Probing the effect of donor-fragment substitution in Mor-DalPhos on palladium-catalyzed C-N and C-C cross-coupling reactivity

Article abstract of DOI:10.1139/cjc-2017-0749

The competitive catalytic screening of 18 known and newly prepared Mor-DalPhos ligand variants in the palladium-catalyzed cross-coupling of chlorobenzene with aniline, octylamine, morpholine, indole, ammonia, or acetone is presented, including ligands derived from the new secondary phosphine HP(^Me2Ad)₂ (^Me2Ad = 3,5-dimethyladamantyl). Although triarylphosphine ancillary ligand variants performed poorly in these test reactions, ligands featuring either PAd₂ or P(^Me2Ad)₂ donors (Ad = 1-adamantyl) gave rise to superior catalytic performance. Multiple Mor-DalPhos variants proved effective in cross-couplings involving aniline, octylamine, or morpholine; conversely, only a smaller subset of ligands proved useful in related cross-couplings of indole, ammonia, or acetone. In the case of the N-arylation of indole, a Mor-DalPhos ligand variant featuring ortho-disposed PAd₂ and dimethylmorpholino donor fragments (L13) proved superior to all other ligands surveyed, including the parent ligand Mor-DalPhos (L5). Conversely, L5 was found to be superior to all other ligands in the palladium-catalyzed monoarylation of ammonia. Ligand L6 (i.e., the P(^Me2Ad)₂ variant of L5) proved superior to all other ligands in the monoarylation of acetone and, with the exception of indole N-arylation, was the most broadly useful of the Mor-DalPhos ligands surveyed herein.

Full text of DOI:10.1139/cjc-2017-0749

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Probing the Effect of Donor-Fragment Substitution in
Mor-DalPhos on Palladium-Catalyzed C-N and C-C
Cross-coupling Reactivity
Sarah M. Crawford,‡ Craig A. Wheaton,‡ Vinayak Mishra, and Mark Stradiotto*
‡ these authors contributed equally to this work
Submitted to the special issue to honor Professor Neil Burford in recognition of his many outstanding
contributions to the chemical community.
Department of Chemistry, Dalhousie University, 6274 Coburg Road, P.O. Box 15000, Halifax, NS, B3H
4R2, Canada.
Fax: 1ꢀ902ꢀ494ꢀ1310; Tel: 1ꢀ902ꢀ494ꢀ7190; Eꢀmail: mark.stradiotto@dal.ca
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ABSTRACT
The competitive catalytic screening of 18 known and newly prepared MorꢀDalPhos ligand
variants in the palladiumꢀcatalyzed crossꢀcoupling of chlorobenzene with aniline, octylamine,
morpholine, indole, ammonia, or acetone is presented, including ligands derived from the new
secondary phosphine HP(Me2Ad)2 (Me2Ad = 3,5ꢀdimethyladamantyl). While triarylphosphine ancillary
ligand variants performed poorly in these test reactions, ligands featuring either PAd2 or P(Me2Ad)2
donors (Ad = 1ꢀadamantyl) gave rise to superior catalytic performance. Multiple MorꢀDalPhos variants
proved effective in crossꢀcouplings involving aniline, octylamine, or morpholine; conversely, only a
smaller subꢀset of ligands proved useful in related crossꢀcouplings of indole, ammonia, or acetone. In the
case of the Nꢀarylation of indole, a MorꢀDalPhos ligand variant featuring orthoꢀdisposed PAd2 and
dimethylmorpholino donor fragments (L13) proved superior to all other ligands surveyed, including the
parent ligand MorꢀDalPhos (L5). Conversely, L5 was found to be superior to all other ligands in the
palladiumꢀcatalyzed monoarylation of ammonia. Ligand L6 (i.e., the P(Me2Ad)2 variant of L5) proved
superior to all other ligands in the monoarylation of acetone, and with the exception of indole Nꢀ
arylation, was the most broadly useful of the MorꢀDalPhos ligands surveyed herein.
Key Words: Amination, Crossꢀcoupling, Ligand design, Palladium.
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INTRODUCTION
Palladiumꢀcatalyzed crossꢀcoupling of (hetero)aryl (pseudo)halides and NH substrates (i.e.
BuchwaldꢀHartwig amination, BHA1) has emerged as a remarkably useful protocol for the synthesis of
(hetero)anilines. The critical role that ancillary ligands play in promoting arylꢀX oxidative addition,
amine substrate binding, and/or arylꢀN reductive elimination in the course of such transformations is
wellꢀestablished.2 Optimal BHA catalyst systems have traditionally relied on: (a) monodentate
phosphine or NHC ligands, with Buchwald’s dialkylbiarylphosphines1c, 3 and Organ’s Nꢀheterocyclic
carbene (NHC)ꢀbased PEPPSI catalysts4 representing noteworthy examples; or (b) strongly chelating
bidentate bisphosphine ligands, including the JosiPhos5 ligand variant CyPFꢀtBu, as demonstrated by
Hartwig and coꢀworkers.1b, 6 In 2010, we initiated the development of what can be considered as an
electronically intermediate class of orthoꢀphenylene chelating ligands for use in addressing outstanding
challenges in BHA and related crossꢀcoupling chemistry, whereby a sterically demanding
dialkylphosphino (or NHC) donor fragment is paired with a less Lewisꢀbasic heteroatomic donor. While
at the time orthoꢀphenylene P,N chelates such as phosphinooxazoline ligands (including Phox7) had
proven useful in a variety of metalꢀcatalyzed transformations, such ligand design concepts had not
previously been employed successfully in the development of stateꢀofꢀtheꢀart ancillary ligands for use in
BHA and related crossꢀcoupling chemistry. In particular, we envisioned that a rigid chelating P,Nꢀligand
structure might provide a means of attaining high levels of monoarylation selectivity with small
nucleophilic coupling partners, thus providing an advantage over monodentate ligands. Moreover, we
envisioned the possibility that P,Nꢀligand hemilability might provide access to both monodentate (e.g.
κ1ꢀP,N) and bidentate (e.g. κ2ꢀP,N) binding modes, which in turn may facilitate both oxidative addition
and reductive elimination steps, for which the electronic demands of the ancillary ligand are normally
orthogonal.
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Following our initial development of MeꢀDalPhos for use broadly in BHA,8 a very brief ancillary
ligand modification survey in the context of ammonia monoarylation enabled the development of Morꢀ
DalPhos;9 the structures of these DalPhos ligands are depicted in Figure 1.10 Notably, MorꢀDalPhos has
since proven to be particularly useful in the selective monoarylation of a range of small, nucleophilic
reaction partners such as ammonia,9, 11 hydrazine,12 and acetone,13 as well as in challenging crossꢀ
couplings involving aryl mesylates,13b in some cases for the first time reported in the literature. While
variants of MorꢀDalPhos featuring pyrrole, pyridine, and benzophenone imine donor fragments in place
of the morpholino group were examined in our initial study,9 their vastly inferior catalytic behavior, as
well as that of MeꢀDalPhos, in the challenging ammonia monoarylation test reaction employed suggests
that the presence of a cyclic dialkylamino donor fragment ortho to the PAd2 group (Ad = 1ꢀadamantyl),
as featured in MorꢀDalPhos, may be particularly important in achieving optimal performance within this
ligand class. Building on these observations, and in an effort to identify highꢀperforming variants of
MorꢀDalPhos, we have subsequently explored the influence of backbone substitution,14 as well as donorꢀ
fragment substitution, on palladiumꢀcatalyzed CꢀN and CꢀC crossꢀcoupling reactivity employing Morꢀ
DalPhos variants. Herein we report on our extensive examination of the latter structural variation,
whereby 18 known or newly prepared MorꢀDalPhos derivatives were systematically screened in test
reactions involving the palladiumꢀcatalyzed crossꢀcoupling of chlorobenzene with aniline, octylamine,
morpholine, indole, ammonia, or acetone, with an emphasis on the examination of ligands featuring
pairings of orthoꢀdisposed PAd2 (or the new dimethylated variant P(Me2Ad)2) and cyclic dialkylamino
donor fragments (Figure 1).
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EXPERIMENTAL
General Considerations. All reactions were set up inside a dinitrogenꢀfilled, inert atmosphere glovebox
(unless otherwise indicated) and isolated under standard benchtop conditions. Toluene and methylene
chloride used in the glovebox were deoxygenated by purging with dinitrogen followed by passage
through a double column solvent purification system equipped either with one aluminaꢀpacked column
and one column packed with copperꢀQ5 reactant (toluene), or two aluminaꢀpacked columns (methylene
chloride). 1,4ꢀDioxane and diethyl ether were dried over Na/benzophenone followed by distillation
under an atmosphere of dinitrogen. tertꢀButanol was dried over CaH2 followed by distillation under an
atmosphere of dinitrogen. All solvents used within the glovebox were stored over activated 4 Å
molecular sieves. Ligands L1ꢀL3,13a L5,9 L7,8 L10,9 and L1315 were prepared according to literature
procedures. All other reagents, solvents and materials were used as received from commercial sources.
Flash column chromatography was performed on silica gel (SiliaFlash P60, Silicycle) or 150 mesh
Brockmann III activated, neutral alumina oxide, as indicated. All 1H NMR (500 MHz or 300 MHz) and
13C NMR (125.8 MHz or 75.4 MHz) spectra were recorded at 300 K. Chemical shifts are expressed in
parts per million (ppm) using the solvent signal as an internal reference. Splitting patterns are indicated
as follows: br, broad; s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet. All coupling
constants (J) are reported in Hertz (Hz). In some cases fewer than expected independent carbon
resonances were observed despite prolonged acquisition times. Mass spectra were obtained using ion
trap (ESI) instruments operating in positive mode and GC data were obtained on an instrument equipped
with a SGE BPꢀ5, 30 m, 0.25 mm i.d. column. Crystallographic data for L16 were obtained at 173(2) K
on a Bruker D8/APEX II CCD diffractometer equipped with a CCD area detector, employing sample
that was mounted in inert oil and transferred to a cold gas stream on the diffractometer. Unit cell
parameters were determined and refined on all reflections. Data reduction, correction for Lorentz
5

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polarization, and absorption correction were each performed. Structure solution and leastꢀsquares
refinement on F2 were used throughout. All nonꢀhydrogen atoms were refined with anisotropic
displacement parameters. Full crystallographic solution and refinement details are provided in the
deposited CIF (CCDCꢀ1824777).
General Catalytic Procedure for the C-N Cross-coupling of 2-Iodo-1-bromobenzene with
Secondary Amines (GP1). In an atmosphere controlled glovebox Pd2(dba)3 (23 mg, 0.025 mmol, 0.01
equiv) and BINAP (46.5 mg, 0.075 mmol, 0.03 equiv) were added to a vial and dissolved in 5 mL THF.
To the vial was added 18ꢀcrownꢀ6 (1.58 g, 6.0 mmol, 1.3 equiv) and NaOtBu (580 mg, 6.0 mmol, 1.3
equiv), the vial was then capped with a PTFE lined septum cap and removed from the glovebox. 2ꢀ
Bromoiodobenzene (650 ꢀL, 5.0 mmol, 1.0 equiv) and amine (610 ꢀL, 5.5 mmol, 1.2 equiv) when then
added via syring and the reaction mixture was stirred at room temperature. Reaction progress was
monitored by use of TLC or GC methods and after complete consumption of the aryl halide (24ꢀ48 h),
the reaction was quenched with 75 mL of water extracted with 100 mL EtOAc two times. The organic
layer was dried with MgSO4, concentrated, and the product was purified by way of column
chromatography. All reactions were conducted on 0.5 to 4.0 mmol scale
General Catalytic Procedure for P-C Cross-coupling of 2-Bromo-1-aminobenzenes with di(1-
adamantyl)phosphine (GP2). To a vial containing HP(Ad)2 (301 mg, 1.0 mmol), NaOtBu (115 mg, 1.2
mmol), and Nꢀ(2ꢀbromophenyl)ꢀN’ꢀmethylpiperazine (255 mg, 1.0 mmol) was added a solution of
Pd(OAc)2 (6.7 mg, 0.03 mmol) and DiPPF (15 mg, 0.036 mmol) in 2.5 mL toluene. The vial was capped
with a PTFE lined screw cap and heated at 110 °C for 18ꢀ48 h. The reaction mixture was then allowed to
cool and filtered through a plug of silica washing with CH2Cl2 (3 x 15 mL). The filtrate was
concentrated and the resulting solid was purified by washing with small solvent aliquots (Et2O or
pentane) or by column chromatography, as indicated.
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Procedures for Ligand Screening. Estimated percent conversion to the target monoarylation products
(average of at least two runs) were determined on the basis of responseꢀfactor corrected GC methods
using a dodecane internal standard, based on calibrations generated from analytically pure samples of
the products and starting materials. Toluene Catalyst Stock Solution: [Pd(cinnamyl)Cl]2 (7.2 mg, 0.015
mmol), ligand (0.06 mmol) and 3 mL of toluene were added to a oven dried vial equipped with a stir bar
and stirred until dissolution was complete. The resulting catalyst stock solution was used immediately.
1,4-Dioxane Catalyst Stock Solution: [Pd(cinnamyl)Cl]2 (4.8 mg, 0.010 mmol), ligand (0.04 mmol) and
2 mL of 1,4ꢀdioxane were added to a oven dried vial equipped with a stir bar and stirred until dissolution
was complete. The resulting catalyst stock solution was used immediately. Cross-Coupling of
Chlorobenzene and Amines: A 0.5 mL aliquot of the toluene stock solution was added to a vial
containing NaOtBu (33.6 mg, 1.4 equiv) and stirred 5 min. Dodecane (40.9 mL, 0.18 mmol) was added
followed by chlorobenzene (25.3 ꢁL, 0.25 mmol, 1.0 equiv) and then 1˚ or 2˚ amine (0.30 mmol, 1.2
equiv, [aniline, 27.3 ꢁL, nꢀoctylamine, 49.5 ꢁL; morpholine, 26.2 ꢁL]) was added and the vial was
sealed with a cap containing a PTFE septum and removed from the glovebox. The reaction mixture was
heated to 110 ˚C with stirring for 18 h. An aliquot was sampled (0.1 to 0.25 mL), filtered through SiO2
into a GC vial, diluted with methylene chloride to approximately 1 mL and analyzed by GC to quantify
conversion to the target products (diphenylamine, Nꢀoctylaniline, and Nꢀphenylmorpholine,
respectively). Cross-Coupling of Chlorobenzene and Indole: A 0.5 mL aliquot of the toluene stock
solution was added to a vial containing NaOtBu (33.6 mg, 1.4 equiv) and indole (30.6 mg, 0.26 mmol,
1.05 equiv). Dodecane (40.9 ꢁL, 0.18 mmol) was added followed by chlorobenzene (25.3 ꢁL, 0.25
mmol, 1.0 equiv) and the vial was sealed with a cap containing a PTFE septum and removed from the
glovebox. The reaction mixture was heated at 110 ˚C with stirring for 18 h. An aliquot was sampled (0.1
to 0.25 mL), filtered through SiO2 into a GC vial, diluted with methylene chloride to approximately 1
7

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mL and analyzed by GC to quantify conversion to the target product, Nꢀphenylindole. Cross-Coupling
of Chlorobenzene and Ammonia or Acetone: A 0.5 mL aliquot of the 1,4ꢀdioxane stock solution was
added to a vial containing NaOtBu (48.1 mg, 2.0 equiv) and stirred 5 min. Dodecane (40.9 ꢁL, 0.18
mmol) was added followed by chlorobenzene (25.3 ꢁL, 0.25 mmol, 1.0 equiv) and then 1,4ꢀdioxane (0.5
mL) and the vial was sealed with a cap containing a PTFE septum and removed from the glovebox. A
0.5 M solution of NH3 in 1,4ꢀdioxane (1.5 mL, 3 equiv) was added and the reaction mixture was heated
to 90 ˚C with stirring for 18 h. An analogous protocol was used for the monoarylation of acetone, with
the exception that Cs2CO3 (163 mg) was used in place of NaOtBu, and acetone (0.5 mL) was used in
place of the NH3 in 1,4ꢀdioxane. An aliquot was sampled (0.1 to 0.25 mL), filtered through SiO2 into a
GC vial, diluted with methylene chloride to approximately 1 mL and analyzed by GC to quantify
conversion to the target products (aniline and phenylacetone).
N-(2-Bromophenyl)-azetidine (precursor to L8). The title compound was synthesized using GP1 and
was isolated as a clear, colorless oil in 53% yield (0.409 g, 1.93 mmol) after column chromatography
(98:2 hexanes:EtOAc). 1H NMR (500 MHz, CDCl3): δ 7.41 (dd, J = 1.5, 7.5 Hz, 1H), 7.18 (ddd, J = 1.5,
7.5, 8.5 Hz, 1H), 6.67 (ddd, J = 1.5, 7.5, 8.5 Hz, 1H), 6.55 (dd, J = 1.5, 8.5 Hz, 1H), 4.06 (t, J = 7.5 Hz,
13
4H), 2.27 (pentet, J = 7.5 Hz, 2H); C{1H} NMR (125.8 MHz, CDCl3): δ 149.5, 134.2, 127.9, 120.3,
114.9, 108.8, 54.3, 17.0; m/z ESI+ found 212.0068 [M+H]+ calculated for C9H1179BrN 212.0069.
N-(2-Bromophenyl)-pyrrolidine (precursor to L9). The title compound was synthesized using GP1
and was isolated as a clear, colorless oil in 81% yield (0.730 g, 3.22 mmol) after column
1
chromatography (pure hexanes to 98:2 hexanes:EtOAc). H NMR (500 MHz, CDCl3): δ 7.51 (dd, J =
1.5, 7.5 Hz, 1H), 7.19 (ddd, J = 1.5, 7.5, 8.5 Hz, 1H), 6.92 (dd, J = 1.5, 8.0 Hz, 1H), 6.74 (ddd, J = 1.5,
13
7.5, 8.0 Hz, 1H), 3.37ꢀ3.35 (m, 4H), 1.96ꢀ1.93 (m, 4H); C{1H} NMR (125.8 MHz, CDCl3): δ 148.8,
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134.7, 127.9, 121.4, 118.0, 113.9, 51.4, 25.8; m/z ESI+ found 226.0237 [M+H]+ calculated for
C10H1379BrN 226.0226.
N-(2-Bromophenyl)-azepane (precursor to L11). The title compound was synthesized using GP1 and
was isolated as a clear, colorless oil in 84% yield (0.849 g, 3.34 mmol) after column chromatography
1
(pure hexanes to 98:2 hexanes:EtOAc). H NMR (500 MHz, CDCl3): δ 7.54 (dd, J = 1.5, 8.0 Hz, 1H),
7.22 (ddd, J = 1.5, 7.5, 8.0 Hz, 1H), 7.11 (dd, J = 1.5, 8.0 Hz, 1H), 6.83 (ddd, J = 1.5, 7.5, 8.0 Hz, 1H),
3.19ꢀ3.17 (m, 4H), 1.84ꢀ1.71 (m, 8H); 13C{1H} NMR (125.8 MHz, CDCl3): δ 153.7, 133.9, 123.5,
123.0, 120.3, 55.8, 29.4, 27.3; m/z ESI+ found 254.0549 [M+H]+ calculated for C12H1779BrN 254.0539.
N-(2-Bromophenyl)-tetrahydroisoquinoline (precursor to L12). The title compound was synthesized
using GP1 and was isolated as a thick yellow oil in 83% yield (1.20 g, 0.41 mmol) after column
1
chromatography (10:1 hexanes:EtOAc). H NMR (CDCl3): δ 7.61 (dd, J = 1.5, 7.9 Hz, 1H), 7.30 (m,
1H), 7.20ꢀ7.15 (m, 4H), 7.11 (m, 1H), 6.95 (td, J = 1.6, 7.6 Hz, 1H), 4.28 (s, 2H), 3.41 (t, J = 5.8 Hz,
2H), 3.07 (t, J = 5.8 Hz, 2H). 13C{1H}NMR (CDCl3): δ 150.6, 134.9, 134.7, 134.1, 129.1, 128.3, 126.53,
126.46, 125.9, 124.4, 121.2, 119.9, 53.7, 50.6, 29.3. m/z ESI+ found 288.0385 [M+H]+ calculated for
C15H1579BrN 288.0382.
N-(2-Bromophenyl)-N’-methylpiperazine (precursor to L14). The title compound was synthesized
using GP1 and was isolated as a thick orange oil after column chromatography (CH2Cl2 to 200:20:1
1
CH2Cl2:MeOH:NH4OH) in 64% yield (725 mg, 3.2 mmol). H NMR (CDCl3): δ 7.56 (dd, J = 1.6, 7.9
Hz, 1H), 7.28 (m, 1H), 7.08 (dd, J = 1.6, 8.0 Hz, 1H), 6.93 (td, J = 1.6, 7.8 Hz, 1H), 3.12 (br s, 4H), 2.68
13
(br s, 4H), 2.42 (s, 3H). C{1H} NMR (CDCl3): δ 150.7, 134.0, 128.5, 124.6, 121.2, 120.1, 55.4, 51.6,
46.3. m/z ESI+ found 255.0485 [M+H]+ calculated for C11H1679BrN2 255.0491.
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N-(2-Bromophenyl)-2-(piperazin-1-yl)pyrimidine (precursor to L15). The title compound was
synthesized using GP1 and was isolated as a clear, yellow oil in 92% yield (1.17 g, 3.67 mmol) after
1
column chromatography (90:10 to 70:30 hexanes:EtOAc). H NMR (500 MHz, CDCl3): δ 8.34 (d, J =
4.5 Hz, 2H), 7.59 (dd, J = 1.5, 8.0 Hz, 1H), 7.28 (ddd, J = 1.5, 7.5, 8.0 Hz, 1H), 7.05 (dd, J = 1.5, 8.0
Hz, 1H), 6.94 (ddd, J = 1.5, 7.5, 8.0 Hz, 1H), 6.51 (t, J = 4.5 Hz, 1H), 4.01 (t, J = 5.0 Hz, 4H), 3.10 (t, J
13
= 5.0 Hz, 4H); C{1H} NMR (125.8 MHz, CDCl3): δ 161.9, 157.9, 150.7, 134.0, 128.4, 124.7, 121.1,
120.2, 110.1, 51.8, 44.2; m/z ESI+ found 319.0550 [M+H]+ calculated for C14H1679BrN4 319.0553.
Di-1-(3,5-dimethyladamantyl)phosphinic chloride. This was prepared following a modification of the
literature procedure for the preparation of di(1ꢀadamantyl)phosphinic chloride.16 1,3ꢀ
Dimethyladamantane (5.0 g, 0.030 mol) and AlCl3 (4.1 g, 0.031 mol) were combined in a Schlenk flask
and purged with N2. 15 mL of PCl3 was added via cannula, and the reaction mixture was heated to reflux
for 5 hours. Excess PCl3 was removed by distillation, and the resulting orange slurry was taken up in
chloroform and cooled to 0 °C. Water was added slowly with vigorous stirring, and subsequent steps
were carried out under bench top conditions. The resulting mixture was Buchner filtered through a bed
of Celite. The layers were separated and the organic phase was dried using Na2SO4 and filtered.
Removal of solvent provided the title compound as a pale yellow solid in 99% yield (6.17 g, 0.015 mol).
1H NMR (500 MHz; CDCl3): δ 2.17ꢀ2.12 (m, 2H, CH), 1.98ꢀ1.92 (m, 4H, CH2), 1.79ꢀ1.69 (m, 8H,
CH2), 1.41 (d, J = 12.5 Hz, 4H, CH2), 1.34 (d, J = 12.6 Hz, 4H, CH2), 1.18 (s, 4H, CH2), 0.86 (s, 12H,
CH3). 31P{1H} NMR (CDCl3, 202 MHz) δ 85.9 (s). 13C{1H} NMR (CDCl3, 126 MHz) δ 50.5 (d, J = 1.9
Hz, CH2), 47.5 (d, J = 59.1 Hz, PC), 43.0 (d, J = 2.5 Hz, CH2), 42.9 (d, J = 2.2 Hz, CH2), 42.7 (d, J = 1.8
Hz, CH2), 42.7 (d, J = 1.8 Hz, CH2), 35.8 (d, J = 1.9 Hz, CH2), 31.1 (s, CCH3), 31.0 (d, J = 1.6 Hz,
CCH3), 30.8 (s, CH3), 29.2 (d, J = 11.9 Hz, CH). HRMS (ESI/[M+Na]+) calcd. for C24H38ClNaOP:
431.2241. Found: 431.2224.
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Di-1-(3,5-dimethyladamantyl)phosphine. This was prepared following a modification of the literature
procedure for the preparation of di(1ꢀadamantyl)phosphine.16 50 mL of dry THF was added to a Schelnk
flask containing 5.76 g of 2. The resulting suspension was cooled to –15 °C, and LiAlH4 (1.28 g) was
slowly added in small portions over 15 minutes, allowing evolution of gas to subside before each
subsequent addition. The reaction was then warmed to ambient temperature and stirred for 1 hour. The
reaction was cooled to –15 °C, and 1 mL of 1M HCl was added very slowly over approximately 10
minutes. An additional 30 mL of 1M HCl was slowly added, resulting in a twoꢀphase system, with the
aqueous phase being highly viscous. The THF layer was transferred via cannula to a Schlenk flask
containing Na2SO4, stirred, and filtered through a sintered glass frit. Removal of solvent in vacuo gave
1
the title compound in 87 % yield (4.72 g, 0.013 mol). H NMR (500 MHz; C6D6): δ 3.01 (d, J = 201.9
Hz, 1H, PH), 1.98ꢀ1.93 (m, 2H, CH), 1.90ꢀ1.86 (m, 2H, CH2), 1.80ꢀ1.76 (m, 2H, CH2), 1.69ꢀ1.63 (m,
4H, CH2), 1.61ꢀ1.51 (m, J = 4.7, 2.3 Hz, 4H, CH2), 1.31 (app. d, J = 12.3 Hz, 4H, CH2), 1.23 (app. d, J =
31
12.4 Hz, 4H, CH2), 1.04 (s, 4H, CH2), 0.80 (s, 12H, CH3); P{1H} NMR (C6D6, 202 MHz) δ 14.8 (s);
13C{1H} NMR (C6D6, 126 MHz) δ 51.0 (s, CH2), 50.4 (d, J = 9.7 Hz, CH2), 50.0 (d, J = 12.3 Hz, CH2),
43.2 (s, CH2), 42.5 (d, J = 9.2 Hz, CH2), 35.7 (d, J = 18.2 Hz, PC), 31.5 (d, J = 7.5 Hz, CCH3), 31.4 (d, J
= 8.5 Hz, CCH3), 31.1 (s, CH3), 30.5 (d, J = 7.3 Hz, CH). HRMS (ESI/[M+H]+) calcd. for C24H40P:
359.2862. Found: 359.2858.
(L4) N-(2-di-tert-butylphosphino)phenyl)-morpholine. The title compound was synthesized using
GP2, substituting di(tertꢀbutyl)phosphine for di(1ꢀadamantyl)phosphine, and was isolated as a white
solid in 72% yield (0.220 g, 0.72 mmol) after column chromatography (90:10 hexanes:EtOAc). 1H NMR
(500 MHz, CDCl3): δ 7.68 (d, J = 8.0 Hz, 1H), 7.31ꢀ7.28 (m, 1H), 7.07ꢀ7.03 (m, 2H), 3.83 (t, J = 4.5 Hz,
4H), 3.06 (t, J = 4.5 Hz, 4H), 1.19 (d, J = 12 Hz, 18H); 13C{1H} NMR (125.8 MHz, CDCl3): δ 159.0 (d,
JPC = 20 Hz), 136.4, 134.0 (d, JPC = 28 Hz), 129.7, 122.8, 120.0, 67.3, 53.6 (d, JPC = 6 Hz), 32.3 (d, JPC
11

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= 26 Hz), 30.9 (d, JPC = 16 Hz); 31P{1H} NMR (CDCl3): δ 18.6; m/z ESI+ found 308.2128 [M+H]+
calculated for C18H31NOP 308.2138.
(L6) N-(2-di-(3,5-dimethyladamantyl)phosphino-1-phenyl)-morpholine. The title compound was
synthesized
using
GP2,
substituting
diꢀ1ꢀ(3,5ꢀdimethyladamantyl)phosphine
for
di(1ꢀ
adamantyl)phosphine, and was isolated as a beige solid in 89% yield (0.922 g, 1.77 mmol) after washing
with cold hexanes. 1H NMR (500 MHz; CDCl3): δ 7.66 (d, J = 7.6 Hz, 1H, 3ꢀPh), 7.30 (td, J = 7.6, 1.3
Hz, 1H, 5ꢀPh), 7.07ꢀ7.03 (m, 2H, 4ꢀPh + 6ꢀPh), 3.82 (t, J = 4.5 Hz, 4H, OCH2), 3.03 (t, J = 4.4 Hz, 4H,
NCH2), 1.99 (m, 2H, Ad CH), 1.75 (m, 4H), 1.62 (d, J = 12.4 Hz, 2H), 1.51ꢀ1.42 (m, 6H), 1.34ꢀ1.23 (m,
8H), 1.10ꢀ1.04 (m, 4H), 0.77 (s, 6H, CH3), 0.74 (s, 6H, CH3). 13C(1H) NMR (CDCl3, 126 MHz): δ 159.4
(d, J = 20.9 Hz), 137.5 (d, J = 3.0 Hz, 3ꢀPh), 131.6 (d, J = 27.4 Hz), 129.6 (s, 5ꢀPh), 122.4 (s, 4ꢀPh),
120.2 (d, J = 3.7 Hz, 6ꢀPh), 67.3 (s, OCH2), 53.5 (d, J = 5.8 Hz, NCH2), 51.1 (s, Ad CH2), 48.7 (d, J =
14.7 Hz, Ad CH2), 48.2 (d, J = 12.5 Hz, Ad CH2), 43.3 (s, Ad CH2), 40.3 (d, J = 11.3 Hz, Ad CH2), 38.1
(d, J = 27.5 Hz, Ad CP), 31.4 (d, J = 6.1 Hz, Ad CCH3), 31.4 (d, J = 5.1 Hz, Ad CCH3), 31.1 (s, CH3),
30.1 (d, J = 8.0 Hz, Ad CH). 31P{1H} NMR (CDCl3, 202 MHz): δ 18.8 (s). HRMS (ESI/[M+H]+) calcd.
for C34H51NOP: 520.3703. Found: 520.3687.
(L8) N-(2-diadamantylphosphino)phenyl)-azetidine. The title compound was synthesized using GP2
and was isolated as a white solid in 61% yield (0.700 g, 2.59 mmol) after column chromatography (95:5
hexanes:EtOAc). 1H NMR (500 MHz, CDCl3): δ 7.56 (dt, J = 2.0, 7.5 Hz, 1H), 7.22ꢀ7.19 (m, 1H), 6.71
(td, J = 1.0, 7.5), 6.46 (ddd, J = 1.0, 5.0, 8.5 Hz, 1H), 4.09 (t, J = 7.2 Hz, 4H), 2.20 (pentet, J = 7.2 Hz,
2H), 1.99ꢀ1.96 (m, 6H), 1.89ꢀ1.87 (m, 12H), 1.67 (bs, 12H); 13C{1H} NMR (125.8 MHz, CDCl3): δ
158.2 (d, JPC = 24 Hz), 138.5, 129.3, 118.1 (d, JPC = 32 Hz), 116.3, 113.1 (d, JPC = 6.1 Hz), 56.2 (d, JPC
= 14 Hz), 42.3 (d, JPC = 13 Hz), 37.4 (d, JPC = 25 Hz), 37.2, 29.1 (d, JPC = 9.0 Hz), 17.3 (d, JPC = 8.1
12

Page 13 of 29
Hz); 31P{1H} NMR (CDCl3): δ 18.4; m/z ESI+ found 434.2954 [M+H]+ calculated for C29H41NP
434.2971.
(L9) N-(2-diadamantylphosphino)phenyl)-pyrrolidine. The title compound was synthesized using
GP2 and was isolated as a light brown solid in 28% yield (0.250 g, 0.56 mmol) after washing with
pentane (3 x 3 mL). 1H NMR (500 MHz, CDCl3): δ 7.65 (dt, J = 1.5, 7.5 Hz, 1H), 7.25ꢀ7.22 (m, 1H),
6.97 (ddd, J = 1.5, 4.5, 8.5 Hz, 1H), 6.85 (td, J = 1.5, 7.0 Hz, 1H), 3.36ꢀ3.34 (m, 4H), 1.98ꢀ1.86 (m,
13
24H), 1.67 (bs, 12H); C{1H} NMR (125.8 MHz, CDCl3): δ 157.5 (d, JPC = 23 Hz), 138.5 (d, JPC = 11
Hz), 129.4, 125.6 (d, JPC = 29 Hz), 118.8, 117.3 (d, JPC = 5.3 Hz), 53.2 (d, JPC = 12 Hz), 42.1 (d, JPC
=
31
13 Hz), 37.3 (d, JPC = 26 Hz), 37.2, 29.1 (d, JPC = 8.5 Hz), 25.4; P{1H} NMR (CDCl3): δ 24.5; m/z
ESI+ found 448.3140 [M+H]+ calculated for C30H43NP 448.3128.
(L11) N-(2-diadamantylphosphino)phenyl)-azepane. The title compound was synthesized using GP2
and was isolated as a light brown solid in 62% yield (0.236 g, 0.50 mmol) after washing with pentane (3
x 3 mL). 1H NMR (500 MHz, CDCl3): δ 7.67 (dt, J = 1.5, 7.5 Hz, 1H), 7.27ꢀ7.24 (m, 1H), 7.12 (ddd, J =
1.0, 4.5, 8.0 Hz, 1H), 6.97 (td, J =1.0, 7.0 Hz, 1H), 3.16 (t, J = 6.0 Hz, 4H), 1.98ꢀ1.88 (m, 18H), 1.77ꢀ
13
1.64 (m, 24H); C{1H} NMR (125.8 MHz, CDCl3): δ 161.5 (d, JPC = 20 Hz), 137.4 (d, JPC = 3.0 Hz),
131.7 (d, JPC = 27 Hz), 129.3, 121.5, 120.4 (d, JPC = 3.5 Hz), 54.8 (d, JPC = 5.5 Hz), 42.0 (d, JPC = 13
31
Hz), 37.3, 36.8 (d, JPC = 28 Hz), 29.2 (d, JPC = 8.3 Hz), 26.2, 24.5; P{1H} NMR (CDCl3): δ 21.1; m/z
ESI+ found 476.3440 [M+H]+ calculated for C32H47NP 476.3441.
(L12) N-(2-(diadamantylphosphino)phenyl)-tetrahydroisoquinoline. The title compound was
synthesized using GP2 and was isolated as a light yellow solid in 56% yield (340 mg, 0.67 mmol) after
washing with Et2O (2 x 5 mL). The 13C spectra showed two signals for each of the
tetrahydroisoquinoline carbons ortho to nitrogen, possibly due to restricted rotation about the CarylꢀN
13

Page 14 of 29
bond. 1H NMR (CDCl3): δ 7.75 (dt, J = 1.4, 7.6 Hz, 1H), 7.31 (m, 1H), 7.18ꢀ7.13 (m, 4H), 7.10ꢀ7.05 (m,
2H), 4.25 (s, 2H), 3.41 (t, J = 5.6 Hz, 2H), 3.00 (t, J = 5.5 Hz, 2H), 2.00ꢀ1.86 (m, 18H), 1.67 (br s, 12H).
13C{1H} NMR (CDCl3): δ 159.9 (d, JPC = 21 Hz), 137.8, 136.1, 135.7 (d, JPC = 2 Hz), 131.3 (d, JPC = 27
Hz), 129.6, 129.1, 126.5, 125.9, 125.6, 122.1, 120.8 (d, JPC = 3 Hz), 54.9 (2), 51.7 (2), 42.0 (d, JPC = 13
31
Hz), 37.2, 36.9 (d, J = 27 Hz), 29.1 (2 unique signals). P{1H} NMR (CDCl3): δ 20.8. m/z ESI+ found
510.3273 [M+H]+ calculated for C35H45NP 510.3284.
(L14) N-(2-(diadamantylphosphino)phenyl)-N’-methylpiperazine. The title compound was
synthesized using GP2 and was isolated as a beige solid in 61% yield (290 mg, 0.61 mmol) after
1
washing with Et2O (2 x 5 mL). H NMR (CDCl3): δ 7.70 (dt, J = 1.4, 7.6 Hz, 1H), 7.29 (m, 1H), 7.09
(ddd, J = 1.1, 4.4, 8.0 Hz, 1H), 7.03 (td, J = 1.2, 7.4 Hz, 1H), 3.10 (br s, 4H), 2.62 (br s, 4H), 2.40 (s,
13
3H), 1.97ꢀ1.89 (m, 18H), 1.71ꢀ1.67 (m, 12H). C{1H} NMR (CDCl3): δ 159.9 (d, JPC = 21 Hz), 137.6,
131.4 (d, JPC = 27 Hz), 129.5, 122.2, 120.3 (d, JPC = 3 Hz), 55.4, 52.9 (d, JPC = 6 Hz), 46.2, 42.1 (d, JPC
31
= 13 Hz), 37.2, 36.9 (d, JPC = 27 Hz), 29.1 (d, JPC = 18 Hz). P{1H} NMR (CDCl3): δ 20.7. m/z ESI+
found 477.3392 [M+H]+ calculated for C31H46N2P 477.3393.
(L15) N-(2-diadamantylphosphino)phenyl)-2-(piperazin-1-yl)pyrimidine. The title compound was
synthesized using GP2 and was isolated as a light brown solid in 88% yield (0.478 g, 0.88 mmol) after
after column chromatography (90:10 hexanes:EtOAc). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J = 5.0
Hz, 2H), 7.71 (apparent d, J = 7.5 Hz, 1H), 7.29 (td, J = 1.5 Hz, 1H), 7.05ꢀ7.02 (m, 2H), 6.48 (t, J = 4.5
Hz, 1H), 3.95 (bs, 4H), 3.11 (t, J = 5.0 Hz, 4H), 1.99ꢀ1.89 (m, 18H), 1.67 (bs, 12H); 13C{1H} NMR
(125.8 MHz, CDCl3): δ 162.4, 159.8 (d, JPC = 21 Hz), 157.8, 137.6 (d, JPC = 3.0 Hz), 131.5 (d, JPC = 28
Hz), 129.5, 122.2, 120.1, 109.8, 53.1 (d, JPC = 5.8 Hz), 44.2, 42.1 (d, JPC =13 Hz), 37.2, 37.0 (d, JPC
=
27 Hz), 29.1 (d, JPC = 9.3 Hz); 31P{1H} NMR (CDCl3): δ 20.6; m/z ESI+ found 541.3451 [M+H]+
calculated for C34H46N4P 541.3455.
14

Page 15 of 29
(L16) N-(2-di-(3,5-dimethyladamantyl)phosphino-1-phenyl)-3,5-dimethylmorpholine. The title
compound was synthesized using GP2 from Nꢀ(2ꢀbromophenyl)ꢀ2,6ꢀdimethylmorpholine15 and diꢀ1ꢀ
(3,5ꢀdimethyladamantyl)phosphine, affording a light yellow powder in 65% yield (715 mg, 1.30 mmol)
after washing with cold hexanes. 1H NMR (500 MHz; CDCl3): δ 7.66 (d, J = 7.7 Hz, 1H, 3ꢀPh), 7.29 (td,
J = 7.6, 1.2 Hz, 1H), 7.05ꢀ7.01 (ov m, 2H, 4ꢀPh + 6ꢀPh), 3.92ꢀ3.86 (m, 2H, OCH), 3.14 (d, J = 11.8 Hz,
2H, NCHH), 2.45 (t, J = 10.5 Hz, 2H, NCHH), 1.99 (m, 2H, Ad), 1.77ꢀ1.71 (m, 4H, Ad), 1.62 (d, J =
12.4 Hz, 2H, Ad), 1.46 (m, 6H, Ad), 1.28 (m, 8H, Ad), 1.19 (s, 3H, CH3 Morph), 1.18 (s, 3H, CH3
13
Morph), 1.07 (q, J = 11.8 Hz, 4H, Ad), 0.77 (s, 6H, CH3 Ad), 0.74 (s, 6H, CH3 Ad). C{1H} NMR
(CDCl3, 126 MHz) δ 159.1 (d, J = 20.5 Hz), 137.5 (d, J = 2.9 Hz, 3ꢀPh), 131.6 (d, J = 27.2 Hz), 129.5 (s,
5ꢀPh), 122.3 (s, 4ꢀPh), 120.4 (d, J = 3.7 Hz, 6ꢀPh), 71.9 (s, OCH), 59.2 (d, J = 5.5 Hz, NCH2), 51.1 (s,
CH2), 48.7 (d, J = 14.7 Hz, CH2), 48.3 (d, J = 13.0 Hz, CH2), 43.3 (s, CH2), 40.3 (d, J = 11.3 Hz, CH2),
38.1 (d, J = 27.5 Hz, CP Ad), 31.4 (d, J = 5.5 Hz, CCH3 Ad), 31.3 (d, J = 4.9 Hz, CCH3 Ad), 31.1 (s,
CCH3 Ad), 30.1 (d, J = 7.8 Hz, CH Ad), 19.2 (s, CH3 Morph). 31P{1H} NMR (CDCl3, 202 MHz) δ 19.0
(s). HRMS (ESI/[M+H]+) calcd. for C36H55NOP: 548.4016. Found: 548.4017.
(L17) N-(3-di-(3,5-dimethyladamantyl)phosphino-2-pyridyl)-morpholine. The title compound was
synthesized
using
GP2
from
Nꢀ(3ꢀbromopyridinꢀ2ꢀyl)morpholine14b
and
diꢀ1ꢀ(3,5ꢀ
dimethyladamantyl)phosphine, affording light yellow crystals in 56% yield (293 mg, 0.56 mmol) after
recrystallization from hexanes. 1H NMR (500 MHz; CDCl3): δ 8.27 (d, J = 4.7 Hz, 1H, Py), 7.89 (d, J =
7.4 Hz, 1H, Py), 6.92 (dd, J = 7.4, 4.8 Hz, 1H, Py), 3.82 (t, J = 4.5 Hz, 4H, OCH2), 3.34 (t, J = 4.1 Hz,
4H, NCH2), 2.00 (m, 2H, Ad), 1.72 (m, 4H, Ad), 1.57 (m, 2H, Ad), 1.44 (m, 6H, Ad), 1.33ꢀ1.28 (m,
10H, Ad), 1.07 (m, 4H, Ad), 0.77 (s, 6H, CH3), 0.75 (s, 6H, CH3). 13C{1H} NMR (CDCl3, 126 MHz): δ
168.4 (d, J = 19.8 Hz, Py), 148.2 (s, Py CH), 146.4 (s, Py CH), 123.5 (d, J = 34.5 Hz, Py), 117.1 (s, Py
CH), 67.1 (s, OCH2), 51.9 (d, J = 9.1 Hz, NCH2), 51.0 (s, CH2 Ad), 48.7 (d, J = 14.7 Hz, CH2 Ad), 48.2
15

Page 16 of 29
(d, J = 12.1 Hz, CH2 Ad), 43.2 (s, CH2 Ad), 40.3 (d, J = 11.3 Hz, CH2 Ad), 38.6 (d, J = 27.5 Hz, CP
Ad), 31.5 (d, J = 5.4 Hz, CCH3 Ad), 31.4 (d, J = 4.2 Hz, CCH3 Ad), 31.1 (s, CH3 Ad), 30.0 (d, J = 8.0
Hz, CH Ad). 31P{1H} NMR (CDCl3, 202 MHz): δ 19.0 (s). HRMS (ESI/[M+H]+) calcd. for
C33H50N2OP: 521.3655. Found: 521.3676.
(L18) N-(3-di-(3,5-dimethyladamantyl)phosphino-2-thienyl)-morpholine. The title compound was
synthesized
using
GP2
from
Nꢀ(3ꢀbromothiophenꢀ2ꢀyl)morpholine14a
and
diꢀ1ꢀ(3,5ꢀ
dimethyladamantyl)phosphine, affording a white powder in 57% yield (170 mg, 0.32 mmol) after
1
purification by column chromatography (10:1 hexanes:EtOAc). H NMR (500 MHz; CDCl3): δ 7.13 (d,
J = 5.6 Hz, 1H, thiophene), 6.93 (d, J = 5.6 Hz, 1H, thiophene), 3.82 (t, J = 4.6 Hz, 4H, OCH2), 3.05 (t,
J = 4.5 Hz, 4H, NCH2), 1.99 (m, 2H, Ad), 1.68 (m, 4H, Ad), 1.56 (d, 2H, Ad), 1.45 (m, 6H, Ad), 1.28
(m, 8H, Ad), 1.07 (m, 4H, Ad), 0.77 (s, 6H, CH3), 0.75 (s, 6H, CH3). 13C{1H} NMR (CDCl3, 126 MHz)
δ 166.5 (d, J = 25.1 Hz), 131.6 (d, J = 4.1 Hz, thio CH), 121.9 (d, J = 27.5 Hz), 116.9 (s, thio CH), 67.1
(s, OCH2), 55.3 (d, J = 3.3 Hz, NCH2), 51.0 (s, CH2 Ad), 48.3 (d, J = 13.3 Hz, CH2 Ad), 48.2 (d, J =
12.5 Hz, CH2 Ad), 43.2 (s, CH2 Ad), 40.2 (d, J = 11.0 Hz, CH2 Ad), 38.2 (d, J = 23.0 Hz, Ad CP), 31.4
(d, J = 5.8 Hz, CCH3 Ad), 31.3 (d, J = 5.2 Hz, CCH3 Ad), 30.1 (s, CH Ad). 31P{1H} NMR (CDCl3, 202
MHz) δ 9.9 (s). HRMS (ESI/[M+H]+) calcd. for C32H49NOPS: 526.3267. Found: 526.3260.
RESULTS AND DISCUSSION
The MorꢀDalPhos ancillary ligand variants (L1ꢀL18) examined herein were prepared in
synthetically useful yields as outlined in Scheme 1, using a methodology analogous to that employed for
the parent MorꢀDalPhos ligand.9 Starting from 2ꢀbromoiodobenzene, the nitrogen donor fragment was
introduced at the iodide position by use of a BHA protocol using Pd2dba3/BINAP; subsequent
palladiumꢀcatalyzed CꢀP crossꢀcoupling of the derived aniline in the presence of Pd(OAc)2/DiPPF
afforded the target P,Nꢀligands L1ꢀL18. Ligands L1ꢀL3,13a L5,9 L7,8 and L109 were reported by our
16

Page 17 of 29
group previously, whereas ligand L1315 was reported for use in oxidative gold catalysis by Zhang and
coꢀworkers during the course of our investigations herein; otherwise, L4, L6, L8ꢀL12, and L14ꢀL18
represent new compounds that are disclosed for the first time herein. In all cases the new MorꢀDalPhos
ligand variants were found to be airꢀstable, and were characterized by use of NMR spectroscopic and
highꢀresolution mass spectrometric techniques, as well as Xꢀray crystallographic methods in the case of
L16 (Figure 2). Notably, ligands L6 and L16ꢀL18 are derived from the new secondary phosphine
HP(Me2Ad)2, which was prepared by using a synthetic method directly analogous to that reported for the
synthesis of HPAd2.16 Combination of 1,3ꢀdimethyladamantane and PCl3 in the presence of AlCl3
afforded after aqueous workup Cl(O)P(Me2Ad)2, which in was be transformed into HP(Me2Ad)2 (86%
overall isolated yield across both steps) upon reduction with LiAlH4.
With a series of systematically modified MorꢀDalPhos ancillary ligand variants in hand (L1ꢀ
L18), we conducted an initial competitive screen of these ligands focused on the palladiumꢀcatalyzed
crossꢀcoupling of chlorobenzene with aniline, octylamine, or morpholine (Figure 3; 2 mol% Pd, 4 mol%
L). Chlorobenzene was chosen specifically given the difficulty associated with the crossꢀcoupling of
aryl chlorides,17 and as a representative substrate lacking electronic or steric activation. Furthermore, the
nucleophiles selected represent relatively easy substrates in BHA chemistry,1a which we viewed as being
an appropriate starting point in our reactivity survey.
The poor performance of the triarylphosphines L1 and L2 in the Nꢀarylation of aniline,
octylamine, or morpholine with chlorobenzene was readily apparent, whereby ≤ 40% conversion to the
target product was noted in all cases. These observations are consistent with the established trend that
strongly electronꢀreleasing ancillary ligands are needed in order to achieve effective catalytic turnover in
palladiumꢀcatalyzed crossꢀcouplings of aryl chlorides.1a, 18 By contrast, a number of dialkylphosphine
MorꢀDalPhos variants proved effective for such transformations. In the Nꢀarylation of aniline, each of
17

Page 18 of 29
L3ꢀL18 afforded >90% conversion to diphenylamine under the test conditions employed. Whereas
analogous crossꢀcouplings of octylamine to give Nꢀoctylaniline also proved to be facile, poor conversion
to product was noted when using L3 and L12. The poor performance of L3 (featuring a PCy2 moiety)
relative to that of L4 or L5 (featuring comparatively larger P(tBu)2 or PAd2 moieties, respectively) in
the Nꢀarylation of octylamine underscores the need for a particularly sterically demanding
dialkylphosphino donor group within the MorꢀDalPhos framework for such crossꢀcouplings. The
inferior behavior of L12 (a benzannulated derivative of L10) in this context may arise from differing
ligation properties of this lessꢀflexible ancillary ligand versus other variants featuring a strictly saturated
sixꢀmembered nitrogen heterocyclic donor group. More variation in the catalytic behavior of L3ꢀL18
was noted in the Nꢀarylation of morpholine, with L4ꢀL7, L17, and L18 affording ≥ 85% conversion to
the target Nꢀphenylmorpholine, and conversely ≤ 70% conversion to product achieved by use of L10,
L12ꢀL15. The apparently divergent performance of the piperidine ligand L10, relative to the
morpholineꢀderived MorꢀDalPhos L5, in the Nꢀarylation of morpholine may arise from the differing
basicity of these fragments (pKa(ammonium) in water: piperidine 11.22; morpholine 8.36). While the
established potential for κ3ꢀP,N,O coordination19 involving L5 that is not feasible with L10 may also
contribute to the desirable performance of L5, such reactivity benefits are not apparent when using the
structurally related piperazine ligands L14 and L15. At first glance it is tempting to attribute the inferior
behavior of the dimethylmorpholino ligand L13 versus the parent L5 in the formation of Nꢀ
phenylmorpholine as arising due to the greater steric demand of L13; however, the efficacy of L16
featuring both methylated morpholino and adamantyl fragments would appear to contradict this
hypothesis. In fact, each of the ancillary ligand variants featuring the P(Me2Ad)2 donor fragment,
including L6, L16, and the heterocyclic variants L17 and L18, were observed to perform well in the Nꢀ
arylation of morpholine.
18

Page 19 of 29
We subsequently turned our attention to what are typically more challenging palladiumꢀ
catalyzed crossꢀcouplings, including the Nꢀarylation of indole,20 as well as the monoarylation of
ammonia or acetone,21 with chlorobenzene (Figure 4). The first of these transformations proved to be
particularly problematic, with no observed conversion to Nꢀphenylindole noted for nine of the 18 Morꢀ
DalPhos variants examined. This observation notwithstanding, the dimethylmorpholino ancillary ligand
L13 afforded quantitative conversion to the target product. While high conversion to product was also
realized by use of the P(Me2Ad)2 variants L6 and L16, the related heterocyclic variants L17 and L18
proved significantly less effective.
The selective monoarylation of ammonia or acetone share the common challenge that the derived
products (i.e., in the case of phenyl electrophiles, aniline or phenylacetone) are often superior substrates
relative to ammonia or acetone, thereby leading to uncontrolled polyarylation even in the presence of
excess nucleophile.21 In this context, MorꢀDalPhos L5 has proven to be one of the most effective
ancillary ligands known for such difficult palladiumꢀcatalyzed crossꢀcouplings.9, 13a In keeping with this
theme, L5 afforded high conversion and selectivity for the monoarylation of ammonia with
chlorobenzene under the test conditions employed herein. While none of the ligands surveyed were
found to outꢀperform L5 in this regard, comparable catalytic behavior was noted when using the
P(Me2Ad)2 analogue L6; ligands L10 (as observed previously9), L13, L16, and L17 also performed
reasonably well in this transformation. In quantifying the formation of diphenylamine as part of this
ancillary ligand screening process, significant competing diarylation (> 20%) was noted in the case of
L3, L7, L9, L14, and L18.
The palladiumꢀcatalyzed selective monoarylation of acetone with chlorobenzene was found to be
a transformation for which a larger number of the MorꢀDalPhos ancillary ligand variants proved capable
(Figure 4). Ligands L6 and L12 proved to be particularly effective in this transformation, affording
19

Page 20 of 29
>90% conversion to phenylacetone, with L14 following very close behind. Unlike L3 and L14 (each
affording ≥80 % conversion to phenylacetone), which generated significant quantities of diphenylamine
in crossꢀcouplings of ammonia (vide supra), the excellent performance of L12 in the monoarylation of
acetone is somewhat surprising, considering that this ligand afforded no conversion to aniline in our
analogous ammonia monoarylation survey.
CONCLUSION
In conclusion, our competitive catalytic screening of a family of MorꢀDalPhos ligand variants in
the palladiumꢀcatalyzed crossꢀcoupling of chlorobenzene with aniline, octylamine, morpholine, indole,
ammonia, or acetone revealed some informative ancillary ligand design trends. Notably,
triarylphosphine variants L1 and L2 performed poorly in these test reactions, likely owing in part to the
challenging nature of the C(sp2)ꢀCl oxidative addition; conversely, ligands featuring either PAd2 or
P(Me2Ad)2 donors in general gave rise to superior catalytic performance. While multiple MorꢀDalPhos
variants proved highly effective for palladiumꢀcatalyzed CꢀN crossꢀcouplings involving aniline,
octylamine, or morpholine, only selected ligands of this type proved useful in the more challenging
crossꢀcouplings of indole, ammonia, or acetone. In the case of the Nꢀarylation of indole, a MorꢀDalPhos
ligand variant featuring orthoꢀdisposed PAd2 and dimethylmorpholino donor fragments (L13) proved
superior to all other ligands surveyed, including the closely related parent MorꢀDalPhos (L5) and the
P(Me2Ad)2 analogue of L13 (i.e., L16); evidently the steric and electronic profile of L13 (versus L5 and
L16) is exquisitely optimized for this indole Nꢀarylation reaction. Conversely, the parent MorꢀDalPhos
(L5) was found to be superior to all other ligands in the palladiumꢀcatalyzed monoarylation of ammonia
with chlorobenzene – an apparent example of “Bercaw’s Law of Initial Optimization22”. Finally, the
20

Page 21 of 29
monoarylation of acetone provided some intriguing results. Ligand L6 (i.e., the P(Me2Ad)2 variant of
parent MorꢀDalPhos L5) proved superior to all other ligands in this transformation. In fact, it can be
argued that with the exception of indole Nꢀarylation, L6 (followed closely by L13 and L16) is the most
broadly useful of the MorꢀDalPhos ligands surveyed herein, thereby highlighting the reactivity benefits
that can be derived from substitution of the adamantyl and morpholino groups of parent MorꢀDalPhos.
While it is our view that the beneficial effect of methylation in this context is associated with increased
ancillary ligand steric demand, perhaps resulting in reduced biꢀmolecular decomposition, more subtle
electronic effects including rendering the donor fragments more electronꢀrich cannot be discounted. This
is not to say that we completely understand all of the observed structureꢀreactivity phenomena; the
efficacy of L12 in the palladiumꢀcatalyzed monoarylation of acetone was particularly surprising, given
that this ligand variant proved inactive in the conceptually related monoarylation of ammonia.
Collectively, the results presented herein serve to underscore the benefits of systematically examining,
through structural modification, an effective ancillary ligand structure, as a means of better
understanding structureꢀreactivity properties and also as an entryꢀpoint to more effective catalytic
systems.
SUPPLEMENTARY MATERIAL
NMR Spectra of the newly prepared ligands and their precursors reported herein.
ACKNOWLEDGEMENT
We thank the Natural Sciences and Engineering Research Council of Canada (Discovery Grant to M.S.;
Undergraduate Student Research Award to V.M.), the Killam Trusts (Research Professorship to M.S.;
Postdoctoral Fellowship to C.A.W.), and Dalhousie University for their generous support of this work.
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REFERENCES
1. (a) RuizꢀCastillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564ꢀ12649; (b) Hartwig, J. F.
Acc. Chem. Res. 2008, 41, 1534ꢀ1544; (c) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008,
47, 6338.
2.
Stradiotto, M.; Lundgren, R. J., Ligand Design in Metal Chemistry: Reactivity and Catalysis.
John Wiley & Sons: Hoboken, NJ, 2016, 1ꢀ405.
3.
4.
Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27.
(a) Kantchev, E. A. B.; O'Brien, C. J.; Organ, M. G. Angew. Chem. Int. Ed. 2007, 46, 2768; (b)
Valente, C.; Calimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem. Int. Ed. 2012,
51, 3314.
5.
3.
6.
Blaser, H. U.; Brieden, W.; Pugin, B.; Spindler, F.; Studer, M.; Togni, A. Top. Catal. 2002, 19,
(a) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586ꢀ6596; (b) Shen, Q. L.;
Hartwig, J. F. Org. Lett. 2008, 10, 4109.
7.
Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
8.
9.
Lundgren, R. J.; SappongꢀKumankumah, A.; Stradiotto, M. Chem. Eur. J. 2010, 16, 1983.
Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M. Angew. Chem. Int. Ed. 2010, 49,
4071.
10.
(a) Lundgren, R. J.; Hesp, K. D.; Stradiotto, M. Synlett 2011, 2443; (b) Lundgren, R. J.;
Stradiotto, M. Aldrichimica Acta 2012, 45, 59.
11. Alsabeh, P. G.; Lundgren, R. J.; McDonald, R.; Seechurn, C. C. C. J.; Colacot, T. J.; Stradiotto,
M. Chem. Eur. J. 2013, 19, 2131.
12. (a) Lundgren, R. J.; Stradiotto, M. Angew. Chem. Int. Ed. 2010, 49, 8686; (b) MacLean, M. A.;
DiezꢀCecilia, E.; Lavery, C. B.; Reed, M. A.; Wang, Y. F.; Weaver, D. F.; Stradiotto, M. Bioorg. Med.
Chem. Lett. 2016, 26, 100.
13.
P. G.; Stradiotto, M. Angew. Chem. Int. Ed. 2013, 52, 7242.
14. (a) A MorꢀDalPhos variant featuring a 2,3ꢀdisubstituted thiophenyl backbone has been shown to
(a) Hesp, K. D.; Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194; (b) Alsabeh,
be inferior in ammonia monoarylation: Cook, E. W. F.; Lavery, C. B.; Wheaton, C. A.; McDonald, R.;
Stradiotto, M. Can. J. Chem. 2015, 93, 326; (b) MacLean, M. A.; Wheaton, C. A.; Stradiotto, M. Can. J.
Chem., dx.doi.org/10.1139/cjcꢀ2017ꢀ0671.
15.
16.
17.
18.
19.
20.
21.
Ji, K. G.; Zhao, Y. L.; Zhang, L. M. Angew. Chem. Int. Ed. 2013, 52, 6508.
Goerlich, J. R.; Schmutzler, R. Phosphorus, Sulfur Silicon Relat. Elem. 1995, 102, 211.
Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
Lundgren, R. J.; Stradiotto, M. Chem. Eur. J. 2012, 18, 9758.
Alsabeh, P. G.; McDonald, R.; Stradiotto, M. Organometallics 2012, 31, 1049.
Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403.
Stradiotto, M. Ancillary Ligand Design in the Development of Palladium Catalysts for
Challenging Selective Monoarylation Reactions. In New Trends in Cross-Coupling: Theory and
Application, Colacot, T. J., Ed. Royal Society of Chemistry: Cambridge, UK, 2014; pp 228ꢀ253.
22.
For a discussion of this law, see p. 294 of the following account: Behenna, D. C.; Stoltz, B. M.
Top. Organometal. Chem. 2013, 44, 281.
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Scheme 1. Synthesis of the MorꢀDalPhos ligand variants examined herein.
Figure 1. Structures of MeꢀDalPhos and MorꢀDalPhos, with sites of structural variation within the latter
as examined herein indicated.
Figure 2. Crystallographically determined structure of L16. Selected interatomic distances (Å): Pꢀaryl
1.8549(12), Nꢀaryl 1.4305(15).
Figure 3. Competitive screening of L1ꢀL18 in palladiumꢀcatalyzed crossꢀcoupling of chlorobenzene
with aniline, octylamine, or morpholine, employing [Pd(cinnamyl)Cl]2 (0.0025 mmol), ligand (0.01
mmol), NaOtBu (0.35 mmol), dodecane (0.18 mmol), chlorobenzene (0.25 mmol), and amine (0.30
mmol) at 110 ˚C for 18 h. Estimated percent conversion to the target monoarylation complex (Yꢀaxis)
determined on the basis of calibrated GC data. See the Experimental Section for full details.
Figure 4. Competitive screening of L1ꢀL18 in palladiumꢀcatalyzed crossꢀcoupling of chlorobenzene
with indole, ammonia, or acetone, employing [Pd(cinnamyl)Cl]2 (0.0025 mmol), ligand (0.01 mmol),
base (NaOtBu or Cs2CO3), dodecane (0.18 mmol), chlorobenzene (0.25 mmol), and indole (0.26 mmol),
ammonia (0.75 mmol), or acetone (0.5 mL) at 110 ˚C (for indole) or 90 ˚C (for ammonia or acetone) for
18 h. Estimated percent conversion to the target monoarylation complex (Yꢀaxis) determined on the
basis of calibrated GC data. See the Experimental Section for full details.
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