Arylation of Amines in Alkane Solvents by using Well-Defined Palladium-N-Heterocyclic Carbene Complexes

Article abstract of DOI:10.1002/cctc.201500841

The use of the ITent-based series of Pd-N-heterocyclic carbenes precatalysts (Tent= Tentacular) enables the Buchwald-Hartwig amine arylation reaction in apolar alkane solvents. The use of such solvents is rare because of their poor solvation properties. Nonetheless, they could be of interest for industrial applications, as they can be disposed of in an energetically favorable manner and may potentially simplify product isolation. The excellent solubility of the precatalysts permitted the desired products to be obtained in yields ranging from 75 to 96 %, even with deactivated and functionalized coupling partners. Fueling cross-couplings: The use of ITent-based Pd precatalysts (Tent=tentacular) enables the Buchwald-Hartwig amine arylation reaction in alkane solvents. Such solvents could be of interest for industrial applications, as they can be disposed of in an energetically favorable manner and may potentially simplify product isolation. Yields ranging from 75 to 96 % are obtained, even with challenging substrates.

Full text of DOI:10.1002/cctc.201500841

DOI: 10.1002/cctc.201500841
Communications
Arylation of Amines in Alkane Solvents by using Well-
Defined Palladium–N-Heterocyclic Carbene Complexes
[b]
[b]
[b]
[a]
Enrico Marelli, Anthony Chartoire, Gaetan Le Duc, and Steven P. Nolan*
[
4]
The use of the ITent-based series of Pd-N-heterocyclic carbenes
precatalysts (Tent= Tentacular) enables the Buchwald–Hartwig
amine arylation reaction in apolar alkane solvents. The use of
such solvents is rare because of their poor solvation properties.
Nonetheless, they could be of interest for industrial applica-
tions, as they can be disposed of in an energetically favorable
manner and may potentially simplify product isolation. The ex-
cellent solubility of the precatalysts permitted the desired
products to be obtained in yields ranging from 75 to 96%,
even with deactivated and functionalized coupling partners.
tions, such as Pd-catalyzed amine arylation [or the Buchwald–
Hartwig (BH) amination reaction] in such a medium would
result in an overall more atom- and energy-economical pro-
cess. BH amination is a simple and selective synthetic tool for
[
5]
the preparation of (poly)arylamine motifs, which are widely
[
6]
found in drugs, agrochemicals, and materials. Although other
[
7]
catalytic systems exist for CÀN bond formation, monoligated
Pd species mostly based on electron-rich phosphines or
[
8]
[
9]
NHCs (N-heterocyclic carbenes) still remain state-of-the-art in
assembling this construct.
During our study of a class of large yet flexible NHC ligands
we commonly call the ITent series (Tent=tentacular, see
[
10]
The development of industrially suitable processes is often
hampered by issues rarely addressed in academia past the dis-
covery stage of chemical research. Important details, such as
waste production and energy efficiency, cannot be overlooked
in any large-scale process in this age of ever “greener” and en-
vironmentally and societally responsible approaches to synthe-
Figure 1), we observed that the long side chains of these li-
[1]
sis. Many guidelines have been published, by industrial re-
searchers and process chemists, suggesting to academics pre-
ferred solvents (and those to avoid) from early-stage chemical
[
2]
discovery. For example, Fischer and co-workers developed
a tool to assess the suitability of a solvent system on large
[
3]
scale by evaluating both its EHS (environmental, health and
safety) and its LCA (life cycle analysis, which assesses the
impact of the solvent from production to disposal) values. Still
today, the amount of solvent that is recycled rather than incin-
erated revolves around the 30% mark. Of the remaining 70%,
the large majority (e.g., chlorinated solvents, water-containing
mixtures, or, in general, solvents with low net calorific value)
[1e]
have to be disposed of in special plants. The Fischer frame-
work has identified alkane solvents, such as heptane and cyclo-
hexane, among the most favorable for industrial application,
because their high calorific power makes their disposal by in-
cineration (directly at the industrial site) favorable for the ener-
getic balance of the plant. The achievement of chemical trans-
formations in alkane solvents would, therefore, be highly desir-
able. In particular, the development of cross-coupling reac-
Figure 1. The Pd(ITent) family of precatalysts. IPent=N,N’-bis[2,6-di(3-pentyl)-
phenyl]imidazol-2-ylidene; IHept=N,N’’-bis[2,6-di(4-heptyl)phenyl]imidazol-
2-ylidene; INon=N,N’-bis[2,6-di(5-nonyl)phenyl]imidazol-2-ylidene.
gands made them remarkably soluble in numerous solvents,
including very apolar examples. This observation, together
with their outstanding performance in a range of cross-cou-
[
a] Prof. Dr. S. P. Nolan
Chemistry Department
College of Science
[
10a,11]
plings,
made us envision the possible use of these in
King Saud University
Riyadh 11451 (Saudi Arabia)
E-mail: stevenpnolan@gmail.com
alkane solvents. Herein, we report the BH amination reaction
under such conditions. Notably, examples of cross-couplings
performed under these conditions are rare and rely on the use
[
b] E. Marelli, Dr. A. Chartoire, Dr. G. Le Duc
EaStChem School of Chemistry
[12]
of specifically designed/functionalized ligands.
University of St Andrews
Our initial efforts focused on the selection of the most ap-
propriate precatalyst for this transformation (see Table 1). Com-
plexes 1–6 were tested in a relatively challenging model reac-
North Haugh, St Andrews, Fife, KY16 9ST (UK)
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201500841.
ChemCatChem 2015, 7, 4021 – 4024
4021
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
[
9e]
what was observed with IPr*-based ligands
bis(2,6-dibenzhydryl-4-methylphenyl)-2-methylene-2,3-dihydro-
H-imidazol-2-ylidene]).This may suggests that the ligand, over
(IPr*=[1,3-
[
a]
Table 1. Optimization of the reaction conditions.
1
the solvent, dictates the selection of the base. The use of inor-
ganic bases, as well as modifying the substitution of the potas-
sium counterion upon using tert-butoxide bases, substantially
lowered the efficiency of the protocol (Table 1, entries 13, 15,
and 16).
[
b]
Entry
Cat.
Pd
Solvent
Base
T
[8C]
Conv.
[%]
[mol%]
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
2
4
6
6
6
6
6
6
6
6
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.05
0.05
0.05
0.05
0.05
0.05
0.05
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
hexane
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
KOt-amyl
KOH
50
50
50
50
50
50
80
80
80
80
80
80
80
80
80
80
2
16
8
29
0
Once the optimized conditions were found, the scope and
limitations of the new protocol were explored. The catalyst
loading was varied if required to reach full conversion of the
starting material (see Scheme 1).
9
The use of unactivated methoxy chloroarenes as well as ster-
ically hindered coupling partners proved suitable (see products
46
50
70
95
21
>99
8
18
8
0
9
a–d). N-Methylaniline was also successfully coupled with un-
activated and heterocyclic chloroarenes (see products 9e and
f). Unactivated, electron-poor aniline derivatives were easily
1
0
1
1
9
1
1
1
1
1
2
3
4
5
6
heptane
heptane
heptane
heptane
coupled (see products 9g–i). Upon moving to alkylamines, we
found that cyclic dialkylamines such as morpholine could be
coupled smoothly with a range of aryl chlorides, including ster-
ically and electronically unactivated ones (see products 9j and
9k); the use of 4-chlorobenzophenone, which is relatively sen-
sitive to basic conditions, was also possible (see product 9o).
heptane
K
2
CO
3
[
[
a] Conditions: 7 (0.55 mmol), 8 (0.5 mmol), base (0.55 mmol), 0.5 m, 20 h.
b] Measured by GC analysis.
tion involving 2,6-dimethylaniline (7) and 4-chloroanisole (8) in
cyclohexane.
To obtain an industrially useful protocol, the comparison
was performed at very low catalyst loading (0.025% mol) in cy-
clohexane at 508C. Cinnamyl (cin)-based precatalysts behaved
generally better than the acetylacetonate (acac) congeners,
probably because of their easier activation under these condi-
tions. Upon raising the temperature to 808C, we observed that
complex 6, [Pd(INon)(cin)Cl] {see Figure 1}, gave 70% GC con-
version after 20 h (Table 1, entry 9). It is interesting to note that
on using more conventional solvents, the IHept ligand gave
better results both in the Buchwald–Hartwig reaction as well
[10a,11]
as in ketone arylation.
It is not straightforward to unam-
biguously address the reasons for this solvent effect on the
performance of slightly different ligands: the higher solubility
of INon-based complexes, owing to their exceedingly long lip-
ophilic side chains, might at least partly explain this behavior.
Differences in (flexible) steric bulk might also be invoked, but
that would not explain the better performance of IHept over
INon under other conditions. A combination of effects might
very well explain the observed performance. The fact that
complex 4 bearing the IHept ligand performed better than 6
at lower temperature might also indicate slower activation of
the bulkier INon congener under the reaction conditions. The
solvent/base system was then optimized with 0.05% mol 6 as
the catalyst: heptane proved slightly superior to cyclohexane
(
Table 1, entries 10 and 12), whereas low conversion was ob-
served in hexane (Table 1, entry 11). Surprisingly, the highly
soluble potassium tert-amylate base performed more poorly
than its tert-butoxide congener (Table 1, entry 14). The lower
efficiency of tert-amylate bases was already observed in previ-
Scheme 1. Scope of the amination in alkane solvents. Conditions: 7
(0.55 mmol, 1.1 equiv.), 8 (0.50 mmol), KOtBu (0.55 mmol, 1.1 equiv.), 0.5m in
heptane, 808C, 20 h. Yields are averaged over two runs. [a] Reaction was
performed in air. [b] Reaction was performed on a 10 mmol scale.
[10a,11]
ous reports dealing with the ITent series,
in contrast with
ChemCatChem 2015, 7, 4021 – 4024
www.chemcatchem.org
4022
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
Acyclic monoalkylamines were also suitable (see products 9l
and 9m), whereas acyclic dialkylamines, such as dibutylamine,
proved more difficult and required a higher catalyst loading to
achieve only moderate yields (see product 9n). A piperazine
derivative was also successfully coupled (see product 9p). To
showcase the robustness of the method, the synthesis of 9e
was also performed without involvement of any dry box or
Schlenk techniques, and still a good yield was obtained. The
scalability of the reaction was also proven by the synthesis of
nitrogen-rich 9p on a 10 mmol scale; the product was ob-
tained in 81% yield after simple workup and purification.
In summary, we developed a protocol for the Buchwald–
Hartwig amination reaction in alkane solvents. The solvent of
choice, heptane, is relatively nontoxic and inexpensive, and the
protocol is robust enough to couple unactivated, functional-
ized, and heterocyclic substrates by using a catalyst loading of
General procedure for the arylation of amines in heptane
Inside a glove box, a vial containing a stirring bar was charged
with KOtBu (62 mg, 0.55 mmol, 1.1 equiv.) and then sealed with
a screw cap fitted with a septum. The aryl chloride (0.50 mmol,
1.0 equiv.) was added at this point if solid, and dissolved in hep-
tane. A stock solution of [Pd(INon)(acac)Cl] (6) in heptane was pre-
pared and taken up by syringe. Outside of the glove box, the
amine and/or the aryl chloride were added if liquids, and the de-
sired amount of stock solution was added last (final volume 1 mL).
Finally, the contents of the vial was stirred overnight at 808C. The
solution was then cooled to room temperature, water (a few
drops) and ethyl acetate (0.5 mL) were added, and the crude mate-
rial was filtered through silica, washing with ethyl acetate (2 mL).
Column chromatography of the crude material (typically hexane/
ethyl acetate=99:1 or hexane/CH
Cl =8:2) gave the desired
2
2
product.
0
.25 mol% or lower. These results highlight that the challenge
Synthesis of 9e in air
of cross-coupling reactions in alkane solvents can be success-
fully addressed and achieved by using homogeneous catalysts
rather than polymer-supported ligands. Our future aims are di-
rected at further developing this area of catalysis in designing
new ligands and examining the activity of these and related
precatalysts.
A screw-cap vial equipped with a stirring bar was charged with
KOtBu (62 mg, 0.55 mmol) and then sealed with a septum cap. Dry,
degassed heptane (0.9 mL) was added through the septum. N-
Methylaniline (59 mg, 60 mL, 0.55 mmol), 4-chloroanisole (71 mg,
6
0 mL, 0.5 mmol), and a stock solution of 6 in heptane (stock solu-
tion: 4.8 mg 6 in 2 mL heptane, 0.1 mL added to the mixture,
.05 mol% catalyst loading) were added. The mixture was stirred
0
at 808C for 20 h, and then the reactor was allowed to cool down.
The reaction was quenched with water (3 drops). The organic
phase was filtered through magnesium sulfate and was washed
with ethyl acetate (2 mL). After evaporation of the volatile com-
pounds, the product was purified by column chromatography
Experimental Section
Synthesis
General procedure for the preparation of [Pd(ITent)(acac)Cl]
precatalysts 1, 3, and 5
(
hexane/CH Cl =8/2) to afford a brown oil.
2 2
A Schlenk flask equipped with a magnetic stirring bar was charged
with ITent·HCl (1.2 equiv.), Pd(acac)2 (152 mg, 0.5 mmol, 1 equiv.)
and dry 1,4-dioxane (5 mL) under an atmosphere of nitrogen. The
mixture was heated at reflux for 24 h. After this time, 1,4-dioxane
was evaporated, and the crude material was dissolved in pentane
Synthesis of 9p in air
A screw-cap vial equipped with a stirring bar was charged with
KOtBu (1.24 g, 11 mmol) and then sealed with a septum cap. Dry,
degassed heptane (9 mL) was added through the septum. 1-Meth-
ylpiperazine (1.10 g, 1.22 mL, 11 mmol), 3-chloropyridine (1.13 g,
(
5 mL). The solution was filtered through a pad of silica covered
with Celite and eluted with pentane (15 mL). After evaporation of
the solvent and drying under high vacuum, the pure desired com-
plex was obtained as a yellow powder.
0
.95 mL, 10 mmol), and a stock solution of 6 in heptane (stock so-
lution: 11.8 mg 6 in 1.2 mL heptane, 1 mL added to the mixture,
.1 mol% catalyst loading) were then added. The mixture was
0
stirred at 808C for 20 h at 600 rpm, and then the reactor was al-
lowed to cool down. The solution was transferred to a separatory
funnel to which was added water (5 mL). The aqueous phase was
extracted with ethyl acetate (4”5 mL). The combined aqueous
General procedure for the preparation of [Pd(ITent)-
(cinnamyl)Cl] precatalysts 2, 4, and 6
phase was washed with brine and then dried (MgSO ). Evaporation
of the solvents under vacuum gave the NMR spectroscopy pure
product (1.44 g, 81%) as an orange oil.
In a glove box, a round-bottomed flask equipped with a magnetic
stirring bar was charged with the NHC·HCl salt (2.2 equiv.) and
KOtBu (135 mg, 2.4 equiv.) in THF (5 ml). The mixture was stirred at
4
room temperature for 3 h and then [Pd(cinnamyl)(m-Cl)] (259 mg,
2
0
.5 mmol, 1 equiv.) was added. The mixture was then stirred over-
Acknowledgements
night at room temperature. After this time, outside the glove box,
THF was evaporated. The crude product was solubilized in CH Cl2
2
We thank the European Research Council (ERC) (Advanced Re-
searcher award-FUNCAT), the Engineering and Physical Sciences
Research Council (EPSRC) (grant no EP/J011053/1), and King Saud
University for funding.
(
(
3 mL), filtered through a pad of Celite, and eluted with CH Cl2
6 mL). After evaporation of the solvents, the complex was dis-
2
solved in pentane (10 mL) and passed through a fritted pad. Pen-
tane was finally evaporated, and after drying under high vacuum,
the pure complex was obtained.
Keywords: alkanes · amination · carbene ligands · cross-
coupling · palladium
ChemCatChem 2015, 7, 4021 – 4024
www.chemcatchem.org
4023
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communications
[
1] a) V. Kumar, K. D. P. Nigam, Green Process. Synth. 2012, 1, 79–107;
b) F. G. Calvo-Flores, ChemSusChem 2009, 2, 905–919; c) R. Dach, J. J.
Song, F. Roschangar, W. Samstag, C. H. Senanayake, Org. Process Res.
Dev. 2012, 16, 1697–1706; d) M. C. Bryan, B. Dillon, L. G. Hamann, G. J.
Hughes, M. E. Kopach, E. A. Peterson, M. Pourashraf, I. Raheem, P. Ri-
chardson, D. Richter, H. F. Sneddon, J. Med. Chem. 2013, 56, 6007–6021;
e) C. Seyler, C. Capello, S. Hellweg, C. Bruder, D. Bayne, A. Huwiler, K.
Hungerbühler, Ind. Eng. Chem. Res. 2006, 45, 7700–7709; f) D. Ott, D.
Kralisch, I. Den cˇ i c´ , V. Hessel, Y. Laribi, P. D. Perrichon, C. Berguerand, L.
Kiwi-Minsker, P. Loeb, ChemSusChem 2014, 7, 3521–3533.
[8] a) D. S. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338–
6361; Angew. Chem. 2008, 120, 6438–6461; b) N. C. Bruno, T. Tudge,
S. L. Buchwald, Chem. Sci. 2013, 4, 916–920; c) A. T. Brusoe, J. F. Hart-
wig, J. Am. Chem. Soc. 2015, 137, 8460–8468; d) S. M. Crawford, C. B.
Lavery, M. Stradiotto, Chem. Eur. J. 2013, 19, 16760–16771; e) A. J.
DeAngelis, P. G. Gildner, R. Chow, T. J. Colacot, J. Org. Chem. 2015, 80,
6794–6813; f) C. C. C. Johansson Seechurn, S. L. Parisel, T. J. Colacot, J.
Org. Chem. 2011, 76, 7918–7932.
[9] a) G. C. Fortman, S. P. Nolan, Chem. Soc. Rev. 2011, 40, 5151–5169; b) C.
Valente, S. Calimsiz, K. H. Hoi, D. Mallik, M. Sayah, M. G. Organ, Angew.
Chem. Int. Ed. 2012, 51, 3314–3332; Angew. Chem. 2012, 124, 3370–
3388; c) N. Marion, E. C. Ecarnot, O. Navarro, D. Amoroso, A. Bell, S. P.
Nolan, J. Org. Chem. 2006, 71, 3816–3821; d) N. Marion, O. Navarro, J.
Mei, E. D. Stevens, N. M. Scott, S. P. Nolan, J. Am. Chem. Soc. 2006, 128,
4101–4111; e) A. Chartoire, X. Frogneux, S. P. Nolan, Adv. Synth. Catal.
2012, 354, 1897–1901; f) W. Fang, J. Jiang, Y. Xu, J. Zhou, T. Tu, Tetrahe-
dron 2013, 69, 673–679; g) K. H. Hoi, J. A. Coggan, M. G. Organ, Chem.
Eur. J. 2013, 19, 843–845.
[
2] a) K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A. Johnson,
H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry, M. Stefaniak, Green Chem.
2008, 10, 31–36; b) R. K. Henderson, C. Jimenez-Gonzalez, D. J. C. Con-
stable, S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks, A. D.
Curzons, Green Chem. 2011, 13, 854–862; c) D. Prat, O. Pardigon, H.-W.
Flemming, S. Letestu, V. Ducandas, P. Isnard, E. Guntrum, T. Senac, S.
Ruisseau, P. Cruciani, P. Hosek, Org. Process Res. Dev. 2013, 17, 1517–
1
525; d) L. Moity, M. Durand, A. Benazzouz, C. Pierlot, V. Molinier, J.-M.
Aubry, Green Chem. 2012, 14, 1132–1145.
[10] a) S. Meiries, G. Le Duc, A. Chartoire, A. Collado, K. Speck, K. S. A. Arach-
chige, A. M. Z. Slawin, S. P. Nolan, Chem. Eur. J. 2013, 19, 17358–17368;
b) S. R. Patrick, A. Collado, S. Meiries, A. M. Z. Slawin, S. P. Nolan, J. Orga-
nomet. Chem. 2015, 775, 152–154.
[11] E. Marelli, M. Corpet, S. R. Davies, S. P. Nolan, Chem. Eur. J. 2014, 20,
17272–17276.
[
[
3] C. Capello, U. Fischer, K. Hungerbuhler, Green Chem. 2007, 9, 927–934.
4] a) J.-P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651–2710; b) C. C. C.
Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus, Angew.
Chem. Int. Ed. 2012, 51, 5062–5085; Angew. Chem. 2012, 124, 5150–
5
174; c) J. G. De Vries, Top. Organomet. Chem. 2012, 42, 1–34.
[
5] a) J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118,
[12] a) D. E. Bergbreiter, Y.-C. Yang, C. E. Hobbs, J. Org. Chem. 2011, 76,
6912–6917; b) D. E. Bergbreiter, H.-L. Su, H. Koizumi, J. Tian, J. Organo-
met. Chem. 2011, 696, 1272–1279.
7
7
215–7216; b) M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1996, 118,
217–7218; c) M. Kienle, S. Reddy Dubbaka, K. Brade, P. Knochel, Eur. J.
Org. Chem. 2007, 4166–4176.
[
[
6] a) M. Liang, J. Chen, Chem. Soc. Rev. 2013, 42, 3453–3488; b) S. L. Buch-
wald, C. Mauger, G. Mignani, U. Scholz, Adv. Synth. Catal. 2006, 348, 23–
3
9; c) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534–1544.
7] a) G. Evano, C. Theunissen, A. Pradal, Nat. Prod. Rep. 2013, 30, 1467–
489; b) A. R. Martin, D. J. Nelson, S. Meiries, A. M. Z. Slawin, S. P. Nolan,
Eur. J. Org. Chem. 2014, 3127–3131.
Received: July 28, 2015
1
Revised: August 26, 2015
Published online on October 20, 2015
ChemCatChem 2015, 7, 4021 – 4024
www.chemcatchem.org
4024
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim