Trifluoromethanesulfonic acid-catalyzed tandem semi-pinacol rearrangement/alkyne-aldehyde metathesis reaction of arylpropagylsulfonamide- tethered 2,3-epoxycyclohexan-1-ols to spiropiperidines

Article abstract of DOI:10.1002/adsc.201100576

A simple and efficient trifluoromethanesulfonic acid-catalyzed cycloisomerization of arylpropagylsulfonamide-tethered 2,3-epoxycyclohexan-1-ols is described. The cyclization proceeds via tandem semi-pinacol rearrangement/alkyne-aldehyde metathesis to affo

Full text of DOI:10.1002/adsc.201100576

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DOI: 10.1002/adsc.201100576
Trifluoromethanesulfonic Acid-Catalyzed Tandem Semi-Pinacol
Rearrangement/Alkyne-Aldehyde Metathesis Reaction of
Arylpropagylsulfonamide-Tethered 2,3-Epoxycyclohexan-1-ols
to Spiropiperidines
Ming-Nan Lin,a Shih-Hui Wu,a and Ming-Chang P. Yeha,*
a
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road, Section 4, Taipei 11677, Taiwan,
Republic of China
Fax : (+886)-2-2932-4249; e-mail: cheyeh@ntnu.edu.tw
Received: July 21, 2011; Published online: December 14, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100576.
Abstract: A simple and efficient trifluoromethane-
sulfonic acid-catalyzed cycloisomerization of aryl-
propagylsulfonamide-tethered 2,3-epoxycyclohexan-
1-ols is described. The cyclization proceeds via
tandem semi-pinacol rearrangement/alkyne-alde-
hyde metathesis to afford spiropiperidines under
mild reaction conditions.
azaspirocycles, most of the catalytic approaches in-
volve addition of nucleophiles to metal-activated
carbon-carbon multiple bonds. From both economical
and environmental points of view, the development of
metal-free catalytic processes is desirable for the syn-
thesis of functionalized azaspirocycles. We have now
demonstrated that trifluoromethanesulfonic (triflic)
acid (TfOH) can be applied, in a catalytic fashion, to
a series of various arylpropagylsulfonamide-tethered
2,3-epoxycyclohexan-1-ols allowing the synthesis of
functionalized spiropiperidines. In this transformation,
a TfOH-induced semi-pinacol-type rearrangement[3]
of the six-membered ring epoxy alcohols occurs to
generate the ring contraction 2-hydroxycyclopentane-
carbaldehyde derivatives. A subsequent TfOH-pro-
Keywords: alkyne/aldehyde metathesis; semi-pina-
col rearrangement; spiropiperidines; tandem reac-
tions; triflic acid
The construction of azaspirocyclic building blocks is moted intramolecular alkyne-aldehyde metathesis[4]
an important synthetic goal because such ring skele- then takes place to afford the spiropiperidines in
tons are present in numerous natural products of bio- good to high yields under mild reaction conditions.
logical interest.[1] Because the availability of function-
The requisite arylpropagylsulfonamide-tethered 2,3-
alized azaspirocyclic building blocks could greatly fa- epoxycyclohexan-1-ols 1 were prepared starting from
cilitate the elaboration of more structurally complex the addition of lithiated dimethyl sulfide to 3-isobut-
compounds, the design of expedient and efficient syn-
ACHTUNGTRENoNGNU xycyclohex-2-en-1-one in THF at room temperature
thetic routes to such intermediates has been actively to produce 3-[(methylthio)methyl]cyclohex-2-en-1-
pursued.[2] Many synthetic methods, as the key step, one. Treatment of the resulting thioether with methyl
have been developed in pursuit of this structure, in- iodide in CH2Cl2 at 408C afforded 3-(iodomethyl)cy-
cluding the platinum(II)-catalyzed intramolecular cy- clohex-2-en-1-one. Reaction of the corresponding ar-
ACHTUNGTRENNUNGclization of cyclic enesulfonamides bearing an alkyne ylpropagylsulfonamide with 3-(iodomethyl)cyclohex-
tether;[2a] the ene-type cyclization of cyclic 1,7-enynes 2-en-1-one in acetone at room temperature followed
with tethered alkynes catalyzed by the cationic palla- by reduction of the resulting enones with NaBH4 in
dium complex;[2b] the samarium(II)-mediated cycliza- MeOH at 08C and subsequent epoxidation with
tion of unsaturated ketolactams;[2c] the intramolecular mCPBA in CH2Cl2 at room temperature provided 1
radical cyclization of cyclic enamines carrying an in 41–62% overall yields.[5] Due to the fact that cat-
alkyl bromide[2d] and the palladium-catalyzed transfor- ionic phosphine gold(I) complexes have emerged as
mation of 3,4-dihydro-2-pyridinones carrying a (2-bro- versatile catalysts for electrophilic activation of al-
mophenyl)ethyl substituent.[2e] Although a transition kynes toward a variety of nucleophiles under mild re-
metal-catalyzed process is a useful protocol to obtain action conditions,[6] we first screened reaction condi-
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Trifluoromethanesulfonic Acid-Catalyzed Tandem Semi-Pinacol Rearrangement/Alkyne-Aldehyde Metathesis
Table 1. Optimization of the reaction conditions.
In order to facilitate analysis and shorten reaction
times, the reaction temperature was increased to
508C. The parent compound 1a did cycloisomerize
smoothly at 508C and a 91% isolated yield of the ex-
pected spiropiperidine 2a was obtained after 40 min
at 508C (Table 1, entry 6). The investigation of vari-
ous solvents in the presence of the TfOH catalyst re-
vealed that dichloromethane, THF, toluene and
CH3CN were less effective and afforded 2a in moder-
ate yields (33–64%, Table 1, entries 7–10). Thus, the
use of TfOH (10 mol%) in DCE at 508C was found
to be the most efficient and was chosen as the stan-
dard reaction conditions. A similar catalytic conden-
sation reaction of electron-rich arenes with aldehydes
using various Lewis acids, for example, AuCl3,
Hg
ACHTUTGNREN(NUG ClO4)2, TlACHTUNGTRNE(NUGN ClO4)3 and Brønsted acids has been re-
ported.[7]
It must be mentioned that attempts to separate the
mixture of two diastereomeric isomers of 2a using
flash column chromatography on silica gel failed. Oxi-
dation of the mixture with 2-iodoxybenzoic acid
(IBX) in refluxing acetone for 6 h gave 9-benzoyl-7-
[a]
Diastereoisomeric ratio.
tosyl-7-azaspiro
ACHTUNGTRNE[NUNG 4.5]dec-9-en-1-one (3a) in nearly
quantitative yield from 2a (Figure 1). The structure
tions for the cycloisomerization of 1a using the two- elucidation of 3a was achieved by X-ray crystallogra-
component catalytic system [PPh3AuCl/AgOTf]. phy.[8]
Thus, treatment of 1a with 5 mol% of PPh3AuCl/
With the optimal reaction conditions, we next ex-
AgOTf in CH2Cl2 at 248C for 10 h gave a 33% yield amined the substrate scope of the TfOH-catalyzed
of spiropiperidine 2a as a mixture of two diastereo- transformation. The results of the TfOH-catalyzed cy-
mers (Table 1, entry 1). The parent compound 1a was cloisomerization reaction of the arylpropagylsulfona-
then subjected to a series of Lewis and Brønsted mide-tethered 2,3-epoxycyclohexan-1-ols 1a–l to pro-
acids and various solvents (Table 1). While boron tri- duce spiropiperidines 2a–l are listed in Table 2. Elec-
fluoride etherate in THF and AgSbF6 in dichloro- tron-neutral and electron-rich arenes at the alkyne
ethane (DCE) could not catalyze the process effi- terminus were proven to be good substrates, as the
ciently (Table 1, entries 2 and 3), NHTf2 (10 mol%) yields of desired spiropiperidines 2a–f as a mixture of
exhibited high catalytic activity in DCE at 248C and diastereomers ranged from 66% to 91% (entries 1–6,
provided 2a in 83% isolated yield after 30 min reac- Table 2). The crude mixture of diastereomeric isomers
tion time (Table 1, entry 4). The use of TfOH of 2c was separated in a ratio of 2:1 using flash
1
(10 mol%) in DCE at 248C for 30 min gave the de- column chromatography on silica gel. The H NMR
sired spiropiperidine 2a (18%) and an additional spectrum of the major isomer exhibited a singlet at
product identified as phenylpropagylsulfonamide- d=6.33 assigned to the vinyl H, a broad singlet at d=
tethered 2-hydroxycyclopentanecarbaldehyde 4 (21%) 4.18 assigned to the H at the carbinol carbon, and two
together with recovery of the starting substrate 1a doublets, centered at d=4.26 and 3.73, assigned to
(47%). Delightfully, the full conversion of 1a into 2a the two diastereotopic methylene protons at the allyl-
was accomplished after 3.5 h at 248C (86% yield, ic carbon. The 1H NMR spectrum of the minor
Table 1, entry 5). Due to the isolation of the semi-pi- isomer exhibited a singlet at d=6.58 assigned to the
nacol rearrangement product, compound 4 (Figure 1) vinyl H, a broad singlet at d=4.21 assigned to the H
is likely to be the key intermediate for the following at the carbinol carbon, and two doublets, centered at
cycloisomerization leading to the spiropiperidine 2a. d=4.11 and 3.69, assigned to the two diastereotopic
methylene protons at the allylic carbon. However,
substrates with a bromine atom at the phenyl ring, for
example, 1g, 1h, or an electron-withdrawing group,
such as an ester or nitro group at the phenyl ring, for
example, 1i–k, were less effective and required pro-
longed reaction times to provide spiropiperidines 2g–
k in 14% to 56% isolated yields (Table 2, entries 7–
11). Moreover, substrate 1l having a methyl group at
Figure 1. Structures of 3a and 4.
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Table 2. Synthesis of spiropiperidines 2.
[a]
All products 2 were subjected to IBX oxidation and characterized as 9-aroyl-7-tosyl-7-azaspiroACTHNUTRGNEUGN[4.5]dec-9-en-1-ones 3.
the alkynyl terminus lowered the catalytic activity of example, 1p, and the cyclization produced spiropiperi-
TfOH and the yield of 2l was diminished to 21% dine 2p in only 43% yield (Figure 2).[9]
(Table 2, entry 12). Unfortunately, the reaction of the
On the basis of the experiment results, a possible
substrate with a terminal alkyne, for example, 1m, re- reaction pathway for the observed TfOH-catalyzed
sulted in decomposition of the starting substrate cycloisomerization of 1a to provide 2a is suggested in
(Table 2, entry 13). It is worthy of mention that sub- Scheme 1. Protonation of the epoxide of 1a with
strates bearing a geminal dimethyl group at C-5 of TfOH led to the oxiranium ion 5, which promoted a
the ring, for example, 1n, 1o, do not interfere with the semi-pinacol rearrangement to give the phenylpropa-
catalytic activity of TfOH as shown by the fact that gylsulfonamide-tethered 2-hydroxycyclopentanecar-
the yields of their corresponding spiropiperidines 2n baldehyde 4 as a mixture of diastereomers. It must be
and 2o were 86% and 93%, respectively. However, mentioned that the usual semi-pinacol rearrangement
the reaction was sluggish with the substrate bearing of 2,3-epoxycyclohexan-1-ols gives 2-hydroxycyclo-
an methyl group at the C-2 position of the ring, for pentanecarbaldehyde 6 (Figure 3), which led to the
formation of cyclopentene-1-carbaldehyde derivatives
after dehydration.[3a] The formation of 2-hydroxycy-
clopentanecarbaldehyde 4 demonstrated that the pre-
ferred reaction pathway for the semi-pinacol rear-
rangement of 5 proceeded via migration of the hy-
droxyalkyl group to the tertiary carbocation. The sim-
ilar unusual semi-pinacol rearrangement had previ-
ously been observed with an a-silyloxymethyl epoxide
having both allylic and tertiary centers.[3c] The follow-
ing TfOH-catalyzed intramolecular alkyne-aldehyde
metathesis started with protonation of the formyl
group of 4 to give the oxonium species 7, which pro-
duced oxete 8 via [2+2]cycloaddition. The intermedi-
ate 8 then underwent [2+2]cycloreversion to afford
spiropiperidine 2a and regenerated the acid in the cat-
alytic cycle.
In summary, we have developed an efficient synthe-
Figure 2. Structures of 1n–p and 2n–p.
sis of 9-benzoyl-7-tosyl-7-azaspiroACTHNGUTERNNU[G 4.5]dec-9-en-1-ols
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Trifluoromethanesulfonic Acid-Catalyzed Tandem Semi-Pinacol Rearrangement/Alkyne-Aldehyde Metathesis
ed under reduced pressure to afford the crude product 2a as
a yellow oil; yield: 93 mg. The crude 2a was used for the
next oxidation step without further purification.
To an oven-dried, 10-mL round-bottom flask equipped
with a stirrer bar and capped with a rubber septum was
added 2a (93 mg, 0.23 mmol), 2-iodoxybenzoic acid (0.14 g,
0.5 mmol) and acetone (2.5 mL) under nitrogen. The reac-
tion mixture was stirred at 558C for 6 h. The reaction mix-
ture was allowed to cool to room temperature and was fil-
tered through a bed of Celite. The filtrate was concentrated
under vacuum, and purified by flash column chromatogra-
phy on silica gel (hexanes/ethyl acetate=10:1) to give 3a as
a colorless solid; yield: 89 mg (0.21 mmol, 87%); mp 197–
1
1988C. H NMR (400 MHz, CDCl3): d=7.71 (d, J=8.0 Hz,
2H), 7.61 (d, J=7.3 Hz, 2H), 7.53 (t, J=7.3 Hz, 1H), 7.42
(t, J=7.6 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 6.28 (s, 1H),
4.43 (d, J=16.6 Hz, 1H), 3.62 (d, J=11.6 Hz, 1H), 3.48 (dd,
J=16.6, 2.0 Hz, 1H), 2.63 (d, J=11.6 Hz, 1H), 2.44 (s, 3H),
2.41–2.28 (m, 3H), 2.12–2.00 (m, 3H); 13C NMR (100 MHz,
CDCl3): d=216.8, 194.5, 144.1, 141.3, 137.0, 135.8, 133.0,
132.3, 129.9 (2C), 129.3 (2C), 128.4 (2C), 127.6 (2C), 53.2,
47.6, 44.4, 38.1, 34.8, 21.5, 19.3; IR (CH2Cl2): n =3062, 2966,
1738, 1645 cmÀ1; HR-MS (EI): m/z=432.1252, calcd. for
C23H23NO4NaS (M+Na+): 432.1246. Crystals suitable for X-
Scheme 1. Plausible reaction mechanism for the TfOH-cata-
ray diffraction analysis were grown from CH2Cl2 and hex-
lyzed cycloisomerization of 1 to 2.
anes.
Supporting Information
Spectroscopic characterization and copies of 1H/13C NMR
1
spectra of two diastereomersi of 2c; H/13C NMR spectra of
compounds 3a–l and X-ray crystallographic information files
for compounds 3a and 3o are available as Supporting Infor-
mation.
Figure 3. Structure of 6.
via TfOH-catalyzed tandem semi-pinacol rearrange-
ment/alkyne-aldehyde metathesis reaction from 2,3-
Acknowledgements
This work was supported by grants from the National Science
Council (NSC 98-2119M-003-004-MY3, NSC 98-2119M-003-
001-MY2) and National Taiwan Normal University.
epoxycyclohexan-1-ols tethered an arylpropagylsulfo-
namide. The advantages of this procedure are the
mild reaction condition and the environmentally
friendly catalyst. Further studies on synthetic applica-
tions of these reactions are currently in progress.
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Experimental Section
General Procedure for Synthesis of 9-Benzoyl-7-tosyl-
7-azaspiroACHTUNGTRENNUNG[4.5]dec-9-en-1-one (3) via TfOH-Catalyz-
ed Tandem Semi-Pinacol Rearrangement/Alkyne-
Aldehyde Metathesis
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(103 mg, 0.25 mmol), TfOH (2.18 mL, 0.025 mmol) and DCE
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