Preparation and application of indolyl secondary phosphine oxides in palladium complexes catalyzed Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1016/j.tet.2013.01.013

Several new indolyl secondary phosphine oxides (SPOs), C₈H ₆N-P(O)(H)(^tBu) (4a′), MeC₈H ₅N-P(O)(H)(^tBu) (4b′), and PhC₈H ₅N-P(O)(H)(^tBu) (4c′), were prepared from the reactions of corresponding 1H-indoles with P^tBuCl₂ and hydrolysis followed. Further reaction of 4a′, a tautomeric form of C ₈H₆N-P(OH)(^tBu) (4a), with Pd(COD)Cl ₂ yielded a di-palladium complex, [(4a)(4a-H⁺)Pd(μ-Cl)] ₂ (6a). Crystal structures of PhC₈H₅N-P(Cl) (^tBu) (3c), (4c′) and (6a) were determined by single-crystal X-ray diffraction methods. The stability of this type of SPO is presumably caused by the indolyl scaffold. In addition, SPOs are air- and moisture-stable preligands and are advantageous for the purpose of storage. In this work, these SPO ligands were employed in the Suzuki-Miyaura cross-coupling reactions as catalytic precursors. This catalytic condition has been tolerated to a variety of functional groups and the coupling reactions underwent efficiently with the arylbromides and arylchlorides, respectively.

Full text of DOI:10.1016/j.tet.2013.01.013

Tetrahedron 69 (2013) 2327e2335
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation and application of indolyl secondary phosphine oxides
in palladium complexes catalyzed SuzukieMiyaura cross-coupling
reaction
*
Yen-Yu Chang, Fung-E Hong
Department of Chemistry, National Chung Hsing University, 250 Kuo-Kuang Road, Taichung 40227, Taiwan
a r t i c l e i n f o
a b s t r a c t
Several new indolyl secondary phosphine oxides (SPOs), C8H6NeP(]O)(H)(tBu) (4a0), MeC8H5NeP(]
O)(H)(tBu) (4b0), and PhC8H5NeP(]O)(H)(tBu) (4c0), were prepared from the reactions of corresponding
1H-indoles with PtBuCl2 and hydrolysis followed. Further reaction of 4a0, a tautomeric form of
Article history:
Received 6 September 2012
Received in revised form 28 December 2012
Accepted 4 January 2013
C8H6NeP(OH)(tBu) (4a), with Pd(COD)Cl2 yielded a di-palladium complex, [(4a)(4a-Hþ)Pd(
m-Cl)]2 (6a).
Available online 17 January 2013
Crystal structures of PhC8H5NeP(Cl)(tBu) (3c), (4c0) and (6a) were determined by single-crystal X-ray
diffraction methods. The stability of this type of SPO is presumably caused by the indolyl scaffold. In
addition, SPOs are air- and moisture-stable preligands and are advantageous for the purpose of storage.
In this work, these SPO ligands were employed in the SuzukieMiyaura cross-coupling reactions as
catalytic precursors. This catalytic condition has been tolerated to a variety of functional groups and the
coupling reactions underwent efficiently with the arylbromides and arylchlorides, respectively.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
SuzukieMiyaura reaction
Secondary phosphine oxide
Palladium
Indolyl
PeN bond
Hydrogen bonding
1. Introduction
partially oxidized and meanwhile maintaining its coordinating
capacity.12 Phosphinous acid (PA), a tautomeric form of its corre-
Modern synthetic chemistry has enjoyed numerously handy ways
of making CeX (X¼C, N, O, S, etc.) bonds through various forms of
cross-coupling reactions.1 Among all those marvelous methods,
SuzukieMiyaura reaction stands out as one of the most employed
methods in constructing diversified biaryls from the reaction of aryl-
halides with arylboronic acids.2 This method has far-reaching appli-
cations in pharmaceuticals,3 materials,4 and agricultural chemistry.5
As demonstrated, ligand plays indispensable role in transition
metal complex catalyzed SuzukieMiyaura reaction.6 Consequently,
exploration of more efficient ligands has been a fruitful field for
synthetic chemists.1e,7 Due to their modifiable steric and electronic
properties,8 for many years, diverse forms of trialky- or triaryl
phosphines have been the most favorite ligands chosen9 in spite of
recent challenges from the so called ‘eco-friendly’ ligands, such as
N-heterocyclic carbenes, oximes, diazabutadienes, amines, and
imines.10 Nevertheless, this type of phosphines are mostly vulner-
able to oxidation and thereafter lessening their bonding capacities
toward soft metals,11 a severe drawback, which limits their exten-
sive applications as authentic soft ligands. It is also not a desirable
character for long-term storage of precious phosphine compounds.
One way to resolve this obstacle is allowing phosphine to be
sponding air-stable secondary phosphine oxide (SPO) in solution, is
a potential candidate and has the capacity as an authentic phos-
phine ligand, which can coordinate to transition metal (Scheme
1).13 For the past few years, various kinds of SPOs were prepared
and their resistances against air and moisture were examined and
validated. Their capacities as effective ligands in cross-coupling
reactions have also been evaluated.12,14
Recently, indole has been employed as the robust scaffold in the
preparation of tri-substituted phosphines (Fig. 1).15 Presumably, the
delocalization of p-electrons in indolyl ring provides the p-accepting
capacity necessary for backbonding from the coordinated transition
metal thus enhances the bonding strength between ligand and
transition metal. Besides, phosphorus donor ligand that possesses
NeP bond in the ligand scaffold presumably could provide an
electron-rich s-donor character on the phosphorus atom, which is
beneficial to the oxidative addition process in the catalytic cycle.
One of the drawbacks of a conventional PeN bond is that it may
not be able to withstand high reaction temperature due to its rel-
atively weak bonding. It is believed that the resonance within
indolylphosphine also provides extra bonding strength for the PeN
bond, which is a character desperately needed for active ligand in
harsh reaction conditions (Fig. 2).16
By combining the merits both from the robust indolyl fragment
and air-/moisture-resisting character of SPO, indolylphosphine
* Corresponding author. E-mail address: fehong@dragon.nchu.edu.tw (F.-E.
Hong).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.013

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Y.-Y. Chang, F.-E. Hong / Tetrahedron 69 (2013) 2327e2335
Scheme 1. Tautomeric equilibrium between a secondary phosphine oxide (SPO) and phosphinous acid (PA) and the formation of PA coordinated metal complex.
their catalytic performances in SuzukieMiyaura cross-coupling
reactions.
2. Results and discussion
2.1. Preparation of indolyl secondary phosphine oxides 4a0ec0
and palladium complex 6a
Fig. 1. Two selected N-indolyl based phosphines.
As shown in Scheme 2, indole (1a) was firstly deprotonated by
slightly excess amount of nBuLi, which led to the formation of
Fig. 2. The resonance forms of indolylphosphine.
could be regarded as a new class of phosphine ligands with stability
and efficiency desperately needed. Herein, we report the prepara-
tion of several indolyl-type SPO ligands and further exploration of
a deprotonated 2a. It was then followed by the addition of the
matching molar amount of tBuPCl2. Non-substituted phosphine
(3a) was yielded in good quantity. The conversion of 3a to its
Scheme 2. Preparations of indolyl secondary phosphine oxides and palladium complexes.

Y.-Y. Chang, F.-E. Hong / Tetrahedron 69 (2013) 2327e2335
2329
corresponding phosphinous acid (4a) was achieved by slowly
adding H2O. In principle, a tautomeric equilibrium is existed be-
tween the secondary phosphine oxide (4a0) and its corresponding
phosphinous acid (4a) under ambient condition. In practical, the
secondary phosphine oxide (4a0) conformer is dominated over its
corresponding phosphinous acid (4a) form in solution. Similarly,
substituted indolyl-type preligands (4b0ec0) and their tautomeric
form (4bec) could be prepared by the same procedures. In-
teresting, it took 2 h, 2 days, and 2 weeks to complete the hydrolysis
for the formation of (4a0), (4b0), and (4c0), respectively. The fact that
it took much longer time for the hydrolysis of 4c0 than that of 4b0
was unexpected since ePh is regarded as much more hydrophilic
than eCH3 group. It was observed that 4c0 only gradually decom-
posed to tert-butylphosphinic acid and indole for several months in
the presence of moisture, an evidence for the air-/moisture-
resisting character of 4c0.
Further reaction of 4a0 with 1 M equivalence of Pd(COD)Cl2 in
THF at 25 ꢀC for 16 h yielded a di-palladium complex, [(4a)(4a-Hþ)
Pd(m-Cl)]2 (6a) (Scheme 2). Presumably, a cis-form of bis-phosphine
Fig. 4. ORTEP diagram of 4c0.
ligands (4a) coordinated PdCl2 complex, cis-(4a)2PdCl2 (5a), was
formed firstly, then converted to 6a. It was evidenced by the ob-
servation of an additional 116 ppm signal, accompanied with
a 103.8 ppm peak for 6a, in 31P NMR by monitoring the progress of
reaction. Eventually, the chemical shift for 5a disappeared and only
signal for 6a remained. Sadly, the conformation of 5a was not fur-
ther validated since crystal-growing process was not successful.
Fortunately, suitable crystals of 6a were obtained for structural
determination. It was later confirmed that 6a is another version of
Li’s POPd1 complex.12r Besides, a side product, PtBu(1H-indolyl)2
(7a), was observed from the reaction, presumably, a result of re-
action of PtBuCl2 with excess 2a.17
non-deprotonated 4a0 in cis-form of a bis-phosphine ligands. This
is one of the unique features of SPO than conventional triar-
ylphosphine in this type of bonding for a palladium complex.
The crystal structure of 6a reveals that the center of the molecule
is a diamond-shaped moiety consisted of four atoms, Pd, Cl(1), Pd(A),
and Cl(1A). Each palladium center is chelated by a combined ligand
from two phosphinous acids (Fig. 5). A hydrogen bonding exists
between oxygen atom (P]O) of the deprotonated phosphinous acid
and hydrogen atom (PeOH) of the phosphinous acid.14b,18 The bond
ꢀ
lengths of P(1)eO(1) and P(2)eO(2) are 1.5363(15) and 1.5326(15) A,
Compounds 3c, 4c0, and 6a were crystallized from saturated
CH2Cl2 solution at 4 ꢀC for several weeks. Their structures were
determined by single-crystal X-ray diffraction methods. The ORTEP
diagrams of 3c, 4c0, and 6a are depicted in Figs. 3e5, respectively.
The crystal structures of 3c and 4c0 reveal the existence of a PeCl
and P]O bonds, respectively. The bond length of P(1)eCl(1) is
respectively. Both are typical single bonds. Each chloride bridges two
palladium atoms. There is a C2 axis passes through the Pd and Pd(1A)
atoms. Two substituents of phosphorous, tBu and indolyl, are
arranged in staggered forms. Both di-valent palladium atoms are
remained.
ꢀ
ꢀ
2.0706(5) A. It is 1.4702(13) A for P(1)eO(1), a typical double bond.
The tautomeric shift of the secondary phosphine oxide 4a0 to its
phosphinous acid form 4a during the coordination is further evi-
denced from the conformation of 6a. We also noticed that intra-
molecular hydrogen-bondings exist between deprotonated and
2.2. Palladium-catalyzed SuzukieMiyaura reactions using
4a0ec0 as ligands
Palladium complexes catalyzed SuzukieMiyaura cross-coupling
reactions of arylhalides and phenylboronic acid were carried out by
employing the newly-prepared N-indolylphosphines (4a0ec0) as
ligands (Scheme 3). Several factors that potentially affect the effi-
ciency of the reaction, including temperature, time, concentration,
base, transition metal/ligand ratio and solvent etc., had been
screened to reach its optimized reaction condition.
The general procedure for the SuzukieMiyaura cross-coupling
reaction under investigation is presented as the follows. Under N2
atmosphere, a 20 mL Schlenk tube was charged with 0.5 mmol of
aryl halide, 0.75 mmol of phenylboronic acid, 1.0 mL of solvent,
1.5 mmol of base, 1.0 mol % of palladium salt, and 2.0 mol % of
a secondary phosphine oxide ligand (4a0, 4b0 or 4c0). The reaction
was executed at preset temperature and time. It was then followed
by work-up processes. The conversion rate was determined from
the measurement of product’s distinct 1H NMR signal against
standard; while, the isolated yield was calculated from the product
purified by column chromatography.
Firstly, the efficiencies of N-indolylphosphines (4a0ec0) as li-
gands were screened. As shown in Table 1, ligand 4a0 was found to
be the best choice from the preliminary results where the reaction
was carried out at 60 ꢀC within 30 min. The substituted indolyl-
phosphines (4b0 & 4c0) performed poorly compared to the (4a0)
probably due to severe steric effect. It is more visualized in the case
of 4b0, where a methyl substituent presents substantially steric
Fig. 3. ORTEP diagram of 3c.

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Y.-Y. Chang, F.-E. Hong / Tetrahedron 69 (2013) 2327e2335
Fig. 5. ORTEP diagram of 6a.
Scheme 3. Indolyl-SPOs assisted palladium-catalyzed SuzukieMiyaura reactions of bromo- or chlorotoluene and substituted phenylboronic acid employing 4a0ec0 as ligands.
Table 2
Table 1
SuzukieMiyaura coupling reactions employed various palladium sourcesa
SuzukieMiyaura coupling reactions employed ligands 4a0ec0
Conv. (%)a
Conv. (%)b
Entry
Palladium source
Conv. (%)b
Entry
Ligand
1
2
3
4
5
6
7
8
Pd(COD)Cl2
Pd(CH3CN)2Cl2
PdCl2
PdBr2
Pd(OAc)2
[Pd(Cl)(C3H5)]2
Pd(NO3)2$H2O
Pd2(dba)3
>99(98)
98(45)
>99(16)
83(37)
97(49)
54(18)
>99(74)
93(9)
1
2
3
4a0
4b0
4c0
98
11
37
7
22
93
a
Conditions: 2-bromotoluene (0.5 mmol), phenylboronic acid (0.75 mmol), KOH
(1.5 mmol), THF (1 mL), and Pd(COD)Cl2 (1.0 mol %), [Pd]/L¼1/2, 60 ꢀC, 0.5 h; de-
termined by 1H NMR.
b
Conditions: 3-chlorotoluene (0.5 mmol), phenylboronic acid (0.75 mmol), KOH
(1.5 mmol), 1,4-dioxane (1 mL), and Pd(COD)Cl2 (5.0 mol %), [Pd]/L¼1/2, 100 ꢀC,
a
The same reaction condition as described in Table 1 except palladium source.
Determined by 1H NMR, 1.0 h; 0.25 h in parentheses.
16 h.
b
hindrance. Since 4a0 outperformed other ligands (4b0 & 4c0),
thereby, reactions were carried out using 4a0 as ligand thereafter.
The efficiencies of several commonly used palladium sources
were evaluated in the SuzukieMiyaura reaction as well. As known,
Pd(OAc)2 is more readily to be reduced in the presence of electron-
rich phosphine.19 While, the reduction of halogenated palladium
salt, such as PdX2 (X: Cl, Br) takes longer time. Therefore, it is al-
ways an expectation that under short reaction time Pd(OAc)2 shall
outperform PdX2. However, as shown in Table 2, excellent perfor-
mances were obtained while using Pd(L)Cl2 (L: none, COD, CH3CN)
as the palladium source for 1 h reaction (entries 1, 2, & 3). Even 98%
conversion was observed in 15 min for using Pd(COD)Cl2. The
performance of Pd(OAc)2 is not as good as expected at short re-
action time, 15 min. Nevertheless, it caught up the rate for longer
reaction period (entry 5). Unexpectedly, rather poor performance
was obtained for a Pd(0) source, Pd2(dba)3, at short reaction time
(entry 8).
most of the cases a well-chosen base is indispensable to excellent
performance of the catalytic reaction.20 As known, the role played
by base in the reaction is also the most ambiguous and un-
predictable one.10d,20b,21 Herein, the impacts of various bases on the
reaction yields were examined under the same reaction condition
as described in footnote of Table 1 except reaction time for 2 h. Five
salts were employed. The conversion rates for KOH, KF, Na2CO3,
K3PO4, and K2CO3 are >99%, 66%, 37%, 32%, and 18%, respectively.
Among all the bases screened, it was found that KOH in THF is the
most effective while the other bases like Na2CO3, K2CO3, KF, and
K3PO4 gave unsatisfactory yields of product. We suspect that the
cation of the base, besides its basicity, might be one of the most
influential factors in this type of reaction.
The solubility of substances and catalyst in solvent is greatly
affected by the polarity of it. A carefully selected solvent is critical to
the performance of the catalytic reaction. Here, eight solvents, THF,
DMF, 1,4-dioxane, DMSO, EA, MeOH, toluene, and hexanes, with
different polarities were tried. The conversion rates are >99%, 93%,
As reported earlier, the rate of SuzukieMiyaura reaction might
be intolerably slow without the presence of appropriate base. For

Y.-Y. Chang, F.-E. Hong / Tetrahedron 69 (2013) 2327e2335
2331
77%, 67%, 65%, 61%, 25%, and <1%, respectively. As revealed, the
combination of KOH with THF (or DMF) leads to excellent results in
short reaction time. Unexpectedly, the performance of toluene is
rather poor. On the other hand, using hexane as solvent gave poor
yield, which is understandable due to poor solubility of palladium
salt in a nonpolar solvent.
In addition, the concentration of the reactants, by changing the
amount of solvents used, indeed affects the catalytic performance
of the reaction. The conversion was almost quantitative (>99%)
while 1 mL THF was used. It dropped to 63% and 28% for employing
2 and 3 mL THF, respectively.
As demonstrated repeatedly, the most commonly employed
ratio of palladium salt to a mono-dentate phosphine ligand is 1:2
for the case of using palladium complex as the catalytic precursor.
As expected, excellent yields were obtained while the ratio of
Pd(COD)Cl2/4a0 is 1:2 either at 60 ꢀC or 30 ꢀC (Table 3, entries 2 &
5).22 Excess amount of ligands even caused retardation of the re-
action rates (entries 3 & 6).
1.0 mL of THF, 1.5 mmol of KOH, 2.0 mol % of Pd(COD)Cl2 and
4.0 mol % of 4a0. The reaction was executed at 60 ꢀC for 1 h and
work-up followed. The conversion rates are 78%, 83%, 48%, 99%,
38%, and 8% for p-tolyl-, 4-acetylphenyl-, 4-methoxyphenyl, 4-
(trifluoromethyl)phenyl-, 4-cyanophenyl-, naphthalen-1-yl-bo-
ronic acid. It was found that the conversion rates were compatible
with the previous reactions except for substance with severe steric
hindrance.
A frequent observation in SuzukieMiyaura coupling reaction
states that a better conversion is achieved with arylhalides bearing
an electron-withdrawing than electron-donating substituent.23
This observed fact presumably is held for the reaction with the
oxidative addition process as the rate-determining-step (r.d.s).
Nevertheless, other unanticipated factors might disturb this con-
clusion. SuzukieMiyaura coupling reactions employing various
substituted arylbromides and phenylboronic acid were pursued
under the preset reaction conditions (Table 4). Interestingly, rela-
tively close performances were observed for substances with
electron-donating groups as well as the electron-withdrawing
cases even reactant bearing substituent with severe steric hin-
drance. It indicates that Pd(COD)Cl2/4a0¼1:2 is a rather efficient
combination of pre-catalyst and exhibits good tolerance of various
functional groups on arylbromides.
Table 3
a
SuzukieMiyaura coupling reactions employed various ratio of Pd(COD)Cl2/4a0
Entry
[Pd]/4a0
Conv. (%)b
1
2
3
4
5
6
1/1
1/2
1/3
1/1
1/2
1/3
94
98
Normally, arylchloride is less reactive than arylbromide in
cross-coupling reactions due to its stronger C(sp2)eCl bond than
that of C(sp2)eBr. To discern the catalytic capacities of 4a0ec0 as
ligands in SuzukieMiyaura reactions, it is better to use less re-
active arylchlorides than arylbromides. Meanwhile, due to the
lower reactivity of 3-chlorotoluene, the following Suzu-
kieMiyaura reactions were carried out at 100 ꢀC to reach rea-
sonable speed.
60
76c
82c
55c
a
The same reaction condition as described in Table 1 except the ratio of palla-
dium salt to ligand and reaction time, 0.25 h.
b
Determined by 1H NMR.
30 ꢀC, 1 h.
c
The efficiencies of N-indolylphosphines (4a0ec0) as ligands in
SuzukieMiyaura reactions of 3-chlorotoluene with phenylboronic
acid were examined. Surprisingly, as shown in Table 1 (the fourth
column), ligand 4c0 outperformed 4a0 and 4b0, which is quite dif-
ferent from the cases of arylbromide (Table 1, the third column).
For comparison, the SuzukieMiyaura cross-coupling reactions
for several substituted arylboronic acids were carried out. Similar
procedures were taken and the reactants are 0.5 mmol of 1-bromo-
2-methylbenzene, 0.75 mmol of substituted phenylboronic acid,
Table 4
SuzukieMiyaura coupling reactions employing various arylhalidesa
Entry
Substrate
Product
Yield (%)b
98(97)
1
2
94(92)
3
4
85(78)
80(80)
5
90(85)
(continued on next page)

2332
Y.-Y. Chang, F.-E. Hong / Tetrahedron 69 (2013) 2327e2335
Table 4 (continued )
Entry
Substrate
Product
Yield (%)b
80(77)
6
7
8
d(91)
d(87)
9
d(80)
10
92(83)
a
The same reaction condition as described in Table 1 except reaction time, 0.25 h.
Determined by 1H NMR, isolated yield in parentheses.
b
As shown previously, a proper combination of solvent/base is
SuzukieMiyaura reactions employing the combination of
Pd(OAc)2/4c0 as catalytic precursor for various substituted aryl-
chlorides and phenylboronic acid were carried out at 100 ꢀC for
24 h (Table 5). A common observation shows that a better con-
version is achieved with arylhalides bearing an electron-
withdrawing than an electron-donating substituent in Suzu-
kieMiyaura coupling reaction. This statement is held here for
these reactions (Table 5 vs 4). As shown, the performances of
arylchlorides bearing an electron-withdrawing in SuzukieMiyaura
coupling reactions are better than cases with electron-donating
substituents. Rather poor performance was observed for hetero-
cyclic case (entry 9).
a crucial factor to the catalytic performance of this reaction. Since
the reactions had to be carried out at high temperature (100 ꢀC) for
reaching reasonable performance, the commonly used solvents,
such as THF is thereby ruled out. Here, four solvents, 1,4-dioxane,
DMSO, DMF, and toluene, with different polarities were tried. The
conversion rates are 39%, 8%, <1%, and 55%, respectively, using
Pd(COD)Cl2 as palladium source for reacting 16 h. The combination
of KOH with toluene led to acceptable results. Unexpectedly, the
performances of DMF and DMSO were rather poor. The yield could
be raised to 72% by using Pd(OAc)2 as palladium source for reacting
24 h.
Table 5
SuzukieMiyaura coupling reactions employing various aryl halidesa
Entry
Substrate
Product
Yield (%)b
1
65
2
3
31
23
4
5
81
69

Y.-Y. Chang, F.-E. Hong / Tetrahedron 69 (2013) 2327e2335
2333
Table 5 (continued )
Entry
Substrate
Product
Yield (%)b
6
7
82
75
8
9
70
trace
a
Conditions: substituted chlorotoluene or 2-chloropyridine (0.5 mmol), phenylboronic acid (0.75 mmol), KOH (1.5 mmol), solvent (1 mL), and Pd(OAc)2 (2 mol %), [Pd]/
4c0¼1/2, 100 ꢀC, 24 h.
b
Isolated yield.
3. Summary
(3a). Caution shall be taken to prevent the formation of (7a) due to
large excess ratio of (2a) to t-butyldichlorophosphine. The forma-
tion of (4a0) through the hydrolysis of (3a) was carried out by
adding adequate amount of water and stirred for certain time.
Certain amount of ethyl acetate was added three times to extract
the product from mixed solution in separatory funnel. The total
collected organic phase was concentrated and pure product was
collected after column chromatography. A pale-yellow solid 4a0
(2.055 g, 9.3 mmol, 93%) was obtained after all solvent was re-
moved by vacuum. Similar procedures for the preparation of 4b0
and 4c0 were carried out. The isolated products 4b0 and 4c0 are in
the yield of 64% (1.504 g, 6.4 mmol) and 73% (2.168 g, 7.3 mmol),
respectively.
Three new indolyl secondary phosphine oxides, 4a0ec0, were
synthesized and characterized. Among all four ligands, 4a0 exhibi-
ted the best performance in SuzukieMiyaura cross-coupling re-
actions for arylbromides. Yet, 4c0 performed better for the cases of
arylchlorides than arylbromides. Although the catalytic perfor-
mances of these indolyl-type SPOs may not be superior to their
trialkyl- or triarylphosphine counterparts, employment of these
compounds in cross-coupling reactions is an applicable choice for
the purpose of long-term storage.
4. Experimental section
4.1. General
4.2.1. Selected spectroscopic data for 4a0. 1H NMR (CDCl3,
d/ppm):
6.98, 8.24 (d, 1H, Jp-H¼505 Hz), 7.71, 7.73 (d, 2H), 7.63, 7.65 (d, 2H),
All reactions were carried out under a nitrogen atmosphere
using standard Schlenk techniques or in a nitrogen-flushed glove
box. Freshly distilled solvents were used. All processes of separa-
tions of the products were performed by column chromatography.
GCeMS analysis was performed on an Agilent 5890 gas chro-
matograph (Restek Rtx-5MS fused silica capillary column: 30 m,
7.22e7.30 (m, 3H), 6.73 (m, 1H),1.18,1.23 (d, 9H); 13C NMR (acetone-
d6,
d/ppm): 23.65(s), 34.71, 35.55(d), 108(d), 113.55(s), 121.51(s),
122.39(s), 123.70(s), 126.47(s), 131.04(s), 138.34(s); 31P NMR (CDCl3,
d
/ppm): 38.4 (d, Jp-H¼507 Hz); HRMS (EIMS): calcd for C12H16NOP;
221.10, found 221.0978.
0.25 mm, 0.5
m
m) with an AgilentÒ 5972 mass selective detector.
4.2.2. Selected spectroscopic data for 4b0. 1H NMR (CDCl3,
d/ppm):
Routine 1H NMR spectra were recorded on a Varian-400 spec-
trometer at 400.00 MHz. The chemical shifts are reported in parts
7.09, 8.35 (d,1H, Jp-H¼505 Hz), 7.70 (s,1H), 7.49 (t,1H), 7.12e7.18 (m,
2H), 6.40 (d, 1H), 2.58 (s, 3H), 1.12, 1.26 (d, 9H); 13C NMR (acetone-
per million relative to internal standards TMS (
NMR spectra were recorded at 162.1 and 100.7 MHz, respectively.
The chemical shifts for the former and the latter are reported in
d
¼0.0). 31P and 13C
d6,
120.17(s), 122.13(s), 122.60(s), 130.52(d), 138.41(s), 139.44(d); 31P
NMR (CDCl3,
d/ppm): 15.67(s), 24.29(s), 35.53, 36.37(d), 108.07(d), 113.75(s),
d
/ppm): 34.1 (d, Jp-H¼508 Hz); HRMS (EIMS): calcd for
ppm relative to internal standards H3PO4 (
respectively. Mass spectra were recorded on JOEL JMS-SX/SX 102A
GC/MS/MS spectrometer.
d
¼0.0) and CHCl3 (
d
¼77),
C13H18NOP; 235.11, found 235.1120.
4.2.3. Selected spectroscopic data for 4c0. 1H NMR (CDCl3,
d/ppm):
6.78, 8.08 (d, 1H, Jp-H¼520 Hz), 8.15,8.17 (d, 1H), 7.23e7.62 (m, 8H),
4.2. Synthesis and characterization of 4a0ec0
6.66 (m, 1H), 0.88, 0.92 (d, 9H); 13C NMR (acetone-d6,
d/ppm):
24.15(s), 35.67, 36.47(d), 109.60(d), 115.67(s), 120.58(s), 122.73(s),
123.38(s), 128.60(s), 128.65(s), 129.79(s), 130.32(s), 132.04(d),
Into
a 100 mL round-bottomed flask was charged with
10.0 mmol (1.18 g) indole (1a). The flask was refilled with N2 before
20 mL THF was added. The flask was kept at ꢁ78 ꢀC while
11.0 mmol n-BuLi (2.5 M in hexane) was slowly added into it. Pre-
sumably, lithio-indole (2a) was obtained after stirring for 15 min. At
another flask, 1.5 M equivalent of t-butyldichlorophosphine was
dissolved in 5 mL THF and kept at 0 ꢀC for a few minutes before (2a)
was transferred to it slowly. The solution was allowed to warm up
to 25 ꢀC and stirred for another 2 h, which led to the formation of
140.44(s),142.30(s); 31P NMR (CDCl3,
d
/ppm): 37.6 (d, Jp-H¼520 Hz);
HRMS (EIMS): calcd for C18H20NOP; 297.13, found 297.1290.
4.2.4. Synthesis and characterization of 6a. A N2 flashed 100 mL
round-bottomed flask was placed 0.10 mmol (22.10 mg) 4a0 and
0.05 mmol (14.28 mg) Pd(COD)Cl2 and 2.5 mL THF. The flask was
kept at 25 ꢀC and stirred for 16 h. A yellow-brown solid 6a was
obtained after all solvent was removed by vacuum. Small amount of

2334
Y.-Y. Chang, F.-E. Hong / Tetrahedron 69 (2013) 2327e2335
174e238; (c) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651e2710; (d)
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CH2Cl2 was added till all solid was dissolved. Large amount of
hexanes was added to assist the participation of the solid. Several
dark brown colored crystallines were obtained in EA/Hexane mixed
solvent for several days and ready for X-ray crystallographic
determination.
€
4.2.5. Selected spectroscopic data for 6a. 1H NMR (CDCl3,
d/ppm):
8.77 (d, J¼8.0 Hz, 1H, indolyl), 7.58e7.54 (m, 2H, indolyl), 7.35e7.20
(m, 2H, indolyl), 6.58e6.53 (m,1H),1.15 (d, J¼18.4 Hz, 3H, t-Bu),1.06
(d, J¼18.8 Hz, 6H, t-Bu); 13C NMR (CDCl3,
d/ppm): 139.4, 130.9,
128.7, 123.4, 122.1, 121.0, 115.0, 106.8 (indolyl), 43.0, 26.6 (t-Bu); 31P
NMR (CDCl3, d/ppm): 103.8.
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4.2.6. General procedure for the SuzukieMiyaura cross-coupling re-
actions. SuzukieMiyaura cross-coupling reactions were performed
according to the following procedures. The four reactants, palladium
source, 4a0ec0, boronic acid and base were placed in a suitable oven-
dried Schlenk flask. It was evacuated for 0.5 h and backfilled with
nitrogen gas before adding solvent and aryl halide through a rubber
septum. The aryl halides being solids at room temperature were
added prior to the evacuation/backfill cycle. The flask was sealed
with a rubber septum and the solution was stirred at the required
temperature for designated hours. Then, the reaction mixture was
diluted with ethyl acetate (3 mL) and the cooled solution poured into
a separatory funnel. The mixture was washed with aqueous NaOH
(1.0 M, 5 mL) and the aqueous layer was extracted with ethyl acetate
(2ꢂ5 mL). The combined organic layer were washed with brine and
dried with anhydrous magnesium sulfate. The dried organic layer
was concentrated in vacuo. The residue was purified by column
chromatography to give the desired product.
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ꢁ
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6a were sealed in thin-walled glass capillaries under nitrogen at-
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Intensity datawere collected in 1350 frames with increasing
u (width
of 0.3ꢀ per frame). The absorption correction was based on the
symmetry equivalent reflections using SADABS program. The space
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thermal parameters were used for all non-H atoms, and fixed iso-
tropic parameters were used for H atoms.25 Crystallographic data for
compounds 3c, 4c0, and 6a are available from Supporting data.
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Acknowledgements
We thank the National Science Council of the R.O.C. (Grant NSC
98-2113-M-005-006-MY3) for financial support.
Supplementary data
Crystallographic data for the structural analysis have been de-
posited with the Cambridge Crystallographic Data Center, CCDC no.
816963, 816964, and 816965 for compounds 3c, 4c0, and 6a, re-
spectively. Copies of this information may be obtained free of
charge from the Director, CCDC,12 Union Road, Cambridge CB2 1EZ,
UK (fax: þ44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk or
www: http://www.ccdc.cam.ac.uk).
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