α,α-Alkylation-Halogenation and Dihalogenation of Sulfoxonium Ylides. A Direct Preparation of Geminal Difunctionalized Ketones

Article abstract of DOI:10.1002/chem.201704609

A one-pot alkylation–halogenation of ketosulfoxonium ylides in the presence of alkyl halides is described. The method furnishes several gem-difunctionalized haloketones (an alkyl and F, Cl, Br, or I) in good yields. Replacing alkyl halides with a mixture of electrophilic halogen species and various halide anions led to gem-dihalogenated ketones containing a combination of the same or two different halogens. Kinetic isotopic effects as well as reaction kinetic experiments give insight to the mechanism of these reactions.

Full text of DOI:10.1002/chem.201704609

A Journal of
Accepted Article
Title: α,α-Alkylation-Halogenation and Dihalogenation of Sulfoxonium
Ylides. A Direct Preparation of Geminal Difunctionalized Ketones
Authors: Rafael Gallo, Anees Ahmad, Gustavo Metzker, and Antonio
Carlos Bender Burtoloso
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α,α-Alkylation-Halogenation and Dihalogenation of Sulfoxonium
Ylides. A Direct Preparation of Geminal Difunctionalized Ketones
Rafael D. C. Gallo[a], Anees Ahmad[a], Gustavo Metzker[a] and Antonio C. B. Burtoloso*[a]
Abstract: A one-pot alkylation-halogenation of ketosulfoxonium
ylides in the presence of alkylhalides is described. The method
furnishes several gem-difunctionalized haloketones (an alkyl and F,
Cl, Br, or I) in good yields. Replacing alkyhalides with a mixture of
electrophilic halogen species and various halide anions led to gem-
dihalogenated ketones containing a combination of the same or two
different halogens. Kinetic isotopic effects as well as reaction kinetic
experiments give insight to the mechanism of these reactions.
ether intermediates, a mixture of products is often observed
when nonsymmetrical mono-haloketones with two enolizable
carbons are prepared.12 Worse yet are the methods used to
prepare geminal dihalogenated ketones in a selective and one-
pot fashion. Few representative examples are known.13-15
Although diazoketones have been the reagents of choice for
that, in the majority of the cases, halogens are added
individually by means of two separate reactions. Finally, to the
best of our knowledge, the literature provides no direct method
for attachment of both an alkyl group and a halogen atom α to a
ketone, in order to synthesize more complex haloketones
(Figure 1A). Therefore, and according to what we envisioned
(illustrated in Figure 1b, Charts A and B), sulfoxonium ylides
could be viable alternatives to preparing mono- and α,α-
dihaloketones (F, Cl, Br, or I) in a direct fashion. Moreover,
sulfoxonium ylides are very stable crystalline solids, safe and
can be easily prepared in kilogram quantities,16 making them
attractive for industrial applications.
Sulfur ylides were described in 1930 by Ingold and Jessop.1
Although almost 90 years has passed, most applications
involving these compounds are related to the pioneering work
developed by Johnson and LaCount,2 Franzen,3 and Corey and
Chaykovsky4 in the 1960s. For example, cyclopropanation,
epoxidation, and aziridination reactions as well as [2,3]
sigmatropic rearrangements are most commonly used.5 New
transformations employing sulfur ylides have been described in
more recent years,5,6 but this has occurred less frequently than
expected when compared to other classes of compounds.
An interesting application of the chemistry of sulfur ylides
that continues to receive little attention is the reaction of
ketosulfoxonium ylides with HCl to prepare α-chloroketones.7
Protonation of the ylide generates a reactive sulfoxonium salt
that upon heating is attacked by the acid counterion with
displacement of DMSO. Recent efforts in our laboratory8 have
demonstrated that sulfoxonium ylides can be protonated by
acids other than HCl, such as arylthiols, to furnish ketothioethers
without catalysis. Mechanistic studies also revealed the course
of these reactions, suggesting that protonation is rate-
determining.8 Recognizing the importance of sulfur ylides in
promoting both nucleophilic and electrophilic reactions, and
inspired by these contributions,7,8 we chose to investigate in
detail their reactivity in the presence of alkylhalides, aiming to
directly prepare geminal alkylated haloketones (Figure 1b, Chart
A). Moreover, by replacing alkylhalides with a mixture of
electrophilic halogen species and halide salts, we considered
whether geminal dihalogenated ketones (containing the same or
different halogens at the same carbon) could be readily
prepared (Figure 1b, Chart B).
Figure 1. Preparation of halo- and geminal dihaloketones via (a) traditional
methods and (b) a one-pot method using sulfoxonium ylides.
α-Haloketones9 have great importance in organic synthesis
as bifunctional intermediates in that they undergo a vast array of
useful transformations.9,10 Unfortunately, most preparatory
methods11 remain limited to electrophilic halogenation of ketones
and the use of hazardous and reactive reagents. Because these
methods always employ enol, enolate, enamine, or silyl enol
We first evaluated the reaction of sulfoxonium ylide 1 and
methyl iodide under various conditions (Table 1). Based on
previous work,8 compound 1 and methyl iodide were mixed in
o
equimolar amounts in acetonitrile (ACN) at 25 C for 24 hours,
and a 22% yield of 2 was achieved (entry 1). Using two
equivalents of the electrophile, the yield almost doubled (entry
2). Prolonged reaction time (entry 3) provided 15% yield and
several byproducts. Investigating solvents other than ACN
(entries 4-10), tetrahydrofuran (THF) and chloroform were found
to provide the best yields (48% and 44%, entries 8 and 10,
respectively). These two, in addition to ACN, were selected for
[a]
Instituto de Química de São Carlos, Universidade de São Paulo,
CEP 13560-970, São Carlos, SP, Brasil.
E-mail: antonio@iqsc.usp.br
Supporting information for this article is given via a link at the end of
the document.
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studies at 40 oC, and THF proved to be the best (62% yield,
entry 11). By lowering the amount of methyl iodide, yield
decreased to 41% (entry 14), and increasing it did not improve
yields either (63%, entry 15). Other variations, such as
increasing temperature, decreasing reaction time, changing
concentrations, and adding potassium iodide (entries 16-20) did
not improve yield. Interestingly, under the conditions shown in
entry 13 using ACN-d3, the yield calculated directly by NMR
(using an internal standard) was 74% (entry 21), indicating some
loss or degradation during work-up and/or purification of the
reactive and volatile haloketone 2. We also repeated entry 11 in
a larger scale (1.0 g of 1), observing an isolated yield of 71%.
Table 2. Scope studies between 1 and various alkyl halides.
Entry
R-X
Product
Yield. (%)[a]
1[b]
EtI
42
2
All-I
BnI
43
60
Table 1. Optimization Studies.
3[c]
Entry
1
2
3
4
5
6
7
8
Solvent
ACN
ACN
Temp (oC)
Time
24h
24h
48h
24h
24h
24h
24h
24h
24h
24h
24h
24h
24h
24h
24h
24h
12h
24h
24h
24h
24h
24h
MeI
%Yield[a],[b],[c]
rt
rt
rt
rt
rt
rt
rt
rt
rt
1 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
2 equiv
1 equiv
3 equiv
2 equiv
2 equiv
2 equiv
2 equiv
3 equiv
2 equiv
2 equiv
22
38
15
32
33
--
4[d]
iPr-I or Cy-I
___
___
RSM
RSM
ACN
Acetone
DMSO
MeOH
AcOEt
THF
Dioxane
CHCl3
THF
CHCl3
ACN
THF
THF
THF
THF
THF
THF
THF
ACN-d3
THF
5[d]
EtBr or n-BuCl
28
48
33
44
62
38
51
41
63
50
46
9
10
11
12
13
14
15
16
17
18
19
20
21
22
rt
6[e,f]
7[h]
8
BnBr
80[g]
81[g]
53[i]
66
40
40
40
40
40
60
40
40
40
40
40
40
BnCl
d]
39[
37[e]
56[f]
74[g]
71[h]
BrCH2CO2Me
MeI + TBACl
MeI + TBABr
MeI + TBAF
[a] Isolated yield. [b] The reaction was performed on 0.3 mmol scale. [c]
conc. 1 M. [d] conc. 0.5 M. [e] conc. 2 M. [f] 20 mol% KI. [g] Not isolated;
Yield by NMR using 1,2,4,5 tetramethylbenzene as an internal standard.
[h] Repetition of entry 11 in a larger scale (1.0 g of 1, 5.1 mmol scale).
9
We next investigated the reaction between ylide 1 and
various alkyl iodides, alkyl chlorides, and alkyl bromides to
evaluate reaction scope. Reaction with ethyl iodide, allyl iodide,
or benzyl iodide, using conditions in entry 11 of Table 1,
furnished the alkylated iodoketones in 44-66% isolated yields
(entries 1-3, Table 2). Reaction with a secondary alkyl iodide or
with aliphatic alkyl chlorides or bromides yielded no reaction:
only starting material was recovered (entries 4-5). Performing
these reactions at higher temperatures, prolonged reaction
times, or in other solvents did not change this result. However,
reaction with more reactive benzyl bromide and benzyl chloride
provided the alkylated-halogenated products in yields of 64%
and 25%, respectively. Changing the solvent to ACN and
increasing the temperature to 80 oC improved the yield to 78-
82% and 79-83%, respectively (entries 6-7). The reaction
between ylide 1 and the reactive methyl bromoacetate also
provided a good yield (entry 8).
10
63
11
12
47
56
BnCl or BnBr
+ KI
[a] Each reaction condition was performed three times. [b] In this reaction
we also observed the formation of 16% of compound 2; [c] The reaction
can also be performed at 25 oC, providing a 48% yield of the benzylated
iodo ketone; [d] Different conditions from 40-80 oC, 24-48 h in THF or ACN;
[e] 64% yield using the standard conditions (entry 11, Table 1); [f] 68-72%
yield replacing THF by ACN in standard condition; [g] ACN at 80 oC; [h]
25% yield using the standard conditions (entry 11, Table 1); [i] 3:1
inseparable mixture of 8 and its β-elimination product.
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As depicted in entry 5 in Table 2, reaction with aliphatic alkyl
chlorides and bromides failed to provide the respective alkylated
chloro- and bromoketones. This problem was easily
circumvented by using an excess of TBACl or TBABr (entries 9
and 10, Table 2). The same result was observed when preparing
a fluoroketone, when an excess of TBAF was added (entry 11).
For reactive alkyl bromides and chlorides such as BnCl and
BnBr, addition of KI to the reaction vessel also furnished good
yields of the alkylated iodide (entry 12) without use of the more
expensive benzyl iodide.
After studying the scope of this alkylation-halogenation
method in the presence of 1 and various alkyl halides, these
reactions were performed in the presence of ten structurally
different sulfoxonium ylides (Figure 2). Ylides 12-16 are
derivatives of model ylide 1 containing electron-donating and
electron-withdrawing groups. Ylides 17-21 are aliphatic, the
former presenting a bulky pivaloyl group and the others
enolizable CH2 groups. Ylide 20 is a derivative from an
aminoacid and ylide 21 from malic acid. In practically all the
cases, moderate to very good yields could be obtained with a
broad of structurally different ylides (5 aromatics and
5
aliphatics). In the case of bulky ylides such as 14 (orto-chloro)
and 17 (pivaloyl), no product and the elimination product 31 was
observed, respectively. It is worth mentioning that for the
aliphatic ylides, no byproducts containing the halogen or the
alkyl group at the other carbon α to the carbonyl group was
observed (a regiochemical problem always encountered in
traditional alkylation and halogenating methods).
To probe into the mechanism of this geminal alkylation-
halogenation reaction, we employed kinetic isotope effect
studies and revealed that the first step (ylide alkylation) is most
likely rate limiting (Figure 3). Performing two sets of reactions
using model ylide 1 in the presence of equal amounts of CH3I
and CD3I showed a kH-to-kD ratio of 0.86 ± 0.01 (carefully
determined using GC-MS in quintuplicate). This is a secondary
kinetic effect that is characteristic for SN2 reactions. Beyond this
kinetic isotope effect study, the fact that the second step does
not discriminate between halide anions with different
nucleophilicities (the one in higher concentration attacks the
sulfoxonium first; see entries 9-12, Table 2) also corroborate a
fast second step. According to the results depicted in Tables 2
and Figure 2, path A (Figure 3) is the primary path, but paths B
and C can also compete depending on the type of ylide and alkyl
halide employed.
Detailed kinetic studies by NMR were also carried out for the
reaction between 1 and methyl iodide (see SI for details), and
they also suggested that the first step is rate limiting. This study
furnished a rate constant value (k) of 3.3 x 10-5 L-mol-1-s-1 and
Figure 2. Scope of the sulfoxonium ylide in the alkylation-halogenation
reaction with methyl iodide and benzyl bromide.
revealed
a global second-order reaction based on the
concentration of both ylide and alkyl halide (Figure 4). The rate
of this alkylation-halogenation reaction can be expressed as v =
3.3 x 10-5 [ylide 1][MeI].
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importance and challenges in preparing fluorinated compounds,
we chose to perform these reactions in the presence of an
electrophilic fluorinating agent and different halides salts (Figure
5). Reaction of ylide 1, 12, 15, 16 and 18 with Selectfluor in the
presence of TBACl, KBr, and KI gave geminal dihalogenated
fluoroketones in moderate yields 49-72%. The combination of
the same halogen was also possible for Cl and Br, leading to
compounds 47 and 48 in 80 and 77% yield respectively.
However, all the attempts to combine two F atoms at the
geminal position were fruitless and a complex mixture of
products were obtained. The results depicted in Figure 5 show a
new entry in the preparation of unsymmetrical geminal
dihalogenated ketones and also open the possibility for an
enantioselective version if chiral electrophilic halogen species
are employed.
Figure 3. Kinetic isotopic effects and a proposed mechanism for the
alkylation-halogenation reaction.
Figure 5. One-pot preparation of di-halogenated haloketones, containing the
same or different halogens.
In summary, we have disclosed
a
novel chemical
transformation that permits attachment of an alkyl group and a
halogen atom, or alternatively, the same or two different halogen
atoms, onto sulfoxonium ylides. This can be performed in a
single transformation and introduces a new entry for preparing
gem-difunctionalized haloketones (an alkyl and F, Cl, Br, or I) or
gem-dihalogenated haloketones (containing a combination of
the same or two different halogens) in good yields. In the past,
basically sequential transformations, adding these groups or
atoms separately, have been reported. We have also provided
insights into a detailed mechanism for these reactions based on
kinetic isotopic effect studies and kinetics, and in doing so,
determined the rate equation and rate constant values.
Experimental setup is easy and consists of mixing all reagents at
once. Moreover, the great stability of sulfoxonium ylides, in
addition to the fact that they are solids, makes them very
attractive in chemistry and for industrial applications.
Figure 4. kinetic studies of the alkylation-halogenation reaction.
We next decided to investigate the possibility of extending
this method to the preparation of dihalogenated ketones,
especially those containing two different halides. Few methods
can be found for synthesizing geminal dihaloketones, containing
the same halogen, in a direct fashion. For the much more
difficult preparation of geminal dihaloketones possessing two
different halogens, except for employing diazoketones,14 only
stepwise methods are described. At this point, and knowing the
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Huang, X.; Kaehlig, H.; Veiros, L. F.; Maulide, N. J. Org. Chem. 2015,
80, 5719.
Acknowledgements
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We would thank FAPESP (Research Supporting Foundation of
the State of Sao Paulo) for financial support (2013/18009-4). We
also thank CNPq for fellowships.
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Keywords: haloketones • fluoroketones • sulfur ylides •
disubstituted ketones
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Rafael Gallo, Anees Ahmad, Gustavo
Metzker and Antonio C B Burtoloso*
Page No. – Page No.
α,α-Alkylation-Halogenation and
Dihalogenation of Sulfoxinium Ylides.
A direct Preparation of Geminal
Difunctionalized Ketones.
Text for Table of Contents
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