In Situ Catalyst Generation and Benchtop-Compatible Entry Points for TiII/TiIV Redox Catalytic Reactions

Article abstract of DOI:10.1021/acs.organomet.8b00474

The development of several in situ generated catalyst systems for Ti-catalyzed oxidative nitrene transfer reactions is reported. The simplest and widely applicable catalyst system, TiCl₄(THF)₂/Zn⁰, can be set up on the benchtop under air. This system uses commercially available reagents and can be used as an entry point for Ti^II/Ti^IV multicomponent redox reactions for the synthesis of pyrroles, α,γ-unsaturated imines, α,β-unsaturated imines, cyclopropylimines, and arenes.

Full text of DOI:10.1021/acs.organomet.8b00474

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
In Situ Catalyst Generation and Benchtop-Compatible Entry Points
for TiII/TiIV Redox Catalytic Reactions
Zachary W. Davis-Gilbert,† Kento Kawakita,‡ Daniel R. Blechschmidt,† Hayato Tsurugi,*,‡
Kazushi Mashima,*,‡ and Ian A. Tonks*,†
†Department of Chemistry, University of MinnesotaTwin Cities, Minneapolis, Minnesota 55455, United States
‡Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka 560-8531, Japan
S
* Supporting Information
ABSTRACT: The development of several in situ generated
catalyst systems for Ti-catalyzed oxidative nitrene transfer
reactions is reported. The simplest and widely applicable
catalyst system, TiCl4(THF)2/Zn0, can be set up on the
benchtop under air. This system uses commercially available
reagents and can be used as an entry point for TiII/TiIV
multicomponent redox reactions for the synthesis of pyrroles,
α,γ-unsaturated imines, α,β-unsaturated imines, cyclopropyli-
mines, and arenes.
INTRODUCTION
■
Over the past several decades, there has been a large effort
toward developing new reactions using less toxic and earth-
abundant transition metals.1 Titanium represents an excellent
source for new catalysis research as it is the second most earth-
abundant transition metal and generally considered to be
nontoxic.2,3 Its differential reactivity (e.g., [2 + 2] cyclo-
addition and electrocyclization) compared to that of the first-
row late transition metals (e.g., groups 9 and 10) allows for the
development of new complementary chemistry. Despite these
apparent advantages, titanium is still underutilized in the
development of “base metal” catalysis. This is partially due to
the fact that late transition metal catalysts (e.g., PdCl2(PPh3)2
or [(TMEDA)Ni(o-tolyl)Cl]) are often air-stable and easy to
handle.4 In contrast, many simple titanium precursors are air-
and moisture-sensitive and can be difficult to handle;
nonetheless, a number of elegant and useful titanium-catalyzed
reactions have been developed.5
Figure 1. Divergent oxidative C−N and C−C bond coupling
Recently, we developed a suite of new titanium-catalyzed
oxidative C−N bond coupling reactions for the synthesis of
pyrroles,6 α,γ-unsaturated imines,7,8 and cyclopropylimines,7
mediated by a formal TiII/TiIV redox couple (Figure 1).
Although these reactions have all utilized relatively simple
titanium imido precatalysts, these precatalysts all require
synthesis and storage under stringent air- and moisture-free
conditions.9 In order to make this oxidative TiII/TiIV manifold
more broadly usable, we aimed to develop a simple route of
entry to allow for benchtop chemistry without the need for a
glovebox or any precatalyst synthesis.
reactions enabled by Ti imido catalysts.
accomplish both two-electron reductions (via β-H abstraction
of Ti-alkyls)10 or one-electron reductions (via Zn or Mn
reduction coupled with weak acid).11 The desired criteria for
our catalyst system include being (1) benchtop-stable, solid Ti
precursors that can be weighed out in air and (2) benchtop-
stable, solid reductants or reductant solutions that can be
Special Issue: Organometallic Complexes of Electropositive Ele-
ments for Selective Synthesis
In this vein, we were inspired by myriad examples of Ti-
catalyzed reductive coupling reactions where simple reductants
(Grignard reagents, alkyl lithiums, Zn, Mn) have been used to
Received: July 6, 2018
© XXXX American Chemical Society
A
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Table 2. Yields (1H NMR) of [2 + 2 + 1] Pyrrole Synthesis
with Various Reductants and Ti Precursors
handled via simple syringe/Schlenk technique. We also aimed
to investigate reagents that are both commercially available and
inexpensive. Herein, we report several in situ generated and
benchtop-compatible systems for Ti-catalyzed oxidative
nitrene transfers via TiII/TiIV couples, including the
optimization and substrate scope of a particularly convenient
to use TiCl4(THF)2/Zn0 combination.
a
RESULTS AND DISCUSSION
■
We began our investigations by attempting [2 + 2 + 1] pyrrole
synthesis from 3-hexyne and azobenzene with 10%
TiCl3(THF)3 as a catalyst. TiCl3(THF)3 was chosen as the
starting point because it has been shown to disproportionate
into TiCl2(THF)4 and TiCl4(THF)2 at 150−200 °C in the
solid state,12 and we envisioned that a solvated disproportio-
nation may occur at lower temperaturespotentially providing
access to an on-cycle low-valent TiII species needed to cleave
azobenzene en route to Ti imido formation.13 Satisfyingly,
reaction of 5 equiv of 3-hexyne (1) with azobenzene (2) and
10% TiCl3(THF)3 at 115 °C gave modest yields of the
expected 2,3,4,5-tetraethyl-1-phenyl-1H-pyrrole (3a) across an
array of polar aromatic solvents (Table 1). These reactions
Table 1. Solvent Scope of TiCl3(THF)3-Catalyzed [2 + 2 +
a
1] Pyrrole Formation
a
Conditions: 0.19 mmol azobenzene, 0.96 mmol 3-hexyne, 0.019
b
mmol TiCl3(THF)3, 0.019 mmol reductant, and 0.09 mmol
trimethoxybenzene as internal standard in 0.5 mL of PhOMe at
115 °C.
solvent
NMR yield
conversion (%)
bromobenzene
toluene
43
57
41 (72)
80
97
c
c
anisole
74 (>99)
reductants of TiIV in reductive coupling reactions.15,16 Neither
of these experiments resulted in productive catalytic reactivity
with TiCl3(THF)3, likely due to deleterious direct reaction
with TiCl3(THF)3 instead of the desired reaction with in situ
disproportionated TiCl4(THF)2.15c Consistent with this
α,α,α-trifluorotoluene
o-dichlorobenzene
40
62
>99
>99
a
Conditions: 0.19 mmol azobenzene, 0.96 mmol 3-hexyne, 0.019
mmol TiCl3(THF)3, 0.1 mmol trimethoxybenzene as internal
standard in 0.5 mL of solvent at 115 °C. % Consumption of
b
n
hypothesis, reaction of BuLi with TiCl4(THF)2 results in a
c
azobenzene. 0.038 mmol TiCl3(THF)3.
high yield (78%) of pyrrole, indicating that direct two-electron
reduction of TiCl4(THF)2 is a viable route to catalyst
activation. Interestingly, reactions with EtMgBr were signifi-
proceeded at roughly half the rate of reactions catalyzed by
preformed [py2TiCl2(NPh)]2, indicating that approximately
half of the Ti in these in situ activated reactions sits as inactive
TiCl4(THF)2consistent with a disproportionation mecha-
nism of activation. Although these reactions were modestly
yielding, they were all plagued by hydroamination side
reactions presumably resulting from radical reactions of
TiCl3(THF)3 or Lewis acid/base reactions of TiCl4(THF)2.
Given the demonstration of TiCl3(THF)3 disproportiona-
tion as a route into TiII/TiIV chemistry, we next sought to
further optimize catalytic pyrrole formation by screening
various reductants in combination with TiCl3(THF)3 and
several TiIV sources (TiCl4(THF)2, Ti(OiPr)4, and
TiF4(THF)2) (Table 2)envisioning that in situ reduction
by an additive would result in more active catalyst than the
inherent 50% maximum from disproportionation. Although
anisole was not the most effective solvent in the initial solvent
screen, we chose to optimize these reactions in anisole because
it is a green solvent.14
n
cantly worse than those with BuLi, although discrepancies
between organomagnesium and organolithium reagents for
titanium reductions have been previously observed.15
Next, we examined Mg0, Al0, Mn0, and Zn0 metal powders as
reductants. None was effective for Ti(OiPr)4 or TiF4(THF)2,
whereas Zn0 was remarkably effective with TiCl4(THF)2,
giving 95% yield of 3a under standard screening conditions
the highest of any examined reducant/precatalyst combination.
Additionally, the TiCl4(THF)2/Zn0 reaction is virtually free of
side products, unlike reactions with TiCl3(THF)3. Interest-
ingly, although Mg0, Al0, and Mn0 failed for all TiIV precursors,
their reaction with TiCl3(THF)3 resulted in slight increases in
pyrrole yield over reactions without added reductant. Based on
the failed in situ reduction of TiIV precursors with these
reductants, these modest yield increases with TiCl3(THF)3
may be related to slow electron transfer kinetics or to impurity
scrubbing effects; however, the precise effect remains unclear.
Similar results are also seen with organosilane reductants 1-
methyl-3,6-bis(trimethylsilyl)-1,4-cyclohexadiene and 2,5-di-
methyl-1,4-bis(trimethylsilyl)-1,4-dihydropyrazine,17 which
n
For these in situ reductions, we first explored adding BuLi
and EtMgBr, which are commonly used as two-electron
B
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Figure 2. 1H NMR spectra of the reaction between TiCl4(THF)2, 0.5 equiv of PhNNPh, and 1.2 equiv of Zn0 in C6D6: (A) t = 0 h; (B) t = 3 h at
100 °C; (C) after heating and addition of 3 equiv of 4-picoline; (D) authentic (4-picoline)3TiCl2(NPh) 4.
are effective for the in situ reduction of TiCl3(THF)3 and
TiCl4(THF)2 precatalysts but not for Ti(OiPr)4 or
TiF4(THF)2. The advantage of these reductants is that the
byproducts, TMSCl and simple arenes (toluene, 2,5-
dimethylpyrazine), can easily be removed from the reaction
in vacuo. Interestingly, the air-stable silane reductant 9,10-
bis(trimethylsilyl)-9,10-dihydroanthracene failed to yield any
product upon reaction with TiCl4(THF)2, likely because it is a
weaker reductant than the other two silanes examined.17a,18
An investigation of the stoichiometric reduction of
TiCl4(THF)2 with Zn0 in the presence of azobenzene provides
insight into how these in situ reductions occur, and how the
catalyst enters the catalytic cycle (Figure 2). Heating
TiCl4(THF)2 with 0.5 equiv of PhNNPh and 1.2 equiv of
Zn0 dust in C6D6 at 100 °C results in complete conversion of
the TiCl4(THF)2 to a mixture of two isomeric
[(THF)2TiCl2(NPh)]2 species (Figure 2B). This mixture can
be converted to a single species, (4-picoline)3TiCl2(NPh) (4),
upon addition of 3 equiv of 4-picoline (Figure 2C). The NMR
of this in situ generated 4 matches well with an independently
synthesized sample of 4 (Figure 2D). Thus, the overall
mechanism of activation for these in situ reductions is through
the formation of a TiNR imido active species from the
reaction of reduced Ti with PhNNPh.
We propose that the initial reaction of reduced Ti with
azobenzene occurs via a TiIII intermediate (Figure 3). This
conclusion is based on several observations: (1) Zn0 is not a
strong enough reductant (E0 = −0.76 V) to directly reduce
TiCl4 to TiCl2 (E0 = −1.62 V);19 (2) previous studies have
shown that coordination of redox-active (π-accepting)
substrates to TiIII can promote further reduction to TiII;19
1
and (3) H NMR studies indicate that azobenzene does not
displace THF in TiCl4(THF)2 (Figure 2A). Thus, it is likely
that the overall mechanism of formation of TiNR from in
situ reduction occurs through the mechanism outlined in
Figure 3: first, single-electron reduction of TiCl4(THF)2 to
TiCl3(THF)n by Zn0, then PhNNPh coordination to
TiCl3(THF)n, followed by a second reduction by Zn0 to
form (η2-PhNNPh)TiCl2(THF)n, and finally disproportiona-
tion of (η2-PhNNPh)TiCl2(THF)n to (NPh)TiCl2(THF)n.
This two-electron manifold is in contrast to the typical one-
electron manifolds commonly encountered with in situ
C
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Table 3. Benchtop and Air-Free Yields of Ti-Catalyzed
Nitrene Transfer Reactions from 10% TiCl4(THF)2/10−
a
20% Zn0 in Situ Catalyst Generation
Figure 3. Activation of TiCl4(THF)2 by Zn0 and entrance into
catalytic cycle for the synthesis of pyrroles.
generated reduced Ti systems. For example, Cp2TiX-based
reagents/intermediates are well-established in a diverse array of
single-electron reactions (e.g., epoxide ring opening, ring-
forming reactions, and HAT reactions), which commonly use
either Mn or Zn alongside a weak acid.5b,11 The ability to
access the two-electron manifold is likely an effect of having
weakly donating halide ligands on Ti in combination with
strongly π-accepting substrates.5b Interestingly, many common
metal reductants used in Ti-mediated reactions (e.g., Al, Mn,
Mg) fail for the [2 + 2 + 1] pyrrole synthesis; this may be due
to over-reduction of the Ti intermediates, metal salt complex
formation (e.g., [Mg(THF)6][TiCl5THF] or (TiCl3)3AlCl3),
or kinetically slow reductions under these conditions.20
Having identified several in situ generated catalytic systems
for Ti-catalyzed nitrene transfer, we next sought to explore the
“benchtop” compatibility and scope of reactions catalyzed by
the TiCl4(THF)2/Zn0 catalyst combination. This system was
chosen for further exploration because it gave the highest yield
for 3a in our initial studies and also because TiCl4(THF)2 is a
commercially available, bench-stable solid: it can be weighed
out in air and stored in a desiccator, obviating the need for a
glovebox or other specialized air-free equipment. Likewise, we
have found that the reaction is relatively insensitive to the
quality/age/oxidized impurities of the Zn0 (see Supporting
Information), making it an ideal reductant for benchtop
protocols.
In these studies (Table 3), we examined several Ti-catalyzed
nitrene transfer reactions under rigorously air-free glovebox
conditions, as well as “benchtop” conditions where all solid
materials were loaded under air before being purged with N2.
Quite remarkably, all Ti-catalyzed [2 + 2 + 1] pyrrole
syntheses are equally effective under both sets of conditions:
internal and terminal alkynes (entries 1−4) both result in high
yields of pyrrole products with regioselectivity similar to that of
previously reported catalysts,6a and heterocoupling reactions6b
(entry 5) also proceed in high yield with excellent selectivity.
The benchtop reaction with 3-hexyne has also been scaled to
greater than 2 g with no loss of fidelity. The terminal alkyne
tBuCCH gave a slightly lower yield under benchtop conditions
(entry 4). For the other Ti-catalyzed nitrene transfer reactions
a
Condition A: 0.19 mmol azobenzene, 0.95 mmol alkyne, 0.019
mmol TiCl4THF2, 0.019 mmol Zn0, 0.1 mmol trimethoxybenzene as
internal standard in 0.5 mL of anisole at 115 °C in an NMR tube;
yields calculated with respect to PhNNPh. Condition B: all solid
reagents were weighed out and loaded into the reaction vessel in air
before being purged with N2; 0.55 mmol azobenzene, 2.74 mmol
alkyne, 0.054 mmol TiCl4THF2, 0.110 mmol Zn0 in 2 mL of anisole.
Trimethoxybenzene was added after being heated for 16 h as external
standard. Yields calculated with respect to PhNNPh. 0.38 mmol
MeCCPh and 0.77 mmol TMSCCPh (condition A), 1.1 mmol
b
c
D
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TiCl3(THF)3 (7.0 mg, 0.019 mmol, 0.1 equiv) were loaded into a 4
mL scintillation vial. To this vial was added 0.5 mL of desired solvent;
the reaction was sealed with a Teflon screw cap, removed from the
glovebox, and heated for 16 h at 115 °C in an oil bath. The reaction
mixture was then cooled to room temperature and loaded into an
Table 3. continued
d
MeCCPh and 2.2 mmol TMSCCPh (condition B). 1.0 mmol alkyne
(condition A), 2.8 mmol alkyne (condition B), 0.2 mmol AdN3
(condition A), 0.56 mmol AdN3 (condition B) used instead of
1
NMR tube, and the No-D H NMR spectrum was collected.
e
PhNNPh. 0.42 mmol substrate (condition A), 1.2 mmol substrate
Example Reaction Optimization (Table 2). Example for Zn0
Powder: Azobenzene (140 mg, 0.76 mmol), 3-hexyne (315 mg, 3.84
mmol), and 1,3,5-trimethoxybenzene (60 mg, 0.36 mmol, as internal
standard) were added to a 2 mL volumetric flask and diluted to 2 mL
with anisole to make a stock solution. TiCl4(THF)2 (6.3 mg, 0.019
mmol), TiCl3(THF)3 (7.0 mg, 0.019 mmol), TiF4(THF)2 (5.1 mg,
0.019 mmol), and Ti(OiPr)4 (5.4 mg, 0.019 mmol) were each added
to separate NMR tubes, and then Zn0 (1.2 mg, 0.019 mmol) and 0.5
mL of the stock solution were added to each NMR tube. The NMR
tubes were then sealed and removed from the glovebox, and t = 0 h
No-D 1H NMR spectra were taken. The NMR tubes were then
heated for 16 h at 115 °C in an oil bath. The NMR tubes were then
f
(condition B). TiCl4(THF)2, PhNNPh, and Zn0 were preheated for 1
g
h before addition of substrate. Yields were obtained after hydrolysis
h
in 2 M HCl. 0.95 mmol 3-hexyne (conditions A), 2.74 mmol
(conditions B).
(entry 6, azide coupling for pyrrole synthesis;6d entry 7,
oxidative ring-opening amination;8 entries 8 and 9, oxidative
carboamination7) as well as alkyne trimerization6e (entry 10),
the in situ air-free protocol resulted in good yields in all cases,
but the benchtop reactions were unsuccessful, presumably due
to catalyst decomposition from advantageous water. These
results highlight the sensitive nature of the transient low-valent
Ti intermediateseven subtle changes in the rates of catalysis
and/or the structure of reagents/stabilizing ligands can impact
the robustness of the reaction protocol.
In summary, we have reported several new in situ catalyst
systems for Ti-catalyzed nitrene transfer reactions. Zn0 is a
particularly effective reductant for TiCl4(THF)2 and
TiCl3(THF)3 precatalysts, yielding low-valent Ti species that
can easily enter nitrene transfer catalytic cycles through
oxidation by azobenzene. Remarkably, these in situ Zn0
reductions can be carried out under “benchtop” conditions,
eliminating the need for specialized air-free equipment.
1
cooled to room temperature, and No-D H NMR spectra were taken
at t = 16 h.
Synthesis of [Ti(NPh)Cl2(4-picoline)3] (4). Compound 4 was
prepared following a modification of the literature procedure for the
preparation of [Ti(NPh)Cl2(THF)2]2.19b In a glovebox, TiCl4 (200
mg, 1.05 mmol, 1.0 equiv) was added to a 20 mL scintillation vial
equipped with a stir bar and diluted with 2 mL of CH2Cl2. To this was
added dropwise a solution of 1,1,1-trimethyl-N-phenyl-N-
(trimethylsilyl)silanamine (250.4 mg, 1.05 mmol, 1.0 equiv) in 2
mL of CH2Cl2. The vial was then sealed with a Teflon screw cap and
heated to 60 °C for 1 h. The vial was then cooled to room
temperature, diluted with 5 mL of hexanes, and filtered on a fine
porosity fritted glass funnel. The black solid was then washed with 3 ×
3 mL of hexanes and transferred back to a 20 mL scintillation vial and
dissolved in 10 mL of CH2Cl2. Next, 0.338 mL of 4-picoline (324 mg,
3.47 mmol, 3.3 equiv) was then added dropwise. The reaction mixture
was then stirred overnight, filtered through a pipet plug of Celite,
layered with hexanes, and precipitated in a −35 °C freezer. The solid
was collected on a fine porosity fritted glass funnel, washed with
hexanes, and dried in vacuo to give the title compound as a tan
EXPERIMENTAL SECTION
■
General Considerations. All air- and moisture-sensitive com-
pounds were manipulated in a glovebox under a nitrogen atmosphere
or on a nitrogen Schlenk line. Solvents for air- and moisture-sensitive
reactions were vacuum distilled from sodium benzophenone ketyl
(C6D6) or CaH2 (PhOMe, C6H5Br, o-Cl2C6H4) or predried on a Pure
Process Technology solvent purification system (hexanes, PhMe,
CH2Cl2, PhCF3). Azobenzene was purchased from TCI America and
purified by flash chromatography using hexanes before grinding the
isolated product in a mortar and pestle and drying in vacuo.
1
powder, 354 mg (69.0% yield). H NMR (400 MHz, C6D6) δ, ppm:
3
9.25 (d, JHH = 6.5 Hz, 4H, o-4-picoline-H), 8.91 (s, 2H, axial o-4-
picoline-H), 7.41 (d, 3JHH = 7.3 Hz, 2H, o-NPh-H), 7.07 (t, 3JHH = 7.7
3
Hz, 2H, m-NPh-H), 6.75 (t, JHH = 7.4 Hz, 1H, p-NPh-H), 6.49 (s,
3
2H, axial m-4-picoline-H), 6.28 (d, JHH = 5.6 Hz, 4H, m-4-picoline-
TiCl3(THF)3,21 TiF4(THF)2,22 and TiCl4(THF)2 were prepared
23
H), 1.67 (s, 3H, axial 4-picoline-CH3), 1.51 (s, 6H, 4-picoline-CH3).
according to literature procedure. Ti(OiPr)4 was purchased from
Sigma-Aldrich and used with no further purification. 3-Hexyne, 1-
phenyl-1-propyne, 4-octyne, and 3,3-dimethyl-1-butyne were pur-
chased from Sigma-Aldrich. Undec-1-en-6-yne,7 (E)-dodec-2-en-7-
yne,7 1-methoxy-4-((2-methylenecyclopropyl)methyl)benzene,8
trimethyl(phenylethynyl)silane,6b 1-methyl-3,6-bis(trimethylsilyl)-
1,4-cyclohexadiene,17a and 2,5-dimethyl-1,4-bis(trimethylsilyl)-1,4-
dihydropyrazine17b were prepared following literature procedure. All
liquid substrates were freeze−pump−thawed three times, brought
into a glovebox, and passed through activated basic alumina before
being stored at −35 °C. PhOMe used outside the glovebox for
benchtop reactions was stored over CaH2 or 4 Å molecular sieves
(can be used filtered or unfiltered). 3-Hexyne used outside the
glovebox for benchtop reactions was stored over activated basic
alumina (to dry and scrub out polar impurities) and filtered prior to
use.
13C NMR (101 MHz, C6D6) δ, ppm: 160.8, 151.9, 151.2, 150.4,
147.6, 128.9, 128.7, 125.0, 124.7, 122.5, 20.9, 20.8.
Example Substrate Scope Experiment (Table 3, Condition
A). Example for 3-Hexyne: Azobenzene (35 mg, 0.19 mmol, 1.0
equiv), 1,3,5-trimethoxybenzene (15 mg, 0.1 mmol, as internal
standard), TiCl4(THF)2 (6.3 mg, 0.019 mmol, 0.1 equiv), and Zn0
(1.2 mg, 0.019 mmol, 0.1 equiv) were added as solids to an NMR
tube, and then 3-hexyne (78.8 mg, 0.95 mmol, 5.0 equiv) and 0.5 mL
of PhOMe were added. The NMR tube was then sealed and removed
from the glovebox, and a t = 0 h No-D 1H NMR spectrum was taken.
The NMR tube was then heated for 16 h at 115 °C in an oil bath. The
1
NMR tube was then cooled to room temperature, and a No-D H
NMR spectrum was taken at t = 16 h.
Example Substrate Scope Experiment (Table 3, Condition
B). Example for 3-Hexyne: Azobenzene (100 mg, 0.55 mmol, 1
equiv), TiCl4(THF)2 (18.0 mg, 0.054 mmol, 0.1 equiv), and Zn0 (6.8
mg, 0.11 mmol, 0.2 equiv) were weighed out on the benchtop and
added to a 100 mL Schlenk flask under air. The flask was then
stoppered with a rubber septum and purged with N2. To this were
then added via syringe 2 mL of anisole (predried over molecular
sieves or CaH2) and then 0.31 mL of 3-hexyne (225 mg, 2.74 mmol, 5
equiv). The septum was then replaced with a reflux condenser fitted
with a N2 inlet, and the flask was heated to 115 °C overnight. The
reaction vessel was then allowed to cool to room temperature, and
1,3,5-trimethoxybenzene (60 mg, 0.36 mmol) was added as an
1H, 13C, HMBC, and No-D NMR spectra were recorded on Bruker
Avance III 500 MHz, Bruker Avance III HD 500 MHz, or Bruker
Avance 400 MHz spectrometers. Chemical shifts are reported with
1
respect to residual protio-solvent impurity for H (s, 7.16 ppm for
C6D5H; s, 7.27 for ppm of CHCl3), and solvent carbons for 13C (t,
128.39 ppm for C6D6) and No-D NMR24 were referenced to 1,3,5-
trimethoxybenzene (s, 6.02 ppm).
Example Reaction Solvent Scope (Table 1). Azobenzene (35
mg, 0.19 mmol, 1.0 equiv), 3-hexyne (78.8 mg, 0.95 mmol, 5.0 equiv),
1,3,5-trimethoxybenzene (15 mg, 0.1 mmol, as internal standard), and
E
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internal standard. A 0.5 mL aliquot of the reaction mixture was loaded
into an NMR tube, and a No-D H NMR spectrum was collected.
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role (Condition B). Azobenzene (1.0 g, 5.5 mmol, 1 equiv),
TiCl4(THF)2 (183 mg, 0.55 mmol, 0.1 equiv), and Zn0 (35 mg, 0.55
mmol, 0.1 equiv) were weighed out on the benchtop and added to a
100 mL Schlenk flask under air. The flask was then stoppered with a
rubber septum and purged with N2. To this were then added via
syringe 10 mL of anisole and then 3.11 mL of 3-hexyne (2.25 g, 27.4
mmol, 5 equiv). The septum was then replaced with a reflux
condenser fitted with a N2 inlet, and the flask was heated to 115 °C
overnight. The reaction vessel was then cooled to 40 °C and dried in
vacuo. The dark red solid was extracted into minimal hexanes, loaded
onto a silica column, and eluted with a 1−5% EtOAc/hexanes
gradient. 1.77 g (64% yield) of 2,3,4,5-tetraethyl-1-phenyl-1H-pyrrole
was collected as a pale yellow oil. Spectral data matched literature.6a
1H NMR (400 MHz, CDCl3) δ, ppm: 7.48−7.43 (m, 2H, m-Ph-H),
́
I.; Mun
P.; García-Ocan
̃
oz-Bascon, J.; Roldan-Molina, E.; Padial, N. M.; Morales, L.
3
̃
a, M.; Oltra, J. E. The Nugent-RajanBabu Reagent: A
7.42−7.36 (m, 1H, p-Ph-H), 7.29 (d, JHH = 7.0 Hz, 2H, o-Ph-H),
3
3
Formidable Tool in Contemporary Radical and Organometallic
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Gilbert, Z. W.; Tonks, I. A. Titanium Redox Catalysis: Insights and
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46, 11522−11528.
2.50 (q, JHH = 7.5 Hz, 4H, −CH2CH3), 2.40 (q, JHH = 7.5 Hz, 4H,
3
3
−CH2CH3), 1.20 (t, JHH = 7.6 Hz, 6H, −CH2CH3), 0.87 (t, JHH
7.5 Hz, 6H, −CH2CH3).
=
ASSOCIATED CONTENT
■
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00474.
Optimization of Zn0 sources, NMR spectra correspond-
ing to entries in Tables 1−3, and scale-up reaction of
2,3,4,5-tetraethyl-1-phenyl-1H-pyrrole (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: tsurugi@chem.es.osaka-u.ac.jp.
*E-mail: mashima@chem.es.osaka-u.ac.jp.
*E-mail: itonks@umn.edu.
ORCID
Hayato Tsurugi: 0000-0003-2942-7705
Kazushi Mashima: 0000-0002-1316-2995
Ian A. Tonks: 0000-0001-8451-8875
Author Contributions
Z.W.D.-G., K.K., and D.C.B. carried out the initial reaction
screens. Z.W.D.-G. optimized the reactions, carried out the
substrate scope experiments, and carried out the mechanistic
experiments. H.T., K.M., and I.A.T. conceived of and directed
the research project. Z.W.D.-G. and I.A.T. wrote the
manuscript. All authors participated in the editing and revision
of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank John E. Ellis (UMN) for synthesizing
the TiCl4(THF)2 used in this work. Financial support was
provided by the University of Minnesota (Doctoral Dis-
sertation Fellowship to ZWD-G), the National Institutes of
Health (1R35GM119457), and the Alfred P. Sloan Foundation
(I.A.T. is a 2017 Sloan Fellow). Equipment for the Chemistry
Department NMR facility was supported through a grant from
the National Institutes of Health (S10OD011952) with
matching funds from the University of Minnesota.
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Dev. 2017, 21, 911−923. (c) Richrath, R. B.; Olyschlager, T.;
Hildebrandt, S.; Enny, D. G.; Fianu, G. D.; Flowers, R. A.; Gansauer,
A. Catalytic, Atom-Economical Radical Arylation of Epoxides. Chem. -
̃
Eur. J. 2018, 24, 6371−6379. (d) Botubol-Ares, J. M.; Duran-Pena, M.
J.; Hanson, J. R.; Hernandez-Galan, R.; Collado, I. G. CpTi(III)Cl
̈
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F
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