Modular synthesis of functionalisable alkoxy-tethered N-heterocyclic carbene ligands and an active catalyst for buchwald-hartwig aminations

Article abstract of DOI:10.1002/adsc.201300903

Modular syntheses of functionalised, alkoxy-tethered 1,3-bis(2,4,6- trimethylphenyl)imidazolium (IMes*H⁺) and 1,3-bis(2,6- diisopropylphen-l)imidazolium (IPr*H⁺) derivatives 1,3-bis(4-alkyl- -2,4,6-trimethylphenyl)imidazolium (IXyOR*H⁺) and 1,3-bis(4-alkyl-oxy-2,6-diisopropylphenyl)imidazolium (IPrOR*H ⁺) are reported. A reliable synthesis of the key starting material 4-amino-3,5-diisopropylphenol is also described. Etherification of hydroxydecorated ligand intermediates before formation of the imidazolium core and subsequent modification, or direct etherification of the versatile synthon IPrOH·HCl, allowed access to various linker types including triethoxysilyl, primary amino and norbornenyl, which are not accessible by other methods. An IPrOR-palladium(II) complex was prepared, and its catalytic activity was evaluated in challenging Buchwald- Hartwig aminations of aryl chlorides. This precatalyst displayed excellent activity and selectivity under mild reaction conditions, achieving in some cases a 10-fold improvement in TOF relative to the IPr-based version. An unexpected activity profile was observed wherein sterically demanding anilines were coupled more easily than those lacking orthosubstitution.

Full text of DOI:10.1002/adsc.201300903

Supporting Information
© Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2013

Modular Synthesis of Functionalizable Alkoxy-Tethered N-
Heterocyclic Carbene Ligands and an Active Catalyst for
Buchwald-Hartwig Aminations
Jamin L Krinsky,a* Alberto Martínez,a Cyril Godard,a Sergio Castillónb and Carmen Clavera*
a Department of Physical and Inorganic Chemistry, Universitat Rovira i Virgili, C/ Marcel·li
Domingo s/n, 43007 Tarragona, Spain. E-mail: carmen.claver@urv.cat
b Department of Analytical and Organic Chemistry, Universitat Rovira i Virgili, C/ Marcel·li
Domingo s/n, 43007 Tarragona, Spain. E-mail: sergio.castillon@urv.cat
Supporting Information
Table of Contents
GC method for GC-FID and GC-MS experiments .................................................................................2
Procedures and characterization data for isolated Buchwald-Hartwig reaction products.......................2
General procedure...............................................................................................................................2
Additional information specific to each reaction................................................................................2
N-(o-tolyl)morpholine (23a)...........................................................................................................2
N-(2-pyridyl)morpholine (23b-c) ...................................................................................................2
N-(1-naphthyl)morpholine (23d)....................................................................................................2
N-(2,6-dimethylphenyl)morpholine (23e).......................................................................................3
N-(2-methoxyphenyl)morpholine (23f) ..........................................................................................3
N-(4-methoxyphenyl)morpholine (23g) .........................................................................................3
N-(o-tolyl)pyrrolidine (23h) ...........................................................................................................3
N-methyl-N'-(o-tolyl)piperazine (23i) ............................................................................................4
N,N-dibutyl-2-methylaniline (23j)..................................................................................................4
N-benzyl-2-methylaniline (23k) .....................................................................................................4
N,2-dimethyl-N-phenylaniline (23l)...............................................................................................4
2-methyl-N-(p-tolyl)aniline (23m) .................................................................................................4
2-methyl-N-phenylaniline (23n).....................................................................................................5
2,4,6-trimethyl-N-(o-tolyl)aniline (23o) .........................................................................................5
2,6-diisopropyl-N-(o-tolyl)aniline (23p) ........................................................................................5
N-(2,6-dimethylphenyl)-2,4,6-trimethylaniline (24a).....................................................................5
N-(2,6-diisopropylphenyl)-2,6-dimethylaniline (24b)....................................................................5
References...............................................................................................................................................6
NMR spectra of new compounds............................................................................................................7
NMR spectra of Buchwald-Hartwig reaction products.........................................................................26
GC traces and mass spectra of Buchwald-Hartwig reaction products ..................................................32
GC-FID traces for the reaction of 21a with 22i, with added aniline 22h..............................................49
- S1-

GC method for GC-FID and GC-MS experiments
The GC-FID method used consisted of: Column; Agilent HP-5, 30 m × 250 μm. Inlet; temp. = 250
°C, pressure = 100.0 kPa, 16:1 split, total flow = 25.0 mL/min, helium carrier. Detector; temp. = 275
°C, hydrogen flow = 40.0 mL/min, air flow 450.0 mL/min, makeup flow (helium) = 45.0 mL/min.
Oven; initial temp. = 45 °C (5 min), ramp = 10 °C/min to 250 °C, hold at 250 °C for 5 min. The GC-
MS measurements were performed in scan mode with a 4 min solvent delay.
Procedures and characterization data for isolated Buchwald-Hartwig reaction products
General procedure
In a drybox, a 5 mL screw topped vial was charged with a stir bar, precatalyst 19 (3.0 mg, 0.0025
mmol, 0.005 equiv.), tBuOK (84 mg, 0.75 mmol, 1.5 equiv.) and amine if solid, capped with a septum
cap and removed to the bench top. The appropriate amine (0.55 mmol, 1.1 equiv.) and solvent (0.5
mL) were added via syringe, and the mixture was allowed to stand for a few minutes. The aryl halide
(0.5 mmol, 1.0 equiv.) was then added via syringe, immediately after which the vial was placed in a
shallow oil bath atop a thermo-regulated hot plate and stirred at 400-500 rpm. The reaction was
quenched with water (2 mL) and extracted with DCM (4 times with 1 mL), passing the DCM extracts
through a small plug of silica gel. The silica plug was then washed with DCM (2 mL), and the
combined extracts evaporated in vacuo.
Additional information specific to each reaction
N-(o-tolyl)morpholine (23a). The reaction vial was charged with 59 μL 2-chlorotoluene (21a) and 48
μL morpholine (22a), and heated at 30 °C for 30 min. The product was obtained as a colorless oil (83
1
mg, 94%) after silica-gel chromatography using hexane then 50:1 hexane/EtOAc as eluent. H NMR
(400 MHz, CDCl3): δ 7.20 (ddd, J = 11.1, 10.6, 8.4, 2H), 7.08-6.88 (m, 2H), 3.98-3.76 (m, 4H), 3.03-
1
2.80 (m, 4H), 2.33 (s, 3H). The H NMR spectrum of the purified product matches that reported
previously[1] and is reproduced below, as is the GC trace and mass spectrum.
N-(2-pyridyl)morpholine (23b-c). 23b: The reaction vial was charged with 48 μL 2-bromopyridine
(21b) and 48 μL morpholine (22a), and heated at 30 °C for 15 min. 23c: The reaction vial was
charged with 47 μL 2-chloropyridine (21c) and 48 μL morpholine (22a) and heated at 30 °C for 15
min. In both cases the product was obtained as a low-melting solid (76 mg, 93%; 79 mg, 96%) after
1
silica-gel chromatography using 4:1 hexane/EtOAc as eluent. H NMR (400 MHz, CDCl3): δ 8.20
(ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 7.50 (ddd, J = 8.6, 7.2, 2.0 Hz, 1H), 6.76-6.49 (m, 2H), 3.99-3.64 (m,
1
4H), 3.64-3.37 (m, 4H). The H NMR spectrum of the purified product matches that reported
previously[2] and is reproduced below, as is the GC trace and mass spectrum.
N-(1-naphthyl)morpholine (23d). The reaction vial was charged with 68 μL technical grade (~10% 2-
chloro isomer) 1-Chloronaphthalene (21d) and 48 μL morpholine (22a), and heated at 30 °C for 15
min. The product was obtained as a white solid (99 mg, 93% combined yield) after silica-gel
chromatography using hexane then 50:1 hexane/EtOAc as eluent. Pure N-(1-naphthyl)morpholine (92
mg) was the first to elute, followed by 7 mg of an isomeric mixture containing N-(2-
- S2-

naphthyl)morpholine. 1H NMR (400 MHz, CDCl3): δ 8.30-8.06 (m, 1H), 7.95-7.73 (m, 1H), 7.58 (d, J
= 8.2 Hz, 1H), 7.54-7.37 (m, 3H), 7.11 (d, J = 7.1 Hz, 1H), 4.12-3.80 (m, 4H), 3.25-2.93 (m, 4H). The
1H NMR spectrum of the purified product matches that reported previously[3] and is reproduced
below, as is the GC trace and mass spectrum.
N-(2,6-dimethylphenyl)morpholine (23e). The reaction vial was charged with 66 μL 2-chloro-1,3-
dimethylbenzene (21e) and 48 μL morpholine (22a), and heated at 40 °C for 90 min. The product was
obtained as a white solid (88 mg, 92%) after silica-gel chromatography using 50:1 hexane/EtOAc as
eluent. 1H NMR (400 MHz, CDCl3): δ 7.11-6.83 (m, 3H), 3.97-3.63 (m, 4H), 3.19-2.99 (m, 4H), 2.36
1
(s, 6H). The H NMR spectrum of the purified product matches that reported previously[4] and is
reproduced below, as is the GC trace and mass spectrum.
N-(2-methoxyphenyl)morpholine (23f). The reaction vial was charged with 64 μL 2-chloroanisole
(21f) and 48 μL morpholine (22a), and heated at 50 °C for 4 h. The product was obtained as a yellow
oil (44 mg, 45% or 82 mg, 84% at 1 mol% cat. loading) after silica-gel chromatography using 20:1
then 10:1 hexane/EtOAc as eluent. 1H NMR (400 MHz, CDCl3): δ 7.06-6.98 (m, 1H), 6.94 (d, J = 4.0
1
Hz, 2H), 6.88 (d, J = 7.9 Hz, 1H), 3.92-3.88 (m, 4H), 3.87 (s, 3H), 3.21-2.91 (m, 4H). The H NMR
spectrum of the purified product matches that reported previously[1] and is reproduced below, as is the
GC trace and mass spectrum.
N-(4-methoxyphenyl)morpholine (23g). The reaction vial was charged with 61 μL 4-chloroanisole
(21g) and 48 μL morpholine (22a), and heated at 50 °C for 30 min. The product was obtained as a
white solid (94 mg, 97%) after silica-gel chromatography using 20:1 then 10:1 hexane/EtOAc as
1
eluent. H NMR (400 MHz, CDCl3): δ T6.93-6.91 (m, 2H), 6.88-6.83 (m, 2H), 3.90-3.84 (m, 4H),
3.78 (s, 3H), 3.09-3.05 (m, 4H). The 1H NMR spectrum of the purified product matches that reported
previously[1] and is reproduced below, as is the GC trace and mass spectrum.
N-(o-tolyl)pyrrolidine (23h). The reaction vial was charged with 59 μL 2-chlorotoluene (21a) and 46
μL pyrrolidine (22b), and heated at 50 °C for 30 min. The product was obtained as a colorless oil (68
1
mg, 84%) after silica-gel chromatography using hexane then 50:1 hexane/EtOAc as eluent. H NMR
(400 MHz, CDCl3): δ 7.15-7.09 (m, 2H), 6.92-6.81 (m, 2H), 3.20 (t, J = 6.5 Hz, 4H), 2.33 (s, 3H),
1.96-1.91 (m, 4H). The 1H NMR spectrum of the purified product matches that reported previously[5]
and is reproduced below, as is the GC trace and mass spectrum.
- S3-

N-methyl-N'-(o-tolyl)piperazine (23i). The reaction vial was charged with 59 μL 2-chlorotoluene
(21a) and 61 μL N-methylpiperazine (22c), and heated at 50 °C for 30 min. The product was obtained
as a yellow oil (86 mg, 90%) after silica-gel chromatography using 25:1 then 10:1 EtOAc/MeOH as
eluent. 1H NMR (400 MHz, CDCl3): δ 7.19-7.14 (m, 2H), 7.06-6.96 (m, 2H), 2.96 (t, J = 4.8 Hz, 4H),
2.60 (br s, 4H), 2.37 (s, 3H), 2.30 (s, 3H). The 1H NMR spectrum of the purified product matches that
reported previously[6] and is reproduced below, as is the GC trace and mass spectrum.
N,N-dibutyl-2-methylaniline (23j). The reaction vial was charged with 59 μL 2-chlorotoluene (21a)
and 93 μL dibutylamine (22d), and heated at 60 °C for 90 min. The product was obtained as a
colorless oil (95 mg, 86%) after silica-gel chromatography using hexane then 50:1 hexane/EtOAc as
1
eluent. H NMR (400 MHz, CDCl3): δ 7.19-7.11 (m, 2H), 7.08 (dd, J = 8.0, 1.5 Hz, 1H), 6.99-6.94
(m, 1H), 2.92-2.87 (m, 4H), 2.29 (s, 3H), 1.43-1.35 (m, 4H), 1.32-1.21 (m, 4H), 0.86 (t, J = 7.3 Hz,
1
6H). The H NMR spectrum of the purified product matches that reported previously[7] and is
reproduced below, as is the GC trace and mass spectrum.
N-benzyl-2-methylaniline (23k). The reaction vial was charged with 59 μL 2-chlorotoluene (21a) and
60 μL benzylamine (22e), and heated at 60 °C for 60 min. The product was obtained as a white solid
1
(90 mg, 91%) after silica-gel chromatography using hexane then 50:1 hexane/EtOAc as eluent. H
NMR (400 MHz, CDCl3): δ 7.42-7.33 (m, 4H), 7.32-7.27 (m, 1H), 7.14-7.07 (m, 2H), 6.72-6.62 (m,
1
2H), 4.39 (s, 2H), 2.18 (s, 3H). The H NMR spectrum of the purified product matches that reported
previously[8] and is reproduced below, as is the GC trace and mass spectrum.
N,2-dimethyl-N-phenylaniline (23l). The reaction vial was charged with 59 μL 2-chlorotoluene (21a)
and 60 μL N-methylaniline (22f), and heated at 60 °C for 60 min. The product was obtained as a
colorless oil (89 mg, 90%) after silica-gel chromatography using hexane then 50:1 hexane/EtOAc as
eluent. 1H NMR (400 MHz, CDCl3): δ 7.31-7.14 (m, 6H), 6.74-6.68 (m, 1H), 6.56-6.52 (m, 2H), 3.23
1
(s, 3H), 2.15 (s, 3H). The H NMR spectrum of the purified product matches that reported
previously[8] and is reproduced below, as is the GC trace and mass spectrum.
2-methyl-N-(p-tolyl)aniline (23m). The reaction vial was charged with 59 μL 2-chlorotoluene (21a)
and 59 mg p-toluidine (22g), and heated at 50 °C for 4 h. Only trace product was observed by GC-
FID/MS, and was not isolated.
- S4-

2-methyl-N-phenylaniline (23n). The reaction vial was charged with 59 μL 2-chlorotoluene (21a) and
50 μL aniline (22h), and heated at 50 °C for 4 h. Only trace product was observed by GC-FID/MS,
and was not isolated.
2,4,6-trimethyl-N-(o-tolyl)aniline (23o). The reaction vial was charged with 59 μL 2-chlorotoluene
(21a) and 77 μL mesidine (22i), and heated at 50 °C for 30 min. The product was obtained as a white
solid (110 mg, 97%) after silica-gel chromatography using hexane then 100:1 hexane/EtOAc as
1
eluent. H NMR (400 MHz, CDCl3): δ 7.12 (dd, J = 7.4, 0.5 Hz, 1H), 6.99-6.93 (m, 3H), 6.71-6.66
(m, 1H), 6.13 (dd, J = 8.1, 1.2 Hz, 1H), 4.87 (br s, 1H), 2.32 (s, 3H), 2.31 (s, 3H), 2.15 (s, 6H). The 1H
NMR spectrum of the purified product matches that reported previously[9] and is reproduced below, as
is the GC trace and mass spectrum.
2,6-diisopropyl-N-(o-tolyl)aniline (23p). The reaction vial was charged with 59 μL 2-chlorotoluene
(21a) and 115 μL (90% technical grade) 2,6-diisopropylaniline (22j), and heated at 50 °C for 2 h. The
product was obtained as a colorless oil (132 mg, 98%) after silica-gel chromatography using hexane
1
then 100:1 hexane/EtOAc as eluent. H NMR (400 MHz, CDCl3): δ 7.30 (dd, J = 8.6, 6.5 Hz, 1H),
7.24-7.21 (m, 2H), 7.13 (dd, J = 7.3, 0.5 Hz, 1H), 6.98-6.93 (m, 1H), 6.70-6.65 (m, 1H), 6.12 (dd, J =
8.1, 1.0 Hz, 1H), 4.91 (s, 1H), 3.11 (sept, J = 6.9 Hz, 2H), 2.35 (s, 3H), 1.18 (d, J = 6.9 Hz, 6H), 1.12
(d, J = 6.9 Hz, 6H). The 1H NMR spectrum of the purified product matches that reported previously[10]
and is reproduced below, as is the GC trace and mass spectrum.
N-(2,6-dimethylphenyl)-2,4,6-trimethylaniline (24a). The reaction vial was charged with 66 μL 2-
chloro-1,3-dimethylbenzene (21e) and 77 μL mesidine (22i), and heated at 50 °C for 30 min. The
product was obtained as a white solid (119 mg, 99%) after silica-gel chromatography using hexane
then 100:1 hexane/EtOAc as eluent. 1H NMR (400 MHz, CDCl3): δ 6.97-6.94 (m, 2H), 6.82-6.76 (m,
1
3H), 4.70 (br s, 1H), 2.25 (s, 3H), 1.99 (s, 6H), 1.99 (s, 6H). The H NMR spectrum of the purified
product matches that reported previously[9,11] and is reproduced below, as is the GC trace and mass
spectrum.
N-(2,6-diisopropylphenyl)-2,6-dimethylaniline (24b). The reaction vial was charged with 66 μL 2-
chloro-1,3-dimethylbenzene (21e) and 115 μL (90% technical grade) 2,6-diisopropylaniline (22j), and
heated at 60 °C for 60 min. The product was obtained as a colorless oil (139 mg, 99%) after silica-gel
1
chromatography using hexane then 100:1 hexane/EtOAc as eluent. H NMR (400 MHz, CDCl3): δ
7.17-7.09 (m, 3H), 6.94 (d, J = 7.5 Hz, 2H), 6.72 (t, J = 7.4 Hz, 1H), 4.79 (s, 1H), 3.15 (sept, J = 6.9
- S5-

1
Hz, 2H), 1.98 (s, 6H), 1.12 (d, J = 6.9 Hz, 12H). The H NMR spectrum of the purified product
matches that reported previously[11] and is reproduced below, as is the GC trace and mass spectrum.
References
[1]
[2]
[3]
Y. Tsuji, K. T. Huh, Y. Ohsugi, Y. Watanabe, J. Org. Chem. 1985, 50, 1365-1370.
S. Wagaw, S. L. Buchwald, J. Org. Chem. 1996, 61, 7240-7241.
C. Meyers, B. U. W. Maes, K. T. J. Loones, G. Bal, G. L. F. Lemière, R. A. Dommisse, J.
Org. Chem. 2004, 69, 6010-6017.
[4]
J. P. Wolfe, H. Tomori, J. P. Sadighi, J. Yin, S. L. Buchwald, J. Org. Chem. 2000, 65, 1158-
1174.
[5]
[6]
[7]
G. Manolikakes, A. Gavryushin, P. Knochel, J. Org. Chem. 2008, 73, 1429-1434.
E. Brenner, R. Schneider, Y. Fort, Tetrahedron 1999, 55, 12829-12842.
J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy, L. M. Alcazar-Roman, J. Org.
Chem. 1999, 64, 5575-5580.
[8]
[9]
N. Kataoka, Q. Shelby, J. P. Stambuli, J. F. Hartwig, J. Org. Chem. 2002, 67, 5553-5566.
L. L. Hill, L. R. Moore, R. Huang, R. Craciun, A. J. Vincent, D. A. Dixon, J. Chou, C. J.
Woltermann, K. H. Shaughnessy, J. Org. Chem. 2006, 71, 5117-5125.
[10]
[11]
J. P. Sadighi, M. C. Harris, S. L. Buchwald, Tetrahedron Lett. 1998, 39, 5327-5330.
L. Ackermann, J. H. Spatz, C. J. Gschrei, R. Born, A. Althammer, Angew. Chem. Int. Ed.
2006, 45, 7627-7630.
- S6-

NMR spectra of new compounds
1H NMR spectrum (400 MHz) of 3 in CDCl3:
- S7-

1H NMR spectrum (400 MHz) of 1b in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 1b in CDCl3:
- S8-

1H NMR spectrum (400 MHz) of 5a in DMSO-d6:
13C{1H} NMR spectrum (100 MHz) of 5a in DMSO-d6:
- S9-

1H NMR spectrum (400 MHz) of 5b in CD3OD:
13C{1H} NMR spectrum (100 MHz) of 5b in CD3OD:
- S10-

1H NMR spectrum (400 MHz) of 6a in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 6a in CDCl3:
- S11-

1H NMR spectrum (400 MHz) of 6b in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 6b in CDCl3:
- S12-

1H NMR spectrum (400 MHz) of 7a in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 7a in CDCl3:
- S13-

1H NMR spectrum (400 MHz) of 7b in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 7b in CDCl3:
- S14-

1H NMR spectrum (400 MHz) of 8a in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 8a in CDCl3:
- S15-

1H NMR spectrum (400 MHz) of 8b in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 8b in CDCl3:
- S16-

1H NMR spectrum (400 MHz) of 9a in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 9a in CDCl3:
- S17-

1H NMR spectrum (400 MHz) of 9b in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 9b in CDCl3:
- S18-

1H NMR spectrum (400 MHz) of 10 in DMSO-d6:
13C{1H} NMR spectrum (100 MHz) of 10 in DMSO-d6:
- S19-

1H NMR spectrum (400 MHz) of 12 in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 12 in CDCl3:
- S20-

1H NMR spectrum (400 MHz) of 13 in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 13 in CDCl3:
- S21-

1H NMR spectrum (400 MHz) of 15 in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 15 in CDCl3:
- S22-

1H NMR spectrum (400 MHz) of 16 in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 16 in CDCl3:
- S23-

1H NMR spectrum (400 MHz) of 17 in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 17 in CDCl3:
- S24-

1H NMR spectrum (400 MHz) of 19 in CDCl3:
13C{1H} NMR spectrum (100 MHz) of 19 in CDCl3:
- S25-

NMR spectra of Buchwald-Hartwig reaction products
1H NMR spectrum (400 MHz) of 23a in CDCl3:
1H NMR spectrum (400 MHz) of 23b in CDCl3:
1H NMR spectrum (400 MHz) of 23c in CDCl3:
- S26-

1H NMR spectrum (400 MHz) of 23d in CDCl3:
1H NMR spectrum (400 MHz) of 23e in CDCl3:
1H NMR spectrum (400 MHz) of 23f in CDCl3:
- S27-

1H NMR spectrum (400 MHz) of 23g in CDCl3:
1H NMR spectrum (400 MHz) of 23h in CDCl3:
1H NMR spectrum (400 MHz) of 23i in CDCl3:
- S28-

1H NMR spectrum (400 MHz) of 23j in CDCl3:
1H NMR spectrum (400 MHz) of 23k in CDCl3:
1H NMR spectrum (400 MHz) of 23l in CDCl3:
- S29-