N-Azinylpyridinium N-aminides: Intermediates for the regioselective synthesis of 3-fluoro-2-aminopyridine derivatives

Full text of DOI:10.1021/jo9813540

J . Org. Chem. 1999, 64, 1007-1010
1007
Sch em e 1
N-Azin ylp yr id in iu m N-Am in id es:
In ter m ed ia tes for th e Regioselective
Syn th esis of 3-F lu or o-2-a m in op yr id in e
Der iva tives
Ara´nzazu Garc´ıa de Viedma,
Valent´ın Mart´ınez-Barrasa, Carolina Burgos,
M. Luisa Izquierdo, and J ulio Alvarez-Builla*
Departamento de Quı´mica Orga´nica, Universidad de Alcala´,
28871 Alcala´ de Henares, Madrid, Spain
Received J uly 13, 1998
The replacement of hydrogen by fluorine in organic
molecules frequently results in dramatic changes in their
properties. Improvement in thermal and oxidative stabil-
ity, alterations of electronic effects, and an increase of
lipophilicity have been described for a large variety of
molecules, with high interest in medicinal chemistry. The
preparation of organofluorine compounds, however, re-
mains a difficult area, and since fluorine itself is so
reactive and difficult to control, alternative methods of
incorporating fluorine into organic molecules are still
required.1-3
On the other hand, some of our work has been
concerned with reactivity of azinyl-N-aminides 1 toward
electrophiles, especially sources of X+ (X ) Cl, Br, I) like
N-halosuccinimides (NXS),4 and the use of 1 as inter-
mediates in the synthesis of 2-aminoazines. Since fluo-
rination has not been achieved this way, we would like
to report the use of xenon difluoride, as an electrophilic
fluorine source, to prepare different fluoro-2-amino-
pyridines.5
preparation avoiding this step. In this context, reaction
of pyridinium N-(pyridin-2′-yl)aminide 1a , followed by
alkylation on the exocyclic nitrogen and final fission of
the N-N bond, could allow the synthesis of the target
compounds (Scheme 1).
Some attempts to prepare fluorinated aminides using
well-known electrophiles such as N-fluoropyridinium
salts,9 N-fluorosulfonamides,10 or N-fluoroazabicycles11,12
did not generate any fluorinated product. Xenon difluo-
ride,13 normally used in the fluorination of vinylstan-
nanes,14 aromatics,15,16 and heteroaromatics17-19 with
variable results, initially produced poor yields of 2a [entry
1, Table 1, method A: portionwise addition at 0 °C of
1.5 mmol of solid xenon difluoride to a dispersion of
potassium carbonate (1.25 mmol) and 1a (1 mmol) in dry
acetonitrile, under an atmosphere of dry argon; entry 2,
Table 1, method B: dropwise addition at -40 °C of 1
mmol of xenon difluoride solution in dry acetonitrile to
a dispersion of potassium carbonate (1.25 mmol) and 1a
(1 mmol) in dry acetonitrile, under an atmosphere of dry
argon]. Finally, 2a (entry 3, Table 1, method C) was
satisfactorily prepared by dropwise addition, at low
temperature (-40 °C), of equimolar amounts of xenon
difluoride solution in dry dichloromethane to a dispersion
of potassium carbonate and 1a in dry dichloromethane,
although small changes in reaction conditions and sol-
vents20 or reactant proportions caused dramatic changes
in the reaction yield. Surprisingly, 2a was identified as
pyridinium N-(3′-fluoropyridin-2′-yl)aminide, while no
5-monofluoro nor difluoro derivatives were detected.21
Resu lts a n d Discu ssion
Halo-2-aminopyridines are intermediates of interest in
the synthesis of relevant biologically active molecules,6
and they are usually prepared by direct halogenation of
the corresponding 2-aminopyridine. However, 3- or 5-
fluoro-2-aminopyridines represent special cases for which
a classical method has been used (Balz-Schiemann
reaction, from the corresponding amino-2-chloropyridine,
and subsequent displacement of chlorine with ammonia).7
For 5-fluoro-2-aminopyridine, an alternate five-step syn-
thesis from 2-amino-5-nitropyridine, through a difluoro-
boryl imidate intermediate, has been recently reported,8
but we found no additional reference for the 3-fluoro
derivative. Both methods use the formation and decom-
position of the corresponding diazonium salt with vari-
able results. As a continuation of our interest in these
kinds of compounds, we planned to study methods of
The assignment of protons for the 2-iminopyridine
moiety in 2a was carried out by means of double
(9) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Tomita,
K. J . Am. Chem. Soc. 1990, 112, 8563.
(1) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chem-
istry; Wiley-Interscience: New York 1991.
(2) Resnati, G. Tethahedron 1993, 49, 9385.
(3) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737.
(4) Burgos, C.; Delgado, F.; Garc´ıa-Navio, J . L.; Izquierdo, M. L.;
Alvarez-Builla, J . Tetrahedron 1995, 51, 8649.
(5) Paquette, L. A. Reagents for Organic Synthesis 815515; J ohn
Wiley and Sons Ltd: New York, 1995.
(10) Differding, E.; Ofner, H. Synlett. 1991, 187.
(11) Banks, R. E.; Mohialdin-Kyaffaf, S. N.; Lal, G. S.; Sharif, Y.;
Syvret, R. G. J . Chem. Soc., Chem. Commun. 1992, 595.
(12) Lal, G. S. J . Org. Chem. 1993, 58, 2791.
(13) Tius, M. A. Tetrahedron 1995, 52, 6605.
(14) Tius, M. A.; Kawakami, J . K. Synth. Commun. 1992, 22, 1461.
(15) Stavber, S.; Zupan, M. Tetrahedron Lett. 1993, 34, 4355.
(16) Wilkinson, J . A. Chem. Rev. 1992, 92, 505.
(6) Randl, S.; Bouzard, D. Heterocycles 1992, 34, 2143.
(7) Saito, N.; Kurihara, T.; Yasuda, S.; Yamanaka, K.; Tsuruta, S.;
Tanaka, T.; Inamori, Y. Yakugaku Zasshi 1968, 88, 1610; Chem. Abstr.
1969, 70, 87639.
(17) Anand, S. P.; Filler, R. J . Fluorine Chem. 1976, 7, 179.
(18) Filler, R. Isr. J . Chem. 1978, 17, 71.
(19) Wang, J .; Scott, I. Tetrahedron Lett. 1994, 35, 3679.
(20) Dukat, W. W.; Holloway, J . H.; Hope, E. G.; Townson, P. J .;
Powell, R. L. J . Fluorine Chem. 1993, 62, 293.
(8) Hand, E. S.; Baker, D. C. Synthesis 1989, 905.
10.1021/jo9813540 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/20/1999

1008 J . Org. Chem., Vol. 64, No. 3, 1999
Ta ble 1. Com p ou n d s 2-4 Obta in ed
Notes
entry
compd
X
Y
R
method
yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2a
2a
2a
2b
2c
2d
3a
3b
3c
3d
3e
4a
4b
4b
4c
4c
4d
4e
H
A
B
C
C
C
C
7
15
60
15
25
18
95b
83
70
64
87
94
84
73
89
70
93
90
H
H
Cl
Br
I
H
H
H
H
Cl
H
H
H
H
H
H
Cl
F igu r e 2. Possible pathways in the reaction Nu- + XF.22
Br
I
I
I
I
H
Me
Et
Pr
Me
H
Me
Me
Et
Et
Pr
D
D
D
D
E
E
F
E
F
E
E
Sch em e 2
Me
a
Yields refer to isolated pure product. All the products were
identified by spectroscopic and literature data. Method A: XeF2,
K2CO3, MeCN, 0 °C. Method B: XeF2, K2CO3, MeCN, -40 °C.
Method C: XeF2, K2CO3, CH2Cl2, -40 °C. Method D: RX, acetone,
rt. Method E: Pt/C, AF, MeOH, 80 °C. Method F: TTMSS, AIBN,
b
t-BuOH, 80 °C. See Experimental Section.
13C NMR spectra in compounds 3b-e by the small
coupling constant between fluorine in the 3-position and
the alkyl group attached on the exocyclic nitrogen.
There has been a considerable dispute about the
possible mechanism of electrophilic fluorination, whether
it could be a simple fluorine transfer or a two-step
pathway, where an electron-transfer precedes a fluorine
radical attack (Figure 2).22 Independent of the path
involved in the process, we would suggest a reaction
course as described in Scheme 2, which agrees with the
formation of the most sterically hindered R-isomer23 and
with the production of HF during the reaction process.
Fluorination was tried with other aminides (1b, Y )
Cl; 1c, Y ) Br; 1d , Y ) I, Scheme 1) under similar
conditions, yielding aminides 2b-d with lower yields.24
Traces of 3,5-dibromo derivative (≈5%) were detected in
the preparation of 2c, probably related with a previously
described ipso substitution.4
The direct alkylation of heterocyclic aminides is usually
unsatisfactory as a preparative method as it mainly
occurs at the most basic endocyclic nitrogen.25 However,
(21) Initially, the crude reaction mixture was tested by 1H NMR.
Reaction of 1a with xenon difluoride leads to 2a as the only fluorinated
identifiable product. Since xenon difluoride is also a strong oxidant
agent, competition between the fluorofunctionalization and oxidation
processes can take place: small amounts of highly colored products
were observed that were removed during the chromatographic proce-
dure (for byproducts Rf ≈ 0.2, for compound 2a Rf ≈ 0.6, silica gel,
ethanol). On the other hand, fluorination of 2a with xenon difluoride
does not provide the difluoro derivative compound, but only oxidized
byproducts were observed. In this way, no fluorinated compounds were
detected in the reaction with other aminides, as pyridinium N-(pyri-
midin-2′-yl)aminide.
F igu r e 1.
resonance experiments and by decoupling spectra and
literature data for the 5-fluoro-2-aminopyridine, obtained
according to Baker et al.8 For compound 2a , on saturating
the unambiguous H6′ signal, at 7.48 ppm, signals at 7.20
ppm (H4′) and 6.40 ppm (H5′) were simplified into two
doublet of doublets. However, for 5-fluoro-2-aminopyri-
dine, on saturating H6 signal at 7.92 ppm, the H3 signal
at 6.46 ppm did not change (Figure 1). The 3-fluorine
position was confirmed in the 1H NMR spectra by the
multiplicity of the methyl group in compound 3b (Y )
H, R ) Me, and X ) I, Scheme 1), which appears as a
doublet due to the long-range coupling with F, and in the
(22) Differding, E.; Ru¨egg, G. M. Tetrahedron Lett. 1991, 32, 3815.
(23) Polishchuk, V. R.; German, L. S. Tetrahedron Lett. 1972, 51,
5169.
(24) The negative charge on the exocyclic nitrogen facilates the
reaction of the pyridine nucleus toward electrophiles. This ability is
decreased for compounds 2a -e due to the high electronegativity of
halogen atom in the 5-position. Lower yields for fluorination in
5-haloaminides could be partially attributed to this effect. On the other
hand, coordination of the xenon difluoride to the halogen in 5-position
could also be an undesirable effect, but some attempts of fluorination
increasing concentration of xenon difluoride did produce complex
mixtures.
(25) Goerdeler, J .; Roth, W. Ber. 1963, 96, 534.

Notes
J . Org. Chem., Vol. 64, No. 3, 1999 1009
Hz), 147.5 (d, J ) 259.5 Hz), 145.3, 140.0 (d, J ) 4.6 Hz), 139.1,
128.3, 121.5 (d, J ) 19.2 Hz), 116.1 (d, J ) 2.2 Hz); MS (EI, 70
eV) m/z (relative intensity) 225 (8, M+), 223 (32, M+), 79 (99).
P yr id in iu m N-(5′-br om o-3′-flu or op yr id in -2′-yl)a m in id e
in pyridinium-N-(2′-azinyl)aminides, endocyclic nitrogen
is partially blocked by an intramolecular hydrogen bond,
making the alkylation regioselective on the exocyclic
nitrogen.26 Fluorinated aminides 2 were reacted, at room
temperature, with the corresponding alkyl halide produc-
ing N-alkyl derivatives 3b-d in good yields.
1
(2c): yellow oil (25%); H NMR (300 MHz, CD3OD) δ 8.76 (dd,
2H, J ) 7.0, 1.2 Hz), 8.14 (tt, 1H, J ) 7.7, 1.2 Hz), 7.86 (dd, 2H,
J ) 7.7, 7.0 Hz), 7.50 (d, 1H, J ) 1.8 Hz), 7.32 (dd, 1H, J )
11.0, 1.8 Hz); MS (EI, 70 eV) m/z (relative intensity) 269 (2, M+),
267 (2, M+), 81 (35), 79 (100), 78 (51).
In a preceding paper,4 we reported the N-N bond
fission in halogenated aminides using formic acid/tri-
ethylamine in the presence of platinum on carbon. In that
way, the unsubstituted 3-fluoro-2-aminopyridine 4a (R
) H, Y ) H, Scheme 1) could be obtained. However, in
the present case involving N-alkyl derivatives, better
results were obtained using ammonium formate (AF)27
(method E) or tris(trimethylsilyl)silane (TTMSS)/AIBN28-30
as a radical-reducing agent (method F). The results are
summarized in Table 1. All the fluoro-2-aminopyridines
obtained were readily decomposed by moist air by warm
ethanol, or upon heating and, thus, appear to be consid-
erably less stable than the pyridinium salts 3. The latter
compounds can be used as stable and handy precursors
of the aminopyridine derivatives.
P yr idin iu m N-(3′-flu or o-5′-iodopyr idin -2′-yl)am in ide (2d):
orange oil (18%); 1H NMR (300 MHz, CD3OD) δ 8.72 (dd, 2H, J
) 6.9, 1.2 Hz), 8.12 (t, 1H, J ) 7.7 Hz), 7.85 (dd, 2H, J ) 7.7,
6.9 Hz), 7.59 (d, 1H, J ) 1.8 Hz), 7.36 (dd, 1H, J ) 11.0, 1.8
Hz); MS (EI, 70 eV) m/z (relative intensity) 315 (48, M+), 188
(12), 127 (59), 79 (100).
N-(3′-F lu or op yr id in -2′-yla m in o)p yr id in iu m Br om id e
Hyd r obr om id e (3a ). To a stirred solution of 0.189 g of 2a (1
mmol) in 5 mL of ethanol was added dropwise in an ice-water
bath 3 mL of HBr 40% in water. The solution was evaporated
in vacuo to dryness, and the crude product 3a was crystallized
from absolute ethanol: white powder (95%); mp 216-20 °C dec;
1H NMR (300 MHz, CD3OD) δ 9.11 (dd, 2H, J ) 6.9, 1.4 Hz),
8.79 (tt, 1H, J ) 7.9, 1.4 Hz), 8.26 (bt, 2H, J ) 7.3 Hz), 7.85 (d,
1H, J ) 4.2 Hz), 7.68 (ddd, 1H, J ) 10.8, 8.1, 1.2 Hz), 7.10 (ddd,
1H, J ) 8.1, 4.2, 3.4 Hz); 13C NMR (75 MHz, CD3OD) δ 148.9,
148.2 (d, J ) 255.1 Hz), 147.9, 146.5 (d, J ) 12.9 Hz), 143.4 (d,
J ) 5.7 Hz), 130.2, 124.9 (d, J ) 15.2 Hz), 120.7 (d, J ) 2.5 Hz).
Anal. Calcd for C10H10N3Br2F: C, 34.22; H, 2.87; N, 11.97.
Found: C, 33.88; H, 3.14; N, 12.24.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Alk yl-N-
(3′-F lu or op yr id in -2′-yl-a m in o)p yr id in iu m Der iva tives 3b-
e. Meth od D (Sch em e 1, Ta ble 1). Alkyl iodide (1.82 mmol)
was added via a syringe to a stirred solution of corresponding 2
(1.22 mmol) in 10 mL of dry acetone. The solution was stirred
at room temperature until full consumption of 2 (1 day for
compound 3b, 3 days for compounds 3c-d ). The resulting
suspension was filtered, and the solid was washed with ether
and crystallized from absolute ethanol.
N -[(3′-F lu or op yr id in -2′-yl)m e t h yla m in o]p yr id in iu m
iod id e (3b): white powder (83%); mp 132-4 °C dec; 1H NMR
(300 MHz, CD3OD) δ 9.32 (d, 2H, J ) 5.4 Hz), 8.78 (t, 1H, J )
7.8 Hz), 8.27 (bt, 2H, J ) 7.3 Hz), 8.11 (d, 1H, J ) 4.7 Hz), 7.69
(ddd, 1H, J ) 11.9, 8.2, 1.4 Hz), 7.30 (ddd, 1H, J ) 8.2, 4.7, 3.2
Hz), 3.78 (d, 3H, J ) 1.1 Hz); 13C NMR (75 MHz, CD3OD) δ 150.8
(d, J ) 259.2 Hz), 148.9, 148.8, 146.9 (d, J ) 9.7 Hz), 144.8 (d,
J ) 5.5 Hz), 130.7, 126.9 (d, J ) 17.4 Hz), 123.9 (d, J ) 2.7 Hz),
43.8 (d, J ) 5.5 Hz). Anal. Calcd for C11H11N3IF: C, 39.90; H,
3.35; N, 12.69. Found: C, 39.69; H, 3.33; N, 12.23.
Exp er im en ta l Section
Gen er a l Meth od s. All experiments were carried out under
an atmosphere of dry argon. 1H, 13C, and 19F spectra were
recorded on a Varian UNITY 300 MHz spectrometer.
The following compounds were prepared according to litera-
ture procedures: pyridinium N-(pyridin-2′-yl)aminide 1a ,26 py-
ridinium N-(5′-chloropyridin-2′-yl)aminide 1b,4 pyridinium N-(5′-
bromopyridin-2′-yl)aminide 1c,4 and pyridinium N-(5′-iodopyridin-
2′-yl)aminide 1d .4
Gen er a l P r oced u r e for th e P r ep a r a tion of P yr id in iu m
N-(3′-F lu or op yr id in -2′-yl)a m in id es 2a -d . Met h od
C
(Sch em e 1, Ta ble 1). A solution of XeF2 (0.100 g, 0.58 mmol)
in 20 mL of dry dichloromethane was added dropwise (rate of
addition 0.5 mL/min) to a stirred suspension of 1 (0.58 mmol)
and anhydrous K2CO3 (0.100 g, 0.72 mmol) in 4 mL of dry
dichloromethane at -40 °C. After being stirred for 30 min,
distilled water (5 mL) was added dropwise at the same temper-
ature. Then, the reaction mixture was allowed to warm to room
temperature. After separation of the organic layer, the aqueous
solution was extracted with ethyl acetate. All the combined
organic extracts were dried (Na2SO4) and concentrated in vacuo,
providing a crude product that was purified using flash chro-
matography (silica gel, ethanol) to yield the corresponding
aminide 2.
N -[(3′-F lu o r o p y r id in -2′-y l)e t h y la m in o ]p y r id in iu m
1
iod id e (3c): white powder (70%); mp 108-10 °C dec; H NMR
(300 MHz, CD3OD) δ 9.33 (d, 2H, J ) 5.1 Hz), 8.77 (t, 1H, J )
7.7 Hz), 8.27 (bt, 2H, J ) 7.3 Hz), 8.15 (d, 1H, J ) 4.7 Hz), 7.69
(ddd, 1H, J ) 11.9, 8.1, 1.4 Hz), 7.32 (ddd, 1H, J ) 8.1, 4.7, 3.4
Hz), 4.19 (bq, 2H, J ) 7.1 Hz), 1.27 (t, 3H, J ) 7.1 Hz); 13C NMR
(75 MHz, CD3OD) δ 151.3 (d, J ) 257.5 Hz), 149.2, 148.7, 146.3
(d, J ) 9.1 Hz), 144.6 (d, J ) 5.5 Hz), 130.6, 126.9 (d, J ) 17.3
Hz), 124.2 (d, J ) 2.0 Hz), 51.9 (d, J ) 2.7 Hz), 12.8. Anal. Calcd
for C12H13N3IF: C, 41.76; H, 3.80; N, 12.17. Found: C, 41.49;
H, 3.43; N, 12.26.
P yr id in iu m N-(3′-flu or op yr id in -2′-yl)a m in id e (2a ): or-
ange plates (60%); mp 120-1 °C dec; H NMR (300 MHz, CD3-
1
OD) δ 8.78 (dd, 2H, J ) 6.5, 1.1 Hz), 8.18 (t, 1H, J ) 7.7 Hz),
7.90 (t, 2H, J ) 7.1 Hz), 7.49 (d, 1H, J ) 5.1 Hz), 7.21 (ddd, 1H,
J ) 11.8, 7.7, 1.4 Hz), 6.46 (m, 1H); 13C NMR (75 MHz, CD3OD)
δ 155.9 (d, J ) 8.3 Hz), 148.6 (d, J ) 253.7 Hz), 145.6, 142.1 (d,
J ) 5.5 Hz), 139.2, 128.7, 121.4 (d, J ) 16.5 Hz), 111.7; 19F NMR
(282 MHz, CFCl3 internal standard, CD3OD) δ -139.10 (dd, J
) 11.9, 3.4 Hz); MS (EI, 70 eV) m/z (relative intensity) 189 (33,
M+), 79 (26). Anal. Calcd for C10H8N3F: C, 63.49; H, 4.26; N,
22.21. Found: C, 63.26; H, 4.38; N, 22.19.
N -[(3′-F lu or op yr id in -2′-yl)p r op yla m in o]p yr id in iu m
1
iod id e (3d ): white powder (64%); mp 168-70 °C dec; H NMR
P yr id in iu m N-(5′-ch lor o-3′-flu or op yr id in -2′-yl)a m in id e
(300 MHz, CD3OD) δ 9.34 (d, 2H, J ) 5.4 Hz), 8.80 (t, 1H, J )
7.8 Hz), 8.27 (bt, 2H, J ) 7.1 Hz), 8.13 (d, 1H, J ) 4.7 Hz), 7.70
(ddd, 1H, J ) 11.5, 8.1, 1.4 Hz), 7.32 (ddd, 1H, J ) 8.1, 4.7, 3.4
Hz), 4.08 (bt, 2H, J ) 7.3 Hz), 1.63 (m, 2H), 1.06 (t, 3H, J ) 7.3
Hz); 13C NMR (75 MHz, CD3OD) δ 151.3, 149.1, 148.8, 146.5 (d,
J ) 9.1 Hz), 144.7 (d, J ) 5.0 Hz), 130.6, 127.0 (d, J ) 18.1 Hz),
124.2, 58.9, 21.5, 11.7. Anal. Calcd for C13H15N3IF: C, 43.47; H,
4.21; N, 11.70. Found: C, 43.49; H, 4.33; N, 11.45.
1
(2b): yellow oil (15%); H NMR (300 MHz, CD3OD) δ 8.77 (dd,
2H, J ) 6.9, 1.1 Hz), 8.16 (tt, 1H, J ) 7.7, 1.1 Hz), 7.87 (dd, 2H,
J ) 7.7, 6.9 Hz), 7.45 (d, 1H, J ) 2.2 Hz), 7.25 (dd, 1H, J )
11.0, 2.2 Hz); 13C NMR (75 MHz, CD3OD) δ 154.8 (d, J ) 6.8
(26) Carceller, R.; Garc´ıa-Nav´ıo, J . L.; Izquierdo, M. L.; Alvarez-
Builla, J .; Fajardo, M.; Go´mez-Sal, P.; Gago, F. Tetrahedron 1994, 50,
4995.
(27) Cortese, N. A.; Heck, R. F. J . Org. Chem. 1977, 42, 3491.
(28) Chatgilialoglu, C.; Griller, D.; Lesage, M. J . Org. Chem. 1988,
53, 3641.
(29) Lesage, M.; Chatgilialoglu, C.; Griller, D. Tetrahedron Lett.
1989, 30, 2733.
(30) Ballestri, M.; Chatgilialoglu, C.; Clark, K. B.; Griller, D.; Giese,
B.; Kopping, B. J . Org. Chem. 1991, 56, 678.
N-[(5′-Ch lor o-3′-flu or op yr id in -2′-yl)m et h yla m in o]p yr i-
d in iu m iod id e (3e): white powder (87%); mp 142-3 °C dec;
1H NMR (300 MHz, CD3OD) δ 9.34 (dd, 2H, J ) 4.9, 1.4 Hz),
8.76 (tt, 1H, J ) 7.8, 1.4 Hz), 8.29 (dt, 2H, J ) 7.8, 4.9 Hz), 8.16
(d, 1H, J ) 1.8 Hz), 7.90 (dd, 1H, J ) 11.1, 1.8 Hz), 3.78 (d, 3H,
J ) 1.4 Hz); 13C NMR (75 MHz, CD3OD) δ 154.8 (d, J ) 6.7 Hz),
147.8 (d, J ) 258.8 Hz), 145.6, 140.3, 139.6, 128.7, 121.8 (d, J )

1010 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
18.0 Hz), 116.5, 59.0 (d, J ) 3.2 Hz). Anal. Calcd for C11H10N3-
IClF: C, 36.14; H, 2.76; N, 11.49. Found: C, 36.49; H, 3.03; N,
11.27.
7.71 (d, 1H, J ) 5.2 Hz), 7.10 (ddd, 1H, J ) 10.9, 7.9, 1.4 Hz),
6.55 (ddd, 1H, J ) 7.9, 5.2, 4.5 Hz), 4.90 (bs, 2H).
(3-F lu or op yr id in -2-yl)m et h yla m in e (4b ): colorless oil,
method E (84%), method F (73%); 1H NMR (300 MHz, CDCl3) δ
7.90 (d, 1H, J ) 4.8 Hz), 7.10 (ddd, 1H, J ) 9.5, 7.7, 1.5 Hz),
6.49 (ddd, 1H, J ) 7.7, 4.8, 3.5 Hz), 4.80 (bs, 1H), 3.03 (d, 3H, J
) 5.2 Hz); MS (EI, 70 eV) m/z (relative intensity) 126 (8, M+),
97 (31).
Gen er a l P r oced u r e for th e P r ep a r a tion of th e Un su b-
stitu ted a n d N-Alk yl-Su bstitu ted N-(3-F lu or o-p yr id in -2-
yl)a m in es 4a -e. Meth od E (Sch em e 1, Ta ble 1). A stirred
dispersion of corresponding 3 (1 mmol) and 0.125 g of Pt/C (5%)
in 37 mL of dry methanol was heated to reflux. Ammonium
formate was portionwise added to the mixture, at the same
temperature, until full consumption of 3 (for compounds 4b-e,
3 mmol at the beginning and 3 mmol after 3 h, and the mixture
was refluxed with stirring for another 4 h). A similar procedure
was used for compound 4a , but after 12 h, TLC analysis showed
that little or no reduction had been produced by the ammonium
formate. Subsequent additions of 2 mmol/day (total addition 20
mmol) provided the reduction product after 7 days. Then, the
reaction mixture was allowed reach room temperature, and the
catalyst was removed by filtration through a Celite pad under
an argon atmosphere. The filtrate was concentrated under
reduced pressure. Then, dry dichloromethane (5 mL) was added
to the residue, the mixture was filtered under argon atmosphere,
and the filtrate was concentrated again. The process was
repeated twice, affording the desired compounds 4. An analytical
sample of 4 was purified by preparative TLC (silica gel, hexanes/
ethyl acetate 3:7). Pure amine was obtained as a wax solid (4a )
or colorless oil (4b-e).
(3-Flu or opyr idin -2-yl)eth ylam in e (4c): colorless oil, method
E (89%), method F (70%); 1H NMR (300 MHz, CDCl3) δ 7.75
(dd, 1H, J ) 4.8, 1.4 Hz), 7.07 (ddd, 1H, J ) 11.7, 7.8, 1.4 Hz),
6.63 (ddd, 1H, J ) 7.8, 4.8, 4.3 Hz), 4.80 (bs, 1H), 3.59 (qi, 2H,
J ) 7.3 Hz), 0.94 (t, 3H, J ) 7.3 Hz); MS (EI, 70 eV) m/z (relative
intensity) 140 (10, M+), 125 (100), 96 (35).
(3-F lu or op yr id in -2-yl)p r op yla m in e (4d ): colorless oil,
1
method E (90%); H NMR (300 MHz, CDCl3) δ 7.82 (dd, 1H, J
) 4.7, 1.4 Hz), 7.08 (ddd, 1H, J ) 11.5, 7.7, 1.4 Hz), 6.46 (ddd,
1H, J ) 7.7, 4.7, 3.0 Hz), 4.90 (bs, 1H), 4.07 (t, 2H, J ) 7.3 Hz),
1.41 (qi, 2H, J ) 7.3 Hz), 0.97 (t, 3H, J ) 7.3 Hz); MS (EI, 70
eV) m/z (relative intensity) 154 (15, M+), 125 (93), 96 (36).
(5-Ch lor o-3-flu or op yr id in -2-yl)m eth yla m in e (4e): color-
1
less oil, method E (90%); H NMR (300 MHz, CDCl3) δ 7.89 (d,
1H, J ) 1.8 Hz), 7.15 (dd, 1H, J ) 10.4, 1.8 Hz), 4.70 (bs, 1H),
3.01 (d, 3H, J ) 4.6 Hz); MS (EI, 70 eV) m/z (relative intensity)
162 (1, M+), 160 (1, M+), 95 (14).
Meth od F . A solution of AIBN (0.328 g, 2 mmol) and TTMSS
(0.498 g, 2 mmol) in 30 mL of dry tert-butyl alcohol was added
dropwise to a stirred suspension of the corresponding 3 (1 mmol)
and K2CO3 (0.276 g, 2 mmol), at 80 °C. The mixture was stirred
1 h at the same temperature. After evaporation in vacuo, the
crude product was purified by flash chromatography (silica gel,
hexanes/ethyl acetate 8:2), yielding 4.
Ack n ow led gm en t. The authors wish to thank the
Comision Interministerial de Ciencia y Tecnolog´ıa
(C.I.C.Y.T.) (Project PM97-0074) and the Vicerrectorado
de Investigacio´n, Universidad de Alcala´, for financial
support (Project E014/97) and one studentship (A.G.V).
3-Flu or opyr idin -2-ylam in e (4a): wax solid; method E (94%);
mp 46-48 °C (lit.8 mp 47-49 °C); 1H NMR (300 MHz, CDCl3) δ
J O9813540