Exploring Homogeneous Conditions for Mild Buchwald-Hartwig Amination in Batch and Flow

Article abstract of DOI:10.1021/acs.oprd.0c00018

Cross-couplings are among the most frequently used reactions in complex molecule synthesis. However, the requirement of stoichiometric base can cause challenges. Harsh, insoluble inorganic bases can lead to poor tolerance of sensitive functional groups, scale-up issues, and difficult adaptation to continuous flow platforms. Herein, we describe the use of high throughput experimentation to identify a number of conditions that enable Buchwald-Hartwig reactions to be carried out using readily available ligands (e.g., XantPhos) with DBU as a soluble, functional-group-tolerant, homogeneous base. Application of this system to diverse aminations in batch and flow are demonstrated, as is the translation of this technique to performing continuous Mizoroki-Heck and Sonogashira coupling reactions.

Full text of DOI:10.1021/acs.oprd.0c00018

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Full Paper
Exploring Homogeneous Conditions for Mild
Buchwald-Hartwig Amination in Batch and Flow
Saeed K. Kashani, Jacob E. Jessiman, and Stephen G. Newman
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00018 • Publication Date (Web): 11 Feb 2020
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Page 1 of 9
Organic Process Research & Development
Exploring Homogeneous Conditions for Mild Buchwald-Hartwig Amination in Batch and Flow
Saeed K. Kashani, Jacob E. Jessiman, Stephen G. Newman*
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Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of
Ottawa, Ottawa, Ontario, Canada, K1N 6N5
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identifying effective biphasic conditions,14 among other
ABSTRACT: Cross-couplings are among the most frequently
strategies.15. While these solutions are promising, there are
used reactions in complex molecule synthesis. However, the
still challenges in generality and scalability that hinder
requirement of stoichiometric base can cause challenges.
Buchwald-Hartwig aminations from being reliably performed
Harsh, insoluble inorganic bases can lead to poor tolerance of
in continuous flow without precipitate formation.
sensitive functional groups, scale-up issues, and difficult
adaptation to continuous flow platforms. Herein, we describe
the use of high throughput experimentation to identify a
number of conditions that enable Buchwald-Hartwig
reactions to be carried out using readily available ligands (e.g.
XantPhos) with DBU as a soluble, functional group tolerant,
homogeneous base. Application of this system to diverse
aminations in batch and flow are demonstrated, as is the
translation of this technique to performing continuous
Mizoroki-Heck and Sonogashira coupling reactions.
Scheme 1. Mild organic bases for cross coupling reactions in
batch and flow.
A.
Previously used bases in the Buchwald-Hartwig amination
X
NHR2
Base
NR2
+
H
Pd
Ligand
R
R
NaOtBu: functional group tolerance issue
K2CO3: generality, solubility, & scalability issue
Traditionally
Base
Recently
DBU w/ AlPhos or tBuBrettPhos as ligand
KEYWORDS: Cross-coupling, flow chemistry, Buchwald-
Hartwig amination; palladium catalysis
B.
This work
Aminations with DBU as base using inexpensive ligands (
)
Performing chemical reactions continuously in microreactors
(“flow chemistry) can provide benefits over batch synthesis,
including improved safety at a range of temperatures and
pressures, smaller reactor volumes, efficient scale-up, and
waste reduction.1 A future where intelligent continuous flow
systems can assist scientists in accessing and manufacturing
complex molecules is particularly appealing.2 While this area
is still in its infancy, recent examples in API manufacturing,
on-demand synthesis, and automated optimization are
promising.3-6 The propensity of solids to clog small reactor
channels is one of the greatest challenges that must be
overcome before continuous synthesis can become universally
applicable. While numerous strategies have been reported,7
these solid-handling issues continue to hinder the progress
and implementation of continuous flow methods.
DBU
inexpensive ligands
Pd &
R
X
R
R'
NR'2
+
N
H
R'
35 hits
high throughput search
480 conditions
Continuous Buchwald-Hartwig, Mizoroki-Heck & Sonogashra couplings
R
Pd
Base
X
R
H
+
+
Base·HX
Ionic liquid
heating zone
T > mp of Base·HX
From the perspective of running Buchwald-Hartwig
aminations in continuous flow, the use of organic bases that
do not form precipitating solid byproducts is appealing.
However, such reports are relatively rare. Examples using
phosphazines and guanidines have recently been reported,16
though they are not economical for scale-up. 1,8-
Diazabicyclo(5.4.0)undec-7-ene (DBU), a milder, ionic liquid-
forming amidine base, has been shown to work in microwave-
irradiated aminations of organononaflates;17 however,
experimental and DFT studies using this species suggested the
barrier to the key deprotonation step is generally
unachievably high.18 Towards the goal of enabling Pd-
catalyzed amination to be performed with this relatively mild
base to provide improved substrate scope, Buchwald and co-
workers recently demonstrated that AlPhos, a designer
phosphine ligand, facilitates the key deprotonation step by
influencing the acidity of Pd-bound amines.19 Researchers at
Bristol-Myers Squibb realized a similar goal,20 noting the
scale-up challenges associated with using insoluble inorganic
bases, by using a combination of DBU as a base, NaTFA as a
salt additive, and either Josiphos or t-BuBrettPhos as a ligand.
These conditions were demonstrated to effectively and
reproducibly enable a range of challenging Buchwald-Hartwig
Our group recently reported the adaptation of the BASF Basel
process8 to allow continuous flow acylation, arylation,
alkylation to be reliably performed without concerns of
clogging, regardless of the choice of solvent or concentration,
by mediating them with bases that form ionic liquid conjugate
acids upon protonation.9 These simple substitution reactions
are among the most frequently run in the pharmaceutical
industry,10 and are thus particularly important to be able to
conduct in automated synthesis platforms. Cross-coupling
reactions are no less important, and their use in complex
molecule synthesis continues to grow.11 The Suzuki-Miyaura
reaction has been frequently reported in flow, in particular
because the use of biphasic conditions allows for dissolution
of organic and inorganic species present.12 Other cross-
couplings are less straightforward to run continuously. In
particular, the Buchwald-Hartwig amination is most
frequently carried out using a strong inorganic base such as
NaOtBu and forms insoluble halide salt (NaX) byproducts
(Scheme 1A). Continuous flow Buchwald-Hartwig aminations
have been successfully achieved, for example, by sonicating
the reactor channels to avoid aggregation of precipitate13 or by
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aminations. While these contributions show great potential
slightly more hits. Most excitingly, the inexpensive ligand
XantPhos was found to be particularly promising. XantPhos
has been previously observed to be an exceptionally effective
ligand for Buchwald-Hartwig amination reactions;29 however,
to our knowledge, its use with DBU as a homogeneous base
has not been reported.
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7
8
for the use of milder organic bases, the relatively high cost of
the ligands used21 may hinder widespread adoption.
Towards the goal of expanding the range of important
chemical reactions that can be reliably performed in
continuous flow, we sought to explore Buchwald-Hartwig
aminations with cost-effective ligands and DBU as an ionic
liquid-forming base (mp DBU•HCl = 66 °C). Numerous
variables can influence the barrier of each key transition state
of catalytic aminations, including the sterics and electronics
of both coupling partners, the choice of solvent, the nature of
Scheme 2. Classification of varied parameters in HTE based
on number of successful with each.
9
Pd source
Temperature
Base
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N
the halide, and most importantly, the ligand. As
a
Pd2(dba)3
100 °C
Fix parameters in HTE
DBU
N
consequence, we anticipated that use of high throughput
experimentation (HTE)22 may allow rapid and efficient
exploration of diverse chemical reaction space to help identify
an effective subset of conditions (Scheme 1B). Herein, we
describe how several ligands, and XantPhos in particular, were
identified for the efficient coupling of electron-poor aryl
halides with nitrogen nucleophiles facilitated by DBU. As a
milder alternative to inorganic bases like KOt-Bu and
LiHMDS, sensitive functionality like nitrile, nitro, and ketone
groups are tolerated. As an ionic liquid-forming base, the
reactions can be readily implemented in a continuous flow
process without concern for precipitate formation and reactor
clogging. Lastly, the strategy of using ionic liquid-forming
bases is demonstrated to be applicable to running continuous
Mizoroki-Heck and Sonogashira reactions, further expanding
the range of chemical reactions that can now be predictably
and reliably run in flow (Scheme 1B).
Varied parameters in HTE
Nucleophiles
Solvent
O
NH
(23 hits)
DMF
NH2
O
Ph
NH2
Ph
NH2
Ph
Toluene (12 hits)
(23 hits)
(7 hits)
(4 hits)
(1 hit)
Cl
Aryl halides
Br
N
Br
OTf
Br
I
NC
(12 hits)
(13 hits)
(4 hits)
(3 hits)
(2 hits)
(1 hit)
Ligands
XantPhos
RuPhos
DPPF
(5 hits)
DavePhos
(5 hits)
DPEPhos
(5 hits)
(11 hits)
(6 hits)
BINAP
(2 hits)
IPr·HCl
(1 hits)
P(o-Tol)3
(0 hits)
P(t-Bu)3
(0 hits)
DPPP
(0 hits)
The key variables of the Buchwald-Hartwig amination, such
as the choice of halide, ligand, and solvent, are interrelated,
and changes to one can impact the relative energies of
multiple steps within the catalytic cycle.23 With this in mind,
While individual optimization of each hit was beyond the
scope of this article, we anticipate that many, if not most, of
these experiments can be tuned to give synthetically viable
yields. Towards confirming this hypothesis, a selection of
successful conditions were reproduced as singleton
experiments, quantified, and subject to brief reoptimization
(Scheme 3). For example, the reaction between 4-
bromobenzonitrile 1a and benzamide 2 in the presence of
XantPhos as a ligand and DMF as a solvent was observed to
give a large product peak in crude GC analysis. Replication and
quantification confirmed a yield of 83%, indicating no further
optimization was needed (Scheme 3A). Repeating the
experiment with the aryl chloride analog instead resulted in a
reduced 20% yield (Table 1, entry 1), consistent with previous
knowledge on the relative challenging of activating these
stronger bonds.
we performed
a high throughput screen where each
combination of six different organohalides, four amine
nucleophiles, 10 commercially available ligands, and two
solvents, all of which have been individually demonstrated in
the literature to be effective choices.24 The metal catalyst
(Pd2(dba)3), concentration (0.1 M), reaction temperature (100
°C), time (18 h), stoichiometry (1.2 equiv amine), and most
importantly, base (DBU, 2 equiv) were fixed to keep the total
number of experiments at a reasonable number.
These 480 experiments were setup in five 96-well plates
using liquid-handling tools to facilitate material transfers.25
The outcome of the reaction was classified as a hit (product
observed by GC-MS) or failure (no product observed) without
rigorous quantification.26 In total, 35 unique hits were
observed, suggesting that previous implications that DBU is
an ineffective base may not be universally true.27 The selection
of ligands, nucleophiles, organohalides, and solvents screened
are provided in Scheme 2, ordered based on the frequency that
they were observed to give a positive result in the high
throughput screen. Several trends were observed. The
electron-deficient organohalides 2-bromopyridine and 4-
bromobenzonitrile were found to be effective more often than
related electron-neutral species. Control experiments in the
absence of catalyst confirmed that this observation was not
related to nucleophilic aromatic substitution background
reactivity.28 Of the amine nucleophiles tested, aniline and
benzamide gave product more often than the more
nucleophilic, less acidic benzylamine and morpholine. Both
toluene and DMF were effective solvents, with DMF providing
Screening different Pd sources (entries 2–4) allowed
identification of [Pd(cinnamyl)Cl]2 as an improved choice
over Pd2(dba)3, Increasing the equivalents of nucleophile
(entry 5), resulted in a slight improvement. Exploring
alternative solvents (entries 6, 7) and metal to ligand ratio
(entry 8) to increase the yield of reaction. Lastly, decreasing
the catalyst load provided 87% NMR yield (85% isolated).
Next, the coupling of aryl bromide 1a and benzyl amine 4
mediated by Xantphos as ligand, DBU as base, and DMF as
solvent was replicated and quantified, providing 5 in 20% yield
(Scheme 3B). Again, minor manipulations to the conditions
enabled the identification of conditions that provide the
desired coupling product in 75% NMR yield (70% isolated)
(See Table S5 in the SI for more information).
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Organic Process Research & Development
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3
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Scheme 3. Identification and optimization of effective Buchwald-Hartwig aminations using DBU as a mild base.
5
6
7
8
HTE hit
HTE hit
A
B
Pd2(dba)3 (2.5 mol%)
83%
20%
X= Br,
X= Cl,
X= Br, 1a
X= Cl, 1b
Pd2(dba)3 (2.5 mol%)
XantPhos (7.5 mol%)
DBU (2 equiv)
20%
XantPhos (7.5 mol%)
DBU (2 equiv)
X
Br
DMF (0.1 M)
O
DMF (0.1 M)
H
N
H
NH2
+
NH2
9
N
+
O
10
11
12
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NC
5
CN
4
NC
3
CN
2
1
75%
1a
87%
After optimization
[Pd(cinnamyl)Cl]2 (1.5 mol%)
After optimization
[Pd(cinnamyl)Cl]2 (2.5 mol%)
XantPhos (7.5 mol%)
DMSO (0.33 M)
XantPhos (6 mol%)
DBU (2 equiv)
PhMe (0.1 M)
DBU (2 equiv)
2 equiv nucleophile
2 equiv nucleophile
C
High Throughput Screen
HTE hit
Pd2(dba)3 (2.5 mol%)
DavePhos (7.5 mol%)
DBU (2 equiv)
trace
6 (Ar-X 4 (Nuc) 10 (Ligand) 2 (Solvent) 1 (Pd Source) 1 (Base)
 




DMF (0.1 M)
OTf
= 480 conditions
NH2
H
N
HTE conditions
+
8
Pd2(dba)3 (2.5 mol%)
Ligand (7.5 mol%)
H
X
N
+
RNH2
1.2 eq
Ar
6
7
After optimization
[Pd(allyl)Cl]2 (2.5 mol%)
DavePhos (10 mol%)
DBU (2 equiv)
Ar
R
85%
DBU (2 equiv)
Solvent (0.1 M)
100 °C, 18 h
0.033 mmol
DMF (0.33 M)
2 eq nucleophile
Given the importance and relative rarity of cross-coupling
reactions with amide nucleophiles,29,30 a brief reaction scope
Table 1. Optimization of coupling amides with aryl halides in
the presence of DBUa
was evaluated using the reaction conditions identified for the
coupling described in Table 1 (Scheme 4). The reaction was
observed to be give amide 3 in good yield regardless of the
choice of halide counterion. This was further confirmed by the
O
Pd source
Cl
XantPhos
H
NH2
+
N
DBU (2 equiv)
Solvent (0.1 M)
100 °C, 18 h
NC
O
NC
1b
2
3
successful
coupling
of
2-bromopyridine,
4-
Entry
Equiv 2
Pd source, Ligand mol%
Solvent
%b Yield
nitrochlorobenzene, and 2-iodobenzonitrile with varied
amides to give products 9–11. Ketones with enolizable protons
are particularly challenging functional groups when
performing coupling reactions in the presence of aggressive
bases such as KOtBu. With our conditions, 4-
bromoacetophenone underwent smooth coupling to form 12
in 79% yield. Similarly, enantioenriched substrates with
enolizable stereocenters are often racemized in the presence
of strong base. Coupling of N-acetyl-L-prolinamide with 4-
bromobenzonitrile gave an excellent yield of the coupling
product 13 with minimal epimerization (92% yield, 94:6 e.r.).31
While this method is currently limited to electron-deficient
organohalides, the broad availability of XantPhos as a ligand,
the mildness of DBU as a base, and the relative challenge of
using amides as nucleophiles in these Pd-catalyzed coupling
reactions make these conditions appealing when viable.
1
1.2
1.2
1.2
1.2
2
Pd2(dba)3 2.5, L= 7.5
DMF
20
2
3
4
5
6
7
8
9
Pd(OAc)2 5, L= 7.5
DMF
25
[Pd(Allyl)Cl]2 2.5, L= 7.5
[Pd(Cinnamyl)Cl]22.5, L= 7.5
[Pd(Cinnamyl)Cl]2 2.5, L= 7.5
[Pd(Cinnamyl)Cl]2 2.5, L= 7.5
[Pd(Cinnamyl)Cl]2 2.5, L= 7.5
[Pd(Cinnamyl)Cl]2 2.5, L= 10
Pd(Cinnamyl)Cl]2 1.5, L= 6
DMF
14
DMF
50
DMF
62
1.2
1.2
2
Dioxane
PhMe
PhMe
PhMe
26
74
88
2
87 (85)c
a Reactions performed on 0.2 mmol scale. b Yield determined
by 1H NMR with 1,3,5-trimethoxy benzene as internal
standard. c Isolated yield.
The best hit for the reaction of organotriflate 6 and aniline 7
was observed with DavePhos as ligand, albeit only in trace
yield (Scheme 3C). Following a similar approach to that
illustrated in Table 1, a brief optimization resulted in
identification of conditions that provided 85% NMR (85%
isolated) yield of 8 (See Table S6 in the SI for more
information).
In addition to the ability to tolerate base-sensitive functional
groups (nitrile, ketone, acidic stereocenter), one of the major
benefits of using DBU as a base is in continuous flow
chemistry. With the development of sophisticated flow
synthesis machines and continuous multistep API
manufacturing as major
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reactions can be performed in flow with use of a typical
1
2
3
4
5
6
7
8
nonpolar solvent (dioxane) and reaction temperature (90 °C).
Similarly, Sonogashira reactions commonly use triethylamine
as a base and generate large quantities of precipitate.
Reactions in flow have been achieved, for example, under high
temperatures using high dilution with a polar solvent or by
design of biphasic conditions.36 Simply using tributylamine as
an ionic liquid-forming base instead enables straightforward
adaptation of batch conditions to flow under reasonable
temperature (90 °C) and concentration (0.25 M) with a non-
polar solvent (THF) (Scheme 5).37
Scheme 4. Selected scope table for the Buchwald-Hartwig
amination in the presence of DBU.a
[Pd(cinnamyl)Cl]2 (1.5 mol%)
R'
O
EWG
EWG
X
+
N
R
XantPhos (6 mol%)
R
NHR'
DBU (2 equiv)
PhMe (0.1 M)
100 °C, 18 h
O
9
(2 eq)
10
11
12
13
14
15
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In conclusion, we have explored the use of DBU as a base on a
range of different Buchwald-Hartwig amination reactions
using relatively inexpensive ligands. High throughput
screening allowed identification of several conditions that
could be rapidly optimized to provide synthetically viable
yields, particularly when using XantPhos as ligand. In addition
to providing an affordable and functional group tolerant set of
conditions, the homogeneity of the reactions and the fact that
the conjugate acid byproduct (DBU•HX) is an ionic liquid
enables smooth translation into continuous flow conditions.
A similar strategy using NBu3 as an ionic liquid-forming base
enables continuous Mizoroki-Heck and Sonogashira
couplings. Given the ubiquity of cross-coupling reactions, we
believe this strategy will help expand the scope and utility of
continuous automation platforms.
O
N
H
N
H
H
N
N
N
O
O
O
NC
O2N
3
9
10
96%
75%
X = Br
X = Cl, 85%
X = Br, 91%
X = I, 70%
X = Cl
H
N
CN
H
N
N
N
O
O
13a
O
O
NC
12
79%
X = Br
11
93%
X = I
O
92%, 94:6 e.r.
X = Br
a
b
Reactions run on 0.2 mmol scale. Isolated yields given.
Reaction run for 2 h.
goals in modern chemistry,3-6 it is important to ensure
Buchwald-Hartwig aminations and related cross-coupling
reactions can be readily implemented in flow without the
hazard of clogging tubular reactors with precipitate.13-15 DBU
is a well behaved liquid and the corresponding conjugate acids
(DBU·HX) are ionic liquids, bearing melting points below 100
°C, making it an appealing alternative to highly basic inorganic
solvents. With this in mind, a selection of the Buchwald-
Hartwig aminations were carried out in a simple flow reactor
using DBU as a base and XantPhos as a ligand. XantPhos Pd
G3 was selected due to its rapid generation of the active
catalytic species, and a mixture of PhMe and MeCN was used
to ensure solubility. An elevated reaction temperature and
increased catalyst loading was required to ensure reactions
reached completion in a reasonable residence time of 1 hour
(Scheme 5). With these modifications,32 a selection of
different organohalides and amide/aniline nucleophiles were
coupled in 78–88% yield in a 1 mL tubular flow reactor with
no precipitate formation, confirming this added benefit of
using DBU as a base in aminations.
ASSOCIATED CONTENT
Supporting
Information:
Experimental
procedures,
characterization of organic molecules, optimization tables.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
stephen.newman@uottawa.ca
ACKNOWLEDGEMENT
Financial support for this work was provided by the University
of Ottawa, the National Science and Engineering Research
Council of Canada (NSERC), the Canada Research Chair
program. The Canadian Foundation for Innovation (CFI) and
the Ontario Ministry of Economic Development and
Innovation are thanked for essential infrastructure. We thank
Apotex Pharma Inc. and the Ontario Centers of Excellence
(OCE) for support via the Voucher of Innovation and
Productivity program. S.K.K thanks Roxanne Clement for
assistance with data generation via high-throughput
experimentation and Ryan J. Sullivan for his help with data
processing.
Lastly, we wished to extend this concept of using ionic
liquid-forming bases in other cross-couplings. Unlike
Buchwald-Hartwig aminations, Mizoroki-Heck reactions are
often performed with triethylamine as a base.33 This results in
the formation of a high melting conjugate acid upon
protonation. Successful examples of continuous flow
Mizoroki-Heck reactions are primarily achieved by, for
example, using dilute conditions,34 and/or high temperatures
with very polar solvents.35 Like DBU, tributylamine forms
ionic liquids upon protonation (mp of NBu3•HCl = 60 °C).
With this simple change, high yielding Mizoroki-Heck
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Scheme 5. Cross couplings in continuous flow using ionic liquid-forming bases.
7
8
Coupling partner
Catalysts
9
Catalyst
Base
R'2N
H
Buchwald-Hartwig
R
X
10
11
12
13
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60
+
R
Base·HX
H
+
H
coupling
partner
Mizoroki-Heck
OMs
P(tBu3
OMs
tres= 30-60 min
Ar
Pd
Pd
N
N
XantPhos
H2
H2
Sonogashira coupling
Ar
H
XantPhos Pd G3
P(t-Bu)3 Pd G3
O
H
N
N
O
O
O2N
NC
19
81%
ArI
18
90%
ArI
15
88%
ArCl
14
85%
ArBr
N
22
83%
ArI
O
H
H
N
N
N
F3C
O
NC
16
81%
ArBr
23
17
78%
ArBr
21
96%
ArBr
O
20
96%
ArI
NC
O
97%
ArI
Buchwald-Hartwig amination conditions: 1 eq of aryl halide, 1 eq of amine, 2 eq of DBU and 5 mol% of the ’’ XantPhos Pd G3’’
using MeCN/PhMe mixture as solvent in a 1 mL stainless-steel flow reactor with 60 min residence time, 140 ˚C. Mizoroki-Heck
coupling: 1 eq of aryl halide, 1.5 eq of olefine, 3 eq of NBu3 and 3 mol% of the “P(t-Bu)3 Pd G3’’ using dioxane as solvent in a 1 mL
PFA flow reactor with 60 min residence time, 90 ˚C. Sonogashira coupling: 1 eq of aryl halide, 1.5 eq of alkyne, 3 eq of NBu3 and
2 mol% of Pd(PPh)3, CuI 2 mol% using THF as solvent in a 1 mL PFA flow reactor with 30 min residence time, 100 ˚C. Isolated
yields.
Campbell, B. M.; Diseroad, W. D.; Heller, M. R.; Howell, J.
R.; Kallman, N. J.; Koenig, T. M.; et al. Kilogram-Scale
Prexasertib Monolactate Monohydrate Synthesis under
Continuous-Flow CGMP Conditions. Science. 2017, 356,
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Internal standard was added for approximating yield by GC-
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Replicating this reaction with KOtBu as base resulted in 0%
yield of 13, instead forming the nucleophilic aromatic
substitution product between the organohalide and the tert-
butoxide nucleophile was observed.
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For praparation of the Pd G3 precatalysts see this paper:
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Organic Process Research & Development
coupling
with DBU?
High throughput search
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Ar
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RNH2
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Batch
Flow
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inexpensive
homogenous
ligands
base
no
clogging
issues
for
applicable
couplings
other
good
functional
group
compatibili
ty
Abstract
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