,
can be efficiently obtained from propargyl vinyl ethers via
a cascade reaction of a propargyl-Claisen rearrangement and
a formal 6-endo-trig cyclization. AgSbF6 and DBU are
sequentially utilized to catalyze this simple one-pot approach
to racemic11 2H-pyrans.
1
4a was not seen by H NMR analysis of both the crude
reaction mixture and the pure product after column chro-
matography.
The complete synthetic protocol was performed by linking
the Ag(I)-catalyzed rearrangement with the cycloisomeriza-
tion catalyzed by DBU in a one-pot manner [(1) substrate
1, 5 mol % of AgSbF6, 23 °C, 60 min, CH2Cl2; (2) 5 mol %
of DBU].14 Table 1 illustrates the scope of this sequence.
Propargyl vinyl ether 1a readily reacted to give 2H-pyran
3a in good yield. Other propargyl vinyl ethers underwent
smooth transformation (entries 2-13); however, the yields
varied, depending on the substituents employed. The rela-
tively low yields for substrates derived from primary
propargylic alcohols (R3 ) H) were due to concomitant furan
formation through 5-exo cyclization (entries 10-12). Of
primary importance, the corresponding 1-oxatrienes 4a-m
were not seen by 1H NMR analysis of crude reaction
mixtures (entries 1-13); in these cases, the cyclic 2H-pyran
form 3 was obtained as the sole product. However, substrate
1n in which R1 is a phenyl group gave the corresponding
1-oxatriene 4n as the predominant product, as did propargyl
vinyl ether 1o with R3 ) Ph.
Our initial attempts failed to define a transition metal
catalyst system that would promote a straight and regiose-
lective heterocyclization of allenic ketone 2 to the desired
2H-pyrans.11 Owing to the ability of 1-oxatrienes to be in
equilibrium with 2H-pyrans, we then envisioned a process
that proceeds through the sequence shown in Scheme 2. On
Scheme 2. 6π-Electrocyclization Approach to 2H-Pyrans 3
(13) For Ag(I)-catalyzed alkyne activation, see inter alia: (a) Marshall,
J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5966. (b) Grissom, J. W.;
Kilingberg, D.; Huang, D.; Slattery, B. J. J. Org. Chem. 1997, 62, 603. (c)
Harrison, T. J.; Dake, G. R. Org. Lett. 2004, 6, 5023. (d) Harrison, T. J.;
Kozak, J. A.; Corbella-Pane´, M.; Dake, G. R. J. Org. Chem. 2006, 71,
4525.
the basis of our observation that cationic silver(I) salts
catalyze the rearrangement of propargyl vinyl ethers 1 to
the corresponding allenylcarbonyl compounds 2,12,13 we
planned to utilize AgSbF6 as a catalyst to obtain allenic
(14) General Procedure. Synthesis of 3a: AgSbF6 (38 mg, 0.11 mmol,
5 mol %) was added to a solution of 1a (570 mg, 2.1 mmol) in CH2Cl2 (10
mL), and the reaction vial was sealed, protected from light, and stirred at
room temperature for 60 min. Then, a solution of DBU (17 mg, 0.11 mmol,
5 mol %) in CH2Cl2 (0.5 mL) was added, and the reaction mixture was
stirred at room temperature for 30 min (until TLC analysis indicated
complete conversion). The mixture was concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel (pentanes/
EtOAc ) 80/20) gave 2H-pyran 3a as a colorless oil (432 mg, 1.59 mmol,
(9) For reaction with 2H-pyrans formed in situ, see: (a) Belosludtsev,
Y. Y.; Borer, B. C.; Taylor, R. J. K. Synthesis 1991, 320. (b) Obrecht, D.
HelV. Chim. Acta 1991, 74, 27. (c) Charoenying, P.; Davies, D. H.;
McKerrecher, D.; Taylor, R. J. K. Tetrahedron Lett. 1996, 37, 1913. (d)
Tius, M. A.; Hu, H.; Kawakami, J. K.; Busch-Petersen, J. J. Org. Chem.
1998, 63, 5971. (e) Obrecht, D.; Zumbrunn, C.; Mu¨ller, K. J. Org. Chem.
1999, 64, 6182.
(10) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925.
(11) During the course of this work, a gold(I)-catalyzed synthesis of
enantioenriched dihydropyrans via chirality transfer utilizing a propargyl-
Claisen rearrangement/6-endo-trig heterocyclization was reported. Our
protocol gives racemic 2H-pyrans: Sherry, B. D.; Maus, L.; Laforteza, B.
N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132.
1
76%). Rf 0.65 (pentanes/EtOAc ) 80/20); H NMR (360 MHz, CDCl3) δ
0.72 (t, J ) 7.1 Hz, 3 H), 1.04 (t, J ) 7.4 Hz, 3 H), 1.74-1.96 (m, 2 H),
2.35 (s, 3 H), 3.81-3.87 (m, 2 H), 4.63 (dt, J ) 3.8, 6.4 Hz, 1 H), 5.29 (d,
J ) 3.8 Hz, 1 H), 7.31-7.34 (m, 3 H), 7.44-7.48 (m, 2 H); 13C NMR
(90.6 MHz, CDCl3) δ 9.6, 13.8, 19.0, 27.3, 60.0, 77.9, 108.3, 116.3, 126.8,
127.3, 128.3, 137.4, 141.1, 166.0, 167.6. LRMS (EI) 272 (10%) [M+], 199
(100%); HRMS 272.1420 [272.1412 calcd for C17H20O3Cl (M+)].
(12) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151.
4796
Org. Lett., Vol. 8, No. 21, 2006

Scheme 3. Synthetic Utility of 2H-Pyrans
Table 1. Formation of 2H-Pyrans 3 from Propargyl Vinyl
Ethers 1a
3
yield
ratio
entry
R1
Me
R2
R3
Et
Et
Et
Et
no. [%]b
(3:4)c
1
2
3
4
5
6
7
8
9
10
11
12
13e
14
15
Ph
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
76
77
63
90d
82
75
72
80
50
61d
59d
53d
72
90
36
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
20:80f
<1:99g
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-tBu(C6H4)
4-PhO(C6H4)
3-thienyl
CH2CH2OTBS Et
CH2(c-C6H11
)
Et
Ph
Ph
Ph
Ph
Me
iPr
CH2Ph
H
H
H
Et
Et
Ph
2-MeO(C6H4)
3-thienyl
nPent Ph
Ph
Me
Ph
CH2(c-C6H11
)
pounds show high stability to electrocyclic ring-opening.
Additionally, these results underscore the potential of
propagyl vinyl ethers as easily accessible starting com-
pounds16 for the formation of different classes of hetero-
cycles, using a rearrangement-heterocyclization strategy.10,12
Work is now in progress to extend the synthetic value of
monocyclic 2H-pyrans.
a Conditions: (1) substrate 1, 5 mol % of AgSbF6, 23 °C, 60 min, CH2Cl2;
(2) 5 mol % of DBU. b Yield of pure product after column chromatography.
c Determined by 1H NMR. d The product contains traces of unidentified
impurities. e The methyl ester was used. f 3n:trans-4n:cis-4n ) 20:30:50.
g 3o:trans-4o:cis-4o ) 0:100:0.
Since 2H-pyrans 3 are prone to slow decomposition at
room temperature, extensive storage should occur at -20
°C. Nevertheless, 2H-pyrans 3a-l can be stored at room
temperature for several days without diminishing their purity.
We have also investigated further transformations of the
2H-pyran products using known chemistry (Scheme 3). For
example, hydrogenation (3i f 5),3h dihydroxylation (3i f
6),15 and nucleophilic addition (3i f 7) have afforded the
anticipated products in modest to good yields.
Acknowledgment. This project was supported by the
Bundesministerium fu¨r Bildung und Forschung, the Fonds
der Chemischen Industrie (FCI), and the Deutsche Fors-
chungsgemeinschaft (DFG).
Supporting Information Available: Representative ex-
perimental procedures for catalytic 2H-pyran formation,
compound characterization data for 3a-o, and copies of 1H
and 13C NMR spectra of 3 and 5-7. This material is available
free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have described a convenient method for
the synthesis of monocyclic 2H-pyrans. Due to their par-
ticular substitution pattern, the resulting heterocyclic com-
OL061856X
(15) Zehnder, L. R.; Wie, L.; Hsung, R. P.; Cole, K. P.; McLaughlin,
M. J.; Shen, H. C.; Skenicka, H. M.; Wang, J.; Zificsak, C. A. Org. Lett.
2001, 14, 2141.
(16) Propargyl vinyl ethers 1 can be prepared in high yield by PMe3-
catalyzed addition of propargyl alcohols to 2-propynoic acid derivatives,
see: Inanaga, J.; Baba, Y.; Hanamoto, T. Chem. Lett. 1993, 241.
Org. Lett., Vol. 8, No. 21, 2006
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