Metal-nitroalkene and aci-nitro intermediates in catalytic enantioselective friedel-crafts reactions of indoles with trans-β-nitrostyrenes

Article abstract of DOI:10.1021/om401125q

The half-sandwich aqua complex (S_Rh,R_C)- [(η⁵-C₅Me₅)Rh{(R)-Prophos}(H ₂O)][SbF₆]₂ (Prophos = propane-1,2- diylbis(diphenylphosphane)) efficiently catalyzes the asymmet

Full text of DOI:10.1021/om401125q

Communication
pubs.acs.org/Organometallics
Metal−Nitroalkene and aci-Nitro Intermediates in Catalytic
Enantioselective Friedel−Crafts Reactions of Indoles with trans-β-
Nitrostyrenes
́
́
Daniel Carmona,* Isabel Mendez, Ricardo Rodrıguez,* Fernando J. Lahoz, Pilar Garcıa-Orduna,
́
̃
and Luis A. Oro
́
́
́
Departamento de Quımica Inorgan
́
ica, Instituto de Sıntesis Quımica y Catal
́
isis Homogen
́
ea (ISQCH), CSIC-Universidad de
Zaragoza, Pedro Cerbuna 12, 50009 Zaragoza, Spain
S
* Supporting Information
ABSTRACT: The half-sandwich aqua complex (SRh,RC)-[(η5-
C5Me5)Rh{(R)-Prophos}(H2O)][SbF6]2 (Prophos = pro-
pane-1,2-diylbis(diphenylphosphane)) efficiently catalyzes the
asymmetric reaction between N-methyl-2-methylindole and
trans-β-nitrostyrenes (up to 94% ee). The metal−nitroalkene
complex involved has been characterized by X-ray crystallography, and the aci-nitro intermediate complex has been
spectroscopically detected. A plausible catalytic cycle is proposed.
he catalytic asymmetric Friedel−Crafts (FC) alkylation of
Taromatic substrates with electron-deficient alkenes is a key
reaction in synthetic organic chemistry that enables the
formation of new C−C bonds.1 In the past few years, the
addition of indoles to nitroolefins has attracted considerable
attention, due to the synthetic versatility of the nitro group,
which allows further derivatization leading to the synthesis of
pharmacologically active molecules.2 A variety of chiral
Figure 1. Catalyst precursor 1.
catalysts, including organocatalysts such as bis-sulfonamides,2k
thioureas,2j,3 and phosphoric acids2f,h,4 as well as Zn,2e,5
reaction with N-methyl-2-methylindole, in which an ee value of
94% was achieved (see the Supporting Information).
A series of trans-β-nitrostyrenes was subsequently inves-
tigated in the reaction with N-methyl-2-methylindole catalyzed
by the rhodium complex 1 (Table 1). In the cases of 3- and 4-
substituted aromatic nitroalkenes, high conversions were also
obtained (entries 3, 4, 6−9, 11, and 13). Probably due to steric
Cu,2d,g,6 and, to a lesser extent, Ni,2a Al,2i Pd,7 and Pt8 salts
(mostly containing nitrogen donor ligands as chiral sources)
have been successfully applied to this reaction.
For metal-based catalytic systems, activation of nitroolefins
through bidentate coordination to the metal2a,5g,6d and
bifunctional mechanisms, which involve the simultaneous
interaction of both the nitroolefin and the indole with the
catalyst,5a,e,f,6a,b have been suggested. On the other hand, Arai
and co-workers have hypothesized the formation of a nitronate
intermediate in the Cu-catalyzed tandem Friedel−Crafts/Henry
reaction of nitroalkenes, indoles, and aldehydes9 as well as in
the Friedel−Crafts/protonation of indoles and nitroacrylates.10
However, to our knowledge, there is no experimental proof for
intermediates involved in these reactions.
Herein, we disclose an unexpected catalytic pathway for the
FC reaction between trans-β-nitrostyrenes and indoles
catalyzed by the aqua complex11 (SRh,RC)-[(η5-C5Me5)Rh-
{(R)-Prophos}(H2O)][SbF6]2 (1; Prophos = propane-1,2-diyl-
bis(diphenylphosphane)) (Figure 1), which involves the
formation of uncommon metal−nitroalkene, metal−aci-nitro,
and free aci-nitro intermediates.12
hindrance, 2-substitution strongly lowered both the yield and
ee (entries 5, 10, and 12). Enantioselection also decreased for
nitroalkenes bearing substituents on the 3- and 4-positions but
to a moderate extent for electron-donating substituents and
more markedly for electron-withdrawing substituents.
To gain some insight into the mechanism of this catalytic
process, the reaction between the catalyst precursor (SRh,RC)-
[(η5-C5Me5)Rh{(R)-Prophos}(H2O)][SbF6]2 (1) and the
substrates N-methyl-2-methylindole and trans-β-nitrostyrene
was studied. Addition of the indole to solutions of 1 did not
produce significant changes in the NMR spectra of the metal
derivative. However, the addition of 1 equiv of nitroalkene at
193 K to CD2Cl2 solutions of 1 in the presence of 4 Å
molecular sieves yielded the clean formation of the nitroalkene
complex 2a (Figure 2). The reaction proceeded diastereose-
At the outset of this work, we examined the catalytic activity
of 1 for the reaction of trans-β-nitrostyrene with a variety of
indoles. In general, enantioselectivities were poor except for the
Received: November 21, 2013
© XXXX American Chemical Society
A
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Table 1. Asymmetric FC Reaction of N-Methyl-2-
a
methylindole with trans-β-Nitrostyrenes
bc
,
d
entry
R
t (min)
conversn (%)
ee (%)
1
H
10
30
15
5
99 (93)
41 (37)
>99 (94)
>99 (93)
32 (25)
>99 (91)
99 (94)
99 (94)
94 (90)
50 (46)
99 (91)
54 (51)
>99 (90)
29 (25)
94
84
92
74
9
2
2-OMe
3-OMe
4-OMe
2-OBn
3-OBn
4-OBn
4-Me
3
4
5
150
5
6
79
81
71
65
27
53
38
66
74
Figure 3. (a) Molecular structure of the cation of (SRh,RC)-[(η5-
C5Me5)Rh{(R)-Prophos}(4-chloro-β-nitrostyrene)][SbF6]2 (2d). Hy-
drogen atoms have been omitted for clarity. (b) Intramolecular CH/π
interactions.
7
10
5
8
9
4-OH
2-Cl
5
10
11
12
13
14
30
10
150
10
180
4-Cl
2-Br
Furthermore, in this conformation the nitroalkene C(39)-Si
face becomes hindered by the pro-S phenyl ring of the P(1)Ph2
group (C(17)−C(22)) and, therefore, the indole attack would
take place preferentially through the Re face, rendering S-
configured Friedel−Crafts products.
4-Br
2,3-(OMe)2
a
Reaction conditions: catalyst 0.03 mmol (5.0 mol %), indole 0.60
mmol, trans-β-nitrostyrene 0.90 mmol, 100 mg of molecular sieves in 4
b
c
mL of CH2Cl2. Based on indole. Determined by NMR. Yield of
isolated product given in parentheses. Determined by HPLC.
After coordination of the nitroalkene, the next step of the
catalytic cycle would be the reaction of the nitroalkene complex
with the indole. To confirm this proposal, the reaction of
preformed 2a with N-methyl-2-methylindole was monitored by
d
1
NMR spectroscopy (Figure 4). Selected regions of the H and
31P NMR spectra are also depicted in Figure 4.
Trace A in Figure 4 shows the spectra at 193 K of 2a in these
regions: residual dichloromethane in the proton NMR
spectrum and the doublet of doublets assigned to the P2
phosphorus nucleus of 2a in the 31P NMR spectrum. After
the addition at 193 K of 5 equiv of the indole and 10 equiv of
trans-β-nitrostyrene, the immediate disappearance of 2a with
concomitant formation of two diastereomers of the rhodium
aci-nitro complex 3 in a ca. 70:30 molar ratio was observed
(Figure 4, trace B). Complexes 3 were characterized by two
pairs of coupled doublets centered at 6.22 (Hα) and 5.29 (Hβ)
ppm (major isomer) and at 6.10 (Hα) and 4.81 (Hβ) ppm
(minor) together with a strongly deshielded broad resonance at
about 17.5 ppm attributed to the OH functionality (trace B).
Correspondingly, the 31P NMR spectrum shows two new
doublets of doublets (one much less abundant) attributed to
the P2 nuclei of two isomers of 3.15 At 193 K, these NMR
spectra did not change for hours. However, when the solution
was heated to 223 K for 20 min and then the NMR spectra
were recorded at 193 K,16 the gradual consumption of the
indole with the concomitant appearance of aci-nitro compound
Figure 2. Metal−nitroalkene complexes 2.
lectively with no apparent intermediates, and notably, it affords
only one of the two possible epimers at the metal, as indicated
by the detection of only one set of NMR signals from 193 to
293 K.
Related rhodium complexes containing trans-β-nitrostyrenes
with different substituents on the nitroalkene aromatic ring
(2b−d) have been prepared in a similar manner. The most
striking feature of their NMR spectra was the strong shielding
observed for the Hβ proton (Figure 2) of the coordinated
nitroalkene (about 1 ppm), with concomitant deshielding of
the Cβ carbon (about 8 ppm), with respect to the free molecule.
The activation of the Cβ toward nucleophilic attack becomes
apparent. On the other hand, the NOE relationship between
the Hβ proton of the nitroalkenes and the aliphatic protons H11,
H21, and H22 of the Prophos ligand (see Figure 1) indicated an
S configuration at the metal in all of the studied complexes.
The crystal structure of the trans-4-chloro-β-nitrostyrene
rhodium derivative 2d has been determined by X-ray
crystallography13 (Figure 3). The most interesting feature of
the structure is the establishment of intramolecular CH/π
interactions involving the Hβ proton (H(39) in Figure 3b) and
the pro-R phenyl ring of the P(2)Ph2 group.14 These
interactions place the Hβ proton of this ligand inside of the
electronic diamagnetic ring current of the phenyl ring of the
P(2)Ph2 group (Figure 3b). and most probably, they are also
operating in solution, giving rise to the strong shielding
observed for this proton in the 1H NMR spectrum.
3
4 (Figure 4) was readily observed: the Hβ (5.58 ppm, J = 8.1
Hz) and OH (13.56 ppm) signals of 4 grew at the expense of
the C3−H indole proton resonance at 6.25 ppm (traces B−E).
Further heating to 223 K gave rise to the progressive and
complete rearrangement of the aci-nitro compound 4 to the
corresponding FC adduct 5.15 On the other hand, when all the
indole was consumed, the remaining trans-β-nitrostyrene
displaced coordinated aci-nitro, regenerating the nitroalkene
complex 2a (trace F).
Taking together all the above experimental data, the catalytic
cycle depicted in Figure 5 can be proposed. The coordinated
water molecule in 1 is displaced by trans-β-nitrostyrene, giving
B
dx.doi.org/10.1021/om401125q | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Communication
detected. This fact, together with the establishment of CH/π
interactions between the Hβ proton of the coordinated
nitroalkene and the pro-R phenyl ring of the P(2)Ph2 group
of the diphosphane, explains the high ee obtained. Detection of
the aci-nitro ligated complex 3 opens the door to application of
complexes of the type 1 in related catalytic processes involving
nitroalkenes as electrophiles as well as to enantioselective
catalytic tandem reactions pivoting around coordinated nitro-
nates. Further studies along these lines are currently under
investigation in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, tables, and a CIF file giving experimental details,
spectroscopic data, and X-ray crystallographic data, including
full details of the structural analysis of complex 2d. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: dcarmona@unizar.es (D.C.); riromar@unizar.es
(R.R.).
■
Notes
The authors declare no competing financial interest.
Figure 4. Selected regions of the 1H and 31P NMR spectra of a 1/10/5
catalyst/trans-β-nitrostyrene/indole molar ratio mixture at 193 K: (A)
spectra of 2a; (B) spectra after the addition of indole and trans-β-
nitrostyrene; (C−E) spectra recorded at 193 K after successive heating
at 223 K for 20 min; (F) spectra after total consumption of the indole.
The asterisk denotes residual CHDCl2.
ACKNOWLEDGMENTS
The authors aknowledge the Ministerio de Educacion
(Grants CTQ 2009-10303/BQU and CTQ 2012-32095) and
■
́
y Ciencia
Gobierno de Aragon
Organometalicos Enantioselectivos) for financial support.
This work was supported by the CONSOLIDER INGENIO
́
(Grupo Consolidado: Catalizadores
́
́
́
2010 program under the project “Factorıa de Cristalizacion”
(CSD2006-0015). R.R. acknowledges the CSIC and European
Social Fund for a JAE-Doc grant.
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(16) At 213 K only broad unresolved NMR signals were recorded.
D
dx.doi.org/10.1021/om401125q | Organometallics XXXX, XXX, XXX−XXX