3-Halotetrahydropyran-4-one derivatives from homopropargyl acetal

Article abstract of DOI:10.1080/00397911.2014.902961

GRAPHICAL ABSTRACT A gold(I)-catalyzed regioselective method for the preparation of 3-bromo/iodo-tetrahydropyran-4-one derivatives from homopropargyl acetal is reported. A one-pot procedure based on a gold(I)-catalyzed Petasis-Ferrier rearrangement/cyclization and subsequent electrophilic halogenation was developed. Corresponding hemiacetals were not suitable substrates for the formation of the 3-halo-pyran derivatives. The present transformation is a useful method to readily afford highly substituted 3-halo-tetrahydropyran-4-ones, which are suitable substrates in a variety of reactions in further synthesis.

Full text of DOI:10.1080/00397911.2014.902961

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3-Halotetrahydropyran-4-one Derivatives
from Homopropargyl Acetal
Jon Erik Aaseng a , Naseem Iqbal a , Jørn Eivind Tungen a , Christian
A. Sperger a & Anne Fiksdahl a
a Department of Chemistry , Norwegian University of Science and
Technology , Trondheim , Norway
Accepted author version posted online: 25 Apr 2014.Published
online: 01 Jul 2014.
To cite this article: Jon Erik Aaseng , Naseem Iqbal , Jørn Eivind Tungen , Christian A. Sperger &
Anne Fiksdahl (2014) 3-Halotetrahydropyran-4-one Derivatives from Homopropargyl Acetal, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:17, 2458-2467, DOI: 10.1080/00397911.2014.902961
To link to this article: http://dx.doi.org/10.1080/00397911.2014.902961
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Synthetic Communications1, 44: 2458–2467, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.902961
3-HALOTETRAHYDROPYRAN-4-ONE DERIVATIVES
FROM HOMOPROPARGYL ACETAL
Jon Erik Aaseng, Naseem Iqbal, Jørn Eivind Tungen,
Christian A. Sperger, and Anne Fiksdahl
Department of Chemistry, Norwegian University of Science and Technology,
Trondheim, Norway
GRAPHICAL ABSTRACT
Abstract A gold(I)-catalyzed regioselective method for the preparation of 3-bromo/
iodo-tetrahydropyran-4-one derivatives from homopropargyl acetal is reported. A one-pot
procedure based on a gold(I)-catalyzed Petasis–Ferrier rearrangement/cyclization and
subsequent electrophilic halogenation was developed. Corresponding hemiacetals were not
suitable substrates for the formation of the 3-halo-pyran derivatives. The present transfor-
mation is a useful method to readily afford highly substituted 3-halo-tetrahydropyran-
4-ones, which are suitable substrates in a variety of reactions in further synthesis.
Keywords Gold; 3-halogenated tetrahydropyran-4-ones; homopropargyl acetals;
Petasis–Ferrier rearrangement
INTRODUCTION
We have recently investigated a variety of cyclization pathways of propargyl
substrates, in particular propargyl acetals, taking place by gold(I)-catalyzed
reactions with vinylic compounds.[1a–1c] Such propargyl derivatives are known
to undergo gold(I)-catalyzed migration-fragmentations to give gold carbenoid
intermediates, which can be trapped with different reagents, typically alkenes, to give
different cycloaddition products. We have seen that the reaction pathway switches
by changing from propargylic esters to acetals. In contrast to the regular olefin
Received January 14, 2014.
Address correspondence to Anne Fiksdahl, Department of Chemistry, Norwegian University of
Science and Technology, NTNU, Høgskoleringen, NO-7491 Trondheim, Norway. E-mail: anne.fiksdahl@
chem.ntnu.no
2458

3-HALOTETRAHYDROPYRAN-4-ONE DERIVATIVES
2459
cyclopropanation[1a] normally taking place with propargyl esters, an atypical
cyclopentenylation by a [2 þ 3] cycloaddition reaction is the favored reaction path-
way for the respective acetals.[1b] Our recent studies have also shown that propargyl
acetals undergo gold(I)-catalyzed [2 þ 5] cycloadditions with benzaldimines to afford
benz[c]azepine products.[1c] An essential feature of the propargyl acetals was their
significantly greater reactivity relative to corresponding propargyl esters.
Homopropargylic derivatives are also versatile substrates for gold(I)-catalyzed
reactions. Gold(I)-catalyzed cyclization of homopropargyl substrates includes
transformation of the respective alcohol,[2a] ether,[2b] amine,[2c–e] amide,[2f] carbonate,
[2g,2h]
azide,[2i] sulfoxide,[2j] and acetal[2k] homopropargyl derivatives. Such reactions
often take place by simple 5-exo-dig or 6-endo-dig attack of the present heteroatom
on the gold(I)-activated alkyne moiety to give five- or six-membered heterocyclic
products, as demonstrated by the gold-catalyzed oxycyclizations of alkynols for
the preparation of pyran derivatives.[2l,2m]
In contrast to the general 5-exo-dig or 6-endo-dig cyclizations of homopro-
pargyl substrates, the gold(I)-catalyzed Petasis–Ferrier rearrangement of homopro-
pargyl (hemi)acetals takes place by inclusion of the acetal moiety in the final cyclic
skeleton. This method has been developed for the cycloisomerization–rearrangement
of homopropargyl hemiacetals (I) to give a range of tetrahydropyran-4-ones (II,
Scheme 1a).[2k] Gold-catalyzed Petasis–Ferrier rearrangements have also been
applied on propargyl substrates to afford benzo[b]oxepin-3(2H)-ones[3] and
benzo[b]azepin-3-ones[4] from 2-(prop-2-ynyloxy)- and 2-(N-(prop-2-ynyl)-N-tosyla-
mino-benzaldehydes, respectively.
Scheme 1. Gold(I)-catalyzed cyclization reactions of homopropargyl (hemi)acetals.

2460
J. E. AASENG ET AL.
As tetrahydropyran-4-ones (Scheme 1) are valuable intermediates for the
synthesis of a large variety of biologically active compounds,[5] we wanted to apply
our experience on the highly reactive propargyl acetals to study gold(I)-catalyzed
cyclization reaction of the extended homopropargyl acetal systems based on the
Petasis–Ferrier rearrangement. Halogenated compounds, incorporating Br and I, are
synthetically interesting suitable substrates for a variety of reactions, in particular metal-
catalyzed cross coupling reactions. To include the incorporation of halogens in pyran
derivatives, we were aiming at developing one-pot procedures, combining acetal forma-
tion, cyclization, and electrophilic halogenation. We have reported a separate study
for the development of gold(I)-catalyzed preparation methods for corresponding
fluorinated pyran-4-ones.[6] We herein present our investigations on gold(I)-catalyzed
reactions to afford highly substituted Br- and I-pyran-4-one derivatives (Scheme 1b).
RESULTS AND DISCUSSION
Petasis–Ferrier Rearrangement
Our studies on propargyl Petasis–Ferrier rearrangements were mainly carried
out on aryl-homopropargyl acetal 2 (Scheme 1b), while previous studies[2k]
were based on alkyl-homopropargyl substrates with a hemiacetal functionality
(I, 4-(ethoxyalkyl)oxy, Scheme 1a). In contrast to the hemiacetals (I), affording an
additional stereogenic center and diastereomeric tetrahydropyran-4-one products
II, the corresponding cyclization of acetals (e.g., 2) would not afford diastereomeric
products (e.g., 4, 5).
The proposed mechanism (Scheme 1a)[2k] involves oxycyclization of the
hemiacetal and the gold(I)-activated alkyne moieties in substrate I to give a vinyl
gold(I) intermediate. A subsequent Petasis–Ferrier rearrangement by a ring-opening–
ring-closing process would proceed via an enolic gold(I) complex, favoring the
cis-product. De-auration and a final hydrolysis of vinyl ether II0 would regenerate
the gold(I) catalyst and afford the tetrahydropyran-4-one product II.
Two-Step Process
Homopropargyl acetal 2 and the respective hemiacetal 3 were prepared from
the homopropargyl alcohol precursor, 1-(4-methoxyphenyl)but-3-yn-1-ol, through
reactions with 2-methoxypropene and ethyl-vinyl ether, as we have described else-
where.[6] A number of gold catalysts have been included in optimization studies in
our previous gold(I)-catalyzed studies on propargyl derivatives.[1a–c] As gold(I) com-
plex 1 ((acetonitrile)[(2-biphenyl)di-tert-butyl-phosphine)gold(I) hexafluoroantimo-
nate) always has proved to be appropriate and most effective, this gold catalyst
was applied for cyclization of homopropargyl acetal 2 to afford tetrahydropyran-4-
one product 5 (50%) by Petasis–Ferrier rearrangement (Scheme 2a). Similar
highly substituted tetrahydropyranones have been prepared by intramolecular
hetero-Michael addition of b-hydroxyenones.[7] The reaction was carried out in
dichloromethane (DCM) at room temperature and was completed in 15 min in the
presence of 5 mol% of (acetonitrile)-[(2-biphenyl)di-tert-butylphosphine]gold(I)
hexafluoroantimonate (1). In previous analogous methods[2k] of propargyl hemiace-
tals (I, Scheme 1a), an additional 1 h treatment with p-TsOH has been required to

3-HALOTETRAHYDROPYRAN-4-ONE DERIVATIVES
2461
Scheme 2. Gold(I)-promoted cyclization and halogenation of homopropargyl alcohol via (a) acetal 2 and
(b) hemiacetal 3.
afford hydrolysis of the vinyl ether precursor II0 to give the final tetrahydropyran-4-
one products (II).
To selectively afford the vinyl methyl ether product 4 (77%), similar to the sug-
gested precursor II0 in Scheme 1a, the workup procedure was altered by including
a basic quench with NEt3. The vinyl pyran derivative 4 also readily provided ketone
5 (60%) by treatment with p-TsOH (30 mol%). Gold-catalyzed cyclization of the
alternative hemiacetal 3 to produce ketone 6 (<50%)[6] proved to be less reproducible
and provided a more complex reaction mixture (Scheme 2b). The potential effect of
triethylamine in the workup was not as distinct as for the first reaction.
A one-pot procedure from the homopropargyl alcohol precursor, including
acetal formation and the subsequent cyclization, successfully afforded product 4 in
approximately the same yield (40%) as by preparation in two steps (50%).
To adjust reaction conditions for the subsequent halogenation step, which
would require more polar solvents to dissolve the electrophilic halogenation agents,
test reactions were carried out, replacing DCM by alternative solvents, such as
acetonitrile and nitromethane. Nitromethane appeared to be a suitable alternative
solvent, affording 70% of product 4 from acetal 2. Reactions in acetonitrile gave
complex product mixtures.
Direct iodination of vinyl methyl ether 4 was performed in nitromethane at
room temperature, using NIS as the electrophilic halogen source. The halogenations
took place in a 3-regioselective manner and the 3-iodo diastereomeric products 7a

2462
J. E. AASENG ET AL.
and 7b (54% total yield) were obtained in a 73:27 ratio. Two equivalents of NIS were
essential for efficient conversion.
One-Pot Method
Based on these results, we were aiming at developing a one-pot procedure
for preparation of halogenated pyran derivatives. The compatibility of different gold
catalysts with electrophilic halogenation reagents has previously been demonstrated.[8–11]
To develop a one-pot method based on a combined [gold]-halogenation agent system,
we showed in introductory studies that an allene derivative 12a of a corresponding
homopropargyl benzoate gave product 13 (59%) by gold(I)-catalyzed iodohydroxylation
in the presence of a [Au]-NIS system (Scheme 3). This is in line with results for
iodoalkoxylation of allenes, reported by others.[11] However, the outcome of the
reaction was dependant on the ester functionality, because the allenic acetate 12b
afforded the 3-iodo-3-butenal product (14, 45%). Similar rearrangement products
have previously been obtained by simple noncatalyzed I2 treatment,[12] proposed to
proceed via a 2,3-iodonium allene adduct, a 1,2-aryl shift, and a final deprotonation.
Indeed, no iodohydroxylation of the allenic benzoate 12a took place in the absence
of gold catalyst, as the iodo-butenal product 14 was formed as the main product.
By applying a [Au]-NIS (2 equiv.) system in nitromethane for a one-pot
synthesis of iodinated products from homopropargyl acetal precursors, the 3-iodo-
pyran derivatives 7a and 7b (ratio 73:27) were readily obtained by a two-step
sequential gold(I)-catalyzed reaction from homopropargyl substrate 2. The yield
(51%) was actually greater than obtained by the two-step procedure (42%). However,
the iodo-products 7a and 7b were rather unstable and decomposed gradually into
complex mixtures by handling, as shown by NMR.
In contrast to the [Au]-NIS (2 equiv) reactions, the combined [Au]-NBS (2
equiv) system afforded the dibromo-products 9 (31%) and 10 (15%) from substrate
2. On the other hand, one equivalent of Selectfluor was sufficient to afford the
corresponding 3-fluoro products from vinyl ether 4 with [Au]-Selectfluor (1 equiv).[6]
Thus, the monobromo-product 8 (50%, diastereomerically pure) was isolated and
identified (1H and 13C NMR) after treatment of substrate 2 with [Au]-NBS (1 equiv).
The formation of the two double-bond dibromo-isomers (9, 10) demonstrates that
isomerization takes place during the halogenation process, as shown in the monoha-
logenation reactions to give I- and Br-products 7 and 8 (see also later discussion).
Scheme 3. Iodination reactions of 2,3-allenol esters.

3-HALOTETRAHYDROPYRAN-4-ONE DERIVATIVES
2463
All the cyclizations, halogenations, and one-pot reactions were carried out
within 15 min at room temperature, showing the high reactivity of both the homo-
propargyl acetal 2 and the pyran vinyl ether derivative 4 to undergo cyclization
and halogenation, respectively. It seemed to be essential for successful one-pot
reactions that the substrate and the gold(I) catalyst were mixed prior to the addition
of the electrophilic halogenation reagents NBS or NIS.
Attempts to similarly provide the iodo- and bromo-products 70 and 80 in one
pot from hemiacetal 3 via pyranone intermediate 6, applying the combined
[Au]-NBS or [Au]-NIS systems, were unsuccessful, and the internally
ethoxy-substituted product 11 was formed as the major product (41%, Scheme 2b).
As the gold-catalyzed cyclization of hemiacetal 3 also proved to be less reproduc-
ible,[6] this homopropargyl derivative turned out not to be a suitable substrate for
the present one-pot preparation of halogenated pyran derivatives. We have
previously observed that the propargyl ethyl hemiacetal moiety may give deviating
reactivity to afford different products.[1c]
Acidic Hydrolysis; Product Modification
The 3-halogenation reactions proceeded regioselectively through double-bond
isomerization, as shown by the transformation of the 3,4-vinyl ether 4 into the
3-halo-4,5-vinyl ethers (7, 8, Schemes 2 and 4). As the vinyl pyran derivative 4
was readily hydrolyzed to provide ketone 5 by treatment with 30 mol% p-TsOH,
Scheme 4. Acid-catalyzed transformations of pyran derivatives.

2464
J. E. AASENG ET AL.
compound 4 was treated with CSA or TFA at 0 ꢀC (Scheme 4) to test whether
a double-bond isomerization of the nonhalogenated precursors would take place
by acid catalysis. No isomerization into the 4,5-vinyl ether was observed, but some
amounts of ketone 5 were detected. Thus, the 3,4- to 4,5-double-bond isomerization
is only favored through the halogenation process.
The mono- and di-bromopyran compounds 8 and 9 were also treated with
p-TsOH with the purpose of performing hydrolysis. They were both resistant
towards acid-catalyzed hydrolysis. The iodo-compounds (7a and 7b) were not
tested, due to their general instability. The corresponding 3-fluoro compound[6]
was shown to undergo ring cleavage to selectively afford the a-fluoro E-conjugated
keto product.
CONCLUSION
We have demonstrated the preparation of 3-iodo- and 3-bromo-pyran-4-one
derivatives 7 and 8 from homopropargyl acetal 2 based on a gold(I)-catalyzed Petasis–
Ferrier rearrangement=cyclization and subsequent regioselective 3-halo-incorporation.
Both a one-pot protocol and a two-step procedure via the tetrahydropyran-4-one
product 4 successfully afforded the halo- products. The corresponding homopropargyl
hemiacetal 3 turned out not to be a suitable substrate for the formation of the
3-halo-pyran derivatives. The present method may be useful to afford highly substituted
3-bromo- and 3-iodo-tetrahydropyran-4-ones, being suitable substrates in a variety of
reaction in further synthesis.
EXPERIMENTAL
All reactions were performed under an argon atmosphere. Commercial-grade
reagents were used as received. Dry solvents were collected from a MB SPS-800 solvent
purification system. All reactions were monitored by gas chromatography (GLC) and
thin-layer chromatography (TLC) using E. Merck silica gel 60 F254 (0.25 mm thickness).
Flash chromatography was carried out using Merck silica gel 60 (0.040–0.063 mm).
High-throughput flash purification (HPFP) (SUPELCO1) was performed on prepacked
1
cartridges (VersaPakTM). H and 13C NMR spectra were recorded using a Bruker
Avance DPX 300- or 400-MHz spectrometer, respectively. Chemical shifts are reported
in ppm (d) downfield from tetramethylsilane (TMS) as internal standard. Coupling
constants (J) are reported in hertz (Hz). The attributions of the chemical shifts were
determined by means of correlation spectroscopy (COSY), heteronuclear multiple
quantum correlation (HMQC), and heteronuclear multiple bond correlation (HMBC)
experiments. Melting points (mp) were determined using a Stuart apparatus. High-
resolution mass spectra (HRMS) were determined with an Agilent 6520 QTOF MS
instrument equipped with a MAT 95XL (TermoQuest Finnigan) MS instrument.
Infrared (IR) spectra were obtained with a Nicolet 20SXC FT-IR spectrometer by using
a Smart Endurance reflexion cell. (Acetonitrile)[(2-biphenyl)di-tert-butyl-phosphine)-
gold(I) hexafluoroantimonate (1) was purchased from Aldrich. 1-(4-Methoxyphenyl)-
but-3-yn-1-ol[13] was prepared according to an adopted procedure described by Ma
et al.[14] 1-Methoxy-4-(1-(2-methoxypropan-2-yloxy)ut-3-ynyl)benzene (2), 1-(1-(1-
-ethoxyethoxy)but-3-ynyl)-4-methoxybenzene (3), 4-methoxy-2-(4-methoxyphenyl)-6,

3-HALOTETRAHYDROPYRAN-4-ONE DERIVATIVES
2465
6-dimethyl-3,6-dihydro-2H-pyran (4), 6-(4-methoxyphenyl)-2,2-dimethyldihydro-2H-
pyran-4(3H)-one (5), and 2-(4-ethoxyphenyl)-6-methyldihydro-2H-pyran-4(3H)-one (6)
were prepared as described in our separate report on 3-fluoropyran-4-one derivatives.[6]
General Procedure for One-Pot [Au]-NBS/-NIS Halo-Cyclization
Reactions of Acetal 2
Gold catalyst 1 (5 mol%) in dry nitromethane (1.5–2.0 ml) was added a solution
of acetal 2 (0.25–0.32 mmol) in nitromethane (1.0–2.0 ml) and stirred for 3 min. NBS
or NIS (1=2 equiv.) was added in one portion and the reaction continued for 15 min.
Dichloromethane (20 ml) and a solution of NaHCO3 (saturated, 10 ml) were added.
The aqueous phase was extracted with additional dichloromethane (10 ml) and the
combined organic phases were dried over MgSO4. The concentrated crude material
was purified with flash (VersaFlash) chromatography to afford the respective
halo-cyclization product.
3-Iodo-4-methoxy-6-(4-methoxyphenyl)-2,2-dimethyl-3,6-
dihydro-2H-pyran (7a/7b)
Method a: Iodination of dihydropyran 4. A solution of dihydropyran 4[6]
(35 mg, 0.14 mmol) in nitromethane (1 ml) was added to a solution of N-iodosuc-
cinimide (63 mg, 2 equiv) in nitromethane (1 ml). The mixture turned orange and
showed full conversion (TLC) after 10 min. After a total of 15 min, the solution
was added to a solution of NaHCO3 (saturated, 10 ml) and dichloromethane
(20 ml). The aqueous phase was extracted with dichloromethane (10 ml), and the
combined organic phases were dried over MgSO4. The products 7a and 7b were
formed in a 73:27 diastereomeric ratio. Purification by VersaFlash chromatography
(1% and 2% EtOAc in n-pentane for 7a and 7b, respectively) provided 20 mg (39%)
yield of 7a (yellow oil) and 8 mg (15%) yield of 7b (dark yellow oil), ratio 73:27.
The products appeared to be rather unstable.
Method b: One-pot gold-catalyzed cyclization/iodination of acetal 2. The
title compound was prepared according to the general procedure. A solution of
acetal 2[6] (61 mg, 0.25 mmol) in nitromethane (1 ml) was added to a solution of gold
catalyst 1 (9.5 mg, 5 mol%) in nitromethane (1.5 ml). After 3 min, neat N-iodosucci-
nimide (110 mg, 2 equiv.) was added to the mixture. NaHCO3 (saturated, 10 ml)
and dichloromethane (20 ml) were added. The organic phase was dried over MgSO4.
Purification provided 7a (34 mg, 37%) and 7b (13 mg, 14%) (ratio: 73:27).
Compound 7a: Rf ¼ 0.42 (5% EtOAc in n-pentane). 1H NMR (400 MHz,
CDCl3) d 7.28 (d, J ¼ 8.9 Hz, 2H, HAr), 6.90 (d, J ¼ 8.9 Hz, 2H, HAr), 4.66 (s, 1H,
H-5), 4.60 (dd, J ¼ 2.1, 0.4 Hz, 1H, H-3), 4.13 (d, J ¼ 1.9 Hz, 1H, H-6), 3.81 (s, 3H,
CH3OCAr), 3.62 (s, 3H,CH3O), 1.46 (s, 3H, CH3C), 1.33 (s, 3H, CH3C). 13C NMR
(100 MHz, CDCl3) d 158.9 (CAr), 154.4 (C-4), 133.5 (CAr), 126.9 (CAr), 113.4 (CAr),
103.1 (C-5), 73.2 (C-2), 72.0 (C-6), 55.2 (CH3OCAr), 54.7 (CH3O), 34.4 (C-3), 29.6
(CH3C), 27.7 (CH3C). IR (neat, cmꢁ1) 2972 (w), 1658 (w), 1613 (w), 1513 (s),
1462 (w), 1359 (m), 1246 (s), 1171 (s), 1091 (s), 1027 (s). HRMS (ESI) calcd. for
C15H19O3I (Mþ) 374.0373; obsd. 374.0372.

2466
J. E. AASENG ET AL.
Compound 7b: Rf ¼ 0.34 (5% EtOAc in n-pentane). 1H NMR (400 MHz,
CDCl3) d 7.42 (d, J ¼ 8.7 Hz, 2H, HAr), 6.89 (d, J ¼ 8.7 Hz, 2H, HAr), 5.34
(t, J ¼ 1.9 Hz, 1H, H-6), 4.66 (d, J ¼ 2.0 Hz, 1H, H-5), 4.49 (d, J ¼ 1.5 Hz, 1H,
H-3), 3.80 (s, 3H, CH3OCAr), 3.58 (s, 3H,CH3O), 1.57 (s, 3H, CH3C), 1.51 (s, 3H,
CH3C). 13C NMR (100 MHz, CDCl3) d 158.9 (CAr), 154.4 (C-4), 134.1 (CAr),
129.0 (CAr), 114.0 (CAr), 103.1 (C-5), 73.2 (C-2), 72.0 (C-6), 55.2 (CH3OCAr), 54.7
(CH3O), 36.5 (C-3), 34.4 (CH3C), 20.5 (CH3C). IR (neat, cmꢁ1) 2971 (w), 1657
(w), 1610 (w), 1512 (s), 1462 (w), 1368 (m), 1246 (s), 1171 (s), 1093 (m), 1028 (s).
HRMS (ESI) calcd. for C15H19O3I (Mþ) 374.0373; obsd. 374.0373.
FUNDING
We thank the Royal Norwegian Society of Sciences and Letters and the
Research Council of Norway for financial support.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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