Efficient preparation of 2-pyridylpyridines using β-N,N-dialkylated aminoacroleins or their equivalent as vinadinium tetrafluoroborate

Article abstract of DOI:10.1246/cl.2005.834

Efficient synthetic procedure for 2-pyridylpyridines using β-N,N-dialkylated aminoacroleins or their equivalent as dipiperidyl vinadinium tetrafluoroborate is described. Copyright

Full text of DOI:10.1246/cl.2005.834

834
Chemistry Letters Vol.34, No.6 (2005)
Efficient Preparation of 2-Pyridylpyridines Using ꢀ-N,N-Dialkylated Aminoacroleins
or their Equivalent as Vinadinium Tetrafluoroborate
Hirokazu Kuwabara, Ken Umihara, Yasushi Furugori, and Isamu Itohꢀ
Synthetic Chemistry Research Laboratory, Sankio Chemical Co., Ltd.,
5-2-3 Higashiyahata, Hiratsuka, Kanagawa 254-0016
(Received February 17, 2005; CL-050214)
Efficient synthetic procedure for 2-pyridylpyridines using
ꢀ-N,N-dialkylated aminoacroleins or their equivalent as dipiper-
idyl vinadinium tetrafluoroborate is described.
Table 1. The preparation of 2-pyridylpyridines using ꢀ-N,N-
dialkylated aminoacroleins as malonaldehyde equivalentsa
Run
Ketone
Aminoacrolein
Productb
Yield/%c
2-Pyridylpyridine derivatives have been well known as fun-
damental building blocks of some potent drugs1–3 and as ligands
in coordination chemistry.4 Since the initial use of Ullmann re-
action for the 2,40-bipyridine synthesis,5 various synthetic proce-
dures for 2-pyridylpyridine derivatives have been developed
containing Suzuki–Miyaura coupling reactions of pyridylboron-
ic acid and halopyridines,6 aza-Diels–Alder methodology from
triazine precursors and 2,5-norbornadiene,7 and the novel ionic
annulation reaction using 2-acetylpyridine and vinamidinium
hexafluorophosphate salt containing Cl group at the ꢀ-position.8
We have studied the more effective synthetic method and devel-
oped two new processes for producing 2-pyridylpyridine deriv-
atives, which we present herein. Our general method is revealed
in Scheme 1.
H
Me
N
N
N
COMe
O
N
N
N
1
2
3
4
51.2
Me
Me
1a
2a
3a
3a
H
N
N
N
N
N
COMe
O
N
68.2
1a
2b
Me
H
Me
N
COMe
Me
O
64.7
1a
2c
3b
6
COMe
O
N
37.0
5
2b
At the first step, we established the new procedure starting
from !-acetylpyridine 1 and several malonaldehyde equivalents
2, the results of which are summarized in Table 1.9 In Run 1,
Michael reaction of 4-acetylpyridine 1a with acrolein 2a and
the subsequent annulation provided the desired 2,40-bipyridine
3a in 51.2% yield. Similarly, when 3-(10-piperidino)acrolein
2b was used, the yield of 3a went up to 68.2% (Run 2). In the
case of commercially available 2-methyl-3-(N,N-dimethyl-
amino)acrolein 2c, 5-methyl-2,40-bipyridine 3b was obtained
in 64.7% yield (Run 3). Analogously, the reaction of acetophe-
none 5 and 2b led to formation of 2-phenylpyridine 6 in 37.0%
yield (Run 4). Naturally, every product had a high purity
(>99:9% from HPLC).
Furthermore, we examined the reactivity of the ionic vinadi-
nium salts which have been reported that electron withdrawing
groups at the ꢀ-position is essential to produce the correspond-
ing 2-pyridine derivatives in good yield.8 We selected dipiperi-
dyl vinadinium salts 4 as an equivalent synthetically to the N,N-
disubstituted aminoacrolein 2, expecting the higher efficiency
aThe typical reaction procedure is as follows; t-BuOK (1 equiv.)
was added to a THF solution of methyl ketone (1 equiv.) and
aminoacrolein (1.05 equiv.), and the mixture was stirred at
40 ꢁC for 10 min. Then, NH4OAc (6 equiv.) and AcOH (6
equiv.) were added and the mixture was heated to 90 ꢁC for
3 h by removing THF gradually to give the desired product. bThe
structure of the product was identified by IR, NMR, and MS
c
spectrometry. Yield based on the starting methyl ketone.
as the initial Michael reaction acceptor. The salt 4a was prepared
newly as a pale yellow powder by treatment of (3-phenylamino-
2-propenylidene)phenylammonium chloride10 and piperidine in
MeOH under reflux for 1 h, removal of the solvent by heꢂating
to 100 ꢁC, and then conversion of the counter ion to BF4 for
the preparation of stable salts against moisture by addition of
42% HBF4 in MeOH–H2O (1:13) in 65–70% total yield. The
salts having a methyl group (4b), a phenyl group (4c), and a
chloro atom (4d) at the ꢀ-position were also prepared from cor-
responding (3-phenylamino-2-propenylidene)phenylammonium
chloride. The results of the ionic annulation reaction using 4 with
acetylpyridines were shown in Table 2. Our procedure provides
the general and smooth annulation reaction with the unsubstitut-
ed methinium salt 4a (Runs 1, 2, and 3) as well as substituted
salts 4b (Run 4), 4c (Run 5), and 4d (Run 6) in fairly good
yields, being versatile as the general construction of various 2-
pyridylpyridines.11
Me
N
R1
1) t-BuOK
O
O
N
N
N
+
+
R2
N
2) NH4OAc
1
1
3
2
Me
R
1) t-BuOK
+
In summary, we developed the new two valuable procedures
for the synthesis of 2-pyridylpyridine derivatives. Noticeably,
both of them do not require any expensive special catalysts
and special equipment, do not cause environmental problems,
and could be operated on an industrial scale.
O
N
N
2) NH4OAc
BF4
4
Scheme 1. Our general reaction scheme.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.6 (2005)
835
Table 2. The preparation of 2-pyridylpyridines using dipiperi-
dyl vinamidinium tetrafluoroborate as a malonaldehyde equiv-
aenta
References
1
D. R. Sidler, R. D. Larsen, M. Chartrain, N. Ikemoto, C. M.
Roberge, C. S. Taylor, W. Li, and G. F. Bills, WO 99/07695
(1999).
Dipiperidylvinamidinium
salt
Productb
Run
Yield/%c
Ketone
2
3
F. Krohnke, Synthesis, 1976, 1.
K. Kamei, N. Maeda, and T. Tatsuoka, WO 99/03847
(1999).
H
N
+
N
COMe
1a
N
N
N
1
88
4
5
6
D. Cui, M. R. Davis, M. Dunn, B. E. Evans, H. P. Kari, B.
Lagu, D. Nagarathnam, K. P. Vyas, and K. Zhang, U. S.
Patent 6,274,585 B1 (2001).
M. Goshaev, O. S. Otroshchenko, A. S. Sadykov, and N.
Kuznetsova, Izv. Akad. Nauk Turkm. SSR, Ser. Fiz.-Tekh.,
Khim. Geol. Nauk, 1970, 114.
For the recent papers on the Suzuki-Miyaura reactions: P.
Meier, S. Legraverant, S. Muller, and J. Schaub, Synthesis,
2003, 551; G. Adjabeng, T. Brenstrum, J. Wilson, C.
Framton, A. Robertson, J. Hillhouse, J. McNulty, and A.
Capretta, Org. Lett., 5, 953 (2003); P. R. Parry, C. Wang,
A. S. Batsanov, M. R. Bryce, and B. Tarbit, J. Org. Chem.,
67, 7541 (2002).
4a
3a
BF4
N
N
N
H
65d
80
+
COMe
2
N
N
N
1b
3c
4a
BF4
H
N
N
N
+
COMe
N
3
1c
3b
BF4
CH3
4a
N
+
CH3
4
N
N
N
COMe
N
N
N
85
1a
3d
BF4
4b
7
8
S. P. Stanforth, B. Tarbit, and M. D. Watson, Tetrahedron
Lett., 44, 693 (2003).
J.-F. Marcoux, F.-A. Marcotte, J. Wu, P. G. Dormer, I. W.
Davies, D. Hughes, and P. J. Reider, J. Org. Chem., 66,
4194 (2001), and references cited therein.
N
C6H5
+
5
6
C6H5
COMe
N
N
N
1a
82
3e
4c
BF4
Cl
N
9
H. Suda and K. Umihara, Jpn. Patent 3032980 (2000);
H. Suda and K. Umihara, U. S. Patent 6,489,483 (2002).
+
Cl
COMe
N
N
N
1a
72
10 S. M. Makin, O. A. Shavrygina, M. I. Berezhnaya, and
T. P. Kolobova, Zh. Org. Khim., 8, 1394 (1972).
11 H. Suda, H. Saitoh, A. Takada, and K. Umihara, Jpn. Patent
2003-160563A (2003).
BF4
4d
3f
aThe typical reaction procedure is as follows; methyl ketone (1
equiv.) was added to a cold solution of t-BuOK (1 equiv.) and
the mixture was stirred at 0 ꢁC for 15 min. The mixture was
added slowly to a suspension of the salt 4 (1.1 equiv.) in THF
and the mixture was warmed to rt for 30 min. After addition of
NH4OAc (4 equiv.) and AcOH (4 equiv.), the mixture was stir-
red at 95 ꢁC for 6 h by removing THF gradually to give the de-
sired product. bThe structure of the product was identified by 1R,
NMR, and MS spectrometry. cYield based on the starting methyl
ketone. dYield was only 8% when 1b and 4a were mixed first in
the absence of t-BuOK due to the formation of isoluble complex.
Published on the web (Advance View) May 21, 2005; DOI 10.1246/cl.2005.834