A new strategy for the synthesis of poly-substituted 3-H, 3-fluoro, or 3-trifluoromethyl pyridines via the tandem C-F bond cleavage protocol

Article abstract of DOI:10.1021/ol101859p

Figure Presented. A new strategy for the synthesis of poly-substituted 3-H, 3-F, and 3-trifluoromethyl pyridines based on C-F bond breaking of the anionically activated fluoroalkyl group is described. A series of 2,6-disubstituted 4-amino pyridines were p

Full text of DOI:10.1021/ol101859p

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4376-4379
A New Strategy for the Synthesis of
Poly-Substituted 3-H, 3-Fluoro, or
3-Trifluoromethyl Pyridines via the
Tandem C-F Bond Cleavage Protocol
Zixian Chen,†,‡ Jiangtao Zhu,† Haibo Xie,† Shan Li,† Yongming Wu,*,† and
Yuefa Gong*,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China, and
School of Chemistry and Chemical Engineering, Huazhong UniVersity of Science and
Technology, Wuhan, 430074, China
ymwu@mail.sioc.ac.cn; gongyf@mail.hust.edu.cn
Received August 9, 2010
ABSTRACT
A new strategy for the synthesis of poly-substituted 3-H, 3-F, and 3-trifluoromethyl pyridines based on C-F bond breaking of the anionically
activated fluoroalkyl group is described. A series of 2,6-disubstituted 4-amino pyridines were prepared through this domino process in high
yields under noble metal-free conditions, making this method a supplement to pyridine synthesis.
The pyridine unit represents an important structural motif
found in natural products and biologically relevant com-
pounds,1 which are the subject of considerable interest as
potent antitumor,2 antimicrobial,3 and antiviral agents4 and
herbicides,5 and it is also a significant component of many
common ligands.6 Therefore, efficient methods for the
synthesis of these compounds are of great significance,7
especially for their fluoro-containing counterparts, as the
(3) (a) Wang, Y.; Dong, X.; Larock, R. C. J. Org. Chem. 2003, 68,
3090–3098. (b) Wachter, G. A.; Davis, M. C.; Martin, A. R.; Franzblau,
S. G. J. Med. Chem. 1998, 41, 2436–2438. (c) Tucker, J. A.; Allwine, D. A.;
Grega, K. C.; Barbachyn, M. R.; Klock, J. L.; Adamski, J. L.; Brickner,
S. J.; Hutchinson, D. K.; Ford, C. W.; Zurenko, G. E.; Conradi, R. A.;
Burton, P. S.; Jensen, R. M. J. Med. Chem. 1998, 41, 3727–3735.
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2004, 47, 4032–4040. (b) Skerlj, R. T.; Zhou, Y.; Wilson, T.; Bridger, G. J.
J. Org. Chem. 2002, 67, 1407–1410.
† Chinese Academy of Sciences.
‡ Huazhong University of Science and Technology.
(1) (a) Henry, G. D. Tetrahedron 2004, 60, 6043–6061. (b) David, O.
Nat. Prod. Rep. 2000, 17, 435–446. (c) Balasubramanian, M.; Keay, J. G.,
In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 5, p 245.
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T.; Hallur, G.; Bai, R.; Van Diest, P. J.; Hamel, E.; Khan, S. R. J. Med.
Chem. 2008, 51, 5953–5957. (b) Kuo, G.; Prouty, C.; Wang, A.; Emanuel,
S.; DeAngelis, A.; Zhang, Y.; Song, F.; Beall, L.; Connolly, P. J.; Karnachi,
P.; Chen, X.; Gruninger, R. H.; Sechler, J.; Fuentes-Pesquera, A.; Middleton,
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Guan, H. J. Agric. Food Chem. 2006, 54, 125–129.
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2004, 126, 8100–8101. (b) Tsuboyama, A.; Iwawaki, H.; Furugori, M.;
Mukaide, T.; Kamatani, J.; Igawa, S.; Moriyama, T.; Miura, S.; Takiguchi,
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10.1021/ol101859p  2010 American Chemical Society
Published on Web 09/02/2010

incorporation of fluorine or fluorine-containing groups into
an organic molecule may lead to improvements in pharma-
cological properties.8 Although synthesis of various substi-
tuted pyridines has been widely covered in the literature and
inspired significantly different strategies,1c,9 methods for the
fluorine-containing substrates are rare,10 and novel methods
for poly-substituted pyridines are still desired. Herein we
report a mild and efficient cascade procedure for chemose-
lective conversion of alkynylimines into the corresponding
substituted pyridines.
Initial experiments were carried out using 3 equiv of
benzylamine 2a with 2.5 equiv of Cs2CO3 in CH3CN at 80
°C. The desired 3-fluoropyridine product 3a was obtained
in 45% yield (Table 1, entry 1), which was confirmed by
crystal diffraction (Figure 1).16 Then other solvents were
The C-F bond is generally regarded as the strongest bond
in organic molecules, so its cleavage has become a current
subject of active investigation, as it provides us an op-
portunity to synthesize nonfluorinated products and partially
fluorinated compounds, which are otherwise inaccessible.11
It has been shown that the anionically activated trifluoro-
methyl group has great utility in the synthesis fluorine-
containing compounds,12 as it is easier to introduce a CF3
group into a molecule then other fluorinated groups. The
C-F bond breaking does rather easily occur when a CF3
group is attached to a π-electron system because of electron
pair acceptance into the π-system, and subsequent extrusion
of a fluoride ion provides the driving force.13 The formed
intermediary gem-difluorovinyl can react with various nu-
cleophiles14 or react with electrophiles when it is attached
to an anion,15 leading to various difluoromethylene building
blocks. Our strategy for the construction of diversely
substituted pyridine derivatives is based on this cascade C-F
cleavage/nucleophilic addition protocol.
Figure 1. X-ray structure of 3a and 5a.
evaluated. Comparing with toluene, DMF, dioxane, and
MeOH, the yield improved considerably when DME (1,2-
(8) (a) Yamazaki, T.; Taguchi, T.; Ojima; I., In Fluorine in Medicinal
Chemistry and Chemical Biology; Ojima, I., Eds.; Wiley-Blackwell:
Weinheim, 2009; pp 3-46. (b) Ioannidis, S.; Lamb, M. L.; Davies, A. M.;
Almeida, L.; Su, M.; Bebernitz, G.; Ye, M.; Bell, K.; Alimzhanov, M.;
Zinda, M. Bioorg. Med. Chem. Lett. 2009, 19, 6524–6528. (c) Balko, T. W.;
Buysse, A. M.; Epp, J. B.; Fields, S. C.; Lowe, C. T.; Keese, R. J.; Richburg,
J. S., III; Ruiz, J. M.; Weimer, M. R.; Green, R. A.; Gast, R. E.; Bryan, K.;
Irvine, N. M.; Lo, W. C.-L.; Brewster, W. K.; Webster, J. D. US6784137,
2004. (d) Phillips, G.; Davey, D. D.; Eagen, K. A.; Koovakkat, S. K.; Liang,
A.; Ng, H. P.; Pinkerton, M.; Trinh, L.; Whitlow, M.; Beatty, A. M.;
Morrissey, M. M. J. Med. Chem. 1999, 42, 1749–1756. (e) Saari, W. S.;
Halczenko, W.; King, S. W.; Huff, J. R.; Guare, J. P.; Hunt, C. A.; Randall,
W. C.; Anderson, P. S.; Lotti, V. J. J. Med. Chem. 1983, 26, 1696–1701.
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10, 325–328. (b) Hu, J.; Zhang, Q.; Yuan, H.; Liu, Q. J. Org. Chem. 2008,
73, 2442–2445. (c) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am.
Chem. Soc. 2007, 129, 10096–10097. (d) Movassaghi, M.; Hill, M. D. J. Am.
Chem. Soc. 2006, 128, 4592–4593. (e) Barluenga, J.; Pozo, C.; Olano, B.
Synthesis 1996, 1996, 133–140. (f) Oliver Kappe, C. Tetrahedron 1993,
49, 6937–6963. (g) Barluenga, J.; Toma´s, M.; Jardo´n, J.; Rubio, E.; Gotor,
V. Synthesis 1989, 1989, 230–232.
As listed in Table 1, N-(1,1,1-trifluoro-4-phenylbut-3-yn-
2-ylidene)aniline 1a and benzylamine 2a were chosen as
model substrates to screen the optimal reaction conditions.
Table 1. Optimization of Reaction Conditionsa
yield (%)b
entry
solvent
base
time (h)
3a
45
30
47
90
59
98 (97)
4a
(10) (a) Fields, S. C.; Lo, W. C.; Brewster, W. K.; Lowe, C. T.
Tetrahedron Lett. 2010, 51, 79–81. (b) von Kieseritzky, F.; Lindstro¨m, J.
Synthesis 2010, 63, 66. (c) Dolbier, W. R.; Xu, Y. J. Fluorine Chem. 2003,
123, 71–73. (d) Fukuhara, T.; Yoneda, N.; Suzuki, A. J. Fluorine Chem.
1988, 38, 435–438. (e) Pews, R. G.; Lysenko, Z. J. Org. Chem. 1985, 50,
5115–5119. (f) Boudakian, M. M. J. Fluorine Chem. 1981, 18, 497–506.
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4061–4063, and references therein.
1
2
3
4
5
6
CH3CN
toluene
DMF
DME
dioxane
THF
Cs2CO3
2
6
2
2
3
-
′′
′′
′′
′′
4
2
-
-
-
′′
2
7
8
9
10
11
12
MeOH
THF
THF
THF
THF
′′
-
2
2
2
12
12
1
5
-
80
72
12
-
-
(13) (a) Uneyama, K. In Organofluorine Chemistry; Blackwell Publish-
ing Ltd.: Oxford, 2006; p 107. (b) Amii, H.; Kobayashi, T.; Hatamoto, Y.;
Uneyama, K. Chem. Commun. 1999, 1323, 1324.
99 (98)
20
0
88
46
KOH
K3PO4
K2CO3
DBU
(14) (a) Kiselyov, A. S.; Piatnitski, E. L.; Doody, J. Org. Lett. 2004, 6,
4061–4063. (b) Ichikawa, J.; Wada, Y.; Miyazaki, H.; Mori, T.; Kuroki,
H. Org. Lett. 2003, 5, 1455–1458.
THF
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2003, 5, 4297–4300. (b) Amii, H.; Kobayashi, T.; Terasawa, H.; Uneyama,
K. Org. Lett. 2001, 3, 3103–3105.
a Reactions were carried out on a 0.3 mmol scale with benzylamine
(3.0 equiv), base (2.5 equiv), and solvent (2 mL) at 80 °C unless otherwise
stated. b Reported yields were based on 1a determined by 19F NMR. Values
in parentheses are of isolated yields.
(16) The X-ray crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre under deposition number 769650
(3a) and 778755 (5a).
Org. Lett., Vol. 12, No. 19, 2010
4377

dimethoxyethane) or THF was used (Table 1, entries 4 and
6). Next, different bases were screened with THF as the
solvent. The weaker bases prolonged the reaction time with
lower yields (Table 1, entries 10 and 11), and no pyridine
was detected when organic base such as DBU was used
(Table 1, entry 12). 4a was isolated without further conver-
sion in the absence of a base (Table 1, entry 8), which can
form the final product in quantitative yield if Cs2CO3 is
added. After optimization, the best reaction conditions were
ascertained as 3 equiv of 2a and 2.5 equiv of Cs2CO3 in
THF at 80 °C.
benzylamines and hetarylmethylamines were tested under the
optimal reaction conditions. In general, the reaction tolerates
various amines containing aryl groups. Amines with electron-
rich aromatic rings showed greater reactivity compared with
those with electron-deficient aryl rings. For example, the
reaction of 4-methylbenzylamine and 1a proceeded in 98%
isolated yield (Table 3, entry 1), while the inactive amines
Table 3. Reactions of 1a with Various Aminesa
With the optimized conditions in hand, we examined the
generality of this process. Other fluoroalkyl substrates were
tested. When CF2Br was in place of CF3, the corresponding
product was formed in good yield (Table 2, entry 1), and
entry
R3
product
yield (%)b
1
2
3
4
5
6
7
8
9
10
p-MeC6H4
o-MeC6H4
3,4-diMeOC6H4
p-ClC6H4
p-CF3C6H4
o-CF3C6H4
1-naphthyl
2-thienyl
3l
98
89
93
85
52
50
93
96
62
80
Table 2. Reactions of Various Alkynylimines with
Benzylaminea
3m
3n
3o
3p
3q
3r
3s
3t
2-pyridyl
2-furyl
entry
Rf
R1
R2
product yield (%)b
3u
a Reactions were carried out on a 0.4 mmol scale in THF (2 mL) with
methylamines (3.0 equiv) and base (2.5 equiv) at 80 °C unless otherwise
stated. b Isolated yields.
1
2
3
4
5
6
7
8
CF2Br
CF2Cl
CF2H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
80
64
80c
74d
99
59
84
90
60
97
96
95
CF3CF2 Ph
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
p-MeC6H4 Ph
such as 4-(trifluoromethyl)benzylamine required longer time
to afford the corresponding pyridine with a reduced yield
(Table 3, entry 5). Because of steric hindrance, the ortho-
substituted benzylamine resulted in a slight decrease in yield
(Table 3, entry 2). Moreover, substrates with a heterocyclic
ring could also provide the product in satisfactory yield
(Table 2, entries 8-10), which may serve as a good ligand,
such as 2,2′-bipyridine. The cyclization process did not occur
when n-butylamine was used, providing 4v as a sole product
in quantitative yield, which could form the pyridine product
if NaH was used as the base (Scheme 1). Surprisingly, a
byproduct dihydropyrimidine 5v was isolated in 32% yield
in addition to the desired compound, while use of a soluble
base t-BuOK yielded 5v as the sole product. Amazingly,
annulation of 4a under this condition also gave a mixture of
3a and 5a, while lowering the temperature to -40 °C led to
formation of 5a only.16
A possible mechanism of this transformation is proposed
in Scheme 2. The first step is the hydroamination of
alkynylimine with amine to form the intermediate vinylogous
amidine 4, which undergoes deprotonation and dehydroflu-
orination to generate an anion and an imine coexisting in
one molecule. When the reaction is carried out at a low
temperature with a soluble base (path a), the in situ generated
amide nucleophile attacks imine immediately without isomer-
ization to form dihydropyrimidine through a kinetically
controlled pathway. Raising the reaction temperature (path
b), however, makes the carbon nucleophilic addition become
n-butyl
p-FC6H4
2-thienyl
COOMe
Ph
Ph
Ph
Ph
Ph
9
10
11
12
p-MeOC6H4
p-CNC6H4
m-MeC6H4
Ph
Ph
3j
3k
a Reactions were carried out on a 0.4 mmol scale in THF (2 mL) with
2a (3.0 equiv) and base (2.5 equiv) at 80 °C unless otherwise stated.
b Isolated yields. c X ) H. d X ) CF3.
the yield for the CF2Cl group was acceptable as well (Table
2, entry 2). Surprisingly, when CF2H and CF3CF2 substrates
were used, the resultant 3-H pyridine and 3-trifluoromethyl
pyridine were obtained, respectively, in favorable yields
(Table 2, entries 3 and 4), rendering more versatility. All
substrates with various alkynyl moieties could be the
candidates. Electron-rich aryl substituents gave excellent
yields (Table 2, entries 5 and 8), while electron-deficient
yields were slightly lower (Table 2, entry 7). When an alkyl
group is attached, a longer reaction time (24 h) was required
with a poorer yield (Table 2, entry 6). An ester group also
afforded the desired products in moderate yield (Table 2,
entry 9). Further studies on the N-aryl group revealed that
electronic effects of its substitution did not significantly affect
the reactivity (Table 2, entries 10-12).
To expand the scope of the intermolecular tandem reaction
of alkynylimine with benzylamine, a variety of substituted
4378
Org. Lett., Vol. 12, No. 19, 2010

Scheme 1
.
Base-Controlled Cyclization Reaction
Scheme 2. Proposed Mechanism
mechanism, and the gem-difluoromethylation based on this
strategy, are currently underway in our laboratory.
an option, rendering a 1,2-dihydropyridine ring under
thermodynamic control, which finalizes the pyridine ring after
proton migration, ꢀ-F elimination, and isomerization, and
an insoluble base can effectively inhibit the kinetic pathway.
In conclusion, we have designed a new strategy for the
chemoselective synthesis of poly-substituted pyridines using
amines and alkynylimines, through a cascade process based
on anionical C-F bond activation. The substituents of the
pyridine ring can be introduced stepwise from initial fluo-
roalkyl acids in high yields.17 A variety of functional groups
can be employed, rendering this method particularly attractive
for the efficient preparation of biologically and medicinally
interesting molecules. Further investigations into the reaction
Acknowledgment. This work was supported by the
National Science Foundation of China (Nos. 20772145).
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products and typical
procedure for the annulation reactions. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL101859P
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