5,5′-Bistriazoles as axially chiral, multidentate ligands: Synthesis, configurational stability and catalytic application of their scandium(iii) complexes

Article abstract of DOI:10.1039/c7cy01518f

The design and development of 5,5′-bistriazoles featuring aminomethyl substituents is discussed. An efficient synthetic procedure for the selective preparation of 4,4′-bis(aminomethyl)-5,5′-bistriazoles from commercially available propargylamine derivativ

Full text of DOI:10.1039/c7cy01518f

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5,5’-Bistriazoles as axially chiral, multidentate ligands: Synthesis,
configurational stability and catalytic application of their
scandium(III) complexes
Received 00th January 20xx,
Accepted 00th January 20xx
Pablo Etayo,*a Eduardo C. Escudero-Adána and Miquel A. Pericàs*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
The design and development of 5,5’-bistriazoles featuring aminomethyl substituents is discussed. An efficient synthetic
procedure for the selective preparation of 4,4’-bis(aminomethyl)-5,5’-bistriazoles from commercially available
propargylamine derivatives and benzyl azide has been optimized. The first experimental determination of the
configurational stability of 5,5’-bistriazoles is disclosed on the basis of rotational energy barriers and half-life times. Fast
racemization was observed for a bistriazole possessing solely axial chirality whereas a more heavily substituted bistriazole
involving axial and central chirality proved to be configurationally stable. A successful catalytic application has been
implemented by using a N,N-dimethylpropargylamine-derived 5,5’-bistriazole as a multidentate ligand controlling the
product selectivity (single vs. double addition) in scandium(III)-catalyzed nucleophilic additions of indoles to isatin
electrophiles.
(N-heterocyclic carbene ligands).8d Consequently, 1,4-
functionalized 1,2,3-triazoles constitute valuable and versatile
ligand systems for transition metals. When acting as N ligands,
1. Introduction
Since the pioneering and independent discoveries by the
groups of Meldal,1 and Fokin and Sharpless2 on the copper-
triazoles generally coordinate to metals through the more
electron-rich N3 nitrogen atom, this leading to the formation
of stable transition metal complexes.8c
catalyzed azide−alkyne cycloaddition (CuAAC), this reaction
has become a commonly employed ligation tool enabling the
Metal-catalyzed transformations mediated by triazole
ligands benefit from the easy fine-tuning of these nitrogen
ligands thanks to the wide structural diversity achievable with
the CuAAC reaction.3 Moreover, the chemical inertness of
triazoles is an additional advantage in view of their use as
metal-supporting platforms in catalysis. In this context, our
synthesis of 1,4-disubstituted 1,2,3-triazoles in
efficient, reliable and regioselective manner.
a
highly
As
3
a
consequence, countless applications for triazole chemistry in
4
diverse disciplines, such as medicinal chemistry,
bioconjugation,5 polymer science6 or supramolecular systems,7
amongst others, have been developed.
laboratory
has
introduced
C3-symmetric,
modular
, Fig. 1),
On the other hand, the coordination organometallic
chemistry of 1,2,3-triazoles is receiving increasing attention,
and this topic has been widely reviewed.8 The presence of two
sp2 nitrogen atoms bearing accessible lone electron pairs
within the triazole ring offers two possible N donor sites (N2
and N3) for binding to metal centers (nitrogen ligands).
tris(triazolyl)methanol (TTM) ligands and derivatives9 (
I
which have proved to be highly efficient oligotriazole ligands in
CuAAC reactions as well as in Cu-catalyzed carbene transfer
reactions. Another highlighted multidentate ligand family
comprises the bistriazole-based tetradentate ligand
architecture II, depicted in Fig. 1 and successfully applied in
Mn-catalyzed epoxidation of terminal olefins. 10 Regarding
examples of oligotriazole-based chiral ligands, our group
Additionally, the highly polarized C−H bond of this heterocycle
enables coordination to metals through the C5 carbon atom
developed
the
preparation
of
the
C2-symmetric
bis(triazolecarboxamido) derivative III (Fig. 1), which was used
as a tetradentate ligand in Mo-catalyzed asymmetric allylic
alkylation reactions.11 Both triazole units proved to be key
elements for catalytic activity and enantioselectivity,
participating in the chelation of the metal. More recently, a
new multidentate chiral ligand design appeared in the
literature, featured by the dimeric Cinchona alkaloid-derived
4,4’-linked bistriazole IV (Fig. 1).12 This chiral system mediated
Cu-catalyzed enantioselective Michael additions, evidencing
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the key role of bistriazole linker for effective chirality transfer.
Interestingly, the bistriazole core was deemed to be a
coordinating site rather than a spacer, and its replacement by
R3
R2
5'
N
R1
M
a
single triazole implied significant decrease in
N
N
N
N
N
enantioselectivity.
5
N
R1
M
N
R2
R3
restricted rotation around
the C5−C5' axis of chirality
Fig. 2 Rational ligand design and proposed working hypothesis.
Many different CuAAC-based synthetic procedures for the
preparation of diverse 4,4’-disubstituted 5,5’-bistriazoles have
been reported in the literature during the last decade.15
However, at a difference with a wide array of functional
groups (alcohol, ether, amide, ester, cyano) the presence of
aminomethyl substituents on the 5,5’-bistriazole framework is
not documented. On the other hand, the opportunities offered
by the 5,5'-bistriazole scaffold in catalysis, although pointed
out by different authors,15a,c,g,j,l,m remain essentially
unexplored.15i,l Also to be noted, the configurational stability
of these heterobiaryl atropisomers has never been studied in
spite of its relevance in view of potential application in
asymmetric catalysis.
We wish to report in the present paper the preparation of
novel 4,4’-bis(aminomethyl)-substituted 5,5’-bistriazoles and
the experimental study of their configurational stability
(rotational energy barriers and half-life times). Additionally,
the atropoisomeric dimer resulting from the reaction of N,N-
dimethylpropargylamine with benzyl azide has been
successfully applied as a multidentate ligand in scandium-
catalyzed nucleophilic additions of indoles to isatin
electrophiles (Scheme 1).
Fig. 1 Selected oligotriazole-based multidentate ligands applied in transition metal-
catalyzed (asymmetric) transformations.
Considering the aforementioned key role of oligotriazole-
based systems as multidentate ligands controlling the outcome
of metal-mediated processes, we devised
bistriazole-based ligand skeleton with
a
novel 5,5’-
a
tailored 4,4’-
disubstitution pattern which confers axial chirality and further
coordination capacities to the atropisomeric ligand core (Fig.
2). Our ligand design involves the presence of metal-
coordinating aminomethyl groups on both triazole units. The
resulting multidentate ligand depicts dual functionality:13 the
amino and triazole functionalities are expected to operate in
concert, with the more basic tertiary amine likely facilitating
the catalytic function by providing additional electron density
on the metal center.14 In this manner, the envisioned ligand
system would involve an intrinsically axially chiral and doubly
chelating 4,4’-difunctionalized 5,5’-bistriazole. This new class
of C2-symmetric oligotriazole ligands presumably could form
two distal, rigid five-membered chelates between the N3
nitrogen of each triazole ring and its proximal amino group
leading to cooperative effects (Fig. 2).
Scheme 1 Ligand-controlled scandium-catalyzed addition of indoles to isatins by using a
4,4'-bis(aminomethyl)-5,5'-bistriazole as a multidentate ligand.
2. Results and Discussion
2.1 Preparation of axially chiral 4,4’-bis(aminomethyl)-substituted
5,5’-bistriazoles
Our approach to 4,4’-bis(aminomethyl)-5,5’-bistriazole 4a
involved a tandem CuAAC−
starting from benzyl
oxidative homocoupling process by
azide and N,N-
(1)
dimethylpropargylamine (2a) as reactive partners (Scheme 2).
2 | J. Name., 2012, 00, 1-3
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The Cu-catalyzed [3+2] cycloaddition reaction between
1 and desired bistriazole 4a could be enhanced by following the
synthetic protocol described by Li and Zhang et al.15h Thus, the
use of catalytic CuBr in a buffered NaOEt/EtOH medium
yielded 80% conversion and 80:20 3a/4a selectivity,
2a has been widely studied in the literature.16 Surprisingly,
despite many different copper-based catalytic systems and
reaction conditions have been applied to perform this
transformation, no formation of 5,5’-bistriazole 4a has ever
been observed, with monotriazole 3a as the single reaction
product reported so far. In fact, it has already been mentioned
before (vide supra) that amines have never been incorporated
into the 5,5’-bistriazole framework.
respectively (entry 4). After column chromatography, the
target 5,5’-bistriazole 4a could be isolated in 19% yield. The 5-
alkynyltriazole 5a, a common side product in 5,5’-bistriazole
formation,15a,c,g,h,j,l,m could also be isolated in trace amount (1%
yield). Gratifyingly, the structure of 4a could be unambiguously
established by single-crystal X-ray diffraction (SCXRD)
analysis.§
Me2N
Me2N
Ph
Table 1 Assessment of literature proceduresa
N
N
Cu source
N
N
N
N
Conv.
+
and/or
Ph
N3
NMe2
Entry
1
Reaction conditionsb
3a/4ac
(%)c
N
base, solvent
atmosphere, T
N
N
1
2a
Cu powder (1.0 equiv.), 1.0
M
aq.
aq.
Na2CO3 (3.0 equiv.), MeCN15a
CuBr (1.0 equiv.), 2.0 aq. Cs2CO3
(2.0 equiv.), MeCN/H2O (1:1)15l
CuI (10 mol%), 2.0 aq. Na2CO3
Ph
Ph
NMe2
CuSO4 (10 mol%), 2.0
M
2
100:0
unwanted
monotriazole
3a
desired
5,5'-bistriazole
4a
M
2
3
4
100
70
100:0
94:6
Scheme 2 Competing formation of monotriazole 3a and 5,5’-bistriazole 4a in the Cu-
catalyzed cycloaddition of azide 1 with alkyne 2a.
M
(3.0 equiv.), MeCN15e
CuBr (10 mol%), NaOEt (2.0
equiv.), EtOH15h
The formation of 5,5’-bistriazoles, originally considered as
minor undesired reaction products, has been observed since
80
80:20
the early days of the CuAAC reaction.2
,17 These products were
a Reaction shown in Scheme 2. b All reactions were conducted by using 1.0 equiv.
of azide 1 and 1.1 equiv. of alkyne 2a under open-air atmosphere and at rt for 24
h. c Determined by 1H NMR analysis of the crude reaction mixture.
found to be formed under oxidative conditions, presumably by
oxidative coupling of copper triazolide species,18 and their
formation could be suppressed under strict exclusion of
oxygen and oxidative impurities.19 Alternatively, it has been
demonstrated how the formation of 5,5’-linked bistriazoles as
the major reaction products can be facilitated by using
appropriate reaction conditions, although this process is
substrate-dependent.15n With these precedents, we set out to
explore the selective synthesis of bistriazole 4a by screening
first some reported conditions for efficient 5,5’-bistriazole
formation (Table 1). In this particular case, however, most of
these procedures were completely inefficient, bistriazole 4a
The latter results (see Table 2, entry 1) were then taken as
the starting point for the optimization of the selective
preparation of 4a. An exhaustive and systematic screening of
different reaction conditions was performed with the goal of
improving the yield of 4a and minimizing or suppressing the
formation of unwanted products 3a and 5a. 1,3-Diyne 6a 20
,
which could arise from a Glaser-type coupling of the terminal
alkyne 2a, was never detected.
being only detected in trace amount (entries 1−3). The ratio of
Table 2 Optimization of the preparation of 4aa
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Entry 1/2a (equiv.)
Modificationsa
Atmosphere T (ºC) Conv. (%)b 3a/4a/5ab 3a/4ab
Isolated yields (%)c
3a: 55; 4a: 19; 5a: 1
not isolated
not isolated
−
1
2
1.0/1.1
1.0/1.1
1.0/1.1
1.0/1.1
1.0/1.1
1.0/1.1
1.0/1.1
2.0/1.0
2.5/1.0
2.5/1.0
2.5/1.0
none
none
open-aird
dry aire
dry aire
dry aire
dry aire
dry aire
dry aire
dry aire
dry aire
oxygenf
dry aire
25
25
25
25
25
25
0
80
91
76:18:6
60:35:5
83:13:4
−
63:37:0
100:0:0
31:64:5
14:84:2
25:73:2
29:63:8
82:15:3
80:20
63:37
87:13
−
63:37
100:0
33:67
14:86
25:75
31:69
84:16
3
CuI as catalyst
Cu(OEt)2 as catalyst
NaOEt (0.30 equiv.)
TFE as solvent
none
100
0
4
5
82
not isolated
6
100
86
3a: 87
7
4a: 22
8
none
0
84
4a: 39
9
none
0
100
85
4a: 54
10
11
none
0
not isolated
not isolated
1,4-NTQg (1.0 equiv.)
0
29
12
2.5/1.0
0.22
0.22
0.22
0.50
0.22
M
in anh. EtOH
dry aire
0
100
16:83:1
16:84
3a: 11; 4a: 59
13
14
15
16
2.5/1.0
2.5/1.0
2.5/1.0
2.5/1.0
M
& NaOMe/MeOHh
dry aire
dry aire
dry aire
dry aire
0
0
0
0
100
100
90
37:53:10
10:38:52
69:27:4
32:64:4
41:59
20:80
72:29
33:67
3a: 20; 4a: 54
4a: 18; 5a: 26
not isolated
4a: 53
M
& NaOiPr/iPrOHi
& NaOBn/BnOHj
M
M
& CuBr (30 mol%)
100
a All reactions were conducted by using 10 mol% of CuBr and 2.0 equiv. of solid NaOEt in anhydrous EtOH (0.11
M
) for 24 h, unless otherwise indicated. b Determined
by 1H NMR analysis of the crude reaction mixture. c Yields of isolated pure products after column chromatography. d Open flask exposed to ambient air atmosphere. e
Flask sealed with a glass tube refilled with anhydrous CaCl2. f Flask connected to an oxygen balloon under atmospheric O2 pressure. g 1,4-Naththoquinone added as an
external oxidant. h 2.0 equiv. of solid NaOMe in anhydrous MeOH. i 2.0 equiv. of solid NaOiPr in anhydrous iPrOH. j 2.0 equiv. of NaOBn solution, 1.0
M in BnOH.
As shown in Table 2, the replacement of open-air the contrary, the use of a solution of NaOBn in benzyl alcohol‡
atmosphere by dry air atmosphere led to an enhancement of afforded unwanted monotriazole 3a as the major product
both conversion and product selectivity, with the ratio of (entry 15). Finally, we tested an increased catalyst loading of
bistriazole 4a increasing from 80:20 to 63:37 3a
respectively (cf. entries 1 and 2). The use of CuI21 (entry 3) or results (cf. entries 12 and 16).
Cu(OEt)2 (entry 4) as the catalyst, or the use of The reaction conditions optimized for the selective synthesis
substoichiometric amount of base (entry 5) did not lead to any of 5,5’-bistriazole 4a (Scheme 3a) from N,N-
/
4a,
CuBr (30 mol%) without finding any improvement on the
a
improvement, while the use of TFE, a solvent much more dimethylpropargylamine (2a) were used to study the influence
acidic than EtOH,‡ completely blocked the formation of 4a of the nature of the amino group on the terminal alkyne on
(entry 6). Temperature was found to be a crucial factor for the product selectivity (Scheme 3). To this end, commercially
reaction outcome. Thus, lowering the reaction temperature available propargylamine derivatives 2b and 2c were reacted
from 25 to 0
only slight decrease in conversion (entry 7). Further
screening revealed the beneficial effect of adding excess of very similar to that obtained with 2a (Scheme 3b).
azide with respect to alkyne 2a, while working at 0 C. The Interestingly, bistriazole 4b could be isolated as its
use of 2.0 equiv. of led to the highest product selectivity diammonium salt 4b·2HCl, as confirmed by means of SCXRD
(14:84:2 3a 4a 5a ratio; entry 8) while the use of slightly analysis.§
higher excess of (2.5 equiv.) further increased the isolated In comparison to N-alkyl-substituted propargylamines 2a and
ºC led to a selectivity switch in favor of 4a, with with benzyl azide (
1).
a
With N-methylpropargylamine (2b), product selectivity was
1
º
1
/
/
1
yield of 4a (from 39% to 54%; entry 9). No improvement on 2b, the use of N-Boc-protected propargylamine 2c under the
the results was observed by conducting the reaction under same reaction conditions favored the monotriazole product
oxygen atmosphere (entry 10), whereas the use of an external
oxidant (1,4-naphthoquinone) was found to be detrimental for that the preferential formation of bistriazoles
both conversion and selectivity (entry 11). electron density at the nitrogen substituent. The better the
The best conditions were found when the reaction was electron-donating ability of the amine, the higher the ratio of
conducted at higher concentration (from 0.11 to 0.22 in 5,5’-bistriazole, with the most electron-rich N,N-
(
3c
/
4c = 64/36) (Scheme 3c). These results tend to indicate
4
correlates with
M
EtOH), with the 5,5’-bistriazole 4a isolated in an optimal 59% dimethylamino group of 2a affording the best results. On the
yield (entry 12). From these optimized conditions, a more basis of control experiments and literature precedents, a
extensive screening aimed to investigate the influence of the dinuclear stepwise mechanism for the formation of 5,5’-
base, defined as
a
buffered alcoholic solution of the bistriazoles
4
has been tentatively proposed.§
corresponding sodium alkoxide, was performed. Reduced
selectivity and lower yield were achieved with the slightly
more acidic NaOMe/MeOH system, in comparison to
NaOEt/EtOH‡ (cf. entries 12 and 13). Complete conversion and
unexpected selectivity were obtained with the more basic
NaOiPr/iPrOH‡ buffer,
a
medium delivering the 5-
alkynyltriazole 5a as the major reaction product (entry 14). On
4 | J. Name., 2012, 00, 1-3
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Me2N
Ph
Me2N
Ph
Me2N
Ph
R2R1N
R2R1N
N
Ph
semi-preparative
chiral HPLC
CuBr (10 mol%)
N
N
N
N
N
NaOEt (2.0 equiv.)
N
N
N
N
N
N
N
N
N
N
N
+
NR1R2
+
+
Ph
N3
N
N
N
N
N
anhydrous EtOH
dry air, 0 ºC, 24 h
enantiomer
separation
N
N
N
N
N
1
2a
c
NR1R2
Ph
NMe2
Ph
NMe2
Ph
NMe2
(2.5 equiv.)
(1.0 equiv.)
Ph
Ph
5,5'-bistriazole
4a
: R1 = R2 = Me
a
rac-4a
(Ra)-4a
(Sa)-4a
: R1 = H; R2 = Me
b
monotriazole
3a
: R1 = H; R2 = Boc
enantiomer
er after 10 min
er after 24 h
c
c
c
1st eluting: 4a-1
2nd eluting: 4a-2
97:3
2:98
58:42
43:57
a)
b)
c)
BocHN
Me2N
Ph
MeHN HCl
Ph
Ph
—
Configurationally labile atropisomers of 4a
N
N
N
N
N
N
N
N
N
N
N
N
Scheme 4 Resolution of racemic bistriazole 4a (rac-4a) by semi-preparative chiral HPLC.
N
N
N
N
N
N
ClH
Ph
NMe2
ratio
, 11% yield
, 59% yield
Ph
—NHMe
Ph
NHBoc
ratio
, 14% yield
, 20% yield
The monitoring of enantiomeric ratios of 4a-1 and 4a-2 as a
2HCl
4a
4b—
4c
function of time by HPLC analyses on a chiral stationary phase
allowed the determination of the rotational/racemization
16:84
3a
4a
(isolated separately
as pure compounds)
/
20:80
/
ratio
64:36 /
3c 4c
3c
4c
3a 4a
3b 4b
, 5% yield
3b
2HCl, 40% yield
energy barrier (
ꢀ
G‡
= ꢀ
G‡rac) of 4a. By following the well-
4b—
(isolated as a 17:83
2HCl mixture)
rot
(isolated as a 58:42
mixture)
established Curran’s method,23 a kind of Eyring plot was built
up from the former data. The slope of the resultant graph was
directly correlated to the racemization rate constant (krac) and
the thermodynamic parameters for the racemization process
were calculated by using the Eyring equation.24 In addition, the
/
/
3c 4c
3b 4b—
Scheme 3 Formation of 5,5’-bistriazoles 4a−c from benzyl azide (1) and propargylamine
derivatives 2a−c.
2.2 Determination of configurational stability of 5,5'-bistriazoles 4
The determination of configurational stability of axially chiral half-life time of racemization (
τ
1/2rac) was determined from the
rate constant (Scheme 5).§ The process was studied at
ambient temperature (25 C) in 85:15 n-hexane/EtOH solution
(HPLC conditions). The free Gibbs activation energy barrier to
racemization (
G‡rac) of atropisomeric bistriazole 4a was
determined to be ca. 18.8 kcal/mol and the corresponding
half-life time ( 1/2rac) was ca. 9 h at 25 C.
5,5’-bistriazoles has never been accomplished to date,
although it has been often stated that quantitative information
on this issue would open new avenues for the application of
these heterobiaryl atropisomers as chiral ligands in transition
metal-mediated asymmetric catalysis,15l,m as it is the case for
biaryl atropisomers.22
º
ꢀ
τ
º
The study of dynamic axial chirality in atropisomeric 5,5’-
bistriazoles for the determinination of the configurational
stability requires to perform kinetic studies allowing the
determination of key physical parameters such as rate
Me2N
Ph
Me2N
Ph
N
N
25 ºC
N
N
N
N
N
N
N
N
n-hexane/EtOH (85:15)
N
N
constants (k), half-life times (
energies (
G‡) for the racemization processes.
As the starting point in this study, we selected bistriazole 4a
τ), and free Gibbs activation
racemization through
rotation: fast process at rt
ꢀ
Ph
NMe2
Ph
NMe2
(Ra)-4a
(Sa)-4a
,
ꢀG‡rot = ꢀG‡rac = 18.8 0.1 kcal/mol
τ1/2rac ≈ 9 h at 25 ºC
where only axial chirality is present. Conditions for semi-
preparative chiral HPLC separation of the enantiomeric
atropisomers were optimized (Scheme 4), and samples of (Ra)-4a
and (Sa)-4a became readily available (the 1st eluting enantiomer
Scheme 5 Rotational energy barrier and half-life time for axially chiral bistriazole 4a
(same results obtained from 4a-1 and 4a-2).
encoded as 4a-1, and the 2nd eluting one as 4a-2).§ The
Since we were particularly interested in configurationally stable
5,5’-bistriazoles for application in asymmetric catalysis, we next
decided to study the influence of bulkier substituents at the
bistriazole core on the rotation barrier of 4. To this end,
enantiopure (S)-N-methyl-N-propargyl-1-phenylethylamine (2d) was
reacted with benzyl azide (1).§ In this case, the conditions
previously optimized for bistriazole 4a afforded a 96:4 mixture of
monotriazole 3d and bistriazole 4d, respectively. After column
chromatography purification, the minor 5,5’-bistriazole 4d was
obtained in 8% yield as a 53:47 mixture of diastereomers (Scheme
6).
enantiomeric purity (ee measurement) of each atropisomer
was evaluated immediately after collecting the perfectly
separated fractions. Chiral HPLC analyses, however, revealed
slight erosion in the enantiopurity of both atropisomers 4a
and 4a . After 24 h in solution, the enantiomeric excesses
drastically droped to 16% ee and 14% ee for 4a and 4a-2,
-1
-
2
−
-1
respectively, according to chiral HPLC (Scheme 4). The
conformational lability of 4a in solution at room temperature
being clear from these results.
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branched group on the amino substituents at C-4 (i.e.; from
methyl to -methylbenzyl) is enough to extend the half-life
time of atropisomers up to >200 days, thus converting
enantio- and diastereomerically pure 5,5´-bistriazoles 4d and
4d into suitable ligand candidates for enantioselective
catalysis applications.
α
-
1
-
2
Scheme 6 Preparation of 4d from chiral, enantiopure alkyne 2d.
The two diastereomers of bistriazole 4d [(S,S,Ra)-4d and
(S,S,Sa)-4d] could be easily separated by means of semi-
preparative HPLC on a chiral stationary phase (the 1st eluting
diastereomer encoded as 4d
).§ To our delight, no epimerization at all was observed in this
case, even after one week in solution (Scheme 7).
-1, and the 2nd eluting one as 4d-
2
Scheme 8 Rotational energy barriers and half-life times for axially and centrally chiral
diastereomeric bistriazoles 4d-1 and 4d-2.
2.3 Application of 5,5’-bistriazoles 4 in the scandium-catalyzed
addition of indoles to isatins
Taking into account the coordinating characteristics of
bistriazoles
4, we decided to explore the use of the
corresponding scandium complexes in catalysis. We selected
Sc(OTf)3 as the metal source for the unique characteristics of
this rare earth metal triflate; i.e., its water-compatibility,
recoverability, and strong Lewis acidity. Furthermore, this
environmentally benign Lewis acid shows extremely high
catalytic activity in many transformations, facilitated by the
small ionic radius of scandium.25
Scheme 7 Resolution of a diastereomeric mixture of bistriazole 4e [(S,S,Ra/Sa)-4e] by
semi-preparative chiral HPLC.
To cover a broader range of temperature, the variable-
temperature (VT) 1H NMR study of 4d
-
1
and 4d
performed in toluene-d8. For both diastereomers, the
epimerization process became detectable at 338 K (65 C). The
results from VT-NMR experiments aided us to fix the
temperature at 348 K (75 C) for further studying the
epimerization kinetics of 4d and 4d in toluene-d8 by means
of dynamic 1H NMR spectroscopy. In this manner, we could
determine the rotational energy barriers ( and
G‡rot) of 4d
4d , respectively, which for these bistriazoles possessing axial
and central chirality correspond to the energy barrier to
epimerization (
G‡epim).§ We have summarized in Scheme 8 all
the relevant information arising from this study. As the most
remarkable conclusion, the simple introduction of an
-2 was
º
In particular, the scandium-catalyzed Friedel
alkylation of indoles ( ) with isatins ( ) emerged as the
application of choice26 for ligands
. This reaction usually
−Crafts (FC)
8
7
º
4
-1
-2
requires the use of multidentate nitrogen ligands at low
temperatures to achieve selectivity in favor of the desired
ꢀ
-1
chiral monoaddition products
(9) (Scheme 9), and we
-2
speculated on the suitability of 4·Sc(OTf)3 to achieve
chemocontrol of this reaction under convenient conditions.
ꢀ
α-
Scheme 9 Product divergence in Sc-catalyzed nucleophilic addition of indoles to isatins.
6 | J. Name., 2012, 00, 1-3
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The target 3-substituted 3-hydroxy-2-oxindole derivatives
927 are prominent core scaffolds commonly encountered in
drug candidates as well as in natural products exhibiting a
broad spectrum of biological and pharmacological activities.
For instance, this privileged pharmacophore constitutes the
core structure of the oncology drug candidate depicted in
(5.0 mol%) and the corresponding ligand by using a 1:1.1
metal-to-ligand ratio. Under these conditions, triazole
ligands 3a and 3d led to equimolar mixtures or exclusive
formation of undesired double addition product 10aa
,
respectively (entries 1 and 2). On the other hand, when 5,5’-
bistriazole 4a was used as the ligand, the desired single
addition product 9aa could be isolated in 93% yield and
Fig. 3, which was reported to display cytotoxic activity
28
against human cancer cell lines.
Other noteworthy
excellent chemoselectivity (96:4 9aa/10aa ratio) (entry 3).
examples (Fig. 3) include the elongation cycle inhibitor ECi829
The same trend was also observed for other isatin
electrophiles as well as indole nucleophiles when comparing
the catalytic performances and reaction outcomes imposed
by monotriazole 3a versus bistriazole 4a as scandium-
(a potent antimicrobial lead drug), the natural alkaloid
30
schewanelline
A
(an antitumor agent), the narrow-
spectrum inhibitor of Campylobacter jejuni (a major cause of
food-borne illness) CCG-198215, 31 and the inhibitor of
preadipocyte differentiation B528,32 potentially useful for
prevention and treatment of obesity, dyslipidemia, fatty liver
or diabetes.
supporting ligands for this transformation.
§
Table 3 Ligand effect in the Sc-catalyzed addition of N-methylindole (8a) to N-
methylisatin (7a)a
In addition, 3-hydroxy-3-indolyl-2-oxindoles containing a
hydroxy-substituted quaternary carbon stereocenter, are
key chiral building blocks used in enantioselective total
syntheses of complex natural products with a wide range of
Me
N
Me
N
Me
N
Sc(OTf)3 (5.0 mol%)
triazole-based
ligand (5.5 mol%)
O
OH
O
+
O
+
O
MeCN, 4 Å MS
rt, 18 h
N
N
N
N
biological activities, such as the fungal-derived alkaloid (
gliocladine C33 or the cyclotryptamine alkaloids (
folicanthine.34
+
+
)-
)-
Me
Me
Me
Me
10aa
−)- and (
7a
8a
9aa
Entry
Ligand
3a
9aa
/
10aab
9aa yield (%)c
10aa yield (%)c
1
2
3
4
5
6
7
8
56:44
0:100
96:4
57
0
36
99
6
3d
HN
N
NH
HO
HO
4a
93
62e
80e
Cl
Cl
O
O
4d
-
-
1
2
100:0d
80:20
0:100
n.r.h
0
N
4d
19
n.d.f
0
Ph
none
4ag
oncology drug candidate
ECi8
0
0
4ai
98:2j
87
1
NH
NH
Me
NH
Me
MeO
HO
HO
a
All reactions were conducted under argon atmosphere on a 0.2 mmol scale
F
Br
by using 1.0 equiv. of isatin 7a and 3.0 equiv. of indole 8a, and proceeded with
full conversion after 18 h at rt, unless otherwise indicated. b Determined by 1
O
O
O
H
N
N
N
c
H
H
NMR analysis of the crude reaction mixture. Yield of isolated pure product
d
e
f
Me
after column chromatography. 70% conversion. Racemic product. Not
determined. g Without Sc(OTf)3. h No reaction. i 1:2.2 metal/ligand ratio tested
by adding 11 mol% of 4a. j 90% conversion.
schewanelline A
CCG-198215
B528
Fig. 3 Selected examples of bioactive 3-hydroxy-3-indolyl-2-oxindole derivatives.
The enantiopure chiral bistriazoles 4d-1 and 4d-2 were
T
he Sc-catalyzed alkylation of N-methylindole (8a) with N-
methylisatin (7a) was chosen as our benchmark reaction,
and both bistriazoles and the corresponding monotriazoles
were evaluated in the reaction (Table 3). Reactions were
next tested in the reaction. While the relative configuration
of the stereogenic centers and axes in these ligands had
some influence on its relative performance (cf. entries 4 and
5, Table 3), in both cases 9aa was isolated as a racemic
product. According to these disappointing results, no further
attention was paid to the possibility of achieving
4
3
all conducted in MeCN in the presence of 4 Å molecular
sieves, and a 3:1 ratio of 8a and 7a, respectively, was used.
The catalyst systems were generated in situ from Sc(OTf)3
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enantiocontrol in the scandium-catalyzed FC reaction
mediated by axially chiral, enantiopure 5,5’-bistriazoles . It
is to be mentioned axially chiral urazoles26c and C2-
symmetric chiral bisoxazolines26a,b are, indeed, able to exert
enantiocontrol in this reaction. In any case, the current
ratios), products
9
being isolated with generally very high
4
yields (87−100%). The structures of products 9aa and 9fa,
derived from N-methylisatin (7a) and N-allylisatin (7f),
respectively, were unambiguously confirmed by SCXRD
analysis.§
design of axially chiral 5,5’-bistriazoles
excellent chemocontrol, delivering the target single addition
products
with optimal product selectivity.26a In this
4
leads to an
We were pleased to find that the FC reaction was also
working notoriously well with the parent indole 8b, bearing
a free NH group, in front of differently substituted isatins
9
regard, a plausible working model for the rationalization of
the observed chemoselectivity through the operation of a
coordination polymer, with scandium atoms connecting 4a
units, has been proposed.§
(Scheme 10B). The reactions of 8b with isatins 7a and 7c
proceeded with very high selectivities in almost all cases,
affording the corresponding products with 78 100%
−i
9
−
isolated yields. Structural characterization of 3-hydroxy-3-
indolyl-2-oxindole products 9eb and 9ib, derived from N-
benzyl-7-trifluoromethylisatin (7e) and N-allyl-5-chloroisatin
The crucial role of 4a as a multidentate ligand dictating the
product selectivity (9aa/10aa ratio) was further confirmed after
performing some control experiments (Table 3, entries 6
−
8). Full
(
7i), respectively, was unambiguously established by means
of SCXRD analysis.§ Interestingly, this ligand-controlled
methodology provided an atom-economical and
conversion was achieved by running the reaction with only
Sc(OTf)3 and no ligand added (entry 7). Under these conditions,
the 3,3-di(indolyl)-2-oxindole 10aa was found to be the exclusive
reaction product, consistently with previous literature results.26a
On the other hand, no reaction at all was observed with 4a in the
absence of Sc(OTf)3 (entry 8). Finally, the influence of the metal-
to-ligand ratio was also investigated. When a double amount of
4a (11 mol%) with respect to Sc(OTf)3 (5.0 mol%) was used,
straightforward access to some biologically relevant
compounds. In particular, 9hb is an important oncology drug
candidate28 (see Fig. 3) while 9ib is a novel C3 regioisomer of
the potent antimicrobial ECi829 (see Fig. 3).
The use of the more challenging N-benzylindole (8c) was
also investigated (Scheme 11). In general, electron-rich
indoles (like 8c) tend to undergo double FC reaction so that
single FC products need to be prepared through indirect
procedures.34c, 35 Gratifyingly, we succeeded to prepare
monoaddition products 9cc (Scheme 11Aa) and 9dc (Scheme
11Ba) from N-phenylisatin (7c) and N-benzylisatin (7d),
conversion slightly decreased
(cf. entries 3 and 8). The
scandium/ligand ratio was accordingly fixed to ca. 1:1, as
previously found for other multidentate ligand systems.26
With the optimized conditions in hand (see Table 3, entry
3), we then explored the substrate scope of the Sc-catalyzed,
Friedel-Crafts-type (FC) hydroxyalkylation of indole
respectively,
in
one-step
and
with
complete
nucleophiles (
8
) with isatins (
7
) in the presence of 4a
.
§
chemoselectivity by using 4a·Sc(OTf)3, although the
reactions could not be driven to completion. All attempts to
improve the yields of 9cc or 9dc by increasing reaction time
Initially, we studied the scope of isatin electrophiles in
front of N-methylindole (8a) as the nucleophile (Scheme
10A). Under the conditions previously optimized with N-
methylisatin 7a, the scope was successfully extended to a
or temperature were unsuccessful, and
a complete
selectivity switch in favor of the doubly alkylated product
10cc (Scheme 11Ab) or 10dc (Scheme 11Bb) was observed
when the loading of catalyst was increased to 10 mol%.
Interestingly, the structures of products 9cc and 10dc could
be unambiguously established by means of SCXRD analysis.§
broad range of N-substituted isatins (7c−g) tolerating aryl,
benzyl, allyl and propargyl N-substituents as well as to the
parent isatin 7b bearing a free NH group. In all cases, the use
of bistriazole 4a led to very high chemoselectivities (9/10
8 | J. Name., 2012, 00, 1-3
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R3
N
R3
R3
N
N
O
Sc(OTf)3 (5.0 mol%)
bistriazole 4a (5.5 mol%)
R2
OH
R2
O
+
O
+
R2
O
MeCN, 4 Å MS
rt, 18 h
N
R1
N
R3
N
R1
N
R1
10
7a−i
8a or 8b
(3.0 equiv.)
9
(15 examples)
(mostly traces)
(1.0 equiv.)
A) N-Methylindole (8a) with isatins
Me
N
Me
Me
N
Me
N
N
OH
OH
OH
OH
O
O
O
O
N
N
N
N
Me
H
Ph
Bn
9aa, 93% yield
(96:4 9aa/10aa)
[ 9aa, X-ray ]
9ba, 49% yield (62% conv.)
(96:4 9ba/10ba)
9ca, 87% yield
(99:1 9ca/10ca)
9da, 88% yield
(90:10 9da/10da)
Me
N
Me
N
Me
N
OH
OH
OH
O
O
O
N
N
N
Bn
CH2CH=CH2
CH2C
CH
CF3
9ea, 100% yield
(100:0 9ea/10ea)
9fa, 89% yield
(89:11 9fa/10fa)
9ga, 89% yield
(100:0 9ga/10ga)
[ 9fa, X-ray ]
B) Indole (8b) with isatins
H
N
H
N
H
H
N
N
OH
OH
OH
O
OH
O
O
O
N
N
N
N
Me
Ph
Bn
Bn
CF3
9ab, 81% yield
(100:0 9ab/10ab )
9cb, 79% yield
(100:0 9cb/10cb)
9db, 84% yield
(98:2 9db/10db)
9eb, 96% yield
(100:0 9eb/10eb)
[ 9eb, X-ray ]
H
N
H
N
H
N
H
N
OH
OH
OH
OH
Cl
Cl
O
O
O
O
N
N
N
N
CH2CH=CH2
CH2C CH
9gb, 84% yield
(98:2 9gb/10gb)
Bn
9hb, 78% yield
(80:20 9hb/10hb)
CH2CH=CH2
9ib, 95% yield
(100:0 9ib/10ib)
9fb, 100% yield
(100:0 9fb/10fb)
[ 9ib, X-ray ]
Scheme 10 Scope of the FC reaction of indoles 8a and 8b with isatins 7a−i catalyzed by 4a·Sc(OTf)3.
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5-bromoindole (8g) and 6-chloroindole (8h) in the reaction
with 7d revealed perfect selectivity but moderate conversion
under standard conditions (5.0 mol% catalyst loading). Also in
these cases, attempts to increase conversion with the use of a
higher catalyst loading led to decreased chemoselectivity. The
solid-state structure of 9dh was unequivocally elucidated by
SCXRD analysis.§
Bn
Bn
Bn
N
N
N
Sc(OTf)3 / 4a
(5.0 / 5.5 mol%
or
O
OH
10 / 11 mol%)
+
+
O
O
O
MeCN, 4 Å MS
rt, 18 h
N
R1
N
N
N
R1
Bn
R1
7c or 7d
(1.0 equiv.)
8c
(3.0 equiv.)
9cc or 9dc
10cc or 10dc
A) N-Phenylisatin (7c) as electrophile
a)
b)
Bn
Bn
Bn
N
N
N
3. Conclusions
OH
A
new family of 5,5’-bistriazole ligands featuring
appropriately tethered aminomethyl substituents ( ) has been
developed. Compounds display axial chirality both in solution
O
O
4
N
N
4
Ph
Ph
and in the solid state, as confirmed by SCXRD
characterization.§
At 5.0 mol% catalyst loading:
9cc, 42% yield (50% conv.)
(100:0 9cc/10cc)
At 10 mol% catalyst loading:
10cc, 65% yield (86% conv.)
(0:100 9cc/10cc)
[ 9cc, X-ray ]
The configurational stability of atropisomeric 5,5’-bistriazoles
B) N-Benzylisatin (7d) as electrophile
4
has been determined for the first time making use of
dynamic chiral HPLC or 1H NMR measurements. While the
solely axially chiral 4a suffers from relatively fast
racemization process (half-life time of ca. 9 h at room
temperature), axially and centrally chiral bistriazole 4d
a)
b)
Bn
Bn
Bn
N
N
N
a
OH
O
O
N
N
,
Bn
Bn
derived from a bulky, enantiopure propargylamine, proved to
be configurationally stable under ambient conditions (half-life
time of up to ca. 201 days).
At 5.0 mol% catalyst loading:
9dc, 32% yield (35% conv.)
(100:0 9dc/10dc)
At 10 mol% catalyst loading:
10dc, 48% yield (70% conv.)
(24:76 9dc/10dc)
[ 10dc, X-ray ]
Scheme 11 Outcome of the FC reaction of isatin 7c or 7d with the challenging
nucleophile N-benzylindole (8c).
The potential of compounds
demonstrated through the implementation of
chemoselective Friedel Crafts-type hydroxyalkylation of
4
as catalytic ligands has been
a
highly
−
The scope of indole substrates in the selective
hydroxyalkylation was completed by exploring the use of
indoles with isatins. This transformation tolerated a very broad
substrate scope (23 examples) while delivering a wide variety
of biologically relevant 3-hydroxy-3-indolyl-2-oxindole
derivatives (including two drug candidates) with good to
excellent yields (79% average yield).
indoles 8d
(Scheme 12). The FC reaction of 5-methoxyindole
catalyzed by 4a·Sc(OTf)3 proceeded with total selectivity and
quantitative yield with both N-methylisatin 7a and N-
benzylisatin 7d). The drug-like, fluorinated 3-hydroxy-3-
−
h
bearing substituents at the aromatic ring
(
8d
)
(
)
(
indolyl-2-oxindoles 9de and 9df were also efficiently prepared.
Finally, the reaction outcome found for the more challenging
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H
N
H
H
N
N
R4
R4
O
Sc(OTf)3 (5.0 mol%)
bistriazole 4a (5.5 mol%)
OH
R4
O
+
R4
O
+
O
MeCN, 4 Å MS
rt, 18 h
N
R1
N
N
R1
N
R1
H
7a or 7d
(1.0 equiv.)
8d−h
(3.0 equiv.)
9
10
(mostly traces)
(6 examples)
H
H
H
N
H
N
N
N
F
OH
OH
OH
OH
MeO
MeO
F
O
O
O
O
N
N
N
N
Me
Bn
Bn
Bn
9ad, 97% yield
(100:0 9ad/10ad)
9dd, 100% yield
(100:0 9dd/10dd)
9de, 71% yield
(95:5 9de/10de)
9df, 71% yield
(95:5 9df/10df)
H
H
N
N
Cl
OH
OH
O
Br
O
N
N
Bn
Bn
At 5.0 mol% catalyst loading:
9dg, 34% yield (35% conv.)
(100:0 9dg/10dg)
At 5.0 mol% catalyst loading:
9dh, 31% yield (40% conv.)
(100:0 9dh/10dh)
[ 9dh, X-ray ]
At 10 mol% catalyst loading:
9dg, 66% yield (75% conv.)
(88:12 9dg/10dg)
At 10 mol% catalyst loading:
9dh, 37% yield (80% conv.)
(53:47 9dh/10dh)
Scheme 12 Scope of the FC reaction of isatin 7a or 7d with indoles 8d−h catalyzed by 4a·Sc(OTf)3.
1
C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem.,
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Acknowledgements
−
2
This work was funded by MINECO (Grant CTQ2015-69136-R),
−
the Generalitat de Catalunya (Grant 2014SGR827) and the
CERCA Programme (Generalitat de Catalunya). We also thank
MINECO for support through the Severo Ochoa Excellence
3
,
−
−
Accreditation 2014−2018 (SEV-2013-0319).
,
1
−
−
Notes and references
4
5
6
For a leading review, see: P. Thirumurugan, D. Matosiuk and
K. Jozwiak, Chem. Rev., 2013, 113, 4905-4979.
For a leading review, see: L. Li and Z. Zhang, Molecules, 2016,
‡ pKa values in water (ordered according to acidity scale):
NaOCH2CF3/TFE = 12.5; NaOBn/BnOH = 15.4; NaOMe/MeOH =
15.5; NaOEt/EtOH = 16.0; NaOiPr/iPrOH = 16.5.
§ See the ESI† for details.
21, 1393/1
For leading reviews, see: (a) K. Kempe, A. Krieg, C. R. Becer
and U. S. Schubert, Chem. Soc. Rev., 2012, 41, 176 191; (b)
−1393/22.
−
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Journal Name
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