Charge-enhanced thiourea catalysts as hydrogen bond donors for Friedel?Crafts Alkylations

Article abstract of DOI:10.1016/j.tet.2019.130757

Charge-enhanced catalysis has emerged as a powerful alternative to the mainstream use of neutral catalysis. With this in mind, we report a catalytic Friedel?Crafts alkylation method catalyzed by a charged thiourea incorporating a cationic cyclopropenium m

Full text of DOI:10.1016/j.tet.2019.130757

Journal Pre-proof
Charge-enhanced thiourea catalysts as hydrogen bond donors for Friedel‒Crafts
Alkylations
Ivor Smajlagic, Brenden Carlson, Nicholas Rosano, Hayden Foy, Travis Dudding
PII:
S0040-4020(19)31150-0
https://doi.org/10.1016/j.tet.2019.130757
TET 130757
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 September 2019
Revised Date: 28 October 2019
Accepted Date: 30 October 2019
Please cite this article as: Smajlagic I, Carlson B, Rosano N, Foy H, Dudding T, Charge-enhanced
thiourea catalysts as hydrogen bond donors for Friedel‒Crafts Alkylations, Tetrahedron (2019), doi:
https://doi.org/10.1016/j.tet.2019.130757.
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Charge-Enhanced Thiourea Catalysts as Hydrogen Bond Donors for
Friedel‒Crafts Alkylations
Ivor Smajlagic, Brenden Carlson, Nicholas Rosano, Hayden Foy and Travis Dudding*
Brock University, 1812 Sir Isaac Brock Way, St. Catharines, ON L2S 3A1, Canada.
ABSTRACT Charge-enhanced catalysis has emerged as a powerful alternative to the mainstream use of neutral catalysis.
With this in mind, we report a catalytic Friedel‒Crafts alkylation method catalyzed by a charged thiourea incorporating a cationic
cyclopropenium moiety. Mechanistic studies, including density functional theory computational calculations, variable time normal-
1
ization analysis, and H NMR binding studies, collectively reveal this charged-enhanced reactivity proceeds by a dual hydrogen
bond-mediated LUMO-lowering mode of substrate activation. Key to these findings is the observed steady-state concentration of
the catalyst with in situ derived monomeric catalytic species predominating under the reaction conditions.
Keywords:
organocatalysis;
thiourea;
cyclopropenium;
Friedel‒Crafts
alkylation;
mechanism;
kinetics
INTRODUCTION
chemical discovery, more and more, has been the use of densi-
ty functional theory (DFT) computational calculations as an
effective and versatile resource for examining reactivity, e.g.,
H-bond orchestrated catalyst–substrate interactions and cataly-
sis. The impetus for this development, inherently, being
linked to the ability of DFT-guided mechanistic investigations
to streamline discovery efforts and circumventive the need for
performing laborious experimental screening studies for po-
tential applications.
Catalysis is a key component of innovative technologies for
the production of bulk and fine chemicals. In this regard,
1
metal-free organocatalyzed processes, e.g., hydrogen bond (H-
bond) catalysis continues to attract widespread attention as
attested for by countless examples over the past two dec-
10
2
,3
ades. Central to these reports, arguably, and future undertak-
ings is the ability to selectively access one, or more, of these
different modes of H-bond activation; however, this is not
always a simple task.
On a related note, inspired by the many remarkable studies
carried out with thiourea catalysts, we recently reported the
synthesis and use of cyclopropenium-functionalized cationic
thiourea 1 as a Brønsted acid catalyst for synthetically relevant
One way for accessing a desired mode of H-bond activation is
through mechanistic understanding. To this end, various em-
pirical methods and/or physical organic parameters are rou-
tinely employed for gaining insight and probing the mechanis-
1
1
pyranylation of alcohols and phenols (Figure 1A, right-hand
side). Notably, this catalyst exhibited both cationic H-bond
donor and electrostatically enhanced character owing to the
cyclopropenium ring system as supported by the computed
molecular electrostatic potential (MEP) surface (Figure 1A,
left-hand side). Given this precedent, we were intrigued by the
prospect of using thiourea 1 as a H-bond catalyst for catalyz-
ing Friedel‒Crafts alkylations. In this aim, we envisioned us-
ing a DFT-augmented approach to initiate our mechanistic
investigation. Realized, this undertaking would add to the
4
tic underpinnings of catalysis. In particular, kinetic studies,
5
determination of pK
a
,
nucleophilicity and electrophilicity
6
7
parameters, and colorimetric assays are often used to provide
insight into reaction profiles. Likewise, modern-day computa-
tional tools offer a powerful means for acquiring mechanistic
understanding and, as such, continue to gain popularity. This
8
is evidenced by numerous reports in drug design, method
development, and material applications. Further to this point,
key in advancing
9
1

synthetic chemists' toolbox of catalysis and mechanistic un-
derstandings, while further demonstrating the utility of mod-
ern-day research programs entrenched in computational and
experimental chemistries.
double H-bond mode of nitro-group binding by the two N‒H
hydrogen bond acceptor groups of 1 with N‒H•••O distances
of 1.95 Å and 2.00 Å (Figure 1C, left-hand side). These H-
bond contacts exhibited characteristic quantum theory of at-
oms in molecules (QTAIM) bond critical points (BCP) with
Accordingly, we contribute here the first instance of a Friedel‒
Crafts alkylation catalyzed by a cyclopropenium-based
charge-enhanced thiourea organocatalyst. Moreover, this work
expands the versatility of cyclopropenium building blocks
within another domain of catalysis, namely dual hydrogen
bond-mediated catalysis. In terms of practicality, ease of cata-
lyst preparation from inexpensive commercial or readily avail-
2
rho (ρ) densities of 0.023 and 0.025 au and Laplacian (∇ ρ)
values of -0.021 and -0.023 au, consistent with strong H-
16
bonding. Further, natural bond orbital (NBO) analysis of the
donor‒acceptor nature of these H-bond interactions, revealed
significant charge transfer from the oxygen lone pairs into the
antibonding σ*-orbitals of the N‒H bonds (E
= 17.5 kcal
n→σ*
12
−1
able reagents in a protecting-group free, operationally simple
two-step synthetic route is a salient strength of this method.
Further, the heterocyclic indole products furnished by this
synthetic approach are prevalent motifs in Nature, such as in
natural products offering broad-spectrum bioactivity, e.g.,
mol ), hence supporting noticeable charge-transfer-based
“partial covalent” H-bonding character (Figure 1C, right-hand
side).
13
antibacterial, antifungal, and anti-inflammatory properties.
The scalability of this method to gram scales is also demon-
strated. Lastly, the computational models reported herein pro-
vide in-depth electronic and structural insight we anticipate
will aid the future design of thiourea and cyclopropeni-
um/cyclopropenimine catalysts, as well as related chiral or-
ganocatalysts.
RESULTS AND DISCUSSION
At the outset of this work in targeting the development of
14
Friedel‒Crafts alkylation method we were aware the majori-
ty of reported organocatalyzed approaches for this transfor-
mation were limited by one or more of the following: (1) poor
substrate scope (2) use of costly reagents and/or expensive
catalyst often prepared by multi-step synthetic routes; (3) lack
of scalability; and (4) high catalyst loadings. From these prec-
edents, we postulated our recently reported thiourea catalyst 1
would serve as a viable organocatalyst for Friedel‒Crafts al-
kylation reactions. Central to this proposition was the prospect
that cationic thiourea 1 would impart a multifaceted charge-
enhanced lowest unoccupied molecular orbital (LUMO)-
lowering element of substrate activation. Thus, in keeping
with our philosophy of utilizing computation to augment ex-
perimental development, we initially turned to DFT to discern
to what, if any, extent thiourea 1 would catalyze the Friedel‒
Crafts alkylation of indoles with Michael acceptor trans-ꢀ-
nitrostyrene (2a).
To this end, we performed computational calculations at the
(
IEFPCM(DCM))ωB97XD/6-311+G(d,p)/def2-
SV//ωB97XD/6-31G(d)/def2-SV level of theory using the
Gaussian 09 program (see Supporting Information and Exper-
imental section for computational details) with dichloro-
methane (DCM) selected as the implicit solvent for these cal-
culations based on the observed solubility of cationic thiourea
1
. Thus, working in the framework of frontier molecular or-
bital (FMO) analysis the LUMO-lowering activation of trans-
-nitrostyrene by 1, in the absence of a counterion for compu-
tational efficiency, was gauged against known Friedel‒Crafts
alkylation H-bond catalyst N,N’-bis[3,5-bis(CF )-
phenyl]thiourea, otherwise commonly referred to as Schrein-
ꢀ
3
5
a,15
Figure 1. (A) Molecular electrostatic potential (MEP) surface of
cationic thiourea catalyst 1. (B) Computed structures of 2a,
AcOH•2a, 3•2a, and 1•2a and their respective LUMO energies in
electronvolts (eV). (C) H-bonding complex 1•2a (left-hand side)
with respective NBO donor–acceptor interactions (right-hand
side) (see Supporting Information and Experimental section for
computational details).
er’s thiourea
(3) and acetic acid, which is an ineffective
catalyst for this conversion. Most illuminating, cationic thiou-
rea 1 was predicted to have the greatest LUMO-lowering ef-
fect as seen by a 0.11 eV reduction in the LUMO energy of
substrate 2a, while the LUMO-lowering effects of thiourea 3
and acetic acid were smaller in magnitude, measuring 0.05 eV
and 0.01 eV (see H-bond complexes Figure 1B). In terms of
the H-bonding manifold of 1•2a, telling, was the presence of a
2

Charged with this insight, our efforts turned toward the exper-
imental use of thiourea 1 as a H-bond catalyst for Friedel‒
Crafts alkylation (Table 1). In this vein, an initial control reac-
tion performed in the absence of catalyst led to essentially no
conversion after 44 hours (entry 1), while sluggish reactivity
was observed using neutral thiourea catalysts 3 and 4 (entries
With optimized reaction conditions in hand, the scope of this
reaction with respect to indole was investigated (Figure 2).
Unprotected indole 5b reacted with trans-ꢀ-nitrostyrene to
afford product 6b in very good yield, while N-protected in-
18
doles 5c and 5d resulted in no conversion, presumably, ow-
ing to reduced indole nucleophilicity imparted by the electron
withdrawing N-tosyl and N-acetyl groups. Next, we explored
the scope of this reaction with respect to the nitroalkene com-
ponent. Non-functionalized 2-furyl and 2-napthyl nitroalkenes
(2b and 2c) reacted to afford products 6e and 6f in good to
excellent yields, while electron-rich alkoxy- and alkyl nitroal-
kenes (2d-g) provided variable yields. For instance, trans-4-
methyl-ꢀ-nitrostyrene (2d) reacted smoothly to afford product
6g in excellent yield, whereas alkoxy substituted trans-ꢀ-
nitrostyrenes (2e-g) all led to poor conversions (6h-j). Further,
halogenated trans-ꢀ-nitrostyrenes (2h-l) provided products
6k-o in good to excellent yields. The high yields of fluorinated
products 6k and electron-poor 6o is notable given the im-
2
and 3). Based on these results and with the aim of improving
reactivity, we investigated the use of various charged thiourea
catalyst salts of 1. The logic for doing this being possible tight
anion binding, i.e., very short intermolecular N–
H•••counteranion contacts as a possible source of attenuated
1
7
reactivity. Corroborating this hypothesis, thiourea 1 with an
inexpensive and weakly coordinating tetrafluoroborate coun-
‒
‒
teranion provided superior results relative to 1•ClO , 1•Cl ,
4
‒
and 1•CF
3
SO
3
(entries 4-7). Next, various solvents were
‒
screened using thiourea 1•BF4 (entries 7-12) resulting in
DCM as the solvent of choice affording an optimal conversion
of 96% (entry 7). This finding comes as no surprise given
solvents with expected H-bond acceptor character are prone to
disrupt catalyst–substrate interactions. Lastly, reducing the
catalyst loadings to 5 mol% and even as low as 1 mol% atten-
uated conversion (entries 13 and 14).
19
portance of organofluorine compounds in pharmaceuticals,
agrochemicals, and material science industries.
2
0
21
[a]
Table 1. Optimization of Reaction Conditions
[b]
entry
solvent
catalyst
catalyst load
conversion
(
mol%)
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
CH
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CH
THF
CHCl
CH CH CN
MeCN
2
-
-
<5%
<5%
34%
82%
10%
46%
96%
64%
36%
90%
29%
58%
50%
18%
2
2
4
10
10
10
10
10
10
10
10
10
10
10
5
2
2
2
2
3
−
2
1•ClO
4
−
2
1•Cl
1•CF SO
1•BF
1•BF
−
2
2
2
3
3
−
−
2
4
C
6
H
5
3
4
−
1•BF
4
−
1
1
1
1
1
0
1
2
3
4
3
1•BF
4
−
3
2
1•BF
4
−
−
1•BF
4
CH
2
Cl
2
1•BF
4
−
CH
2
Cl
2
1•BF
4
1
[
a]
Reactions were performed at room temperature using the fol-
lowing conditions: 0.5 mmol 2a, 1.5 mmol 5a, 0.05 mmol cata-
‒
Figure 2. Employment of Thiourea 1•BF4 for Friedel‒
Crafts Alkylation
[a]
[b]
lyst, and 0.5 mL solvent for 44 h. Conversion was determined
via H NMR spectroscopic analysis of the crude reaction mix-
tures. This involved monitoring the disappearance of the signal at
.00 ppm for (2a) and appearance of the signal at 5.21 ppm for
1
[a]
Reactions were performed at room temperature using the fol-
lowing conditions: 0.5 mmol of respective nitroalkene, 1.5 mmol
, and 0.5 mL DCM for 44
h. The yields of isolated products are reported after flash chroma-
8
‒
4
of respective indole, 0.05 mmol 1•BF
the FC alkylated product (6a).
3

[
b]
tography. No reaction occurred using these N-functionalized
indoles.
Figure 3. Plot of time (h) vs. concentration (M) for two inde-
pendent starting concentrations of trans-ꢀ-nitrostyrene performed
under synthetically relevant conditions for the determination of
Next, the practicality of this reaction was demonstrated by the
gram-scale preparation of Friedel‒Crafts alkylation product 6a
in excellent yield (97%, 1.8 g), Scheme 1.
‒
thiourea 1•BF4 robustness via same excess experiment.
Overlay of the two curves as seen in Figure 3 is telling of
steady-state catalyst concentration with catalytic turnover af-
fected by neither catalyst deactivation nor product inhibition
(see SI for further details). Further analysis revealed a 0.8-
order dependency in catalyst indicative of a high proportion of
the catalyst persisting as monomeric species in solution, much
Scheme 1. Gram-Scale Reaction Catalyzed by Thiourea
‒
1
•BF4
23
unlike that of previous thiourea-catalyzed processes (Figure
). This divergence, presumably, arising from key structural
4
differences, i.e., the bulky cyclopropenium diisopropylamine
substituents abating formation of dimeric or higher-order ag-
gregate complexes. Collectively, these kinetic results shed
light and speak to the value of incorporating cyclopropenium
building blocks as core components of H-bond organocata-
lysts, such as thiourea catalysts.
1
.6
1.6
1.4
1.2
1
1
.4
Finally, to probe the underlying mechanism of this Friedel‒
1.2
1
Crafts reactivity and thereby determine the reaction order and
‒
stability of catalyst 1•BF
4
, we performed binding studies in
0.8
0.8
0.6
0.4
0.2
0
0
0
0
.6
.4
.2
0
conjunction with variable time normalization analysis
VTNA). The latter being a timely qualitative method for ex-
tracting mechanistic information from reaction profiles under
(
4
a,22
0
5
10
15
20
25
30
35
40
45
50
0
2
4
6
8
10
12
14
16
synthetically relevant conditions.
Addition of increasing
t (h)
t[cat]0.5
equivalents of substrate trans-ꢀ-nitrostyrene (2a) to catalyst
1
.6
1.6
1.4
1.2
1
‒
1
•BF4 in CDCl resulted in a slight downfield shift of the N–
1.4
1.2
1
3
1
H hydrogen atom ( H NMR, ∆ꢁ = 0.04 ppm), thus, consistent
with a LUMO-lowering mode of substrate activation, as op-
posed to a Brønsted acid mode of reactivity, see SI. Next, the
robustness of the catalyst was probed by a VTNA “same ex-
cess” experiment (Figure 3).
0
0
0
0
.8
.6
.4
.2
0
0.8
0.6
0.4
0.2
0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
t[cat]0.8
t[cat]
1
Figure 4. Plot of time (h) vs. concentration (M) for two inde-
‒
pendent starting concentrations of thiourea 1•BF4 (blue triangle -
0
.168 M; red square - 0.084 M) performed under synthetically
relevant conditions (top left). Plots of normalized time scale
ꢂ[ꢃꢄꢂ]ꢅꢆ) vs. concentration (M) for the determination of the or-
(
der in catalyst (top right and bottom).
On the basis of the above findings, the tentative DFT support-
ed catalytic cycle depicted in Figure 5 is offered. The cycle
initiates in formation of complex 1•2a, which subsequently
reacts by rate-determining indole addition transition state TS1
≠
−1
with a Gibbs free activation energy (∆G ) of 20.5 kcal mol
relative to the separate starting reagents and catalyst. Salient
features of this transition state include a C···C bond-forming
distance of 2.05 Å associated with a synclinal orientation of
the styrene and indole substrates as defined by dihedral angle
θ
C(1)-C(2)-C(3)-C(4) measuring -52.1 ̊. Further was a slightly skewed
double H-bond manifold with N−H•••O distances of 1.84 Å
and 1.75 Å linked to a Z,Z-thiourea conformation. Though less
obvious, was stabilizing charge polarized π−π stacking be-
tween the indole ring and the nitroalkene, clearly visible from
the green isosurfaces in the non-covalent interaction (NCI)
plot of Figure 5. From TS1 zwitterionic nitronate-
azocarbenium intermediate 1•6a’ ensues that following a se-
ries of proton transfer events leads to exergonic product (6a)
formation and catalyst turnover.
CONCLUSION
4

To recap, in building upon the timely relevance of cyclopro-
penium ions, we have advanced a charge-enhanced cationic
thiourea-catalyzed Friedel‒Crafts alkylation method. Versatili-
ty, scalability, ease of catalyst preparation and operational
simplicity are hallmarks of this method. Inherent to the mech-
anism of these Friedel‒Crafts alkylations is a steady-state con-
centration of a monomeric charged thiourea catalyst, much at
odds with existing state-of-the-art reactivity patterns accessi-
ble using thiourea catalysts. Additionally, DFT calculations
timized structures were further refined by single point calcu-
lations performed at the ωB97XD/6-311+G(d,p)/def2-SV lev-
el of theory using the integral equation formalism polarizable
continuum model (IEFPCM) with the default parameters of
2
6
dichloromethane (ε = 8.9) to account for solvent. The ther-
mal corrections to the Gibbs free energies (temperature =
298.15 K) computed at the lower level of theory (ωB97XD/6-
31G(d)/def2-SV) were added to the electronic energies ob-
tained from the single point calculations to provide the final
reported Gibbs free energies. NBO analysis with program
NBO 6 using second-order perturbation theory was used to
estimate the contributions of nitro group oxygen lone pair
donation into the antibonding σ*-orbitals of the N‒H bonds of
cationic thiourea 1. The 3D images of all optimized geome-
1
and H NMR binding studies revealed a dual hydrogen bond-
mediated LUMO-lowering mode of substrate activation is
pivotal to this reactivity. Collectively, the findings of this
study provide a compelling basis for the development and
future use of cyclopropenium frameworks as charged con-
structs for enabling catalysis.
2
7
tries were generated with CYLview. Natural bond orbital
2
8
29
images were produced using Chemcraft. GaussView5 was
used to construct all structures prior to optimization and to
visualize the output from the Gaussian 09 calculations. The
3
0
program AIM2000 was used to compute the quantum theory
of atoms in molecules (QTAIM) rho (ρ) densities and Laplaci-
2
an (∇ ρ) values at the respective bond critical points (BCP).
The reported non-covalent interaction (NCI) plot (isovalue =
0
.3, min = -0.05 and max = 0.05), lowest unoccupied molecu-
lar orbital (LUMO) diagrams (isovalue = -0.05) and molecular
electrostatic potential (MEP) surface (isovalue = 0.001, min =
31
2
5.7 and max = 90.4) were calculated using the B3LYP-D3
functional with a LAVP*+ basis set using the program Jaguar
3
2
of the Schrödinger software package.
MATERIALS AND METHODS
Materials were obtained from commercial suppliers and were
used without further purification unless otherwise specified.
The solvents dichloromethane (DCM), toluene, chloroform,
propionitrile, and acetonitrile were distilled using calcium
hydride (CaH ), whereas tetrahydrofuran was distilled from
2
2
sodium/benzophenone, all under an inert atmosphere (N ).
Reactions were performed under an inert atmosphere in oven-
dried glassware. Reactions were monitored by thin layer
chromatography (TLC) using TLC silica gel 60 F254, EMD
Millipore Corporation, and visualized using handheld UV
lamps. Flash column chromatography was performed on ul-
trapure silica gel (230-400 mesh). NMR spectra were obtained
1
13
19
with a Bruker DPX-300 ( H 300 MHz, C 75.5 MHz,
F
2
92.4 MHz) in CDCl . The observed chemical shifts are re-
3
ported as δ-values in ppm relative to tetramethylsilane (TMS).
Coupling constants (J) are recorded as Hz. Multiplicities are
reported as follows: s (singlet), d (doublet), t (triplet), m (mul-
tiplet), dd (doublet of doublets), br (broad singlet). Mass spec-
tra were obtained on an MSI/Kratos concept IS mass spec-
Figure 5. Mechanistic proposal for thiourea-catalyzed (1)
Friedel‒Crafts alkylation. Reported relative Gibbs free ener-
gies in kcal mol are enclosed in parentheses (see Supporting
Information and Experimental section for computational de-
tails).
-1
33
34
35
38
trometer. trans-ꢀ-nitrostyrene derivatives, catalysts 1, 2,
‒11
‒ 11
36
37
1
•Cl and 1•BF4 , and indole derivatives 5a, 5c, and 5d
were prepared according to literature procedures.
EXPERIMENTAL SECTION
N-[2,3-Bis(diisopropylamino)cyclopropenium]-N’-phenyl-
‒
‒
COMPUTATIONAL METHODS
thiourea•ClO4 (1)•ClO .
4
‒
Quantum mechanical calculations were performed using
Thiourea 1•Cl (100 mg, 0.24 mmol) was dissolved in DCM
(2.00 mL) and washed with saturated bicarbonate (1 x 6.0
mL). The conjugate base was then acidified with a 3 M solu-
2
4
Gaussian 09. All geometry optimizations were performed
25
using the ωB97XD functional with a 6-31G(d)/def2-SV ba-
sis set. The optimized geometries were verified as transition
state structures (one imaginary frequency) or minima (zero
imaginary frequencies) by frequency calculations. Intrinsic
reaction coordinate (IRC) calculations were performed to con-
firm that all transition state structures were linked to relevant
minima. The energies of the ωB97XD/6-31G(d)/def2-SV op-
tion of 70% HClO4(aq) (1 x 4.0 mL), dried over MgSO and
4
concentrated in vacuo to afford a viscous green oil. The oil
was then triturated with diethyl ether (2 x 5.0 mL) to furnish
‒
thiourea 1•ClO as a pale-green solid (98 mg, 85%). Mp:
4
o
1
o
125−127 C; H NMR (300 MHz, CDCl , 25 C): ꢁ =
3
1.40−1.42 (d, J = 6.8 Hz; 24H), 4.05−4.14 (m, 4H), 7.19−7.24
5

1
(
(
(
t, J = 7.4 Hz; 1H), 7.35−7.40 (t, J = 7.6 Hz; 2H), 7.75−7.78
(132 mg, 90%) colourless oil. H NMR (300 MHz, CDCl , 25
3
13
1
o
d, J = 7.8 Hz; 2H), 9.30 (s, 1H), 9.75 (s, 1H); C{ H} NMR
C): δ = 2.34 (s, 3H), 3.77 (s, 3H), 4.90−4.97 (dd, J = 12.4, 8.6
Hz; 1H), 5.03−5.10 (dd, J = 12.2, 7.3 Hz; 1H), 5.17−5.23 (t, J
o
75.5 MHz, CDCl , 25 C): ꢁ = 21.9, 51.9, 106.2, 123.5,
3
1
26.1, 126.4 128.7, 138.2, 178.1.
= 7.9 Hz; 1H), 6.88 (s, 1H), 7.08−7.17 (m, 3H), 7.22−7.33 (m,
4
H), 7.48−7.50 (d, J = 7.9 Hz; 1H).
N-[2,3-Bis(diisopropylamino)cyclopropenium]-N’-phenyl-
‒
‒
40
thiourea•CF SO (1)•CF SO .
3-(1-(4-methoxy)-2-nitroethyl)-1-methyl-1H-indole (6h).
3
3
3
3
‒
1
Thiourea 1•Cl (100 mg, 0.24 mmol) was dissolved in DCM
2.00 mL) and washed with saturated bicarbonate (6.0 mL).
(81 mg, 52%) colourless oil. H NMR (300 MHz, CDCl
3
, 25
o
(
C): δ = 3.77 (s, 3H), 3.82 (s, 3H), 4.93−4.97 (dd, J = 12.4, 8.6
Hz; 1H), 5.04−5.11 (dd, J = 12.3, 7.4 Hz; 1H), 5.17−5.23 (t, J
= 7.9 Hz; 1H), 6.91−6.93 (d, J = 8.7 Hz; 3H), 7.12−7.18 (m,
1H), 7.28−7.37 (m, 4H), 7.51−7.54 (d, J = 7.9 Hz; 1H).
The conjugate base was then acidified with a 3 M solution of
trifluoromethanesulfonic acid (1 x 2.0 mL), dried over MgSO4
and concentrated in vacuo to afford a viscous green oil. The
4
1
oil was then triturated with diethyl ether (2 x 5.0 mL) to fur-
3
-(1-(3,4-dimethoxy)-2-nitroethyl)-1-methyl-1H-indole (6i).
‒
nish thiourea 1•CF
3
SO
3
as a pale-green solid (96 mg, 76%).
1
o
o
1
o
(32 mg, 19%) yellow oil. H NMR (300 MHz, CDCl
δ = 3.77 (s, 3H), 3.85 (s, 3H), 3.88 (s, 3H), 4.89−4.96 (dd, J =
2.2, 8.6 Hz; 1H), 5.03−5.09 (dd, J = 12.2, 7.2 Hz; 1H),
3
, 25 C):
Mp: 147−149 C; H NMR (300 MHz, CDCl , 25 C): ꢁ =
3
1
.39−1.41 (d, J = 6.8 Hz; 24H), 4.01−4.15 (m, 4H), 7.17−7.22
1
(
(
(
1
t, J = 7.4 Hz; 1H), 7.34−7.39 (t, J = 7.6 Hz; 2H), 7.77−7.80
13
1
5.13−5.18 (t, J = 8.0 Hz; 1H), 6.83−6.93 (m, 4H), 7.08−7.13
(m, 1H), 7.23−7.34 (m, 2H), 7.48−7.50 (d, J = 7.9 Hz; 1H).
d, J = 7.9 Hz; 2H), 9.84 (s, 1H), 10.1 (s, 1H); C{ H} NMR
o
75.5 MHz, CDCl , 25 C): ꢁ = 21.9, 51.9, 106.6, 123.4,
3
19
1
3
-(1-(4-benzyloxy)-2-nitroethyl)-1-methyl-1H-indole (6j).
25.9, 126.8 128.6, 138.4, 178.3; F{ H} NMR (292.4 MHz,
o
1
CDCl , 25 C) ꢁ = -78.3.
(77 mg, 40%) colorless oil. H NMR (300 MHz, CDCl , 25
3
3
o
C): δ = 3.77 (s, 3H), 4.88−4.95 (dd, J = 12.3, 8.7 Hz; 1H),
Representative Procedure for the Thiourea-Catalyzed
Friedel‒Crafts Alkylation.
5
.03−5.09 (dd, J = 12.3, 7.8 Hz; 1H), 5.05 (s, 2H), 5.14−5.20
(
(
t, J = 7.9 Hz; 1H), 6.88 (s, 1H), 6.95−6.99 (m, 2H), 7.09−7.14
m, 1H), 7.24−7.45 (m, 10H); C{ H} NMR (75.5 MHz,
To an oven-dried 5.0 mL round-bottom flask charged with
13
1
‒
thiourea 1•BF4 (24 mg, 10 mol%); respective indole (1.5
o
CDCl , 25 C): δ = 32.8, 40.9, 70.1, 79.8, 109.5, 113.1, 115.2,
1
1
mmol) and nitroalkene (0.5 mmol) were combined and subse-
quently diluted in dichloromethane (0.5 mL). The resulting
solution was stirred for 44 hours at room temperature under an
inert atmosphere. Reaction progress was monitored via TLC.
After removal of the solvent, the crude material was subjected
to flash chromatography using a hexanes/ethyl acetate solvent
system to yield the Friedel‒Crafts alkylated product.
3
19.1, 119.4, 122.2, 126.3, 126.5, 127.5, 128.0, 128.6, 128.8,
31.7, 136.9, 137.3, 158.2; HRMS (EI) = m/z: [M+H] calc’d
+
for C H O N , 386.1636; found: 386.1627.
24 22
3
2
3-(1-(4-fluorophenyl)-2-nitroethyl)-1-methyl-1H-indole
(6k).
4
0
1
(
137 mg, 92%) yellow oil. H NMR (300 MHz, CDCl , 25
C): δ = 3.78 (s, 3H), 4.89−4.96 (dd, J = 12.4, 8.7 Hz; 1H),
3
o
Characterization Data of the Products (6a-o). NMR data
are consistent with the literature.
5
1
.04−5.10 (dd, J = 12.4, 7.2 Hz; 1H), 5.17−5.23 (t, J = 7.9 Hz;
H), 6.88 (s, 1H), 7.01−7.14 (m, 3H), 7.25−7.36 (m, 4H),
3
9
1
-methyl-3-(2-nitro-1-phenylethyl)-1H-indole (6a).
1
7.43−7.46 (d, J = 8.0 Hz; 1H).
(
129 mg, 92%), pink solid. H NMR (300 MHz, CDCl , 25
C): ꢁ = 3.78 (s, 3H), 4.93−5.00 (dd, J = 12.3, 8.5 Hz; 1H),
3
40
o
3
-(1-(4-chlorophenyl)-2-nitroethyl)-1-methyl-1H-indole (6l).
1
5
1
7
.05−5.12 (dd, J = 12.4, 7.4 Hz; 1H), 5.19−5.24 (t, J = 7.9 Hz;
H), 6.89 (s, 1H), 7.07−7.13 (t, J = 6.9 Hz; 1H), 7.23−7.39 (m,
H), 7.47−7.49 (d, J = 7.9 Hz; 1H).
(141 mg, 82%) colorless oil. H NMR (300 MHz, CDCl , 25
3
o
C): δ = 3.78 (s, 3H), 4.89−4.96 (dd, J = 12.5, 8.7 Hz; 1H),
5.03−5.10 (dd, J = 12.3, 7.2 Hz; 1H), 5.17−5.22 (t, J = 7.8 Hz;
1H), 6.89 (s, 1H), 7.10−7.16 (m, 1H), 7.26−7.36 (m, 6H),
7.44−7.47 (d, J = 7.9 Hz; 1H).
39
3
-(2-nitro-1-phenylethyl)-1H-indole (6b).
1
(
115 mg, 86%), brown solid. H NMR (300 MHz, CDCl , 25
3
o
3-(1-(3-chlorophenyl)-2-nitroethyl)-1-methyl-1H-indole
C): ꢁ = 4.94−5.01 (dd, J = 12.3, 8.4 Hz; 1H), 5.06−5.13 (dd,
40
(
6m).
(136 mg, 79%) colorless oil. H NMR (300 MHz, CDCl , 25
3
J = 12.3, 7.6 Hz; 1H), 5.19−5.25 (t, J = 7.9 Hz; 1H),
1
7
1
.05−7.13 (m, 2H), 7.20−7.39 (m, 7H), 7.46−7.49 (d, J = 7.9;
o
H), 8.09 (br, 1H).
C): δ = 3.78 (s, 3H), 4.88−4.95 (dd, J = 12.5, 8.6 Hz; 1H),
5.02−5.09 (dd, J = 12.6, 7.4 Hz; 1H), 5.16−5.21 (t, J = 7.9 Hz;
3
9
3
-(1-(furan-2-yl)-2-nitroethyl)-1-methyl-1H-indole (6e).
1
7
H), 6.90 (s, 1H), 7.09−7.14 (m, 1H), 7.24−7.29 (m, 4H),
.32−7.35 (m, 2H), 7.44−7.47 (d, J = 8.0 Hz; 1H).
1
(
124 mg, 92%) yellow oil. H NMR (300 MHz, CDCl , 25
3
o
C): δ = 3.78 (s, 3H), 4.91−4.98 (dd, J = 12.5, 7.4 Hz; 1H),
3
-(1-(4-bromophenyl)-2-nitroethyl)-1-methyl-1H-indole
5
1
.05−5.12 (dd, J = 12.5, 8.1 Hz; 1H), 5.27−5.32 (t, J = 7.7 Hz;
H), 6.22−6.23 (d, J = 3.3 Hz; 1H), 6.36−6.37 (dd, J = 3.1, 1.9
4
0
(
6n).
1
Hz; 1H), 7.03 (s, 1H), 7.16−7.21 (m, 1H), 7.28−7.38 (m, 1H),
(156 mg, 87%) colorless oil. H NMR (300 MHz, CDCl
3
, 25
C): δ = 3.79 (s, 3H), 4.90−4.97 (dd, J = 12.5, 8.7 Hz; 1H),
o
7
.43−7.44 (d, J = 1.1 Hz; 3H), 7.60−7.62 (d, J = 7.9 Hz; 1H).
5
.03−5.09 (dd, J = 12.5, 7.2 Hz; 1H), 5.14−5.20 (t, J = 7.7 Hz;
1
-methyl-3-(1-(naphthalen-2-yl)-2-nitroethyl)-1H-indole
4
0
1H), 6.87 (s, 1H), 7.08−7.13 (m, 1H), 7.23−7.34 (m, 4H),
7
2
(
6f).
101 mg, 61%) yellow oil. H NMR (300 MHz, CDCl
.42−7.44 (d, J = 8.0 Hz; 1H), 7.46−7.49 (dd, J = 6.6, 1.8 Hz;
H).
1
(
3
, 25
o
C): δ = 3.5 (s, 3H), 5.11−5.14 (dd, J = 7.4, 1.3 Hz; 2H),
1
-methyl-3-(2-nitro-1-(4-(trifluoromethyl)phenyl)ethyl)-1H-
6
7
2
1
.07−6.12 (t, J = 7.7 Hz; 1H), 6.86 (s, 1H), 7.07−7.12 (m, 1H),
.23−7.34 (m, 2H), 7.39−7.60 (m, 5H), 7.80−7.83 (dd, J = 6.5,
.8 Hz; 1H), 7.90−7.93 (m, 1H), 8.27−8.30 (d, J = 7.9 Hz;
H).
39
indole (6o).
1
(160 mg, 92%) yellow oil. H NMR (300 MHz, CDCl , 25
3
o
C): δ = 3.79 (s, 3H), 4.95−5.02 (dd, J = 12.7, 8.8 Hz; 1H),
5.07−5.13 (dd, J = 12.7, 7.2 Hz; 1H), 5.26−5.31 (t, J = 7.9 Hz;
4
0
1
-methyl-3-(2-nitro-1-p-tolylethyl)-1H-indole (6g).
6

1
7
H), 6.89 (s, 1H), 7.01−7.16 (m, 1H), 7.26−7.36 (m, 2H),
.40−7.52 (m, 3H), 7.61−7.63 (d, J = 8.2 Hz; 2H).
(2) For timely reviews of organocatalysis, see: (a) Auvil TJ,
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633−2646. (b) Phipps RJ, Hamilton GL, Toste FD. Na-
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Chem. 2012; 14: 1821−1849. (e) Doyle AG, Jacobsen
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Two separate reactions were conducted in oven-dried 25.0 mL
1: 2406−2447. (d) Wende RC, Schreiner PR. Green
round-bottom flasks charged with 10 mol% catalyst (0.168 M,
‒
0
.335 mmol) (1•BF ) to which was added trans-ꢀ-
4
nitrostyrene (1.68- or 1.00 M; 3.35-, or 2.00 mmol) (2a) and
(
(
(
3) For select reviews on H-bond catalysis and Brønsted acid
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-methylindole (5.03- or 4.35 M; 10.1- or 8.70 mmol) (5a)
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2
9
16−223. (b) Akiyama T, Mori K. Chem. Rev. 2015; 115:
277−9306.
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atmosphere. Reaction progress was determined by H NMR
(
CDCl ) spectroscopy analyses of aliquots taken periodically.
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4) (a) Nielsen CD-T, Burés J. Chem. Sci. 2019; 10:
This involved monitoring the disappearance of the signal at
.00 ppm for (2a) and appearance of the signal at 5.21 ppm for
3
1
48−353. (b) Blackmond DG. J. Am. Chem. Soc. 2015;
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the FC alkylated product (6a).
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Chem. Soc. 2012; 134: 15621−15623.
Two separate reactions were conducted in oven-dried 25.0 mL
round-bottom flasks charged with either 5- or 10 mol% cata-
‒
lyst (0.084- or 0.168 M; 0.168- or 0.335 mmol) (1•BF
4
) to
which was added trans-ꢀ-nitrostyrene (1.68 M, 3.35 mmol)
2a) and 1-methylindole (5.03 M, 10.1 mmol) (5a) diluted in
.0 mL DCM at room temperature under an inert atmosphere.
(
2
1
Reaction progress was determined by H NMR (CDCl ) spec-
3
troscopy analyses of aliquots taken periodically. This involved
monitoring the disappearance of the signal at 8.00 ppm for
(
2a) and appearance of the signal at 5.21 ppm for the FC al-
(8) (a) Leelananda SP, Lindert S. Beilstein J. Org. Chem.
2016; 12: 2694−2718. (b) Sliwoski G, Kothiwale S,
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kylated product (6a).
3
34−395.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
(
9) (a) Evans JD, Fraux G, Gaillac R, Kohen D, Trousselet F,
Vanson J-M, Coudert F-X. Chem. Mater. 2017; 29:
1
99−212. (b) Butler KT, Frost JM, Skelton JM, Svane
KL, Walsh A. Chem. Soc. Rev. 2016; 45: 6138−6146.
10) For select examples utilizing DFT-augmented approaches,
see: (a) Sun Z, Wang Q, Xu Y, Wang ZA. RSC Adv. 2015;
Computational calculations, as well as, kinetic studies and NMR
spectra for all reported compounds (PDF)
(
5
: 84284−84289. (b) Du X, Gao X, Hu W, Yu J, Luo Z,
AUTHOR INFORMATION
Corresponding Author
Cen K. J. Phys. Chem. C 2014; 118: 13617−13622. (c)
Mirabdolbaghi R, Dudding T. Org. Lett. 2012; 14:
3
748−3751. (d) Rostamikia G, Janik MJ. Energy Environ.
*
E-mail: tdudding@brocku.ca
Sci. 2010; 3: 1262−1274. For reviews, see: Grajciar L,
Heard CJ, Bondarenko AA, Polynski MV, Meeprasert J,
Pidko EA, Nachtigall P. Chem. Soc. Rev. 2018; 47:
Author Contributions
The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
8
307−8348.
(
11) Smajlagic I, Durán R, Pilkington M, Dudding T. J. Org.
Chem. 2018; 83: 13973−13980.
(
(
12) Young IS, Baran PS. Nature Chemistry 2009; 1: 193−205.
13) For reviews on privileged indole scaffold and applica-
tions, see: (a) Xu P-W, Yu J-S, Chen C, Cao Z-Y, Zhou F,
Zhou J. ACS Catal. 2019; 9: 1820−1882. (b) Ziarani GM,
Moradi R, Ahmadi T, Lashgari N. RSC Adv. 2018; 8:
ORCID
Travis Dudding: 0000-0002-2239-0818
ACKNOWLEDGMENT
Travis Dudding acknowledges financial support from the Natural
Science and Engineering Research Council (NSERC) Discovery
grant (2019-04205). Computations were carried out using facili-
ties at SHARCNET (Shared Hierarchical Academic Research
Computing Network: www.sharcnet.ca) and Compute/Calcul
Canada.
1
3
2069−12103. (c) Shiri M. Chem. Rev. 2012; 112:
508−3549.
(
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Chem. Int. Ed. 2005; 44: 6576‒6579. (b) Ganesh M,
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15) (a) Lippert KM, Hof K, Gerbig D, Ley D, Hausmann H,
Guenther S, Schreiner PR. Eur. J. Org. Chem. 2012;
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8

Department of Chemistry
Faculty of Mathematics and Science
Niagara Region
1812 Sir Isaac Brock Way
St. Catharines, ON
L2S 3A1 Canada
T 905-688-5550 x3405
F 905-682-9020
tdudding@brocku.ca
October 28, 2019
Dear Editor,
It is with great pleasure that we submit our manuscript entitled:
Charge-Enhanced Thiourea Catalysts as Hydrogen Bond Donors for Friedel‒Crafts
Alkylations
by Ivor Smajlagic, Brenden Carlson, Nicholas Rosano, Hayden Foy and Travis Dudding*
Highlights:
•
The concept of “charge-enhanced acidity” offers insights to improving catalyst
activation;
•
•
The utility of cyclopropenium frameworks as charged constructs enable catalysis;
The use of variable time normalization analysis (VTNA) as a timely qualitative method in
1
addition to H NMR binding studies probe the underlying mechanism of Friedel‒Crafts
alkylation reactions;
•
Computational calculations are powerful tools for acquiring mechanistic insight and
directing the development of catalytic methodologies;
Sincerely,
Professor Travis Dudding
Department of Chemistry, Brock University
St. Catharines, Ontario, L2S 3A1
Office: MC E219, Phone: 905-688-5550 x3405
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Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: