Iron-catalyzed [2 + 2 + 2] cycloaddition of trifluoromethyl group substituted unsymmetrical internal alkynes

Article abstract of DOI:10.1039/c4ra06973k

Iron-catalyzed [2 + 2 + 2] intermolecular cycloaddition of trifluoromethyl group substituted unsymmetrical internal alkynes afforded the corresponding trifluoromethyl group substituted benzene derivatives in high yield with excellent selectivity. This jou

Full text of DOI:10.1039/c4ra06973k

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Iron-catalyzed [2 + 2 + 2] cycloaddition of
trifluoromethyl group substituted unsymmetrical
internal alkynes†
Cite this: RSC Adv., 2014, 4, 41353
Received 11th July 2014
Accepted 27th August 2014
*
Maki Minakawa, Tomoki Ishikawa, Junya Namioka, Souichirou Hirooka, Biao Zhou
*
and Motoi Kawatsura
DOI: 10.1039/c4ra06973k
www.rsc.org/advances
Iron-catalyzed [2 + 2 + 2] intermolecular cycloaddition of tri- It was found that the cyclotrimerization of 1a with 5 mol% of
fluoromethyl group substituted unsymmetrical internal alkynes FeCl2 for 36 h led to the desired product in 87% yield with a 95%
afforded the corresponding trifluoromethyl group substituted regioselectivity without formation of byproducts (entry 5). The
benzene derivatives in high yield with excellent selectivity.
yield from trimerization 1a was insufficient in the absence of
ZnI2 (entry 6). The combination of Zn/ZnI2 is assumed to play an
important role to promote such a process.7 The reaction with
DPPE, DPPB, or PPh3 as a ligand resulted in lower yield of the
desired product (entries 7–9). The catalytic amount of Zn was
not effective in the reaction. The use of 3.0 equiv. of Zn was
necessary for the efficient cyclotrimerization.
We next examined the iron-catalyzed [2 + 2 + 2] cyclo-
trimerization of various CF3-alkynes 1b–m under the optimized
reaction conditions (Table 2). For the reaction of 1b–e, which
has an electron-withdrawing group at the para-position on the
benzene ring, the corresponding CF3-benzene derivatives 2b–e
were formed in up to 96% isolated yield with high
Triuoromethyl group (–CF3) substituted benzene derivatives
are important structural motifs due to their interesting biolog-
ical activities.1 One of the most efficient synthetic methods of
benzene derivatives is transition metal-catalyzed [2 + 2 + 2]
cycloaddition of alkynes.2 Although various types of transition
metal catalysts and substrates have been investigated for inter-
and intramolecular reactions,2 iron-catalyzed [2 + 2 + 2] inter-
molecular cycloadditions have remained a challenging topic.3,4
To the best of our knowledge, there are no examples of CF3-
substituted benzene derivatives that were produced via iron-
catalyzed [2 + 2 + 2] cycloaddition.2a,5 Previously, we reported
ruthenium-catalyzed [2 + 2 + 2] cyclotrimerization of CF3-
substituted internal alkynes.5c Here, we report the development
of iron-catalyzed [2 + 2 + 2] cycloaddition of CF3-substituted
internal alkynes. The protocol gave access to arenes bearing the
CF3 group as important structural motifs.1
Table 1 Iron-catalyzed cyclotrimerization of 1-(4-methyl-phenyl)-
3,3,3-trifluoropropyne (1a)
We initially examined the trimerization of CF3-substituted
unsymmetrical internal alkyne 1a in the presence of iron cata-
lyst under various reaction conditions (Table 1). The cyclo-
trimerization of CF3-alkyne 1a using FeI2 (20 mol%) with DPPP
as a ligand under Zn and ZnI2 in CH3CN at 80 ꢀC for 12 h led to
the corresponding CF3-substituted benzene 2a in 66% yield
with a 92% regioselectivity (entry 1). The trimerization using
FeCl2 gave the desired product 2a in 79% yield with a 94%
regioselectivity (entry 2). Replacing FeCl2 with Fe(OTf)2 or FeCl3,
the decrease of desired product was observed (entries 3 and 4).6
Entry
[Fe] (mol%)
Ligand
Time (h)
Yielda (%)
2a : 3ab
1
2
3
4
5
6c
7
8
9
FeI2 (20)
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPE
DPPB
12
12
12
12
36
36
36
36
36
66
79
68
49
87
10
21
<2
<2
92 : 8
94 : 6
95 : 5
93 : 7
95 : 5
95 : 5
94 : 6
N.D.
FeCl2 (20)
Fe(OTf)2 (20)
FeCl3 (20)
FeCl2 (5)
FeCl2 (5)
FeCl2 (5)
FeCl2 (5)
FeCl2 (5)
Department of Chemistry, College of Humanities
& Science, Nihon University,
Sakurajosui, Setagaya-ku, Tokyo 156-8550, Japan. E-mail: minakawa@chs.nihon-u.
ac.jp; kawatsur@chs.nihon-u.ac.jp
d
PPh3
N.D.
† Electronic supplementary information (ESI) available. CCDC 1012045. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra06973k
a
b
Isolated yield of 2a and 3a. Ratio was determined by 1H and/or 19F
NMR of the crude materials. c Without ZnI2. d 20 mol%.
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Table 2 Iron-catalyzed cyclotrimerization of CF3-alkynes 1b–n
Scheme 1 Proposed mechanism.
Entry
1
Yielda (%)
2 : 3b
3).9 No reaction was observed in 40 mol% of zinc (entry 4).10 It
should be noted that no reaction was observed in the absence of
iron catalyst (entry 9).
1
2
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
96
96
86
80
79
62
73
65
92
83
84
<2
<2
95 : 5
95 : 5
94 : 6
94 : 6
95 : 5
93 : 7
93 : 7
93 : 7
96 : 4
96 : 4
96 : 4
N.D.
3c,d
4
Next, the cycloaddition of CF3-alkynes 1 with 1,6-diynes 4
was performed in the optimized reaction conditions (Table 4).
The reaction of 1a and 1h bearing an electron-donating group at
the para-position on the benzene ring with 4a gave the corre-
sponding CF3-benzene derivative 5aa and 5ha in 92% and 94%
yield, respectively (entries 1 and 5). For the reaction of 1c or 1n,
which has an electron-withdrawing group at the para-position
on the benzene ring with 4a, cycloadduct 5ca and 5na was
formed in 90% and 94% yield, respectively (entries 2 and 8). The
carbocyclization of 1j bearing an electron-donating group at the
meta-position on the benzene ring with 4a afforded 5ja in 88%
yield. The cycloaddition of 1m bearing an electron-donating
group at the ortho-position on the benzene ring took place to
give 5ja in 82% yield. The reaction of 1h with various 1,6-diynes
4b–e proceeded in the similar conditions to afford 5hb–e in up
to 97% isolated yield.
5
6c
7d
8c
9
10
11
12
13
N.D.
a
Isolated yield of 2 and 3. b Ratio was determined by 1H and/or 19F NMR
of the crude materials. c 60 h. d FeCl2 (7.5 mol%), DPPP (15 mol%), ZnI2
(11.3 mol%).
regioselectivity (entries 1–4). In contrast, the cycloaddition
using 1h and 1i having an electron-donating group at the para-
position on the benzene ring gave 2h and 2i with 93% regio-
selectivity in 73% and 65% yield, respectively (entries 7 and 8).
The cycloaddition of 1j–l also afforded 2j–l in up to 92% isolated
yield with 96% regioselectivity (entries 9–11). For the reaction of
1m and 1o bearing a functional group at the ortho-position on
the benzene ring was not effective to give a small amount of
products (entry 12 and 13). When the reaction was performed
using 1-phenyl-1-propyne, 1-phenyl-2-trimethylsilyl acetylene,
or ethyl phenyl propiolate, the trimerization did not proceed in
the similar conditions.8 A plausible mechanism is depicted in
Scheme 1. The coordination of two CF3-alkynes 1 to the Fe(0)
complex is followed by an oxidative cyclometalation to give the
ferracyclopentadiene I.4,7 An additional insertion of CF3-alkyne
1 and reductive elimination subsequently afford the regiose-
lective cyclotrimerization product 2.
Furthermore, our reaction conditions of the iron-catalyzed
cyclotrimerization using CF3-alkynes were applied to the [2 + 2 +
2] cycloaddition of CF3-alkyne 1c with 1,6-diyne 4a (Table 3).
Under the similar conditions, treatment of 1c with 4a afforded
the corresponding CF3-benzene 5ca in 17% yield (entry 1). The
reaction without a ligand increased the yield of the desired
product to give 5ca in 75% yield (entry 2). We were pleased to
nd that the reaction of 1c with 4a under air conditions
successfully promoted the formation of 5ca in 90% yield (entry
We also performed the iron-catalyzed [2 + 2 + 2] carbocycli-
zation of CF3-alkyne with unsymmetrical 1,6-diynes (eqn 1).
The cycloaddition reaction of CF3-alkyne 1a with unsymmetrical
Table 3 Iron-catalyzed [2 + 2 + 2] carbocyclization of 1-(4-chlor-
ophenyl)-3,3,3-trifluoropropyne (1c) with 1,6-diyne 4aa
Entry
[Fe] (mol%)
Additive (mol%)
Yieldb (%)
1c
2
3
4
5
6
7
8
9
FeCl2 (5)
FeI2 (20)
FeI2 (20)
FeI2 (20)
FeCl2 (20)
FeBr2 (20)
Fe(OTf)2 (20)
FeCl3 (20)
—
Zn/ZnI2 (300/7.5)
Zn (200)
Zn (200)
Zn (40)
Zn (200)
Zn (200)
Zn (200)
Zn (200)
Zn (200)
17
75
90
0
83
<1
0
67
0
a
Under air. b Isolated yield. c DPPP (10 mol%), CH3CN (0.3 mL), under
nitrogen.
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Table 4 Iron-catalyzed [2 + 2 + 2] carbocyclization of CF3-alkynes 1
with symmetrical diynes 4a
alkyne with 1,6-diyne follows a similar mechanism to that of
well-established mechanism.4
A plausible mechanism is
depicted in Scheme 2. The coordination of 1.6-diyne 4 to the
Fe(0) complex is followed by an oxidative cyclometalation to give
the ferracyclopentadiene II. Insertion of CF3-alkyne 1 and
reductive elimination subsequently afford the cycloadduct 5. In
the carbocyclization, CH3CN may act as a ligand.11
Entry
1
1
4
Yieldb (%)
92
1a: Ar ¼ 4-MeC6H4
4a
4a
4a
4a
4a
4a
4a
4a
(1)
2
3
4
5
6
7
8
1c: Ar ¼ 4-ClC6H4
1f: Ar ¼ Ph
90
92
90
94
88
82
94
1g: Ar ¼ 4-PhC6H4
1h: Ar ¼ 4-MeOC6H4
1j: Ar ¼ 3-MeC6H4
1m: Ar ¼ 2-MeOC6H4
1n: Ar ¼ 4-CF3C6H4
9c
1h
1h
1h
97
79
Conclusions
4b
4c
We demonstrated the iron-catalyzed [2 + 2 + 2] intermolecular
cyclotrimerization of triuoromethyl-substituted internal
alkynes to give the corresponding triuoromethylated benzene
derivatives in high yield with excellent regioselectivity. We also
succeeded in the iron-catalyzed [2 + 2 + 2] carbocyclization of the
CF3-alkyne with 1,6-diynes. A key intermediate in the selective
iron-catalyzed [2 + 2 + 2] cycloadditions would be a ferracyclo-
pentadiene intermediate.
10d
11c
75
76
4d
4e
12e
1h
Notes and references
a
b
Under air. Isolated yield. c 24 h. d FeI2 (25 mol%). e 48 h.
¨
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