Suzuki-miyaura cross-coupling of unprotected, nitrogen-rich heterocycles: Substrate scope and mechanistic investigation

Article abstract of DOI:10.1021/ja4064469

The Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles using precatalysts P1 or P2 is reported. The procedure allows for the reaction of variously substituted indazole, benzimidazole, pyrazole, indole, oxindole, and azaindole halides under mild conditions in good to excellent yields. Additionally, the mechanism behind the inhibitory effect of unprotected azoles on Pd-catalyzed cross-coupling reactions is described based on evidence gained through experimental, crystallographic, and theoretical investigations.

Full text of DOI:10.1021/ja4064469

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Article
Suzuki-Miyaura Cross-Coupling of Unprotected, Nitrogen-Rich
Heterocycles: Substrate Scope and Mechanistic Investigation
Alexander Duefert, Kelvin L. Billingsley, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4064469 • Publication Date (Web): 02 Aug 2013
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Suzuki-Miyaura Cross-Coupling of Unprotected, Nitrogen-
Rich Heterocycles: Substrate Scope and Mechanistic Investi-
gation
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M. Alexander Düfert, Kelvin L. Billingsley and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
ABSTRACT: The Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles using precatalysts P1 or P2 is report-
ed. The procedure allows for the reaction of variously substituted indazole, benzimidazole, pyrazole, indole, oxindole and azaindole
halides under mild conditions in good to excellent yields. Additionally, the mechanism behind the inhibitory effect of unprotected
azoles on Pd-catalyzed cross-coupling reactions is described based on evidence gained through experimental, crystallographic, and
theoretical investigations.
there are only a few examples of Suzuki-Miyaura reactions of
substrates containing an unprotected azole,9,10 and these typi-
cally employ costly starting materials and require strong bases
and/or high catalyst loadings. Though these heterocycles are
common amongst biologically-active compounds, the reasons
for the generally observed low yields of these substrates have
so far not been examined in detail. Either the low reactivity of
the corresponding oxidative addition complex or an inhibition
of Pd(II) by starting material or product was proposed, but not
further investigated.11
Herein, we report a method for the Suzuki-Miyaura cou-
pling of a wide range of unprotected azoles, such as indazoles,
benzimidazoles, pyrazoles, indoles, oxindoles, and azaindoles,
under relatively mild conditions. Additionally, we provide
insight into the mechanism behind the inhibitory effects of
acidic NH groups on Pd-catalyzed cross-coupling reactions.
1. Introduction
The ability to combine aromatic heterocyclic fragments is an
important and challenging subset of the field of C-C cross-
coupling reactions with implications both in academic and
industrial settings.1 Heterocyclic structures are often key frag-
ments of biologically active molecules and many drugs con-
tain nitrogen-rich heterocyclic moieties such as pyrimidines,
piperazines or benzimidazoles, as well as indoles and inda-
zoles.2 Of these, annulated azoles bearing relatively acidic NH
groups are key components in several important compounds
(see Figure 1).
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2. Results and Discussion
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We began our study by evaluating the coupling of 3-
chloroindazole both unprotected (1a) and protected with an N-
benzyl group (1b) using conditions that we have previously
reported (Scheme 1).12
Figure 1. Bioactive molecules containing free N-H azole moie-
ties.3
Unfortunately, many of the standard protocols for palladi-
um-catalyzed C-C bond-forming cross-coupling reactions fail
in the presence of substrates bearing free N-H groups.4 In-
stead, such molecules are obtained either via construction of
the heterocyclic rings with the desired residues already at-
tached,5 or via functionalization using the corresponding N-
protected analogues.6 While these routes have merit, they are
often limited in substrate scope and/or necessarily require
extra protection/deprotection steps. Thus, access to facile
methods for the direct use of these acidic, nitrogen-rich heter-
ocycles in palladium-catalyzed C-C cross-coupling processes
is highly desirable.7
The Suzuki-Miyaura coupling is arguably the most im-
portant C-C-coupling method practiced today due to its broad
substrate scope, high level of functional group tolerance, and,
with modern catalysts, high turnover rates.8 However, to date
Scheme 1. Suzuki-Miyaura cross-coupling of unprotected and
Bn-protected 3-chloroindazole (1a,b).
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Table 1. Influence of ligands and Pd sources on the Suzuki-
Miyaura cross-coupling of 3-chloroindazole.[a]
1
2
3
4
bromoimidazole and phenylboronic acid was also attempted
under these reaction conditions but provided the product only
in low yield (31%) due to incomplete conversion of the het-
eroaryl bromide.
5
Table 2. Coupling of 3-chloroindazole derivatives to boronic
6
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acids.[a],[b]
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[a] Reaction conditions: 3-chloroindazole (0.25 mmol), 5-
indole boronic acid (0.50 mmol), Pd source (2 mol%), ligand
(3 mol%), K3PO4 (0.50 mmol), dioxane (1 mL), H2O (0.2 mL),
100 °C, 15 h. [b] Determined by GC. [c] Determined by HPLC.
[d] 2.5 mol% of P2 was used.
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For the protected chloroindazole 1b the desired product was
obtained in high yield. In contrast, for unprotected 1a no
product was observed. We found that by increasing the reac-
tion temperature to 100 °C and by employing 2.0 equivalents
of boronic acid, a modest yield of coupled product could be
obtained for 1a. An examination of different palladium
sources and ligands was carried out (Table 1) and we found
that protocols that employed SPhos and XPhos provided the
coupled product in the highest yields.13 While the use of
Pd2dba3 as the palladium source provided the product in up to
56% yield, the use of our second generation precatalysts P1
and P2 provided the best results; with P2 the product was
formed in 80% yield. Additionally, a higher turnover rate and
thus less protodeboronation was observed in the presence of
SPhos precatalyst P2 as opposed to when Pd(OAc)2 or Pd2dba3
were employed. In the absence of ligand, no reaction oc-
curred.14
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[a] Reaction conditions: aryl halide (1.00 mmol), boronic acid
(2.00 mmol), P2 (2.0-3.5 mol%), K3PO4 (2.00 mmol), dioxane
(4 mL), H2O (1 mL), 100 °C, 15-20 h. [b] Isolated yields repre-
sent the average of two runs.
Table 3. Coupling of 2-benzimidazole to boronic acids.[a],[b]
Having identified a successful method,15 a variety of aryl
and heteroaryl boronic acids were successfully coupled with
substituted indazole and benzimidazole chlorides (Table 2, 3).
All reactions reached full conversion within 15-20 hours and
gave the corresponding products in good to excellent yields. A
diverse set of heterocyclic structures and sensitive functional
groups were tolerated. In general, moderate catalyst loadings
were sufficient for reactions employing both electron-rich aryl
halides or electron-rich boronic acids.
It was also possible to couple 3- and 4-bromopyrazole,16 alt-
hough the reactions required a slightly increased quantity of
catalyst and the addition of another equivalent of ligand rela-
tive to palladium. In these cases the use of XPhos-derived
precatalyst P1 provided higher yields of products. Thus, 4-aryl
and 3-aryl pyrazoles were isolated in good to very good yields
(61-86%, Table 4). Generally, 3-bromopyrazoles tend to react
faster than 4-bromopyrazoles. The reaction of 4-
[a] Reaction conditions: aryl halide (1.00 mmol), boronic acid
(2.00 mmol), P2 (2.5-3.5 mol%), K3PO4 (2.00 mmol), dioxane
(4 mL), H2O (1 mL), 100 °C, 15-20 h. [b] Isolated yields repre-
sent the average of two runs.
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Table 4. Coupling of bromopyrazole to boronic acids.[a],[b]
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Scheme 2. Synthesis of JNK3-inhibitor 8.
[a] Reaction conditions: aryl halide (1.00 mmol), boronic acid
(2.00 mmol), P1 (6-7 mol%), K3PO4 (2.00 mmol), dioxane
(4 mL), H2O (1 mL), 100 °C, 24 h. [b] Isolated yields represent
the average of two runs. [c] P1:XPhos ratio is 1:1.5.
While this new methodology allows for the direct formation
of a wide range of biaryl-containing unprotected azoles, some
limitations still remain with respect to substrate scope. For
example, the presence of acidic functional groups on the bo-
ronic acid that can potentially bind to the palladium center
(carboxylic acids, phenols, pyrazole) appears to inhibit the
reaction. Additionally, the use of very unstable boronic acids
(4-pyridyl, 2-benzothienyl) in conjunction with halo-pyrazole,
indazole and benzimidazole coupling partners primarily re-
sulted in protodeboronation and, subsequently, low product
yields (<5%) due to the use of higher temperature (>60 °C)
reaction conditions.
We also found that chloroindoles, oxindoles and azaindoles
were excellent substrates under these conditions. In fact, these
coupling reactions proceeded with lower quantities of catalyst
(1.0-1.5 %), fewer equivalents of boronic acid (1.5 eq.), in
shorter reaction times, and at lower temperatures (60 °C),
while still providing the desired products in excellent yields
(91-99%). These milder conditions even allowed for the use of
less stable boronic acids such as 6-fluoro-3-pyridyl and 2-
benzofuranyl boronic acid (5a, 5d), which are known to readi-
ly undergo protodeboronation.12a Precatalyst P1 gave superior
results, while the use of P2 did not lead to significant for-
mation of product (Table 5).
3. Mechanistic investigation
In order to understand the low reactivity of these substrates
under classical cross-coupling conditions we chose to investi-
gate their effect on the reaction mechanism. We reasoned that
the most probable mechanisms for inhibition were: 1. com-
plexation of the metal center and thus deactivation of the cata-
lyst, 2. a high energy barrier for oxidative addition of ArX or
3. a high energy barrier for reductive elimination to form
product. While the first possibility could be influenced by
several factors, oxidative addition and reductive elimination
are primarily dependent upon the structures and properties of
the substrates and catalysts.
3.1 Experimental studies: metal complexation. Under
standard conditions (as in Table 5) 6-chloroindole readily re-
acts with phenyl boronic acid to give the coupling product in
97% yield. However, upon addition of indazole (10a) or ben-
zimidazole (11a), product formation is inhibited. Not surpris-
ingly, the addition of indole (9a) itself has no such effect
(Scheme 3).
Table 5. Coupling of indole, azaindole and oxindole chlorides to
boronic acids.[a],[b]
[a] Reaction conditions: aryl halide (1.00 mmol), boronic acid
(1.50 mmol), P1 (1.0-1.5 mol%), K3PO4 (2.00 mmol), dioxane
(4 mL), H2O (1 mL), 60 °C, 5-8 h. [b] Isolated yields represent
the average of two runs.
To illustrate the utility of our method we prepared the c-Jun
N-terminal kinase 3 inhibitor 8 in two steps from commercial-
ly available indazole 6 (Scheme 2).17 Suzuki-Miyaura cross-
coupling provided the 3-arylindazole 7 in excellent yield
(95%). Intermediate 7 was then subjected to a Pd-catalyzed C-
N bond-forming reaction to provide N-arylamine 8 in 82%
yield over the two steps.18
Scheme 3. Influence of additives on the Suzuki-Miyaura reaction
of 6-chloroindole.
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Comparing the reactivity with the acidity of the substrates is
informative. Under typical Suzuki-Miyaura conditions, more
acidic substrates often exist mainly in their deprotonated form.
In particular, there is a significant decrease in the rates of reac-
tion for indazole substrates as compared to indole ones, which
correlates with a difference in the ratio of azole-H to azole-
anion (based on their respective pKa values). While the less
acidic indoles, oxindoles and azaindoles should be found
mainly in their neutral form under the reaction conditions, the
predominant state of indazoles, benzimidazoles, pyrazoles and
imidazoles would likely be as the corresponding anions as
their pKa values are less than that of H2O (Figure 2).19,20
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Figure 2. (a) Relative reactivity of heteroaryl halides in the Suzu-
ki-Miyaura cross coupling and (b) pKa values (in H2O) of the
parent compounds and relevant derivatives.19
Figure 3. Effect of 1H- and 1-methyl-heterocyclic additives on
the yield of the Suzuki coupling between 6-chloroindole and phe-
nylboronic acid.22,23
Given this, we hypothesized that the formation of N-azolyl
palladium complexes might account for the decreased reactivi-
ty of more acidic substrates.21 The presence of electron-
donating groups increases the pKa along with the reactivity,
electron-withdrawing groups display the opposite trend.20 The
effect of the substituents on the pKa values of the parent het-
erocycles is likely due to an increased stabilization of the
deprotonated form. While this similarity in trend between
acidity and a decrease in reactivity holds true for annulated
azoles, it does not account for the lower reactivity of pyrazole
and imidazole halides when compared with indazole and ben-
zimidazole derived substrates (see below for a discussion of
other effects than acidity on the overall reactivity). Moreover,
we could not completely rule out complexation of the basic
imine-type nitrogen atoms as being the cause of reduced reac-
tion rates. To this end, we examined the influence of the addi-
tion of several heterocycles as well as their N-methyl ana-
logues on the yield of the cross-coupling between 6-
chloroindole and phenylboronic acid. As depicted in Figure 2,
in all cases the addition of the heterocycle led to a decreased
yield (compared to the reaction with no additional heterocycle
added) after a reaction time of 2 h. However, the influence of
the N-methyl analogs is significantly smaller than that of the
unprotected NH-heterocycles. The biggest difference was ob-
served in the comparison of 1H- vs 1-Me-benzimidazole,
showing a difference in inhibition of about two orders of
magnitude (11a vs. 11b). Thus, while the imine-type basic
nitrogen does seem to have an inhibitory effect, as especially
evident in the case of 12b, the observed suppression of prod-
uct formation is more strongly correlated with the presence of
the acidic NH groups.
The addition of more boronic acid can partially counteract
this inhibitory effect, as can raising the reaction temperature
(see Figures S1, S2 in the Supporting Information). The for-
mer likely rules out a direct complexation of the Pd(0) species
by an azolyl anion as the reverse process should be insensitive
to added boronic acid.
Efforts were undertaken to characterize potential intermedi-
ates in the catalytic cycle. To this end, we prepared and isolat-
ed [SPhos-Pd(Ph)Cl] and [SPhos-Pd(Ph)OH],24,25 as well as
dimeric Pd(II) azolyl complex 14 with indazole as the bridging
ligand. Whether the dimeric species 14 or the corresponding
monomer would be favored in solution is not clear but likely
depends on the solvent employed.26
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species that could be observed by 31P-NMR spectroscopy in
the reaction of 14 under the latter conditions.
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Scheme 5. Influence of the halide substitution on the conver-
sion of 3- and 4-haloindazoles.
We also briefly investigated the effect of the halide position
(from ArX) on the overall reaction progress. As above, 3- and
4-bromoindazole were allowed to react with 3-
fluorobenzeneboronic acid (Scheme 5). Unexpectedly, we
found that the reaction employing 4-bromoindazole resulted in
less product formation than the one using 3-bromoindazole.
We thus hypothesized that the observed reactivity difference
between the aryl halide regioisomers could be due to product
inhibition. While the aryl halide substrates should display only
minor differences in their steric properties, the products’ steric
demand should be markedly different. We therefore examined
the influence of the cross-coupling products and the parent
heterocycles on the yield of the cross-coupling between
Figure 4. Crystal structure of indazole-bridged Pd complex 14.
To assess whether 14 could be formed from [SPhos-
Pd(Ph)Cl] (15) or [SPhos-Pd(Ph)OH] (16), both complexes
were allowed to react with potassium indazolide. After only
20 minutes at room temperature, 14 was formed in 63% and
82% yield, respectively, as evidenced by the characteristic
chemical shift of the ligated phosphine (31P-NMR).27 The ease
of formation of 14 from 15 and 16 is consistent with 14 being
an off-cycle species, in which the catalyst mainly resides
(Scheme 4).28
Scheme 4. Formation of dimer 14 from 15 or 16.
Additionally, we tested how 14 would compare as catalyst
in the Suzuki-Miyaura cross-coupling under our new condi-
tions for indazole halides (Table 2) and under standard cross-
coupling conditions.12a Interestingly, no difference in kinetic
behavior was observed in the cross-coupling of 3-
chloroindazole with 3-fluorophenylboronic acid, under our
conditions for indazole halides (2.0 mol% catalyst, 2.00 eq.
K3PO4, dioxane/H2O 4:1, 100 °C, 15 h), when either 14 or P2
was used as the precatalyst. In contrast, the reaction of 3-
chloroanisole and 2,6-dimethylphenylboronic acid gave no
product with 14 as catalyst under standard Suzuki-Miyaura
conditions (2.0 mol% catalyst, 2.00 eq. K3PO4, dioxane/H2O
4:1, 25 °C, 18 h) but good conversion was achieved with 15
(see Figures S3, S4 in the Supporting Information).29,30 Even
after three days at room temperature, complex 14 was the only
Figure 5. Effect of heterocyclic additives on the yield of the Su-
zuki-Miyaura coupling between 6-chloroindole and phenyl-
boronic acid.22,23
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6-chloroindole and phenylboronic acid. As can be seen (Figure
5), while the effect of added 4-phenylindazole (10d) and inda-
zole (10a) are comparable, 3-substituted azole 10c inhibits the
reaction to a much lesser extent. The same decrease in inhibi-
tion can be observed when comparing benzimidazoles 11a and
11c. Again there is only small difference between the inhibito-
ry effect of 4-phenylimidazole (12c) and imidazole (12a) it-
self, showing the difficulty of these substrates in cross-
coupling reactions.31 We postulate that these trends can be
attributed to the ability of the parent heterocycles, as well as
some select coupling products, to form azole-bridged dimers
or trimers, which most products cannot due to steric reasons
(see Figure 6). Products that cannot form dimeric structures
for steric reasons should inhibit the cross-coupling to a lesser
degree, as has been observed, since dimer formation is poten-
tially the major reason for the observed catalyst deactivation.
Thus, it appears likely that the catalyst can mainly be found as
dimeric complex 14 in the case of 1,2-azoles. It is not known
whether a bridged 1,3-azolyl Pd(II) complex could also occur
in reactions involving (benz)imidazole halides. However, such
complexes are known.32 While for indole, indazole and ben-
zimidazole the increased inhibition of the cross-coupling reac-
tion can be correlated with the increased acidity of the NH
functional group, pyrazole and imidazole inhibit reactions
more strongly but, conversely, are less acidic than their annu-
lated congeners. This is probably due to the increased basicity
of the imine-type nitrogen in starting materials as well as
products (cf. Figure 3) in conjunction with smaller steric de-
mand.33 In addition, we cannot rule out an influence of the
different electronic properties of the substrates or products,
which could additionally explanation minor reactivity differ-
ences, e.g. between regioisomers.
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Figure 7. Calculated energies in THF (B3LYP/6-31+G(d,p)) for
the oxidative addition, reductive elimination and the equilibrium
between 15 and 17. For oxidative addition, anionic aryl halides
refer to the corresponding deprotonated azole chlorides.
The oxidative addition step was investigated for several aryl
halides: phenyl, 5-indolyl, 3-indazolyl, 3-pyrazolyl and 4-
imidazolyl chloride. The calculated activation energies for the
neutral aryl halides range from 14.4 to 19.4 kcal/mol.34 For
comparison, the energy barriers for some deprotonated aryl
halides were also included,35 which show an increase in acti-
vation energy of about 4-6 kcal/mol. This effect mirrors gen-
erally observed reactivity trends as these substrates would be
even more electron-rich. We also calculated the energy barrier
in the reductive elimination step for these heteroaryl groups.
The activation energy ranges from 5.3 to 6.9 kcal/mol, sup-
porting the fact that biarylphosphine ligands allow for the
ready reductive elimination in reactions of these substrate
combinations.36 Overall, both in the case of the oxidative addi-
tion as well as the reductive elimination, these values are
comparatively small and cannot explain the low reactivity of
unprotected, acidic heterocycles observed in most cross-
coupling reactions. For completeness, we also investigated the
thermodynamic equilibrium between the chloro-Pd(II) com-
plex 15 and the corresponding azolyl species 17. In all cases,
the azolyl complex 17 is energetically favored but the energy
difference is very small. From all of this data, we can conclude
that primarily the innate inhibitory effect of the heterocycles,
not their oxidative addition or reductive elimination energet-
ics, determine the overall reactivity.
3.3 Proposed mechanism and nucleophile effect. Based
on the experimental and theoretical data, we propose the fol-
lowing mechanism for the Suzuki-Miyaura cross-coupling in
the presence of an inhibitory azole such as indazole (Scheme
6), which should also be applicable to other azoles as inhibi-
tors. The presence of 1,2- or 1,3-azoles likely leads to the for-
mation of monomeric or oligomeric Pd(II) intermediates (14,
17) that act as Pd reservoirs. For 3-chloroindazole and 2-
chlorobenzimidazole as halides, the formation of dimers 20,
21 or the corresponding deprotonated azole-bridged complex-
es is also feasible.37 Depending on the reaction conditions, the
transmetallation could either occur through [Pd-Cl] (15) or
[Pd-OH] (16). However, a direct reaction of 17 with phenyl
Figure 6. Potential steric interaction in the postulated dimers
containing 10d (A), 10c or 13c (B) or 13d (C).
3.2 Computational studies: oxidative addition, reductive
elimination and metal complexation. Besides complexation
of the metal center, we additionally considered the oxidative
addition and reductive elimination as being potentially rate-
limiting. Thus, in addition to these experimental observations
DFT calculations were undertaken to obtain the energy barri-
ers for the oxidative addition as well as the reductive elimina-
tion of different aryl groups (Figure 7).24 Moreover, the rela-
tive energies of complexes 15 and 17 were investigated (see
Supporting Information for details).
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8
boronate cannot be ruled out.38 As was observed, the presence
always applicable due to issues of functional group compati-
of additional boronic acid helps countermand the inhibitory
effect by shifting the equilibrium back in favor of 15 or 16.
Based on the calculated relative stabilities of 15 vs. 17, which
only slightly favor the Pd-azolyl complexes, the rate determin-
ing step should therefore be the transmetallation.
bility, this principle can aid in the selection of appropriate
cross-coupling conditions in the presence of nitrogen-rich,
unprotected heterocycles.
4. Conclusion
'ꢜꢗꢙꢒ ꢜ&)
ꢚꢍꢜꢗ
In conclusion, we have developed an operatively simple and
efficient general procedure for the Suzuki-Miyaura cross-
coupling of several classes of unprotected azole halides. We
have demonstrated the utility of this method in a straightfor-
ward synthesis of kinase inhibitor 8 in two steps from com-
mercially available starting materials. With this methodology
in hand, arylated azoles may be selectively accessed in a direct
manner without the need of N-protection. A Pd-azolyl inter-
mediate has been isolated that we propose is the catalytic rest-
ing state in the cross-coupling reaction of nitrogen-rich, acidic
heterocycles. The presented experimental and computational
mechanistic work is consistent with the transmetallation as the
rate determining step in the cross-coupling reaction. This
knowledge should prove useful in selecting optimal conditions
and nucleophile/electrophile combinations while circumvent-
ing catalyst deactivation.
ꢚꢍꢂꢃ
ꢔꢕ
ꢚꢍ
ꢀ
ꢀ
9
ꢜ&
ꢅ
ꢚꢍ
'ꢜꢗꢙꢒ ꢜ& ꢂꢃ
ꢔꢖ
ꢚꢍ
'ꢜꢗꢙꢒ ꢜ&
ꢔꢙ
'ꢜꢗꢙꢒ
ꢈ
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14
15
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ꢜꢗ9ꢔꢄꢁꢖꢓ
ꢜꢗ
ꢔꢘ
ꢔꢚꢁ
ꢂꢃꢈ
ꢄꢁꢈ
ꢜꢗ9ꢔꢄꢁꢖꢅ
ꢚꢍ
'ꢜꢗꢙꢒ ꢜ&
ꢔꢗ
ꢚꢍ
ꢔꢚꢁ
ꢀ
'ꢜꢗꢙꢒ ꢜ&
ꢄꢁ
ꢀ
ꢔꢛ
ꢁꢀ
ꢀꢁ
ꢂꢃ
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ꢀ
ꢅ
ꢀ
ꢜ&
ꢜ&
ꢅ
'ꢜꢗꢙꢒ
'ꢜꢗꢙꢒ
ꢀꢚ
ꢀꢔ
ASSOCIATED CONTENT
Supporting Information. Experimental, spectroscopic and com-
putational details as well as X-ray structural parameters for 14 and
16. Cartesian coordinates of all calculated intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 6. Proposed catalytic cycle in the presence of indazole
and potential intermediates 20, 21.
Indeed, when changing the nature of the nucleophile a dras-
tic difference in reactivity can be observed, which can be
roughly correlated with the relative nucleophilicity of the or-
ganometallic species.39 While boronic acids only react slug-
gishly, organozinc and especially organomagnesium nucleo-
philes are able to affect an efficient reaction turnover in the
presence of indazole (Scheme 7).40
AUTHOR INFORMATION
Corresponding Author
sbuchwal@mit.edu
Notes
The authors declare the following competing financial interest(s):
MIT has patents on the ligands used in this work for which SLB
receives royalty payments.
ACKNOWLEDGMENT
We thank the National Institutes of Health for financial support of
this project (GM46059). M.A.D. is indebted to the DFG for a
postdoctoral fellowship. We thank H. Harbrecht and T. Kinzel for
initial studies in the synthesis of 16, M. Su for computational and
experimental assistance, G. Teverovskiy, E. Vinogradova and M.
McGowan for helpful discussions and P. Müller for X-Ray struc-
tural analysis of 14 and 16.
Scheme 7. Comparison of different cross-coupling methods in
the presence of unprotected indazole.
This phenomenon indicates that the energetically unfavored
reverse reaction of 17/14 to 15/16 is not the cause for the low
reactivity observed in the case of the Suzuki and Stille cross-
coupling reaction, but rather points again to transmetallation
as the rate determining step.41 However, the existence of an
equilibrium between 17/14 and 15/16 favoring the N-azolyl
species additionally necessitates elevated temperatures of up
to 100 °C and extended reaction times. Thus, when using
strongly nucleophilic organometallic coupling partners (or-
ganomagnesium and organozinc nucleophiles), the transmetal-
lation should be fast enough to ensure efficient reaction turno-
ver and help push the equilibrium back from the off-cycle
species 17 or 14 into the active transmetallating species (15 or
16, depending on the nucleophile and reaction conditions).
Thus, when faced with unreactive substrate combinations, the
use of alternative aryl nucleophiles could promote the for-
mation of the desired cross-coupling products. Although not
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dppe. Only BINAP gave conversions nearly as good as SPhos. All
other ligands fell short of SPhos. Also see Ref. (9m).
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58
59
60
(15) All chemicals can be weighed under air and stored on the
benchtop.
(16) Unsubstituted, unprotected 3-, 4- or 5-halopyrazoles have
not been previously reported in literature to successfully undergo
Suzuki-Miyaura, Negishi or Stille cross-coupling reactions. See ref.
7b.
(5)
(a) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644-
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(19) Catalan, J.; Abboud, J. L. M.; Elguero, J. Adv. Heterocycl.
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(20) Only few pKa values for NH acidic heterocycles have been
reported in H2O as opposed to DMSO as solvent. Please refer to
reference 19 for an in-depth discussion of these compounds’ acidity.
(21) The reaction of deprotonated starting material or product
with the boronic acid could additionally lead to formation of a Lewis
acid/base pair, potentially binding and deactivating the boronic acid:
In the presence of potassium indazolide (2.0 eq.) in THF-d8 (BF3⋅OEt2
(6)
(a) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007,
36, 1173-1193. (b) Knochel, P.; Schade, M. A.; Bernhardt, S.;
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(a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.
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as standard),
a
distinct shift in the 11B-NMR spectrum of
phenylboronic acid from 29.9 to 5.0 ppm was observed, which is
indicative of a tetrahedral, anionic boronate species. The presence of
indole led to no change, whereas indazole gave two signals at 31.9
(major) and 23.5 ppm (minor).
(8)
(a) Suzuki, A. Angew. Chem. Int. Ed. 2011, 50, 6722-
6737. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
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(22) The overlaid curves in figure 3, 5 are only meant as visual
guidance. They were not fitted but are simply smoothed using the B-
Spline option, as implemented in Origin 7.0.
(23) Some of the data points were taken twice by setting up the
reaction a second time to insure reproducibility. In those cases, the
measured yield was within 1%.
(24) Complex 15 has been previously isolated by our group.
See: Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Organometallics
2007, 26, 2183-2192.
(9)
(a) Wu, T. Y. H.; Schultz, P. G.; Ding, S. Org. Lett. 2003,
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Int. Ed. 2006, 45, 1282-1284. (c) Billingsley, K.; Buchwald, S. L. J.
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H.; Choi, M.; Yu, B.-W.; Ryoo, R.; Taher, A.; Hossain, S.; Jin, M.-J.
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Hasník, Z.; Pohl, R.; Hocek, M. Synthesis 2006, 3515-3526. (h)
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P. Y.; Lau, C. P.; Kwong, F. Y. Chem. Eur. J. 2010, 16, 7996-8001.
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Monguchi, Y.; Sajiki, H. Chem. Commun. 2007, 5069-5071. (k)
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12, 5142-5148. (l) Robbins, D. W.; Hartwig, J. F. Org. Lett. 2012,
14, 4266-4269. (m) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org.
Chem. 2007, 72, 8543-8546.
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461-470. (b) Amatore, C.; Jutand, A.; Le Duc, G. Chem. Eur. J.
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Organometallics 1996, 15, 5242–5245. (f) Hayashi, Y.; Wada, S.;
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(26) One major signal and two minor ones could be observed by
31P-NMR spectroscopy in CD2Cl2. In THF-d8 as solvent, one major
signal could be detected as well as 3 minor species.
(27) The formation of Pd(II) pyrazolyl species has been
previously reported starting both from [Pd-OH] and [Pd-I]
complexes: Driver, M. S., Hartwig, J. F. Organometallics 1997, 16,
5706-5715.
(28) The reverse reaction starting from 14 to either 15 or 16 led
to no product formation. Other examples of 1,2-azole bridged Pd(II)
complexes have been previously reported: (a) López, G.; Ruiz, J.;
Garcia, G.; Vicente, C.; Casabó, J.; Molins, E.; Miravitlles, C. Inorg.
Chem. 1991, 30, 2605-2610. (b) Espinet, P.; Gallego, A. M.;
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Martínez-Ilarduya, J. M. J. Organomet. Chem. 2002, 663, 108-117.
(29) 15 was chosen over P2 for comparing reactivity at room
temperature to accommodate for a potential lag in activation of P2.
(10) Recently, the coupling of benzimidazole-derived potassium
trifluoroarylborates was reported: Molander, G. A.; Ajayi, K. Org.
Lett. 2012, 14, 4242-4245.
(11) (a) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2010,
132, 11416-11417. (b) Smith, G. B.; Dezeny, G. C.; Hughes, D. L.;
King, A. O.; Verhoeven, T. R. J. Org. Chem. 1994, 59, 8151-8156.
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I.; Zlotin, S. G. Russ. Chem. Bull. Int.Ed. 2006, 55, 118-122. (d)
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A. V. Organometallics 2012, 31, 7753-7808.
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(30) At 100 °C, no difference in reactivity was observed
1
2
3
4
5
6
7
8
between 14 and 15 as catalyst in the reaction of 3-chloroanisole and
2,6-dimethylphenylboronic acid.
(31) The observed product inhibition explains why 4-
bromopyrazole generally reacts more slowly than its 3-bromo isomer,
often resulting in lower yields.
(32) Steffen, A.; Braun, T.; Neumann, B.; Stammler, H.-G.
Angew. Chem. Int. Ed. 2007, 46, 8674-8678.
(33) The exact inhibition mechanism of compounds bearing
basic imine-type nitrogen atoms was not further investigated but
probably also involves complexation of Pd(II) intermediates.
(34) Oxidative addition with SPhosPd(0) can occur even at
-40 °C: Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 6686-6687.
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(35) The transition state of the oxidative addition for
deprotonated 4-imidazole chloride was successfully computed in the
gas phase but yielded two imaginary frequencies in THF.
(36) Selected examples for challenging reductive eliminations
using biarylphosphine ligands: (a) Su, M.; Buchwald, S. L. Angew.
Chem. Int. Ed. 2012, 51, 4710-4713. (b) Cho, E. J.; Senecal, T. D.;
Kinzel, T.; Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science, 2010,
328, 1679-1681. (c) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang,
Y.; Garcia-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009,
325, 1661-1664. (d) Salvi, L.; Davis, N. R.; Ali, S. Z.; Buchwald, S.
L. Org. Lett. 2012, 14, 170-173. Also see ref 8c.
(37) In the attempted formation of the oxidative addition
complexes with 3-chloroindazole as electrophile, several phosphine
species could be observed by 31P-NMR spectroscopy.
(38) The formation of small quantitites of free ligand could be
observed after several hours when monitoring 14 by 31P-NMR in the
presence of PhMgBr at room temperature.
(39) (a) Berionni, G.; Maji, B.; Knochel, P.; Mayr, H. Chem.
Sci. 2012, 3, 878-882. (b) Pratihar, S.; Roy, S. Organometallics
2011, 30, 3257–3269.
(40) The chosen conditions were selected from published
methods to minimize variation of the catalyst system (Pd/XPhos) and
therefore allow a representative comparison. In the absence of
indazole, all reactions gave the desired product in 91-99% yield. See
the Supporting Information for details.
(41) The proposed mechanism outlined in Scheme 7 should also
be applicable to other cross-coupling reactions. Complex 16 should
however only be relevant for Suzuki-Miyaura cross-coupling
reactions.
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