(DiMeIHeptCl)Pd: A Low-Load Catalyst for Solvent-Free (Melt) Amination

Article abstract of DOI:10.1021/acs.joc.1c01057

(DiMeIHeptCl)Pd, a hyper-branched N-aryl Pd NHC catalyst, has been shown to be efficient at performing amine arylation reactions in solvent-free ("melt") conditions. The highly lipophilic environment of the alkyl chains flanking the Pd center serves as lubricant to allow the complex to navigate through the paste-like environment of these mixtures. The protocol can be used on a multi-gram scale to make a variety of aniline derivatives, including substrates containing alcohol moieties.

Full text of DOI:10.1021/acs.joc.1c01057

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(DiMeIHeptCl)Pd: A Low-Load Catalyst for Solvent-Free (Melt)
Amination
Volodymyr Semeniuchenko, Sepideh Sharif, Jonathan Day, Nalin Chandrasoma, William J. Pietro,
Jeffrey Manthorpe, Wilfried M. Braje, and Michael G. Organ*
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ABSTRACT: (DiMeIHeptCl)Pd, a hyper-branched N-aryl Pd
NHC catalyst, has been shown to be efficient at performing
amine arylation reactions in solvent-free (“melt”) conditions. The
highly lipophilic environment of the alkyl chains flanking the Pd
center serves as lubricant to allow the complex to navigate through
the paste-like environment of these mixtures. The protocol can be
used on a multi-gram scale to make a variety of aniline derivatives,
including substrates containing alcohol moieties.
coupling melt reactions, one explores the Pd(NHC) catalyst
core,15 which intersects with the work performed in our group.
Generally, NHC ligands are widely used and make Pd
catalysis very efficient.32−36 We reasoned that, if we could
make the NHC suitably “greasy”, it would improve its ability to
migrate through the melt paste by creating its own liquid shell/
environment in which coupling can occur. In this way, less
catalyst could perform the same task as reactions with higher
loads due to the enhanced mobility of the catalyst through the
semi-solid matrix of the melt. Pd-DiMeIHeptCl (Cl refers to the
chlorines on the NHC (N-heterocyclic carbene) core), shown
in Figure 1 in two precatalyst forms 1a and 1b, is decorated
with eight isobutyl groups off the benzylic position of the N-
aryl substituent on the NHC core, making it highly lipophilic.
The Pd center is profoundly hindered, which will serve
multiple purposes as a melt-catalyst candidate. The hindrance
will ensure that the metal is primarily only ligated to the NHC,
ensuring its high reactivity in oxidative addition and entering
the amination catalytic cycle. Further, London dispersion
interactions introduced by bulky alkyl chains about Pd(0)
facilitate interaction with the oxidative addition partner37 and
help prevent catalyst death.37,38 Taken together, these
attributes stemming from the complex’s dense placement of
branched alkyl chains around the metal should reduce greatly
the quantity of catalyst necessary for this purpose. Both 1a and
1b precatalysts were crystallized and characterized by SC-XRD
(Figure 1 and the Supporting Information (SI)).
INTRODUCTION
■
Organic solvents remain the major contributor to the E-Factor
(Environmental Factor, defined as the ratio of the mass of
waste generated per unit of product produced) for small-
molecule, fine chemical manufacturing.1,2 Perhaps the most
straightforward approach to lowering solvent-related E-Factor
is to eliminate reaction solvent altogether.1,2 This technique
has had some success in metal-catalyzed cross-coupling,3−6
which encompasses a broad variety of bond-forming reactions
that are widely employed in fine chemical synthesis. A reaction
that is of particular interest in our group is metal-catalyzed
amination.7−13 In light of the intense interest in C−N bond
formation in many different fine chemical sectors (e.g.,
pharmaceuticals, agrochemicals, electronics),14 a number of
teams have worked toward making this widely employed
transformation solvent-free as there would be a notable impact
on lowering the process’s E-Factor.15−31 In addition, perform-
ing reactions without solvent maximizes the reactants’
concentration, hence the transformation rate.
By their nature, cross-coupling reactions contain significant
amounts of solids. Bases, such as various metal carbonates or
phosphates, and salt additives, such as LiBr, are generally solids
and, in many cases, so too are the organic starting materials
and/or products. Melts generally rely on at least one of the
reagents being a liquid, thereby acting as the solvent/lubricant
for the reaction. Even so, most reaction mixtures are more of a
paste than a free-flowing liquid, which limits diffusion and
slows or prevents/stalls transformations. This means that
higher catalyst loads are necessary to ensure that there is some
in all regions of the melt to drive the chemistry
forward.16,17,19−29 This serves to counteract the E-Factor
gain associated with eliminating reaction solvent. From two
articles15,18 reporting 0.1 mol % Pd complex load for C−N
Received: May 5, 2021
Published: July 13, 2021
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of 1a, the reaction was complete in just 15 min at 50 °C. These
coupling conditions worked well with both aryl bromides and
aryl chlorides, with only one example (4) working noticeably
better at 80 °C. Compound 2 could be formed in 75 min at
0.01 mol % load of 1a, or in 2 h at r.t. with 0.1 mol % load of
1a, providing the initial mixture was well stirred. All results
disclosed in this article were obtained with rigorous exclusion
of air in a nitrogen-filled glovebox. We performed the
transformation to prepare 2 under air and obtained the
product in slightly lower yield (90%), but this was
accompanied by some very minor air oxidation (see
Experimental Section for details).
We next examined the coupling of aryl bromides to alkyl
amines (12−16, Table 2). Although alkylamines are more
nucleophilic, catalytic coupling also involves Pd(amine)
deprotonation, which is faster for arylamines.8,39 The latter
effect must be dominating, as arylation of alkylamines in a melt
required higher temperatures. We have found precatalyst 1b
was notably superior to 1a under such conditions, although we
have no concrete explanation for this at this time. Anilines
(17−20, 22), carbazole (21), and indole (23) also could be
coupled effectively using 1b. We examined representative aryl
chlorides and found similar levels of conversion using
NaOtAm as base, which helps suppress aryl ether40,41 and
phenol42 formation. Further, coupling leading to TPD (N,N′-
bis(3-mthylphenyl)-N,N′-diphenylbenzidine, compound 18,
Table 2) went well, which is of note due to the application
of this compound in the hole transport layer of OLED
devices.43−46 In our experiments, we have found that KOtBu
and NaOtBu were interchangeable for most reactions; only
TPD (18) preparation required KOtBu as the reaction failed
with NaOtBu. Coupling of styryl bromide with diarylamines is
relevant for the manufacture of polymeric layers of photo-
electronic devices;47,48 in particular, the polymer containing
the di(4-tert-butylphenyl)phenylamine group (as in compound
22) was shown to be a p-type organic semiconductor and was
employed to create a hole transport layer.49 One can notice
that coupling with diarylamines was performed either at 50 °C
(19, 22) or at 120 °C (17, 18). Precatalyst 1b was used for
both cases, but at 50 °C, 0.1 mol % of 1b gave maximum 60%
conversion. To push the reaction further at 50 °C, we had to
use 0.2 mol % of 1b. An easy solution to this problem was to
increase the reaction temperature; however, this was not
tolerated by styrenes, which polymerized under these
conditions.
Figure 1. Structure of Pd precatalysts used in this study.
RESULTS AND DISCUSSION
■
We began our investigation with aniline nucleophiles employ-
ing 4-methylaniline (1.2 equiv) and 1-bromo-4-tert-butylben-
zene as electrophile (product 2, Table 1). With only 0.1 mol %
Table 1. Pd-Catalyzed Amination of Aryl Bromides and
Chlorides with Aniline Nucleophiles under Melt Conditions
a
Using (DiMeIHeptCl)Pd(cinnamyl)Cl (1a)
We then explored the ability to couple the same aniline
twice, i.e., diarylation (Scheme 1). Coupling leading to 24 with
1a went very well, whereas, in the case of 22, dicoupling
proceeded to 51% yield. This reaction was complicated by
competing Heck coupling of amino-styrenes with the
bromoarene, and a similar result was observed on attempted
coupling of 10 with 1-bromo-4-tert-butylbenzene.
Next, we thought it would be interesting to investigate the
coupling of partners decorated with a reactive functional
group. We have observed redox processes leading to formation
of various products and we have found how this can be
suppressed. The unwanted redox processes could be catalyzed
by KOtBu, known to initiate SET reactions,50,51 by a
homogeneous Pd catalyst and heterogeneous elemental
palladium. The latter is a product of Pd(NHC) complex
decomposition52 and was observed in our reaction mixtures
after quenching. Elemental palladium is a known catalyst of
transfer hydrogenation being able to extract hydrogen from all
a
Yields are reported on material purified by column chromatography
on silica gel or neutral alumina.
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Table 2. Pd-Catalyzed Amination of Aryl Chlorides with
Alkyl Amine, Aniline, and Heterocyclic Nucleophiles under
Melt Conditions Using (DiMeIHeptCl)Pd(morpholine)Cl2
Scheme 1. Diarylations under Melt Conditions Using
(DiMeIHeptCl)Pd(cinnamyl)Cl (1a)
a
(1b)
(25 and 26) and the amine (27). Application of our standard
coupling conditions resulted in formation of desired coupling
products in low to modest yields, which was typically
accompanied by the formation of redox-associated byproducts.
The byproducts were identified by GC-MS to be N-aryl
iminoquinones and biphenyls (derived from ArBr). As Pd
complexes are known to be able to oxidize hydroquinones to
quinones,56 we suggest a similar oxidation of N-aryl-4-
aminophenols could lead to N-aryl iminoquinones. The
reduced compound in this case was the aryl bromide, which
was partially transformed into the corresponding biphenyl.
Another problem introduced by phenols is their nucleophil-
icity. In earlier experiments, we determined that O-
nucleophiles slow this coupling when KOH or LiOiPr was
used as base. Deprotonation of phenol by KOtBu led to the
same effect. We attribute slow coupling to the nucleophilic
phenolate ion and coordinating N-aryl iminoquinone.
Our solution to this phenolate problem was addition of a
Lewis acid. A common method to couple phenol-containing
partners is with LiHMDS as base;13,57 however, in melt
conditions, this gave negligible yields. On the basis of the
literature,58−62 we propose that Lewis acids react with the
phenol to form a neutral species of the type ArOAl(OAlk)2 or
ArOTi(OAlk)3, thus masking nucleophilic phenolate and
making oxidation to N-aryl iminoquinones impossible. On
the other hand, Lewis acids could also promote reductive
elimination.63
Coupling also proceeded nicely with benzyl alcohols (28
and 29). Benzyl alcohols are readily oxidized by Pd(II)
complexes, which are intermediates of Pd-catalyzed C−N
coupling.64 In our standard reaction conditions, we observed
the desired coupling product (2- or 4-(arylamino)benzyl
alcohol), as well as its reduced (2- or 4-(arylamino)toluene)
and oxidized (2- or 4-(arylamino)benzaldehyde) derivatives.
The imine, formed in situ from excessive o-toluidine and 4-(p-
tolylamino)benzaldehyde, was isolated and characterized (see
the SI for details). Suppression of these unwanted side
reactions was achieved by in situ O-silylation using a NaOtBu/
HMDS mixture, thus making oxidation less favorable.
Deprotection of the product happened on silica gel
chromatography. Utilization of LiHMDS for this coupling
was less efficient as the reaction initiated too fast and led to
a
Yields are reported on material purified by column chromatography
b
on silica gel, neutral alumina, or florisil. For primary amines and
aniline nucleophiles, 1.2 equiv of the amine is used. For secondary
amine nucleophiles, 1.05 equiv of amine is used. Four equivalents of
piperazine was used. Compounds 12, 13, 14, 15, and 17 were also
prepared from 1-chloro-4-tert-butylbenzene under similar conditions
(yields are given in brackets).
c
d
available sources, thus oxidizing them, and transferring H2 to
other compounds.53−55
First, we considered aminations where the substrate had an
acidic hydrogen to see if that posed any issues for the coupling
under our melt conditions (Scheme 2). We performed three
couplings of phenols, as both the oxidative addition partner
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Scheme 2. Coupling of Substrates Possessing OH Groups
under Melt Conditions Using
Scheme 3. Multi-Gram Quantity Couplings under Melt
Conditions Using (DiMeIHeptCl)PdCl(cinnamyl) (1a) or
(DiMeIHeptCl)PdCl2(morpholine) (1b)
(DiMeIHeptCl)PdCl(cinnamyl) (1a)
alcohols in either coupling partner. The procedure is scalable
to at least the multi-gram scale and was useful to prepare
compounds of interest to a number of sectors including small
molecule pharmaceutical, agrochemical, and materials (e.g.,
electronics) companies.
immediate cementation, making it impossible to push it to high
conversion.
Finally, encouraged by the results above, we wanted to
examine the scalability of this melt chemistry (Scheme 3).
Conversion of the electrophile was quantitative when the crude
product mixtures were assessed by 1H NMR spectroscopy, and
isolation provided multi-gram quantities of the target anilines.
Compounds 11 and 14 were directly distilled from reaction
mixtures, thus excluding any solvent usage though the whole
synthetic procedure.
EXPERIMENTAL SECTION
■
General Information. Glovebox manipulations were performed
in an MBraun Unilab glovebox under an atmosphere of dry nitrogen;
to avoid static electrical effects on weighing powders, all vials were
wrapped in aluminum foil. All reagents were purchased from Sigma-
Aldrich, Alfa Aesar, Oakwood, AK Scientific, and Combi-Blocks and
were used without further purification unless noted otherwise. The
ligands for 1a and 1b were obtained from Total Synthesis Ltd.,
Toronto, Canada. All reaction vials and rare earth stir bars (egg
shaped) were purchased from VWR. Analytical thin layer chromatog-
raphy (TLC) was performed on 200 μm thick silica gel (Silicycle), or
neutral alumina precoated aluminum plates, and spots were visualized
with UV light (254 nm). Metal beads for the heating bath were
purchased from Lab Armor. Preparative TLC (PTLC) was performed
on Silicycle 20 × 20 cm plates with a 2 mm layer of 40−63 μm 60 Å
silica gel, and bands were visualized with UV light (254 nm). Column
chromatography purifications were carried out using Biotage Isolera
or Biotage Isolera Four instruments on Santai iLOK-SL silica gel
CONCLUSIONS
■
In summary, we have developed solvent-free (melt) amine
arylation protocols to assemble aniline products using a hyper-
branched Pd-NHC precatalyst [(DiMeIHeptCl)Pd) (1). The
morpholine variant of this complex (1b) appears to tolerate
higher temperatures associated with this procedure when
compared to its π-allyl counterpart 1a. The procedure
accommodates aniline, alkylamine, carbazole, and indole
nucleophiles, while being tolerant of both alkyl and aryl
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(40−63 μm, 60 Å, 10 or 20 g), Santai iLOK neutral alumina (50−75
μm, 55 Å, 24 or 50 g), or Santali iLOK-SL neutral alumina (50−75
μm, 55 Å, 24 g) columns, observing UV absorption at 254 and 280
nm for fraction collection, unless noted otherwise.
a preheated oil bath at 70 °C, stirred for 16 h, and then cooled to
room temperature. Solvent was removed in vacuo, and the residue was
redissolved in CH2Cl2 (20 mL). The mixture was then passed through
a silica gel plug wetted with pentane, eluting with CH2Cl2 until the
filtrate ran clear. The resulting orange solution was concentrated, and
the solid was recrystallized from CH2Cl2 (minimal)/pentane using a
rotavap. The precipitate was then isolated by filtration and washed
with cold pentane. The recrystallization process was repeated twice
more, or until no more solid could be isolated. The product was then
dried under high vacuum to give a yellow solid (8.23 g, 81%).
Mp 190−191 °C (decomposition). δ 7.43 (t, J = 7.7 Hz, 2H, 4-
CH), 7.30 (d, J = 7.7 Hz, 4H, 3-CH), 7.23 (m, 2H, 2-CHPh), 7.14−
7.11 (m, 3H, indirectly assigned: 7.13 4-CHPh, 7.12 3-CHPh), 5.24 (m,
2-CHcinnamyl), 4.61 (d, J = 13.2 Hz, 3-CHcinnamyl), 2.82 (br s, 4H, 4′-
CH), 1.82 (br s, 8H, 6′-CH and 5′-CH2), 1.69 (br m, 8H, 3′-CH2 and
5′-CH2), 1.58 (br s, 4H, 2′-CH), 1.42 (m, 4H, 3′-CH2), 0.96 (d, J =
6.2 Hz, 12H, 7′′-CH3), 0.87 (d, J = 6.2 Hz, 12H, 7′-CH3), 0.83 (d, J =
NMR spectra were recorded on Bruker AVANCE III HD 500 or
AVANCE III HD 600 spectrometers. No-D NMR spectra (using non-
deuterated solvents in lock off conditions) were performed using
proton gradient shimming on the most intensive solvent peak. Percent
1
conversion was assessed either by H NMR or quantitative 13C{1H}
NMR spectroscopy by integration of products signals relative to those
of residual starting material. Quantitative 13C{1H} NMR spectra were
collected with inverse gated decoupling using a waltz65 decoupling
pulse sequence; the 90° excitation pulse was followed by 1.1 s
1
acquisition and 15 s relaxation (256 transients were collected). H
NMR spectra were internally referenced to TMS, 13C{1H} NMR
spectra were internally referenced to the carbon signal(s) of the
solvent, and 15N NMR spectra were externally referenced to liquid
ammonia (Bruker scale). The following abbreviations are used to
describe peak multiplicities: s = singlet, br s = broad singlet, d =
doublet, t = triplet, q = quartet, spt = septet, m = multiplet, dd =
doublet of doublets, dt = doublet of triplets, td = triplet of doublets,
ddd = doublet of doublet of doublets, qd = quartet of doublets. For all
isolated compounds, 2D NMR spectra (NOAH-BSC65,66 where single
FID is separated into 13C−1H HMBC, 13C−1H edited HSQC and
6.4 Hz, 12H, 1′′-CH3), 0.79 (d, J = 6.4 Hz, 12H, 1′-CH3) ppm, 1-
cinnamyl
CH2
is broadened to baseline; 13C{1H} NMR (150 MHz,
CDCl3) δ 182.4 (CPd), 144.5 (2-C), 137.0 (1-CPh), 136.0 (1-C),
129.4 (4-CH), 128.2 (2-CHPh), 128.1 (3-CHPh), 127.2 (4-CHPh),
126.7 (3-CH), 120.2 (CCl), 108.3 (2-CHcinnamyl), 93.3 (3-CHcinnamyl),
49.0 (1-CH2cinnamyl), 43.9 (3′-CH2), 42.2 (br s, 5′-CH2), 36.6 (4′-
CH), 25.4 (2C, 6′-CH and 7′-CH3), 25.1 (2′-CH), 24.5 (7′′-CH3),
24.3 (1′-CH3), 23.2 (br s, 1′′-CH3) ppm. HRMS (ESI/TOF) m/z:
1
1H−1H COSY, 15N−1H HMBC and H−1H NOESY for cases of
+
[M − Cl]+ calcd for C60H91Cl2N2 1015.5589; found 1015.5554.
separated spin systems) were collected to ensure atoms connectivity
and identity of products; NMR peaks assignment was done with help
of these 2D experiments.
A single crystal for XRD was grown by slow evaporation of toluene
solution of this complex.
(SP-4-1)-[1,3-Bis(2,6-bis(2,6-dimethylheptan-4-yl)phenyl)-4,5-di-
chloro-1H-imidazol-2-ylidene]dichloro(morpholine-κ-N4)-
palladium, [Pd(DiMeIHeptCl)(morpholine)Cl2] (1b). For all cases,
unstabilized Et2O was used in this procedure. Under air, a 10 mL
microwave vial was charged by 410.0 mg (1 equiv) of [Pd-
(DiMeIHeptCl)(cinnamyl)Cl] (1a) and 3.9 mL (20 equiv) of a 2
M HCl solution in Et2O. This mixture was heated in a Biotage
Initiator microwave to 70 °C for 10 h. These conditions are very
important for suitable yield of the bridged chloride complex
[Pd(DiMeIHeptCl)Cl2]2; lower temperature leads to low conversion,
whereas higher temperature leads to decomposition. At this point, we
did not try to isolate [Pd(DiMeIHeptCl)Cl2]2 and used it crude for
morpholine coordination. Following forming the dimer, all volatiles
were evaporated under a stream of nitrogen; then the residue was
dried under 100 mTorr vacuum for 4 h to remove the last traces of
HCl. Complex [Pd(DiMeIHeptCl)Cl2]2 was redissolved in 2 mL of
Et2O, and 0.17 mL (5 equiv) of morpholine was added. The mixture
was stirred for 1 h, then adsorbed on silica gel PTLC plate. The plate
was placed in a large desiccator and dried under 100 mTorr vacuum
after which it was eluated for 1 min by DCM to make a sharp starting
line of crude mixture, and again placed in the desiccator and dried
under vacuum. After drying the plate, it was eluted to the top using a
pentane-Et2O mixture (4:1), doped with 3 vol % of morpholine
(doping is essential to prevent the retro reaction to form
[Pd(DiMeIHeptCl)Cl2]2 on silica gel). This gave a band with Rf
0.71, from which 66.1 mg of a side product was eluted with Et2O. We
could not assign a formula to this side product by NMR spectroscopy,
nor could we obtain X-ray quality crystals. Et2O elution of another
band with Rf 0.55 gave 326.2 mg (79.2%) of the target complex after
drying under 100 mTorr vacuum.
All mono- and diarylamines presented in this article promote
chloroform degradation by UV light or oxygen. Paramagnetic
broadening of peaks in NMR spectra is not an indication of product
poor quality. However, broadening can be avoided by using absolute
CDCl3 and protection of NMR samples from UV light (incl.
sunlight), or by choosing a different solvent. Commercially available
CDCl3 was filtrated through basic alumina and stored in an amber-
glass bottle over metallic silver; for most samples, this solvent gave
excellent NMR spectra. In instances where poor spectra were
obtained, CDCl3 was degassed by bubbling nitrogen through it for
20 min, after which it was distilled over P2O5. Absolute CDCl3 was
stored over metallic silver in a light-protected Straus flask under
nitrogen.
GC-MS analysis was performed on Agilent 6890N (GC) and
5975B (MS) instruments on an Agilent HP-5MS column (30 m ×
0.250 mm, 0.25 μm film thickness).
High resolution mass spectrometry (HRMS) analysis was
performed by the John L. Holmes Mass Spectrometry Facility at
the University of Ottawa on Kratos Concept 2S (electron impact
ionizer, magnetic sector analyzer) or Waters Global (electrospray
ionizer, time-of-flight analyzer) instruments.
́
Elemental analysis was performed in Jan Veizer Stable Isotope
Laboratory at the University of Ottawa on an Elementar Isotope Cube
EA instrument. Silver capsules were used for halogen-containing
compounds.
Single crystal X-ray data were collected on a Bruker KAPPA Apex
II Diffractometer equipped with an Apex II CCD detector, using Mo
Kα X-ray radiation. A single crystal of compound 1a was grown by
slow evaporation of toluene solution; a crystal of compound 1b was
grown by slow evaporation of pentane solution.
The isolated product contained variable quantities of morpholine
or Et2O in different batches, as well as some unidentified
contaminants. We could roughly assess its purity to be 90% by
mass, and the minor component was ignored in catalysis (i.e., for
catalytic reaction was always assumed purity to be 100%).
Complex 1b is air stable, and all operations with it can be
performed at room temperature. Long time storage was at −20 °C,
and we have not tested how stable it is on storage at r.t. This complex
obtained by elution from silica gel scratched from the PTLC plate was
smeared in a 100 mL flask, which made it difficult to work with. To
simplify handling, we redissolved it in a minimal quantity of DCM
and transferred it to a 1 dram vial. Solvent was evaporated under a
All solid reagents involved in melt reactions were ground in an
agate mortar and stored in an inert atmosphere; only minor caking of
these solids occurred on storage.
[1,3-Bis[2,6-bis[3-methyl-1-(2-methylpropyl)butyl]phenyl]-4,5-di-
chloro-1,3-dihydro-2H-imidazol-2-ylidene]chloro[(1,2,3-η)-1-phe-
nyl-2-propen-1-yl]palladium, [Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a).
A 500 mL three-neck round-bottom flask equipped with a stir bar was
flame-dried and cooled under nitrogen. To this were added NaOtBu
(1.19 g, 12.05 mmol), [(cinnamyl)PdCl]2 (2.84 g, 5.30 mmol), and
1,3-bis(2,6-bis(2,6-dimethylheptan-4-yl)phenyl)-4,5-dichloro-1H-imi-
dazol-3-ium chloride (8.0 g, 9.64 mmol). The flask was purged with
argon, and dry THF (110 mL) was added. The mixture was placed in
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stream of nitrogen, and the residue was dried under vacuum. Then the
content was redissolved in 1−2 mL of benzene, cooled to −196 °C,
placed in a small desiccator, and lyophilized in a 100 mTorr vacuum
overnight. Lyophilized 1b was a light-yellow, fluffy powder that was
easy to work with.
on silica gel or neutral aluminum oxide. Base-sensitive products were
quenched by addition of NaH2PO4·2H2O or KH2PO4 (equivalent
quantity to base) before adding water and DCM.
Caution! Quenching by water and CDCl3 must be avoided! We have
observed unwanted reactivity between CDCl3 with the base and crude
products, which negatively impacted analysis.
Mp 165−166 °C (decomposition). 1H NMR (600 MHz, CDCl3) δ
7.45 (t, J = 7.8 Hz, 2H, 4-CH), 7.36 (d, J = 7.8 Hz, 4H, 3-CH), 3.63
(dd, J = 12.0, 3.0 Hz, 2H, OCH2), 3.26 (td, J = 12.0, 1.8 Hz, 2H,
OCH2), 3.11 (qd, J = 12.9, 3.0 Hz, 2H, NCH2), 2.94 (m, 4H, 4′-CH),
2.78 (t, J = 12.1 Hz, 1H, NH), 2.59 (d, J = 13.2 Hz, 2H, NCH2), 2.06
(m, 4H, 3′-CH2), 2.01−1.92 (m, 8H, indirectly assigned: 1.98 3′-
CH2, 1.92 2′-CH), 1.64−1.53 (m, 8H, indirectly assigned: 1.60 5′-
CH2, 1.55 6′-CH), 1.45 (m, 4H, 5′-CH2), 1.00 (d, J = 6.6 Hz, 12H,
1′′-CH3), 0.94 (d, J = 6.2 Hz, 12H, 1′-CH3), 0.83 (d, J = 6.4 Hz, 12H,
Quenching Procedure E, Applicable for Products Insoluble,
or Sparingly Soluble in Dichloromethane. The reaction was
quenched by addition of 5 mL of water, after which the mixture was
stirred or sonicated for 30 min, filtered, and washed well with water
(ca. 80 mL). The solid together with frit was placed in a vacuum
desiccator and dried under vacuum at 100 mTorr. Once dry, a small
sample of the solid was dissolved in appropriate solvent (DCM,
CDCl3, THF, CD3OD, or DMSO-d6) and analyzed by NMR
spectroscopy. For experiments selected for purification, the crude
product was washed off from the frit with suitable solvent, adsorbed
on silica gel or Celite, and purified by LC on silica gel or neutral
aluminum oxide.
Base-sensitive products were quenched by addition of NaH2PO4·
2H2O or KH2PO4 (equivalent quantity to base) before adding water.
4-(tert-Butyl)-N-(p-tolyl)aniline (2). Following general procedures
B and D, 1.0 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(cinnamyl)Cl]
(1a), 202.4 mg (1 equiv) of 4-tert-butylbromobenzene, 122.1 mg (1.2
equiv) of p-toluidine, and 159.8 mg (1.5 equiv) of KOtBu were
heated to 50 °C for 15 min (or left running at r.t. for 2 h). After
workup, the crude mixture was dissolved in hexanes and poured
directly on top of a 10 g silica gel column and the product was eluted
with a gradient of 100% hexane to 10% ethyl acetate in hexanes. After
drying under vacuum at 200 mTorr, 214.5 mg of 2 (94%) was
obtained as a yellow oil, which crystallized on storage.
7-CH3), 0.74 (d, J = 6.4 Hz, 12H, 7′′-CH3) ppm; 13C{1H} NMR
̀
(150 MHz, CDCl3) δ 158.7 (CPd), 145.4 (2-C), 134.5 (1-C), 129.4
(4-CH), 126.9 (3-CH), 120.8 (CCl), 67.9 (OCH2), 47.9 (NCH2),
44.2 (5′-CH2), 43.2 (3′-CH2), 36.9 (4′-CH), 26.1 (2′-CH), 25.3 (1′-
CH3), 25.0 (6′-CH), 24.3 (7′′-CH3), 24.2 (1′′-CH3), 23.1 (7′-CH3)
ppm; 15N NMR (1H−15N HMBC projection, 60 MHz, CDCl3) δ
188.9 (NNHC), 17.3 (NH) ppm. Anal. Calcd for C55H91Cl4N3OPd: C,
62.41; H, 8.67; N, 3.97. Found: C, 62.11; H, 8.32; N, 3.76
A single crystal for XRD was grown by slow evaporation of pentane
solution of this complex.
General Procedure A for C−N Coupling, Applicable for
Both Liquid Nucleophile and Electrophile. In a glovebox, a 2
dram vial (for reactions at 25−80 °C) or a 10 mL microwave vial (for
reaction at higher temperature) was charged with 1−2 mg of solid
catalyst. Quantities of other reagents were calculated based on the
loading of the Pd precatalyst. Liquid electrophile and nucleophile
were then added, and the vial was shaken for a few seconds, after
which solid base was added. Immediately after this, a stir bar was
added, the vial was sealed, and the contents were stirred vigorously for
30 s at r.t. In certain cases, mechanical stirring by spatula was
necessary owing to rapid cementation of the mixture and magnetic
stirring was not possible. The vial was then taken out of the glovebox
and immersed in a preheated metal-bead bath, and the contents were
stirred at 1200 rpm at the specified temperature for the time
indicated.
General Procedure B for C−N Coupling, Applicable When
Either Nucleophile or Electrophile Is Solid. In a glovebox, a 2
dram vial (for reactions at 25−80 °C) or a 10 mL microwave vial (for
reactions requiring higher temperature) was charged with 1−2 mg of
solid catalyst. Quantities of other reagents were calculated based on
the loading of the Pd precatalyst. Then the vial was charged with solid
base and solid reagent, and the contents were stirred by a metal
spatula. The liquid reagent was added, followed immediately by the
stir bar, after which the vial was sealed, and the contents were stirred
vigorously for 30 s at r.t. In certain cases, mechanical stirring by a
spatula was needed, as mixture cementation occurred very fast and
magnetic stirring was not possible. The vial was then taken out of the
glovebox and immersed in a preheated metal-bead bath, and the
contents were stirred at 1200 rpm at the specified temperature for the
time indicated.
General Procedure C for C−N Coupling, Applicable for Both
Solid Nucleophile and Electrophile. For this case, the order of
addition does not appear to be critical. Everything was done according
to general procedure B, and after all solids were added, the contents
were stirred well by metallic spatula. The stir bar was then added, and
the vial sealed taken out of the glovebox and immersed in a preheated
metal-bead bath. The content was stirred at 1200 rpm at the specified
temperature for the time indicated.
Quenching Procedure D, Applicable for Products Soluble in
Dichloromethane. The reaction was quenched by the addition of
water (2 mL), followed by 2 mL of dichloromethane (DCM). The
mixture was shaken, and the DCM layer was taken for No-D NMR
analysis. If the reaction was selected for purification, the DCM layer
was separated, and the aqueous layer was extracted by DCM (3 × 2
mL). The combined organic extracts were dried over anhydrous
Na2SO4, filtered, and evaporated. Final purification was done by LC
The same procedure employing 1.4 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a), 224.2 mg (1 equiv) of 4-
tert-butylchlorobenzene, 170.9 mg (1.2 equiv) of p-toluidine, and
223.7 mg (1.5 equiv) of KOtBu yielded 308.6 mg (97.0%) of after
column chromatography.
0.01 Mol% 1a Coupling Reaction to Prepare 2. The experiment
with 0.01% precatalyst was conducted in the following manner.
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a, 1.0 mg) was dissolved in 1 mL
of benzene, and 0.1 mL of this solution was transferred to 2 dram vial,
frozen, and lyophilized in vacuum (200 mTorr). This gave 100 μg of
solid precatalyst, whose load with respect to the aryl bromide was 0.01
mol %. Further operations were conducted according to general
procedures B and D employing 202.4 mg (1 equiv) of 4-tert-
butylbromobenzene, 122.1 mg (1.2 equiv) of p-toluidine, and 159.8
mg (1.5 equiv) of KOtBu. After heating with stirring to 50 °C for 75
min, 215.7 mg of 2 (95%) was isolated as described above.
Performing reaction under air was done in a similar way, according to
general procedures B and D. 1.4 mg of [Pd(DiMeIHeptCl)-
(cinnamyl)Cl] (1a), 170.9 mg (1.2 equiv) of p-toluidine, and 223.7
mg (1.5 equiv) of KOtBu were charged to a 2 dram vial under air as
quickly as possible and stirred by a metallic spatula for a few seconds.
This resulted in mixture blackening. Then 4-tert-butylbromobenzene
(283.3 mg, 1 equiv) was added, followed by a magnetic stir bar. The
vial was corked, and the content was vigorously stirred at r.t. for 30 s.
At this point, the content was totally black (vs green under an inert
atmosphere). The vial was heated for 15 min at 50 °C; then workup
and chromatographic purification were performed as described above.
This gave 286.1 mg (90%) of the desired product as a dark orange oil
(vs yellow oil obtained under an inert atmosphere).
For this compound, paramagnetic broadening was significant even
after only a brief exposure in CDCl3 to sunlight. To avoid this, the
sample was kept in darkness; the use of absolute CDCl3 was not
necessary.
Mp 46−47 °C (lit. 48−50 °C).67 1H NMR (600 MHz, CDCl3) δ
7.22 (dt, J = 8.7, 2.5 Hz, 2H, 3-CH), 7.00 (d, J = 8.6 Hz, 2H, 3′-CH),
6.92−6.87 (m, 4H, indirectly assigned: 6.91 2-CH, 6.89 2′-CH), 5.39
(br s, NH), 2.24 (s, 3H, 4′-Me), 1.27 (s, 9H, 4-tBu) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ 143.4 (4-C), 141.2 (1-C), 140.9 (1′-C),
130.2 (4′-C), 129.9 (3′-CH), 126.1 (3-CH), 118.2 (2′-CH), 117.2
(2-CH), 34.1 (CMe3), 31.6 (CMe3), 20.7 (4′-Me) ppm; 15N NMR
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(1H−15N HMBC projection, 60 MHz, CDCl3) δ 79.0 ppm. The
spectral data are consistent with those reported in the literature.68
N-(4-(tert-Butyl)phenyl)-2,6-dimethylaniline (3). Following gen-
eral procedures A and D, 1.5 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(cinnamyl)Cl] (1a), 303.5 mg (1 equiv) of 4-tert-butylbromobenzene,
207.1 mg (1.2 equiv) of 2,6-dimethylaniline, and 239.7 mg (1.5
equiv) of KOtBu were heated to 50 °C for 15 min. After workup, the
crude mixture was dissolved in hexanes and poured directly on top of
a 10 g silica gel column and the product was eluted using a gradient of
100% hexane to 10% ethyl acetate in hexanes. After drying under
vacuum at 200 mTorr, 315.9 mg of 3 (98%) was obtained as a
colorless solid.
and 191.8 mg (1.5 equiv) of KOtBu were heated to 50 °C for 15 min.
After workup, the crude mixture was dissolved in DCM, adsorbed on
silica gel, and evaporated. This silica gel was transferred on top of a 10
g silica gel column and eluted with a gradient of 100% hexane to 2%
ethyl acetate in hexanes, followed by 2% ethyl acetate in hexanes until
the product eluted. Both eluents were doped by 3 vol % of NEt3. After
drying under vacuum at 200 mTorr, 236 mg of 6 (92%) was obtained
as an off-white solid.
This compound catalyzes rapid photo- or oxidative decomposition
of CDCl3; this solvent was not suitable for NMR spectroscopy. There
are indications that this compound has an available low lying triplet
state, especially under action of acid. It is EPR active in the solid state
(singlet with g-factor 2.0029) and turns deep blue on silica gel; the
color disappears on elution. As well, 6 turns blue on UV irradiation of
1
Mp 89−90 °C. H NMR (600 MHz, CDCl3) δ 7.16 (dt, J = 8.7,
2.5 Hz, 2H, 3′-CH), 7.10 (d, J = 7.3 Hz, 2H, 3-CH), 7.05 (m, 1H, 4-
CH), 6.45 (dt, J = 8.7, 2.5 Hz, 2H, 2′-CH), 5.10 (br s, NH), 2.20 (s,
6H, 2-Me), 1.27 (s, 9H, 4′-tBu) ppm; 13C{1H} NMR (150 MHz,
CDCl3) δ 143.8 (4′-C), 141.1 (1′-C), 138.9 (1-C), 135.6 (2-CMe),
128.6 (3-CH), 126.0 (3′-CH), 125.5 (4-CH), 113.6 (2′-CH), 34.0
(CMe3), 31.7 (CMe3), 20.7 (2-CMe) ppm; 15N NMR (1H−15N
HMBC projection, 60 MHz, CDCl3) δ 71.3 ppm. The spectral data
are consistent with those reported in the literature.69
1
its methanol solution. Peaks in its H NMR spectra were broad in
CD3OD and DMSO-d6, but sharp in acetone-d6 and absolute C6D6.
Two articles72,73 report NMR spectra of this compound in DMSO-d6;
we observed peak broadening in the 1H NMR spectrum of this
compound in DMSO-d6, although chemical shifts were the same as
those reported. The 13C{1H} NMR spectrum in acetone-d6 showed
satellites near 3-C, 4-C, 1′-C, and 2′-C, probably due to formation of
metastable enamine (N1,N1-dimethyl-N4-(prop-1-en-2-yl)-N4-(p-
4-Methoxy-N-(p-tolyl)aniline (4). Following general procedures B
and D, 1.4 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a),
248.6 mg (1 equiv) of 4-bromoanisole, 170.9 mg (1.2 equiv) of p-
toluidine, and 223.7 mg (1.5 equiv) of KOtBu were heated to 50 °C
for 15 min. After workup, the crude mixture was dissolved in DCM,
adsorbed on silica gel, and evaporated. This silica gel was transferred
on top of a 10 g silica gel column and eluted using a gradient of 100%
hexane to 5% ethyl acetate in hexanes, followed by 5% ethyl acetate in
hexanes until the product eluted. After drying under vacuum at 200
mTorr, 254.8 mg of 4 (90%) was obtained as an off-white solid.
The same procedure employing 2.4 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a), 325.0 mg (1 equiv) of 4-
chloroanisole, 293.0 mg (1.2 equiv) of p-toluidine, and 383.6 mg (1.5
equiv) of KOtBu yielded 465.5 mg of 4 (96%). The coupling reaction
was conducted at 80 °C for 15 min or at 50 °C for 12 h in this case.
For this compound, paramagnetic broadening was significant even
after brief exposure of its CDCl3 solution to sunlight. To avoid this,
the sample was kept in darkness; the use of absolute CDCl3 was not
necessary. Mp 86−87 °C (lit. 82 °C).70 1H NMR (600 MHz, CDCl3)
δ 7.04−6.99 (m, 4H, indirectly assigned: 7.03 3′-CH, 7.01 2-CH),
6.86−6.82 (m, 4H, indirectly assigned: 6.85 2′-CH, 6.83 3-CH), 5.38
(br s, NH), 3.78 (s, 3H, OMe), 2.27 (s, 3H, 4′-Me) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ 154.9 (4-C), 142.5 (1′-C), 136.7 (1-C),
129.9 (3′-CH), 129.4 (4′-CMe), 121.2 (2-CH), 116.7 (2′-CH), 114.8
(3-CH), 55.73 (OMe), 20.69 (4′-CMe) ppm; 15N NMR (1H−15N
HMBC projection, 60 MHz, CDCl3) δ 76.3 ppm. The spectral data
are consistent with those reported in the literature.70
1
tolyl)benzene-1,4-diamine). Also, the H NMR spectrum in CH2Cl2
showed sharp signals, but only immediately after reaction quenching,
when the CH2Cl2 solution was extracted from water containing KOH
derived from excessive KOtBu.
1
Mp 94−95 °C. H NMR (600 MHz, acetone-d6) δ 7.01 (dt, J =
8.7, 2.5 Hz, 2H, 3-CH), 6.96 (d, J = 8.4 Hz, 2H, 3′-CH), 6.83 (dt, J =
8.4, 2.5 Hz, 2H, 2′-CH), 6.74 (br dt, J = 8.7, 2.5 Hz, 3H, 2-CH and
NH), 2.86 (s, 6H, NMe2), 2.20 (s, 3H, 4′-CMe) ppm; 13C{1H} NMR
(150 MHz, acetone-d6) δ 147.4 (1-C), 144.78 and 144.71 (1′-C),
134.72 and 134.66 (4-C), 130.3 (3-CH), 127.9 (4′-CMe), 122.17 and
122.10 (3-CH), 115.97 and 115.93 (2′-CH), 114.9 (2-CH), 41.4
(NMe2), 20.6 (4′-CMe) ppm; 15N NMR (1H−15N HMBC projection,
60 MHz, acetone-d6) δ 76.4 (NH), 36.1 (NMe). 1H NMR (600 MHz,
C6D6) δ 7.00 (dt, J = 8.8, 2.5 Hz, 2H, 3-CH), 6.98 (d, J = 8.4 Hz, 2H,
3′-CH), 6.83 (dt, J = 8.4, 2.5 Hz, 2H, 2′-CH), 6.60 (dt, J = 8.8, 2.5
Hz, 2H, 2-CH), 4.85 (br s, 1H, NH), 2.54 (s, 6H, NMe2), 2.17 (s,
3H, 4′-CMe) ppm; 13C{1H} NMR (150 MHz, C6D6) δ 147.3 (1-C),
144.2 (1′-C), 133.8 (4-C), 130.1 (3-CH), 128.3−127.8 (C6D6,
indirectly assigned 3-CH at 128.14), 122.9 (3-CH), 116.0 (2′-CH),
114.5 (2-CH), 41.0 (NMe2), 20.7 (4′-CMe) ppm; 15N NMR
(1H−15N HMBC projection, 60 MHz, C6D6) δ 75.3 (NH), 35.9
+
(NMe). HRMS (ESI/TOF) m/z: [M + H]+ calcd for C15H19N2
227.1548; found 227.1534.
4-Methyl-N-(4-(methylthio)phenyl)aniline (7). Following general
procedures B and D, 1.5 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(cinnamyl)Cl] (1a), 289.3 mg (1 equiv) of (4-bromophenyl)-
(methyl)sulfane, 183.1 mg (1.2 equiv) of p-toluidine, and 239.7 mg
(1.5 equiv) of KOtBu were heated to 50 °C for 15 min. After workup,
the crude mixture was dissolved in DCM, adsorbed on silica gel, and
evaporated. This silica gel was transferred on top of a 10 g silica gel
column and eluted with a gradient of 100% hexane to 5% ethyl acetate
in hexanes, followed by 5% ethyl acetate in hexanes until the product
eluted. After drying under vacuum at 200 mTorr, 297 mg (91%) of 7
was obtained as an off-white solid.
4-(tert-Butyl)-N-phenylaniline (5). Following general procedures A
and D, 1.0 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a),
202.4 mg (1 equiv) of 4-tert-butylbromobenzene, 106.1 mg (1.2
equiv) of aniline, and 159.8 mg (1.5 equiv) of KOtBu were heated to
50 °C for 15 min. After workup, the crude mixture was dissolved in
hexanes and poured directly on top of a 10 g silica gel column and
eluted with a gradient of 100% hexane gradient to 10% ethyl acetate in
hexanes. After drying under vacuum at 200 mTorr, 208 mg of 5
(97%) was obtained as a colorless solid.
Mp 86−87 °C (lit. 81−82 °C).74 1H NMR (600 MHz, CDCl3) δ
7.21 (dt, J = 8.8, 2.5 Hz, 2H, 3′-CH), 7.07 (d, J = 8.3 Hz, 2H, 3-CH),
6.97 (d, J = 8.3 Hz, 2H, 2-CH), 6.94 (br d, J = 8.8 Hz, 2H, 2′-CH),
5.57 (br s, NH), 2.43 (s, 3H, SMe), 2.29 (s, 3H, 4-Me) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ 142.4 (1′-C), 140.2 (1-C), 131.2 (4-
CMe), 130.3 (3′-CH), 130.0 (3-CH), 128.1 (4′-CS), 119.0 (2-CH),
117.7 (2′-CH), 20.8 (4-Me), 18.23 (4′-SMe) ppm; 15N NMR
(1H−15N HMBC projection, 60 MHz, CDCl3) δ 80.3 ppm. The
spectral data are consistent with those reported in the literature.75
4-(tert-Butyl)-N-methyl-N-phenylaniline (8). Following general
procedures A and D, 1.6 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(cinnamyl)Cl] (1a), 323.8 mg (1 equiv) of 1-bromo-4-(tert-
butyl)benzene, 170.9 mg (1.05 equiv) of N-methylaniline, and
255.7 mg (1.5 equiv) of KOtBu were heated to 50 °C for 15 min.
Mp 67−68 °C (lit. 66−67 °C).71 1H NMR (600 MHz, CDCl3) δ
7.29 (dt, J = 8.6, 2.5 Hz, 2H, 3-CH), 7.23 (m, 2H, 3′-CH), 7.03 (dt, J
= 8.6, 2.5 Hz, 4H, 2-CH and 2′-CH), 6.88 (tt, J = 7.3, 0.9 Hz, 1H, 4′-
CH), 5.61 (br s, NH), 1.31 (s, 9H, 4-tBu) ppm; 13C{1H} NMR (150
MHz, CDCl3) δ 144.3 (4-C), 143.8 (1′-C), 140.4 (1-C), 129.4 (3′-
CH), 126.3 (3-CH), 120.5 (4′-CH), 118.2 (2-CH), 117.2 (2′-CH),
34.3 (4-CMe3), 31.6 (4-CMe3) ppm; 15N NMR (1H−15N HMBC
projection, 60 MHz, CDCl3) δ 80.5 ppm. The spectral data are
consistent with those reported in the literature.71
N1,N1-Dimethyl-N4-(p-tolyl)benzene-1,4-diamine (6). Following
general procedures C and D, 1.2 mg (0.1 mol %) of [Pd-
(DiMeIHeptCl)(cinnamyl)Cl] (1a), 228.0 mg (1 equiv) of 4-
bromo-N,N-dimethylaniline, 146.5 mg (1.2 equiv) of p-toluidine,
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After workup, the crude mixture was dissolved in hexanes and poured
directly on top of a 10 g silica gel column and eluted with 100%
hexanes. After drying under vacuum at 200 mTorr, 350 mg (96%) of
8 was obtained as a yellow oil.
The same procedure employing 1.3 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a), 208.2 mg (1 equiv) of 4-
tert-butylchlorobenzene, 138.9 mg (1.05 equiv) of N-methylaniline,
and 207.8 mg (1.5 equiv) of KOtBu yielded 289 mg (98%) of 8 after
chromatography.
a 24 g neutral alumina column and eluted with a gradient of 100%
hexane to 5% ethyl acetate in hexanes. After drying under vacuum at
200 mTorr, 268 mg (93%) of 10 was obtained as an orange oil, which
crystallized on storage at −20 °C and remained solid on thawing to
r.t.
Large Scale Synthesis of 10. The synthesis was performed in the
following manner. A 100 mL pear-shaped flask, stir bar, 10 cm
Vigreux column, rubber septum, and balloon attached to a syringe
needle were placed into the glovebox. The top joint of the Vigreux
column was corked by a rubber septum and pierced by a needle
equipped with a balloon. The flask was wrapped in aluminum foil and
charged with 16.3 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(cinnamyl)-
Cl] (1a), 34.1 mg (1 mol %) of BHT, 50.0 mg (2 mol %) of HMDS,
3.2984 g (1 equiv) of 1-bromo-4-(tert-butyl)benzene, and 2.0287 g
(1.1 equiv) of 4-aminostyrene. The content was stirred magnetically
for a few seconds. KOtBu (2.6051 g, 1.5 equiv) was added to the
reaction mixture as quickly as possible after which the flask was
corked by a Vigreux column, and the content was immediately stirred
magnetically. In 30−60 s, an exotherm was observed with gentle
refluxing of tBuOH. The balloon mounted on top of the Vigreux
column had to protect the glovebox atmosphere from these gases. The
assembled apparatus was taken out of the glovebox and placed in a
metal-bead bath preheated to 50 °C, and the mixture was stirred at
1200 rpm for 12 h. After cooling to r.t., the Vigreux column was
removed and the reaction was quenched with water (20 mL) and
DCM (20 mL). After separating the phases, the aqueous phase was
washed with DCM (2 × 20 mL) and the combined organic extracts
were dried over anhydrous Na2SO4, filtrated, and evaporated. The
crude product was dissolved in hexanes (50 mL) and injected into a
stack of consecutively connected two Santai iLOK 50 g neutral
alumina columns. Elution was performed with hexanes, and after the
BHT peak was fully eluted (observation on 280 nm; BHT does not
absorb UV light at 254 nm), the solvent polarity was increased to 2%
EtOAc, which eluted the target compound as a very broad peak.
Evaporation of all fractions containing product and drying under
vacuum at 200 mTorr provided 3.51 g (90%) of an orange oil, which
crystallized on storage at −20 °C.
1H NMR (600 MHz, CDCl3) δ 7.30 (dt, J = 8.7, 2.5 Hz, 2H, 3-
CH), 7.24 (m, 3′-CH and CHCl3), 7.00 (dt, J = 8.7, 2.5 Hz, 2H, 2-
CH), 6.96 (m, 2H, 2′-CH), 6.89 (tt, J = 7.3, 1.0 Hz, 1H, 4′-CH), 3.29
(s, 3H, NMe), 1.31 (s, 9H, tBu) ppm; 13C{1H} NMR (150 MHz,
CDCl3) δ 149.3 (1′-C), 146.5 (1-C), 144.9 (4-C), 129.2 (3′-CH),
126.2 (3-CH), 121.4 (2-CH), 120.4 (4′-CH), 119.1 (2′-CH), 40.4
(NMe), 34.3 (CMe3), 31.60 (CMe3) ppm; 15N NMR (1H−15N
HMBC projection, 60 MHz, CDCl3) δ 64.8 ppm. The spectral data
are consistent with those reported in the literature.69
4-Methyl-N-(4-vinylphenyl)aniline (9). For this reaction, we used
97% pure 4-bromostyrene stabilized by 3,5-di-tert-butylcatechol (0.1
mol %), supplied by AK Scientific. Following general procedures A
and D, 1.9 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a),
330.2 mg (1 equiv) of 4-bromostyrene, 232.0 mg (1.2 equiv) of p-
toluidine, and 303.7 mg (1.5 equiv) of KOtBu were heated to 50 °C
for 15 min. After workup, the combined DCM extracts after drying
were adsorbed on Celite and dried in vacuum. This Celite was placed
into a loading cartridge atop of a Santai neutral alumina column (24
g), and the product was eluted using a gradient of 100% hexane to 5%
ethyl acetate in hexanes, followed by 5% ethyl acetate in hexanes until
the product eluted. After drying under vacuum at 200 mTorr, 289 mg
(77%) of 9 was obtained as a colorless solid.
This product rapidly decomposes on silica gel and is very sensitive
to UV light. Unlike other products described above, 9 simply
decomposes under UV irradiation. Decomposition products are not
paramagnetic, and the decomposition rate strongly depends on
solvent. It is very fast in DCM and CDCl3, slower in EtOAc, and very
slow in hexanes. We were able to use UV detection at 254 and 280
nm for chromatography at a flow rate of 18 mL/min, which minimizes
exposure to UV light. Brief exposure does not result in significant
decomposition. We also checked the stability of 9 in CDCl3 where it
remained intact after 24 h in darkness, whereas decomposition was
very fast upon exposure to sunlight.
1
Mp 58−59 °C. H NMR (600 MHz, CDCl3) δ 7.29 (dt, J = 8.6,
2.5 Hz, 4H, 3-CH and 3′-CH), 7.03 (dt, J = 8.6, 2.5 Hz Hz, 2H 2-
CH), 6.97 (dt, J = 8.6, 2.5 Hz, 2H, 2′-CH), 6.64 (dd, J = 17.6, 10.8
Hz, 1H, CHvinyl), 5.65 (br s, 1H, NH), 5.59 (dd, J = 17.6, 0.9 Hz, 1H,
CH2vinyl), 5.09 (dd, J = 10.8, 0.9 Hz, 1H, CH2vinyl), 1.31 (tBu) ppm;
13C{1H} NMR (150 MHz, CDCl3) δ 144.6 (4-C), 143.5 (1′-C),
140.1 (1-C), 136.5 (CHvinyl), 130.0 (4′-C), 127.4 (3′-CH), 126.3 (3-
CH), 118.5 (2-CH), 116.8 (2′-CH), 111.0 (CH2vinyl), 34.3 (4-CMe3),
31.6 (4-CMe3) ppm; 15N NMR (1H−15N HMBC projection, 60
MHz, CDCl3) δ 81.8 ppm. HRMS (ESI/TOF) m/z: [M + H]+ calcd
for C18H22N+ 252.1752; found 252.1773.
Mp 84−85 °C (lit. 71−73 °C).76 1H NMR (600 MHz, CDCl3) δ
7.29 (dt, J = 8.5, 2.2 Hz, 2H, 3′-CH), 7.09 (d, J = 8.1 Hz, 2H 3-CH),
7.00 (d, J = 8.1 Hz, 2H, 2-CH), 6.95 (dt, J = 8.5, 2.2 Hz, 2H, 2′-CH),
6.64 (dd, J = 17.6, 10.8 Hz, 1H, CHvinyl), 5.65 (br s, 1H, NH), 5.59
(dd, J = 17.6, 0.7 Hz, 1H, CH2vinyl), 5.09 (dd, J = 10.8, 0.7 Hz, 1H,
CH2vinyl), 2.31 (CH3) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ
143.8 (1′-C), 140.0 (1-C), 136.5 (CHvinyl), 131.3 (4-C), 130.02 (3-
CH), 129.97 (4′-C), 127.4 (3′-CH), 119.3 (2-CH), 116.6 (2′-CH),
110.9 (CH2vinyl), 20.9 (Me) ppm; 15N NMR (1H−15N HMBC
projection, 60 MHz, CDCl3) δ 81.4 ppm. The spectral data are
consistent with those reported in the literature.76
4-(tert-Butyl)-N-(4-vinylphenyl)aniline (10). For this reaction, we
used 97% pure 4-aminostyrene stabilized by KOH (0.5 mol %),
supplied by Oakwood. KOH is an inhibitor of Pd-catalyzed coupling;
thus it was inactivated by addition of HMDS. We also had to add
BHT to the reaction mixture to inhibit polymerization. Addition order
is very important for this reaction. In the glovebox, a 2 dram vial was
wrapped in aluminum foil and charged with 1.2 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a), 2.5 mg (1 mol %) of BHT,
3.7 mg (2 mol %) of HMDS, 242.8 mg (1 equiv) of 4-tert-
butylbromobenzene, and 162.9 mg (1.2 equiv) of 4-aminostyrene.
The mixture was stirred briefly, 191.8 mg (1.5 equiv) of KOtBu was
added, the vial was closed, and the content was immediately stirred
magnetically at r.t. for a few seconds. The vial was taken out of the
glovebox and inserted in a preheated metal-bead bath, and the
mixture was stirred at 1200 rpm for 12 h at 50 °C. Quenching was
performed according to the general procedure D. After workup, the
crude mixture was dissolved in hexanes and poured directly on top of
3-Methyl-N-phenylaniline (11). Following general procedures A
and D, 1.8 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a),
292.3 mg (1 equiv) of 3-bromotoluene, 191.0 mg (1.2 equiv) of
aniline, and 287.7 mg (1.5 equiv) of KOtBu were heated to 50 °C for
15 min. After workup, the crude mixture was dissolved in hexanes and
poured directly on top of a 10 g silica gel column and eluted with a
gradient of 100% hexane gradient to 5% ethyl acetate in hexanes. After
drying under vacuum at 200 mTorr, 273 mg (87%) was obtained as a
colorless oil.
Large Scale Synthesis of 11. The synthesis was performed in the
following manner. A 50 mL pear-shaped flask, stir bar, 10 cm Vigreux
column, rubber septum, and balloon attached to a syringe needle were
placed into the glovebox. The top joint of the Vigreux column was
corked by a rubber septum and pierced by a needle equipped with a
balloon. The flask was wrapped in aluminum foil and charged with
33.4 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a),
5.4241 g (1 equiv) of 3-bromotoluene, and 2.9535 g (1 equiv) of
aniline. The content was stirred magnetically for a few seconds.
KOtBu (3.9145 g, 1.1 equiv) was added to the reaction mixture as
quickly as possible after which the flask was corked by the Vigreux
column, and the content was immediately stirred magnetically. In 30−
60 s, an exotherm was observed with gentle refluxing of tBuOH. The
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balloon mounted on top of the Vigreux column had to protect the
glovebox atmosphere from any harmful gas. The assembled apparatus
was taken out of the glovebox and placed in a metal-bead bath
preheated to 50 °C, and the mixture was stirred at 1200 rpm for 15
min. After cooling to r.t., the Vigreux column was removed, and a
small sample was removed with a metal spatula and washed into an
NMR with CH2Cl2 to check conversion by No-D NMR tube, which
was quantitative. A short path distillation head with an attached
fractional distillation spider and flasks was mounted on the flask. The
product was distilled off under vacuum, collecting a fraction with bp
127 °C (1200 mTorr). This gave 3.8846 g (66.8%) of the desired
product as a colorless oil, which crystallized on storage.
9H, tBu), 1.22 (m, 1H, 4′-CH2), 1.14 (m, 2H, 2′-CH2) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ 145.2 (1-C), 139.7 (4-C), 126.1 (3-CH),
112.9 (2-CH), 52.0 (1′-CH), 33.9 (4-CMe3), 33.8 (2′-CH2), 31.7 (4-
CMe3), 26.1 (4′-CH2), 25.2 (3′-CH2) ppm; 15N NMR (1H−15N
HMBC projection, 60 MHz, CDCl3) δ 76.8 ppm. The spectral data
are consistent with those reported in the literature.80
N,4-Di-tert-butylaniline (14). Following general procedures A and
D, 1.0 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(morpholine)Cl2] (1b),
201.3 (1 equiv) of 1-bromo-4-(tert-butyl)benzene, 82.9 mg (1.2
equiv) of tert-butylamine, and 159.0 mg (1.5 equiv) of KOtBu were
heated to 120 °C for 15 min. After workup, the crude mixture was
dissolved in hexanes and poured directly on top of a 10 g silica gel
column and eluted with 100% hexane until N,4-di-tert-butyl-N-(4-
(tert-butyl)phenyl)aniline came out. Then a gradient to 10% ethyl
acetate in hexanes was utilized to elute the product. After drying
under vacuum at 5 mbar vacuum, 175.5 mg (91%) of 14 was obtained
as a colorless oil that solidified on storage at −20 °C, along with 7.7
mg (4.8%) of the di-addition product (for characterization data, see
below).
The same procedure employing 1.1 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(morpholine)Cl2] (1b), 175.3 mg (1 equiv) of
4-tert-butylchlorobenzene, 91.2 mg (1.2 equiv) of tert-butylamine, and
171.7 mg (1.5 equiv) of NaOtAm was performed at 120 °C for 3 h.
After workup, the combined DCM extracts were passed through a
florisil column and eluated with DCM. Evaporation of eluates and
drying under vacuum at 5 mbar provides 203.4 mg (93%) of 14
contaminated with a small amount of N,4-di-tert-butyl-N-(4-(tert-
butyl)phenyl)aniline (2.0%) and 4-tert-butylphenol (0.6%).
Large Scale Synthesis of 14. The synthesis was performed in the
following manner. A 50 mL pear-shaped flask, stir bar, 10 cm Vigreux
column, rubber septum, and balloon attached to a syringe needle were
placed into the glovebox. The top joint of the Vigreux column was
corked by a rubber septum and pierced by a needle equipped with a
balloon. The top joint of the Vigreux column was corked by a rubber
septum and pierced by a needle equipped with a balloon. The flask
was wrapped in aluminum foil and charged with 30.0 mg (0.1 mol %)
of [Pd(DiMeIHeptCl)(morpholine)Cl2] (1b), 6.0396 g (1 equiv) of
1-bromo-4-(tert-butyl)benzene, and 2.4874 g (1.2 equiv) of tert-
butylamine. The content was stirred magnetically for a few seconds,
and 4.7701 g (1.5 equiv) of KOtBu was added to the reaction mixture
as quickly as possible. The flask was corked with the Vigreux column,
and the mixture was immediately stirred magnetically. In 30−60 s, an
exotherm was observed with gentle refluxing of of tBuOH and
tBuNH2. The balloon mounted on top of the Vigreux column
protected the glovebox atmosphere from any harmful gas. The
assembled apparatus was taken out of the glovebox and placed in an
oil bath preheated to 120 °C. At this temperature, the reaction was
stirred at 1200 rpm for 15 min, then cooled to r.t. Under air, the
Vigreux column was changed to a short path distillation head with an
attached fractional distillation spider and flasks. The product was
distilled off under vacuum, collecting a fraction with bp 94 °C (750
mTorr) to 92 °C (500 mTorr) to 98 °C (820 mTorr). The pressure
fluctuated during fraction collection, which led to an inconsistent
boiling point. This gave 4.7703 g (79%) of 14 as a clear oil that
contained a trace of 1-(tert-butoxy)-4-(tert-butyl)benzene according
to NMR and GC-MS analysis.
Mp 35−36 °C (lit. 31−32 °C).77 1H NMR (600 MHz, CDCl3) δ
7.26 (m, CHCl3 and 3′-CH), 7.15 (td, J = 7.4, 1.0 Hz, 1H, 5-CH),
7.06 (m, 2H, 2′-CH), 6.92 (tt, J = 7.5, 1.0 Hz, 1H, 4′-CH), 6.90−6.87
(m, 2H, indirectly assigned: 6.89 2-CH, 6.88 6-CH), 6.75 (d, J = 7.4
Hz, 1H, 4-CH), 5.76 (br s, 1H, NH), 2.30 (s, 3H, 3-Me) ppm;
13C{1H} NMR (150 MHz, CDCl3) δ 143.3 (1′-C), 143.2 (1-C),
139.4 (3-C), 129.5 (3′-CH), 129.3 (5-CH), 122.1 (4-CH), 121.1 (4′-
CH), 118.7 (2-CH), 118.0 (2′-CH), 115.1 (6-CH), 21.7 (3-Me)
ppm; 15N NMR (1H−15N HMBC projection, 60 MHz, CDCl3) δ 82.0
ppm. The spectral data are consistent with those reported in the
literature.78
4-(tert-Butyl)-N-octylaniline (12). Following general procedures A
and D, 1.3 mg (0.1 mol %) of [Pd(DiMeIHeptCl)(morpholine)Cl2]
(1b), 261.7 (1 equiv) of 1-bromo-4-(tert-butyl)benzene, 190.5 mg
(1.2 equiv) of n-octylamine, and 206.7 mg (1.5 equiv) of KOtBu were
heated to 50 °C for 15 min. After workup, the crude mixture was
dissolved in hexanes and poured directly on top of a 10 g silica gel
column and eluted with a gradient of 100% hexane to 10% ethyl
acetate in hexanes. After drying under vacuum at 200 mTorr, 302.3
mg (94.2%) of 12 was obtained as a colorless oil.
A similar procedure employing 1.6 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(morpholine)Cl2] (1b), 254.9 mg (1 equiv) of
4-tert-butylchlorobenzene, 234.4 mg (1.2 equiv) of n-octylamine, and
249.7 mg (1.5 equiv) of NaOtAm was performed at 120 °C for 1 h.
After workup, the combined DCM extracts were passed through a
florisil column while eluting with DCM. After drying under vacuum at
200 mTorr, 393.5 mg (98%) of 12 was obtained contaminated with a
tiny amount of diaryloctylamine.
1H NMR (600 MHz, CDCl3) δ 7.20 (dt, J = 8.6, 2.5 Hz, 2H, 3-
CH), 6.56 (dt, J = 8.6, 2.5 Hz, 2H, 2-CH), 3.48 (br s, 1H, NH), 3.08
(t, J = 7.3 Hz, 2H, 1′-CH2), 1.60 (q, J = 7.3 Hz, 2H, 2′-CH2), 1.38
(m, 2H, 3′-CH2), 1.34−1.23 (m, 17H, indirectly assigned: 1.31 4′-
CH2, 1.29 7′-CH2, 1.28 5′-CH2, 1.27 tBu, 1.26 6′-CH2), 0.88 (t, J =
7.1 Hz, 3H, 8′-CH3) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ
146.4 (1-C), 139.93 (4-C), 126.1 (3-CH), 112.5 (2-CH), 44.4 (1′-
CH2), 34.0 (4′-CMe3), 32.0 (6′-CH2), 31.7 (4′-CMe3), 29.8 (2′-
CH2), 29.6 (4′-CH2), 29.4 (5′-CH2), 27.3 (3′-CH2), 22.8 (7′-CH2),
14.3 (8′-CH3) ppm; 15N NMR (1H−15N HMBC projection, 60 MHz,
CDCl3) δ 61.2 ppm. The spectral data are consistent with those
reported in the literature.79
4-(tert-Butyl)-N-cyclohexylaniline (13). Following general proce-
dures A and D, 1.2 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(morpholine)Cl2] (1b), 241.6 (1 equiv) of 4-tert-butylbromobenzene,
134.9 mg (1.2 equiv) of cyclohexylamine, and 190.8 mg (1.5 equiv) of
KOtBu were heated to 120 °C for 15 min. After workup, the
combined DCM extracts were passed through a florisil column while
eluting with DCM. After drying under vacuum at 200 mTorr for 2 h,
258.8 mg (99%) of 13 was obtained as a light yellow oil.
1H NMR (600 MHz, CDCl3) δ 7.17 (dt, J = 8.7, 2.5 Hz, 2H, 3-
CH), 6.70 (dt, J = 8.7, 2.5 Hz, 2H, 2-CH), 3.33 (br s, 1H, NH), 1.31
(s, 9H, NtBu), 1.28 (s, 9H, CtBu) ppm; 13C{1H} NMR (150 MHz,
CDCl3) δ 144.3 (1-CN), 141.4 (4-C), 125.8 (3-CH), 117.8 (2-CH),
51.6 (NCMe3), 34.0 (CCMe3), 31.7 (CCMe3), 30.3 (NCMe3) ppm;
15N NMR (1H−15N HMBC projection, 60 MHz, CDCl3) δ 85.1 ppm.
The spectral data are consistent with those reported in the
literature.81
A similar procedure employing 1.1 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(morpholine)Cl2] (1b), 175.3 mg (1 equiv) of
4-tert-butylchlorobenzene, 123.7 mg (1.2 equiv) of cyclohexylamine,
and 171.7 mg (1.5 equiv) of NaOtAm was performed at 120 °C for 1
h. The same workup yielded 238.0 mg (98%) of 13 contaminated
with a tiny amount of diarylcyclohexylamine.
N,4-Di-tert-butyl-N-(4-(tert-butyl)phenyl)aniline was isolated as a
byproduct (7.7 mg, 4.8% yield, colorless solid) in the small scale
preparation of N,4-di-tert-butylaniline (14).
1H NMR (600 MHz, CDCl3) δ 7.18 (d, J = 8.8, 2.5 Hz, 2H, 3-
CH), 6.54 (d, J = 8.8, 2.5 Hz, 2H, 2-CH), 3.42 (br s, 1H, NH), 3.22
(ttt, J = 10.2, 3.7 Hz, 1H, 1′-CH), 2.04 (m, 2H, 2′-CH2), 1.75 (m,
2H, 3′-CH2), 1.64 (m, 1H, 4′-CH2), 1.36 (m, 2H, 3′-CH2), 1.27 (s,
1
Mp 96−97 °C. H NMR (600 MHz, CDCl3) δ 7.21 (dt, J = 8.7,
2.5 Hz, 2H, 3-CH), 6.91 (dt, J = 8.7, 2.5 Hz, 2H, 2-CH), 1.38 (s, 9H,
NtBu), 1.28 (s, 18H, CtBu) ppm; 13C{1H} NMR (150 MHz, CDCl3)
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δ 146.0 (1-CN), 144.6 (4-C), 126.0 (2-CH), 125.4 (3-CH), 55.6
(NCMe3), 34.2 (CCMe3), 31.6 (CCMe3), 30.2 (NCMe3) ppm; 15N
NMR (1H−15N HMBC projection, 60 MHz, CDCl3) δ 87.0 ppm.
HRMS (ESI/TOF) m/z: [M + H]+ calcd for C24H36N+ 338.2848;
found 338.2865.
The same procedure employing 1.5 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1b), 239.0 mg (1 equiv) of 4-
tert-butylchlorobenzene, 251.8 mg (1.05 equiv) of diphenylamine, and
238.5 mg (1.5 equiv) of KOtBu yielded 416.5 mg (98%) of 17.
Mp 66−67 °C (lit. 52−53 °C,84 74−75 °C,85 77−79 °C).7 1H
NMR (600 MHz, CDCl3) δ 7.26−7.20 (m, indirectly assigned: 7.24
CHCl3, 7.24 3-CH, 7.22 3′-CH), 7.08 (d, J = 7.9 Hz, 4H, 2′-CH),
7.01 (dt, J = 8.6, 2.5 Hz, 2H, 2-CH), 6.97 (t, J = 7.2 Hz, 2H, 4′-CH),
1.31 (s, 9H, tBu) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 148.1
(1′-C), 145.9 (4-C), 145.1 (1-C), 129.2 (3′-CH), 126.2 (3-CH),
124.1 (2-CH), 124.0 (2′-CH), 122.4 (4′-CH), 34.4 (4-CMe3), 31.6
(4-CMe3) ppm; 15N NMR (1H−15N HMBC projection, 60 MHz,
CDCl3) δ 94.0 ppm. The spectral data are consistent with those
reported in the literature.71
4-(4-(tert-Butyl)phenyl)morpholine (15). Following general pro-
cedures A and D, 1.2 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(morpholine)Cl2] (1b), 241.6 mg (1 equiv) of 1-bromo-4-(tert-
butyl)benzene, 103.7 mg (1.05 equiv) of morpholine, and 190.8 mg
(1.5 equiv) of KOtBu were heated to 120 °C for 15 min. After
workup, the combined DCM extracts were passed through a florisil
column and eluted with DCM. Evaporation of eluates and drying in a
200 mTorr vacuum yielded 226.9 mg (89%) of 15 as an off-white
solid which contained a small amount of 4-tert-butyl-phenol.
The same procedure employing 1.3 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(morpholine)Cl2] (1b), 207.1 mg (1 equiv) of
4-tert-butylchlorobenzene, 112.3 (1.05 equiv) of morpholine, and
206.7 mg (1.5 equiv) of KOtBu yielded 254.4 mg (92%) of 15
containing a small amount 4-tert-butyl-phenol.
N4,N4′-Diphenyl-N4,N4’-di-m-tolyl-[1,1′-biphenyl]-4,4′-diamine
(TPD, 18). Following general procedures B and D, 1.5 mg (0.2 mol %)
of [Pd(DiMeIHeptCl)(morpholine)Cl2] (1b), 221.1 mg (1 equiv) of
4,4′-dibromobiphenyl, 272.7 mg (2.1 equiv) of 3-methyl-N-phenyl-
aniline, and 238.5 mg (3 equiv) of KOtBu were heated to 120 °C for
3 h. After workup, the combined DCM extracts were evaporated and
the residue was redissolved in 10 mL of absolute DCM, 1 mL of NEt3,
and 1 mL of acetyl chloride. The flask was corked, the solution was
stirred for 14 h, and the reaction was quenched with 10 mL of 2 M
NaOH. The phases were separated, and the aqueous phase was
extracted with DCM (2 × 10 mL). The combined organic extracts
were adsorbed on silica gel and evaporated. This silica was placed on
top of a 10 g silica gel column and eluted using a gradient of 100%
hexanes to 5% EtOAc in hexanes, after which 5% EtOAc in hexanes
was used until the product eluted. This provided 315.3 mg (87.1%) of
18 as a colorless solid after drying under vacuum at 100 mTorr.
On silica gel, acidic, neutral, and basic alumina, TPD is co-eluted
with unreacted 3-methyl-N-phenylaniline. The only way to obtain 18
pure was to derivatize diarylamine with acetyl chloride. We have also
investigated this coupling performed in a deficiency of 3-methyl-N-
phenylaniline; this gave impure 18, which we were unable to purify.
Mp 170−171 °C. 1H NMR (600 MHz, CDCl3) δ 7.44 (dt, J = 8.6,
2.5 Hz, 4H, 2-CHbiphenyl), 7.25 (t, J = 7.5 Hz, CHCl3 and 3-CHPh),
7.14 (t, J = 7.7 Hz, 2H, 5-CHmTol), 7.12−7.09 (m, 8H, indirectly
assigned: 7.10 3-CHbiphenyl, 7.10 2-CHPh), 7.00 (t, J = 7.5 Hz, 2H, 4-
CHPh), 6.95 (s, 2H, 2-CHmTol), 6.92 (d, J = 7.7 Hz, 6-CHmTol), 6.84
(d, J = 7.7 Hz, 2H, 4-CHmTol), 2.26 (s, 6H, 3-MemTol) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ 147.9 (1-CNPh), 147.8 (1-CNmTol), 146.9
(4-CNbiphenyl), 139.3 (3-CmTol), 134.7 (1-Cbiphenyl), 129.3 (3-CHPh),
129.2 (5-CHmTol), 127.4 (2-CHbiphenyl), 125.2 (2-CHmTol), 124.3 (2-
CHPh), 124.2 (3-CHbiphenyl), 124.0 (2-CHmTol), 122.8 (4-CHPh),
121.8 (6-CHmTol), 21.6 (3-MemTol) ppm; 15N NMR (1H−15N HMBC
projection, 60 MHz, CDCl3) δ 94.9 ppm. The spectral data are
consistent with those reported in the literature.86
Mp 65−66 °C (lit. 59−62 °C).82 1H NMR (600 MHz, CDCl3) δ
7.30 (dt, J = 8.9, 2.1 Hz, 2H, 3-CH), 6.86 (dt, J = 8.9, 2.1 Hz, 2H, 2-
CH), 3.85 (t, J = 4.8 Hz, 4H, OCH2), 3.13 (t, J = 4.8 Hz, 4H, NCH2),
1.29 (tBu) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 149.0 (1-C),
142.9 (4-C), 126.1 (3-CH), 115.5 (2-CH), 67.1 (OCH2), 49.7
(NCH2), 34.1 (CMe3), 31.6 (CMe3) ppm; 15N NMR (1H−15N
HMBC projection, 60 MHz, CDCl3) δ 56.8 ppm. The spectral data
are consistent with those reported in the literature.24
1-(4-(tert-Butyl)phenyl)piperazine (16). Following general proce-
dures B and D, 1.1 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(morpholine)Cl2] (1b), 221.5 mg (1 equiv) of 4-tert-butylbromo-
benzene, 358.0 mg (4 equiv) of piperazine, and 149.8 mg (1.5 equiv)
of NaOtBu were heated to 120 °C for 15 min. After workup, the
crude mixture was dissolved in DCM and poured directly on top of a
10 g silica gel column (DCM does not eluate the product at all). Both
eluents were doped by 3 vol % of NEt3. The column was washed with
EtOAc until the peak of the byproduct (1,4-bis(4-(tert-butyl)phenyl)-
piperazine; for characterization data, see below) was fully eluted. This
was followed by a gradient of EtOAc to 10% MeOH in EtOAc, after
which 10% MeOH in EtOAc was used until the product eluted from
the column. Evaporation of fractions and drying under a vacuum of
100 mTorr gave 219.8 mg (97%) of 16 as a colorless solid.
1
Mp 133−134 °C. H NMR (600 MHz, CDCl3) δ 7.27 (d, J = 8.9
Hz, 2H, 3′-CH), 6.85 (d, J = 8.9 Hz, 2H, 2′-CH), 3.08 (m, 4H, 2-
CH2), 2.98 (m, 4H, 3-CH2), 2.37 (br s, 1H, 4-NH), 1.27 (s, 9H, tBu)
ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 149.2 (1′-CN), 142.2 (4′-
C), 125.7 (3′-CH), 115.6 (2′-CH), 50.3 (2-CH2), 45.9 (3-CH2), 33.8
(4′-CMe3), 31.3 (4′-CMe3) ppm; 15N NMR (1H−15N HMBC
projection, 60 MHz, CDCl3) δ 59.2 (1-N), 29.4 (4-NH) ppm. The
spectral data are consistent with those reported in the literature.83
1,4-Bis(4-(tert-butyl)phenyl)piperazine was isolated as a byproduct
(5.6 mg yield, 3.1%, off-white solid) in preparation of 1-(4-(tert-
butyl)phenyl)piperazine (16).
N,N-Diphenyl-4-vinylaniline (19). Following general procedures B
and D, 1.9 mg (0.2 mol %) of [Pd(DiMeIHeptCl)(morpholine)Cl2],
167.1 mg (1 equiv) of 4-bromostyrene, 159.5 mg (1.05 equiv) of
diphenylamine, and 151.1 mg (1.5 equiv) of KOtBu were heated to
50 °C for 14 h. After workup, the combined DCM extracts were dried
over anhydrous Na2SO4, filtrated, adsorbed on Celite, and dried in
vacuum. This Celite was placed in a loading cartridge placed before a
Santai neutral alumina column (24 g), and the product was eluted
with hexanes. After drying under vacuum at 100 mTorr, 165 mg
(67%) of 19 was obtained as a colorless solid.
Mp 227−228 °C (decomposition). 1H NMR (600 MHz, CDCl3) δ
7.31 (dt, J = 8.7, 2.5 Hz, 4H, 3-CH), 6.93 (dt, J = 8.7, 2.5 Hz, 2-CH),
3.31 (s, 8H, CH2), 1.30 (s, 18H, tBu) ppm; 13C{1H} NMR (150
MHz, CDCl3) δ 149.0 (1-C), 142.9 (4-C), 126.1 (3-CH), 116.2 (2-
CH), 49.8 (CH2), 34.1 (4-CMe3), 31.6 (4-CMe3) ppm; 15N NMR
(1H−15N HMBC projection, 60 MHz, CDCl3) δ 57.8 ppm. HRMS
1
+
(ESI/TOF) m/z: [M + H]+ calcd for C24H35N2 351.2800; found
Mp 94−95 °C. H NMR (600 MHz, CDCl3) δ 7.25 (dt, J = 8.5,
2.5 Hz, 2H, 3-CH), 7.21 (br t, J = 7.4, Hz, 4H, 3′-CH), 7.07 (m, 4H,
2′-CH), 7.00 (dt, J = 8.5, 2.5 Hz, 2H, 2-CH), 6.98 (tt, 7.4, 1.0 Hz, 2H,
4′-CH), 6.63 (dd, J = 17.6, 10.8 Hz, 1H, CHvinyl), 5.61 (dd, J = 17.6,
0.7 Hz, 1H, CH2vinyl), 5.12 (dd, J = 10.8, 0.7 Hz, 1H, CH2vinyl) ppm;
13C{1H} NMR (150 MHz, CDCl3) δ 147.7 (1′-C), 147.6 (1-C),
136.3 (CHvinyl), 132.0 (4-C), 129.4 (3′-CH), 127.2 (3-CH), 124.5
(2′-CH), 123.7 (2-CH), 123.0 (4′-CH), 112.3 (CH2vinyl) ppm; 15N
NMR (1H−15N HMBC projection, 60 MHz, CDCl3) δ 96.1 ppm.
The spectral data are consistent with those reported in the
literature.87,88
351.2970.
4-(tert-Butyl)-N,N-diphenylaniline (17). Following general proce-
dures B and D, 1.3 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(morpholine)Cl2] (1b), 261.7 mg (1 equiv) of 4-tert-butylbromo-
benzene, 218.2 mg (1.05 equiv) of diphenylamine, and 206.7 mg (1.5
equiv) of KOtBu were heated to 120 °C for 1 h. After workup, the
crude mixture was dissolved in hexanes and poured directly on top of
a 10 g silica gel column and eluted with hexanes. After drying under
vacuum at 200 mTorr vacuum, 346.3 mg (94%) was obtained as a
colorless solid.
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4-(p-Tolylamino)benzamide (20). Following general procedures C
and E, 1.5 mg (0.2 mol %) of [Pd(DiMeIHeptCl)(morpholine)Cl2]
(1b), 141.7 mg (1 equiv) of 4-bromobenzamide, 91.1 mg (1.2 equiv)
of p-toluidine, and 198.8 mg (2.5 equiv) of KOtBu were heated to
120 °C for 14 h. After workup, the crude product was diluted with
MeOH, added to silica gel, and evaporated. This silica was placed on
top of a 20 g silica gel column and eluted with a gradient of 100%
hexane to 60% ethyl acetate in hexanes, after which 60% ethyl acetate
in hexanes was used until the product eluted from the column. After
drying under vacuum at 200 mTorr, 132.7 mg (83%) was obtained as
a colorless solid. Although the crude product was well soluble in
MeOD, once purified, 20 was sparingly soluble in MeOH, MeCN,
and EtOAc; thus the NMR spectra in CD3OD were recorded as a
suspension.
1-(4-(tert-Butyl)phenyl)-1H-indole (23). Following general proce-
dures B and D, 1.3 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(morpholine)Cl2] (1b), 261.7 mg (1 equiv) of 4-tert-butylbromo-
benzene, 151.1 mg (1.05 equiv) of indole, and 177.0 mg (1.5 equiv)
of NaOtBu were heated to 100 °C for 14 h (reaction performed at
120 °C for 1 h gave almost the same results). After workup, the
combined DCM extracts were dried over anhydrous Na2SO4, filtered,
adsorbed on silica gel, and dried in vacuum. This silica gel was
transferred on top of a 10 g silica gel column. The column was eluted
by hexanes (2 column volumes), then ramping polarity to 5% EtOAc
(10 column volumes), then isocratic. The mixture of the two stated
products was coeluated by 2% EtOAc in hexanes during gradient. The
related fractions were evaporated, redissolved in DCM, and adsorbed
on silica gel. This silica was reloaded on top of a 20 g silica gel column
and eluted with hexanes, yielding 23 first, followed by 1,3-bis(4-(tert-
butyl)phenyl)-1H-indole (for characterization data, see below).
Evaporation of related fractions and drying under vacuum at 100
mTorr vacuum provided 250.8 mg (82%) of 23 as a colorless solid.
1
Mp 208−209 °C. H NMR (600 MHz, CD3OD) δ (7.72, dt, J =
8.8, 2.5 Hz, 2H, 2-CH), 7.11 (d, J = 8.4 Hz, 2H, 3′-CH), 7.06 (d, J =
8.4 Hz, 2H, 2′-CH), 6.98 (dt, J = 8.8, 2.5 Hz, 2H, 3-CH), 2.29 (s, 3H,
4′-Me) ppm; 13C{1H} NMR (150 MHz, CD3OD) δ 172.2
(CONH2), 150.5 (4-CN), 140.8 (1′-CN), 133.3 (4′-C), 131.1 (3′-
CH), 130.7 (2-CH), 124.0 (1-C), 121.7 (2′-CH), 115.1 (3-CH), 21.1
(4′-Me); 15N NMR (1H−15N HMBC projection, 60 MHz, CD3OD)
δ 88.9 (4-NH) ppm, CONH2 was not visible. S (ESI/TOF) found
(calculated): [M + Na+] 249.1012 (249.1004) Da.
1
Mp 116−117 °C. H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 7.9
Hz, 1H, 4-CH), 7.53 (d, J = 8.3 Hz, 1H, 7-CH), 7.44 (dt, J = 8.5, 2.5
Hz, 2H, 3′-CH), 7.35 (dt, J = 8.5, 2.5 Hz, 2H, 2′-CH), 7.25 (d, J = 3.2
Hz, 1H, 2-CH), 7.17 (m, 1H, 6-CH), 7.13 (m, 1H, 5-CH), 6.62 (d, J
= 3.2 Hz, 1H, 3-CH), 1.33 (s, 9H, tBu) ppm; 13C{1H} NMR (150
MHz, CDCl3) δ 149.5 (4′-C), 137.3 (1′-C), 136.0 (8-C), 129.3 (9-
C), 128.1 (2-CH), 126.5 (3′-CH), 124.0 (2′-CH), 122.3 (6-CH),
121.2 (4-CH), 120.3 (5-CH), 110.7 (7-CH), 103.4 (3-CH), 34.7 (4′-
CMe3), 31.5 (4′-CMe3) ppm; 15N NMR (1H−15N HMBC projection,
60 MHz, CDCl3) δ 145.4 ppm. The spectral data are consistent with
those reported in the literature.71
9-(4-(tert-Butyl)phenyl)-9H-carbazole (21). Following general
procedures B and D, 1.0 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(morpholine)Cl2] (1b), 201.3 mg (1 equiv) of 4-tert-butylbromo-
benzene, 165.9 mg (1.05 equiv) of carbazole, and 156.1 mg (1.5
equiv) of NaOtAm were heated to 120 °C for 14 h. After workup, the
crude mixture was dissolved in DCM, adsorbed on silica gel, and
evaporated. This silica gel was transferred on top of a 20 g silica gel
column and eluted with hexanes. After drying under vacuum at 100
mTorr, 217.6 mg (77%) of 21 was obtained as a white solid.
The same result was observed employing 0.2 mol % of
[Pd(DiMeIHeptCl)(morpholine)Cl2] (1b) under the same condi-
tions. The reaction yield depended very much on the carbazole
supplier; the best was the 98% pure one, purchased from Combi-
Blocks.
1,3-Bis(4-(tert-butyl)phenyl)-1H-indole was isolated as a byproduct
(42.2 mg, 18.0%, colorless solid) in preparation of 1-(4-(tert-
butyl)phenyl)-1H-indole (23).
1
Mp 163−164 °C. H NMR (600 MHz, CDCl3) δ 7.99 (br d, J =
7.3 Hz, 1H, 4-CH, NOE with 7.64 ppm peak), 7.64 (dt, J = 8.4, 2.5
Hz, 2H, 2-CHCAr, NOE with 7.99 ppm peak), 7.59 (br d, J = 7.7 Hz,
1H, 7-CH NOE with 7.45 ppm peak), 7.52 (dt, J = 8.6, 2.5 Hz, 2H, 3-
CHNAr), 7.49 (dt, J = 8.4, 2.5 Hz, 2H, 3-CHCAr), 7.45 (m, 3H, 2-
CHNAr and 2-CH, NOE with 7.59 ppm peak), 7.24 (m, 1H, 6-CH),
1
Mp 187−188 °C. H NMR (600 MHz, CD3OD) δ 8.14 (dt, J =
7.21 (m, 1H, 5-CH), 1.384 (s, 9H, 4-tBuNAr), 1.380 (s, 9H, 4-tBuCAr
)
7.7, 0.8 Hz, 2H, 4-CH), 7.60 (dt, J = 8.5, 2.5 Hz, 2H, 3′-CH), 7.48
(dt, J = 8.5, 2.5 Hz, 2H, 2′-CH), 7.42 (dt, J = 8.1, 0.9 Hz, 2H, 1-CH),
7.39 (m, 2H, 2-CH), 7.27 (m, 2H, 3-CH), 1.42 (s, 9H, tBu) ppm;
13C{1H} NMR (150 MHz, CD3OD) δ 150.6 (4′-C), 141.1 (9a-CN),
ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 149.8 (4-CNAr), 149.1 (4-
C
CAr), 137.1 (1-CNNAr), 136.8 (8-C), 132.4 (1-CCAr), 127.4 (2-
CHCAr), 127.3 (9-C), 126.6 (3-CHNAr), 125.9 (3-CHCAr), 125.6 (2-
C), 124.2 (2-CHNAr), 122.7 (6-CH), 120.7 (5-CH), 120.3 (4-CH),
118.8 (3-C), 111.0 (7-CH), 34.8 (4-CMe3NAr), 34.7 (4-CMe3CAr),
31.58 (4-CMe3NAr), 31.55 (4-CMe3CAr) ppm; 15N NMR (1H−15N
HMBC projection, 60 MHz, CDCl3) δ 144.4 ppm. HRMS (EI) m/z:
[M]+ calcd for C28H31N+ 381.2457; found 381.24444.
135.1 (1′-CN), 126.9 (3′-CH), 126.7 (2′-CH), 125.9 (2-CH), 123.4
(4a-C), 120.4 (4-CH), 119.8 (3-CH), 110.0 (1-CH), 34.9 (4′-CMe3),
31.6 (4′-CMe3) ppm; 15N NMR (1H−15N HMBC projection, 60
MHz, CD3OD) δ 126.1 ppm. The spectral data are consistent with
those reported in the literature.24
4-(tert-Butyl)-N-(4-(tert-butyl)phenyl)-N-(p-tolyl)aniline (24).
Following general procedures B and D, 1.7 mg (0.2 mol %) of
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a), 344.0 mg (2 equiv) of 4-tert-
butylbromobenzene, 86.5 mg (1 equiv) of p-toluidine, and 271.7 mg
(3 equiv) of KOtBu were heated to 50 °C for 14 h. After workup, the
crude mixture was dissolved in hexanes and poured directly on top of
a 10 g silica gel column and eluted with a gradient of 100% hexane to
10% ethyl acetate in hexanes. After drying under vacuum at 200
mTorr, 278.9 mg yield (93.0%) of 24 was obtained as a white solid.
Mp 121−122 °C. 1H NMR (600 MHz, CDCl3) δ 7.22 (dd, J = 8.6,
2.5 Hz, 4H, 3-CH), 7.04 (d, J = 8.3 Hz, 2H, 3′-CH), 7.01−6.96 (m,
6H, indirectly assigned: 6.99 2′-CH, 6.98 2-CH), 2.30 (s, 3H, 4′-Me),
1.30 (s, 18H, 4-tBu) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 145.7
(1′-CN), 145.5 (1-CN), 145.0 (4-C), 132.1 (4′-C), 129.9 (3′-CH),
126.0 (3-CH), 124.5 (2′-CH), 123.2 (2-CH), 34.4 (4-CMe3), 31.6
(4-CMe3), 21.0 (4′-Me) ppm; 15N NMR (1H−15N HMBC projection,
60 MHz, CDCl3) δ 91.4 ppm. HRMS (ESI/TOF) m/z: [M + H]+
calcd for C27H37N+ 372.2691; found 372.2689.
4-(tert-Butyl)-N-(4-(tert-butyl)phenyl)-N-(4-vinylphenyl)aniline
(22). Following general procedures B and D, 1.6 mg (0.2 mol %) of
[Pd(DiMeIHeptCl)(morpholine)Cl2] (1b), 138.3 mg (1 equiv) of 4-
bromostyrene, 223.3 mg (1.05 equiv) of bis(4-(tert-butyl)phenyl)-
amine, and 127.2 mg (1.5 equiv) of KOtBu were heated to 50 °C for
14 h. After workup, the combined DCM extracts were dried over
anhydrous Na2SO4, filtered, adsorbed on Celite, and dried in vacuum.
This Celite was placed in a loading cartridge atop of a Santai neutral
alumina column (24 g), and the product was eluted with hexanes.
After drying under vacuum at 100 mTorr, 220.2 mg (76%) of 22 was
obtained as a colorless solid.
1
Mp 155−156 °C. H NMR (600 MHz, CDCl3) δ 7.22 (m, 6H, 2-
CHAr‑vinyl and 3-CHAr‑tBu), 7.00 (dt, J = 8.6, 2.5 Hz, 4H, 2-CHAr‑tBu),
6.98 (br d, J = 8.6 Hz, 2H, 2-CHAr‑vinyl), 6.62 (dd, J = 17.6, 10.8 Hz,
1H, CHvinyl), 5.58 (d, J = 17.6 Hz, 1H, CH2vinyl), 5.09 (d, J = 10.8 Hz,
1H, CH2Ar‑vinyl), 1.29 (s, 18H, tBu) ppm; 13C{1H} NMR (150 MHz,
CDCl3) δ 147.9 (1-CNAr‑vinyl), 145.8 (4-CAr‑tBu), 145.0 (1-CNAr‑tBu),
136.5 (CHvinyl), 131.2 (4-CAr‑vinyl), 127.0 (3-CHAr‑vinyl), 126.2 (3-
CHAr‑tBu), 124.1 (2-CHAr‑tBu), 122.9 (2-CHAr‑vinyl), 111.7 (CH2Ar‑vinyl),
34.4 (CMe3), 31.6 (CMe3) ppm; 15N NMR (1H−15N HMBC
projection, 60 MHz, CDCl3) δ 94.1 ppm. The spectral data are
consistent with those reported in the literature.89
Attempt of 4-Styrylamine Diarylation by 4-tert-Butylbromoben-
zene. For this reaction, we used 97% pure 4-aminostyrene stabilized
by KOH (0.5 mol %), supplied by Oakwood. KOH is an inhibitor of
Pd-catalyzed coupling; thus it was deactivated by the addition of
HMDS. We also had to add BHT to the reaction mixture to inhibit
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Article
polymerization. Addition order is very important for this reaction. In
the glovebox, a 2 dram vial was wrapped in aluminum foil and charged
with 1.2 mg (0.2 mol %) of [Pd(DiMeiHeptCl)(cinnamyl)Cl] (1a),
2.5 mg (1 mol %) of BHT, 3.7 mg (2 mol %) of HMDS, 242.8 mg (2
equiv) of 4-tert-butylbromobenzene, and 67.9 mg (1 equiv) of 4-
aminostyrene. The mixture was stirred for a few seconds after which
191.8 mg (3 equiv) of KOtBu was added, the vial was closed, and the
content was immediately stirred magnetically at r.t. for a few seconds.
The vial was taken out of the glovebox and inserted in a preheated
metal-bead bath, and the mixture was stirred at 1200 rpm at 80 °C for
14 h. Quenching was performed according to general procedure D.
After workup, the crude mixture was dissolved in hexanes and poured
directly on top of a 24 g neutral alumina column. The column was
eluted by hexanes (7 column volumes), then ramping polarity to 5%
EtOAc (6 column volumes), then isocratic. The first compound
eluted by hexanes was the desired product; evaporation and drying
under vacuum at 100 mTorr provided 112.2 mg (51.3%) of 4-(tert-
butyl)-N-(4-(tert-butyl)phenyl)-N-(4-vinylphenyl)aniline (22). The sec-
ond compound was also eluted by hexanes, which, following the same
solvent removal process, provided 51.8 mg (17.6%) of N,N-bis(4-tert-
butylphenyl)-4-[2-(4-tert-butylphenyl)ethenyl]benzenamine. The third
compound (7.2 mg, 5.0%) eluted at the end of the gradient ramp
was 4-(tert-butyl)-N-(4-vinylphenyl)aniline (10). Immediately follow-
ing 10 came the forth compound 11.7 mg (8.2%), which was
identified to be 4-tert-butyl-N-[4-[2-(4-tert-butylphenyl)ethenyl]phenyl]
benzenamine.
column. Chromatographic purification and drying in the same manner
as described for the previous experiment provided 114.5 mg (21.1%)
of 4-(tert-butyl)-N-(4-(tert-butyl)phenyl)-N-(4-vinylphenyl)aniline (22),
183.8 mg (50.3%) of N,N-bis(4-tert-butylphenyl)-4-[2-(4-tert-
butylphenyl)ethenyl]benzenamine, 95.6 mg (25.6%) of unreacted 4-
(tert-butyl)-N-(4-vinylphenyl)aniline (10), and 129.6 mg (23.8%) of 4-
tert-butyl-N-[4-[2-(4-tert-butylphenyl)ethenyl]phenyl]benzenamine.
3-(p-Tolylamino)phenol (25). Addition order is important for this
experiment. In a nitrogen filled glovebox, a 2 dram vial was wrapped
in aluminum foil and charged with 1.6 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a), 426.2 mg (2.5 equiv) of
KOtBu, and 195.3 mg (1.2 equiv) of p-toluidine. The content was
stirred by a metal spatula, and then 453.4 mg (1.05 equiv) of
Ti(OiPr)4 was added, followed by 262.8 mg (1 equiv) of 3-
bromophenol. Immediately after addition, the mixture was stirred
magnetically for a few seconds until exothermic initiation and
cementation happened. Following this, the vial was taken out of the
glovebox and placed in a preheated metal-bead bath. The content was
stirred at 1200 rpm at 50 °C for 15 min and was quenched by
addition of 517 mg (2.7 equiv) of KH2PO4, water, and DCM. The
content was stirred by a spatula. The mixture was filtered, and the
filter cake was washed well with DCM. The phases were separated,
and the aqueous phase was washed with DCM (3 × 2 mL). The
combined DCM extracts were dried over anhydrous Na2SO4,
concentrated, adsorbed on Celite, evaporated, and dried. This Celite
was placed in a loading cartridge placed before a Santai neutral
alumina column (24 g), and the product was eluted by a gradient of
100% hexane to 30% ethyl acetate in hexanes, then isocratic. The
product was dried under vacuum at 100 mTorr vacuum to a constant
mass, providing 257.1 mg (82%) of 25 as a light brown oil. NMR has
shown some residual EtOAc, which could not be removed in vacuum.
1H NMR (600 MHz, CDCl3) δ 7.11−7.06 (m, 3H, indirectly
assigned: 7.09 3′-CH, 7.07 5-CH), 7.01 (dt, J = 8.4, 2.5 Hz, 2H, 2′-
CH), 6.54 (ddd, J = 8.1, 2.2, 0.6 Hz, 1H, 4-CH), 6.49 (t, J = 2.2 Hz,
1H, 2-CH), 6.32 (ddd, J = 8.1, 2.2, 0.6 Hz, 1H, 6-CH), 5.59 (br s, 1H,
NH), 4.71 (br s, 1H, OH), 2.31 (s, 3H, 4′-Me) ppm; 13C{1H} NMR
(150 MHz, CDCl3) δ 156.7 (1-CO), 145.9 (3-CN), 139.8 (1′-CN),
131.6 (4′-C), 130.5 (5-CH), 130.0 (3′-CH), 119.9 (2′-CH), 109.3
(4-CH), 107.1 (6-CH), 103.1 (2-CH), 20.9 (4′-Me); 15N NMR
(1H−15N HMBC projection, 60 MHz, CDCl3) δ 81.0 ppm. The
spectral data are consistent with those reported in the literature.90
4-(p-Tolylamino)phenol (26). Addition order is important for this
experiment. In the glovebox, a 2 dram vial was wrapped in aluminum
foil and charged with 1.2 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(cinnamyl)Cl] (1a), 197.1 mg (1 equiv) of 4-bromophenol, and 467.8
mg (1.5 equiv) of 90% (technical grade) Al(OtBu)3. The content was
stirred by a metal spatula for a few seconds, and then by a magnetic
stir bar at r.t. for 10 min, which resulted in the formation of white
cemented solid. Following this, 191.8 mg (1.5 equiv) of KOtBu and
146.5 mg (1.2 equiv) of p-toluidine were added and the mixture was
stirred by a spatula. Within a few seconds, the mixture melted and the
color changed to ochre. The vial was taken out of the glovebox and
placed in a preheated metal-bead bath. The content was stirred at
1200 rpm at 50 °C for 15 min, after which the reaction was quenched
with the addition of 2 mL of sat. aqueous NH4Cl and DCM. The
mixture was then sonicated in an ultrasound bath for 5 min and
stirred magnetically for 5 min, which resulted in separation of the
DCM layer from the aqueous gel. 10 mL of 0.9 M aqueous Rochelle
salt was added, which disrupted the gel. The phases were separated,
and the aqueous layer was extracted by DCM (3 × 5 mL). The
combined organic extracts were dried over anhydrous Na2SO4,
concentrated, adsorbed on Celite, evaporated, and dried. This Celite
was placed atop of a Santai neutral alumina column (20 g). Elution
began with hexanes, and the polarity was ramped to 30% EtOAc in
hexanes over 5 column volumes (CV) and then continued
isocratically with 30% EtOAc. Immediately following the elution of
unreacted p-toluidine, the eluent polarity was ramped to 100% EtOAc
within 1 CV, 100% EtOAc was left running for 1 CV, and then the
polarity was ramped to 10% MeOH in EtOAc within 1 CV, after
which isocratic elution with 10% MeOH in EtOAc was continued.
N,N-Bis(4-tert-butylphenyl)-4-[2-(4-tert-butylphenyl)ethenyl]-
benzenamine, light brown solid.
1
Mp 172−173 °C. H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 8.5
Hz, 2H, 2′′-CHCAr), 7.35 (d, J = 8.5 Hz, 2H, 3′′-CHCAr), 7.34 (d, J =
8.8 Hz, 2H, 3-CH), 7.25 (dt, J = 8.8, 2.5 Hz, 4H, 3′-CHNAr), 7.04−
6.99 (m, 7H, indirectly assigned: 7.02 2-CH and 2′-CHNAr, 7.01 1-
CHethenyl), 6.95 (d, J = 16.0 Hz, 1H, 2-CHethenyl), 1.32 (4′′-tBuCAr),
1.30 (4′-tBuNAr); 13C{1H} NMR (150 MHz, CDCl3) δ 150.4 (4′′-
C
CAr), 147.6 (1-C), 145.9 (4′-CNAr), 145.0 (1′-CNAr), 135.1 (1-CCAr),
131.1 (4-C), 127.7 (1-CHethenyl), 127.3 (3-CH), 126.5 (2-CHethenyl),
126.2 (3′-CHNAr), 126.1 (2′′-CHCAr), 125.7 (3′′-CHCAr), 124.2 (2′-
CHNAr), 123.0 (2-CH), 34.7 (4′′-CMe3CAr), 34.4 (4′-CMe3NAr), 31.6
(4′-CMe3NAr), 31.5 (4′′-CMe3CAr) ppm; 15N NMR (1H−15N HMBC
projection, 60 MHz, CDCl3) δ 94.4 ppm. HRMS (EI) m/z: [M]+
calcd for C38H45N+ 515.3552; found 515.35773.
4-tert-Butyl-N-[4-[2-(4-tert-butylphenyl)ethenyl]phenyl]-
benzenamine, light brown solid.
1
Mp 148−149 °C. H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 8.4
Hz, 2H, 2′′-CHCAr), 7.40 (d, J = 8.4 Hz, 2H, 3′-CH), 7.36 (d, J = 8.4
Hz, 2H, 3′′-CHCAr), 7.31 (dt, J = 8.4, 2.5 Hz, 2H, 3-CHNAr), 7.05 (dt,
J = 8.4, 2.5 Hz, 2H, 2-CHNAr), 7.02 (d, J = 8.4 Hz, 2H, 2′-CH), 7.02
(d, J = 16.3 Hz, 1H, 1-CHethenyl), 6.95 (d, J = 16.3 Hz, 1H, 2-
CHethenyl), 5.70 (br s, 1H, NH), 1.33 (s, 9H, 4′′-tBuCAr), 1.32 (s, 9H,
4-tBuNAr) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 150.2 (4-CNAr),
144.5 (4′′-CCAr), 143.2 (1′-CN), 139.9 (1-CNNAr), 135.1 (1′′-CCAr),
129.9 (4′-C), 127.7 (1-CHethenyl), 127.5 (3′-CH), 126.2 (3-CHNAr),
125.9 (2′′-CHCAr), 125.7 (2-CHethenyl), 125.6 (3′′-CHCAr), 118.4 (2-
CHNAr), 116.9 (2′-CH), 34.6 (4′′-CMe3CAr), 34.2 (4-CMe3), 31.5 (4-
CMe3), 31.4 (4′′-CMe3CAr) ppm; 15N NMR (1H−15N HMBC
projection, 60 MHz, CDCl3) δ 82.2 ppm. HRMS (ESI/TOF) m/z:
[M + H]+ calcd for C28H34N+ 384.2691; found 384.2709.
Attempt of 4-(tert-Butyl)-N-(4-vinylphenyl)aniline (10) N-Aryla-
tion. In the glovebox, a 2 dram vial was wrapped in aluminum foil and
charged with 1.5 mg (0.1 mol %) of [Pd(DiMeiHeptCl)(morpholine)-
Cl2] (1b), 3.1 mg (1 mol %) of BHT, 238.5 mg (1.5 equiv) of KOtBu,
and 374.0 mg (1.0 equiv) of 4-(tert-butyl)-N-(4-vinylphenyl)aniline.
The mixture was stirred by a spatula; then 302.0 mg (1 equiv) of 4-
tert-butylbromobenzene was added. A stir bar was placed in the vial,
and it was corked. For a few seconds, the mixture was stirred
magnetically at r.t.; then the vial was taken out of glovebox and
inserted in a preheated metal-bead bath. The mixture was stirred at
1200 rpm at 120 °C for 1 h. Quenching was performed according to
general procedure D. After workup, the crude mixture was dissolved
in hexanes and poured directly on top of a 24 g neutral alumina
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The desired product started to elute by 100% EtOAc, but we knew it
is partially adsorbed irreversibly until MeOH is added, which is the
reason this elution procedure was developed. The product was eluted
in two fractions, one when 100% EtOAc has hit the column, and the
second when MeOH has reached it. Both fractions were combined,
evaporated, and dried under vacuum at 100 mTorr, providing 170.3
mg (73%) of 26 as a light-brown solid containing a tiny quantity of 4-
bromophenol.
Immediately after that, the vial was corked and the content was
vigorously stirred magnetically for ca. 30 s, until exothermic initiation
happened, which resulted in reaction mixture cementation. Following
this, the flask was taken out of the glovebox and placed in a preheated
metal-bead bath and the mixture was stirred at 1200 rpm at 50 °C for
15 min. The reaction was quenched with 2 mL of water and 2 mL of
DCM. The DCM layer was separated and analyzed by No-D NMR,
which illustrated the product to be 4-methyl-N-(4-(((trimethylsilyl)-
oxy)methyl)phenyl)-aniline. The remaining aqueous phase was
extracted by DCM (3 × 2 mL), and the combined organic extracts
were dried over anhydrous Na2SO4, filtrated, and adsorbed on silica
gel. This silica was placed on top of a 10 g silica gel column and eluted
with a gradient of 100 hexanes to 30% EtOAc in hexanes, then
isocratic, providing 302.6 mg (90%) of 28 as off-white solid. 4-
Methyl-N-(4-(((trimethylsilyl)oxy)methyl)phenyl)aniline and 4-
methyl-N-(4-(p-tolylamino)benzylidene)aniline were also isolated as
byproducts (see characterization data below).
1
Mp 123−124 °C. H NMR (600 MHz, CDCl3) δ 7.03 (d, J = 8.2
Hz, 2H, 3′-CH), 6.96 (dt, J = 8.8, 2.8 Hz, 2H, 3-CH), 6.84 (d, J = 8.2
Hz, 2H, 2′-CH), 6.76 (dt, J = 8.8, 2.8 Hz, 2H, 2-CH), 5.37 (br s, 1H,
NH), 4.61 (br s, 1H, OH), 2.27 (s, 3H, 4′-Me) ppm; 13C{1H} NMR
(150 MHz, CDCl3) δ 150.6 (1-CO), 142.5 (1′-CN), 136.9 (4-CN),
130.0 (3′-CH), 129.6 (4′-C), 121.4 (3-CH), 116.8 (2′-CH), 116.2
(2-CH), 20.7 (4′-Me) ppm; 15N NMR (1H−15N HMBC projection,
60 MHz, CDCl3) δ 76.0 ppm. The spectral data are consistent with
those reported in the literature.90
4-((4-(tert-Butyl)phenyl)amino)phenol (27). Addition order is
important for this experiment. In the glovebox, a 2 dram vial was
wrapped in aluminum foil and charged with 1.5 mg (0.1 mol %) of
[Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a), 239.7 mg (1.5 equiv) of
KOtBu, and 186.5 mg (1.2 equiv) of 4-aminophenol. The content was
stirred by a metal spatula after which 506.0 mg (1.25 equiv) of
Ti(OiPr)4 was added, and the mixture was stirred magnetically for a
few seconds. Thereafter, 303.5 mg (1 equiv) of 4-tert-butylbromo-
phenol was added and the content was stirred magnetically for a few
seconds. The vial was taken out of the glovebox and placed in a
preheated metal-bead bath. The content was stirred at 1200 rpm at 50
°C for 15 min, and the reaction was quenched with the addition of 2
mL of sat. aqueous NH4Cl and DCM. The mixture was filtrated
through Celite, and the filter cake was washed well with DCM. A
sample was taken from the DCM extract and subjected to No-D
NMR, showing the product (90.2 mol %) and tert-butylbenzene
(reduced educt, 9.8 mol %). The organic phase was dried over
anhydrous Na2SO4, filtrated through a 1 cm plug of Na2SO4, and then
washed well with DCM. The filtrate was concentrated, adsorbed on
silica gel, and dried in vacuum. This silica was placed on top of a 10 g
silica gel column and eluted with hexanes (1 column volume),
followed by ramping the polarity to 10% EtOAc over 5 column
volumes, then isocratic with 10% EtOAc, providing 294.3 mg (86%) g
of 27 as a light brown solid after drying under vacuum at 200 mTorr
until a constant mass. NMR has shown some residual EtOAc, which
could not be removed in vacuum.
Mp 103−104 °C. 1H NMR (600 MHz, CDCl3) δ 7.22 (dt, J = 8.4,
2.5 Hz, 2H, 2-CH), 7.09 (d, J = 8.3 Hz, 2H, 3′-CH), 7.00−6.96 (m,
4H, indirectly assigned: 6.99 2′-CH, 6.97 3-CH), 5.64 (br s, 1H,
NH), 4.57 (s, 2H, OCH2), 2.30 (s, 3H, 4′-Me), 1.68 (OH and water)
ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 143.8 (4-CN), 140.2 (1′-
CN), 132.7 (1-C), 131.2 (4′-C), 130.0 (3′-CH), 128.5 (2-CH), 119.1
(2′-CH), 116.9 (3-CH), 65.3 (OCH2), 20.8 (4′-Me) ppm; 15N NMR
(1H−15N HMBC projection, 60 MHz, CDCl3) δ 80.5 ppm. HRMS
(ESI/TOF) m/z: [M + H]+ calcd for C14H16NO+ 214.1232; found
214.1223.
4-Methyl-N-(4-(((trimethylsilyl)oxy)methyl)phenyl)aniline was iso-
lated as a byproduct (22.1 mg, 4.9%, brown oil) in preparation of
(4-(p-tolylamino)phenyl)methanol (28). This substance is not stable
on storage under air and is quickly desilylated by atmospheric
moisture.
1H NMR (600 MHz, CDCl3) δ 7.22 (dt, J = 8.4, 2.5 Hz, 2H, 3′-
CH), 7.08 (d, J = 8.3 Hz, 2H, 3-CH), 7.03−6.97 (m, 4H, indirectly
assigned: 7.00 2-CH, 6.99 2′-CH), 5.61 (br s, 1H, NH), 4.63 (s, 2H,
4′-CH2O), 2.32 (s, 3H, 4-Me), 0.17 (s, 9H, SiMe3) ppm; 13C{1H}
NMR (150 MHz, CDCl3) δ 143.1 (1′-CN), 140.6 (1-C), 133.0 (4′-
C), 130.8 (4-C), 130.0 (3-CH), 128.3 (3′-CH), 118.7 (2-CH), 117.2
(2′-CH), 64.7 (4′-CH2O), 20.8 (4-Me), −0.2 (SiMe3) ppm; 15N
NMR (1H−15N HMBC projection, 60 MHz, CDCl3) δ 80.0 ppm.
HRMS (EI) m/z: [M]+ calcd for C17H23NOSi+ 285.1549; found
285.15377.
4-Methyl-N-(4-(p-tolylamino)benzylidene)aniline was isolated as a
byproduct (5.1 mg, 1.1%, brick red solid) in preparation of (4-(p-
tolylamino)phenyl)methanol (28).
This reaction also could be done in the absence of Lewis acid, but
with lower conversion. We have observed the formation of 4-((4-(tert-
butyl)phenyl)imino)cyclohexa-2,5-dienone (iminoquinone) in this
case, which inhibits further Pd coupling. The formation of
iminoquinone is caused by undesired Pd-catalyzed redox processes,
as quenching of the reaction in the glovebox with deoxygenated
aqueous KH2PO4 and DCM also resulted in iminoquinone formation.
Other Lewis acids including aluminum tert-butoxide, boron tert-
butoxide, titanium tert-butoxide, tetrakis((trimethylsilyl)oxy)titanium,
and tert-butyl borate led to worse results.
Mp 117−118 °C. 1H NMR (600 MHz, CDCl3) δ 8.34 (s, 1H, N
CH), 7.75 (dt, J = 8.6, 2.5 Hz, 2H, 3′-CH), 7.18 (d, J = 8.2 Hz, 2H, 3-
CHNTol), 7.15 (d, J = 8.3 Hz, 2H, 3-CHNHTol), 7.11 (d, J = 8.2 Hz,
2H, 2-CHNTol), 7.08 (d, J = 8.3 Hz, 2H, 2-CHNHTol), 7.00 (dt, J = 8.6,
2.5 Hz, 2H, 2′-CH), 5.90 (br s, 1H, NH), 2.36 (s, 3H, 4-MeNTol), 2.34
(s, 3H, 4-MeNHTol) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 159.3
(NCH), 150.2 (1-CNNTol), 147.3 (1′-C), 138.7 (1-CNNHTol), 135.2
(4-CNTol), 132.8 (4-CNHTol), 130.6 (3′-CH), 130.2 (3-CHNHTol),
129.8 (3-CHNTol), 128.2 (4′-C), 120.94 (2-CHNTol), 120.88 (2-
CHNHTol), 115.2 (2′-CH), 21.1 (4-MeNTol), 21.0 (4-MeNHTol) ppm;
15N NMR (1H−15N HMBC projection, 60 MHz, CDCl3) δ 84.9
(NH), 308.3 (NCH) ppm. HRMS (ESI/TOF) m/z: [M + H]+
Mp 100−101 °C. 1H NMR (600 MHz, CDCl3) δ 7.24 (dt, J = 8.6,
2.5 Hz, CHCl3 and 3′-CH), 6.99 (dt, J = 8.8, 2.9 Hz, 2H, 3-CH), 6.87
(dt, J = 8.6, 2.5 Hz, 2H, 2′-CH), 6.76 (dt, J = 8.8, 2.9 Hz, 2H, 2-CH),
5.40 (br s, 1H, NH), 4.58 (br s, 1H, OH), 1.29 (s, 9H, tBu) ppm;
13C{1H} NMR (150 MHz, CDCl3) δ 150.7 (1-CO), 142.9 (4′-C),
142.5 (1′-CN), 136.6 (4-CN), 126.2 (3′-CH), 121.7 (3-CH), 116.2
(2-CH), 116.0 (2′-CH), 34.19 (4′-CMe3), 31.6 (4′-CMe3) ppm; 15N
NMR (1H−15N HMBC projection, 60 MHz, CDCl3) δ 76.0 ppm. MS
(ESI/TOF) found (calculated): HRMS (ESI/TOF) m/z: [M + H]+
+
calcd for C21H21N2 301.1705; found 301.1717.
(2-((4-(tert-Butyl)phenyl)amino)phenyl)methanol (29). In the
glovebox, a 2 dram vial was wrapped in aluminum foil and was
charged consecutively with 1.6 mg (0.1 mol %) of [Pd-
(DiMeIHeptCl)(cinnamyl)Cl] (1a), 323.8 mg (1 equiv) of 4-tert-
butylbromobenzene, 224.5 mg (1.2 equiv) of 2-aminobenzyl alcohol,
and 294.2 mg (1.2 equiv) of HMDS. The content was stirred for a few
seconds, and then the vial was charged as quickly as possible with
394.2 mg (2.7 equiv) of NaOtBu. Immediately after that, the vial was
corked and the content was vigorously stirred magnetically for ca. 30 s
until exothermic initiation happened, which resulted in reaction
mixture cementation. Following this, the flask was taken out of the
glovebox, placed in a preheated metal-bead bath, and stirred at 1200
+
calcd for C15H19N2 242.1545; found 242.1538.
(4-(p-Tolylamino)phenyl)methanol (28). In the glovebox, a 2
dram vial was wrapped in aluminum foil and was charged
consecutively with 1.6 mg (0.1 mol %) of [Pd(DiMeIHeptCl)-
(cinnamyl)Cl] (1a), 294 mg (1 equiv) of 4-bromobenzyl alcohol,
195.3 mg (1.2 equiv) of p-toluidine, and 255 mg (1 equiv) of HMDS.
The content was stirred for a few seconds, and then the vial was
charged as quickly as possible with 365.0 mg (2.5 equiv) of NaOtBu.
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1
rpm at 50 °C for 15 min. The reaction was quenched with 2 mL of
water and 2 mL of DCM. The DCM layer was separated and analyzed
by No-D NMR, confirming the presence of N-(4-(tert-butyl)phenyl)-
2-(((trimethylsilyl)oxy)methyl)aniline. The remaining aqueous phase
was extracted with DCM (3 × 2 mL), and the combined organic
extracts were dried over anhydrous Na2SO4, filtrated, and evaporated.
The crude product was dissolved in hexanes and poured on top of a
20 g silica gel column. The product was eluted using a gradient of
100% hexanes to 100% DCM, then isocratic, providing 305.8 mg
(79%) of 29 as a brown solid after drying under vacuum at 200
mTorr.
Mp 68−69 °C. H NMR (600 MHz, CDCl3) δ 7.32 (dt, J = 8.6,
2.2 Hz, 2H, 3-CH), 7.27 (m, 2H, 3′-CH), 7.07 (m, 2H, 2′-CH), 7.01
(dt, J = 8.6, 2.2 Hz, 2H, 2-CH), 6.94 (tt, J = 7.4, 1.0 Hz, 1H, 4′-CH),
6.65 (dd, J = 17.6, 10.8 Hz, 1H, CHvinyl), 5.73 (br s, 1H, NH), 5.61
(dd, J = 17.6, 0.8 Hz, 1H, CH2vinyl), 5.11 (dd, J = 10.8, 0.8 Hz, 1H,
CH2vinyl) ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 142.94 (1-CN),
142.85 (1′-CN), 136.5 (CHvinyl), 130.6 (4-C), 129.5 (3′-CH), 127.4
(3-CH), 121.4 (4′-CH), 118.2 (2′-CH), 117.5 (2-CH), 111.3
(CH2vinyl) ppm; 15N NMR (1H−15N HMBC projection, 60 MHz,
CDCl3) δ 83.0 ppm. The spectral data are consistent with those
reported in the literature.91
Mp 75−76 °C. 1H NMR (600 MHz, CDCl3) δ 7.33 (d, J = 8.1 Hz,
1H, 3-CH), 7.28 (dd, J = 8.6, 2.5 Hz, 2H, 3′-CH), 7.19 (td, J = 7.7,
1.5 Hz, 1H, 4-CH), 7.15 (dd, J = 7.3, 1.1 Hz, 1H, 6-CH), 7.01 (dd, J
= 8.6, 2.5 Hz, 2H, 2′-CH), 6.83 (t, J = 7.3 Hz, 5-CH), 6.73 (br s, 1H,
NH), 4.66 (s, 2H, OCH2), 1.92 (br s, 1H, OH), 1.31 (s, 9H, tBu)
ppm; 13C{1H} NMR (150 MHz, CDCl3) δ 144.1 (4′-C), 143.7 (2-
CN), 140.3 (1′-CN), 129.7 (3-CH), 129.3 (4-CH), 128.0 (1-C),
126.2 (3′-CH), 120.0 (5-CH), 118.4 (2′-CH), 116.6 (3-CH), 64.7
(OCH2), 34.3 (4′-CMe3), 31.6 (4′-CMe3) ppm; 15N NMR (1H−15N
HMBC projection, 60 MHz, CDCl3) δ 77.5 ppm. HRMS (ESI/TOF)
m/z: [M + H]+ calcd for C17H22NO+ 278.1521; found 278.1546.
N-Phenyl-4-vinylaniline (30). Large scale preparation. For this
reaction, we used 97% pure 4-bromostyrene stabilized by 3,5-di-tert-
butylcatechol (0.1 mol %), supplied by AK Scientific.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01057.
1H and 13C NMR spectra of isolated compounds and
byproducts. Detailed crystallographic data for complexes
1a and 1b PDF)
Accession Codes
CCDC 2071914 and 2071915 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
A 100 mL pear-shaped flask, stir bar, 10 cm Vigreux column, rubber
septum, and balloon attached to a syringe needle were placed into the
glovebox. The top joint of the Vigreux column was corked by a rubber
septum and pierced by a needle equipped with a balloon. The flask
was wrapped in aluminum foil and charged with 28.4 mg (0.1 mol %)
of [Pd(DiMeIHeptCl)(cinnamyl)Cl] (1a), 4.9362 g (1 equiv) of 4-
bromostyrene, and 2.5114 g (1 equiv) of aniline. The content was
stirred magnetically for a few seconds, followed by the rapid addition
of 3.3285 g (1.1 equiv) of KOtBu. Immediately after that, the flask
was corked by the Vigreux column, and the content was immediately
stirred magnetically. In 30−60 s, this resulted in initiation of a mild
exotherm with refluxing of tBuOH. The balloon mounted on top of
the Vigreux column protected the glovebox atmosphere from any gas
evolved. The assembled apparatus was taken out of glovebox and
placed in a metal-bead bath preheated to 50 °C. After stirring at 1200
rpm for 15 min, the mixture was cooled to r.t. and the reaction was
quenched with water (20 mL) and EtOAc (20 mL). This formed a
stable emulsion that was broken by the addition of aqueous saturated
Na2SO4 solution. The layers were separated, and the organic phase
was washed with aqueous saturated Na2SO4 (50 mL). The organic
extract was dried over anhydrous Na2SO4, filtrated, and washed with
EtOAc. 50 g of neutral aluminum oxide was added to this solution,
which was then evaporated and dried under vacuum at 100 mTorr.
This alumina was transferred to a paper thimble and placed to a
Soxhlet extractor. The desired product was extracted by boiling
pentane for 24 h. To the receiving flask (where pentane was boiling)
was added 6 mg of BHT before extraction started to inhibit
polymerization. The product is sensitive to overheating, so we used a
flat bottom Erlenmeyer flask as receiving flask and placed it directly
on a hot plate, setting the temperature to 90 °C. The whole apparatus
was wrapped in aluminum foil to insulate the contents, which led to a
gentle boil, thus avoiding overheating during extraction. After
extraction completed, the apparatus was cooled to r.t. and the
pentane extract was evaporated and dried under vacuum at 100
mTorr for 48 h, providing 3.2774 g (62.2%) of 30 as light yellow
solid. Diffusion NMR spectroscopy conducted on the product did not
reveal any noticeable quantity of polymeric material. The remaining
thimble was further extracted with boiling Et2O for 24 h; however,
this provided only a mixture of unidentified compounds. Thus, most
of the product was extracted by pentane. Drying for 48 h was needed
to remove traces of aniline.
AUTHOR INFORMATION
■
Corresponding Author
Michael G. Organ − Centre for Catalysis Research and
Innovation (CCRI), Department of Chemistry and
Biomolecular Sciences, University of Ottawa, Ottawa,
Ontario K1N 6N5, Canada; Department of Chemistry, York
University, Toronto, Ontario M3J 1P3, Canada;
orcid.org/0000-0002-4625-5696; Email: organ@
uottawa.ca
Authors
Volodymyr Semeniuchenko − Centre for Catalysis Research
and Innovation (CCRI), Department of Chemistry and
Biomolecular Sciences, University of Ottawa, Ottawa,
Ontario K1N 6N5, Canada
Sepideh Sharif − Department of Chemistry, Carleton
University, Ottawa, Ontario K1S 5B6, Canada
Jonathan Day − Department of Chemistry, York University,
Toronto, Ontario M3J 1P3, Canada
Nalin Chandrasoma − Department of Chemistry, Carleton
University, Ottawa, Ontario K1S 5B6, Canada; Department
of Chemistry, York University, Toronto, Ontario M3J 1P3,
Canada
William J. Pietro − Department of Chemistry, York University,
Toronto, Ontario M3J 1P3, Canada; orcid.org/0000-
0001-5083-2022
Jeffrey Manthorpe − Department of Chemistry, Carleton
University, Ottawa, Ontario K1S 5B6, Canada
Wilfried M. Braje − AbbVie Deutschland GmbH & Co. KG,
Neuroscience Discovery Research, Knollstrasse 67061
Ludwigshafen, Germany
For this compound, all properties, respectively, stability and
disposition to decomposition are the same as those for 4-methyl-N-
(4-vinylphenyl)aniline (9).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01057
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reaction under solvent-free conditions. Dalton Transactions 2019, 48,
3447−3452.
Notes
The authors declare the following competing financial
interest(s): The PI receives royalty payments for the sales of
catalysts in this manuscript.
(17) Topchiy, M. A.; Asachenko, A. F.; Nechaev, M. S. Solvent-Free
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Secondary Amines. Eur. J. Org. Chem. 2014, 2014, 3319−3322.
(18) Harrak, Y.; Romero, M.; Constans, P.; Pujol, M. D. Preparation
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Org. Chem. 2006, 3, 29−34.
ACKNOWLEDGMENTS
■
M.G.O. acknowledges MITACS Canada (IT18598) and
NSERC Canada (grants: RGPIN-2018-05584 and CRDPJ
445703 - 12) for their support of this research program. The
authors gratefully acknowledge helpful suggestions from
Professor Howard Alper during this project.
(19) Basolo, L.; Bernasconi, A.; Borsini, E.; Broggini, G.; Beccalli, E.
M. Solvent-Free, Microwave-Assisted N-Arylation of Indolines by
using Low Palladium Catalyst Loadings. ChemSusChem 2011, 4,
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(21) Gajare, A. S.; Toyota, K.; Yoshifuji, M.; Ozawa, F. Solvent Free
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Catalyzed by a (π-Allyl)palladium Complex Bearing a Diphosphini-
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