Au-catalyzed piperidine synthesis via tandem acyloxy migration/ intramolecular [3 + 2] cycloaddition of enynyl esters

Article abstract of DOI:10.1021/ol202746s

An Au-catalyzed tandem protocol involving enynyl ester isomerization and subsequent intramolecular [3 + 2] cyclization has been developed. This strategy provides an efficient approach for the synthesis of polyfunctional piperidines, which are subunits of

Full text of DOI:10.1021/ol202746s

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6448–6451
Au-Catalyzed Piperidine Synthesis via
Tandem Acyloxy Migration/Intramolecular
[3 þ 2] Cycloaddition of Enynyl Esters
Huaiji Zheng,† Xing Huo,† Changgui Zhao,† Peng Jing,† Juan Yang,† Bowen Fang,†
and Xuegong She*,†,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Gansu 730000, People’s Republic of China,
and ‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou
Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000,
People’s Republic of China
shexg@lzu.edu.cn
Received October 13, 2011
ABSTRACT
An Au-catalyzed tandem protocol involving enynyl ester isomerization and subsequent intramolecular [3 þ 2] cyclization has been developed.
This strategy provides an efficient approach for the synthesis of polyfunctional piperidines, which are subunits of many bioactive molecules.
The importance of nitrogen heterocycles, especially
piperidine and pyrrolidine types, as subunits of bioactive
molecules stimulates the development of new synthetic
Scheme 1. PtCl2-Catalyzed [3 þ 2] Cycloaddition of Enynyl
Esters
methods.1 Our recent success in a PtCl2-catalyzed [3 þ 2]
cycloaddition of enynyl esters2 led us to wonder whether
such a transformation procedure could be applied to
nitrogen-containing substrates to further extend the utility
of this method, as outlined in Scheme 1.
(1) Trost, B. M.; Pinkerton, A. B.; Kremzow, D. J. Am. Chem. Soc.
2000, 122, 12007. See also: The Alkaloids: Chemistry and Biology; Codell,
G. A., Ed.; Academic Press: San Diego, CA, 2000; Vol. 54 and others in this
series.
(2) Zheng, H.; Zheng, J.; Yu, B.; Chen, Q.; Wang, X.; He, Y.; Yang,
Z.; She, X. J. Am. Chem. Soc. 2010, 132, 1788. Most recently, a new type
of reaction involving [3 þ 2] cycloaddition/hydrolytic Michael addition/
retro-Aldol reaction of propargylic esters has been reported:Cai, S.; Liu,
Z.; Zhang, W.; Zhao, X.; Wang, Z. Angew. Chem., Int. Ed. 2011, 50, 1.
(3) (a) Lutton, J. M.; Parry, R. W. J. Am. Chem. Soc. 1954, 76, 4271.
(b) Furstner, A.; Davies, P. W.; Gress, T. J. Am. Chem. Soc. 2005, 127,
8244.
In our previous work, harsh conditions (high tempera-
ture and an atmosphere of CO3) were necessary for such
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10.1021/ol202746s
Published on Web 11/15/2011
2011 American Chemical Society

transformations. Therefore, the balance between the sta-
bility and the reactivity of nitrogen-tethered substrates
needs tobeadjusted. Inaddition, the activity of the catalyst
may be significantly affected by the unique nature of
nitrogen, which is completely different from oxygen or
carbon. Nevertheless, the importance of the target stimu-
lated us to investigate the possibilities of the conversion
from nitrogen-containing substrates to the pyrrolidine or
piperidine skeleton.
the piperidines (4cꢀf) were obtained in good to excellent
yield (entries 2ꢀ5). The scope of this reaction was also
expanded to the homopropargylic amide 1g, and the
structurally differential piperidine 4g was successfully
produced in 73% yield (entry 6). It was noteworthy that
1g was also tested with the PtCl2/CO system and only the
starting material was recovered after 5 h.
Table 1. Piperidines Synthesis through Au-Catalyzed [3 þ 2]
Cycloaddition of Enynyl Estersa
Initially, p-toluenesulfonamide 1a was selected to investi-
gate this transformation (eq 1). Fortunately, piperidine
4a was formed in 53% yield under PtCl2/CO in toluene at
60 °C for 1 h. Interestingly, the yield was significantly
increased to 89% at room temperature via AuClPPh3/
AgSbF6 catalysis,4 which did not serve well in our previous
work. In this case, wet dichloromethane5 was used as
solvent for the hydrolysis of ketal intermediate 3 to form
4a. The relative configuration of the three substituents in
the piperidine was consistent with our previous observa-
tions (see the X-ray data), which was due to the highly
stereospecific control through the cycloaddition reaction.
With this result in hand, a series of substituted enynyl
esters joined by a sulfonamide were then investigated via
AuClPPh3/AgSbF6 catalysis and various synthetically va-
luable multisubstituted piperidines were obtained in good
to excellent yields (Tables 1 and 2). It was found that this
tandem reaction has a wide range of substrate scope, where
C4ꢀC8 positions can have various substituent patterns.
The substituent effect at the C6 position was first investi-
gated. 1b possessing a PhCH2CH2 substituent at C6 was
converted to 4b in excellent yield (entry 1, Table 1). How-
ever, this substituent was at the axial position instead of the
expected equatorial position. The other two ketone chains
preferred equatorial positions, while the hydroxyl group
preferred an axial position (see X-ray, Figure 1). Other
i
i
substituents (e.g., Bu, Pr, Cy), even the very bulky sub-
stituent tBu at C6 of the substrate, were also tolerated, and
(4) For recent work on gold-catalyzed [3 þ 2] cycloadditions, see:
(a) Melhado, A. D.; Amarante, G. W.; Wang, Z. J.; Luparia, M.; Toste,
F. D. J. Am. Chem. Soc. 2011, 133, 3517. (b) Yang, C.-Y.; Wang, C.-D.;
Tian, S.-F.; Liu, R.-S. Adv. Synth. Catal. 2010, 352, 1605. (c) Li, C.-W.;
Lin, G.-Y.; Liu, R.-S. Chem.;Eur. J. 2010, 16, 5803. (d) Zhang, G.;
Zhang, L. J. Am. Chem. Soc. 2008, 130, 12598. (e) Melhado, A. D.;
Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 12638. (f) Huang,
X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398. (g) Partyka, D. V.;
Updegraff, J. B., III; Zeller, M.; Hunter, A. D.; Gray, T. G. Organome-
tallics 2007, 26, 183. (h) Kusama, H.; Miyashita, Y.; Takaya, J.;
Iwasawa, N. Org. Lett. 2006, 8, 289. (i) Kim, N.; Kim, Y.; Park, W.;
a Reaction conditions: enynyl ester (0.1 M in wet DCM), 5 mol % of
AuClPPh3, 5 mol % of AgSbF6, rt, 1 h. b Isolated yields. c PtCl2/CO,
PhMe, 60 °C, 5 h.
Next, we found that substitutions at C7ꢀC8 positions,
which were close to the CꢀC double bonds, inevitably led
to the formation of hydrolyzed and partially hydrolyzed
bicyclic products. Therefore, by using dry CH2Cl2 as
solvent to prevent the occurrence of hydrolysis, dihydro-
furans 5hꢀk were successfully obtained as single product
in good yield (entries 1ꢀ4, Table 2). In contrast, such enol
ꢀ
Sung, D.; Gupta, A. K.; Oh, C. H. Org. Lett. 2005, 7, 5289. (j) Ade, A.;
Cerrada, E.; Contel, M.; Laguna, M.; Merino, P.; Tejero, T. J. Organo-
met. Chem. 2004, 689, 1788. (k) For the use of gold ctalysis in total
synthesis, see: Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37,
1766.
(5) Generated by shaking distilled CH2Cl2 with deionized water in a
separatory funnel. See: (a) Hashmi, A. S. K.; Molinari, L.; Rominger, F.;
Oeser, T. Eur. J. Org. Chem. 2011, 2256. (b) Zhang, L.; Wang, S. J. Am.
Chem. Soc. 2006, 128, 1442.
Org. Lett., Vol. 13, No. 24, 2011
6449

ether products were converted to aromatic ketones by an
aromatization/elimination process.6 Through this method,
the C4 dimethyl-substituted substrates 1l and 1m were
converted to cyclized product 5l and 5m, respectively,
although the substituents were very close to the CꢀC triple
bonds (entries 5 and 6).7
On the basis of the success of piperidine synthesis, we
then turned our attention to the synthesis of pyrrolidines.
Many reactions involving cycloisomerization of 1,6-en-
ynes to form cyclized products including pyrrolidines were
reported,8 but 1,6-enynes with a propargylic ester moiety
in one substrate have not been fully studied yet since the
competition between cycloisomerization of enynes and
1,2-acyloxy or 1,3-acyloxy migration9 of propargylic esters
may lead to the complicated products.10
Figure 1. X-ray of 4b.
Table 2. Modified Au-Catalyzed Cycloaddition of Enynyl Estersa
Table 3. Pyrrolidine Synthesis in the Au-Catalyzed Reactions of
Enynyl Estersa
a Reaction conditions: enynyl ester (0.1 M in wet DCM), 5 mol % of
AuClPPh3, 5 mol % of AgSbF6,rt,1h.b Isolated yields. c Dry DCM was used.
(6) Hashmi, A. S. K.; Pankajakshan, S.; Rudolph, M.; Enns, E.;
Bander, T.; Rominger, F.; Frey, W. Adv. Synth. Catal. 2009, 351, 2855.
(7) The most common side reaction was decomposed to sulfonamide
and propargylic ester moieties. This phenomenon was more obvious in
1m when wet CH2Cl2 was used, see below:
(8) For the first conversion of an enyne-type substrate in gold
catalysis, see: Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem.
Soc. 2000, 122, 11553. For reviews on enyne cycloisomerization, see: (a)
ꢁ
ꢁ~
Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (b)
^
Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008,
ꢁ
ꢁ
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47, 4268. (c) Nieto-Oberhuber, C.; Lοpez, S.; Jimenez-Nunez, E.;
Echavarren, A. M. Chem.;Eur. J. 2006, 12, 5916. (d) Zhang, Z.; Zhu,
G.; Tong, X.; Wang, F.; Xie, X.; Wang, J.; Jiang, L. Curr. Org. Chem.
2006, 10, 1457. (e) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal.
2006, 348, 2271. (f) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006,
45, 200. (g) Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (h) Diver,
S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317. (i) Echavarren, A. M.;
Nevado, C. Chem. Soc. Rev. 2004, 33, 431. (j) Anrbe, L.; Domınguez, G.;
Perez-Castells, J. Chem.;Eur. J. 2004, 10, 4938. (k) Mendez, M.;
Mamane, V.; Furstner, A. Chemtracts 2003, 16, 397. (l) Echavarren,
~
ꢁ
ꢁ
€
ꢁ
~
A. M.; Mendez, M.; Munoz, M. P.; Nevado, C.; Martın-Matute, B.;
ꢁ
a Reaction conditions: enynyl ester (0.1 M in dry DCM), 5 mol % of
AuClPPh3, 5 mol % of AgSbF6, rt, 1 h. b Isolated yields.
Nieto-Oberhuber, C.; Cardenas, D. J. Pure Appl. Chem. 2004, 76, 453.
(m) Lloyd-Jones, G. Org. Biomol. Chem. 2003, 1, 215. (n) Aubert, C.;
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6450
Org. Lett., Vol. 13, No. 24, 2011

reaction. For substrate 6b, the desired [3 þ 2] cycloaddition
product 8 was isolated in 45% yield in dry CH2Cl2 along
with the formation of 9 and 10 (entry 2). The generation of
9 and 10 probably experienced the same intermediate 11,
which was derived from cycloisomerization of enyne
(Scheme 2).11 Then a 1,2-shift of H (path a) or OBz
(path b) lead to 9 or 10. An alternative route for the
formation of 10 was the intramolecular [2 þ 1] cycloaddi-
tion of 12, which was derived from 6b through 1,2-acyloxy
migration.
Scheme 2. Mechanistic Possibilities for the Rearrangements of
1,6-Enynyl Esters
In conclusion, we have developed an Au-catalyzed new
type of tandem reaction involving enynyl ester isomeriza-
tion and subsequent intramolecular [3 þ 2] cyclization.
This methodology has broad applications, providing
the corresponding cyclized products in good yields and
with excellent stereoselectivities. Here the Au(I)-catalyzed
cycloisomerization of nitrogen-containing enynyl esters
strategy provides an efficient approach for the synthesis
of polyfunctional piperidines and pyrrolidines. Further
studies that take advantage of this tandem protocol to
address complex synthetic issues are ongoing.
Thus 1,6-enynyl ester 6a without any substituent on the
side chain was first selected to test this process, and
pyrrolidine 7 was obtained as the main product in 66%
yield (entry 1, Table 3). However, methyl-substituted
olefin offered severe disadvantages to the anticipated
Acknowledgment. This research was supported by the
Fundamental Research Funds for the Central Univer-
sities (lzujbky-2010-222), the MOST (2010CB833200),
the NSFC (21072086, 20872054, 20732002), and Program
111. The authors also thank Prof. Dr. Chun-An Fan
(SKLAOC, Lanzhou University) for helpful discussions.
(9) For reviews, see: (a) Marion, N.; Nolan, S. P. Angew. Chem., Int.
Ed. 2007, 46, 2750. (b) Marco-Contelles, J.; Soriano, E. Chem.;Eur. J.
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2007, 13, 1350. (c) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed.
2007, 46, 3410. (d) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
ꢀ
(10) Marion, N.; Lemiere, G.; Correa, A.; Costabile, C.; Ramon,
R. S.; Moreau, X.; de Fremont, P.; Dahmane, R.; Hours, A.; Lesage, D.;
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Tabet, J.-C.; Goddard, J.-P.; Gandon, V.; Cavallo, L.; Fensterbank, L.;
Malacria, M.; Nolan, S. P. Chem.;Eur. J. 2009, 15, 3243.
(11) Recent review on the mechanism in homogenous gold catalysis:
Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
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