Tunable titanocene lewis acid catalysts for selective friedel-crafts reaction of indoles and N-sulfonylaldimines

Article abstract of DOI:10.1002/ejoc.201501122

A newc strategy to control the selective Friedel-Crafts reaction of indoles and imines under mild conditions was developed. Phenol derivatives were established as efficient ligands to finely tune the activity of titanocene dichloride. Cp₂TiCl₂ and phenol catalyzed the mono-Friedel-Crafts reaction of indoles and N-sulfonyl aldimines with good yields (91 %), whereas o-aminophenol significantly enhanced the activity of the titanocene catalyst and promoted the synthesis of bisindole with excellent yields (98 %). The new organometallic Lewis acid catalysts are air-tolerant, can be used with low catalyst loading (3 mmol-%) and are compatible with -NO₂, -F, -Cl, -Br, and -OMe (30 examples with yields from good to excellent). The titanocene catalysts were fully characterized by NMR and HRMS analysis. The results suggest that Cp₂TiCl(OC₆H₅) (I) and Cp₂TiCl(OC₆H₄NH₃⁺Cl^-) (II) were catalytic species for the mono- and double-Friedel-Crafts reactions, respectively. Distinguished from single functional acid catalysts I, catalyst II showed a catalytic cooperative effect of two acid components, which led to a fine tuning of the reactivity as well as to the selectivity of the desired reaction pathways. A Ti-catalyzed, highly selective Friedel-Crafts reaction of indoles and imines has been developed. Cp₂TiCl₂ and phenol, with a single Lewis acid site, catalyzed the mono-Friedel-Crafts reaction of indoles and N-sulfonylaldimines, whereas o-aminophenol enhanced the acidity of titancene catalyst, enabling both Lewis and Bronsted acid sites to promote the synthesis of bisindole.

Full text of DOI:10.1002/ejoc.201501122

DOI: 10.1002/ejoc.201501122
Full Paper
Selective Catalysis
Tunable Titanocene Lewis Acid Catalysts for Selective Friedel–
Crafts Reaction of Indoles and N-Sulfonylaldimines
Xiu Wang,[a][‡] Zhenhua Wang,[a][‡] Guofang Zhang,[a] Weiqiang Zhang,[a] Ya Wu,*[a] and
Ziwei Gao*[a]
Abstract: A new strategy to control the selective Friedel–Crafts (3 mmol-%) and are compatible with –NO2, –F, –Cl, –Br, and
reaction of indoles and imines under mild conditions was devel- –OMe (30 examples with yields from good to excellent). The
oped. Phenol derivatives were established as efficient ligands titanocene catalysts were fully characterized by NMR and HRMS
to finely tune the activity of titanocene dichloride. Cp2TiCl2 and analysis. The results suggest that Cp2TiCl(OC6H5) (I) and
phenol catalyzed the mono-Friedel–Crafts reaction of indoles Cp2TiCl(OC6H4NH3+Cl–) (II) were catalytic species for the mono-
and N-sulfonyl aldimines with good yields (91 %), whereas o- and double-Friedel–Crafts reactions, respectively. Distinguished
aminophenol significantly enhanced the activity of the titano- from single functional acid catalysts I, catalyst II showed a cata-
cene catalyst and promoted the synthesis of bisindole with ex- lytic cooperative effect of two acid components, which led to a
cellent yields (98 %). The new organometallic Lewis acid cata- fine tuning of the reactivity as well as to the selectivity of the
lysts are air-tolerant, can be used with low catalyst loading desired reaction pathways.
Introduction
the double-Friedel–Crafts reaction was achieved. This case ef-
fectively confirmed that the selectivity of the Friedel–Crafts re-
action can be controlled by tuning the Lewis acidity of catalysts.
Unfortunately, metal triflates are intrinsically unstable and re-
quire inert atmosphere for manipulation. Therefore, a tunable
organometallic Lewis catalyst that can be adjusted by altering
the ligands, and that can be used to promote the selective
Friedel–Crafts reaction, is appealing.
Indolylalkane and its derivatives are a class of metabolites that
are widely distributed in flowering plants and in continental or
marine protozoa. Both 3-indolylmethanamine and bis(3-indol-
yl)methane derivatives are pivotal structural motifs of natural
products, pharmaceuticals, and agrochemicals. They are also
key intermediates for the synthesis of complexes of alkaloids,
which can be used to build dendrimer skeletons.[1] Friedel–
Crafts reactions represent the main thoroughfare by which C–C
bonds are introduced on the indole framework.[2] Consequently,
numerous catalytic systems have been developed for the
mono-Friedel–Crafts reaction such as SnCl4,[3] InCl3,[4]
Titanocene dichloride is of great interest as an organometal-
lic Lewis acid precursor because of its kinetic stability, diverse
range of coordination modes and electronically tunable Lewis
acid centers.[16] Moreover, the coordination of soft organome-
tallic acceptors with hard donors of Brønsted acids might pro-
vide a new dimension for cooperative binary acid catalysis that
exhibit unexpected reactivity and selectivity patterns. Varying
co-ligands might change Lewis acidity of titanocene catalysts,
and therefore activate organic substrates for a desirable cata-
lytic cycle.[17]
Cu(OTf)2,[5] Yb(OTf)3 and bis(oxazoline)-CuII.[7] For double-
[6]
Friedel–Crafts reaction of indoles, FeCl3,[8] In(OTf)3,[9] Y(OTf)3,[10]
Dy(OTf)3,[11] LiClO4,[12] and [Ir(COD)(SnCl3)Cl(m-Cl)]2
showed
[13]
significant activity. However, most of these methods are limited
to the catalysis of either mono- or double-Friedel–Crafts reac-
tion because it is difficult to tune and tailor the acidity of the
Lewis acid catalyst.[14]
Jorge[15] attempted to develop a tunable catalyst system in
which the mono-Friedel–Crafts reaction of indoles and imines
was catalyzed by CuI(OTf), whereas in the presence of CuII(OTf)2
Herein, we reported a binary acid system featuring an air-
stable organometallic precursor, titanocene dichloride, com-
bined with simple organic cooperative Brønsted acids, which
catalyzed mild and highly efficient Friedel–Crafts reactions of
indoles and N-sulfonyl-substituted aldimines. Oxygen hard do-
nor ligands are important in the design of efficient catalysts
of early transition metals.[18] The mono-Friedel–Crafts products
were selectively obtained in good yields with phenol as ligand,
whereas the use of o-aminophenol as a co-ligand afforded bis-
indole with excellent yields. This mild, operationally simple, and
functional group compatible method is characterized by an ex-
quisite selectivity profile that is dictated by the mode of coordi-
nation. The mechanistic studies, including 1H NMR titration and
[a] Key Laboratory of Applied Surface and Colloid Chemistry, MOE, School of
Chemistry and Chemical Engineering, Shaanxi Normal University,
Xi'an 710062, P. R. China
E-mail: wuya@snnu.edu.cn
zwgao@snnu.edu.cn
http://english.snnu.edu.cn/
[‡] Xiu Wang and Zhenhua Wang contributed equally to this paper.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501122.
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ESI(+)-MS analysis, elucidated the interaction between Cp2TiCl2
and co-ligands, which illuminated an unexpected chemoselect-
ivity of the Friedel–Crafts reactions.
Results and Discussion
In light of our previous findings that salicylato-titanocene com-
plexes function as organometallic Lewis acids,[19] a selection of
oxygen donor ligands were examined in the reaction of N-
methylindole (1a) and N-(2-chlorobenzylidene)-4-methyl-
benzenesulfonamide (2a). Given the synergistic effect in C–C
forming reactions using binary catalysts of organometallic
Lewis acid and Brønsted acids, 5-sulfosalicylic acid, phthalic
acid, benzoic acid, and anthranilic acid were evaluated. None of
them provide satisfactory results, which indicated that strong
acids were unsuitable for the selective Friedel–Crafts reaction. We
hypothesized that a higher activity of binary acid systems could
be achieved by employing weak acids such as phenol and ana-
logues (Scheme 1). Gratifyingly, phenol drastically accelerated
the titanocene-catalyzed mono-Friedel–Crafts reaction and af-
forded 3a in 91 % yield with 95 % selectivity (3a/4a 95:5). The
use of functionalized phenols gave disappointing results. Strik-
ingly, the use of p-aminophenol as co-ligand resulted in a se-
lectivity switch under identical reaction conditions, favoring the
formation of 4a. To highlight the crucial and beneficial role
played by the amino group on the selectivity of the Friedel–
Crafts reaction, the amino group was masked and the catalyst
showed a preference for the formation of 3a. Parallel experi-
ments were performed to consider the effect of the steric and
electronic nature of the functional groups. Reactions with sub-
strates bearing an amino group in the meta- or para-position
of phenol were not comparable with o-aminophenol in terms
of reactivity or chemoselectivity because the steric hindrance
had a negative effect on coordination. o-Aminophenol was
found to be superior for the double-Friedel–Crafts reaction, af-
fording 98 % yield and up to 98 % selectivity (3a/4a 2:98). Fur-
ther screening involving substrates with other functional
groups such as methyl-, chloro-, or nitro-groups on the o-
aminophenol was also conducted. Benzene-1,2-diamine, featur-
ing two amino groups, was shown to be a valid ligand, indicat-
ing that oxygen is an integral part of complex formation
through coordination with titanium. This result supports the
conclusion that the coordination between phenol and
[Cp2TiCl2] is crucial for the formation of 3a and suppressed
competitive formation of 4a under basic conditions. On the
other hand, [Cp2TiCl2] coordinated with o-aminophenol, which
successfully tuned mono-Friedel–Crafts reaction to complete
double-Friedel–Crafts reaction. Control experiments carried out
under the same conditions showed, not surprisingly, that
[Cp2TiCl2] was almost inert in promoting the Friedel–Crafts reac-
tion; only 39 % yield of 3a was isolated.
Scheme 1. The effect of the ligand on the Ti-catalyzed selective Friedel–Crafts
reaction.
4–5). Upon reducing the catalyst loading to 3 mol-%, 3a was
isolated in 70 % yield and 4a in 90 % yield by employing differ-
ent co-ligands (entry 3). The use of an increased amount of 1a
gave 3a in excellent yield (91 %) and with a selectivity of up to
95 % (entry 6). The use of one extra equivalent of indole might
make the catalytic system less acidic and prevent 3a from being
consumed to produce 4a.[20] The 2:1 ratio of 1a and 2a was
also optimum for the double Friedel–Crafts reaction, producing
the product in 98 % yield and with 98 % selectivity (entry 6).
With the optimal reaction conditions in hand, we set out to
explore the generality of the mono-Friedel–Crafts reaction with
respect to a variety of indole derivatives and N-sulfonylald-
imines. As shown in Table 1, regardless of the electronic and
steric nature of the substituents, [Cp2TiCl2]-catalyzed mono-
Friedel–Crafts reaction provided exclusively the 3-indolylmeth-
anamine products in moderate to good yields, depending on
the employed co-ligands. Both electron-rich indole derivatives
and heteroaromatic compounds proved to be very effective,
affording the Friedel–Crafts addition products in good yields
(78–91 %) as single regioisomers (entries 1–5). The reactions of
N-methylindole and indole proceeded particularly smoothly to
afford the corresponding products in 91 and 89 %, respectively
(entries 1 and 2). Interestingly, the incorporation of bulky sub-
stituents at C2 of the indole did not have a detrimental effect
Emboldened by our initial success, a wide range of reaction on the reactivity (entry 3). N-(4-Methylphenyl)sulfonylarylimines
parameters were examined to determine the optimized reac- with various R4 groups reacted smoothly to give the corre-
tion conditions. As shown in Table S1 (see the Supporting Infor- sponding products in good yields. Weak electron-withdrawing
mation), the screening results indicated that a higher catalyst groups (entries 8–10) such as F, Cl, Br at the 4-position gave
loading (> 5 %) had a negative impact on the reaction (entries higher yields than substrates with an electron-donating group
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Table 1. Titanocene-catalyzed selective Friedel–Crafts reaction.[a]
Entry
1
2
Yield [%][b]
3
R1
R2
R3
R4
4
1
2
3
4
5
6
7
8
Me
H
H
H
H
Me
H
H
H
H
OPh
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
o-Cl
H
3a (91)
3b (89)
3c (78)
3e (79)
3f (80)
3d (56)
3g (84)
3i (84)
3j (89)
3k (78)
3l (53)
3m (67)
3n (70)
3o (62)
3h (82)
4a (98)
4b (93)
4c (90)
4e (98)
4f (84)
4d (80)
4g (95)
4i (90)
4j (97)
4k (90)
4l (70)
4m (85)
4n (74)
4o (87)
4h (90)
H
pyrrole
H
H
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
Br
H
Me
Me
Me
Me
Me
Me
Me
H
p-F
9
p-Cl
p-Br
p-NO2
o-OMe
p-OMe
p-OMe
H
10
11
12
13
14
15
H
[a] Reaction conditions: indole (2.0 mmol), N-sulfonylaldimine (1.0 mmol), [Cp2TiCl2] (0.03 mmol), phenol (0.06 mmol) or o-aminophenol (0.06 mmol), 25 °C,
CH3CN. [b] Isolated yield obtained after purification by column chromatography.
such as MeO (entries 12 and 13). Substrates with strong elec- I. The peak area ratio of the Cp protons of the new titanocene
tron-withdrawing groups such as nitro-substituted arylimine re- complex species I to Ha of the aromatic ring at δ = 6.63 ppm
acted much more slowly and gave relatively low yield (en- (red diamond) was 10:2, which presumably meant that only one
try 11).
We then examined the scope of the double-Friedel–Crafts
molecule of phenol was in coordination. The presence of the
new species was further supported by ESI(+)-MS experiments
performed in the positive ion mode (Scheme S1 in the Support-
ing Information). The ion peak at m/z 270.9534, corresponding
to [I-Cl]+, was detected in the CH3CN solution of Cp2TiCl2 and
phenol. The cationic titanocene moiety could be considered as
an evidence for the coordination between Cp2TiCl2 and phenol.
Moreover, other groups[22,23] have experimentally demonstrated
reaction. The reactions of various indole derivatives with 2a
were not significantly influenced by the electronic properties of
the indole ring (Table 1, entries 1–6). For example, 1-methyl-, 2-
methyl-, 5-benzyloxy-indole and indole, with electron-donating
groups, were all excellent substrates for the reaction, resulting
in 90–98 % yield, with up to 93 % selectivity. The introduction
of an electron-withdrawing group onto the indole ring led to a
slight decrease in yield (entry 6). The generality of the reaction
was further extended by varying the imines. Aryl imines with
different electronic properties (entries 9–10, 11, and 14–15)
could be readily converted into the desired adducts in 85–97 %
yield with excellent selectivity. The use of a strong electron-
withdrawing or an electron-donating group as R4 group in the
para-position was detrimental to the performance of the reac-
tion (entries 11 and 13).
To shed light on the action of titanocene Lewis acid catalysts
for selective Friedel–Crafts reaction, the interaction between
Cp2TiCl2 and co-ligands were investigated by 1H NMR and
ESI(+)-MS analysis. 1H NMR experiments, which were conducted
using Cp2TiCl2 and phenol in CDCl3 (Figure 1), showed that no
coordination occurred and only one Cp singlet of Cp2TiCl2 at
δ = 6.59 ppm (purple triangles) was detected. When base
aniline was added,[21] a new titanocene complex species I was
formed, which resonated at δ = 6.39 ppm (red circle). The signal
of I increased whereas that of Cp2TiCl2 declined gradually. Fi-
nally, the mixture was composed almost completely of complex
Figure 1. 1H NMR spectra of a titration of a mixture of [Cp2TiCl2] (1.0 equiv.)
and phenol (2.0 equiv.) in CDCl3. ▲ Cp protons of [Cp2TiCl2]; ● Cp protons of
[Cp2TiCl(OPh)]; Spectrum a obtained from a mixture of Cp2TiCl2 and phenol;
Spectrum b obtained by adding aniline (1.0 equiv.) to a.
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that coordination of epoxides to Cp2TiCl2 is accompanied by scribed above. 1H NMR spectra were recorded using Cp2TiCl2
dissociation of the chloride anion to form the true and o-aminophenol in [D6]DMSO (Figure 2). Cp protons of the
cationic active species. Therefore, it can be concluded that in new titanocene complex species II at δ = 6.48 ppm (red circle)
the mono-Friedel–Crafts reaction, precatalyst titanocene dichlo-
ride is readily converted into one detectable titanocene species
in CD3Cl and presumably Cp2TiCl(OC6H5) I complex was the true
catalyst.
were observed. The active hydrogen atom of II was observed
at δ = 9.75 ppm (red diamond), and this atom represented the
key to changing the pathway from mono- to double-Friedel–
Crafts reaction. Ion peaks at m/z 286.0693 and 322.0451, corre-
The interaction between Cp2TiCl2 and o-aminophenol was sponding to [II-2Cl]2+ and [II-Cl]+, respectively, were detected
further illustrated by conducting the same experiments de- (Scheme S2 and S3 in the Supporting Information). The cationic
Figure 2. 1H NMR spectra of a titration of a mixture of [Cp2TiCl2] (1.0 equiv.) and o-aminophenol (2.0 equiv.) in [D6]DMSO. ▲ Cp protons of [Cp2TiCl2]; ● Cp
protons of [Cp2TiCl(OPhNH3+Cl–)]; ◆ active hydrogen of [Cp2TiCl(OPhNH3+Cl–)]; Spectrum c obtained from the o-amniophenol; Spectrum d obtained by adding
Cp2TiCl2 to c.
Scheme 2. Proposed mechanism for titanocene-catalyzed selective Friedel–Crafts reactions.
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EtOH was collected in the oil–water separator and released at regu-
lar intervals. After cooling, the residue of the reaction was recrystal-
lized twice from EtOAc/hexanes.
titanocene moieties could be considered as a support for
coordination of Cp2TiCl2 with one molecule of o-aminophenol.
This suggested that in the double-Friedel–Crafts reaction,
precatalyst titanocene dichloride was easily converted into
the detectable titanocene species in [D6]DMSO, and
Cp2TiCl(OC6H4NH3+Cl–) II might be the true catalyst.
General Procedure for the Catalytic Mono-Friedel–Crafts Reac-
tion: A nitrogen-flushed 10 mL test tube, equipped with a magnetic
stirrer and a septum, was charged with N-sulfonyl aldimines 1
(1.0 mmol) and indole 2 (2.0 mmol) in one portion. Cp2TiCl2
(0.03 mmol) and phenol (0.06 mmol) were added at 25 °C in CH3CN
and the mixture was stirred until the reaction was completed as
indicated by TLC. The solvent was removed under reduced pressure
and the residue was purified by flash column chromatography on
neutral silica gel (ethyl acetate/n-hexane) to afford the product,
A
proposed cooperative catalytic cycle is outlined in
Scheme 2. Titanocene dichloride coordinates with phenol and
transforms into [Cp2Ti(OC6H5)]+ [I-Cl]+ with the single functional
Lewis acid site. The first step is the formation of A, which is
formed by coordination of N-sulfonylaldimine with oxophic TiIV
ion. N-Sulfonylaldimine is activated by I to increase the electro-
philicity of the imine carbon of A. The nucleophilic carbon of
indole attacks the imine carbon of A leading to the formation
of the Friedel–Crafts product in transition state B. Once the
product is released, Ti chelate ion I is regenerated. Similarly,
Cp2TiCl2 coordinates with o-aminophenol to produce catalyst
Cp2TiCl(OC6H4NH3+Cl–) II ion, which bears both Lewis and Brøn-
sted acid sites. Subsequently the addition of N-sulfonylaldimine
1
which was characterized by H and 13C NMR spectroscopy.
General Procedure for the Catalytic Double-Friedel–Crafts Reac-
tion: A nitrogen-flushed 10 mL test tube, equipped with a magnetic
stirrer and a septum, was charged with N-sulfonylaldimines 1
(1.0 mmol) and indole 2 (2.0 mmol) in one portion. Cp2TiCl2
(0.03 mmol) and o-aminophenol (0.06 mmol) were added at 25 °C
in CH3CN and the mixture was stirred until the reaction was com-
pleted as indicated by TLC. The solvent was removed under reduced
with indole leads to the formation of 3-indolylmethanamine pressure and the residue was purified by flash column chromatogra-
phy on neutral silica gel (ethyl acetate/n-hexane) to afford the prod-
through states C and D. The association of 3-indolylmethan-
amine from II triggers its reaction with another indole to form
bisindole compounds[24] (see the transition state E). Then the
Ti chelate ion II is again formed.
1
uct, which was characterized by H and 13C NMR spectroscopy.
Acknowledgments
This work was supported by the 111 Project (B14041), grants
from the National Natural Science Foundation of China (NSFC)
(grant numbers 21271124, 21272186, 21371112, and 21446014),
the Fundamental Funds Research for the Central Universities
(grant number GK201501005), and the Program for Changjiang
Scholars and Innovative Research Team in University (IRT_
14R33).
Conclusions
We have developed a highly selective Friedel–Crafts reaction of
indoles and imines catalyzed by cooperative organometallic
Lewis and Brønsted acid catalysts. Based on mechanistic
studies, it can be speculated that Cp2TiCl(OC6H5) I and
Cp2TiCl(OC6H4NH3+Cl–) II are catalytic species for mono- and
double-Friedel–Crafts reactions, respectively. These results re-
vealed an unexpected selectivity in the Friedel–Crafts reactions
that was achieved by single Lewis acid and cooperative Lewis/
Brønsted acid catalysis. With their unprecedented selectivity
these practical organometallic catalysts can be used to achieve
both mono-Friedel–Crafts reaction of indoles and N-sulfonylald-
imines catalyzed by Cp2TiCl2 and phenol in good yields, and o-
aminophenol assisted titanocene catalyst promoted the synthe-
sis of bisindole in excellent yields. This method thus provides a
direct and broadly applicable synthetic approach to 3-indolyl-
methanamines and bisindole compounds.
Keywords: Chemoselectivity · Titanium · Lewis acids ·
Cooperative catalysis · Friedel–Crafts reaction
[1] a) G. Bartoli, G. Bencivenni, R. Dalpozzo, Chem. Soc. Rev. 2010, 39, 4449–
4465; b) Q. L. He, F. L. Sun, X. J. Zheng, S. L. You, Synlett 2009, 7, 1111–
1114.
[2] a) Y. Qian, G. Y. Ma, A. F. Lv, H. L. Zhu, J. Zhao, V. H. Rawal, Chem. Commun.
2010, 46, 3004–3006; b) M. Bandini, A. Melloni, A. Umani-Ronchi, Angew.
Chem. Int. Ed. 2004, 43, 550–556; Angew. Chem. 2004, 116, 560; c) M.
Bandini, A. Melloni, S. Tommasi, A. Umani-Ronchi, Synlett 2005, 1199–
1222; d) T. Poulsen, K. A. Jorgensen, Chem. Rev. 2008, 108, 2903–2915;
e) S. L. You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190–2201; f) M.
Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 2009, 48, 9608–9644; Angew.
Chem. 2009, 121, 9786; g) V. Terrasson, R. M. de Figueiredo, J. M. Cam-
pagne, Eur. J. Org. Chem. 2010, 14, 2635–2655; h) M. Zeng, S.-L. You,
Synlett 2010, 1289–1301; i) G. A. Olah, R. Khrisnamurti, G. K. S. Prakash,
Compr. Org. Synth. 1991, 3, 293–339.
[3] H. H. Yang, B. Cui, G. P. Wu, Z. W. Miao, R. Y. Chen, Tetrahedron 2012, 68,
4830–4837.
[4] B. Y. Li, Z. J. Li, X. B. Meng, Carbohydr. Res. 2010, 345, 1708–1712.
[5] Y. X. Jia, J. H. Xie, H. F. Duan, L. X. Wang, Q. L. Zhou, Org. Lett. 2006, 8,
1621–1624.
Experimental Section
Physical Measurements: 1H and 13C NMR spectra were recorded
with a Bruker EQUINX55 (400 MHz for 1H; 101 MHz for 13C) spec-
trometer in CDCl3 or [D6]DMSO.
General Procedure for the Preparation of N-Sulfonyl Aldimines:
N-Sulfonylaldimines described were prepared by condensation of
the corresponding aldehydes with p-toluenesulfonamide according
to the reported procedure with minor modifications: the aldehyde
(25.0 mmol), p-toluenesulfonamide (25.0 mmol), and Si(OEt)4
(27.5 mmol, 1.1 equiv.) were combined in a flask equipped with an
oil–water separator and heated at 160 °C for 10 h. The produced
[6] G. Grach, A. Dinut, S. Marque, J. Marrot, R. Giland, D. Prim, Org. Biomol.
Chem. 2011, 9, 497–503.
[7] L. Liu, Q. Zhao, F. Du, H. Chen, Z. Qin, B. Fu, Tetrahedron: Asymmetry
2011, 22, 1874–1878.
[8] P. Thirupathi, S. S. Kim, J. Org. Chem. 2012, 75, 5240–5249.
[9] Y. C. Chen, Z. F. Xie, Chin. J. Org. Chem. 2012, 32, 462–471.
Eur. J. Org. Chem. 2016, 502–507
www.eurjoc.org
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[10]
B. M. Kariuki, S. A. Macgregor, M. F. Mahon, K. J. Cavell, D. M. Murphy,
M. K. Whittlesey, Chem. Eur. J. 2013, 19, 2158–2167; d) F. A. LeBlanc, W. E.
Piers, M. Parvez, Angew. Chem. Int. Ed. 2014, 53, 789–792; Angew. Chem.
2014, 126, 808.
G. Grach, A. Dinut, S. Marque, J. Marrot, R. Gil, D. Prim, Org. Biomol. Chem.
2011, 9, 497–503.
[11]
[12]
X. L. Mi, J. Q. He, J. P. Cheng, Tetrahedron Lett. 2004, 45, 4567–4570.
P. N. Chatterjee, A. K. Maity, S. S. Mohapatra, S. Roy, Tetrahedron 2013,
69, 2816–2826.
[19] Y. Wu, C. Chen, G. Jia, X. Y. Zhu, H. M. Sun, G. F. Zhang, W. Q. Zhang,
Z. W. Gao, Chem. Eur. J. 2014, 20, 1–7.
[20] K. Wu, Y. J. Jiang, Y. S. Fan, D. Sha, S. Q. Zhang, Chem. Eur. J. 2013, 19,
474–478.
[21] In mono-Friedel–Crafts reaction, one extra equivalent of indole might
make the catalytic system less acidic. Just like indole, here aniline plays
a role of base to promote the coordination of Cp2TiCl2 with phenol. The
extra equivalent also makes Figure 1 more concise, straightforward, and
easy to analyze.
[22] S. P. Morcillo, D. Miguel, A. J. Mota, J. Justicia, J. M. Cuerva, J. Am. Chem.
Soc. 2014, 136, 6943–6951.
[23] A. Cangönül, M. Behlendorf, A. Gansäuer, M. V. Gastel, Inorg. Chem. 2013,
52, 11859–11866.
[24] a) M. Bandini, A. Melloni, A. Umani-Ronchi, Angew. Chem. Int. Ed. 2004,
43, 550–556; Angew. Chem. 2004, 116, 560; b) Y. Jia, J. Xie, H. Duan, L.
Wang, Q. Zhou, Org. Lett. 2006, 8, 1621–1624; c) M. Johannsen, Chem.
Commun. 1999, 21, 2233–2234; d) J. Esquivias, R. M. Arrayas, J. C. Carret-
ero, Angew. Chem. Int. Ed. 2006, 45, 629–633; Angew. Chem. 2006, 118,
645; e) X. L. Mi, S. Z. Luo, J. Q. He, J. P. Cheng, Tetrahedron Lett. 2004, 45,
4567–4570.
[13]
J. Liu, T. He, L. Wang, Tetrahedron 2011, 67, 3420–3426.
[14] a) P. Borkar, P. Weghe, B. V. S. Reddy, J. S. Yadav, R. Gree, Chem. Commun.
2012, 48, 9316–9318; b) S. Reddy, J. S. Yadav, B. Sridhar, R. Gre, J. Org.
Chem. 2011, 76, 7677–7690; c) L. Zhu, J. Lv, S. Luo, Org. Lett. 2013, 15,
4496–4499; d) E. Gmez-Bengoa, J. M. Garca, S. Jimnez, I. Lapuerta, A.
Mielgo, J. M. Odriozola, I. Otazo, J. Razkin, I. Urruzuno, S. Vera, M. Oiar-
bide, C. Palomo, Chem. Sci. 2013, 4, 3198–3204; e) G. Wang, J. Zhao, Y.
Zhou, B. Wang, J. Qu, J. Org. Chem. 2010, 75, 5326–5329.
[15] J. Esquivias, R. Gomez Arrayas, J. C. Carretero, Angew. Chem. Int. Ed. 2006,
45, 629–633; Angew. Chem. 2006, 118, 645.
[16] a) W. Beck, K. Suenkel, Chem. Rev. 1988, 88, 1405–1421; b) R. E. Dout-
hwaite, Annu. Rep. Prog. Chem. 2003, 99, 349–369; c) A. L. Noffke, A.
Habtemariam, A. M. Pizarro, P. J. Sadler, Chem. Commun. 2012, 48, 5219–
5246; d) A. Glokner, M. Tamm, Chem. Soc. Rev. 2013, 42, 128–142.
[17] For reviews, see: a) T. Akiyama, Chem. Rev. 2007, 107, 5744–5758; b) M.
Rueping, B. J. Nachtsheim, W. Ieawsuwan, I. Atodiresei, Angew. Chem. Int.
Ed. 2011, 50, 6706–6720; Angew. Chem. 2011, 123, 6838.
[18] a) A. Ficks, R. M. Hiney, R. W. Harrington, D. G. Gilheany, L. J. Higham,
Dalton Trans. 2012, 41, 3515–3522; b) M. A. Courtemanche, J. Larouche,
M. A. Lgar, W. Bi, L. Maron, F. G. Fontaine, Organometallics 2013, 32,
6804–6811; c) M. J. Page, W. Y. Lu, R. C. Poulten, E. Carter, A. G. Algarra,
Received: August 30, 2015
Published Online: November 30, 2015
Eur. J. Org. Chem. 2016, 502–507
www.eurjoc.org
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