A soluble copper(I) source and stable salts of volatile ligands for copper-catalyzed C-X couplings

Article abstract of DOI:10.1021/jo300905w

A stable adduct of CuI with Bu₄NI, soluble in organic solvents, has been identified as an effective catalyst for copper-catalyzed C-N and C-O couplings. In addition, stable nonhygroscopic salts of some high performance ligands (diamine MsOH salts/CuX and copper(II) diketonates) were shown to be of similar and sometimes greater reactivity compared to the literature reagents for these couplings. Furthermore, these more robust conditions result in more reproducible results.

Full text of DOI:10.1021/jo300905w

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Note
A Soluble Copper(I) Source and Stable Salts of
Volatile Ligands for Copper-Catalyzed C-X Couplings
Peter Emmanuel Maligres, Shane W. Krska, and Peter G. Dormer
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo300905w • Publication Date (Web): 13 Aug 2012
Downloaded from http://pubs.acs.org on August 19, 2012
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A Soluble Copper(I) Source and Stable Salts of Volatile Ligands for
Copper-Catalyzed C-X Couplings
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Peter E. Maligres,* Shane W. Krska and Peter G. Dormer
Department of Process Research, Merck & Co., Inc, Rahway, NJ 07065
EꢀMail: peter_maligres@merck.com
Abstract
A stable adduct of CuI with Bu4NI, soluble in organic solvents has been identified as an
effective catalyst for copperꢀcatalyzed CꢀN and CꢀO couplings. In addition, stable nonꢀ
hygroscopic salts of some high performance ligands (diamine MsOH salts/CuX and
copper(II) diketonates) were shown to be of similar and sometimes greater reactivity to the
literature reagents for these couplings. Furthermore, these more robust conditions result in
more reproducible results.
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The copperꢀcatalyzed crossꢀcoupling reactions of aryl halides with amine, alcohol and thiol
nucleophiles have found widespread application in synthetic organic chemistry and industrial
processes. 1 ꢀ 2 Despite their utility, anecdotal reports suggest these couplings can be
notoriously unreliable, due in part to the insolubility of the copper source and base in the
reaction medium. In addition, many of the highꢀperformance ligands which have been
developed for this class of reactions possess nonꢀideal physical and chemical properties such
as volatility, hygroscopicity and in some cases air sensitivity. To address these issues, we
report here the development of stable, nonꢀvolatile and nonꢀhygroscopic salts of certain highꢀ
performance ligands and their use in Cuꢀcatalyzed crossꢀcoupling reactions.3 In addition, we
have identified a stable Cu(I) double salt which is readily soluble in most organic solvents
and serves as a superior metal precursor for these reactions compared to traditional copper
salts .
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To address the issue of stability and ease of handling for some commonly used diamine
ligands, a number of acids (H2SO4, MsOH, TfOH, HBF4, HPF6) 4 were screened that
possessed conjugate bases with low coordinating potential. Of all the acids tested,
methanesulfonic acid (MsOH) was found to give crystalline, airꢀstable, nonꢀhygroscopic salts
of diamines 1ꢀ4 (Scheme 1). To evaluate the performance of these salts as sources of the
free ligand under crossꢀcoupling conditions, all were tested against the model reaction
involving the coupling of indole (8) with 4ꢀiodoanisole (9).5,6,7 The results shown in Table 1
using Cs2CO3 as base in three different solvents verify the MsOH salts of 1ꢀ4 perform as well
as or better than the free diamine ligands in most cases.8 The improvement was most evident
for ligand 2, which possesses the highest volatility of those tested. Furthermore, comparison
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of free ligand 2 to 2•2MsOH in triplicate experiments showed the standard deviation for
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yield variation using the MsOH salt was an order of magnitude less than using the free ligand
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S
CHEME 1. Ligands for Cu-catalyzed cross-coupling.
NMe2
NH2
NH2
NHMe
NHMe
NHMe
NMe2
NHMe
1
2
3
4
O
O
O
O
O
O
5-H
6-H
7-H
T
ABLE 1. Evaluation of diamine MsOH salts in the N-arylation of indole.a
Yield
Solvent Ligand Free MsOH
base
30
49
70
33
41
57
96
93
88
97
96
66
salt
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54
96
96
78
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96
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9
toluene
CPMEb
DMAc
toluene
CPME
DMAc
toluene
CPME
DMAc
1
1
1
2
2
2
3
3
3
4
4
4
10 toluene
11 CPME
12 DMAc
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a General reaction conditions: 1 ꢀmol of CuI, 4 ꢀmol of diamine ligand as either the free
5
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7
8
9
base or MsOH salt, 12 ꢀmol of 8, 10 ꢀmol of 9, 40 ꢀmol of Cs2CO3 in 0.1 mL of solvent;
130 °C, 24h. Assay yields based on iodide 9 calculated from quantitative HPLC using
internal standard. Virtually no (<2%) dehalogenation or homocoupling of iodide 9 was
observed. b CPME = Cyclopentyl methyl ether
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For the diketone ligands 5ꢀ7, the potassium diketonate salts could be prepared and were
found to be stable under nitrogen atmosphere, although they were not stable indefinitely in
air. When these salts were tested as ligands in the Nꢀarylation of indole with 4ꢀiodoanisole,
they performed more poorly than the corresponding free diketones (Table 2, Conditions A &
B) Under the assmption that poor solubility of the potassium diketonates was contributing to
their reduced reaction performance, the phase transfer catalyst nꢀBu4NI was tested as an
additive (Table 2, Condition C).10 This combination gave yields across the various ligands
and reaction solvents that matched, or in many cases exceeded, those obtained with the free
ligands. This intriguing finding suggested nꢀBu4NI might be affecting more than just the
solubility of the ligand. Indeed, the poor solubility of CuI, the copper source of choice for
most couplings, in most organic solvents can cause issues with catalyst activity and
reproducibility. Copper(I) iodide forms a stable, isolable double salt with nBu4NI
(11);11,12,13,14 however, its use in catalysis has not been explored until now.15 We were able to
prepare multigram quantities of 11 from CuI and nꢀBu4NI in THF followed by addition of
MTBE and crystallization. Complex 11 is a stable crystalline solid very soluble in THF and
CH2Cl2, as well as the typical polar aprotic solvents. Using complex 11 as the copper source
in the indole arylation test reaction with the potassium diketonate ligand salts (Table 2,
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Condition D) not surprisingly gave results very similar to those seen using the admixture of
CuI and nꢀBu4NI (Table 2, Condition C). The use of the double salt was preferred, however,
for issues of simplicity and ease of handling.
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=
I
(nBu4N+)2
I Cu Cu I
I
11
Although formation of the potassium diketonate salts afforded solid ligands with lower
volatility and more desirable handling properties compared to the free ligands, the poor
stability and solubility of these salts limited their ultimate utility, even though the latter
effects could be mitigated by the addition of nꢀBu4NI or the use of 11 as copper source. The
ideal ligand salt would be an air and moisture stable solid, soluble in organic solvents and
would incorporate the copper metal. Thus, copper(II) diketonates 52Cu, 62Cu and 72Cu
(Scheme 2) were readily synthesized and found to be air stable solids which are readily
soluble in organic solvents.16 Furthermore, these complexes exhibited excellent catalytic
activity in the model reaction shown in Table 2, in most cases matching the best activity seen
with the other systems, and in the case of ligand 6 in CPME or DMAC giving clearly
superior performance to the other systems (Table 2, Entries 5 and 6). For the coupling of 8
with 9 using as little as 1 mol% of 2•2MsOH/11 or 72Cu gave ≥ 97% conversion to 10 with
3 equiv Cs2CO3 in toluene at 130 °C after 24h.
S
CHEME 2. Copper(II) diketonates.
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tBu
tBu
tBu
tBu
O
O
O
O
O
O
O
O
Cu
Cu
O
O
O
O
Cu
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52Cu
62Cu
72Cu
T
ABLE 2. Evaluation of diketonate salts in the N-arylation of indole.a
Conditionsb
Solvent Ligand A
B
C
D
E
1 toluene
2 CPME
3 DMAc
4 toluene
5 CPME
6 DMAc
7 toluene
8 CPME
9 DMAc
87 67 96 96 89
91 81 93 96 94
95 84 89 95 90
54 18 88 80 85
72 48 78 76 91
63 64 83 74 99
90 49 85 90 89
91 86 85 91 90
75 72 90 92 96
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a General reaction conditions: see Table 1. b Conditions: A) 40 mol% free ligand, 10% CuI;
B) 10% CuI, 40 mol% LigandꢀK; C) 10% CuI, 40 mol% LigandꢀK, 10 mol% nBu4NI; D) 40
mol% LigandꢀK, 10 mol% 11; E) 10 mol% Ligand2ꢀCu. Assay yields based on iodide 9
calculated from quantitative HPLC using internal standard. Virtually no (<2%)
dehalogenation or homocoupling of iodide 9 was observed in all reactions.
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In order to show scope and utility for the new conditions, twelve substrates 12ꢀ23 bearing a
variety of nitrogen and oxygen nucleophilic centers were coupled to 4ꢀiodobiphenyl in
dioxane using Cs2CO3 as base (Table 3), and the results compared to those obtained using the
free ligands and CuI as copper source. Employing the MsOH salts of diamine ligands 2-4 in
conjuction with 11 as copper source, good to excellent yields of products were obtained in
the Nꢀarylation of various amides and heterocycles (Table 3, Condition A). In many cases,
the results with the ligand salt closely mirrored that obtained with the free ligand (e.g., 13, 15,
16 and 17) or showed slight improvement (cf. 12, 18, 19).17,18,19,20,21,22 However, with
indazole substrate 14 the traditional conditions almost completely failed to yield any coupled
product, while the ligand salt with 11 gave excellent yields of coupled product. Likewise, the
Cu(II) salt of diketone ligand 5 gave dramatically higher yields in the Nꢀarylation of
hydantoin 20 than those obtained with the free ligand system. Marked improvements in yield
were also seen in the CꢀO couplings of phenol 21 and aliphatic alcohol 23 with pꢀ
iodobiphenyl catalyzed by Cu(II) salts of ligands 5 and 6.23,24,25
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T
ABLE 3. Scope and utility of copper-catalyzed N- and O-arylation conditions.a
12
18
Ligand 3
A: 88(85)%
B: 71%
Ligand 4c
A: 63/10(62/6)%
B: 42/6%
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Ligand 3
A: 97(93)%
B: 94%
Ligand 2
A: 96(90)%
B: 88%
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Ligand 3
A: 94(89)%
B: 10%
Ligand 5
C: 97(90)%
B: 7%
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Ligand 3
A: 90(80)%
B: 91%
Ligand 5
C: 88(85)%
B: 42%
Ligand 4c
A: 48/24(49/21)%
B: 48/18%
Ligand 7c
C: 72/22(66/23)%
B: 67/26%
17
23
Ligand 4
A: 84(82)%
B: 85%
Ligand 7
C: 86(83)%
B: 50%
a Solution assay yields determined using quantitative HPLC. Isolated yields are given in
parentheses. Yields based on the nucleophile 12ꢀ15, 17, 19ꢀ21, 23. In cases where mono and
bisꢀarylation mixtures were obtained yields are based on iodide 24. b General reaction
conditions: 1.0 equiv. of NuꢀH 12ꢀ23, 1.2 equiv. of 24, 4 equiv. of Cs2CO3, 0.1 M in 1,4ꢀ
dioxane at 130 °C, 24h. Specific conditions: A) 10 mol% of 11, 40 mol% of ligand MsOH
salt; B) 10 mol% of CuI, 40 mol% of free ligand; C) 10 mol% of Ligand2ꢀCu. Toluene and
c
DMAc were explored as solvents as well (full details in Supporting Information) Mixtures
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of monoꢀ and bisꢀarylated products were obtained; yields of monoꢀarylated/bisꢀarylated
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products based on iodide 24 are displayed.
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Further scope was demonstrated for the electrophilic coupling partner using aryl, vinyl and
alkynyl bromides and iodides (Table 4) using 11 as the copper source and the MsOH salt of
the ligand. The results were similar to those obtained in the literature using free ligands with
a conventional copper source such as CuI. Electron rich aryl bromides and iodides 25ꢀ28
gave good yields of coupled products.18,22 Vinyl bromide 29 smoothly reacted with
oxazolidinone 19 to provide enamine 37.17 Ynamine 38 was obtained from
halophenylacetylenes 30 and 3126 as well as from 1,1ꢀdibromoalkyne 32.27
T
ABLE 4. Scope and utility of copper-catalyzed C-N coupling conditions with various
halides.a
Halide
Nucleophile Product
25: X=Br
26: X=I
96% condition A
96% condition A
27: X=Br
28: X=I
86% condition B
88% condition B
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95% condition C
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30: X=Br
31: X=I
76% condition D
82% condition D
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80% condition E
a In all reactions 1.2 equiv of halide was used. Condition A: 5 mol% 11, 10 mol% 2•2MsOH,
3 equiv K2CO3 in 1,4ꢀdioxane, 110 °C, 24h. Condition B: 5 mol% 11, 10 mol% 2•2MsOH, 3
equiv K2CO3 in toluene, 100 °C, 24h. Condition C: 5 mol% 11, 10 mol% 2•2MsOH, 3 equiv
K2CO3 in toluene, 90 °C, 24h. Condition D: 5 mol% 11, 10 mol% 2•2MsOH, 3 equiv K2CO3
in toluene, 110 °C, 24h. Condition E: 12 mol% 11, 18 mol% 2•2MsOH, 5 equiv Cs2CO3 in
1,4ꢀdioxane, 60 °C, 24h. Isolated yields after chromatography are displayed.
In conclusion, we have demonstrated that stable, easily handled MsOH salts of volatile
diamine ligands perform as well as the free diamines. We have also demonstrated the utility
of copper(I) double salt 11 which performs as well as or better than CuI as copper source and
gives more reproducible results. Finally, we have shown that copper(II) diketonates perform
as well as or superior to the free diketones or their potassium salts. The stability and
solubility of 11 and the copper(II) diketonates will make copper catalyzed couplings more
reliable and robust reactions.
Experimental section
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N,N,N',N'-Tetraemethylethylenediamine bis(methanesulfonic acid) salt (1•2MsOH).
Methanesulfonic acid (40 mmol) in 1:1 (vol/vol) EtOAcꢀEtOH (10 mL) was added over 10
min to N,N,N',N'ꢀtetramethylethylenediamine (40 mmol) in 1:1 (vol/vol) EtOAcꢀEtOH (10
mL) in a 100 mL 3 neck round bottom flask equipped with a reflux condenser and magnetic
stirrer. The temperature was allowed to reach reflux during the addition and EtOAc (30 mL)
was added over 10 min at 60 °C. The resulting slurry was cooled to 5 °C over 30 min and
filtered. The solid was washed with 4:1 (vol/vol) EtOAcꢀEtOH (20 mL) and EtOAc (20 mL)
then dried under a stream of nitrogen to provide 1•2MsOH (10.61 g, 86%). White crystalline
solid: mp: 147ꢀ149 °C. 1H NMR (400MHz, D2O) δ 3.68 (s, 4H), 3.03 (s, 12H), 2.85 (s, 6H).
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13C NMR (100MHz, CDCl3) δ 51.1, 43.5, 38.5. Anal. Calcd. for C8H24N2O6S2: C, 31.15; H,
7.84; N, 9.08; O, 31.13; S, 20.79. Found: C, 31.16; H, 7.67; N, 9.03.
N,N'-Dimethylethylenediamine
bis(methanesulfonic
acid)
salt
(2•2MsOH).
Methanesulfonic acid (60 mmol) in EtOH (5 mL) was added over 10 min to N,N'ꢀ
dimethylethylenediamine (40 mmol) in EtOH (5 mL) in a 100 mL 3 neck round bottom flask
equipped with a reflux condenser and magnetic stirrer. The temperature was allowed to reach
reflux during the addition and EtOAc (30 mL) was added over 10 min at 60 °C. The resulting
slurry was cooled to 5 °C over 30 min and filtered. The solid was washed with 9:1 (vol/vol)
EtOAcꢀEtOH (20 mL) and EtOAc (20 mL) then dried under a stream of nitrogen to provide
1
2•2MsOH (8.16 g, 73%). White crystalline solid: mp: 103ꢀ105 °C. H NMR (400MHz,
CD3SOCD3) δ 8.64 (br s, 4H), 3.23 (s, 4H), 2.62 (s, 6H), 2.45 (s, 6H). 13C NMR (100MHz,
CD3SOCD3) δ 43.9. 39.7, 32.9. Anal. Calcd. for C6H20N2O6S2: C, 25.70; H, 7.19; N, 9.99; O,
34.24; S, 22.87. Found: C, 25.72; H, 7.33; N, 9.89.
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trans-1,2-Cyclohexanediamine methanesulfonic acid salt (3•MsOH). Methanesulfonic
acid (25 mmol) in EtOAc (10 mL) was added over 10 min to transꢀ1,2ꢀcyclohexanediamine
(25 mmol) in EtOAc (20 mL) in a 100 mL 3 neck round bottom flask equipped with a reflux
condenser and magnetic stirrer. The temperature was allowed to reach reflux during the
addition. The resulting slurry was cooled to 5 °C over 30 min and filtered. The solid was
washed with EtOAc (20 mL) then dried under a stream of nitrogen to provide 3•MsOH (5.13
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g, 98%). White crystalline solid: mp: 107ꢀ109 °C. H NMR (400MHz, CD3SOCD3) δ 5.28
(br s, 5H), 2.51 (m, 2H), 2.36 (s, 3H), 1.88 (m, 2H), 1.64 (m, 2H), 1.18 (m, 4H). 13C NMR
(100MHz, CD3SOCD3) δ 54.3, 39.7, 32.3, 24.2. Anal. Calcd. for C7H18N2O3S: C, 39.98; H,
8.63; N, 13.32; O, 22.82; S, 15.25. Found: C, 39.64; H, 8.81; N, 13.06.
trans-N,N'-Dimethyl-1,2-Cyclohexanediamine
bis(methanesulfonic
acid)
salt
(4•2MsOH). Methanesulfonic acid (40 mmol) in EtOAc (10 mL) was added over 10 min to
trans-N,N'ꢀdimethylethylenediamine (20 mmol) in EtOAc (20 mL) in a 100 mL 3 neck round
bottom flask equipped with a reflux condenser and magnetic stirrer. The temperature was
allowed to reach reflux during the addition. The resulting slurry was cooled to 5 °C over 30
min and filtered. The solid was washed with EtOAc (20 mL) then dried under a stream of
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nitrogen to provide 4•2MsOH (6.61 g, 99%). White crystalline solid: mp: 151ꢀ153 °C. H
NMR (500MHz, CD3SOCD3) δ 8.70 (br s, 4H), 3.40 (m, 2H), 2.65 (s, 6H), 2.45 (s, 6H), 2.06
(m, 2H), 1.64 (m, 2H), 1.57 (m, 2H), 1.30 (m, 2H). 13C NMR (125MHz, CD3SOCD3) δ 55.8,
30.4, 24.2, 21.1. Anal. Calcd. for C10H26N2O6S2: C, 35.91; H, 7.84; N, 8.38; O, 28.70; S,
19.17. Found: C, 36.02; H, 8.10; N, 8.24.
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Bis(2-isobutyrylcyclohexanone) copper(II) complex (72Cu). A 500mL round bottomed
flask equipped with a magnetic stir bar was charged with Cu(OAc)2•H2O (19.97g 0.10mol),
methanol (200mL), and water (20mL). The mixture was heated to reflux to give a
homogenous blueꢀgreen solution, and a solution of 2ꢀisobutyrylcyclohexanone (33.65g,
0.20mol) in MeOH (20mL) was added over 30ꢀ60seconds to give a homogenous olive green
solution. The mixture was cooled to 20 °C over 1h and water (200mL) was added over 1h.
The solid was filtered off and was washed with 1:1 vol/vol methanolꢀwater (200mL), then
with ice cold methanol (50mL), then with ice cold tBuOMe (50mL) and finally with hexane
(200mL). The solid was dried under a stream of nitrogen to provide the copper (II) diketonate
salt (35.5g, 89%) as air stable fluffy solid. Olive green crystalline solid: mp: 200ꢀ201 °C.
Anal. Calcd. for C20H30CuO4: C, 60.36; H, 7.60; Cu, 15.97; O, 16.08. Found: C, 60.20; H,
7.53; Cu, 16.23; N, <0.05.
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Copper (I) iodide tetra n-butylammonium iodide dimeric complex (nBu4N+)2(Cu2I4)=
(11). A 3L 3ꢀneck round bottomed flask equipped with mechanical stirrer was charged with
CuI (209.48g, 1.10mol), nBu4NI (410.01g, 1.11mol) and peroxide free (inhibited with BHT)
anhydrous deoxygenated THF (500mL) under nitrogen atmosphere. The mixture was
warmed (48 °C) until a homogenous colorless to pale yellow solution was obtained. The
mixture was cooled to 30 °C and several mg of crystalline (nBu4N+)2(Cu2I4)= was added. The
mixture was cooled to 6 °C over 60 min and degassed tBuOMe (750mL) was added over 1h
at 6°C. The mixture was stirred for 1h at 6 °C. The crystalline solid was filtered off and
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washed with degassed 2:1 vol/vol tBuOMeꢀTHF (450mL), then with 9:1 vol/vol tBuOMeꢀ
THF (450mL) and finally with tBuOMe (800mL). The solid was dried under a stream of
nitrogen to provide (nBu4N+)2(Cu2I4)= (615.8g) in virtually quantitative yield as a white to
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pale tan granular crystalline solid (MW=559.82 as monomer); mp: 90ꢀ92 °C. H NMR
(500MHz, CDCl3) δ 3.32 (m, 16H), 1.71 (m, 16H), 1.51 (apparent hextet, J = 7.3 Hz, 16H),
1.05 (t, J = 7.3 Hz, 24H). 13C NMR (125MHz, CDCl3) δ 59.6, 24.6, 20.1, 14.0. Anal. Calcd.
for C32H72Cu2I4N2: C, 34.33; H, 6.48; Cu, 11.35; I, 45.34; N, 2.50. Found: C, 34.54; H,
6.63; Cu, 11.11; N, 2.43.
Procedures for reactions conducted to determine isolated yields. All reactions were
performed under nitrogen with magnetic stirring. Reactions were performed in the cases of
nucleophilic substrates 10 and 12ꢀ19 using 1.5 mmol nucleophile, 1.8 mmol 24, 0.15 mmol
11, 0.6mmol ligand salt (shown in Table 3) and 6 mmol Cs2CO3 in 1,4ꢀdioxane (2 mL),
130 °C, 24h; in case of nucleophilic substrates 20ꢀ23 using 1.5 mmol nucleophile, 1.5 mmol
24, 0.15 mmol ligand2Cu and 6mmol Cs2CO3 in 1,4ꢀdioxane (2 mL), 130 °C, 24h. Reactions
were followed by workup with CHCl3/5% aq Na2EDTA and crystallization by addition of
heptane. Isolated yields are based on the nucleophile 12ꢀ15, 17, 19ꢀ21, 23. In cases where
mono and bisꢀarylation mixtures were obtained from substrates 16, 18, and 22 isolated yields
are based on iodide 24; and are for monoarylated/bisarylated product mixtures that
cocrystallized during isolation. Pure samples of monoarylated and bisarylated products were
prepared by purification of the monoarylated/bisarylated mixtures by preparative TLC (silica,
tBuOMe/hexane)
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1-(4-methoxyphenyl)-1H-indole (10). 305mg, 91% yield. White crystalline solid: mp: 70ꢀ
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71 °C. H NMR (500MHz, CDCl3) δ 7.72 (m, 1H), 7.49 (dd, J = 8.3, 0.6 Hz, 1H), 7.43 (m,
8
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2H), 7.31 (d, J = 3.2 Hz, 1H), 7.24 (m, 1H), 7.19 (m, 1H), 706 (m, 2H), 7.34 (d, J = 3.2 Hz,
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1H), 3.90 (s, 3H). C NMR (125MHz, CDCl3) δ 158.5, 136.6, 133.1, 129.2, 128.5, 126.2,
122.3, 121.2, 120.3, 114.9, 110.6, 103.1, 55.8. MS (ESI): 224 [M + H]+. Anal. Calcd. for
C15H13NO: C, 80.69; H, 5.87; N, 6.27; O, 7.17. Found: C, 80.49; H, 5.59; N, 6.10.
9-([1,1'-biphenyl]-4-yl)-9H-carbazole (12a). 407mg, 85% yield. White crystalline solid:
D
1
mp: 223ꢀ224 °C. H NMR (400MHz, CDCl3) δ 8.20 (ddd, J = 7.7, 0.8, 0.8 Hz, 2H), 7.85
(ddd, J = 8.6, 2.3, 2.3 Hz, 2H), 7.72 (ddd, J = 7.4, 1.7, 1.7 Hz, 2H), 7.67 (ddd, J = 8.9,2.2, 2.2
Hz, 2H), 7.56ꢀ7.42 (m, 7H), 7.34 (ddd, J = 7.4, 7.4, 1.2 Hz, 2H). 13C NMR (100MHz,
CDCl3) δ 141.1, 140.53, 140.50, 137.1, 129.2, 128.7, 127.9, 127.6, 127.6, 127.4, 126.2, 123.7,
120.5, 120.2. MS (ESI): 320 [M + H]+. Anal. Calcd. for C24H17N: C, 90.25; H, 5.36; N, 4.39.
Found: C, 90.01; H, 5.01; N, 4.16.
1-([1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole (13a). 377mg, 93% yield. White crystalline
solid: mp: 173ꢀ174 °C. 1H NMR (500MHz, CDCl3) δ 8.17 (m, 1H), 7.92 (m, 1H), 7.80 (dt, J
= 9.1, 2.3 Hz, 2H), 7.66 (m, 2H), 7.61 (om, 3H), 7.51 (m, 2H), 7.43 (m, 1H), 7.37 (om, 2H).
13C NMR (125MHz, CDCl3) δ 144.4, 142.4, 141.3, 140.0, 135.7, 133.9, 129.2, 128.9, 128.1,
127.3, 124.5, 123.9, 123.0, 120.9, 110.7. MS (ESI): 271 [M + H]+. Anal. Calcd. for
C19H14N2: C, 84.42; H, 5.22; N, 10.36. Found: C, 84.12; H, 4.97; N, 10.04.
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1-([1,1'-biphenyl]-4-yl)-1H-indazole (14a). 361mg, 89% yield. White crystalline solid: mp:
5
6
7
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169ꢀ170 °C. H NMR (500MHz, CDCl3) δ 8.25 (s, 1H), 7.83 (om, 4H), 7.79 (m, 2H), 7.68
13
8
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(m, 2H), 7.59 (m, 3H), 7.40 (m, 1H), 7.27 (m, 1H). C NMR (125MHz, CDCl3) δ 140.4,
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139.7, 139.6, 139.0, 135.7, 129.1, 128.2, 127.7, 127.4, 127.3, 125.6, 123.1, 121.8, 121.6,
110.7. MS (ESI): 271. HRMS (ESI) found m/z 271.1222 [M + H]+, calcd for C19H14N2 + H
271.1230.
2-([1,1'-biphenyl]-4-yl)phthalazin-1(2H)-one (15a). 358mg, 80% yield. White crystalline
1
solid: mp: 187ꢀ189 °C. H NMR (400MHz, CDCl3) δ 8.55 (m, 1H), 8.33 (s, 1H), 7.85 (om,
13
2H), 7.80ꢀ7.76 (om, 3H), 7.72 (m, 2H), 7.65 (m, 2H), 7.48 (m, 2H), 7.39 (m, 1H). C NMR
(100MHz, CDCl3) δ 159.4, 141.3, 140.8, 140.7, 138.8, 133.7, 132.2, 129.7, 129.0, 128.8,
127.7, 127.5, 127.4, 126.3, 126.1. MS (ESI): 299. HRMS (ESI) found m/z 299.1170 [M +
H]+, calcd for C20H14N2O + H 299.1179.
Cocrystallized mixture of 16a and 16b: 402mg, 70% yield.
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N-([1,1'-biphenyl]-4-yl)benzamide (16a).
D
White crystalline solid: mp: 233ꢀ234 °C. H
NMR (400MHz, CD3SOCD3) δ 10.35 (s, 1H), 7.98 (m, 2H), 7.91 (m, 2H), 7.69 (m, 4H), 7.61
(m, 1H), 7.56 (m, 2H), 7.46 (m, 2H), 7.34 (m, 1H). 13C NMR (100MHz, CD3SOCD3) δ 165.5,
139.7, 138,7, 135.2, 134.9, 131.6, 128..9, 128.4, 127.6, 127.0, 126.8, 126.3, 120.6. MS (ESI):
274 [M + H]+. Anal. Calcd. for C19H15NO: C, 83.49; H, 5.53; N, 5.12; O, 5.85. Found: C,
83.37; H, 5.45; N, 5.09.
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N,N-di([1,1'-biphenyl]-4-yl)benzamide (16b). White crystalline solid: mp: 208ꢀ209 °C. H
NMR (400MHz, CD3SOCD3) δ 7.65 (m, 8H), 7.51 (m, 2H), 7.45 (m, 4H), 7.37ꢀ7.27 (m, 9H).
13C NMR (100MHz, CDCl3) δ 170.9, 143.3, 140.3, 139.4, 136.3, 130.5, 129.5, 129.0, 128.2,
128.0, 127.9, 127.7, 127.2. MS (ESI): 426 [M + H]+.
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N-([1,1'-biphenyl]-4-yl)-N-phenylacetamide (17a). 853mg, 82%. White crystalline solid:
D
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mp: 106ꢀ107 °C. H NMR (400MHz, CDCl3, 25 °C) δ 7.59 (m, 4H), 7.47ꢀ7.32 (om, 10H),
1
2.12 (s, 3H). H NMR (600MHz, CD3SOCD3, 77 °C) δ 7.64 (m, 4H), 7.47ꢀ7.29 (om, 10H),
13
1.99 (s, 3H). C NMR (150MHz, CD3SOCD3, 77 °C) δ 169.7, 143.8, 143.1, 139.9, 139.1
(br), 129.7, 129.3, 128.3 (br), 127.9, 127.8, 127.4 (br), 127.1, 23.8. MS (ESI): 288 [M + H]+.
Cocrystallized mixture of 18a and 18b: 412mg, 68% yield.
N-([1,1'-biphenyl]-4-yl)-4-methylbenzenesulfonamide (18a). White crystalline solid: mp:
D
1
157ꢀ158 °C. H NMR (400MHz, CD3SOCD3) δ 10.35 (s, 1H), 7.70 (m, 2H), 7.55 (m, 4H),
13
7.42ꢀ7.28 (m, 5H), 7.19 (m, 2H), 3.34 (s, 3H). C NMR (125MHz, CD3SOCD3) δ 143.3,
139.3, 137.2, 136.8, 135.5, 129.7, 128.9, 127.3, 127.2, 126.7, 126.2, 120.1, 20.9. MS (ESI):
324 [M + H]+. Anal. Calcd. for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33; O, 9.89; S, 9.91.
Found: C, 70.46; H, 5.30; N, 4.36.
N,N-di([1,1'-biphenyl]-4-yl)-4-methylbenzenesulfonamide (18b). White crystalline solid:
mp: 182ꢀ183 °C. 1H NMR (500MHz, CDCl3) δ 7.69 (dt, J = 8.3, 1.8 Hz, 2H), 7.57 (om, 8H),
7.45 (m, 4H), 7.38 (om, 6H), (d, J = 8.1 Hz, 2H), 2.47 (s, 3H). 13C NMR (125MHz, CDCl3) δ
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143.9, 140.9, 140.5, 140.3, 137.8, 129.8, 129.0 128.6, 128.2, 128.1, 127.8, 127.3, 21.8. MS
(ESI): 476 [M + H]+. Anal. Calcd. for C31H25NO2S: C, 78.29; H, 5.30; N, 2.95; O, 6.73; S,
6.74. Found: C, 77.99; H, 5.19; N, 2.94.
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3-([1,1'-biphenyl]-4-yl)-4-benzyloxazolidin-2-one (19a). 445mg, 90%. White crystalline
solid: mp: 151ꢀ152 °C. 1H NMR (500MHz, CDCl3) δ 7.69ꢀ7.61 (om, 6H), 7.47 (m, 2H), 7.38
(m, 1H), 7.34 (m, 2H), 7.30 (m, 1H), 7.17 (m, 2H), 4.71 (dddd, J = 9.4, 8.8, 4.8, 3.5 Hz, 1H),
4.39 (t, J = 8.5 Hz, 1H), 4.25 (dd, J = 8.8, 4.8 Hz, 1H), 3.21 (dd, J = 13.8, 3.5 Hz, 1H), 2.83
(dd, J = 13.8, 9.4 Hz, 1H). 13C NMR (125MHz, CDCl3) δ 155.7, 140.4, 138.3, 136.1, 135.4,
129.4, 129.2, 129.1, 128.2, 127.6, 127.5, 127.2, 122.0, 66.3, 57.5, 38.0. MS (ESI): 330 [M +
H]+. Anal. Calcd. for C22H19NO2: C, 80.22; H, 5.81; N, 4.25; O, 9.71. Found: C, 80.24; H,
5.64; N, 4.20.
1-([1,1'-biphenyl]-4-yl)-5,5-dimethyl-3-phenylimidazolidine-2,4-dione (20a). 481mg, 90%.
1
White crystalline solid: mp: 128ꢀ129 °C. H NMR (500MHz, CDCl3) δ 7.69 (ddd, J = 8.6,
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2.2, 2.2 Hz, 2H), 7.62 (m, 2H), 7.55ꢀ7.47 (om, 6H), 7.43ꢀ7.38 (om, 4H), 1.62 (s, 6H). C
NMR (125MHz, CDCl3) δ 175.4, 154.2, 141.7, 140.3, 133.4, 132.1, 129.3, 129.2, 129.1,
128.5, 128.3, 128.0, 127.4, 126.3, 63.7, 24.4. MS (ESI): 357 [M + H]+. Anal. Calcd. for
C23H20N2O2: C, 77.51; H, 5.66; N, 7.86; O, 8.98. Found: C, 77.14; H, 5.55; N, 7.74.
1
4,4''-oxydi-1,1'-biphenyl (21a). 411mg, 85%. White crystalline solid: mp: 198ꢀ199 °C. H
NMR (500MHz, CDCl3) δ 7.59 (m, 8H), 7.45 (m, 4H), 7.35 (m, 2H), 7.14 (m, 4H). 13C NMR
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(125MHz, CDCl3) δ 157.0, 140.8, 136.7, 129.0, 128.7, 127.3, 127.1, 119.4. Anal Calcd. for
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C24H18O: C, 89.41; H, 5.63; O, 4.96. Found: C, 89.38; H, 5.59; N, <0.05.
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Cocrystallized mixture of 22a and 22b: 583mg, 89% yield.
N-([1,1'-biphenyl]-4-ylmethyl)-[1,1'-biphenyl]-4-amine (22a). White crystalline solid: mp:
1
180ꢀ182 °C. H NMR (500MHz, CD3SOCD3) δ 7.64 (m, 4H), 7.52 (m, 2H), 7.45 (om, 4H),
7.40ꢀ7.33 (om, 5H), 7.20 (t, J = 7.3 Hz, 1H), 6.69 (m, 2H), 6.48 (t, J = 6.1 Hz, 1H), 4.36 (d, J
13
= 6.1 Hz, 2H). C NMR (100MHz, CD3SOCD3) δ 148.2, 140.5, 140.0, 139.5, 138.6, 128.9,
128.7, 127.7, 127.5, 127.2, 127.1, 126.6, 126.5, 125.7, 125.4, 112.7, 46.0. MS (ESI): 336 [M
+ H]+. Anal. Calcd. for C25H21N: C, 89.51; H, 6.31; N, 4.18. Found: C, 89.88; H, 5.97; N,
3.90.
N-([1,1'-biphenyl]-4-yl)-N-([1,1'-biphenyl]-4-ylmethyl)-[1,1'-biphenyl]-4-amine
(22b).
1
White crystalline solid: mp: 197ꢀ198 °C. H NMR (500MHz, CDCl3) δ 7.60 (m, 8H), 7.55
(m, 4H), 7.49ꢀ7.42 (om, 8H), 7.37ꢀ7.31 (om, 3H), 7.25 (m, 4H), 5.15 (s, 2H). 13C NMR
(125MHz, CDCl3) δ 147.4, 141.1, 140.9, 140.1, 138.3, 134.5, 129.0, 128.9, 128.1, 127.6,
127.4, 127.3, 127.2, 126.9, 126.8, 121.1, 56.3. MS (ESI): 488. HRMS (ESI) found m/z
488.2381 [M + H]+, calcd for C37H29N + H 488.2378.
N-(2-([1,1'-Biphenyl]-4-yloxy)ethyl)-N,4-dimethylbenzenesulfonamide (23a). 475mg,
83% yield. White crystalline solid: mp: 154ꢀ155 °C. 1H NMR (400MHz, CDCl3) δ 7.73 (ddd,
J = 8.3, 1.9, 1.9 Hz, 2H), 7.57ꢀ7.50 (om, 4H), 7.43 (m, 2H), 7.32 (m, 3H), 6.93 (ddd, J = 8.9,
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2.6, 2.6 Hz, 2H), 4.20 (t, J = 5.7 Hz, 2H), 3.48 (t, J = 5.7 Hz, 2H), 2.95 (s, 3H), 2.44 (s, 3H).
13C NMR (100MHz, CDCl3) δ 158.0, 143.7, 140.9, 135.2, 134.5, 130.0, 128.9, 128.4, 127.6,
127.0, 126.9, 115.0, 67.3, 49.6, 36.8, 21.7. MS (ESI): 382 [M + H]+. Anal. Calcd. for
C22H23NO3S: C, 69.26; H, 6.08; N, 3.67; O, 12.58; S, 8.41. Found: C, 68.89; H, 5.70; N,
3.58.
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1-(p-Tolyl)-1H-indole (25).
From bromide 25: A mixture of 8 (140 mg, 1.2 mmol), bromide 25 (171 mg, 1 mmol), 11 (28
mg, 0.05mmol), 2•2MsOH (29 mg, 0.1 mmol), K2CO3 (415 mg, 3 mmol) and 1,4ꢀdioxane (3
mL) was heated to 110 °C with magnetic stirring for 24h. The mixture was cooled, filtered
and chromatographed on silica gel using EtOAc/heptane to provide 35 (96%). White
crystalline solid: mp: 38ꢀ39 °C. 1H NMR (500MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.62
(d, J = 8.0 Hz, 1H), 7.47 (m, 2H), 7.39 (om, 3H), 7.31 (t, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz,
13
1H), 6.75 (d, J = 2.6 Hz, 1H), 2.52 (s, 3H). C NMR (125MHz, CDCl3) δ 137.5, 136.5,
136.2, 130.3, 129.4, 128.3, 124.5, 122.4, 121.3, 120.4, 110.7, 103.4, 21.2. MS (ESI): 208 [M
+ H]+.
From iodide 26: Same procedure as above except bromide 25 was replaced with iodide 26
(218 mg, 1mmol). (200 mg, 96%).
1-(3,5-Dimethylphenyl)pyrrolidin-2-one (36).
From bromide 27: A mixture of 33 (102 mg, 1.2 mmol), bromide 27 (185 mg, 1 mmol), 11
(28 mg, 0.05mmol), 2•2MsOH (29 mg, 0.1 mmol), K2CO3 (415 mg, 3 mmol) and toluene (3
mL) was heated to 100 °C with magnetic stirring for 24h. The mixture was cooled, filtered
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and chromatographed on silica gel using EtOAc/heptane to provide 36 (86%). White
crystalline solid: mp: 96ꢀ98 °C. 1H NMR (400MHz, CDCl3) δ 7.22 (2, 1H), 6.82 (s, 1H), 3.84
7
13
8
9
(m, 2H), 2.59 (m, 2H), 2.33 (s, 6H). 2.14 (m, 2H). C NMR (100MHz, CDCl3) δ 174.3,
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139.5, 138.6, 126.6, 119 1, 49.3, 33.0, 21.7, 18.3. MS (ESI): 190 [M + H]+.
From iodide 28: Same procedure as above except bromide 27 was replaced with iodide 28
(232 mg, 1 mmol). (182 mg, 88%).
4-Benzyl-3-(2-methylprop-1-en-1-yl)oxazolidin-2-one (37). A mixture of 19 (213 mg, 1.2
mmol), bromide 29 (135 mg, 1 mmol), 11 (28 mg, 0.05mmol), 2•2MsOH (29 mg, 0.1 mmol),
K2CO3 (415 mg, 3 mmol) and toluene (3 mL) was heated to 90 °C with magnetic stirring for
24h. The mixture was cooled, filtered and chromatographed on silica gel using
1
EtOAc/heptane to provide 35 (95%). White crystalline solid: mp: 58ꢀ60 °C. H NMR
(400MHz, CDCl3) δ 7.36ꢀ7.23 (m, 3H), 7.16 (m, 2H), 5.70 (apparent heptet, J = 1.4 Hz, 1H),
4.25 (m, 1H), 4.13 (om, 2H), 3.10 (dd, J = 13.6, 3.8 Hz, 1H), 2.68 (dd, J = 13.6, 9.1 Hz, 1H),
13
1.81 (d, J = 1.2 Hz, 3H), 1.76 (d, J = 1.2 Hz, 3H). C NMR (100MHz, CDCl3) δ 156.7,
135.8, 134.2, 129.3, 129.0, 127.3, 117.2, 66.9, 58.8, 38.8, 22.8, 18.5. MS (ESI): 232 [M +
H]+.
4-Phenyl-3-(phenylethynyl)oxazolidin-2-one (38).
From bromide 30: A mixture of 34 (196 mg, 1.2 mmol), bromide 30 (181 mg, 1 mmol), 11
(28 mg, 0.05mmol), 2•2MsOH (29 mg, 0.1 mmol), K2CO3 (415 mg, 3 mmol) and toluene (3
mL) was heated to 110 °C with magnetic stirring for 24h. The mixture was cooled, filtered
and chromatographed on silica gel using EtOAc/heptane to provide 35 (200 mg, 76%). White
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crystalline solid: mp: 132ꢀ134 °C. H NMR (400MHz, CDCl3) δ 7.51ꢀ7.42 (om, 5H), 7.27
5
(m, 5H), 5.17 (dd, J = 8.6, 7.2 Hz, 1H), 4.82 (t, J = 8.9 Hz, 1H), 4.35 (dd, J = 8.9, 7.2 Hz,
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7
13
8
1H). C NMR (100MHz, CDCl3) δ 155.7, 136.3, 131.7, 129.8, 129.6, 128.4, 128.3, 127.1,
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122.3, 78.2,73.1, 71.0, 62.5. MS (ESI): 264 [M + H]+.
From iodide 31: Same procedure as above except bromide 30 was replaced with iodide 31
(228 mg, 1mmol); (216 mg, 82%).
From dibromoolefin 32: A mixture of 34 (196 mg, 1.2 mmol), dibromoolefin 32 (262 mg, 1
mmol), 11 (67 mg, 0.12mmol), 2•2MsOH (52 mg, 0.18 mmol), Cs2CO3 (1.63g, 5 mmol) and
1,4ꢀdioxane (3 mL) was heated to 60 °C with magnetic stirring for 24h. The mixture was
cooled, filtered and chromatographed on silica gel using EtOAc/heptane to provide 35 (200
mg, 76%).
Acknowledgment. We thank Drs. Fanyu Meng, Thomas J. Novak, Vincent Van Nostrand
and Charles W. Ross for their mass spectroscopy support.
1
Supporting Information. General experimental methods, detailed tables of results and copies of H
13
and C NMR spectra for compounds 10, 12aꢀ23a, 16b, 18b and 22b. This material is available free
of charge via the Internet at http://pubs.acs.org.
References and Notes
1 For reviews see: (a) Ma, D.; Jiang, Y. Chimia 2011, 65, 914ꢀ918. (b) Surry, D. S.; Buchwald, S. L. Chemical
Science 2010, 1, 13ꢀ31. (c) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 6954ꢀ6971. (d) Ma, D.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450ꢀ1460. (e) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
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3054ꢀ3131. (f) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337ꢀ2364. (g) Ley. S. V.;
Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400ꢀ5449.
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9
2 For some recent examples see: (a) Xiong, X.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 2552ꢀ2555. (b) Xinye, Y.;
Hui, X.; Ye, Z.; Yisheng, L.; Yihua, Z.; Yongwen, J.; Ma, D. Chin. J. Chem. 2012, 30, 875ꢀ880. (c) Shafir, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742ꢀ8743.
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3 Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295ꢀ4298.
4 MsOH was chosen for use in this study due to its stability, convenience, cost, safety and consistent formation
of crystalline nonꢀhygroscopic amine salts.
5 Nandurkar, N. S.; Bhanushali, M. J.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett. 2007, 48, 6573ꢀ6576.
6 Jammi, S.; Sakthivel, S.; Rout, L.; Mukherjee, T.; Mandal, S.; Mitra, R.; Saha, P.; Punniyamurthy, T. J. Org.
Chem. 2009, 74, 1971ꢀ1976.
7 Swapna, K.; Murthy, S. N.; Nageswar, Y. V. D. Eur. J. Org. Chem. 2010, 6678ꢀ6684.
8 The use of K3PO4 as base gave similar results.
9 See Table S5 in Supporting Information.
10 Quaternary ammonium salts have been used in copper catalyzed couplings, see: Yang, CꢀT.; Fu, Y.; Huang,
YꢀB.; Yi, J.; Guo, QꢀX.; Liu, L. Angew. Chem. Int. Ed. 2009, 48, 7398 –7401.
11 Nilsson, M. Acta Chem. Scand. 1982, B36, 125ꢀ126.
12 Asplund, M.; Jagner, S.; Nilsson, M. Acta Chem. Scand. 1982, A36, 751ꢀ755.
13 Allenmark, S.; Sandin, M.; Nilsson, M. Acta Chem. Scand. 1985, B39, 879ꢀ881.
14 Complex 11 has recently become available from SigmaꢀAldrich, Inc. (cat# 762504).
15 Liedholm, B.; Nilsson, M. Acta Chem. Scand. 1988, B42, 289ꢀ293.
16 Complex 72Cu has recently become available from SigmaꢀAldrich, Inc. (cat# 762431).
17 Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667ꢀ3669.
18 Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421ꢀ7428.
19 Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78ꢀ88.
20 Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727ꢀ7729.
21 Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578ꢀ5587.
22 Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684ꢀ11688.
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23 Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett 2002, 4, 1623ꢀ1626.
24 Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3490ꢀ3491.
25 Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 6205ꢀ6213.
26 Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas,
C. J. J. Am. Chem. Soc. 2003, 125, 2368ꢀ2369.
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27 Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G Angew. Chem. Int. Ed. 2009, 48, 4381ꢀ4385.
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