Ion-tagged phosphines as ligands for suzuki coupling of aryl halides in a phosphonium ionic liquid

Article abstract of DOI:10.1055/s-0033-1340846

Gramine-based N-substituted phosphines were synthesized and utilized as ligands in Suzuki-Miyaura coupling of aryl bromides and chlorides in the room temperature ionic liquid trihexyltetradecylphosphonium bis(trifluoromethanesulfonyl)imide. Increased yiel

Full text of DOI:10.1055/s-0033-1340846

LETTER
▌977
lIeottenr -Tagged Phosphines as Ligands for Suzuki Coupling of Aryl Halides in a
Phosphonium Ionic Liquid
Ion-Tagged Phosphines for Suzuki Coupling
Adam J. Keith,a Stephen D. Kosik,b L. M. Viranga Tillekeratne,b Mark R. Mason*a
a
Department of Chemistry and School of Green Chemistry and Engineering, The University of Toledo, Toledo, OH 43606, USA
Fax +1(419)5304033; E-mail: mmason5@utoledo.edu
b
Department of Medicinal and Biological Chemistry and School of Green Chemistry and Engineering, The University of Toledo, Toledo,
OH 43606, USA
Received: 31.12.2013; Accepted after revision: 28.01.2014
sequently reported the use of N-indolyl phosphines for
Abstract: Gramine-based N-substituted phosphines were synthe-
Suzuki–Miyaura cross-coupling reactions. The major
sized and utilized as ligands in Suzuki–Miyaura coupling of aryl
drawback of these phosphine ligand sets is the difficulty
in recovering the palladium catalyst and the high catalyst
bromides and chlorides in the room temperature ionic liquid tri-
hexyltetradecylphosphonium bis(trifluoromethanesulfonyl)imide.
Increased yields were achieved with ion-tagged ligands compared loading.
to ligands bearing pendant amines, likely due to higher solubility of
The high cost of palladium and increasingly stringent en-
the former. Cyclohexyl groups on the phosphine moiety generally
resulted in higher yields than tert-butyl groups. In addition, a bipha-
sic ionic liquid/water system outperformed catalysis in neat ionic
liquid and provided higher yields at lower temperatures.
vironmental regulations warrant innovations which recy-
cle the catalyst, reduce metal leaching, or minimize
catalyst loading. A commonly employed strategy to ad-
dress catalyst recyclability and leaching is application of
ionic liquids (ILs) as reaction media.10 The active catalytic
species in IL is believed to be mononuclear palladium(0),
but upon heating the palladium aggregates, leading to for-
mation of inactive palladium black.11 It has been proposed
by Dyson and co-workers12 that some ILs act as nanopar-
ticle stabilizers and reduce palladium black clustering.
Palladium nanoparticles13 are believed to act as reservoirs
for mononuclear metal species, allowing for increased
catalytic activity. Recycling of active catalyst in IL may
be achieved by developing a catalyst with high affinity for
the ionic liquid and using an immiscible solvent to extract
products and unreacted starting materials. Although there
are a number of examples of Suzuki–Miyaura coupling re-
actions in ionic liquids, only a few use phosphonium-
based ILs.14 Even though phosphonium-based ILs are
miscible with a broad spectrum of organic solvents, a sys-
tem can be envisioned where extraction is conducted us-
ing supercritical CO2.15–20 Such a system would also have
the added advantage of eliminating the undesirable effects
resulting from use of organic solvents.
Key words: palladium, catalysis, ionic liquids, cross-coupling,
green chemistry
Biaryls are commonly utilized motifs in the synthesis of
biologically active compounds, including pharmaceuti-
cals and herbicides.1,2 They are commonly prepared by
metal-catalyzed sp2–sp2 carbon–carbon bond-formation
reactions of aryl halides, a widely used method of which
is the Suzuki–Miyaura (SM) coupling reaction between
aryl halides and aryl boronic acids.3,4 In view of the vast
potential of this reaction in the synthesis of commercially
important compounds, efforts are being made to modify
the reaction conditions to make it more amenable to
‘greener’ solvents and milder reaction conditions. Be-
sides, the reaction is slow when aryl chlorides, especially
those with deactivating electron-donating substituents,
are used. Therefore, new catalysts that improve the effi-
ciency of the reaction with less reactive and more com-
monly available aryl chlorides as substrates are being
sought.
Herein we report the use of room temperature ionic liquid
trihexyltetradecylphosphonium bis(trifluoromethylsulfo-
nyl)imide ([P66614][NTf2]) as reaction medium for palladi-
um-catalyzed Suzuki–Miyaura coupling of phenylboronic
acid and aryl halides using a new class of indole-based
phosphine ligands. The synthesis of N-dialkylphosphino-
gramine ligands and their grammonium salts is also de-
scribed. The addition of pendant amino and, especially,
ammonium moieties to indole enhances ligand and cata-
lyst solubility in ionic liquids and may allow catalyst re-
cycling. Use of ion-tagged phosphines for improvement
of solubility in polar solvents and ILs is well document-
ed.21–24
Ligation of palladium by phosphorus donors is the most
commonly employed strategy for increasing catalytic ac-
tivity in SM reactions. The biaryl phosphine ligands re-
ported by Buchwald and co-workers are highly
successful, even for the coupling of chloroarenes.5 Li-
gands developed by Beller and co-workers, which feature
a dialkyl phosphine moiety bonded to the C2 position of
indole, are also commonly used and commercially avail-
able.6 The Mason group has previously reported the syn-
thesis of N-indolyl7 and gramine-substituted phosphines,8
similar to the Beller ligands. Kwong and co-workers9 sub-
SYNLETT 2014, 25, 0977–0982
Advanced online publication: 14.03.2014
Sterically demanding25 and electron-rich26,27 phosphines
constitute the most active and widely employed ligands in
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340846; Art ID: ST-2013-S1178-L
© Georg Thieme Verlag Stuttgart · New York

978
A. J. Keith et al.
LETTER
Suzuki–Miyaura reactions. However, sensitivity to oxy- these ligands improve the efficiency of the dipalladium
gen and high cost are drawbacks that limit their general dibenzylideneacetone catalyst.
applicability. N-Dialkylphosphinogramines (1, 2) are at-
tractive as ligands because they are easily prepared from
Catalyst screening was then conducted in trihexyltetra-
decylphosphonium
bis(trifluoromethylsulfonyl)imide
inexpensive materials and exhibit robust stability com-
pared to many alkyl phosphines. Methylation of the pen-
dant amine to produce the corresponding ammonium salts
(1a, 2a) is an efficient and inexpensive method of increas-
ing the solubility of these compounds in ionic liquids.
([P66614][NTf2]) IL as solvent (Table 1). Higher yields
were observed with the ligands carrying pendant ionic
ammonium groups (1a and 2a) compared to the non-ionic
ligands. This could be attributed to the higher solubility of
the ionic phosphine ligands in the ionic liquid. Solubility
Phosphines 1 and 2 were synthesized by the reaction of tests indicated an approximately five-fold increase in the
deprotonated gramine with t-Bu2PCl and Cy2PCl, respec- solubility of ligands in IL upon conversion to the ammo-
tively (Scheme 1). Subsequent methylation with iodo- nium salt. In general the yields obtained with non-ionic li-
methane afforded the ion-tagged phosphines 1a and 2a.
gands in IL were comparable to yields obtained in DMF
under similar conditions.
NMe2
NMe2
i) n-BuLi; ii) R2PCl
Table 1 Suzuki Coupling of 4-Arylhalides and Phenylboronic Acid
in [P66614][NTf2] at 180 °Ca
N
N
H
THF, 20 h, 20 °C
X
B(OH)2
PR2
1 R = t-Bu 83%
2 R = Cy 49%
Pd2(dba)3 (1.5 mol%)
ligand (3.6 mol%)
Cs2CO3 (1.5 equiv)
+
R
NMe3+I–
NMe2
R
MeI
Entry
R
X
Ligand
Yield (%)b
Thermal
N
N
THF, 16 h, 20 °C
MW
PR2
PR2
1a R = t-Bu 91%
2a R = Cy 96%
1
2
Me
Me
Me
Me
Me
CF3
CF3
CF3
CF3
CF3
Me
Me
Me
Me
Me
CF3
CF3
CF3
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
1
15
34
20
32
0
13
15
13
20
0
1a
2
Scheme 1
3
The new phosphines were characterized by NMR (1H,
13C, 31P) spectroscopy, mass spectrometry (ESI), and ele-
mental analysis. The molecular structure of 1a was further
confirmed by X-ray crystallography (Figure 1). Charac-
terization details are provided in the experimental section
and representative spectra are available in the supporting
information.
4
2a
none
1
5
6
25
33
48
61
13
49
45
34
54
14
49
58
46
64
41
31
23
58
60
12
26
28
29
45
14
39
47
55
58
41
7
1a
2
8
9
2a
none
1
10
11
12
13
14
15
16
17
18
19
20
1a
2
2a
none
1
Figure 1 ORTEP diagram of 1a cation. Hydrogen atoms and iodide
ion omitted for clarity.
1a
2
Initial catalyst screening was conducted using 4-chloro-
toluene with dimethylformamide (DMF) as the solvent.
As expected, higher yields were obtained for the non-
methylated ligands (1 and 2) due to their higher solubility
in DMF (results not shown). No product was obtained in
the absence of phosphine ligands, thus confirming that
2a
none
a Reaction time: 48 h, thermal; 3 h, microwave (MW).
b GC yields.
Synlett 2014, 25, 977–982
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ion-Tagged Phosphines for Suzuki Coupling
979
The rate-limiting step of Suzuki–Miyaura reaction is the cipitate of palladium black following heating and the ionic
oxidative addition of the aryl halide to palladium(0). Elec- liquid phase was reproducibly yellow in color. A variable
tron-withdrawing substituents on the aryl ring therefore temperature study showed no significant reduction in
activate the aryl halide to oxidative addition. As expected, product when the reaction temperature was lowered from
switching the substituent from methyl to trifluoromethyl 180 °C to 160 °C in the binary mixture for 4-chlorotolu-
resulted in a significant increase in the reaction yields (Ta- ene. However, decreasing the temperature further resulted
ble 1, entries 6–10). Interestingly, better yields were ob- in lower yields.
tained with ligands carrying less bulky dicyclo-
hexylphosphino compared to those with di-tert-bu-
tylphosphino groups. This is likely due to higher accessi-
bility of metal site when the phosphine is smaller in size.
Table 2 Suzuki Coupling of 4-Arylhalides and Phenylboronic Acid
in [P66614][NTf2] and Water at 160 °Ca
X
B(OH)2
Pd2(dba)3 (1.5 mol%)
ligand (3.6 mol%)
With aryl chlorides with trifluoromethyl activating group,
some conversion was observed in the absence of ligands
albeit in significantly lower quantities (Table 1, entry 10).
For deactivating methyl substituents, higher yields were
obtained with more reactive aryl bromides (Table 1, en-
tries 11–15). The substituent effects too were as predicted
with aryl chlorides, with methyl resulting in much lower
yields than trifluoromethyl. However, the substituent ef-
fect is less pronounced with aryl bromides, underscoring
the need for effective catalytic systems for unactivated
aryl halides in Suzuki–Miyaura reaction. As was observed
for aryl chlorides with activating trifluoromethyl groups,
little product formation was observed in the absence of li-
gand with aryl bromides with deactivating methyl group
(Table 1, entry 15).
Cs2CO3 (1.5 equiv)
+
R
R
Entry
R
X
Ligand
Yield (%)b
Thermal MW
1
2
Me
Me
Me
Me
CF3
CF3
CF3
CF3
Me
Me
Me
Me
CF3
CF3
CF3
CF3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
1
19
40
39
49
62
77
68
83
64
87
90
96
48
98
83
99
17
45
25
54
56
79
67
85
57
82
90
91
46
99
74
99
1a
2
3
4
2a
1
5
6
1a
2
Highest yields were observed with 4-bromobenzotrifluo-
ride, the most active of the substrates tested. In fact, trials
conducted in the absence of ligand saw a significant in-
crease in yield (Table 1, entry 20).
7
8
2a
1
9
Although the yields were better when a phosphine ligand
was added, the differences were not as significant as with
the less active substrates. This large increase in yield in
the absence of a phosphine ligand is likely due to 4-bro-
mobenzotrifluoride being reactive enough that nanoparti-
cles are rate competitive with the phosphine complex.
10
11
12
13
14
15
16
1a
2
2a
1
Microwave heating has become a common method to de-
crease reaction times in organic syntheses and, in particu-
1a
2
lar, Suzuki–Miyaura cross-coupling reactions.28
A
general trend across Table 1 is that traditional thermal
heating produced better yields than the microwave heat-
ing. Nevertheless, microwave conversion takes less time
and is much more energy efficient.
2a
a Reaction time: 48 h, thermal; 3 h, microwave (MW).
b GC yields.
Welton,29 Dyson,12a and others have reported that adding
water or alcohols to SM cross-coupling reactions in ILs
increases product yields, presumably due to increased sol-
ubility of the base. Our catalytic trials with non-ionic
amine ligands in neat ionic liquid always contained some
undissolved base. To test the effect of water, a second set
of screenings was conducted using an ionic liquid/water
mixture as solvent (Table 2). The results were very pro-
nounced. Not only the yields were increased, but the reac-
tions became more reproducible. In neat ionic liquid there
was often noticeable palladium black formation and the
reaction mixture after heating ranged in color from yellow
to violet. When water was added there was little to no pre-
The results of Table 2 mimic those of Table 1 with similar
trends observed based on the activity of the aryl halide,
but with improved yields and lower standard deviations
between replicated runs. In particular the yields with aryl
chlorides were much improved. For many of the catalytic
trials with aryl bromides the reactions gave almost quan-
titative yields (Table 2, entries 12, 14 and 16). In order to
further alleviate the harsh temperatures used, a set of cat-
alytic trials was conducted at 120 °C (Table 3). The yields
obtained were comparable to those obtained at 160 °C,
and in some instances were even better (Table 3, entries 1,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 977–982

980
A. J. Keith et al.
LETTER
group members for suggestions on the preparation, purification, and
handling of ionic liquids, and Dr. Kristin Kirschbaum and Chris
Gianopoulos for advice on the crystallographic refinement and so-
lution for 1a.
3, and 4), probably due to decomposition of product at
higher temperatures.
Table 3 Suzuki Coupling of 4-Arylbromides and Phenylboronic
Acid in [P66614][NTf2] and Water at 120 °C
X
B(OH)2
(dba)3 (1.5 mol%)
Pd2
Supporting Information for this article is available online at
ligand (3.6 mol%)
Cs2CO3 (1.5 equiv)
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
+
R
References and Notes
R
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R
X
Ligand
Yield (%)b
Thermal MW
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1
2
3
4
5
6
7
8
Me
Me
Me
Me
CF3
CF3
CF3
CF3
Br
Br
Br
Br
Br
Br
Br
Br
1
79
78
97
98
52
99
82
99
80
69
97
98
50
99
78
97
1a
2
2a
1
1a
2
2a
a Reaction time: 48 h, thermal; 3 h, microwave (MW).
b GC yields.
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In conclusion, two dialkylphosphinogramines (1, 2) and
their ion-tagged derivatives (1a, 2a) have been prepared
and fully characterized.30 These phosphines are effective
as ligands for Suzuki–Miyaura cross-coupling of aryl ha-
lides with phenylboronic acid in a phosphonium IL with
either traditional or microwave heating. The ion-tagged
derivatives exhibit dramatically increased solubility in
the IL and increased product yield compared with those
for the neutral ligands 1 and 2. Interestingly, ligands with
dicyclohexylphosphino groups were found to give higher
yields compared to ligands with more sterically demand-
ing di-tert-butylphosphino substituents. Addition of wa-
ter to the IL also led to a dramatic increase in yields at
lower temperature. Although promising and easily syn-
thesized, the catalyst systems reported here do not func-
tion under the milder conditions achievable using the
Buchwald,5 Beller,6 or Kwong9 ligands in traditional or-
ganic solvents or ion-tagged phosphines reported to func-
tion under mild conditions in [bmpy][NTf2]/H2O.22,23
Derivatives of ligands 1 and 2 do provide opportunity for
further optimization as recyclable catalysts in the SM re-
action. In this context, SM coupling reactions with elec-
tron-rich C2-substituted dialkylphosphinogramines are
in progress and those results will be reported elsewhere.
Acknowledgment
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484.
Partial funding of this research was provided by the Interdisciplina-
ry Research Initiation program at The University of Toledo. The au-
thors thank Cytec for providing tetradecyltrihexylphosphonium
chloride free of charge. We thank Professor Jared Anderson and his
Synlett 2014, 25, 977–982
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ion-Tagged Phosphines for Suzuki Coupling
981
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Synthesis of 1-(Dicyclohexylphosphino)-3-
dimethylaminomethylindole (2): A solution of n-
butyllithium (1.6 M, 3.7 mL, 5.9 mmol) in hexanes was
added via syringe to a cooled (–78 °C) solution of gramine
(1.01 g, 5.8 mmol) in THF (25 mL). The resulting yellow
solution was stirred for 1 h at r.t. before cooling again to –78
°C. A solution of Cy2PCl (1.35 g, 5.8 mmol) in THF (5 mL)
was added via cannula. The reaction solution was stirred for
20 h at ambient temperature, after which the volatiles were
removed in vacuo. The waxy yellow solid was dissolved in
CH2Cl2, the insoluble solids were removed by filtration over
a pad of Celite on a sintered glass funnel, and CH2Cl2 was
removed in vacuo. Colorless crystals of 1-(dicyclohexyl-
phosphino)-3-dimethylaminomethyl indole (1.05 g, 49%)
were grown from the slow evaporation of MeCN at r.t.; mp
71 °C. 1H NMR (600 MHz, CDCl3): δ = 7.73 (d, 3JHH = 7.8
Hz, 1 H, H7), 7.62 (d, 3JHH = 7.8 Hz, 1 H, H4), 7.20 (t, 3JHH
= 6.6 Hz, 1 H, H6), 7.14 (s, 1 H, H2), 7.12 (t, 3JHH = 8.4 Hz,
1 H, H5), 3.63 (s, 2 H, CH2), 2.28 (s, 6 H, NMe2), 2.09 (br s,
2 H, Cy), 1.85 (d, J = 10.8 Hz, 2 H, Cy), 1.76 (d, J = 13.2 Hz,
2 H, Cy), 1.65 (m, 4 H, Cy), 1.47 (br s, 2 H, Cy), 1.31 (m, 2
H, Cy), 1.14 (m, 8 H, Cy). 13C NMR (150.8 MHz, CDCl3): δ
= 143.4 (br s, C4a), 129.7 (br s, C2), 127.9 (br s, C7a), 122.1
(s, C6), 120.1 (br s, C5), 119.2 (s, C4), 116.3 (s, C3) 112.7
(d, 3JCP =16.0 Hz, C7), 54.9 (s, CH2), 45.6 (s, NMe2), 36.5
(d, 2JCP = 14.5 Hz, PCHCH2), 29.5 (d, 1JCP = 20.5 Hz, PCH),
28.2 (d, 3JCP = 6.7 Hz, PCHCH2CH2), 26.9 (d, 2JCP = 13.8 Hz,
PCHCH2), 26.8 (d, 3JCP = 7.6 Hz, PCHCH2CH2), 26.4 (s,
PCHCH2CH2CH2). 31P NMR (161.9 MHz, CDCl3): δ = 48.7
(s). MS (ESI): m/z (%) = 393.6 (34) [MNa]+, 371.5 (5)
[MH]+, 326.6 (100) [M – NMe2]+. Anal. Calcd for
(29) McLachlan, F.; Mathews, C. J.; Smith, P. J.; Welton, T.
Organometallics 2003, 22, 5350.
(30) Synthesis of 1-(Di-tert-butylphosphino)-3-di-
methylaminomethylindole (1): A solution of n-butyl-
lithium (1.6 M, 7.2 mL, 11.5 mmol) in hexanes was added
via syringe to a cooled (–78 °C) solution of gramine (2.01 g,
11.5 mmol) in THF (50 mL). The resulting yellow solution
was stirred for 1 h at r.t. before again cooling to –78 °C. A
solution of t-Bu2PCl (2.083 g, 11.53 mmol) in THF (5 mL)
was added via cannula. The reaction solution was stirred for
20 h at ambient temperature, after which the volatiles were
removed in vacuo. The waxy yellow solid was dissolved in
CH2Cl2 and the precipitated solids were removed by
filtration over a pad of Celite on a sintered glass funnel.
CH2Cl2 was removed in vacuo. Colorless crystals of 1-(di-
tert-butylphosphino)-3-dimethylaminomethylindole (2.93
g, 83%) were grown from the slow evaporation of MeCN at
r.t.; mp 80 °C. 1H NMR (600 MHz, CDCl3): δ = 7.84 (d, 3JHH
= 7.8 Hz, 1 H, H7), 7.65 (d, 3JHH = 7.8 Hz, 1 H, H4), 7.35 (s,
1 H, H2), 7.21 (t, 3JHH = 7.8 Hz, 1 H, H6), 7.14 (t, 3JHH = 7.8
Hz, 1 H, H5), 3.64 (s, 2 H, CH2), 2.28 (s, 6 H, NMe2), 1.22
(d, 3JHP = 13.2 Hz, 18 H, CMe3). 13C NMR (150.8 MHz,
CDCl3): δ = 144.5 (s, C4a), 129.9 (d, 2JCP = 8.9 Hz, C2),
129.0 (d, C7a), 122.1 (d, C6), 120.1 (s, C5), 119.0 (s, C4),
116.1 (s, C3), 113.2 (d, 3JCP = 20.2 Hz, C7), 55.0 (s, CH2),
C23H35N2P: C, 74.56; H, 9.52; N, 7.56. Found: C, 74.90; H,
9.82; N, 7.38.
Synthesis of 1-(Dicyclohexylphosphino)-3-trimethyl-
ammonium-methylindole Iodide (2a): Iodomethane
(0.193 g, 1.36 mmol) was added to a solution of compound
2 (0.503 g, 1.36 mmol) in toluene (30 mL) via syringe. The
reaction mixture was stirred for 16 h at ambient temperature,
after which the white powder was isolated by filtration. 1-
(Dicyclohexylphosphino)-3-trimethylammonium-methyl-
indole iodide (0.67 g, 96%) was obtained by washing the
solid with Et2O (10 mL) and drying in vacuo; mp 202 °C
(dec.). 1H NMR (600 MHz, DMSO-d6): δ = 7.88 (s, 1 H, H2),
7.82 (d, 3JHH = 7.8 Hz, 1 H, H7), 7.72 (d, 3JHH = 7.8 Hz, 1 H,
H4), 7.24 (t, 3JHH = 7.2 Hz, 1 H, H5), 7.20 (t, 3JHH = 7.2 Hz,
1 H, H6), 5.14 (s, 2 H, CH2), 3.42 (s, 9 H, NMe3), 2.29 (s, 2
H, Cy), 1.85 (br d, J = 8.3 Hz, 2 H, Cy), 1.72 (d, J = 11.4 Hz,
2 H, Cy), 1.61 (d, J = 8.3 Hz, 4 H, Cy), 1.36 (m, 4 H, Cy),
1.20 (m, 2 H, Cy), 1.05 (m, 6 H, Cy). 13C NMR (150.8 MHz,
DMSO-d6): δ = 142.3 (s, C7a), 134.8 (s, C2), 128.9 (s, C4a),
122.7 (s, C5), 121.1 (s, C6), 118.9 (s, C7), 112.6 (s, C4),
45.6 (s, NMe2), 35.3 (d, 1JCP = 25.0 Hz, PC), 29.4 (d, 2JCP
=
16.4 Hz, PCMe3). 31P NMR (161.9 MHz, CDCl3): δ = 71.3
(s). MS (ESI): m/z (%) = 341.1 (5) [MNa]+, 318.6 (18)
[MH]+, 274.2 (100) [M – NMe2]+. Anal. Calcd for
C19H31N2P: C, 71.66; H, 9.81; N, 8.80. Found: C, 71.70; H,
10.39; N, 8.83.
Synthesis of 1-(Di-tert-butylphosphino)-3-trimethyl-
ammoniummethylindole Iodide (1a): Iodomethane (0.391
g, 2.75 mmol) was added to a solution of compound 1 (0.844
g, 2.75 mmol) in toluene (60 mL) via syringe. The reaction
mixture was stirred for 16 h at ambient temperature after
which the white powder was isolated via filtration. 1-(Di-
tert-butylphosphino)-3-trimethylammoniummethylindole
iodide (1.15 g, 91%) was obtained by washing the solids
with hexanes (10 mL) and drying in vacuo; mp 224 °C
(dec.). 1H NMR (600 MHz, DMSO-d6): δ = 8.03 (s, 1 H, H2),
7.83 (m, 2 H, H4, H7), 7.27 (t, 3JHH = 7.8 Hz, 1 H, H5), 7.22
(t, 3JHH = 7.8 Hz, 1 H, H6), 4.78 (s, 2 H, CH2), 3.08 (s, 9 H,
NMe3), 1.18 (d, 3JHP = 12.8 Hz, 18 H, CMe3). 13C NMR
(150.8 MHz, DMSO-d6): δ = 143.5 (d, 2JCP = 20.51 Hz, C7a),
136.3 (s, C2), 128.2 (d, C4a), 122.7 (s, C5), 121.1 (s, C6),
118.9 (s, C7), 113.1 (s, C4), 106.3 (s, C3), 60.1 (s, CH2), 51.7
(s, NMe3), 34.7 (d, 1JCP = 25.49 Hz, PC), 28.7 (d,
106.2 (s, C3), 60.1 (s, CH2), 51.6 (s, NMe3), 35.1 (d, 2JCP
=
15.0 Hz, PCHCH2), 28.7 (d, 1JCP = 18.7 Hz, PCH), 27.6 (d,
3JCP = 6.1 Hz, PCHCH2CH2), 26.0 (d, 2JCP = 13.7 Hz,
PCHCH2), 25.8 (d, 3JCP = 7.5 Hz, PCHCH2CH2), 25.7 (s,
PCHCH2CH2CH2). 31P NMR (161.9 MHz, CDCl3): δ = 55.2
(s). MS (ESI): m/z (%) = 326.2 (100) [M – NMe3]+. Anal.
Calcd for C24H38N2PI: C, 56.25; H, 7.47; N, 5.47. Found: C,
56.28; H, 7.57; N, 5.40.
General Procedure for Suzuki–Miyaura Coupling
Reactions (Thermal): Phenylboronic acid (50.6 mg, 0.415
mmol), Pd2(dba)3 (5.2 mg, 0.00566 mmol), ligand (0.0136
mmol), cesium carbonate (184.3 mg, 0.566 mmol), and aryl
halide (0.377 mmol) were sequentially added to a 10-mL
conical microwave vial in an inert atmosphere dry box. The
mixture was suspended in [P66614][NTf2] (1.0 mL) and
degassed H2O (0.6 mL) as appropriate (Tables 2 and 3) and
2JCP = 15.99 Hz, PCMe3). 31P NMR (161.9 MHz, DMSO-d6):
δ = 75.0 (s). MS (ESI): m/z (%) = 274.1 (100) [M – NMe3]+.
Anal. Calcd for C20H34N2PI: C, 52.18; H, 7.44; N, 6.08.
Found: C, 52.26; H, 7.77; N, 6.06.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 977–982

982
A. J. Keith et al.
LETTER
stirred for 48 h at 180 °C in the sealed vial immersed in an
oil bath. The reaction mixture was diluted with Et2O (1.0
mL) containing 1% decane and filtered through a pad of
Celite. A 0.1-mL aliquot was diluted with Et2O (0.9 mL) and
analyzed by GC–FID. Yields reported are the average of
triplicate trials.
and stirred for 3 h at 180 °C in the sealed vial in a Biotage
Initiator microwave synthesizer. The reaction mixture was
diluted with Et2O (1.0 mL) containing 1% decane and
filtered through a pad of Celite. A 0.1-mL aliquot was
diluted with Et2O (0.9 mL) and analyzed by GC–FID. Yields
reported are the average of triplicate trials.
General Procedure for Suzuki–Miyaura Coupling
Reactions (Microwave): Phenylboronic acid (50.6 mg,
0.415 mmol), Pd2(dba)3 (5.2 mg, 0.00566 mmol), ligand
(0.0136 mmol), cesium carbonate (184.3 mg, 0.566 mmol),
and aryl halide (0.377 mmol) were sequentially added to a
10-mL conical microwave vial in an inert atmosphere dry
box. The mixture was suspended in [P66614][NTf2] (1.0 mL)
and degassed H2O (0.6 mL) as appropriate (Tables 2 and 3)
Crystallographic data (excluding structure factors) for 1a
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication CCDC 943804.
Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK, [fax: +44(1223)336033 or e-mail:
deposit@ccdc.cam.ac.Uk].
Synlett 2014, 25, 977–982
© Georg Thieme Verlag Stuttgart · New York

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