Silver-catalyzed intramolecular aminofluorination of activated allenes

Article abstract of DOI:10.1002/anie.201103225

A nice combination: The intramolecular oxidative aminofluorination of allenes using silver catalysis and FN(SO₂Ph)₂ as the fluorinating reagent has been developed. This reaction represents an efficient method for the synthesis of various 4-fluoro-2,5-dihydropyrrole compounds. Further transformation provided the corresponding fluorinated pyrrole derivatives in good yields (see scheme).

Full text of DOI:10.1002/anie.201103225

Communications
DOI: 10.1002/anie.201103225
Organofluorine Chemistry
Silver-Catalyzed Intramolecular Aminofluorination of Activated
Allenes**
Tao Xu, Xin Mu, Haihui Peng, and Guosheng Liu*
The replacement of hydrogen by fluorine in organic mole-
cules frequently leads to dramatic changes of their properties,
such as solubility, metabolic stability, and bioavailability.[1]
Among these organofluorine molecules, fluorinated hetero-
cycles have been extensively used as important building
blocks for the synthesis of anticholinergic, antiemetic, and
antispastic drugs as well as enzyme inhibitors.[2] Thus, the
efficient synthesis of these fluorinated heterocycles has
attracted more attention.[3,4]
Recently, several research groups have described methods
for the efficient synthesis of aryl fluoride using transition-
metal catalysts.[5,6] For instance, Buchwald and co-workers
reported a palladium-catalyzed cross-coupling reaction of
aryl triflate and CsF.[5a] The groups of Sanford and Yu
explored the palladium-catalyzed oxidative fluorination of
have been applied to catalyze the fluorination of alkynes.[7]
Sadighi and co-workers documented the hydrofluorination of
alkynes,[7a] and the groups of Gouverneur[7b] and Nevado[7c–d]
À
each reported the fluorination of alkynes to create vinyl C F
bond. This approach involved an oxidative fluorination of
vinyl–Au species bearing an adjacent carbonyl group using
SelectFluor as fluorinating reagent.
Recent studies on intramolecular aminofluorination of
À
alkenes by our group demonstrated that the Csp3 F bond
formation can be achieved through oxidative cleavage of the
Csp3 Pd bond.[8] Thus, we decided to investigate the reactivity
À
of allenes toward aminofluorination, which not only repre-
sents an efficient strategy to build up a heterocyclic skeleton
bearing a vinyl fluoride moiety, but also provides a good
À
opportunity to study the oxidative fluorination of vinyl C M
arenes through C H bond activation by using electrophilic
species.[9] Herein, we reported a novel silver-catalyzed intra-
molecular aminofluorination of allenes for the synthesis of 4-
À
fluorinating reagents 1 or 2 (Scheme 1).[5b–c] Ritter and co-
workers reported a silver-catalyzed fluorination of aryl
stannanes with SelectFluor.[6] Meanwhile, Au complexes
À
fluoro-2,5-dihydropyrroles, in which the vinyl C Ag bond is
[10,11]
À
cleaved using NFSI to afford vinyl C F bonds.
In
addition, further convenient aromatization of fluorinated
dihydropyrroles readily afforded the corresponding 4-fluoro-
pyrrole derivatives (Scheme 1).
The initial investigation focused on the cyclization of
allene 3a using a Pd catalyst. Unfortunately, no desired
fluorinated product 4a was observed under our previous
reaction condition AgF/PhI(OPiv)2, and only a trace amount
of hydoramination product 5a was detected (Table 1,
Table 1: Screening results of reaction conditions.[a]
Entry Catalyst (mol%) [F]/[O] (equiv)
4a [%][b] 5a [%][b]
Scheme 1. The concept of aminofluorination of allenes.
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
1
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
–
AgF (2)/PhI(OPiv)2 (2)
NFSI (3)
AgF (2)/NFSI (3)
AgF (2)/NFSI (3)
NFSI (3)
0
0
7
0
2[c]
3
8
84
5
57
1
4
4
5
[*] T. Xu, X. Mu, H. Peng, Prof. Dr. G. Liu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
AgF (10)
6
7
AgNO3 (10)
AgNO3 (20)
AgNO3 (20)
–
NFSI (3)
NFSI (1.5)
NFSI (1.5)
NFSI (1.5)
84
88
0
1
1
5
8[d]
9
354 Fenglin Road, Shanghai, 200032 (China)
E-mail: gliu@mail.sioc.ac.cn
0
0
10
11
12
13
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
SelectFluor (1.5)
XeF2 (1.5)
1 (1.5)
17
5
0
53
69
26
80
[**] We are grateful for the financial support from the Chinese Academy
of Science, the National Natural Science Foundation of China
(20821002, 20872155, 20972175, and 20923005), the National Basic
Research Program of China (973-2011CB808700), and the Science
and Technology Commission of the Shanghai Municipality
(08dj1400100).
2 (1.5)
0
[a] Reactions were conducted on a 0.1 mmol scale. [b] Yield determined
by 1H NMR spectroscopy with N,N-dimethyl trifluoroacetamide as an
internal standard. [c] Bathocuproine (15 mol%) as ligand. [d] Without
K2CO3. Piv=pivaloyl, TS=4-toluenesulfonyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103225.
8176
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Angew. Chem. Int. Ed. 2011, 50, 8176 –8179

entry 1).[8] An application of an alternative catalytic system
for aminofluorination of styrenes using NFSI[12] also failed
to proceed (entry 2). Combination of the above two
reaction systems using NFSI instead of PhI(OPiv)2 as the
oxidant, afforded a small amount of aminofluorination
product 4a (entry 3). Surprisingly, control experiment in
the absence of Pd catalyst significantly improved the yield
of 4a to 84% yield and the hydroamination reaction was
inhibited (entry 4). These results indicate that the reaction
is mediated by a stoichiometric amount of AgF rather than
Pd complex. Further studies on the catalytic reaction were
carried out. The use of AgNO3 (20 mol%) proved to give
the best yield (entries 5–7). Notably, both AgNO3 and
K2CO3 are crucial for the successful transformation
(entries 8 and 9).[13] Other electrophilic fluorinating
reagents, such as SelectFluor, XeF2, and N-fluoropyridi-
nium 1 and 2, were ineffective for aminofluorination.[14]
Instead, the hydroamination product was the dominated
product (entries 10–13). Although formation of the vinyl
I
À
C F bond mediated by Ag has been reported, the
fluorination only occurs with toxic vinyl stannanes using
expensive XeF2 as the fluorinating reagent.[15]
Under standard condition, the substrate scope of the
aminofluorination reaction was investigated (Scheme 2).
The effect of having a protection group on the nitrogen
atom was firstly examined. Compared to allene 3a with a
4-toluenesulfonyl protecting group, the substrate having
carbamate did not yield aminofluorination product 4b.
The substrates with various substituents at the C3-position
were further studied. The results in Scheme 2 show that
substrates possessing an electron-withdrawing or aromatic
group are suitable reactants (4c–4r). Meanwhile the allene
substrates with alkyl group (4s–4t) gave low yields (35%
and 28%, respectively).[16] Among them, the allene
substrates with an electron-withdrawing group at C3
exhibited very good reactivity, and those reactions
afforded the corresponding products 4c–4k in good to
excellent yields. In addition, a substrate with three
substituents still had a very good reactivity to generate
fluorinated product 4j in 83% yield. In contrast, the
substrates with the aryl group at C3 also smoothly
underwent aminofluorination to generate products 4l–4r
but in moderate yields. Finally, when the substrates
bearing one more tethered carbon atom between the
allene and amine, the reactions also proceeded very well
and afforded six-membered products 4u and 4v in 70%
and 52% yield, respectively.
Scheme 2. Silver-catalyzed aminofluorination of allenes. Reaction condi-
tions were the same as for Table 1, entry 7. The yields of isolated product
are given. [a] NFSI (3 equiv) and K2CO3 (4 equiv). [b] Starting material 3j is
a mixture of two isomers (d.r. 1:1). Bn=benzyl, Boc=tert-butoxycarbonyl.
Subsequently, a study on the aromatization of 4-
fluoro-2,5-dihydropyrrole compounds were undertaken to
synthesize fluorinated pyrrole derivatives.[17,18] Results
shown in Scheme 3 suggest that the aminofluorination
products 4 can be efficiently converted into 4-fluoropyr-
roles 6 by treatment with the strong base KOtBu, or
sequential oxidation by DDQ and removal of the protect-
ing group by EtONa—no defluorination reaction was
observed in these reactions.
Scheme 3. The aromatization of 4-fluoro-2,5-dihydropyrolles. Condition A:
KOtBu (3 equiv), DMSO, RT or 508C for 2 h; Condition B: 1) DDQ
(3 equiv), benzene, 1108C, 5 h; 2) EtONa (5 equiv), EtOH, 308C, 1 h. The
Owing to the rarity of silver-catalyzed redox catalytic
system,[6,19] mechanistic details of this aminofluorination
remains elusive at the moment. However, our preliminary yields of isolated product are given.
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Communications
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Scheme 4. The proposed mechanism for silver(I)-catalyzed amino-
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À
study shows that oxidative cleavage of the vinyl C Ag bond
À
may be involved in the C F bond formation (Scheme 4).
During optimization of the reaction condition, the observa-
tions of aminofluorination and hydroamination product
formation suggest that the reaction might involve a vinyl–
sliver intermediate I generated from silver-catalyzed amina-
À
tion of allene. To probe the mechanism of C F bond
formation, a vinyl–silver complex I that is generated in situ
from substrate 7 by treatment with nBuLi and AgNO3,[20] was
treated with NFSI in the presence of K2CO3, and amino-
fluorination product 4m was formed in 32% yield
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À
À
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electron redox chemistry.[6a] Moreover, addition of 2,6-di-tert-
butylphenol or 2,2,6,6-tetramethylpiperidine-1-oxyl as free
radical scavengers did not obviously influence the fluorina-
tion,[23] thus suggesting that a radical pathway is unlikely.
In conclusion, a novel silver-catalyzed intramolecular
oxidative aminofluorination of allenes has been reported, in
which NFSI functioned as the fluorinating reagent. This
methodology provided an efficient route to synthesize 4-
fluoro-2,5-dihydropyrrole compounds, and this type of prod-
uct can be conveniently converted into fluorinated pyrrole
derivatives. Further mechanistic study is in progress.
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Received: May 11, 2011
Published online: July 14, 2011
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Keywords: allenes · aminofluorination ·
fluorinated heterocycles · oxidation · silver
.
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À
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À
[11] For an example on the cleavage of a C Ag bond using NCS to
À
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À
[13] Other transition-metal complexes, such as CuBr, [(PPh3)AuCl]
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[20] The vinyl C Ag complex can be generated in situ from a vinyl
I
À
C Li complex and a Ag complex by transmetalation, for details
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[16] Only a trace amount aminofluorination product was obtained in
the reaction of substrate N-(4-phenylbuta-2,3-dienyl)-N-tosyl-
amine.
[17] For synthesis of fluoropyrroles, see: a) R. Surmont, G. Verniest,
F. Colpaert, G. Macdonald, J. W. Thuring, F. Deroose, N.
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[21] The reaction also afforded the desired aminofluorination
product 4m in the absence of K2CO3, but in lower yield
(17%). In addition, no fluorinated product 4m was observed in
the absence of AgNO3. For details, see the Supporting Informa-
tion.
[22] The electrophilic fluorinating reagents can be used as fluorinat-
ing resource, as well as oxidant, see the following review: K. M.
Engle, T.-S. Mei, X. Wang. J.-Q. Yu, Angew. Chem. 2011, 123,
1514 – 1528; Angew. Chem. Int. Ed. 2011, 50, 1478 – 1491.
[23] Reactions of 3l afforded aminofluorination product 4l in 57%
or 50% yield in the presence of BHT (1 equiv) or TEMPO
(1 equiv), respectively.
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