A simple and highly efficient iron catalyst for a [2+2+2] cycloaddition to form pyridines

Article abstract of DOI:10.1002/anie.201102001

Joined by iron: The iron catalyst for the formation of pyridines at room temperature (see scheme), which was generated in situ from an inorganic iron salt and a diphosphine ligand, exhibited high reactivity and regioselectivity. Copyright

Full text of DOI:10.1002/anie.201102001

Communications
DOI: 10.1002/anie.201102001
[2+2+2] Cycloaddition
A Simple and Highly Efficient Iron Catalyst for a
[2+2+2] Cycloaddition to Form Pyridines**
Chunxiang Wang, Xincheng Li, Fan Wu, and Boshun Wan*
Transition-metal-catalyzed
[2+2+2] cycloaddition
reactions that use two alkynes and a nitrile is the
most straightforward and powerful strategy for the
construction of multisubstituted pyridines with high
atom efficiency.[1,2] The iron-catalyzed [2+2+2] cyclo-
addition to form pyridines remains a great challenge in
this field,[3,4] although significant efforts have been
made in various catalytic systems (e.g. Co,[5] Ru,[6]
Rh,[7] Ni,[8] Ti,[9] Zr/Ni[10]) in the last few decades.
Guerchais and co-workers described a stoichiometric
reaction between an FeI complex (Scheme 1, struc-
ture A) and alkynes with a 73% yield.[4a] Meanwhile,
Zenneck and co-workers developed a cycloaddition
reaction catalyzed by an Fe0 complex (Scheme 1,
structure B),[4b,c] however, this approach gave low
chemoselectivity and had a complicated procedure
for catalyst preparation. A very recent example
revealed that no pyridine products were observed
from alkynes under iron catalyst even when nitrile was
used as the solvent.[11] Therefore, the development of a
simple and highly efficient iron catalyst to exclusively
generate pyridine compounds would be a useful
contribution to this area. Herein, we disclose the
Scheme 1. Iron catalysts used for the [2+2+2] cycloaddition to form pyridines.
TMS=trimethylsilyl.
[2+2+2] cycloaddition of diynes and unactivated nitriles at
room temperature using a simple iron salt as the catalyst
precursor, thus resulting in the production of pyridines with
up to 98% yield of isolated product.
iron salt and phosphine ligands might initiate the reaction
through ligand exchange, and thereby promote the oxidative
cyclization between an alkyne and an alkyne or a nitrile
followed by the formation of metallacycle intermediate
(Scheme 1, Step 2). Considering that the formation of ben-
zene rings can be somewhat inhibited in the presence of a
certain amount of nitrile compounds[4a]—the nature of the
ligand has a dramatic effect on the reaction product—it is
possible to generate pyridines with high efficiency when the
appropriate iron salt and ligand are used.
Initially, diyne 1a and benzonitrile 2a were used as model
substrates for the optimization of the cycloaddition reaction
conditions, and the results are summarized in Table 1. In the
first instance, we employed the iron salt FeCl3 as the catalyst
precursor, 1,2-bis(diphenylphosphino)ethane (dppe) as the
ligand, and 2a as the solvent (Table 1, entries 1–4). No desired
product was observed in the absence of dppe, as expected, and
only trace amounts of 3a were obtained when FeCl3/dppe was
used as the catalyst in a 1:1 ratio (6% yield, entry 2).[15] Given
that the amount of ligand can strongly affect the catalytic
efficiency, different metal/ligand ratios were screened. The
yield was dramatically improved to 97% when a 1:2 mixture
of metal and ligand was used (entry 3), however, further
increasing the ratio to 1:3 drastically decreased the yield
(entry 4, 38%). Sequential investigations of other iron salts,
solvents, and ligands (entries 5–9) showed that the combina-
tion of FeBr2 or FeI2 with 1,3-bis(diphenylphosphino)propane
Two important steps are generally involved in
[2+2+2] cycloaddition: 1) formation of a metallacycle inter-
mediate by oxidative cyclization and 2) subsequent reductive
elimination to produce pyridines (the “common mecha-
nism”).[2] The formation of a metallacycle intermediate[12,13]
from a low-valent metal species plays a crucial role in the
whole process. Inspired by an investigation by Holland and
co-workers revealing that alkynes bind more tightly than
phosphines to low-valent iron center,[14] we envisioned that
low-valent iron catalysts generated in situ from an inorganic
[*] C. X. Wang, Dr. X. C. Li, F. Wu, Prof. Dr. B. S. Wan
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (China)
Fax: (+86)411-8437-9223
E-mail: bswan@dicp.ac.cn
[**] Financial support from the National Basic Research Program of
China (2010CB833300) is gratefully acknowledged. We also thank
Dr. Chunqing Liu (UOP), Prof. Yonggui Zhou, and Dr. Wei Wang for
proof-reading this manuscript as well as Prof. Sentaro Okamoto
(Kanagawa University) for helpful discussion on experiment details.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102001.
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Angew. Chem. Int. Ed. 2011, 50, 7162 –7166

Table 1: Screening of reaction conditions.[a]
with internal substituents (Scheme 2, (11) and (18)) or
without a tertiary center on the tether chain (Scheme 2,
(19)–(21)) each furnished the corresponding pyridines with
good yields, although slightly lower yields were observed for
the terminal diynes (Scheme 2, (11), (17), and (18)). Impor-
tantly, diynes with unsymmetrical terminal substituents
produced the corresponding pyridines as a single regioisomer
when using this catalytic system (Scheme 2, (12), (13), (14),
(20), and (21)).[18]
After determining the efficiency of the present iron
catalysis, we then turned our attention to the mechanism.
Two possible pathways are proposed in Scheme 3. To gather
evidence to support one of these hypotheses, two intermo-
lecular [2+2+2] cycloaddition reactions were carried out
(Scheme 4). As expected, cyclotrimerization of monoalkynes
exclusively produced the 1,2,4-trisubstituted benzene 11 in
55% yield, and indicated that a ferracyclopentadiene inter-
mediate[12] was formed during cycloaddition [Scheme 4,
Eq. (2)]. In addition, intermolecular cyclotrimerization of
phenylacetylene with 5 equivalents of CH3CN gave two
pyridine isomers,[19] 13 and 14, in 60% and 6% yield,
respectively, thus suggesting that the formation of an azafer-
racyclopentadiene intermediate[20,21] is responsible for the
regioselectivity [Scheme 4, Eq. (3)]. Therefore, both path-
Entry
Iron salt
Ligand
Cat. loading
[mol%][b]
Conv.
[%][c]
Yield of
3a [%][c]
1[d,e]
2[e,f]
3[e]
4[e,g]
5
6
7
8
9
10
11
12
13
14
15[h]
16[d]
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeBr3
FeBr2
FeI2
FeCl3
FeBr2
FeI2
FeI2
FeI2
–
20
20
20
20
20
20
20
20
20
10
10
10
5
0
29
99
45
97
100
99
100
100
16
0
6
97
38
92
97
89
quant.
quant.
9
dppe
dppe
dppe
dppe
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
dppp
75
68
100
100
13
54
0
quant.
quant.
6
50
0
2.5
5
5
FeI2
FeI2
[a] Reaction conditions: 0.25 mmol of 1a, 10 equiv of 2a, x mol% of iron
salt, 2x mol% of ligand, 2x mol% of Zn, 1 mL of THF at RT for 24 h
unless otherwise stated. [b] Catalyst loading was based on the iron salt.
[c] Determined by GC using a pyridine derivative as the internal
standard; average of two runs. [d] Without Zn. [e] 2a was used as the
solvent. [f] FeCl3/dppe=1:1. [g] FeCl3/dppe=1:3. [h] 5 equiv of 2a was
used. THF=tetrahydrofuran.
(dppp) in THF gave a quantitative yield of 3a, even when
10 equivalents of nitriles were employed.[16] Lowering the
catalyst loading to 10 mol% resulted in a remarkable
decrease in the product yield for FeCl3 and FeBr2 (entries 10
and 11). In contrast, excellent results were obtained using
only 5 mol% FeI2 as the catalyst (entry 13). However,
further decreasing the catalyst loading jeopardized the yield
(entry 14), and reaction with either a lower amount of nitrile
or without a reductant proved less efficient (entries 15 and
16). On the basis of the product yield, we chose the
optimized reaction conditions as follows: 10 mol% of FeI2
as the catalyst precursor, 20 mol% of dppp as the ligand,
and 20 mol% of Zn dust as the reductant with 10 equiv-
alents of nitrile in THF at room temperature for 24 hours.
With the optimized reaction conditions in hand, we
tested the scope of the reaction using various diynes and
unactivated nitriles. As shown in Scheme 2, both aryl and
alkyl nitriles reacted efficiently and produced the desired
pyridines with good to excellent yields. Notably, the
reactions with benzonitrile and acetonitrile proceeded
effectively even when 5 mol% of catalyst was used
(Scheme 2, (1) and (4)). In addition, nitriles bearing
longer chains (Scheme 2, (6) and (7)) or sterically hindered
moieties (Scheme 2, (2), (3), (8), and (9)) also produced the
cycloadducts with reasonable yields. Interestingly, when
(Z)-2-butenenitrile was used as the coupling partner, diyne
1a selectively reacted with its cyano group to give the target
product with a moderate yield without the formation of the
1,3-cyclohexadiene derivative (Scheme 2, (10)).[17] Diynes
Scheme 2. Iron-catalyzed cycloaddition of diynes and unactivated nitriles.
Reaction conditions: 1 (0.5 mmol), 2 (5 mmol), FeI2 (10 mol%), dppp (20
mol%), Zn (20 mol%), 2 mL THF at RT for 24 h unless otherwise stated.
[a] Yield of isolated product (average of two runs). [b] 5 mol% of catalyst.
[c] 20 equiv of nitrile. Bn=benzyl, Ts=4-toluenesulfonyl.
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zation of the diyne and benzonitrile was preferred.
Thus, both cycloadducts 3m and 15 should be
obtained, and the latter should be the major product
because of its minor steric repulsion. However, 3m
was the only observed product, thus revealing that
the ferracyclopentadiene intermediate was not
formed in this process and that Pathway A
(Scheme 3) was not accessible. Subsequently,
another competition experiment between acetoni-
trile and 3 equivalents of phenylacetylenes was
conducted [Scheme 5, Eq. (5)], and this reaction
only provided a small amount of pyridine product 13
(8%). No desired product 11 was formed.[22] Based
on these results, we envision that the formation of
the ferracyclopentadiene intermediate is strongly
inhibited in the presence of nitrile [Eq. (2) vs.
Eq. (5)] and that Pathway B is more favorable. As
outlined in Scheme 2, although intramolecular cyclo-
addition of azaferracyclopentadiene intermediates 9
and 10 showed a reversed regioselectivity (Scheme 3,
Pathway B), intermediate 10 is preferred to produce
the observed product 8 as a result of the relatively
minor interaction between the bulky ligand and the
terminal alkyne substituent.
Scheme 3. Possible pathways to form pyridines.
In summary, for the first time we have developed
a simple and highly efficient method for the iron-
catalyzed [2+2+2] cycloaddition of diynes and unac-
tivated nitriles leading to pyridine compounds at
room temperature. The catalyst is generated in situ
from an inorganic iron salt and a diphosphine ligand
and exhibited high reactivity and regioselectivity.
The appropriate ligand as well as the metal/ligand
ratio plays a crucial role on the catalytic efficiency.
Further investigation of the mechanism is currently
underway.
Scheme 4. Intermolecular [2+2+2] cycloaddition reactions.
ways in Scheme 3 are feasible for the production of pyridine
compounds.
Experimental Section
Representative procedure: FeI2 (15.6 mg, 0.05 mmol) and dppp
(42.4 mg, 0.10 mmol) were weighed in the glove box and placed in a
dried Schlenk tube. Subsequently, distilled THF (2 mL) was added.
The resulting mixture was stirred at RT for 30 min to afford an
orange/yellow clear solution, at which time Zn dust (6.5 mg,
0.10 mmol) was added. After stirring for an additional 30 min, diyne
(0.5 mmol) was added followed by the nitrile (5 mmol), and the
reaction was kept stirring for 24 h until the majority of
the starting diyne was consumed. The solvent was
evaporated and the crude product was directly purified
by flash column chromatography on silica gel (eluent:
petroleum ether/ethyl acetate) to give the desired
pyridine.
To further understand the mechanism, a regioselective
cycloaddition reaction of unsymmetrical diyne 1b and
1 equivalent of benzonitrile was performed [Scheme 5,
Eq. (4)]. When 1b was exposed to the iron catalyst in the
presence of 1 equivalent of nitrile, intramolecular oxidative
cyclization of 1b rather than intermolecular oxidative cycli-
Received: March 22, 2011
Published online: June 22, 2011
Keywords: cycloaddition · heterocycles · iron ·
.
nitriles · pyridines
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[12] A ferracyclopentadiene intermediate was previously isolated
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[13] A ferracyclopentadiene intermediate was proposed in the iron-
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[15] A similar result was observed in the iron-catalyzed intramolec-
ular cyclotrimerization of triynes to annulated benzenes: see
Ref. [13c].
[16] For complete details of the screening of different iron salts,
ligands, and solvents, please see the Supporting Information.
[17] A similar selectivity was observed by Tanaka et al. using cationic
rhodium catalyst: see Ref. [7a].
[18] The large size difference between the terminal substituents plays
a crucial role in the regioselectivity of these cycloaddition
reactions; for details please see Ref. [5 m] and T. N. Tekavec,
A. M. Arif, J. Louie, Tetrahedron 2004, 60, 7431.
[19] Cycloaddition of internal alkyne (e.g. 3-hexyne) with benzoni-
trile only afforded 2,3,4,5-tetraethyl-6-phenyl pyridine in 12%
yield. It was rather astonishing that the cycloaddition of the
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diyne analogue 3,9-dodecadiyne with benzonitrile afforded the
desired product in 95% yield (3v), whereas 3-hexyne only gave
trace amounts of the product. The reason for these reaction
outcomes is still unknown.
[20] An azaruthenacyclopentadiene intermediate has been previ-
ously reported: see Ref. [6c] and [6e].
[21] In related studies, the reaction of 5-hexynenitrile with excess
phenylacetylene (3 equiv) was tested. Unexpectedly, the com-
plete intermolecular cycloadduct 16 was obtained in 39% yield,
and only trace amounts of the anticipated cycloadduct 17 was
observed (monitored by TLC and GC-MS analysis). This
outcome may ascribe to the competitive reactivity of different
alkynes towards the nitrile.
[22] When prolonging the reaction time to 96 h, both 2,3,6-trisub-
stituted pyridine 13 and 1,2,4-triphenly benzene 11 were
detected, in 47% and 7% yield, respectively.
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