Empirical and Computational Insights into N-Arylation Reactions Catalyzed by Palladium meta-Terarylphosphine Catalyst

Article abstract of DOI:10.1002/cplu.201700042

An in situ generated Pd–Cy*Phine catalyst has been successfully applied to the N-arylation of primary and secondary amines, and it exhibited high performance across multiple substrate classes. The performance induced by the meta-terarylphosphine motif of the Cy*Phine ligand for C?N cross-coupling displayed only subtle differences to that of its biarylphosphine congener XPhos. DFT studies demonstrated comparable reaction energetics in the catalytic cycle steps for both Pd–Cy*Phine and Pd–XPhos, which was consistent with previous findings. The computational investigation also indicated that a putative rate-determining step occurred after amine binding, which was likely to have annulled the expected benefits of having a meta-terarylphosphine ligand architecture.

Full text of DOI:10.1002/cplu.201700042

Accepted Article
Title: Empirical & Computational Insights into N-Arylation Reactions
Catalyzed by Pd-meta-Terarylphosphine Catalyst
Authors: Fui Fong Yong, Adrian M. Mak, Wenqin Wu, Michael B.
Sullivan, Edward G. Robins, Charles W. Johannes, Howard
Jong, and Yee Hwee Lim
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Empirical & Computational Insights into N-Arylation Reactions
Catalyzed by Pd-meta-Terarylphosphine Catalyst
Fui Fong Yong,+[a] Adrian M. Mak,+[b] Wenqin Wu,[a] Michael B. Sullivan,[b] Edward G. Robins,[c] Charles
W. Johannes,[a] Howard Jong,*[a] and Yee Hwee Lim*[a]
Dedication ((optional))
conditions for different substrate classes, or their performance
may be limited to specific substrates classes or types. Palladium
catalysts that utilize ligands such as t-Bu3P, Q-Phos and N-
heterocyclic carbenes,[11] for example, have the propensity to be
excellent for the N-arylation of secondary amines, but less
reactive towards the coupling of primary amines.[2c] Similarly,
RuPhos is touted as the recommended option for the Pd-
catalyzed N-arylation of secondary amines[2e,8b] while ligands,
such as Josiphos and BrettPhos are very effective for the N-
arylation of primary amines demonstrating outstanding activity
and selectivity.[2d,2e,9b] The relationship between these ligand
designs and their reactivity profile is often unclear. Further
complications arise with numerous other factors playing
influential roles (e.g. choice of bases, amines, palladium
sources, solvent, and temperature), which could significantly
affect the reactivity outcome and the mechanism of palladium-
catalyzed N-arylation reactions.[14]
Abstract: The application of the in situ Pd-Cy*Phine catalyst has
been successfully employed to the N-arylation of primary and
secondary amines and exhibited high-performance broadly across
multiple substrate classes. Compared to its biarylphosphine
congener XPhos, the performance induced by the meta-
terarylphosphine motif of Cy*Phine ligand for C-N cross-coupling
revealed only subtle differences. DFT studies demonstrated
comparable reaction energetics in the catalytic cycle steps for both
Pd-Cy*Phine and Pd-XPhos, which was consistent with previous
findings. The computational investigation also indicated that a
putative rate-determining step is occurring after amine binding,
which likely annulled the expected benefits of having a meta-
terarylphosphine ligand architecture.
Recent work by Harvey and Fey et al.[15] and Norrby et
al.[16] provided valuable insight into the mechanism of the
coupling of phenylbromide and morpholine. Key findings by
Harvey and Fey et al.[15] included evidence from the DFT studies
of a β-hydride elimination pathway that competes with reductive
elimination. However, in this instance, the use of bulky
phosphine ligands disfavored the former pathway. Norrby et
al.[16] investigated the effects of different bases in various
solvents for Pd-catalyzed N-arylation employing either
monodentate (t-Bu3P), or bidentate (BINAP) ligands.
Computationally, the effectiveness of using a tert-butoxide base
in both polar and non-polar solvent was rationalised.
Introduction
The palladium-catalyzed C-N cross-coupling (also referred
to as Buchwald-Hartwig amination)[1,2] has revolutionised the
synthesis of N-arylated alkyl and aryl amines industrially[3-5] and
academically.[2e] There exists a plethora of literature[6-11] that
describes palladium-catalyzed N-arylation using a variety of
ligand designs. Amongst the different ligand architectures,
phosphine-based ligands[7-10] are the most commonly employed.
The structure of these phosphine ligands range from simple
motifs, such as trialkylphosphines (e.g. t-Bu3P)[7] to more
sophisticated designs such as triaminophosphines (i.e. P[N(i-
Bu)CH2CH2]3N),[10a-b,10k] ferrocenyl monophosphines (e.g. Q-
Phos)[2c,9b] and ferrocenyl diphosphines (e.g. DtBPF[9b] and
Josiphos[12]). Nonetheless, the use of bulky, multi-ringed
To date, the Pd catalyst system that provides the widest
substrate scope (accessing both primary and secondary amines)
with high selectivity and reactivity is the concurrent use of
RuPhos and BrettPhos. This combination approach effectively
manifests complementary catalysis of different active species
[17,18]
during the reaction.
phosphines
featuring
N-substituted
heterocycles
(e.g.
OMe
cataCXium PIntB),[10d] or biaryl-based backbones, pioneered by
Beller[13] and Buchwald[8] respectively, have proven to be among
OMe
A
1
A
A
1
1
PAd2
6
PCy2
MeO
PAd2
6
6
1'
the most versatile and popular ligand types.
Despite considerable advancements, the eclectic collection
of N-arylation catalysts often operate in different reaction
i-Pr
i-Pr
F
1'
1'
i-Pr
i-Pr
i-Pr
i-Pr
B
3'
B
B
3'
3'
F
C
F
C
i-Pr
C
i-Pr
Cy*Phine
i-Pr
F
nBu
nBu
HGPhos
AlPhos
[a]
Organic Chemistry, Institute of Chemical and Engineering Sciences
(ICES), Agency for Science, Technology and Research (A*STAR),
8 Biomedical Grove, Neuros, #07-01, Singapore 138665.
E-mails: lim_yee_hwee@ices.a-star.edu.sg; howard_jong@ices.a-
star.edu.sg
Figure 1. Meta-terarylphosphine systems reported as supporting ligands in
palladium-catalyzed cross-coupling reactions.
[b]
[c]
+
Institute of High Performance Computing (IHPC), Agency for
Science, Technology and Research (A*STAR),
1 Fusionopolis Way, #16-16 Connexis, Singapore 138632.
Singapore Bioimaging Consortium (SBIC), Agency for Science,
Technology and Research (A*STAR),
Recently,
the
monodentate
meta-terarylphosphine
architecture[19] (Figure 1) has proven to be an excellent promoter
of palladium-catalyzed C-C, C-B and C-F cross-coupling
reactions exhibiting a significant advantage over their respective
biarylphosphine analogue. Reactions such as copper-free
Sonogashira coupling,[20] the Mizoroki-Heck reaction,[21]
11 Biopolis Way, Helios, #02-02, Singapore 138667.
Equal contributions
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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decarboxylative coupling,[22] and borylation-Suzuki-Miyaura
sequences[23] have been recently reported using the Cy*Phine
ligand. Advancements in nucleophilic aryl fluorination have been
demonstrated using the HGPhos and AlPhos ligands.[24]
Encouraged by the excellent performance and broad
applicability of Pd-Cy*Phine in various C-C bond forming
reactions[20-23] (Scheme 1), we envisaged that this system might
also achieve enhanced performance for N-arylation.
ref. 23
refs. 20, 22
R2B
R2
C

B coupling
R1
C

C coupling
R1
R1
A
1
PCy2
6
R3
1'
ref. 21
i-Pr
i-Pr
B
3'
C

C coupling
R6
C
i-Pr
R4
N
ref. 23
R5
?
Cy*Phine
R1
R1
C

C coupling
C

N coupling
[a] Unless otherwise stated, the reactions were carried out with alkyl or aryl
amines (0.6 mmol), aryl chlorides or heteroaryl chlorides (0.5 mmol), Pd2(dba)3
(1 mol%), Cy*Phine (4 mol%), t-BuONa (1.4 equiv.) in THF (0.75 mL) at
100 °C for 15 h. Isolated yield (average of two runs). [b] 2 mol% of Pd2(dba)3
and 8 mol% Cy*Phine were used instead. [c] Toluene was used instead of
THF; yields were obtained by 1H NMR using hexamethylbenzene as an
internal standard.
Scheme 1. Palladium-catalyzed cross-couplings using Cy*Phine as the
supporting ligand.
Results and Discussion
A survey of literature conditions for palladium-catalyzed N-
arylation reaction revealed several notable trends such as the
use of Pd2(dba)3 and Pd(OAc)2 with t-BuONa or LHMDS as the
base. Also, these combinations were proven effective in dioxane,
toluene, or THF solvent. In our studies, a focus on aryl chlorides
was made as they are more cost effective and readily available
than other aryl halides and pseudohalides. Therefore, for our
initial comparative studies of Pd-Cy*Phine in N-arylation, we
chose to investigate the coupling of aniline with 3-chloropyridine
(Table 1). N-Arylation with chloroaniline proved to be very
successful providing 3c in 99% yield using Pd2(dba)3, Cy*Phine
and t-BuONa in THF; toluene was also evaluated but was found
to be less proficient for benzyl and secondary alkyl amines
(Table 1, 3a-3d, yields shown in parentheses).[25] Encouraged by
the success of our initial results, we proceed to investigate the
scope and applicability of this general condition to a more
diverse set of substrates. Selected results are in Table 1 with an
extended range of substrates provided in the Supporting
Information (Table 1A).
An evaluation of the substrate diversity revealed good to
excellent catalyst performance across all four classes of amine
substrates using the same reaction conditions. However, the
results also indicated that Pd-Cy*Phine was comparatively less
effective when the amines were at the extremes of being
electron rich (3e, 3i), conjugated (3g) or electron poor (3k).
Challenges also arose with increasing complexity of the chloro-
heterocycle coupling partner increased (3b > 3f > 3j). As these
trends are commonly exhibited by other state-of-the-art Pd
catalysts, our results indicated that Pd-Cy*Phine is competitive
in C-N cross-coupling reactions.
Table 2. Comparison of Pd-Cy*Phine and Pd-XPhos catalyzed N-arylation of
primary amines using the general protocol.[a]
Entry
Product
Pd-Cy*Phine[b]
Pd-XPhos[b]
1
>99 (83:0:17)[c]
>99 (89:0:11)[c]
Table 1. The representative scope of the Pd-Cy*Phine catalyzed N-arylation of
aryl chlorides or heteroaryl chlorides using the general protocol.[a]
2
3
76 (64:4:8)[c]
>99 (99)
79 (47:29:3)[c]
>99 (99)
[a] Each reaction was carried out with amine (1.2 mmol), aryl chloride or
heteroaryl chloride (1.0 mmol), Pd2(dba)3 (1 mol%), Cy*Phine or XPhos (4
mol%), t-BuONa (1.4 equiv.) in THF (1.5 mL) at 100 °C for 1 hour. [b] Values
referred to substrate conversion and product(s) distribution in parentheses. [c]
Product ratio represents the ratio of mono-N-arylation vs. di-N-arylation vs.
proto-dehalogenation observed for both Pd-Cy*Phine and Pd-XPhos catalyst
systems.
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The performance similarity between Pd-Cy*Phine and Pd-
and Pd-XPhos, respectively) and appeared to be rate-
determining. However, an alternative fate is plausible for LM2
with a potentially lower barrier for both Pd-XPhos and Pd-
Cy*Phine. Drawing on our insights from the previous study on
the mechanism of copper-free Sonogashira cross-coupling
reactions,[27] a likely possibility is a base-assisted amine binding
(BAB) pathway for LM2 to LM3A (Figure 3, blue). In this case,
BAB for Cy*Phine has a much lower barrier of 25.7 kJ/mol
corresponding to the coordination of tBuO- to aniline, which
provides a viable off-cycle route of LM2 towards the end
products. The BAB barriers for Pd-XPhos are expected to be
same to those of Pd-Cy*Phine since the reactants in the
pathway are common and do not include the catalyst. The
existence of the off-cycle BAB pathway is consistent with the
results from Shekhar and Hartwig, who showed that reaction
rates are independent of the concentration of base.[28]
Other unlikely but possible fates of LM2 considered
include: (i) direct binding of the t-BuO- base, (ii) C-P bond
rotation, and (iii) dearomative rearrangement (DR) of the ligand.
The direct binding of the t-BuO- base is likely to progress
via low barrier and highly exergonic steps (Table S2), which was
attributed by Norrby et al.[16] and McMullin et al.[29] to be a
diffusion-controlled process. While this is energetically
favourable, a mechanism which describes the removal of
coordinated Cl- from the Pd center has yet to be elucidated.
Secondly, the rotation of the C-P bond in LM2 can facilitate
subsequent amine binding as proposed by Barder and
Buchwald.[14,30] It is noteworthy that this torsional rotation was
shown to have a barrier of approximately 77 kJ/mol as
calculated by Barder et al.,[30] which is higher than the barrier
calculated for BAB. This process was also calculated to be
endergonic for Pd-XPhos and Pd-Cy*Phine, by 39.8 and 47.7
kJ/mol, respectively (Table S2).
XPhos in N-arylation reactions[8c-e] became evident after an
evaluation under identical conditions (Table 2). From the
comparison, the N-arylation of primary aliphatic amines (i.e. n-
hexylamine with either 2-chloroanisole, or 3-chloropyridine) and
primary aryl amines (i.e. 1-chloro-4-tert-butylbenzene and
aniline) gave comparable outcomes regarding rate and
conversion. The only anomaly appeared to be the coupling of 3-
chloropyridine with n-hexylamine, which furnished improved
selectivity for the mono-N-arylated product (16:1 vs. 2:1) when
Cy*Phine ligand was employed.[26]
Intrigued by these results, we sought to probe the
mechanism of these two systems computationally to gain an
understanding to rationalise these experimental observations.
While an in-depth analysis of all the different ligand designs
relevant to N-arylation cross-coupling is beyond the scope of this
article, a comparison of the biaryl- and m-terarylphosphine
ligands using first-principle DFT models provides early insights
and offers a plausible rationale for the correlation of catalyst
structure with performance.
The study was initiated with the investigation of four key
reaction steps in the generally accepted catalytic cycle for N-
arylation[2] using 1-chloro-4-tert-butylbenzene (S1) and aniline
(S2) as model substrates (Figure 2). Consideration for both the
“cis-“ and “trans-“ arrangements of the complexes LM2, LM3
and LM4 and their respective spatial arrangements are detailed
in Figure S1 (see Supporting Information). For clarity, the
discussion herein is based on the more likely cis-conformers.
LM2 may also undergo off-cycle DR pathways in which the
ligand L may be modified. In our previous study on copper-free
Sonogashira cross-coupling, the influence of the meta-
terarylphosphine architecture was shown to hinder the
deleterious off-cycle DR of the catalyst.[27] Herein, the barriers for
the DR were calculated to be notably higher than for the AB step,
at 102.1 and 164.7 kJ/mol for Pd-XPhos and Pd-Cy*Phine,
respectively. The availability of the low-barrier BAB off-cycle
pathway facilitates rapid conversion of LM2 to LM3A and other
post-amine-added intermediates, minimizing the buildup of LM2
to undergo inefficient DR processes and catalyst modification. A
summary of the Gibbs free energies of the possible reactions of
LM2 along with the barriers (where available) is provided in
Table S2 of the Supporting Information for reference and
comparison.
Figure 2. Generally accepted catalytic cycle for palladium-catalyzed N-
arylation of aryl chloride and aniline. Ar = 4-tert-butylphenyl.
In comparison to the DFT studies by Harvey and Fey et
al.,[15] and Norrby et al.,[16] our investigation is differentiated
primarily by the use of a different catalyst architecture, as well as
a different amine—both of which are expected to impact the
outcome significantly. For example, morpholine (pKa 8.49), the
system studied by Norrby et al.,[16] is more Lewis basic than
aniline (pKa of 4.6),[31] which is used in our models. As a result,
the former was computationally assessed to only deprotonate
after coordination to Pd, but such a determination using aniline
The Gibbs free energies of activation (∆G‡) and reaction
(∆G) at 298 K of the steps in the catalytic cycle for both Pd-
Cy*Phine and Pd-XPhos are provided in Table S1. For clarity,
only the Gibbs free energy reaction profile for the N-arylation
mediated by the cis-conformer of Pd-Cy*Phine is shown in
Figure 3. A cursory inspection revealed that the AB step had the
highest barriers (∆G‡ = 123.3 and 84.6 kJ/mol for Pd-Cy*Phine
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was less obvious. Norrby et al. addressed the possible
sequence of events as follows: (a) a base coordinates to Pd and
the halide is eliminated sequentially, or (b) an external base
deprotonates the amine while it stays coordinated to Pd. The
binding of the weaker proton donor, morpholine, to Pd is
necessary for subsequent deprotonation by t-BuO-, but this may
not be the case for aniline, where our proposed off-cycle BAB
route is independent of the catalyst. A common consideration in
the mechanistic proposal of Norrby et al.[16] is the dissociation of
the coordinated halide from the Pd center before the
coordination of t-BuO- base to the Pd center. In our mechanistic
proposal, we considered an alternative scenario, where a five-
coordinate Pd complex is formed, and the halide, Cl- is removed
along with the protonated base t-BuOH as a hydrogen-bonded
complex t-BuOH…Cl. Pd-Cl dissociation in the style of Norrby et
al.[16] is not considered as Pd-Cl bond is much stronger than the
Pd-Br bond; the bond dissociation energy of Pd(II)-Cl was
calculated by Houk et al.[32] to be 384.5 kJ/mol, which is too high
for this process to be feasible given the mild experimental
conditions.
The varying benefits of different ligand architectures can
be drawn when our investigation is compared with that by
Harvey and Fey et al.[15] The steric bulk of the t-Bu3P ligand was
proposed to prevent unwanted side reactions such as
dimerization and β-hydride elimination. In the case of Pd-
Cy*Phine, the Cy*Phine ligand may prevent the deleterious off-
cycle dearomative rearrangement of the catalyst, which is not a
factor for t-Bu3P systems.
The barriers for the post-amine binding steps–amine
deprotonation (AD) and reductive elimination (RE), 69.2 and
73.9 kJ/mol, respectively–are calculated to be significantly
higher than the BAB barrier of 25.7 kJ/mol (Figure 3). Despite
the differences, the assignment of the rate-determining step and
the identification of the catalyst’s resting state are difficult due to
the similar activation barriers for AD and RE. Furthermore, the
assignment of the resting state will also depend on the nature of
the amine. Nonetheless, with the putative rate-determining step
for the N-arylation likely to occur post-amine addition, this
suggests that biarylphosphine ligands (i.e. XPhos) are not likely
to be susceptible to unproductive off-cycle events at the LM2
state.[27] The increased distance between the Pd center and
Ring B for LM3, LM3A, LM3B and LM4 (Table S3) further
buttresses the rationale. This evidence, together with the similar
reaction barriers between Pd-Cy*Phine and Pd-XPhos,
corroborate the similar performance observed for Pd-Cy*Phine
and Pd-XPhos in N-arylation catalysis.
As multi-ringed phosphine ligands are being used more
widely, gaining access to a relevant mechanistic understanding
on the 3′ substitution becomes more critical to facilitate catalyst
selection and development. As such, efforts in our group to
apply this knowledge for the benefit of other cross-coupling
applications are underway.
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Figure 3. Schematic Gibbs free energy reaction profile (in kJ/mol) for the N-arylation of 1-chloro-4-tert-butylbenzene (S1) and aniline (S2) mediated by cis-conformer of Pd-Cy*Phine. Ar = 4-tert-butylphenyl
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(d, J = 2.8 Hz, 1 H), 8.15 (dd, J = 4.8, 1.4 Hz, 1 H), 7.43 (ddd, J = 8.3, 2.8,
1.4 Hz, 1 H), 7.34 – 7.27 (m, 2 H), 7.18 (dd, J = 8.3, 4.7 Hz, 1 H), 7.12 –
7.06 (m, 2 H), 7.00 (tt, J = 7.4, 1.2 Hz, 1 H), 5.96 (s, 1 H) ppm. 13C-NMR
(100 MHz, CDCl3)  = 142.01, 141.53, 140.25, 139.88, 129.70, 123.94,
123.70, 122.34, 118.66 ppm.
Conclusions
In summary, we have demonstrated that the meta-
N-methyl-N-phenylpyridin-3-amine (3d):[38] Following the general
procedure using N-methylaniline (0.0649 mL, 0.6 mmol) and 3-
chloropyridine (0.0476 mL, 0.5 mmol) gave a crude product which was
purified by flash chromatography using 68:32 petroleum ether/ethyl
acetate to afford 3d as yellow oil (92 mg, 99% yield). 1H-NMR (400 MHz,
CDCl3)  = 8.30 (d, J = 2.8 Hz, 1 H), 8.12 (dd, J = 4.7, 1.4 Hz, 1 H), 7.36
– 7.27 (m, 2 H), 7.21 (ddd, J = 8.4, 2.9, 1.5 Hz, 1 H), 7.16 – 7.02 (m, 4 H),
3.31 (s, 3 H) ppm. 13C-NMR (100 MHz, CDCl3)  = 147.92, 145.22,
141.01, 140.43, 129.66, 124.81, 123.50, 123.39, 122.53, 40.05 ppm.
terarylphosphine based catalyst, Pd-Cy*Phine, is broadly
efficient for N-arylation reactions. Generic reaction conditions
were developed to couple four classes of amines with heteroaryl
chlorides. However, the performance exhibited was found to be
comparable to its biarylphosphine-based analogue, Pd-XPhos,
for which DFT studies were employed to rationalise the results.
Computational data indicated that the rate-determining step of
the Pd-Cy*Phine catalytic cycle occurring after the amine
binding step negated the benefits of having the meta-
terarylphosphine ligand architecture. This information provides a
greater understanding of how the mechanistic component of
various cross-coupling reactions correlates with the catalyst
architecture. Despite the many complexities involved in cross-
coupling reactions, the evidence presented here can serve as a
general guideline to facilitate catalyst selection and development
for N-arylation and other cross-coupling applications.
N-Hexyl-2-methoxyaniline (3e):[39] Following the general procedure
using hexylamine (0.0785 mL, 0.6 mmol) and 2-chloroanisole (0.0635 mL,
0.5 mmol) gave
a crude product which was purified by flash
chromatography using 96:4 petroleum ether/ethyl acetate to afford 3e as
a pale purple oil (84 mg, 81% yield). 1H-NMR (400 MHz, CDCl3) 6.91
(td, J = 7.6, 1.4 Hz, 1 H), 6.80 (dd, J = 7.9, 1.4 Hz, 1 H), 6.73 – 6.61 (m, 2
H), 3.88 (s, 3 H), 3.16 (t, J = 7.2 Hz, 2 H), 1.78 – 1.62 (m, 2 H), 1.52 –
1.29 (m, 6 H), 1.06 – 0.86 (m, 3 H) ppm. 13C-NMR (100 MHz, CDCl3)
146.90, 138.61, 121.44, 116.24, 109.94, 109.52, 55.50, 43.91, 31.81,
29.66, 27.05, 22.74, 14.14 ppm.
4-(pyrazin-2-yl)morpholine (3f):[35] Following the general procedure
using morpholine (0.0525 mL, 0.6 mmol) and 2-chloropyrazine (0.0446
mL, 0.5 mmol) gave a crude product which was purified by flash
chromatography using 50:50 petroleum ether/ethyl acetate to afford 3f as
yellow oil (73 mg, 88% yield). 1H-NMR (400 MHz, CDCl3)  = 8.15 – 8.03
(m, 2 H), 7.87 (d, J = 2.4 Hz, 1 H), 3.85 – 3.77 (m, 4 H), 3.54 (dd, J = 5.8,
3.6 Hz, 4 H) ppm. 13C-NMR (100 MHz, CDCl3) = 155.22, 141.92,
133.51, 130.91, 66.63, 44.93 ppm.
Experimental Section
General Procedure for the N-arylation of alkyl and aryl amines: A
sealable reaction tube was charged with Pd2(dba)3 (0.001 equiv.),
Cy*Phine (0.004 equiv.), t-BuONa (1.4 equiv.) and tetrahydrofuran (THF)
(0.666 mM). Next, the aryl halide (0.5 mmol) and the amine (1.2 equiv.)
were added to this reaction vial, sealed with a Teflon-lined septum and
stirred at 100 °C for 15 h. The reaction mixture was then cooled to room
temperature and diluted with dichloromethane. The resulting solution was
directly filtered through a pad of Celite. The solvent of the combined
organic extracts was removed under reduced pressure. The crude
product was purified by silica-gel column chromatography to afford the N-
arylated product. The identity and purity of known products were
confirmed by 1H and 13C NMR spectroscopic analysis.
4-((4-vinylphenyl)amino)benzonitrile (3g):
Following the general
procedure using 4-vinylaniline (0.0703 mL, 0.6 mmol) and 4-
chlorobenzonitrile (68.8 mg, 0.5 mmol) gave a crude product which was
purified by flash chromatography using 50:10 petroleum ether/ethyl
acetate to afford 3g as an off-white solid (93mg, 84% yield). 1H-NMR
(400 MHz, CD3CN)  = 7.51 (d, J = 8.6 Hz, 2 H), 7.42 (d, J = 8.3 Hz, 2
H), 7.26 (s, 1 H), 7.14 (d, J = 8.4 Hz, 2 H), 7.12 – 7.03 (m, 2 H), 6.71 (dd,
J = 17.6, 10.9 Hz, 1 H), 5.71 (dd, J = 17.6, 1.0 Hz, 1 H), 5.17 (d, J = 10.9
Hz, 1 H) ppm. 13C-NMR (101 MHz, CD3CN)  = 149.07, 141.31, 137.18,
N-Benzyl-(3-pyridyl)amine (3a):[33,34] Following the general procedure
using benzylamine (0.0655 mL, 0.6 mmol) and 3-chloropyridine (0.0476
mL, 0.5 mmol) gave a crude product which was purified by flash
chromatography using 60:40 petroleum ether/ethyl acetate to afford 3a
as a yellow solid (83 mg, 90% yield). 1H-NMR (400 MHz, CDCl3)  = 8.08
(d, J = 3.0 Hz, 1 H), 7.96 (dd, J = 4.7, 1.4 Hz, 1 H), 7.39 – 7.32 (m, 4 H),
7.32 – 7.26 (m, 1 H), 7.10 – 7.03 (m, 1 H), 6.88 (ddd, J = 8.3, 2.9, 1.4 Hz,
1 H), 4.34 (s, 2 H) ppm. 13C-NMR (100 MHz, CDCl3)  = 144.25, 138.80,
138.63, 136.12, 128.89, 127.62, 127.52, 123.87, 118.82, 48.01 ppm.
134.68, 133.44, 128.26, 121.00, 120.68, 118.30, 116.12, 112.98, 101.87
+
ppm. HRMS (ESI): cald. For C15H13N2 [M+H]+ 221.1073
; found
221.1067.
6-methoxy-N-methyl-N-phenylpyridazin-3-amine (3h):[40] Following the
general procedure using N-methylaniline (0.130 mL, 1.2 mmol) and 3-
chloro-6-methoxypyridazine (0.145g, 1.0 mmol) gave a crude product
which was purified by flash chromatography using 85:15 petroleum ether/
ethyl acetate to afford 3h as a yellow solid (213 mg, 99% yield). 1H-NMR
(600 MHz, CDCl3)  = 7.38 (dd, J = 8.3, 7.4 Hz, 2 H), 7.23 – 7.13 (m, 3 H),
6.82 (d, J = 9.6 Hz, 1 H), 6.66 (d, J = 9.6 Hz, 1 H), 4.03 (s, 3 H), 3.52 (s,
3 H) ppm. 13C-NMR (151 MHz, CDCl3)  = 160.12, 156.87, 146.67,
129.99, 125.98, 125.80, 120.40, 118.84, 54.40, 39.27 ppm.
N-(3-pyridyl)morpholine (3b):[35,36] Following the general procedure
using morpholine (0.0525 mL, 0.6 mmol) and 3-chloropyridine (0.0476
mL, 0.5 mmol) gave a crude product which was purified by flash
chromatography using 60:40 petroleum ether/ethyl acetate to afford 3b
as yellow oil (82 mg, 99% yield). 1H-NMR (600 MHz, CDCl3)  = 8.16 (t, J
= 1.9 Hz, 1 H), 7.98 (t, J = 3.0 Hz, 1 H), 7.05 (dd, J = 3.2, 1.7 Hz, 2 H),
3.79 – 3.67 (m, 4 H), 3.10 – 2.98 (m, 4 H) ppm. 13C-NMR (100 MHz,
CDCl3) = 146.85, 140.77, 138.01, 123.46, 122.05, 66.53, 48.46 ppm.
4-(tert-butyl)-N-cyclohexylaniline (3i):[40] Following the general
procedure using cyclohexylamine (0.0686 mL, 0.6 mmol) and 1-tert-butyl-
4-chlorobenzene (0.0835 mL, 0.5 mmol) gave a crude product which was
purified by flash chromatography using 10:1 petroleum ether/ethyl
acetate to afford 3i as a yellow liquid (100 mg, 86% yield). 1H-NMR (600
MHz, CDCl3)  = 7.32 – 7.26 (m, 2 H), 6.68 – 6.62 (m, 2 H), 3.49 (s, 1 H),
3.37 – 3.28 (m, 1 H), 2.37 – 2.33 (m, 1 H), 2.19 – 2.11 (m, 2 H), 1.86 (dt,
J = 13.6, 4.1 Hz, 2 H), 1.75 (dt, J = 13.1, 4.2 Hz, 1 H), 1.46 (ddd, J = 16.9,
N-phenylpyridin-3-amine (3c):[34,37] Following the general procedure
using aniline (0.0547 mL, 0.6 mmol) and 3-chloropyridine (0.0476 mL,
0.5 mmol) gave
a crude product which was purified by flash
chromatography using 60:40 petroleum ether/ethyl acetate to afford 3c
as yellow solid (84 mg, 99% yield). H-NMR (400 MHz, CDCl3)  = 8.40
1
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9.2, 2.4 Hz, 3 H), 1.43 – 1.35 (m, 10 H), 1.35 – 1.18 (m, 3 H) ppm. 13C-
NMR (100 MHz, CDCl3)  = 145.10, 126.13, 113.08, 52.16, 33.94, 33.77,
31.71, 26.12, 25.18 ppm.
Acknowledgements
The authors thank Dr. Yong Yang for the synthesis of Cy*Phine,
Mdm Wong Lai Kwai (NUS) for the HRMS analyses and the
Experimental Therapeutic Center (ETC) for the use of their NMR
facility. Financial support was provided by the A*STAR Joint
Council Organisation (JCO), the Singapore 1st JCO
Developmental Programme (DP) (grant JCO 1230400020 to
Y.H.L., E.R. and C.W.J.), the A*STAR Institute of Chemical and
Engineering Sciences (ICES), the A*STAR Singapore
Bioimaging Consortium (SBIC) and the A*STAR Institute of High
Performance Computing (IHPC). This work was also supported
by the A*STAR Computational Resource Centre (A*CRC)
through the use of its high-performance computing facilities.
4-(imidazo[1,2-b]pyridazin-6-yl)morpholine
(3j): Prepared from
Pd2(dba)3 (9.2 mg, 0.01 mmol), Cy*Phine (22.1 mg, 0.04 mmol), t-BuONa
(67.3 mg, 1.4 equiv.), THF (0.5 ml), morpholine (0.0525 mL, 0.6 mmol)
and 6-chloroimidazo[1,2-b]pyridazine (0.0767 g, 0.5 mmol) gave a crude
product which was purified by flash chromatography using 10:90
methanol/dichloromethane to afford 3j as white solid. (66 mg, 65% yield).
1H-NMR (600 MHz, CDCl3)  = 7.79 (dt, J = 9.9, 0.8 Hz, 1 H), 7.68 (s, 1
H), 7.62 – 7.50 (m, 1 H), 6.82 (d, J = 9.9 Hz, 1 H), 3.90 – 3.77 (m, 4 H),
3.52 – 3.41 (m, 4 H) ppm. 13C-NMR (151 MHz, CDCl3)  = 155.24,
136.22, 131.30, 125.88, 116.76, 110.30, 66.53, 46.62ppm. HRMS (ESI):
cald. For C10H13N4O+ [M+H]+ 205.1011 ; found 205.1084.
4-((2-methoxyphenyl)amino)benzonitrile (3k):[41] Following the general
procedure using 4-aminobenzonitrile (70.9 mg, 0.6 mmol) and 2-
chloroanisole (0.0635 mL, 0.5 mmol) gave a crude product which was
purified by flash chromatography using 40:20 petroleum ether/ethyl
acetate to afford 3k as a yellow solid (100 mg, 89% yield). 1H-NMR (400
MHz, CDCl3)  = 7.50 – 7.44 (m, 2 H), 7.35 (dd, J = 8.1, 1.6 Hz, 1 H),
7.08 – 7.02 (m, 3 H), 6.98 – 6.92 (m, 2 H), 3.87 (s, 3 H) ppm. 13C-NMR
(100 MHz, CDCl3) = 150.18, 147.63, 133.63, 129.60, 123.35, 120.78,
119.95, 118.92, 115.50, 111.22, 101.57, 55.68 ppm.
Keywords: Cross-coupling • N-arylation • Amines • Palladium •
Meta-terarylphosphine
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1
acetate to afford 3l as a purple solid (257 mg, 93% yield). H-NMR (600
MHz, CDCl3)  = 8.72 – 8.60 (m, 2 H), 7.71 (ddd, J = 8.1, 2.6, 1.5 Hz, 1
H), 7.49 (ddd, J = 8.1, 4.8, 0.8 Hz, 1 H), 7.10 (dd, J = 7.5, 1.7 Hz, 2 H),
6.91 (dtd, J = 23.1, 7.4, 1.5 Hz, 4 H), 6.32 (dd, J = 8.0, 1.4 Hz, 2 H) ppm.
13C-NMR (151 MHz, CDCl3)  = 150.83, 148.40, 143.58, 138.36, 136.95,
127.32, 127.09, 124.93, 123.51, 122.67, 117.47 ppm. HRMS (ESI): cald.
For C17H13N2S+ [M+H]+ 277.0721 ; found 277.0795.
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Computational Methods
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The application of the in situ Pd-Cy*Phine catalyst has been successfully employed
to the N-arylation of primary and secondary amines and exhibited high-performance
broadly across multiple substrate classes. Compared to its biarylphosphine
congener XPhos, the performance induced by the meta-terarylphosphine motif of
Cy*Phine ligand for C-N cross-coupling revealed only subtle differences. DFT
studies demonstrated comparable reaction energetics in the catalytic cycle steps for
both Pd-Cy*Phine and Pd-XPhos, which was consistent with previous findings. The
computational investigation also indicated that a putative rate-determining step is
occurring after amine binding, which likely annulled the expected benefits of having
a meta-terarylphosphine ligand architecture.
Empirical & Computational Insights
into N-Arylation Reactions Catalyzed
by Pd-meta-Terarylphosphine
Catalyst
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