Iron-catalyzed domino indole fluorination/allenic aza-Claisen rearrangement

Article abstract of DOI:10.1039/c6cc02012g

The synthesis of 2-allenyl-2-substituted-3,3-difluoroindolines has been accomplished, taking advantage of the reaction between N-allenyl-indoles and Selectfluor under iron catalysis.

Full text of DOI:10.1039/c6cc02012g

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Iron-catalyzed domino indole fluorination/allenic aza–Claisen
rearrangement
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
a
a
Benito Alcaide,* Pedro Almendros,* Sara Cembellín, Teresa Martínez del Campo,* and
a
Alejandro Muñoz
DOI: 10.1039/x0xx00000x
www.rsc.org/
The synthesis of 2-allenyl-2-substituted-3,3-difluoroindolines has
been accomplished taking advantage of the reaction between N-
allenyl-indoles and Selectfluor under iron catalysis.
a) Cascades C3-difluorination/C2-functionalisation of indoles (previous work)
R1
F
R1
R1
F F
F
NFSI
NFSI
O
N
R2
N
R2
N
O
refer. 4e
refer. 4d
Fluoroorganic molecules feature peculiar biological activities
1
because of their improved lipophilicity and metabolic stability. The
n = 0, 1
( )
n
difluoromethyl moiety is particularly relevant due to its isopolar and
2
b) Claisen-type rearrangement of indoles (previous work)
R2
isosteric nature with the C(CH
3
)
2
, C=O or hydroxyl groups. On the
R2
O
other hand, the dearomatization of indoles has received
considerable attention in organic synthesis because of the
3
3
R1
R O C
R1
R O C
2
2
Pd(SbF6)2
refer. 6c
•
3
bioactivity of the resulting indolines. Considerable efforts have
N
H
O
N
H
been devoted to the fluorination of functionalised indoles [Scheme
4
1
, Eq. (1a)], because this methodology is a direct entry to diverse
c) Cascade C3-difluorination/Claisen-type rearrangement of indoles (this work)
R1 R1 R1
fluorinated indoline structures. However, to the best of our
knowledge, there is lack of studies of the fluorofunctionalisation of
the allenic indole moiety. This is rather surprising taking into
F
F F
F
R2
R2
5
R2
account the rich chemistry of the allene moiety.
N
N
N
H
As far as we know, the allene N1–C2 Claisen rearrangement of
indoles has not been previously reported, being the C2–C3 Claisen
rearrangement of indoles to form allenyl oxindoles the only related
•
3
•
R
6
Scheme 1 Indole as platform for difluorination and allenic Claisen-type
precedent [Scheme 1, Eq. (1b)]. We envisioned that allenic
rearrangement: Previous and current proposals.
fluorinated indolines could be formed if a rearrangement step is
associated to the fluorination sequence. This would be a highly
valuable transformation because an additional allene moiety would
be installed in the product serving as a platform for further
functionalization. Considering the important properties of both
polyfluorinated molecules as well as fused indolines, the β-amino
Our initial efforts focused on the application of electrophilic
fluorination to the selective construction of difluoroindolines having
a quaternary center. Allenic indole 2a was chosen as a model
substrate for the fluorofunctionalisation reaction. Attempts to
profitably generate a difluoroindoline structure from 2a by using
7
1
,2-diene moiety of 2-allenyl-2-substituted-3,3-difluoroindolines
Selectfluor without additives failed. A more promising result was
may be a useful handle for cyclization reactions, and consequently
encountered through the addition of sodium bicarbonate, although
the more of the starting material kept unreacted. Besides, 3,3-
difluoroindoline 3a was isolated along with a minor component, the
unstable 3-fluoroindole 4a (Scheme 2).
for the achievement of difluorinated N-fused indolines. Herein we
report
an
iron-catalyzed
tandem
process,
namely,
6
fluorination/allenic aza–Claisen rearrangement which forms 2-
allenyl-2-substituted-3,3-difluoroindolines [Scheme 1, Eq. (1c)].
F
F
Selectfluor (200 mol%)
F
unreacted
+
+
N
Ph
N
H
Ph
N
Ph 2a (60%)
3
NaHCO (200 mol%)
CH CN, rt, 24 h
3
•
•
•
2
a
3a (20%)
4a (8%)
Selectfluor (200 mol%)
CH CN, rt, 24 h
starting material
3
Scheme 2 Reaction of 1-allenyl-2-phenyl-indole 2a with Selectfluor.
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To mitigate the poor reactivity of allenylindole 2a as well as the fluorination/allenic aza–Claisen rearrangement. The steric
formation of intermediate 4a, we intended the activation of the properties of the substituents in the indole moiety did not affect
allene moiety through Lewis acid catalysis (Table 1). Initially, in significantly the reactivity, with tert-butylphenyl and naphthalen-2-
order to get a better result in the formation of product 3a, we yl functionalized indoles 2e,f performing well in the
8
attempted a gold-catalyzed reaction. Fortunately, the addition of difluoroindolines 3e,f formation. Besides, no matter whether
[
(Ph P)AuNTf ] (5 mol%) allow us to efficiently transform in just one electron-withdrawing (such as 4-ClC H and 4-FC H ) or electron-
3
2
6
4
6
4
6 4
hour substrate 2a into 2-allenyl-2-phenyl-3,3-difluoroindoline 3a in donating groups (such as 4-MeC H ) are introduced to the 2-aryl
a totally selective fashion (Table 1, entry 1). It was interesting at this substituent as far as conversions are concerned. The presence of
point to test the catalytic abilities of different metallic salts. The substituents at the benzene fused ring provided the same reactivity
difluorination/rearrangement sequence could also be catalyzed by pattern independently of the electronic nature, such as in
PtCl
2
, InCl
3
, and HfCl
4
but with slightly diminished effectiveness. substrates 2g,h, bearing EDG, or in substrates 2i–k, bearing EWG.
gave similar results to the Gagosz’ Taking into account all the examples of Scheme 3, the reaction
Interestingly, the use of Fe(OTf)
3
catalyst (Table 1, entry 5). Taking into account the inexpensiveness proved to be functional group tolerant. Complete conversion was
1
and eco-friendliness of iron(III) salts, we decided to develop further observed by TLC and H NMR analysis of the crude reaction
the Fe(OTf)
200 mol%) was used as the fluorination reagent, the spots on the detected. Unfortunately, some decomposition was observed on
tin-layer chromatographic (TLC) plate of the reaction mixture look sensitive fluoroindolines during purification by flash
3
-catalyzed fluoro-rearrangement. When Selectfluor mixtures of indole-tethered allenes 2, and no side-products were
(
3
very clean. However, alternative fluorine sources such as N- chromatography, which may be responsible for the moderate
fluorobenzenesulfonimide afforded poorer results. Among all the isolated yields. Nicely, using deactivated silica gel during
solvents examined, acetonitrile proved to be the best choice, chromatographic purification resulted in a detectable (5–10%)
affording product 3a in a good 81% yield (Scheme 3). The metal- improvement in the isolated yields of products 3 and 5. Even more
catalysed reaction between indole 2a and Selectfluor in absence of interestingly, nitro- and cyano-derivatives 3j and 3k did not require
3
NaHCO did not go to completion, thus highlighting the importance further purification and were obtained in excellent yields.
of the base for the success of the difluoroindoline formation.
F
R2
Selectfluor (200 mol%)
Fe(OTf)3 (5 mol%)
R2
Table 1. Selective fluorination/rearrangement sequence of allenyl indole 2a
F
under modified metal-catalyzed conditions.
R1
R1
N
N
H
NaHCO
3
(200 mol%)
F
CH CN, rt, 0.5 h
metallic salt (5 mol%)
Selectfluor (200 mol%)
3
•
F
•
N
Ph
N
Ph
NaHCO
3
(200 mol%)
2a R1 = Ph, R2 = H
3
a (83%)
H
2b R1 = 4-ClC H , R = H
2
CH CN, rt, 0.5 h
3
3b (66%)
3c (40%)
3d (48%)
3e (43%)
3f (55%)
3g (52%)
3h (42%)
3i (44%)
6
4
•
2c R
1
= 4-FC H , R
2
= H
•
6 4
d R1 = 4-MeC H , R = H
2
2
6
4
2
a
3a
e R1 = 4-tBuC H , R = H
2
2
6
4
a
2f R1 = naphthalen-2-yl, R2 = H
Entry
metallic salt
Yield
g R1 = 4-MeC H , R = Me
2
2
2
2
2
2
6
4
h R1 = 4-MeC H , R = OMe
2
6
4
[
(Ph
3
P)AuNTf
2
]
83%
1
2
3
4
i R1 = 4-MeC H , R = F
2
6
4
j R1 = Ph, R2 = NO2
k R1 = Ph, R2 = CN
3j (92%)a
3k (97%)a
PtCl
2
71%
63%
64%
81%
InCl
3
Scheme 3 Synthesis of 2-aryl-2-(buta-2,3-dienyl)-3,3-difluoroindolines 3a–i.
a
Chromatographic purification was not necessary.
HfCl
4
3
Despite its usefulness, the catalytic C–F bond formation at sp
Fe(OTf)
3
5
carbon centres using electrophilic reagents remains a synthetic
3
a
challenge, because incorporation of fluorine into sp –hybridized
Yield of pure, isolated product with correct analytical and spectral data.
1
0
carbons is achieved through nucleophilic fluorination reactions.
Originally, we were attempting the iron-catalysed
difluorofunctionalisation/rearrangement sequence of N-
To explore the effects of various substrates on
fluorofunctionalisation reactions, a number of new indole-tethered
allenes were synthesized. As shown in Scheme S1 (see ESI†),
starting materials, allenes 2a–m were made from the corresponding
terminal alkynes 1a–m by treatment with paraformaldehyde in the
presence of diisopropylamine and copper(I) bromide (Crabbé
allenylindole 2l under Fe(III) catalysis (5 mol%) in the presence of
Selectfluor (200 mol%). The expected product 3l was the minor
component, but, surprisingly, a 20% yield of the trifluoroindoline 5l
was obtained. Consequently, our studies focused on developing a
more efficient transformation. The reaction product 5l could only
be obtained in reasonable yield using a higher fluorination reagent
loading. Worthy of note, after considerable experimentation we
were able to find suitable conditions for the controllable formation
of both type of adducts 3 and 5 (Scheme 4). 1-Allenyl-2-methyl-
9
reaction).
With an optimized fluorofunctionalisation system in hand, we
investigated the behaviour of 1-(buta-2,3-dienyl)-2-aryl-1H-indoles
2
b–i. As shown in Scheme 3, all 1-allenyl-2-aryl-substituted
substrates exhibited excellent reactivity in the domino indole
3 3
indoles 2 on exposure to the system Fe(OTf) (5 mol%), NaHCO
2
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o
(
200 mol%), and Selectfluor (200 mol%) in acetonitrile at 0 C, exclusively lead to 2-aryl-3,3-difluoroindoline adducts 3, the 2-
exclusively afforded 2-methyl-3,3-difluoroindolines 3 in just 5 methyl counterparts produce 2-fluoromethyl-3,3-difluoroindoline
minutes. By contrast, the reaction of substrates 2 with Fe(OTf) (5 products 5.
mol%), NaHCO (350 mol%), and Selectfluor (350 mol%) in
3
3
NaHCO
3
acetonitrile at room temperature, did allow the sole formation of 2-
fluoromethyl-3,3-difluoroindolines 5. Unfortunately, compound 2n,
with a methoxy substituent at the C5 indole moiety, only led to
several unidentified products upon treatment with Selectfluor.
Nitro adduct 5q did not require further purification and was
obtained in nearly quantitative yield.
R2
[N]F
R2
H
R2
[N]F
F
F
R1
R
1
R1
N
N
N
2
(R1 = Ar)
•
6
•
H
2
CO
3
4
•
Selectfluor = [N]F
F
Selectfluor (200 mol%)
Selectfluor (350 mol%)
Fe(OTf) (5 mol%)
F
R
R
R
F
Fe(OTf)
NaHCO3 (200 mol%)
CH
CN, 0 oC, 5 min
3
(5 mol%)
3
F
R2
F
formal allenic R2
aza-Claisen
F
R2
MLn
F
F
N
H
N
NaHCO3 (350 mol%)
CH CN, rt, 5 min
N
H
F
F
R1
F
3
3
R1
R1
•
•
N
–ML
n
N
N
•
H
+
H
•
3
3
3
3
3
3
l (47%)
2l R = H
5l (48%)
m (48%)
n (0%)
2m R = Me
2n R = OMe
2o R = Cl
5m (51%)
5n (0%)
3
•
7-M
ML
n
7
•
M = metal
o (41%)
p (42%)
q (57%)
5o (45%)
5p (54%)
2p R = Br
a
Scheme 5 Tentative mechanistic explanation for the Selectfluor-promoted
metal-catalyzed synthesis of 2-(allenyl)-2-aryl-3,3-difluoroindolines 3.
2q R = NO
2
5q (91%)
Scheme 4 Synthesis of 2-(buta-2,3-dienyl)-3,3-difluoro-2-methyl indolines 3
and 2-(buta-2,3-dienyl)-2-fluoromethyl-3,3-difluoroindolines 5.
Chromatographic purification was not necessary.
NaHCO
3
H
R2
[N]F
R1
R2
R2
[N]F
N
F
a
F
1
R1
1
N
N
R
We monitored the reaction of N-allenylindole 2b by both H NMR
1
9
and
intermediates (Figures S1 and S2, see ESI†). Because of the
paramagnetic character of Fe(OTf) we did select [(Ph P)AuNTf ] as
F NMR spectroscopy in order to track the reaction
2
(R1 = Me)
•
6
•
H
2
CO
3
4
•
Selectfluor = [N]F
3
3
2
F
F
F
catalyst. Unfortunately, results were inconclusive. Although merely
speculative at this time, the iron-catalysed generation of 2-(allenyl)-
R2
R2
R2
F
–H
F[N]
F
F
N
N
N
2-aryl-3,3-difluoroindolines 3 should proceed as outlined in Scheme
H
5. Accordingly, we initially propose a Selectfluor-assisted indole
•
•
•
monofluorination to form 2-substituted-3-fluoroindoles
represented by intermediate 6. Taking into account that the
reaction does not work without NaHCO , it may be safe to propose
that NaHCO should act as a base to facilitate the deprotonation of
iminium species 8 to give the aromatic 3-fluoroindoles 4.
4
as
9
8
7
3
F
F
F
R2
F
R2
F
formal allenic R2
aza-Claisen
3
ML
n
F
1
1,12
After
F
F
F
N
N
–MLn
N
H
delivering the first fluorine atom, again Selectfluor attacks the
indole C2–C3 double bond to form difluorospecies 7. This attack
occurs because of the stability of the resulting intermediate
iminium cation 7. Next, the metallic catalyst and 7 forms metal-
coordinate allene 7-M, further inducing a formal allenic aza–Claisen
rearrangement, which liberates 2-substituted-2-(buta-2,3-dienyl)-
•
+
H
1
0
10-M
M = metal
MLn
5
•
•
Scheme 6 Tentative mechanistic explanation for the Selectfluor-promoted
metal-catalyzed synthesis of 2-(allenyl)-2-fluoromethyl-3,3-difluoroindolines
5
.
3,3-difluoroindolines 3 with concomitant regeneration of the
F
F F
catalytic species.
F
5 mol % PdCl2
DMF, rt, 24 h
To investigate the reversibility of the fluorination/rearrangement
process, 2-(allenyl)-2-phenyl-3,3-difluoroindoline 3a was treated
under metal-catalyzed conditions. Interestingly, it was found that 1-
R
Br
+
R
N
N
H
•
(buta-2,3-dienyl)-3-fluoro-2-phenyl-1H-indole 4a was produced,
which may point to formal retro-allenic aza-Claisen
a
3a R = Ph
11a (50%)
11b (46%)
11l (32%)
3
3
b R = 4ClC H
rearrangement process, with the concomitant formation of 3-
fluoro-2-phenyl-1H-indole, in which a N–C bond cleavage has
occurred (Scheme S2, see ESI†). This outcome demonstrated that
the fluorination/rearrangement sequence had a certain degree of
reversibility under the promotion of [(Ph P)AuNTf ] or Fe(OTf) .
6
4
l R = Me
Scheme 7 Synthesis of 10,10-difluoro-tetrahydropyrido[1,2-a]indoles 11 and
2.
1
3
2
3
A related pathway for the iron-catalysed generation of 2-
N-Fused indolines are widely spread natural products
1
3,14
(
allenyl)-2-fluoromethyl-3,3-difluoroindolines
5
is outlined in which exhibit relevant biological properties.
Owing to the
Scheme 6. A similar scenario to the first and second fluorination can efficacy and functional group tolerance of transition metal
be postulated for the third fluorination, through the attack of catalyzed coupling reactions in forming C–heteroatom bonds
Selectfluor to the enamine double bond of 9 to form iminium starting from allenes, we envisioned that our 2-allenyl-3,3-
species 10. Thus, whereas the 1-(allenyl)-2-aryl-1H-indoles
difluoroindolines may be synthetically interesting building
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blocks for the preparation of N-fused indoline derivatives. The
carbocyclization–functionalisation of the aminoallene subunit
was realized when allyl bromide was added in the palladium-
selected reviews, see: (b) T. Lechel, F. Pfrengle, H.-U. Reissig and R.
Zimmer, ChemCatChem, 2013, , 2100; (c) S. Yu and S. Ma, Angew.
Chem. Int. Ed., 2012, 51, 3074; (d) N. Krause and C. Winter, Chem.
Rev., 2011, 111, 1994; (e) C. Aubert, L. Fensterbank, P. Garcia, M.
Malacria and A. Simonneau, Chem. Rev., 2011, 111, 1954; (f) A. S. K.
Hashmi, Angew. Chem. Int. Ed., 2000, 39, 3590.
5
catalyzed transformation of 2-allenyl-1H-indoles
N-fused indolines 11 (Scheme 7).
3 to generate
In conclusion, an efficient iron-catalyzed Selectfluor-
assisted synthetic route to 2-allenyl-2-substituted-3,3-
difluoroindolines from easily accessible N-allenyl-indole
substrates under mild conditions has been reported. The
Fe(III)/Selectfluor system enables the highly selective
difluorofunctionalisation/aza–Claisen rearrangement sequence
of various 1-allenyl-2-aryl-indoles at ambient temperature.
Besides, trifluoroderivatives can be achieved starting from 1-
allenyl-2-methyl substrates. Future work could be directed
towards the development of an asymmetric version.
6
For a review on the aza–Claisen rearrangement, see: (a) K. C.
Majumdar, T. Bhattacharyya, B. Chattopadhyay and B. Sinha,
Synthesis, 2009, 2117. For the C2–C3 Claisen rearrangement of
indoles to form allenyl oxindoles, see: (b) T. Cao, E. C. Linton, J.
Deitch, S. Berritt and M. C. Kozlowski, J. Org. Chem., 2012, 77
,
11034; (c) T. Cao, J. Deitch, E. C. Linton and M. C. Kozlowski, Angew.
Chem. Int. Ed., 2012, 51, 2448.
For a fluoro-heterocyclisation reaction promoted by Selectfluor in
the absence of any metal catalyst or base, see: D. Parmar and M.
7
8
Rueping, Chem. Commun., 2014, 50, 13928.
Gold complexes have been used extensively for the synthetic
community due to their powerful soft Lewis acidic nature. For
selected reviews on gold catalysis, see: (a) A. S. K. Hashmi, Accounts
Chem. Res., 2014, 47, 864; (b) C. Obradors and A. M. Echavarren,
Accounts Chem. Res., 2014, 47, 902; (c) B. Alcaide and P. Almendros,
Accounts Chem. Res., 2014, 47, 939; (d) L. Fensterbank and M.
Malacria, Accounts Chem. Res., 2014, 47, 953; (e) M. Rudolph and A.
S. K. Hashmi, Chem. Soc. Rev., 2012, 41, 2448; (f) A. Corma, A. Leyva-
Pérez and M. J. Sabater, Chem. Rev., 2011, 111, 1657; (g) N. Krause
and C. Winter, Chem. Rev., 2011, 111, 1994; (h) A. S. K. Hashmi,
Angew. Chem. Int. Ed., 2010, 49, 5232. For the gold(I)-catalyzed
propargyl Claisen rearrangement, see: (i) B. D. Sherry, F. D. Toste, J.
Am. Chem. Soc., 2004, 126, 15978. (j) For the gold(I)-catalyzed
tandem alkoxylation/Claisen rearrangement, see: H. Wu, W. Zi, G. Li,
H. Lu and F. D. Toste, Angew. Chem. Int. Ed., 2015, 54, 8529.
Support for this work by MINECO and FEDER (Projects
CTQ2012-33664-C02-01, CTQ2012-33664-C02-02, CTQ2015-
65060-C2-1-P, and CTQ2015-65060-C2-2-P) is gratefully
acknowledged. S. C. thanks MEC for a predoctoral contract.
Notes and references
1
(a) Fluorine in Pharmaceutical and Medicinal Chemistry: From
Biophysical Aspects to Clinical Applications, V. Gouverneur and K.
Müller, Imperial College Press, London, 2012; (b) Fluorine in
Medicinal Chemistry and Chemical Biology, I. Ojima, Wiley-
Blackwell, Chichester, U.K., 2009; (c) Bioorganic and Medicinal
Chemistry of Fluorine, J.-P. Bégué and D. Bonnet-Delpon, John Wiley
9
(a) J. Kuang and S. Ma, J. Org. Chem., 2009, 74, 1763; (b) P. Crabbé,
H. Fillion, D. André and J. L. Luche, J. Chem. Soc., Chem. Commun.,
&
Sons, Hoboken, 2008; (d) D O’Hagan, Chem. Soc. Rev., 2008, 37
08; (e) S. Purser, P. R. Moore, S. Swallow and V. Gouverneur, Chem.
,
1
979, 860.
3
Soc. Rev., 2008, 37, 320.
1
1
0 For a recent review, see: J. Wu, Tetrahedron Lett., 2014, 55, 4289.
1 Although the isolation of 1-(buta-2,3-dienyl)-3-fluoro-2-phenyl-1H-
indole 4a from the uncatalyzed reaction of 2a outlined in Scheme 2
was fortuitous, some information has been gathered in favor of the
pathway shown in Scheme 6.
2
3
For a review, see: N. A. Meanwell, J. Med. Chem., 2011, 54, 2529.
For reviews on dearomatization of indoles and heteroaromatic
compounds, see: (a) N. Denizot, T. Tomakinian, R. Beaud, C.
Kouklovsky and G. Vincent, Tetrahedron Lett., 2015, 56, 4413; (b) S.
P. Roche, J.-J. Y. Tendoung, and B. Tréguier, Tetrahedron, 2015, 71,
1
2
In order to see if compound 4a is able to rearrange to 3a under
metal catalysis, reaction of 4a with a catalytic amount of either
3
4
549; (c) Q. Ding, X. Zhou, and R. Fan, Org. Biomol. Chem., 2014, 12,
807. For bioactive indolines, see: (d) T. Hata, Y. Sano, R. Sugawara,
Fe(OTf)
Selectfluor and NaHCO
3
or [(Ph
3
P)AuNTf
2
] was conducted in the presence of
3
. The reaction did proceed well to give 3,3-
A. Matsumae, K. Kanamori, T. Shima and T. Hoshi, J. Antibiot. Ser. A,
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