Palladium-Catalyzed Amidation and Amination of (Hetero)aryl Chlorides under Homogeneous Conditions Enabled by a Soluble DBU/NaTFA Dual-Base System

Article abstract of DOI:10.1021/acs.oprd.9b00196

The palladium-catalyzed coupling of aryl and heteroaryl chlorides with primary amides under mild homogeneous reaction conditions is reported. Successful C-N coupling is enabled by the use of a unique "dual-base" system consisting of DBU and NaTFA, which serve as proton acceptor and halide scavenger, respectively, using low catalyst loadings (0.5 mol %) with readily available, air-stable palladium precatalysts. The DBU/NaTFA system also enables the room-temperature coupling of primary aryl amines with aryl chlorides and is tolerant of a variety of base-sensitive functional groups.

Full text of DOI:10.1021/acs.oprd.9b00196

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Amidation and Amination of (Hetero)aryl
Chlorides under Homogeneous Conditions Enabled by a Soluble
DBU/NaTFA Dual-Base System
Gregory L. Beutner, John R. Coombs, Rebecca A. Green, Bahar Inankur, Dong Lin, Jun Qiu,
Frederick Roberts, Eric M. Simmons,* and Steven R. Wisniewski
Chemical & Synthetic Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903,
United States
S
* Supporting Information
ABSTRACT: The palladium-catalyzed coupling of aryl and heteroaryl chlorides with primary amides under mild homogeneous
reaction conditions is reported. Successful C−N coupling is enabled by the use of a unique “dual-base” system consisting of
DBU and NaTFA, which serve as proton acceptor and halide scavenger, respectively, using low catalyst loadings (0.5 mol %)
with readily available, air-stable palladium precatalysts. The DBU/NaTFA system also enables the room-temperature coupling
of primary aryl amines with aryl chlorides and is tolerant of a variety of base-sensitive functional groups.
KEYWORDS: C−N coupling, Pd-catalyzed, homogeneous, DBU, halide scavenger, sodium trifluoroacetate
catalyzed by parts per million levels of Pd.4 However, these
conditions are generally incompatible with many base-sensitive
functional groups that are prevalent in pharmaceutically
INTRODUCTION
■
The palladium-catalyzed C−N coupling of aryl halides and
amines is a highly valuable transformation for the industrial-
relevant substrates, such as keto, ester, nitrile, and nitro
scale synthesis of complex amines1 and is particularly
groups,5 necessitating the use of weak inorganic bases such as
important in the preparation of active pharmaceutical
3c
Cs2CO3,6 K3PO4,3a,4c,7 or K2CO3 for couplings with
ingredients (APIs) and their synthetic intermediates.2 Simple
substrates containing these moieties. Similarly, the arylation
aryl bromides and chlorides often undergo amination with high
of amides, which are among the most challenging substrates for
Pd-catalyzed C−N coupling,1d inherently generates products
efficiency when strong inorganic bases such as NaOt-Bu, KOt-
Bu, and LiHMDS are employed1c (Scheme 1a), as exemplified
that are prone to base-mediated hydrolysis, and the couplings
by room-temperature couplings with anilines and secondary
of such nucleophiles also are most frequently performed with
alkyl amines3 and the arylation of primary alkyl amines
10
Cs2CO3,8 K3PO4,9 or K2CO3 (Scheme 1b).
The use of weak inorganic bases in Pd-catalyzed C−N
coupling is notoriously complicated by their poor solubility in
organic solvents.11 Not only does this dictate that elevated
reaction temperatures (typically ≥80 °C) and high catalyst
loadings are often required to achieve reasonable reaction
rates, but the heterogeneous nature of the reaction mixture also
leads to a number of other factors impacting the reaction
kinetics that are difficult to predict, including effects of the lot,
form, particle size, and particle shape of the base12,13 as well as
effects of water content (both added and adventitious).13,14
Furthermore, pronounced changes in reaction rate are often
observed when moving from small-scale reactions conducted
with magnetic stirring, where a grinding effect of the stir bar
can lead to an increase in base surface area, to overhead stirring
where such grinding effects are absent.15 While milling of the
base can compensate for the lack of beneficial grinding with
overhead stirring,16,17 mixing effects may be observed when
Scheme 1. Bases Employed in the Pd-Catalyzed Amination
and Amidation of Aryl Halides
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
Received: May 1, 2019
© XXXX American Chemical Society
A
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Article
reactions are performed in vessels with different size or
configuration18 or when different agitation speeds are employ-
ed.16b The combined impact of these complex factors renders
the development and scale-up of transformations employing
heterogeneous bases a highly challenging and time-consuming
process.15,16b,18a,19
of aryl triflates and bromides using DBU.30 However, a single
coupling of an aryl chloride was demonstrated, and the Pd(0)
complex employed for the majority of the reported examples
currently has limited commercial availability. Thus, despite this
important advance, generally effective conditions for Pd-
catalyzed C−N coupling of aryl chlorides under mild
homogeneous conditions using widely available ligands
remained unknown.
To address the inherent limitations associated with the use
of insoluble inorganic bases, several groups have reported
conditions for C−N coupling using soluble inorganic or
organic bases. Organ and co-workers have elegantly employed
the hindered phenoxide salts potassium chromanoxide20 and
NaBHT21 for the palladium-catalyzed arylation of primary
amines. Unfortunately, these bases are currently not
commercially available and must be freshly prepared prior to
use for optimal performance.21a Scientists at Merck reported
the use of the organic superbase P2Et phosphazene for room-
temperature palladium-catalyzed C−N coupling of aryl halides
in nano- and microscale experiments.22 While suitable for
application in drug discovery, the high cost (ca. $40,000/mol)
and limited commercial availability of this base are prohibitive
for use on a manufacturing scale. Thus, there remains a need
for the identification of conditions under which the coupling of
pharmaceutically relevant (hetero)aryl halides and nitrogen
nucleophiles can be effected with a mild, soluble base that is
inexpensive and readily available in bulk quantities. Here we
report the development of a cost-effective, homogeneous dual-
base system that addresses the complications associated with
insoluble inorganic bases and demonstrate its applicability to
the coupling of aryl chlorides with primary amide and aryl
amine coupling partners. The DBU/NaTFA dual-base system
(ca. $40/mol) disclosed herein (Scheme 1c) satisfies the
aforementioned criteria for a readily scalable process and can
be employed in the coupling of (hetero)aryl chlorides with a
variety of nitrogen nucleophiles.
Motivated by a challenging late-stage amidation of a
complex heteroaryl chloride in an API synthesis that employed
K2CO3,23 we sought to identify a soluble base that would
obviate the scale- and particle-size-dependent reaction kinetics
inherent to heterogeneous bases. The moderately strong
organic base DBU was an ideal candidate since it is both
inexpensive and readily available on a bulk scale.24 However,
prior theoretical studies on Pd/P(t-Bu)3-catalyzed amination
reactions with DBU identified a prohibitively high energy
barrier for amine deprotonation due to the energetic penalty of
charge separation in dissociating bromide from the oxidative
addition complex in nonpolar solvents.25 While a cationic
complex was calculated to be energetically accessible in polar
solvents, it was found to form a stable complex with DBU that
hinders the subsequent transmetalation. In addition, con-
current experimental studies conducted with Pd/BINAP using
DBU, as well several other strong organic bases,26 all gave <5%
conversion, in stark contrast to the >99% conversion using
NaOt-Bu.25 Thus, soluble organic bases are unlikely to be
effective for Pd-catalyzed C−N coupling of aryl chlorides using
simple phosphine ligands.27
We considered that an additional factor limiting the utility of
organic bases in Pd-catalyzed C−N coupling could arise from a
buildup of soluble halide species in the reaction mixture that
may inhibit coordination of the amine nucleophile to the
arylpalladium intermediate and slow the transmetalation step,
which has been shown to be rate-limiting for the arylation of
primary and secondary amides.31 The addition of soluble
chloride31a,32 and iodide31c,32b salts has been reported to give a
marked decrease in both the rates and yields of couplings of
aryl triflates and bromides. On the basis of these observations,
we hypothesized that the use of a salt additive containing a
weakly coordinating counteranion33 might render a suitable
organic base effective for Pd-catalyzed C−N coupling of aryl
chlorides by sequestering the liberated chloride as an “M”Cl
salt. A related halide-scavenging approach was employed
recently by Morken and co-workers, who reported the use of
NaOTf34 and KOTf35 as scavengers for chloride and bromide,
respectively, in Pd-catalyzed conjunctive cross-couplings.36,37
Becica and Dobereiner reported the use of both main-group
and lanthanide triflate salts as additives in the Pd/Xantphos-
catalyzed C−N coupling of aryl bromides and amides using
Cs2CO3 as the base,38 which lends further support for the
halide-scavenging hypothesis but notably does not address the
inherent challenges associated with heterogeneous reaction
conditions.
RESULTS AND DISCUSSION
■
Investigation of Amine Bases and Chloride Scav-
engers. Our efforts toward the development of a scalable,
homogeneous reaction system for C−N coupling focused on
the use of aryl chlorides, which generally are more readily
available and significantly less expensive than the correspond-
ing aryl bromides and are thus more desirable for large-scale
syntheses.39 We first investigated couplings with primary amide
nucleophiles. The tB-BrettPhos ligand developed by Buchwald
and co-workers is a highly effective ligand for this challenging
transformation and has been shown to promote such couplings
with 1.0 mol % Pd and K3PO4 as the base in t-BuOH at 110
°C.9b,31a For our initial studies, we elected to use the complex
[(tB-BrettPhos)Pd(Allyl)]OTf [Pd-1] recently developed by
Johnson Matthey as a convenient single-component catalyst
precursor.40 As expected, the use of DBU alone gave very low
conversion of 1a41 (Table 1, entry 1). In accord with our
hypothesis, NaOTf and KOTf both proved to be effective
additives that led to full conversion of 1a in conjunction with
DBU as the base (entries 2 and 3).34,36 We were pleased to
find that sodium trifluoroacetate (NaTFA), which is
approximately 7.5 times less expensive than NaOTf on a
kilogram scale, gave virtually identical reaction performance
compared to NaOTf (entry 4). Incomplete conversion was
observed in the presence of the more nucleophilic 2-
ethylhexanoate anion of NaEHA (entry 5), while the use of
NaOPh (entry 6) gave full conversion of 1a but also led to
detectable amounts of a C−O coupling byproduct. Other
strong organic bases such as MTBD (entry 7) also proved
Until recently, the sole example of a DBU-mediated, Pd-
catalyzed C−N coupling was a single report on the coupling of
aryl nonaflates with aniline, imine, and amide nucleophiles at
elevated temperatures (115−175 °C) under microwave-
assisted conditions.28,29 In 2018, while our studies were in
progress, Buchwald and co-workers disclosed that a bulky
dialkyl triarylmonophosphine-containing Pd(0) complex was
capable of promoting the amination and amidation of a range
B
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Table 1. Survey of Amine Bases and Soluble Chloride
Scavengers
Table 2. Amidation of Base-Sensitive Aryl Chlorides under
DBU/NaTFA Dual-Base Conditions
a
a b
,
b
entry
base
additive
solvent
DME
DME
DME
DME
DME
DME
DME
DME
2-MeTHF
t-AmOH
EtOAc
DMF
conv. (%) yield (%)
1
2
3
4
5
6
7
8
9
DBU
DBU
DBU
DBU
DBU
DBU
MTBD
DIPEA
DBU
DBU
DBU
DBU
−
11
>99
>99
>99
57
11
94
94
95
46
93
95
ND
90
92
92
86
NaOTf
KOTf
NaTFA
NaEHA
NaOPh
NaTFA
NaTFA
NaTFA
NaTFA
NaTFA
NaTFA
>99
>99
<5
>99
>99
>99
96
a
b
10
11
12
Isolated yields. Reaction conditions: 1.0 mmol of ArCl, 1.2 equiv of
amide, 0.5 mol % [(tB-BrettPhos)Pd(Allyl)]OTf [Pd-1], 1.5 equiv of
c
DBU, 1.2 equiv of NaTFA, DME (0.50 M), 60 °C. 0.5 mmol of
ArCl, 1.5 equiv of amide, 0.7−0.9 mol % Pd-1, MeCN, 65 °C.
a
Reaction conditions: 0.25 mmol of ArCl, 1.2 equiv of amide, 0.5 mol
% [(tB-BrettPhos)Pd(Allyl)]OTf [Pd-1], 1.2 equiv of base, 1.2 equiv
of additive, solvent (0.25 M), 60 °C, 16 h. DBU = 1,8-
Table 3. Amidation of (Hetero)aryl Chlorides under DBU/
NaTFA Dual-Base Conditions
b
diazabicyclo[5.4.0]undec-7-ene. Solution yields determined by 19F
a b
,
NMR spectroscopy.
effective, whereas weaker bases such as DIPEA gave minimal
conversion (entry 8; also see Table S2). Because of the lower
cost of DBU and NaTFA compared with other bases and
chloride scavengers, we focused on the DBU/NaTFA “dual-
base” system for further studies. Guided by solubility screening
data that indicated high solubility of NaTFA in a range of
organic solvents42 (Table S3), we subsequently discovered that
the DBU/NaTFA-mediated coupling conditions are compara-
bly effective in a variety of common solvents, including 2-
MeTHF, t-AmOH, and EtOAc16b (entries 9−11; also see
Table S4). Remarkably, the C−N coupling also proceeds in
dipolar aprotic solvents such as DMF (entry 12), albeit with
slightly diminished conversion and yield.
Couplings of Base-Sensitive Aryl Chlorides with
Primary Amides. With a suitable chloride scavenger
identified, we first sought to determine whether the DBU/
NaTFA conditions could be utilized with aryl chlorides
containing functional groups that are generally incompatible
with strong inorganic bases. As shown in Table 2, the DBU/
NaTFA dual-base system is tolerant of a wide range of base-
sensitive moieties, with aryl chloride substrates containing ester
(3b), nitrile (3c), nitro (3d), ketone (3e and 3f), and aldehyde
(3g) functional groups undergoing amidation in 64−86%
isolated yield. While it is known that electron-deficient aryl
chlorides (e.g., 1b−g) are generally more reactive substrates in
Pd-catalyzed cross-couplings compared with electron-neutral
and electron-rich aryl chlorides, we were pleased to find that
chlorobenzene also underwent amidation under the DBU/
NaTFA dual-base conditions with comparable efficiency (3h,
72% yield). This latter finding thus prompted further study of
less activated (hetero)aryl chloride substrates.
a
b
Isolated yields. Reaction conditions: 2.0 mmol of ArCl, 1.2 equiv of
amide, 0.5 mol % [(tB-BrettPhos)Pd(Allyl)]OTf [Pd-1], 1.2 equiv of
DBU, 1.2 equiv of NaTFA, 2-MeTHF (0.50 M), 60 °C. 2.0 mmol of
ArBr. 0.25 mol % [(Allyl)PdCl]2, 0.55 mol % SL-J009-1 [Pd-2]. 1.0
c
d
e
mmol of ArCl.
nucleophiles were successfully coupled with 5-chloroquinoline
using the DBU/NaTFA dual-base system, including aryl and
alkyl amides (3a and 3j) and sulfonamides (3k and 3l) as well
as the ammonia surrogates formamide (3m) and tert-butyl
carbamate (3n). While not studied extensively, aryl bromides
also proved to be viable coupling partners, with 5-bromo-2-
fluorotoluene undergoing coupling with 5-fluoropicolina-
mide43 to give 3o. While 2-chloropyridine derivatives were
found to react sluggishly with Pd-1 as the catalyst, these
substrates were readily coupled using a catalyst generated in
situ from [(Allyl)PdCl]2 and SL-J009-1 (CyPF-tBu).1b,4b With
Couplings of (Hetero)aryl Chlorides with Primary
Amides. Having established an encouraging functional group
tolerance for the DBU/NaTFA conditions, we sought to more
broadly investigate the scope of the (hetero)aryl chloride
amidation reaction. As shown in Table 3, a variety of amide
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this catalyst system, denoted as [Pd-2], amidation was
successfully achieved with both 2-chloroquinoline (3p−r)
and a secondary-amide-containing 2-chloropyridine substrate
(3s).
Couplings of Aryl Chlorides with Primary Aryl
Amines. With a promising substrate scope demonstrated for
the amidation of (hetero)aryl chlorides using two comple-
mentary catalyst systems, we next sought to extend our studies
to other nitrogen nucleophiles. We discovered that the DBU/
NaTFA dual-base system also enables the coupling of aryl
chlorides and primary aryl amines under mild conditions using
Buchwald’s tB-XPhos-Pd-G3 palladacycle [Pd-3].44 The scope
of the couplings of primary aryl amines is shown in Table 4. In
underwent coupling (5i), as did an electron-rich aryl bromide
(5j).
Robustness Study of Primary Aryl Amine Couplings.
To facilitate a detailed comparison of the functional group
tolerance of the DBU/NaTFA dual-base system to that of
classic aryl amine coupling conditions employing strong
inorganic bases, we conducted a Glorius robustness study45
for the coupling of 2-chlorotoluene with aniline at room
temperature. Twenty-three different additives were spiked into
the reaction mixture (each at 1.0 equiv) to probe the scope and
limitations of the C−N coupling. On the basis of the initial
data set, several additives were also tested at 50 °C. A summary
of the key results can be seen in Figure 1.46 Similar results were
observed for the DBU/NaTFA and NaOt-Bu conditions with
several additives, such as an alkyl chloride, dialkyl ketone, and
protected pyrrole. In general, however, the NaOt-Bu
conditions provided higher levels of conversion at room
temperature compared with the dual-base system. For example,
the addition of 4H-chromen-4-one, butyl thiophene, and oct-4-
yne inhibited the DBU/NaTFA dual-base system, whereas
complete conversion was observed with NaOt-Bu, even though
the amount of additive remained between 53 and 95%.
On the other hand, the strength of the dual-base system is
evident from a comparison of the results for base-sensitive
additives. Although the conversion at room temperature is
generally high for both systems with additives such as
nitrobenzene, methyl benzoate, benzonitrile, acetophenone,
and p-tolualdehyde, the amount of additive remaining varies
greatly. In all cases, >95% of the additive remains for the
DBU/NaTFA dual-base system, whereas appreciable con-
sumption is observed in the case of NaOt-Bu. While simple
substrates may perform well in C−N coupling at room
temperature, the increased molecular complexity typical of
many pharmaceutically relevant substrates could require an
increase in reaction temperature to observe high levels of
conversion. Therefore, we also tested the reactions with these
base-sensitive additives at 50 °C, and the results are more
interesting compared with those at room temperature. The
mild nature of the dual-base system is again confirmed, with
high levels of conversion still observed and >85% additive
remaining in all cases. However, the same set of reactions
utilizing NaOt-Bu perform worse at higher temperature, with
lower amounts of product formed in all cases. While the
amount of additive remaining for methyl benzoate and
benzonitrile with NaOt-Bu is greater at 50 °C compared
with room temperature, several new impurities are observed at
the end of the reaction.
Table 4. Amination of Aryl Chlorides and Bromides under
a b
,
DBU/NaTFA Dual-Base Conditions
a
b
Isolated yields. Reaction conditions: 2.0 mmol of ArCl, 1.2 equiv of
amine, 0.5 mol % tB-XPhos-Pd-G3 [Pd-3], 1.2 equiv of DBU, 1.2
c
equiv of NaTFA, 2-MeTHF (0.50 M), 20−50 °C. 1.0 mmol of ArCl,
d
1.5 equiv of DBU, DME (0.50 M), 20 °C. 0.5 mol % [(tB-
e
XPhos)Pd(Allyl)]OTf [Pd-4]. 2.0 mmol of ArBr.
Reaction Kinetics for Amidation with DBU/NaTFA
versus K2CO3. As noted previously, the heterogeneous
reaction conditions that are inherent to the use of the weak
inorganic bases most commonly employed for C−N coupling
of amide nucleophiles present numerous challenges for scale-
up. Among these complications, highly variable reaction rates
that depend on a variety of complex parameters are frequently
observed. The homogeneous reaction conditions afforded by
the DBU/NaTFA dual-base system obviate many of these
challenges, specifically effects of the form, particle size, and
shape of the base as well as grinding effects from magnetic
stirring. Additionally, the dual-base system also has the
potential to overcome the reaction temperature limitations
commonly resulting from the low solubility of inorganic bases
in organic solvents,11 which often lead to very low reaction
rates at temperatures below 60 °C.
line with the previous results with amide nucleophiles, aryl
chlorides bearing base-sensitive functional groups such as ester
(5a), ketone (5b), and nitrile (5c) proved to be excellent
coupling partners, readily undergoing amination with aniline
catalyzed by 0.5 mol % Pd-3 at room temperature in good
yields. Protic functionalities were also compatible with the
DBU/NaTFA conditions, including hydroxyl (5d), amide
(5e), and carbamate (5f), with the latter coupling employing
the aryl bromide electrophile. Though not tested extensively
for these couplings, the Johnson Matthey precatalyst [(tB-
XPhos)Pd(Allyl)]OTf [Pd-4]40a gave virtually identical
performance in the reaction to form 5e (97% yield with 0.5
mol % Pd-4 vs 98% yield with 0.5 mol % Pd-3). Ortho
substitution on the aryl chloride was also well-tolerated (5g
and 5h), with the amination of 2-chlorotoluene proceeding at
room temperature. A heteroaryl amine nucleophile also
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Figure 1. Robustness study for the amination of 2-chlorotoluene with DBU/NaTFA and NaOt-Bu. Note: for Additive Remaining values, 98.0
corresponds to >98% and 1.0 corresponds to <1.0%.
To gain preliminary insight into the reaction kinetics with
DBU/NaTFA in comparison with commonly used weak
inorganic bases, we monitored the amidation of 2-chloroquino-
line with isobutyramide using DBU/NaTFA or K2CO3 as the
base. As shown in Figure 2, the reaction catalyzed by 0.5 mol %
Pd-2 at 45 °C proceeds smoothly with DBU/NaTFA, reaching
>99% conversion in approximately 7 h. In contrast, with
K2CO3 as base the reaction is significantly slower, reaching
∼50% conversion after 12 h. The use of commercially available
325 mesh K2CO3 provides a slight increase in reaction rate
compared with granular K2CO3 (see Figures S1 and S2), an
effect that can be expected to become more pronounced when
moving to overhead stirring, but the reaction is still sluggish
compared with the DBU/NaTFA dual-base conditions.
Interestingly, the combination of DBU and K2CO3 leads to a
slightly lower reaction rate compared with K2CO3 alone,
consistent with the reversible formation of an off-cycle DBU-
bound catalyst resting state.30b In line with our observations
with Pd-1, DBU alone gave only trace conversion.
Amidation on a Multigram Scale under DBU/NaTFA
Dual-Base Conditions. To test of the scalability of the dual-
base system, we conducted the amidation of 2-chloroquinoline
with isobutyramide on a 15 g scale using DBU/NaTFA
conditions. As shown in Figure 3, the profile for this reaction,
conducted with overhead mechanical stirring, matched very
closely with the profile that was observed in the vial-scale
kinetics runs using magnetic stir bars. Similarly, the 82% yield
of 3p for the 15 g reaction is also in line with the value from
the 2.0 mmol scale reaction (88% yield). These data suggest
that the DBU/NaTFA dual-base system is not subject to the
same scale-dependent reaction variability typically observed
with inorganic bases.
Amination under DBU/NaTFA Dual-Base Conditions
with Complex Substrates. Our initial findings also indicate
that the DBU/NaTFA dual-base conditions can be applied to
the amination of complex substrates representative of the
Figure 2. Reaction profiles for the amidation of 2-chloroquinoline
with DBU/NaTFA and K2CO3 using 0.25 mol % [(Allyl)PdCl]2 and
0.55 mol % SL-J009-1 [Pd-2] at 45 °C: (top) disappearance of 2-
chloroquinoline; (bottom) formation of C−N-coupled product 3p.
intermediates typically found in the synthesis of APIs. As
shown in Scheme 2, the challenging C−N coupling of
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involving the insoluble weak inorganic bases Cs2CO3, K3PO4,
and K2CO3. Further studies to extend the scope of aryl halides
and nucleophiles that can be coupled using dual-base
conditions are currently in progress in our laboratories.
EXPERIMENTAL SECTION
■
General Information. All operations were performed
under a nitrogen atmosphere. Starting materials, reagents,
and solvents were used as received from the commercial
vendors. UPLC analysis was performed using an Agilent
Poroshell EC-C18 column (1.9 μm, 2.1 mm × 50 mm) and the
following conditions: mobile phase A, 5:95 acetonitrile/water
with 0.05% TFA; mobile phase B, 95:5 acetonitrile/water with
0.05% TFA; gradient, 0% B to 100% B over 2.0 min then 100%
B for 0.5 min; injection volume, 1 μL; flow rate, 1.0 mL/min;
oven temperature, 40 °C; detection by UV at 220 nm.
General Procedures for Amidation and Amination
Using DBU/NaTFA Dual-Base Conditions. Amidation of
(Hetero)aryl Chlorides Using [(tB-BrettPhos)Pd(Allyl)]OTf
[Pd-1]. To an 8 mL screw-cap vial were charged the aryl
halide substrate 1 (1−2 mmol), amide nucleophile 2 (1.2
equiv), sodium trifluoroacetate (1.2 equiv), and a magnetic stir
bar. Under an atmosphere of N2, 2-MeTHF (2−4 mL for an
aryl halide concentration of 0.50 M) and DBU (1.2 equiv)
were added, followed by a solution of [Pd-1] in MeCN (100−
200 μL for a Pd concentration of 0.050 M). The vial was
capped and heated to 60 °C for the specified amount of time.
Amination of (Hetero)aryl Chlorides and Bromides Using
tB-XPhos-Pd-G3 [Pd-3]. To an 8 mL screw-cap vial was
charged the aryl halide substrate 1 (1−2 mmol), aryl amine
nucleophile 4 (1.2 equiv), sodium trifluoroacetate (1.2 equiv),
and a magnetic stir bar. Under an atmosphere of N2, 2-MeTHF
(2−4 mL for an aryl halide concentration of 0.50 M) and DBU
(1.2 equiv) were added, followed by a solution of [Pd-3] in
MeCN (100−200 μL for a Pd concentration of 0.050 M). The
vial was capped, and the reaction mixture was stirred at 20−50
°C for the specified amount of time.
Figure 3. Reaction profiles for the amidation of 2-chloroquinoline
with DBU/NaTFA using 0.25 mol % [(Allyl)PdCl]2 and 0.55 mol %
SL-J009-1 [Pd-2] at 50 °C on the vial scale (with a magnetic stir bar)
and on a 15 g scale (with overhead mechanical stirring).
Scheme 2. Amination of Rivaroxaban under DBU/NaTFA
Dual-Base Conditions
rivaroxaban (6) with heteroaryl amine 747 was readily achieved
under dual-base conditions catalyzed by 2 mol % Pd-1,
delivering 8 in 80% isolated yield.48 The use of DMAc as a
cosolvent was essential for the success of this coupling because
of the low solubility of 6 in the solvents typically used for C−N
coupling. This cosolvent strategy may prove beneficial for
effecting related C−N couplings of substrates with challenging
solubility properties using dual-base conditions.
Coupling of 2-Chloroquinoline (1p) and Isobutyr-
amide (2p) Using DBU/NaTFA and [Pd-2]. Catalyst
Preparation. The catalyst solution was prepared by combining
[(Allyl)PdCl]2 (85.6 mg, 0.25 mol %) and SL-J009-1 (280 mg,
0.55 mol %) in 2-MeTHF (30 mL). The contents of the vial
were inerted by subsurface N2 sparging for 30 min at room
temperature.
CONCLUSION
Reaction. An inert 250 mL glass reactor equipped with an
overhead agitator with a half-moon blade was prepared. A
portion of the total 2-MeTHF (183 mL, 2 mL/mmol based on
1p) was charged into the reactor to achieve a minimum
stirrable volume, and agitation was started at room temper-
ature. 2-Chloroquinoline (15 g, 91.7 mmol), isobutyramide
(9.68 g, 1.2 equiv), and NaTFA (15.3 g, 1.2 equiv) were
charged to the reactor through a funnel followed by DBU
(16.5 mL, 1.2 equiv). The remainder of the 2-MeTHF was
added to the reactor as a rinse of the addition port and reactor
wall. The reactor was then sealed, and the solution was inerted
via subsurface N2 sparging until a headspace O2 level of <700
ppm was achieved. The solution was then heated to the
reaction temperature (50 °C) prior to charging with the
catalyst solution. At t = 0 min, the catalyst solution was
transferred to the main reactor via cannula to keep the
contents of the reactor and catalyst solution vial inert. The
reactor was kept under a N2 blanket throughout the reaction
age. At specified time intervals, samples were withdrawn from
■
We have reported the development of a scalable, cost-effective
(ca. $40/mol) DBU/NaTFA dual-base system that decouples
the proton transfer and halide sequestration events in Pd-
catalyzed C−N coupling reactions. These dual-base conditions
enable the coupling of (hetero)aryl chlorides with primary
amide and aryl amine nucleophiles under mild homogeneous
conditions using low catalyst loadings (typically 0.5 mol %) of
either preformed or in situ-generated Pd complexes ligated by
mono- or bisphosphine ligands. A number of electron-deficient
and electron-neutral aryl chlorides undergo DBU/NaTFA-
mediated amination at room temperature, including those
bearing base-sensitive functional groups that render them
incompatible with classical C−N coupling conditions employ-
ing strong bases such as NaOt-Bu and LiHMDS. The DBU/
NaTFA dual-base system constitutes the first set of general,
practical conditions for homogeneous Pd-catalyzed amidation
of aryl chlorides, thereby avoiding the notorious challenges
associated with the development and scale-up of couplings
F
DOI: 10.1021/acs.oprd.9b00196
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Article
(4) (a) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Highly
Reactive, General, and Long-Lived Catalysts for Coupling Heteroaryl
and Aryl Chlorides with Primary Nitrogen Nucleophiles. Angew.
Chem., Int. Ed. 2005, 44, 1371−1375. (b) Shen, Q.; Ogata, T.;
Hartwig, J. F. Highly Reactive, General and Long-Lived Catalysts for
Palladium-Catalyzed Amination of Heteroaryl and Aryl Chlorides,
Bromides, and Iodides: Scope and Structure−Activity Relationships. J.
Am. Chem. Soc. 2008, 130, 6586−6596. (c) Shen, Q.; Hartwig, J. F.
[(CyPF-tBu)PdCl2]: An Air-Stable, One-Component, Highly Effi-
cient Catalyst for Amination of Heteroaryl and Aryl Halides. Org. Lett.
2008, 10, 4109−4112.
(5) For the use of LiHMDS with substrates containing hydroxyl,
amide, and keto groups, see: Harris, M. C.; Huang, X.; Buchwald, S. L.
Improved Functional Group Compatibility in the Palladium-
Catalyzed Synthesis of Aryl Amines. Org. Lett. 2002, 4, 2885−2888.
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the reactor using an Easy Sampler (Mettler Toledo) under
inert conditions and quenched in a vial at 350-fold dilution
with 50:50 v/v MeCN/water (at 20 °C), which was used as
both the quench and diluent. Upon completion of the
sampling protocol, samples were transferred to UPLC vials
and filtered for UPLC analysis. Quantitative UPLC analysis of
the postreaction stream indicated an 82% yield of 3p.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00196.
■
S
Experimental details, characterization data and NMR
spectra for C−N coupling products (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: eric.simmons@bms.com.
■
(7) Park, N. H.; Vinogradova, E. V.; Surry, D. S.; Buchwald, S. L.
Design of New Ligands for the Palladium-Catalyzed Arylation of α-
Branched Secondary Amines. Angew. Chem., Int. Ed. 2015, 54, 8259−
8262.
ORCID
Gregory L. Beutner: 0000-0001-8779-1404
Rebecca A. Green: 0000-0002-8492-3122
Jun Qiu: 0000-0002-2733-7979
Eric M. Simmons: 0000-0002-3854-1561
Steven R. Wisniewski: 0000-0001-6035-4394
(8) (a) Yin, J.; Buchwald, S. L. Palladium-Catalyzed Intermolecular
Coupling of Aryl Halides and Amides. Org. Lett. 2000, 2, 1101−1104.
(b) Wybon, C. C. D.; Mensch, C.; Hollanders, K.; Gadais, C.;
Herrebout, W. A.; Ballet, S.; Maes, B. U. W. Zn-Catalyzed tert-Butyl
Nicotinate-Directed Amide Cleavage as a Biomimic of Metallo-
Exopeptidase Activity. ACS Catal. 2018, 8, 203−218.
(9) (a) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Water-
Mediated Catalyst Preactivation: An Efficient Protocol for C-N Cross-
Coupling Reactions. Org. Lett. 2008, 10, 3505−3508. (b) Fors, B. P.;
Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L. An efficient system for the
Pd-catalyzed cross-coupling of amides and aryl chlorides. Tetrahedron
2009, 65, 6576−6583.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Robert Waltermire, Dr. Srinivas Tummala, and
Dr. Jacob Janey for support of this work. We acknowledge
Sloan Ayers for his assistance with the NMR structural
assignment of 3m and Michael Peddicord for assistance with
acquiring HRMS data.
(10) Crawford, S. M.; Lavery, C. B.; Stradiotto, M. Bippy Phos: A
Single Ligand With Unprecedented Scope in the Buchwald−Hartwig
Amination of (Hetero)aryl Chlorides. Chem. - Eur. J. 2013, 19,
16760−16771.
(11) Cella, J. A.; Bacon, S. W. Preparation of dialkyl carbonates via
the phase-transfer-catalyzed alkylation of alkali metal carbonate and
bicarbonate salts. J. Org. Chem. 1984, 49, 1122−1125.
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