A new synthetic route to p -methoxy-2,6-disubstituted anilines and their conversion into n-heterocyclic carbene precursors

Article abstract of DOI:10.1055/s-0033-1340105

The development of new N-heterocyclic carbenes (NHC) is a key feature in this now mainstream research area to access novel chemical properties and reactivity that are essential for the discovery of original applications. Up to now, only a few reliable methods have proven suitable for the preparation of methoxylated anilines to ultimately access methoxylated NHC. We are pleased to report here a straightforward and scalable approach to address this matter. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340105

LETTER
▌393
letter
A New Synthetic Route to p-Methoxy-2,6-disubstituted Anilines and their Con-
version into N-Heterocyclic Carbene Precursors
New Synthetic Route to p-Methoxy-2,6-disubstituted Anilines
Sebastien Meiries, Steven P. Nolan*
EaStCHEM School of Chemistry, University of St. Andrews, St. Andrews, KY16 9ST, UK
Fax +44(1334)463808; E-mail: snolan@st-andrews.ac.uk
Received: 10.09.2013; Accepted after revision: 14.10.2013
eter for the stabilization of metal–NHC complexes and the
Abstract: The development of new N-heterocyclic carbenes
ultimate optimization of their catalytic properties.4,5 How-
(NHC) is a key feature in this now mainstream research area to ac-
ever, unlike the IPr*OMe which was easily accessed from
cess novel chemical properties and reactivity that are essential for
the discovery of original applications. Up to now, only a few reli-
the inexpensive and commercially available p-anisidine,4
able methods have proven suitable for the preparation of methoxyl- the synthesis of ITentsOMe required the preparation of non-
ated anilines to ultimately access methoxylated NHC. We are
pleased to report here a straightforward and scalable approach to ad-
dress this matter.
readily available p-methoxyanilyl NHC precursors in a
rapid and cost-effective manner.
Key words: ligands, nucleophilic aromatic, copper, catalysis, car-
R
R
benes
R
R
N
N
••
X
X
R
R
The discovery of the first bottleable-free N-heterocyclic
carbenes (NHCs) by Arduengo in 19911 opened new ho-
rizons in organic and organometallic chemistry and in ca-
talysis.2 Since the late 1990s, NHCs have become
essential tools in chemistry and their use has resulted in a
plethora of applications.2 The further development of
these existing applications and the discovery of others lie
into the success of designing tailor-made NHC.
R
R
IPr*i
R = Ph
R = Me lX = H
R = Et X = H
X = Me
IPr*OMe iii. R = Ph ll X = OMe
IPri
IPrOMe
R = Me lX = OMe
IPenti
IHepti
INon i
IPentOMe R = Et ll X = OMe
IHeptOMe R = n-Pr X = OMe
INonOMe R = n-Bu X = OMe
R = n-Pr X = H
R = n-Bu X = H
Figure 1 Known NHC vs. methoxylated NHC
To our surprise, a literature search revealed a lack of reli-
able procedure to achieve the p-methoxylation of anilines.
The historical Bamberger rearrangement7 reported for the
conversion of 2,6-dimethylnitrobenzene into 2,6-dimeth-
yl-4-aminophenol first appeared as an attractive method
(Equation 1).8 However, this two-step process starting
from nitroarenes is limited by its temperamental behavior
and its substrate specificity. Moreover, the final 4-amino-
phenol generated in low yield remains to be selectively
methylated. These serious drawbacks forced us to envis-
age another strategy.
Among the many possible uses of NHCs, their role as li-
gands in transition-metal catalysis is of major interest. In
this context, the use of very bulky but flexible NHCs has
been shown to be beneficial to the catalytic activity of
metal–NHC complexes.3 More recently an increase of
their σ-donation ability by appropriate modification of
their anilyl N-substituents was successfully employed for
tuning these properties.4 More precisely, comparison be-
tween sterically hindered IPr* and IPr*OMe (Figure 1) re-
vealed that the additional methoxy substituent had a
positive impact in palladium-catalyzed Buchwald–
Hartwig arylamination.4
NO2
NH2
In order to further investigate this concept and to ultimate-
ly examine its ramifications in catalysis, the preparation
of other methoxylated NHC (NHCOMe) was necessary.
The recently reported ‘ITent’ series appeared to be ideally
suited for this task (Figure 1). The ITent NHC family,
with ‘Tent’ standing for ‘Tentacular’, was very recently
described by us as a new class of NHC bearing highly
flexible bulk.5 This class of NHC includes the well-known
IPr, Organ’s IPent,6 and the IHept and INon more recently
reported by us.5 Their flexible bulk increases significantly
as the size of the R alkyl groups become larger: IPr > IPent
> IHept > INon. This feature is considered as a key param-
1) Zn, NH4Cl
EtOH, H2O
2) H2SO4, H2O
OH
< 6%
Equation 1 Bamberger rearrangement of 2,6-dimethylnitrobenzene
The well-known copper-catalyzed Ullmann C–O cou-
pling was next explored for the methoxylation of the
known ITent anilines 1–45 in para position. This more di-
rect approach, based on the coupling of alcohols and aryl
halides, has received significant attention.9 However, free
aniline moieties were incompatible with this reaction and
required to be first protected as pyrrole to secure good
conversions.10 Interestingly, a single-step alternative de-
SYNLETT 2014, 25, 0393–0398
Advanced online publication: 03.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340105; Art ID: ST-2013-R0868-L
© Georg Thieme Verlag Stuttgart · New York

394
S. Meiries, S. P. Nolan
LETTER
scribed by Buchwald reported the copper-mediated Ull- vent (MeOH) beyond its boiling point in a thick-glass
man C–O coupling of unprotected iodoanilines.11 This Schlenk reactor/flask. Most importantly, the inexpensive
methodology appeared more suitable to achieve our goal. 1,10-phenanthroline proved to be a suitable ligand and no
anhydrous conditions were required.13,14 The use of aryl
A straightforward procedure12 was successfully employed
iodides as starting substrates was also crucial for the suc-
cess of the coupling. Although no optimization of the base
for the iodination of the ITent anilines 1–45 (Scheme 1).
The resulting p-iodoanilines 5–8 were obtained in excel-
or the catalyst loading was attempted, our preliminary
lent yield and purity with no purification needed and were
data strongly suggest that much lower quantities of cop-
then subjected to the Buchwald–Ullman conditions.11
per(I) iodide and 1,10-phenanthroline could be used with-
However, in our hands, no coupling was observed, and
further attempts all failed to give the desired p-methoxy-
anilines (Scheme 1). Interestingly, a modified procedure
out detrimental effects on the reaction overall yield. Other
alkoxylations using others alcohols as solvents could very
possibly be used and this hypothesis is currently being ex-
using 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4Phen)
plored.
in place of the inexpensive 1,10-phenanthroline was later
reported by Buchwald13 and successfully utilized by Lou-
R
NH2
R
ie.14 Although Me4Phen was described as a more efficient
ligand for copper-catalyzed C–O couplings, its cost ap-
peared to be a major issue. Most importantly, this new
protocol required strictly anhydrous conditions.13,14
glyoxal (40% in H2O)
HCOOH (cat.)
R
R
MeOH
r.t., overnight
I
5–8
R
NH2
R
R
NH2
R
I2
R
R
R
sat. aq Na2CO3
R
R
R
CuI, Cs2CO3
1,10-phenanthroline
R
R
N
N
cyclohexane
r.t., overnight
I
I
MeOH, overnight
120 °C, sealed tube
1 R = Me
2 R = Et
3 R = n-Pr
4 R = n-Bu
R
R
I
R
R
5 R = Me quant.
6 R = Et 96%
7 R = n-Pr 87%
8 R = n-Bu 96%
9 R = Me 97%
10 R = Et 92%
11 R = n-Pr 89%
12 R = n-Bu 95%
CuI, Cs2CO3
1,10-phenanthroline
R
NH2
R
R
NH2
R
R
R
R
NH2
R
R
R
R
R
R
R
X
N
N
R
R
MeOH, overnight
+
MeO
OMe
120 °C, sealed tube
R
R
I
OMe
R
R
OMe
Scheme 1 Initial methoxylation strategy
13 R = Me 0%
17 R = Me 73%
18 R = Et 0%
19 R = n-Pr 0%
20 R = n-Bu 0%
14 R = Et quant.
15 R = n-Pr 97%
16 R = n-Bu 94%
As our search for a cost-effective process continued, the
protection of the aniline moiety was instead reconsidered.
The classical diimine precursors of imidazolium chloride
salts were envisaged as ideally suited candidates for this
reaction. Indeed, the diimine bridge may possibly act as a
perfect protecting group, in the same way as pyrrole,10 and
allow for our methoxylation to take place. Consequently,
the newly prepared p-iodoanilines 5–8 were reacted with
glyoxal to easily afford the desired diimines 9–12 in good
yields and excellent purity (Scheme 2). Straightforward
purification by flash column chromatography was prefer-
ably employed on small scale for yield accuracy, as re-
ported in the supplementary information. However, larger
quantities were usually isolated by simple filtration at the
end of the reaction after appropriate cooling, providing
the pure products 9–12 in similar yields. The p-iodo-
diimines 9–12 were then subjected to the initial Buchwald
methoxylation conditions.11 After optimization, very en-
couraging results were obtained. The initial premix of
copper and 1,10-phenanthroline, together with the use of
pressure (4 bar) was demonstrated to be critical for the
substitution to take place. However, the internal pressure
needed (4 bar) was simply generated by heating the sol-
Scheme 2 New methoxylation strategy
This methoxylation procedure appeared to be very
straightforward and convenient, high yielding and scal-
able, requiring only minimal purification. Surprisingly,
the methoxylation of IPr diimine 9 underwent the simul-
taneous cleavage of the diimine bridge over the course of
the reaction, providing the unexpected free p-methoxyan-
iline 17 rather than the expected p-methoxydiimine 13
(Scheme 2). Conversely, methoxylation of IPent, IHept,
and INon p-iododiimines 10–12, showed only traces of
free p-methoxyanilines (<3%). This observation is partic-
ularly interesting as it experimentally supports that, re-
gardless of the apparent structural similarity between the
ITent family members, a dramatic steric difference really
does exist between these congeners. This experimental
observation is critical and supports our working hypothe-
sis in designing ITent NHC as sterically hindered but flex-
ible NHC ligands for enhanced catalysis.5
The free p-methoxyaniline 17, which is by far the most
readily accessible and scalable, was easily purified by dis-
tillation under reduced pressure. The resulting aniline 17
Synlett 2014, 25, 393–398
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Synthetic Route to p-Methoxy-2,6-disubstituted Anilines
395
was obtained in large quantity and excellent purity and pared (S)ITentOMe·HCl 21–26 salts are currently being in-
was converted into the corresponding diimine through the vestigated as promising ligands for homogenous catalysis.
standard procedure (Equation 2).
N
N
LAH (2.4 M in THF)
glyoxal (40% in H2O)
HCOOH (cat.)
N
N
MeO
OMe
THF
17
0 °C to r.t.
MeO
OMe
MeOH
r.t., overnight
13
13
72%
HCl (4 M in dioxane)
NH HN
Equation 2 Preparation of diimine 13
HC(OEt)3
120 °C, 96%
MeO
OMe
25
The p-methoxydiimines 13–16 were all obtained in excel-
lent purity and did not require any further purification
(Scheme 2 and Equation 2). However, flash column chro-
matography was used to guarantee the complete removal
of any copper traces for ultimate catalytic applications as
well as to confirm the near quantitative yields. On larger
scales, the solid p-methoxydiimines 13–16 were also suc-
cessfully further purified by recrystallization when need-
ed. Finally, diimines 13–16 were all converted into their
corresponding imidazolium chlorides via the usual
(CHO)n/ZnCl2/HCl procedure4 in good yield and CHN
purity (Equation 3).15 It must be noted that the Hinter-
mann cylization procedure16 with TMSCl was also suc-
cessfully used to obtain 21 as a whiter solid in similar
yield and purity. However, it proved inefficient for the cy-
clization of bulkier diimines.5
N
N
MeO
OMe
Cl
26
Scheme 3 Preparation of p-methoxylatedimidazolinium chloride 26
Finally, in order to demonstrate the versatility of our ap-
proach, and compare it to the literature,9 the diimine
bridge was easily cleaved to release the free anilines. The
p-methoxydiimines 14–16 were efficiently deprotected to
the free anilines 18–20 with great ease, good yields, and
excellent purity, proving that the diimine functionality can
also be considered as an inexpensive conventional pro-
tecting group (Equation 4). These reaction/deprotection
conditions were not optimized.
R
R
R
R
(CHO)n, ZnCl2
HCl (4 M in dioxane)
N
N
R
R
R
R
HCl
(37% in H2O)
MeO
OMe
N
N
THF, 70 °C
R
R
R
R
R
MeO
OMe
THF, 20 min
r.t. to 100 °C
13–16
R
R
R
R
R
R
14–16
R
N
N
R
NH2
R
MeO
OMe
R
R
R
R
R
Cl
R
21 R = Me 88%
22 R = Et 65%
23 R = n-Pr 60%
24 R = n-Bu 66%15
OMe
18 R = Et
19 R = n-Pr 85%
20 R = n-Bu 89%
86%
Equation 3 Preparation of p-methoxylatedimidazolium chlorides
Equation 4 Cleavage of diimine-protecting bridge
As recently described by Organ,17 bulky saturated imidaz-
olinium chlorides such as SIPent·HCl could not be made
via the standard HC(OEt)3 cyclization procedure. The
same observation was made here for the preparation of
SIPr*·HCl, SIPr*OMe·HCl, or SITent·HCl as their anilyl
groups were too bulky to allow the cyclization to take
place. However, in the case of SIPrOMe·HCl 26, cycliza-
tion proceeded smoothly (Scheme 3). Compound 26 was
obtained as a bright white powder in 94% yield (2 steps
from 13) in using the slightly modified LiAlH4 reduction–
HC(OEt)3 cyclization two-step sequence. The newly pre-
A new inexpensive, rapid, and easy-to-handle methodolo-
gy has been developed for the high-yield synthesis of me-
thoxylated anilines. The key step is an air- and moisture-
robust copper-catalyzed methoxylation which could be
extended to other alkoxylations. This methodology not
only provided a reliable and reproducible way to prepare
p-methoxyanilines efficiently, but also provided access to
a new range of electronically enriched NHC. It should
also be noted that preliminary results confirmed the possi-
bility of applying our method to multiple substitutions. In-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 393–398

396
S. Meiries, S. P. Nolan
LETTER
(4) Meiries, S.; Speck, K.; Cordes, D. B.; Slawin, A. M. Z.;
Nolan, S. P. Organometallics 2013, 32, 330.
(5) Meiries, S.; Le Duc, G.; Chartoire, A.; Collado, A.; Speck,
K.; Athukorala Arachchige, K. S.; Slawin, A. M. Z.; Nolan,
S. P. Chem. Eur. J. 2013, 19, in press; DOI:
deed, polyiodoanilyl diimines were proved to be suitable
candidates to access polyalkoxylated anilines or diimines.
Acknowledgment
10.1002/chem.201302471.
We gratefully acknowledge the EC for funding through the seventh
framework program SYNFLOW and the ERC for an Advanced Re-
searcher Award to S.P.N. (FUNCAT). Julie Mayen is also thanked
for her precious help for the scale up of IPrOMe·HCl 21 and
SIPrOMe·HCl 26. Rockwood Lithium is thanked for its generous gift
of cesium carbonate. We thank the EPSRC National Mass Spectro-
metry Service Center in Swansea for mass spectrometric analyses.
S.P.N. is a Royal Society Wolfson Research Merit Award holder.
(6) (a) Valente, C.; Çalimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah,
M.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 3314.
(b) Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson, A.
C.; Organ, M. G. Chem. Eur. J. 2011, 17, 3086. (c) Hoi, K.
H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson, A. C.; Organ,
M. G. Chem. Eur. J. 2012, 18, 145.
(7) (a) Rising, A.; Bamberger, E. Justus Liebigs Ann. Chem.
1901, 316, 257. (b) Bamberger, E. Ber. Dtsch. Chem. Ges.
1894, 27, 1347. (c) Bamberger, E. Ber. Dtsch. Chem. Ges.
1894, 27, 1548.
(8) Kjaer, A. M.; Ulstrup, J. J. Am. Chem. Soc. 1988, 110, 3874.
(9) (a) Moroz, A. A.; Shvartsberg, M. S. Russ. Chem. Rev. 1974,
43, 679. (b) Williams, A. L.; Kinney, R. E.; Bridger, R. F.
J. Org. Chem. 1967, 32, 2501. (c) McKillop, A.; Howarth,
B. D.; Kobylecki, R. J. Synth. Commun. 1974, 4, 35.
(d) Bacon, R. G. R.; Rennison, S. C. J. Chem. Soc. C 1969,
312. (e) Keegstra, M. A.; Peters, T. H. A.; Brandsma, L.
Tetrahedron 1992, 48, 3633.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. The proce-
dures for the syntheses of compounds 6, 10, 14, 18, 22 and 13, 17,
25, 26 are provided as typical procedures in References and Notes.18Sunpgipotr
noIrfmoinatSunogIoirfmintprat
References and Notes
(1) Arduengo, A. J.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
1991, 133, 361.
(10) (a) Ragan, J. A.; Makowski, T. W.; Castaldi, M. J.; Hill, P.
D. Synthesis 1998, 1599. (b) Ragan, J. A.; Makowski, T. W.;
Castaldi, M. J.; Hill, P. D. Org. Synth. 2002, 78, 63.
(c) Ragan, J. A.; Makowski, T. W.; Castaldi, M. J.; Hill, P.
D. Org. Synth. 2004, 10, 418.
(11) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973.
(12) Hospital, A.; Gibard, C.; Gaulier, C.; Nauton, L.; Thery, V.;
El-Ghozzi, M.; Avignant, D.; Cisnetti, F.; Gautier, A. Dalton
Trans. 2012, 41, 6803.
(13) Altman, R. A.; Shafir, A.; Choi, A.; Lichtor, P. A.;
Buchwald, S. L. J. Org. Chem. 2008, 73, 284.
(14) (a) D’Souza, B. R.; Lane, T. K.; Louie, J. Org. Lett. 2011,
13, 2936. (b) Lane, T. K.; D’Souza, B. R.; Louie, J. J. Org.
Chem. 2012, 77, 7555.
(15) All imidazolium chlorides 21–23 and 26 were obtained as
pure white powders as confirmed by elemental analysis.
However INonOMe·HCl 24 was contaminated by an
undetermined impurity forming during the cyclization step.
All efforts to suppress the formation of this impurity or to
further purify INonOMe·HCl 24 were unsuccessful. However,
INonOMe·HCl 24 was successfully taken on crude to other
transformations that allowed for the ultimate elimination of
the impurity.
(16) Hintermann, L. Beilstein J. Org. Chem. 2007, 3, 1.
(17) Tsimerman, M.; Mallik, D.; Matsuo, T.; Otani, T.; Tamao,
K.; Organ, M. G. Chem. Commun. 2012, 48, 10352.
(18) 4-Iodo-2,6-di(3-pentyl)aniline (6, R = Et)
A solution of aniline 2 (2.40 g, 10.3 mmol, 1.0 equiv) in
cyclohexane (7.0 mL) was treated with a sat. aq solution of
Na2CO3 (2.90 mL, ca. 5.7 mmol, 0.6 equiv) followed by
solid iodine (2.90 g, 11.4 mmol, 1.1 equiv) at r.t. The
reaction was stirred overnight at r.t. (11 h). The crude
solution was diluted with Et2O (15 mL) and washed with a
sat. aq solution of Na2S2O3 (3 × 10 mL). The organic layer
was then dried over anhydrous Na2SO4 and concentrated
under vacuum. The resulting dark greenish to black oil (4.10
g) was obtained in excellent purity but was preferably
filtered through silica and eluted with a 1% solution of Et2O
in pentane to remove some of the colored impurities.
Solvents were evaporated to afford the pure desired
iodoaniline 6 as an orange crystalline solid (3.53 g, 96%). 1H
NMR (400 MHz, CDCl3): δ = 0.83 (12 H, t, J = 2 × 7.4 Hz,
(2) (a) Nolan, S. P. N-Heterocyclic Carbenes in Synthesis;
Wiley-VCH: Weinheim, 2006, 1–304. (b) Glorius, F. N-
Heterocyclic Carbenes in Transition Metal Catalysis, In
Topics in Organometallic Chemistry; Vol. 21; Springer:
Berlin, Heidelberg, 2007, 1–218. (c) Cazin, C. S. J. N-
Heterocyclic Carbenes in Transition Metal Catalysis and
Organocatalysis; Springer: Berlin, Heidelberg, 2011, 1–
356. (d) Marion, N.; Nolan, S. P. Chem. Soc. Rev. 2008, 37,
1776. (e) Köcher, C.; Herrmann, W. A. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2162. (f) Bugaut, X.; Glorius, F. Chem.
Soc. Rev. 2012, 41, 3511. (g) Kühl, O. Chem. Soc. Rev.
2007, 36, 592. (h) Herrmann, W. A. Angew. Chem. Int. Ed.
2002, 41, 1290. (i) Fortman, G. C.; Nolan, S. P. Chem. Soc.
Rev. 2011, 40, 5151. (j) Díez-González, S.; Marion, N.;
Nolan, S. P. Chem. Rev. 2009, 109, 3612. (k) Arduengo, A.
J. III. Acc. Chem. Res. 1999, 32, 913.
(3) (a) Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C.
Chem. Commun. 2002, 2704. (b) Altenhoff, G.; Goddard,
R.; Lehmann, C. W.; Glorius, F. Angew. Chem. Int. Ed.
2003, 42, 3690. (c) Altenhoff, G.; Goddard, R.; Lehmann, C.
W.; Glorius, F. J. Am. Chem. Soc. 2004, 126, 15195.
(d) Würtz, S.; Glorius, F. Acc. Chem. Res. 2008, 41, 1523.
(e) Würtz, S.; Lohre, C.; Fröhlich, R.; Bergander, K.;
Glorius, F. J. Am. Chem. Soc. 2009, 131, 8344. (f) Lavallo,
V.; Canac, Y.; Präsang, C.; Donnadieu, B.; Bertrand, G.
Angew. Chem. Int. Ed. 2005, 44, 5705. (g) Lavallo, V.;
Canac, Y.; DeHope, A.; Donnadieu, B.; Bertrand, G. Angew.
Chem. Int. Ed. 2005, 44, 7236. (h) Lavallo, V.; Frey, G. D.;
Kousar, S.; Donnadieu, B.; Bertrand, G. Proc. Natl. Acad.
Sci. U.S.A. 2007, 104, 13569. (i) Lavallo, V.; Frey, G.;
Donnadieu, B.; Soleilhavoup, M.; Bertrand, G. Angew.
Chem. Int. Ed. 2008, 47, 5224. (j) Organ, M. G.; Çalimsiz,
S.; Sayah, M.; Hoi, K. H.; Lough, A. J. Angew. Chem. Int.
Ed. 2009, 48, 2383. (k) Valente, C.; Çalimsiz, S.; Hoi, K. H.;
Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem. Int. Ed.
2012, 51, 2. (l) Christmann, U.; Vilar, R. Angew. Chem Int.
Ed. 2005, 44, 366. (m) Yamashita, M.; Goto, K.;
Kawashima, T. J. Am. Chem. Soc. 2005, 127, 7294. (n) Sato,
H.; Fujihara, T.; Obora, Y.; Tokunaga, M.; Kiyosu, J.; Tsuji,
Y. Chem. Commun. 2007, 269. (o) Chianese, A. R.; Mo, A.;
Datta, D. Organometallics 2009, 28, 465.
Synlett 2014, 25, 393–398
© Georg Thieme Verlag Stuttgart · New York

LETTER
New Synthetic Route to p-Methoxy-2,6-disubstituted Anilines
397
4 × CH3), 1.57 (4 H, m, 2 × CH2), 1.70 (4 H, m, 2 × CH2),
CDCl3): δ = 0.81 (24 H, d, J = 6.9 Hz, 8 × CH3), 3.04 (4 H,
m, 4 × CH), 3.87 (OCH3), 6.79 (4 H, s, 4 × Hm-Ar), 8.14 (2 H,
s, 2 × HC=N). 13C NMR (100 MHz, CDCl3): δ = 23.3 (8 ×
CH3), 28.1 (4 × CH), 55.1 (2 × OCH3), 108.6 (4 × CHm-Ar),
138.6 (4 × CIVo-Ar), 141.6 (2 × NCIVAr), 157.2 (2 × OCIVAr),
163.5 (2 × HC=N). HRMS (NSI+): m/z calcd for
2.40 (2 H, m, 2 × CH), 3.64 (2 H, v br s, NH2), 7.15 (2 H, s,
Hm-Ar). 13C NMR (100 MHz, CDCl3): δ = 11.9 (4 × CH3),
27.9 (4 × CH2), 42.2 (2 × CH), 81.3 (I-CIVAr), 132.6 (2 ×
CIVo-Ar), 132.7 (2 x× CHm-Ar), 142.5 (NCIVAr). HRMS (NSI+):
m/z calcd for C16H27NI: 360.1183; found: 360.1186 [M +
H]+.
C28H41O2N2: 437.3163; found: 437.3158 [M + H]+.
N,N′-Bis[4-methoxy-2,6-di(3-pentyl)phenyl]1,4-
N,N′-Bis[4-iodo-2,6-di(3-pentyl)phenyl]1,4-
diazabutadiene (10, R = Et)
diazabutadiene (14, R = Et)A sealed tube was charged with
MeOH (20 mL), CuI (450 mg, 2.36 mmol, 0.5 equiv),
phenanthroline (681 mg, 3.78 mmol, 0.8 equiv), and Cs2CO3
(6.26 g, 19.2 mmol, 4.3 equiv) at r.t. To this brown mixture
was added the starting diiododiimine 10 (3.33 g, 4.50 mmol,
1.0 equiv), and the reaction was stirred overnight (10 h) at
110 °C. The reaction was allowed to cool to r.t. and was
filtered through cotton wool. The remaining solid was
washed with Et2O (3 × 20 mL), and the filtrate was
transferred into a separating funnel. The organic layer was
washed with 10% NH4OH (3 × 20 mL), then brine (20 mL),
and was then dried over anhydrous Na2SO4. Concentration
in vacuo afforded the crude dimethoxydiimine as viscous
brown oil (2.60 g) that was filtered through silica and eluted
with pentane. The filtrate was evaporated to yield the pure
desired diimine 14 as brown viscous oil (2.47 g, quant.). 1H
NMR (400 MHz, CDCl3): δ = 0.81 (24 H, t, J = 7.3 Hz, 8 ×
CH3), 1.47–1.73 (16 H, m, 8 × CH2), 2.54 (4 H, m, 4 × CH),
3.82 (OCH3), 6.65 (4 H, s, 4 × Hm-Ar), 8.02 (2 H, s, 2 ×
HC=N). 13C NMR (100 MHz, CDCl3): δ = 12.1 (8 × CH3),
28.9 (8 × CH2), 42.6 (4 × CH), 55.1 (OCH3), 109.2 (4 ×
CHm-Ar), 135.6 (4 × CIVo-Ar), 144.8 (2 × NCIVAr), 157.0 (2 ×
OCIVAr), 164.4 (2 × HC=N). HRMS (NSI+): m/z calcd for
C36H57O2N2: 549.4415; found: 549.4403 [M + H]+.
1,3-Bis[4-methoxy-2,6-di(3-pentyl)phenyl]imidazolium
Chloride (22, R = Et, IPentOMe·HCl)
A solution of diimine 14 (2.30 g, 4.19 mmol, 1.0 equiv) in
THF (164 mL) was treated with anhydrous ZnCl2 (571 mg,
4.19 mmol, 1.0 equiv) at 70 °C and stirred for 5 min. p-
Formaldehyde (132 mg, 4.40 mmol, 1.1 equiv) was
subsequently added followed by the dropwise addition of
anhydrous HCl (4.0 M in dioxane, 1.6 mL, 6.4 mmol, 1.5
equiv). The reaction was stirred for 3 h at 70 °C and
concentrated under vacuum. The residue was dissolved in
EtOAc (150 mL) and was washed with H2O (3 × 100 mL)
and brine (100 mL). The combined aqueous phases were
extracted with EtOAc (50 mL), and the organic phases were
combined and dried over anhydrous MgSO4. The solvent
was evaporated under vacuum, and the resulting brown solid
(2.62 g) was triturated with pentane (3 × 65 mL) affording
the pure desired imidazolium chloride 22 (1.62 g, 65%) as a
beige solid. 1H NMR (400 MHz, CDCl3): δ = 0.58 (12 H, t,
J = 7.4 Hz, 4 × CH3), 0.63 (12 H, t, J = 7.4 Hz, 4 × CH3),
1.32–1.58 (16 H, m, 8 × CH2), 1.68 (4 H, m, 4 × CH), 3.70
(6 H, s, 2 × OCH3), 6.56 (4 H, s, 4 × Hm-Ar), 7.90 (2 H, s, 2 ×
HC=N), 8.38 (1 H, s, NCHN). 13C NMR (100 MHz, CDCl3):
δ = 11.9 (4 × CH3), 12.0 (4 × CH3), 28.0 (4 × CH2), 28.7 (4
× CH2), 43.2 (4 × CH), 55.2 (2 × OCH3), 110.0 (4 × CHm-Ar),
125.0 (4 × CIVo-Ar), 127.7 (2 × HC=N), 136.4 (NCHN), 143.6
(2 × NCIVAr), 161.4 (2 × OCIVAr). Anal. Calcd for
A solution of 4-iodoaniline 6 (3.53 g, 9.82 mmol, 2.0 equiv)
in MeOH (20 mL) was treated with formic acid (1 drop)
followed by the dropwise addition of glyoxal (40% in H2O,
640 μL, 5.82 mmol, 1.2 equiv) at 70 °C. The solution was
stirred at this temperature for 3 h, and the MeOH was
evaporated under vaccum and replaced by Et2O. The
solution was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash
column chromatography (silica gel, 1–5% Et2O in pentane)
to yield the pure desired diimine 10 as a bright yellow solid
(3.33 g, 92%). 1H NMR (400 MHz, CDCl3): δ = 0.79 (24 H,
t, J = 7.4 Hz, 8 × CH3), 1.53 (8 H, m, 4 × CH2), 1.64 (8 H, m,
4 × CH2), 2.40 (4 H, m, 4 × CH), 7.37 (4 H, m, Hm-Ar), 7.96
(2 H, s, 2 × CH=N). 13C NMR (100 MHz, CDCl3): δ = 12.1
(8 × CH3), 28.8 (8 × CH2), 42.5 (4 × CH), 90.0 (2 × ICIVp-Ar),
133.0 (2 × CHm-Ar), 136.5 (2 × CIVo-Ar), 150.5 (2 × NCIVAr),
163.9 (2 × CH=N). HRMS (NSI+): m/z calcd for C34H51N2I2:
741.2136; found: 741.2139 [M + H]+.
4-Methoxy-2,6-diisopropylaniline (17, R = Me)
A sealed tube was charged with MeOH (50 mL), CuI (2.46
g, 12.9 mmol, 0.5 equiv), phenanthroline (3.73 g, 20.7
mmol, 0.8 equiv), and Cs2CO3 (34.2 g, 105 mmol, 4.3 equiv)
at r.t. To this brown mixture was added the starting
diiododiimine 9 (15.4 g, 24.5 mmol, 1.0 equiv), and the
reaction was stirred overnight (10 h) at 110 °C. The reaction
was allowed to cool down to r.t. and was filtered through
cotton wool. The remaining solid was washed with Et2O (3
× 50 mL), and the filtrate was transferred into a separating
funnel. The organic layer was washed with 10% NH4OH
(3 × 50 mL), then brine (50 mL), and was then dried over
anhydrous Na2SO4. Concentration in vacuo afforded the
crude methoxyaniline as viscous brown oil (10.4 g) that was
purified by flash column chromatography (silica gel, 5–50%
Et2O in pentane). The pure desired methoxyaniline 17 was
obtained as dark reddish viscous oil (7.40 g, 73%). On larger
scale, the crude oil was successfully purified by distillation
under reduced pressure (110–120 °C at 0.8 mbar). Our data
were in full agreement with those reported in the
literature.13b,14 1H NMR (400 MHz, CDCl3): δ = 1.34 (12
H, d, J = 6.7 Hz, 4 × CH3), 3.04 (2 H, m, 2 × CH), 3.52 (2 H,
v br s, NH2), 3.85 (3 H, s, OCH3), 6.73 (2 H, s, Hm-Ar). 13
C
NMR (100 MHz, CDCl3): δ = 22.3 (4 × CH3), 28.0 (2 × CH),
55.4 (OCH3), 108.5 (2 × CHm-Ar), 133.8 (NCIVAr), 134.1 (2 ×
CIVo-Ar), 152.6 (OCIVAr).
N,N′-Bis(4-methoxy-2,6-diisopropylphenyl)1,4-
diazabutadiene (13, R = Me)
A solution of 4-methoxy-2,6-diisopropylaniline (17, 15.2 g,
73.4 mmol, 2.0 equiv) in MeOH (300 mL) was treated with
formic acid (2 drops) followed by the dropwise addition of
glyoxal (40% in H2O, 6.43 mL, 74.4 mmol, 1.0 equiv) at r.t.
The solution was stirred at this temperature for 2 h, and the
MeOH was evaporated under vacuum and replaced by
pentane (300 mL). The solution was dried over anhydrous
Na2SO4, filtered, and partially concentrated in vacuo.
Although good purity was obtained, the residual oil was
preferably purified by flash column chromatography (silica
gel, 10% Et2O in pentane) to yield the pure desired diimine
13 as an orange solid (11.5 g, 72%). 1H NMR (400 MHz,
C35H53ClN2: C, 74.40; H, 9.62; N, 4.69. Found: C, 74.30; H,
9.79; N, 4.74.
N,N′-Bis-(4-methoxy-2,6-
diisopropylphenylamino)ethane (25)
A solution of diimine 13 (11.5 g, 26.3 mmol, 1.0 equiv) in
anhydrous THF (200 mL) was cooled to –20 °C and treated
with LiAlH4 (2.4 M in THF, 44.0 mL, 106 mmol, 4.0 equiv).
Upon addition of LiAlH4, the yellow solution rapidly turned
very dark purple and important bubbling was observed.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 393–398

398
S. Meiries, S. P. Nolan
LETTER
After 15 min at –20 °C, the color of the reaction changed
back to clear orange, and the reaction was allowed to stirr for
45 min at r.t. The reaction was then cooled to 0 °C, diluted
with Et2O (200 mL), and carefully quenched with H2O (5.0
mL). After stirring for 10 min, a 15% aqueous solution of
NaOH (5.0 mL) was added, followed by H2O (12 mL). The
suspension was allowed to warm to r.t. and was stirred for 15
min before anhydrous MgSO4 was added until a fine solid
was obtained. The solids were discarded by filtration, and
the filtrate was concentrated in vacuo affording a clear
orange and very viscous oil (11.80 g) in excellent purity.
However, the oil was preferably purified by flash column
chromatography (silica, 10–20% Et2O in pentane) to provide
the pure desired diamine 25 as an orange viscous oil (11.35
g, 98%). 1H NMR (400 MHz, CDCl3: δ = 1.26 (24 H, d, J =
6.9 Hz, 4 × CH3), 3.08 (6 H, v br s, 2 × CH2 + 2 × NH), 3.40
(4 H, m, 4 × CH), 3.82 (6 H, m, 2 × OCH3), 6.68 (4 H, s, 4 ×
Hm-Ar). 13C NMR (100 MHz, CDCl3: δ = 24.2 (8 × CH3), 27.9
(4 × CH), 52.6 (2 × CH2), 55.2 (2 × OCH3), 108.9 (4 ×
CHm-Ar), 136.4 (2 × OCIVp-Ar), 144.6 (4 × CIVo-Ar), 156.2 (2 ×
NCIVAr). HRMS (NSI+): m/z calcd for C28H45O2N2:
imidazolinium chloride 25 was obtained as a bright white
powder (7.80 g, 96%). 1H NMR (400 MHz, CDCl3): δ = 1.14
(12 H, d, J = 6.9 Hz, 4 × CH3), 1.25 (12 H, d, J = 6.9 Hz, 4
× CH3), 2.84 (4 H, m, 4 × CH), 3.74 (6 H, m, 2 × OCH3), 4.58
(4 H, s, 2 × NCH2), 6.62 (4 H, s, 4 × Hm-Ar), 8.64 (1 H, s,
N=CHN). 13C NMR (100 MHz, CDCl3): δ = 23.3 (4 × CH3),
25.1 (4 × CH3), 29.1 (4 × CH), 55.2 (2 × OCH3), 109.8 (4 ×
CHm-Ar), 121.9 (2 × CHp-Ar), 147.4 (4 × CIVo-Ar), 159.4
(NCHN), 161.1 (2 × NCIVAr). Anal. Calcd for C29H43ClN2O2:
C, 71.51; H, 8.90; N, 5.75. Found: C, 71.40; H, 9.01; N, 5.85.
4-Methoxy-2,6-di(3-pentyl)aniline (18, R = Et)
A solution of IPent diimine 14 (2.75 g, 5.01 mmol, 1.0
equiv) in EtOH (23 mL) was treated with a HCl solution
(37% in H2O, 11.6 mL, 120 mmol, 28 equiv) at r.t. The
reaction turned brown upon the addition of HCl and after 10
min at r.t. it was allowed to stir at 100 °C for a further 10
min. The reaction was cooled to r.t. and carefully neutralized
with a sat. aq solution of NaOH (6 mL). The mixture was
then extracted with pentane (3 × 25 mL), dried over
anhydrous Na2SO4, and concentrated under vacuum. The
crude aniline (5.05 g) was obtained in excellent purity but
was preferably purified by flash column chromatography
(silica, 1–5% Et2O in pentane) to afford the pure desired
aniline 18 as an orange clear viscous oil (2.28 g, 86%). 1H
NMR (400 MHz, CDCl3): δ = 0.84 (12 H, t, J = 7.4 Hz, 4 ×
CH3), 1.51–1.78 (8 H, m, 4 × CH2), 2.53 (2 H, m, 2 × CH),
3.34 (2 H, v br s, NH2), 3.76 (3 H, s, OCH3), 6.51 (2 H, s,
Hm-Ar). 13C NMR (100 MHz, CDCl3): δ = 12.0 (4 × CH3),
28.2 (4 × CH2), 42.5 (2 × CH), 55.4 (OCH3), 109.5 (2 ×
CHm-Ar), 132.0 (2 × CIVo-Ar), 136.3 (OCIVAr), 152.7 (NCIVAr).
HRMS (NSI+): m/z calcd for C17H30ON: 264.2322; found:
264.2321 [M + H]+ .
441.3476; found: 441.3470 [M + H]+.
1,3-Bis-(4-methoxy-2,4-diisopropylphenyl)-
imidazolinium Chloride (26, SIPrOMe·HCl)
A solution of diamine 25 (7.35 g, 16.7 mmol, 1.0 equiv) in
triethyl orthoformate (60 mL) was heated to 120 °C and
treated with the rapid addition of HCl (4.0 M in dioxane, 5.0
mL, 1.2 equiv). Upon addition of HCl, the clear solution
immediately turned into a white suspension, and the stirring
was continued for 10 min at 120 °C. The reaction was cooled
to r.t. and was diluted with pentane (60 mL). The white solid
was isolated by filtration and washed with pentane (3 × 60
mL). After drying under high vacuum, the desired
Synlett 2014, 25, 393–398
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.