Synthesis of 2-methyl-4-methoxydiphenylamine by palladium catalyzed C-N coupling - High synthetic versatility by use of a flexible catalytic system

Article abstract of DOI:10.1016/j.tet.2005.03.139

The synthetic versatility of the Buchwald-Hartwig Amination is demonstrated by the synthesis of the industrially important intermediate 2-methyl-4-methoxydiphenylamine. Using four routes differing in the choice of the starting materials, the diarylamine could be synthesized in excellent yields, however, each reaction required a different combination of ligand, base and solvent. This new approach is compared to established industrial routes.

Full text of DOI:10.1016/j.tet.2005.03.139

Tetrahedron 61 (2005) 6379–6385
Synthesis of 2-methyl-4-methoxydiphenylamine by palladium
catalyzed C–N coupling—high synthetic versatility by use of
a flexible catalytic system
*
¨
Ulrich Scholz and Bjorn Schlummer
Lanxess-AG Deutschland, Fine Chemicals Research & Development, 51369 Leverkusen, Germany
Received 27 October 2004; revised 3 February 2005; accepted 4 March 2005
Available online 17 May 2005
Abstract—The synthetic versatility of the Buchwald–Hartwig Amination is demonstrated by the synthesis of the industrially important
intermediate 2-methyl-4-methoxydiphenylamine. Using four routes differing in the choice of the starting materials, the diarylamine could be
synthesized in excellent yields, however, each reaction required a different combination of ligand, base and solvent. This new approach is
compared to established industrial routes.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
MMDPA IV itself is a common intermediate in fine
chemical industry and has lately been cited frequently in
the context of the aminofluoran dye family, a dye class
useful for thermographic and pressure sensitive recording.3
Requests for the manufacture of highly substituted anilines
occur with increasing frequency and intensity in fine
chemical business these days. Especially, in the exciting
fields of functional dyes, xerographic or electronically
conducting materials, we frequently observe the structural
motif of the diphenylamines.
Although not being active in this field of application
ourselves, we became aware of this product MMDPA IV,
since it in principle could be made by application of
the Buchwald–Hartwig Amination,4 a technology that the
fine chemical department of Lanxess, formerly Bayer
Chemicals, has identified to be one of the contemporary
key chemical technologies in organic synthesis.5,17
While the past 150 years of organic synthesis have brought
forth a considerable amount of techniques to set up this
structure,1 still continuously uncommon synthetic
approaches are revealed. For example, the title compound
2-methyl-4-methoxydiphenylamine IV (MMDPA) can be
produced by a transfer hydrogenation as demonstrated by
the Mitsui company2 (Scheme 1).
We therefore were eager to show that MMDPA IV could be
made by use of this technology (Scheme 2), but also, since
this technology involves the use of expensive transition
metals and complex phosphine ligands, whether it can be
made economically.
2. Results and discussion
Scheme 2 shows four possible approaches to MMDPA IV
both from bromo- and chloroarenes VIII and VII as starting
materials, but also by coupling of the corresponding
functionalized aniline I. The possibility to use different
combinations of starting materials represents a charming
feature of this new technology, since the starting materials
could in principle be picked depending on their availability
and price on the market. For the rest of this paper, the four
approaches will be abbreviated as ways A to D.
Scheme 1. Mitsui process to generate MMDPA IV.
Keywords: Buchwald–Hartwig Amination; Palladium; Homogeneous
catalysis; Diarylamines.
*
Corresponding author. E-mail: ulrich.scholz.us@lanxess.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.139

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Scheme 2. Four possible ways to MMDPA IV by C–N coupling.
To check the validity of our approach, we set up a reaction
screening to make MMDPA IV. The reactions were run in a
block with either 48 or 12 parallel reactions6 under argon.
Generally, we run these screenings using an internal
standard, therefore allowing the determination of GC yields.
However, in our experience the results of a screening in the
early phase, that is, with no prior experience in the reaction
observed, can be misleading by judgement of the GC yield.
We often observed that the conversion of the starting
material gives a better first overview of a new reaction.
Since we always repeat the selected results on scale and
isolate the products, we can ensure the correlation of
conversion and yield in the cases we discuss here.
experience, this quality of Pd[0]-complex guarantees best
results concerning reproducibility in the screening.
In addition to palladium, a phosphine ligand is necessary to
catalyze the reaction. The current literature reveals
numerous structurally different phosphines that lead to
completely different catalysts with different activity.
We therefore screened up to eight ligands for this
transformation as illustrated in Scheme 3.
Another important factor is the stoichiometric use of a base
that is necessary to run this reaction. We chose from a set of
up to six bases, most of them have previously been reported
as being rather effective. The bases used were cesium
carbonate,7,14 potassium carbonate,11 sodium carbonate,
cesium fluoride, potassium phosphate7,15 and sodium tert-
butylate.8
The palladium source we used was industrial grade
palladium–dibenzylideneacetone (Pd2(dba)3). To our
The solvent may play an important role in Buchwald–
Hartwig Aminations, examples in the current literature
mostly focus on either toluene or dioxane. However, several
examples were reported in which DMF, NMP, alcohols or
even aqueous media were successful.4a In this work, we
restricted ourselves to either toluene, xylenes or aniline.
The first reaction to be examined was system B, the
condensation of aniline VI and 4-methoxy-2-methylbromo-
benzene VIII in a toluene solution at 110 8C (Fig. 1).
One quickly notes that ligand 5 shows very high conversion
of the starting material with several inorganic bases. Also
ligand 8 gives high conversions with the very common C–N
coupling bases Cs2CO3 and NaOtBu.
We then tested the same reaction under different conditions
(i.e., in refluxing aniline instead of a toluene solution). Here,
aniline serves as a solvent as well as a reagent for this
transformation. Its excess and the elevated temperature are
likely to have a positive influence on the conversion. We
restricted ourselves to an array of four ligands and three
bases (Fig. 2).
Scheme 3. Typical phosphine ligands7–13 for Buchwald–Hartwig Amin-
ations used in the screening.

U. Scholz, B. Schlummer / Tetrahedron 61 (2005) 6379–6385
6381
Figure 1. Screening of system B in toluene at 110 8C. Reported is the conversion of starting material. Reactions were run with 1 equiv aniline, 1 equiv
methoxy-2-methylbromobenzene, 1.4 equiv base, 0.5 mol% of Pd2(dba)3 and 2 mol% of phosphine (1 mol% of phosphine for 4 and 8).
Under these conditions one can observe full conversion of
starting material with simple PPh3 6 using Cs2CO3 as base.
In fact, Cs2CO3 also gives full conversion using Buchwald’s
ligand 5 and BINAP 8.
When we looked at system C, in which aniline VI is reacted
with 4-methoxy-2-methyl-chlorobenzene VII, the current
literature suggests to expect worse results compared to the
corresponding arylbromide coupling.4 This could be
confirmed when running the screening under standard
conditions in toluene solution at 110 8C (Fig. 3).
Since especially the results with ligand 6 seemed interesting
from a scale up perspective, we repeated the reaction on the
level of 1 mol of starting material and were able to isolate a
yield of 93% of MMDPA IV after distillation.
However, still two results of the screening may be
considered as good enough for further elaboration. Again
the known combination of Buchwald ligand 5 with the
strong base sodium tert-butylate creates an efficient system,
but even better conversion was observed using P(tBu)3 717
in combination with potassium phosphate.
Again we used the possibility of aniline of serving both as
solvent and amine part for the reaction and ran a smaller
screening in refluxing aniline (Fig. 4).
We observed an increase in activity due to the changed
media and temperature, with highest conversions using the
combination of Buchwald ligand 5 either with potassium
phosphate or cesium carbonate as base.
One of the results with ligand 5 and potassium phosphate
was confirmed on the level of 1 mol of starting material.
Similar to the case of aryl bromide VIII, a yield of 96% of
the desired MMDPA IV could be isolated after distillation.
When regarding system D, in which 4-methoxy-2-methyl-
aniline I can be used as one of the starting materials, one
should expect smooth conversion to MMDPA IV. A rather
electron rich aniline is coupled with a moderately active aryl
bromide, therefore, constituting ideal conditions for a C–N
coupling (Fig. 5).
Figure 2. Screening of system B in aniline at 184 8C. Reported is the
conversion of starting material. Reactions were run using 1 equiv aniline,
1 equiv methoxy-2-methylbromobenzene, 1.4 equiv base, 0.5 mol% of
Pd2(dba)3 and 2 mol% of phosphine 5, 1 mol% of phosphine 4 and 8,
4 mol% of phosphine 6.

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Figure 3. Screening of system C in toluene at 110 8C. Reported is the conversion of starting material. Reactions were run with 1 equiv aniline, 1 equiv
methoxy-2-methylchlorobenzene, 1.4 equiv base, 0.5 mol% of Pd2(dba)3 and 2 mol% of phosphine (1 mol% of phosphine for 4 and 8).
Since a positive effect of high temperatures for this
reaction was noted in previous experiments, xylenes
were chosen as the solvent and reactions were run at
120 8C. The two ligands 5 and 8 gave very high
conversions with all three bases we examined, therefore
all these combinations could be picked for a scale-up.
the combination of BINAP 8 and cesium carbonate
represented the best screening result, we chose this one
for scale up.
Reduction of the catalyst loading quickly showed that
1 mol% of catalyst is actually needed (Table 1) when
reaction time was fixed to be 24 h. Lower amounts of
catalyst resulted in incomplete conversion of the starting
material.
Important to note is the good result again for PPh3
6
using sodium tert-butylate as base, therefore rendering
another rather simple approach for MMDPA IV. Since,
Figure 4. Screening of system C in aniline at 184 8C. Reported is the
conversion of starting material. Reactions were run using 1 equiv aniline,
1 equiv methoxy-2-methylchlorobenzene, 1.4 equiv base, 0.5 mol% of
Pd2(dba)3 and 2 mol% of phosphine 5, 1 mol% of phosphine 4 and 8,
4 mol% of phosphine 6.
Figure 5. Screening of system D: 1 equiv bromobenzene, 1 equiv 4-
methoxymethylaniline, 1.4 equiv base, xylenes, 120 8C, 24 h. Reported is
the conversion of starting material. Reactions were run using 0.5 mol% of
Pd2(dba)3 and 2 mol% of phosphine 5, 1 mol% of phosphine 4 and 8,
4 mol% of phosphine 6.

U. Scholz, B. Schlummer / Tetrahedron 61 (2005) 6379–6385
6383
Table 1. Reduction of catalyst loading in system D: 1 equiv bromobenzene,
1 equiv 4-methoxymethylaniline, ratio of Pd2(dba)3 to BINAP 8:1:2,
1.4 equiv Cs2CO3, xylenes, 120 8C, 24 h
While in general this system A gave several combinations
with moderate to good yields, using ligand 5 together with
potassium phosphate lead to nearly full conversion of the
starting materials in the screening.
Entry
System
Catalyst concentration
(mol%)
Conversion
(%)
The result could be confirmed when running the reaction
on the scale of 1 mol of starting material. A total of 95% of
MMDPA IV was isolated after distillation of the crude
mixture.
1
2
3
4
D
D
D
D
1
0.1
0.05
0.01
100
9
2
0
To complete the picture we attempted to run the reaction in
a heterogeneous fashion using palladium on charcoal,
cesium carbonate as base and PPh3 6 as ligand. We
deliberately chose a ligand that was favourable rather by
material cost than by chemical performance. This allowed
us to set up a reaction model that was comparable to the
original synthesis by Mitsui (Scheme 1) from an economical
point of view. In that case, a catalyst loading of 5% (w/w) of
5% Pd/C16 with ligand 6 present in the system resulted in
poor conversion of a maximum of 12% using cesium
carbonate as base. Therefore, we concluded that a
heterogeneous version of this amination reaction could not
compete with the homogeneous counterpart.
On the scale of 1 mol of reactants, using 0.5 mol% of
Pd2(dba)3 with BINAP 8 as ligand and cesium carbonate as
base but toluene instead of xylenes as solvent at reflux, a
95% yield of MMDPA IV was isolated.
The final combination of starting materials is denoted as
system A in Scheme 2. The coupling of chlorobenzene IX
and 4-methoxy-2-methylaniline I represents a somewhat
more difficult example of a Buchwald–Hartwig Amination.
It can nevertheless be regarded as the most attractive
combination from an economical point of view. When
checking the availability and price of all starting materials
encountered so far, this combination will lead to the lowest
material cost.
3. Summary
We therefore, conducted a screening run in xylenes at
120 8C (Fig. 6).
While generally speaking the cleverly designed transfer
hydrogenation published by Mitsui (Scheme 1) is hard to
match, we were able to generate a set of four reaction
procedures that allow the production of MMDPA IV on the
medium scale at high yield. These four procedures are
summarized in Table 2.
From our point of view, a true but often underestimated
strength of the Buchwald–Hartwig Amination becomes
obvious in this study: not only the possibility to perform
new chemical transformations that would be difficult to do
otherwise, this new methodology also allows for a synthetic
flexibility unknown from other chemical transformations to
date. This adds a new freedom to synthesis which will help
to tackle today’s demanding targets from a chemical point
of view.
4. Experimental
4.1. General
Figure 6. Screening of system A in xylenes at 120 8C. Reported is the
conversion of starting material. Reactions were run using 1 equiv
chlorobenzene, 1 equiv methoxy-2-methylaniline, 1.4 equiv base,
0.5 mol% of Pd2(dba)3 and 2 mol% of phosphine 5, 1 mol% of phosphine
4 and 8, 4 mol% of phosphine 6.
Industrial grade Pd2(dba)3 was purchased from Umicore.
Industrial grade Cesiumcarbonate was purchased from
Chemetall. Industrial grade Potassium phosphate was
purchased from Guilani. All other components were
Table 2. Overview of conditions chosen for scale up runs with isolated yields: 1 equiv of arylhalide, 1 equiv of amine, 1.4 equiv of base were used
Entry
System
Conditions
Yield/%
1
2
3
4
A
D
C
B
2 mol% 5, 0.5 mol% Pd2(dba)3, K3PO4, toluene, 110 8C
1 mol% BINAP 8, 0.5 mol% Pd2(dba)3, Cs2CO3, toluene, 110 8C
2 mol% 5, 0.5 mol% Pd2(dba)3, K3PO4, aniline, 184 8C
4 mol% PPh3 6, 0.5 mol% Pd2(dba)3, Cs2CO3, aniline, 184 8C
95
95
96
93

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U. Scholz, B. Schlummer / Tetrahedron 61 (2005) 6379–6385
either produced internally or purchased from catalogue
companies.
CH3–H2O), 167 (MCKCH3–CH3O), 154, 128, 77 (C6HC5 ).
1H NMR (400 MHz): dZ7.11–7.21 (m, 3H); 6.68–6.83 (m,
5H); 5.18 (s, br, 1H); 3.79 (s, 3H); 2.21 (s, 3H) ppm. 13C
NMR (100 MHz): dZ156.2 (q); 146.2 (q); 134.0 (q); 133.4;
129.2 (2C); 125.0; 118.7; 116.3; 114.7 (2C); 111.8; 55.4
(CH3O); 18.2 (CH3) ppm.
Gas chromatographical analysis was done on a HP 5890
Serie II Gas chromatograph, using nitrogen as carrier
(0.6 bar) with a SE 30, 0.32 mm ID, 0.25 mm FD column.
4.1.1. Screenings. Inorganic bases used were ground in a
standard laboratory mill and dried under vacuum overnight.
The bases were then weighed in individual vials and stored
under nitrogen. Screenings were run in HCP Stir Blocks.6
4.1.3. Synthesis of MMDMA according to system D. The
procedure was repeated in the same apparatus as described
in experiment 2 except that 158.6 g (99%, 1 mol) of
bromobenzene, 6.7 g (O99%, 10 mmol) of ligand BINAP
8 and 395.2 g (O99%, 1.2 mol) of Cs2CO3 were used.
The Block was fitted with oven dried 20 ml reaction tubes
with magnetic stir bars and septum. The tubes were
evacuated and flushed with argon three times via a needle
manifold. Stock solutions of the ligands were prepared in
Schlenck glassware under argon as 0.2–1.0 M solutions in
degassed toluene or aniline. The stock solutions were added
to the vials by means of a syringe. Stock solutions of the
starting materials and dodecane as internal standard were
prepared in degassed solvents (either toluene, xylenes or
aniline). Pd2(dba)3 was added last to the stock solution. This
stock solution was distributed by syringe. The bases were
added by quickly opening the vials while flushing with
argon. The block was heated for the indicated time at the
indicated temperature. Heating was then discontinued
and the reaction tubes were allowed to cool to 40 8C,
diluted with ethylacetate and an aqueous buffer 7 solution
(Riedel-de Haen, order no. 33546). Small samples of the
organic solution were cleared by filtration over celite and
analyzed by GC.
Of the distilled product 204.2 g (O99%, 95% of theoretical
yield) were collected and identified as MMDMA by
analytical comparison to the product of experiment 2.
4.1.4. Synthesis of MMDMA according to system C. The
procedure was repeated in the same apparatus as described
in experiment 2 except that 158.2 g (99%, 1 mol) of 4-
methoxy-2-methylchlorotoluene were dissolved in 750 ml
of aniline. PPh3 6 (10.6 g) (99%, 40 mmol) together with
4.6 g of Pd2(dba)3 (O99%, 5 mmol) were added. K3PO4
(254.4 g) (O99%, 1.2 mol) was added last. The mixture was
heated with a jacket temperature of 190 8C for 8 h.
Of the distilled product 206.8 g (O99%, 96% of theoretical
yield) was collected and identified as MMDMA by
analytical comparison to the product of experiment 2.
4.1.5. Synthesis of MMDMA according to system B. The
procedure was repeated in the same apparatus as described
in experiment 2 except that 205.2 g 4-methoxy-2-methyl-
bromotoluene (98%, 1 mol) was dissolved in 750 ml of
aniline 7.9 g of ligand 5 (O99%, 20 mmol) together with
4.6 g of Pd2(dba)3 (O99%, 5 mmol) were added. Cs2CO3
(395.2 g) (O99%, 1.2 mol) was added last. The mixture was
heated with a jacket temperature of 190 8C for 8 h.
4.1.2. Synthesis of MMDMA according to system A. A 2 l
jacketed glass reactor, fitted with reflux condenser,
mechanical stirrer and an internal thermometer was heated
to 90 8C and flushed with nitrogen for 30 min. The
jacket was allowed to cool to room temperature and
113.7 g (99%, 1 mol) of chlorobenzene, 154.0 g (98%,
1.1 mol), 4-methoxy-2-methylaniline and 750 ml of toluene
were added. The mixture was degassed with nitrogen for
20 min at room temperature. A slight nitrogen pressure was
maintained on the apparatus during the reaction. 7.9 g of
ligand 5 (O99%, 20 mmol) together with 4.6 g of Pd2(dba)3
(O99%, 5 mmol) were added. The apparatus was closed
and the catalyst allowed to dissolve by stirring for additional
10 min. K3PO4 (232.0 g) (O99%, 1.4 mol) were added and
the vessel was heated to a jacket temperature of 125 8C
within 40 min. The temperature was maintained for 8 h. The
reaction was then cooled to 50 8C and 500 ml of brine were
added. The mixture was stirred for 30 min at 50 8C, the
stirrer was then turned off and phases allowed to separate for
15 min. The aqueous phase was discharged through the
bottom drain and the remaining organic solution concen-
trated by distillation under reduced pressure until the total
volume of the organic phase had reached about 250 ml. The
remaining organic solution was the transferred to a smaller
setup for high vacuum distillation. The crude was distilled
over a 50 cm column filled with 4 mm Raschig rings
(approximately eight theoretical plates) at a reflux ratio
of 3/1 at 0.3 mbar. The product distilled at 140–150 8C
and 204.6 g (O99% by GC, 95% of theoretical yield)
were collected and analyzed by GC–MS, 13C and 1H NMR
GC–MS: m/eZ213 (MC), 198 (MCKCH3), 180 (MCK
Of the distilled product 200.3 g (O99%, 96% of theoretical
yield) were collected and identified as MMDMA by
analytical comparison to the product of experiment 2.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tet.2005.03.139
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