Gold-catalyzed efficient synthesis of azepan-4-ones via a two-step [5+2] annulation

Article abstract of DOI:10.1039/c001314e

A surprisingly efficient synthesis of azepan-4-ones via a two-step [5+2] annulation is developed. This reaction involves a key gold catalysis and shows generally high regioselectivities and good to excellent diastereoselectivities.

Full text of DOI:10.1039/c001314e

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Gold-catalyzed efficient synthesis of azepan-4-ones via a two-step [5 + 2]
annulationw
Li Cui, Longwu Ye and Liming Zhang*
Received (in College Park, MD, USA) 20th January 2010, Accepted 18th February 2010
First published as an Advance Article on the web 30th March 2010
DOI: 10.1039/c001314e
A surprisingly efficient synthesis of azepan-4-ones via a two-step
[5 + 2] annulation is developed. This reaction involves a key gold
catalysis and shows generally high regioselectivities and good to
excellent diastereoselectivities.
Azepane, a seven-membered N-heterocycle, is a building block
Scheme 2 Initial studies.
frequently found in various natural products1 including
stenine,1b galanthamine,1c and croomine1d and a large array
as bicyclic azepan-4-one 2 instead of cyclopentanone 3. This
of compounds studied in medicinal chemistry.2 Although
structural assignment was initially supported by the lack of
symmetry in the 13C NMR spectrum of deoxygenated 2
functionalized azepanes can be prepared via various
approaches,3 methods based on synthetically flexible and
(i.e., compound 4) and later corroborated by X-ray crystallo-
graphy (vide infra). No cyclopentanone 3 or its dehydro-
amination product, cyclopentenone, was observed. Different
gold(I) catalysts as well as AuCl3 and PtCl2 were screened, and
(2-biphenyl)Cy2PAuNTf211 was found to be the most efficient,
furnishing 2 in 79% isolated yield. Of note, Tf2NH did not
catalyze this reaction.
versatile cycloaddition or annulation approaches are still
much needed, and only a few examples4 have been reported.
Herein we report a gold-catalyzed efficient and flexible
synthesis of azepan-4-ones via a two-step [5 + 2] annulation.
We previously reported a two-step synthesis of piperidin-4-
ones in a two-step [4 + 2] manner.5 It is speculated that a
similar [5 + 2] sequence might be possible, which would
afford synthetically versatile azepan-4-ones (Scheme 1).6 This
sequence might involve a gold carbene intermediate (i.e., A)
via a gold-catalyzed intramolecular alkyne oxidation and
require favoring a challenging formal 1,7-C(sp3)–H insertion
by carbene A7 over a seemingly more feasible formal
1,5-C(sp3)–H insertion in the ring formation step.8,9
The scope of this surprising chemistry was studied in a
two-step sequence: (1) alkylation with in-situ generated
5-iodopent-1-yne in refluxing MeCN for 12 h using K2CO3
as base; (2) m-CPBA (1 equiv.) oxidation followed by
(2-biphenyl)Cy2PAuNTf2 (5 mol%) catalysis at 0 1C. As
shown in Table 1, the alkylation step was expectedly efficient
and, to our delight, the one-pot oxidation/gold catalysis was in
general efficient as well; together, these two steps constituted
an efficient synthesis of azepan-4-ones via [5 + 2] annulation.
For symmetric secondary amines (entries 1–4), the two-step
sequence tolerated phenyl (entry 1) or TBSO (entry 2) groups
and allowed the formation of bicyclic azepan-4-ones fused
with either a pyrrolidine (entry 3) or another azepane ring
(entry 4) in good yields.
We tested the hypothesis, nevertheless, by subjecting
N-(pent-4-yn-1-yl)piperidine (1) first to m-CPBA oxidation
10
and then to Ph3PAuNTf2 catalysis without isolating the
N-oxide intermediate (Scheme 2). The major product was
isolated in 53% yield and, to our delight and surprise, assigned
Fortuitously, 6a was crystalline, and its azepane skeleton
was confirmed by X-ray crystallography (Fig. 1).
For non-symmetric secondary amines, this chemistry was
sensitive to steric difference and in most cases good to excellent
regioselectivities were observed. For example, a Me group
participated in the ring formation highly selectively over a
primary alkyl (entry 5) or a benzyl (entry 6) group, yielding
only one azepan-4-one product in each case. Comparing an
n-butyl and a benzyl group was rather revealing. As shown in
entry 7, the former was surprisingly favored over the latter
albeit to a small extent, which, however, could be rationalized
by the fact that phenyl is bigger than n-propyl. A further example
substantiated this rationale: with a bulkier 2-bromophenyl
group, the selectivity was increased to 410 : 1 (entry 8).
Notably, the 2-bromobenzyl group is a removable group
and can be employed in radical translocation reactions.12
While clearly sterics outplayed electronics in determining
regioselectivity, under similar steric environment, however,
Scheme 1 A two-step [5 + 2] annulation toward the synthesis of
azepan-4-ones?.
Department of Chemistry and Biochemistry, University of California,
CA 93106, Santa Barbara. E-mail: zhang@chem.ucsb.edu;
Fax: (+01) (805) 893-4120
w Electronic supplementary information (ESI) available: Experimental
procedure, 1H and 13C NMR spectra, and the X-ray structure of
compound 6a. CCDC 762367. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c001314e
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Table 1 Synthesis of azepan-4-ones via a two-step, 5 + 2 annulation
process: scope study
Yield (%)
1st
step
2nd
step
Entrya Substrate
1
Productb
Fig. 1 ORTEP drawing of compound 6a.
99
98
88
83
78
85
87
51c
80
89
69
85
electronic difference could provide significant regioselectivity.
For example, 1,2,3,4-tetrahydroisoquinoline underwent exclusive
formal insertion into its benzylic C–H bond, yielding tricyclic
azepan-4-one 6i in 70% yield (entry 9). While no significant
selectivity between PMB (p-MeOBn) and Bn was observed
(entry 10), the low selectivity in the case of 5k (6k/6k0 = 1.2/1)
was surprising and in contrast to what was previously
observed in the synthesis of piperidin-4-ones (exclusive insertion
into the butyl group).5a The selectivity was improved to 5/1
using Et3PAuNTf2 as catalyst (entry 11). The sensitivity of this
chemistry to sterics was further evident as the gold catalysis in
the case of sterically demanding N-butyl-3-pentanamine
proceeded sluggishly and no azepan-4-one product was isolated.
In contrast, 2-methylpiperidine reacted smoothly to yield
bicyclic azepan-4-one 6l in 74% yield (entry 12). Although
the NH group of 2-methylpiperidine is similarly flanked by a
secondary and a primary carbon centers, the ring structure
likely alleviated steric hindrance for the gold catalysis.
Importantly, this reaction showed good diastereoselectivity
and excellent regioselectivity. Even better diastereoselectivities
were observed in the cases of 4-methylpiperidine (entry 13) and
methyl prolinate hydrochloride (entry 14). While (2-biphenyl)-
Cy2PAuNTf2 was generally the catalyst to use, in some cases
(entries 7, 11 and 14), Et3PAuNTf2 gave better results.
Substitutions on the pent-4-ynyl chain were readily tolerated at
the 1, 2 and 3 positions (eqn (1)–(3)), leading to azepan-4-ones
with substitutions at the 5, 6 and 7 positions in fairly good yields.
Notably, decreased regioselectivity was observed with substrate
11, indicating the subtlety of regiochemistry control.
2
3
4
5
6
7
93
73d,e
8
91
71c
9
80
99
70
10
63f
11
90
93d,g 12
ð1Þ
ð2Þ
87
74
84
90
13
76h
71d
14
a
The reaction concentration was 1 M for the first step and 0.05 M for
b
c
the second step. Regioselectivity, if not indicated, is 420 : 1. Reaction
time: 8 h. Et3PAuNTf2 (5 mol%) was used instead. Reaction time:
d
e
ð3Þ
We have discovered a gold-catalyzed efficient synthesis of
f
6 h. An inseparable mixture. A ratio of 1.2/1 was observed using
g
h
(2-biphenyl)Cy2PAuNTf2 as catalyst. Reaction time: 3.5 h.
azepan-4-ones via a two-step [5 + 2] annulation. This reaction
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is sensitive to steric differences and can in general be highly
regioselective. Good to excellent diastereoselectivities can be
achieved. This chemistry opens an easy, flexible, and efficient
route to access various azepane derivatives. The detailed
mechanism of this surprising reaction is currently probed
and the results will be reported in due course.
6 This is characteristically different from our early work on tetra-
hydrobenzazepin-4-one synthesis (L. Cui, G. Zhang, Y. Peng and
L. Zhang, Org. Lett., 2009, 11, 1225–1228), where the cyclization
step proceeded most likely via an electrophilic aromatic
substitution.
7 This formal insertion could mechanistically require a rare 1,7-
hydride migration over an aliphatic carbon chain; for an example,
see: (a) K. Nishide, Y. Shigeta, K. Obata and M. Node, J. Am.
Chem. Soc., 1996, 118, 13103–13104; (b) M. Node, K. Nishide,
Y. Shigeta, H. Shiraki and K. Obata, J. Am. Chem. Soc., 2000, 122,
1927–1936. For 1,7-hydrogen migrations in highly conjugated
systems, see: (c) C. W. Spangler, B. Keys and D. C. Bookbinder,
J. Chem. Soc., Perkin Trans. 2, 1979, 810–813; (d) R.-L. Chen and
R. S. H. Liu, Tetrahedron, 1996, 52, 7809–7816; for a radical case,
see: (e) A. L. J. Beckwith and D. R. Boate, J. Chem. Soc., Chem.
Commun., 1985, 797–798.
We gratefully thank Sloan Fellowship, NIH (R01
GM084254) and UCSB for generous financial support and
Dr Guang Wu for help with X-ray crystallography.
Notes and references
1 For a review, see: (a) D. O’Hagan, Nat. Prod. Rep., 1997, 14, 637;
(b) S. Ueo, H. Irie and H. Harada, Chem. Pharm. Bull., 1967, 15,
768–770; (c) W. C. Wildman, Alkaloids, 1968, 11, 348, and references
cited therein; (d) T. Noro, S. Fukushima, A. Ueno, T. Miyase,
Y. Iitaka and Y. Saiki, Chem. Pharm. Bull., 1979, 27, 1495–1497.
2 A simple SciFinder search for azepane-containing compounds
studied for biological activities retrieved more than 25000 hits.
3 For selected examples or reviews, see: (a) E. J. Kantorowski and
M. J. Kurth, Tetrahedron, 2000, 56, 4317–4353; (b) K. Maruyama
and Y. Kubo, Chem. Lett., 1978, 769–772; (c) J. Diamond,
W. F. Bruce and F. T. Tyson, J. Med. Chem., 1964, 7, 57–60;
(d) I. Ryu, H. Miyazato, H. Kuriyama, K. Matsu, M. Tojino,
T. Fukuyama, S. Minakata and M. Komatsu, J. Am. Chem. Soc.,
8 For examples of hydride migration in gold catalysis, see:
(a) S. Bhunia and R.-S. Liu, J. Am. Chem. Soc., 2008, 130,
16488–16489; (b) V. K.-Y. Lo, M.-K. Wong and C.-M. Che,
Org. Lett., 2008, 10, 517–519; (c) E. Jimenez-Nu´ nez,
´
M. Raducan, T. Lauterbach, K. Molawi, C. R. Solorio and
A. M. Echavarren, Angew. Chem., Int. Ed., 2009, 48, 6152–6155;
(d) J. Barluenga, A. Fernandez, F. Rodriguez and F. J. Fananas,
Chem.–Eur. J., 2009, 15, 8121–8123; (e) V. Lavallo, G. D. Frey,
B. Donnadieu, M. Soleilhavoup and G. Bertrand, Angew. Chem.,
Int. Ed., 2008, 47, 5224–5228.
9 For examples of hydrogens a to a heteroatom migrating as a
hydride, see: (a) S. J. Pastine, K. M. McQuaid and D. Sames,
´
J. Am. Chem. Soc., 2005, 127, 12180–12181; (b) P. Matyus,
2003, 125, 5632–5633; (e) J. Aube, P. M. Burgett and Y. Wang,
´
Tetrahedron Lett., 1988, 29, 151–154; (f) C. Brocke, M. A. Brimble,
D. S. H. Lin and M. D. McLeod, Synlett, 2004, 2359–2363.
4 For selected examples, see: (a) P. A. Wender, T. M. Pedersen and
M. J. C. Scanio, J. Am. Chem. Soc., 2002, 124, 15154–15155;
(b) B. M. Trost and C. M. Marrs, J. Am. Chem. Soc., 1993, 115,
6636–6645; (c) N. D. Shapiro and F. D. Toste, J. Am. Chem. Soc.,
2008, 130, 9244–9245.
5 (a) L. Cui, Y. Peng and L. Zhang, J. Am. Chem. Soc., 2009, 131,
8394–8395. For an application in natural product synthesis, see:
(b) L. Cui and L. Zhang, Sci. China B: Chem., 2010, 53, 113–118.
O. Elias, P. Tapolcsanyi, A. Polonka-Balint and B. Halasz-Dajka,
Synthesis, 2006, 2625–2639; (c) S. Murarka, I. Deb, C. Zhang and
D. Seidel, J. Am. Chem. Soc., 2009, 131, 13226.
10 N. Mezailles, L. Ricard and F. Gagosz, Org. Lett., 2005, 7,
´
4133–4136.
11 L. Cui, G. Zhang and L. Zhang, Bioorg. Med. Chem. Lett., 2009,
19, 3884–3887.
12 K. Takasu, H. Ohsato and M. Ihara, Org. Lett., 2003, 5,
3017–3020.
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Chem. Commun., 2010, 46, 3351–3353 | 3353