Development of fluorination methods using continuous-flow microreactors

Article abstract of DOI:10.1016/j.tet.2009.05.083

The safe and reliable use of various fluorination methods including nucleophilic fluorination (DAST), trifluoromethylation (Ruppert's reagent) and electrophilic fluorination (Selectfluor) in a continuous-flow microreactor is reported. Special a

Full text of DOI:10.1016/j.tet.2009.05.083

Tetrahedron 65 (2009) 6611–6625
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of fluorination methods using continuous-flow microreactors
*
Marcus Baumann, Ian R. Baxendale, Laetitia J. Martin, Steven V. Ley
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The safe and reliable use of various fluorination methods including nucleophilic fluorination (DAST),
trifluoromethylation (Ruppert’s reagent) and electrophilic fluorination (SelectfluorÒ) in a continuous-
flow microreactor is reported. Special attention was given to the use of in-line scavenging procedures in
order to obtain clean products without the need for further purification.
Received 18 March 2009
Received in revised form 26 May 2009
Accepted 27 May 2009
Available online 6 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Dedication with respect and congratulations
to Professor Larry Overman on the receipt of
the Tetrahedron Prize
1. Introduction
Fluorinated molecules are found in many commercially impor-
tant products.1 This is because fluorination can dramatically im-
prove the properties of compounds especially against metabolic
degradation in pharmaceutical or in agrochemical applications.
However, the introduction of fluorine is not always straightforward
and can add considerably to the cost of goods owing to the haz-
ardous nature of the reagents used to introduce fluorine or the
inherent expense of specific fluorinated building blocks.
In this work we report on the development of several methods
to incorporate fluorine into various substrates using flow micro-
reactor devices.2 Flow chemical processes are becoming in-
creasingly useful in the assembly of molecules since these methods
readily accommodate automation and reaction optimization.3 They
can provide many efficiency gains through the generation of less
waste, telescoped reaction processes,4 and lower solvent usage
when compared with more conventional batch reactions. Also their
ability to contain hazardous, obnoxious or reactive intermediates
adds to their value owing to their improved safety features.5 Sim-
ilarly by incorporating immobilized reagents and scavengers of by-
products into the flow lines enhanced product purities are obtained
without the need for routine unit operations such as crystallization,
distillation, chromatography or aqueous work-up protocols.6
Flow chemistry has been shown to enhance many synthetic
transformations; of particular importance is the introduction of fluo-
rine into organic substrates.7 Herein we report in full on the use of
diethylaminosulfur trifluoride (DAST), (1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo-[2.2.2]octane) bis(tetrafluoroborate) (SelectfluorÒ),
* Corresponding author.
Figure 1. Vapourtec R2þR4 flow system.
E-mail address: svl1000@cam.ac.uk (S.V. Ley).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.083

6612
M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
and trimethylsilyl trifluoromethane (TMS-CF3, Ruppert’s reagent) as
complimentary methods for the effective incorporation of fluorine
moieties.
2. Results and discussion
In the first set of experiments we evaluated the use of DAST as
a commonly used reagent to bring about the conversion of alcohols
and carbonyl compounds to their corresponding fluoro derivatives.
While this reagent is extremely effective it is problematic in that it
is volatile, reacts violently with water and readily undergoes dis-
mutation to SF4 and (Et2N)2SF2 when heated to temperatures in
excess of 90 ꢀC.8 In addition the by-products of the reactions are
corrosive and will readily etch standard laboratory glassware.
Consequently, the use of DAST in a continuous-flow reactor using
inert plastic flow tubes (PEEK, PTFE, PFA) provides flexibility, scale-
up opportunity, and enhanced safety of operation. The flow reactor
chosen for this study was the commercially available Vapourtec
R2þ/R4 modular device9 (Fig. 1). This convenient set-up employs
Scheme 1. General flow reactor schematic for DAST reactions.
Table 1
Fluorination products starting from alcohols; isolated yields
Entry
1
Starting material
Fluorination product
Yield (%)
73
Entry
2
Starting material
OH
Fluorination product
Yield (%)
87
N
N
N
N
F
F
OH
Cl
Cl
2a
1a
2b
1b
OH
F
HO
F
Cl
Cl
3
97
4
83
O
O
O
O
NO2
NO2
4a
4b
3a
3b
OMe
OMe
O
O
OH
F
5
65
6
88
N
N
O2N
HO
F
O2N
5b
5a
6a
6b
8b
8c
Br
F
CO2Me
Br OH
Br
TrO
F
TrO
OH
7
92
8
92
CO2Me
CO2Me
F
7a
7b
8a
F
OH
OH
F
9
96
10
80
O
O
F
9b
10a
9a
10b
NO2
NO2
I
OH
I
O
O
N
11
82
12
87
N
11a
11b
F
OH
12a
12b

M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
6613
a self-calibrating dual pumping system and the ability to load the
corrosive DAST reagent via a PFA injection loop mounted on the
R2þ module. This reagent stream can be readily mixed in a T-piece
joining the equivalent substrate flow stream and progressing into
a convection flow coil (CFC, 9 mL volume, 1 mm i.d.) located on the
R4 unit (Fig. 1). Temperatures of up to 90 ꢀC were used with DCM as
solvent with boiling suppressed using an in-line backpressure
regulator (BPR) operating at 6.9 bar (100 psi).
Typically, concentrations ranging between 0.5 and 1.0 M of the
DAST reagent were used for these experiments (Scheme 1; X¼O or
OH). The DAST and the substrate were loaded into two identical
sample loops (2 mL internal volume, PEEK, 0.16 mm i.d.), which were
followed by a plug of silica gel (w2 g) to effect quenching and re-
moval of residual DASTand other side products. During this tandem
quenching and scavenger step evolution of CO2 was observed, but
was easily contained within the reactor due to the presence of the
BPR. The final product was then obtained without the need for
further purification following evaporation of the solvent giving
products with purities above 95% as determined by LC/MS and 1H
NMR. The exiting flow stream following sequestration was also
analyzed for inorganic fluoride content using a standardized test
kit11 but no fluoride contaminants were detected.
The initial substrates examined for the reaction in flow using
DAST in the apparatus described above were alcohols.12 Accord-
ingly, the primary alcohols 1a–12a were reacted to give in good
yields the corresponding monofluorides (Table 1).
What should be noted from the table is that many sensitive
functionalities such as esters, acetals, amides, epoxides, ethers, and
vinyl iodides remain intact during the reaction. In the case of ge-
raniol (2a) the quaternary fluoride (2b) was produced as the sole
eluted at 150 mL/min per channel. The combined streams were then
directed through the CFC, which was maintained at temperatures
between 70 and 90 ꢀC giving a heated residence time of 27 min.
The exiting flow stream from the CFC reactor was directed into
a glass column (10 mm bore i.d., 150 mm length)10 packed with
a two compartment bed of powdered calcium carbonate (w2 g)
Table 2
Fluorination of carbonyl compounds using DAST; isolated yields
Entry
Starting material
Fluorination product
Yield (%)
Entry
Starting material
Fluorination product
Yield (%)
Cl
Cl
O
F
N
N
N
N
MeO
MeO
H
H
F
F
13
86
14
75
H
F
F
N
Cl
O
N
Cl
F
O
F
14a
14b
13a
13b
O
15
17
83
89
16
18
96
75
H
F
O2N
O2N
15a
15b
16a
16b
O
H
F
F
O
F
O
O
O
H
F
N
N
O
N
N
N
N
18a
18b
17a
17b
O
F
H
F
O
H
F
N
N
Cl
Cl
N
N
19
21
87
20
50
F
20a
20b
19a
19b
O
F
O
F
F
O
O
H
F
O
O
0
22
73
N
H
N
H
N
N
22a
22b
21a
21b
O
O
O
O
CN
O
Cl
F
N
CN
O
23
94
24
96
N
Cl
N
Cl
N
N
O
N
F
F
O
24a
24b
O
O
O
23a
23b

6614
M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
product, while in the case of the Baylis–Hillman adduct (8a) two
allylic fluoride products (8b) and (8c, single isomer) were observed
as a 1:1 mixture of regioisomers but in good overall combined yield.
Substrate (5a) also proved problematic leading under the reaction
conditions to a mixture of the desired product (5b) and the elimi-
nated nitrostyrene (35% by crude 1H NMR). However, this impurity
could be easily removed by passage of the post reaction mixture
through a column containing Quadrapure-BZA a high-loading
macroporous benzyl amine resin (QP-BZA).13
In order to further expand the scope of this reaction we also
examined the conversion of a small collection of aldehydes and
ketones to their corresponding difluorides using the same flow
procedure. In these experiments we used 2 equiv of the DAST re-
agent with the CFC operating at 80 ꢀC. For electron-deficient alde-
hydes the reactions were generally rapid requiring residence times
of only 27 min while electron-donating systems needed slightly
longer reaction times of approximately 45 min equating to flow
rates of 100 mL/min per channel. Once again the products were
obtained in excellent yield and purity following the previously
established in-line impurity scavenging process (Table 2).
With the electron-rich aldehyde (20a) we noticed only a 50%
conversion to the desired product (20b) while starting material 21a
failed to react entirely. DAST is also known to be less efficient for the
analogous conversion of ketones to their corresponding difluor-
ides.14 Nevertheless, for isatin (22a) and the commercially in-
one loaded with a solution of SelectfluorÒ (0.1 M MeCN) and the
other with the substrate (in MeCN). The reagents are pumped from
the R2þ unit into a mixing T-piece and on into the CFC mounted on
the Vapourtec R4 unit (CFC, 9 mL internal volume, 1 mm i.d.). The
coil reactor is heated at between 100 and 120 ꢀC and the material
pumped at a combined flow rate of 300 mL/min giving a final resi-
dence time of 27 min. The product solution upon exiting the CFC
cooled rapidly and was directly scavenged by passage through
a mixed bed of Amberlyst 21 and 15 resins contained in a glass
column (10 mm bore i.d., 150 mm length). In optimization of this
process we determined that better overall yields and purities were
obtained using the alternative Quadrapure-SA and -DMA scavenger
resins.13 These scavengers ensured the complete removal of excess
reagents, by-products, and starting carbonyl compound via its enol
form to give clean products in high yield and purities being in ex-
cess of 95% as determined by both LC/MS and 1H NMR (Scheme 2).
The products of these fluorination reactions are listed in Table 4.
Normally monofluorinated species are the primary products al-
though with very reactive substrates such as the trifluoroacetyl de-
rivative 34adifluorinationoccursrapidlytogive34b. Consequently, in
order to avoid mixed fluorination products 2 equiv of the SelectfluorÒ
reagent was employed to drive this particular reaction to completion.
The second variant of the SelectfluorÒ process employs a similar
reactor set-up but introduces olefinic substrates into the second
channel together with wet acetic acid (<5 mol % water) to effect an
overall fluoro-Ritter reaction process giving acetamide products
teresting a-ketoester (23a) good yields of the resultant difluorides
were realized. Although in the case of isatin, owing to its poor
solubility in DCM, this was first dissolved in MeCN and mixed with
the DAST stream in the normal fashion. The results contained in
Table 2 again demonstrate that the reaction is tolerant of many
functional groups such as nitro’s, alkenes, acetals, amines, nitriles,
esters, and various heterocycles. In one isolated experiment we also
showed that an acid chloride (24a) could be used as a precursor for
the corresponding acid fluoride. While this reaction proceeded well
giving 24b in 96% isolated yield we were never able to further
transform this to the trifluoride substitution product even using
a 3 equiv excess of the DAST reagent at 100 ꢀC.
(Table 5). A generic set of conditions using a flow rate of 150 mL/min
per channel and a CFC (9 mL) temperature of 120 ꢀC were de-
termined. This generated the acetamide products in good overall
yield and excellent purity. Interestingly, in the case of styrene 39a the
corresponding alcohol was obtained instead of the usual acetamide.
While only a limited number of examples have been investigated
the reaction is interesting in that both fluorine and nitrogen sub-
stituents are installed into the starting material in a single operation.
Additional investigations are currently underway to determine the
substrate scope and to expand the range of nitrile nucleophiles.
Finally, in order to introduce trifluoromethyl groups into organic
precursors we have used the Ruppert reagent in a flow chemistry
process. This was based upon an earlier study from our group17
whereby we showed that the Ruppert reagent reacted with alde-
hydes to give trifluoromethyl addition products in the presence of
an immobilized fluoride source. In this new work we demonstrate
the use of a monolithic polymer18 constructed in a flow tube to
deliver fluoride and effect the addition reaction.
Finally, we have also shown the DAST reagent to be particularly
effective at dehydrating b-hydroxy amides and converting these to
oxazolines. Starting from serinol-derived amides this method is
also suitable to cyclodehydrate and subsequently fluorinate the
substrate in a single operation furnishing fluoromethyl oxazoline
(28b) in high yield (Table 3).
The experiments were conducted using a similar procedure as
previously described using the two-reagent loop set-up. The sub-
strate (0.25 M in DCM) and the DAST reagent (0.25 or 0.5 M) were
In order to prepare the ion-exchange type monolith19 we firstly
prepared a homogeneous mixture of vinyl benzyl chloride (30% v/v),
divinyl benzyl chloride (20% v/v, as cross-linker), AIBN (1% w/w),
and dodecanol (50% v/v) as the porogen (Scheme 3). After heating
this mixture in an appropriately sized glass column (10 mm i.d. bore,
100 mm length) in the R4 unit at 80 ꢀC for 20 h the monolith was
allowed to cure and subsequently washed to elute any unreacted
soluble monomers and the porogen. This yielded a white single-
piece monolith (6.2 g dry weight) with a chloride loading of
4.1 mmol/g.20 Further functionalization by displacement of the
benzylic chloride with trimethylamine and subsequent ion-ex-
change using an aqueous solution of potassium fluoride furnished
the desired fluoride monolith. During our investigations we also
prepared the analogous triethylammonium fluoride monolith,
however, its performance was much less in our trifluoromethylation
reactions and gave significantly higher back-pressures.
combined in a T-piece at a combined flow rate of 300 mL/min then
passed into the CFC (9 mL internal volume) heated at 70–80 ꢀC. The
dual quenching and scavenging process was performed upon the
exiting flow stream, which following solvent evaporation furnished
the cyclized products. Again, in these reactions the yields and pu-
rities of the products following the flow process were excellent and
the embedded stereogenic centers remained unaffected during the
transformation.
A popular alternative reagent to DAST for the fluorination of
organic substrates is SelectfluorÒ.15 This commercially available
electrophilic fluorinating agent is a relatively stable crystalline
solid, procurable at scale. The solid material is stable up to 100 ꢀC16
and can be used in a number of solvents of which MeCN is by far the
most common owing to its ionic nature and solubility of about
50 mg/mL (0.14 M). In order to demonstrate the use of SelectfluorÒ
under flow chemistry conditions in a microreactor format we have
examined two different reactions. The first of these involves
The reactorconfiguration foreffecting the reaction of the Ruppert
reagent with aldehydes involved the usual two-injection loop sys-
tem (2 mL internal volume) and T-piece mixing (Scheme 4). One
sample loop was loaded with the aldehyde dissolved in THF (0.25 M,
1 equiv) and the other with the Ruppert reagent dissolved in the
same solvent (0.3 M,1.2 equiv). The combined reaction mixture was
a
-fluorination of activated carbonyl compounds to the corres-
ponding fluoride (or difluoride in one case). In these examples the
reactor configuration requires two independent injection loops,

M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
6615
Yield (%)
95
Table 3
Cyclodehydration reactions using DAST; isolated yields
Entry
Starting material
Fluorination product
Cl
Cl
H
N
H
N
25
N
N
N
N
HO
HO
N
OH
OH
N
Ph
Ph
Ph
O
O
O
Ph
O
O
O
25b
25a
Cl
Cl
H
N
H
N
26
92
N
N
O
O
26b
26a
O
O
N
Br
Br
O
N
O
N
27
91
HO
NH
O
MeO
MeO
O
27b
27a
F
Cl
F
Cl
F
HO
HO
O
N
28
87
N
O
N
O
N
O
H
28a
28b
4 equiv) in a third glass tube (10 mm i.d. bore, 100 mm length). The
alcohol products were subsequently isolated in good yield and pu-
rity following only evaporation of the solvent (Table 6).
By way of demonstrating the usefulness of the synthesized prod-
ucts from these reactions we also showed that 42b could be oxidized
using MnO2 packed in a flow tube to afford the trifluoroacetyl de-
rivative 51 in 93% isolated yield (Scheme 5). Alternatively, by passage
of 42b through the DAST microreactor arrangement described earlier
we obtained the tetrafluoride derivative (52) in 89% yield. Un-
fortunately, treating 51 with 2 equivof DASTatelevated temperatures
(80 ꢀC) did not furnish the expected pentafluoro compound.
3. Conclusion
In summary, we have demonstrated the safe and convenient ap-
plication of a series of fluorination methods including nucleophilic
fluorination, electrophilic fluorination and trifluoromethylation fa-
cilitated usinga modular flowreactor. Althoughsomeof thereagents
employed are known to be toxic and difficult to work with in batch-
mode the flow set-up proved to be very reliable and easy to use.
Applying in-line scavenging procedures to yield clean products
(purities >95%) without the need of further work-ups were found to
be of great benefit. In addition, the use of back-pressure regulators at
the end of the flow stream allowed us to regularly superheat the
solvent and hence accelerate the reactions.
Scheme 2. Flow schematic for SelectfluorÒ reactions.
flowed through the monolithic fluoride column and then pumped
through two CFCs (2ꢁ10 mL internal volume, 1 mm i.d.) heated on
the R4 unit at 40 ꢀC giving residence times of about 2 h.
The addition products were subsequently purified using various
scavenger resins. Excess Ruppert reagent was trapped using a bed of
PS-benzaldehyde (Argonaut Technologies, 1.2 mmol/g, 3 equiv) in
a glass tube (10 mm i.d. bore, 100 mm length). The intermediate
silylated alcohol products were deprotected in-line using a QP-SA
resin (3 mmol/g, 4 equiv.) in a second glass column (10 mm i.d. bore,
100 mm length) and finally any unreacted aldehyde was removed
using a bed of PS-TsNHNH2 (Argonaut Technologies, 2.84 mmol/g,
4. Experimental section
4.1. General
All solvents were distilled prior to use and stored under argon.
Melting points were determined using an OptiMelt automated
melting point system available from Stanford Research Systems and

6616
M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
Table 4
a
-Fluorination of activated carbonyls using SelectfluorÒ; isolated yields
Entry
Starting material
Fluorination product
Yield (%)
90
Entry
30
Starting material
Fluorination product
O
Yield (%)
89
CN
O
O
O
NC
F
OEt
OEt
29
O
O
F
29b
30a
30b
29a
Cl
Cl
O
O
F
N
H
N
H
O
O
O
O
O
NH
O
NH
31
82
32
82
F
32b
32a
Cl
Cl
31a
31b
O
O
O
O
O
O
F
CF3
CF3
33
93
34
83
F
F
MeO
O
OEt
MeO
O
OEt
33a
33b
34a
34b
Table 5
SelectfluorÒ as fluorination reagent in Ritter reactions; isolated yields
Entry
Starting material
Fluorination product
Yield (%)
Entry
Starting material
Fluorination product
Yield (%)
83
NHAc
NHAc
F
Cl
35
97
36
F
Cl
35a
36a
35b
36b
NHAc
F
F
37
39
86
38
96
91
NHAc
37a
37b
38a
38b
OH
F
NHAc
F
86
40
F
F
40a
39b
40b
39a
are calibrated against Phenacetin (mp 136 ꢀC). 1H NMR spectra
were recorded on a Bruker Avance DPX-400 or DRX-600 spec-
trometer with residual CDCl3 as the internal reference. 13C NMR
Scheme 3. Preparation of the fluoride monolith.
Scheme 4. General flow set-up for the trifluoromethylation reactions.

M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
6617
Table 6
Trifluoromethylation of aldehydes using Ruppert’s reagent; isolated yields
Entry
Starting Material
Fluorination Product
Yield (%)
84
Entry
42
Starting Material
Fluorination Product
Yield (%)
76
O
OH
O
OH
O
O
H
CF3
NO2
H
CF3
41
O
NO2
O
NO2
NO2
42b
42a
41b
41a
H
CF3
HO
O
Me
N
Me
N
H
O
CF3
OH
S
S
43
88
44
79
CF3
N
CF3
N
44a
44b
N
Me
N
Me
43b
43a
OH
CF3
O
H
O
CF3
OH
O
O
H
45
47
86
80
46
48
84
87
N
N
46a
46b
45a
45b
O
H
OH
Cl
F3C
Me
Br OH
CF3
Br
O
Cl
Me
H
N
N
N
N
N
47a
47b
48b
48a
Me
F3C
Me
O
O
O
OH
CF3
N
H
H
49
88
50
83
Me
Me
OH
49b
O
50b
50a
49a
Table 7
LC/MS conditions
Time (min)
MeCN (%)
Flow rate (mL/minꢂ1
)
0.00
3.00
5.00
5.50
8.00
5
95
95
5
1
1
1
1
1
5
carried out using a reversed-phase gradient of MeCN/water with
both solvents containing 0.1% formic acid. The gradient is described
in Table 7. For HRMS an LCT Premier Micromass spectrometer was
used.
4.1.1. General procedure for DAST reactions
Stock solutions of the substrate and DAST both dissolved in dry
DCM (2 mL, 0.5–1 M) were prepared and injected into separate
injection loops of the R2þ unit of the Vapourtec flow system. The
reagent streams were combined in a standard T-piece and directed
into a CFC heated at temperatures ranging between 70 and 90 ꢀC
using the R4 unit of the Vapourtec system. After leaving the CFC, the
reaction mixture was passed into a glass column containing a plug
of CaCO3 (w2 g) and a plug of silica gel (w2 g) in order to quench
and trap any fluoride by-products. The pure product was collected
and isolated after evaporation of the solvent.
Scheme 5. Derivatization of trifluoroethanols in flow.
spectra were also recorded in CDCl3 on the same spectrometers
with the central peak of the residual solvent as the internal refer-
ence using the deuterated solvent as internal deuterium lock. COSY,
DEPT 135, HMQC, and HMBC spectroscopic techniques were used to
aid the assignment of signals in the 13C NMR spectra. IR spectra
were recorded on a Perkin–Elmer SpectrumOne FT-IR spectrometer
neat. Letters in the parentheses refer to relative absorbency of the
peak: w, weak, <40% of the main peak; m, medium, 41–74% of the
main peak; s, strong, >74% of the main peak. LC/MS analysis was
performed on an Agilent HP 1100 chromatograph (Luna Max RP
column) attached to an HPLC/MSD mass spectrometer. Elution was
4.1.2. General procedure for SelectfluorÒ reactions
Using the R2þR4 flow reactor, solutions of the substrate (2 mL,
0.1 M in MeCN) and SelectfluorÒ (2 mL, 0.1 M in MeCN) were

6618
M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
loaded into individual 2 mL sample loops and combined in a T-
mixing piece at flow rates between 0.1 and 0.2 mL/min. This re-
action mixture was then directed through a CFC reactor heated at
120 ꢀC giving residence times between 27 and 60 min. The out
stream then entered an Omnifit glass column containing an excess
of QP-DMA and QP-SA in order to remove the ionic SelectfluorÒ
reagent by-product as well as residual starting material in case of
activated enol compounds. The product was isolated after removal
of the solvent under reduced pressure.
of 27 min. The product was obtained as a colorless oil (97% yield,
99% purity). Yield: 97%, tR¼4.42 min, m/z¼no mass detected; 1H
NMR (600 MHz, CDCl3):
d
/ppm 7.86 (1H, s), 7.57 (1H, d, J¼7.8 Hz),
7.51 (1H, d, J¼7.8 Hz), 5.42 (2H, d, J¼46.8 Hz); 13C NMR (150 MHz,
CDCl3):
d
/ppm 147.9 (C), 136.7 (C, d, J¼18 Hz), 132.2 (CH), 131.2 (CH,
d, J¼6 Hz), 127.0 (C, d, J¼2 Hz), 123.7 (CH, d, J¼8 Hz), 82.2 (CH2, d,
J¼170 Hz); 19F NMR (376 MHz, CDCl3):
/ppm ꢂ213.3 (s). IR (neat):
d
n
3081.8 (w), 2961.2 (w), 1610.1 (w), 1571.7 (w), 1532.7 (s), 1480.9
(m), 1353.2 (s), 1218.5 (m), 1049.9 (m), 1023.7 (m), 892.9 (m), 829.0
(m), 807.2 (m), 753.6 (m), 670.0 (w) cmꢂ1. HRMS calculated for
C7H5NClO2F: 188.9982, found: 188.9987.
4.1.3. General procedure for Ruppert reactions
A solution of aldehyde (0.5 mmol, 1 equiv) in 2 mL of dry THF
was prepared and combined in flow with a stream of Ruppert’s
reagent (0.6 mmol, 1.2 equiv) dissolved in 2 mL of dry THF using
a T-piece. The reaction mixture was flowed through the monolithic
fluoride column at ambient temperature and then pumped through
two 10-mL CFCs heated on an R4 unit at 40 ꢀC (residence time
100 min). After leaving the CFCs, the reaction mixture was purified
using various scavenger resins in-line. Excess Ruppert’s reagent
was trapped using a bed of PS-benzaldehyde (Argonaut Technolo-
gies, 1.2 mmol/g, 3 equiv) in an Omnifit glass tube (10 mm i.d. bore,
100 mm length). Silylated alcohol product was deprotected in-line
using an Amberlyst 15 (1 mmol/g, 4 equiv) in an Omnifit glass
column (10 mm i.d. bore, 100 mm length) and finally the unreacted
aldehyde was removed using a bed of PS-TsNHNH2 (Argonaut
Technologies, 2.84 mmol/g, 4 equiv) in an Omnifit glass tube
(10 mm i.d. bore, 100 mm length). The pure product was collected
and isolated after evaporation of the solvent.
4.5. 2-(4-Fluorobutoxy)-tetrahydro-2H-pyran (4b)
Prepared from 4-(tetrahydro-2H-pyran-2-yloxy)-butan-1-ol
(174 mg, 1 mmol) and DAST (140 m
L, 1 mmol) at 80 ꢀC with a resi-
dence time of 50 min. The product was obtained as a colorless oil
(83% yield, 95% purity). Yield: 83%, tR¼4.64 min, m/z¼no mass
detected; 1H NMR (600 MHz, CDCl3):
d
/ppm 4.56 (1H, t, J¼3.6 Hz),
4.47 (1H, t, J¼6.0 Hz), 4.39 (1H, t, J¼6.0 Hz), 3.85 (1H, td, J¼6.6,
3.1 Hz), 3.70–3.80 (1H, m), 3.45–3.55 (1H, m), 3.33–3.43 (1H, m),
1.45–1.85 (10H, m); 13C NMR (150 MHz, CDCl3):
d/ppm 98.9 (CH),
84.0 (CH2, d, J¼163 Hz), 67.3 (CH2), 62.3 (CH2), 30.2 (CH2, d,
J¼20 Hz), 29.3 (CH2), 25.4 (CH2), 22.0 (CH2, d, J¼7 Hz), 19.6 (CH2);
19F NMR (376 MHz, CDCl3):
d
/ppm ꢂ218.6 (s). IR (neat):
n 2941.4
(m), 2868.9 (m), 1738.9 (w), 1454.7 (w), 1353.1 (w), 1200.8 (w),
1242.1 (w), 1160.5 (w), 1121.9 (s), 1077.7 (s), 1033.4 (s), 991.9 (s),
905.5 (m), 869.9 (m), 814.0 (w), 734.4 (m) cmꢂ1
.
4.2. 6-Chloro-2-(fluoromethyl)imidazo[1,2-a]pyridine (1b)
Prepared from 6-chloroimidazo[1,2-a]pyridine-2-yl-methanol
4.6. (1-Fluoro-2-nitroethyl)benzene (5b)
Prepared from 2-nitro-1-phenyl-ethanol (167 mg, 1 mmol)
and DAST (140 m
L, 1 mmol) at 80 ꢀC with a residence time of
27 min. The product was obtained as yellow oil (65% yield, 95%
purity) after scavenging by passage of the reaction mixture
through a column of QP-BZA (500 mg; 2 mmol). Yield: 65%,
tR¼4.35 min, m/z¼no mass detected; 1H NMR (600 MHz, CDCl3):
(182 mg, 1 mmol) and DAST (140 m
L, 1 mmol) at 70 ꢀC with a resi-
dence time of 27 min. The product was obtained as a white solid
(73% yield, 95% purity). Yield: 73%, tR¼0.60 min, m/z¼185.2
(MþHþ); 1H NMR (600 MHz, CDCl3):
d/ppm 8.17 (1H, s), 7.64 (1H, d,
J¼2.2 Hz), 7.55 (1H, d, J¼9.6 Hz), 7.17 (1H, d, J¼9.6, 2.2 Hz), 5.54 (2H,
d, J¼47.8 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 143.8 (C), 143.0 (C,
d
/ppm 7.35–7.50 (5H, m), 6.18 (1H, app. ddd, J¼45.6, 9.7, 1.9 Hz),
d, J¼20 Hz), 126.6 (CH), 123.7 (CH), 121.0 (C), 118.3 (CH), 111.6 (CH),
4.80–4.90 (1H, m), 4.60 (1H, app. ddd, J¼32.4, 13.8, 2.9 Hz); 13C
78.9 (CH2, d, J¼170 Hz); 19F NMR (376 MHz, CDCl3):
/ppm ꢂ211.5
d
NMR (150 MHz, CDCl3):
d
/ppm 134.1 (C, d, J¼20 Hz), 129.2 (2 CH,
(s); IR (neat):
n 3064.4 (m), 2965.0 (w), 1519.9 (m), 1495.2 (m),
d, J¼6 Hz), 129.1 (C), 125.7 (2ꢁCH, d, J¼6 Hz), 89.9 (CH, d,
1430.7 (m), 1327.1 (s), 1185.7 (m), 1074.2 (s), 1023.8 (s), 1002.1 (s),
950.8 (s), 839.4 (m), 798.7 (s), 707.9 (s) cmꢂ1. HRMS calculated for
C8H7ClFN2: 185.0284, found: 185.0276.
J¼177 Hz), 79.3 (CH2, d, J¼27 Hz); 19F NMR (376 MHz, CDCl3):
d/
ppm ꢂ179.6 (s). IR (neat):
n 2921.5 (m), 2852.6 (m), 1634.4 (m),
1556.8 (s), 1519.1 (s), 1450.0 (m), 1378.7 (m), 1342.6 (s), 1043.8
(m), 765.1 (m), 736.9 (m), 698.3 (m) cmꢂ1
.
4.3. 3-Fluoro-3,7-dimethylocta-1,6-diene (2b)
Prepared from geraniol (154 mg, 1 mmol) and DAST (140
m
L,
4.7. (S)-(2-(Fluoromethyl)pyrrolidin-1-yl)(2-
methoxyphenyl)methanone (6b)
1 mmol) at 70 ꢀC with a residence time of 27 min. The product
was obtained as yellow oil after evaporation of solvent (82% yield,
95% purity). Yield: 82%, tR¼4.64 min, m/z¼no mass detected. 1H
Prepared from (S)-(2-(hydroxymethyl)pyrrolidin-1-yl)(2-meth-
NMR (600 MHz, CDCl3):
d
/ppm 5.88 (1H, td, J¼17.7, 11.0 Hz), 5.26
oxyphenyl)methanone (117 mg, 0.5 mmol) and DAST (70 mL,
(1H, d, J¼17.5 Hz), 5.05–5.15 (2H, m), 1.95–2.20 (2H, m), 1.68 (3H,
0.5 mmol) at 75 ꢀC with a residence time of 27 min. The product was
obtained as colorless oil after evaporation of solvent (88% yield, 95%
purity). Yield: 88%, tR¼4.01 min, m/z¼238.0 (MþHþ); 1H NMR
s), 1.63–1.73 (2H, m), 1.59 (3H, s), 1.40 (3H, d, J¼21.7 Hz); 13C NMR
(150 MHz, CDCl3):
d
/ppm 140.7 (CH, d, J¼23 Hz), 131.8 (C), 123.8
(CH), 113.1 (CH2, d, J¼11 Hz), 95.9 (C, d, J¼170 Hz), 40.3 (CH2, d,
(600 MHz, CDCl3):
d
/ppm 7.33 (1H, t, J¼7.2 Hz), 7.25 (1H, d, J¼7.2 Hz),
J¼23 Hz), 25.6 (CH3), 25.2 (CH3, d, J¼26 Hz), 22.2 (CH2, d, J¼5 Hz),
6.96 (1H, t, J¼7.2 Hz), 6.90 (1H, d, J¼7.2 Hz), 4.77 (1H, ddd, J¼48.6, 7.5,
4.2 Hz), 4.59 (1H, ddd, J¼46.8, 9.3, 2.7 Hz), 4.44 (1H, m), 3.82 (3H, s),
2.00–2.13 (2H, m), 1.94 (1H, m), 1.78 (1H, m); 13C NMR (150 MHz,
17.5 (CH3); 19F NMR (376 MHz, CDCl3):
d
/ppm ꢂ208.1 (s); IR
(neat):
1188.0 (m), 1113.6 (m), 990.2 (s), 926.5 (s), 897.3 (s), 832.3 (m),
735.8 (m) cmꢂ1
n 2970. (s), 2917.3 (s), 1449.6 (s), 1410.9 (m), 1376.2 (s),
CDCl3): d/ppm 168.2 (C), 155.2 (C), 130.4 (CH), 127.7 (CH), 127.2 (C),
.
120.8 (CH), 111.2 (CH), 83.1 (CH2, d, J¼170 Hz), 56.4 (CH, d, J¼21 Hz),
55.6 (CH3), 48.5 (CH2), 27.0 (CH2), 24.4 (CH2); 19F NMR (376 MHz,
4.4. 1-Chloro-4-(fluoromethyl)-2-nitrobenzene (3b)
CDCl3):
d
/ppm ꢂ231.9 (s). IR (neat):
n 2968.2 (w), 2882.3 (w), 1625.6
(s), 1600.5 (s), 1492.2 (m), 1460.6 (s), 1437.3 (s), 1410.1 (s), 1280.6 (m),
Prepared from (4-chloro-3-nitrophenyl)-methanol (187 mg,
1 mmol) and DAST (140 m
L, 1 mmol) at 70 ꢀC with a residence time
1245.5(s),1108.6(m),1046.3(m),1015.0(s), 890.4 (w), 754.1(s) cmꢂ1
HRMS calculated for C13H17NO2F: 238.1243, found: 238.1245.
;

M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
6619
4.8. ((3-Fluoro-2-methylpropoxy)methanetriyl)-
4.12. 4-Fluoromethyl-5-(3-nitrophenyl)-oxazole (12b)
tribenzene (7b)
Prepared from (5-(3-nitrophenyl)oxazol-4-yl)methanol (220 mg,
1 mmol) and DAST (140
L, 1 mmol) at 65 ꢀC with a residence time
Prepared from 2-methyl-3-(trityloxy)propan-1-ol (166 mg,
m
0.5 mmol) and DAST (70
m
L, 0.5 mmol) at 70 ꢀC with a residence
of 27 min. The product was obtained as brown solid (86% yield, 95%
time of 27 min. The product was obtained as colorless oil (93% yield,
purity). Yield: 86%, tR¼4.16 min, m/z¼245.8 (MþNaþ); 1H NMR
95% purity). Yield: 93%, tR: 5.23 min, m/z¼318.0 (MꢂF); 1H NMR
(400 MHz, CDCl3):
d
/ppm 8.55 (1H, s), 8.26 (1H, d, J¼8.0 Hz), 8.03
(600 MHz, CDCl3):
d/ppm 7.46–7.55 (6H, m), 7.32–7.37 (6H, m),
(1H, d, J¼8.0 Hz), 7.98 (1H, s), 7.69 (1H, t, J¼8.0 Hz), 5.51 (2H, d,
7.24–7.29 (3H, m), 4.40–4.60 (2H, m), 3.11–3.16 (2H, d, J¼7.20 Hz),
J¼48.4 Hz); 13C NMR (100 MHz, CDCl3):
d/ppm 150.2 (CH),148.8 (C),
2.12–2.22 (1H, m), 1.01–1.04 (2H, d, J¼7.2 Hz); 13C NMR (150 MHz,
148.4 (C, d, J¼7 Hz),132.1 (C), 131.9 (CH, d, J¼3 Hz),130.3 (CH),128.8
CDCl3): d/ppm 144.2 (C), 128.7 (CH), 127.8 (CH), 127.0 (CH), 86.0
(C, d, J¼3 Hz), 123.9 (CH), 121.2 (CH, d, J¼3 Hz), 76.4 (CH2, d,
(CH2, d, J¼165 Hz), 64.3 (CH2, d, J¼6 Hz), 52.1 (C), 35.2 (CH, d,
J¼164 Hz); 19F NMR (376 MHz, CDCl3):
/ppm ꢂ207.5 (s). IR (neat)
d
J¼18 Hz), 13.3 (CH3, d, J¼6 Hz); 19F NMR (376 MHz, CDCl3):
d
/ppm
n
¼3098.6 (m), 1535.5 (s), 1504.6 (m), 1465.3 (m), 1402.6 (m), 1345.7
ꢂ226.4 (s); IR (neat):
n
3057.7 (m), 2963.7 (m), 1490.2 (m), 1448.8
(s), 1326.5 (m), 1131.2 (m), 1024.1 (m), 972.8 (s), 952.6 (s), 872.9 (m),
(m), 1219.2 (w), 1154.4 (w), 1074.3 (s), 1032.5 (m), 1014.6 (m), 909.6
(m), 763.1 (s), 745.9 (s), 707.1 (s) cmꢂ1. HRMS calculated for
C23H23OFNa: 357.1631, found: 357.1644.
806.2 (m), 768.4 (m), 742.5 (m), 732.9 (s), 683.3 (m), 667.9 (m) cmꢂ1
.
HRMS calculated for C10H7N2O3F: 222.0426, found: 222.0435.
4.13. 6-Chloro-2-(difluoromethyl)imidazo[1,2-a]-
4.9. (2S,3S)-2-(Fluoromethyl)-3-phenyloxirane21 (9b)
pyridine (13b)
Prepared from 6-chloroimidazo[1,2-a]pyridine-2-carbaldehyde
Prepared from ((2S,3S)-3-phenyloxiran-2-yl)methanol (150 mg,
(180 mg, 1 mmol) and DAST (280 m
L, 2 mmol) at 80 ꢀC with a resi-
1 mmol) and DAST (140 m
L, 1 mmol) at 50 ꢀC with a residence time
dence time of 45 min. The product was obtained as a white solid
of 27 min. The product was obtained as colorless oil (86% yield, 96%
purity). Yield: 86%, tR¼3.84 min, m/z¼no mass detected; 1H NMR
(86% yield, 96% purity). Yield: 86%, tR¼3.62 min, m/z¼203.2
(MþHþ); 1H NMR (600 MHz, CDCl3):
d/ppm 8.20 (1H, s), 7.78 (1H,
(600 MHz, CDCl3):
d
/ppm 7.28–7.40 (5H, m), 4.74 (1H, ddd, J¼2.4,
s), 7.59 (1H, d, J¼9.6 Hz), 7.23 (1H, dd, J¼9.6, 2.4 Hz), 6.85 (1H, t,
10.8, 47.4 Hz), 4.51 (1H, ddd, J¼4.8, 10.2, 46.8 Hz), 3.87 (1H, s), 3.30–
J¼55.2 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 143.8 (C), 141.3 (C, t,
3.34 (1H, m); 13C NMR (150 MHz, CDCl3)
d
/ppm 136.0 (C), 128.6
J¼28 Hz), 127.4 (CH), 124.0 (CH), 121.8 (C), 118.7 (CH), 111.4 (CH, t,
(2ꢁCH), 128.5 (CH), 125.7 (2ꢁCH), 82.5 (CH2F, d, J¼171 Hz), 59.7
J¼235 Hz),110.9 (CH), 19F NMR (376 MHz, CDCl3):
/ppm ꢂ114.3 (s);
d
(CH, d, J¼23 Hz), 55.4 (CH, d, J¼8 Hz); 19F NMR (376 MHz, CDCl3)
d/
IR (neat):
n 3089.0 (w), 2989.0 (w), 1562.6 (m), 1520.4 (m), 1504.5
ppm ꢂ228.6 (s); IR (neat) ¼1497.1 (w), 1456.0 (w), 1204.4 (w),
n
(m), 1384.5 (m), 1307.0 (m), 1250.3 (m), 1169.1 (m), 1067.9 (s),
1067.8 (m), 998.0 (m), 881.9 (m), 840.1 (m), 748.2 (m), 696.8
(s) cmꢂ1
1000.6 (s), 981.9 (s), 852.0 (m), 794.5 (s), 765.4 (s), 703.7 (s) cmꢂ1
HRMS calculated for C8H6ClN2F2: 203.0182, found: 203.0178.
;
.
4.10. (1R,2S,4R)-2-Fluoro-1-isopropyl-4-methylcyclo-
hexane (10b)
4.14. 2-Chloro-3-(difluoromethyl)-6-methoxyquinoline (14b)
Prepared from 2-chloro-6-methoxyquinoline-3-carbaldehyde
(110 mg, 0.5 mmol) and DAST (140
L, 1 mmol) at 80 ꢀC with a resi-
Prepared from (1S,2R,5S)-2-2-isopropyl-5-methylcyclo-hex-
m
anol (156 mg, 1 mmol) and DAST (140 m
L, 1 mmol) at 70 ꢀC with
dence time of 45 min. The product was obtained as awhite solid (84%
yield, 99% purity). Yield: 84%, tR¼4.64 min, m/z¼244.3 (MþHþ); 1H
a residence time of 40 min. The product was obtained as col-
orless oil (80% yield, 95% purity). Yield: 80%, tR¼2.60 min,
NMR (600 MHz, CDCl3):
d
/ppm 8.36 (1H, s), 7.94 (1H, d, J¼9.2 Hz),
m/z¼no mass detected; 1H NMR (600 MHz, CDCl3):
d/ppm 4.31
7.46 (1H, dd, J¼9.2, 2.7 Hz), 7.14 (1H, d, J¼2.7 Hz), 7.02 (1H, t,
J¼54.6 Hz), 3.94 (3H, s); 13C NMR (150 MHz, CDCl3):
d/ppm 158.7 (C),
(1H, dtd, J¼49.8, 10.8, 4.8 Hz), 2.00–2.15 (2H, m), 1.60–1.75 (2H,
m), 1.40–1.50 (1H, m), 1.15–1.25 (1H, m), 0.80–1.10 (9H, m), 0.78
144.6 (C, t, J¼5 Hz), 144.4 (C), 135.4 (CH, t, J¼7 Hz), 129.8 (CH), 127.5
(C), 126.0 (C, t, J¼23 Hz), 124.9 (CH), 111.7 (CH, t, J¼239 Hz), 105.6
(3H, d, J¼6.6 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 93.3 (CH,
(CH), 55.7 (CH3); 19F NMR (376 MHz, CDCl3):
d/ppm ꢂ116.1 (s). IR
d, J¼173 Hz), 48.1 (CH, d, J¼78 Hz), 41.5 (CH2, d, J¼18 Hz), 34.1
(CH2, d, J¼20 Hz), 31.2 (CH, d, J¼11 Hz), 26.5 (CH, d, J¼3 Hz),
23.3 (CH2, d, J¼68 Hz), 22.0 (CH3), 20.4 (CH3), 17.0 (CH3); 19F
(neat): n 3065.7 (w), 3020.1 (w), 1620.4 (m), 1594.3 (m), 1574.5 (m),
1498.2 (s), 1450.4 (m), 1420.4 (m), 1384.2 (m), 1338.0 (s), 1233.5 (s),
1203.4 (s), 1191.0 (s), 1167.8 (m), 1094.5 (s), 1060.1 (s), 1048.1 (s),
NMR (376 MHz, CDCl3):
(m), 2923.3 (m), 2869.1 (m), 1455.9 (m), 1370.4 (w), 1191.0 (m),
939 (m), 902.5 (s), 848.9 (s), 743.4 (s) cmꢂ1
d
/ppm ꢂ175.1 (s); IR (neat) ¼2953.3
n
1024.1 (s), 959.0 (m), 926.9 (m), 838.4 (s), 828.3 (s), 743.8 (m) cmꢂ1
HRMS calculated for C11H9NOF2Cl: 244.0341, found: 244.0346.
;
.
4.11. (S,Z)-4-Fluoro-2-iodopent-2-ene (11b)
4.15. (R)-8,8-Difluoro-2,6-dimethyloct-2-ene22 (15b)
Prepared from (R,Z)-4-iodopent-3-en-2-ol (212 mg, 1 mmol)
Prepared from (R)-(þ)-citronellal (154 mg, 1 mmol) and DAST
(280
L, 2 mmol) at 80 ꢀC with a residence time of 45 min. The
and DAST (140
m
L,1 mmol) at 60 ꢀC with a residence time of 27 min.
m
The product was obtained as yellow oil (83% yield, 96% purity).
product was obtained as colorless oil (83% yield, 95% purity). Yield:
Yield: 83%, tR¼4.51 min, m/z¼no mass detected; 1H NMR (600 MHz,
83%, tR¼5.23 min, m/z¼no mass detected; 1H NMR (600 MHz,
CDCl3):
d
/ppm 5.70 (1H, m), 5.12 (1H, dquin, J¼48.0, 6.6 Hz), 2.54
CDCl3):
d
/ppm 5.85 (1H, tt, J¼4.9, 56.9 Hz), 5.08 (1H, t, J¼7.1 Hz),
(3H, d, J¼4.2 Hz), 1.40 (3H, dd, J¼24.0, 6.6 Hz); 13C NMR (150 MHz,
2.00 (2H, m), 1.75–1.90 (1H, m), 1.66 (3H, s), 1.61 (3H, s), 1.50–1.70
CDCl3):
d
/ppm 135.0 (CH, d, J¼24 Hz), 102.6 (C, d, J¼14 Hz), 94.0
(2H, m), 1.35–1.45 (1H, m), 1.20–1.30 (1H, m), 0.97 (3H, d, J¼6.6 Hz);
(CH, d, J¼161 Hz), 33.8 (CH3, d, J¼2 Hz), 20.4 (CH3, d, J¼26 Hz); 19
F
13C NMR (150 MHz, CDCl3):
d/ppm 131.6 (C), 124.1 (CH), 117.1 (CH, t,
NMR (376 MHz, CDCl3):
d/ppm ꢂ168.5 (s). IR (neat)
n
¼2972.3 (m),
J¼237 Hz), 40.9 (CH2, t, J¼20 Hz), 37.0 (CH2), 27.5 (CH, t, J¼5 Hz),
2925.5 (m), 1648.5 (m), 1445.9 (m), 1404.3 (m), 1373.9 (m), 1250.4
(m), 1199.3 (m), 1085.2 (s), 882.8 (m) cmꢂ1
25.6 (CH3), 25.2 (CH2), 19.5 (CH3), 17.5 (CH3); 19F NMR (376 MHz,
.
CDCl3):
d/ppm ꢂ114.76 (s). IR (neat):
n 2960.2 (s), 2923.0 (s), 2856.0

6620
M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
(m), 1452.6 (m), 1401.4 (m), 1377.8 (m), 1120.9 (s), 1037.2 (s), 740.2
(m) cmꢂ1
(2ꢁCH), 112.1 (C, t, J¼29 Hz), 110.8 (CH, t, J¼230 Hz), 13.1 (CH3); 19
F
.
NMR (376 MHz, CDCl3):
d
/ppm ꢂ110.9 (s); IR (neat):
n 2924.3 (w),
1595.3 (w), 1559.9 (m), 1500.7 (m), 1485.5 (m), 1461.8 (m), 1422.9
(m),1380.6 (m),1363.8 (s),1211.8 (m),1077.1 (s),1006.2 (s), 796.8 (s),
4.16. (E)-1-(3,3-Difluoroprop-1-enyl)-4-nitrobenzene (16b)
Prepared from (E)-3-(4-nitrophenyl)acrylaldehyde (177 mg,
1 mmol) and DAST (280 m
L, 2 mmol) at 80 ꢀC with a residence time
757.8 (s), 693.9 (s) cmꢂ1
; HRMS calculated for C11H10N2F2Cl:
243.0501, found: 243.0511. Melting point: 56.5–58.2 ꢀC.
of 45 min. The product was obtained as a yellow solid (96% yield,
4.20. 2-(Difluoromethyl)-1-methyl-1H-indole (20b)
95% purity). Yield: 96%, tR¼4.58 min, m/z¼no mass detected; 1H
NMR (600 MHz, CDCl3):
d
/ppm 8.22 (2H, d, J¼8.7 Hz), 7.59 (2H, d,
Prepared from 1-methyl-1H-indole-2-carbaldehyde (159 mg,
1 mmol) and DAST (280 m
L, 2 mmol) at 80 ꢀC with a residence time
J¼8.7 Hz), 6.96 (1H, dt, J¼16.2, 3.0 Hz), 6.35–6.43 (1H, m), 6.29 (1H,
td, J¼55.5, 5.0 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 148.1 (C),
of 45 min. The product was obtained as an off-white solid (50% yield,
97% purity) after scavenging residual aldehyde starting material
with PS-TsNHNH2 (150 mg). Yield: 50%, tR¼4.56 min, m/z¼no mass
140.6 (C), 134.5 (CH, t, J¼12 Hz), 127.9 (2ꢁCH), 125.2 (CH, t,
J¼24 Hz), 124.1 (2ꢁCH), 114.2 (CH, t, J¼233 Hz); 19F NMR (376 MHz,
detected; 1H NMR (600 MHz, CDCl3):
d
/ppm 7.67 (1H, d, J¼7.8 Hz),
CDCl3):
d
/ppm ꢂ112.0 (s). IR (neat):
n 1678.7 (w), 1665.0 (w), 1596.4
(m), 1514.9 (s), 1419.4 (w), 1383.8 (m), 1339.6 (s), 1297.5 (s), 1133.9
(s), 1110.0 (m), 1057.3 (m), 1007.2 (s), 971.7 (s), 955.9 (s), 865.4 (s),
7.39 (1H, d, J¼7.8 Hz), 7.35 (1H, t, J¼7.8 Hz), 7.17 (1H, t, J¼7.8 Hz),
6.82 (1H, t, J¼53.4 Hz), 6.75 (1H, br s), 3.88 (3H, s); 13C NMR
820.5 (s), 746.3 (s), 709.7 (m), 683.2 (m) cmꢂ1
.
(150 MHz, CDCl3):
d
/ppm 138.7 (C), 131.0 (C, t, J¼22.5 Hz), 126.2 (C),
123.8 (CH), 121.8 (CH), 120.2 (CH), 111.3 (CH, t, J¼232.5 Hz), 109.6
(CH), 104.5 (CH, t, J¼7.5 Hz), 30.8 (CH3, t, J¼2.4 Hz); 19F NMR
4.17. 4-(Difluoromethyl)-2-(pyridine-2-yl)-quinoline (17b)
(376 MHz, CDCl3):
d
/ppm ꢂ109.6 (s). IR (neat):
n 2926.3 (w), 1556.6
Prepared from 2-(pyridin-2-yl)-quinoline-4-carbaldehyde (117 mg,
0.5 mmol) and DAST (140 m
L, 1 mmol) at 80 ꢀC with a residence
(w),1469.8 (m),1401.1 (m),1373.8 (m),1347.6 (m),1241.4 (w),1185.5
(m), 1156.3 (m), 1144.2 (m), 1055.2 (m), 1004.6 (s), 911.2 (m), 850.2
(m), 795.6 (m), 751.1 (m), 737.4 (s), 671.3 (m) cmꢂ1. HRMS calculated
for C10H9NF2: 181.0703, found: 181.0698.
time of 45 min. The product was obtained as an off-white solid (89%
yield, 97% purity). Yield: 89%, tR¼4.69 min, m/z¼257.3 (MþHþ); 1H
NMR (600 MHz, CDCl3):
d
/ppm 8.77 (1H, s), 8.76 (1H, d, J¼4.8 Hz),
8.67 (1H, d, J¼7.8 Hz), 8.26 (1H, d, J¼7.8 Hz), 8.16 (1H, d, J¼7.8 Hz),
7.89 (1H, t, J¼7.8 Hz), 7.80 (1H, t, J¼7.8 Hz), 7.65 (1H, t, J¼7.8 Hz),
7.36–7.41 (1H, m), 7.18 (1H, t, J¼54.0 Hz); 13C NMR (150 MHz,
4.21. 3,3-Difluoroindolin-2-one24 (22b)
Prepared from isatin (147 mg, 1 mmol, in MeCN) and DAST
(280 m
L, 2 mmol) at 80 ꢀC with a residence time of 45 min. The
CDCl3): d/ppm 155.8 (C), 155.4 (C), 149.2 (CH), 148.5 (C), 138.5 (C, t,
J¼21 Hz), 137.0 (CH), 130.7 (CH), 130.0 (CH), 128.0 (CH), 124.4 (CH),
product was obtained as a yellow solid (71% yield, 95% purity) after
scavenging residual aldehyde starting material with PS-TsNHNH2
(100 mg). Yield: 71%, tR¼3.92 min, m/z¼170.2 (MþHþ); 1H NMR
124.0 (C), 123.6 (CH), 121.7 (CH), 116.6 (CH, t, J¼8 Hz), 114.3 (CF2H, t,
J¼240 Hz); 19F NMR (376 MHz, CDCl3):
/ppm ꢂ113.7 (s). IR (neat):
d
n
3067.8 (w), 2921.3 (w), 1612.6 (w), 1590.3 (w), 1556.8 (w), 1510.7
(600 MHz, CDCl3):
d
/ppm 8.46 (br s), 7.54 (1H, d, J¼7.8 Hz), 7.45 (1H,
(w), 1481.2 (w), 1441.7 (w), 1397.9 (m), 1367.1 (w), 1281.9 (m),
1242.6 (m), 1203.1 (m), 1166.6 (w), 1141.5 (w), 1109.0 (s), 1068.0 (m),
1045.0 (m), 1012.3 (s), 994.8 (s), 894.0 (s), 866.2 (s), 795.1 (s), 786.6
(s), 763.3 (s), 741.6 (s), 725.6 (s), 666.3 (m) cmꢂ1; HRMS calculated
for C15H11N2F2: 257.0890, found: 257.0879.
t, J¼7.8 Hz), 7.16 (1H, t, J¼7.8 Hz), 6.96 (1H, d, J¼7.8 Hz); 13C NMR
(150 MHz, CDCl3):
d
/ppm 167.0 (C, t, J¼30 Hz), 141.0 (C, t, J¼7 Hz),
133.7 (CH), 125.1 (CH), 124.0 (CH), 120.3 (C, t, J¼23 Hz), 111.6 (CH),
110.8 (CF2, t, J¼249 Hz); 19F NMR (376 MHz, CDCl3):
/ppm ꢂ112.0
d
(s); IR (neat): n 3175.3 (w), 3121.9 (w),1747.2 (s),1625.9 (s),1475.1 (s),
4.18. 5-(Difluoromethyl)benzo[d][1,3]dioxole23 (18b)
1414.0 (w), 1318.9 (w), 1284.0 (m), 1207.2 (s), 1158.7 (m), 1130.0 (m),
1075.9 (s), 983.9 (m), 950.3 (m), 767.2 (s), 745.0 (m), 726.6 (s) cmꢂ1
.
HRMS calculated for C8H5NOF2Na: 192.0233, found: 192.0231.
Prepared from piperonal (150 mg, 1 mmol) and DAST (280 mL,
2 mmol) at 80 ꢀC with a residence time of 45 min. The product was
obtained as a white solid (75% yield, 95% purity) after scavenging
residual aldehyde starting material with PS-TsNHNH2 (100 mg).
Yield: 75%, tR¼4.35 min, m/z¼no mass detected; 1H NMR
4.22. Methyl-2(2-(6-(2-cyanophenoxy)-pyrimidin-4-yloxy)-
phenyl)-2,2-difluoroacetate (23b)
(600 MHz, CDCl3):
d
/ppm 6.95–6.99 (2H, m), 6.85 (1H, d, J¼7.8 Hz),
Prepared from methyl-2-(2-(6-(2-cyanophenoxy)-pyrimidin-4-
6.54 (1H, t, J¼56.6 Hz), 6.01 (2H, s); 13C NMR (150 MHz, CDCl3):
d
/
yloxy)-phenyl)-2-oxoacetate (125 mg, 0.33 mmol) and DAST (94 mL,
ppm 149.5 (C), 148.0 (C), 128.3 (C, t, J¼23 Hz), 120.1 (CH, t, J¼7 Hz),
114.6 (CH, t, J¼237 Hz),108.2 (CH),105.8 (CH, t, J¼7 Hz),101.5 (CH2);
0.66 mmol) at 80 ꢀC with a residence time of 45 min. The product
was obtained as colorless oil (94% yield, 95% purity). Yield: 94%,
19F NMR (376 MHz, CDCl3):
d
/ppm ꢂ108.2 (s). IR (neat):
n
2902.0
tR¼4.79 min, m/z¼398.3 (MþHþ); 1H NMR (600 MHz, CDCl3):
d/
(w), 1505.9 (m), 1494.5 (m), 1450.2 (s), 1408.6 (m), 1351.3 (m),
1253.7 (s), 1137.9 (m), 1104.8 (m), 1061.9 (m), 1039.6 (s), 932.6 (m),
ppm 8.38 (1H, s), 7.80 (1H, dd, J¼1.2, 7.8 Hz), 7.73 (1H, dd, J¼1.2,
7.8 Hz), 7.69 (1H, td, J¼1.2, 7.8 Hz), 7.60 (1H, t, J¼7.8 Hz), 7.42 (1H, t,
J¼7.8 Hz), 7.39 (1H, t, J¼7.8 Hz), 7.34 (1H, d, J¼7.8 Hz), 7.28 (1H, d,
869.0 (m), 815.8 (m), 792.7 (m) cmꢂ1
.
J¼7.8 Hz), 6.58 (1H, s), 3.79 (3H, s); 13C NMR (150 MHz, CDCl3):
d/
4.19. 5-Chloro-4-(difluoromethyl)-3-methyl-1-phenyl-1H-
pyrazole (19b)
ppm 170.7 (C), 170.2 (C), 163.7 (C, t, J¼19 Hz), 157.8 (CH), 154.0 (C),
149.5 (C, t, J¼5 Hz), 134.3 (CH), 133.6 (CH), 132.3 (CH), 127.0 (CH, t,
J¼8 Hz), 126.2 (CH), 126.1 (CH), 125.8 (C, t, J¼5 Hz), 123.4 (CH), 123.1
(CH), 115.2 (C), 111.8 (CH, t, J¼249 Hz), 107.4 (C), 93.5 (CH), 53.6
Prepared from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-car-
baldehyde (220 mg, 1 mmol) and DAST (280
m
L, 2 mmol) at 80 ꢀC
(CH3); 19F NMR (376 MHz, CDCl3):
d
/ppm ꢂ102.5 (s); IR (neat):
n
with a residence time of 45 min. The product was obtained as a white
2233.7 (w),1775.8 (m),1594.4 (m),1566.6 (s),1486.5 (m),1443.5 (s),
1379.3 (m), 1280.0 (m), 1244.7 (m), 1204.0 (m), 1143.9 (m), 1129.3
(s), 1078.0 (s), 1041.4 (m), 1000.6 (m), 984.4 (m), 844.1 (m), 761.9
(m), 737.0 (m) cmꢂ1; HRMS calculated for C20H14N3O4F2: 398.0952,
found: 398.0956.
solid (87% yield, 97% purity). Yield: 87%, tR¼4.70 min, m/z¼243.3
(MþHþ); 1H NMR (600 MHz, CDCl3):
d/ppm 7.40–7.55 (5H, m), 6.68
(1H, t, J¼54.2 Hz), 2.44 (3H, s); 13C NMR (150 MHz, CDCl3):
d/ppm
148 (C), 137.5 (C), 129.1 (2ꢁCH), 128.7 (CH), 127.2 (C, t, J¼8 Hz), 125.1

M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
6621
4.23. 6-Chloronicotinoyl fluoride (24b)
1208.8 (s),1178.4 (s),1118.1 (s),1090.2 (s),1041.4 (m), 982.5 (s), 962.4
(m), 943.3 (m), 887.1 (m), 796.8 (m), 726.5 (m), 677.1 (m) cmꢂ1
HRMS calculated for C8H8N2O4Br: 274.9667, found: 274.9670.
;
Prepared from 6-chloronicotinoyl chloride (175 mg, 1 mmol)
and DAST (140 m
L,1 mmol) at 70 ꢀC with a residence time of 45 min.
The product was obtained as an off-white solid (96% yield, 97%
4.27. 3-(2-Chloro-6-fluorophenyl)-4-(4-fluoromethyl)-4,5-
dihydrooxazol-2-yl-5-methylisoxazole (28b)
purity). Yield: 96%, tR¼2.01 min, m/z¼159.9 (oxonium species); 1H
NMR (600 MHz, CDCl3):
d
/ppm 8.97 (1H, d, J¼2.0 Hz), 8.23 (1H, dd,
J¼8.4, 2.0 Hz), 7.51 (1H, d, J¼8.4 Hz); 13C NMR (150 MHz, CDCl3):
d/
Prepared from 3-(2-chloro-6-fluorophenyl)-N-(1,3-dihydroxy-
propan-2-yl)-5-methylisoxazole-4-carboxamide (328 mg, 1 mmol)
and DAST (280 m
L, 1 mmol) at 75 ꢀC with a residence time of
ppm 158.1 (C), 155.1 (C, d, J¼342 Hz), 152.5 (CH), 140.8 (CH, d,
J¼3 Hz), 125.0 (CH), 120.3 (C, d, J¼63 Hz); 19F NMR (376 MHz,
CDCl3):
d
/ppm ꢂ149.9 (s); IR (neat):
n
3100.5 (w), 3046.6 (m),1810.2
27 min. The product was obtained as off-white solid (87% yield, 97%
(s), 1586.5 (s), 1560.3 (m), 1454.5 (s), 1377.1 (m), 1293.6 (m), 1243.1
(s), 1147.9 (m), 1110.0 (s), 1040.4 (s), 995.8 (s), 853.8 (m), 796.7 (m),
purity). Yield 87%, tR¼4.49 min, m/z¼312.8 (MþHþ); 1H NMR
(600 MHz, CDCl3):
d
/ppm 7.35–7.40 (1H, m), 7.28 (1H, d, J¼8.4 Hz),
754.5 (s), 708.7 (m), 686.3 (m) cmꢂ1
.
7.08 (1H, t, J¼8.4 Hz), 4.38 (3H, m), 4.20 (2H, dt, J¼8.4, 50.1 Hz), 2.76
(3H, s); 13C NMR (150 MHz, CDCl3):
d
/ppm 173.1 (C), 160.7 (C, d,
4.24. 2,20-(4-Chloropyridine-2,6-diyl)bis(4-phenyl-4,5-
dihydrooxazole)25 (25b)
J¼251 Hz), 158.6 (C), 155.0 (C), 135.3 (C, d, J¼3 Hz), 131.4 (CH, d,
J¼9 Hz), 125.1 (CH, d, J¼3 Hz), 117.6 (C, d, J¼18 Hz), 114.0 (CH, d,
J¼23 Hz), 106.5 (C), 83.6 (CH2, d, J¼171 Hz), 68.7 (CH2, d, J¼5 Hz),
Prepared from 4-chloro-N2,N6-bis(2-hydroxy-1-phenylethyl)-
65.8 (CH, d, J¼21 Hz), 13.1 (CH3); 19F NMR (376 MHz, CDCl3):
d/ppm
pyridine-2,6-dicarboxamide (110 mg, 0.25 mmol) and DAST (70
m
L,
ꢂ110.0 (s), ꢂ230.7 (s); IR (neat):
n 2959.5 (w), 2906.5 (w),1675.8 (s),
0.5 mmol) at 80 ꢀC with a residence time of 45 min. The product
was obtained as colorless oil (95% yield, 95% purity). Yield: 95%,
1615.9 (s), 1574.3 (s), 1457.4 (s), 1251.5 (s), 1103.2 (m), 1069.8 (m),
983.9 (m), 900.3 (s), 787.1 (s), 730.9 (m) cmꢂ1. HRMS calculated for
C14H12N2O2F2Cl: 313.0555, found: 313.0565.
tR¼4.95 min, m/z¼404.3 (MþHþ); 1H NMR (600 MHz, CDCl3):
d/
ppm 8.34 (1H, s), 7.36 (2H, t, J¼7.8 Hz), 7.28–7.35 (3H, m), 5.46 (1H,
dd, J¼9.6, 9.6 Hz), 4.93 (1H, dd, J¼9.0, 9.0 Hz), 4.43 (1H, dd, J¼10.2,
4.28. 2-Fluoro-3-oxo-2-phenylbutanenitrile (29b)
10.2 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 162.6 (C), 148.0 (C),
145.6 (C), 141.3 (C), 128.9 (2ꢁCH), 127.9 (CH), 126.8 (2ꢁCH), 126.4
Prepared from 3-oxo-2-phenylbutanenitrile (159 mg, 1 mmol)
and SelectfluorÒ (390 mg, 1.1 mmol) at 110 ꢀC with a residence time
of 27 min. The product was obtained as colorless oil (90% yield, 95%
purity). Yield: 90%, tR¼4.29 min, m/z¼176.8 (MþHþ); 1H NMR
(CH), 75.7 (CH2), 70.3 (CH); IR (neat): 2930.3 (w),1671.4 (s), 1639.4
n
(s), 1518.1 (s), 1454.2 (m), 1406.4 (m), 1379.9 (s), 1314.4 (m), 1235.1
(m), 1188.6 (m), 1148.0 (m), 1063.1 (m), 977.2 (w), 914.2 (w), 754.5
(m), 700.2 (w) cmꢂ1; HRMS calculated for C23H19N3O2Cl: 404.1166,
found: 404.1169.
(600 MHz, CDCl3):
d/ppm 7.53–7.57 (2H, m), 7.47–7.51 (3H, m), 2.31
(3H, s); 13C NMR (150 MHz, CDCl3):
d
/ppm 195.4 (C, d, J¼29 Hz),
131.0 (CH, d, J¼2 Hz), 130.8 (C, d, J¼24 Hz), 129.5 (2ꢁCH), 124.9
(2ꢁCH, d, J¼6 Hz), 114.2 (C, d, J¼33 Hz), 92.7 (C, d, J¼198 Hz), 23.6
4.25. (4S,40S)-2,20-(4-Chloropyridine-2,6-diyl)bis(4-isopropyl-
4,4-dihydrooxazole)26 (26b)
(CH3); 19F NMR (376 MHz, CDCl3):
d
/ppm ꢂ153.9 (s); IR (neat)
n
¼1741.7 (s), 1676.1 (w), 1494.3 (w), 1452.2 (m), 1419.6 (w), 1359.8
(m), 1216.1 (m), 1195.0 (m), 1123.6 (m), 1099.2 (m), 1070.4 (m),
926.2 (w), 754.5 (s), 737.7 (s), 695.5 (s) cmꢂ1
Prepared from 4-chloro-N2,N6-bis((S)-1-hydroxy-3-methyl-
butan-2-yl)pyridine-2,6-dicarboxamide (371 mg, 1.0 mmol) and
DAST (280 m
L, 2.0 mmol) at 80 ꢀC with a residence time of 45 min.
.
The product was obtained as colorless oil (92% yield, 96% purity).
4.29. Ethyl-2-fluoro-3-oxo-3-phenylpropanoate27 (30b)
Yield: 92%, tR¼4.57 min, m/z¼335.9 (MþHþ); 1H NMR (600 MHz,
CDCl3):
d
/ppm 8.18 (2H, s), 4.53 (2H, t, J¼9.0 Hz), 4.22 (2H, t,
Prepared from ethyl-3-oxo-3-phenylpropanoate (192 mg,
1 mmol) and SelectfluorÒ (390 mg, 1.1 mmol) at 120 ꢀC with a res-
idence time of 27 min. The product was obtained as colorless oil
(89% yield, 95% purity). Yield: 89%, tR¼4.27 min, m/z¼209.1 (M-
J¼8.4 Hz), 4.12–4.17 (2H, m), 1.85 (2H, app. sextet, J¼6.6 Hz), 1.03
(6H, d, J¼6.6 Hz), 0.93 (6H, d, J¼6.6 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 161.4 (C), 148.0 (C), 145.5 (C), 125.8 (C), 72.8 (CH), 71.3 (CH2),
32.8 (CH), 18.9 (CH3), 18.3 (CH3). IR (neat):
n
2960.0 (m), 2915.5 (m),
Hþ); 1H NMR (600 MHz, CDCl3)
d
/ppm 8.02 (2H, d, J¼8.4 Hz), 7.62
1642.2 (s), 1562.4 (s), 1467.6 (m), 1381.5 (s), 1366.2 (m), 1270.2 (m),
1236.9 (s), 1150.8 (m), 975.2 (s), 937.4 (s), 910.8 (m), 886.5 (m),
787.5 (s), 730.7 (s) cmꢂ1; HRMS calculated for C17H23N3O2Cl:
336.1479, found: 336.1494.
(1H, t, J¼8.4 Hz), 7.48 (2H, t, J¼8.4 Hz), 5.87 (1H, d, J¼48.6 Hz), 4.28
(2H, qd, J¼2.4, 7.2 Hz), 1.23 (3H, t, J¼7.2 Hz); 13C NMR (150 MHz,
CDCl3)
d
/ppm 189.5 (C, d, J¼20 Hz), 164.9 (C, d, J¼24 Hz),134.5 (CH),
133.4 (C, d, J¼2 Hz), 129.5 (2ꢁCH, d, J¼2 Hz), 128.8 (2ꢁCH), 89.9
(CHF, d, J¼197 Hz), 62.6 (CH2), 13.9 (CH3); 19F NMR (376 MHz,
4.26. 4-Methyl-2-(2-bromooxazol-4-yl)-4,5-dihydrooxazole-
4-carboxylate (27b)
CDCl3):
d
/ppm ꢂ190.5 (s); IR (neat) ¼2985.6 (w), 1758.5 (s), 1693.2
n
(s), 1597.7 (m), 1449.7 (m), 1372.27 (m), 1242.5 (s), 1202.0 (s), 1096.1
(s), 1015.0 (s), 976.4 (m), 943.0 (w), 925.3 (w), 882.8 (m), 854.1 (w),
A
solution of methyl-2-(2-bromooxazole-4-carboxamido)-3-
hydroxypropanoate (292 mg, 1 mmol) in 2 mL DCM was prepared
and combined with a stream of DAST (140 L,1.0 mmol) dissolved in
771.4 (w), 746.6 (w), 688.1 (s) cmꢂ1
C11H12O3F: 211.0770, found: 211.0779.
; HRMS calculated for
m
2 mL DCM using a T-piece. This solution was pumped through the
CFC at 80 ꢀC with a residence time of 27 min. The product was
obtained as off-white solid after removal of solvents. Yield: 91%,
4.30. N1-N3-Bis(4-chlorophenyl)-2-fluoromalonamide (31b)
Prepared from N1,N3-bis(4-chlorophenyl)malonamide (161 mg,
0.5 mmol) and SelectfluorÒ (195 mg, 0.55 mmol) at 120 ꢀC with
a residence time of 45 min. The product was obtained as off-white
solid (82% yield, 96% purity). Yield: 82%, tR¼4.68 min, m/z¼340.8
tR¼2.33 min, m/z¼275.7 (MþHþ); 1H NMR (600 MHz, CDCl3):
d/ppm
8.08 (1H, s), 4.80–4.89 (1H, m), 4.60–4.66 (1H, m), 4.50–4.54 (1H, m),
3.72 (3H, s); 13C NMR (150 MHz, CDCl3):
148.3 (C), 143.0 (CH), 131.7 (C), 69.8 (CH2), 68.3 (CH), 52.7 (CH3); IR
(neat): 3144.9 (w), 2955.4 (w), 1738.5 (s), 1678.1 (m), 1585.0 (m),
1556.8 (m), 1523.5 (s), 1437.4 (m),1364.5 (m), 1317.8 (m), 1278.3 (m),
d/ppm 170.8 (C), 158.7 (C),
(MþHþ); 1H NMR (600 MHz, CDCl3):
/ppm 8.86 (2H, 2ꢁNH), 7.52
d
n
(4H, d, J¼9.0 Hz), 7.30 (4H, d, J¼9.0 Hz), 5.50 (1H, CHF, d,
J¼48.0 Hz); 13C NMR (150 MHz, CDCl3):
/ppm 162.4 (C, d, J¼21 Hz),
d

6622
M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
134.7 (C), 130.7 (C), 129.2 (2ꢁCH), 121.6 (2ꢁCH), 86.3 (CHF, d,
7.26–7.35 (5H, m), 6.11 (1H, s), 5.10 (1H, ddd, J¼2.4, 9.0, 26.4 Hz),
4.90–5.05 (1H, m), 2.08 (3H, s), 1.40 (3H, dd, J¼6.6, 24.0 Hz); 13C
J¼200 Hz); 19F NMR (376 MHz, CDCl3):
/ppm ꢂ195.6 (s); IR (neat)
d
n
¼3283.4 (m), 3075.9 (w), 1714.8 (s), 1599.5 (s), 1532.3 (s), 1490.5
NMR (150 MHz, CDCl3):
d/ppm 169.7 (C), 139.4 (C), 128.7 (2ꢁCH),
(s), 1402.4 (s), 1309.9 (m), 1245.4 (m), 1113.8 (m), 1091.8 (s), 1014.0
127.8 (CH), 127.0 (2ꢁCH), 92.2 (CH, d, J¼173 Hz), 56.4 (CH, d,
(m), 823.8 (s), 752.8 (m) cmꢂ1
;
HRMS calculated for
J¼18 Hz), 23.3 (CH3, s), 18.5 (CH3, d, J¼23 Hz); 19F NMR (376 MHz,
C15H12N2O2FCl2: 341.0260, found: 341.0272.
CDCl3):
d
/ppm ꢂ186.2 (s). Minor diastereoisomer: 1H NMR
(600 MHz, CDCl3): d/ppm 7.30–7.38 (5H, m), 6.21 (1H, s), 4.90–5.08
4.31. 2-Acetyl-2-fluorocyclopentanone (32b)
(2H, m), 2.02 (3H, s), 1.17 (3H, dd, J¼6.0, 24.0 Hz). 13C NMR
(150 MHz, CDCl3):
d/ppm 169.1 (C), 136.6 (C), 128.6 (2ꢁCH), 128.4
Prepared from 2-acetylcyclopentane (126 mg, 1 mmol) and
SelectfluorÒ (390 mg, 1.1 mmol) at 100 ꢀC with a residence time of
45 min. The product was obtained as colorless oil (82% yield, 95%
purity). Yield: 82%, tR¼3.12 min, m/z¼no mass detected; 1H NMR
(2ꢁCH, d, J¼2 Hz), 128.1 (CH), 91.9 (CH, d, J¼173 Hz), 57.1 (CH, d,
J¼18 Hz), 23.4 (CH3), 17.8 (CH3, d, J¼21 Hz); 19F NMR (376 MHz,
CDCl3):
d/ppm ꢂ189.1 (s); IR (neat): ¼3316.0 (m), 2991.8 (w),
n
2935.9 (w), 1649.4 (s), 1538.5 (s), 1448.8 (m), 1371.7 (s), 1296.3 (m),
1274.1 (m), 1203.7 (m), 1066.2 (s), 1029.5 (m), 931.1 (m), 848.2 (m),
(600 MHz, CDCl3):
d
/ppm 2.45–2.55 (1H, m), 2.40 (2H, t, J¼7.8 Hz),
2.32 (3H, app. d, J¼5.4 Hz), 2.05–2.19 (3H, m); 13C NMR (150 MHz,
746.5 (s), 699.0 (s), 675.6 (s) cmꢂ1
C11H15NOF: 196.1138, found: 196.1136.
; HRMS: calculated for
CDCl3)
d
/ppm 209.0 (C, d, J¼16 Hz), 205.8 (C, d, J¼31 Hz),100.8 (C, d,
J¼199 Hz), 35.7 (CH2), 32.7 (CH2, d, J¼20 Hz), 26.5 (CH3), 17.6 (CH2,
d, J¼4 Hz); 19F NMR (376 MHz, CDCl3)
d/ppm ꢂ160.9 (s); IR (neat)
4.35. N-(1-(4-(Chloromethyl)phenyl)-2-fluoroethyl)-
acetamide (36b)
n
¼2972.0 (w), 1759.2 (s), 1714.7 (s), 1420.0 (w), 1403.3 (w), 1358.9
(m), 1259.9 (w), 1166.5 (m), 1122.7 (m), 1032.4 (m), 983.9 (m), 914.3
(m), 815.0 (w) cmꢂ1
.
Prepared from 4-vinylbenzylchloride (152 mg, 1 mmol) and
SelectfluorÒ (390 mg, 1.1 mmol) in the presence of acetic acid
(50 m
L) at 120 ꢀC with a residence time of 27 min. The product was
4.32. Ethyl-2-fluoro-3-(4-methoxyphenyl)-3-oxo-
propanoate (33b)
obtained as a white solid, yield: 83%, tR¼3.82 min, m/z¼229.8
(MþHþ); Melting point: 94.5–98.4 ꢀC; 1H NMR (600 MHz, CDCl3):
Prepared from ethyl-3-(4-methoxyphenyl)-3-oxopropanoate
(222 mg, 1 mmol) and SelectfluorÒ (390 mg, 1.1 mmol) at 120 ꢀC
with a residence time of 27 min. The product was obtained as col-
orless oil (93% yield, 98% purity). Yield: 93%, tR¼4.30 min, m/z
d
/ppm 7.38 (2H, d, J¼8.4 Hz), 7.33 (2H, d, J¼8.4 Hz), 6.27 (1H, d,
J¼6.6 Hz), 5.25 (1H, app. ddt, J¼4.2, 7.8, 25.8 Hz), 4.65 (app. dddd,
J¼3.6, 9.6, 20.4, 47.4 Hz), 4.57 (2H, s), 2.04 (3H, s); 13C NMR
(150 MHz, CDCl3):
d
/ppm 169.7 (C), 138.2 (C, d, J¼3 Hz), 137.3 (C),
¼240.9 (MþHþ); 1H NMR (600 MHz, CDCl3):
d
/ppm 8.00 (2H, d,
129.0 (2ꢁCH), 127.4 (2ꢁCH), 84.6 (CHF, d, J¼171 Hz), 52.8 (CH, d,
J¼8.4 Hz), 6.93 (2H, d, J¼8.4 Hz), 5.82 (1H, d, J¼48.6 Hz), 4.20–4.30
J¼18 Hz), 45.7 (CH2), 23.2 (CH3); 19F NMR (376 MHz, CDCl3):
d/ppm
(2H, m), 3.85 (3H, s),1.22 (3H, t, J¼7.2 Hz).13C NMR (150 MHz, CDCl3)
ꢂ227.7 (s); IR (neat): ¼3290.9 (m), 1640.6 (s), 1542.8 (s), 1515.8 (s),
n
d
/ppm 187.8 (C, d, J¼2 Hz), 165.2 (C, d, J¼2 Hz), 164.6 (C), 132.0
1442.4 (m), 1371.5 (m), 1295.7 (m), 1267.3 (m), 1108.6 (w), 1049.2
(w), 1019.1 (m), 899.9 (w), 833.3 (w), 794.2 (w), 737.6 (w), 679.7
(m); HRMS: calculated for C11H14NOFCl: 230.0748, found:
230.0752.
(2ꢁCH), 126.3 (C), 114.1 (2ꢁCH), 89.9 (CHF, d, J¼197 Hz), 62.5 (CH2),
55.5 (CH3), 13.9 (CH3); 19F NMR (376 MHz, CDCl3)
/ppm ꢂ189.9 (s);
IR (neat)
1512.9 (m), 1466.8 (m), 1424.0 (m), 1251.8 (s), 1172.7 (s), 1092.0 (s),
1024.9 (s), 941.6 (m), 887.0 (m), 842.0 (s), 798.0 (m) cmꢂ1; HRMS
calculated for C10H14O4F: 241.0876, found: 241.0873.
d
n
¼2985.7 (w), 1758.4 (s), 1682.4 (s), 1598.6 (s), 1574.5 (m),
4.36. N-(2-Fluoro-2,3-dihydro-1H-inden-1-yl)acetamide (37b)
Prepared from 1H-indene (116 mg, 1 mmol) and SelectfluorÒ
(390 mg, 1.1 mmol) in the presence of acetic acid (50 m
L) at 120 ꢀC
4.33. 2,2,4,4,4-Pentafluoro-1-(naphthalen-2-yl)butane-1,3-
dione (34b)
with a residence time of 27 min. The product was isolated as
a white solid, yield: 86%, tR¼3.54 min, m/z¼193.8 (MþHþ). Major
Prepared from 4,4,4-trifluoro-1-(naphthylen-2-yl)butane-1,3-
dione (266 mg, 1 mmol) and SelectfluorÒ (780 mg, 2.2 mmol) at
110 ꢀC with a residence time of 45 min. The product was obtained as
off-white solid (83% yield, 98% purity). Yield: 83%, tR¼4.48 min, m/z
diastereoisomer: 1H NMR (600 MHz, CDCl3):
d/ppm 7.20–7.35 (4H,
m), 6.01 (1H, s), 5.62 (1H, ddd, J¼4.1, 9.2, 26.1 Hz), 5.35 (1H, app. dt,
J¼3.7, 54.0 Hz), 3.05–3.39 (2H, m), 2.13 (3H, s); 13C NMR (150 MHz,
CDCl3): d/ppm 170.4 (C), 139.9 (C), 138.8 (C), 128.3 (CH), 127.4 (CH),
¼no mass detected; 1H NMR (600 MHz, CDCl3):
d
/ppm 8.71 (1H, s),
125.2 (CH), 123.8 (CH), 94.9 (CHF, d, J¼180 Hz), 56.8 (CH, d,
8.02 (1H, d, J¼7.8 Hz), 7.97 (1H, d, J¼8.4 Hz), 7.89 (1H, d, J¼9.0 Hz),
J¼17 Hz), 37.4 (CH2, d, J¼23 Hz), 23.2 (CH3); 19F NMR (376 MHz,
7.87 (1H, d, J¼8.4 Hz), 7.67 (1H, t, J¼7.2 Hz), 7.58 (1H, t, J¼7.2 Hz); 13C
CDCl3):
d
/ppm ꢂ195.8 (s). Minor diastereoisomer: 1H NMR
NMR (150 MHz, CDCl3)
(CH, m),132.1 (C),130.4 (CH),130.1 (CH),128.7 (CH),127.8 (CH),127.3
d
/ppm 191.2 (C, t, J¼29 Hz), 136.4 (C), 134.1
(600 MHz, CDCl3): d/ppm 7.28–7.33 (4H, m), 5.45–5.55 (2H, m),
5.319 (1H, app. dt, J¼3.0, 45.0 Hz), 3.35 (1H, app. dt, J¼6.0, 21.6 Hz),
(CH), 124.5 (C), 121.1 (C, q, J¼308 Hz), 111.9 (C, t, J¼267 Hz), 93.0 (C,
3.14 (1H, app. dt, J¼6.0, 21.6 Hz), 2.08 (3H, s); 13C NMR (150 MHz,
qt, J¼6, 33 Hz); 19F NMR (376 MHz, CDCl3)
d
/ppm ꢂ81.1 (CF2, t,
CDCl3): d/ppm 169.8 (C), 139.6 (C), 139.2 (C), 129.1 (CH), 127.7 (CH),
J¼11.3 Hz), ꢂ111.6 (CF3, q, J¼11.3 Hz); IR (neat)
n
¼1671.4 (s), 1625.9
125.3 (CH), 124.8 (CH), 98.1 (CH, d, J¼195 Hz), 60.3 (CH2), 37.2 (CH),
(m), 1598.0 (m), 1468.4 (m), 1404.0 (m), 1366.6 (m), 1261.2 (m),
1196.5 (s), 1168.3 (s), 1108.2 (s), 1066.2 (s), 974.1 (m), 935.0 (m),
23.9 (CH3); 19F NMR (376 MHz, CDCl3):
d
/ppm ꢂ180.0 (s); IR (neat):
n¼3275.2 (s), 1654.2 (s), 1555.0 (s), 1371.6 (m), 1293.5 (m), 1034.4
823.6 (m), 798.9 (s), 755.1 (m), 740.0 (m), 721.2 (m) cmꢂ1
.
(m), 811.4 (m), 738.6 (s); HRMS: calculated for C11H12NOFNa:
216.0801, found: 216.0802.
4.34. N-(2-Fluoro-1-phenylpropyl)acetamide (35b)
4.37. N-(2-Fluoro-1-phenylcyclohexyl)acetamide (38b)
Prepared from (E)-prop-1-enylbenzene (118 mg, 1 mmol) and
SelectfluorÒ (390 mg, 1.1 mmol) in the presence of acetic acid
Prepared from cyclohexenylbenzene (158 mg, 1 mmol) and
SelectfluorÒ (390 mg, 1.1 mmol) in the presence of acetic acid
(50
obtained as colorless oil. Yield: 96%, tR¼4.10 min, m/z¼236.1
(50 m
L) at 120 ꢀC with a residence time of 27 min. The product was
obtained as colorless oil. Yield: 97%, tR¼3.87 min, m/z¼175.8
m
L) at 120 ꢀC with a residence time of 27 min. The product was
(MꢂHF). Major diastereoisomer: 1H NMR (600 MHz, CDCl3):
d/ppm

M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
6623
(MþHþ). Major diastereoisomer: 1H NMR (600 MHz, CDCl3):
d
/ppm
4.40. 2,2,2-Trifluoro-1-(2-nitrophenyl)ethanol (41b)
7.40 (2H, d, J¼7.8 Hz), 7.35 (2H, t, J¼7.8 Hz), 7.26 (1H, t, J¼7.8 Hz),
5.85 (1H, s), 4.70 (1H, ddd, J¼4.5, 10.8, 46.2 Hz), 3.14 (1H, m), 2.10
(3H, s), 2.00–2.08 (1H, m), 1.77–1.89 (3H, m), 1.56–1.62 (1H, m),
Prepared from 2-nitrobenzaldehyde (151 mg, 1 mmol) and
trimethyl(trifluoromethyl)silane (156 mg, 1.1 mmol) at 40 ꢀC with
a residence time of 100 min. The product was obtained as yellow
oil. Yield: 84%, tR¼4.20 min, m/z¼222.1 (MþH); 1H NMR
1.40–1.50 (2H, m); 13C NMR (150 MHz, CDCl3):
d/ppm 169.7 (C),
142.3 (C), 128.3 (2ꢁCH), 127.2 (CH), 126.0 (2ꢁCH), 96.3 (CH, d,
J¼181.5 Hz), 62.2 (C, d, J¼15 Hz), 32.2 (CH2, d, J¼3 Hz), 28.2 (CH2, d,
J¼20 Hz), 24.5 (CH3), 23.3 (CH2, d, J¼11 Hz), 21.0 (CH2); 19F NMR
(400 MHz, CDCl3):
d
/ppm 8.03 (1H, dd, J¼0.8, 8.2 Hz), 7.97 (1H, d,
J¼7.9 Hz), 7.74 (1H, m), 7.59 (1H, m), 6.18 (1H, q, J¼6.0 Hz), 2.94
(1H, m); 13C NMR (100 MHz, CDCl3):
/ppm 148.6 (C), 133.6 (CH),
130.3 (CH), 129.5 (CH), 128.9 (C), 125.0 (CH), 123.9 (C, q,
(376 MHz, CDCl3):
NMR (600 MHz, CDCl3):
d
/ppm ꢂ185.8 (s). Minor diastereoisomer: 1H
d
d
/ppm 7.75 (2H, d, J¼7.8 Hz), 7.34 (2H, t,
J¼7.8 Hz), 7.26 (1H, t, J¼7.8 Hz), 5.63 (1H, dd, J¼4.8, 47.4 Hz), 5.53
J¼281 Hz), 66.9 (CH, q, J¼32 Hz); IR (neat) ¼3482 (br), 2932 (w),
n
(1H, s), 2.37–2.42 (1H, m), 2.17–2.22 (1H, m), 1.96 (3H, s), 1.80–1.93
1701 (w), 1526 (s), 1348 (s), 1259 (m), 1173 (s), 1125 (s), 1100 (m),
1061 (m), 787 (m), 711(s) cmꢂ1; Microanalysis: C: 44.15, H: 2.96,
N: 6.08%.
(1H, m), 1.50–1.74 (5H, m); 13C NMR (150 MHz, CDCl3):
d/ppm 169.3
(C),142.8 (C),128.3 (2ꢁCH),127.3 (CH),126.7 (2ꢁCH, d, J¼4 Hz), 91.1
(CH, d, J¼175 Hz), 60.3 (C, d, J¼22 Hz), 31.5 (CH2, d, J¼2 Hz), 27.5
(CH2, d, J¼20 Hz), 24.4 (CH3), 21.3 (CH2), 20.0 (CH2, d, J¼4 Hz); 19F
4.41. 2,2,2-Trifluoro-1-(5-nitrobenzo[d][1,3]dioxol-6-
yl)ethanol (42b)
NMR (376 MHz, CDCl3):
d
/ppm ꢂ189.5 (s); IR (neat): ¼3308.5 (w),
n
2939.6 (m), 1655.2 (s), 1535.4 (m), 1446.0 (m), 1370.3 (m), 1293.9
(m), 1041.9 (m), 1028.7 (m), 909.3 (s), 728.7 (s), 696.4 (s) cmꢂ1
HRMS: calculated for C14H19NOF: 236.1451, found: 236.1461.
;
Prepared from 6-nitrobenzo[b][1,3]dioxole-5-carbaldehyde
(195 mg, 1 mmol) and trimethyl(trifluoromethyl)silane (156 mg,
1.1 mmol) at 40 ꢀC with a residence time of 100 min. The product
was obtained as yellow oil. Yield: 76%, tR¼4.27 min, m/z¼no mass
4.38. 1-Fluoro-1-(4-fluorophenyl)ethanol (39b)
detected; 1H NMR (400 MHz, CDCl3):
d/ppm 7.52 (1H, s), 7.33 (1H,
Prepared from (1-fluoro-4-prop-1-en-2-yl)benzene (136 mg,
1 mmol) and SelectfluorÒ (390 mg, 1.1 mmol) in the presence of
acetic acid (50 m
L) at 120 ꢀC with a residence time of 27 min. The
s), 6.10–6.25 (3H, m), 3.27 (1H, s); 13C NMR (100 MHz, CDCl3):
d/
ppm 152.3 (C), 148.6 (C), 143.0 (C), 126.0 (C), 123.9 (C, q, J¼281 Hz,
CF3), 108.2 (CH), 105.8 (CH), 103.4 (CH2), 66.8 (CH, q, J¼32 Hz); IR
product was obtained as colorless oil. Yield: 86%, tR¼3.79 min,
m/z¼154.9 (MꢂH2O). 1H NMR (600 MHz, CDCl3):
d
/ppm 7.42–7.50
(neat)
n
¼3511 (br), 3134 (w), 2923 (w), 1618 (m), 1524 (s), 1507 (s),
1486 (s), 1332 (s), 1257 (s), 1169 (s), 1119 (s), 1076 (m), 1033
(s) cmꢂ1; Microanalysis: C: 40.65, H: 2.47, N: 5.27%.
(2H, m), 7.05 (2H, t, J¼9.0 Hz), 4.41 (2H, ddd, J¼9.6, 33.6, 48.0 Hz),
1.58 (3H, d, J¼2.4 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 162.1 (C,
d, J¼245 Hz), 138.9 (C, t, J¼4 Hz), 127.1 (2ꢁCH, d, J¼9 Hz), 115.1
(2ꢁCH, d, J¼21 Hz), 89.5 (CH2, d, J¼177 Hz), 73.5 (C, d, J¼18 Hz),
4.42. 2,2,2-Trifluoro-1-(5-(4-(trifluoromethyl)-1-methyl-1H-
pyrazol-3-yl)thiophen-2-yl)ethanol (43b)
25.3 (CH3, d, J¼3 Hz); 19F NMR (376 MHz, CDCl3):
/ppm ꢂ115.5 (s),
d
ꢂ222.8 (s); IR (neat): ¼3426.0 (OH), 2985.6 (w), 1664.2 (w), 1603.4
n
(m), 1509.1 (s), 1461.1 (w), 1373.6 (w), 1225.1 (s), 1161.7 (m), 1012.8
(s), 873.2 (m), 834.8 (s), 815.3 (m), 725.4 (m) cmꢂ1; HRMS: calcu-
lated for C9H8F2: 154.0594, found: 154.0589 (dehydrated species).
Prepared from 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-
3-yl)thiophene-2-carbaldehyde (260 mg, 1 mmol) and trime-
thyl(trifluoromethyl)silane (156 mg, 1.1 mmol) at 40 ꢀC with
a residence time of 100 min. The product was obtained as
yellow solid. Yield: 89%, tR¼4.65 min, m/z¼331.1 (MþHþ).
4.39. N-(2-Fluoro-1,2,3,4-tetrahydronaphthalen-1-
yl)acetamide (40b)
Melting point: 100.6–103.1 ꢀC. 1H NMR (400 MHz, CDCl3):
d/
ppm 7.20 (1H, d, J¼3.7 Hz), 7.11 (1H, d, J¼3.7 Hz), 6.78 (1H, s),
5.24 (1H, q, J¼6.4 Hz), 4.00 (3H, s), 3.43 (1H, s); 13C NMR
Prepared from 1,2-dihydronaphthalene (130 mg, 1 mmol) and
SelectfluorÒ (390 mg, 1.1 mmol) in the presence of acetic acid
(100 MHz, CDCl3):
d/ppm 145.2 (C), 136.4 (C), 136.2 (C), 133.5
(50 m
L) at 120 ꢀC with a residence time of 27 min. The product was
(C, q, J¼39 Hz), 127.8 (CH), 124.1 (CH), 123.1 (C, q, J¼281 Hz,
obtained as colorless oil. Yield: 91%, tR¼3.77 min, m/z¼208.0
CF3), 119.7 (C, q, J¼281 Hz), 104.6 (CH), 69.3 (CH, q, J¼34 Hz),
(MþHþ). Major diastereoisomer: 1H NMR (600 MHz, CDCl3):
d/ppm
38.1 (CH3); 19F NMR (376 MHz, CDCl3)
d
/ppm ꢂ60.9 (s), ꢂ78.8
7.25–7.27 (1H, m), 7.19–7.21 (2H, m), 7.11–7.13 (1H, m), 6.03 (1H, d,
J¼7.2 Hz), 5.37 (1H, dd, J¼9.0, 31.2 Hz), 5.07 (1H, app. ddt, J¼3.3,
50.4 Hz), 3.08 (1H, ddd, J¼6.0, 12.0, 22.8 Hz), 2.76 (1H, dd, J¼6.0,
16.2 Hz), 2.31–2.38 (1H, m), 2.14 (3H, s), 2.01 (1H, dddd, J¼6.0, 12.6,
(s); IR (neat)
n
¼3253 (br), 2968 (w), 1543 (m), 1499 (m), 1427
(m), 1266 (s), 1256 (s), 1150 (m), 1114 (s), 1085 (s), 1038 (s), 926
(m), 808 (s), 695 (s) cmꢂ1; HRMS calculated for C11H9N2OF6S:
331.0340, found: 331.0336.
26.4, 42.6 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 170.2 (C), 136.0
(C), 133.6 (C), 128.5 (CH), 127.5 (CH), 127.4 (CH), 126.6 (CH), 89.3
(CH, d, J¼171 Hz), 49.8 (CH, d, J¼18 Hz), 26.6 (CH2, d, J¼21 Hz), 23.6
4.43. 2,2,2-Trifluoro-1-(1-methyl-1H-indol-2-yl)ethanol (44b)
(CH2, d, J¼6 Hz), 23.4 (CH3); 19F NMR (376 MHz, CDCl3):
d/ppm
ꢂ202.1 (s). Minor diastereoisomer: 1H NMR (600 MHz, CDCl3):
d
/
Prepared from 1-methyl-1H-indole-2-carbaldehyde (159 mg,
1 mmol) and trimethyl(trifluoromethyl)silane (156 mg, 1.1 mmol) at
40 ꢀC with a residence time of 100 min. The product was obtained as
orange oil. Yield¼79%, tR¼4.47 min, m/z¼230.1 (MþHþ); 1H NMR
ppm 7.26–7.28 (1H, m), 7.20–7.23 (2H, m), 7.11–7.14 (1H, m), 5.55
(1H, d, J¼4.8 Hz), 5.22–5.30 (1H, m), 4.87 (1H, app. ddt, J¼2.4, 7.8,
48.0 Hz), 2.96–3.04 (1H, m), 2.83 (1H, ddd, J¼6.0, 12.0, 16.8 Hz),
2.15–2.24 (1H, m), 2.06 (3H, s); 13C NMR (150 MHz, CDCl3):
d/ppm
(400 MHz, CDCl3):
d
/ppm 7.64 (1H, d, J¼7.7 Hz), 7.26–7.40 (2H), 7.16
169.6 (C), 135.9 (C), 129.1 (CH). 128.7 (CH), 127.8 (CH), 127.0 (CH),
(1H, m), 6.70 (1H, s), 5.23 (1H, q, J¼6.5 Hz), 3.77 (3H, s), 2.98 (1H, br
s); 13C NMR (100 MHz, CDCl3):
/ppm 138.1 (C), 132.1 (C), 126.9 (C),
124.2 (C, q, J¼281 Hz, CF3), 122.9 (CH), 121.4 (CH), 120.2 (CH), 109.5
90.1 (CH, d, J¼180 Hz), 51.4 (CH, d, J¼27 Hz), 25.6 (CH2, d, J¼20 Hz),
d
25.0 (CH2, d, J¼8 Hz), 23.4 (CH3); 19F NMR (376 MHz, CDCl3):
d/ppm
ꢂ185.1 (s); IR (neat):
n
¼3243.0 (m), 3053.7 (m), 1635.9 (s), 1551.8
(CH), 102.4 (CH), 67.0 (CH, q, J¼34 Hz), 30.4 (CH3); IR (neat) ¼3301
n
(s), 1492.3 (m), 1435.9 (m), 1373.1 (s), 1294.4 (m), 1061.9 (m), 1014.3
(br), 2948 (m), 1615 (w), 1470 (m), 1352 (w), 1272 (m), 1169 (s), 1145
(s), 1120 (s), 1067 (w), 921 (w), 794 (w), 751 (m) cmꢂ1; HRMS cal-
culated for C11H11NOF3: 230.0793, found: 230.0790.
(m), 940.3 (m), 852.2 (m), 743.8 (s), 726.8 (m), 702.8 (m) cmꢂ1
HRMS: calculated for C12H15NOF: 208.1138, found: 208.1141.
;

6624
M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
4.44. 2,2,2-Trifluoro-1-(pyridine-3-yl)ethanol (45b)
4.48. 2,2,2-Trifluoro-1-(3,5-dimethylisoxazol-4-yl)-
ethanol (49b)
Prepared from nicotinaldehyde (107 mg, 1 mmol) and trime-
thyl(trifluoromethyl)silane (156 mg, 1.1 mmol) at 40 ꢀC with a resi-
dence time of 100 min. The product was obtained as white solid.
Yield: 86%, tR¼0.46 min, m/z¼177.6 (MþHþ); 1H NMR (400 MHz,
Prepared from 3,5-dimethylisoxazole-4-carbaldehyde (125 mg,
1 mmol) and trimethyl(trifluoromethyl)silane (156 mg,1.1 mmol) at
40 ꢀC with a residence time of 100 min. The product was obtained as
yellow oil. Yield¼88%, tR¼3.81 min, m/z¼196 (MþH); 1H NMR
CDCl3):
d
/ppm 8.61 (1H, br s), 8.57 (1H, br s), 7.90 (1H, d, J¼7.9 Hz),
7.38 (1H, dd, J¼4.9, 7.9 Hz), 5.08 (1H, q, J¼6.7 Hz); 13C NMR
(400 MHz, CDCl3):
d
/ppm 4.94 (1H, q, J¼7.0 Hz), 3.73 (1H, br s), 2.43
(100 MHz, CDCl3):
d
/ppm 149.9 (CH), 148.4 (CH), 135.8 (CH), 130.9
(3H, s), 2.28 (3H, s); 13C NMR (100 MHz, CDCl3):
159.3 (C),124.6 (C, q, J¼281 Hz, CF3),108.9 (C), 65.3 (CH, q, J¼34 Hz),
11.5 (CH3),10.4 (CH3); 19F NMR (376 MHz, CDCl3)
/ppm ꢂ78.8 (s); IR
d/ppm 168.9 (C),
(C), 124.1 (CF3, q, J¼280 Hz), 123.8 (CH), 50.5 (CH, q, J¼32 Hz); 19F
NMR (376 MHz, CDCl3):
d/ppm ꢂ78.1 (s); IR (neat)
n
¼3400–2800
d
(br), 2854.8 (m), 1602.3 (w), 1585.9 (w), 1432.2 (m), 1351.7 (m),
1266.4 (s), 1170.9 (s), 1132.0 (s), 1089.4 (m), 1046.8 (m), 1032.8 (m),
871.5 (m), 847.6 (w), 800.9 (m), 718.7 (s) cmꢂ1; HRMS calculated for
C7H7NO3F: 178.0480, found: 178.0480.
(neat)
n
¼3333 (br), 2976 (m), 2878 (w),1636 (m),1428 (m),1269 (s),
1170 (s),1133 (s),1087 (m),1043 (s), 853 (m), 807 (m), 713 (m) cmꢂ1
HRMS calculated for C7H9NO2F3: 196.0585, found: 196.0585.
;
4.49. 1,1,1 Trifluoro-4-phenylpentan-2-ol (50b)
4.45. 1-(Benzofuran-2-yl)-2,2,2-trifluoroethanol (46b)
Prepared from 3-phenylbutanal (148 mg, 1 mmol) and trime-
thyl(trifluoromethyl)silane (156 mg, 1.1 mmol) at 40 ꢀC with a resi-
dence time of 100 min. The product was obtained as yellow oil.
Yield¼83%; tR¼4.24 min, m/z¼no mass detected. Diastereoisomer 1:
Prepared from benzofuran-2-carbaldehyde (146 mg, 1 mmol)
and trimethyl(trifluoromethyl)silane (156 mg, 1.1 mmol) at 40 ꢀC
with a residence time of 100 min. The product was obtained as
yellow oil. Yield¼84%, tR¼4.39 min, m/z¼no mass detected; 1H
1H NMR (600 MHz, CDCl3):
d
/ppm 7.33 (2H, t, J¼7.6 Hz), 7.20–7.25
(3H, m), 4.00 (1H, sextet, J¼6.5 Hz), 3.09 (1H, app. q, J¼7.2 Hz), 2.08
NMR (400 MHz, CDCl3):
d
/ppm 7.61 (1H, d, J¼7.7 Hz), 7.52 (1H, d,
(1H, br s), 1.88–1.97 (2H, m), 1.33 (3H, d, J¼7.3 Hz); 13C NMR
J¼8.3 Hz), 7.36 (1H, t, J¼7.7 Hz), 7.28 (1H, t, J¼7.7 Hz), 6.90 (1H, s),
5.20 (1H, q, J¼6.4 Hz), 2.79 (1H, br s); 13C NMR (100 MHz, CDCl3):
d
/
(150 MHz, CDCl3): d/ppm 146.2 (C), 128.8 (2CH), 127.1 (2CH), 126.6
(CH), 127.7 (CF3, q, J¼289 Hz), 69.1 (CH, q, J¼31 Hz), 38.1 (CH2), 35.5
(CH), 23.2 (CH3); 19F NMR (376 MHz, CDCl3)
/ppm ꢂ80.1 (s). Di-
astereoisomer 2: 1H NMR (600 MHz, CDCl3):
/ppm 7.35 (2H, t,
ppm 155 (C). 149.4 (C), 127.4 (C), 125.5 (CH), 123.4 (C, q, J¼281 Hz,
d
CF3), 123.4 (CH), 121.7 (CH), 111.6 (CH), 107.0 (CH), 67.8 (CH, q,
J¼34 Hz); 19F NMR (376 MHz, CDCl3)
/ppm ꢂ77.7 (s); IR (neat)
d
d
J¼7.6 Hz), 7.15–7.25 (3H, m), 3.57 (1H, sextet, J¼6.4 Hz), 3.03 (1H,
n
¼3392 (br), 2978 (w), 2881 (w), 1455 (m), 1268 (m), 1253 (m), 1172
app. q, J¼7.2 Hz), 2.02 (1H, br s), 1.85–1.97 (2H, m), 1.31 (3H, d,
(s),1140 (s),1120 (s),1067 (m), 964 (m), 813 (m), 749 (s), 741 (s), 700
(s) cmꢂ1; Microanalysis: C: 55.91; H: 3.61%.
J¼7.3 Hz); 13C NMR (150 MHz, CDCl3):
d/ppm 144.8 (C), 128.7 (2CH),
126.8 (2CH), 126.5 (CH), 125.2 (CF3, q, J¼278 Hz), 68.5 (CH, q,
J¼30 Hz), 37.5 (CH2), 35.4 (CH), 21.1 (CH3); 19F NMR (376 MHz,
4.46. 1-(2-Bromophenyl)-2,2,2-trifluoroethanol (47b)
CDCl3)
d
/ppm ꢂ80.4 (s); IR (neat) ¼3409 (m), 2963.2 (w), 1494.7
n
(w), 1453.4 (w), 1275.9 (m), 1165.0 (m), 1134.2 (s), 907.9 (s), 763.5
(m), 731.5 (s), 699.8 (s) cmꢂ1
Prepared from 2-bromobenzaldehyde (184 mg, 1 mmol) and
trimethyl(trifluoromethyl)silane (156 mg, 1.1 mmol) at 40 ꢀC with
a residence time of 100 min. The product was obtained as col-
orless oil. Yield¼80%, tR¼4.45 min, m/z¼no mass detected; 1H
.
4.50. 2,2,2-Trifluoro-1-(6-nitrobenzo[d][1,3]dioxol-5-
yl)ethanone (51)
NMR (600 MHz, CDCl3):
d
/ppm 7.68 (1H, d, J¼7.8 Hz), 7.57 (1H, d,
J¼7.8 Hz), 7.37 (1H, t, J¼7.8 Hz), 7.23 (1H, dt, J¼1.8, 7.8 Hz), 5.58
Prepared from 2,2,2-trifluoro-1-(5-nitrobenzo[d][1,3]-dioxol-6-yl)-
ethanol (42b, 183 mg, 0.5 mmol) in DCM was flowed through a glass
column (6.6 mm i.d.ꢁ10 cm, with adjustable end pieces) packed
with manganese dioxide (870 mg, 10 mmol) heated at 110 ꢀC with
a residence time of 30 min. The product was obtained as yellow
oil. Yield: 93%, tR¼4.51 min, m/z¼no mass detected; 1H NMR
(1H, q, J¼6.6 Hz), 2.71 (1H, br s); 13C NMR (150 MHz, CDCl3):
d/
ppm 134.3 (C), 132.8 (CH), 130.7 (CH), 129.4 (CH), 127.7 (CH),
124.7 (CF3, q, J¼281 Hz), 123.8 (C), 70.9 (CH, q, J¼32 Hz); 19F NMR
(376 MHz, CDCl3):
d
/ppm ꢂ77.8 (s); IR (neat)
n
¼3382.7 (br),
2919.1 (m), 2850.7 (m), 1464.0 (m), 1440.4 (m), 1265.9 (m), 1174.4
(s), 1123.9 (s), 1080.0 (m), 1024.9 (m), 755.5 (m), 729.5 (m), 673.6
(600 MHz, CDCl3):
NMR (150 MHz, CDCl3):
150.8 (C), 141.4 (C), 126.4 (C), 115.4 (CF3, q, J¼285 Hz), 107.3 (CH),
104.8 (CH), 104.3 (CH2); 19F NMR (376 MHz, CDCl3)
/ppm ꢂ76.0
(s); IR (neat)
d C
/ppm 7.66 (1H, s), 6.84 (1H, s), 6.26 (2H, s). 13
(m) cmꢂ1
.
d/ppm 183.0 (C, q, J¼39 Hz), 153.5 (C),
4.47. 1-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2,2,2-
trifluoroethanol (48b)
d
n
¼2922.2 (w), 1746.5 (m), 1606.4 (w), 1527.5 (m),
1507.7 (s), 1483.7 (s), 1433.3 (m), 1371.0 (m), 1333.6 (s), 1265.2 (s),
1208.4 (s), 1133.8 (s), 1033.0 (s), 921.7 (s), 875.9 (s), 773.5 (m),
Prepared from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carbaldehyde (220 mg, 1 mmol) and trimethyl(trifluoromethyl)-
silane (156 mg,1.1 mmol) at 40 ꢀC with a residence time of 100 min.
The product was obtained as white solid. Yield¼87%, tR¼4.47 min,
m/z¼291.1 (MþHþ); melting point: 153.2–154.6 ꢀC. 1H NMR
738.1 (s) cmꢂ1
.
4.51. 5-Nitro-6-(1,2,2,2-tetrafluoroethyl)benzo[d][1,3]-
dioxole (52)
(400 MHz, CDCl3):
d
/ppm 7.39–7.54 (5H, m), 5.06 (1H, q, J¼7.2 Hz),
2.92 (1H, br s), 2.40 (3H, s); 13C NMR (100 MHz, CDCl3):
d
/ppm
Prepared from 2,2,2-trifluoro-1-(5-nitrobenzo[d][1,3]-dioxol-
149.4 (C), 137.7 (C), 129.1 (2ꢁCH), 128.6 (CH), 127.3 (C), 125.2
6-yl)ethanol (42b, 183 mg, 0.5 mmol) and DAST (70 mL, 0.5 mmol)
(2ꢁCH), 124.7 (C, q, J¼281 Hz, CF3), 110.9 (C), 66.4 (CH, q, J¼34 Hz),
at 70 ꢀC with a residence time of 27 min. The product was
13.4 (CH3); 19F NMR (376 MHz, CDCl3)
d
/ppm ꢂ78.1 (s); IR (neat)
obtained as light brown oil. Yield: 89%, tR¼4.62 min, m/z¼248.0
n
¼3123 (br), 2934 (w), 2872 (w), 1599 (w), 1557 (w), 1505 (m), 1266
(MꢂF); 1H NMR (600 MHz, CDCl3):
d/ppm 7.65 (1H, s), 7.19 (1H, s),
(m), 1175 (m), 1164 (m), 1131 (s), 1123 (s), 855 (m), 804 (s), 765 (s),
694 (s) cmꢂ1; HRMS calculated for C12H11N2OF3Cl: 291.0512, found:
291.0511.
6.82 (1H, dq, J¼5.4, 44.4 Hz), 6.20 (2H, app. d, J¼7.8 Hz); 13C NMR
(150 MHz, CDCl3): d/ppm 152.6 (C), 149.4 (C), 142.5 (C), 122.5 (C, d,
J¼23 Hz), 121.8 (CF3, dq, J¼29, 290 Hz), 107.4 (CH, d, J¼15 Hz),

M. Baumann et al. / Tetrahedron 65 (2009) 6611–6625
6625
106.1 (CH), 103.7 (CH2), 84.1 (CHF, dq, J¼35, 185 Hz); 19F NMR
Seeberger, P. H., Blume, T., Eds.; Springer: Berlin, Heidelberg, 2007; Vol. 1, 2006-
3, pp 151–185; (b) Solinas, A.; Taddei, M. Synthesis 2007, 16, 2409–2453; (c) Ley,
S. V.; Baxendale, I. R.; Myers, R. M. In Combinatorial Synthesis of Natural Prod-
uct-Based Libraries; Boldi, A. M., Ed.; CRC: Boca-Raton, FL, 2006; pp 131–163;
(d) Hodge, P. Ind. Eng. Chem. Res. 2005, 44, 8542–8553; (e) Bhattacharyya, S.
Mol. Diversity 2005, 9, 253–257; (f) Baxendale, I. R.; Ley, S. V. Curr. Org. Chem.
2005, 9, 1521–1534; (g) Hodge, P. Curr. Opin. Chem. Biol. 2003, 7, 362–373; (h)
Ley, S. V.; Baxendale, I. R.; Brusotti, G.; Caldarelli, M.; Massi, A.; Nesi, M. Il
Farmaco 2002, 57, 321–330; (i) Ley, S. V.; Baxendale, I. R. Chem. Rec. 2002, 2,
377–388; (j) Baxendale, I. R.; Ernst, M.; Krahnert, W.-R.; Ley, S. V. Synlett 2002,
1641–1644; (k) Ley, S. V.; Baxendale, I. R. Nat. Rev. Drug Discov 2002, 1, 573–
586; (l) Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem., Int. Ed.
2001, 40, 650–679; (m) Eames, J.; Watkinson, M. Eur. J. Org. Chem. 2001, 7,
1213–1224; (n) Sherrington, D. C. J. Polym. Sci., Part A: Polym. Chem. 2001, 39,
2364–2377; (o) Bhattacharyya, S. Ind. J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 2001, 40B, 878–890; (p) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson,
P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, I.; Taylor, S. J.
J. Chem. Soc., Perkin Trans. 1 2000, 3815–4195; (q) Baxendale, I. R.; Ley, S. V.
Bioorg. Med. Chem. Lett. 2000, 10, 1983–1986.
(376 MHz, CDCl3):
d
/ppm ꢂ77.8 (d, J¼11.3 Hz), ꢂ193.7 (q,
J¼11.3 Hz); IR (neat) ¼2922.0 (w), 1617.2 (w), 1529.8 (m), 1508.2
n
(s), 1487.6 (s), 1428.0 (m), 1358.8 (m), 1334.4 (s), 1309.1 (m),
1261.2 (s), 1188.5 (s), 1134.7 (s), 1060.1 (m), 1033.2 (s), 928.2 (m),
884.8 (m), 867.6 (m), 850.4 (m), 819.5 (m), 803.5 (m), 758.7 (m),
708.9 (m) cmꢂ1
.
Acknowledgements
We gratefully acknowledge financial support from the EPSRC
(to I.R.B.), the Cambridge European Trust. and the Ralph Raphael
Studentship award (to M.B.), Novartis (to L.J.M.) and the BP En-
dowment (to S.V.L.).
7. (a) Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett 2008, 2111–2114; (b)
Gustafsson, T.; Gilmour, R.; Seeberger, P. H. Chem. Commun. 2008, 3022–3024;
(c) Chambers, R. D.; Fox, M. A.; Sandford, G.; Trmcic, J.; Goeta, A. J. Fluorine
Chem. 2007, 128, 29–33.
References and notes
1. (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305–321; (b) Kirk, K. L. Curr. Top.
Med. Chem. 2006, 6, 1447–1464; (c) Jairaj, V.; Koul, V. K. PharmaChem. 2006, 5,
24–32; (d) Turnbull, M. D.; Carter, N. B.; Dennison, S.; Deacon, J.; Holley, R.
Chimia 2004, 58, 159–162; (e) Lang, R. W. Chemistry of Organic Fluorine Com-
pounds II. ACS Monograph; American Chemical Society: Washington, DC, 1995;
Vol. 187, p 1143.
2. Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V.; Smith, C. D. Heterogeneous
Reactions. In Microreactors in Organic Chemistry and Catalysis; Wirth, T., Ed.;
Wiley-VCH: Weinheim, 2008; Chapter 4.2, pp 84–122.
8. Messina, P. A.; Mange, K. C.; Middleton, W. J. J. Fluorine Chem. 1989, 42, 137–143.
9. Vapourtec R2þ/R4 units are available from Vapourtec Ltd, Place Farm, Ingham,
Suffolk IP31 1NQ, UK. Website: http://www.vapourtec.co.uk. See also http://
leyitc.ch.cam.ac.uk/equipment.html for images of the equipment.
10. Commercially available OmnifitÒ glass chromatography columns with adjust-
able height-end pieces (plunger). Typically, the polymer-supported reagent is
placed in an appropriately sized Omnifit columnÒ, usually 10 mm bore by
150 mm length, or shorter and the plungers are adjusted to relevant bed
heights and the ploymer swelled/washed with solvent. Website: http://www.
omnifit.com.
11. Available from Macherey-Nagel GmbH & Co. Dueren, Germany.
12. Das, S.; Chandrasekhar, S.; Yadav, J. S.; Gre, R. Tetrahedron Lett. 2007, 48, 5305–
5307.
13. Quadrapure Benzylamine (QP-BZA), Quadrapure Sulfonic Acid (QP-SA), and
Quadrapure Dimethylamine (QP-DMA) are high-loading scavengers commer-
cially availlable from Reaxa. Website: http://www.reaxa.com.
14. Buss, C. W.; Coe, P. L.; Tatlow, J. C. J. Fluorine Chem. 1986, 34, 83–104.
15. (a) Lal, G. S. Synth. Commun. 1995, 25, 725–737; (b) Banks, R. E.; Lawrence, N. J.;
Popplewell, A. L. J. Chem. Soc., Chem. Commun. 1994, 343–344; (c) Zupan, M.;
Iskra, J.; Stavber, S. J. Fluorine Chem. 1995, 70, 7–8; (d) Matthews, D. P.; Miller,
S. C.; Jarvi, E. T.; Sabol, J. S.; McCarthy, J. R. Tetrahedron Lett. 1993, 34, 3057–
3060; (e) Brunaus, M.; Dell, C. P.; Owton, W. M. J. Fluorine Chem. 1994, 68,
201–203; (f) Hodson, H. F.; Madge, D. J.; Slawin, A. N. Z.; Widdawson, D. A.;
Williams, D. J. Tetrahedron 1994, 5, 1899–1906; (g) Stavber, S.; Zupan, M.
J. Chem. Soc., Chem. Commun. 1994, 149–150; (h) Lal, G. S. J. Org. Chem. 1993,
58, 2791–2796; (i) Banks, R. E.; Mohialdin-Khaffa, S. N.; Lal, G. S.; Sharif, I.;
Syvret, R. G. J. Chem. Soc., Chem. Commun. 1992, 595–596.
3. (a) Benito-Lo´pez, F.; Egberink, R. J. M.; Reinhoudt, D. N.; Verboom, W. Tetra-
hedron 2008, 64, 10023–10040; (b) Baxendale, I. R.; Ley, S. V.; Smith, C. D.;
Tamborini, L.; Voica, A.-F. J. Comb. Chem. 2008, 10, 851–857; (c) Ley, S. V.;
Baxendale, I. R. In Proceedings of Bozen Symposium, Systems Chemistry; Beilstein
Institute, 2008; pp 65–85; (d) Baxendale, I. R.; Hayward, J. J.; Ley, S. V.; Tranmer,
G. K. ChemMedChem. 2007, 2, 768–788; (e) Sedelmeier, J.; Ley, S. V.; Baxendale,
I. R. Green Chem. 2009, 11, 683–685; (f) Ahmed-Omer, B.; Brandt, J. C.; Wirth, T.
Org. Biomol. Chem. 2007, 5, 355–359; (g) Mason, B. P.; Price, K. E.; Steinbacher, J. L.;
Bogdan, A. R.; McQuade, D. T. Chem. Rev. 2007,107, 2300–2318; (h) Glasnov, V. T. N.;
Kappe, C. O. Macromol. Rapid Commun. 2007, 28, 395–410; (i) Kirschning, A.;
Solodenko, W.; Mennecke, K. Chem.dEur. J. 2006, 12, 5972–5990; (j) Baxendale,
I. R.; Pitts, M. R. Chem. Today 2006, 24, 41–45; (k) Baxendale, I. R.; Griffiths-
Jones, C. M.; Ley, S. V.; Tranmer, G. K. Synlett 2006, 427–430; (l) Baumann, M.;
Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231–
5234; (m) Ja¨hnisch, K.; Hessel, V.; Lo¨we, H.; Baerns, M. Angew. Chem., Int. Ed.
2004, 43, 406–446; (n) Jas, G.; Kirschning, A. Chem.dEur. J. 2003, 9, 5708–5723;
(o) Hodge, P. Curr. Opin. Chem. Biol. 2003, 7, 362–373.
4. (a) Palmieri, A.; Ley, S. V.; Hammond, K.; Polyzos, A.; Baxendale, I. R. Tetrahe-
dron Lett. 2009, 50, 3287–3289; (b) Baxendale, I. R.; Ley, S. V.; Mansfield, A. C.;
Smith, C. D. Angew. Chem., Int. Ed. 2009, 48, 4017–4021; (c) Palmieri,A.;Ley, S. V.;
Polyzos, A.; Ladlow, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2009, 5, 23–39; (d)
Pelleter, J.; Renaud, F. Org. Process. Res. Dev., in press. doi:10.1021/op8002695; (e)
Hafez, A. M.; Taggi, A. E.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 2001, 123, 10853–
10859; (f) Smith, C. D.; Baxendale, I. R.; Tranmer, G. K.; Baumann, M.; Smith, S. C.;
Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1562–1568; (g) Smith, C. J.;
Iglesias-Sigu¨enza, F. J.; Baxendale, I. R.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 2758–
2761; (h) Griffiths-Jones, C. M.; Hopkin, M. D.;Jo¨nssen, D.;Ley, S. V.; Tapolczay, D. J.;
Vickerstaffe, E.; Ladlow, M. J. Comb. Chem. 2007, 9, 422–430; (i) Baumann, M.;
Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tranmer, G. K. Org. Lett. 2006, 8, 5231–5234;
(j) Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K. Chem.dEur. J.
2006,12, 4407–4416; (k) Baxendale, I. R.; Deeley, J.; Griffiths-Jones, C. M.; Ley, S. V.;
Saaby, S.;Tranmer, G. K. Chem. Commun. 2006, 2566–2568; (l) Saaby, S.; Baxendale,
I. R.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 3365–3368.
16. http://www.scottecatalog.com/images.nsf/Images/Selectfluor/$FILE/Selectfluor.
pdf [accessed 06.03.09].
17. Baxendale, I. R.; Ley, S. V.; Lumeras, W.; Nesi, M. Comb. Chem. High Throughput
Screening 2002, 5, 197–199.
18. (a) Kirschning, A.; Solodenko, W.; Mennecke, K. Chem.dEur. J. 2006, 12, 5972–
5990; (b) Kunz, U.; Kirschning, A.; Wen, H.-L.; Solodenko, W.; Cecilia, C.; Kappe,
C. O.; Turek, T. Catal. Today 2005, 105, 318–324; (c) Solodenko, W.; Wen, H.-L.;
Leue, S.; Stuhlmann, F.; Sourkouni-Argirusi, G.; Jas, G.; Schonfeld, H.; Kunz, U.;
Kirschning, A. Eur. J. Org. Chem. 2004, 17, 3601–3610; (d) Jas, G.; Kirschning, A.
Chem.dEur. J. 2003, 9, 5708–5723; (e) Svec, F.; Frechet, J. M. J. Chem. Mater.
1995, 7, 707–715; (f) Svec, F.; Frechet, J. M. J. Anal. Chem. 1992, 62, 820–822.
19. (a) Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. J.; Smith, C. D. Org. Biomol.
Chem., in preparation; (b) Nikbin, N.; Ladlow, M.; Ley, S. V. Org. Process Res. Dev.
2007, 11, 458–462.
20. Loading of monolithic resins was determined by elemental analysis based on
chloride content.
5. (a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D. Org. Biomol.
Chem. 2008, 6,1587–1593; (b) Yoshida, J. Flash Chemistry: Fast Organic Synthesis in
Microsystems; Wiley-VCH: Weinheim, 2008; ISBN 978-0-470-03586-3; (c) Bau-
mann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.; Smith, C. D.; Tierney, J. P. Org.
Biomol. Chem. 2008, 6, 1577–1586; (d) Smith, C. D.; Baxendale, I. R.; Lanners, S.;
Hayward, J. J.; Smith, S. C.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 1559–1561; (e)
Hornung, C. H.; Mackley, M. R.; Baxendale, I. R.; Ley, S. V. Org. Process Res. Dev.
2007, 11, 399–405; (f) Nikbin, N.; Ladlow, M.; Ley, S. V. Org. Process Res. Dev. 2007,
11, 458–462; (g) Hessel, V.; Lo¨we, H.; Mu¨ller, A.; Kolb, G. Chemical Micro Process
Engineering; Wiley-VCH: Weinheim, 2005; ISBN 3-527-30998-5; (h) Hessel, V.;
Hardt, S.; Lo¨we, H. Chemical Micro Process Engineering; 2004; ISBN 527-30741-9.
6. (a) Baxendale, I. R.; Ley, S. V. In New Avenues to Efficient Chemical Synthesis:
Emerging Technologies. Ernst Schering Foundation Symposium Proceedings;
21. Kitazume, T.; Ebata, T. J. Fluorine Chem. 2004, 125, 1509–1511.
22. Furuya, T.; Fukuhara, T.; Hara, S. J. Fluorine Chem. 2005, 126, 721–725.
23. Singh, R. P.; Chakraborty, D.; Shreeve, J. M. J. Fluorine Chem. 2001, 111, 153–160.
24. Tse, M. K.; Bhor, S.; Klawonn, M.; Anilkumar, G.; Jiao, H.; Doebler, C.; Span-
nenberg, A.; Maegerlein, W.; Hugl, H.; Beller, M. Chem.dEur. J. 2006, 12, 1855–
1874.
25. Torres, J. C.; Garden, S. J.; Pinto, A. C.; da Silva, F. S. Q.; Boechat, N. Tetrahedron
1999, 55, 1881–1892.
26. Nishiyama, H.; Yamaguchi, S.; Kondo, M.; Itoh, K. J. Org. Chem. 2002, 57, 4306–
4309.
27. Kim, D. Y.; Lee, Y. M.; Young, J. C. Tetrahedron 1999, 55, 12983–12990.