N -difluoromethylation of imidazoles and benzimidazoles using the ruppert-prakash reagent under neutral conditions

Article abstract of DOI:10.1021/ol403007j

Direct N-difluoromethylation of imidazoles and benzimidazoles has been achieved using TMS-CF₃ (the Ruppert-Prakash reagent) under neutral conditions. Difluoromethylated products were obtained in good-to-excellent yields. Inexpensive, commercial

Full text of DOI:10.1021/ol403007j

Letter
pubs.acs.org/OrgLett
N‑Difluoromethylation of Imidazoles and Benzimidazoles Using the
Ruppert−Prakash Reagent under Neutral Conditions
G. K. Surya Prakash,* Sankarganesh Krishnamoorthy, Somesh K. Ganesh, Aditya Kulkarni, Ralf Haiges,
and George A. Olah
Donald P. and Katherine B. Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California,
Los Angeles, California 90089-1661, United States
S
* Supporting Information
ABSTRACT: Direct N-difluoromethylation of imidazoles and benzimidazoles
has been achieved using TMS-CF3 (the Ruppert−Prakash reagent) under
neutral conditions. Difluoromethylated products were obtained in good-to-
excellent yields. Inexpensive, commercially available starting materials, neutral
conditions, and shorter reaction times are advantages of this methodology.
Reactions are accessible through conventional as well as microwave irradiation
conditions.
elective fluorination and fluoroalkylation of organic
precursors for the preparation of N-heterocyclic carbenes,
Scompounds result in products that have significantly which are useful organocatalysts and ligands for transition metal
altered electronic and skeletal features. Such fluorinated
compounds are greatly utilized in the areas of medicines,
agrochemicals, materials chemistry, and catalysis.1 Among the
fluoroalkyl groups, the difluoromethyl group is of key interest
as it resembles conventional hydrogen bond donors (N−H,
O−H). However, it exhibits enhanced lipophilicity. Moreover,
it can serve as a nonconventional hydrogen bond donor (F2C−
H) and a weak hydrogen bond acceptor (C−F) through
fluorine. Difluoromethylation has attracted significant atten-
tion2 in the pharmaceutical industry as the CF2H moiety, when
introduced, appreciably affects the pharmacokinetic properties,
namely membrane permeability, bioavailability, binding affinity,
metabolic stability, and lipophilicity of drug candidates.3
Consequently, the CF2H moiety is notably considered in
isostere-based drug design.4 The commercial pharmaceuticals
Eflornithine,5 Pantaprazole,6 and Garenoxacin,7 the marketed
agrochemicals Sulfentrazone8 and Carfentrazone-ethyl,9 and
related potential drug candidates10 all have CF2H functionality
(Figure 1). Imidazoles and benzimidazoles are key structural
units, prevalent in biological systems, and have wide
applications in medicine,11 material sciences,12 and catalysis.13
Furthermore, fluorinated alkyl and arylated imidazoles and
related structures are studied for the preparation of novel
imidazolium salts, which can be used as ionic liquids,14 and as
catalyzed reactions.15 In this context, selective introduction of
the difluoromethyl group onto the imidazole and benzimidazole
nitrogen is of great interest.
There are several methods in the literature to obtain 1-
difluoromethylimidazoles and benzimidazoles using different
reagents. Ozone-depleting chlorodifluoromethane is one of the
frequently used reagents.16 The others are sodium trifluor-
oacetate,17 methyl chlorodifluoroacetate,18 chlorodifluorometh-
yl phenyl sulfone,19 N-tosyl-S-difluoromethyl-S-phenylsulfox-
imine,20 and the more recent sodium chlorodifluoroacetate21
and TMSCF2Br.22,23 Hu et al., in their recent work,
demonstrated the versatility of TMSCF2Br in the difluor-
omethylation of heteroatom nucleophiles. However, when they
used TMSCF3 in place of TMSCF2Br, they found no product
formation. Although effective and versatile, the lack of
commercial availability of TMSCF2Br and the strongly basic
conditions put limitations on the method. Moreover, in their
procedure TMSCF2Br is derived either from TMSCF3 using
BBr3 or TMSCF2H with NBS.
Previously, the Hu and Prakash groups reported the
generation of difluorocarbene from the Ruppert−Prakash
reagent24 (TMSCF3) and successfully added it across alkenes,
alkynes,25a and Sn−H bonds25b under neutral conditions using
metal halides and nonmetallic fluorides (CaI2, NaI, TBAT,
TMAF) as initiators. Now, we report the one-step difluor-
omethylation of imidazoles and benzimidazoles in triglyme
using TMSCF3 and LiI as the initiator under neutral conditions.
1H-Benzimidazole was chosen as the model substrate for the
reaction screening (Table 1; details in the Supporting
Information). Screening for optimized conditions using
previously reported carbene generation and addition methods
Received: October 20, 2013
Figure 1. Bioactive compounds containing the difluoromethyl group.
© XXXX American Chemical Society
A
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Letter
a
We optimized the reactions with 1H-benzimidazole (Table 2,
entry 1), LiI, and triglyme under microwave conditions, and the
Table 1. Solvent and Initiator Screening
Table 2. Substrate Scope
b
entry
solvent
MX (equiv)
temp (°C) time (h) conv (%)
1
DMA
DMA
DMA
DMA
THF
CaI2 (0.15)
K2CO3 (1.0)
TBAT (0.1)
KF (0.5)
100
0.67
12
20
23
54
56
50
14
45
8
2
80
3
rt
2
2
4
rt
5
LiHMDS (1.2)
KF (0.5)
−78
40
21
14
24
7
6
HMPA
THF
7
LiI (0.5)
90
8
THF
t-BuOLi (1.2)
LiI (1.5)
−78
140
9
THF
72
8
63
70
72
10
11
triglyme
triglyme
LiI (1.2)
140
LiI (1.2)
170 (MW)
1
a
Reactions were carried out on a 0.25 mmol scale with 3 equiv of
b
TMSCF3. The conversion was determined by 19F NMR spectroscopy
using trifluorotoluene as internal standard. Entries 6 and 7 were
brought to rt from −78 °C. Entry 11 was further optimized (see the
Supporting Information for details).
led to low conversions. For example, with CaI2 in DMA gave
20% (Table 1, entry 1), whereas NaI (THF) produced 30%
conversion. Use of fluoride initiators such as TBAT and KF in
DMA or LiHMDS in THF resulted in 50% conversion (Table
1, entries 3−5) with most of the TMSCF3 consumed. However,
our attempts to optimize the conditions met with little success.
Interestingly, lithium iodide in THF produced 45% conversion
after 24 h at 90 °C (Table 1, entry 7) but still unreacted
TMSCF3 was left behind. It was postulated that the generation
of insoluble LiF during the course of the reaction would help to
push the carbene generation reaction forward, thereby resulting
in an increased yield of the difluoromethylated product
(Scheme 1). At the same time, the fluoride generated during
Scheme 1. Proposed Mechanism
Conditions 1: 0.25 mmol, microwave heating, 170 °C, 1.5 h.
a
Conditions 2: conventional heating, 170 °C, 3 h. Heated for 120
b
c
min. Formed two isomers in a 1:1 ratio (based on 19F NMR). Eluted
d
e
together as a mixture. Product not isolated. Isomers formed MW
(34:7); thermal (29:6), only the major isomer was isolated (10b).
f
Conversions were determined by 19F NMR spectroscopy using
g
trifluorotoluene as an internal standard. Isolated yield.
amounts of TMSCF3 and LiI were varied to achieve an
optimum conversion. It was observed that higher amounts of
TMSCF3 or LiI and longer reaction times resulted in lower
yields. This is probably due to decomposition of the
difluoromethylated product to CF2HI. The optimized con-
ditions and the substrate scope are shown in Table 2. The
reactions can also be carried out under conventional heating
conditions albeit with longer reaction times (∼3 h).
Imidazoles and benzimidazoles showed similar reactivity with
electron-donating and -withdrawing substituents, whereas
triazole and 4-azabenzimidazole produced the desired products
in lower yields. Substituted imidazole and benzimidazoles
produced both of the regioisomers (Table 2, entries 3−5 and
10). In the case of 4-nitroimidazole, only one isomer was
observed because of stereoelectronic constraints. Diphenyl-
amine, acetanilide, N-methylbenzenesulfonamide, and indole
failed to give products under these conditions.
carbene formation would be trapped by Li(I) cation preventing
a runaway reaction with the silyl group. Higher boiling ethereal
solvents like triglyme enabled the reactions to be performed
safely at higher temperatures. Reactions carried out with KF,
NaF resulted in complete consumption of TMSCF3 with no
product formation probably due to rapid decomposition of
TMSCF3 to CF3H, carbene oligomers and other undesired side
products. Control reactions carried out in triglyme (a) without
LiI (metal salt initiator) and (b) with LiF both resulted in no
product formation. However, an equal amount of unreacted
TMSCF3 was left behind (details in the Supporting
Information). These results prompted us to postulate that
Li(I) cation plays a key role in controlling the availability of
fluoride in the reaction mixture, which otherwise will undergo
runaway reaction with TMSCF3. Hence, LiI was chosen to
optimize the reaction conditions.
B
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Letter
We decided to showcase the application of this methodology
by introducing the CF2H group into biologically active
molecules. Caffeine has been known to influence cell cycle
function, bringing about programmed cell death and also
affecting important regulatory proteins, for instance, the tumor
suppressor protein.26 Difluoromethylation of theophylline
(Scheme 2) gave the difluoromethylated analogue of caffeine
Scheme 3. Synthesis of N-Difluoromethylated Ligand for
Amyloid β-Peptide Inhibitor Pt Complex
a
a,b
Scheme 2. N-Difluoromethylation of Theophylline*,
a
Isolated yield.
molecular nucleophilic substitution of N-difluoromethyl
carbanion on the quinoline ring. The optimization and
investigation of the mechanistic aspects of these applications
are currently underway.
In summary, we have successfully demonstrated the
difluoromethylation of imidazoles, benzimidazoles, and related
molecules using TMSCF3 and LiI under neutral conditions.
The difluoromethylated products were obtained in good-to-
excellent yield in relatively short reaction times.
*
MW: 0.25 mmol, 170 °C, 1.5 h. Conventional heating: 170 °C, 3 h.
a
Gram scale: 10 mmol, 170 °C 2 h. Conversions were determined by
19F NMR spectrascopy using trifluorotoluene internal standard.
b
Isolated yield (see the Supporting Information for further details).
ASSOCIATED CONTENT
* Supporting Information
General experimental procedure and spectroscopic data of all
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
(11b) and isocaffeine (11a) in 3:2 ratio.27,28 Single-crystal X-
ray diffraction (Figure 2) showed the presence of weak
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gprakash@usc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Loker Hydrocarbon Research
Institute and the National Science Foundation for CRIF
Grant No. 1048807 (for X-ray diffractormeter) is gratefully
acknowledged.
REFERENCES
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