Organocatalysis through halogen-bond activation

Article abstract of DOI:10.1055/s-2008-1042935

Haloperfluoroalkanes have been used as catalysts for the reduction of 2-phenylquinoline to its corresponding 1,2,3,4-tetrahydro derivative using a Hantzsch ester as reductand. The results suggest a substrate activation by halogen bonding. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042935

900
LETTER
Organocatalysis through Halogen-Bond Activation
Halogen
Bonding
nin Organocat
g
alysis elika Bruckmann, Miguel A. Pena, Carsten Bolm*
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52056 Aachen, Germany
Fax +49(241)8092391; E-mail: Carsten.Bolm@oc.rwth-aachen.de
Received 14 January 2008
developed.9,10 The results of our study are presented in
Table 1.
Abstract: Haloperfluoroalkanes have been used as catalysts for the
reduction of 2-phenylquinoline to its corresponding 1,2,3,4-tetrahy-
dro derivative using a Hantzsch ester as reductand. The results sug-
gest a substrate activation by halogen bonding.
First it was confirmed that under the chosen reaction con-
ditions (dichloromethane or toluene solutions at 25 °C or
Key words: amine synthesis, halogen bonding, imine reduction, 60 °C, respectively) no uncatalyzed (background) reduc-
organocatalysis, quinoline reduction
tion of 1a by 2 occurred (Table 1, entries 1 and 2).
Then, the effect of the presence of various perfluorinated
haloalkanes was studied. Under standard conditions, 10
In the emerging field of organocatalysis, hydrogen bond-
mol% of the haloalkane and 2.2 equivalents of Hantzsch
ester 2 were used.11 Except in one case (entry 3), the for-
ing is one of the most important noncovalent interactions
that allows the activation of an electrophile towards a nu-
cleophilic attack.1,2 Much less attention has been paid to
Table 1 Reduction of 2-Phenylquinoline (1a) in the Presence of
Haloperfluoroalkanesa
activations by other atoms, which can also act as electron
acceptors. For example, attractive interactions between
EtO2C
Me
CO2Et
halogen atoms and electron donors have been known for
more than one century,3 and for their characterization the
term ‘halogen bond’ was introduced a few years ago.
Thus, halogen bonding describes any noncovalent interac-
tion between a halogen atom acting as a Lewis acid and an
electron donor (Lewis base).4
(2.2 equiv)
Me
N
2
H
RFI or RFBr
(1 or 10 mol%)
N
1a
CH2Cl2 or toluene,
25 or 60 °C,
N
H
Since halogen bonds are strong, specific, and directional
interactions, they can give rise to well-defined supramo-
lecular structures.5 Thus, halogen bonding has gained im-
portance in crystal engineering as well as in the
interpretation of biological systems and processes.6 Al-
though this type of interaction shows many similarities to
hydrogen bonding, to the best of our knowledge it has not
yet been applied to organocatalysis. An additional attrac-
tion of this approach is the potential of rendering the pro-
cess asymmetric using enantiopure haloalkanes.7
24 or 96 h
3a
Entry RFX
Amount
(mol%) of RFX
Solvent
Temp Yieldof
(°C) 3a (%)a
1
2
–
–
–
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
60
25
60
25
25
60
25
60
25
25
25
25
25
–
–
–
3
BrCF2CBrFCF3
BrCF2CBrFCF3
CF3CF2CFICF3
CF3(CF2)5I
10
10
10
10
10
10
10
10
10
1
–
4
39 (67)b
72b
35b
63b
20b
12b
90
Inspired by the examples of molecular aggregations based
on attractive interactions between organic halides
(X = Br, I) and nitrogen-containing compounds,5a,b we
initiated our exploratory study by focusing on the activa-
tion of C=N bonds by haloalkanes towards electrophilic
hydride additions. In particular, the effect of highly fluor-
inated iodoalkanes was of interest, since those were
known to form the strongest halogen bonds to sp2-type ni-
trogens. As specific test reaction, the transfer hydrogena-
tion of 2-phenylquinoline (1a) by Hantzsch ester 2 was
selected. This type of heteroaryl reduction is well-estab-
lished,8 and even organocatalytic asymmetric versions in-
volving chiral Brønstedt acid catalysts have recently been
5
6
7
CF3(CF2)5I
8
CF3(CF2)5Br
CF3(CF2)5Br
CF3(CF2)6I
9
10
11
12
13
14
CF3(CF2)7I
98
CF3(CF2)7I
69b
38b
88
CF3(CF2)7Br
CF3(CF2)9I
10
10
SYNLETT 2008, No. 6, pp 0900–0902
x
x.
x
x.
2
0
0
8
a Isolated by column chromatography.
b The reaction time was 96 h.
Advanced online publication: 11.03.2008
DOI: 10.1055/s-2008-1042935; Art ID: G01107ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Halogen Bonding in Organocatalysis
901
mation of the expected tetrahydroquinoline 3a was ob- TEMPO and perfluoroalkylhalides13 and an assumed in-
served confirming our initial hypothesis. As indicated by teraction between the latter compounds and the naphtha-
the comparison of entries 6, 10, and 11 of Table 1, the ac- lene derivative leading to a catalyst inhibition. In contrast,
tivity enhancement of the perfluorinated iodoalkanes in- in the presence of AIBN the reduction of 1a to give 3a
creased with the length of the carbon chain. Only proceeded well. Presumably, under those conditions an al-
perfluorodecyliodide (entry 14) was an exception, which ternative mechanism operates affording the product in an
could be due to the low solubility of this compound. Per- exceptional >90% yield on a radical pathway.
fluorinated iodoalkanes were more active than their bro-
Table 2 Substrate Scope of the Reduction of 2-Substituted Quino-
lines in the Presence of Haloperfluoroalkanes
mo counterparts (compare entries 6 vs. 8 and 12 vs. 13).
Use of perfluorohexyliodide in dichloromethane at 25 °C
even allowed a reduction of the catalyst loading from 10
mol% to 1 mol% (entries 11 and 12) leading to 3a in re-
markable 69% yield (after 96 h).
2 (2.2 equiv),
CF3(CF2)7I (10 mol%)
R1
R1
CH2Cl2, 25 °C,
24 or 96 h
N
R2
N
R2
H
In order to detect the proposed N–halo interaction various
NMR experiments were performed (using CD2Cl2 solu-
tions of substrate 1a, Hantzsch ester 2, and perfluorooctyl-
iodide as activator). After 3 hours product 3a was
identified in the reaction mixture, and full conversion was
achieved after 24 hours. No signal shifts were found in the
1H NMR spectra. This contrasted the 13C NMR behavior,
where in the reaction mixture the quinoline signals were
slightly shifted to lower field (by 0.01–0.06 ppm). We in-
terpret this difference in chemical shift as indication for a
weak interaction between the quinoline nitrogen and the
iodide of the perfluoro compound. This suggestion was
supported by the 19F NMR spectra, in which the signal for
the CF2I group resonated at lower magnetic field
(Dd = 0.1 ppm). For the CF2 and CF3 signals a downfield
shift of ca. 0.06 ppm was observed. Analogous shifts have
been reported with respect to other interactions between
haloperfluoroalkanes and nitrogen-containing hydrocar-
bons.5d,12 As expected, all chemical shifts were strongly
concentration dependant.
The 13C and 19F NMR studies in the absence of reductant
2, using a 1:1 mixture of the 1-iodoperfluorooctane and
quinoline 1a in CD2Cl2 (ca. 0.07 M) showed a similar shift
behavior, supporting the suggested N···I interaction also
in this case. At higher concentrations (e.g., 1 M) a larger
chemical-shift variation Dd (1.1 ppm for CF2I and 0.15–
0.44 ppm for CF3 and CF2) was observed. However, since
under those conditions the haloperfluroalkane was not
completely soluble leading to a two-phase system, the lat-
ter data should be noted with caution.
1b–g
3b–h
Entry
R1
H
R2
Product
3b
Yield of 3 (%)a
1
2
3
4
5
6
7
Me
82b
75
98
83
70
74
88
Me
F
Me
3c
Me
3d
H
Et
3e
H
i-Bu
2-tolyl
2-furyl
3f
H
3g
H
3h
a Isolated by column chromatography.
b The reaction time was 24 h (instead of the common 96 h).
Finally, the substrate scope was investigated. Table 2
shows the respective results. Using perfluorooctyliodide
(10 mol%) as activator a range of 2-substituted quinolines
could efficiently be reduced at room temperature using
Hantzsch ester 2 as reductant. The highest yield (98%)
was observed in the reduction of 6-fluoro-substituted 2-
methylquinoline 1d (entry 3). A comparison of that result
with the ones achieved in the conversions of the corre-
sponding 6-methyl- and 6-unsubstituted quinolines 1c and
1b, respectively, indicated that electron-poor quinolines
were better substrates than electron-rich ones. Steric mod-
ifications at the 2-position had only a minor effect on the
reaction process.
To our surprise, attempts to perform NMR studies of mix-
tures of Hantzsch ester 2 and 1-iodoperfluorooctane in the
absence of substrate 1a led to decomposition of the halop-
erfluroalkane within a few hours. Thus, the presence of
the quinoline appeared to ‘protect’ the perfluoroalkylha-
lide from being destructed by the reductant.
In summary, we have shown that the quinoline reduction
of 1 with Hantzsch ester 2 leading to the corresponding
1,2,3,4-tetrahydroquinoline derivative 3 can be catalyzed
by haloperfluroalkanes. It is suggested that the reaction
mechanism involves an activation of the heterocycle by
halogen bonding arising from a Hal–N interactions. Fur-
ther studies are ongoing trying to demonstrate this new
and potentially useful concept in other organocatalyses.
In order to further analyze the hypothesized reductive re-
action path and to determine if alternative reaction mech-
anisms were operating, the reaction shown in Table 1 was
performed in the presence of additives. Both 4-acetamino-
TEMPO and 1,8-bis(dimethylamino)naphthalene ham-
pered the conversion of 1a and 2 into product 3a. These
observations can be explained on the basis of the known
formation of halogen-bonded complexes between of
Acknowledgment
This research was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft within their priority pro-
gram SPP 1179. A.B. thanks DFG (GRK 440) for a predoctoral fel-
Synlett 2008, No. 6, 900–902 © Thieme Stuttgart · New York

902
A. Bruckmann et al.
LETTER
lowship. M.A.P. acknowledges Xunta de Galicia (Spain) for a
postdoctoral fellowship.
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atmosphere at the appropriate temperature for the indicated
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Synlett 2008, No. 6, 900–902 © Thieme Stuttgart · New York