An oxidant-free single-step synthesis of tetra-or disubstituted symmetrical pyridine derivatives by a Hf(OTf)4-catalyzed annulation

Article abstract of DOI:10.1055/s-0030-1260978

The Hf(OTf)₄-catalyzed unprecedented annulation of an enamine with triethyl orthoformate leading to the preparation of tetrasubstituted symmetrical pyridine derivatives without an oxidant is described. This method accommodated the single-step synthesis of a disubstituted symmetrical pyridine using an acetophenone derivative, triethyl orthoformate, and ammonium acetate (NH₄OAc). Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260978

LETTER
2029
An Oxidant-Free Single-Step Synthesis of Tetra- or Disubstituted Symmetrical
Pyridine Derivatives by a Hf(OTf)4-Catalyzed Annulation
Single-Step
S
yn
o
thesis of Te
t
s
ra- or
D
is
h
ubstituted Sy
i
mmetr
a
ical
P
yridin
k
es i Sasada, Fuminori Kobayashi, Masato Moriuchi, Norio Sakai, Takeo Konakahara*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba
278-8510, Japan
Fax +81(4)71239326; E-mail: konaka@rs.noda.tus.ac.jp
Received 5 January 2011
been reported.16 In this letter, we report on the preliminary
Abstract: The Hf(OTf)4-catalyzed unprecedented annulation of an
results of the unprecedented synthesis of the pyridine.
Moreover, we disclose the use of acetophenone deriva-
tives and ammonium acetate, instead of the enamine, to
enamine with triethyl orthoformate leading to the preparation of tet-
rasubstituted symmetrical pyridine derivatives without an oxidant is
described. This method accommodated the single-step synthesis of
a disubstituted symmetrical pyridine using an acetophenone deriva- produce disubstituted symmetrical pyridines.
tive, triethyl orthoformate, and ammonium acetate (NH4OAc).
Key words: heterocycles, pyridines, hafnium triflate, enamines,
orthoesters
cat. ZnCl2
NH4OAc
R1
R1
R2
R1
R2
R1
R2
cat. Hf(OTf)4
route b
N
route a
H2N
R2
N
N
+
(previous work)
(this work)
Symmetrical pyridine nuclei are widely found in a variety
of natural products and biologically active substances.1
Although a number of approaches to the synthesis of a py-
ridine derivative have been reported by a number of or-
ganic and pharmaceutical chemists,1–5 the general
procedure for the preparation of a symmetrical pyridine
skeleton has been restricted to a two-step synthetic route
via the Hantzsch-type synthesis6,7 of symmetrical 1,4-
dihydropyridine derivatives,8,9 followed by the aroma-
tization of 1,4-dihydropyridines using increased stoichio-
metric amounts of an oxidant.10 In addition, this synthetic
process often requires stoichiometric additives such as a
strong base and acid, a prolonged time-frame, and harsh
reaction conditions that result in a decline in the desired
product yield. Hence, the development of an efficient
acid-catalyzed single-step synthesis of symmetrical pyri-
dine derivatives using no oxidants, and with a shortened
time-frame, is highly desirable.
CH(OEt)3
Scheme 1 Previous and current synthesis methods
Initially, the starting materials, enamines 3a–d, were eas-
ily prepared by the reaction of an a-acidic compound 1
with a nitrile 2 in THF at –70 °C for one hour in the pres-
ence of LDA, as reported previously.14,17,18
Annulation of the prepared enamine 3a with orthoester 4
was then examined, and the results are listed in Table 1.
When the reaction of enamine 3a (0.50 mmol) with
orthoester 4 (1.5 mL, 20 equiv for 3a) was performed with
neither a solvent nor a catalyst at room temperature for 16
hours, the annulation did not occur (entry 1). Addition of
a typical Lewis acid, such as ZnBr2, MgBr2·OEt2, InCl3,
BF3·OEt2, or AlCl3, was also ineffective for the reaction
(entries 2–6). On the other hand, use of Yb(OTf)3 and
Cu(OTf)2 was effective for an improvement in the yield of
pyridine 5a to moderate, but the undesirable product 6
was formed in 28% and 40% yields, respectively (entries
7 and 8). Employment of Hf(OTf)4 also gave the desired
product 5a and the undesired product 6 in 74% and 24%
yields, respectively (entry 10). It was noteworthy that use
of CHCl3 as a solvent and reduction of the equivalent of
orthoester 4 to one equivalent for 3a decreased the forma-
tion of by-product 6 to a trace amount (entry 13). More-
over, when the reaction temperature was raised to 60 °C,
the product 5a was selectively obtained as a sole product
in 76% yield (entry 16).
We previously reported that Lewis acid mediated annula-
tion of an enamine derivative11,12 with an orthoester leads
to the synthesis of a variety of nitrogen-containing hetero-
cyclic compounds.13 In a previous paper,14 we found that
the ZnCl2-catalyzed reaction of an enamine with an
orthoester leads to the synthesis of pyrimidine derivatives
(route a in Scheme 1). During our ongoing studies of a
practical synthetic process for nitrogen-containing hetero-
cycles using a functionalized enamine and an orthoester,
15
we found that Hf(OTf)4 catalyzes the annulation of an
enamine with triethyl orthoformate leading to the highly
selective synthesis of tetrasubstituted symmetrical pyri-
dine derivatives (route b). To our knowledge, a single-step
synthesis of the pyridine derivative through annulation of
an enamine with an orthoester as a C1 unit is yet to have
To explore the scope of the method, the reaction was ex-
amined using several enamines. The results are summa-
rized in Table 2. When enamines 3b and 3c, having an
electron-donating group on the benzene ring, were em-
ployed, the desired symmetrical pyridine derivatives 5b
and 5c were obtained in good yields (entries 2 and 3). In
contrast, use of enamine 3d, which contains a chloro sub-
stituent, produced the corresponding product 5d in mod-
SYNLETT 2011, No. 14, pp 2029–2034
x
x
.x
x
.2
0
1
1
Advanced online publication: 03.08.2011
DOI: 10.1055/s-0030-1260978; Art ID: U00211ST
© Georg Thieme Verlag Stuttgart · New York

2030
T. Sasada et al.
LETTER
Table 1 Examination of the Synthesis of Pyridine Derivative 5a
N
N
N
N
O
O
O
O
Me
Me
Me
Me
Lewis acid
solvent
N
+
CH(OEt)3
+
4
Ph
N
Ph
N
5a
Ph
H2N
Ph
6
3a
Entry
4 (equiv)
Lewis acid (equiv)
Solvent
Temp (°C)
Time (h)
Yield (%)a
5a
6
1
2
20
20
20
20
20
20
20
20
20
20
20
20
1
none
none
none
none
none
none
none
none
none
none
none
none
none
CHCl3
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
60
16
16
16
16
16
16
16
16
16
8
NR
ND
ND
11
ZnBr2 (0.1)
ND
ND
7
3
MgBr·OEt2 (0.1)
InCl3 (0.1)
4
5
BF3·OEt2 (0.1)
AlCl3 (0.1)
14
trace
trace
28
6
26
7
Yb(OTf)3 (0.1)
Cu(OTf)2 (0.1)
HfCl4 (0.1)
44
8
45
40
9
36
trace
24
10
11
12
13
14
15
16
Hf(OTf)4 (0.1)
Hf(OTf)4 (0.3)
Hf(OTf)4 (0.05)
Hf(OTf)4 (0.1)
Hf(OTf)4 (0.1)
Hf(OTf)4 (0.1)
Hf(OTf)4 (0.1)
(74)
62
8
11
8
48
30
8
61b
48b
51b
(76)
trace
trace
trace
trace
1
8
1
toluene
CHCl3
8
1
1.5
a NMR yield (isolated yield); NR = no reaction; ND = not determined.
b Average of two runs.
erate yield (entry 4). Similarly, use of enamines 3e and 3f A plausible mechanism for this Hf(OTf)4-catalyzed annu-
gave the desired products 5e and 5f in 83% and 60% lation is shown in Scheme 2. Previously, we have reported
yields, respectively (entries 5 and 6), as they have a meth- a ZnCl2-catalyzed three-component synthesis of 4,5-di-
yl group instead of a phenyl group, and they have an elec- substituted pyrimidines from an enamine, an orthoester,
tron-withdrawing group, either an ester or a nitrile.
and ammonium acetate.14 Hf(OTf)4 is a Lewis acid harder
than ZnCl2,19 and the imine 10 is a Lewis base harder than
ketone 7 (or the orthoester 4).20 According to HASB prin-
ciple, Hf(OTf)4 binds strongly with 10 which is an tau-
tomer of the enamine 3, and ZnCl2 has a tendency to bind
with 4. Firstly, Hf(OTf)4 coordination with the imine 10 is
followed by a reaction of the activated imine with the
starting enamine 3 (or the enamine intermediate generated
from an a-acidic ketone and NH4OAc), which leads to the
formation of intermediate 11 with liberation of ammonia
(Scheme 2).
Moreover, as shown in Table 3, we applied the present
method to the direct synthesis of disubstituted symmetri-
cal pyridine derivatives 9 from acetophenone derivative 7
with NH4OAc as a nitrogen source. Unfortunately, the re-
action conditions shown in Table 2 were ineffective for
the preparation of the desired pyridine derivative 9a (entry
1). However, changing the solvent to toluene, increasing
the amount of the catalyst to an equivalent of 0.5, and rais-
ing the reaction temperature to 100 °C dramatically im-
proved the product yield to 85% (entry 3). With these
reaction conditions, we examined the preparation of di- Finally, tautomeric bisenamine 12 reacts with the ortho-
substituted pyridine derivatives using several acetophe- ester 4, which is weakly activated by Hf(OTf)4, to produce
none derivatives. All reactions successfully proceeded to the corresponding tetra- or disubstituted symmetrical
produce the corresponding symmetrical pyridine deriva- pyridine 5/9 through intramolecular cyclization of the 3-
tives 9b–d in moderate to good yields (entries 4–6).
azatriene intermediate 13.
Synlett 2011, No. 14, 2029–2034 © Thieme Stuttgart · New York

LETTER
Single-Step Synthesis of Tetra- or Disubstituted Symmetrical Pyridines
2031
R1
R2
R1
R2
R1
R2
R1
R2
– H2O, – AcOH
+
NH4OAc
10
NH
NH2
O
NH
8
10
3
7
Hf(OTf)4
R1
R1
H
R1
R2
R1
R2
H
R1
R2
R2
N
H
R2
NH2
N
12
3
11
NH3
EtO
EtO
OEt
OEt
R1
R1
R2
R1
R1
4
Hf(OTf)4
2 EtOH
N
R2
R2
R2
N
5/9
13
EtOH
Scheme 2 A plausible mechanism
Table 2 Synthesis of Tetrasubstituted Symmetrical Pyridines 5
Hf(OTf)4
(0.1 equiv)
R1
R1
R1
+
CH(OEt)3
CHCl3
60 °C
4
H2N
R2
R2
N
R2
3
5
Entry
Enamine 3
Time (h)
Pyridine 5
Yield (%)a
N
N
N
O
O
O
Me
Me
R
Me
N
H2N
R
R
1
2
3
4
5
3a
3b
3c
3d
1.5
1.5
1.5
1.5
2
R = H
5a
76
65
73
50
83
R = MeO
5b
R = Me
5c
R = Cl
5d
EtO2C
H2N
EtO2C
CO2Et
Me
Me
Me
5e
N
3e
NC
6b
3
60
NC
CN
Me
Me
N
H2N
Me
5f
3f
a Isolated yield.
b Two equivalents of 4 were used.
In conclusion, we have demonstrated that Hf(OTf)4 cata- nium acetate to produce the disubstituted symmetrical
lyzes not only the annulation of an enamine with triethyl pyridines.
orthoformate leading to the single-step synthesis of tetra-
substituted symmetrical pyridine derivatives, but it also
catalyzes the one-pot, three-component coupling reaction
of an acetophenone derivative, an orthoester, and ammo-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2011, No. 14, 2029–2034 © Thieme Stuttgart · New York

2032
T. Sasada et al.
LETTER
Table 3 Synthesis of Disubstituted Symmetrical Pyridines 9
Me
Hf(OTf)4
solvent
+
CH(OEt)3
+
NH4OAc
Ar
O
4
Ar
N
Ar
8
7
(3 equiv)
9
(2 equiv)
Entry
Ketone 7
Solvent
Hf(OTf)4 (equiv) Temp (°C)
Time (h)
9
Yield (%)a
Ar
1
2
3
4
5
6
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
Ph
7a
CHCl3
toluene
toluene
toluene
toluene
toluene
0.1
0.1
0.5
0.5
0.5
0.5
60
72
72
1
9a
9a
9a
9b
9c
9d
8
7a
7a
7b
7c
7d
100
100
100
100
100
51
(85)
(72)
(54)
(60)
1
1
4-ClC6H4
6
a NMR yield (isolated yield).
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Acknowledgment
This work was partially supported by a grant from the Japan Private
School Promotion Foundation, 2008 and 2009, Grant-in-Aid for
Scientific Research from MEXT (16550148), 2004–2005, Grant-in-
Aid for Scientific Research from MEXT (21590025), 2009–2011,
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