Nuances in Fundamental Suzuki-Miyaura Cross-Couplings Employing [Pd(PPh3)4]: Poor Reactivity of Aryl Iodides at Lower Temperatures

Article abstract of DOI:10.1021/acs.organomet.8b00189

We have explored fundamental Pd-catalyzed C_sp²-C_sp² Suzuki-Miyaura cross-couplings of aryl iodides (Ar-I) employing "classical" Pd/PPh₃ catalyst systems. Surprisingly, we observed particularly inefficient couplings of these ostensibly reactive electrophiles in a range of conventional solvent mixtures at lower temperatures (50 °C), which was in stark contrast to analogous reactions featuring the equivalent aryl bromides. This feature of well-established Pd/PPh₃-mediated Suzuki-Miyaura reactions has received scant attention in the literature. Most significantly, our studies suggest that the inefficient coupling of aryl iodides at lower temperatures derives from the unexpectedly poor turnover of the key on-cycle intermediate trans-[Pd(PPh₃)₂(Ar)(I)] (or related Pd^II-I species) in the presence of PPh₃.

Full text of DOI:10.1021/acs.organomet.8b00189

This is an open access article published under an ACS AuthorChoice License, which permits
copying and redistribution of the article or any adaptations for non-commercial purposes.
Article
Cite This: Organometallics XXXX, XXX, XXX−XXX
Nuances in Fundamental Suzuki−Miyaura Cross-Couplings
Employing [Pd(PPh3)4]: Poor Reactivity of Aryl Iodides at Lower
Temperatures
Curtis C. Ho, Angus Olding, Jason A. Smith, and Alex C. Bissember*
School of Natural Sciences − Chemistry, University of Tasmania, Hobart, Tasmania 7001, Australia
S
* Supporting Information
2
ABSTRACT: We have explored fundamental Pd-catalyzed Csp −
2
Csp Suzuki−Miyaura cross-couplings of aryl iodides (Ar−I)
employing “classical” Pd/PPh3 catalyst systems. Surprisingly, we
observed particularly inefficient couplings of these ostensibly
reactive electrophiles in a range of conventional solvent mixtures
at lower temperatures (∼50 °C), which was in stark contrast to
analogous reactions featuring the equivalent aryl bromides. This
feature of well-established Pd/PPh3-mediated Suzuki−Miyaura reactions has received scant attention in the literature. Most
significantly, our studies suggest that the inefficient coupling of aryl iodides at lower temperatures derives from the unexpectedly
poor turnover of the key on-cycle intermediate trans-[Pd(PPh3)2(Ar)(I)] (or related PdII−I species) in the presence of PPh3.
Scheme 1. Results of Pd-Catalyzed Suzuki−Miyaura
INTRODUCTION
■
Couplings Reported by Novak and Wallow in 19948
The Suzuki−Miyaura reaction is arguably one of the most
important transition-metal-catalyzed C−C coupling processes
in organic synthesis.1,2 Underscoring this, the 2010 Nobel Prize
was awarded to Heck, Negishi, and Suzuki “for palladium-
catalyzed cross-couplings in organic synthesis”.3 The identi-
fication and development of various alkylphosphine ligands
have contributed to enhancing the scope, efficiency, and utility
2
2
of a range of Pd-catalyzed Csp −Csp couplings, including the
Suzuki−Miyaura reaction.4 Nevertheless, more traditional
catalyst systems featuring arylphosphine ligands, including the
venerable precatalyst [Pd(PPh3)4], still feature heavily in these
pivotal transformations.1b The oxidative addition of aryl halides
to phosphine-ligated Pd(0) complexes has been studied
extensively,5 and it is generally accepted that the relative rates
for the oxidative addition of aryl halides (Ar−X) to these Pd(0)
species typically follow the trend Ar−I > Ar−Br > Ar−Cl.5b,6
While we were in the process of developing a new
undergraduate laboratory experiment focused on exploring
key features of the Suzuki−Miyaura reactions utilizing a Pd/
PPh3 catalyst system,7 we were intrigued by results that
counterintuitively suggested the very poor reactivity of aryl
iodides at ∼50 °C. This was in stark contrast to efficient
couplings of the equivalent aryl bromides at the same
temperatures. After searching the literature, we could only
identify one published report of similar behavior in Suzuki−
Miyaura reactions, which was disclosed by Novak and Wallow
over 20 years ago (Scheme 1).8,9 These two data points, which
were not directly discussed in their work, also tentatively
suggested the inefficient coupling of 1-iodo-4-nitrobenzene
under these conditions. To our knowledge, the specific reasons
for this surprising behavior has not been investigated further:
hence, the study reported herein.
RESULTS AND DISCUSSION
■
In order to explore these observations in more detail, we
employed standard Suzuki−Miyaura reaction conditions that
would allow us to conduct experiments across a broad
temperature range.10 Thus, reactions of phenylboronic acid
with p-iodo- and p-bromotoluene, respectively, in the presence
of [Pd(PPh3)4] at 100 and 80 °C, provided efficient couplings
(Table 1, entries 1 and 2). When the analogous Suzuki−
Miyaura couplings were conducted at 70 and 60 °C, the
efficiency of reactions featuring p-iodotoluene (1) decreased
significantly; especially in comparison to equivalent reactions
using bromide 2 (entries 3 and 4). Most notably, in reactions
with iodide 1 at 50 °C, limited cross-coupling occurred and the
results clearly suggested that reaction with bromide 2 was much
more efficient in comparison (Table 1, entry 5, and Figure
1).11,12 Analogous results were observed in THF/H2O or
acetone/H2O solvent mixtures, while employing DMF/H2O
provided a notable difference in the relative efficiencies of
electrophiles 1 and 2 (entries 6−8). The substitution of
Na2CO3 for either K2CO3 or NaOH did not provide significant
differences (entries 9 and 10).13 In general, the substitution of
Received: March 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00189
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
equivalent bromides, and this uniform trend was observed
across a range of sterically and electronically varied aryl halides
and boronic acids (Table 2). In reactions at 50 °C, featuring
Table 1. Respective Suzuki−Miyaura Couplings of Iodide 1
and Bromide 2 with PhB(OH)2: Influence of Reaction
Parameters
Table 2. Investigating Electronic and Steric Effects in
Suzuki−Miyaura Couplings
a
yield (%)
entry
Ar′
Ar″
using Ar−I
using Ar−Br
1
2
3
4
5
6
o-tol
Ph
8 (6)
5 (3)
59 (40)
52 (35)
55 (38)
74 (53)
59 (49)
52 (41)
50 (39)
m-tol
Ph
p-OMeC6H4
Ph
10 (8)
p-NO2C6H4
Ph
17 (11)
12 (10)
15 (14)
16 (13)
Ph
Ph
Ph
p-tol
p-OMeC6H4
p-NO2C6H4
b
7
a
Determined via GC with the aid of a calibrated internal standard
(average of two experiments). Yields after 0.25 h are given in
b
parentheses. Reaction performed at 70 °C.
a
sodium phenyltrihydroxyborate as the nucleophile, couplings
were also more efficient employing bromide 2 in comparison to
iodide 1 (Table 3, entry 1). We then explored whether
Determined via gas chromatography (GC) with the aid of a calibrated
internal standard (average of two experiments). Yields after 0.25 h are
given in parentheses. THF used instead of n-PrOH. Acetone used
instead of n-PrOH. DMF used instead of n-PrOH. K2CO3 used
instead of Na2CO3. NaOH used instead of Na2CO3.
b
c
d
e
f
Table 3. Respective Suzuki−Miyaura Couplings of Iodide 1
and Bromide 2: Influence of Nucleophiles
a
yield (%)
entry
nucleophile
temp (°C)
using 1
using 2
b
1
Ph-B(OH)3Na
Ph-Bpin
50
100
80
15 (13)
89 (89)
87 (62)
7 (7)
57 (57)
95 (81)
85 (79)
61 (43)
67 (43)
50 (25)
12 (2)
2
3
4
5
6
7
Ph-Bpin
Ph−Bpin
Ph-BF3K
Ph-BF3K
Ph-BF3K
50
100
80
77 (72)
47 (34)
<2 (<2)
50
a
Figure 1. Formation of biaryl 3 in respective Suzuki−Miyaura
couplings employing iodide 1 (red) and bromide 2 (blue) at 50 °C
(conditions: Table 1, entry 5). Each data point represents the average
of two experiments with yields determined via GC with the aid of a
calibrated internal standard.
Determined via GC with the aid of a calibrated internal standard
(average of two experiments). Yields after 0.25 h are provided in
parentheses. Na2CO3 not added.
b
substituting phenylboronic acid with either phenylboronic acid
pinacol ester or potassium phenyltrifluoroborate would also
provide similar results. In general, analogous trends were
observed using phenylboronic acid pinacol ester (Table 3,
entries 2−4). Less discernible trends were evident in coupling
reactions using potassium phenyltrifluoroborate (Table 3,
entries 5−7).18,19
We then investigated the effects of other ligands in Pd-
catalyzed Suzuki−Miyaura couplings. Employing monodentate
ligands that are bulkier than PPh3 provided both efficient (P(o-
tol)3) and inefficient (TTMPP) couplings of iodides (Table 4,
entries 1−3). Ligands with cone angles similar to that of PPh3
(AsPh3 and P(p-tol)3) facilitated cross-couplings of iodides
effectively (entries 4 and 5). The presence of monodentate
ligands that are electronically similar to PPh3 (AsPh3, P(o-tol)3,
P(p-tol)3, and PBn3) and more electron deficient (P(2-furyl)3,
1% [Pd(PPh3)4] for 1% Pd(OAc)2/PPh3 (2 or 4%) provided
similar results (entries 11−16).14−16 Notably, employing either
1% Pd(OAc)2/1% PPh3 or “ligandless” conditions (no PPh3)
provided efficient iodide couplings at 50 °C (entries 17 and
18). This demonstrates the adverse effect that the presence of
PPh3 has on the efficiency of the coupling of aryl iodides
relative to bromides at ∼50 °C, which is consistent with Novak
and Wallow’s observations (Scheme 1) and other pioneering
studies highlighting the acceleration of Suzuki−Miyaura
couplings under “ligandless” conditions.8,17
Next, we investigated the role of electronic and steric effects
on reactions using various pairs of electrophiles and
nucleophiles. In this way, we demonstrated more generally
that iodides were less efficient coupling partners relative to the
B
DOI: 10.1021/acs.organomet.8b00189
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 4. Respective Suzuki−Miyaura Couplings of Iodide 1
and Bromide 2: Influence of Ligands
a
yield (%)
e
b
c
entry
ligand
PPh3
θ (deg)
ν (cm−1
)
using 1
using 2
may be generated either by the reaction of oxidative addition
adduct A with a boronate (path A, Figure 2) or via the reaction
1
2
3
4
5
6
7
8
9
145
194
184
142
145
133
130
139.5
2068.9
2066.6
11 (9)
66 (50)
6 (5)
68 (57)
61 (56)
47 (27)
22 (18)
51 (39)
9 (9)
P(o-tol)3
TTMPP
AsPh3
2067.9
2066.7
2078.4
2075.9
2066.1
57 (50)
43 (35)
51 (44)
66 (53)
39 (26)
42 (20)
47 (31)
3 (3)
P(p-tol)3
P(2-furyl)3
P(OPh)3
PBn3
54 (49)
42 (34)
28 (9)
dppf
d
10
dppf
25 (9)
Figure 2. Two fundamental pathways leading to pretransmetalation
intermediate C in Suzuki−Miyaura couplings.
11
dppe
<2 (<2)
<2 (<2)
d
12
dppe
<2 (<2)
a
Determined via gas chromatography (GC) with the aid of a calibrated
internal standard (average of two experiments). Yields after 0.25 h are
of hydroxo-Pd species B with a boronic acid (path B). It is
acknowledged that this transmetalation process is particularly
complicated, nuanced, and subtly influenced by a range of
factors.22,26−28 A number of research groups have investigated
the kinetics of transmetalation experimentally, and in these
particular cases their results indicated that path B was more
kinetically favorable than path A (Figure 2).22,26,28e,f Specifi-
cally, the results of studies exploring the transmetalation of
trans-[Pd(PPh3)2(Ar)(X)] (X = Br, I) under both stoichio-
metric and catalytic conditions demonstrate that the respective
rates of the Suzuki−Miyaura reactions are consistent with
transmetalation likely occurring via the reaction of hydroxo-Pd
species with arylboronic acids (Path B).22,26,28a,b This process is
orders of magnitude faster than the reaction of trans-
[Pd(PPh3)2(Ar)(X)] with an aryltrihydroxyborate (path
A).22,26,29
With the aforementioned issues in mind, we focused on
investigating the chemical competence of trans-[Pd(PPh3)2(p-
tol)(I)] in both n-PrOH/H2O and DMF/H2O. We chose to
also perform experiments in the latter solvent, as we had
previously demonstrated that, in this particular mixture, the
relatively efficient coupling of p-iodotoluene conspicuously
contrasted with results obtained in n-PrOH and other organic
cosolvents (Table 1, entries 5−8). Reactions in both solvent
mixtures clearly demonstrated that trans-[Pd(PPh3)2(p-tol)(I)]
is a chemically competent species at 50 °C (Table 5, entry 1).
Interestingly, when the equivalent reactions were performed in
the presence of 2% PPh3, very low yields of product 3 were
obtained in n-PrOH/H2O while cross-coupling still occurred in
DMF/H2O (Table 5, entry 2). These data indicated that the
poor turnover of key on-cycle intermediate trans-[Pd(PPh3)2(p-
tol)(I)], in the presence of PPh3, may be responsible for
inefficient Suzuki−Miyaura couplings of aryl iodides in n-PrOH
cosolvent mixtures at lower temperatures.
b
c
given in parentheses. Tolman cone angle.9,20 Tolman electronic
d
parameter (IR frequency of Ni(CO)3L).9,20a,21 1% ligand used.
e
Abbreviations: TTMPP, tris(2,4,6-trimethoxyphenyl)phosphine;
dppf, 1,1′-ferrocenediylbis(diphenylphosphine); dppe, bis-
(diphenylphosphino)ethane.
P(OPh)3) all led to efficient couplings (entries 1, 2, and 4−8).
Thus, no clear correlations between the steric or electronic
properties of monodentate ligands and reaction efficiency could
be identified on the basis of these results. However, in general,
these data are consistent with relevant observations reported by
Farina and Krishnan in Pd-catalyzed Stille couplings.9 We also
performed reactions with bidentate phosphine ligands dppf and
dppe, which provided differing results (entries 9−12).
In competition experiments between p-iodo- and p-
bromotoluene employing [Pd(PPh3)4], the catalyst differ-
entiated effectively between these electrophiles at both 50
and 80 °C (eq 1). These data are consistent with oxidative
addition not being the turnover-limiting step of the catalytic
cycle in the case of iodide 1 at these temperatures.22 31P NMR
spectroscopy indicates that the predominant resting states of
the Pd catalyst are trans-[Pd(PPh3)2(p-tol)(I)] and trans-
[Pd(PPh3)2I2] during the early stages of the reaction (eq
2).23−25 When taken together, these results suggest that
transmetalation may be the turnover-limiting step in the
process featuring iodide 1 at 50 °C.
In related experiments, we illustrated the chemical
competence of trans-[Pd(PPh3)2I2], [Pd(PPh3)(p-tol)(μ-I)]2,
and [Pd(PPh3)(p-tol)(μ-OH)]2 (Table 5, entries 3−5). The
results of equivalent experiments performed in the presence of
2% PPh3 led to less efficient Suzuki−Miyaura couplings (entries
6−8). It is possible that the inability of these PdII−I
intermediates to efficiently re-enter the catalytic cycle, in the
2
2
Indeed, in Pd-catalyzed Csp −Csp Suzuki−Miyaura trans-
formations employing aryl iodides, it is often proposed that the
turnover-limiting step involves transmetalation.22,26 Two
fundamental pretransmetalation pathways are postulated to
operate.27,28 Specifically, pretransmetalation intermediate C28a,b
C
DOI: 10.1021/acs.organomet.8b00189
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 5. Exploring the Chemical Competence of Various
Pd(II) Species in Suzuki−Miyaura Couplings
a
Determined via GC with the aid of a calibrated internal standard
Figure 3. Formation of biaryl 3 in reactions employing trans-
[Pd(PPh3)2(p-tol)(I)] (4a) (solid red line), [Pd−I] 4a + 6 equiv of
PPh3 (dashed red line), trans-[Pd(PPh3)2(p-tol)(Br)] (4b) (solid blue
line), [Pd−Br] 4b + 6 equiv PPh3 (dashed blue line), [Pd−OH] 5
(solid black line), and [Pd−OH] 5 + 6 equiv PPh3 (dashed black line).
A 0.5 equiv amount of [Pd(PPh3)(p-tol)(μ-OH)]2 was used in these
experiments (and no Na2CO3 was used in these reactions). Yields
were determined via GC with the aid of a calibrated internal standard
(average of two experiments).
(average of two experiments). Yields after 0.25 h are given in
parentheses. 0.5% [Pd] employed.
b
presence of PPh3, may also contribute to the inefficient
couplings of iodides. Notably, we determined that trans-
[Pd(PPh3)2(p-tol)(Br)] is a chemically competent species in
reactions employing p-bromotoluene in the presence of 2%
PPh3 (Scheme 2).
Scheme 2. Investigating the Chemical Competence of trans-
[Pd(PPh3)2(p-tol)(Br)] in Suzuki−Miyaura Couplings
a
Determined via GC with the aid of a calibrated internal standard
(average of two experiments). Yields after 0.25 h are given in
parentheses.
Next, we investigated transmetalation in Suzuki−Miyaura
couplings employing trans-[Pd(PPh3)2(p-tol)(I)] (4a, red),
trans-[Pd(PPh3)2(p-tol)(Br)] (4b, blue), and [Pd(PPh3)(p-
tol)(μ-OH)]2 (5, black), respectively (Figure 3).30 When these
experiments were performed in the presence of PPh3, the rate
of product formation significantly decreased for complexes 4a
(dashed red) and 4b (dashed blue), respectively. These
observations are consistent with recent studies by Denmark
and co-workers which illustrated that added phosphine reduces
the rate of transmetalation in Suzuki−Miyaura couplings.28a,b,31
Interestingly, the presence of PPh3 did not significantly affect
the rate of product formation from Pd−OH complex 5 (dashed
black). Our experiments illustrate that, in the presence of PPh3,
productive cross-coupling from trans-[Pd(PPh3)2(p-tol)(I)] is
particularly inefficient.32 It is possible that the poor reactivity of
aryl iodides observed in couplings performed in the presence of
PPh3 may relate to the inefficient formation of key PdII−OH
intermediate B (Figure 2) under the reaction conditions.
When we monitored Pd-catalyzed Suzuki−Miyaura couplings
employing either 6% PPh3 (Figure 4, red) or 6% P(2-furyl)3
(blue), we observed results consistent with our aforementioned
data (Tables 1 and 4). In an experiment featuring both PPh3
and P(2-furyl)3 (Figure 4, black),33 it appeared that the former
Figure 4. Formation of biaryl 3 in reactions employing: 6% PPh3
(red), 6% P(2-furyl)3 (blue), and 3% PPh3 and 3% P(2-furyl)3 (black).
Yields were determined via GC with the aid of a calibrated internal
standard (average of two experiments).
phosphine had a greater influence on the progress of the
reaction than the latter. Farina and Krishnan noted similar
effects in Pd-catalyzed Stille couplings employing this mixed
ligand system.9 Their subsequent NMR experiments demon-
strated the “stronger thermodynamic affinity” of PPh3 for
Pd(II) relative to P(2-furyl)3 (eq 3).9,34 We explored the effects
of either PPh3 or P(2-furyl)3 on Suzuki−Miyaura reactions
employing trans-[Pd{P(2-furyl)3}2(p-tol)(I)] (Scheme 3).
These results reinforce the poor reactivity observed in
couplings performed in the presence of PPh3.
When the aforementioned results described in this study are
taken together, we suggest that the poor turnover of trans-
D
DOI: 10.1021/acs.organomet.8b00189
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Scheme 3. Investigating the Chemical Competence of trans-
[Pd{P(2-furyl)3}2(p-tol)(I)] in Suzuki−Miyaura Couplings
AUTHOR INFORMATION
Corresponding Author
*E-mail for A.C.B.: alex.bissember@utas.edu.au.
■
ORCID
Jason A. Smith: 0000-0001-6313-3298
Alex C. Bissember: 0000-0001-5515-2878
Notes
The authors declare no competing financial interest.
a
ACKNOWLEDGMENTS
Determined via GC with the aid of a calibrated internal standard
■
(average of two experiments). Yields after 0.25 h are given in
parentheses.
The authors acknowledge the University of Tasmania School of
Natural Sciences − Chemistry for financial support, the
University of Tasmania Central Science Laboratory for access
to NMR spectroscopy services, Mr. Brendon Schollum for
assistance with gas chromatography, and Prof. Allan Canty and
Prof. Justin Mohr for helpful discussions. A.O. thanks the
University of Tasmania for a Dean’s Summer Research
Scholarship.
[Pd(PPh3)2(p-tol)(I)] (or related PdII−I species) in the
presence of PPh3 may be responsible for inefficient Suzuki−
Miyaura couplings of aryl iodides employing [Pd(PPh3)4] at
lower temperatures. Throughout, where we have suggested
potential reasons for the poor reactivity of aryl iodides in
Suzuki−Miyaura cross-couplings at lower temperatures, we
have refrained from making direct comparisons to analogous
reactions featuring bromide electrophiles as part of this
discussion. We have also avoided speculating on the reasons
for the differing efficiency of couplings of aryl iodides
performed in n-PrOH/H2O in comparison to DMF/H2O
solvent mixtures. In these cases, the differing biphasic natures of
these reaction conditions and related issues, such as the
common ion effect and boron speciation, complicate these
matters and limit our capacity to make such comparisons.
Lloyd-Jones and Lennox have provided an erudite overview
considering these issues within the context of Suzuki−Miyaura
coupling chemistry.27
REFERENCES
■
(1) See, for example: (a) Choi, J.; Fu, G. C. Science 2017, 356,
eaaf7230. (b) Metal-Catalyzed Cross-Coupling Reactions and More, 3rd
ed.; de Meijere, A., Brase, S., Oestreich, M., Eds.; Wiley-VCH:
̈
Weinheim, Germany, 2014. (c) Magano, J.; Dunetz, J. R. Chem. Rev.
2011, 111, 2177−2250. (d) Torborg, C.; Beller, M. Adv. Synth. Catal.
2009, 351, 3027−3043. (e) Corbet, J.-P.; Mignani, G. Chem. Rev.
2006, 106, 2651−2710.
(2) For selected reviews on the Suzuki−Miyaura cross-coupling
reactions, see: (a) Hussain, I.; Capricho, J.; Yawer, M. A. Adv. Synth.
Catal. 2016, 358, 3320−3349. (b) Lennox, A. J. J.; Lloyd-Jones, G. C.
Chem. Soc. Rev. 2014, 43, 412−443. (c) Suzuki, A. Chem. Commun.
2005, 4759−4763.
(3) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062−5085.
(4) For selected reviews on the applications of alkylphosphane
ligands in Pd-catalyzed C−C cross-coupling reactions, see: (a) Rossi,
R.; Bellina, F.; Lessi, M.; Manzini, C.; Marianetti, G.; Perego, L. A.
Curr. Org. Chem. 2015, 19, 1302−1409. (b) Li, H.; Johansson
Seechurn, C. C. C.; Colacot, T. J. ACS Catal. 2012, 2, 1147−1164.
(c) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555−1564.
(5) For selected studies on oxidative addition to Pd(0) complexes
featuring phosphine ligands, see: (a) Goossen, L. J.; Koley, D.;
Hermann, H. L.; Thiel, W. Organometallics 2005, 24, 2398−2410.
(b) Senn, H. M.; Ziegler, T. Organometallics 2004, 23, 2980−2988.
(c) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314−321.
(d) Casado, A. L.; Espinet, P. Organometallics 1998, 17, 954−959.
(e) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117, 5373−5374.
(f) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030−
3039. (g) Amatore, C.; Jutand, A.; Suarez, A. J. Am. Chem. Soc. 1993,
CONCLUSIONS
■
Although an array of phosphine-ligated Pd catalyst systems are
employed in Suzuki−Miyaura couplings, the use of [Pd-
(PPh3)4] (or related PPh3-based systems) is still prevalent,
particularly in more applied settings. This study, which notably
had its origins in the undergraduate laboratory, has revealed the
profound (and somewhat surprising) effects that subtle changes
in reaction conditions can have on the efficiency of
2
2
fundamental Csp −Csp Suzuki−Miyaura couplings of aryl
iodides employing “classical” Pd/PPh3 catalyst systems. Our
data indicate that, in the presence of PPh3, the poor turnover of
trans-[Pd(PPh3)2(p-tol)(I)] (or related PdII−I species) may be
responsible for the inefficient coupling of aryl iodides in various
conventional solvent mixtures at lower temperatures. These
2
2
findings are worth considering, particularly when Csp −Csp
115, 9531−9541. (h) Amatore, C.; Pfluger, F. Organometallics 1990, 9,
2276−2282. (i) Fauvarque, J.-F.; Pfluger, F. J. Organomet. Chem. 1981,
208, 419−427. (j) Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10,
434. (k) Fitton, P.; Rick, E. A. J. Organomet. Chem. 1971, 28, 287−291.
(6) Organotransition Metal Chemistry From Bonding to Catalysis;
Hartwig, J. F., Ed.; University Science Books: Sausalito, CA, 2010;
Chapter 19.
̈
cross-couplings of aryl iodides are performed at lower
temperatures, and can inform the development of optimized
reaction conditions in this manifold. We anticipate that our
work will contribute to providing a more nuanced under-
standing of “textbook” Pd-catalyzed Suzuki−Miyaura couplings
of fundamental electrophile classes employing the prototypical
phosphine ligand PPh3.
̈
(7) Pullen, R.; Olding, A.; Smith, J. A.; Bissember, A. C. Manuscript
in preparation.
ASSOCIATED CONTENT
(8) Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034−5037.
(9) The poor reactivity of aryl iodides with vinyltributyltin in Stille
couplings employing Pd/PPh3 at ∼50 °C has been reported; see:
Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585−9595.
(10) Huff, B. E.; Koenig, T. M.; Mitchell, D.; Staszak, M. A. Org.
Synth. 1998, 75, 53.
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00189.
Experimental procedures and compound characterization
data (PDF)
(11) In general, iodide consumption was comparable to product
yield.
E
DOI: 10.1021/acs.organomet.8b00189
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(12) Analogous results were obtained in experiments employing
higher [Pd(PPh3)4] loadings (2.5% and 5%) (see the Supporting
Information).
(13) We also investigated the effect of incrementally varying the
Na2CO3 loading on the outcome of the reaction at 70 °C. Our results
suggest that the Na2CO3 loading (1−5 equiv) has little effect on the
efficiency of reactions employing p-iodotoluene (see the Supporting
Information). Substituting either Cs2CO3 or NMe4OH for Na2CO3
also provided inefficient couplings of p-iodotoluene (see the
Supporting Information).
(26) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116−
2119.
(27) For a recent review on transmetalation in the Suzuki−Miyaura
cross-coupling, see: Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem.,
Int. Ed. 2013, 52, 7362−7370.
(28) For selected studies on transmetalation in the Suzuki−Miyaura
cross-coupling, see: refs 22 and 26. (a) Thomas, A. A.; Wang, H.;
Zahrt, A. F.; Denmark, S. E. J. Am. Chem. Soc. 2017, 139, 3805−3821.
(b) Thomas, A. A.; Denmark, S. E. Science 2016, 352, 329−332.
́
(c) Ortuno, M. A.; Lledos, A.; Maseras, F.; Ujaque, G. ChemCatChem
̃
2014, 6, 3132−3138. (d) Lima, C. F. R. A. C.; Rodrigues, A. S. M. C.;
Silva, V. L. M.; Silva, A. M. S.; Santos, L. M. N. B. F. ChemCatChem
2014, 6, 1291−1302. (e) Amatore, C.; Jutand, A.; Le Duc, G. Chem. -
Eur. J. 2012, 18, 6616−6625. (f) Schmidt, A. F.; Kurokhtina, A. A.;
Larina, E. V. Russ. J. Gen. Chem. 2011, 81, 1573−1574. (g) Butters, M.;
Harvey, J.; Jover, J.; Lennox, A.; Lloyd-Jones, G.; Murray, P. Angew.
Chem., Int. Ed. 2010, 49, 5156−5160. (h) Huang, Y.-L.; Weng, C.-M.;
Hong, F.-E. Chem. - Eur. J. 2008, 14, 4426−4434. (i) Braga, A. A. C.;
Ujaque, G.; Maseras, F. Organometallics 2006, 25, 3647−3658.
(14) We also performed experiments employing higher PPh3
loadings (see the Supporting Information).
(15) It has been established that PPh3 can effect the reduction of
Pd(OAc)2 to generate catalytically active Pd(0) species. See, for
example: ref 5c. (a) Carole, W. A.; Colacot, T. J. Chem. - Eur. J. 2016,
22, 7686−7695. (b) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M.
́
Organometallics 1995, 14, 1818−1826. (c) Amatore, C.; Jutand, A.;
M’Barki, M. Organometallics 1992, 11, 3009−3013.
(16) Pd(OAc)2 was used in preference to Pdx(dba)y, as challenges in
establishing the exact speciation and purity of the latter have been
identified. See, for example: (a) Amatore, C.; Jutand, A. Coord. Chem.
Rev. 1998, 178−180, 511−528. (b) Zalesskiy, S. S.; Ananikov, V. P.
Organometallics 2012, 31, 2302−2309.
(17) See, for example: Bumagin, N. A.; Bykov, V. V.; Beletskaya, I. P.
Bull. Acad. Sci. USSR, Div. Chem. Sci. 1989, 38, 2206; Bull. Acad. Sci.
USSR, Div. Chem. Sci. (Engl. Transl.) 1989, 38, 2206.
(18) We also performed experiments investigating the effect of halide
additives (20% NH4I, NH4Br, NH4F, NMe4I, NMe4Br, NMe4Cl, LiBr,
LiCl, KBr, KCl, CsBr, or CsCl) on Suzuki−Miyaura couplings (see the
Supporting Information).
́
(j) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Lledos, A.; Maseras,
F. J. Organomet. Chem. 2006, 691, 4459−4466. (k) Braga, A. A. C.;
Morgon, N. H.; Ujaque, G.; Maseras, F. J. Am. Chem. Soc. 2005, 127,
9298−9307. (l) Miyaura, N. J. Organomet. Chem. 2002, 653, 54−57.
(m) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461−470.
(n) Aliprantis, A. O.; Canary, J. W. J. Am. Chem. Soc. 1994, 116, 6985−
6986. (o) Smith, G. B.; Dezeny, G. C.; Hughes, D. L.; King, A. O.;
Verhoeven, T. J. Org. Chem. 1994, 59, 8151−8156. (p) Thomas, A. A.;
Zahrt, A. F.; Delaney, C. P.; Denmark, S. E. J. Am. Chem. Soc. 2018,
140, 4401−4416.
(29) Lloyd-Jones and Lennox note that “Elucidation of the dominant
pathway to transmetalation is not at all straightforward: one must
establish the kinetically active boron and palladium intermediates, and
they may not necessarily be the most abundant species present in the
medium.”.27
(30) Detailed studies exploring the transmetalation of trans-
[Pd(PPh3)2(Ph)(I)] with p-tol-B(OH)3K (and 18-crown-6) and
Pd(PPh3)(Ph)(μ-OH)]2 with p-tol-B(OH)2 under stoichiometric
conditions were performed in THF/H2O solvent mixtures.26 Extensive
studies employing electrochemical methods to investigate the
transmetalation of trans-[Pd(PPh3)2(Ar)(X)] with Ar-B(OH)2 (n-
Bu4NOH as the base) under catalytic conditions were performed in a
DMF/MeOH solvent mixture.22
(19) It is generally acknowledged that defining key transmetalation
intermediates is even more complicated with aryltrifluoroborate
nucleophiles. See, for example: Lennox, A. J. J.; Lloyd-Jones, G. C.
Isr. J. Chem. 2010, 50, 664−674 and references cited therein.
(20) (a) Andersen, N. G.; Keay, B. A. Chem. Rev. 2001, 101, 997−
1030. (b) Niemeyer, Z. L.; Milo, A.; Hickey, D. P.; Sigman, M. S. Nat.
Chem. 2016, 8, 610−617.
(21) (a) Tolman, C. A. J. Am. Chem. Soc. 1970, 92, 2953−2956.
(b) Otto, S.; Roodt, A. Inorg. Chim. Acta 2004, 357, 1−10.
(c) Ackermann, M.; Pascariu, A.; Hocher, T.; Siehl, H.-U.; Berge, S.
̈
J. Am. Chem. Soc. 2006, 128, 8434−8440.
(22) The observation that oxidative addition is not the turnover-
limiting step in this reaction is consistent with previous studies. See,
for example: Amatore, C.; Jutand, A.; Le Duc, G. Chem. - Eur. J. 2011,
17, 2492−2503 and references cited therein.
(23) It was reported that trans-[Pd(PPh3)2I2] was formed in reactions
with [Pd(PPh3)4] and (iodoethynyl)benzene (in addition to the
expected oxidative addition product). See: (a) Weigelt, M.; Becher, D.;
Poetsch, E.; Bruhn, C.; Steinborn, D. Z. Anorg. Allg. Chem. 1999, 625,
1542−1547. The formation of trans-[Pd(PPh3)2I2] from trans-
[Pd(PPh3)2(R)(I)] has also been reported: (b) Gulia, N.; Pigulski, B.;
Szafert, S. Organometallics 2015, 34, 673−682. trans-[Pd(PPh3)2I2]
was also formed in reactions with [Pd(PPh3)4] and 9-iodo-m-
carborane. See: (c) Marshall, W. J.; Young, R. J., Jr.; Grushin, V. V.
Organometallics 2001, 20, 523−533.
(24) We were also able to isolate and characterize trans-
[Pd(PPh3)2I2]. The spectroscopic data obtained on this compound
were consistent both with equivalent data reported in the literature
and also with an authentic sample of trans-[Pd(PPh3)2I2] that we
prepared via a literature procedure: Hahn, F. E.; Lugger, T.; Beinhoff,
M. Z. Naturforsch. B Chem. Sci. 2004, 59, 196−201.
(31) Germane observations regarding the adverse effect of PPh3 have
also been reported in Pd-catalyzed Stille cross-couplings; see ref 9.
(a) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino, C., Jr J.
Org. Chem. 1990, 55, 5833−5847. (b) Scott, W. J.; Stille, J. K. J. Am.
Chem. Soc. 1986, 108, 3033−3040.
(32) The reaction of trans-[(Pd(PPh3)2(p-NCC6H4)(X)] (X = Cl,
Br, I) with PhB(OH)2 was studied as a function of initial hydroxide
concentration in DMF. In this way, the following reactivity order was
determined: [Pd−I] > [Pd−Br] > [Pd−Cl].22
(33) For a study focused on the reactivity of Pd(0) complexes
derived from mixtures of Pd(dba)2 and PPh3 and P(2-furyl)3 ligands,
see for example: Amatore, C.; Jutand, A.; Meyer, G.; Atmani, H.;
Khalil, F.; Chahdi, F. O. Organometallics 1998, 17, 2958−2964.
(34) Farina and Krishnan also state “When a large excess of P(2-
furyl)3 was added to a solution of trans-[Pd(PPh3)2(Ph)(I)] and PPh3,
no trace of trans-[Pd{P(2-furyl)3}2(Ph)(I)] was observed, the
corresponding signal for P(2-furyl)3 being the only new peak in the
spectrum.”.9
(25) When the study shown in eq 2 was performed in DMF/H2O
instead of n-PrOH/H2O, similar results were obtained. When the
experiment shown in eq 2 was performed using p-bromotoluene
instead of p-iodotoluene, 31P NMR spectroscopy indicated that trans-
[Pd(PPh3)2Br2] was not present in the reaction mixture. trans-
[Pd(PPh3)2Br2] was also not observed in equivalent experiments
performed in DMF/H2O.
F
DOI: 10.1021/acs.organomet.8b00189
Organometallics XXXX, XXX, XXX−XXX