Hypoiodous acid initiated rearrangement of tertiary propargylic alcohols to α-iodoenones

Article abstract of DOI:10.1039/c2ob26360b

In the presence of an oxidant, sodium iodide is converted into hypoiodous acid which effects the rearrangement of tertiary propargylic alcohols to α-iodoenones in good yields.

Full text of DOI:10.1039/c2ob26360b

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Hypoiodous acid initiated rearrangement of tertiary propargylic alcohols to
α-iodoenones†
Wesley J. Moran* and Arantxa Rodríguez*
Received 7th June 2012, Accepted 2nd October 2012
DOI: 10.1039/c2ob26360b
In the presence of an oxidant, sodium iodide is converted
into hypoiodous acid which effects the rearrangement of ter-
tiary propargylic alcohols to α-iodoenones in good yields.
Polyvalent iodine species are mild and selective reagents that
have attracted significant attention in organic synthesis because
of their range of useful reactivity, low toxicity, and ease of use
and handling.1 The majority of research has concentrated on the
use of iodine(III) and iodine(V) compounds, however very
recently iodite(I) and iodite(III) species have emerged as useful
oxidants in a handful of reactions.2
Substituted propargylic alcohols are readily prepared from
aldehydes/ketones and terminal alkynes and serve as versatile
synthetic intermediates.3 They have been utilized as starting
Scheme 1 Polyvalent iodine mediated rearrangements of tertiary pro-
materials in a variety of processes including polyvalent iodine
mediated transformations such as the NIS mediated rearrange-
ment/iodination of acyclic tertiary propargylic alcohols (e.g. 1),4
and the polymer supported iodobenzene diacetate mediated ring
expansion/iodination of 1-alkynylcycloalkanols (e.g. 2a) to
β-iodoenones 3 (Scheme 1).5 Both of these reactions involve car-
bonyl formation as the driving force in 1,2-rearrangement
processes.
pargylic alcohols.
Bovonsombat and McNelis showed that the three tertiary pro-
pargylic alcohols 2a–c could be rearranged to α-iodoenones
4a–c in moderate yields using one equivalent of NIS and 0.1
equivalents of Koser’s reagent (PhI(OH)OTs) in methanol
(Scheme 2).6 Little preference for either alkene isomer was
observed. Intriguingly, under these conditions the oxygen is the
migrating group. Zhang and co-workers reported a related
gold-catalyzed rearrangement of propargylic acetates to
α-iodoenones.7
Scheme 2 NIS mediated rearrangement.
acid), however its reactivity has been little studied.2 At the start
of our investigation with cyclic tertiary propargylic alcohols 2,
four possible outcomes were identified: (i) no reaction; (ii)
rearrangement with ring expansion; (iii) rearrangement without
ring expansion; or (iv) a new reaction.
As part of a wider program to investigate the reactivity of
polyvalent iodine species, we were interested in developing
rearrangements of tertiary propargylic alcohols such as 2 utiliz-
ing hypoiodite species. It is known that treating iodide with oxi-
dants can lead to the formation of hypoiodous acid (or iodic
In the event, alcohol 2d was treated with m-CPBA, p-toluene-
sulfonic acid and sodium iodide in acetonitrile at room tempera-
ture (Table 1, entry 1). Perhaps unsurprisingly, the strong acid
led to dehydration of the starting material and enyne 5 was iso-
lated in 83% yield. Presumably, the alkene was not epoxidised as
the m-CPBA had been used up in oxidising the iodide. Changing
the acid to trifluoroacetic acid also led to isolation of enyne 5 in
80% yield (entry 2). With acetic acid, rearrangement occurred,
without ring expansion, to provide α-iodoenone 4d but in only
9% yield (entry 3).8 Changing to trichloroacetic acid, the
α-iodoenone 4d was formed in 50% yield (entry 4). Exchanging
sodium iodide for tetrabutylammonium iodide led to a similar
Department of Chemical and Biological Sciences, University of
Huddersfield, Huddersfield HD1 3DH, UK. E-mail: w.j.moran@hud.ac.uk,
a.r.menendez@hud.ac.uk; Fax: +44 (0)1484 472182;
Tel: +44 (0)1484 473741
†Electronic supplementary information (ESI) available: General exper-
imental methods, compound characterisation data, copies of NMR
spectra. See DOI: 10.1039/c2ob26360b
8590 | Org. Biomol. Chem., 2012, 10, 8590–8592
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Table 1 Hypoiodite initiated rearrangement
Entry
Acid
Iodide
Yielda (%)
1
2
3
4
5
6
7
4-Toluenesulfonic acid monohydrate
Trifluoroacetic acid
Acetic acid
Trichloroacetic acid
Trichloroacetic acid
Trichloroacetic acid
—
NaI
NaI
NaI
NaI
Bu4NI
NaI
NaI
83 (5)
80 (5)
9b (4d)
50b (4d)
50b (4d)
75c (4d)
8b (4d)
a Yield of pure isolated product. b Yield determined by 1H NMR
analysis. c 3 equiv. of m-CPBA used.
1
yield of product however the H NMR spectrum of the crude
reaction mixture was noticeably messier, therefore the use of
sodium iodide was preferred (entry 5). The amount of oxidant
was increased to three equivalents and 75% of the α-iodoenone
3 was isolated (entry 6). The reaction was carried out without the
acid which led to product formation, however in just 8% yield
(entry 7). None of the ring expanded product 3d was evident in
any of these reactions. Trichloroacetic acid is envisaged to have
just the right acidity to lead to formation of 4 without causing
formation of enyne 5. The use of hydrogen peroxide in place of
m-CPBA led to no reaction.
Scheme 3 Scope of rearrangement process.
With the optimized conditions in hand, the scope of the
rearrangement process was investigated (Scheme 3).‡ Varying
the aromatic substituent had no adverse effect on the reaction
outcome and the α-iodoenones were formed in good yields.
Increasing the size of the ring to six, seven and eight membered
and using open chain substrates also led to efficient rearrange-
ments in all cases studied. Unsymmetrical substrate 2p (R1
=
Me, R2 = Et) underwent rearrangement to provide 4p as a
1 : 1 mixture of separable E and Z alkene isomers, whereas 2q
(R1 = Me, R2 = t-Bu) rearranged stereoselectively to 4q (only
the E isomer could be identified by NMR analysis of the crude
reaction mixture).9 These results can be rationalised by consider-
ation of the steric interactions. In the former case, methyl and
ethyl are of similar size whereas a tert-butyl group is much
larger than a methyl substituent. The phenyl ketone group can
rotate out of the plane of the alkene leaving more space for the
tert-butyl. However, this result is surprising considering the
NIS-mediated rearrangement of 2c to 4c only gave a 1 : 1.5 E/Z
ratio (vide supra).
Scheme 4 Postulated hypoiodous acid initiated rearrangement
mechanism.
generates the final product 4. Iodide can also be oxidised to iodic
acid (HIO3), and hypoiodous acid can disproportionate into iodic
acid and iodine;10 however, as the final product is an alkenyl
iodide, hypoiodous acid is probably the reactive species. Reaction
with iodine should lead to formation of ring-expanded product 3,
however this compound is not observed.
In conclusion, we have demonstrated that in situ generated
hypoiodous acid initiates the rearrangement of tertiary pro-
pargylic alcohols to α-iodoenones in good yields. This process is
exceptionally simple to carry out and the products are potentially
valuable for further synthesis.11 Related studies are in progress
and will be reported in due course.
The use of alkyl substituted alkynes led to very low conver-
sions (<10%) to the α-iodoenones. Whereas secondary propargyl
alcohols failed to rearrange at all under these conditions.
The mechanism of this rearrangement is postulated to proceed
through oxidation of the iodide to hypoiodous acid (HOI) which
reacts with the alkyne to generate an iodonium cation (Scheme 4).
Addition of water, followed by a proton transfer and loss of water
We thank the University of Huddersfield for funding.
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2012, 14, 1158; (d) L. Ma, X. Wang, W. Yu and B. Han, Chem.
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Notes and references
‡Typical reaction procedure: Substituted propargylic alcohol
2
(0.21 mmol), m-CPBA (109 mg, 0.63 mmol), sodium iodide (31 mg,
0.21 mmol) and trichloroacetic acid (51 mg, 0.31 mmol) were dissolved
in acetonitrile (1 mL) at room temperature under a nitrogen atmosphere
and stirred overnight. The reaction mixture was quenched with saturated
aqueous sodium thiosulfate solution and extracted with CH2Cl2. The
organic layer was washed with saturated aqueous sodium bicarbonate
solution, dried over MgSO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography (silica
gel, petroleum ether/ethyl acetate) to afford the corresponding
α-iodoenone 4.
1 For reviews on hypervalent iodine chemistry, see: (a) V. V. Zhdankin,
J. Org. Chem., 2011, 76, 1158; (b) V. V. Zhdankin, ARKIVOC, 2009, 1;
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V. V. Zhdankin, Chem. Rev., 1996, 96, 1123.
6 P. Bovonsombat and E. McNelis, Tetrahedron Lett., 1993, 34,
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7 (a) M. Yu, G. Zhang and L. Zhang, Tetrahedron, 2009, 65, 1846;
(b) M. Yu, G. Zhang and L. Zhang, Org. Lett., 2007, 9, 2147.
8 Compounds 3d and 4d are distinguishable by 1H NMR as shown in
ref. 4a and 5a.
9 E-isomer assigned with the aid of NOESY experiments; see ESI† for
further details.
10 5HIO → HIO3 + 2I2 + 2H2O.
2 (a) A. Yoshimura, K. R. Middleton, C. Zhu, V. N. Nemykin and
V. V. Zhdankin, Angew. Chem., Int. Ed., 2012, 51, 8059; (b) Z. Liu,
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11 For example, see: E. Negishi, J. Organomet. Chem., 1999, 576, 179.
8592 | Org. Biomol. Chem., 2012, 10, 8590–8592
This journal is © The Royal Society of Chemistry 2012