An efficient synthesis of (fluoromethyl)pyridylamines for labeling with fluorine-18

Article abstract of DOI:10.1021/jo990994f

We have described a two-step method for the preparation of (fluoromethyl)pyridyl-substituted amines. The sequence involves fluoride ion displacement of methanesulfonates (mesylates) of 6-chloro-α-hydroxy-2- and - 3-picolines, followed by arylation of the amine by chloropicoline. We have called this sequence fluorination-N-arylation. 1-Phenylpiperazine has been used as a model amine. Two key precursors for this sequence are the mesylates of 6-chloro-α-hydroxy-2- and -3-picolines. The former was synthesized in four steps from 6-chloro-2-picoline in 78% yield and the latter in three steps from 6-chloronicotinic acid in 53% yield. This fluorination-N-arylation sequence is sufficiently rapid and efficient for the preparation of a variety of aryl-substituted amine compounds labeled with the short half-life (t( 1/2 ) = 110 min) positron-emitting radionuclide fluorine-18.

Full text of DOI:10.1021/jo990994f

8576
J . Org. Chem. 1999, 64, 8576-8581
An Efficien t Syn th esis of (F lu or om eth yl)p yr id yla m in es for
La belin g w ith F lu or in e-18
Kyo Chul Lee and Dae Yoon Chi*
Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Korea
Received J une 22, 1999
We have described a two-step method for the preparation of (fluoromethyl)pyridyl-substituted
amines. The sequence involves fluoride ion displacement of methanesulfonates (mesylates) of
6-chloro-R-hydroxy-2- and -3-picolines, followed by arylation of the amine by chloropicoline. We
have called this sequence fluorination-N-arylation. 1-Phenylpiperazine has been used as a model
amine. Two key precursors for this sequence are the mesylates of 6-chloro-R-hydroxy-2- and -3-
picolines. The former was synthesized in four steps from 6-chloro-2-picoline in 78% yield and the
latter in three steps from 6-chloronicotinic acid in 53% yield. This fluorination-N-arylation sequence
is sufficiently rapid and efficient for the preparation of a variety of aryl-substituted amine compounds
labeled with the short half-life (t1/2 ) 110 min) positron-emitting radionuclide fluorine-18.
Sch em e 1
In tr od u ction
Although positron-emitting radiopharmaceuticals la-
beled with the short-lived positron emitting radionuclide
fluorine-18 (t1/2 ) 110 min) are being increasingly used
in clinical diagnosis, there are few chemical processes
suitable for the introduction of fluorine-18 into the
organic molecules. We have described a two-step process
for the preparation of [18F]fluoroalkyl-substituted amines
and amides that involves a fluoride ion displacement of
highly reactive trifluoromethylsulfonate (triflate)-substi-
tuted alkyl halide followed by an N-alkylation step in
1986.1 This amine fluoroalkyation sequence has been
widely used by us and others to prepare [18F]fluoroalkyl-
substituted ligands for neuroreceptors.2,3 More recently,
fluorobenzylation,4 fluorobenzoylation,5 and (fluorometh-
yl)benzylation6 methods have been developed using re-
lated fluorination-N-alkylation sequences (Scheme 1).
As part of a program to develop some dopamine D4
receptor antagonists as potential imaging agents for
positron emission tomography (PET), we needed a new
method to introduce fluroine-18. Kulagowski et al. re-
ported that 7-azaindole 1 is an antagonist having high
* To whom correspondence should be addressed. Tel: +82-32-860-
7686. Fax: +82-32-867-5604. E-mail: dychi@ inha.ac.kr.
(1) (a) Chi, D. Y.; Kilbourn, M. R.; Katzenellenbogen, J . A.; Brodack,
J . W.; Welch, M. J . Appl. Radiat. Isot. 1986, 37, 1173. (b) Chi, D. Y.;
Kilbourn, M. R.; Katzenellenbogen, J . A.; Brodack, J . W.; Welch, M. J .
J . Org. Chem. 1987, 52, 658.
(2) (a) Welch, M. J .; Katzenellenbogen, J . A.; Mathias, C. J .; Brodack,
J . W.; Carlson, K. E.; Chi, D. Y.; Dence, C. S.; Kilbourn, M. R.;
Perlmutter, J . S.; Raichle, M. E.; Ter-Pogossian, M. M. Nucl. Med. Biol.
1988, 15, 83-97. (b) Shiue, C.-Y.; Bai, L.-Q.; Teng, R.; Wolf, A. P. J .
Labeled Compd. Radiopharm. 1987, 24, 53-64. (c) Kiesewetter, D. O.;
Brucke, T.; Finn, R. D. Appl. Radiat. Isot. 1989, 40, 455. (d) Mulhol-
land, G. K.; J ung, Y.-W.; Wieland, D. M.; Kilbourn, M. R.; Kuhl, D. E.
J . Labeled Compd. Radiopharm. 1993, 33, 583. (e) Wilson, A. A.;
Dasilva, J . N.; Houle, S. Appl. Radiat. Isot. 1995, 46, 765.
(3) (a) Shiue, C.-Y.; Bai, L.-Q.; Teng, R.; Wolf, A. P. J . Labeled
Compd. Radiopharm. 1987, 24, 53. (b) Block, D.; Coenen, H. H.; Laufer,
P.; Stoklin, G. J . Labeled Compd. Radiopharm. 1986, 23, 1042.
(4) Mach, R. H.; Scripko, J . G.; Ehrenkaufer, R. L.; Morton, T. E. J .
Labeled Compd. Radiopharm. 1991, 30, 154.
affinity and selectivity for the D4 receptor, relative to the
D2 and D3 receptors.7 On the basis of the structure of
compound 1, we designed compounds 2 and 3 as target
compounds by introducing a [18F]fluoromethyl group as
(5) Eastman, R. C.; Carson, R. E.; J acobson, K. A.; Shai, Y.;
Channing, M. A.; Dunn, B. B.; Bacher, J . D.; Baas, E.; J ones, E.; Kirk,
K. L.; Lesniak, M. A.; Roth, J . Diabetes 1992, 41, 855.
(6) Choe, Y. S.; Song, D. H.; Lee, K.-J .; Kim, S. E.; Choi, Y.; Lee, K.
H.; Kim, B.-T.; Oh, S. J .; Chi, D. Y. Appl. Radiat. Isot. 1998, 49, 1173.
(7) Kulagowski, J . J .; Broughton, H. B.; Curtis, N. R.; Mawar, I.
M.; Ridgill, M. P.; Baker, R.; Emms, F.; Freedman, S. B.; Marwood,
R.; Patel, S.; Patel, S.; Ragan, C. I.; Leeson, P. D. J . Med. Chem. 1996,
39, 1941.
10.1021/jo990994f CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

(Fluoromethyl)pyridylation of Amines
J . Org. Chem., Vol. 64, No. 23, 1999 8577
Sch em e 2
Sch em e 3a
a
well as nitrogen atom (including its N-oxide) into the
phenyl ring. As shown in Scheme 1, fluorination-N-
arylation could be a very useful method to prepare these
target compounds in fluorine-18 labeled form. This
procedure uses a direct nucleophilic substitution of
fluoride ion, which is suitable for preparation of F-18
labeled compounds with a high specific activity, a re-
quirement for many site-specific imaging agents.
Key: (a) m-CPBA, CHCl3, 50 °C, 12 h, 99%; (b) Ac2O, H2SO4,
110 °C, 3 h; (c) K2CO3, MeOH/H2O, rt, 15 min, 83% from 9; (d)
MsCl, Et3N, CH2Cl2, 0 °C, 30 min, 96%; (e) m-CPBA, CHCl3, 50
°C, 12 h, 99%; (f) nBu4NF‚xH2O, Et3N, CH3CN, reflux, 4 h, 43%.
ally slow, the use of chlorobenzenes is not practical for
labeling with fluorine-18. A comparison of the SNAr
reactions of chlorobenzene and chloropyridines with
methoxide ion shows reaction rates of 2-, 3-, and 4-chlo-
ropyridine to be 2.76 × 108, 9.12 × 104, and 7.43 × 109,
respectively, relative to the rate of chlorobenzene.9a When
we have performed the SNAr reaction of 2-chloropyridine
with N-phenylpiperazine, the reaction has not been
successful.
A comparison of SNAr reactions of chloro-1-methylpy-
ridinium ions with methoxide ion shows these reaction
rates of 2-, 3-, and 4-chloro-1-methylpyridinium to be 1.28
× 1021, 2.62 × 1013, and 4.23 × 1019, respectively, relative
to the rate of chlorobenzene.9a Thus, N-methyl salts of
chloropyridines react faster than their nonalkylated
analogues by roughly a factor of 1010. The rationale for
using chloropyridinium N-oxide is as follows: (1) the
removal of the methyl group of 1-methylpyridiniums is
not always easy; (2) chloropyridinium N-oxides are
readily deoxygenated; (3) their SNAr reactivity is expected
to be between that of chloropyridines and the chloro-1-
methylpyridinium ions. (In the literature, the SNAr
reactions rates of 2-, 3-, and 4-chloropyridinium N-oxide
with methoxide ion are 5.32 × 1012, 1.00 × 1010, and 8.14
× 1012, respectively.)9b
Despite the usefulness of the fluorination-N-arylation
sequence, however, there have been no reports on the use
of this sequence for labeling with fluorine-18. Here, we
report the first example of this fluorination-N-arylation
sequence.
Resu lts a n d Discu ssion
Gen er a l Str a tegy. A retrosynthetic scheme to the
6-amino-R-fluoro-2-picoline 4 and its N-oxide 5 using the
two-step process is outlined in Scheme 2. Compound 4
could be obtained by deoxygenation of N-oxide 5. The
amine can be arylated with chloropicoline N-oxide 6
by a nucleophilic aromatic substitution displacement
(SNAr) reaction. 6-Chloro-R-hydroxy-2-picoline N-oxide
can be derivatized as the moderately reactive sulfonate
ester (e.g., mesylate, 7); fluoride ion displaces the mesy-
late, providing 6. In this paper, we describe a method
for the rapid and efficient synthesis of 6-amino-R-fluoro-
2-picoline N-oxide using a two-step process: (1) fluoride
ion displacement of a mesylate, followed by (2) N-aryla-
tion with 6-chloro-R-fluoro-2-picoline N-oxide 6. These
two reactions can be conducted as a “one-pot” reaction.
Recently, N-oxide compounds themselves have been
shown to have reasonable metabolic stability and en-
hanced bioavailability.8 Because the N-oxide can easily
be removed by treatment with PCl3, the (fluoromethyl)-
pyridyl-substituted amine can be used either as the
N-oxide 5 or the amine itself (4), thereby providing two
potentially interesting compounds having a different
polarity.
Syn th esis of 6-Ch lor o-r-m eth a n esu lfon yloxy-2-
p icolin e N-Oxid e (7) a n d F lu or in a tion . The prepara-
tion of 6-chloro-R-methanesulfonyloxy-2-picoline N-
oxide 7, the precursor of a two-step process, is shown in
Scheme 3.
Overnight treatment of 6-chloro-2-picoline (8) with
m-CPBA at 50 °C in chloroform provides the N-oxide 9
in 99% isolated yield. Use of other peroxides such as
hydrogen peroxide gave lower yields. Because the N-oxide
is very polar, it is easily lost during standard aqueous
workup. However, after quenching with a minimum
amount of water, removal of solvent and silica gel
(8) (a) Mallams, A. K.; Rossman, R. R.; Doll, R. J .; Girijavallabhan,
V. M.; Ganguly, A. K.; Petrin, J .; Wang, L.; Patton, R.; Bishop, W. R.;
Carr, D. M.; Kirschmeier, P.; Catino, J . J .; Bryant, M. S.; Chen, K.-J .;
Korfmacher, W. A.; Nardo, C.; Wang, S.; Nomeir, A. A.; Lin, C.-C.; Li,
Z.; Chen, J .; Lee, S.; Dell, J .; Lipari, P.; Malkowski, M.; Yaremko, B.;
King, I.; Liu, M. J . Med. Chem. 1998, 41, 877. (b) Bell, I. M.; Erb, J .
M.; Freidinger, R. M.; Gallicchio, S. N.; Guare, J . P.; Guidotti, M. T.;
Halpin, R. A.; Hobbs, D. W.; Homnick, C. F.; Kuo, M. S.; Lis, E. V.;
Mathre, D. J .; Michelson, S. R.; Pawluczyk, J . M.; Pettibone, D. J .;
Reiss, D. R.; Vickers, S.; Williams, P. D.; Woyden, C. J . J . Med. Chem.
1998, 41, 2146.
(9) (a) Newkome, G. R.; Paudler, W. W. In Contemporary Hetero-
cyclic Chemistry; J ohn Wiley & Sons: New York, 1982; pp 262-263.
(b) J oule, J . A.; Mills, K.; Smith, G. F. In Heterocyclic Chemistry, 3rd
ed.; Chapman and Hall: London, 1995; p 25.
The SNAr reaction has been used for the arylation of
amines. As the SNAr reaction of chlorobenzene is gener-

8578 J . Org. Chem., Vol. 64, No. 23, 1999
Lee and Chi
Sch em e 4a
Sch em e 5a
a
Key: (a) 1-phenylpiperazine, Et3N, DMF, 180 °C, 2 h, 53%;
(b) PCl3, CHCl3, rt, 2 h, 99%.
Sch em e 6a
a
Key: (a) 1-phenylpiperazine, Et3N, EtOH/CH3CN, 130 °C, 3
h, 44%; (b) PCl3, CHCl3, rt, 2 h, 99%.
a
Key: (a) BH3‚S(CH3)2, THF, reflux, 16 h, 79%; (b) m-CPBA,
CHCl3, 50 °C, 12 h, 92%; (c) MsCl, Et3N, CH2Cl2, 0 °C, 20 min,
73%; (d) nBu4NF, Et3N, THF, reflux, 4 h, 30%; (e) MsCl, Et3N,
CH2Cl2, 0 °C, 20 min, 76%; (f) nBu4NF, Et3N, THF, reflux, 4 h,
49%; (g) m-CPBA, CHCl3, 50 °C, 12 h, 12%; (h) m-CPBA, CHCl3,
50 °C, 12 h, 5%.
tion of 6-chloro-R-fluoro-3-picoline (16) with 1-phenylpip-
erazine. However, the reactivity of the pyridine ring is
not sufficient for this SNAr reaction to proceed. As
discussed previously in the General Strategy section, the
electron density of each carbon of pyridine is changed
significantly upon the formation of the N-oxide. The
negative charge on oxygen makes the C4 and C2 (or
C6) carbons negative by resonance. However, the induc-
tive effect of the positive charge on nitrogen diminishes
the resonance effect on the C2 carbon, consequently
making the C2 carbon more positive. Thus, the SNAr
reaction of the N-oxide compound on C2 carbon proceeds
more easily.
chromatography afforded N-oxide 9 in high yield. Upon
treatment with acetic anhydride, this material under-
went a novel rearrangement to provide a 2-picoline
acetate,10 which was saponified with potassium carbonate
in 2:1 MeOH/H2O to give alcohol 10 in 83% yield from 9.
Mesylation of alcohol 10, followed by oxidation with
m-CPBA, afforded a key intermediate, mesylate N-oxide
7, in high yield.
1
In H NMR, the CH2 peaks of compounds 10, 11, and
The optimized yields for the SNAr reaction of 6 and 16
were 53 and 44% (Schemes 5 and 6). In the reaction of
6, only monoaminated product 19 was obtained. On the
other hand, in the reaction of 16, diaminated product 23
was also obtained. A possible explanation for this is that
the fluoromethylene group is activated toward nucleo-
philic attack by hyperconjugation, which is induced by
resonance donation by the lone pair electron on the
nitrogen of monoaminated product 21. Removal of N-
oxide was carried out by the treatment of compounds 19
and 21 with phosphorus trichloride to give 20 and 22,
respectively, in quantitative yield.
7 each appeared at characteristic chemical shifts, δ 4.64,
5.29, and 5.47, respectively, resulting in easy identifica-
tion. The displacement reaction of mesylate 7 with
fluoride ion proceeded within 30 min at 110 °C in
acetonitrile when an appropriate soluble source of fluo-
ride ion such as n-Bu4NF was used. The introduction of
fluorine is easily identified by 1H NMR, in which the
signal for the doublet peaks of CH2F group at 5.66 ppm
is a doublet due to typical geminal coupling with fluorine
(J ) 46.8 Hz).
Syn th esis of 6-Ch lor o-r-m eth a n esu lfon yloxy-3-
p icolin e N-Oxid e (15) a n d F lu or in a tion . Reduction
of 6-chloronicotinic acid with borane dimethyl sulfide was
performed in THF at reflux for 16 h, providing alcohol
13. As shown in Scheme 4, three transformation routes
are possible from compound 13 to compound 16, b-c-d,
e-h-d, and e-f-g. By comparison of the N-oxidation
steps b, h, and g, we found that step b gave high yield
(92%), whereas the other steps h (5%) and g (12%) gave
much lower yields. Both mesylates 17 and 15 were
obtained from alcohols 13 and 14, respectively, at 0 °C,
in reasonable yield. If the reaction temperature was
raised above 0 °C by adding mesyl chloride too rapidly,
R-chloro-6-chloro-3-picoline was obtained.
(Flu or om eth yl)pyr idylation of am in e. 1-Phenylpip-
erazine was used as a model compound for the amine
arylation step (Schemes 5 and 6). The reaction of both
N-oxides 6 and 16 proceeded with moderate to good
efficiency in DMF. To prepare 1-phenyl-4-(R-fluoro-3-
picolin-6-yl)piperazine (22), we performed the SNAr reac-
One might suspect that fluorine in the “benzylic
position” in compounds 20 and 22 might not be stable
toward in vivo metabolism due to the electron deficiency
generated by the pyridine ring. Although some radiotrac-
ers, such as 3-(4-([18F]fluoromethyl)phenyl)ecgonine11 and
(10) Ochiai, E. In Aromatic Amine Oxides; Elsevier: New York, 1967;
pp 290-302.

(Fluoromethyl)pyridylation of Amines
J . Org. Chem., Vol. 64, No. 23, 1999 8579
Hz); 13C NMR (50 MHz, CDCl3) δ 62.46, 117.43, 121.01, 137.87,
148.80, 159.78; MS (CI) m/z 144 (MH+). Anal. Calcd for C6H6-
ClNO: C, 50.20; H, 4.21; N, 9.76. Found: C, 49.99; H, 4.24;
N, 9.75.
([18F]fluoromethyl)benzoylated insulin,5 which have ben-
zylic fluoride, showed good in vivo stability, in general
benzylic fluorides do not have good in vivo stability.
However, according to our experience, the in vivo stability
of fluorine-substituted radiopharmaceuticals depends on
the position as well as the electronic density of the
methylene group of benzylic fluoride.12 In this regard, one
might expect (fluoromethyl)pyridines to be more stable
than the corresponding fluorobenzyl compounds. How-
ever, the introduction of amino groups such as phen-
ylpiperazinyl on the C6 position of the pyridine ring will
increase the electron density of pyridine ring, which may
increase its metabolic lability. To avoid the instability of
benzylic fluoride, we are applying this method to homolo-
gated compounds such as 6-chloro-2-(2-fluoroethyl)pyri-
dine N-oxide and 6-chloro-2-(3-fluoropropyl)pyridine N-
oxide.
6-Ch lor o-r-m et h a n esu lfon yloxy-2-p icolin e (11). To
6-chloro-R-hydroxy-2-picoline (1.23 g, 8.60 mmol) in meth-
ylene chloride (20 mL) were added triethylamine (1.80 mL,
12.90 mmol) and methanesulfonyl chloride (666 µL, 8.60
mmol) at 0 °C. After 30 min, the reaction mixture was
quenched with H2O. The reaction mixture was extracted with
methylene chloride, and the organic layer was dried (Na2SO4)
and evaporated. Flash column chromatography (80%
EtOAc/hexane) provided 11 (1.82 g, 96%) as a yellow oil: 1H
NMR (200 MHz, CDCl3) δ 3.14 (s, 3H), 5.29 (s, 2H), 7.35 (d,
1H, J ) 8.2 Hz), 7.43 (d, 1H, J ) 6.8 Hz), 7.75 (t, 1H, J ) 7.3
Hz); 13C NMR (50 MHz, CDCl3) δ 36.35, 68.71, 119.03, 122.66,
138.13, 152.90; MS (EI) m/z 221 (M+). Anal. Calcd for C7H8-
ClNO3S: C, 37.93; H, 3.64; N, 6.32; S, 14.47. Found: C, 38.25;
H, 3.73; N, 6.30; S, 14.41.
6-Ch lor o-r-m eth an esu lfon yloxy-2-picolin e N-Oxide (7).
To 6-chloro-R-methanesulfonyloxy-2-picoline (679 mg, 3.07
mmol) in chloroform (10 mL) was added m-CPBA (795 mg,
4.61 mmol) at room temperature, and then the mixture was
heated to 50 °C for 12 h. The reaction mixture was dried
(Na2SO4) and concentrated. The product 7 was obtained as a
yellow solid (342 mg, 47%) by flash column chromatography
(cosolvents: 80% EtOAc/hexane, 2% MeOH/CH2Cl2) and re-
crystallization (40% EtOAc/hexane): mp 98.5-98.8 °C; 1H
NMR (200 MHz, CDCl3) δ 3.20 (s, 3H), 5.47 (s, 2H), 7.29 (t,
1H, J ) 7.9 Hz), 7.53 (t, 2H, J ) 8.4 Hz); 13C NMR (50 MHz,
CDCl3) δ 35.94, 63.81, 121.09, 123.76, 124.87, 140.50, 144.97;
MS (EI) m/z 237 (M+). Anal. Calcd. for C7H8ClNO4S: C, 35.38;
H, 3.39; N, 5.89; S, 13.49. Found: C, 35.60; H, 3.40; N, 5.85;
S, 13.14.
6-Ch lor o-r-flu or o-2-p icolin e N-Oxid e (6). To 6-chloro-
R-methanesulfonyloxy-2-picoline N-oxide (461 mg, 1.95 mmol)
in acetonitrile (10 mL) was added tetra-n-butylammonium
fluoride hydrate (615 mg, 1.95 mmol), and the mixture was
heated at 80 °C for 4 h (or 110 °C for 30 min in a pressure
bottle). The reaction mixture was extracted with ethyl ace-
tate and washed (H2O, brine), and the organic layer was dried
(Na2SO4) and evaporated. Flash column chromatography (80%
EtOAc/hexane) provided 6 (136 mg, 43%) as a yellow oil: 1H
NMR (200 MHz, CDCl3) δ 5.66 (d, 2H, J ) 46.8 Hz), 7.31 (t,
1H, J ) 7.6 Hz), 7.45 (d, 1H, J ) 7.4 Hz), 7.52 (d, 1H, J ) 7.8
Hz); 13C NMR (50 MHz, CDCl3) δ 77.19 (d, J ) 171.9 Hz),
118.50, 118.67, 123.76; MS (CI) m/z 162 (MH+). Anal. Calcd
for C6H5ClFNO: C, 44.61; H, 3.12; N, 8.67. Found: C, 45.01;
H, 3.39; N, 8.80.
r-F lu or o-6-(4-p h en ylp ip er a zin yl)-2-p icolin e N-Oxid e
(19). In a 5 mL Reacti‚vial, to 6-chloro-R-fluoro-2-picoline
N-oxide (47 mg, 0.29 mmol) in 1.5 mL of DMF were added
triethylamine (61 µL, 0.44 mmol) and 1-phenylpiperazine (45
µL, 0.29 mmol), and then the reaction mixture was heated 180
°C for 2 h. After the reaction mixture was cooled to room
temperature, it was extracted with methylene chloride, washed
(H2O, brine), and dried (Na2SO4). After the organic layer was
removed by vacuum, flash column chromatography (80%
EtOAc/hexane) provided 19 (33 mg, 40%) as a brown oil: 1H
NMR (200 MHz, CDCl3) δ 3.31-3.51 (m, 8H), 5.58 (d, 2H,
J ) 47.4 Hz), 6.80-6.93 (m, 4H), 7.07 (d, 1H, J ) 9.0 Hz),
7.19-7.30 (m, 3H); 13C NMR (50 MHz, CDCl3) δ 46.12, 47.47,
77.48 (d, J ) 170.7 Hz), 112.70, 112.88, 114.90, 118.69, 125.24,
127.59, 149.58, 152.61; MS (CI) m/z 288 (MH+); HRMS calcd
for C16H18FN3O 288.1512, found 288.1519.
r-F lu or o-6-(4-p h en ylp ip er a zin yl)-2-p icolin e (20). In a
5 mL Reacti‚vial, to R-fluoro-6-(4-phenylpiperazinyl)-2-picoline
N-oxide (33 mg, 0.11 mmol) in 2 mL of chloroform was added
trichlorophosphine (12 µL, 0.14 mmol), and then the reaction
mixture was stirred at room temperature for 2 h. The reaction
mixture was extracted with chloroform, washed (H2O, brine),
and dried (Na2SO4). After the organic layer was removed by
vacuum, flash column chromatography (10% EtOAc/hexane)
provided 20 (30 mg, 99%) as a yellow oil: 1H NMR (200 MHz,
CDCl3) δ 3.29 (t, 4H, J ) 5.1 Hz), 3.71 (t, 4H, J ) 5.2 Hz),
In conclusion, the methodsfluorination-N-arylations
that we have described for the preparation of (fluoro-
methyl)pyridine-substituted amines is sufficiently rapid
and efficient that it appears suitable for the prepararion
of a variety of aryl-substituted amine compounds labeled
with the short half-life (t1/2 ) 110 min) positron-emitting
radionuclide fluorine-18. Elsewhere, we will report a
detailed study of this two-step method with regard to its
applicability for labeling with fluorine-18.
Exp er im en ta l Section
Gen er a l Meth od s. All reagents and solvents were obtained
from Lancaster and Aldrich Chemical Co. Dimethylformamide
(DMF) was distilled before use and stored over 4 Å molecular
sieves. 1H NMR spectra were recorded at 200 MHz, and 13C
NMR spectra were recorded at 50 MHz. Low-resolution
electron impact (EI) and chemical ionization (CI) mass spectra
were recorded at Inha University Facility. Elemental analyses
were carried out at Inha University Microanalytical Labora-
tory.
6-Ch lor o-2-p icolin e N-Oxid e (9). To 6-chloro-2-picoline
(2.00 g, 15.75 mmol) in chloroform (10 mL) was added m-CPBA
(6.32 g, 23.62 mmol) at room temperature. The reaction
mixture was heated to 50 °C for 12 h. The reaction was
quenched by adding water (2 mL). After evaporation of solvent
in vacuo, flash column chromatography (50% EtOAc/hexane)
provided 9 (2.10 g, 99%) as a yellow oil: 1H NMR (200
MHz, CDCl3) δ 2.54 (s, 3H), 7.08 (t, 1H, J ) 7.8 Hz), 7.19 (d,
1H, J ) 6.4 Hz), 7.38 (d, 1H, J ) 7.4 Hz); 13C NMR (50 MHz,
CDCl3) δ 16.68, 122.66, 122.97, 123.51, 140.26, 149.27; MS (EI)
m/z 143 (M+); HRMS calcd for C6H6ClNO 144.0216, found
144.0217.
6-Ch lor o-r-h yd r oxy-2-p icolin e (10). To 6-chloro-2-pi-
coline N-oxide (944 mg, 6.60 mmol) in acetic anhydride (20
mL) was added concentrated sulfuric acid (three drops) at room
temperature. This mixture was heated to 110 °C for 3 h and
then allowed to stand at room temperature overnight. The
reaction mixture was extracted with ethyl acetate and washed
(NaHCO3, H2O, brine). The organic layer was dried (Na2SO4)
and concentrated. Crude acetate was taken up in 20 mL of
methanol and 10 mL of H2O, and potassium carbonate (3.0 g)
was added. After 15 min, the solvent was evaporated, and the
residue was dissolved in methylene chloride. The solution was
dried (Na2SO4) and concentrated. Flash column chromatog-
raphy (50% EtOAc/hexane) provided 10 (815 mg, 83%) as a
yellow oil: 1H NMR (200 MHz, CDCl3) δ 4.64 (s, 2H), 7.09 (d,
1H, J ) 7.6 Hz), 7.24 (d, 1H, J ) 7.6 Hz), 7.55 (t, 1H, J ) 7.7
(11) Barrio, J . R.; Petric A.; Satyamurthy, N.; Huang, S. C.; Yu, D.
C. J . Nucl. Med. 1994, 35S, 83P.
(12) Oh, S. J .; Choe, Y. S.; Kim, S. E.; Choi, Y.; Lee, K. H.; Ha, H.
J .; Kim, B.-T.; Lee, K. C.; Chi, D. Y. J . Labeled Compd. Radiopharm.
1997, 40, 26-28.

8580 J . Org. Chem., Vol. 64, No. 23, 1999
Lee and Chi
5.33 (d, 2H, J ) 47.2 Hz), 6.64 (d, 1H, J ) 8.4 Hz), 6.80 (d,
1H, J ) 7.4 Hz), 6.86-7.00 (m, 3H), 7.26-7.34 (m, 2H), 7.55
(t, 1H, J ) 7.8 Hz); 13C NMR (50 MHz, CDCl3) δ 43.48, 47.51,
83.10 (d, J ) 168.4 Hz), 104.60, 108.28, 114.71, 118.41, 127.51,
136.56; MS (EI) m/z 271 (M+); HRMS calcd for C16H18FN3
271.1485, found 271.1484.
6-Ch lor o-r-h yd r oxy-3-p icolin e (13). To 6-chloronicotinic
acid (1.98 g, 12.61 mmol) in dried THF (30 mL) was added
borane dimethyl sulfide complex (2.35 mL, 26.40 mmol), and
then the mixture was refluxed for 16 h. The reaction mixture
was cooled to room temperature, quenched with 10% HCl,
extracted with ethyl acetate, washed (H2O, brine), and dried
(Na2SO4). After the organic layer was evaporated, flash column
chromatography (60% EtOAc/hexane) provided 13 (1.43 g,
79%) as a white solid: mp 53.8-54.2 °C; 1H NMR (200 MHz,
CDCl3) δ 4.52 (s, 2H), 7.14 (d, 1H, J ) 8.2 Hz), 7.55 (dd, 1H,
J ) 8.2, 2.4 Hz), 8.11 (d, 1H, J ) 2.4 Hz); 13C NMR (50 MHz,
CDCl3) δ 59.26, 122.47, 134.40, 136.34, 146.10, 148.10; MS (CI)
m/z 144 (MH+). Anal. Calcd for C6H6NO: C, 50.20; H, 4.21;
N, 9.76. Found: C, 50.56; H, 4.40; N, 9.71.
6-Ch lor o-r-m et h a n esu lfon yloxy-3-p icolin e (17). To
6-chloro-R-hydroxy-3-picoline (1.43 g, 10.00 mmol) in methyl-
ene chloride (25 mL) were added triethylamine (1531 µL, 10.99
mmol) and methanesulfonyl chloride (773 µL, 9.99 mmol) at 0
°C for 20 min. The reaction mixture was quenched with H2O
and extracted with methylene chloride. After the organic layer
was dried (Na2SO4) and evaporated, flash column chromatog-
raphy (60% EtOAc/hexane) provided mesylate 17 (1.68 g, 76%)
as a white solid: mp 75.6-75.9 °C; 1H NMR (200 MHz, CDCl3)
δ 3.04 (s, 3H), 5.24 (s, 2H), 7.40 (d, 1H, J ) 8.0 Hz), 7.75 (d,
1H, J ) 7.6 Hz), 8.44 (s, 1H); 13C NMR (50 MHz, CDCl3) δ
36.35, 68.77, 119.12, 122.73, 138.25; MS (CI) m/z 222 (MH+).
Anal. Calcd. for C7H8ClNO3S: C, 37.93; H, 3.64; N, 6.32; S,
14.47. Found: C, 37.86; H, 3.29; N, 6.23; S, 14.54.
6-Ch lor o-r-flu or o-3-p icolin e (18). To 6-chloro-R-meth-
anesulfonyloxy-3-picoline (6.34 g, 2.87 mmol) in dried THF (30
mL) was added tetra-n-butylammonium fluoride (1 M THF
solution, 8.0.29 mmol), and the mixture was refluxed for 4 h.
The reaction mixture was extracted with methylene chloride
and washed (H2O, brine). After the organic layer was dried
(Na2SO4) and evaporated, flash column chromatography (60%
EtOAc/hexane) provided 18 (2.04 g, 49%) as a yellow oil: 1H
NMR (200 MHz, CDCl3) δ 5.30 (d, 2H, J ) 4 7.6 Hz, CH2),
7.26 (d, 1H, J ) 8.4 Hz, C4-H), 7.60 (d, 1H, J ) 8.4 Hz, C3-
H), 8.29 (s, 1H, C6-H); 13C NMR (50 MHz, CDCl3) δ 79.52 (d,
J ) 167.3 Hz), 122.63, 129.01 (d, J ) 18.2 Hz, C3), 136.44 (d,
J ) 5.3 Hz, C4), 147.00 (d, J ) 6.5 Hz, C2), 150.12; MS (CI)
m/z 146 (MH+); HRMS calcd for C6H5ClFN 146.0173, found
146.0169.
6-Ch lor o-r-m eth an esu lfon yloxy-3-picolin e N-Oxide (15).
To 6-chloro-R-methanesulfonyloxy-3-picoline (602 mg, 2.72
mmol) in chloroform (10 mL) was added m-CPBA (705 mg,
4.09 mmol) at room temperature. This mixture was heated to
50 °C for 12 h. The reaction mixture was dried (Na2SO4) and
concentrated. Flash column chromatography (2% MeOH/
CH2Cl2) provided 15 (31 mg, 5%) as a yellow oil: 1H NMR
(200 MHz, CDCl3) δ 3.01 (s, 3H), 5.09 (s, 2H), 7.23 (dd, 1H, J
) 8.4, 1.4 Hz), 7.44 (d, 1H, J ) 8.4 Hz), 8.35 (d, 1H, J ) 1.4
Hz); 13C NMR (50 MHz, CDCl3) δ 36.13, 64.63, 124.84, 125.62,
130.42, 138.28, 140.25; MS (EI) m/z 237 (M+). Anal. Calcd for
C7H8ClNO4S: C, 35.38; H, 3.39; N, 5.89; S, 13.49. Found: C,
35.62; H, 3.34; N, 5.80.
6-Ch lor o-r-m eth an esu lfon yloxy-3-picolin e N-Oxide (15).
To 6-chloro-R-hydroxy-3-picoline N-oxide (303 mg, 1.91 mmol)
in methylene chloride (15 mL) were added triethylamine (397
µL, 2.85 mmol) and methanesulfonyl chloride (146 µL, 1.90
mmol) to 0 °C for 20 min. The reaction mixture was dried
(Na2SO4) and evaporated. Flash column chromatography (10%
MeOH/CH2Cl2) provided 15 (328 mg, 73%) as a yellow oil: 1H
NMR (200 MHz, CDCl3) δ 3.01 (s, 3H), 5.09 (s, 2H), 7.23 (dd,
1H, J ) 8.4, 1.4 Hz), 7.44 (d, 1H, J ) 8.4 Hz), 8.35 (d, 1H, J
) 1.4 Hz); 13C NMR (50 MHz, CDCl3) δ 36.13, 64.63, 124.84,
125.62, 130.42, 138.28, 140.25; MS (EI) m/z 237 (M+). Anal.
Calcd for C7H8ClNO4S: C, 35.38; H, 3.39; N, 5.89; S, 13.49.
Found: C, 35.62; H, 3.34; N, 5.80.
6-Ch lor o-r-flu or o-3-p icolin e N-Oxid e (16). To 6-chloro-
R-methanesulfonyloxy-3-picoline N-oxide (98 mg, 0.41 mmol)
in acetonitrile (2 mL) were added triethylamine (86 µL, 0.62
mmol) and tetra-n-butylammonium fluoride‚trihydrate (130
mg, 0.41 mmol) at room temperature. This mixture was
refluxed for 3 h. The reaction mixture was concentrated. Flash
column chromatography (80% EtOAc/hexane) provided 16
(20 mg, 30%) as a pale brown solid: mp 99.4-99.8 °C; 1H
NMR (200 MHz, CDCl3) δ 5.30 (d, 2H, J ) 46.6 Hz), 7.15 (d,
1H, J ) 8.4 Hz), 7.47 (d, 1H, J ) 8.4 Hz), 8.32 (s, 1H); 13C
NMR (50 MHz, CDCl3) δ 78.44 (d, J ) 171.8 Hz), 122.34 (d, J
) 6.1 Hz), 125.39, 132.08 (d, J ) 19.0 Hz), 137.15 (d, J ) 8.0
Hz), 140.21; MS (CI) m/z 162 (MH+). Anal. Calcd for C6H5-
FClNO: C, 44.61; H, 3.12; N, 8.67. Found: C, 44.43; H, 3.32;
N, 8.28.
r-F lu or o-6-(4-p h en ylp ip er a zin yl)-3-p icolin e N-Oxid e
(21). To 6-chloro-R-fluoro-3-picoline N-oxide (57 mg, 0.35
mmol) in 5 mL of acetonitrile and 5 mL of ethanol was added
triethylamine (54 µL, 0.39 mmol) and 1-phenylpiperazine (53
µL, 0.35 mmol), and then the reaction mixture was heated 130
°C for 3 h. After the reaction mixture was cooled to room
temperature, it was extracted with methylene chloride, washed
(H2O, brine), and dried (Na2SO4). After the organic layer was
removed by vacuum, flash column chromatography (5% MeOH/
CH2Cl2) provided 21 (42 mg, 44%) as a brown oil: 1H NMR
(200 MHz, CDCl3) δ 3.38-3.62 (m, 8H), 5.27 (d, 2H, J ) 47.6
Hz), 6.90-7.00 (m, 5H), 7.23-7.34 (m, 3H); 13C NMR (50 MHz,
CDCl3) δ 46.18, 47.53, 77.51 (J ) 169.9 Hz), 111.42, 112.67,
112.84, 114.87, 118.66, 125.10, 127.55, 149.51; MS (CI) m/z
288 (MH+); HRMS calcd for C16H18FN3O 288.1512, found
288.1511.
6-Ch lor o-r-flu or o-3-p icolin e N-Oxid e (16). To 6-chloro-
R-fluoro-3-picoline (328 mg, 2.26 mmol) in chloroform (10 mL)
was added m-CPBA (586 mg, 3.39 mmol) at room temperature.
This mixture was heated at 50 °C for 12 h. The reaction
mixture was dried (Na2SO4) and concentrated. Flash column
chromatography (2% MeOH/CH2Cl2) provided 16 (57 mg, 12%)
1
as a pale brown solid: mp 99.4-99.8 °C; H NMR (200 MHz,
CDCl3) δ 5.30 (d, 2H, J ) 46.6 Hz), 7.15 (d, 1H, J ) 8.4 Hz),
7.47 (d, 1H, J ) 8.4 Hz), 8.32 (s, 1H); 13C NMR (50 MHz,
CDCl3) δ 78.44 (d, J ) 171.8 Hz), 122.34 (d, J ) 6.1 Hz), 125.39,
132.08 (d, J ) 19.0 Hz), 137.15 (d, J ) 8.0 Hz), 140.21; MS
(CI) m/z 162 (MH+). Anal. Calcd for C6H5FClNO: C, 44.61; H,
3.12; N, 8.67. Found: C, 44.43; H, 3.32; N, 8.28.
r-F lu or o-6-(4-p h en ylp ip er a zin yl)-3-p icolin e (22). In a
5 mL Reacti•vial, to R-fluoro-6-(4-phenylpiperazinyl)-3-picoline
N-oxide (23 mg, 0.08 mmol) in 2 mL of chloroform was added
trichlorophosphine (8.4 µL, 0.10 mmol), and then the reaction
mixture was stirred at room temperature for 2 h. The reaction
mixture was extracted with chloroform, washed (H2O, brine),
and dried (Na2SO4). After the organic layer was removed by
vacuum, flash column chromatography (10% EtOAc/hexane)
provided 22 (0.08 mg, 99%) as a yellow oil: 1H NMR (200 MHz,
CDCl3) δ 3.29 (t, 4H, J ) 5.2 Hz), 3.71 (t, 4H, J ) 5.2 Hz),
5.33 (d, 2H, J ) 47.2 Hz), 6.64 (d, 1H, J ) 8.4 Hz), 6.78-7.00
(m, 4H), 7.26-7.34 (m, 2H), 7.55 (t, 1H, J ) 7.9 Hz); 13C NMR
(50 MHz, CDCl3) δ 43.48, 47.51, 83.10 (d, J ) 168.4 Hz),
104.60, 108.28, 114.71, 118.41, 127.51, 136.56; MS (CI) m/z
272 (MH+); HRMS calcd for C16H18FN3 272.1563, found
272.1567.
6-Ch lor o-r-h ydr oxy-3-picolin e N-Oxide (14). To 6-chloro-
R-hydroxy-3-picoline (700 mg, 4.90 mmol) in chloroform (20
mL) was added m-CPBA (1839 mg, 5.86 mmol) at room
temperature. This mixture was heated to 50 °C for 12 h. The
reaction mixture was dried (Na2SO4) and concentrated. Flash
column chromatography (10% MeOH/CH2Cl2) provided 14 (719
mg, 92%) as a white solid: mp 101.1-101.4 °C; 1H NMR (200
MHz, CDCl3) δ 4.61 (s, 2H), 7.16 (dd, 1H, J ) 8.4, 2.0 Hz),
7.35 (d, 1H, J ) 8.4 Hz), 8.29 (d, 1H, J ) 2.0 Hz); 13C NMR
(50 MHz, CDCl3) δ 59.09, 124.64, 125.06, 131.13, 137.31,
138.26; MS (EI) m/z 159 (M+); HRMS calcd for C6H6ClNO2
159.0087, found 159.0089.

(Fluoromethyl)pyridylation of Amines
J . Org. Chem., Vol. 64, No. 23, 1999 8581
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 6, 7, 8-11, and 13-22. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. This research was supported by
the Korea Science and Engineering Fund (No 97-03-01-
01-5-L), and to Professor J ohn A. Katzenellenbogen and
Dr. Yearn Seong Choe for helpful discussions.
J O990994F