P-phenyl-2,2,6,6-tetramethylphosphorinan-4-ol: An air-stable p,o-type ligand for palladium-mediated cross-coupling reactions

Article abstract of DOI:10.1002/ejoc.201001099

A two-step entry to a chemically robust, hindered P,O-type phosphorinane-based ligand and its application toward Pd-mediated cross-coupling reactions of unactivated aryl chlorides is presented. A two-step entry to a chemically robust, hindered P,O-type phosphorinane-based ligand and its application toward Pd-mediated cross-coupling reactions of unactivated aryl chlorides is presented. Copyright

Full text of DOI:10.1002/ejoc.201001099

FULL PAPER
DOI: 10.1002/ejoc.201001099
P-Phenyl-2,2,6,6-tetramethylphosphorinan-4-ol: An Air-Stable P,O-Type
Ligand for Palladium-Mediated Cross-Coupling Reactions
Ehsan Ullah,[a] James McNulty,*[a] Vladimir Larichev,[a] and Al J. Robertson[b]
Keywords: Phosphane ligands / Palladium / Organopalladium chemistry / Amination
A two-step entry to a chemically robust, hindered P,O-type
phosphorinane-based ligand and its application toward Pd-
mediated cross-coupling reactions of unactivated aryl chlo-
rides is presented.
Introduction
Palladium-catalyzed bond-forming reactions have been
extensively investigated over the last few decades. Many of
these reactions are now routinely employed in effecting
carbon-carbon and carbon-heteroatom bond connections,
often with remarkable chemo- and stereoselectivity and
complete positional control.[1,2] Applications towards the
synthesis of agrochemicals, pharmaceuticals and fine chem-
icals continue to advance.[3] The continued improvements
to supporting ligands has expanded the scope of substrates
that enter such catalytic cycles to include the most challeng-
ing unactivated (electron-rich), sterically demanding aryl
chlorides.
A difficulty in the development of phosphane ligands for
Pd-mediated cross-coupling chemistry remains the advance-
ment of chemically robust (particularly to molecular oxy-
gen) ligands of applicability to a range of challenging cross-
coupling reactions. The P-disubstituted-biarylphosphanes
(for example SPhos and A, Figure 1) introduced by Buch-
wald and co-workers have allowed for remarkable advances
along these lines[4] although the capricious nature of indi-
vidual ligands to activate a given substrate has also been
documented. Pd complexes of the ligand SPhos (Figure 1)
proved generally applicable in Suzuki–Miyaura reactions of
congested aryl bromides while, most interestingly, the triar-
ylphosphane A (Figure 1) proved highly effective in activa-
ting ortho-substituted electron-rich aryl chlorides.[4b] Acti-
vation of other electron-rich aryl chlorides with biaryl li-
agnds has been reported to be problematic in other cases.[5]
The use of ferrocene-based triarylphosphane ligands has
also been reported in the Suzuki cross-coupling of unacti-
vated, hindered aryl chlorides.[4e,4f]
Figure 1. Selected examples of hemilabile phosphane ligands.
The development of novel structural classes of ligand
that can effect these problematic cross-coupling reactions is
an active area of investigation. Select examples include the
P,O-type indolylphosphanes B introduced by Kwong and
co-workers,[6] and the pyrrole and imidazole based systems
C introduced by Beller (Figure 1).[7] A modified indolyl-
phosphane was recently reported that proved highly effec-
tive in the synthesis of hindered biaryl systems.[6c] Other
useful sterically demanding, conformationally restricted li-
gands have been developed containing N-heterocyclic car-
bene ligands.[8] The desire to activate inexpensive, readily
available aryl chlorides has been a driving force behind the
development and application of many of these ligands.[8,9]
We have been interested in the development of a robust,
readily available ligand based on a phosphorinane scaffold
(Figure 2, 1b, 2b).[10] This ligand architecture incorporates
a variably substituted phosphane within a rigid, bulky di-
tert-butyl-like framework. We recently reported that Pd
complexes of the P-cyclohexyl-4-hydroxy-substituted ligand
2b were most efficient in a range of Suzuki–Miyaura reac-
tions with aryl chlorides, including hindered, electron-rich
systems such as 2,4-dimethoxychlorobenzene.
[a] Department of Chemistry, McMaster University
1280 Main Street West, Hamilton, Ontario, L8S 4M1, Canada
Fax: +1-905-522 2509
E-mail: jmcnult@mcmaster.ca
[b] Cytec Canada, Inc.,
P. O. Box 240, Niagara Falls, Ontario, L2E 6T4, Canada
Figure 2. Bi- and monodentate complexes of ligands 2a/b.
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Air-Stable Ligand for Pd-Mediated Cross-Coupling Reactions
The P,O-type ligand 2b incorporates a novel mono- phosphanes is elusive although clearly the introduction of
dentate/bidentate design feature involving a chair-boat con- one aryl group (contrasting 2b to 2a) contributes signifi-
formational flip. The remote 4-hydroxy substituent was de- cantly to the stability of ligand 2a.
signed to allow formation of a reactive monodentate L1-
Pd0 species through a ring flip to the chair conformer as
shown at the bottom of Figure 2, to stabilize the unsatu-
rated catalyst in the boat conformer outside of the catalytic
cycle and as a means of assisting reductive elimination pro-
cesses. Ligand 2b proved highly effective in activating aryl
chlorides in the Suzuki–Miyaura reaction,[10a] nonetheless
the ligand itself was prone to oxidation. The reactivity
of Pd-catalysts derived from certain P-aryl-biarylphos-
phanes[4b,4e,9k] as well an expected increase in stability
prompted us to investigate the reactivity of the correspond-
ing P-phenylphosphorinan-4-ol ligand 2a. In this paper, we
Figure 3. Bar graph showing the phosphane oxide formation moni-
tored by 31P-NMR[12a] for ligands 2a and 2b.
report the short synthesis of ligand 2a, its remarkable sta-
bility to molecular oxygen under aerobic conditions as well
as its versatility in effecting a range of problematic Pd-
mediated cross-coupling reactions.
The general utility of the ligand 2a was next investigated
in a series of Pd-mediated cross-coupling processes. Condi-
tions for the Suzuki–Miyaura reaction were readily iden-
Table 1. Suzuki cross-coupling reactions using ligand 2a.[a]
Results and Discussion
The required P-phenylphosphorin-4-ol ligands 2a and P-
cyclohexylphosphorin-4-ol 2b were prepared as outlined in
Scheme 1. Tandem inter- and intramolecular Michael ad-
dition of the primary phosphane to phorone[11] followed by
LAH-mediated ketone reduction provided access to both
ligands on a multi-gram scale.
Scheme 1. Synthesis of ligand 2a/b.
The stability of ligands 2a and 2b to aerobic conditions
was monitored over a period of one month (Figure 3). Both
ligands proved to be robust on short-term exposure to oxy-
gen, however ligand 2a proved to be exceptionally stable.
This phosphane stability is reminiscent of that observed
with bulky P-substituted, constrained ortho-substituted bi-
arylphosphanes.[12a] The biarylphosphanes are conforma-
tionally restrained through restricted Aryl–P bond rotation
while ligand 2a is intrinsically restrained within the phos-
phorinane ring; inversion at phosphorus is unlikely under
ambient conditions. A chair-to-chair ring flip on 2a would
also require introduction of the bulky Ph and hydroxy sub-
stituents into axial positions. It is not clear, using the
Barder–Buchwald model[12a] why oxidation of 2a cannot
readily proceed from the axial lone pair on phosphorus in
2a, we note only that both types of ligand consist of a con-
formationally restricted sterically hindered phosphane. A
marked dichotomy in primary phosphane stability was also
recently described by Gilheany and co-workers.[12b] A unify-
[a] Reaction conditions: 1.0 equiv. of aryl halide, 2.0 equiv. of bo-
ronic acid, 3.0 equiv. of Cs2CO3, Pd(OAc)2 1.0 mol-%, ligand
3.0 mol-%, toluene 5.0 mL, 110 °C, 12–16 h. [b] Isolated product
ing concept that explains the unusual stability of certain after column chromatography.
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E. Ullah, J. McNulty, V. Larichev, A. J. Robertson
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tified using 1.0 mol-% palladium(II) acetate and cesium carb- challenging hindered pairings proved to be slower as ex-
onate as base. Little to no conversion occurred at room pected, however increasing the catalyst loading (Pd 2.0%,
temperature using ligand 2a under these conditions and the 2a 6.0%), and reaction time to 48 h, allowed good conver-
reactions were performed under a standard condition in tol- sion and we were able to isolate the sterically hindered bi-
uene at 110 °C. A selection of examples is reported in aryl products in fairly good yield. In most cases, elevated
Table 1, focusing on aryl chlorides. A series of electron-rich, temperatures (110 °C) are required to activate challenging
electron-deficient and sterically hindered ortho-substituted aryl chlorides. The mild conditions (room temp. to 40 °C)
chlorobenzene derivatives could readily be activated with employed using the Buchwald catalyst highlight another of
the Pd complex of 2a and coupled with arylboronic acids the remarkable features of the biaryl catalyst.[4b] In other
(entries 1 to 7). Also of interest was the efficient cross-cou- examples, Beller’s pyrrole-based system[9k] and Fu’s ferro-
pling of the electron poor 4-acetylphenylboronic acid with cene-based ligand[4e] allowed cross-coupling of select chal-
chlorobenzene (entry 9). As expected, bromo- and iodo- lenging aryl chlorides at 60 and 70 °C respectively.
benzene derivatives reacted without incident providing the
corresponding biaryls in high yield.
We next investigated the use of palladium complexes of
the same ligand 2a in the Buchwald–Hartwig amination re-
The effectiveness of ligand 2a in Suzuki–Miyaura cross action.[13] We had previously found catalysts prepared from
coupling was further investigated in the synthesis of a range P-isobutyl-2,2,6,6-tetramethylphosphorinane and the pre-
of hindered biaryls from unactivated aryl chloride sub- cursor Pd2(dba)3 to be highly active in this reaction per-
strates and hindered, ortho-substituted arylboronic acids. formed in toluene or ionic liquid media.[13o] Efficient amin-
The results are summarized in Table 2. The reactions pro- ation protocols are of much current interest in the synthesis
ceeded slowly in toluene at 110 °C under the conditions re- of pharmaceutical intermediates[14] as well as functionalized
ported in Table 1. For example, 1-chloro-2,4-dimethoxyben- triarylamines which are the key components in a variety of
zene (Table 2, entry 3) reacted with phenylboronic acid in materials including organic photoconductors, light-emitting
the presence of 1.0% Pd and 3.0% 2a to give the biaryl diodes and photovoltaic cells.[15] Complicating factors have
in 74% yield after 16 h. The reactions involving the more been identified in the reaction, particularly where weakly
Table 3. Amination reactions using ligand 2a.[a]
Table 2. Suzuki cross-coupling reactions using ligand 2a.[a]
[a] Reaction conditions: 1.0 equiv. of aryl halide, 1.5 equiv. of bo-
ronic acid, 3.0 equiv. of Cs2CO3, Pd(OAc)2 2.0 mol-%, ligand
6.0 mol-%, toluene, 48 h. [b] Isolated yield after column
chromatography. [c] Pd(OAc)2 1.0 mol-%, ligand 3.0 mol-%, 16 h.
[a] Reaction conditions: 1.0 equiv. aryl halide, 1.2 equiv. amine,
1.4 equiv. NaOtBu, 1.0 mol-% Pd2(dba)3, 3.0 mol-% ligand, diox-
ane 4.0 mL, 100 °C, 12 h. [b] Isloated yield after column
chromatography.
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Air-Stable Ligand for Pd-Mediated Cross-Coupling Reactions
nucleophilic diarylamines are employed and anionic[13o] and
solvent effects[16] described. A highly effective catalyst was
readily generated from ligand 2a and shown to be effective
in the cross-coupling of a series of amines with aryl halides
as summarized in Table 3. Amination of aryl chlorides, in-
cluding electron-rich 4-methoxychlorobenzene, proceeded
efficiently with morpholine as well as with a weaker aniline
nucleophile. In addition, diarylamines, including hindered
ortho-substituted derivatives could be coupled to aryl bro-
ted with a central condenser and side connector sealed with a Tef-
lon®-coated silicone septa, under N2 at 110 °C for 30 min to melt
and break apart the sodium. Dichloro-phenylphosphane (6.8 mL,
50 mmol) was added dropwise via syringe; approximately 0.5 mL
was added first followed by the dropwise addition of the remainder
over a 2-hour period. The reaction mixture was stirred overnight
(16 h) at 110 °C forming a yellow precipitate of the disodium salt
of phenylphosphane. The condenser was connected to a stillhead
under N2, the solvent was removed and reaction mixture dried un-
der high vacuum at 60–80 °C. The vacuum pump was equipped
mides providing valuable, differentially substituted triaryl- with an in-line dry-ice trap to collect volatiles. Dry diether (50 mL)
was injected into the reaction flask and the disodium salt of phenyl-
phosphane slurry was quenched with degassed glacial acetic acid
(7.5 mL, 0.125 mol) at –10 to 0 °C with dropwise addition over a
period of 5 h under N2 flow to remove liberated hydrogen and pre-
vent pressure build-up. The ether was evaporated (50 °C) under N2
amines in good yield.
Conclusion
A short, efficient synthesis of a new sterically hindered flow. The product phenylphosphane was then fractionally distilled
under nitrogen at 120 °C and 180 °C into sealed reaction vessels
cooled to 0 °C. The first fraction (collected at 120 °C) was essen-
tially of acetic acid; the second fraction (180 °C) was of phenyl-
phosphane (5.0 g, 45 mmol, 90%). Overall distillation takes up to
4–5 h. The phenylphosphane so obtained was used immediately.
Phorone (8.6 mL, 55 mmol) was injected into the flask containing
phenylphosphane (no solvent) and the reaction mixture was stirred
at 150 °C for 15 h. Volatile compounds were stripped off at 100 °C
under high vacuum to give the product as a light-brown liquid that
solidified on cooling. This crude product was distilled under high
P,O-type phosphane ligand involving double Michael ad-
dition of phenylphosphane to phorone is described. Ligand
2a proved to be significantly more stable under aerobic con-
ditions in comparison to the P-cyclohexyl derivative 2b.
Palladium complexes could be readily formed from ligand
2a that proved efficient in activating a range of aryl halides,
including challenging electron-rich and ortho-substituted
derivatives in the Suzuki–Miyaura reaction, as well as cou-
pling amines and weakly nucleophilic diarylamines with a
range of aryl halides. Although activation of the most chal- vacuum. A first fraction (145–155 °C/1 Torr) was collected yielding
1a (5.8 g, 47%). A higher boiling fraction (190–210 °C/0.5 Torr)
contained the phosphane oxide. 1H NMR (200 MHz, CDCl3,
25 °C): δ = 7.60–7.90 (m, 2 H, Ar-H), 7.30–7.55 (m, 3 H, Ar-H),
2.75–3.10 (m, 2 H, CH2), 2.15–2.45 (m, 2 H, CH2), 1.32 (d, J =
18 Hz, 6 H, CH3), 0.93 (d, J = 11 Hz, 6 H, CH3) ppm. 13C NMR
(50 MHz, CDCl3): δ = 211.7, 135.9, 135.5, 128.4, 128.3, 129.7, 52.9,
lenging aryl chlorides required heating, with few excep-
tions[4b,4e,9k] the phosphorinane ligand 2a compares favour-
ably with other phosphanes in effecting cross-coupling reac-
tions with hindered, unactivated aryl chlorides.[4e,4f,5–9] At-
tractive features of this scaffold are the rapid synthetic ac-
cess to the ligand 2a, in two steps from commercial materi-
als, and further tunability possible through varying the
nature of the secondary phosphane employed and derivati-
zation of the remote hydroxy group. Further modifications
to ligand 2a along these lines and application to other
metal-mediated cross-coupling processes are under investi-
gation.
35.2 [d, J(P,C) = 18 Hz], 31.0 (d, JP,C = 31 Hz), 30.1 (d, JP,C
=
9 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ = 20.37 ppm.
General Procedure for Synthesis of P-Phenyl-2,2,6,6-tetrameth-
ylphosphorinan-4-ol (2a): An oven-dry two-neck flask containing a
magnetic stirring bar and a pressure-dropping funnel was charged
with LiAlH4 (0.152 g, 4.027 mmol). LiAlH4 was degassed at high
vacuum and backfilled with argon. Dry THF (10.0 mL) was added
and the suspension cooled to –10 °C. P-phenyl-2,2,6,6-tetrameth-
ylphosphorin-4-one 1a (0.500 g, 2.013 mmol) was dissolved in THF
(15.0 mL) and transferred to the LAH suspension dropwise via a
pressure-dropping funnel. The addition was completed in one hour
and the reaction mixture was further stirred for 12 h. The reaction
mixture was quenched by dropwise addition of 2–3 mL degassed
10% NaOH solution and stirred until the precipitate dissolved. The
reaction mixture was filtered through a pad of celite under argon,
using degassed ethyl acetate to wash. Solvent was removed under
high vacuum and the material was purified over silica gel
chromatography (2.5ϫ45 cm, 20% EtOAc/hexanes, Rf = 0.18)
yielding 2a (0.430 g, 85.4%) as a colorless solid. 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.75 (br. s, 2 H, Ar-H), 7.43–7.39
(m, 3 H, Ar-H), 4.15–3.78 (m, 1 H, CHOH), 2.06–1.73 (m, 4 H,
Experimental Section
General: Reactions were carried out under nitrogen in oven-dried
glassware. Monocyclohexylphosphane and phenyldichlorophos-
phane were obtained from Cytec industries, all other fine chemicals
were obtained from Aldrich. CIMS were run on a Micromass
Quattro Ultima spectrometer fitted with a direct injection probe
(DIP) with ionization energy set at 70 eV and HRMS (EI) were
1
performed with a Micromass Q-Tof Ultima spectrometer. H, 13C
and 31P spectra were recorded on a Bruker 200 and AV 600 spec-
trometer in CDCl3 with TMS as internal standard. Chemical shifts
(δ) are reported in ppm downfield of TMS and coupling constants
(J) are expressed in Hz. All 31P NMR experiments were measured
relative to an external standard (H3PO4, 0 ppm).
CH2), 1.39–1.38 (m, 6 H, CH3), 1.15–1.05 (m, 6 H, CH3) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 137.2 (d, JP,C = 23 Hz), 129.7, 127.7
(m), 66.1, 51.1 (d, JP,C = 12 Hz), 32.7–31.9 (m, 2 C), 26.5 (d, JP,C
= 4.5 Hz) ppm. 31P NMR (81 MHz, CDCl3): δ = 21.7 ppm. HRMS
(CI+-TOF): calculated for C15H29OP: 250.1487, found 250.1497.
Caution: All phosphanes should be considered to be pyrophoric.
Contact with atmospheric oxygen must be avoided, particularly
during the thermal addition reactions.
General Procedure for Synthesis of 2,2,6,6-Tetramethyl-P-phenyl-
phosphorinone (1a): Sodium metal (5.2 g, 0.225 mol) was stirred
vigorously in dry dioxane (40 mL) in a 100 mL reaction vessel, fit-
Aerial Oxidation of Ligands 2a and 2b: (Figure 3) Reactions were
conducted in clean dry NMR tubes. The ligand 2a (15.0 mg,
0.060 mmol) and ligand 2b (15.0 mg, 0.058 mmol) were dissolved
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E. Ullah, J. McNulty, V. Larichev, A. J. Robertson
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in CDCl3 (2.0 mL) in separate NMR tubes. The tubes were
clamped and a continuous stream of dry air was slowly passed
through a Teflon® tube connected to the top of the NMR tubes.
Solvent volume was maintained on a daily basis and 31P NMR was
carried out (Figure 3) over a period of one month to determine the
degree of phosphane oxide formation. The percent oxidation was
calculated as the ratio of the integral of the peak corresponding to
the phosphane oxide divided by the sum of the integrals corre-
sponding to the starting phosphane and phosphane oxide, multi-
plied by 100.
(50 MHz, CDCl3): δ = 143.5, 139.5, 130.5, 129.1 (2 C), 128.9 (2 C),
128.5, 127.8, 127.2, 118.7, 115.6 ppm.
2-Methoxybiphenyl: (Table 1, entry 8) 1H NMR (200 MHz, CDCl3,
25 °C): δ = 7.63–7.56 (m, 3 H, Ar-H), 7.50–7.43 (m, 4 H, Ar-H),
7.05 (d, J = 8.8 Hz, 2 H, Ar-H), 3.90 (s, 3 H, OCH3) ppm. 13C
NMR (50 MHz, CDCl3): δ = 159.2, 141.0, 133.8, 128.8 (2 C), 128.2
(2 C), 126.8 (2 C), 126.7 (2 C), 114.3, 55.4 ppm.
4-Phenylacetophenone: (Table 1, entry 9) 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 8.06 (d, J = 8.0 Hz, 2 H, Ar-H), 7.71–7.62 (m,
4 H, Ar-H), 7.49–7.45 (m, 3 H, Ar-H), 2.64 (s, 3 H, CH3O) ppm.
13C NMR (50 MHz, CDCl3): δ = 197.8, 145.8, 140.0, 135.9, 129.0
(2 C), 129.0 (2 C), 128.3, 127.3 (2 C), 127.3 (2 C), 26.7 ppm.
General Procedure for Suzuki–Miyaura Cross Coupling: (Table 1)
An oven-dried Schlenk flask, equipped with a magnetic stirring
bar was charged with phenylboronic acid (85.5 mg, 0.701 mmol),
Cs2CO3 (342.1 mg, 1.050 mmol) and ligand 2a (2.62 mg,
0.010 mmol). After evacuation and refilling with nitrogen,
4-chloroanisole (50.0 mg, 0.350 mmol), Pd(OAc)2 (0.78 mg,
0.0030 mmol), and freshly distilled toluene (5.0 mL) were injected
sequentially. The system was further evacuated and flushed with
nitrogen thrice and then placed into preheated oil bath (110 °C)
for 12 h. After completion of reaction, the reaction mixture was
quenched with water and diluted with ethyl acetate. Organic layer
was separated and aqueous layer was washed with EtOAc. The
combined organic phases were dried with MgSO4, filtered and the
solvent was removed at reduced pressure. The crude product was
then purified by column chromatography to give 4-methoxybi-
phenyl in (0.0555 g, 86%) as a colourless solid. The physical and
spectroscopic data of all biphenyl compounds (Table 1, entry 1–12)
were identical to those previously described.[10c,17a–17c]
1
Biphenyl: (Table 1, entry 10) H NMR (200 MHz, CDCl3, 25 °C):
δ = 7.82–7.78 (m, 4 H, Ar-H), 7.66–7.53 (m, 6 H, Ar-H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 141.5 (2 C), 129.0 (3 C), 127.5 (4 C),
127.4 (3 C) ppm.
4-Methylbiphenyl: (Table 1, entry 11) 1H NMR (200 MHz, CDCl3,
25 °C): δ = 7.70 (d, J = 7.0 Hz, 2 H, Ar-H), 7.63–7.59 (m, 2 H, Ar-
H), 7.54–7.46 (m, 3 H, Ar-H), 7.38–7.34 (m, 2 H, Ar-H), 2.50 (s, 3
H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 141.3, 138.5,
137.2, 129.6 (3 C), 128.9 (3 C), 127.1 (3 C), 21.2 ppm.
4-Methoxybiphenyl: (Table 1, entry 12) 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.68 (d, J = 6.6 Hz, 2 H, Ar-H), 7.58–7.43 (m,
5 H, Ar-H), 7.10 (d, J = 8.4 Hz, 2 H, Ar-H), 3.93 (s, 3 H, OCH3)
ppm. 13C NMR (50 MHz, CDCl3): δ = 159.3, 140.9, 136.0, 128.9
(2 C), 128.3 (2 C), 126.9 (3 C), 114.4 (2 C), 55.4 ppm.
General Procedure for Suzuki–Miyaura Cross Coupling: (Table 2)
An oven-dried Schlenk flask, equipped with a magnetic stirring bar
was charged with 2,3,4-trimethoxy phenylboronic acid (27.0 mg,
0.128 mmol), Cs2CO3 (83.4 mg, 0.256 mmol) and ligand 2a
(1.28 mg, 0.0051 mmol). After evacuation and refilling with nitro-
gen, 4-chloroanisole (12.1 mg, 0.0854 mmol), Pd(OAc)2 (0.38 mg,
0.0017 mmol), and freshly distilled toluene (2.0 mL) were injected
sequentially. The system was further evacuated and flushed with
nitrogen thrice and then placed into preheated oil bath (110 °C) for
48 h. After completion of reaction, the reaction mixture was co-
oled, quenched with water and diluted with ethyl acetate. The or-
ganic layer was separated and aqueous layer was washed with
EtOAc. The combined organic phases were dried with MgSO4, fil-
tered and the solvent was removed at reduced pressure. The crude
product was then purified by column chromatography to give
2,2Ј,3,4-tetramethoxybiphenyl in (0.0178 g, 65%) yield. The physi-
cal and spectroscopic data of all biphenyl compounds (Table 1a,
entry 1–7) were identical to those previously described.[4b,17c,17f]
4-Phenylacetophenone: (Table 1, entry 1) 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 8.04 (d, J = 8.0 Hz, 2 H, Ar-H), 7.71–7.62 (m,
4 H, Ar-H), 7.49–7.45 (m, 3 H, Ar-H), 2.64 (s, 3 H, COCH3) ppm.
13C NMR (50 MHz, CDCl3): δ = 197.8, 145.8, 140.0, 135.9, 129.0
(2 C), 129.0 (2 C), 128.3, 127.3 (2 C), 127.3 (2 C), 26.7 ppm.
4-Phenylbenzaldehyde: (Table 1, entry 2) 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 10.06 (s, 1 H, HCO), 7.98 (d, J = 8.0 Hz, 2 H,
Ar-H), 7.77–7.63 (m, 4 H, Ar-H), 7.50–7.46 (m, 3 H, Ar-H) ppm.
13C NMR (50 MHz, CDCl3): δ = 192.0, 147.2, 139.7, 135.2, 130.4
(2 C), 129.1 (2 C), 128.5, 127.5 (2 C), 127.4 (2 C) ppm.
1
4-Methylbiphenyl: (Table 1, entry 3) H NMR (200 MHz, CDCl3,
25 °C): δ = 7.70 (d, J = 7.0 Hz, 2 H, Ar-H), 7.63–7.59 (m, 2 H, Ar-
H), 7.54–7.46 (m, 3 H, Ar-H), 7.38–7.34 (m, 2 H, Ar-H), 2.50 (s, 3
H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 141.3, 138.5,
137.2, 129.6 (3 C), 128.9 (3 C), 127.1 (3 C), 21.2 ppm.
4-Methoxybiphenyl: (Table 1, entry 4) 1H NMR (200 MHz, CDCl3,
25 °C): δ = 7.68 (d, J = 6.6 Hz, 2 H, Ar-H), 7.58–7.43 (m, 5 H, Ar-
H), 7.10 (d, J = 8.4 Hz, 2 H, Ar-H), 3.93 (s, 3 H, OCH3) ppm. 13C
NMR (50 MHz, CDCl3): δ = 159.3, 141.0, 136.0, 128.9 (2 C), 128.3
(2 C), 126.9 (3 C), 114.4 (2 C), 55.4 ppm.
2,2Ј,3,4-Tetramethoxybiphenyl: (Table 2, entry 1) 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.40–7.21 (m, 2 H, Ar-H), 7.01–6.94
(m, 3 H, Ar-H), 6.73 (d, J = 8.8 Hz, 1 H, Ar-H), 3.92 (s, 3 H,
OCH3), 3.91 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3), 3.73 (s, 3 H,
OCH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 156.0, 152.5, 152.0,
141.0, 130.4, 128.0, 126.4, 124.3, 122.6, 119.2, 109.6, 105.7, 59.7,
54.9, 54.9, 54.5 ppm.
1
Biphenyl: (Table 1, entry 5) H NMR (200 MHz, CDCl3, 25 °C): δ
= 7.82–7.78 (m, 4 H, Ar-H), 7.66–7.53 (m, 6 H, AR-H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 141.5 (2 C), 129.0 (3 C), 127.5 (4 C),
127.4 (3 C) ppm.
2,3,4-Trimethoxy-2Ј-methylbiphenyl: (Table 2, entry 2) 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.23–7.22 (m, 4 H, Ar-H), 6.86 (d,
J = 8.6 Hz, 1 H, Ar-H) 6.72 (d, J = 8.4 Hz, 1 H, Ar-H), 3.94 (s, 3
H, OCH3), 3.92 (s, 3 H, OCH3), 3.58 (s, 3 H, OCH3), 2.19 (s, 3 H,
CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 153.0, 151.4, 136.9,
131.5, 130.1, 129.8, 127.3, 125.4, 125.0, 120.4, 111.1, 107.0, 61.1,
56.0, 55.7, 20.2 ppm.
1
4-Methylbiphenyl: (Table 1, entry 6) H NMR (200 MHz, CDCl3,
25 °C): δ = 7.70 (d, J = 7.0 Hz, 2 H, Ar-H), 7.63–7.59 (m, 2 H, Ar-
H), 7.54–7.46 (m, 3 H, Ar-H), 7.38–7.34 (m, 2 H, Ar-H), 2.50 (s, 3
H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 141.3, 138.5,
137.1, 129.6 (3 C), 128.9 (3 C), 127.1 (3 C), 21.2 ppm.
2-Aminobiphenyl: (Table 1, entry 7) 1H NMR (200 MHz, CDCl3,
25 °C): δ = 7.47–7.35 (m, 5 H, Ar-H), 7.17–7.13 (m, 2 H, Ar-H), 2,4-Dimethoxybiphenyl: (Table 2, entry 3) 1H NMR (200 MHz,
6.88–6.80 (m, 2 H, Ar-H), 3.77 (s, 2 H, NH2) ppm. 13C NMR CDCl3, 25 °C): δ = 7.56–7.55 (m, 2 H, Ar-H), 7.52–7.38 (m, 2 H,
6828
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6824–6830

Air-Stable Ligand for Pd-Mediated Cross-Coupling Reactions
Ar-H), 7.36–7.30 (m, 2 H, Ar-H), 6.63–6.60 (m, 2 H, Ar-H), 3.88 N-(4-Methoxyphenyl)morpholine: (Table 3, entry 4) 1H NMR
(s, 3 H, OCH3), 3.82 (s, 3 H, OCH3) ppm. 13C NMR (50 MHz, (200 MHz, CDCl3, 25 °C): δ = 6.92–6.91 (br. s, 4 H, Ar-H), 3.92
CDCl3): δ = 160.3, 157.5, 138.4, 131.3, 129.5 (2 C), 128.0 (2 C), (t, J = 4.4 Hz, 4 H, CH2O), 3.81 (s, 3 H, OCH3), 3.10 (t, J = 4.6 Hz,
126.5, 123.6, 104.6, 99.0, 55.6, 55.5 ppm.
4 H, CH3N) ppm. 13C NMR (50 MHz, CDCl3): δ = 153.0, 144.5,
117.5 (2 C), 115.2 (2 C), 67.4 (2 C), 55.3, 54.8 (2 C) ppm.
2-Methoxy-2Ј-methylbiphenyl: (Table 2, entry 4) 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.47 (br. d, 2 H, Ar-H), 7.34–7.22
(m, 4 H, Ar-H), 7.07–6.97 (m, 2 H, Ar-H), 3.82 (s, 3 H, OCH3),
2.41 (s, 3 H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 156.5,
136.7, 135.6, 130.9, 129.7, 129.5 (2 C), 128.8 (2 C), 128.4, 120.8,
111.21, 55.60, 21.33 ppm.
4-Methoxy-N-phenylaniline: (Table 3, entry 5) 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.30–7.22 (m, 5 H, Ar-H), 7.14 (d, J = 8.8 Hz,
2 H, Ar-H), 6.97–6.88 (m, 5 H, Ar-H), 5.53 (s, 1 H, NH), 3.84 (s,
3 H, OCH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 155.3, 145.2,
135.8, 129.4 (2 C), 122.3 (2 C), 119.6 (2 C), 115.7 (2 C), 114.7 (2 C),
55.6 ppm. HRMS (EI+-TOF): calculated for C13H13NO: 199.0997,
found 119.1004.
2,2Ј-Dimethoxybiphenyl: (Table 2, entry 5) 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.34–7.27 (m, 4 H, Ar-H), 7.01–6.97 (m, 4 H,
Ar-H), 3.79 (s, 6 H, OCH3) ppm. 13C NMR (50 MHz, CDCl3): δ
= 157.0 (2 C), 131.5 (2 C), 128.7 (2 C), 127.8 (2 C), 120.4 (2 C),
111.1 (2 C), 55.7 (2 C) ppm.
1
4-(Diphenylamino)biphenyl: (Table 3, entry 6) H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.63 (d, J = 7.0 Hz, 2 H, Ar-H), 7.54–7.42 (m,
4 H, Ar-H), 7.35–7.28 (m, 5 H, Ar-H), 7.20–7.11 (m, 6 H, Ar-H),
7.01–7.04 (m, 2 H, Ar-H) ppm. 13C NMR (50 MHz, CDCl3): δ =
147.8 (2 C), 147.2, 140.7, 135.2, 129.4 (3 C), 128.8 (2 C), 127.9 (2
C), 126.9 (2 C), 126.7 (3 C), 124.5 (3 C), 124.0 (2 C), 123.0 (2 C)
ppm. HRMS (EI+-TOF): calculated for C24H19N: 321.1517, found
321.1508.
2,2Ј-Dimethylbiphenyl: (Table 2, entry 6) 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 7.27–7.14 (m, 4 H, Ar-H), 7.011–7.02 (m, 4 H,
Ar-H), 2.07 (s, 6 H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ =
138.7 (2 C), 136.4 (2 C), 129.5 (2 C), 128.7 (2 C), 127.8 (2 C), 126.4
(2 C), 21.2 (2 C) ppm.
4-[(3-Methoxyphenyl)phenylamino]biphenyl: (Table 3, entry 7) 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 7.63 (d, J = 7.2 Hz, 2 H, Ar-
H), 7.54–7.42 (m, 4 H, Ar-H), 7.38–7.30 (m, 4 H, Ar-H), 7.28–7.17
(m, 4 H, Ar-H), 7.08–7.04 (m, 1 H, Ar-H), 6.75 (d, J = 7.8 Hz, 2
H, Ar-H), 6.63 (d, J = 8.0 Hz, 1 H, Ar-H), 3.77 (s, 3 H, OCH3)
ppm. 13C NMR (50 MHz, CDCl3): δ = 158.2, 147.8, 147.3, 140.7,
139.6 (2 C), 135.2 (2 C), 129.6, 129.4 (2 C), 128.8 (2 C), 127.9 (2 C),
126.9, 126.7 (2 C), 124.5 (2 C), 124.0, 123.0, 122.6, 111.1, 56.4 ppm.
HRMS (EI+-TOF): calculated for C25H21NO: 351.1623, found
351.1642.
2-Methoxy-2Ј-methylbiphenyl: (Table 2, entry 7) 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.47 (br. d, 2 H, Ar-H), 7.34–7.22
(m, 4 H, Ar-H), 7.07–6.97 (m, 2 H, Ar-H), 3.82 (s, 3 H, OCH3),
2.41 (s, 3 H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 156.5,
136.7, 135.6, 130.9 (2 C), 129.5 (2 C), 128.8 (2 C), 128.4, 120.8 (2
C), 55.60, 21.33 ppm.
General Procedure for the Buchwald-Hartwig Amination of Aryl Ha-
lides: (Table 3) An oven-dry Schlenk flask containing a magnetic
stirring bar was charged with ligand 2a (2.62 mg, 0.0100 mmol),
Pd2(dba)3 (3.20 mg, 0.00300 mmol) and NaOtBu (48.0 mg,
4-[Bis(2,4-Dimethylphenyl)amino]biphenyl: (Table 3, entry 8) 1H
NMR (200 MHz, CDCl3, 25 °C): δ = 7.64 (d, J = 7.2 Hz, 2 H, Ar-
H), 7.53–7.44 (m, 4 H, Ar-H), 7.39–7.30 (m, 1 H, Ar-H), 7.16–7.09
(m, 4 H, Ar-H), 7.01–6.93 (m, 4 H, Ar-H), 2.31 (s, 6 H, CH3), 2.26
(s, 3 H, CH3) ppm. 13C NMR (50 MHz, CDCl3): δ = 147.9, 145.6
(2 C), 140.9, 137.6 (2 C), 133.8, 131.5 (2 C), 130.5 (2 C), 128.8 (2
C), 127.6 (2 C), 126.7 (3 C), 126.2 (2 C), 122.8 (2 C), 122.6 (2
C), 20.0 (2 C), 19.3 (2 C) ppm. HRMS (EI+-TOF): calculated for
C28H27N: 377.2144, found 377.2139.
0.490 mmol)
under
nitrogen.
4-chloroanisole
(50.0 mg,
0.350 mmol), morpholine (0.0360 mL, 0.420 mmol) and freshly dis-
tilled dioxane (4 mL) were added sequentially. The reaction mixture
was degassed three times and stirred at 100 °C for 12 h. After cool-
ing to room temperature, 10 mL of EtOAc was added and the mix-
ture was washed with 5 mL of brine. The organic layer was sepa-
rated, dried with Na2SO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography to give
N-(4-methoxyphenyl)morpholine (0.059 g, 87%) yield. The physi-
cal and spectroscopic data of all other isolated compounds
(Table 2 entry 1–6) were identical to those previously descri-
bed.[13d,13p,17c,17d,17g,17h]
Acknowledgments
N-(4-Methylphenyl)morpholine: (Table 3, entry 1) 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.15 (d, J = 4.6 Hz, 2 H, Ar-H),
6.88 (d, J = 8.6 Hz, 2 H, Ar-H), 3.92 (t, J = 4.4 Hz, 4 H, CH2O),
3.10 (t, J = 4.6 Hz, 4 H, CH2N), 2.32 (s, 3 H, CH3) ppm. 13C NMR
(50 MHz, CDCl3): δ = 149.2, 129.8 (2 C), 129.7 (2 C), 116.1, 67.5
(2 C), 50.0 (2 C), 20.5 ppm.
We thank the Natural Sciences and Engineering Research Council
and Cytec Canada for financial support of this work.
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6.88 (d, J = 8.6 Hz, 2 H, Ar-H), 3.92 (t, J = 4.4 Hz, 4 H, CH2O),
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(2 C), 50.0 (2 C), 20.5 ppm.
Eur. J. Org. Chem. 2010, 6824–6830
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6829

E. Ullah, J. McNulty, V. Larichev, A. J. Robertson
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Received: August 4, 2010
Published Online: October 25, 2010
6830
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6824–6830