Preparation of p-substituted tetrafluoropyridyl derivatives via the tetrafluoropyridylcopper reagent

Article abstract of DOI:10.1016/j.jfluchem.2011.10.001

A new and improved preparation of 4-iodo-2,3,5,6-tetrafluoropyridine from pentafluoropyridine is described. This iodopyridine is utilized for the in situ preparation of the 4-tetrafluoropyridylcopper reagent, 1, via two methods. The first method involves metathesis of the 4-tetrafluoropyridylcadmium reagent with Cu(I)Br at room temperature. The requisite cadmium reagent was readily prepared in situ via reaction between 4-iodotetrafluoropyridine with acid-washed cadmium powder in DMF at room temperature. The second method involves the in situ reaction of 4-tetrafluoropyridyltributyl-phosphonium tetrafluoroborate with Na₂CO₃ and Cu(I)Br in DMF at room temperature. 1 readily undergoes reaction with allylic halides, vinyl iodides, aryl halides, acid chlorides and acetylenic iodides at room temperature to stereospecifically afford the corresponding 4-tetrafluoropyridyl derivatives. An alternative route to the alkyne derivatives was developed via the Pd(0) catalyzed reaction of 4-iodotetrafluoropyridine with 1-alkynes.

Full text of DOI:10.1016/j.jfluchem.2011.10.001

Journal of Fluorine Chemistry 135 (2012) 144–154
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Preparation of p-substituted tetrafluoropyridyl derivatives via the
tetrafluoropyridylcopper reagent§
*
Ba Van Nguyen, Donald J. Burton
Department of Chemistry, The University of Iowa, Iowa City, IA 52242, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
A new and improved preparation of 4-iodo-2,3,5,6-tetrafluoropyridine from pentafluoropyridine is
described. This iodopyridine is utilized for the in situ preparation of the 4-tetrafluoropyridylcopper
reagent, 1, via two methods. The first method involves metathesis of the 4-tetrafluoropyridylcadmium
reagent with Cu(I)Br at room temperature. The requisite cadmium reagent was readily prepared in situ
via reaction between 4-iodotetrafluoropyridine with acid-washed cadmium powder in DMF at room
temperature. The second method involves the in situ reaction of 4-tetrafluoropyridyltributyl-
phosphonium tetrafluoroborate with Na2CO3 and Cu(I)Br in DMF at room temperature. 1 readily
undergoes reaction with allylic halides, vinyl iodides, aryl halides, acid chlorides and acetylenic iodides
at room temperature to stereospecifically afford the corresponding 4-tetrafluoropyridyl derivatives. An
alternative route to the alkyne derivatives was developed via the Pd(0) catalyzed reaction of 4-
iodotetrafluoropyridine with 1-alkynes.
Received 5 August 2011
Received in revised form 8 September 2011
Accepted 1 October 2011
Available online 6 October 2011
Keywords:
4-Tetrafluoropyridylcopper reagent
4-Iodotetrafluoropyridine
Organometallic reagents
Coupling reactions
4-Tetrafluoropridyl derivatives
Pd(0) catalyzed reactions
ß 2011 Elsevier B.V. All rights reserved.
1. Introduction
MgBr
Cu
The chemistry of pentafluoropyridine has been investigated
since the early 1960s. The majority of reactions of pentafluor-
opyridine involve the replacement of the 4-fluorine atom by
nucleophilic reagents [1]. Nucleophilic reactions are useful for the
introduction of certain functional groups into the perfluoropyr-
idine nucleus; however, this methodology does have some
disadvantages, in that only nucleophiles can be introduced and
the nucleophilic substitution may give more than one product. In
addition, nucleophilic substitution is not readily applicable to the
preparation of functionalized pyridines. Alternatively, organome-
tallic reagents, such as 4-tetrafluoropyridyllithium or magnesium
reagents have been utilized to prepare functionalized 4-tetra-
fluoropyridyl derivatives, Eq. (1) [2].
(2)
1) 0ºC , THF, 20 h
2) warm to RT
F
N
+ Cu(I)Cl
F
N
The pyridylcopper reagent was coupled with iodotrifluoroethene
to give (4-tetrafluoropyridyl)trifluoroethene, Eq. (3) [4]. By-pro-
ducts included 2,3,5,6-tetrafluoropyridine, 4-iodo-tetrafluoropyr-
idine and bis (4,40-tetrafluoropyridine). The disadvantages of this
approach are low temperature preparation of the organolithium or
Grignard reagent is required and that the 4-bromo- or 4-iodotetra-
fluoropyridine precursors to the organometallic intermediates are
isolated in moderate yields from multistep syntheses.
Cu
CF=CF2
H
Li
CO2H
50ºC
(3)
+
F2C=CFI
+ others
F
N
F
(1)
1) CO2
2) H3O+
hexane
-60 ºC
F
+ n-BuLi
F
N
F
N
, 50%
N
N
56%
The corresponding Grignard reagent is somewhat more stable
than the lithium reagent and has also been utilized to prepare the
4-tetrafluoropridylcopper reagent, Eq. (2) [3].
2. Results and discussion
2.1. Preparation of 4-iodotetrafluoropyridine
§
Presented in part at the 20th Winter Fluorine Conference, St. Petersburg Beach,
FL; January 2011, Abstract #35.
4-Iodotetrafluoropyridine has been prepared by a one-step
reaction from pentafluoropyridine via the high temperature
reaction of the pyridine with iodide ion as the nucleophile,
* Corresponding author. Tel.: +1 319 335 1363; fax: +1 319 335 1270.
E-mail addresses: donald-burton@uiowa.edu, mburton105@gmail.com
(D.J. Burton).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.10.001

B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
145
Eq. (4) [5]. Efforts to improve the conversion (longer reaction
times) made little difference in the yield of the 4-iodopyridine but
generated additional by-products [5], Eq. (5).
Although 4-iodotetrafluoropyridine is easily obtained from
the purified, isolated phosphonium salt intermediate, the entire
transformation (Eq. (7)) can be carried out as
synthesis.
a one pot
I
2.2. In situ preparation of the 4-tetrafluoropyridylcopper reagent
DMF
150ºC
20 h
F
+ NaI
F
N
(4)
N
We have recently described the in situ preparation of perfluor-
oarylcadmium reagents via direct reaction of a perfluoroaryl halide
with cadmium [7–10]. Similarly, 4-tetrafluoropryidylcadmium
formation readily occurs when 4-iodotetrafluoropyridine is reacted
withacid-washedcadmiumpowder inDMF atRT. Subsequentin situ
exchange of the arylcadmium reagent with Cu(I)Br provides the
corresponding 4-tetrafluoropridylcopper reagent, 1, Eq. (8) [11].
The cadmium reagent has been previously prepared via pyrolysis of
the cadmium-4-tetrafluoro-pyridylcarboxylate [12]. The thermal
stability of a solution of 1 is excellent. When 1 was stored in a
degassed, sealed tube at RT for 48 h, no decomposition was
observed. When a solution of 1 was heated at 90 8C for 3 h, the
color of the solution changes slightly from brown to dark brown,
but the 19F NMR spectrum of the reagent exhibits no significant
changes.
50% conversion
I
H
DMF
150 ºC
40 h
N
F
F N (5)
F
N
+ NaI
+
F
N
F
N
10%
+
58%
13%
The authors demonstrated that prolonged reaction of the 4-
iodotetrafluoropyridine with iodide ion at 150 8C promoted attack
by the iodide ion on the iodopyridine to generate the tetrafluor-
opyridyl anion – which accounted for the by-products at long
reaction times.
Thus, our first objective was to identify an improved method to
this key precursor. We have reported a general route to (Z)-1-
iodoperfluoroolefins via the reaction of the perfluoroolefin with n-
tributylphosphine at low temperatures. The resultant vinyl (Z)-
phosphorane is subsequently reacted in situ with boron trifluoride
etherate to afford the (Z)-perfluoroalkenyltributylphosphonium
tetrafluoroborate. Subsequent in situ cleavage of the tetrafluor-
oborate salt with either Na2CO3/I2 or KF/I2 affords stereospecifi-
cally the (Z)-1-iodoperfluoroalkene, illustrated in Eq. (6) with
perfluoropropene [6]. Since the sp2 carbon of the perfluoroolefin is
readily attacked by the nucleophilic tertiary phosphine, we
anticipated that the highly reactive pentafluoropyridine would
behave similarly. To our delight, we found that pentafluoropyr-
idine reacted rapidly with n-tributylphosphine at ꢀ45 to ꢀ35 8C in
dry diethyl ether to generate the 4-pyridylphosphorane. Subse-
quent addition of BF3ꢁEt2O to the cold phosphorane solution
provided the corresponding phosphonium tetrafluoroborate in
95% yield. Subsequent reaction of the tetrafluoroborate salt with
Na2CO3/I2 in dry DMF gave (after flash distillation) a 19F NMR yield
of 92% 4-iodotetrafluoropyridine in DMF. Subsequent workup
provided a 75% isolated yield of the 4-iodotetrafluoropyridine as a
white solid, mp 49–51 8C (reported mp 47–48 8C [5]), Eq. (7).
I
CdX
Cu
Cd
DMF
RT
Cu(I)Br
DMF
RT
F
N
F
N
F
N
1
99%
(8)
15 min
30 min
2.3. Reaction of 1 with allylic halides and propargyl tosylate
1 reacts smoothly with primary allylic halides to form the
corresponding coupling product in high yields at RT (Table 1).
Secondary allylic halides, such as (Z)-4-chloro-2-pentene, also
stereospecifically give a good yield (74%) of the coupled product, 4,
Eq. (9).
H
H
H
H
RT
DMF
1
+
F
(9)
H3C
CH(Cl)CH3
N
H3C
CH(CH3)
74%
4
1) n-Bu3P
-78ºC
2) BF3 Et2O
3) warm to RT
_
BF4
F3C
F
F
F
F3C
F
F
In all cases, no evidence of substitution at the
SN02 mechanism was observed. In contrast to CF2HCu [13], 1 does
not attack the -carbon of these allylic halides to form g-
g-carbon via an
P(F)Bu3-n
g
substituted products. In the case of propargyl tosylate, 1 gave only
the 2,3,5,6-tetrafluoropyridyl substituted allene, 6, Eq. (10). The
(6)
Na2CO3
I2
allene product was formed by attack of 1 at the
g-carbon of
propargyl tosylate via an SN02 mechanism, similar to other
F3C
F
F
I
+
Bu
3P-F
Bu
3P
I
_
BF4
BF3 Et2O
-40 ºC
warm to RT
n-Bu3P
Et2O
-40ºC
Na2CO3
(7)
F
N
F
N
F
N
F
N
I2
DMF
75%
95%

146
B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
Cu
Table 1
Rx. of
with allylic halides and propargyl tosylate.
F
N
Cu
DMF
RT
+ R-X
F
N
N F
R
Compd. #
R–X
Pdt.
%Yielda
N F
N F
N F
CH2CH=C(CH3)2
CH-CH=CHCH3
2
3
4
(CH3)2C5CHCH2Br
61
82
74
Br
CHClCH3
H3C
H
H
(Z)
CH3
(Z)
5
86
63
H
H
F N
H
CH2
H
CH2Cl
HCBB CCH2OTs
6
N F
CH=C=CH2
a
Isolated yields.
Cu
Table 2
Rx.
of with vinyl iodides and aryl iodides.
F
N
Cu
DMF
RT
+ R-X
F
N
N F
R
Compd. #
7
R–X
Pdt
% Yielda
85
Pdt
F
R-X
F3C
F
F3C
F
F
I
F
N
8
9
85
91
CH3(CH2)2CH2
CH3(CH2)2CH2
H
H
H
I
H
F
N
CF2CF2CF2
H
CH2(CH2)2CH3
I
CF2CF2CF2
H
CH2(CH2)2CH3
F
N
CO2Et
I
CO2Et
10
80
N
F
a
Isolated yields.
reactions previously reported with propargyl tosylate and
fluorinated copper reagents [14].
2.4. Reaction of 1 with vinyl iodides and aryl iodide
Coupling of 1 with internal and terminal vinyl iodides occurs at
RT to afford the expected coupled products with perfluorinated,
non-fluorinated or partially fluorinated vinyl iodides (Table 2). In
all cases, the stereochemistry of the starting vinyl iodide is retained
in the products and there is no detectable metal-halogen exchange
by 19F NMR analysis of the reaction mixture. The stereochemistry
of the (Z)-and (E)-isomers could be verified by the NMR coupling
constants of the vinyl fluorines of the products. For example, 1,
reacts with (Z)-1-iodopentafluoropropene at RT under a nitrogen
HC CCH2
N
N
F
F
DMF
RT
1 + HC CCH2OTs
(10)
, 6
H2C=C=CH
6, 63%

B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
147
atmosphere to give an 85% isolated yield of (E)-1-(2,3,5,6-
bond intact, Eq. (14).
tetrafluoropyridyl)pentafluoropropene, 7, in which the coupling
constant between the two vinylic fluorines is 140.0 Hz. In the case
of a hydrocarbon substrate, 1 reacts with (E)-1-iodo-1-hexene to
form (E)-1-(2,3,5,6-tetrafluoropyridyl)-1-hexene, 8, in 85% yield.
The coupling constant of the two vinylic hydrogens is 16.3 Hz, cf.
Eqs. (11) and (12). 1 also reacts smoothly with a functionalized aryl
iodide to give the expected tetrafluoropyridyl coupled product, 10.
Br
Br
O
DMF
RT
2 h
(14)
C
F N
, 85%
C
O
1
+
Cl
14
2.6. Reaction of 1 with 1-iodoalkynes
F3C
F
F
F3C
F
F
I
DMF
RT
3 h
+
1
, 85%
1-Iodoalkynes react exothermically with 1 at RT to give the
corresponding coupled products in high yields (Table 4). In most
cases, the reaction is complete in less than 30 min with the
substituent groups on the alkynyl iodides showing little effect on
the rate of the coupling reaction. In all cases, there is no evidence of
exchange between the alkyne and the copper reagent or other
fluorine-containing products in these reactions that could be
detected by 19F NMR analysis of the reaction mixture. Both alkyl,
aryl and functionalized 1-iodoalkynes reacted readily, Eq. (15).
(11)
(12)
F
N
7
CH3(CH2)2CH2
H
H
I
DMF
30 min
RT
+
CH3(CH2)2CH2
H
1
H
, 85%
F
N
8
DMF
RT
30 min
C C I + 1
C
C
F N
(15)
85%
20
2.5. Reaction of 1 with acyl halides
The coupling of 1 with acyl halides occurs smoothly at RT to give
a variety of ketones in 72–93% isolated yields (Table 3). For
example, 1 reacts with 3-carbomethoxypropionyl chloride at RT to
give methyl-4-(2,3,5,6-tetrafluoropyridyl)-4-oxo-butanoate, 12 in
83% yield, Eq. (13). Both aryl and alkyl acyl halides react readily.
2.7. Pd catalyzed reaction of 4-iodotetrafluoropyridine with 1-alkynes
The coupling reaction between 4-tetrafluoropyridylcopper and
1-iodoalkynes is an excellent reaction. However, its synthetic
utility is limited, since 1-iodoalkynes are not commercially
available, and hydroxyl or amino substituted 1-iodoalkynes are
difficult to prepare. The key to overcoming this problem is to utilize
methodology which directly introduces the alkynyl group to 4-
iodotetrafluoropyridine utilizing terminal alkynes [15–18], thus
avoiding the necessity of the 1-iodoalkyne.
O
O
O
O
RT
DMF
1.5 h
1 + CH3O C CH2CH2C
CH3O C CH2CH2C
83%
Cl
F N
12
(13)
Although DMF is generally a convenient solvent for orgnocop-
per chemistry, we found that it hindered formation of this
organocopper complex under Pd-catalyzed conditions. 4-Iodote-
trafluoropyridine did not couple to terminal alkynes in the
Interestingly, the reaction of 4- or 2-bromobenzoyl chloride
gave only the ketone products, 14 and 15, leaving the aryl bromine
Cu
Table 3
Rx. of
with acid chlorides.
F
N
CO2Et
N
F
Compd. #
RC(O)Cl
Pdt.
% Yielda
77
11
12
13
CH3CH2C(O)Cl
F
N
C(O)CH2CH3
CH3OC(O)CH2CH2C(O)Cl
83
78
85
CH3OC(O)CH2CH2C(O)
F
N
F
N
C(O)
C(O)Cl
Br
14
Br
H
F
F
N
N
C(O)
C(O)
C(O)Cl
15
16
72
93
Br
C(O)Cl
Br
O
C
H
H
N
F
C(O)Cl
H
a
Isolated yields.

148
B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
Cu
Table 4
Rx. of
with acetylenic iodides.
F
N
Cu
DMF
RT
CR
+ IC
N F
C C R
F
N
Compd. #
ICBB CR
Pdt.
%Yielda
87
17
18
19
20
21
a
CH3(CH2)2CH2CBB Cl
N
C CCH2(CH2)2CH3
C CCH2OCH3
C CCH2OCH(OEt)CH3
C C
F
CH3OCH2CBB Cl
82
71
85
91
N F
CH3CH(OEt)OCH2CBB Cl
N
F
C Cl
C Cl
N F
N F
C C
Isolated yields.
presence of DMF, triethylamine, Cu(I)I salts, and Pd(PPh3)2Cl2.
However, in the absence of DMF, the coupling reaction proceeded
smoothly (Table 5). An advantage of this alternative methodology is
that a variety of functionalized alkynes can be employed. For
example, 4-iodotetrafluoropyridine reacts with 1-ethynylcyclohex-
ylamine in Et3N, catalyzed by Pd(0) at 70 8C to afford 73% of (2,3,5,6-
tetrafluoropyridyl) (1-amino-cyclohexyl)-ethyne, 22, Eq. (16). Sim-
ilarly, the corresponding hydroxyl derivative provided the hydroxyl
substituted 4-tetrafluoropyridyl derivative, 23. Interestingly, water
and methanol can be tolerated under these reaction conditions. For
example, when (Z)-1-methoxy-1-butene-3-yne, commercially
available as 50 weight% solution of methanol–water, 4–1, was
utilized as a substrate, the corresponding (Z)-1-methoxy-4-(2,3,5,6-
tetrafluoropyridyl)-1-butene-3-ynl, 25, was isolated in 35% yield.
I
2.8. In situ formation of the 4-tetraflluoropyridylcopper reagent
directly from 4-tetrafluoropyridyltributylphosphonium
tetrafluoroborate
When 4-tetrafluoropyridyltributylphosphonium tetrafluoro-
borate was treated with Na2CO3/I2, 4-iodotetrafluoropyridine
was formed in good yield (cf. Eq. (7)). We speculated that sodium
carbonate assisted formation of the 4-tetrafluoropyridyl anion,
which was subsequently trapped by I2. Thus, we rationalized that
the phosphonium salt, when treated with Na2CO3, would
generate the 4-tetrafluoropyridyl anion which could also be
trapped in situ with a copper(I) salt, such as Cu(I)Br. Thus, we
treated the phosphonium tetrafluoborate salt in DMF with
Na2CO3/Cu(I)/Br at RT and found that the 4-tetrafluoropyridyl-
copper reagent was indeed in situ formed. Subsequent treatment
of this solution with several coupling partners, produced the 4-
tetrafluoropyridyl derivatives in yields similar to the copper
reagent generated from the corresponding cadmium reagent, cf.
Table 6. Allylic halides and acid chlorides worked well. In only
one case did we observe a distinct difference in reactivity. When
NH2
NH2
PdCl2(PPh3)2
+ H
F
F
N
C
N
C C
C
Cu(I)I
70 ºC
22 , 73%
(16)
Table 5
Reaction of 4-iodotetrafluoropyridine with terminal alkynes catalyzed by Pd.
I
PdCl2(PPh3)2
Cu(I)I
Et3N, 70ºC
+ HC CR
N F
C C R
F
N
Compd. #
21
HCBB CR
Pdt.
%Yielda
88
HC
C
N
C
C
C
F
C
22
23
73
71
H2N
H2N
C
N F
H C C
HO
HO
C
N F
F
H C C
24
25
HCBB C–C(CH3)2OH
92
35
C C C(CH3)2OH
H
C
H
H
C
H
OCH3
N
C
HC
F
OCH3
a
Isolated yields.

B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
149
+
Bu3P
Table 6
_
BF4
Rx. of
with Na2CO3/Cu(I)Br + functional derivatives.
F
N
+
Bu3P
_
BF4
Na2CO3
N
R
+ R-X
F
F
Cu(I)Br
N
DMF/RT
Compd. #
R–X
Pdt.
% Yielda
2
64
H3C
H3C
H
H3C
H3C
H
CH2
CH2Br
F N
3
69
78
Br
F N
16
H
C
H
C
O
C
O
C
C
H
Cl
C
H
N
F
26
49
66
Br
N F
C(O)
C
O
Cl
N
O
15
Br
C Cl
O
Br
C
F N
a
Isolated yields.
2-bromobenzoyl chloride was reacted with the copper reagent,
formed from the 4-tetrafluoropyridyltributylphosphonium salt,
both the acyl halide functionality and the 2-bromoaryl substitu-
ent coupled with the copper reagent, Eq. (17). The 4-bromo
analog gave only coupling with the acyl function, Eq. (18).
Additional experiments are required to determine why the
activated 2-bromo substituent couples under these conditions,
but not under conditions used with the preparation of the copper
reagent via exchange with the corresponding cadmium reagent.
Supporting evidence for this proposed mechanism is as follows:
(1) if moisture is present, 4-hydrotetrafluoropyridine is formed as
a by-product; (2) if benzaldehyde is used as a partner with
Na2CO3, a 30% yield of the addition product of the anion to
benzaldehyde was isolated.
3. Experimental
_
+
Bu
3PBF4
3.1. General experimental procedures
O
C
O
C
Na2CO3
All reactions were monitored by 19F NMR analysis of the
reaction mixtures on a JEOL FX90Q spectrometer. The 1H, 19F, 13C
NMR spectra of the final products were obtained on a Bruker AC-
300 spectrometer (CDCl3, CFCl3 or TMS internal references).
+ Cl
F
N
, 49%
F
N
Cu(I)Br
DMF/RT
2 h
Br
26
F
N
(17)
_
4
+
PBF
Bu3
O
O
C
Na2CO3
(18)
F
F
+ Cl
C
Br
N
Br, 66%
Cu(I)Br
DMF/RT
3 h
N
15
2.9. Mechanism of formation of the 4-tetrafluoropyridylcopper
FTIR was recorded on a Mattson Cygnes 100 spectrometer as
CCl4 solutions in a 0.1 cm path length cell. Low-resolution mass
spectra were obtained on a TRIO-GC–MS and high resolution mass
spectra were obtained on a VG Analytical H-250J at 70 eV by the
University of Iowa Mass Spectrometry personnel. GLPC analysis
was recorded on a Hewlett Packard 5890A gas chromatograph with
an OV-101 column and thermal conductivity detector. Melting
points were obtained on a Thomas Hoover Capillary melting point
apparatus in open-ended capillaries and are uncorrected. All
starting materials were obtained from commercial sources and
reagent and 4-iodo-tetrafluoropyridine from 4-tetrafluoropyridyl
tributylphosphonium tetrafluoroborate, Scheme 1
Attack by carbonate on the phosphonium center produces an
intermediate that collapses with loss of CO2 and Bu3P55O to
produce the 4-tetrafluoropyridyl anion. If I2 is utilized as a partner
in the Na2CO3 reaction, the 4-iodotetrafluoropyridine is formed. If
Cu(I)Br is employed as the partner, the anion is trapped by the
Cu(I) salt to afford the 4-tetrafluoropyridylcopper reagent.

150
B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
(relative intensity): 277 (M+, 100), 150 (40), 100 (45). HRMS calc’d.
for C5F4NI 276.9012, obsv’d. 276.9004.
O
C
_
O Na+ + NaBF4
Bu
3P
O
3.4. Preparation of 4-(2,3,5,6-tetrafluoropyridyl)cadmium reagent
_
+
=
Na2+CO3
Bu
F
3 PBF4
N
A dry, two-necked, 50 mL round-bottomed flask equipped with
a nitrogen inlet, a Teflon coated stir-bar, and septum port was
charged with 5.0 g (18.0 mmol) of 4-iodo-2,3,5,6-tetrafluoropyr-
idine and 2.2 g (20.0 mmol) of acid-washed cadmium powder in
20 mL of dry DMF. The reaction was stirred under a nitrogen
atmosphere at room temperature. After stirring for 15 min, the 4-
iodo-2,3,5,6-tetrafluoropyridine was completely consumed as
-CO2
-Bu3P
F
N
O
F
N
Cu(I)Br
I2
determined by 19F NMR analysis, 19F NMR (CFCl3, DMF)
ꢀ98.0 ppm (m, 2F), ꢀ118.0 ppm (m, 2F).
d
I
Cu
F
N
F
N
3.5. Preparation of 4-(2,3,5,6-tetrafluoropyridyl)copper reagent, 1
Scheme 1. Mechanism of cleavage of phosphonium salt with Na2CO3.
A dry, two-necked, 50 mL round-bottomed flask equipped with
an nitrogen inlet, a Teflon coated stir-bar, and septum port was
charged with 2.9 g (20.0 mmol) of Cu(I)Br. The cadmium reagent
described above was added to the flask via syringe. The reaction
mixture was stirred under a nitrogen atmosphere at room
temperature. After stirring for 30 min, the cadmium reagent was
completely consumed as determined by 19F NMR analysis, 19F NMR
(CFCl3, DMF) ꢀ99.3 ppm (m, 2F), ꢀ117.4 ppm (m, 2F).
used directly or by methods previously developed in this
laboratory.
3.2. Preparation of 4-(2,3,5,6-
tetrafluoropyridyl)tributylphosphonium tetrafluoroborate
A dry, 1 l three-necked flask was equipped with a mechanical
3.6. Preparation of (E)-1-phenyl-3-(2,3,5,6-tetrafluoropyridyl)-1-
stirrer,
a
pressure-equalized addition funnel, and
a
low
propene, 5
temperature thermometer. The flask was charged with 300 mL
of anhydrous diethyl ether and 25.0 g (148 mmol) of penta-
In a typical experimental procedure, a dry, two-necked, 50 mL
round-bottomed flask equipped with a nitrogen inlet, septum port,
and a Teflon coated stir-bar was charged with 5 mL of dry DMF and
0.76 g (5.0 mmol) of (E)-cinnamyl chloride. The solution was
stirred under an argon atmosphere at room temperature, then a
solution of 1 (5.0 mmol) was added dropwise via syringe. After
stirring at room temperature for 1.5 h, the copper reagent had been
completely consumed as determined by 19F NMR analysis. The
mixture was poured into 200 mL of water and extracted with 3ꢂ
100 mL of CH2Cl2. The organic layer was separated, washed with
3ꢂ 100 mL of water, dried over anhydrous MgSO4, gravity filtered,
then concentrated using a rotary evaporator. The crude product
was introduced onto a silica-gel column, 3.5 cm o.d. ꢂ 20.0 cm
fluoropyridine. The resultant solution was stirred under
a
nitrogen atmosphere and cooled to ꢀ40 8C in an isopropanol/
dry ice bath. n-Tributylphosphine (30.0 g, 149 mmol) was added
dropwise to the solution via the pressure-equalized addition
funnel over 2 h at ꢀ45 to ꢀ35 8C; then 21.0 g (149 mmol) of
BF3ꢁOEt2 was added dropwise via syringe. The reaction mixture
was stirred and warmed to RT. At this point, a white solid
deposited on the flask wall. The solvent was removed via syringe
and the solid was washed with 3ꢂ 100 mL of anhydrous diethyl
ether under a N2 atmosphere. The white solid was dried under
vacuum for 15 min to give 61.8 g (95%) of 4-(2,3,5,6-tetrafluor-
opryidyl)tributylphosphonium tetrafluoroborate. 19F NMR:
d
ꢀ86.6 (m, 2F), ꢀ131.1 (m, 2F), ꢀ151.8 (s, 4F); 1H NMR:
d
d
2.7 (m,
144.7
long (Baker, 40 mm), and eluted with hexane. The elute containing
3
6H), 1.6 m (12H), 1.0 (t, JHH = 7.1 Hz, 9H); 13C NMR:
the product was collected and the solvent was removed by rotary
evaporation followed by evaporation under vacuum to give 1.15 g
(86%) yield of (E)-1-phenyl-3-(2,3,5,6-tetrafluoropyridyl)-1-pro-
1
1
(dm, JCF = 251.3 Hz), 143.1 (dm, JCF = 265.1 Hz), 113.6 (dt,
1JCP = 64.2 Hz, JCF = 17.1 Hz), 20.2 (d, JCP = 44.7 Hz), 13.1 (s)
2
1
23.8 (s), 23.6 (s); 31P NMR:
d
38.0 (m).
pene as a solid, mp: 92–94 8C. 19F NMR:
d
ꢀ91.9 (m, 2F), ꢀ145.7 (m,
3
3
2F); 1H NMR:
d
3.6 (dm, JHH = 6.9 Hz, 2H), 6.2 (dt, JHH = 15.6 Hz,
3.3. Preparation of 4-iodo-2,3.,5,6-tetrafluoropyridine
3JHH = 6.9 Hz, 1H), 6.5 (d, 3JHH = 15.7 Hz, 1H), 7.3 (m, 5H). 13C NMR:
d
143.4 (dtm, 1JCF = 244.1 Hz, 2JCF = 16.6 Hz), 140.4 (dm,
1JCF = 256.3 Hz), 132.9 (tm, JCF = 20.0 Hz), 136.3 (s), 133.8 (s),
2
The flask containing the phosphonium tetrafluoroborate was
re-pressurized with N2. Then, 250 mL of dry DMF, 94.0 g
(370 mmol) I2, and 39.3 g (370 mmol) of Na2CO3 were added
under a nitrogen atmosphere. The reaction mixture was stirred at
RT for 2 h; then flash distilled to give a mixture of DMF and
product. This mixture was poured into a sodium bisulfite solution.
The lower layer was separated, diluted with 200 mL Et2O, and
washed with 4ꢂ 300 mL H2O. The organic layer was separated and
dried over anhydrous MgSO4. The drying agent was removed by
gravity filtration and the product concentrated via rotary
evaporation. The last traces of solvent were removed under
vacuum at 0 8C to give 30.8 g (75%) of a white solid, mp 49–51 8C, 4-
128.6 (s), 127.9 (s), 126.3 (s), 122.2 (s), 27.7 (s). FTIR: (CCl4, cmꢀ1
)
1644.8 (m), 1469.6 (s), 1412.6 (m), 1253.4 (m), 964.4 (m). GC–MS:
m/z (relative intensity) 268 (M++1, 15.1), 267 (M+, 100.0), 266
(38.5), 247 (29.0), 117 (27.4), 91 (53.2), 77 (19.1). HRMS: calc’d. for
C14F4H9N 267.0671, obsv’d. 267.0655.
3.7. Preparation of 1-(2,3,5,6-tetrafluoropyridyl)-3-methyl-2-butene, 2
Similarly, 2 was prepared from 0.75 g (5.0 mmol) of 4-bromo-2-
methyl-2-butene in 5 mL of dry DMF and (5.0 mmol) of 1. Usual
work-up gave 0.7 g (61%) of 2, GLPC purity 98.4%. 19F NMR:
d
ꢀ92.3
1.7 (s, 3H), 1.8 (s, 3H), 3.5 (d,
143.4
iodo-2,3,5,6-tetrafluoropyridine. 19F NMR:
d
ꢀ89.9 m (2F), ꢀ123.1
(m, 2F), ꢀ145.3 (m, 2F); 1H NMR:
d
1
3
(m, 2F). 13C NMR:
d
143.7 (dm, JCF = 257.4 Hz), 142.8 (dm,
3JHH = 7.4 Hz, 2H), 5.2 (tm, JHH = 7.5 Hz, 1H). 13C NMR:
d
1JCF = 199.0 Hz), 88.7 (t, 2JCF = 26.1 Hz). FTIR (CCl4, cmꢀ1): 1612 (m),
1457 (s), 1442 (s), 1223 (m), 944 (m), 834 (m). GC–MS, m/z
(dm, JCF = 243.9 Hz), 140.4 (dm, JCF = 253.8 Hz), 134.4 (tt,
1
1
3
2JCF = 17.1, JCF = 4.6 Hz), 136.5 (s), 117.1 (s), 22.9 (s), 25.7 (s),

B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
151
1
1
17.7 (s). FTIR: (CCl4, cmꢀ1) 2917.6 (w), 1645.2 (m), 1472.0 (s),
1254.2 (m). GC–MS: m/z (relative intensity) 219 (M +, 100.0), 204
(70.4), 184 (68.6), 277 (47.3), 164 (46.7), 69 (14.8). HRMS: calc’d.
for C10F4H9N 219.0671, obsv’d. 219.0672.
144.1 (dm, JCF = 257.5 Hz), 139.7 (dm, JCF = 259.1 Hz), 129.9 (tt,
2JCF = 12.1 Hz, JCF = 5.5 Hz), 114.9 (m), 34.6 (s), 31.0 (s), 22.6 (s),
3
14.0 (s). FTIR: (CCl4, cmꢀ1): 1639.1 (m), 1470.9 (s), 977.9 (m). GC–
MS: m/z (relative intensity) 233 (M+, 8.8), 204 (4.4), 177 (100.0), 69
(21.5), 56 (37.1).
3.8. Preparation of 3-(2,3,5,6-tetrafluoropyridyl)cyclohexene, 3
3.13. Preparation of ethyl 2-(2,3,5,6-tetrafluoropyridyl)benzoate, 10
Similarly, 3, was prepared from 0.8 g (5.0 mmol) of 3-
bromocyclohexene in 5 mL of dry DMF and (5.0 mmol) of 1.
Usual work-up gave 0.95 g (82%) of 3 as a clear liquid, GLPC purity
Similarly, 10 was prepared from 1.4 g (5.0 mmol) of ethyl-2-
iodobenzoate in 5 mL of dry DMF and (5.0 mmol) of 1. Usual work-
100.0%. 19F NMR:
d
ꢀ92.4 (m, 2F), ꢀ144.6 (m, 2F). 1H NMR:
d
1.8
up gave 1.2 g (80%) of 10, mp 73–74 8C. 19F NMR:
d
ꢀ92.1 (m, 2F),
3
(m, 2H), 2.0 (m, 2H), 2.1 (m, 2H), 4.0 (m, 1H), 5.6 (dm,
ꢀ143.8 (m, 2F); 1H NMR:
d
1.2 (t, JHH = 7.1 Hz, 3H), 4.3 (q,
3JHH = 10.0 Hz, 1H), 5.9 (m, 1H); 13C NMR:
d
143.6 (dm,
3JHH = 7.1 Hz, 2H), 7.3 (dm, 3JHH = 7.5 Hz, 1H), 7.6 (m, 2H) 8.2 (dm,
1JCF = 242.7 Hz), 140.8 (dm, 1JCF = 250.7 Hz), 138.5 (tt,
3JHH = 7.8 Hz. 1H); 13C NMR:
d
165.5 (s), 143.4 (dm, 1JCF = 243.9 Hz),
3
1
2
3
2JCF = 18.0 Hz, JCF = 4.6 Hz), 129.5 (s), 125.2 (s), 33.6 (s), 28.1
139.4 (dm, JCF = 256.7 Hz), 134.8 (tt, JCF = 17.1 Hz, JCF = 3.3 Hz),
132.7 (s), 131.5 (s), 131.0 (s), 130.6 (s), 130.3 (s), 126.9 (s), 61.7 (s),
13.9 (s). FTIR: (CCl4, cmꢀ1): 1727.7 (s, C55O), 1645.8 (m), 1468.9 (s),
1269.3 (s), 1158.3 (m), 1081.0 (m), 957.1 (m). GC–MS: m/z (relative
intensity) 299 (M+, 34.3), 254 (63.4), 251 (100.0), 226 (26.4), 223
(28.6), 207 (26.7), 171 (23.1), 150 (15.4). HRMS: calc’d. for
(s), 24.3 (s), 22.1 (s). FTIR: (CCl4, cmꢀ1) 1469.5 (s), 958.7 (m). GC–
MS: m/z (relative intensity) 231 (M+, 68.1), 216 (100.0), 202 (31.2),
183 (46.0), 170 (29.2), 54 (78.7).
3.9. Preparation of (Z)-4-(2,3,5,6-tetrafluoropyridyl)-2-pentene, 4
C14F4H9NO2 299.0569, obsv’d. 299.0560.
Similarly, 4 was prepared from 0.5 g (5.0 mmol) of (Z)-4-chloro-
2-pentene in 5 mL of dry DMF and (5.0 mmol) of 1. Usual work-up
3.14. Preparation of (E)-1,1,1,2,2,3,3-heptafluoro-5-(2.3,5,6-
gave 0.8 g (74%) of 4, GLPC purity 99.4%. 19F NMR:
d
ꢀ92.4 (m, 2F),
tetrafluoropyridyl)-4-nonene, 9
3
ꢀ144.9 (m, 2F). 1H NMR:
d
1.5 (d, JHH = 6.9 Hz, 3H), 1.7 (d,
3JHH = 4.5 Hz, 3H), 4.0 (m, 1H), 5.6 (m, 2H). 13C NMR:
d
143.9 (dm,
Similarly, 9 was prepared from 1.9 g (7.0 mmol) of (E)-
1,1,1,2,2,3,3-heptafluoro-5-iodo-4-nonene in 5 mL of dry DMF
1
1JCF = 259.0 Hz), 140.5 (dm, JCF = 264.6 Hz), 130.2 (m), 130.4 (s),
127.9 (s), 34.6 (s), 18.9 (s), 17.6 (s).
and (5.0 mmol) of 1. Usual work-up gave 1.8 g (91%) of 9 as a liquid,
GLPC purity 100.0%. 19F NMR:
d
ꢀ143.2 (m, 2F), ꢀ128.3 (s, 2F),
3.10. Preparation of 1-(2,3,5,6-tetrafluoropyridyl)-1,2-propadiene 6
ꢀ108.2 (m, 2F), ꢀ89.7 (m, 2F), ꢀ80.8 (t, 4JFF = 8.7 Hz, 3F); 1H NMR:
d
3
0.9 (t, JHH = 6.7 Hz, 3H), 1.3 (m, 4H), 2.7 (m, 2H), 5.7 (t,
1
Similarly, 6 was prepared from 1.0 g (7.0 mmol) of propargyl
tosylate in 5 mL of dry DMF and (5.0 mmol) of 1. Usual work-up
3JHF = 14.5 Hz, 1H); 13C NMR:
d
143.8 (dm, JCF = 246.8 Hz), 143.3
1
2
(s), 139.1 (dm, JCF = 259.7 Hz), 133.5 (t, JCF = 16.5 Hz), 121.3 (t,
gave 0.6 g (63%) of 6, GLPC purity 100.0%. 19F NMR:
d
ꢀ92.7 (m, 2F),
2JCF = 24.1 Hz), 117.9 (qt, JCF = 287.0, JCF = 34.1 Hz), 114.0 (tt,
1
2
ꢀ144.6 (m, 2F). 1H NMR:
d
6.3 (t, JHH = 6.9 Hz, 1H), 5.3 (d,
1JCF = 254.1 Hz, 2JCF = 31.2 Hz), 108.9 (triplet of sextet,
4
4JHH = 6.9 Hz, 2H); 13C NMR: 214.5 (s), 143.5 (dm, 1JCF = 243.8 Hz),
1JCF = 264.9 Hz, JCF = 37.7 Hz), 31.5 (s), 30.1 (s), 22.5 (s), 13.4 (s).
2
1
2
139.1 (dm, JCF = 261.6 Hz), 127.5 (tm, JCF = 11.6 Hz). 80.1 (t,
3JCF = 2.8 Hz), 78.7 (s). FTIR: (CCl4, cmꢀ1): 1933.1 (w, C55C55C),
1639.8 (m), 1476.7 (s), 1423.7 (m). GC–MS: m/z (relative intensity)
189 (M+, 100.0), 170 (31.1), 162 (15.1). HRMS: calc’d. for C8F4H3N
189.0202, obsv’d. 189.0188.
FTIR: (CCl4, cmꢀ1): 1468.2 (s), 1231.3 (s), 1180.8 (m), 1116.1 (m),
971.8 (m). GC–MS: m/z (relative intensity) 401 (M+, 17.4), 359
(100.0).
3.15. Preparation of 1-(2,3,5,6-tetrafluoropyridine)-1-propanone, 11
3.11. Preparation of (E)-1-(2,3,5,6-
Similarly, 11 was prepared from 0.5 g (5.0 mmol) of propionyl
chloride in 5 mL of dry DMF and (5.0 mmol) of 1. Usual work-up
tetrafluoropyridyl)pentafluoropropene, 7
gave 0.8 g (77%) of 11, GLPC purity 98.7%. 19F NMR:
d
ꢀ88.8 (m, 2F),
3
Similarly, 7 was prepared from 1.3 g (5.0 mmol) of (Z)-1-iodo-
1-pentafluoropropene in 5 mL of dry DMF and (5.0 mmol) of 1.
ꢀ143.6 (m, 2F); 1H NMR:
d
1.3 (t, JHH = 7.2 Hz, 3H), 2.9 (q,
3JHH = 7.2 Hz, 2H); 13C NMR:
d
194.0 (m), 143.4 (dm,
1JCF = 262.1 Hz),
Usual work-up gave 1.2 g (85%) of 7, GLPC purity 99.5%. 19F NMR:
d
1JCF = 247.8 Hz),
138.3
(dm,
131.9 (t,
ꢀ68.7 (dd, 3JFF = 20.4, 4JFF = 10.2 Hz, 3F), ꢀ87.9 (m, 2F), ꢀ137.5 (m,
2JCF = 18.3 Hz), 37.9 (s), 6.6 (s). FTIR: (CCl4, cmꢀ1): 1729.4 (m,
C55O), 1466.8 (s), 1269.2 (m), 956.4 (m). GC–MS: m/z (relative
intensity) 207 (M+, 44.9), 178 (100.0), 150 (38.0), 57 (83.3).
3
3
2F), ꢀ141.7 (dm, JFF = 140.0 Hz, 1F), ꢀ157.0 (dm, JFF = 140.0 Hz,
1F). 13C NMR:
d 144.5 (dm, JCF = 245.1 Hz), 142.6 (ddm,
1
1JCF = 259.7 Hz, 2JCF = 42.3 Hz), 140.9 (ddm, 1JCF = 260.9 Hz,
2JCF = 46.3 Hz), 140.1 (dm, JCF = 276.4 Hz), 119.9 (m), 118.6
3.16. Preparation of methyl-4-(2,3,5,6-tetrafluoropyridyl)-4-oxo-
1
1
2
3
(qdd, JCF = 273.4 Hz, JCF = 35.3 Hz, JCF = 4.6 Hz). FTIR: (CCl4,
cmꢀ1): 1481.1 (s), 1380.8 (m), 1223.5 (s), 1170.7 (s), 967.9 (m).
GC–MS: m/z (relative intensity) 281 (M+, 4.8), 117 (100.0), 105
(20.6). HRMS: calc’d. for C8F9N 280.9887, obsv’d. 280.9879.
butanoate, 12
Similarly, 12 was prepared from 0.75 g (5.0 mmol) of 3-
carbomethoxypropionyl chloride in 5 mL of dry DMF and
(5.0 mmol) of 1. Usual work-up gave 1.1 g (83%) of 12, GLPC
3.12. Preparation of (E)-1-(2,3,5,6-tetrafluoropyridyl)-1-hexene, 8
purity 98.6%. 19F NMR:
d
ꢀ88.5 (m, 2F), ꢀ142.9 (m, 2F); 1H NMR:
d
3
3
2.8 (t, JHH = 6.5 Hz, 2H), 3.2 (t, JHH = 6.5 Hz, 2H), 3.7 (s, 3H); 13C
Similarly, 8 was prepared from 1.3 g (6.0 mmol) of (E)-1-iodo-
1-hexene in 4 mL of dry DMF and (5.0 mmol) of 1. Usual work-up
NMR: d
192.4 (s), 172.4 (s), 144.1 (dm, 1JCF = 247.8 Hz), 139.1 (dm,
1JCF = 264.0 Hz), 131.4 (t, 2JCF = 17.0 Hz), 52.2 (s), 39.5 (s), 27.8 (s).
FTIR: (CCl4, cmꢀ1): 1740.9 (m, C55O), 1468.4 (s), 1274.5 (m). GC–
MS: m/z (relative intensity) 265 (M+, 12.9), 234 (53.5), 178 (100.0),
150 (18.5), 115 (10.9). HRMS: calc’d. for C10F4H7NO2 265.0362,
obsv’d. 265.0361.
gave 1.0 g (85%) of 8, GLPC purity 98.3%. 19F NMR:
d
ꢀ93.1 (m, 2F),
ꢀ146.4 (m, 2F). 1H NMR:
d
0.9 (t, 3JHH = 7.2 Hz, 3H), 1.4 (m, 2H), 1.5
3
(m, 2H), 2.3 (m, 2H), 6.4 (d, JHH = 16.3 Hz, 1H), 6.9 (dt,
3JHH = 16.3 Hz, 3JHH = 7.0 Hz, 1H). 13C NMR: 147.3 (t, 3JCF = 7.6 Hz),
d

152
B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
3.17. Preparation of 4-benzoyl-2,3,5,6-tetrafluoropyridine, 13
cmꢀ1): 2250.8 (w, CBB C), 1638.3 (m), 1470.0 (s), 962.9 (m). GC–MS:
m/z (relative intensity) 231 (M+, 3.3), 216 (100.00), 188 (20.9).
HRMS: calc’d. for C11F4H9N 231.0671, obsv’d. 231.0678.
Similarly, 13 was prepared from 0.7 g (5.0 mmol) of benzoyl
chloride in 5 mL of dry DMF and (5.0 mmol) of 1. Usual work-up
gave 1.0 g (78%) of 13, GLPC purity 100.0%. 19F NMR:
d
ꢀ88.9 (m,
3.22. Preparation of 1-(2,3,5,6-tetrafluoropyridyl)-3-methoxy-1-
3
2F), ꢀ142.3 (m, 2F); 1H NMR:
d
7.5 (t, JHH = 7.6 Hz, 2H), 7.7 (tm,
propyne, 18
3
3JHH = 7.4 Hz, 1H), 7.9 (d, JHH = 8.1 Hz, 2H); 13C NMR:
d 184.6 (s),
1
1
143.8 (dm, JCF = 247.0 Hz), 138.2 (dm, JCF = 262.1 Hz), 131.9 (t,
2JCF = 19.6 Hz), 129.9 (s), 135.9 (s), 135.0 (s) 129.6 (s). FTIR: (CCl4,
cmꢀ1): 1693.4 (s, C55O), 1491.9 (m), 1648.0 (s), 1418.0 (m), 1318.8
(m), 1288.6 (s), 969.1 (m), 832.7 (m). GC–MS: m/z (relative
intensity) 255 (M+, 62.8), 105 (100.0), 77 (67.3).
Similarly, 18 was prepared from 1.4 g (7.0 mmol) of 1-iodo-3-
methoxypropyne in 5 mL of dry DMF and (5.0 mmol) of 1. Usual
work-up gave 0.9 g (82%) of 18 as a liquid, GLPC purity 100.0%. 19
F
NMR:
d
ꢀ90.6 (m, 2F), ꢀ138.6 (m, 2F); 1H NMR:
d 3.5 (s, 3H), 4.4 (s,
143.8 (dm, JCF = 245.1 Hz), 142.6 (dm,
1
2H); 13C NMR:
d
1JCF = 164.4 Hz), 117.0 (tt, JCF = 16.6 Hz, JCF = 4.5 Hz), 103.8 (t,
2
3
3
3.18. Preparation of 4-(2-bromobenzoyl)-2,3,5,6-tetrafluoropridine, 14
4JCF = 3.4 Hz), 70.8 (t, JCF = 3.9 Hz), 60.4 (s), 58.2 (s). FTIR: (CCl4,
cmꢀ1): 2250.8 (CBB C), 1638.9 (m), 1471.1 (s), 1095.8 (m), 964.3 (m).
GC–MS: m/z (relative intensity) 219 (M+, 6.2), 204 (3.3), 188
(100.0), 175 (7.5), 150 (4.4), 69 (21.7).
Similarly, 14 was prepared from 1.1 g (5.0 mmol) of 2-
bromobenzoyl chloride in 5 mL of dry DMF and (5.0 mmol) of 1.
Usual work-up gave 1.4 g (85%) of 14 as a white solid, mp: 74–
75 8C. 19F NMR:
d
ꢀ88.9 (m, 2F), ꢀ142.6 (m, 2F); 1H NMR:
d
7.6 (m,
3.23. Preparation of 3-(1-ethoxyethoxy)-1-(2,3,5,6-
2H), 7.7 (m, 2H); 13C NMR:
d
184.8 (s), 143.6 (dm, 1JCF = 248.1 Hz),
tetrafluoropyridyl)-propyne, 19
129.1 (dm, 1JCF = 264.8 Hz), 131.6 (m), 137.1 (s), 134.7 (s), 131.9 (s),
128.2 (s), 127.7 (s), 121.1 (s). FTIR: (CCl4, cmꢀ1) 1687.8 (w, C55O),
1466.7 (s), 1297.1 (m), 970.8 (m). GC–MS: m/z (relative intensity)
335 (M+, 22.8), 333 (M+, 23.5), 254 (6.9), 185 (98.8), 183 (100.0),
157 (33.4), 155 (34.5). HRMS: calc’d. for C12F4H4NO79Br 332.9412,
obsv’d. 332.9419.
Similarly, 19 was prepared from 1.8 g (7.0 mmol) of 3-(1-
ethoxyethoxy)-1-iodopropyne in 5 mL of dry DMF and (5.0 mmol)
of 1. Usual work-up gave 1.0 g (71%) of 19 as a white solid, mp: 52–
56 8C. 19F NMR:
d
ꢀ90.8 (m, 2F), ꢀ138.6 (m, 2F); 1H NMR:
d 1.2 (t,
3JHH = 7.1 Hz, 3H), 1.4 (d, 3JHH = 5.3 Hz, 3H), 3.7–3.5 (m, 2H), 4.3 (s,
3
2H), 4.9 (q, JHH = 5.3 Hz, 1H); 13C NMR:
d 143.9 (dm,
3.19. Preparation of 4-(4-bromobenzoyl)-2,3,5,6-tetrafluoropyridine,
1JCF = 245.1 Hz), 142.6 (dm, 1JCF = 264.5 Hz), 117.0 (tt,
3
4
15
2JCF = 16.3 Hz, JCF = 4.7 Hz), 104.5 (t, JCF = 3.4 Hz), 70.0 (t,
3JCF = 3.8 Hz), 99.6 (s), 61.6 (s), 52.9 (s), 19.8 (s), 15.4 (s). FTIR:
(CCl4, cmꢀ1): 2254.5 (w, CBB C), 1638.5 (m), 1471.1 (s), 1104.4 (m),
964.3 (m). GC–MS: m/z (relative intensity) 205 (M+ꢀC4H9O, 50.3),
204 (45.5), 188 (35.0), 186 (27.2), 157 (29.5), 156 (40.5), 106 (27.2).
Similarly, 15 was prepared from 1.1 g (5.0 mmol) of 4-
bromobenzoyl chloride in 5 mL of dry DMF and (5.0 mmol) of 1.
Usual work-up gave 1.2 g (72%) of 15 as a white solid, mp: 85–86 8C.
19F NMR:
NMR:
d
ꢀ88.3 (m, 2F), ꢀ141.9 (m, 2F); 1H NMR 7.7 (m, 4H); 13
C
1
d
183.5 (s), 143.7 (dm, JCF = 252.5 Hz), 138.6 (dm,
3.24. Preparation of (2,3,5,6-tetrafluoropyridyl)-(1-
1JCF = 262.7 Hz), 131.3 (m), 133.6 (s), 132.9 (s), 131.6 (s), 131.1 (s).
FTIR: (CCl4, cmꢀ1): 1690.5 (s, C55O), 1588.5 (m), 1467.7 (s), 1287.6
(m), 1071.8 (m), 949.9 (m). GC–MS: m/z (relative intensity) 335 (M+,
45.4), 333 (41.6), 185 (100.0), 183 (82.3), 157 (38.3), 155 (42.7), 150
(16.6), 76 (41.1).
cyclohexenyl)ethyne, 20
Similarly, 20 was prepared from 1.8 g (7.7 mmol) of 1-iodo-2-
(1-cyclohexenyl)ethyne in 5 mL of dry DMF and (5.0 mmol) of 1.
Usual work-up gave 1.1 g (85%) of 20 as a white solid, mp: 64–
65 8C. 19F NMR:
d
ꢀ91.6 (m, 2F), ꢀ139.5 (m, 2F); 1H NMR:
d 1.7 (m,
143.5 (dm,
3.20. Preparation of (E)-3-phenyl-1-(2,3,5,6-tetrafluoropyridyl)-2-
4H), 2.2 (m, 4H), 6.5 (m, 1H); 13C NMR:
d
1
propene-1-one, 16
1JCF = 244.7 Hz), 141.8 (dm, JCF = 262.7 Hz), 141.1 (s), 119.6 (s),
2
3
4
118.1 (tt, JCF = 16.7 Hz, JCF = 4.5 Hz), 109.1 (t, JCF = 3.0 Hz), 71.2
3
Similarly, 16 was prepared from 0.83 g (5.0 mmol) of (E)-
cinnamoyl chloride in 5 mL of dry DMF and (5.0 mmol) of 1. Usual
(t, JCF = 4.3 Hz), 28.4 (s), 26.1 (s), 22.1 (s), 21.2 (s). FTIR: (CCl4,
cmꢀ1): 2941.7 (m), 2211.6 (m, CBB C), 1621.2 (m), 1473.5 (s), 1182.3
(m), 943.7 (m). GC–MS: m/z (relative intensity) 255 (M+, 100.0),
239 (25.0), 208 (51.3), 191 (19.9), 151 (34.3), 128 (93.6), 94 (54.2).
work-up gave 1.3 g (93%) of 16 as a white solid, mp: 87–88 8C. 19
F
NMR:
d
ꢀ88.8 (m, 2F), ꢀ142.6 (m, 2F); 1H NMR:
d 7.0 (dm,
3JHH = 16.2 Hz, 1H), 7.4–7.6 (m, 6H); 13C NMR:
d 183.3 (s), 150.1 (s),
1
1
143.8 (dm, JCF = 236.8 Hz), 138.9 (dm, JCF = 262.7 Hz), 131.8 (t,
2JCF = 18.0 Hz), 133.3 (s), 132.3 (s), 129.3 (s), 129.2 (s), 125.3(s). FTIR:
(CCl4, cmꢀ1): 1671.6 (s, C55O), 1625.8 (m), 1606.6 (m), 1466.2 (s),
1450.9 (m), 1409.4 (m), 1287.6 (s), 1261.9 (m), 976.2 (m). GC–MS:
m/z (relative intensity) 281 (M+, 54.1), 280 (100.0), 131 (49.3), 103
(74.6), 77 (53.4).
3.25. Preparation of 1-(2,3,5,6-tetrafluoropyridyl)-2-phenylethyne, 21
Similarly, 21 was prepared from 1.8 g (8.0 mmol) of 1-iodo-2-
phenylethyne in 5 mL of dry DMF and (5.0 mmol) of 1. Usual work-
up gave 1.1 g (91%) of 21 as a white solid, mp: 120–121 8C. 19F
NMR:
d
ꢀ91.1 (m, 2F), ꢀ138.8 (m, 2F); 1H NMR:
d 7.4 (m, 3H), 7.6
143.6 (dm, JCF = 242.2 Hz), 141.9 (dm,
(m, 2H); 13C NMR:
d
1
3.21. Preparation of 1-(2,3,5,6-tetrafluoropridyl)-1-hexyne, 17
1JCF = 263.8 Hz), 132.4 (s), 130.7 (s), 128.8 (s), 120.6 (s), 117.5 (tt,
2JCF = 16.2 Hz, JCF = 4.2 Hz), 106.7 (t, JCF = 3.4 Hz), 73.5 (t,
3JCF = 3.8 Hz). FTIR: (CCl4, cmꢀ1): 2224.7 (m, CBB C), 1635.9 (m),
1455.2 (s). GC–MS: m/z (relative intensity) 251 (M+, 100.0).
3
4
Similarly, 17 was prepared from 1.4 g (7.0 mmol) of 1-
iodohexyne in 5 mL of dry DMF and (5.0 mmol) of 1. Usual
work-up gave 1.0 g (87%) of 17 as a clear liquid, GLPC purity 100.0%.
19F NMR:
d
ꢀ91.6 (m, 2F), ꢀ139.8 (m, 2F); 1H NMR:
d
1.0 (t,
3.26. Preparation of 2 via the phosphoniumtetrafluorobroate
methodology
3JHH = 7.3 Hz, 3H), 1.5 (m, 2H), 1.6 (m, 2H), 2.6 (t, 3JHH = 7.1 Hz, 2H);
13C NMR: 143.8 (dm, 1JCF = 244.3 Hz), 142.7 (dm, 1JCF = 262.5 Hz),
d
2
3
4
118.2 (tt, JCF = 16.7 Hz, JCF = 4.5 Hz), 110.4 (t, JCF = 3.2 Hz), 65.6
In a typical experimental procedure, a dry 50 mL, two-necked,
round-bottomed flask equipped with a septum port, a Teflon
3
(t, JCF = 3.8 Hz), 30.3 (s), 22.2 (s), 19.9 (s), 13.6 (s). FTIR: (CCl4,

B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
153
coated stir-bar, and a water condenser topped with a nitrogen
inlet, was charged with 3.1 g (7.0 mmol) of 4-tetrafluoropyridyl-
tributylphosphonium tetrafluoroborate, 1.1 g (10.0 mmol) of
Na2CO3, 1.0 g (7.0 mmol) of Cu(I)Br, and 15 mL of DMF. The
solution was stirred under a nitrogen atmosphere, then 0.8 g
(5.3 mmol) of 4-bromo-2-methyl-2-butene was added to the
reaction mixture and stirred overnight at room temperature. The
reaction mixture was loaded onto a chromatography column
packed with silica gel, and the product was eluted with hexane/
CH2Cl2 (8/2). Thin-layer chromatography was used to monitor the
fractionation. The fraction which contained the product was
concentrated by rotary evaporation. Any last traces of solvent were
removed under vacuum. The yield was 0.7 g (64%) of 2, GLPC purity
100%.
(10.0 mmol) of 4-iodo-2,3,5,6-tetrafluoropyridine, 0.18 g, 5.0 mol.%
of PdCl2 (PPh3)2, 0.03 g (3.0 mol.%) of Cu(I)I and 20 mL of Et3N. The
solution was stirred under a N2 atmosphere and heated overnight at
70 8C. After complete consumption of the iodopyridine (determined
by 19F NMR analysis of the reaction mixture), the reaction mixture
was cooled to RT, gravity filtered, and the solid was washed with
20 mL CH2Cl2. The filtrate was concentrated by rotary evaporation,
loaded onto a silica-gel chromatography column and the product
eluted with hexane. Thin-layer chromatography was used to
monitor the fractionation. The fraction that contained the product
was concentratedbyrotary evaporation;any lasttracesofsolid were
removed under vacuum. The yield of 21 (white solid) was 2.2 g
(88%). The data was similar to the data reported in 3.25. GC–MS: (m/
z) (relative intensity): 251 (M+, 100.0). HRMS: calc’d. for C13F4H4N
251.0358; obsv’d. 251.0373.
3.27. Preparation of 3 via the phosphonium tetrafluoroborate
methodology
3.32. Preparation of 1-(2,3,56-tetrafluoropyridyl)-2-(1-
aminocyclohexyl)ethyne, 22
Similarly,
3
was prepared from 3.1 g (7.0 mmol) of 4-
1.1 g
tetrafluoropyridyltributylphosphoniumtetrafluoroborate,
Similar to 3.31, 1.5 g (12.0 mmol) of 1-ethynylcyclohexylamine,
2.8 g (10.0 mmol) of 4-iodotetrafluoropyridine, 0.18 g (5.0 mol.%)
of PdCl2(PPh3)2, 0.03 g (3.0 mol.%) Cu(I)I and 20 mL of Et3N gave
after chromatography (CH2Cl2/acetone, 8/2) 2.0 g (73%), GLPC
(10.0 mmol) of Na2CO3, 1.0 g (7.0 mmol) of Cu(I)Br, 15 mL of
DMF, and 0.8 g (5.0 mmol) of 3-bromo-1-cyclohexene. Usual work-
up gave 0.8 g (69%) of 3, GLPC purity 97%.
purity, 100%, of liquid 22. 19F NMR:
1H NMR: 1.2–1.8 (m, 10H), 2.0 (m, 2H); 13C NMR: (CDCl3, TMS):
143.2 (dm, JCF = 244.6 Hz), 141.7 (dm, JCF = 263.1 Hz), 117.3 (tt,
d
ꢀ91.3 (m, 2F), ꢀ139.2 (m, 2F);
3.28. Preparation of 16 via the phosphoniumtetrafluoroborate
methodology
d
d
1
1
3
4
2JCF = 16.2 Hz, JCF = 3.9 Hz), 114.5 (t, JCF = 2.9 Hz), 67.2 (t,
3JCF = 4.1 Hz), 50.6 (s), 39.5 (s), 24.9 (s), 22.9 (s). FTIR: (CCl4,
cmꢀ1): 2938.7 (m), 2222.5 (w, CBB C), 1637.4 (m), 1469.8 (s), 964
(m). GC–MS (m/z) (relative intensity): 272 (M+, 0.9), 243 (16.1), 229
(100.0), 216 (12.6), 201 (13.6). HRMS: calc’d. for C13F4H12N2
272.0937; obsv’d. 272.0927.
Similarly, 16 was prepared from 3.1 g (7.0 mmol) of 4-
tetrafluoropyridyltributylphosphoniumtetrafluoroborate.
1.1 g
(10.0 mmol) of Na2CO3, 1.0 g (7.0 mmol) of Cu(I)Br, 15 mL of
DMF, and 0.8 g (5.0 mmol) of (E)-cinnamoyl chloride. Usual work-
up gave 1.1 g (78%) of 16.
3.29. Preparation of 4-[2,3,5,6-(tetrafluoropyridyl)]-benzoyl-2,3,5,6
tetrafluoropyridine 26 via the phosphonium tetrafluoroborate
methodology
3.33. Preparation of 1-(2,3,5,6-tetrafluoropridyl)-2-(1-
hydroxycyclohexyl) ethyne, 23
Similar to 3.31, 1.5 g (12.0 mmol) of 1-ethynyl-1-cyclohex-
anol, 2.8 g (10.0 mmol) of 4-iodotetrafluoropyridine, 0.18 g
(5.0 mol.%) of PdCl2(PPh3)2, 0.03 g (3.0 mol.%) Cu(I)I and 20 mL
of Et3N gave, after chromatography (ether/CH2Cl2, 2/8), 2.0 g (73%
Similarly, 26 was prepared from 3.1 g (7.0 mmol) of 4-
tetrafluoropyridltributylphosphoniumtetrafluoroborate,
1.1 g
(10.0 mmol) of Na2CO3, 1.0 g (7.0 mmol) of Cu(I)Br, 15 mL of
DMF and 1.1 g (5.0 mmol) of 2-bromobenzoyl chloride. Usual
work-up gave 0.5 g (49%) of 26 as a light yellow solid, mp: 154–
156 8C. 19F NMR: ꢀ87.8 (m, 2F), ꢀ90.9 (m, 2F), ꢀ141.5 (m, 2F),
ꢀ143.7 (m, 2F); 1H NMR: 7.5 (d, J = 7.6 Hz, 1H), 7.7 (m, 2H), 7.9 (td,
of 23 as a white solid, mp 67–68 8C. 19F NMR:
d
ꢀ90.8 (m, 2F),
ꢀ138.7 (m, 2F); 1H NMR: 1.3–2.2 (m, 10H), 2.3 (s, 1H); 13C NMR:
d
143.4 (dm, 1JCF = 245.3 Hz), 142.0 (dm, 1JCF = 263.9 Hz), 116.9 (tm,
2JCF = 16.1 Hz), 111.1 (t, 4JCF = 3.3 Hz), 68.7 (t, 3JCF = 10.9 Hz), 69.5
(s), 39.3 (s), 24.9 (s), 23.1 (s). FTIR: CCl4, cmꢀ1): 2940.9 (m), 2236.4
(w, CBB C), 1638 (m), 1469.7 (s), 1069.4 (m), 966.2 (s). GC–MS m/z
(relative intensity): 273 (M+, 1.6), 255 (11.7), 230 (59.3), 217
(62.2), 202 (36.2), 188 (25.9), 175 (30.1), 149 (47.7), 55 (71.9), 40
(100.0). HRMS: calc’d. for C13F4H11NO 273.0777, obsv’d.
273.0774.
4
3J HH = 7.3 Hz, JHH = 1.5 Hz, 1H); 13C NMR: 184.2 (s), 143.9 (dm,
1
1JCF = 246.6 Hz), 138.6 (dm, JCF = 264.8 Hz), 135.1 (s), 134.2 (s),
132.8 (m), 132.5 (s), 132.2 (s), 131.2 (s), 130.4 (tm, 2JCF = 18.6 Hz),
126.4 (s). FTIR: 1699.9 (w, C55O), 1471.4 (s). GC–MS: m/z (relative
intensity) 404 (M+, 50.3), 385 (12.3), 254 (100.0), 226 (40.6), 206
(33.7), 150 (17.3).
3.30. Preparation of 15 via the phosphonium tetrafluoroborate
3.34. Preparation of 4-(2,3,5,6-tetrafluoropyridyl)-2-methyl-3-
methodology
butyne-2-ol, 24
Similarly, 15 was prepared from 3.1 g (7.0 mmol) of 4-
tetrafluoropyridyltributyl-phosphoniumtetrafluoroborate, 1.1 g
(10.0 mmol) of Na2CO3, 1.0 g (7.0 mmol) of Cu(I)Br, 15 mL of
DMF, and 1.1 g (5.0 mmol) of 4-bromobenzoyl chloride. Usual
work-up gave 1.1 g (66%) of 15.
Similar to 3.31, 1.0 g (12.0 mmol) of 2-methyl-3-butyne-2-ol,
2.8 g
(10.0 mmol)
of
4-iodotetrafluoropyridine,
0.18 g
(5.0 mol.%) of PdCl2(PPh3)2, 0.03 g (3.0 mol.%) Cu(I)I and 20 mL
of Et3N, gave after chromatography (CH2Cl2), 2.1 g (92%) of 24 as
a white solid, mp 56–58 8C, 19F NMR:
d
ꢀ91.1 (m, 2F), ꢀ138.9
(m, 2F); 1H NMR:
d
1.7 (s, 6H), 3.4 (s, 1H); 13C NMR (CDCl3, TMS):
1
1
3.31. Preparation of 1-(2,3,5,6-tetrafluoropyridyl)-2-phenylethyne,
d
143.4 (dm, JCF = 245.2 Hz), 142.2 (dm, JCF = 264.2 Hz), 117.2
2
3
4
21 via Pd coupling
(tt, JCF = 16.0 Hz, JCF = 4.6 Hz), 111.9 (t, JCF = 3.4 Hz), 66.7 (t,
3JCF = 3.7 Hz), 66.1 (s). 30.2 (s). FTIR: (CCl4, cmꢀ1): 2238.6 (w,
CBB C), 1637.7 (m), 1469.9 (s), 966.2 (m). GC–MS: (m/z)
(relative intensity): 233 (M+, 1.4), 218 (100.0), 175 (13.0), 43
(67).
A dry 50 mL, two-necked flask, equipped with a rubber septum, a
Teflon coated stir bar and a water condenser topped with a nitrogen
inlet, was charged with 1.2 g (12.0 mmol) of phenylacetylene, 2.8 g

154
B. Van Nguyen, D.J. Burton / Journal of Fluorine Chemistry 135 (2012) 144–154
3.35. Preparation of (Z)-1-methoxy-4-(2,3,5,6-tetrafluoropyridyl)-1-
route to the alkyne derivatives was developed via the Pd(0)
butene-3-yne, 25
catalyzed reaction of 4-iodotetrafluoroyridine with 1-alkynes.
Acknowledgements
Similar to 3.31, 1.0 g (12.0 mmol) of (Z)-1-methoxy-1-butene-
3-yne, 2.8 g (10.0 mmol) of 4-iodotetrafluoropyridine, 0.18 g
(5.0 mol.%) of PdCl2(PPh3)2, 0.03 g (3.0 mol.%) Cu(I)I and 20 mL
Et3N gave, after chromatography (petroleum ether), 0.8 g (35%) of
We thank the National Science Foundation (NSF) for support of
this research.
25 as a white solid, mp 45–47 8C, 19F NMR:
d
ꢀ91.8 (m, 2F), ꢀ139.6
3
(m, 2F); 1H NMR:
d
3.9 (s, 3H), 4.8 (d, JHH = 6.5 Hz, 1H), 6.6 (d,
References
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d
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4. Conclusions
A new and improved preparation of 4-iodo-2,3,5,6-tetrafluor-
opyridine is described. The 4-iodo-2,3,5,6-tetrafluoropyridine is
utilized for the in situ preparation of the 4-tetrafluoropridylcopper
reagent via two methods This copper reagent readily undergoes
reaction with allylic halides, vinyl iodides, aryl halides, acid
chlorides and acetylenic iodides to stereospecificially afford the
corresponding 4-tetrafluoropyridyl derivatives. An alternative