Electrophilic alkynylation of ketones using hypervalent iodine

Article abstract of DOI:10.1039/c4cc00608a

A new method for the electrophilic α-alkynylation of ketones was developed using hypervalent iodine under mild and metal-free conditions. Carbonyl compounds containing an α-acetylene group were obtained in good to excellent yields for several ketones using 1-[(trimethylsilyl)ethynyl]-1,2- benziodoxol-3(1H)-one (TMS-EBX) as an alkynylation agent in the presence of t-BuOK and TBAF in THF as solvent. Under the same conditions, an aldehyde was alkynylated. This journal is the Partner Organisations 2014.

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ARTICLE TYPE
Electrophilic Alkynylation of Ketones Using Hypervalent Iodine
Aline Utakaa, Livia N. Cavalcantia, and Luiz F. Silva Jr.a*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
in the presence of gold and an amine. The alkynation product was
a minor component.
5
A new method for the electrophilic αꢀalkynylation of ketones
was developed using hypervalent iodine under mild and
metalꢀfree conditions. Carbonyl compounds containing an αꢀ
acetylene group were obtained in good to excellent yields for
55
Herein, we report a practical, metalꢀfree and efficient
electrophilic αꢀalkynylation of nonꢀactivated cyclic ketones using
hypervalent iodine reagent. The protocol was also applied to an
aldehyde. Additionally, this procedure is an important tool to
broaden the scope of available methods to afford quaternary
60 carbon centers (Scheme 1, equation c).
Scheme 1. Strategies for the αꢀalkynylation of carbonyl
compounds.
several
ketones
using
1ꢀ[(trimethylsilyl)ethynyl]ꢀ1,2ꢀ
10 benziodoxolꢀ3(1H)ꢀone (TMSꢀEBX) as alkynylation agent in
the presence of tꢀBuOK and TBAF in THF as solvent. Under
the same conditions, an aldehyde was alkynylated.
The αꢀfunctionalization of carbonyl compounds, such as
alkylation, acylation, arylation, and alkynylation, is one of the
15 most important class of reaction in organic synthesis. Among the
aforementioned transformations, the αꢀalkynylation seems to be
the less explored. Acetylenes are versatile functional groups in
organic chemistry.1 Their unique properties and reactivity allow
formation of complex molecular structures making them very
20 interesting intermediates in synthetic strategies.1 Therefore, the
development of new methods to add this group in a molecule is a
valuable tool for carbonꢀcarbon bond formation and functional
group interconversion.
There are two strategies to carry out the αꢀalkynylation of
25 carbonyl compounds. The most utilized relies on a nucleophilic
source of the acetylene component that typically reacts with αꢀ
halocarbonyl compounds. Included on this approach are several
metal catalyzed reactions where the majority of examples utilizes
only esters and amides as the carbonyl partner (Scheme 1,
30 equation a).2
An alternative and much less explored route is using an
electrophilic source of an alkyne.3 In this scenario, easy to obtain
and user friendly hypervalent iodine reagents4 are particularly
promising.3a,5 Over the years, numerous strategies for the αꢀ
35 alkynylation of carbonyl compounds have been described using a
variety of hypervalent iodine compounds.6 Nonetheless, the scope
of the carbonyl compounds is still restricted to βꢀketo esters (and
related methyleneꢀactivated compounds) (Scheme 1, equation b).
There are only two reports regarding the direct αꢀ
40 alkynylation of nonꢀactivated carbonyl compounds. Yamaguchi
and coꢀworkers described the αꢀethynylation of ketones with
chlorosilylethyne using trialkylgallium to generate the enolate.7
Kende and his group reported the reaction of ketones with 1ꢀ
chloroalkynes in the presence of LDA/HMPA.8 In the latter
45 method, two steps are necessary to obtain terminal alkynes, using
dichloroacetylene as acetylene component. To the best of our
knowledge, there are no precedents for the αꢀalkynylation of
aldehydes utilizing either nucleophilic or electrophilic
alkynylating reagents. Other research groups have been trying the
50 same type of alkynylation without success. For example, the
recent work of Huang and coꢀworkers described the reaction of
aldehydes with TMSꢀEBX. However, only allenes were obtained
We began the optimization of the reaction conditions for the αꢀ
65 alkynylation of nonꢀactivated ketones using ketone 1a as model
substrate. Previous work have shown the superior properties of 1ꢀ
[(trimethylsilyl)ethynyl]ꢀ1,2ꢀbenziodoxolꢀ3(1H)ꢀone (TMSꢀEBX,
2a) over other alkynylating agents6g,6h,9 and, consequently, all
optimization was made utilizing this electrophilic compound..
70 First, the protocol developed by Waser and coꢀworkers for
activated carbonyl compounds was applied.6g,6h Unfortunately,
the combination of TMSꢀEBX as alkynylating reagent and
tetrabutylammonium fluoride (TBAF) as base in THF at ꢀ78 ºC
was not efficient to provide the desired αꢀacetylene product and
75 only starting material was recovered (Table 1, entry 1).
Considering the difference in pKa between βꢀketo esters and
ketones, other bases were tested. No desired product was
observed when K2CO3 and CsF were utilized (entries 2 and 3).
The use of stronger base, such as NaH afforded 3a in only 41%
80 along with undesired side products formation (entry 4). Very
good yields were achieved using LiHMDS and tꢀBuOK (entries 5
and 6). Using inexpensive and readily available tꢀBuOK, other
solvents were tested. The reaction in Et2O or in CH2Cl2 provided
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lower yields when compared to THF (entries 7ꢀ8). Finally, when
the reaction was performed at higher temperatures, undesired side
product formation was observed diminishing the efficacy of the
method (entries 9 and 10). In summary, the best result (89%
yield) was obtained utilizing tꢀBuOK at ꢀ78 °C in THF (entry 6).
To avoid any decomposition of TMSꢀEBX in the reaction
medium,6g this electrophilic reagent is added after the formation
of the enolate from ketone and base. This is another difference
when compared to the procedure described by Waser and coꢀ
derivative 4i gave the alkynylated product in only 30% yield,
whereas the corresponding thiophene compound 4j led to the
desired product in very good yield (entries 9ꢀ10). As expected,
45 alkynylation on the aromatic ring was not observed. This
transformation only takes place in the presence of a metal
catalyst.11 The reaction condition was also efficient to alkynylate
nonꢀcyclic ketone 4k, affording the desired product in 74% yield
(entry 11). Unfortunately, under the developed set of conditions,
50 nonꢀaromatic ketones such as 4ꢀphenylcyclohexanone did not
yield the desired alkynylated product and only starting material
was recovered. Other bases were tried (e.g. NaH, BuLi,
LiHMDS, LDA), however in all cases the αꢀethynylated product
was not observed.
5
10 workers.6g,6h
Table 1. Optimization of the αꢀalkynylation reaction[a].
55 Table 2. Scope of the αꢀalkynylation of ketones:
monoalkynylation.[a]
[a] Reaction conditions: 0.100 mmol of 1a, 0.125 mmol of base, 0.130
mmol of TMSꢀEBX (2), 0.130 mmol of TBAF, solvent 0.100 M, 6 h. [b]
15 Yield determined by GC using dodecane as internal standard. [c] Starting
material recovered. [d] Other products were formed.
The scope of the αꢀalkynylation reaction for diverse ketones
was then examined, starting with αꢀsubstituted substrates. On a 1
20 mmol scale, 3a was obtained in 93 % yield after 3 h (Table 2,
entry 1). Similar yield was observed using 2ꢀ
phenylcyclohexanone (1b), as substrate (entry 2). Good results
were obtained with 2ꢀtetralones 1cꢀd that bear methyl and ethyl
substituents, respectively (entries 3ꢀ4). Indane derivative 1e led to
25 the alkynylated product 3e in 85% yield.
The optimized conditions were applied toward a series of nonꢀ
substituted cyclic ketones, where two alkynyl groups would be
introduced. Indanone (4a) gave the desired compound 5a in 69%
yield (Table 3, entry 1). Higher yields were observed for 1ꢀ
30 tetralone (4b) and benzosuberone (4c) (entries 2ꢀ3). The reaction
with 2ꢀtetralone (4d) gave the desired product in only 42% yield,
probably due to the fast decomposition of the substrate (entry 4).
The reaction of methyl and methoxy substituted aromatic rings
with hypervalent iodine reagents can be problematic.10
35 Fortunately, these groups are well tolerated in the alkynylation.
The methyl substituted tetralone 4e led to 5e in excellent yield
(entry 5). Bisꢀacetylenic compounds 5fꢀg were formed in 60 and
75% yield, respectively from the methoxy ketones 4fꢀg (entries 6ꢀ
7). Lower yield (43%) was obtained when the substrate bears a
40 bromine atom in the aromatic ring (entry 8). The behavior of
heterocyclic aromatic rings was also investigated. Furan
[a] Reaction conditions: 1.00 mmol of 1, 1.25 mmol of base, 1.30 mmol
of TMSꢀEBX (2), 1.30 mmol of TBAF, THF, ꢀ78 °C, 2ꢀ10 h. [b] Isolated
60 yield after purification by column chromatography.
The reactivity of other alkynylating compounds was tested,
using 2ꢀphenylcyclohexanone (1b) as substrate and TIPSꢀEBX
(2b)6h and Ochiai´s reagent (2c)6c as electrophilic component.
65 Product 3b was obtained using these reagents, albeit lower yields
and longer reaction time was observed, comparing to the reaction
using TMSꢀEBX, which afford the product in only 2 h (Scheme 2
and Table 2, entry 2).
70
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Me3Si
I
O
O
O
Scheme 2. Reactivity of different alkynating reagents
+
O
4
(2a)
5
TMS-EBX
Yield (%)[b]
Substrate
Product
O
Entry
O
1
69
4a
5a
O
O
2
80
4b
5b
5
The αꢀalkynylation of aldehyde 6a was also investigated.
To our delight, this transformation took place smoothly under the
same conditions used for the ketones, as verified by TLC, GCꢀ
MS, and NMR analysis. However, all attempts to purify the crude
product by column chromatography were unsuccessful. Based on
O
O
3
4
81
42
10 our previous experience on related aldehydes,12 we decided to
reduce the aldehyde in situ using NaBH4. Indeed, the
corresponding alkynylated alcohol 7a could be isolated in pure
form (Scheme 3). Although the purification of the alkynylated
aldehyde was difficult, the crude material can certainly be used
15 on other transformations, as reported for similar compounds.13
The nonꢀaromatic cyclohexanecarboxaldehyde did not afford the
desired alkynylated product under the developed set of
conditions.
4c
5c
O
O
4d
5d
O
O
92[c]
5
6
20 Scheme 3. Oneꢀpot Alkynylation/reduction of aldehyde 6a.
4e
5e
O
O
60
OMe
OMe
5f
4f
O
O
MeO
MeO
MeO
75[c]
7
8
MeO
Br
4g
5g
O
O
Table 3. Scope of the αꢀalkynylation of ketones:
Br
43[d]
dialkynylation.[a]
4h
5h
O
O
9
30
74
O
O
S
4i
4j
5i
O
O
10
S
5j
O
O
Ph
11
74
Ph
4k
5k
25
[a] Reaction conditions: 1.0 mmol of 4, 2.5 mmol of tꢀBuOK, 2.6 mmol
of TMSꢀEBX (2), 2.6 mmol of TBAF, THF, ꢀ78 °C, 1ꢀ10 h. [b] Isolated
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DOI: 10.1039/C4CC00608A
yield after purification by column chromatography. [c] 3.0 mmol tꢀBuOK.
[d] 0.3 mmol of 4h.
Stang, Tetrahedron 1998, 54, 10927ꢀ10966; c) M. S. Yusubov, A. V.
Maskaev, V. V. Zhdankin, Arkivoc 2011, 370ꢀ409; d) J. P. Brand, D.
F. Gonzalez, S. Nicolai, J. Waser, Chem. Comm. 2011, 47, 102ꢀ115;
e) E. A. Merritt, B. Olofsson, Synthesis 2011, 517ꢀ538.
55
60
65
70
75
80
85
The proposed mechanism for αꢀalkynylation is shown in
Scheme 3 using 1a as example.6g,6h In presence of base, this
ketone gives enolate 8. EBX (9) is originated by reaction of
TMSꢀEBX (2) with TBAF. Nucleophilic attack of enolate 8 into
6
For selected examples, see: a) F. M. Beringer, S. A. Galton, J. Org.
Chem. 1965, 30, 1930ꢀ1934; b) M. Ochiai, M. Kunishima, Y. Nagao,
K. Fuji, M. Shiro, E. Fujita, J. Am. Chem. Soc. 1986, 108, 8281ꢀ
8283; c) M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, M. Kunishima, S.
Tani, Y. Nagao, J. Chem. Soc., Chem. Comm. 1990, 118ꢀ119; d) M.
D. Bachi, N. Barner, C. M. Crittell, P. J. Stang, B. L. Williamson, J.
Org. Chem. 1991, 56, 3912ꢀ3915; e) T. Kitamura, K. Nagata, H.
Taniguchi, Tetrahedron Lett. 1995, 36, 1081ꢀ1084; f) T. Kitamura, T.
Fukuoka, L. Zheng, T. Fujimoto, H. Taniguchi, Y. Fujiwara, Bull.
Chem. Soc. Jpn. 1996, 69, 2649ꢀ2654; g) D. F. Gonzalez, J. P. Brand,
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2097ꢀ2100.
5
the electrophilic αꢀcarbon of
9
furnishes carbene 11.6b
Rearrangement of this carbene leads to the isolated product 3a.6c
10 Scheme 3. Mechanism for the αꢀalkynylation of carbonyl
compounds.
7
a) Y. Nishimura, R. Amemiya, M. Yamaguchi, Tetrahedron Lett.
2006, 47, 1839ꢀ1843; b) M. Yamaguchi, Y. Nishimura, Chem.
Comm. 2008, 35ꢀ48.
A. S. Kende, P. Fludzinski, J. H. Hill, W. Swenson, J. Clardy, J. Am.
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8
9
Wang, Z.; Li, X.; Huang, Y. Angew. Chem. Int. Ed. 2013, 52, 14219
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Commun. 2013, 49, 11224ꢀ11226; b) F. A. Siqueira, E. E. Ishikawa,
A. Fogaça, A. T. Faccio, V. M. T. Carneiro, R. R. S. Soares, A.
Utaka, I. R. M. Tébeká, M. Bielawski, B. Olofsson, L. F. Silva, Jr., J.
Braz. Chem. Soc. 2011, 22, 1795ꢀ1807; c) M. Ochiai, A. Yoshimura,
K. Miyamoto, Tetrahedron Lett. 2009, 50, 4792; d) K. Miyamoto, Y.
Sei, K. Yamaguchi, M. Ochiai, J. Am. Chem. Soc. 2009, 131, 1382.
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In conclusion, a new method for the electrophilic αꢀ
15 alkynylation of ketones and aldehydes was developed using
TMSꢀEBX under mild and metalꢀfree conditions. Carbonyl
compounds bearing an αꢀacetylene group were obtained in good
to excellent yields. The pKa values of the substrates are in the
range from at least 17.6 (2ꢀtetralone) to 24.7 (1ꢀtetralone). To the
20 best of our knowledge the examples presented here represent the
only effective electrophilic αꢀalkynylation of ketones and
aldehydes employing hypervalent iodine reagent. Additional
studies are ongoing on our group to increase the scope of the
methodology to nonꢀcyclic aromatic and aliphatic ketones as well
25 as an asymmetric version of the reaction.
95
2566; b) L. F. Silva, Jr., M. V. Craveiro, Org. Lett. 2008, 10, 5417ꢀ
5420; c) E. Skucas, D. W. C. MacMillan, J. Am. Chem. Soc. 2012,
134, 9090ꢀ9093.
Notes and references
a Instituto de Química, Universidade de São Paulo, CP 26077, CEP
05513-970, São Paulo –SP, Brazil.
* Corresponding Author: luizfsjr@iq.usp.br.
30 † Electronic Supplementary Information (ESI) available: [Experimental
procedures and characterization data]. See DOI: 10.1039/b000000x/
1
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35
40
45
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2
3
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4
5
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