Biaryls made easy: PEPPSI and the Kumada-Tamao-Corriu reaction

Article abstract of DOI:10.1002/chem.200601360

An easily employed, highly versatile Kumada-Tamao-Corriu (KTC) protocol utilizing the PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabilization and Initiation) precatalysts 1 and 2 is detailed. The ease-of-use of these catalysts and the synthesis of a wide range of hindered biaryls, large coupling partners and drug-like heterocycles, in high yield, makes the PEPPSI-KTC protocol very attractive. The high reactivity of the PEPPSI system allowed a tetra-ortho substituted heterocycle, 11 to be synthesized at room temperature for the first time using any protocol. The PEPPSI protocols also tolerated the Boc protecting group and phenols required no protection in modified conditions. A relatively large scale (10g) reaction was also performed with no loss in performance. Furthermore, PEPPSI IPr, 1, was compared to previously reported highly active phosphine ligands 42, 43, and 44 and was shown to result in significantly better yields under identical conditions. Finally, we demonstrated that the PEPPSI catalyst system is very adept at performing sequential KTC coupling reactions, analogous to multicomponent reactions, which allow complex polyaryl and polyheteroaryl architectures to be produced in one single operation.

Full text of DOI:10.1002/chem.200601360

DOI: 10.1002/chem.200601360
Biaryls Made Easy: PEPPSI and the Kumada–Tamao–Corriu Reaction
Michael G. Organ,* Mirvat Abdel-Hadi, Stephanie Avola, Niloufar Hadei,
[
a]
Joanna Nasielski, Christopher J. OꢀBrien, and Cory Valente
Abstract: An easily employed, highly
versatile Kumada–Tamao–Corriu
KTC) protocol utilizing the PEPPSI
Pyridine, Enhanced, Precatalyst, Prep-
aration, Stabilization and Initiation)
precatalysts 1 and 2 is detailed. The
ease-of-use of these catalysts and the
synthesis of a wide range of hindered
biaryls, large coupling partners and
drug-like heterocycles, in high yield,
makes the PEPPSI-KTC protocol very
attractive. The high reactivity of the
PEPPSI system allowed a tetra-ortho-
substituted heterocycle, 11 to be syn-
thesized at room temperature for the
first time using any protocol. The
PEPPSI protocols also tolerated the
Boc protecting group and phenols re-
quired no protection in modified condi-
tions. A relatively large scale (10 g) re-
action was also performed with no loss
in performance. Furthermore, PEPPSI-
IPr, 1, was compared to previously re-
ported highly active phosphine ligands
42, 43, and 44 and was shown to result
in significantly better yields under
identical conditions. Finally, we demon-
strated that the PEPPSI catalyst system
is very adept at performing sequential
KTC coupling reactions, analogous to
multicomponent reactions, which allow
complex polyaryl and polyheteroaryl
architectures to be produced in one
single operation.
(
(
Keywords: alkanes · CÀC coupling ·
heterocycles · palladium
Introduction
carbonÀhalide bond followed by transmetalation, and finally
reductive elimination to deliver the product with regenera-
[1]
0
[8]
Since their discovery by Grignard, organomagnesium com-
pounds have become fundamental reagents in synthetic or-
tion of the active Pd complex (Scheme 1).
Since these pioneering coupling studies with Grignard re-
[2]
[8,9]
ganic chemistry. Their applications are numerous and
many have been employed in the synthesis of complex mol-
ecules. Indeed, the first transition-metal-catalyzed cross-
agents the use of organoboron
tion), organozinc
(Suzuki–Miyaura reac-
[8,10]
[8,11]
(Negishi reaction) and organotin
[3]
(Stille reaction) reagents have to a large degree replaced the
use of Grignard reagents in cross-coupling reactions. This is
generally due to the enhanced functional group tolerance
that boron, zinc and tin organometallic species possess in
II
coupling reaction employed Grignard reagents with Ni
complexes and was discovered in 1972 independently by
[4]
[5]
Kumada and Corriu, who built on earlier ground-break-
[6]
ing work by Kharasch and Fuchs. However, it was Mura-
hashi who was the first to report the use of catalytic palladi-
[
7]
um in the Kumada–Tamao–Corriu (KTC) reaction in 1975.
The mechanism this cross-coupling reaction is believed to
0
follow, involves oxidative addition of a Pd species into the
[
a] Prof. M. G. Organ, M. Abdel-Hadi, S. Avola, N. Hadei, J. Nasielski,
Dr. C. J. OꢀBrien, C. Valente
Department of Chemistry, York University
4
700 Keele Street, Toronto, Ontario, M3J 1P3 (Canada)
Fax : (+1)416-736-5936
E-mail: organ@yorku.ca
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author: Preparation of 2,
cross-coupling procedures for the preparation of compounds 5–40
and full characterization data.
Scheme 1. Simplified Kumada–Tamao–Corriu (KTC) mechanism.
150
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Chem. Eur. J. 2007, 13, 150 – 157

FULL PAPER
[
2]
comparison with Grignard reagents. The KTC reaction has
therefore become, somewhat the poorer relation of these
kilograms of the same target. This last point is especially im-
portant for such protocols to have any serious acceptance in
industry. Working towards these objectives we chose to in-
[8]
now well established cross-coupling protocols.
quently, it is not surprising that only modest development of
Conse-
[15]
vestigate the use of our most successful complex 1 in the
[12]
[12e]
the KTC reaction has taken place in recent years. This is
unfortunate as the use of Grignard reagents does have some
significant advantages over organoboron and zinc reagents.
Indeed, organomagnesium (or organolithium) reagents are
normally employed in the synthesis of organoboron and zinc
KTC reaction using the conditions developed by Beller
as a starting point (Table 1). As expected we found PEPPSI-
IPr, 1 to function as an excellent catalyst in a variety of con-
ditions (Table 1, entries 1–20). Using modified Beller condi-
[12e]
tions,
THF/DMI mixtures, (Table 1, entries 4 and 5) led
[8,13]
species,
therefore their direct use in coupling reactions
to an acceptable yield after 24 h.
would reduce handling and step count. Furthermore, the
synthesis of Grignard reagents and their stabilities are well
known as evidenced by their extensive presence in the
Table 1. Optimization of reaction conditions.
[8a,14]
chemical literature,
their only major draw back being
functional group tolerance. However, in situations where a
Grignard-sensitive functionality is not present, the KTC re-
action represents an exceedingly efficient method for the
construction of carbonÀcarbon bonds, biaryl synthesis in
[
a,b]
Entry
Additive
Solvent
T [8C]
Yield [%]
particular. In our continuing efforts to further advance the
appeal and routine use of N-heterocyclic carbene (NHC)-
based cross-coupling methodology, we decided to investigate
the use of the PEPPSI (Pyridine, Enhanced, Precatalyst,
Preparation, Stabilization, and Initiation) series of com-
1
2
–
–
THF
THF/DME 1:1
RT
RT
10
RT
RT
50
50
50
50
50
RT
RT
73
RT
RT
50
50
50
50
50
7
5
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
–
THF/DME 2:1
RT
THF/DMI 1:1
THF/DMI 2:1
THF
THF/DME 1:1
THF/DME 2:1
THF/DMI 1:1
THF/DMI 2:1
THF
–
–
–
–
–
–
–
68
74
66 (60)
75
80
77 (74)
67
61 (60)
69
[15]
plexes 1–4
(Figure 1) in this under used, yet potentially
extremely valuable cross-coupling reaction.
0
1
2
2 equiv LiCl
2 equiv LiCl
THF/DME 1:1
32 equiv LiCl
THF/DME 2:1
RT
THF/DMI 1:1
THF/DMI 2:1
THF
4
5
6
7
8
9
0
2 equiv LiCl
71
56
74 (77)
67
73
2 equiv LiCl
2 equiv LiCl
2 equiv LiCl
2 equiv LiCl
2 equiv LiCl
2 equiv LiCl
THF/DME 1:1
THF/DME 2:1
THF/DMI 1:1
THF/DMI 2:1
46
51
[
(
a] Reaction Conditions: PEPPSI-IPr, 1, (2 mol%), p-chloroanisole
0.5 mmol), p-tolylmagnesium bromide (0.8 mmol), total volume of sol-
vent 1.6 mL. Yield determined by GC/MS/MS using a calibrated internal
standard (undecane) and reactions were performed in duplicate.
[
b] Control experiments with no catalyst showed no conversion in all
cases. DME = 1,2-dimethoxyethane, DMI = 1,3-dimethylimidazolidin-
-one.
2
Figure 1. PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabili-
zation and Initiation) complexes.
Following these encouraging results, we then investigated
how solvent composition and additives affected the
PEPPSI-catalyzed KTC reaction. The use of THF (Table 1,
entry 1) or THF/DME mixtures (Table 1, entries 2 and 3)
proved ineffective at room temperature although good re-
sults were obtained when the reactions were heated
(Table 1, entries 6 to 10) or conducted in the presence of
Results and Discussion
When attempting to design any coupling protocol we believe
the final process must fulfill three main criteria: 1) The pro-
tocol must be employed easily without the need for a glove-
box, specialized handling of the catalyst or precatalyst or
[15a]
LiCl
(Table 1, entries 11 to 15).
After identifying these optimal conditions, we then sub-
mitted complexes 1–4 (Figure 2) to the test reaction shown
in order to evaluate the importance of steric bulk in the vi-
cinity of the metal center on conversion. PEPPSI-IPr, 1, and
PEPPSI-SIPr, 2, were equally highly effective, yielding 85
and 80% of the cross-coupled product, respectively, over a
24 h period at 508C. In contrast, the less sterically encum-
[16]
non-routine purification or handling of solvents;
2) the
protocol must be amenable to a significant array of sub-
strates and in particular heterocycles; 3) the procedure must
be insensitive to change in scale, meaning that the same pro-
tocol developed to produce milligrams of product can be
used with minimal, if any change to produce grams, or even
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151

M. G. Organ et al.
bered PEPPSI-IEt, 3, and PEPPSI-IMes, 4, were substantial-
ly less effective producing only 15 and 4%, respectively
(
Figure 2). These results clearly demonstrate a relationship
Figure 3. Effect of temperature on the KTC reaction utilizing PEPPSI
complexes 1 (*) and 2 (!). Results indicate that PEPPSI-SIPr, 2, per-
forms better than PEPPSI-IPr, 1, at lower temperatures, whether this is
due to easier activation of PEPPSI-SIPr, 2, or that 2 is intrinsically more
active is not yet understood. Reaction conditions: PEPPSI complexes 1
or 2, (2 mol%), p-chloroanisole 0.5 mmol, p-tolylmagnesium bromide
Figure 2. Evaluation of PEPPSI complexes 1–4 in KTC reaction. Sterical-
ly encumbered PEPPSI-IPr, 1, and PEPPSI-SIPr, 2, gave high yields
(
0.8 mmol), total volume of THF 1.6 mL, at specified temperature, 24 h.
8
5% and 80%, respectively. However, PEPPSI-IEt, 3, and PEPPSI-IMes,
Yield determined by GC/MS/MS using a calibrated internal standard (un-
decane); reactions were performed in duplicate and control experiments
with no catalyst showed no conversion.
4
, gave much lower yields, 15 and 4%, respectively. These results suggest
that a sterically congested palladium metal center is essential to achieve
high yields in the KTC reaction. Reaction Conditions: PEPPSI com-
plexes 1–4, (2 mol%), p-chloroanisole 0.5 mmol, p-tolylmagnesium bro-
mide (0.8 mmol), total volume of THF 1.6 mL, 508C, 24 h. Yield was de-
termined by GC/MS/MS using a calibrated internal standard (undecane);
reactions were performed in duplicate and control experiments with no
catalyst showed no conversion.
between a sterically constrained metal center and high
cross-coupling yields. This lends support to the rational that
the enhancement of reductive elimination is important. In
an effort to further probe the reactivity of 1 and 2, the
cross-couplings were performed over a range of tempera-
tures between room temperature and 808C (Figure 3). Inter-
estingly, we found that 2 was significantly superior to 1 at
low temperatures; there was a major and dramatic increase
in yield when the reaction temperature was increased from
2
5 to 408C when employing 2 (Figure 3) that did not take
Figure 4. Effect of reaction time on the Kumada–Tamao–Corriu (KTC)
reaction utilizing PEPPSI complexes 1 (*) and 2 (!). Results indicate
place with 1. However, there was a less dramatic, though
pronounced, increase in yield between 40 and 608C when
utilizing 1 (Figure 3). Whether the superiority of 2 at low
temperatures is due to an increase in the rate of complex ac-
tivation or that 2 is simply intrinsically more active due to
increased flexibility of the saturated complex is not yet un-
that PEPPSI-SIPr 2-catalyzed reactions occur faster than those utilizing
PEPPSI-IPr, 1. This may be due to the increase flexibility of the saturat-
ed NHC ligand over the corresponding unsaturated one. Reaction condi-
tions: PEPPSI complexes 1 or 2, (2 mol%), p-chloroanisole 0.5 mmol, p-
tolylmagnesium bromide (0.8 mmol), total volume of THF 1.6 mL, 508C,
for specified time. Yield determined by GC/MS/MS using a calibrated in-
ternal standard (undecane); reactions were performed in duplicate and
control experiments with no catalyst showed no conversion.
[17]
derstood. However the difference in activity is significant
and well-defined.
Further differences in the behavior of PEPPSI complexes
1
and 2 were observed when the KTC reaction was followed
over a 24 h period (Figure 4). Again, 2 out performs the re-
lated unsaturated 1 as there was a definite increase in rate
when 2 is used (Figure 4). Once more it is difficult to pin-
point the exact reasons for this increase; nevertheless we be-
lieve the enhancement of “flexible steric-bulk” in relation to
the metal centerꢀs topography is critical to the success of
ed (Figure 2). Therefore, it is not untenable to suggest the
increased flexibility afforded to complex 2 with the saturat-
ed imidazole ring in the NHC ligand may account for the
enhanced performance at low temperatures. During the var-
ious steps of the catalytic cycle the NHC ligand bound to
the Pd metal center must bend and flex, the aromatic
groups attached to the nitrogens rock back and forth to
both accept the incoming reaction partners and expel the
[18]
these PEPPSI-catalyzed KTC reactions. The effect of the
metalꢀs steric environment was unambiguously demonstrat-
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PEPPSI: Biaryls Made Easy
FULL PAPER
[a]
coupled product. Therefore, the increased range of move-
ment of the saturated NHC ligand over the unsaturated
NHC ligand is noteworthy.
Table 2. Preliminary substrate evaluation.
[17]
The above optimization studies yielded a variety of effec-
tive cross-coupling protocols with the use of either PEPPSI
complex 1 or 2 resulting in high yields. However, these cou-
pling partners are not representative of substrates that
would normally be of great interest and use by the wider
synthetic community.
THF/DMI (2:1)
Therefore we embarked on a thorough evaluation of cou-
pling partners utilizing the spectrum of condition outline
above. Preliminary cross-couplings were performed at 508C
THF/DME (1:1)
(
Table 2). The use of a THF/DMI mixture allow the synthe-
sis of hindered biaryl 5 (Table 2) whereas heterocycles 6 and
were effectively produced utilizing a THF/DME combina-
7
THF
tion (Table 2). Nevertheless, the use of a single solvent
would greatly simplify the protocol and pleasingly THF was
found to be a very effective solvent with hindered biaryls (5
and 10, Table 2) and heterocyclic compounds (11 to 14
Table 2) formed from the corresponding organo-bromides
and -chlorides in reasonable to high yields. Notable results
are the formation of tetrasubstituted heterocycle 11 and the
tolerance of unprotected hydroxyl groups that allowed for
the rapid synthesis of biaryl 15 and heterocycle 16 in high
yield, with the addition of 1 equiv of NaH before Grignard
addition. The synthesis of 16 was also performed on a 10 g
scale with a yield of 85% demonstrating the scalability of
the protocol.
Following these promising early results, 1 and in select
cases 2 were evaluated in room temperature cross-couplings;
it is important to note no effort was made to minimize reac-
tion time (Table 3). Utilization of mixed solvent conditions,
THF/DMI or THF/DME, allowed the synthesis of a variety
of heterocyclic biaryls (Table 3); again aryl bromides or
chlorides were equally effective partners in the room tem-
perature KTC reaction. Noteworthy examples are the toler-
ance of the Boc protecting group, 19, and the synthesis of
drug-like heterocycles 18, 21 and 27 (THF/DMI and THF/
DME conditions, Table 3). Gratifyingly, the employment of
THF alone led to the easy production of a considerable
array of biaryls (THF conditions, Table 3). Significant results
are the production of 12 to 14, 30 and 37 in which the cou-
pling of two large fragments and the tolerance of a Boc pro-
tecting group is achieved at room temperature. These results
are important if the formation of a CÀC bond is required
[
a] Modifications from the conditions above are outline immediately
below the product. For detailed reaction procedures, see Supporting In-
late in synthesis, as might be the case in total synthesis or
drug production. The formation of 11, a tetra-ortho-substi-
tuted heterocyclic biaryl, is, to the best of our knowledge,
the first time such a hindered product has been produced a
room temperature with any cross-coupling protocol. The
coupling of biaryl Grignard reagents to indole, benzothio-
phene and quinoline-derived halides to form 12, 13 and 14
formation. [b] Yielded 99% when the reaction was performed with 2.
[
c] Reaction conducted using PEPPSI-SIPr, 2 (2 mol%).
[19]
ductive polymers. The production of more routine drug-
like biaryls was also readily achieved (6, 7, 28, 29, 31, 35 and
36, THF conditions, Table 3). It is also worth pointing out
that medicinal chemists in industry are concerned that many
new catalysts and cross-coupling protocols that are claimed
to be very active are only demonstrated to be effective on
low molecular weight partners (e.g. simple biaryls); when
(
THF conditions, Table 3) and the coupling of thiophene
units in 31 and 34, which are often very problematic part-
ners for Pd-catalyzed coupling, all proceed very smoothly.
Such syntheses represent a significant result for the materi-
als area as polymeric thiophenes are currently used in con-
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153

M. G. Organ et al.
[
a]
Table 3. Room temperature KTC couplings.
THF/DMI (2:1)
Subsequent to the develop-
ment of an easily-employed
KTC protocol, we decided to
investigate the use of 1 in se-
quential cross-coupling reac-
tions (SCRs, Table 4); the use
of such sequenced reactions
would allow large molecular
frameworks to be constructed
in a single “one-pot” operation.
Preliminary results (Table 4)
are encouraging as the synthesis
of tetracycles 39 and 40 pro-
ceeded in very good yield over
the two couplings.
THF
Interestingly, during the syn-
thesis of 35 (Table 3) an inter-
mediate in the synthesis of het-
eroaromatic 39 (Table 4) a sig-
nificant exotherm was observed
immediately upon mixing of 1
and the oxidative addition part-
ner that prompted us to evalu-
ate the use of 1 in low tempera-
ture KTC reactions (Table 5).
The synthesis of heterocycle
3
5 was conducted at RT, 0 and
À208C (Table 5). A rapid and
exothermic reaction resulted
when the reaction was carried
out at RT and 08C; however at
À208C the vigorous boiling of
the solvent was contained. At
RT, the reaction was complete
in 30 minutes, where as the
À208C the reaction was finish-
ed in 2 h. The reactivity of the
PEPPSI-IPr-NHC system opens
the way for thermally unstable
Grignards, and related reagents,
to be utilized in the KTC reac-
tion. Importantly, the use of
THF/DME (1:1)
[
Pd(PPh ) ], still the most com-
A
H
R
U
G
3 4
monly-used cross-coupling cata-
lyst, yielded no product at room
temperature. However, subse-
quent addition of 1 to this reac-
tion resulted in an exotherm
and complete formation of
[
a] Modifications from the conditions above are outline immediately below the product. For detailed reaction
procedures, information, see Supporting Information. [b] Reaction conducted using 2 (2 mol%). [c] Yielded
0% when the reaction was performed with 2.
9
product.
these methods are used to prepare compounds that are not
only heteroatom containing, but in the range of 400–600 Da,
most fail. This can be the result of poor solubility or in-
creased bulk of the larger, more structurally complex cou-
pling partners; the routine production of compounds such as
It is important when develop-
ing any cross-coupling protocol to place it in context with
the current state-of-the-art procedures. In order to ascertain
how 1 performs in relation to current highly active systems,
we decided to run a comparative study with phosphines
[20]
[21]
[22]
[23]
14, 30 and 37, (Tables 2 and 3) offer promise to address this
42, 43 and 44 as they represent the best current phos-
concern.
phines commercially available, with wide generality, for
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PEPPSI: Biaryls Made Easy
FULL PAPER
[
a]
Table 4. Sequential cross-coupling reactions.
SCR couplings
[
a] Isolated yield.
[
a]
Table 5. Low-temperature Kumada–Tamao–Corriu (KTC) reaction.
T
Observation
Yield [%]
t [h]
[
b]
RT
exotherm
exotherm
exotherm contained
87
81
64
0.5
0.5
2
[
b]
0
8C
À208C
[
a] Isolated yield of duplicate reactions. [b] While the reaction was stirred
for 0.5 h before being quenched, they were judge by GC/MS to be com-
plete once the exotherm had subsided.
cross-coupling procedures when used in conjunction with a
suitable palladium source (Figure 5). As mentioned [Pd-
A
C
H
T
R
E
U
N
G
(PPh ) ], 41, is still the most widely employed palladium cat-
3 4
[24]
alyst, so we opted to evaluate it as well. The crude NMR
spectra after workup (Figure 5) show that 1 out performs all
of the current highly-active hindered phosphines and 41 as it
gave the cross-coupled product cleanly in high yield (quanti-
tative) at room-temperature; all other catalysts resulted in
minimal conversion in this moderately challenging coupling
reaction.
Conclusion
Figure 5. Comparison of PEPPSI-IPr,1 with the current state-of-the-art
In summary we have developed an easily employed, highly
versatile Kumada–Tamao–Corriu (KTC) protocol utilizing
the PEPPSI precatalysts 1 and 2. The ease-of-use and syn-
thesis of a wide range of hindered biaryls, large coupling
partners and drug-like heterocycles make the PEPPSI-KTC
protocol highly attractive. The PEPPSI complex and oxida-
tive addition partner can simply be weighed, the flask
purged with argon the Grignard added; we believe such an
easily employed protocol is ideal for medicinal chemistry
and parallel synthetic applications with modern liquid han-
dling equipment. The development of a variety of conditions
allows for substantial tuning of the reaction to maximize sol-
ubility and reaction rate dependent on the reactants em-
ployed. The activity of the PEPPSI-SIPr system allowed
phosphines and widely employed Pd
show that PEPPSI-IPr, 1 out performs the highly active phosphines 42,
3, and 44, and also commonly use [Pd(PPh ]. Additionally, when utiliz-
A
H
R
U
G
3 4
(PPh ) . The crude NMR spectra
4
A
H
R
U
G
3 4
)
ing PEPPSI-IPr, 1, the product is formed cleanly with little byproduct
formation, illustrated by the crude NMR. [a] With these ligands, 1 mol%
Pd dba was used as a palladium source.
2 3
tetra-ortho-substituted heterocycle 11 to be synthesized at
room temperature, the first time this has been accomplished
with any cross-coupling protocol. With certain substrates the
reaction can be performed at À208C. Such low temperature
conditions may allow for the coupling of Grignard reagents
that decompose under previous protocols. The PEPPSI pro-
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155

M. G. Organ et al.
tocols also tolerated the Boc protecting group and phenols
required no protection using modified conditions. Impor-
tantly, a larger-scale preparation of 16 (10 g) was also con-
ducted with no loss in performance or yield. Furthermore,
for the synthesis of heterocycle 35, complex 1 was compared
to previously reported highly-active phosphine ligands 42,
Grignard reagent (0.6 mmol, 1.2 equiv). The resulting mixture was al-
lowed to stir at room temperature for the specified amount of time.
When the reaction was deemed complete by TLC analysis, the second
Grignard reagent (0.8 mmol, 1.6 equiv) was added. The resulting solution
was allowed to stir at the specified temperature for the specified period
of time. Once product was identified, the general work-up procedure for
compound isolation was followed.
43, and 44 these studies showed that the use of 1 resulted in
significantly better yields under identical conditions. Finally,
we have also demonstrated that the PEPPSI catalyst system
is very adept at performing sequential KTC coupling reac-
tions in a manner analogous to multi-component reaction
chemistry to build remarkably complex polyaryl and polyhe-
teroaryl architectures in one single operation that can be ap-
plied readily to medicinal chemistry, natural product synthe-
sis and material science applications.
Acknowledgements
We thank ORDCF and NSERC Canada for financial support and Al-
drich Inc. for the generous gift of PEPPSI-IPr and PEPPSI-SIPr precata-
lysts and cross-coupling substrates.
[
[
1] V. Grignard, Compt. Rend. Acad. Sci. Paris 1900, 130, 1322–1324.
2] a) J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry,
Oxford University Press, New York, 2001; b) M. B. Smith, J. March,
Marchꢀs Advanced Organic Chemistry: Reactions Mechanisms, and
Structures, 5th ed., Wiley, Chichester, 2000.
Experimental Section
Kumada–Tamao–Corriu (KTC) cross-coupling procedures
[3] a) K. C. Nicolaou, A. Snyder, Classics in Total Synthesis II: Targets,
Strategies, Methods, Wiley-VCH, Weinheim, 2003; b) K. C. Nicolaou,
E. J. Sorensen, Classics in Total Synthesis, VCH, Weinheim, 1996.
Procedure A (THF/DMI): Under air, a vial equipped with a stir-bar was
charged with complex 1 (6.8 mg, 2 mol%), sealed with a septum, and
purged with argon. Distilled THF (0.26 to 0.7 mL) and dry DMI (0.53to
[
4] K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972, 94,
374–4376.
4
0
.7 mL) were added by syringe and stirred for 1–2 minutes, after which
the aryl halide (0.5 mmol), and n-undecane (GC/MS internal standard,
0 mL) were injected via syringe. Alternatively, if the aryl halide was
[
[
[
5] R. J. P. Corriu, J. P. Masse, Chem. Commun. 1972, 144.
6] M. S. Kharasch, C. F. Fuchs, J. Am. Chem. Soc. 1943, 65, 504–507.
7] M. Yamamura, I. Moritani, S. Murahashi, J. Organomet. Chem.
5
solid at room temperature, it was weighed out and added to the vial in
air following complex 1 addition. After 1–2 minutes of stirring, the
Grignard reagent (0.65 to 0.8 mmol, 1.3to 1.6 equiv) was added in one
rapid shot by syringe. The septum was replaced with a Teflon-lined screw
cap under an inert atmosphere and the reaction mixture was allowed to
stir for approximately 24 h at RT/508C prior to GC/MS and/or TLC anal-
ysis. Once product was identified, the general work-up procedure for
compound isolation was followed.
1
975, 91, C39–C42.
[
8] a) A. de Meijere, F. Diederich, Metal-Catalyzed Cross-Coupling Re-
actions, 2nd ed., Wiley-VCH, Weinheim, 2004; b) E. Negishi, Hand-
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New York, 2002.
[
9] For seminal papers on boron cross-couplings see: a) E. Negishi, in
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Brewster), Plenum Press, New York, 1978, pp. 285–317; b) E. Ne-
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Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20, 3437–3440; d) A.
Suzuki, J. Organomet. Chem. 2002, 653, 83–90.
Procedure B (THF/DME): Under air, a vial equipped with a stir-bar was
charged with complex 1 or 2 (6.8 mg, 2 mol%), sealed with a septum,
and purged with argon. Dry THF (0.35 mL) and dry DME (0.8 to
1
.0 mL) was added by syringe and stirred for 1–2 minutes, after which
the aryl halide (0.5 mmol), and n-undecane (GC/MS internal standard,
0 mL) were injected via syringe. Alternatively, if the aryl halide was
[
[
10] For seminal papers on zinc cross-couplings see: A. O. King, N. Oku-
kado, E. Negishi, Chem. Commun. 1977, 683–684; a) E. Negishi,
A. O. King, N. Okukado, J. Org. Chem. 1977, 42, 1821–1823.
11] For seminal papers on tin cross-couplings see: a) M. Kosugi, S. Sasa-
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Kosugi, Y. Shimizu, T. Migita, Chem. Lett. 1977, 1423–1424; c) D.
Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636–3638;
d) J. K. Stille, Angew. Chem. 1986, 98, 504–519; Angew. Chem. Int.
Ed. Engl. 1986, 25, 508–524.
5
solid at room temperature, it was weighed out and added to the vial in
air following complex 1 addition. After 1–2 minutes of stirring, the
Grignard reagent (1.3to 1.6 equiv) was added in one rapid shot by sy-
ringe. The septum was replaced with a Teflon-lined screw cap under an
inert atmosphere and the reaction mixture was allowed to stir for approx-
imately 24 h at RT or 508C prior to GC/MS and/or TLC analysis. Once
product was identified, the general work-up procedure for compound iso-
lation was followed.
[
12] a) L. Ackermann, A. Althammer, Org. Lett. 2006, 8, 3457–3460;
b) N. Roques, L. Saint-Jalmes, Tetrahedron Lett. 2006, 47, 3375–
Procedure C (THF): Under air, a vial equipped with a stir-bar was charg-
ed with complex 1 or 2 (6.8 mg, 2 mol%), sealed with a septum, and
purged with argon. The aryl halide (0.5 mmol), and n-undecane (only for
GC/MS analysis, internal standard, 50 mL) were injected via syringe. Al-
ternatively, if the aryl halide was solid at room temperature, it was weigh-
ed out and added to the vial in air following PEPPSI complex 1 (or 2)
addition. The Grignard reagent (0.8 mmol, 1.6 equiv), prepared in THF,
was added in one rapid shot by syringe, followed by septum replacement
with a Teflon-lined screw cap under an inert atmosphere. The reaction
mixture was allowed to stir for approximately 24 h at RT/508C prior to
GC/MS and/or TLC analysis. Once product was identified, the general
work-up procedure for compound isolation was followed.
3
2
378; c) M. E. Limmert, A. H. Roy, J. F. Hartwig, J. Org. Chem.
005, 70, 9364–9370; d) A. C. Frisch, A. Zapf, O. Briel, B. Kayser,
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6
87, 403–409; f) J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu, N.
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154.
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Grignard Reagents, Marcel Dekker, New York, 1996; c) B. J. Wake-
field, Organomagnesium Methods in Organic Synthesis, Academic
Press, London, 1995.
Sequential cross-coupling (SCR) procedure: Under air, a 10 mL round
bottom flask equipped with a stir-bar was charged with complex 1
(
6.8 mg, 2 mol%), sealed with a septum, and purged with argon (3”). To
this was added directly the aryl halide (0.5 mmol) followed by the first
156
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Chem. Eur. J. 2007, 13, 150 – 157

PEPPSI: Biaryls Made Easy
FULL PAPER
[
15] a) M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B. Kantchev,
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[20] Shared opinions from medicinal chemists during discussions with
M.G.O. on consultancy visits to Pfizer, Merck, Eli Lilly and Compa-
ny, and Bristol-Myer Squibb.
4
743–4748.
[
16] The use of ultra-pure solvents or their handling in a glove-box
should be avoided as this can lead to results that may be difficult to
reproduce under normal synthetic organic conditions and practices.
17] Unpublished results.
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2
[
19] a) D. Iarossi, A. Mucci, F. Parenti, L. Schenetti, R. Seeber, C. Zanar-
Received: September 21, 2006
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Published online: December 4, 2006
Chem. Eur. J. 2007, 13, 150 – 157
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
157