Base-mediated syntheses of new 6,6′-di(polyfluoroalkoxy)-2,2′-bipyridines with 100% regioselectivity

Article abstract of DOI:10.1055/s-2003-39173

Reactions of N,N-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) (MEC-31) (1) with fluorinated alcohols R_fOH [R_f = CF₃CH₂, CH₂FCH₂, CF₃CF₂CH₂, CHF₂CF₂CH₂, (CF₃)₂CH] 2a-e, in the presence of a base at 70°C without solvent, gave good yields of 6,6′-di(polyfluoroalkoxy)-2,2′-bipyridines 3a-e with 100% regioselectivity. Triethylamine with 1, produced 6,6′-difluoro-2,2-bipyridine (4).

Full text of DOI:10.1055/s-2003-39173

SHORT PAPER
1009
Base-Mediated Syntheses of New 6,6 -Di(polyfluoroalkoxy)-2,2 -Bipyridines
with 100% Regioselectivity
D
i(polyfluoroalko
a
xy)-2,2 -B
j
ipyridin
e
es
w
ith 10
n
0%
R
egiose
l
d
ectivity ra P. Singh, Gary V. Eggers, Jean’ne M. Shreeve*
Department of Chemistry, University of Idaho, Moscow, ID 83844-2343, USA
Fax 208(885)9146; E-mail: jshreeve@uidaho.edu
Received 20 December 2002
Earlier we demonstrated that when a mixture of 1 (2
Abstract: Reactions of N,N-difluoro-2,2 -bipyridinium bis(tet-
rafluoroborate) (MEC-31) (1) with fluorinated alcohols RfOH
[Rf = CF3CH2, CH2FCH2, CF3CF2CH2, CHF2CF2CH2, (CF3)2CH]
2a–e, in the presence of a base at 70 °C without solvent, gave good
mmol) with trifluoroethanol (2a) (5 mL) was heated as
high as 70 °C for 2 days, no reaction occurred. However,
when the same reaction was carried out in the presence of
yields of 6,6 -di(polyfluoroalkoxy)-2,2 -bipyridines 3a–e with 1-morpholino-1-cyclohexene (2 mmol) at 25 °C for 24
100% regioselectivity. Triethylamine with 1, produced 6,6 -difluo-
ro-2,2-bipyridine (4).
hours, 3a was isolated in 52% yield. At 70 °C, the yield of
3a was improved to 85%. Using 1-pyrrolidino-1-cyclo-
Key words: alcohols, fluorine, pyridines, regioselectivity
hexene (2 mmol), under identical conditions, 3a was iso-
lated in 85% yield. We have found that the use of other
amines, such as triethylamine, tri-n-butylamine, morpho-
line and pyridine also gave 3a. For the latter three, lower
yields were obtained (Table 1). The reaction of 1 with oth-
er fluorinated alcohols 2b–e, using either 1-morpholino-
1-cyclohexene or 1-pyrrolidino-1-cyclohexene, led to the
formation of 6,6 -di(polyfluoroalkoxy)-2,2 -bipyridines
3a–e in 70–80% yields (Scheme 2). Reaction of 1 with ex-
cess of triethylamine, in the absence of fluorinated alco-
hols, gave 4 in 82% isolated yields. The use of
triethylamine in the synthesis of 3a–e is recommended
due to lower cost, greater ease of handling and separation
of the product from the reaction mixture. These reactions
show 100% regioselectivity: no other isomers were iden-
tified by NMR. The regioselectivity was confirmed by de-
termining the single crystal structure of 3a. All the
In the past several years, electrophilic fluorinating re-
agents have been used extensively to introduce fluorine
into a variety of organic substrates.1–5 However, recently
we reported6 a new application of N,N-difluoro-2,2 -bipy-
ridinium bis(tetrafluoroborate) (MEC-31) (1) to synthe-
size 6,6 -dialkoxy-2,2 -bipyridines in very good isolated
yields and with excellent regioselectivity as shown in
Scheme 1. The syntheses of the polyfluoroalkoxy bipy-
ridines from polyfluoroalcohols did not proceed under
analogous conditions. Because of their importance7 as in-
dustrial and medicinal compounds, as analytical reagents,
and as ligands for the preparation of metal complexes with
catalytic activity, the synthesis of the 6,6 -dialkoxy-2,2 -
bipyridines are of interest. The usual synthesis involves
the in situ generation of the Ni(0) complex, Ni[P(C6H5)3]4,
from nickel dichloride and triphenylphosphine. This is
followed by the coupling reaction of 2-methoxy-6-ha-
lopyridine.8 However, in our attempts to fluorinate ena-
mines electrophilically, we have found a simple base-
mediated, high-yield synthesis of various 6,6 -di(poly-
fluoroalkoxy)-2,2 -bipyridines with 100% regioselectivi-
ty and in good yields.
Table 1 Reaction of MEC-31 (1) with Excess Trifluoroethanol in
the Presence of Various Basesa
Bases
Conditions: temp Yield 3a (%)
(°C), time (h)
24, 24
70, 20
70, 20
52
85
85
Et3N
70, 20
70, 20
70, 20
82
72
60
(C4H9)3N
Scheme 1
70, 20
68
a All reactions were carried out with MEC-31 (1) (2 mmol) and base
(2 mmol) in excess trifluoroethanol.
Synthesis 2003, No. 7, Print: 20 05 2003.
Art Id.1437-210X,E;2003,0,07,1009,1011,ftx,en;M05502SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1010
R. P. Singh et al.
SHORT PAPER
Scheme 2
products were characterized by spectroscopic data and el-
emental analysis. Reactions of longer chain polyfluoroal-
cohols (e.g., HOCH2CF2CF2CF2CF2H) or bulky
polyfluoroalcohols [e.g., (CF3)3COH] were found to be
sluggish with the 2,2 -bipyridines being formed in trace
amounts along with significant quantities of 4.
Based on the literature,3,9 a reaction mechanism for the
formation of 3a–e and 4 is given in Scheme 3. Since the
fluorine atoms are very electron-withdrawing, 1 and 5 can
Scheme 3
(30 mL) and washed with H2O (3 × 30 mL). The organic layer was
dried (MgSO4) and filtered. Removal of the solvent gave 3a, which
was purified by crystallization using CH2Cl2 and pentane as a mix-
ture (2:1).
be suggested as reasonable resonance structures. In the Yield: 82%; mp 143–144 °C.
presence of a nucleophile, such as RO–, attack occurs at
the N-fluorocarbocation with concomitant loss of HF to
give the isolated 6,6 -dialkoxybipyridines (Scheme 1).6 A
similar reaction does not occur with RfOH. However,
upon addition of a base, the reaction with RfO– proceeds
as with RO–. Due to the higher acidity of the proton alpha
to nitrogen compared to other ring protons, only the 6,6 -
di(polyfluoroalkoxy) derivatives are formed. Under basic
conditions, in the absence of potential nucleophiles, the
IR (KBr film): 2900, 1575, 1439, 1257, 1155, 871, 737 cm–1.
1H NMR (300 MHz, CDCl3): = 4.82 (q, 4 H, J = 8.5 Hz), 6.83 (d,
2 H, J = 8 Hz), 7.71 (t, 2 H, 7.6 Hz), 7.95 (d, 2 H, J = 7.4 Hz).
13C NMR (75 MHz, CDCl3): = 62.0 (q, J = 36 Hz, CH2CF3),
111.5, 115.1, 123.8 (q, J = 277 Hz, CH2CF3), 140.1, 152.6, 161.1.
19F NMR (282 MHz, CDCl3): = –74.04 (t, 6 F, J = 9.3 Hz).
MS (EI): m/z (%) = 353 (M+ + H, 100), 352 (M+, 25), 333 (M+ – F,
+
46), 313 (M+ – HF2, 1), 283 (M+ – CF3, 6), 175 (C5H3NOCHCH3 ,
1), 93 (C5H3NO+, 1).
–
less reactive BF4 attacks the N-fluorocarbocation with
Anal. Calcd. for C14H10F6N2O2: C, 47.74; H, 2.86. Found: C, 47.84;
H, 2.71.
loss of HF to form 4 in 82% yield. In most of the reactions
in the presence of RfO–, small amounts of 4 are formed es-
pecially if the rate of nucleophilic attack is slow, e.g., with
(CF3)2CHO– or CF3CF2CH2O–. Reaction of 4 with an ex-
cess of 2,2,2-trifluoroethanol (2a) at 70 °C or in the pres-
ence of base failed to form 3a. No reaction occurred with
methanol as well. Based on these experimental observa-
tions it can be concluded that the nucleophile, RfO–, is
X-Ray crystallographic data: crystal system, orthorhombic; space
group, Iba2; unit cell dimensions, a = 16.6449(12) Å,
b = 17.4045(12) Å, c = 7.4855(5) Å, = 90º, = 90º, = 90º;
Z = 8; F(000) = 1168; R1 (all data) = 0.0483, wR2 = 0.0617.
Compound 3b
Yield: 80%; mp 80 °C.
–
much more reactive than BF4 which leads to good yields
IR (KBr film): 2923, 1568, 1443, 1312, 1261, 1146, 1017, 868, 782
cm–1.
of 3a–e and essentially precludes the formation of 4.
1H NMR (300 MHz, CDCl3): = 3.77 (dt, 4 H, J = 46, 4 Hz), 4.63
(dq, J = 25, 4 Hz), 6.75 (2 H, d, J = 8 Hz), 7.63 (t, 2 H, J = 7.63 Hz),
7.88 (d, 2 H, J = 7.5 Hz).
1H, 13C amd 19F NMR spectra were recorded in CDCl3 on a 500
MHz spectrometer operating at 500.13 MHz, 125.75 MHz, and
470.56 MHz respectively. Chemical shifts are reported in ppm rel-
ative to the apporpriate standard. GC/MS spectra were determined
on an apprpriate spectrometer. IR spectra were recorded using KBr
pellets for solids. Elemental analyses were performed by Desert An-
alytics Laboratory, Tucson, AZ, and the Shanghai Institute of Or-
ganic Chemistry.
19F NMR (282 MHz, CDCl3): = –224.70 (tt, 2 F, J = 46, 25 Hz).
MS (EI): m/z (%) = 280 (M+, 72), 259 [(M+ – HF + H), 4], 247
[(M+ – CH2F, 45], 232 [M+ – (CH2CH2F + H), 100], 213 [M+ – (2 ×
CH2F + H), 64].
Anal. Calcd for C14H14 F2N2O2: C, 60.00; H, 5.03. Found: C, 60.20;
H, 5.12.
Compound 3a; General Procedure
Compound 3c
Yield: 75%; mp 89–90 °C.
Et3N (3 mmol) was taken in a flask and trifluoroethanol (5 mL) was
added at 0 °C followed by the addition of 1 (3 mmol). The reaction
mixture was warmed to 25 °C, and heated at 60 °C for 15 h. The ex-
cess trifluoroethanol and other volatile materials were removed in
vacuo and trapped at –196 °C. The residue was taken up in CH2Cl2
IR (KBr film): 2951, 1576, 1435, 1304, 1259, 1189, 1147, 1101,
983, 794, 937, 735, 622 cm–1;
Synthesis 2003, No. 7, 1009–1011 ISSN 1234-567-89 © Thieme Stuttgart · New York

SHORT PAPER
Di(polyfluoroalkoxy)-2,2 -Bipyridines with 100% Regioselectivity
1011
1H NMR (300 MHz, CDCl3): = 4.90 (t, 4 H, J = 12 Hz), 6.84 (d,
2 H, J = 8 Hz), 7.72 (t, 2 H, 7.5 Hz), 7.96 (d, 2 H, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3): = 60.9 (t, J = 27.5 Hz, CH2CF2CF3),
111.5, 115.2, 112.8 (tq, JCF = 2254 Hz, CF2CF3, JCCF = 38 Hz,
CF2CF3), 118.79 (qt, JCF = 286 Hz, CF2CF3, JCCF = 35 Hz, CF2CF3),
140.2, 152.6, 161.1.
moved. The residue was dissolved in CH2Cl2 and washed with H2O.
The organic phase was separated, dried (MgSO4) and filtered. Re-
moval of solvent gave the product, which was purified by crystalli-
zation.
Yield: 82%; mp 173–174 °C.
IR (KBr): 2923, 1568, 1435, 1284, 1251, 1145, 1076, 1018, 785,
721 cm–1.
19F NMR (282 MHz, CDCl3): = –83.81 (s, 6 F), –123.44 (t, 4 F,
J
CH = 12 Hz).
1H NMR (300 MHz, CDCl3): = 6.83 (dd, 2 H, J = 2.8, 8.0 Hz),
7.85 (q, 2 H, 7.8 Hz), 8.21 (dd, 2 H, J = 2.3, 7.5 Hz).
19C NMR (75 MHz, CDCl3): = 110.32 (d, J = 37.1 Hz), 118.48 (d,
J = 3.8 Hz), 142.0 (d, J = 7.6 Hz), 153.2 (d, J = 13 Hz), 163.09 (d,
J = 237.6 Hz).
MS (EI): m/z (%) = 453 (M+ + H, 100), 452 (M+, 20), 433 (M+ – F,
27), 413 (M+ – HF2, 1), 383 (M+ – CF3, 1), 303 (M+ – CF3CF2CH2O,
6).
Anal. Calcd for C16H10 F10N2O2: C, 42.49; H, 2.23. Found: C, 42.54;
H, 2.07.
19F NMR (282 MHz, CDCl3): = –67.00 (d, 2 F, J = 6.5 Hz).
Anal. Calcd. for C10H6F2N2: C, 62.50; H, 3.15. Found: C, 62.14; H,
2.95.
Compound 3d
Yield: 72%; mp 114–115 °C.
IR (KBr film): 2950, 1571, 1435, 1357, 1267, 1197, 1096, 989, 929,
860, 836, 789, 731, 704 cm–1.
1H NMR (300 MHz, CDCl3): = 4.79 (t, 4 H, J = 12.5 Hz), 5.99 (tt,
2 H, J = 53, 4.7 Hz), 6.79 (d, 2 H, J = 8.1 Hz), 7.71 (t, 2 H, J = 7.7
Hz), 7.97 (d, 2 H, J = 7.4 Hz).
Acknowledgments
This work was supported by the National Science Foundation
(Grant No. CHE – 9720365) and by the Petroleum Research Fund,
administered by ACS. We are grateful to Dr. Kazuhiro Shimokawa
of Daikin Industries for the gift of MEC-31. We are also thankful to
Drs. G. Knerr and A. Blumenfeld for measuring MS and NMR spec-
tra, respectively.
13C NMR (75 MHz, CDCl3):
= 62.0 (t, J = 29.9 Hz,
CH2CF2CF2H), 109.6 (tt, J = 251, 34.6 Hz), 115.2 (tt, J = 250, 34.6
Hz), 140.4, 153.1, 161.5.
19F NMR (282 MHz, CDCl3): = –125.02 (q, 4 F, JCH, 8.5 Hz), –
139.29 (d, 4 F, JCF = 50.7 Hz).
References
MS (EI): m/z (%) = 416 (M+, 70), 315 (M+ – CF2CF2H, 100), 285
(M+ – OCH2CF2CF2H, 17), 192 (M+ – C5H3NOCH2CF2CF2H, 1).
(1) (a) Furin, G. G. Synthetic Aspects of the Fluorination of
Organic Compounds; Harwood Academic Publisher:
London, 1991. (b) Furin, G. G. Introduction of Fluorine by
N-F Compounds, In Methods of Organic Chemistry
(Houben-Weyl) Organo-Fluorine Compounds; Thieme:
Stuttgart, New York, 1999, 432–499.
(2) (a) Taylor, S. D.; Kotoris, C. C.; Hum, G. Tetrahedron 1999,
55, 12431. (b) McClinton, M. A.; McClinton, D. A.
Tetrahedron 1992, 48, 6555.
Anal. Calcd for C16H12 F8N2O2: C, 46.17; H, 2.91. Found: C, 46.00;
H, 3.12.
Compound 3e
Yield: 72%; mp 149–150 °C.
IR (KBr film): 2969, 1574, 1436, 1386, 1350, 1270, 1164, 1109,
900, 792, 733, 686 cm–1.
(3) (a) Rozen, S. Chem. Rev. 1996, 96, 1717. (b) Hebel, D.;
Rozen, S. J. Org. Chem. 1991, 56, 6298.
1H NMR (300 MHz, CDCl3): = 6.54 (sept, 2 H, J = 6 Hz), 6.96 (d,
2 H, J = 8 Hz), 7.82 (t, 2 H, 7.8 Hz), 7.97 (d, 2 H, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3): = 68.3 [sept, J = 35 Hz, CH(CF3)2],
112.2, 117.2, 121.6 [q, JCF = 287, CH(CF3)2], 141.6, 152.8, 160.0.
(4) (a) Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96,
1737. (b) Wilkinson, J. A. Chem. Rev. 1992, 92, 505.
(5) Singh, R. P.; Shreeve, J. M. J. Chem Commun. 2001, 116.
(6) Manandhar, S.; Singh, R. P.; Shreeve, J. M. J. Org. Chem.
2002, 67, 6415.
(7) (a) Rocaboy, C.; Hampel, F.; Gladysz, J. A. J. Org. Chem.
2002, 67, 6863; and references therein. (b) Newkome, G.
R.; Puckeff, W. E.; Kiefer, G. E.; Gupta, V. K.; Xia, Y.;
Coreil, M.; Hackney, A. J. Org. Chem. 1982, 47, 4116.
(c) Zassinovich, G.; Mestroni, G.; Camus, A. J. Organomet.
Chem. 1979, 168, C37.
19F NMR (282 MHz, CDCl3): = –73.62 (d, 12 F, J = 6 Hz).
MS (EI): m/z (%) = 489 (M+ + H, 24), 488 (M+, 100), 469 (M+ – F,
+
15), 321 [M+ – (CF3)2CHO, 2], 69 (CF3 , 1).
Anal. Calcd for C16H8 F12N2O2: C, 39.36; H, 1.67. Found: C, 39.35;
H, 1.47.
Compound 4
(8) Tiecco, M.; Testaferri, L.; Cianell, D.; Montanucci, M.
Synthesis 1984, 736.
(9) Rozen, S. Acc. Chem. Res. 1996, 29, 243.
MEC-31 (1) (1.8 g, 5 mmol) was added as a powder in small por-
tions directly to an excess of Et3N at 0 °C. Reaction takes place vig-
orously with the generation of heat. After complete addition, the
reaction mixture was stirred at 25 °C for 1 h. Excess Et3N was re-
Synthesis 2003, No. 7, 1009–1011 ISSN 1234-567-89 © Thieme Stuttgart · New York