Regioselective dihalohydration reactions of propargylic alcohols: Gold-catalyzed and noncatalyzed reactions

Article abstract of DOI:10.1002/anie.201405348

The regioselective conversion of propargylic alcohols into previously unreported α,α-diiodo-β-hydroxyketones was achieved by treatment with N-iodosuccinimide in the presence of a gold catalyst. The corresponding α,α-dichloro-β-hydroxyketones were obtained

Full text of DOI:10.1002/anie.201405348

Angewandte
Chemie
DOI: 10.1002/anie.201405348
Halogenation
Regioselective Dihalohydration Reactions of Propargylic Alcohols:
Gold-Catalyzed and Non-Catalyzed Reactions**
Jarryl M. DꢀOyley, Abil E. Aliev, and Tom D. Sheppard*
Abstract: The regioselective conversion of propargylic alco-
hols into previously unreported a,a-diiodo-b-hydroxyketones
was achieved by treatment with N-iodosuccinimide in the
presence of a gold catalyst. The corresponding a,a-dichloro-b-
hydroxyketones were obtained by treatment with trichloroiso-
cyanuric acid in the absence of a catalyst. The latter reaction
can be extended to other alkynols. These transformations can
be used to prepare potentially useful halogenated building
blocks. Preliminary mechanistic studies suggest that the
reaction involves participation of the acetonitrile solvent in
the formation of a 5-halo-1,3-oxazine intermediate.
Scheme 1. Transformations of propargylic alcohols.
P
ropargylic alcohols are useful and readily accessible
intermediates for organic synthesis, containing both an
alcohol and a carbon–carbon triple bond which can undergo
a variety of useful reactions.[1] Numerous catalytic trans-
formations of these compounds have been reported in recent
years including their conversion into aromatic heterocycles[2]
and the substitution of the alcohol group with a variety of
nucleophiles.[3] The Meyer–Schuster rearrangement of prop-
argylic alcohols into enones is a particularly useful reaction
(Scheme 1, A),[4,5] providing an extremely effective alterna-
tive to the olefination of carbonyl compounds with phospho-
rus reagents. Recently a number of variants have been
reported which enable functionalization of the proposed
vinylmetal intermediate with a halogen,[6] an aryl group,[7] or
a trifluoromethyl group[8] to give a-substituted enone prod-
ucts (Scheme 1, B). Here we report a new reaction pathway, in
which the formation of a 5-halo-1,3-oxazine intermediate by
reaction of a propargylic alcohol with acetonitrile, enables
a highly regioselective dihalohydration reaction to be ach-
ieved. Depending on the nature of X, this pathway can be
accessed with or without a gold catalyst.
Scheme 2. Reaction of alcohol 1a with gold catalyst and NIS.
preparation of a-haloenones, we reacted propargylic alcohol
1a with gold catalyst[9] and N-iodosuccinimide (NIS) in PhMe
at room temperature (Scheme 2 and Table 1). This provided
the a-iodoenone 2a in good yield as hoped (entry 1).
Interestingly, however, a small amount of a ketone by-
product was isolated from the reaction mixture, which was
identified as a,a-diiodo-b-hydroxyketone 3a. To the best of
our knowledge, there are no previous reports of the synthesis
of a,a-diiodo-b-hydroxyketones in the literature so the fact
that this unusual compound could be obtained from readily
available materials was of considerable interest. Furthermore,
the gold-catalyzed regioselective dihalohydration of an
alkyne is unprecedented.[10,11] We therefore sought to opti-
mize the reaction conditions to provide 3a as the major
product.
In an initial experiment in which we sought to extend our
procedure for the Meyer–Schuster rearrangement[4] to the
[*] J. M. D’Oyley, Dr. A. E. Aliev, Dr. T. D. Sheppard
Department of Chemistry, University College London
20 Gordon St, London, WC1H 0AJ (UK)
E-mail: tom.sheppard@ucl.ac.uk
Table 1: Optimization of the diiodohydration reaction.[12]
Entry
Solvent
NIS (equiv)
t
Yield
Homepage: http://www.tomsheppard.eu
1
2
3
4
5
6
7
8
PhMe
1.2
1.2
2.4
2.2
2.2
2.2
2.1
2.1
2 h
18 h
5 h
45 min
45 min
30 min
1 h
71% (2a)[a]
18% (3a)
49% (3a)
50% (3a)
38% (3a)
64% (3a)
71% (3a)
0%[b]
[**] We would like to thank the UCL Drug Discovery PhD Program and
UCL (studentship to J.M.D.) and the Engineering and Physical
Sciences Research Council for supporting this work.
PhMe:H2O 20:1
PhMe:H2O 20:1
Et2O:H2O 20:1
THF:H2O 20:1
MeCN:H2O 20:1
MeCN:H2O 10:1
MeCN:H2O 10:1
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405348.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
18 h
[a] Small quantities of 3a were observed. [b] The gold catalyst was
omitted.
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Addition of water to the reaction mixture resulted in an
increased yield of the diiodoketone 3a (entry 2). Increasing
the quantity of NIS led to a further increase in yield as
expected (entry 3). Subsequently, the effect of solvent was
explored with Et2O and THF proving no more effective than
PhMe (entries 4,5), but MeCN giving a promising increase in
yield (entry 6) and a much cleaner crude product. A further
improvement was obtained by increasing the quantity of
water, and the number of equivalents of NIS could be reduced
to 2.1 without detrimental effect on the conversion (entry 7).
In a control experiment in the absence of gold catalyst, no
formation of 3a (or 2a) was observed. A wide range of Au
catalysts could be used,[12] though PPh3AuNTf2 gave a cleaner
conversion so this was employed for subsequent reactions.
We next set out to determine the scope of the reaction by
applying these conditions to various propargylic alcohols
(Scheme 3). Pleasingly, a selection of different a,a-diiodo-b-
Scheme 4. Dichlorohydration reactions. [a] NMR yield; [b] 2 equiv.
TCICA.
cohol (4m) could be prepared in acceptable yield from the
corresponding dialkynol using two equivalents of TCICA.
When the diiodohydration reaction was applied to
enantioenriched alcohol (R)-1d,[15] diiodohydroxyketone
(R)-3d was obtained with complete retention of enantiomeric
purity (Scheme 5), whereas dichlorohydroxyketone (R)-4d
was obtained with a slight reduction in the enantiopurity.
Scheme 3. Synthesis of a-diiodo-b-hydroxyketones. Tol=p-tolyl;
PMP=p-methoxyphenyl.
Scheme 5. Dihalohydrations of an enantioenriched propargylic alcohol.
hydroxyketones 3a–3i could be obtained in moderate to
excellent yield from the corresponding alcohols. As well as
secondary alcohols, a primary alcohol (3c) could also be
employed. Tertiary alcohols were not suitable substrates,
though this is perhaps unsurprising given the large steric
demands of the geminal diiodo unit. The reaction could also
be applied to the synthesis of a diiodohydroxyester (3i) from
the corresponding alkynyl ether.
Given the synthetic interest in chlorolipid natural prod-
ucts,[13] many of which contain geminal dichlorides, we elected
to explore whether this reaction could be extended to the
synthesis of a,a-dichloro-b-hydroxyketones 4 (Scheme 4).
Disappointingly, no reaction was observed with N-chlorosuc-
cinimide as the halogenating reagent, but employing trichlor-
oisocyanuric acid (TCICA) enabled the a,a-dichloro-b-
hydroxyketone 4a to be obtained in good yield.[12] Suprisingly,
this dichlorohydration reaction occurred even in the absence
of a gold catalyst.[14] The dichlorohydration reaction could be
applied to a wide range of propargylic alcohols to give the
corresponding dichlorohydroxyketones (4a–4h, 4k–4l) or
dichlorohydroxyesters (4i–4j) in generally good yield. The
reaction was applicable to primary (4c), secondary (4a, 4b,
4d–4j) and tertiary (4k) propargylic alcohols, although a poor
yield was obtained with a low molecular weight primary
propargylic alcohol (4l). A symmetrical tetrachlorodiketoal-
Thus, in combination with the many methods available for
accessing enantioenriched propargylic alcohols,[15,16] the novel
dihalohydration reactions described above provide viable
routes to enantioenriched aldol products formally derived
from dihalomethyl ketone enolates. Given the fact that there
are currently no viable methods for achieving asymmetric
aldol reactions with these enolates, this approach could be
especially valuable.[17] It should also be noted that a,a-
dihalocarbonyl compounds have been shown to possess useful
biological activity,[18] as well as being applicable to a range of
[19]
À
À
C C and C heteroatom bond forming reactions.
Pleasingly, the dichlorohydration reaction could be
extended to the synthesis of dichlorolactols from a range of
alkynols containing different spacers between the alcohol and
alkyne group (Scheme 6). The reaction was applied to the
formation of both five-membered (6a–6d) and six-membered
dichlorolactols (6e–6g) via both endo (6a–6c, 6e–6 f) and exo
(6d, 6g) cyclization reactions. Attempted formation of
a seven-membered lactol was unsuccessful, but the corre-
sponding dichlorohydroxyketone was obtained in good yield
(6h).
Primary and tertiary dichloroketoalcohols 4c and 4k
could be reduced with NaBH4 to give dichlorodiols 7c and 7k
2
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Scheme 6. Synthesis of dichlorolactols from alkynols. [a] NMR yield;
[b] 1:1 mixture of diastereoisomers.
Scheme 8. Control experiments and isolation of potential intermedi-
ates.
formation of N-acylimidate ester 11 as a significant by-
product in the dichlorohydration reaction. Both 10 and 11
were obtained as single geometrical isomers with the N-acyl
group cis to the halogenated carbon atom.[24]
In order to account for these observations, we propose
a mechanism[25] for the diiodohydration reaction (Scheme 9)
in which initial activation of the alkyne by IAuY2 induces
nucleophilic attack of MeCN to give intermediate 12, which
undergoes cyclization to give 13, followed by reductive
elimination[26,27] to give 14a and an AuI salt which is
reoxidized. The dichlorohydration reaction involves forma-
tion of 14b, generated via addition of MeCN to the alkyne
activated by the electrophilic chlorine source. The dihaloke-
tone products 3/4, are then formed by direct halogenation of
oxazine 14 (possibly mediated by gold where X = I) and
hydrolysis to give acyl imine 16, which is hydrolyzed to the
product. When water is not present, [3,3]-sigmatropic rear-
rangement of 14a gives N-acyl imine 17 which leads to a-
haloenone formation. This mechanism would account for the
significant beneficial effect of MeCN on the dihalohydration
reactions as the 5-halooxazine intermediate facilitates double
halogenation by acting as a long-lived “enol” equivalent.
Most significantly, however, the formation of the cyclic
oxazine intermediate 14 would account for the fact that
Scheme 7. Selective reduction reactions of dichlorohydroxyketones and
dichlorolactols.
respectively (Scheme 7). Secondary dichloroketoalcohol 4e
readily underwent diastereoselective reduction with
Me4NB(OAc)3H[20] in good yield to give anti-7e as the
major product. Dichlorolactol 6e could be reduced with
NaBH4 to the dichlorodiol 8, or converted into the dichloro-
tetrahydropyran derivative 9 by reduction with Et3SiH/
BF3·OEt2.
We next turned our attention to the mechanism of these
unusual dihalohydration reactions. Given the fact that an
enantioenriched alcohol does not racemize during the reac-
tion (Scheme 5), the dihalohydration cannot proceed via an
intermediate haloenone.[6b] The reaction does not take place
in the absence of the gold catalyst (Table 1, entry 8), and in
the absence of NIS, propargylic alcohol 1a does not undergo
reaction with PPh3AuNTf2 in MeCN-H2O (Scheme 8),
despite the fact that this catalyst promotes the Meyer–
Schuster rearrangement in other solvent systems (PhMe-
MeOH).[4] This suggests that oxidation of the AuI complex by
NIS may lead to generation of a reactive AuIII species.[21,22]
Alternatively, the gold salt may act as a Lewis acid to activate
the NIS.[23] The former hypothesis is supported by the fact that
AuBr3 is a competent catalyst for the reaction. However, we
were unable to observe the formation of a potential catalytic
species upon treatment of an NMR sample of PPh3AuNTf2
with NIS.[12]
Further insight into the possible reaction mechanism was
provided by the fact that N-acylimine 10 could be isolated
from reaction of 1a with PPh3AuNTf2/NIS in the absence of
water. Similarly, reaction of alcohol 1j with TCICA led to the
Scheme 9. Possible mechanisms for the dihalohydration reactions.
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Published online: && &&, &&&&
Keywords: gold · halogenation · homogeneous catalysis ·
.
ketones · reaction mechanisms
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Communications
Halogenation
With or without gold: Propargylic alco-
hols were converted into a,a-diiodo-b-
hydroxyketones by treatment withN-
iodosuccinimide in the presence of a gold
catalyst. a,a-Dichloro-b-hydroxyketones
were prepared without a catalyst by
reaction of propargylic alcohols with tri-
chloroisocyanuric acid. Mechanistic
studies suggest that both of these reac-
tions proceed via the formation of5-
halooxazines, formed by participation of
the acetonitrile solvent.
J. M. D’Oyley, A. E. Aliev,
T. D. Sheppard*
&&&& — &&&&
Regioselective Dihalohydration Reactions
of Propargylic Alcohols: Gold-Catalyzed
and Non-Catalyzed Reactions
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These are not the final page numbers!