Copper-catalyzed 1,2-addition of α-carbonyl iodides to alkynes

Article abstract of DOI:10.1002/anie.201410279

β,γ-Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β-γ-unsaturated ketones through 1,2-addition of α-carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)-trichostatin A, a histone deacetylase inhibitor.

Full text of DOI:10.1002/anie.201410279

Angewandte
Chemie
DOI: 10.1002/anie.201410279
Synthetic Methods
Copper-Catalyzed 1,2-Addition of a-Carbonyl Iodides to Alkynes**
Tao Xu and Xile Hu*
Abstract: b,g-Unsaturated ketones are an important class of
organic molecules. Herein, copper catalysis has been devel-
oped for the synthesis of b-g-unsaturated ketones through 1,2-
addition of a-carbonyl iodides to alkynes. The reactions exhibit
wide substrate scope and high functional group tolerance. The
reaction products are versatile synthetic intermediates to
complex small molecules. The method was applied for the
formal synthesis of (Æ)-trichostatin A, a histone deacetylase
inhibitor.
b,g-Alkenyl ketones are a recurring motif in natural
products and biologically active compounds (Figure 1).[1] For
Figure 1. Selected complex molecules containing a b,g-alkenyl ketone
motif.
example, trichostatin A is a histone deacetylase inhibitor and
has potent antitumor activity;[2] likewise, lactimidomycin is
a promising antitumor agent with a strong antiproliferative
effect on tumor cells.[3]
a-Alkenylation of carbonyl compounds is a general
method for the synthesis of b,g-alkenyl carbonyl com-
pounds.[4] Among various a-alkenylation methods, metal-
catalyzed coupling reactions with a-halo carbonyl compounds
are attractive because of the ready accessibility of a-halo
carbonyl derivatives. Fu and Lou reported Ni-catalyzed cross-
coupling reactions of a-bromo ketones with alkenylzirconium
reagents (Scheme 1a).[4a] Lei and co-workers reported
Ni-catalyzed Heck-type cross coupling of a-bromo esters
and amides with styrene derivatives (Scheme 1b).[4b] Herein,
we report a complimentary a-alkenylation method utilizing
a-bromo ketones and alkynes as reaction partners. In the
presence of a Cu catalyst and KI, the reactions yield
b,g-alkenyl ketones with a transformable alkenyl iodide
functional group (Scheme 1c). The reactions can be consid-
ered as 1,2-addition reactions of a-iodo ketones to alkynes.[5]
Although several examples of addition reactions of a-iodo
Scheme 1. Comparison of synthetic methods for the preparation of
esters and a-iodo amides to alkenes[6] and alkynes[7] have been
b,g-alkenyl ketones using a-bromo carbonyl compounds. DME=
dimethoxyethane. dppp=1,3-bis(diphenylphosphino)propane.
Cp=cyclopentadiene.
reported, the scope of these reactions is limited.
Recently, we found that perfluoroalkyl radicals could be
generated from perfluoroalkyl iodides in the presence of
Cs2CO3 and FeBr2.[8] The perfluoroalkyl radicals then could
add to alkenes and alkynes under Fe catalysis. We hypothe-
sized that a-ketone radicals might be generated under similar
conditions from a-iodo ketones; addition of these radicals to
alkynes would yield b,g-alkenyl iodoketones. To test this
hypothesis, the addition of 2-iodopropiophenone, generated
in situ from 2-bromopropiophenone (1a) and KI, to 1-octyne
(2a) was examined (Table 1). However, no product was
formed using the conditions previously developed for
[*] Dr. T. Xu, Prof. Dr. X. L. Hu
Laboratory of Inorganic Synthesis and Catalysis
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
ISCI-LSCI, BCH 3305, 1015 Lausanne (Switzerland)
E-mail: xile.hu@epfl.ch
Fe-catalyzed perfluoroalkylation (Table 1, entry 1).[8]
A
screening of catalysts (see Supporting Information) showed
that Cu(OTf)2 in combination with ligand II could catalyze
this reaction in toluene in a 57% yield (entry 2). Replacement
of Cu(OTf)2 by other copper salts led to lower yields
(entries 3 and 4). Without Cu(OTf)2 or ligand, the reaction
was less efficient (entries 5,6). Decreasing the loading of
Cs2CO3 to 60 mol% increased the yield to 73% (entry 7). In
Homepage: http://lsci.epfl.ch
[**] This work is supported by a European Research Council (ERC)
starting grant (number 257096).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410279.
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Table 1: Optimization of reaction conditions.[a]
Table 2: Scope of copper-catalyzed 1,2-addition of iodopropiophenone
to alkynes.[a]
Entry Catalyst
Base (loading)
Cs2CO3 (80%)
Conversion (2a) Yield (Z/E)[b]
1[c]
2
3
FeBr2
25%
81%
95%
74%
56%
60%
89%
40%
85%
59%
72%
41%
92%
0 (–)
Cu(OTf)2 Cs2CO3 (150%)
CuI Cs2CO3 (150%)
Cu(acac)2 Cs2CO3 (150%)
Cs2CO3 (150%)
57% (6.2)
47% (5.3)
21% (>19)
32% (5.3)
24% (3.8)
73%(4.0)
0 (–)
31% (3.8)
0 (–)
0 (–)
4
5
–
6[d]
7
Cu(OTf)2 Cs2CO3 (150%)
Cu(OTf)2 Cs2CO3 (60%)
8
Cu(OTf)2
–
9
Cu(OTf)2 K2CO3(60%)
Cu(OTf)2 tBuONa(60%)
Cu(OTf)2 TEA(60%)
Cu(OTf)2 Cs2CO3(60%)
Cu(OTf)2 Cs2CO3(60%)
10
11
12[e]
13[f]
17% (3.3)
76% (3.3)
[a] The reactions were conducted on a 0.25 mmol scale in toluene
(1.0 mL) under N2. [b] The yields and the ratios were determined by GC
using n-decane as the internal standard. [c] The reaction was conducted
in dioxane at 608C without ligand II. [d] Without ligand II. [e] The
reaction was conducted in air. [f] The reaction was conducted on
a 0.5 mmol scale with Cu(OTf)2 (5 mol%) and ligand II (6 mol%) in
toluene (1.0 mL).
the absence of Cs2CO3, no addition product was formed
(entry 8). Replacement of Cs2CO3 by K2CO3, tBuONa, or
triethylamine (TEA) led to a lower or no yield (entries 9–11).
The reaction required a nitrogen atmosphere to proceed; in
air the yield was only 17% (entry 12). Racemic and enantio-
merically pure forms of ligand II gave identical yields. The
loading of catalyst could be decreased to 5 mol%, to give
optimized conditions of: Cu(OTf)2 as catalyst (5 mol%),
ligand II (6 mol%), as substrates 2-bromopropiophenone
(2 equiv), KI (2 equiv), and alkyne (1 equiv), and Cs2CO3
(0.6 equiv) as base (Table 1, entry 13).[9]
[a] Reaction conditions : 1a (2.0 equiv), 2 (0.5 mmol), Cu(OTf)2
(5 mol%), ligand II (6 mol%), Cs2CO3 (60 mol%), KI (2.0 equiv),
toluene (1 mL), 1008C, 24 h, under N2; yields of isolated product were
given and Z/E ratios are given in parentheses. [b] Cu(OTf)2 (10 mol%),
ligand II (12 mol%). [c] The ratio was measured using H NMR
spectroscopy.
1
With the optimized conditions in hands, the copper-
catalyzed method was first applied for the reactions of
2-bromopropiophenone (1a) with various alkynes
(Table 2).[10] Addition is efficient not only to alkyl alkynes
but also to aryl alkynes. Primary (to give products 3a and
3h–n), secondary (to give cyclic 3c or acyclic 3d) and tertiary
(to give 3e) alkyl alkynes as well as silylacetylenes (to give 3 f
and 3g) were all suitable substrates. The addition to alkyl
alkynes is Z-isomer selective, with a Z:E ratio generally
greater than 3:1. The selectivity correlated with the bulkiness
of the alkyl substituents, and Z:E ratios greater than 50:1
were obtained with silyl and tertiary alkyl alkynes (to give
products 3e, 3 f, 3g). On the other hand, the addition to aryl
alkynes gives an equal mixture of Z and E isomers (3b). The
reactions have high functional group tolerance. Ester (3h),
ketone (3i), ether (3j, 3k), amide (3m), acetal (3n), thioether
(3j), aryl halide (3k), and alkyl halide (3l) groups were all
compatible. Addition to internal alkynes is not efficient. For
example, the reaction of 1a with 5-decyne gave the product
only in 8% yield.
The scope of a-carbonyl ketone reagents in the reaction
was then explored using (triisopropylsilyl)acetylene as the
reaction partner (Table 3). Aryl ketones with substitution at
the ortho (4a), meta (4b), or para position (4c) all reacted to
give the corresponding products in high yields and good
selectivity. Reagents containing an electron-withdrawing
CF3 group (to give product 4c) or an electron-donating
OMe group (4d) were tolerated. The R’ functional group is
not limited to methyl substituents. Substrates with n-propyl
(to give 4e), isopropyl (4 f), benzyl (4g), and functionalized
alkyl group (4h, 4i) in this position were all transformed
smoothly and with high selectivity. However, when the
Rꢀ functional group was a proton or a secondary alkyl group
(to give product 4m), the reaction was unsuccessful. The
method is not limited to aryl ketones. An amide (4j) and
a Weinreb amide (4k) could also be employed. a-Alkenyl-
ation was successful on a substrate containing an Evans-type
auxiliary 4l, albeit with a low diastereoselectivity.
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Table 3: Scope of copper-catalyzed addition of a-carbonylbromides to
(triisopropylsilyl)acetylene (2 f).[a]
Scheme 2. Further functionalization of b,g-unsaturated ketones.
dppf=1,1’-bis(diphenylphosphino)ferrocene. TEA=triethylamine.
[a] Reaction conditions : 1 (2.0 equiv), 2 f (0.5 mmol), Cu(OTf)2
(5 mol%), ligand II (6 mol%), Cs2CO3 (60 mol%), KI (2.0 equiv),
toluene (1 mL), 1008C, 24 h, under N2; yields of isolated product were
given and the Z/E ratios (given in parentheses) were measured using
1H NMR spectroscopy. [b] Reaction time was 48 h. [c] Cu(OTf)2
(10 mol%), ligand II (12 mol%),1k (3.0 equiv), KI (3.0 equiv).
[d] Cu(OTf)2 (10 mol%), ligand II (12 mol%). Bn=benzyl.
d.r.=diastereomeric ratio.
Scheme 3. Formal total synthesis of (Æ)-trichostatin A. TBAF=tetra-
butylammonium fluoride.
The Cu-catalyzed a-alkenylation method produces b,g-
unsaturated ketones with an alkenyl iodide group. These
compounds are versatile synthetic intermediates. For exam-
ple, reduction of the ketone group by LiAlH4 gave a homo-
allylic alcohol 5a in a high yield and moderate regioselectivity
[Scheme 2, Eq. (1a)]. With CuI as catalyst and tBuONa as
base, the vinyl iodide ketone was easily converted into
a substituted furan 5b [Eq. (1b)]. As expected, the vinyl
iodide group was amenable to cross-coupling reactions, such
as Sonogashira coupling to form product 5c [Eq. (2)] and
Suzuki coupling giving 5d [Eq. (3)]. Importantly, products
containing the Weinreb amide group could be transformed to
give alkyl (5e) and alkynyl ketones (5 f) [Scheme 2, Eq. (4)].
Thus, even though alkyl and alkynyl ketones are not suitable
substrates for the direct alkenylation reaction, their equiv-
alent alkenylation can be achieved using Weinreb amides as
starting reagents.
To further illustrate the utility of the Cu-catalyzed a-
alkenylation reaction, the method was applied for the formal
synthesis of (Æ)-trichostatin A (Scheme 3).[11] The addition
reaction of substrate 1o to the TIPS-protected propynol 2o
(TIPS = triisopropylsilyl) gave the product 6a in a 52% yield
and with a Z/E ratio of 4.3:1. Pd-catalyzed Negishi coupling of
6a with MeZnCl installed the methyl group at the g position,
giving product 6b in an 86% yield. Desilylation gave the
alcohol 6c in a 92% yield, which was oxidized with the Dess–
Martin reagent to the aldehyde 6d in a 75% yield. Horner–
Wadsworth–Emmons reaction of 6d produced the diene ester
6e in
a 73% yield; intermediate 6e was previously
transformed to (Æ)-trichostatin in a one-step reaction.[11a]
To give some insight into the mechanism of the addition
reaction, several experiments using radical probes were
performed. In the presence of 2,2,6,6-tetramethylpiperidi-
nooxy (TEMPO; 1 equiv), most of the reactants remained
and no addition product was formed; however, alkylated
TEMPO was not detected probably as a result of the steric
hindrance of this bulky alkyl group (see Table S2 in the
Supporting Information for the detailed outcome of the
reaction). To further verify the possibility of a radical process,
the addition reaction was conducted in the presence of
additional radical probes including 2,6-di-tert-butyl-4-
methylphenol (BHT, 1.0 equiv) and 1,1-diphenylethylene
(DPE, 2.5 equiv).[6a] Indeed, the reaction was inhibited by
both BHTand DPE. In the presence of BHT, the alkyl radical
was trapped as 7a in 43% yield [Scheme 4, Eq. (5)]; in the
presence of DPE, the alkyl radical was trapped by the olefin
to give 7b in 32% yield respectively [Eq. (6)].[12] These results
suggest that the a-carbonyl alkyl radical is produced in the
addition reaction. A radical mechanism is also consistent with
previous work showing that in the presence of a metal salt,
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Scheme 5. Hypothetical catalytic cycle.
Cs2CO3 is able to generate the alkyl radical from activated
alkyl halides at an elevated temperature.[8]
The mechanism of the a-alkenylation reaction is subject
to further study, so only a hypothetical catalytic cycle is
proposed here based on the above results (Scheme 5). The
reaction starts from the in situ generation of an a-iodo ketone
from the reaction of the a-bromo ketone with KI. Consistent
with this, the reaction of 1a with 2a in the absence of KI under
otherwise standard conditions gave the vinyl bromide product
in only 11% yield. Activation of a-iodo ketone by Cs2CO3,
possibly with the involvement of the copper catalyst, leads to
an a-ketone radical (i). Coordination of both the a-ketone
radical and alkyne to Cu gives intermediate (ii). Intramolec-
ular addition of a-ketone radical to the alkyne then gives
g-ketone vinyl radical (iii, iv) which reacts with a second
molecule of a-iodo ketone to yield the addition product and
regenerate the a-ketone radical (intermediate iii or iv to
form i). The Z/E selectivity of the reaction likely depends on
the relative stability of intermediates (iii) and (iv).
In summary, Cu-catalyzed 1,2-addition of a-iodo ketones
to alkynes has been developed as an efficient method for
a-alkenylation of ketones. The method employs readily
available reagents and has broad scope and high functional-
group tolerance. The resulting b,g-alkenyl iodo ketones prove
to be versatile synthetic intermediates. The synthetic utility of
the method was further demonstrated in the formal synthesis
of (Æ)-trichostatin A.
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[9] No enantioselectivity was detected in the product.
Received: October 20, 2014
Published online: && &&, &&&&
[10] The reactions with 2-iodopropiophenone (without KI) or 2-
chloropropiophenone (with KI) gave the product 3a in 76% and
45% yields, respectively, with similar Z/E selectivity.
Keywords: 1,2-addition reactions · alkynes · copper · ketones ·
olefination
.
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[12] Compound 7a was formed in only 2% GC yield in the reaction
in the absence of the copper–ligand catalyst.
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Communications
Synthetic Methods
T. Xu, X. L. Hu*
&&&& — &&&&
Copper-Catalyzed 1,2-Addition of a-
Carbonyl Iodides to Alkynes
A versatile method: Copper catalysis is
employed in the synthesis of b,g-unsatu-
rated ketones through the 1,2-addition of
a-carbonyl iodides to alkynes. The reac-
tions exhibit wide substrate scope and
high functional group tolerance. The
method was applied for the formalsyn-
thesis of (Æ)-trichostatin A, a histone
deacetylase inhibitor.
6
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