P2Et Phosphazene: A Mild, Functional Group Tolerant Base for Soluble, Room Temperature Pd-Catalyzed C-N, C-O, and C-C Cross-Coupling Reactions

Article abstract of DOI:10.1021/acs.orglett.5b01648

The non-nucleophilic organic superbase P₂Et phosphazene can enable a broad range of palladium-catalyzed cross-coupling reactions, including C-C, C-N, and C-O couplings of aryl chlorides, bromides, and iodides at room temperature. The mildness a

Full text of DOI:10.1021/acs.orglett.5b01648

Letter
pubs.acs.org/OrgLett
P2Et Phosphazene: A Mild, Functional Group Tolerant Base for
Soluble, Room Temperature Pd-Catalyzed C−N, C−O, and C−C Cross-
Coupling Reactions
Alexander Buitrago Santanilla, Melodie Christensen, Louis-Charles Campeau, Ian W. Davies,
and Spencer D. Dreher*
Department of Process Chemistry, Merck Research Laboratories, Merck and Co. Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: The non-nucleophilic organic superbase P2Et
phosphazene can enable a broad range of palladium-catalyzed
cross-coupling reactions, including C−C, C−N, and C−O
couplings of aryl chlorides, bromides, and iodides at room
temperature. The mildness and substrate compatibility of this
chemistry can deliver immediate synthetic utility for the
preparation of complex molecules.
ver the past two decades, rational mechanism-based
evolution of ligand structure has enabled the develop-
byproducts, which may lead to undesired side reactions
associated with metallic bases. In addition, superbases are
soluble in a wide variety of organic solvents and tend to lead to
fully solubilized reactions that can have advantages in
reproducibility relative to heterogeneous cross-coupling reac-
tions. Finally, organic superbases offer the opportunity to tune
steric and electronic properties, an advantage that is absent in
current state-of-the-art technologies.
O
ment of tremendous new reactivity in palladium-catalyzed
cross-coupling reactions.1 This ligand evolution, along with the
advancement of palladium precatalyst complexes,2 has enabled
ambient temperature catalysis, greatly improving the reaction
tolerance of sensitive functionality on substrates. The alkali
metal bases that can promote ambient temperature Pd-
couplings, such as NaOtBu and LiHMDS, however, can be
incompatible with base-sensitive functionality and can act as
nucleophiles themselves in cross-couplings,3 while weaker
inorganic bases such as K3PO4, K2CO3, and Cs2CO3 are
insoluble and typically require the use of higher temperatures
(>60 °C), which can also lead to substrate decomposition. In
principle soluble organic bases could be used in Pd catalysis;
however, common amine bases are either not basic enough, can
bind and inhibit palladium catalysts,4 or can decompose under
reaction conditions,5 limiting their use in catalysis.
We desired to develop homogeneous room temperature Pd-
catalyzed reactions in the context of miniaturized nanomole-
scale high-throughput experimentation screening.7d We there-
fore elected to evaluate superbases in these reactions over a
broad range of Pd-catalyzed reactions. To this end, we studied
the Pd-catalyzed cross-coupling of 3-bromopyridine 5, with
seven representative nucleophiles 6−12 (1° amine, 2° amine,
1° alcohol, water, 1° amide, malonate, and aryl boronate ester)
under 96 different conditions, screening four commercially
available organic superbases8 spanning a range of pKBH+ and
different steric environments, four Buchwald second or third
generation precatalysts,2 and six solvents. The electrophile 3-
bromopyridine 5 was chosen as a model substrate for this work
because it is important for new catalytic systems to be able to
overcome the problematic reaction inhibition of N-heterocyclic
substrates,9 which are critical in pharmaceutical drug discovery.
The results shown in Scheme 2 reveal a matrix of optimal
conditions for each nucleophile involving different base−
catalyst−solvent combinations.
We reasoned that organic superbases,6 which can be both
strongly basic (reported pKBH+ values up to ∼47 in MeCN)
and highly hindered around their Lewis basic cores, should
minimize catalyst inhibition (Scheme 1) resulting in high
reactivity and are non-nucleophilic so they may be very
substrate tolerant as well. Organic superbases, which are largely
unexplored in transition-metal catalysis,7 are also attractive
because they do not form Lewis or Brønsted acidic counterion
In general, P2Et phosphazene10 4 showed significantly higher
reactivity than the other bases and, in combination with
tBuXPhos or tBuBrettPhos G3 precatalysts, showed strong
reactivity across all of the diverse nucleophiles examined. In
addition to the nucleophiles reported here, these conditions
Scheme 1. Organic Superbases in Pd-Catalyzed Cross-
Coupling Reactions
Received: June 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01648
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a
Scheme 2. Nucleophile and Solvent Scope
a
Reaction conditions: L Pd G2 or G3 (Buchwald second/third Generation precatalyst, 0.5 μmol), 5 (10 μmol), 6−12 (15 μmol), solvent (0.1 M in
5), rt, 22 h. L1 was different per nucleophile (6, 8, BrettPhos; 7, RuPhos; 9, 10 RockPhos; 11, Ad2nBuP; 12, XPhos), L2 = AdBrettPhos, L3 = t-
BuBrettPhos, L4 = t-BuXPhos. S1 = Tol., S2 = CPME, S3 = THF, S4 = tert-amyl alcohol, S5 = NMP, S6 = DMSO. Heat map color guide: red, 0−
50%; yellow, 50−90%; green, >90−100% conversion.
were also found to couple carbamates, amidines, sulfonamides,
and N-heterocycles.7d While Pd cross-coupling catalysts are
typically optimized to very specific conditions for each new
class of nucleophile coupling (catalyst, base, and solvent
choices), the observed general reactivity with P2Et offers an
advantage to practitioners. Of additional note was the excellent
reactivity of P2Et across diverse solvents such as the nonpolar
solvent toluene, ethereal solvents THF and CPME, polar
aprotic solvents DMSO and NMP, and the protic solvent tert-
amyl alcohol. We next sought to evaluate the relative reactivity
of various aryl electrophiles with the P2Et base (Table 1),
investigating the performance of 3-pyridyl bromide, chloride,
and iodide with the same seven representative nucleophiles.11
All of the electrophilic coupling partners gave complete
conversion and excellent yields with each nucleophile in either
DMSO or tert-amyl alcohol, using between 1 and 5 mol %
catalyst. The P2Et system represents the first non-nucleophilic,
ambient temperature, soluble coupling conditions for most of
the nucleophile couplings reported in this work which should
have important implications in complex synthetic settings such
as natural products synthesis and drug discovery.12
In order to evaluate the functional group tolerability of the
P2Et system, we employed a robustness test approach13 in
which we added equimolar amounts of aryl ester 16 or alkyl
ester 17 to a secondary C−N coupling reaction of piperidine 7,
to 3-bromopyridine 5 (Table 2).14 Successful C−N coupling in
a
Table 1. Electrophile Scope Scale-up Experiments
a
Table 2. Amine Coupling Ester Robustness Test
a
Reaction conditions: RuPhos Pd G2 for all reactions except entries 5
and 10, where used tBuXPhos Pd G3, and entries 3 and 8, which used
tBu3P Pd G2 (1 μmol), 5 (20 μmol), 6−12 (30 μmol), 16−17 (20
μmol), P2Et (40 μmol), THF (0.2 M in 5), rt, 22 h. *Reaction run at
85 °C.
the presence of aryl and alkyl esters can be challenging due to
competitive side-product formation resulting from Claisen
condensations and/or ester amidation, especially in the
presence of an inhibiting heterocyclic substrate. Reactions
using the strong organometallic bases NaOtBu, LiHMDS, and
Zn(HMDS)2 at ambient temperature (and also at 85 °C) gave
low conversion to product and pronounced decomposition of
the esters to the aforementioned Claisen and amidation side
products. As expected, the use of Cs2CO3 protected the esters
a
Reaction conditions: tBuXPhos (2, 4, or 10 μmol), 5, 13, 14, 15 (200
μmol), 6−12 (300 μmol), P2-Et (400 μmol), DMSO (0.2 M in 5), rt,
b
c
22 h.. tBuBrettPhos Pd G3 used instead of tBuXPhos. tert-Amyl
d
alcohol. MTBD. Reported yields were determined by 1H NMR
analysis. See Supporting Information for details.
B
DOI: 10.1021/acs.orglett.5b01648
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Letter
from side reactions, but at the expense of lower conversion
even at 85 °C. By contrast, P2Et afforded complete conversion
and excellent yields in the C−N coupling at room temperature,
and the esters were largely untouched.15 We next evaluated the
prospect that the P2Et system would be mild enough to
hydroxylate the heteroaryl bromide 13 in the presence of alkyl
and aryl esters.16 Indeed we were able to cleanly form the
desired hydroxypyridine 18 without touching the esters (Table
3).
profiles of reactions moderated by P2Et relative to other organic
superbases in a Pd C−N arylation reaction (Figure 2).
a
Table 3. Water Coupling Ester Robustness Test
Figure 2. Reaction rates of Pd C−N arylations. Reaction conditions: t-
BuXPhos Pd G3 (5 mol %), 3-bromo-5-phenylpyridine (13, 400
μmol), 4-phenylpiperidine (7, 600 μmol), base (1−4, 800 μmol),
DMSO (0.2 M in 13), rt.
Our initial reaction screening (Scheme 2) showed that
BTMG, MTBD, and P2Et were competent bases to promote
effective C−N coupling while DBU was unreactive. In this
kinetic profiling, however, MTBD and BTMG both show a
significantly slower reaction course relative to P2Et. This
observed behavior of DBU, BTMG, and MTBD is consistent
with Lewis basic catalyst inhibition, recently attributed through
DFT calculations to the formation of highly stable prereductive
elimination complexes in which both the phosphine ligand and
Lewis base are coordinated to Pd.4 It is possible that P2Et, when
presented with a suitably hindered Pd-phosphine complex, may
not inhibit catalysis because of a high level of steric congestion
which would result from its binding to the catalyst. The fact
that BrettPhos and RuPhos, which have been demonstrated for
room temperature C−N couplings with strong metal bases,18
do not work at all with P2Et as the base provides further
evidence for this hypothesis. These ligands bear dicyclohexyl-
phosphines, while the catalysts that are effective with P2Et
feature di-tert-butyl or diadamantyl phosphines. These results
strongly suggest that there is a certain threshold of steric
congestion on the phosphine which can prevent catalyst
inhibition by P2Et. However, effects related to phosphine
electron density cannot be dismissed at this point in our study.
In conclusion, organic superbases can enable a broad reaction
scope of electro- and nucleophiles in Pd-catalyzed cross-
coupling reactions. The P2Et system was found to have distinct
reactivity across a diverse set of reactions at room temperature
in a variety of solvents. Importantly, in contrast to previously
reported methods, this system is highly tolerant of base
sensitive functional groups as demonstrated via a robustness
test with esters and by C−N arylation of a densely
functionalized substrate. Organic superbases offer an alternative
variable for design in this important class of reactions to
combine with ligand design and development. The relationship
between the base’s pKBH+ and steric parameters opens a new
avenue for potential tunability of the base structure, enabling
substrate-specific reactivity and expanded use in other
transition-metal catalyzed reactions. Studies aimed at increasing
understanding of the high reactivity of organic superbases and
optimizing their structures are ongoing.
a
Reaction conditions: tBuBrettPhos Pd G3 (5 μmol), 13 (100 μmol),
10 (150 μmol), 16−17 (100 μmol), P2Et (200 μmol), THF (0.2 M in
5), rt, 22 h.
Encouraged by these results, we evaluated the application of
our system toward a complex pharmaceutically relevant target,
which we had previously observed to be base sensitive.17
A
comparative study with the conditions that were used in Table
3 was undertaken for the coupling of densely functionalized
heteroaryl bromide 19 with the base-sensitive piperazine 20
and is presented in Figure 1.
Figure 1. Complex aryl halide Pd C−N arylation. Reaction conditions:
Reactions used RuPhos Pd G2 (for LiHMDS/NaOtBu), tBu3P Pd G2
(for Zn(HMDS)2) and tBuXPhos Pd G3 (for P2Et). Aryl bromide 19
(5 μmol), amine 20 (7.5 μmol), base (10 μmol), 16 h. Percentages are
based on liquid chromatography analysis of crude reactions. *10 mol
% tBuXPhos Pd G3, P2Et (15 μmol) gave a 67% isolated yield of 21
on 200 μmol scale.
The use of P2Et as a base in this reaction at ambient
temperature resulted in superior reactivity and functional group
tolerance when compared to other methods. This study also
highlights the negative impact that heating can have on
complex substrates. For instance, the use of Cs2CO3 at 85 °C
led to complete substrate decomposition and no product
formation.
In order to better understand the remarkable reactivity
conferred by P2Et phosphazene, we compared the initial kinetic
C
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Surry, D. S.; Buchwald, S. L. Org. Lett. 2013, 15, 3734. (h) Yang, Y.;
Oldenhuis, N. J.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 615.
(i) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132,
14073. (j) Lee, B. K.; Biscoe, M. R.; Buchwald, S. L. Tetrahedron Lett.
2009, 50, 3672.
(10) Schwesinger, R.; Schlempe, H.; Hasenfratz, C.; Willaredt, J.;
Dambacher, T.; Breuera, T.; Ottaway, C.; Fletschingera, M.; Boele, J.;
Fritz, H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01648.
■
S
AUTHOR INFORMATION
Corresponding Author
■
(11) 5-Phenyl-3-bromopyridine 13 was used in place of 5 for the
water couplings because the product was easier to quantify by UPLC
analysis. Also, the aryl chloride and aryl iodide variants of 13 are not
commercially available and were not interrogated.
*E-mail: spencer_dreher@merck.com.
Notes
(12) P2Et Phosphazene has been minimally used in transition metal
catalysis, likely due to the current expense of this base. For many
complex, sensitive synthetic targets in drug discovery or natural
products synthesis, the cost of the reaction substrate prepared through
multistep synthesis is much higher than this base cost.
(13) For leading references on robustness screening, as well as an
example of ester stability issues in C−N coupling: (a) Collins, K. D.;
Glorius, F. Nat. Chem. 2013, 5, 597. (b) Collins, K. D.; Glorius, F. Acc.
Chem. Res. 2015, 48, 619.
(14) Conditions chosen for this study and those for the complex aryl
halide study (in Figure 1) are similar to those previously reported in
the literature: (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27.
(b) Lee, D. Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169.
(15) The use of P2Et/tBuXPHOS with tert-amyl alcohol, conditions
that were found to be most reactive for several reactions, also gave full
conversion with 3-chloropyridine 14 and piperidine 7 in the presence
of esters 16 and 17, with minimal ester decomposition.
(16) Room temperature hydroxylation has been recently reported;
however, nonactivated N-heterocyclic substrates require heating:
(a) Lavery, C. B.; Rotta-Loria, N. L.; McDonald, R.; Stradiotto, M.
Adv. Synth. Catal. 2013, 355, 981. (b) Cheung, C. W.; Buchwald, S. L.
J. Org. Chem. 2014, 79, 5351. (c) Sergeev, A. G.; Schulz, T.; Torborg,
C.; Spannenberg, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
2009, 48, 7595.
(17) Stamford, A. W.; Scott, J. D.; Li, S. W.; Babu, S.; Tadesse, D.;
Hunter, R.; Wu, Y.; Misiaszek, J.; Cumming, J. N.; Gilbert, E. J.;
Huang, C.; McKittrick, B. A.; Hong, L.; Guo, T.; Zhu, Z.; Strickland,
C.; Orth, P.; Voigt, J. H.; Kennedy, M. E.; Chen, X.; Kuvelkar, R.;
Hodgson, R.; Hyde, L. A.; Cox, K.; Favreau, L.; Parker, E. M.;
Greenlee, W. J. ACS Med. Chem. Lett. 2012, 3, 897.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Merck Research Laboratories (MRL)
Postdoctoral Research Program for financial support of A.B.S.;
MRL Colleagues Drs. Tim Cernak, Ana Bellomo, Alan Hyde,
Jingjun Yin, Rebecca Ruck, and Artis Klapars for helpful
discussions; Nicholas Perrotto for assistance with Chemspeed
robotics; and Jake Waldman for lab assistance.
REFERENCES
■
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Org. Lett. XXXX, XXX, XXX−XXX