Low-valent niobium-catalyzed intermolecular [2 + 2 + 2] cycloaddition of tert -butylacetylene and arylnitriles to form 2,3,6-trisubstituted pyridine derivatives

Article abstract of DOI:10.1021/jo401399y

A catalytic system based on low-valent niobium has been developed, consisting of NbCl₅, Zn, and an alkoxysilane. This combination has been shown to be an efficient catalyst for the synthesis of pyridine derivatives from the intermolecular cycloaddition of alkynes and nitriles via a niobacyclopentadiene intermediate.

Full text of DOI:10.1021/jo401399y

Note
pubs.acs.org/joc
Low-Valent Niobium-Catalyzed Intermolecular [2 + 2 + 2]
Cycloaddition of tert-Butylacetylene and Arylnitriles to Form 2,3,6-
Trisubstituted Pyridine Derivatives
Yasushi Satoh and Yasushi Obora*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita,
Osaka 564-8680, Japan
S
* Supporting Information
ABSTRACT: A catalytic system based on low-valent niobium has been
developed, consisting of NbCl5, Zn, and an alkoxysilane. This
combination has been shown to be an efficient catalyst for the synthesis
of pyridine derivatives from the intermolecular cycloaddition of alkynes
and nitriles via a niobacyclopentadiene intermediate.
yridines are an important class of azaheterocyclic
compounds and include natural products, biologically
with alkynenitriles.14 In addition, our research group has
reported the NbCl5-mediated intermolecular cycloaddition
reaction of alkynes with benzonitriles.15 This reaction did not
produce pyridines, though, and instead gave pyrimidines when
using a stoichiometric amount of NbCl5 (Scheme 1, “Previous
work”).
P
active substances,1 functional materials2 and ligands.3 By way of
example, niacin and vitamin B6 are both well-known pyridine
derivatives. Neutral pyridine-based pillaring ligands are also
employed in the construction of metal−organic frameworks
(MOFs), since they can be fully exchanged with different
pyridine-based ligands to enable “stepwise” MOF synthesis.4
Among the methods available for the preparation of
pyridines, the transition-metal-catalyzed cycloaddition reaction
of alkynes with nitriles is of particular importance, since this
methodology is capable of introducing various substituent
groups onto the pyridine ring.5−11 Many of the reported
cycloaddition reactions have been intramolecular reactions
using α,ω-diynes or cyanoalkynes. For instance, Takeuchi and
co-workers reported that pyridines could be produced from the
Ir-catalyzed [2 + 2 + 2] cycloaddition of α,ω-diynes with
nitriles.8
Scheme 1. Transition-Metal-Catalyzed [2 + 2 + 2]
Cycloaddition of Alkynes with Nitriles
Recently, we reported that the NbCl3(DME)16 is a useful
catalyst for the selective synthesis of 1,3-cyclohexadienes from
the reaction of alkynes with alkenes.17 We additionally
determined that the NbCl5/hydrosilane system serves as an
efficient low-valent Nb catalyst for the selective cycloaddition of
alkynes and alkenes to form 1,3-cyclohexadienes.17c
In this paper, we report the intermolecular [2 + 2 + 2]
cycloaddition of terminal alkynes and nitriles, catalyzed by low-
valent Nb (generated in situ from NbCl5, Zn and Ph2Si-
(OMe)2), leading to 2,3,6-trisubstituted pyridines in high yields
(Scheme 1, “This work”).
Initially, tert-butylacetylene (1a) and benzonitrile (2a) were
used as model substrates for the optimization of the
cycloaddition reaction conditions, with the results presented
in Table 1. We investigated various low-valent niobium species.
When 1a (1 mmol) was reacted with 2a (3 mmol) in the
presence of NbCl3(DME) (0.2 mmol) in toluene (2 mL) at 80
°C for 16 h, the reaction produced trisubstituted pyridine (3a)
in 11% yield as well as 4a in 36% yield (entry 1). Previously, we
Alternatively, the transition-metal-catalyzed intermolecular [2
+ 2 + 2] cross-cycloaddition reaction between two alkyne
molecules and one nitrile is one of the simplest and most atom-
economical methods for preparing pyridines. However, little
work has been reported in this field because of the difficulty in
controlling the chemo- and regioselectivity of the reaction.
Wakatsuki and Yamazaki reported a Co-catalyzed reaction that
was the first example of the synthesis of pyridines via the [2 + 2
+ 2] intermolecular cycloaddition reactions of alkynes with
nitriles.6a These intra- and intermolecular cycloaddition
reactions typically employ late transition metals as catalysts,
such as Co,6 Rh,7 Ir,8 Ni,9 Ru10 and Fe.11
The synthesis of pyridines in this manner has not yet been
achieved using early transition metals as catalysts. Some
stoichiometric reactions employing early transition metals
have, however, been reported, such as the synthesis of pyridines
from two alkynes, a nitrile and Ti(OiPr)2,12 the Zr/Ni-
mediated cyclotrimerization of alkynes and nitriles to give
pentasubstituted pyridines13 and the preparation of tetrasub-
stituted pyridines from the reaction of Ta-alkyne complexes
Received: June 29, 2013
Published: July 14, 2013
© 2013 American Chemical Society
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Note
Using the optimized conditions shown in Table 1, entry 7,
the reactions of various nitriles (2) were examined (Table 2).
Table 1. NbCl5/Zn/Ph2Si(OMe)2 Catalyzed Reaction of tert-
Butylacetylene (1a) with Benzonitrile (2a) under Various
a
Conditions
Table 2. NbCl5/Zn/Ph2Si(OMe)2 Catalyzed Reactions of
Acetylenes (1) and Nitriles (2) Leading to 2,3,6-
a
Trisubstituted Pyridines
b
yield (%)
entry
catalyst
additive
none
3a
4a
36
c
1
NbCl3(DME)
NbCl5
11(95)
c
g
g
2
none
n.d.
n.d.
41
43
17
18
10
27
15
7
3
4
5
6
7
NbCl5
none
26(77)
33(88)
70(97)
72(98)
82[74](98)
64(98)
38(96)
27(96)
47(71)
trace
NbCl5
PhSiMe3
NbCl5
PhSi(OMe)3
MeSi(OMe)3
Ph2Si(OMe)2
Ph2Si(OMe)2
Ph2Si(OMe)2
Ph2Si(OMe)2
Ph2Si(OMe)2
Ph2Si(OMe)2
Ph2Si(OMe)2
NbCl5
NbCl5
d
8
e
NbCl5
9
NbCl5
f
10
NbCl5
11
12
13
NbCl3(DME)
TaCl5
15
8
g
g
ZrCl4
n.d.
n.d.
a
Reaction conditions: 1a (1 mmol), 2a (3 mmol), catalyst (0.2 mmol),
Zn (1.2 mmol) and additive (0.6 mmol) in toluene (2 mL) at 80 °C
b
for 16 h under Ar. Yields were determined by GC on the basis of the
quantity of 1a used. All are GC yields except the value in the square
brackets. The numbers in parentheses show the selectivity (%) of the
c
d
2,3,6-substituted adduct. Without Zn. 1a (1 mmol) and 2a (0.5
e
f
mmol) were used. Zn (0.2 mmol) was used. NbCl5 (0.1 mmol), Zn
(1.1 mmol), Ph2Si(OMe)2 (0.3 mmol) were used. Not detected by
g
GC.
reported that NbCl5 is an effective agent for the activation of
nitriles.15 We therefore applied NbCl5 to this reaction;
however, the result was that neither 3a nor 4a18 were observed
in the products (entry 2). When low-valent Nb species were
instead generated by NbCl5 in conjunction with Zn,19 3a was
obtained in 26% yield with good regioselectivity (entry 3). The
data related to subsequent screening of silane compounds as
additives are shown in entries 4−7 and reveal that alkoxysilanes
are effective for this reaction. Between the two alkoxysilanes
tested, Ph2Si(OMe)2 demonstrated the most pronounced
influence on reactivity, producing 3a in the best yield with
excellent regioselectivity. However, other additives (AgSbF6,
1,1-bis(diphenyldiphosphino)methane), and biacetyl-bis-
(phenylimine)) exhibited no activity in the formation of
pyridine derivatives. On the basis of the results of these
experiments, the presence of alkoxy substituents on the silyl
group is useful for the cycloaddition of alkynes and nitriles
(entry 4 vs entry 5). Interestingly, even when 1a and 2a were
allowed to react in a stoichiometric molar ratio (1a:2a = 2:1),
the yield of the product was still acceptable at 64% (entry 8). As
the catalyst precursor for this reaction, the Nb(V) complex
NbCl5 appears to be highly efficient. While NbCl3(DME) was
used as catalyst under these conditions, 3a was obtained in
moderate yield (entry 11). When early transtion-metal
analogues, TaCl5 and ZrCl4, were used as the catalyst, even
though 1a was evidently converted during the course of the
reaction, almost none of the desired pyridine derivative was
observed (entries 12 and 13).
a
Reaction conditions: See optimized conditions (Table 1, entry 7).
b
2,3,6-Trisubstituted pyridines were all obtained with >96%
c
regioselectivity. Yields were determined by GC on the basis of the
quantity of 1 used. TES = triethylsilyl.
d
1a was reacted with various benzonitriles with substituents on
the benzene ring (2a−2g) under the optimized conditions
(entries 1−7). The benzonitrile derivatives 4-tolunitrile (2b), 4-
chlorobenzonitrile (2c), 4-(trifluoromethyl)benzonitrile (2d),
4-cyanobenzoate (2e) and 3-tolunitrile (2f) participated in the
reaction, and the corresponding 2,3,6-trisubstituted pyridines
(3b−3f) were obtained in 51−82% yields with high chemo-
selectivities and excellent regioselectivities. When 2-tolunitrile
(2g) was applied to this reaction, the desired pyridines (3g)
were obtained in 48% yield with excellent regioselectivity,
although substituted benzenes from the cyclotrimerization of
1a were also obtained in 23% yield.
We next investigated the scope of the reaction using various
benzylnitriles (entries 8−12). Phenylacetonitrile (2h) and its
derivatives 4-methylphenylacetonitrile (2i), 4-chlorophenylace-
tonitrile (2j), 4-methoxyphenylacetonitrile (2k) and 3,4-
dichlorophenylacetonitrile (2l) all underwent reaction, and
the corresponding pyridines (3h−3l) were obtained in 66−89%
yields. The reaction of 3-phenylpropanenitrile (2m) with 1a
afforded the corresponding 2,3,6-trisubstituted pyridine in 71%
yield with 98% regioselectivity (entry 13). The reaction was
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Note
sluggish with aliphatic nitriles such as octanenitrile, trimethyl-
silyl cyanide, and ethyl cyanoformate and did not afford desired
pyridines under these conditions. The use of tert-butylacetylene
(1a) was a suitable substrate in the present reaction. However,
when triethylsilylacetylene (1b) was used in the reaction, it
underwent conversion to a moderate extent, and a negligible
amount of the formation of the desired pyridine was detected
(entry 14). The reaction with methyl propiolate did not give
any corresponding product. The reaction of certain terminal
alkynes with 2a was observed to preferentially result in
cyclotrimerization of the alkyne rather than cross-cyclo-
trimerization of the alkyne and nitrile. As an example, when
phenylacetylene (1c) was used in the reaction, trace amount of
the desired pyridine derivative was detected, whereas 4c was
obtained in 39% yield (entry 15). In case of the reaction of
dynes or internal alkynes with 2a, alkynes were converted, but
any products were not obtained.
Scheme 3. Reaction of 1a and 2a via the Formation of A
ments between differently substituted phenylacetoniriles
(Figures S2−S4 in Supporting Information). On the basis of
these competition experiments, substantial electronic effect on
aryl ring relevant to the coordination of Nb center was not
observed. On the basis of these results, our proposed reaction
mechanism is shown in Figure 1. In this reaction pathway, the
In general, the results detailed above are notable since they
demonstrate the preparation of pyridine derivatives via
reactions involving catalysis by a low-valent early transition
metal.
The synthesis of pyridines via the transition-metal-catalyzed
cycloaddition reactions of alkynes with nitriles, as demonstrated
in this work, may proceed via two possible transition metal
intermediates.20 These two intermediates are presented in
Scheme 2. Depending on the path, the key intermediate in the
Scheme 2. Investigation of the Formation of Niobacyclic
Intermediates
Figure 1. Proposed reaction mechanisms for the formation of pyridine
derivatives.
initial step is the generation of the low-valent niobium species
from NbCl5, in which Zn19 acts as a reducing agent. It should
be noted that this active low-valent Nb species might also be
stabilized by the alkoxysilane, and generated chloro(methoxy)-
diphenylsilane.21 Subsequently, the oxidative cycloaddition of
two alkyne molecules to low-valent [Nb] takes place and forms
the niobacyclopentadiene intermediate (A).18 Migratory
insertion of the nitrile into A produces the aza-niobaheptatriene
intermediate (B), and B forms the corresponding pyridine
derivative (3) via C. All attempts to isolate or fully characterize
the 5-membered niobacyclic intermediates (A) and their
corresponding 7-membered niobacyclic intermediates (B)
have been unsuccessful because of the instability of these
niobium species.
In conclusion, we have developed a low-valent niobium
catalyzed [2 + 2 + 2] intermolecular cycloaddition reaction
between terminal alkynes and nitriles to form 2,3,6-
trisubstituted pyridine derivatives. This catalytic system is the
first example of the synthesis of pyridines from the reaction of
alkynes with nitriles using an early transition metal.
reaction is either niobacyclopentadiene (A) or aza-niobacyclo-
pentadiene (A′). To determine which of these two
intermediates is the most plausible, we performed experiments
to assess the formation of either compound (Scheme 2). We
first examined the stoichiometric reaction of 1a with 2a under
optimized condition (Scheme 2). The reaction mixture was
stirred at room temperature for 3 h, after which it was
quenched with either H2O or D2O to hydrolyze or deuteriolyze
whichever key intermediate had formed (A or A′). The results
of GC analysis of the products showed that the diene (5)
derived from the niobacyclopentadiene complex (A)18 was
obtained in 19% (77% D incorporated after deuteriolysis) yield,
while the aza-diene (6) or hydrolysis product (7) derived from
A′ was not observed. After the in situ formation of this
niobacyclopentadiene complex, the reaction mixture was stirred
at 80 °C for 16 h (i.e., standard conditions), and the
corresponding pyridine derivative (3a) was obtained in 16%
yield (Scheme 3). Furthermore, to get more insights of reaction
mechanism, we performed intermolecular competition experi-
EXPERIMENTAL PROCEDURE
■
General Methods. GLC analysis was performed with a flame
ionization detector using a 0.22 mm × 25 m capillary column (BP-5).
1H and 13C NMR were measured at 400 and 100 MHz, respectively, in
CDCl3 with Me4Si as the internal standard. The products were
characterized by 1H NMR, 13C NMR, HMQC and HMBC.
Compounds 4a,23 4b,18 and 524 are known compounds, which have
previously been reported.
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Note
Typical Reaction Procedure for the Preparation of 3a (Entry
7, Table 1). A mixture of tert-butylacetylene (1a) (82 mg, 1 mmol),
benzonitrile (2a) (309 mg, 3 mmol), NbCl5 (54 mg, 0.2 mmol), Zn
(78 mg, 1.2 mmol), Ph2Si(OMe)2 (146 mg, 0.6 mmol) and toluene (2
mL) was stirred for 16 h at 80 °C under Ar. The yields of the products
were estimated from the peak areas on the basis of the internal
standard technique using GC, and 3a was obtained in 82% yield. The
products 3a were isolated by silica gel column chromatography (n-
hexane:EtOAc = 100:0 to 50:1 as eluent) in 74% yield 99 mg) as
yellow liquid.
Typical Reaction Procedure for the Preparation of 5
(Scheme 2). A mixture of tert-butylacetylene (1a) (49 mg, 0.5
mmol), benzonitrile (2a) (154 mg, 1.5 mmol), NbCl5 (135 mg, 0.5
mmol), Zn (65 mg, 1.0 mmol), Ph2Si(OMe)2 (365 mg, 1.5 mmol) and
toluene (3 mL) was stirred for 3 h at room tempreture under Ar.
Thereafter, the formation of Nb-cyclopentadiene complex (A) was
verified by hydrolysis or deuteriolysis of the reaction mixture affording
5. The yields of the products were estimated from the peak areas on
the basis of the internal standard technique using GC, and 5 was
obtained in 19% yield.
(relative intensity) 281 (61) [M+], 266 (100), 225 (20), 191 (1), 167
(2), 91 (4), 77 (2), 57(2); HRMS (EI-TOF) m/z calcd for C20H27N
[M]+ 281.2144, found 281.2137.
3c: yield 82% (123 mg), yellow liquid; 1H NMR (400 MHz,
CDCl3) δ 0.95 (s, 9H), 1.01 (s, 9H), 6.84−7.62 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 30.4 (CH3), 30.8 (CH3), 35.0 (C), 37.8(C),
114.0 (CH), 114.5 (CH), 128.2 (2CH), 128.6 (2CH), 134.4 (C),
139.0 (C), 154.2 (C), 160.7 (C), 169.0 (C); IR (neat, cm−1) 2976,
2872, 1598, 1496; GC−MS (EI) m/z (relative intensity) 301 (54)
[M+], 286 (100), 245 (18), 111 (1), 77 (3), 57(4); HRMS (EI-TOF)
m/z calcd for C19H24ClN [M]+ 301.1597, found 301.1593.
3d: yield 51% (85 mg), yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 1.28 (s, 9H), 1.34 (s, 9H), 7.25−8.11 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 30.3 (CH3), 30.8 (CH3), 35.0 (C), 37.8 (C), 114.6 (CH),
116.1 (CH), 124.0 (C), 125.42 (2CH), 127.2 (2CH), 130.2 (C),
143.9 (C), 154.0 (C), 160.9 (C), 169.2 (C); 19F NMR (400 MHz,
CDCl3) δ = −62.4 (s, CF3); IR (neat, cm−1)2968, 2872, 1620, 1411;
GC−MS (EI) m/z (relative intensity) 335 (48) [M+], 334 (47), 320
(100), 305 (12), 279 (14), 222 (1), 77 (1), 57 (3); HRMS (EI-TOF)
m/z calcd for C20H24F3N [M]+ 335.1861, found 335.1868.
3e: yield 53% (86 mg), yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 1.25 (s, 9H), 1.32 (s, 9H), 3.8 (s, 3H), 7.21 (s, 1H), 7.49 (s, 1H),
8.07 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 30.3 (CH3), 30.8
(CH3), 34.9 (C), 37.7 (C), 114.7 (CH), 114.9 (CH), 126.7 (2CH),
129.7 (C), 129.8 (2CH), 144.6(C), 154.1 (C), 160.6 (C), 166.9 (C),
169.0 (C); IR (neat, cm−1) 2978, 2870, 1730, 1394, 1112; GC−MS
(EI) m/z (relative intensity) 325 (52) [M+], 310 (100), 269 (18), 2
67(3), 190 (5), 79(1), 77 (2), 57 (3); HRMS (EI-TOF) m/z calcd for
C21H27NO2 [M]+ 325.2042, found 325.2029.
Typical Reaction Procedure for the Preparation of 3a
(Scheme 3). A mixture of tert-butylacetylene (1a) (49 mg, 0.5
mmol), benzonitrile (2a) (154 mg, 1.5 mmol), NbCl5 (135 mg, 0.5
mmol), Zn (65 mg, 1.0 mmol), Ph2Si(OMe)2 (365 mg, 1.5 mmol) and
toluene (3 mL) was stirred for 3 h at room tempreture under Ar.
Subsequently, the reaction mixture was stirred at 80 °C for 16 h. The
yields of the products were estimated from the peak areas on the basis
of the internal standard technique using GC, and 3a was obtained in
16% yield.
Typical Reaction Procedure for Figure S2 (Supporting
Information). A mixture of tert-butylacetylene (1a) (82 mg, 1
mmol), phenylacetonitrile (2h) (177 mg, 1.5 mmol), 4-methylpheny-
lacetonitrile (2i) (197 mg, 1.5 mmol) NbCl5 (54 mg, 0.2 mmol), Zn
(78 mg, 1.2 mmol), Ph2Si(OMe)2 (146 mg, 0.6 mmol) and toluene (2
mL) was stirred for 16 h at 80 °C under Ar. The yields of the products
were estimated from the peak areas on the basis of the internal
standard technique using GC, and 3h, 3i, and 4a were obtained
respectively in 26, 29, and 10% yields.
3f: yield 71% (100 mg), yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 1.25 (s, 9H), 1.34 (s, 9H), 2.33 (s, 3H), 7.07−7.77 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 21.6 (CH3), 30.4 (CH3), 30.8 (CH3),
34.9 (C), 37.8 (C), 114.0 (CH), 114.4 (CH), 124.2 (CH), 127.7
(CH), 128.4 (CH), 129.1 (CH), 138.0 (C), 140.6 (C), 155.7 (C),
160.3 (C), 168.7 (C); IR (neat, cm−1) 2963, 2868, 1597, 1249; GC−
MS (EI) m/z (relative intensity) 281 (64) [M+], 266 (100), 225 (17),
210 (6), 169 (1), 91 (4), 77 (1), 57(1); HRMS (EI-TOF) m/z calcd
for C20H27N [M]+ 281.2144, found 281.2137.
3g: yield 48% (67 mg), yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 1.26 (s, 9H), 1.32 (s, 9H), 2.35 (s, 3H), 7.12−7.37 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 20.8 (CH3), 30.4 (CH3), 30.8 (CH3),
34.9 (C), 37.8 (C), 113.3 (CH), 118.1 (CH), 125.7 (CH), 127.8
(CH), 129.8 (CH), 130.9 (CH), 136.4 (C), 141.5 (C), 158.4 (C),
159.9 (C), 168.2 (C); IR (neat, cm−1) 2964, 2904, 1701, 1595, 1404;
GC−MS (EI) m/z (relative intensity) 281 (92) [M+], 266 (99), 225
(18), 210 (5), 169 (2), 91 (6), 77 (2), 57(3); HRMS (EI-TOF) m/z
calcd for C20H27N [M]+ 281.2143, found 281.2137.
Typical Reaction Procedure for Figure S3 (Supporting
Information). A mixture of tert-butylacetylene (1a) (82 mg, 1
mmol), 4-methylphenylacetonitrile (2i) (197 mg, 1.5 mmol), 4-
chlorophenylacetonitrile (2j) (227 mg, 1.5 mmol) NbCl5 (54 mg, 0.2
mmol), Zn (78 mg, 1.2 mmol), Ph2Si(OMe)2 (146 mg, 0.6 mmol) and
toluene (2 mL) was stirred for 16 h at 80 °C under Ar. The yields of
the products were estimated from the peak areas on the basis of the
internal standard technique using GC, and 3h, 3j, and 4a were
obtained respectively in 19, 17, and 11% yields.
Typical Reaction Procedure for Figure S4 (Supporting
Information). A mixture of tert-butylacetylene (1a) (82 mg, 1
mmol), phenylacetonitrile (2i) (177 mg, 1.5 mmol), 4-chloropheny-
lacetonitrile (2j) (227 mg, 1.5 mmol) NbCl5 (54 mg, 0.2 mmol), Zn
(78 mg, 1.2 mmol), Ph2Si(OMe)2 (146 mg, 0.6 mmol) and toluene (2
mL) was stirred for 16 h at 80 °C under Ar. The yields of the products
were estimated from the peak areas on the basis of the internal
standard technique using GC, and 3i, 3j, and 4a were obtained
respectively in 11, 14, and 15% yields.
3h: yield 87% (122 mg), yellow liquid; 1H NMR (400 MHz,
CDCl3) δ 1.24 (s, 9H), 1.36 (s, 9H), 4.10 (s, 2H), 6.88−7.33 (m, 7H);
13C NMR (100 MHz, CDCl3) δ 30.3 (CH3), 30.7 (CH3), 34.7 (C),
37.5 (C), 45.0 (CH2), 113.0 (CH), 116.7 (CH), 125.9 (2CH), 128.2
(2CH), 129.1 (CH), 140.5(C), 159.0 (C), 160.1 (C), 168.5 (C); IR
(neat, cm−1) 2965, 2868, 1685, 1598, 1558; GC−MS (EI) m/z
(relative intensity) 281 (80) [M+], 266 (100), 225 (19), 168 (2), 91
(11), 79 (2), 77 (3), 57(2); HRMS (EI-TOF) m/z calcd for C20H27N
[M]+ 281.2144, found 281.2144.
3a: yield 74% (99 mg), yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 1.36 (s, 9H), 1.43 (s, 9H), 7.27−8.09 (m, 7H); 13C NMR (100
MHz, CDCl3) δ30.4 (CH3), 30.8 (CH3), 35.0 (C), 37.8 (C), 114.2
(CH), 114.24 (CH), 127.0 (2CH), 128.4 (2CH), 128.5 (CH), 140.6
(C), 155.4 (C), 160.4 (C), 168.8 (C); IR (neat, cm−1) 2962, 2868,
1597, 1301; GC−MS (EI) m/z (relative intensity) 267 (62) [M+], 252
(100), 211 (19), 154 (2), 79 (1), 77 (4), 57(57); HRMS (EI-TOF)
m/z calcd for C19H25N [M]+ 267.1987, found 267.1975.
3i: yield 85% (125 mg), yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 1.17 (s, 9H), 1.27 (s, 9H), 3.96 (s, 2H), 6.79−7.17 (m, 6H); 13C
NMR (100 MHz, CDCl3) δ 30.3 (CH3), 30.7 (CH3), 34.7 (C), 37.5
(C), 44.3 (CH2), 113.1 (CH), 116.6 (CH), 128.3 (2CH), 130.4
(2CH), 131.7 (C), 138.9 (C), 158.5 (C), 160.3 (C), 168.6 (C); IR
(neat, cm−1) 2958, 2868, 1706, 1598, 1514; GC−MS (EI) m/z
(relative intensity) 295 (100) [M+], 280 (46), 266 (3), 166 (2), 77
(2), 57(5); HRMS (EI-TOF) m/z calcd for C21H29N [M]+ 295.2300,
found 295.2297.
3b: yield 74% (104 mg), yellow liquid; 1H NMR (400 MHz,
CDCl3) δ 1.26 (s, 9H), 1.34 (s, 9H), 2.29 (s, 3H), 7.10−7.89 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 21.2 (CH3), 30.4 (CH3), 30.8 (CH3),
34.9 (C), 37.8 (C), 113.9 (CH), 114.0 (CH), 126.9 (2CH), 129.2
(2CH), 137.8 (C), 138.2 (C), 155.5 (C), 160.3 (C), 168.7 (C); IR
(neat, cm−1) 2962, 2868, 1597, 1477, 1394; GC−MS (EI) m/z
3j: yield 89% (140 mg), yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 1.16 (s, 9H), 1.28 (s, 9H), 2.23 (s, 3H), 3.98 (s, 2H), 6.80−7.16 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 21.0 (CH3), 30.3 (CH3), 30.7
(CH3), 34.7 (C), 37.5 (C), 44.6 (CH2), 112.9 (CH), 116.6 (CH),
128.93 (2CH), 128.94 (2CH), 135.3 (C), 137.4.5(C), 159.3 (C),
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Note
160.0 (C), 168.4 (C); IR (neat, cm−1) 2972, 2906, 1706, 1598, 1404,
1361; GC−MS (EI) m/z (relative intensity) 315 (58) [M+], 300
(100), 243 (2), 125 (5), 91 (4), 79 (1), 77 (2), 57(4); HRMS (EI-
TOF) m/z calcd for C20H26ClN [M]+ 315.1754, found 315.1751.
3k: yield 66% (103 mg), yellow liquid; 1H NMR (400 MHz,
CDCl3) δ 1.20 (s, 9H), 1.30 (s, 9H), 3.65 (s, 3H), 3.99 (s,2H), 6.72−
7.18 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 30.3 (CH3), 30.6
(CH3), 34.7 (C), 37.4 (C), 43.8 (CH2), 55.1 (CH3), 113.6 (CH),
116.7 (CH), 127.8 (2CH), 130.0 (2CH), 132.3 (C), 134.5 (C), 157.9
(C), 159.4, 168.1 (C); IR (neat, cm−1) 2970, 2904, 1598, 1361, 1176;
GC−MS (EI) m/z (relative intensity) 311 (100), 297 (56), 281 (1),
253 (19), 194 (1), 148 (1), 92 (2), 77 (2); HRMS (EI-TOF) m/z
calcd for C21H29NO, [M]+ 311.2249, found 311.2256.
(5) Selected reviews for the systhesis of pyridines from transition-
metal-catalyzed [2 + 2 + 2] cycloaddition reaction: (a) Vollhardt, K. P.
C. Angew. Chem. 1984, 96, 525;(b) Angew. Chem., Int. Ed. Engl. 1984,
23, 539. (c) Bonnemann, H. Angew. Chem. 1985, 97, 264;(d) Angew.
̈
Chem., Int. Ed. Engl. 1985, 24, 248. (e) Varela, J. A.; Saa,
2003, 103, 3787. (f) Domínguez, G.; Perez-Castells, J. Chem. Soc. Rev.
2011, 40, 3430.
́
C. Chem. Rev.
́
(6) Selected examples for Co-catalyzed [2 + 2 + 2] cycloaddition to
form pyridines: (a) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem.
Commun. 1973, 280. (b) Goswami, A.; Ohtaki, K.; Kase, K.; Ito, T.;
Okamoto, S. Adv. Synth. Catal. 2008, 350, 143. (c) Kase, K.; Goswani,
A.; Ohtaki, K.; Tanabe, E.; Saino, N.; Okamoto, S. Org. Lett. 2007, 9,
931. (d) Hapke, M.; Kral, K.; Fischer, C.; Spannenberg, A.; Gutnov,
A.; Redkin, D.; Heller, B. J. Org. Chem. 2010, 75, 3993.
(7) Selected examples for Rh-catalyzed [2 + 2 + 2] cycloaddition to
form pyridines: (a) Tanaka, K.; Suzuki, N.; Nishida, G. Eur. J. Org.
Chem. 2006, 3917. (b) Komine, Y.; Tanaka, K. Org. Lett. 2010, 12,
1312.
(8) Examples for Ir-catalyzed [2 + 2 + 2] cycloaddition to form
pyridines: Onodera, G.; Shimizu, Y.; Kimura, J.; Kobayashi, J.; Ebihara,
Y.; Kondo, K.; Sakata, K.; Takeuchi, R. J. Am. Chem. Soc. 2012, 134,
10515.
(9) Selected examples for Ni-catalyzed [2 + 2 + 2] cycloaddition to
form pyridines: (a) McCormick, M. M.; Duong, H. A.; Zuo, G.; Louie,
J. J. Am. Chem. Soc. 2005, 127, 5030. (b) Kumar, P.; Prescher, S.;
Louie, J. Angew. Chem., Int. Ed. 2011, 50, 10694.
3l: yield 75% (131 mg), yellow liquid; 1H NMR (400 MHz, CDCl3)
δ 1.18 (s, 9H), 1.27 (s, 9H), 3.94 (s, 2H), 6.81−7.40 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 30.3 (CH3), 30.3 (CH3), 30.7 (CH3),
34.8 (C), 37.5 (C), 43.9 (CH2), 113.4 (CH), 116.7 (CH), 127.8
(CH), 128.6 (CH), 130.0 (CH), 131.1 (C), 131.9 (C), 140.6 (C),
157.6 (C), 160.5 (C), 168.8 (C); IR (neat, cm−1) 2966, 2868, 1598,
1548, 1471, 1215; GC−MS (EI) m/z (relative intensity) 349 (49)
[M+], 334 (100), 2314 (1), 307 (84), 292 (14), 204 (1), 158 (7), 144
(2), 77 (2), 91 (4), 57(1); HRMS (EI-TOF) m/z calcd for
C20H2535Cl37ClN [M]+ 351.1335, found 351.1136; HRMS (EI-TOF)
m/z calcd for C20H25Cl2N [M]+ 349.1364, found 349.1342.
3m: yield 71% (105 mg), yellow liquid; 1H NMR (400 MHz,
CDCl3) δ 1.17 (s, 9H), 1.31 (s, 9H), 3.00 (s, 4H), 6.73−7.19 (m, 7H);
13C NMR (100 MHz, CDCl3) δ 30.3 (CH3), 30.7 (CH3), 34.7 (C),
35.8 (CH2), 37.8 (C), 40.0 (CH2), 112.9 (CH), 116.9 (CH), 125.6
(2CH), 128.1 (2CH), 128.5 (CH), 134.5 (C), 142.1 (C), 149.2 (C),
168.1 (C); IR (neat, cm−1) 2962, 2904, 1598, 1409, 1361; GC−MS
(EI) m/z (relative intensity) 295 (100) [M+], 238 (5), 218 (37), 191
(13), 105 (2), 77 (2), 57(3); HRMS (EI-TOF) m/z calcd for C21H29N
[M]+ 295.2300, found 295.2306.
(10) Selected examples for Ru-catalyzed [2 + 2 + 2] cycloaddition to
́
form pyridines: (a) Varela, J. A.; Carlos, L.; Saa, C. J. Org. Chem. 2003,
68, 8595. (b) Yamamoto, Y.; Kinpara, K.; Ogawa, R.; Nishiyama, H.;
Itoh, K. Chem.Eur. J. 2006, 12, 5618.
(11) Selected examples for Fe-catalyzed [2 + 2 + 2] cycloaddition to
form pyridines: (a) Souza, B. R. D.; Lane, T. K.; Louie, J. Org. Lett.
2011, 13, 2936. (b) Wang, C.; Li, X.; Wu, F.; Wan, B. Angew. Chem.,
Int. Ed. 2011, 50, 7162.
ASSOCIATED CONTENT
* Supporting Information
(12) Selected examples for Ti-mediated [2 + 2 + 2] cycloaddition to
form pyridines: (a) Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J. Am.
Chem. Soc. 2002, 124, 3518. (b) Tanaka, R.; Yuza, A.; Watai, Y.;
Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005,
127, 7774.
(13) Selected examples for Zr-mediated [2 + 2 + 2] cycloaddition to
form pyridines: (a) Takahashi, T.; Tsai, F.-Y.; Kotora, M. J. Am. Chem.
Soc. 2000, 122, 4994. (b) Takahashi, T.; Tsai, L. Y.; Wang, H.; Kondo,
Y.; Yamanaka, M.; Nakajima, M.; Kotora, M. J. Am. Chem. Soc. 2002,
124, 5059.
■
S
Figures S1−S4, Tables S1−S3, experimental, characterization
and original NMR spectra for products 3. This material is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
*E-mail: obora@kansai-u.ac.jp.
■
(14) Examples for Ta-mediated [2 + 2 + 2] cycloaddition to form
pyridines: Takai, K.; Yamada, M.; Utimoto, K. Chem. Lett. 1995, 851.
(15) Satoh, Y.; Yasuda, K.; Obora, Y. Organometallics 2012, 31, 5235.
(16) (a) Roskamp, E. J.; Pedersen, S. F. J. Am. Chem. Soc. 1987, 109,
6551. (b) Hartung, J. B.; Pedersen, S. F. J. Am. Chem. Soc. 1989, 111,
5468. (c) Obora, Y.; Kimura, M.; Ohtake, T.; Tokunaga, M.; Tsuji, Y.
Organometallics 2006, 25, 2097 and references therein.
(17) (a) Obora, Y.; Takeshita, K.; Ishii, Y. Org. Biomol. Chem. 2009,
7, 428. (b) Satoh, Y.; Obora, Y. Org. Lett. 2011, 13, 2568. (c) Satoh, Y.;
Obora, Y. J. Org. Chem. 2011, 76, 8569.
(18) (a) Kataoka, Y.; Miyai, J.; Oshima, K.; Takai, K.; Utimoto, K. J.
Org. Chem. 1992, 57, 1973. (b) Oshiki, T.; Nomoto, H.; Tanaka, K.;
Takai, K. Bull. Chem. Soc. Jpn. 2004, 77, 1009 and references therein.
(19) (a) Kataoka, Y.; Miyai, J.; Oshima, K.; Takai, K.; Utimoto, K. J.
Org. Chem. 1992, 57, 1973. (b) Arai, S.; Takita, S.; Nishida, A. Eur. J.
Org. Chem. 2005, 5262. (c) Oh, K.; W. Kanabe, E. Tetrahedron 2009,
65, 2966.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grant-in Aid for Scientific
Research (KAKENHI), MEXT-Supported Program for the
Strategic Research Foundation at Private Universities (2010-
2014), and the Kansai University Expenditures for Support of
Training Young Scholars, 2012.
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