Simple N-Heterocyclic Carbenes as Ligands in Ullmann-Type Ether and Thioether Formations

Article abstract of DOI:10.1002/adsc.201600316

A simple N-heterocyclic carbene (NHC) derived from 1-methyl-3-ethylimidazolium tetrafluoroborate was found to be an efficient ligand for a range of copper-catalyzed cross-coupling reactions, leading to the formation of aromatic ethers and thioethers. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600316

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DOI: 10.1002/adsc.201600316
Simple N-Heterocyclic Carbenes as Ligands in Ullmann-Type
Ether and Thioether Formations
Jiang-Ping Wu,a,* Anjan K. Saha,a Nizar Haddad,a Carl A. Busacca,a
Jon C. Lorenz,a Heewon Lee,a and Chris H. Senanayakea
a
Chemical Development, Boehringer-Ingelheim Pharmaceuticals, P.O. Box 368, Ridgefield, CT 06877, USA
E-mail: jiang-ping.wu@boehringer-Ingelheim.com
Received: March 22, 2016; Revised: April 3, 2016; Published online: May 3, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600316.
Abstract: A simple N-heterocyclic carbene (NHC)
derived from 1-methyl-3-ethylimidazolium tetra-
fluoroborate was found to be an efficient ligand for
a range of copper-catalyzed cross-coupling reac-
tions, leading to the formation of aromatic ethers
and thioethers.
zolium or dihydroimidazolium salts are effective li-
gands for Ullmann-type reactions.[10,11]
Our interest in NHCs started during a search for
a method for the conversion of compound 1 to com-
pound 2 (Scheme 1), a synthetic intermediate of one
of our companyꢀs drug candidates for treatment of
cardiovascular deceases.[12] We were particularly inter-
ested in copper-catalyzed cross-coupling reactions due
Keywords: copper ligands; copper-catalyzed cross-
coupling reactions; formation of aromatic ethers;
formation of aromatic thioethers; N-heterocyclic
carbenes; Ullmann reactions
Transition metal-catalyzed cross-coupling reactions
are among the most convenient methods for the for-
mation of aryl C X bonds, where X can be C, O, S
Scheme 1. Targeted cross-coupling reaction.
À
and N, among others. These methodologies have
found wide applications in organic synthesis.[1,2] The
majority of these synthetic applications utilize palladi-
um-based catalysts, for which large selections of li-
gands are available to assist various transformations.[1]
On the contrary, copper-catalyzed cross-coupling re-
actions[2] are considerably less utilized, in spite of the
long history[3] and economic advantages[4] associated
with copper catalysts. For pharmaceutical synthesis,
the use of copper catalysts offers additional advantag-
es in that the regulatory limits for residual metals in
drug substances are considerably higher for copper
than for palladium or other heavy metals.[5] To a large
extent, the under-utilization of copper catalysts in
cross-coupling reactions can be attributed to the limit-
ed variety of available ligands. Interests in developing
more efficient and structurally diversified ligands for
copper-catalyzed ether formation reactions, often re-
ferred to as Ullmann-type reactions, have persisted in
recent years.[2] In this communication, we report our
discovery that simple N-heterocyclic carbenes
(NHCs) derived in situ from readily available imida- Figure 1. N-Heterocyclic carbene precursors.
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to the economic as well as regulatory advantages as- sary to run the reaction under dilute conditions to
sociated with using copper catalysts.[4,5] Screening of avoid racemization at the C-2 chiral center.[7] Unable
known Ullmann-type conditions revealed copper to find a replacement for 1,10-phenanthroline from
iodide (CuI)/1,10-phenanthroline[6] as a useful cata- literature precedence, we initiated a search for new li-
lyst. However, this procedure proved difficult to gands for this copper-catalyzed transformation. N-het-
scale-up partly because the residual copper-phenan- erocyclic carbenes, known as ligands for copper-cata-
throline complexes, insoluble in both organic and lyzed 1,4-additions,[8] as well as for promoting palladi-
aqueous phases, prevented clean phase separation um- or nickel-catalyzed cross-coupling reactions,[9] ap-
during aqueous work-up. More seriously, it was neces- peared likely candidates. The recent reports that pre-
formed
NHC-Cu-CF3
complexes
transferred
trifluoromethyl groups to aromatic iodides, and that
preformed trinuclear copper(I)-carbene complexes
catalyzed certain Ullman-type reactions, strengthened
this reasoning.[10,11]
Table 1. Screening of NHC ligands in copper-catalyzed cycli-
zation of compound 1.[a,b,c,d]
Entry
Ligand
Conversion [%]
Several commercially available imidazolium and di-
hydroimidazolium salts (Figure 1) were tested as the
NHC precursors. Following a modified Ullmann pro-
tocol,[6] compound 1 was refluxed in toluene in the
presence of 2.2 equivalents of Cs2CO3, 0.10 equivalent
1
2
3
4
5
6
7
none
L1
L2
L3
L4
L5
L6
0
99
80
92
42
62
57
Table 3. Intramolecular ether formations catalyzed by CuI-
L1.[a]
[a]
Reaction condition: CuI (0.1 equiv.), ligand (0.12 equiv.),
Cs2CO3 (2.2 equiv.), toluene/NMP (30:1), 1108C, 16 h.
Conversion rates were determined by HPLC analysis.
Reactions carried out on 50–100 mg scales in sealed
tubes under a nitrogen atmosphere.
[b]
[c]
[d]
Degree of racemization was not monitored during the in-
itial screenings.
Table 2. Effects of solvent, base and copper source for con-
verting compound 1 to 2 using L1 as the ligand.[a,b]
En- Solvent
try
Base
Copper
Salt
Conv.
[%]
1
2
3
4
toluene/NMP Cs2CO3
toluene/NMP t-BuOK
toluene/NMP K2CO3
toluene/NMP Hünigꢀs
base
CuI
CuI
CuI
CuI
99
0
0
37
5
6
toluene/NMP K3PO4
toluene/NMP Cs2CO3
CuI
40
98
CuCO3,
Cu(OH)2
CuBr·SMe2
CuCl
Cu(OAc)2
CuOTf
Cu(ACN)4 PF6
CuI
7
8
9
toluene/NMP Cs2CO3
toluene/NMP Cs2CO3
toluene/NMP Cs2CO3
92
84
34
91
86
0
50
94
90
10 toluene/NMP Cs2CO3
11 toluene/NMP Cs2CO3
12 NMP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
13 1,4-dioxane
14 acetonitrile
15 n-propioni-
trile
CuI
CuI
CuI
16[c] n-butyroni-
trile
Cs2CO3
CuI
90
[a]
Reaction condition: CuI (0.1 equiv.), L1 (0.12 equiv.),
[a]
Reaction condition: CuI (0.1 equiv.), L1 (0.12 equiv.),
base (2.2 equiv.), solvent, 1108C, 16 h in sealed tubes.
Volume ratio of toluene/NMP was 30:1.
Cs2CO3 (2.2 equiv.), n-propionitrile, 988C.
Unless otherwise noted, yields are of isolated products
and are not optimized.
Conversion rate.
[b]
[b]
[c]
[c]
Substrate for this reaction was 7a.
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of CuI, and 0.12 equivalent of an imidazolium or di- chiral purity was improved to >99% ee upon crystalli-
hydroimidazolium salt. A small amount of N-methyl- zation (see the Experimental Section).
2-pyrrolidone (NMP) was added to improve the solu-
Following these initial results, general reaction pa-
bility of the imidazolium/dihydroimidazolium salts. rameters were investigated. Cesium carbonate proved
After 16 h, conversions of 42% to 99% were observed to be the most effective base, as all other bases
(Table 1). A control experiment where no NHC tested, including potassium phosphate tribasic,
ligand was included did not produce any desired Hünigꢀs base, t-BuOK and K2CO3, were either inac-
product 2 (Table 1, entry 1). Of the ligand precursors tive (Table 2, entries 2 and 3) or considerably less ef-
tested, 1,3-dialkyl derivatives were active in general fective (Table 2, entries 4 and 5). The source of
(Table 1, entries 2–4), while the results for the diaryl copper seemed not critical, as a range of copper salts,
analogs varied (Table 1, entries 5–7).
including CuCl, CuBr·SMe2, CuOTf, Cu(CH3CN)4PF6
The inexpensive 1-methyl-3-ethylimidazolium salt and CuCO3·Cu(OH)2, were found to be equally active
(L1) was selected for further experiment. On a 20 g (Table 2, entries 6–8, 10 and 11). An exception was
scale under the aforementioned conditions, compound Cu(OAc)2 which was considerably less active
1 was converted to compound 2 cleanly after 16 h at (Table 2, entry 9). Solvent effects were prominent. No
1108C. The chiral purity of the crude product 2 was reaction was detected in NMP. Partial conversion was
determined by HPLC to be 95% ee, slightly lower observed in 1,4-dioxane. The reactions in nitrile sol-
than that of the starting material 1 (98% ee). The vents, including acetonitrile, n-propionitrile and n-bu-
tyronitrile, all worked well (Table 2, entries 12–16).
The scope of the NHC/Cu-catalyzed cross-coupling
reaction was explored. Intramolecular ether forma-
tion worked well (Table 3, entries 1, 2, and 4–6)
Table 4. Intermolecular couplings with phenol nucleo-
philes.[a,c]
except when the hydroxy group was hindered
(Table 3, entry 3).
Intermolecular ether formations involving phenol
nucleophiles were fast and clean, reaching complete
conversions in a few hours (Table 4). Even aromatic
bromides and chlorides were suitable substrates
(Table 4, entries 4 and 5). It should be noted that sev-
eral aliphatic alcohols also worked as the nucleo-
philes, though at lower reaction rates (Table 5).
Table 5. Intermolecular couplings with aliphatic nucleo-
philes.[a,c]
[a]
[a]
Reaction condition A: CuI (0.1 equiv.), L1 (0.12 equiv.),
Cs2CO3 (2.2 equiv.), n-propionitrile, 988C. Reaction con-
dition B: CuI (0.1 equiv.), L1 (0.12 equiv.), Cs2CO3
(2.2 equiv.), n-butyronitrile, 1158C.
Yields are for isolated products and are not optimized.
1.2–1.5 equivalents of phenols were used.
Reaction condition A: CuI (0.1 equiv.), L1 (0.12 equiv.),
Cs2CO3 (2.2 equiv.), n-propionitrile, 988C. Reaction con-
dition B: CuI (0.1 equiv.), L1 (0.12 equiv.), Cs2CO3
(2.2 equiv.), n-butyronitrile, 1158C.
Yields are for isolated products and are not optimized.
10 equivalents of alcohols were used.
[b]
[c]
[b]
[c]
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Table 6. Intermolecular couplings with thiophenols/thiols.[a,c]
toxic alternatives to heavy metal-based catalysts for
Ullmann-type cross-coupling reactions.
Experimental Section
Typical Experiment for Conversion of Compound
1 to 2 using L1-Cu Catalyst
A mixture of compound 1 (20.0 g, 54.8 mmol), CuI (1.04 g,
5.48 mmol, 0.10 equiv.), L1 (1.30 g, 6.57 mmol, 0.12 equiv.)
and Cs2CO3 (39.3 g, 120.5 mmol, 2.2 equiv.) in toluene
(300 mL) and NMP (10 mL) was refluxed for about 16 h.
After cooling to room temperature, the reaction mixture
was filtered, washed with water and concentrated. The
crude product was suspended in 2-propanol (40 mL), heated
to ~708C until a solution is obtained, and then cooled to
58C. The resulting solid slurry was filtered to give com-
pound 2 as an off-white crystalline solid; yield: 9.4 g (72%,
>99% ee).
Acknowledgements
We thank the Boehringer-Ingelheim-Pfizer-Glaxo-Smith-
Kline-Abbvie Non-Precious Metal Catalysis Consortium for
general discussions in this area.
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