Nucleophilic bromo- and iododifluoromethylation of aldehydes

Article abstract of DOI:10.1021/ol501674n

A method for bromo- and iododifluoromethylation of aldehydes using bromo- and iodo-substituted difluoromethyl silicon reagents (Me₃SiCF ₂X) is described. The reaction is performed in the presence of a combination of tetrabutylammonium and lithium salts Bu₄NX/LiX (X = Br or I) in propionitrile. It is believed that, in this process, a short-lived halodifluoromethyl carbanion serves as nucleophile, which is reversibly generated from difluorocarbene and a halide anion.

Full text of DOI:10.1021/ol501674n

Letter
pubs.acs.org/OrgLett
Nucleophilic Bromo- and Iododifluoromethylation of Aldehydes
Mikhail D. Kosobokov, Vitalij V. Levin, Marina I. Struchkova, and Alexander D. Dilman*
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian Federation
S
* Supporting Information
ABSTRACT: A method for bromo- and iododifluoromethylation of
aldehydes using bromo- and iodo-substituted difluoromethyl silicon
reagents (Me3SiCF2X) is described. The reaction is performed in the
presence of a combination of tetrabutylammonium and lithium salts
Bu4NX/LiX (X = Br or I) in propionitrile. It is believed that, in this
process, a short-lived halodifluoromethyl carbanion serves as
nucleophile, which is reversibly generated from difluorocarbene and
a halide anion.
ue to the importance of organofluorine compounds in the
pharmaceutical and agrochemical industries, as well as in
can generate difluorocarbene even in the presence of weak
D
Lewis bases such as chloride and bromide ions.9,10 In this work,
we describe nucleophilic bromo- and iododifluoromethylation
of aldehydes with corresponding silanes in a process, which
relies on reverse generation of carbanionic species from
difluorocarbene11 and the halide anion.
materials science,1 significant progress has been achieved in the
development of a methodology for their synthesis. Among
diverse approaches for the introduction of a fluorinated group
into organic molecules,2,3 methods for nucleophilic fluoroalky-
lation have become most popular.3 While various organo-
metallics can serve as equivalents of fluorinated carbanions,4
fluorinated silanes have emerged as the most convenient and
widely applicable reagents for nucleophilic fluoroalkylation
reactions.3a−e
While (bromodifluoromethyl)trimethylsilane (1a) can be
readily obtained from the Ruppert−Prakash reagent,6h,9a
iodinated silane (1b) has not been known. We prepared silane
1b from silane 1a in 70% yield by the bromine/zinc
exchange10b followed by iodination (Scheme 2). Similar to
1a, the reagent 1b is a distillable liquid, which can be
conveniently handled in air.
To exhibit nucleophilic reactivity, fluorinated silanes have to
be activated by a silaphilic Lewis base (e.g., fluoride anion)
through the generation of a pentacoordinate intermediate,
which reacts with a suitable electrophile (e.g., aldehyde)
(Scheme 1). Reactions of the Ruppert−Prakash reagent (X =
F)3a−e and chloro-substituted analog (X = Cl),5 as well as many
other functionalized silanes,6 follow this pathway. However,
reactions of a bromo-substituted silane (X = Br) with aldehydes
mediated by a fluoride ion have been unsuccessful,7 presumably
owing to facile decomposition of a pentacoordinate inter-
mediate to difluorocarbene.8 Indeed, silane Me3SiCF2Br (1a)
Scheme 2. Synthesis of Silane 1b
Benzaldehyde (2a) was selected as a model substrate, and its
reaction with silane 1a was investigated (Table 1). The
reactions were typically performed in refluxing propionitrile
(around 100 °C), and reaction mixtures were analyzed by 19F
NMR spectroscopy. Employment of 3 equiv of 1a along with 5
mol % of tetrabutylammonium bromide for 2 h provided 12%
of silylated product 3a (entry 1). Increasing the amount of
bromide salt provided a notable improvement, and finally, using
1.1 equiv of Bu4NBr lead after desilylative workup to product
4a in 78% isolated yield (entry 3). Performing the reaction at a
lower temperature (refluxing acetonitrile) or with a decreased
amount of silane 1a gave inferior results (entries 4 and 5).
However, when we tested p-methoxybenzaldehyde (2b)
under these conditions, product 3b was formed in 31% yield,
with the rest being the unreacted aldehyde (entry 6). Increasing
Scheme 1. Trapping of Fluorinated Carbanions
Received: June 10, 2014
© XXXX American Chemical Society
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Letter
Table 1. Optimization of Bromodifluoromethylation of
Table 2. Bromo- and Iododifluoromethylation of Aldehydes
Aldehydes
a
no.
R
1a, equiv Bu4NBr/LiBr, equiv time, h yield of 3, %
1
2
3
H
3
0.05/0
0.5/0
1.1/0
1.1/0
1.1/0
1.1/0
3/0
2
2
2
2
2
2
2
2
2
5
5
5
12
60
3
b
3
79 (78 )
c
4
3
51
29
31
48
83
61
5
1.5
3
6
MeO
7
3
8
6
1.1/0
1.1/0.5
1.1/0.5
0/1.6
0/2
9
3
d
10
11
3
3
92 (92 )
76
e
12
3
88
a
b
Determined by 19F NMR using PhCF3 as internal standard. Isolated
c
yield of product 4a. Reaction performed in refluxing acetonitrile.
d
e
Isolated yield of product 4b. Reaction performed in diglyme at 100
°C.
the concentration of Bu4NBr up to 3 equiv had little effect
(entry 7), while use of a huge excess of the silane seemed
impractical (entry 8). We reasoned that the reaction rate can be
increased by the addition of a metal salt capable of exerting
Lewis acidic activation of the carbonyl group. Rewardingly,
addition of 0.5 equiv of lithium bromide virtually doubled the
product yield (cf. entries 6 and 9). Finally, increasing the
reaction time to 5 h allowed isolation of alcohol 4b in 92% yield
(entry 10). The use of lithium bromide without the
tetrabutylammonium counterpart gave inferior results (entries
11 and 12).
Under the optimized conditions, a series of aldehydes were
reacted with silane 1a (Table 2, entries 1−11). Aromatic
aldehydes bearing donating and withdrawing substituents,
heterocyclic aldehydes, unsaturated, and nonenolizable aliphatic
aldehydes afforded products 4a−l in high yields. Electron-
withdrawing nitro and ester groups accelerated the nucleophilic
addition, and the reactions were complete within 2 h (entries 3
and 4). For sterically hindered aldehydes a longer reation time
and 3 equiv of both ammonium and lithium salts were needed
(entries 7 and 11). Fortunately, α-methylcinnamaldehyde gave
addition product 4k in 89% yield, while 19F NMR analysis or
crude material indicated only small amounts (ca. 5%) of
difluorocyclopropane byproducts. However, hydrocinnamalde-
hyde gave a complex mixture, presumably, owing to its
propensity to aldolization. The reaction of acetophenone was
also unsuccessful with the product being formed in less than
10% yield. The ester group is tolerated (for an aromatic
substrate, see entry 4, whereas, in the reaction of an aliphatic
ester, methyl 4-phenylbutanoate, no product was detected).
a
b
Isolated yield. 3 equiv of each Bu4NBr and LiBr were used.
Reactions of aldehydes with iodo-substituted silane 1b were
performed using the Bu4NI/LiI system under similar
conditions. Typically, the reactions proceeded slower compared
to those with silane 1a. Nevertheless, good yields of
iododifluoroalkylation products were achieved after heating
for 10 h (entries 12−16).
Concerning the reaction mechanism, two pathways can be
considered (Scheme 3). In path (a), the halide anion reversibly
generates a difluorocarbene through the intermediacy of
halodifluoromethyl carbanion 5. While the latter species is
believed to be very short-lived, it can be trapped with the
appropriate electrophile. A lithium salt can activate the carbonyl
group though some association of the lithium cation with
B
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Letter
reversible generation of difluorocarbene, iodo-substituted silane
1b was combined with tetrabutylammonium bromide in the
presence of 1,1-diphenylethylene (eq 3). The halogen exchange
proceeded rapidly even at room temperature, and in 7 min
silane 1a and cyclopropane 6 were detected.14 Taken together,
these observations support path (a), in which the nucleophilic
species 5 is generated from the interaction of difluorocarbene
with a halide anion.
Scheme 3. Reaction Mechanism
In summary, a convenient method for nucleophilic bromo-
and iododifluoromethylation of aldehydes by means of
corresponding silicon reagents is described. The use of a
stoichiometric amount of a halide anion is important to achieve
good yields of products. The role of the halide is believed to
trap difluorocarbene generating a transient halodifluoromethyl
carbanion.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, compound characterization data,
copies of NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: adil25@mail.ru.
Author Contributions
carbanionic species 5 cannot be excluded. In an alternative
mechanism, path (b), the halodifluoromethyl group can be
transferred in a concerted fashion from a pentacoordinate
siliconate intermediate.
To gain some mechanistic information, several experiments
were carried out (Scheme 4). Thus, when the reaction of
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
Scheme 4. Mechanistic Studies
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Russian Science Foundation
(Project 14-13-00034).
■
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