Catalytic stereoselective benzylic C-H functionalizations by oxidative C-H activation and organocatalysis

Article abstract of DOI:10.1039/b910185c

An organocatalytic stereoselective α-alkylation reaction of aldehydes based on C-H activation is presented.

Full text of DOI:10.1039/b910185c

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Catalytic stereoselective benzylic C–H functionalizations by oxidative
C–H activation and organocatalysisw
Fides Benfatti, Montse Guiteras Capdevila, Luca Zoli, Elena Benedetto
and Pier Giorgio Cozzi*
Received (in Cambridge, UK) 22nd May 2009, Accepted 31st July 2009
First published as an Advance Article on the web 18th August 2009
DOI: 10.1039/b910185c
An organocatalytic stereoselective a-alkylation reaction of
aldehydes based on C–H activation is presented.
substrates mediated by DDQ have been reported.8,15 The
reaction was effectively promoted when operating in CH3NO2
or CH2Cl2. Among all the organocatalysts tested, the reaction
was promoted by the MacMillan-type of catalyst 8,16 while
chiral diphenylprolinol TBS ether catalyst17 did not prove
effective in this transformation. Catalyst 8 performed better
then other MacMillan-type imidazolidinone catalysts. Selected
key experiments are presented in Table 1. The enantiomeric
excesses were maximized at low temperature (À25 1C) by the
use of CH2Cl2 as the reaction solvent.
The activation of C–H bonds has attracted much attention in
both the academy and industry because of its many potential
advantages.1 It is anticipated that the formation of new C–X
bonds (X = C, O, N, S) via activation of C–H bonds will
have a great impact in the field of stereoselective synthesis.2
Asymmetric reactions based on the activation of sp3 C–H
bonds have been studied in depth,3 particularly using the metal
carbenoid insertion of sp3 C–H bonds.4 Recently, we have
demonstrated the possibility of using the SN1-type reaction in
organocatalysis.5 Our work combined two powerful concepts:
enamine catalysis and Mayr’s electrophilicity scale.6 We have
used stabilized carbocations generated by benzylic alcohols
in situ for the enantioselective a-alkylation of aldehydes.7
However, as carbocations can be also generated under
oxidative reaction conditions by benzylic carbon-hydrogen
bond activation8 we wondered whether activation of C–H
bonds of alkanes could be coupled with a direct stereoselective
organocatalytic reaction.9 This new methodology has enormous
potential, as all concepts developed in organocatalytic reactions
can be used in the direct functionalization of C–H bonds, with
all the advantages of simple reaction conditions, and absence
of metal catalysts.
We have tested several modes of addition. DDQ was
added in portions (3–4 portion), or in one portion but the
enantiomeric excess was not improved. The addition of DDQ
by syringe pump18 stopped the reaction, and no conversion
was observed. Other oxidants, such as K3Fe(CN)6, Fe(acac)3,
K2S2O8, AgOTf, Cu(OAc)2, and CAN resulted in no reaction
or decomposition of the catalyst. With the optimised
reaction condition, other substrates (2–7) and aldehydes were
investigated (Table 2). A comprehensive list of the other
substrates tested in the reaction is reported in the supporting
information. In general, xanthene 1 reacts smoothly with
different aldehydes, resulting in high yield and good stereo-
selection of the desired products (entries 1–5). Oxidation of
1,3,5-cycloheptatriene 2 gave the stable tropylium cation. In
performing the reaction with the substrate 2 we noted that the
counter ion of the catalyst was crucial in order to obtain good
enantiomeric excesses (see supporting information), and by the
use of catalyst 9 the alkylated product was isolated in
high yield with moderate to good stereoselectivity. Other
catalysts prepared in situ with different acids (see supporting
information) gave the desired adduct with diminished
stereoselectivity. Compound 3 was obtained by the reduction
In this contribution we present an organocatalytic stereo-
selective a-alkylation reaction of aldehydes based on C–H
activation reactions. In order to set up a C–H activation
reaction with organocatalytic reactions several challenges
need to be addressed. In particular, water generated during
the formation of the enamine in situ could react with the
carbocation.10 We reasoned that performing the reaction of
alkyl aromatic compounds with weak C–H bonds (Fig. 1)
could result in the facile generation of the carbocation,
mediated by an oxidant.11 However, the stability of the
carbocation is also crucial for this type of reaction,12 and
on the basis of our previous findings concerning SN1-type
reactions, we set up a series of model reactions with xanthene
1, octanal, and a variety of organocatalysts. We performed the
model reaction choosing DDQ as the oxidant.13 DDQ is a
well-known oxidizing reagent for organic synthesis,14 and
the coupling reaction between nucleophiles and benzylic
Department of Chemistry ‘‘G. Ciamician’’, Via Selmi 2,
40126 Bologna, Italy. E-mail: piergiorgio.cozzi@.unibo.it
w Electronic supplementary information (ESI) available: Experimental
details and supplementary figures. See DOI: 10.1039/b910185c
Fig. 1 Organocatalytic functionalization by C–H activation with
compounds 1–7.
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Table 1 Organocatalytic functionalization by C–H activation with
compound 1
Table 2 Organocatalytic C–H activation with compounds 1–7
Entrya
T 1C
Solvent
Time/h
Yield (%)b
ee (%)c
1
2
3
4
RT
RT
RT
RT
0
CH3CN
DMF
DCM
CH3NO2
DCM
CH3NO2
DCM
DCM
DCM
DCM
1
1
0.50
Traces
—
62
50
81
55
90
65
52
—
—
45
70
69
56
79
77
70
70
0.50
5
3
3
4
4
4
4
6
0
7d
8
À25
À25
À25
À25
9e
10f
74
a
All the reactions were carried out at the indicated temperature.
c
Isolated yield after chromatographic purification. Evaluated by
b
d
chiral HPLC analysis. The reaction was carried out under nitrogen
e
with degassed solvents and adding portion wise the oxidant. The
Entry
Product
Yieldb
d.r.c
e.e (%)d
f
reaction was carried out using 15 mol% of MacMillan catalyst. The
reaction was carried out without TFA (trifluoroacetic acid) as
additive.
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
2a
2c
2d
3a
4a
4f
75
50
66
90
30
90
30
30
30
50
40
57
57
33
55
40
—
—
—
—
—
—
—
68
78
68
78
74
46
38
70
of the corresponding flavylium salt as reported in literature.19
A flavanoid derivative 3a was obtained using catalyst 8 in
modest yield and moderate stereoselectivity. It is worth
mentioning that the addition of p-nucleophiles to a flavylium
carbocation was described by Mayr.20 Finally, the direct
functionalization of indole derivatives was possible by a direct
C–H activation. As carbocation derived for indolyl
alcohols resulted in high ees in our SN1-type of reaction,5 we
investigated the indole derivatives 4–7 as model substrates,
prepared as reported in the literature from the reaction of
2-methylindole with aromatic aldehydes in the presence of
Et3SiH.21 Interestingly, the reaction occurred in minutes but
only when operating at low temperatures, in the presence of
2 equiv. MeOH, it was possible to obtain a moderate yield.
Remarkably, we observed good stereoselection in the reaction
with 5. The major diastereoisomer obtained in this case was
the syn isomer.5,22
—
9
2 : 1e
1 : 1
1 : 1
1 : 9
1 : 9
1 : 1
3 : 1
1 : 1
min 10; maj 62
anti 82; syn 62
anti 69; syn 59
anti;f syn 86
anti 60; syn 77
anti 66; syn 65
anti 74; syn 50
anti 86; syn 79
10
11
12
13
14
15
16
5a
5f
6a
6f
7a
a
All the reactions were carried out at À25 1C under nitrogen under
strictly anaerobic conditions. Catalyst aldehyde and substrates were
b
mixed at RT, then DDQ was added at À25 1C. Isolated yield after
chromatographic purification. Estimated by 1H NMR on the crude
c
product. The ratio is indicate anti vs. syn, assigned on the basis
of 1H NMR and HPLC, see ref. 8. The absolute and relative
configuration for products 4a, 4f, 5a, 5f, 6a, 6f, and 7a was assigned
on the basis of HPLC retention time, 1H NMR spectra, and
comparison with syn products obtained with a different synthetic
d
The absolute configuration of the products 1b and 2c
derived from xanthene 1 and from 1,3,5-cycloheptatriene 2
were established by chemical correlation through alkylation of
oxazolidinone derivatives (Scheme 1).23 9H-Xanthen-9-ol 8
was treated with titanium enolate derived from the
N-propionyl oxazolidinone 9,24 and the product was reduced
with SuperHydride in THF to gave the (R) alcohol 11, an
enantiomer of the alcohol obtained by the reduction of 1b.
The oxazolidinone 13 was obtained by the reaction of
commercially available tropylium tetrafluoroborate 12 with
the lithium enolate of ethylacetate,26 its successive hydrolysis
and coupling with (S)-benzyloxazolidinone. Alkylation of 13
with ethyl iodide was performed in like manner to Evans,25
and successive reduction with SuperHydride afforded the
procedure; see ref. 5. Evaluated by chiral HPLC analysis (see ESI
e
for detailsw). The diastereoisomer ratio was not assigned. The
indicated values are major diastereoisomer against minor. The ee
of the minor diastereoisomer was not determined.
f
alcohols 14, identical to the (S) alcohol obtained by reduction
of 2c. In both cases the configurations of the isolated products
were in agreement with the addition of carbocation from the
less hindered face of the enamine (Fig. 2).27
In summary, we have reported a stereoselective alkylation of
benzylic C–H merging an oxidative C–H activation reaction
with organocatalysis. Further work to improve yields
and stereoselectivity of the present reaction by tailored
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Notes and references
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Scheme
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This work was supported by PRIN 2007 (Progetto
Nazionale: Sintesi e Stereocontrollo di Molecole Organiche
per lo Sviluppo di Metodologie Innovative di Interesse
Applicativo) Financial support from the European Community
(Fp7-201431 CATAFLU.OR project) is acknowledged for a
fellowship to F.B.
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Chem. Commun., 2009, 5919–5921 | 5921