Cationic iron-catalyzed intramolecular alkyne-hydroarylation with electron-deficient arenes

Article abstract of DOI:10.1039/b920695g

Fe(OTf)₃ effectively catalyzed intramolecular hydroarylation of aryl-substituted alkynes with electron-deficient arenes under mild conditions.

Full text of DOI:10.1039/b920695g

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Cationic iron-catalyzed intramolecular alkyne-hydroarylation
with electron-deficient arenesw
Kimihiro Komeyama,* Ryoichi Igawa and Ken Takaki*
Received (in Cambridge, UK) 7th October 2009, Accepted 20th November 2009
First published as an Advance Article on the web 12th January 2010
DOI: 10.1039/b920695g
Fe(OTf)3 effectively catalyzed intramolecular hydroarylation
of aryl-substituted alkynes with electron-deficient arenes under
mild conditions.
Table 1 Iron-catalyzed hydroarylation of N-proparlgylanilines 1a
Transition metal-catalyzed hydroarylation of alkynes has
attracted much attention in the pivotal areas of synthesis
of conjugated aromatic compounds in an atom-economical
manner.1 Moreover, the importance of its intramolecular
reaction has been widely recognized as a feasible approach
to cyclic vinylarene frameworks. Although numerous examples
have been reported,2 a number of problems remain unresolved:
(1) in some cases, expensive catalysts are necessary to promote
the reaction; (2) a mixture of exo- and endo-cyclization
products is contaminated;2f and (3) there are limitations in
the types of performable substrates, especially, electron-rich
aryl nucleophiles are crucial, electron-deficient ones do not
participate, so far.3 During our investigation on catalytic
activities of iron complexes,4 we found unprecedented reactivity
in the cationic iron catalyst, Fe(OTf)3, for hydroarylation of
alkynes with electron-deficient arenes.
Substrate
R1
R2
1
Entry
Time/h Product 2 Yield/%b
1
2
3
4
5
6
7
H
Ph
Ph
4-tol 1d
1b
1c
8
2b
2c
2d
2e
2f
2g
2h
2i
90
81
67
76
79
71
76
10
57
19
13
46
4-Br
2-Br
4-F
5
22
4
Ph
1e
1f
4-CO2Me Ph
20
10
12
14
24
48
4-NO2
3,5-F2
4-Me
4-tol 1g
Ph
Ph
Ph
Ph
Ph
Ph
1h
1i
1i
1j
1k 48
1l 48
8c
9c
10c
11c
12c
4-Me
2i
2j
4-MeO
2-MeO
2-iPr
2k
2l
a
Conditions: substrate (0.15 mmol), Fe(OTf)3 (15 mmol), DCE
(0.5 mL). Isolated yield. 20 mol% Fe(OTf)3.
b
c
With optimized conditions in hand, we examined the
scope and limitation of aryl nucleophiles (Table 1). Similar
to electron-neutral phenyl ring 1b (entry 1), substrates bearing
halogen, 4-Br 1c, 2-Br 1d, and 4-F 1e, were also efficiently
converted into 1,2-dihydroquinolines 2c, 2d, and 2e in 81%,
67%, and 76% yields, respectively, without loss of halogen
functions (entries 2–4). Many electron-poor arenes possessing
4-CO2Me, 4-NO2, and 3,5-F2 groups (1f, 1g, and 1h) took part
in the reaction, giving rise to the desired products 2f, 2g, and
2h in high yields (entries 4–6). In sharp contrast, electron-rich
aryl rings depressed the transformation (entries 8–12) counter-
intuitively. Thus, the reactions of substrates with 4-Me 1i,
4-MeO 1j, 2-MeO 1k, and 2-iPr 1l were very slow, even with
twice the amounts of the catalyst and it was necessary to have
longer reaction times to obtain the products in moderate yields
(entries 8–12).
ð1Þ
Treatment of 1-tol-3-(N-tosyl-4-cyanoanilino)prop-1-yne (1a)
with Fe(OTf)3 (10 mol%) afforded 1,2-dihydroquinoline 2a in
85% yield through exclusive 6-endo-dig cyclization (eqn (1)).
Although Cu(OTf)2 was a slightly effective catalyst (22% yield),
conventional catalysts such as PtCl2, Sc(OTf)3, In(OTf)3,
GaCl3, AlCl3, and BF3ꢀOEt2 in similar hydroarylation did
not provide 2a, and most of 1a was recovered unchanged. Of
iron catalysts, the high catalytic activity strongly depended
on its counter anion, thus replacement of OTf with BF4,
ClO4, CF3CO2, and Cl extremely decreased the activity.5
1,2-Dichloroethane (DCE) and nitromethane were the solvent
of choice, whereas acetonitrile, toluene, and 1,4-dioxane were
unfavorable.6
During the investigation, the important role of terminal
attachments R2 in the present hydroarylation was recognized
(Table 2). When the terminal phenyl group of 1b was replaced
with electron-deficient aryl rings (4-CF3C6H4 1m,
4-MeO2CC6H4 1n, and 2-MeO2CC6H4 1o), n-Bu 1p, H 1q,
and Br 1r, these substrates hardly produced the products
(entries 1–6). On the other hand, electron-rich aryl substituents
such as 4-MeC6H4 1s, 4-(MeOCH2)C6H4 1t,7 4-MeOC6H4
1u, and 2-MeOC6H4 1v, 2,3,4-(MeO)3C6H2 1w drastically
increased the reaction rate, leading to the corresponding
Department of Chemistry and Chemical Engineering,
Graduate School of Engineering, Hiroshima University,
Kagamiyama, 739-8527, Higashi-Hiroshima, Japan.
E-mail: kkome@hiroshima-u.ac.jp; Fax: +81 82 424 5494;
Tel: +81 82 424 7747
w Electronic supplementary information (ESI) available: Experimental
procedure and characterization data. CCDC 750245. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b920695g
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Table 2 Effect of terminal attachments R2
investigated (eqn (2) and (3)). As a result, the reaction rates
were found to be nearly equal (kH/kD = 0.95).9
ð2Þ
Substrate
R2
1
Time/h Product 2 Yield/%a
Entry
1
2
3
4
5
6
7
8
4-CF3C6H4
4-MeO2CC H4
2-MeO2CC6H4
n-Bu
H
Br
4-MeC6H4
4-(MeOCH2)C6H4
4-MeOC6H4
2-MeOC6H4
1m 96
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
Trace
Trace
Trace
7
0
0
83
65
75
72
77
1n
1o
1p
1q
1r
1s
1t
96
96
43
24
24
3
6
4
ð3Þ
9
10
11
1u
1v
1
1
This result indicates that the cyclization proceeds via a Friedel–
Crafts type reaction, wherein the vinyl cation often works as a
key intermediate.2b–d Although, it is known that various Lewis
acids produce the vinyl cation from alkynyl arenes, the present
reaction was efficiently promoted only by Fe(OTf)3. More-
over, the progress of the iron-catalyzed hydroarylation
strongly depended on the electronic characters of two aryl
rings, that is, electron-deficiency of Ar1 and electron-richness
of Ar2 drastically accelerated the reaction (Fig. 1). By
considering these findings, we envisaged that the present
hydroarylation might employ a cationic iron-arene inter-
mediate as depicted in Scheme 1. Thus, the coordination of
the electrophilic iron center to the aryl ring of 1 or 3 would
afford two types of iron-arene complexes A and B.10 When
electronic density of the aryl ring Ar2 is higher than that of
Ar1, generation of the arene complex A would be superior to
that of B. A would efficiently produce the vinyl cation C due to
p-electron delocalization between the arene and the con-
jugated alkyne as shown in the alkynyl chromium-arene
complexes.11 In contrast, the non-conjugated arene complex B
would not be suitable for the vinyl cation formation. Arylation
of C could produce the intermediate D, and then sequential
deprotontion would yield the product 2 or 4 and the catalyst.
In conclusion, inexpensive and environmentally benign iron
complex Fe(OTf)3 has been proven to be an effective catalyst
for intramolecular hydroarylation of aryl-substituted alkynes
to form 1,2-dihydroquinolines and phenanthrenes in good to
high yields.z Of special importance, the cationic iron-catalyst
permits the participation of electron-deficient aryl nucleo-
philes, which provides unprecedented and valuable examples
of hydroarylation. The definite role of the iron catalyst in the
present reaction is not clear, but the unique reaction mode
would most likely be induced by the generated cationic
2, 3,4-(MeO)3C6H4 1w
1
a
Isolated yield.
1,2-dihydroquinolines in good to high yields (65–83%) within
4 h (entries 7–11).
The Fe(OTf)3-catalyzed hydroarylation could also be
extended to the cyclization of ortho-alkynyl biaryls
3
(Table 3). Various electron-deficient aryl nucleophiles bearing
CN, CO2Me, NO2, CF3, and F, and an electron-neutral
phenyl ring were perfectly tolerated to provide phenanthrene
derivatives 4a–4f in high yields via exclusive 6-endo-dig
cyclization mode (entries 1–6).8 Interestingly, electron-rich
aryl nucleophile like 4-anisyl substrate 3g also participated
in the reaction, but, 5-exo-dig cyclization corporately occurred
along with the 6-endo-dig reaction (entry 7). In addition,
similar to Table 2, the lack of the electron density of terminal
aryl rings of o-alkynyl biaryl also inhibited the reaction. That
is, the transformation of 40-nitro-2-[(4-nitrophenyl)ethynyl]-
1,10-biphenyl did not progress at all even though a longer
reaction time (96 h) was used.
To gain an insight into the reaction mechanism, a kinetic
isotope effect for the cyclization of 1b and 1b-d5 was carefully
Table 3 Iron-catalyzed hydroarylation of o-alkynyl biaryls 3
Substrate
R3
3
Entry
Time/h
Product 4
Yield/%a
1
2
3
4
4-CN
3a
3b
3c
3d
3e
3f
12
2
6
7
2
4a
4b
4c
4d
4e
4f
87
85
79
95
91
86
68
4-CO2Me
4-NO2
4-CF3
3,5-F2
H
5
6
1
3
7b
4-MeO
3g
4g
a
b
Isolated yield. 9-Benzylidene-2-methoxyfluorene was obtained in
11% yield.
Fig. 1 Preferred electronic properties of the two arenes.
Chem. Commun., 2010, 46, 1748–1750 | 1749
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1 For the review: (a) C. Jia, T. Kitamura and Y. Fujiwara, Acc.
Chem. Res., 2001, 34, 633; (b) F. Kakiuchi and N. Chatani, Adv.
Synth. Catal., 2003, 345, 1077; (c) M. Bandini, E. Emer,
S. Tommasi and A. Umani-Ronchi, Eur. J. Org. Chem., 2006,
3527; (d) T. Kitamura, Eur. J. Org. Chem., 2009, 1111.
2 (a) Y. Kido and M. Yamaguchi, J. Org. Chem., 1998, 63, 8086;
(b) Y. Kido, S. Yoshimura, M. Yamaguchi and T. Uchimaru, Bull.
Chem. Soc. Jpn., 1999, 72, 1445; (c) N. Chatani, H. Inoue, T. Ikeda
and S. Murai, J. Org. Chem., 2000, 65, 4913; (d) T. Tsuchimoto,
T. Maeda, E. Shirakawa and Y. Kawakami, Chem. Commun.,
2000, 1573; (e) M. T. Reetz and K. Sommer, Eur. J. Org. Chem.,
2003, 3485; (f) V. Mamane, P. Hannen and A. Furstner,
¨
Chem.–Eur. J., 2004, 10, 4556; (g) C. Nevado and
A. M. Echavarren, Chem.–Eur. J., 2005, 11, 3155.
3 Very recently, hydroarylation of alkynes through oxidative
addition of C–H bonds on very electron-poor aryl rings with low
valent late transition metal catalysts were reported. Pd:
(a) N. Chernyak and V. Gevorgyan, J. Am. Chem. Soc., 2008,
130, 5636. Ni; (b) Y. Nakao, N. Kashihara, K. S. Kanyiva and
T. Hiyama, J. Am. Chem. Soc., 2008, 130, 16170; (c) K. S. Kanyiva,
Y. Nakao and T. Hiyama, Angew. Chem., Int. Ed., 2007, 46, 8872.
4 (a) K. Komeyama, T. Morimoto and K. Takaki, Angew. Chem.,
Int. Ed., 2006, 45, 2938; (b) K. Komeyama, T. Morimoto,
Y. Nakayama and K. Takaki, Tetrahedron Lett., 2007, 48, 3259;
(c) K. Komeyama, Y. Mieno, S. Yukawa, T. Morimoto and
K. Takaki, Chem. Lett., 2007, 36, 752; (d) K. Komeyama,
R. Igawa, T. Morimoto and K. Takaki, Chem. Lett., 2009, 38, 724.
5 Reactivities of various iron catalysts (yield of 2a, conversion of 1a):
Fe(BF4)3 (8%, 11%); Fe(ClO4)3 (2%, 45%); Fe(CF3CO2)3 (0%,
11%); and FeCl3 (4%, 30%). Lu and Campagne reported FeCl3-
catalyzed hydroarylation of alkynes with electron-rich arenes. See:
(a) R. Li, S. R. Wang and W. Lu, Org. Lett., 2007, 9, 2219;
(b) C. D. Zotto, J. Wehbe, D. Virieux and J.-M. Campagne,
Synlett, 2008, 2033. TfOH also provided 2a in only 20% yield
with complete consumption of 1a.
6 Yields of 2a using various solvents: 1,2-dichloroethane (85%) 4
nitromethane (70%) c toluene (11%) 4 acetonitrile (9%) 4
1,4-dioxane (trace).
7 Treatment of 1t with FeCl3 (10 mol%) provided a complex
mixture, in which a negligible amount of 2t was formed (o5%
yield).
8 Exact structure of 4e was determined by X-ray analysis.
9 The vinyl proton of 1,2-dihydroquinoline 2b was deuterated in the
presence of D2O (1 equiv.) under the similar conditions (eqn (4)).
In eqn (3), 2b-d4 could be afforded by the reaction of 2b-d5 and
contaminated water
Scheme 1 Plausible reaction mechanism of cationic-iron catalyzed
intramolecular alkyne-hydroarylation.
iron-arene complexes during the reaction. Studies on details of
mechanistic aspects and extension of this protocol are in
progress.
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan. K.K. acknowledges
financial supports from Kinki Invention Center and Furukawa
technical foundation. Finally, we thank Dr H. Fukuoka for
X-ray analysis of 4e.
Notes and references
z General procedure for hydroarylation of 1a: In a 20 mL Schlenk tube,
a mixture of 1a (60.0 mg, 0.15 mmol), Fe(OTf)3 (7.5 mg, 15 mmmol),
and DCE (0.5 mL) was heated at 80 1C for 3 h. After cooling to room
temperature, the reaction mixture was passed through a short silica gel
column with diethyl ether, and then concentrated in vacuo. The
obtained crude product was purified by column chromatography with
hexane/ethyl acetate (5 : 1) to afford 6-cyano-4-tolyl-1-tosyl-1,2-
dihydroquinoline (2a) in 85% yield (51.0 mg). Isolated as a white solid
(Mp. 162.0–163.0 1C); Rf (SiO2, hexane:EtOAc = 5 : 1) = 0.28;
1H NMR (CDCl3, 270.05 MHz) d 2.32 (3H, s), 2.36 (3H, s), 4.57
(2H, d, J = 4.5 Hz), 5.67 (1H, t, J = 4.5 Hz), 6.59 (2H, d, J = 7.9 Hz),
7.10 (4H, d, J = 8.0 Hz), 7.17 (1H, d, J = 2.0 Hz), 7.36 (2H, d, J =
8.2 Hz), 7.58 (1H, dd, J = 8.2, 2.0 Hz), 7.89 (1H, d, J = 8.2 Hz);
13C NMR (CDCl3, 67.80 MHz) d 21.2, 21.4, 45.3, 110.0, 123.1,
127.3, 127.9, 128.2, 129.1, 129.4, 129.8, 131.4, 131.9, 133.8,
135.8, 137.3, 138.2, 139.6, 144.1, 146.7; HRMS m/z (EI): M+ calcd
for C24H20N2O2S, 400.1245; found 400.1235.
Crystal Data: Chemical formula and formula weight (M):
C20H12F2. Unit-cell dimensions (angstrom or pm, degrees) and
volume, with estimated standard deviations: a = 5.6736(8), b =
23.503(3), c = 10.7482(17), beta = 107.425(5). Temperature: 296.1.
Crystal system: monoclinic. Space group symbol (if non-standard
setting give related standard setting): P121/n1. No. of formula units
in unit cell (Z): 4. Number of reflections measured: 13 109 and number
of independent reflections: 3137. Rint: 0.036. Final R values (and
whether quoted for all or observed data): 0.0335. CCDC no.: 750245.
10 (a) D. Astruc, Tetrahedron, 1983, 39, 4027; (b) S. Ohta, Y. Ohki,
Y. Ikagawa, R. Suizu and K. Tatsumi, J. Organomet. Chem., 2007,
692, 4792–4799.
11 T. J. J. Muller, M. Ansorge and H. J. Lindner, Chem. Ber., 1996,
129, 1433.
¨
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This journal is The Royal Society of Chemistry 2010
1750 | Chem. Commun., 2010, 46, 1748–1750