Catalytic SNAr reaction of non-activated fluoroarenes with amines via Ru η6-arene complexes

Article abstract of DOI:10.1039/b919413d

Ru-catalyzed S_NAr reaction of non-activated fluoroarenes with secondary amines proceeded through η⁶-arene complexes to give aminated products in up to 79% yield.

Full text of DOI:10.1039/b919413d

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Catalytic SNAr reaction of non-activated fluoroarenes with amines
via Ru g6-arene complexesw
Maiko Otsuka, Kohei Endo and Takanori Shibata*
Received (in College Park, MD, USA) 17th September 2009, Accepted 4th November 2009
First published as an Advance Article on the web 26th November 2009
DOI: 10.1039/b919413d
Ru-catalyzed SNAr reaction of non-activated fluoroarenes with
secondary amines proceeded through g6-arene complexes to give
aminated products in up to 79% yield.
example, [RhCp*Cl2]2 with AgPF6,5 [Ru(p-cymene)OTf2]n,6
7
and [Rh(cod)2]BF4 were submitted, and finally, we were
pleased to find that a Ru catalyst, prepared from Ru(cod)-
(2-methylallyl)2, 1,5-bis(diphenylphosphino)pentane (DPPPent),
and trifluoromethanesulfonic acid (TfOH)8 showed high
activity. Actually, morpholine (1 equiv.) and p-fluorotoluene
(5 equiv.) were added in refluxed 1,4-dioxane to the above-
mentioned Ru complex (5 mol%), and the reaction proceeded
to furnish aminated product 1 in 48% isolated yield.9 Under
the same reaction conditions, only a trace amount of aminated
product 1 was obtained in the reaction of p-chlorotoluene,
moreover, no product was detected in the reaction of
p-bromotoluene or p-iodotoluene. These results imply that the
present transformation proceeds by SNAr reaction (Scheme 2).
In order to improve the yield, we screened several phosphine
ligands (Table 1, entries 1–4). When 1,5-bis(di-tert-butyl-
phosphino)pentane (DtPPent) was used as a more electron-
rich and bulky analogue of DPPPent, product 1 was obtained
in low yield (entry 1). BINAP also realized a catalytic reaction
but the yield was also low (entry 2). In contrast, 1,10-bis-
(diphenylphosphino)ferrocene (DPPF) and triphenylphosphine,
The nucleophilic aromatic substitution (SNAr) reaction of
haloarenes is
a widely used transformation in organic
syntheses; multi-substituted arenes, including several pharma-
ceutical products and natural products, have been synthesized
using this method. However, the SNAr reaction generally
requires ‘‘electron-poor’’ aromatic compounds with strong
electron-withdrawing group(s), such as nitro and cyano
groups, because the aromatic ring is intrinsically electron-rich,
and haloarenes without electron-withdrawing group(s),
namely non-activated haloarenes, are not suitable as electro-
philes in the SNAr reaction.1 The conversion into a transition
metal Z6-arene complex is a commonly used protocol for
making haloarenes more electron-poor, and even non-activated
haloarenes undergo SNAr reaction by complexation.2
However, the main drawback of this procedure is that it
requires the use of stoichiometric amounts of transition metals
that are attached to and detached from the benzene ring. In
this regard, there has been no practical catalytic SNAr reaction
using relatively electron-rich haloarenes.3 The purpose of our
study is to develop the first catalytic SNAr reaction of non-
activated fluoroarenes with amines.4
a
monodentate ligand, achieve comparable yields with
DPPPent (entries 3 and 4). The yields of these reactions
were still moderate because morpholine was not completely
consumed after 24 h. Then we assumed that in situ generated
HF would inhibit the catalytic activity, and further investigated
the additives that could capture HF. The addition of triethyl-
amine as a base did not improve the yield of product 1
We hypothesized that the desired catalytic SNAr reaction
could be realized according to the following mechanism
(Scheme 1). First, a catalyst M associates with a haloarene
to yield a transition metal Z6-arene complex A. Second, it
undergoes nucleophilic attack and is converted into metal
Z6-arene complex B. Third, the complex dissociates
a
substituted arene as a product, and the catalyst is regenerated.
The most difficult problem in this catalysis would be the arene-
exchange step from catalyst-product complex B to catalyst-
substrate complex A.
We chose p-fluorotoluene as a model haloarene with an
electron-donating group, because fluoroarene is the most
reactive among haloarenes in the SNAr reaction. The reaction
of p-fluorotoluene with morpholine was examined in the
presence of catalytic amounts of transition metal complexes,
which are known to form metal Z6-arene complexes. For
Department of Chemistry and Biochemistry, School of Advanced
Science and Engineering, Waseda University, Shinjuku, Tokyo,
169-8555, Japan. E-mail: tshibata@waseda.jp;
Fax: +81-3-5286-8098; Tel: +81-3-5286-8098
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data. See DOI: 10.1039/b919413d
Scheme 1 Proposed reaction mechanism of catalytic SNAr reaction
via Ru Z6-arene complexes.
ꢀc
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Table 2 Screening of fluoroarenes in Ru-catalyzed SNAr reactiona
Entry
1
Substrate
Product
Time/h
24
Yield (%)
72
Scheme 2 Ru-catalyzed reaction of morpholine with p-halotoluenes.
(entry 5). In the presence of K2CO3 or 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU), the reaction did not proceed at
all. We next used silane as a good scavenger of the fluoride
anion (entries 6–8): triethylsilane certainly furnished better
results (64% yield). When triethylamine was added, the
yield exceeded 70% (entry 9).10 The use of both triethylsilane
and triethylamine was also effective in the case of triphenyl-
phosphine; the yield improved significantly (entry 10).
2
3
24
24
79
54
Under the optimal conditions, we first examined the sub-
strate scope of non-activated fluoroarenes (Table 2). The
reaction of fluorobenzene with morpholine furnished product
2 in good yield (entry 1). Moreover, in the case of m-fluoro-
toluene, the best yield of 79% was achieved (entry 2). The
reaction of 4-fluoro-o-xylene, possessing two electron-
donating groups, also proceeded to yield product 4 in
moderate yield (entry 3). The methoxy group was tolerable
as a substituent of fluoroarene, and the catalytic reaction of
o-, m- and p-fluoroanisoles also proceeded. In these cases, the
reaction was conducted without triethylsilane, because the
corresponding products 5–7 readily react with silane
(entries 4–6). It is noteworthy that a fluoroarene with an
amino group, which is a strong electron-donating group,
underwent the catalytic SNAr reaction, albeit in low yield
(entry 7). In the case of fluorostyrene, the SNAr reaction
proceeded in moderate yield, but the product was reduced
partially at the olefinic moiety (entry 8).
4
5
6
36
36
36
30b
58b
38b
p-MeO
m-MeO
o-MeO
5 (p-MeO)
6 (m-MeO)
7 (o-MeO)
7
24
36
25
8
57c
a
Reaction conditions: fluoroarene/morpholine/Ru cat. = 5 : 1 : 0.05
(0.4 mmol of morpholine) in dioxane. Ru cat. was prepared from
Ru(cod)(2-methylallyl)2 (5 mol%), DPPPent (7 mol%), and TfOH
b
c
(10 mol%). Et3N (1.5 equiv.) was added without Et3SiH. 4-Ethyl-
1-morpholinobenzene was included (30% of the product).
Table 1 Screening of ligands and additives in Ru-catalyzed SNAr
reactiona
We next examined the scope of amines as nucleophiles in the
reaction with p-fluorotoluene (Table 3). Cyclic amines, such as
piperidine, N-methylpiperazine, and pyrrolidine, furnished
aminated products in moderate to good yield (entries 1–3).
The catalytic SNAr reaction proceeded for acyclic amines as
well, albeit lower yields (entries 4–6). In contrast, the reaction
did not proceed with N-methyl aniline. These results show that
high nucleophilicity is crucial to achieve a high yield.
Entry
Ligand
Additive
Yield (%)
We investigated evidence for the formation of Ru Z6-arene
complexes as intermediates, and attempted to characterize
intermediates 17 and 18 in Scheme 3, which correspond to A
and B, respectively in Scheme 1, by NMR and mass analyses.
First, an excess amount of fluorobenzene-d5 was added to a
mixture of Ru(cod)(2-methylallyl)2, DPPPent, and TfOH in
1
2
3
4
5
6
7
8
9
10
DtPPent
BINAP
DPPF
—
—
—
—
20
20
44
50
45
64
53
40
72
68
2 PPh3
DPPPent
DPPPent
DPPPent
DPPPent
DPPPent
2 PPh3
Et3N
Et3SiH
(EtO)3SiH
Ph3SiH
Et3N, Et3SiH
Et3N, Et3SiH
THF-d8; the mixture was then heated at 80 1C for 10 min. 31
P
NMR analysis of the resulting solution at room temperature
showed a single peak at 65.7 ppm, which was almost in
agreement with the 31P NMR spectrum of the pincer-type
Ru Z6-arene complex prepared from styrene or p-cymene with
the Ru catalyst in THF.8 The ESI-MS analysis showed an
a
Reaction conditions: fluoroarene/morpholine/Ru/DPPPent/TfOH =
5 : 1 : 0.05 : 0.07 : 0.10 (0.4 mmol of morpholine) in dioxane.
ꢀc
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Table 3 Screening of amines in Ru-catalyzed SNAr reactiona
The above results strongly suggest that the catalytic SNAr
reaction proceeds via Ru Z6-arene complexes.11
In conclusion, we achieved SNAr reactions of non-activated
fluoroarenes with amines using Ru-Z6 arene complex as a
catalytic template. To the best of out knowledge, the present
reaction is the first example of a catalytic conversion of the
C–F bond of fluoroarenes into a C–N bond. We are carrying
out further studies on the elucidation of the reaction mechanism
and the modification of catalysts.
Yield
(%)
Entry
1
Substrate
Product
This work was supported by a Waseda University Grant for
Special Research Projects. We are also grateful to the Japan
Society for the Promotion of Science for the fellowship
support to M. Otsuka.
75
2
3
75
55
Notes and references
1 Nucleophilic substitution reaction of non-activated haloarenes
proceeded only when strong anionic nucleophiles, such as lithium
amides and alkoxides, were used: (a) R. Huisgen and J. Sauer,
Chem. Ber., 1958, 91, 1453; (b) G. Wittig, H. J. Schmidt and
H. Renner, Chem. Ber., 1962, 95, 2377; (c) J. R. Rodriguez,
J. Agejas and A. B. Bueno, Tetrahedron Lett., 2006, 47, 5661.
2 (a) M. F. Semmelhack and A. Chlenov, in Transition Metal Arene
p-Complexes in Organic Synthesis and Catalysts, ed. E. P. Kundig,
¨
4
5
6
n-Hex, Me
Bn, Me
c-Hex, H
13 (R,R’=n-Hex, Me)
14 (R,R’=Bn Me)
15 (R,R’=c-Hex, H)
44
20
22
Springer-Verlag,
Heidelberg,
Germany,
2004,
p.
43;
(b) M. F. Semmelhack, in Comprehensive Organometallic Chemistry
II, ed. A. W. Abel, F. G. A. Stone and G. Wilkinson, Pergamon,
New York, vol. 12, 1995, p. 979.
3 Only limited catalytic system using modified cyclopentadienyl Rh
complexes was reported in SNAr reaction using oxygen nucleo-
philes: (a) R. P. Houghton and M. Voyle, J. Chem. Soc., Perkin
Trans. 1, 1984, 925; (b) L. I. Goryunov, V. V. Litvak and
V. D. Shteingarts, Zhurn. Org. Khim., 1987, 23, 1230.
a
Reaction conditions: fluoroarene/morpholine/Ru cat. = 5 : 1 : 0.05
(0.4 mmol of morpholine) in dioxane. Ru cat. was prepared from
Ru(cod)(2-methylallyl)2 (5 mol%), DPPPent (7 mol%), and TfOH
(10 mol%).
4 For selected examples of SNAr reactions of non-activated
fluoroarene with amines using a stoichiometric amount of transition
metals, see: (a) W. Braun, B. Calmuschi-Cula, U. Englert,
expected peak for [Ru(dpppent)(Z6-fluorobenzene-d5)]+
(m/z = 642.1, 19%), moreover, the detected isotope pattern
matches with the theoretical isotope pattern (see ESIw). Next,
an excess amount of morpholine was added to the reaction
mixture containing complex 17, and the generation of Ru
Z6-arene complex 18 was also ascertained by the 31P NMR
analysis (68.1 ppm) and ESI-MS analysis [Ru(dpppent)-
(Z6-morpholinobenzene-d5)]+ (m/z = 709.2, 27%) (see ESIw).
K. Hofener, E. Alberico and A. Salzer, Eur. J. Org. Chem., 2008,
¨
2065; (b) K. Kamikawa, S. Kinoshita, M. Furusyo, S. Takemoto,
H. Matsuzaka and M. Uemura, J. Org. Chem., 2007, 72, 3394;
(c) C. Baldoli, S. Maiorana, E. Licandro, L. Casiraghi, G. Zinzalla,
P. Seneci, E. D. Magistris, A. Paio and C. Marchioro, J. Comb.
Chem., 2003, 5, 809; (d) F.-E. Hong, S.-C. Lo, M.-W. Liou,
L.-F. Chou and C.-C. Lin, J. Organomet. Chem., 1996, 516, 123;
(e) J. P. Gilday and D. A. Widdowson, Tetrahedron Lett., 1986, 27,
5525.
5 [RhCp*Cl2]2 was used as an analogue of modified cyclopentadienyl
Rh complex; see ref. 3.
6 For selected examples, see: (a) E. L. Velarde, R. A. Stephen,
R. N. Mansour, L. T. Hoang and D. J. Burkey, J. Am. Chem.
Soc., 2003, 125, 1188; (b) A. Schluter, K. Bieber and
W. S. Sheldrick, Inorg. Chim. Acta, 2002, 340, 35; (c) S. Chen,
V. Carperos, B. Noll, R. J. Swope and M. R. DuBois, Organo-
metallics, 1995, 14, 1221.
7 (a) H. Matsuzawa, Y. Tanabe, Y. Miyake and Y. Nishibayashi,
Organometallics, 2008, 27, 4021; (b) M. Maekawa, N. Hashimoto,
K. Sugimoto, T. Kuroda-Sowa, Y. Suenaga and M. Munakata,
Inorg. Chim. Acta, 2003, 344, 143.
8 J. Takaya and J. F. Hartwig, J. Am. Chem. Soc., 2005, 127, 5756.
9 This reaction did not proceed at all without the Ru catalyst in
refluxed dioxane.
10 The present catalytic reaction proceeded even with 1–4 equiv. of
fluorotoluene, but the yield was lower (22–60%) (see ESIw).
11 The same experiment was conducted with bromobenzene, and the
Ru Z6-bromobenzene complex was detected by 31P NMR and ESI-MS
analyses, but SNAr reaction did not proceed by the addition of an
excess amount of morpholine (see ESIw).
Scheme 3 Characterization of Ru Z6-arene complexes 17 and 18.
ꢀc
This journal is The Royal Society of Chemistry 2010
338 | Chem. Commun., 2010, 46, 336–338