Formal alkyne aza-prins cyclization: Gold(I)-catalyzed cycloisomerization of mixed N,O-acetals generated from homopropargylic amines to highly substituted piperidines

Article abstract of DOI:10.1021/ja906744r

(Chemical Equation Presented). A new gold(I)-catalyzed cycloisomerization to access highly substituted piperidines has been developed. By combining a conceptually new way of generating iminium ions using cationic gold(I) complexes and an efficient cyclization reaction that can minimize a potentially competing aza-Cope rearrangement, the proposed reaction successfully circumvents a long-standing problem in the classical aza-Prins reaction. Synthetic utility of the catalytic reaction was demonstrated by a synthesis of optically active 2-alkyl-piperidin-4-one.

Full text of DOI:10.1021/ja906744r

Published on Web 09/28/2009
Formal Alkyne Aza-Prins Cyclization: Gold(I)-Catalyzed Cycloisomerization of
Mixed N,O-Acetals Generated from Homopropargylic Amines to Highly
Substituted Piperidines
Cheoljae Kim, Hyo Jin Bae, Ji Hyung Lee, Wook Jeong, Haejin Kim, Vasu Sampath, and
Young Ho Rhee*
Department of Chemistry, POSTECH (Pohang UniVersity of Science and Technology), Hyoja-dong San 31, Pohang,
Kyungbuk, Republic of Korea 790-784
Received August 10, 2009; E-mail: yhrhee@postech.ac.kr
Scheme 1. Two Pathways for the Cycloisomerization of A
Highly substituted piperidines are found in numerous bioactive
alkaloid natural products and pharmaceuticals.1 Thus, considerable
attention has been paid to the synthesis of this moiety.2 We
envisioned that cycloisomerization of mixed N,O-acetal A generated
from homoproparygylic amines to 4-methoxy-1,2,3,6-tetrahydro-
pyridine B (Scheme 1) would be highly useful in accessing
piperidine frameworks, because the enol ether could be easily
transformed into other functional groups.
Based on the well-established chemistry of iminium ions, we
initially considered using an oxophilic metal-catalyzed method
depicted in pathway 1.3 In this scenario, the key step involves the
endocyclization of iminium ion C onto alkynes (alkyne aza-Prins
reaction).4 Apparently simple reactions of this type have been
surprisingly rare, due to the slow cyclization of C to form unstable
vinyl cation D and the rapidly competing aza-Cope rearrangement
of C (eq 1).5 In fact, this type of alkyne aza-Prins reaction reported
in the literature has been limited to the 4-amino-1-butyne substrates
possessing no branch alkyl groups.6,7
Table 1. Optimization of the Reaction Condition
catalyst
(mol %)
additive
(mol %)
time
(min)
entry
substrate
product
yielda
86b
1
2
3
4
1a
1a
1b
1b
4b (2)
4b (2)
4b (2)
4b (2)
-
10
2a
2a
2b
2b
96 (95c)
55d
2,6-DBP (1.6) 10
10
2,6-DBP (1.6) 10
-
91 (89c)
a
b
c
Isolated yield.
Ketone 3a was obtained in 10% yield.
Isolated
yield of the ketone after hydration. d Ketone 3b was obtained in 35% yield.
with little effect on the catalytic efficiency (entry 2).12b,c The synthetic
utility of 2a was easily demonstrated by the conversion into 3a in
99% yield under acidic conditions. Interestingly, even the cbz-derived
mixed acetal 1b was successfully engaged in the reaction to give the
mixture of cycloisomerization product 2b and the ketone 3b in
comparable 90% combined yield.12d,e Again, addition of 2,6-DBP
suppressed the hydration, improving the yield of 2b to 91%. The
unstable methoxytetrahydro-pyridine 2b was then converted into
piperidin-4-one 3b in 98% yield.12f
In view of the above-mentioned inherent problems associated
with the classical alkyne aza-Prins reactions, we envisioned an
alternative pathway promoted by the addition of the methoxy group
onto the metal-activated alkynes (pathway 2).8,9 Even though
generation of iminium ion F via this pathway is unprecedented,
we were highly encouraged by alkoxycyclization-induced generation
of an oxacarbenium ion reported by Zhang.10 Moreover, the
methoxy group should accelerate cyclization of F (Scheme 1) to
form relatively stable carbocation G. Thus, we anticipated that
potential limitations derived from aza-Cope rearrangement of F
could be minimized in this pathway (eq 1).11
To test the viability of this catalytic cycle, we examined easily
accessible mixed N,O-acetal 1a possessing an electron-withdrawing
tosyl group. Based on our previous experience in the related area,9b
we explored various cationic gold(I) complexes. While using 2 mol
% of 4a showed poor conversion (∼10%), switching to a more
electrophilic complex 4b (2 mol %) quickly completed the reaction to
generate the methoxypyridine 2a in 86% yield (Table 1, entry 1) with
no hydrolysis of the starting material.12a In this case, formation of the
piperidin-4-one 3a (∼10% yield) was noted, which arose from the
hydration of 2a. After extensive efforts to minimize this undesired
hydration, we discovered that the addition of 1.6 mol % (0.8 equiv to
Au) of 2,6-di-tert-butylpyridine (2,6-DBP) improved the yield to 96%
With the optimized conditions in hand, we explored the scope of
the gold(I)-catalyzed cycloisomerization using mixed acetals generated
from tosyl- or cbz-protected homopropargylic amines (Table 2).13
Moreover, all cycloisomerization products except for entry 3 were
converted into the corresponding piperidin-4-ones for characteriza-
tion.14 Remarkable chemoselectivity was noted. For example, a
potentially competing Friedel-Craft reaction of the acyliminium ion
generated from substrate 5 was not observed (entry 1). The reaction
was also compatible with terminal olefin (entry 2), and even with the
acid-labile cyclic acetal group (entry 3). Next, we explored the effect
of alkyl substitution on the cycloisomerization. Elimination (entry 4)
or addition (entry 5) of an akyl group at the homopropargylic position
9
14660 J. AM. CHEM. SOC. 2009, 131, 14660–14661
10.1021/ja906744r CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of the Gold(I)-Catalyzed Reaction
amines. This new gold(I)-catalyzed reaction successfully circumvents
a long-standing problem of the classical aza-Prins reaction and, thus,
opens up a new way to access piperidine alkaloids. Extrapolation of
the reaction to the stereoselective synthesis of 2,6-disubstituted
piperidines and tetrahydropyrans, as well as the application to the total
synthesis of bioactive natural products, is in progress.
Acknowledgment. This work was supported by KOSEF through
EPB center (2009-0063313), the Korea Research Foundation funded
by MEST (KRF-2009-0073749), and the BK21 project program.
Supporting Information Available: Experimental details and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139, and references cited therein.
(2) (a) Celestini, P.; Danieli, B.; Lesma, G.; Sacchetti, A.; Silvani, A.; Passarella,
D.; Virdis, A. Org. Lett. 2002, 4, 1367, and references cited therein. (b)
For a recent gold(I)-catalyzed approach to piperidin-4-ones, see: Cui, L.;
Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131, 8394.
(3) For reviews on the aza-Prins reactions, see:(a) Speckamp, W. N.; Hiemstra,
H. Tetrahedron 1985, 41, 4367. (b) Hiemstra, H.; Speckamp, W. N. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, O., Heathcock,
C. H., Eds.; Pergamon: New York, 1991: Vol. 2, p 1047.
(4) (a) For a recent discussion on the 2-aza Cope rearrangement of iminium
ions, see:Aron, Z. D.; Overman, L. E. Org. Lett. 2005, 7, 913, and references
cited therein. (b) Similar problems have been noted in the aza-Prins
cyclization, see: Hart, D. J.; Yang, T.-K. J. Org. Chem. 1985, 50, 235.
(5) Unlike the endo-cyclization, the exo-cyclization of iminium ion derived
from 5-amino-1-pentynes to access piperidine alkaloids is well-known, see:
Metais, E.; Overman, L. E.; Rodriguez, M. I.; Stearns, B. A. J. Org. Chem.
1997, 62, 9210, and references cited therein.
(6) (a) Castelhano, A. L.; Krantz, A. J. Am. Chem. Soc. 1984, 106, 1877. (b)
Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 1988, 110, 612. (c)
Schoemaker, H. E.; Boer-Terpstra, Tj.; Dijkink, J.; Speckamp, W. N.
Tetrahedron 1980, 36, 143. (d) Miranda, P. O.; Carballo, R. M.; Mart´ın,
V. S.; Padro´n, J. I. Org. Lett. 2009, 11, 357.
(7) Our attempts for the cycloisomerization of the 1a using various oxophilic
Lewis/Brønsted acids also failed to give 2a or the ketone 3a.
a Racemic substrates. b Two-step yield. c Isolated yield of the
cycloisomerization product. d Not measured. e 2,6-DBP was not used.
slowed the reaction, requiring 5 mol % catalyst loading for complete
conversion. In the latter case, hydration was not observed even when
the reaction was performed without 2,6-DBP. Although alkyl substitu-
tion at the propargylic position in an acyclic substrate had little effect
(entry 6), similar substitution in cyclic substrates possessing a cis-
relationship of the alkyne and amine group slowed the reaction (entries
7-9). While the cycloisomerization of the cyclopentane substrate 17
(entry 7) and cycloheptane substrate 21 (entry 9) was quickly completed
at rt with 5 mol % catalyst loading, the reaction of cyclohexane
substrate 19 was much slower. In this case, hydration of the
cycloisomerization product was observed. Thus, the cycloisomerization
was performed without 2,6-DBP. The crude mixture was then treated
with p-TsOH to give the piperidin-4-one 20 in 63% yield. Interestingly,
trans-isomer 23 was more reactive than the cis-isomer 19, providing
the cycloisomerization product in 84% yield in the presence of 2 mol
% catalyst.
(8) For selected reviews on the alkynophilic metal-catalyzed reactions, see:(a)
Hashmi, A. S. K.; Rudolph, M. Chem. Soc. ReV. 2008, 37, 1766. (b) Arcadi,
A. Chem. ReV. 2008, 108, 3266. (c) Li, Z.; Brouwer, C.; He, C. Chem. ReV.
2008, 108, 3239. (d) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV.
2008, 108, 3351. (e) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. ReV. 2008,
108, 3326. (f) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410. (g) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006, 348,
2271. (h) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
(9) For selected examples of catalytic reactions initiated by alkoxycyclization
onto alkynes, see:(a) Dube´, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
12062. (b) Bae, H. J.; Baskar, B.; An, S. E.; Cheong, J. Y.; Thangadurai,
D. T.; Hwang, I.-C.; Rhee, Y. H. Angew. Chem., Int. Ed. 2008, 47, 2263.
(c) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005,
127, 15022. (d) Fu¨rstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127,
15024. (e) Hashmi, A. S. K.; Sinha, P. AdV. Synth. Catal. 2004, 346, 432.
(f) Hashmi, A. S. K.; Bu¨hrle, M.; Salathe´, R.; Bats, J. W. AdV. Synth. Catal.
2008, 350, 2059.
(10) Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 12598.
(11) For related discussion in silicon-directed aza-Prins reaction, see: Castro, P.;
Overman, L. E.; Zhang, X.; Mariano, P. S. Tetrahedron Lett. 1993, 34, 5243.
(b) For an example of Prins reaction in the gold(I)-catalyzed reaction, see:
Jime´nez-Nu´n˜ez, E.; Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M.
Angew. Chem., Int. Ed. 2006, 45, 5452.
(12) (a) The catalysts 4a and 4b were generated in situ from AuPR3Cl and AgSbF6.
(b) Using molecular sieves to remove water significantly lowered the yield. (c)
Employing more than 0.8 equiv of 2,6-DBP to the Au complex significantly
slowed the reaction. (d) Changing the counteranions (AgBF4, AgOTf) led to
poorer conversion. (e) Using AgSbF6 or HF showed no cycloisomerization.
(f) One-pot reaction of substrate 1b (2 mol % catalyst 4a, then 10 mol %
p-TsOH) led to the formation of ketone 3b in slightly lower 85% yield.
(13) For the detailed procedure for the synthesis of all substrates including
enantioenriched compound 25, see the Supporting Information.
(14) Formation of single compound for the cycloisomerization was unambigu-
ously confirmed by the 1H NMR spectrum.
Notably, no epimerization was observed in the reaction of the
substrates possessing alkyl groups at the propargylic position.14 This
result indeed supports our hypothesis that the cyclization of the
intermediate F is significantly faster than the competing aza-Cope
rearrangement (eq 1). This rationale is further strengthened by the
reaction of enantioenriched substrate 25,13 which produced 26 in
93% yield (two steps) with no loss of ee (eq 3).15 Furthermore,
this example firmly establishes the utility of the proposed reaction
in the synthesis of optically active piperidin-4-ones.
(15) At this stage, however, an alternative explanation involving sigmatropic
rearrangement of F and the subsequent stereospecific cyclization of F′ (see
eq 1) cannot be completely ruled out.
In summary, we have developed a gold(I)-catalyzed formal alkyne
aza-Prins reaction of mixed N,O-acetals derived from homopropargylic
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