Facile catalytic SNAr reaction of nonactivated fluoroarenes with amines using η6-benzene ruthenium(II) complex

Article abstract of DOI:10.1055/s-0030-1258774

Catalytic S_NAr reaction of fluoroarenes possessing no electron-withdrawing group(s) with cyclic amines was achieved using a readily accessible Ru catalyst, which was prepared from [Ru(benzene)Cl₂] ₂, AgOTf, and P(p-FC₆H₄)₃. The coexistence of molecular sieves MS4A realized high conversion and various substituted aryl amines were obtained in good to high yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258774

LETTER
2601
Facile Catalytic S Ar Reaction of Nonactivated Fluoroarenes with Amines
N
6
Using h -Benzene Ruthenium(II) Complex
a
a
b
a
S
M
A
r
Reactionof
N
ona
a
ctivated Fl
i
uoroar
k
nes
w
ith
A
m
o
ines Otsuka, Hiroya Yokoyama, Kohei Endo, Takanori Shibata*
N
a
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University,
Okubo, Shinjuku, Tokyo 169-8555, Japan
b
Waseda Institute for Advanced Study, Nishiwaseda, Shinjuku, Tokyo 169-8050, Japan
Fax +81(3)52868098; E-mail: tshibata@waseda.jp
Received 30 July 2010
Moreover, the addition of triethylamine and triethylsilane
was needed for high conversion. We next explored a more
facile protocol using h -arene ruthenium(II) complex
such as 1, which directly provides the key intermediate 2
Abstract: Catalytic S Ar reaction of fluoroarenes possessing no
electron-withdrawing group(s) with cyclic amines was achieved us-
ing a readily accessible Ru catalyst, which was prepared from
N
6
[
Ru(benzene)Cl ] , AgOTf, and P(p-FC H ) . The coexistence of
2 2 6 4 3
molecular sieves MS4A realized high conversion and various sub- by arene exchange with fluoroarenes (Scheme 2).
stituted aryl amines were obtained in good to high yields.
Key words: catalysis, S Ar reaction, ruthenium, fluoroarenes,
amines
R
F
R'
R'
N
F
Nu
R'
Nu-H
Ru
Ru
Ru
SNAr reaction
L
L
L
L
L
L
The nucleophilic aromatic substitution (S Ar) reaction of
L = ligand
N
2
haloarene is one of the most established and practical re-
actions to synthesize various substituted arenes. Electron-
deficient aromatic compounds with strong electron-with-
drawing group(s), such as nitro and cyano groups, can be
submitted to this reaction, while nonactivated arenes,
which have no electron-withdrawing substituent(s), are
1
6
Scheme 2 Exchange of h -arene ligand following S Ar reaction
N
6
With these facts in mind, we examined h -benzene ruthe-
nium(II)–phosphine complex, using the dichloro(ben-
zene)ruthenium(II) dimer {[Ru(benzene)Cl ] } as a stable
1
generally inappropriate substrates.
2 2
precursor. The dichloro(arene)ruthenium(II) dimers are
widely used as precursors for various monomeric Ru cat-
alysts. For example, they are mostly used for the prepara-
tion of ruthenium–chiral diphosphine catalysts in
asymmetric hydrogenation, but their use as arene tem-
plates in catalytic reaction has never been reported as far
as we know. The reaction of p-fluorotoluene with mor-
pholine was chosen as a model reaction (Table 1). When
Recently, we developed the first catalytic S Ar reaction of
N
nonactivated fluoroarenes with amines using a ruthenium
2
,3
catalyst (Scheme 1). The stoichiometric use of transi-
6
tion metal h -arene complex, such as chromium carbonyl
complex, had been a common protocol for the S Ar reac-
N
4
tion of electron-rich arenes, therefore, our results could
eliminate the stepwise process where the transition metal
must be attached and detached.5
[
Ru(benzene)Cl ] was used with PPh in refluxing 1,4-di-
2 2 3
oxane, the reaction did not proceed at all (entry 1). Next,
we examined a few silver salts for the preparation of cat-
ionic complexes, which are expected to induce facile are-
ne exchange. As a result, the desired aminated product 3
was obtained and AgOTf gave the best yield among them
Ru(cod)(2-methylallyl)2 (5 mol%)
DPPPent (7 mol%)
TfOH (10 mol%)
Et3SiH (1 equiv)
Et3N (1 equiv)
R3
F
H
N
R1
N
R2
+
R2
R3 dioxane, reflux, 24 h
R1
(
entries 2–4).7
5
equiv
1 equiv
We then screened phosphine ligands. As for monodentate
ligands, electron-rich monodentate phosphines, such as
P(p-MeC H ) and P(p-MeOC H ) gave comparable re-
Scheme 1 Our previous work on catalytic S Ar reaction
N
6
4 3
6
4 3
In our previous paper, however, we used thermally sensi- sults with PPh . In contrast, electron-deficient monoden-
3
tive ruthenium complex [Ru(cod)(2-methylallyl) ], DPP- tate phosphine P(p-FC H ) improved the yield up to 55%,
2
6
4 3
Pent [1,5-bis(diphenylphosphino)pentane], and strong but more electron-deficient P(p-CF C H ) did not give
3
6
4 3
acid (trifluoromethanesulfonic acid) for the preparation of better results (entries 5–8). Bidentate ligands, such as DP-
6
Ru h -fluoroarene complex, which is the key intermediate PB, DPPPent and DPPF, also facilitated the reaction but
6
in the S Ar reaction (complex 2 shown in Scheme 2).
the yields did not exceed that of P(p-FC H ) (entries 9–
N
6 4 3
1
1). For the further optimization, we examined organic
bases as HF scavenger and the addition of triethylamine
realized the yield of 60% (entries 12–14). Inorganic bases,
such as K CO and Na CO , were ineffective but molecu-
SYNLETT 2010, No. 17, pp 2601–2606
Advanced online publication: 30.09.2010
DOI: 10.1055/s-0030-1258774; Art ID: U07110ST
x
x
.x
x
.2
0
1
0
2
3
2
3
©
Georg Thieme Verlag Stuttgart · New York

2
602
M. Otsuka et al.
LETTER
Table 1 Screening of Reaction Conditions
[
Ru(benzene)Cl2]2 (2.5 mol%)
H
N
O
F
Ag salt (10.5 mol%)
ligand (12 mol%)
N
+
additive (1 equiv)
dioxane, reflux, 24 h
O
5
equiv
1 equiv
3
Entry
Ag salt
Ligand
PPh3
PPh3
PPh3
PPh3
Additive
Yield (%)
1
2
3
4
5
6
7
8
9a
–
–
–
–
–
–
–
–
–
–
–
–
NR
48
27
34
39
41
55
45
26
34
40
63
17
1
AgOTf
AgBF4
AgSbF6
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
P(p-MeC H )
4 3
6
P(p-MeOC H )
4 3
6
P(p-FC H )
4 3
6
P(p-CF C H )
4 3
3
6
DPPF
DPPB
1
1
1
1
1
1
0a
1a
2
DPPPent
P(p-FC H )
Et N
6
4
3
3
3
3
3
3
P(p-FC H )
TMEDA
pyridine
MS4A
6
4
4
P(p-FC H )
6 4
5b
P(p-FC H )
80
6
4
a
Diphosphine ligand (6 mol%) was used.
MS4A (40 mg) was used in the 0.4-mmol scale reaction. DPPF: 1,1-bis(diphenylphosphino)ferrocene, DPPB: 1,4-bis(diphenylphosphino)bu-
b
tane, TMEDA: N,N,N¢,N′-tetramethylethylenediamine.
8
9
lar sieves 4A (MS4A) promoted this reaction and the 4 and 5). In the case of sterically hindered o-fluorotolu-
highest yield of 80% was achieved (entry 15).
ene, the yield was moderate (entry 6). Methoxy-substitut-
ed fluoroarenes were also available for this reaction
With the optimized conditions in hand, we then examined
the substrate scope in the present catalytic system
(
entries 7–9). Even a fluoroarene bearing two methoxy
groups also realized a catalytic reaction (entry 10). Dime-
thylamino group is more electron-donating than methoxy
group, but it could be furnished into the substrate (entry
(
Table 2). Fluorobenzene, m-fluorotoluene, and fluoroxy-
lene underwent S Ar reaction and furnished the corre-
N
sponding products in high yields (entries 1–3).
Fluoroarenes bearing ethyl group and allyl group also
achieved good yields but double-bond isomerization oc-
curred to give styrene derivative in the latter case (entries
10,11
1
1).
Table 2 Screening of Fluoroarenes in the Reaction with Morpholine
[
Ru(benzene)Cl2]2 (2.5 mol%)
AgOTf (10.5 mol%)
P(p-FC6H4)3 (12 mol%)
H
N
O
F
N
R
+
4
Å MS, dioxane, reflux, 24 h
O
R
5
equiv
1 equiv
Entry
Substrate
Product
Yield (%)
82
O
F
1
N
Synlett 2010, No. 17, 2601–2606 © Thieme Stuttgart · New York

LETTER
SNAr Reaction of Nonactivated Fluoroarenes with Amines
2603
Table 2 Screening of Fluoroarenes in the Reaction with Morpholine (continued)
[
Ru(benzene)Cl2]2 (2.5 mol%)
AgOTf (10.5 mol%)
P(p-FC6H4)3 (12 mol%)
H
N
O
F
N
R
+
4
Å MS, dioxane, reflux, 24 h
O
R
5
equiv
1 equiv
Entry
Substrate
Product
Yield (%)
83
O
F
N
2
O
F
N
3
81
O
F
F
4
5
6
7
N
70
68a
44
50
O
N
O
F
N
O
F
N
OMe
OMe
O
F
N
8
9
57
55
30
47
OMe
OMe
O
F
N
MeO
MeO
O
F
OMe
N
OMe
1
0
1
OMe
OMe
O
F
N
1
NMe2
NMe2
a
E:Z = 18:1.
Synlett 2010, No. 17, 2601–2606 © Thieme Stuttgart · New York

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M. Otsuka et al.
LETTER
[
Ru(benzene)Cl2]2 (5 mol%)
H
N
AgOTf (21 mol%)
X
F
P(p-FC6H4)3 (24 mol%)
N
+
4
Å MS, dioxane, reflux, 24 h
X
5
equiv
1 equiv
X = CH2, NMe
X = CH2: 61%
NMe: 63%
Scheme 3 SNAr reaction of fluorotoluene with piperidine and N-methylpiperazine
The results of the reactions of other amines with p-fluoro-
toluene are shown in Scheme 3. Piperidine and N-meth-
ylpiperazine were also good substrates and gave the
corresponding products in good yields (Scheme 3).
F
F
Ru
Ru
(
p-FC6H4)3P
OTf
P(p-FC6H4)3
(p-FC6H4)3P
OTf
We supposed that the reaction proceeds via cationic Ru
P(p-FC6H4)3
6
h -arene complexes A, B and C, which possess arene, two
A
B
phosphines and a trifluoromethanesulfonate group as
weakly coordinating ligands (Scheme 4). We actually
confirmed the reaction intermediates by ESI mass analy-
detected by MS ([M-TfOH]+)
detected by MS ([M-TfOH]+)
H
N
6
sis. Ru h -benzene complex A was prepared from
[
Ru(benzene)Cl ] , AgOTf and P(p-FC H ) in 1,4-diox-
O
N
2
2
6
4 3
1
2,13
ane.
It was treated with excess amounts of p-fluorotol-
O
Ru
uene, and heated at reflux for four hours. Then the
resulting mixture was analyzed by ESI mass analysis. As
(
p-FC6H4)3P
OTf
P(p-FC6H4)3
6
a result, the expected ruthenium h -fluorotoluene com-
C
1
3
detected by MS ([M-TfOH]+)
plex B was detected (Figure 1). Addition of morpholine
6
converted the complex B into the ruthenium h -morpholi-
Scheme 4 Proposed and confirmed scheme via cationic ruthenium
notoluene complex C, which was also detected
6
h -arene complexes
1
3
(Figure 2).
Figure 1 Detection of complex B prepared by arene exchange with complex A
Synlett 2010, No. 17, 2601–2606 © Thieme Stuttgart · New York

LETTER
SNAr Reaction of Nonactivated Fluoroarenes with Amines
2605
Figure 2 Detection of complex C prepared by S Ar reaction of complex B with morpholine
N
In conclusion, we have developed a facile ruthenium-
23, 1230.
(
4) (a) Semmelhack, M. F.; Chlenov, A. Transition Metal Arene
p-Complexes in Organic Synthesis and Catalysis; Kündig,
E. P., Ed.; Springer-Verlag: Berlin / Germany, 2004, 43.
catalyzed S Ar reaction using dichloro(benzene)rutheni-
N
1
4
um(II) dimer as a catalyst precursor. The cationic spe-
cies were generated by the addition of silver salt in the
(b) Semmelhack, M. F. In Comprehensive Organometallic
presence of P(p-FC H ) , and the reaction key intermedi-
6
4 3
Chemistry II, Vol. 12; Abel, E. W.; Stone, F. G. A.;
Wilkinson, G., Eds.; Pergamon: New York, 1995, 979.
ates were directly generated in situ by arene exchange
with fluoroarenes. The reaction of various fluoroarenes
with cyclic amines efficiently proceeded in the coexist-
ence with MS4A and the corresponding aminated prod-
ucts were obtained in good to high yields.
(5) For recent examples of the S Ar reactions of nonactivated
N
fluoroarene with amines using a stoichiometric amount of
transition metals, see: (a) Braun, W.; Calmuschi-Cula, B.;
Englert, U.; Höfener, K.; Alberico, E.; Salzer, A. Eur. J.
Org. Chem. 2008, 12, 2065. (b) Kamikawa, K.; Kinoshita,
S.; Furusyo, M.; Takemoto, S.; Matsuzaka, H.; Uemura, M.
J. Org. Chem. 2007, 72, 3394. (c) Baldoli, C.; Maiorana, S.;
Licandro, E.; Casiraghi, L.; Zinzalla, G.; Seneci, P.;
Magistris, E. D.; Paio, A.; Marchioro, C. J. Comb. Chem.
2003, 5, 809.
Acknowledgment
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.
(6) Takaya, J.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 5756.
(
7) Dichloro(p-cymene)ruthenium(II) dimer was also a good
precursor and product 3 was obtained in the comparable
yield (49%).
Reference and Notes
(
8) Molecular sieves were suggested to operate as solid base:
(
1) Strong anionic nucleophiles, such as lithium amides and
(
1
a) Okachi, T.; Fujimoto, K.; Onaka, M. Org. Lett. 2002, 4,
667. (b) Ono, F.; Ohta, Y.; Hasegawa, M.; Kanemasa, S.
alkoxides, were used in S Ar reaction of nonactivated
N
haloarenes: (a) Huisgen, R.; Sauer, J. Chem. Ber. 1958, 91,
Tetrahedron Lett. 2009, 50, 2111.
1453. (b) Wittig, G.; Schmidt, H. J.; Renner, H. Chem. Ber.
(
9) When 1-allyl-4-fluorobenzene was submitted under the
previous conditions (ref. 2), the yield of the styrene
derivative was low (21%). Moreover, a hydrogenated by-
product also formed, because silane was used as an additive.
1
962, 95, 2377. (c) Rodriguez, J. R.; Agejas, J.; Bueno,
A. B. Tetrahedron Lett. 2006, 47, 5661.
(
(
2) Otsuka, M.; Endo, K.; Shibata, T. Chem. Commun. 2010, 46,
336.
(
10) Excess amounts of fluoroarenes would be needed for
efficient arene exchange: when 1-dimethylamino-4-
fluorobenzene (3 equiv) was used, the yield significantly
decreased to 30%.
3) There had been limited examples of catalytic S Ar reaction
N
with oxygen nucleophiles using modified cyclopentadienyl
rhodium complexes: (a) Houghton, R. P.; Voyle, M.; Price,
R. J. Chem. Soc., Perkin Trans. 1 1984, 925. (b) Goryunov,
L. I.; Litvak, V. V.; Shteingarts, V. D. Zh. Org. Khim. 1987,
Synlett 2010, No. 17, 2601–2606 © Thieme Stuttgart · New York

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606
M. Otsuka et al.
LETTER
(
(
11) When the reaction was examined at the higher reaction
Schlenk tube. To this container, the mixture of
[Ru(benzene)Cl ] (5.0 mg, 0.010 mmol) and AgOTf (10.8
temperature (160 °C), the yield decreased to 25%.
12) [Ru(p-cymene)(OTf)(dppben)]OTf [DPPBen: 1,2-
bis(diphenylphosphino)benzene] was synthesized and
characterized by X-ray single crystal structural analysis:
2
2
mg, 0.042 mmol) in acetone was transferred with a syringe
filter. After acetone was excluded, a 1,4-dioxane solution
(0.10 mL) of P(p-FC H ) (15.2 mg, 0.048 mmol), p-
6
4 3
(
2
2
a) Oe, Y.; Ohta, T.; Ito, Y. Sci. Eng. Rev. Doshisha Univ.
009, 50, 30. (b) Oe, Y.; Ohta, T.; Ito, Y. Tetrahedron Lett.
fluorotoluene (220 mL, 2.0 mmol) and morpholine (35 mL,
0.40 mmol) was added. The reaction mixture was stirred
under reflux for 24 h, then MS4A was filtered off. After the
filtrate was evaporated, the crude products were purified by
thin-layer chromatography (hexane–AcOEt = 10:1) to give
analytically pure 3 (80%).
010, 51, 2806.
+
(
(
13) The detected isotopic patterns of A, B and C ([M – TfOH] )
by ESI–MS matched with the theoretical isotope patterns.
14) Typical Procedure (Entry 15 in Table 1): Under an
atmosphere of argon, MS4A (40 mg) was dried up in a
Synlett 2010, No. 17, 2601–2606 © Thieme Stuttgart · New York

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