One-Pot Sequential Kumada–Tamao–Corriu Couplings of (Hetero)Aryl Polyhalides in the Presence of Grignard-Sensitive Functional Groups Using Pd-PEPPSI-IPentCl

Article abstract of DOI:10.1002/chem.201901150

We report a general and rapid chemoselective Kumada–Tamao–Corriu (KTC) cross-coupling of aryl bromides in the presence of chlorides or triflates with functionalized Grignard reagents at 0 °C in 15 min by using Pd-PEPPSI-IPent^Cl (C4). Nucleophiles and electrophiles (or both) can contain Grignard-sensitive functional groups (-CN, -COOR, etc.). Control experiments together with DFT calculations suggest that transmetallation is rate limiting for the selective cross-coupling of Br in the presence of Cl/OTf with functionalized Grignard reagents. One-pot sequential KTC/KTC cross-couplings with bromo–chloro arenes have been demonstrated for the first time. We also report the one-pot sequential KTC/Negishi cross-couplings using C4 showcasing the versatility of this methodology.

Full text of DOI:10.1002/chem.201901150

DOI: 10.1002/chem.201901150
Communication
&
Organic Chemistry
One-Pot Sequential Kumada–Tamao–Corriu Couplings of
(Hetero)Aryl Polyhalides in the Presence of Grignard-Sensitive
Functional Groups Using Pd-PEPPSI-IPentCl**
Narayan Sinha,[a, b] Pier Alexandre Champagne,[b] Michael J. Rodriguez,[c] Yu Lu,[c]
Michael E. Kopach,[c] David Mitchell,[c] and Michael G. Organ*[a, b]
veloping the direct coupling of Grignards would streamline
coupling, providing the compatibility issue could be overcome.
Knochel and co-workers have made significant contributions
in the development of methods to prepare Grignard reagents
by metal–halogen exchange with iPrMgCl,[6] for which the re-
agent can be formed at temperatures below which it will react
with other functional groups, such as esters and nitriles. With
such stable Grignards accessible, two strategies have been
used to maintain functional-group compatibility during cross-
coupling. The first is simply to maintain the cool temperatures
during the coupling, which necessitates the requirement for a
high reactivity catalyst.[3j,k] The second is to add the Grignard
slowly to the coupling solution at a higher temperature with
less reactive catalysts to allow coupling to compete with side
reactions.[3b]
Abstract: We report a general and rapid chemoselective
Kumada–Tamao–Corriu (KTC) cross-coupling of aryl bro-
mides in the presence of chlorides or triflates with func-
tionalized Grignard reagents at 08C in 15 min by using
Pd-PEPPSI-IPentCl (C4). Nucleophiles and electrophiles (or
both) can contain Grignard-sensitive functional groups
(-CN, -COOR, etc.). Control experiments together with DFT
calculations suggest that transmetallation is rate limiting
for the selective cross-coupling of Br in the presence of
Cl/OTf with functionalized Grignard reagents. One-pot se-
quential KTC/KTC cross-couplings with bromo–chloro
arenes have been demonstrated for the first time. We also
report the one-pot sequential KTC/Negishi cross-couplings
using C4 showcasing the versatility of this methodology.
Another aspect of selectivity that is impacted by catalyst re-
activity is chemoselectivity with oxidative addition (OA) part-
ners bearing more than one halide/pseudohalide. The ability
to couple multiple times in one single operation is generally
regarded as efficient (and even “green”) and is, therefore, desir-
able. Such approaches are also advantageous to continuous
processing unit operations. The Schoenebeck group has devel-
oped a (tBu)3P PdI dimer precatalyst that is capable of coupling
bromides at room temperature, but not chlorides or triflates,
to provide monocoupled products.[3a] Even with a high excess
of the Grignard, chlorides and triflates are untouched.
Since the time of Kharasch,[1] the cross-coupling of Grignard re-
agents[2] using transition-metal catalysts has been recognized
as a powerful means of making CÀC bonds.[3] This is especially
useful between two centers for which direct substitution is not
readily possible (e.g., between two sp2 carbon atoms). One of
the historical problems associated with the use of Grignard re-
agents is functional-group compatibility, owing to the strong
basicity and nucleophilicity of the carbanion. The high toler-
ance of base-sensitive functional groups is one reason why the
use of organoborane derivatives (the Suzuki–Miyaura Reaction)
is popular for cross-coupling.[4,5] However, (hetero)aromatic ver-
sions of these organometallics often are derived from the cor-
responding Grignard (or organolithium) reagent, so further de-
A significant step forward for this methodology would be to
include base-sensitive functional groups, for example, -CN,
-COOR, etc., in the aryl halide partner (Scheme 1) in which
functionalized Knochel-type Grignard reagents[6] could be em-
ployed in such chemoselective cross-couplings. We envisioned
that a new level in catalytic efficiency could be reached if one
single, highly reactive catalyst was used to couple richly func-
tionalized substrates, using temperature to differentially acti-
vate one OA site in the presence of a second one.
[a] Dr. N. Sinha, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, Ontario, M3J 1P3 (Canada)
[b] Dr. N. Sinha, Dr. P. A. Champagne, Prof. M. G. Organ
Centre for Catalysis Research and Innovation (CCRI)
and Department of Chemistry and Biomolecular Sciences
University of Ottawa, Ottawa, Ontario, K1N 6N5 (Canada)
E-mail: organ@uottawa.ca
We began our investigation reacting 1 with 2 (prepared
from 4-iodobenzonitrile and iPrMgCl·LiCl, see the Supporting
Information for details) at 08C by using Pd-PEPPSI precata-
lysts.[7,8] Pd-PEPPSI-IPentCl (C4) in toluene was found to provide
the best result, affording 3 in 91% isolated yield after just
15 min (Table 1, entry 1). Lowering the Grignard reagent (2)
from 1.5 to 1.2 equivalents slightly decreased conversion
(entry 5), whereas halving the catalyst load of C4 had no
impact (entry 6). At room temperature, the reaction sped to
70% conversion after just 5 min. (entry 7). Switching THF for
[c] Dr. M. J. Rodriguez, Dr. Y. Lu, Dr. M. E. Kopach, Dr. D. Mitchell
Lilly Research Laboratories, Indianapolis, IN 46285 (USA)
[**] Pd-PEPPSI-IPentCl =[1,3-bis(2,6-diisopentylphenyl)-4,5-dichloroimidazol-2-yli-
dene](3-chloropyridyl)palladium(II)dichloride.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.201901150.
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Scheme 1. Chemoselective KTC coupling of aryl halides and functionalized Grignards and one-pot sequential cross-coupling.
Table 1. Optimization of chemoselective KTC cross-coupling of 4-chloro-
bromobenzene (1) with 4-cyanophenyl magnesium chloride (2).[a]
Table 2. Scope study of chemoselective KTC cross-coupling of bromo–
chloro/triflate-arenes with functionalized Grignard reagents.[a]
Entry
Deviation from standard conditions
Conv. [%][b]
1
2
3
4
5
6
7
8
9
none
95 (91)[c]
39
61
67
83
92
73
94
C1 instead of C4
C2 instead of C4
C3 instead of C4
1.2 equiv of 2 instead of 1.5 equiv
C4 (1 mol%)
238C, 5 min
THF instead of toluene
C5 (1 mol%) instead of C4
27
[a] Reaction conditions: 1 (0.5 mmol), 2 (1.5 equiv), C4 (2 mol%), toluene
(1 mL), 08C, 15 min. [b] Percentage conversion was assessed by 1H NMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
[c] Isolated yield (average of two runs) after purification by column chro-
matography.
toluene caused no significant change (entry 8). Using PdI dimer
C5[3a] led to 27% conversion of 3 (entry 9).
With robust conditions in hand, the scope of the transforma-
tion was evaluated on bromo–chloro substrates, including het-
erocycles (13–15) (Table 2). Base-sensitive functional groups
(e.g., esters, nitriles) can be either on the OA partner (12, 18,
and 19), the Grignard reagent (3–6 and 13–17), or both (e.g.,
[a] Reaction conditions: (Het)ArÀX (0.5 mmol), ArMgX (1.5 equiv), C4
(2 mol%), toluene (1 mL), 08C, 15 min. Isolated yield (average of 2 runs)
after purification by column chromatography. [b] 1.2 equiv of ArMgX was
used.
7–9). Various aryl Grignard reagents[6] were coupled chemose-
lectively in good to excellent yields. The catalyst exhibits the
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same selectivity of bromides over triflates (16, 17), which
vastly expands the applicability of the methodology as any
bromo phenol would now become a suitable starting material.
The only side-product we observed during the reaction of 1
and 2 using our best conditions (Table 1, entry 1) resulted from
trace homocoupling of the Grignard reagent. We could not
find any sign of the di-coupling product, which would have re-
sulted from OA at the CÀCl bond. To understand this remark-
able chemoselectivity, we performed a series of control experi-
ments at 08C (Scheme 2). When 20, 21, and 2 were reacted
using optimized conditions, 64% conversion of 20 to 22 oc-
curred and no chloride coupling product (23) was observed
(Scheme 2a).
That Schemes 2c and 2e have simply flipped the reaction
partners shows that reductive elimination (RE) cannot be prob-
lematic. To better understand the mechanism and to try to un-
derstand the reactivity of the Cl site, we carried out a reaction
between an electron-poor (activated) aryl chloride (30) and an
electron-poor (deactivated) nucleophile (2) (Scheme 2 f). The
result observed was 33% conversion to 31. So, as expected,
making the OA partner more electron-poor activates the slug-
gish CÀCl bond. Interestingly however, switching electron-poor
nucleophile 2 to an electron-neutral one (26) doubled conver-
sion of 30 to 32 (67%, Scheme 2g). While it is generally ac-
cepted that CÀBr will oxidatively add faster than CÀCl to Pd0,
these experiments suggest transmetallation (TM) is involved in
the selectivity shown by diminishing conversion at the chloride
site.
To ensure no substrate specificity, we switched the halides
leading to 24 and 25 (Scheme 2b), and still the CÀBr bond
was the only one activated. In the absence of a competing
substrate, aryl chloride 25 remained unreactive with 2, even at
room temperature (Scheme 2c). Changing the electron-defi-
cient nucleophile (2) to a more electron-neutral partner (26)
led to minor coupling (i.e., 27, Scheme 2d). Next, an electron-
poor aryl chloride (28) and an electron-rich Grignard reagent
(29) were reacted together providing good conversion to 22
(Scheme 2e).
To examine this reactivity pattern computationally, we stud-
ied the reaction surface of the coupling using DFT calculations
(Figure 1, see the Supporting Information for full details and
optimized structures). We used 1 and 2 as the model coupling
partners, assuming that the active catalytic species (i.e.,
IPentCl–Pd0) forms readily in situ by reduction of precatalyst C4
(Figure 1). Binding of 1 to the Pd0–NHC complex yields 33,
from which two OA transition states (TS) are available. The cal-
1
Scheme 2. Control experiments to examine the rate-determining step of this KTC reaction at 08C. Conversions were measured by H NMR spectroscopy.
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Figure 1. Free energy surface for oxidative addition and transmetallation of bromochloroarene 1 with Grignard reagent 2, catalyzed by C4. DFT calculations at
the wB97X-D/Def2TZVPP/SDD(Pd)/SMD(PhMe)// wB97X-D/Def2TZVP/LANL2DZ(Pd) level of theory.
culated barrier for bromide OA is 7.4 kcalmolÀ1, whereas that chloro arene and C4 was added a functionalized Grignard re-
for chloride activation is 15.3 kcalmolÀ1, which would mirror agent at 08C. After stirring for 15 min., a second Grignard re-
the complete selectivity observed experimentally. This pre- agent was added and the resulting mixture stirred for 30 min
ferred interaction of Pd with Br is shown again in the PdII com- at 08C yielding functionalized triaryl compounds (37–39) in
plexes following OA, as 34b is 4.8 kcalmolÀ1 more stable than good yields. As Pd-PEPPSI-IPentCl (C4) is a highly reactive cata-
34a. For TM, binding of p-CNPhMgBr (2) to 35a/b must first lyst,[7] we also explored the one-pot sequential KTC/Negishi
occur and is endergonic. From both 35a/b, TM TS is irreversi- cross-couplings of bromo-chloro/triflate-arenes, first with func-
ble as formation of complexes 36a/b is greatly exergonic. Fol- tionalized Grignard reagents and then alkyl or aryl zinc re-
lowing favorable decomplexation of the MgBrX salt from 36a/ agents. This procedure proceeded smoothly to provide substi-
b and facile RE, the biaryl products are obtained and the cata- tuted biaryls (40–42) and triaryls (43–46), including heterocy-
lyst is regenerated.
cles (43, 44). For both sequential KTC/KTC and KTC/Negishi
For both halides, TM TS is higher in energy than OA TS, sup- couplings, no additional catalyst or special handling is required
porting the idea that TM is rate-determining in this system. as products were obtained by simply adding Grignard or alkyl/
However, the case of chloride activation is most interesting. aryl zinc reagents, respectively. Such one-pot sequential KTC/
First, our calculations predict that chloride OA will be reversi- KTC and KTC/Negishi cross-couplings were previously unre-
ble, as 34a is as stable as the pre-reaction complex 33. This ported.[9,10]
could explain why aryl chlorides only seem to react with good
In summary, we have demonstrated herein a low tempera-
(electron-rich) nucleophiles for which TM TS will be easier to ture, rapid and efficient method for the chemoselective KTC
traverse. Second, although the two barriers for reaction of the cross-coupling of poly(pseudo)halogenated arenes with func-
chloride are very close in free energy (6.0 vs. 7.9 kcalmolÀ1), tionalized Grignard reagents. The functionalized Grignard re-
their difference is small enough that substituents on either re- agents couple smoothly with CÀBr in the presence of CÀCl or
agent might change which step becomes rate-determining. CÀOTf to form functionalized biaryl chlorides/triflates.
Indeed, on going from p-CNPhMgBr to p-MePhMgBr, the differ- Grignard-sensitive functional groups were used both in the
ence between the two barriers shrinks to only 0.5 kcalmolÀ1 [11]
.
electrophile and in the nucleophile. A one-pot sequential KTC/
Therefore, it is likely that with very electron-rich Grignard re- KTC as well as KTC/Negishi coupling has also been developed
agents, OA may become rate-determining, whereas for elec- for the first time. A single set of conditions allowed difunction-
tron-poor nucleophiles, we have shown that TM is clearly the alization of (hetero)aryl polyhalides. This methodology would
limiting step.[11]
prove useful in applications for the divergent synthesis of mol-
As we have seen that activated aryl chlorides can be cou- ecules and to prepare building blocks for the process chemis-
pled with Grignard reagents even at 08C, we were interested try and medicinal chemistry in the pharmaceutical and agro-
in trying to develop a one-pot, sequential KTC/KTC couplings chemical industries.
of bromo–chloro arenes (Table 3). To a solution of bromo–
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[a] Reaction conditions: For the first step, arylhalides (0.5 mmol), Aryl-
MgCl (1.2 equiv), Pd-PEPPSI-IPentCl (C4, 5 mol%), toluene (1 mL), 08C, 15–
30 min. For the second step in the sequence, add Aryl-MgBr (1.5 equiv),
08C, 30 min or Alkyl/Aryl-ZnCl (2.5 equiv), 608C, 18 h. Isolated yield (two
steps, average of two runs) following column chromatography. [b] THF
was used instead of toluene.
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Acknowledgements
This work was supported by NSERC (Canada) in the form of a
Discovery Grant and by the Lilly Research Award Program
(LRAP).
[8] All the Pd-PEPPSI precatalysts were obtained from Total Synthesis Ltd
(http://www.totalsynthesis.ca).
[9] For one-pot tandem/sequential double Suzuki–Miyaura coupling of
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Conflict of interest
The authors declare the following competing financial inter-
est(s): Catalysts used in this work are commercially available,
and team members receive royalty payments from their sales.
Keywords: chemoselective coupling
functionalized Grignard reagents · Pd-PEPPSI · sequential
coupling
·
cross-coupling
·
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[11] For DFT calculations using PhMgBr and p-MePhMgBr instead of
p-CNPhMgBr, see the Supporting Information.
Manuscript received: March 11, 2019
Version of record online: && &&, 0000
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COMMUNICATION
&
Organic Chemistry
N. Sinha, P. A. Champagne,
M. J. Rodriguez, Y. Lu, M. E. Kopach,
D. Mitchell, M. G. Organ*
&& – &&
One-Pot Sequential Kumada–Tamao–
Corriu Couplings of (Hetero)Aryl
Polyhalides in the Presence of
Grignard-Sensitive Functional Groups
Using Pd-PEPPSI-IPentCl
All-in-One! A general and efficient che-
moselective Kumada–Tamao–Corriu
(KTC) coupling of an aryl bromide in the
presence of a chloride or triflate with
functionalized Grignard reagents using
Pd-PEPPSI-IPentCl has been described to
prepare functionalized biaryl chlorides
or triflates. We also demonstrated a
one-pot sequential KTC/KTC and KTC/
Negishi couplings using a single set of
conditions (see scheme).
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