An easy access to fluoroalkanes by deoxygenative hydrofluorination of carbonyl compounds via their tosylhydrazones

Article abstract of DOI:10.1039/c3cc00122a

An efficient and operationally simple synthesis of fluoroalkanes by deoxygenative hydrofluorination of carbonyl compounds via their tosylhydrazone surrogates is reported. The reaction can be carried out in a one-pot procedure directly from carbonyl compounds.

Full text of DOI:10.1039/c3cc00122a

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An easy access to fluoroalkanes by deoxygenative
hydrofluorination of carbonyl compounds via their
tosylhydrazones†
Cite this: Chem. Commun., 2013,
49, 2154
Received 6th January 2013,
Accepted 29th January 2013
Arvind K. Yadav, Vishnu P. Srivastava and Lal Dhar S. Yadav*
DOI: 10.1039/c3cc00122a
www.rsc.org/chemcomm
An efficient and operationally simple synthesis of fluoroalkanes by employed as a source for the safe generation of diazo compounds
deoxygenative hydrofluorination of carbonyl compounds via their and carbenes to merge with different types of transition-metal-
tosylhydrazone surrogates is reported. The reaction can be carried catalysed transformations, such as cyclopropanations,11a asym-
out in a one-pot procedure directly from carbonyl compounds.
metric epoxidations,11b aziridinations11c and C–H insertion
reactions.11d Recently, tosylhydrazones have emerged as efficient
carbonyl surrogates that offer a strategic platform to execute
unconventional and complex synthetic transformations of carbonyl
compounds in a very simple way obviating transition metal
catalysis.12 For example, elegant methods have recently been
explored furnishing synthetically useful C–C12a and C–Nu12b–d
(Nu = O, S, N) bonds via metal-free reductive coupling of
tosylhydrazones (Scheme 1(a) and (b), respectively). Having
been fascinated by these reports and in continuation of our
recent research focusing on strategic synthetic transformations
utilizing carbonyl functionality,13 we devised the present C–F
bond formation by deoxygenative hydrofluorination of carbonyl
compounds via their tosylhydrazone surrogates as depicted in
Scheme 1(c).
The unique nature of a carbon–fluorine bond often imparts desir-
able physical, chemical and biological properties with minimal steric
interference,1 thereby playing an intrinsic role in pharmaceuticals,2,3
agrochemicals,4 materials5 and tracers for positron emission tomo-
graphy (PET).6 The fluorine atom strategically occurs in approxi-
mately 30% of all agrochemicals and 20% of all pharmaceuticals,
including drugs such as Cipro, Lipitor, Lexapro and Prozac, and
these data are expected to grow further through the 21st century.2
Moreover, organofluorine intermediates having a benzylic fluoride
or a fluorine substituent directly adjacent to a heteroaryl motif have
become significantly active ingredients in drug and agrochemical
discovery,7 thus efficient methods to incorporate this magic halogen
into organic molecules are of great interest.
In the extensively studied area of fluorination reactions,
numerous fluorinating reagents have been introduced with the
objective of providing enhanced selectivity and ease of handling.8
For example, electrophilic reagents: N-fluoro reagents,9a XeF2,9b
PhSeF3 and PhTeF5,9c and nucleophilic reagents pyridine HF
In order to achieve our goal, we initially attempted a reaction
of acetophenone-derived tosylhydrazone (1a) as a model sub-
strate and BF3Áetherate as a fluoride source in refluxing toluene
using potassium carbonate as a base but disappointingly, the
desired fluoroalkane 2a could not be obtained. Instead, a
mixture of cis- and trans-2,3-diphenyl-2-butenes was isolated
in 62% yield (Table 1, entry 1), which might be formed
(Olah’s reagent),10a Et3NÁ3HF,10b DAST10c and Deoxo-Fluor.10d
A
general and straightforward approach for the synthesis of alkyl
fluorides relies on deoxygenative fluorination of alcoholic C–OH
to C–F, aldehydic HCQO to HCF2, ketonic >CQO to >CF2 and
–COOH to –CF3, and DAST and Deoxo-Fluor are the reagents of
choice for these transformations.10c,d Surprisingly, deoxygenative
hydrofluorination of carbonyl compounds (>CQO - CHF) has
hitherto been unknown although this fundamental reaction
would widen the scope of chemistry and utility of carbonyls.
Tosylhydrazones are readily available and stable reagents
with diverse synthetic applications.11 They have been extensively
¨
by dimerisation of the carbene PhCMe generated in situ.
Green Synthesis Lab, Department of Chemistry, University of Allahabad,
Allahabad-211002, India. E-mail: ldsyadav@hotmail.com; Fax: +91 5322460533;
Tel: +91 5322500652
Scheme 1 Reductive coupling of carbonyl compounds via their tosylhydrazone
† Electronic supplementary information (ESI) available: Experimental details and
characterisation data for all compounds. See DOI: 10.1039/c3cc00122a
surrogates.
c
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Table 1 Optimisation of reaction conditions for reductive hydrofluorination of
tosylhydrazone 1aa
Table 2 Reductive fluorination of tosylhydrazones 1 with Et3NÁ3HFa
Entry
1
Product 2
Time (h)
2
Yieldb,c (%)
Entry Fluorine source Base
Solvent
Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
BF3ÁEt2O
KF
CsF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
KOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
3
4
4
3
2
3
4
4
4
4
4
4
0
0
0
79
85
26
35
Trace
Trace
53
51
62
85
PyridineÁnHF
Et3NÁ3HF
Et3NÁ3HF
Et3NÁ3HF
Et3NÁ3HF
Et3NÁ3HF
Et3NÁ3HF
Et3NÁ3HF
Et3NÁ3HF
2
3
2
2
90
93
Et3N
9
DABCO Toluene
10
11
12
K2CO3
K2CO3
K2CO3
THF
Dioxane
MeCN
a
Reaction conditions: 1a (1 mmol), fluorine source (1.5 mmol),
base (5.0 mmol), solvent 4 mL, under a N2 atmosphere at reflux.
b
Isolated yield.
4
3
63
Then, KF and CsF were tested as fluoride sources but they also did
not produce 2a. Finally, we turned our attention to N-fluoro reagents
and examined pyridineÁnHF (Olah’s reagent) and Et3NÁ3HF. To our
delight, both of these worked well and afforded the desired product
2a in 79 and 85% yields, respectively (Table 1, entries 4 and 5). Thus,
Et3NÁ3HF was chosen for the present study. Next, we examined the
influence of bases and solvents on the reaction. K2CO3 was found to
be the best among the screened bases Li2CO3, K2CO3, KOH, Et3N
and DABCO (Table 1, entry 5). Probably because K2CO3 is mild and
poorly soluble in toluene, which releases the diazo compound slowly
into the solution, thereby minimising side reactions. Among the
tested solvents, toluene was most suitable in terms of yield and
reaction time (Table 1, entry 5).
At the final stage of development of the present protocol for
conversion of carbonyl compounds into fluoroalkanes, the scope of
the reaction was investigated under the optimised conditions and
the results are compiled in Table 2. The generality of the method
was demonstrated across a wide range of aldehydes and ketones,
including aromatic, heterocyclic and aliphatic, which were converted
into the corresponding fluoroalkanes in good to excellent yields
(63–93%) and high purity. A variety of subtituents such as Me, Cl,
Br, NO2 and MeO were tolerated. In general, the substrates
bearing an electron-withdrawing group in an aryl moiety required
longer reaction time and afforded lower yields of fluoroalkanes as
compared to those bearing an electron-donating group (Table 2,
entries 4, 11–13 compared to entries 2, 3 and 10).
5
6
2
2
79
81
7
8
9
3
3
2
76
78
82
10
3
87
11
12
2
2
71
73
Prompted by the easy preparation of tosylhydrazones by the
reaction of tosylhydrazides and carbonyl compounds, we also
attempted the deoxygenative hydrofluorination in a one-pot
procedure (Scheme 2). To our delight, it worked well to afford
the desired fluoroalkanes 2 without the isolation of the inter-
mediate tosylhydrazones 1 (for details, see ESI†).
13
14
3
3
67
80
On the basis of the above experimental results and the
literature reports,12 a plausible mechanism for the reductive
fluorination of tosylhydrazones 1 is depicted in Scheme 3.
Tosylhydrazones undergo thermolysis under basic conditions
c
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Table 2 (continued )
We sincerely thank the SAIF, Punjab University, Chandigarh,
for providing spectra. One of us (A.K.Y.) is grateful to the CSIR,
New Delhi, for the award of a Junior Research Fellowship.
Entry
15
Product 2
Time (h)
Yieldb,c (%)
Notes and references
2
88
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R. Saha, Future Med. Chem., 2009, 1, 777; (e) Bioorganic and Medicinal
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A Critical Review, ed. M. Hudlicky and A. E. Pavlath, ACS Monograph 187,
American Chemical Society, Washington DC, 1995.
16
17
2
2
75
2 K. Mu¨ller, C. Faeh and F. Diederich, Science, 2007, 317, 1881.
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79
77
4 P. Jeschke, ChemBioChem, 2004, 5, 570.
5 M. H. Hung, W. B. Farnham, A. E. Feiring and S. Rozen, in Fluoro-
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18
3
6 S. M. Ametamey, M. Honer and P. A. Schubiger, Chem. Rev., 2008,
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a
b
For the experimental procedure, see ESI. Yield of isolated and
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c
purified products 2. For the characterisation data of fluoroalkanes 2,
see ESI.
Scheme 2 One-pot deoxygenative hydrofluorination of carbonyl compounds.
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Scheme 3 Plausible mechanistic pathway for insertion of carbene into the
H–F bond.
to generate diazo compounds 4 in situ, which subsequently
form a carbene intermediate 5 with the loss of nitrogen. Finally,
insertion of the carbene into the H–F bond affords the desired
fluoroalkanes 2.
ˇ
ˇ
12 (a) J. Barluenga, M. Tomas-Gamasa, F. Aznar and C. Valdes, Nat.
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Chem., 2009, 1, 494; (b) J. Barluenga, M. Tomas-Gamasa, F. Aznar
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In conclusion, we have developed a fundamental reaction
for an efficient synthesis of monofluoroalkanes by deoxygena-
tive hydrofluorination of carbonyl compounds via tosylhydra-
zone intermediates. Notably, the reaction can be performed in a
one-pot procedure starting directly from a carbonyl compound.
The protocol is advantageous especially in terms of availability
of starting materials, operational simplicity and functional-
group tolerance.
ˇ
ˇ
(d) J. Barluenga, M. Tomas-Gamasa, F. Aznar and C. Valdes, Angew.
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c
2156 Chem. Commun., 2013, 49, 2154--2156
This journal is The Royal Society of Chemistry 2013