A Method for Identifying and Developing Functional Group Tolerant Catalytic Reactions: Application to the Buchwald-Hartwig Amination

Article abstract of DOI:10.1021/acs.joc.7b00201

Transition-metal catalysis has revolutionized organic synthesis, but difficulties can often be encountered when applied to highly functionalized molecules, such as pharmaceuticals and their precursors. This results in discovery collections that are enrich

Full text of DOI:10.1021/acs.joc.7b00201

Subscriber access provided by University of Newcastle, Australia
Article
A Method for Identifying and Developing Functional Group Tolerant
Catalytic Reactions: Application to the Buchwald-Hartwig Amination
Jeffery Richardson, J. Craig Ruble, Elizabeth A Love, and Simon Berritt
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00201 • Publication Date (Web): 28 Feb 2017
Downloaded from http://pubs.acs.org on March 3, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 11
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A Method for Identifying and Developing Functional Group Tolerant
Catalytic Reactions: Application to the Buchwald-Hartwig Amina-
tion
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jeffery Richardson1*, J. Craig Ruble2, Elizabeth A. Love3, and Simon Berritt4
1 Discovery Chemistry Research and Technologies, Eli Lilly and Company Limited, Erl Wood Manor, Windlesham,
Surrey, GU20 6PH, United Kingdom.
2 Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana 46285, United
States.
3 Translational Research Office Drug Discovery Group, University College London School of Pharmacy, 29-39
Brunswick Square, London, WC1N 1AX, United Kingdom.
4 Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry, University of Pennsyl-
vania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
ABSTRACT: Transition metal catalysis has revolutionized organic synthesis but difficulties can often be encountered
when applied to highly functionalized molecules, such as pharmaceuticals and their precursors. This results in discovery
collections that are enriched in substances possessing less desirable properties (high lipophilicity, low polar surface area).
Masking groups are often employed to circumvent this problem, which is in opposition to the inherent ideality of these
methods for green chemistry and atom economy. A general screening methodology, related to robustness screening de-
scribed by Glorius et al., builds a broad understanding the impact of individual functional groups on the success of a
transformation under various conditions and provides a simple framework for identifying new conditions that tolerate
challenging functional groups. Application of this approach to profile the conditions for the Buchwald-Hartwig amination
and rapidly identify bespoke conditions for challenging substrate classes is described.
1. Introduction Drug discovery programs frequently
call upon compound libraries to establish structure-
activity relationships, testing hypotheses around binding
affinity and efficacy, in addition to absorption, distribu-
tion, metabolism and excretion properties of potential
drug candidates. The ability to efficiently prepare these
diverse libraries is vital to the success of drug discovery
programs, so robust and reliable methods that tolerate
the presence of diverse functional groups are essential. In
spite of the many “general” reaction conditions that are
described in the literature, the preparation of diverse li-
braries of compounds for determination of structure-
activity relationships best demonstrates some important
challenges for new methodologies, especially in catalysis.
Cernak, Dreher and co-workers at Merck recently dis-
closed an analysis of 2149 metal-catalyzed C-N couplings
performed in the synthesis of highly functionalized drug
leads.1 This revealed that 55% of reactions failed to deliver
any product at all and pointed to the “growing recogni-
tion that the tendency of polar, highly functionalized
compounds to fail in catalysis may actually enrich com-
pound sets in hydrophobic molecules that are less likely
to become successful drug candidates.”2 Similarly, the
increased number of protecting group manipulations that
appears in the pharmaceutical patent literature over the
last 30 years has been attributed to increased use of cata-
lytic methods that frequently do not tolerate drug-like
functional groups without protection.3 This opposes the
goals of green chemistry,4 atom economy5 and protecting
group free manipulations6 that are becoming increasingly
important in modern organic chemistry.
One of the challenges in preparing a library of com-
pounds seeking to explore different dimensions of proper-
ty space is that the chemistry used to prepare each library
member is likely to perform differently. Ideally, for any
given transformation, a single set of reaction conditions
would exist that is effective for all conceivable substrates.
Since the various starting materials are likely to have dif-
ferent properties (reactivity, stability and solubility) and
purities, this is extremely unlikely. Although synthetic
methodology publications typically describe the scope of
a new method and presents several examples of the toler-
ance of certain functional groups, it is often the case that
there is not enough directly comparable data in the litera-
ture to draw conclusions as to which method might work
when applied to a highly functionalized substrate. Indeed,
a key issue with literature mining and reaction databases
is that hits are inherently enriched in older conditions,
leading
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 11
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Model Buchwald-Hartwig amination reaction and overview of approach to identify functional group
tolerant conditions.
to the possible conclusion that newer conditions do not
tolerate certain functional groups due to lack of exempli-
fication. Furthermore, negative results are not always re-
ported. Therefore, a systematic approach is required that
compares the numerous existing conditions for a particu-
lar transformation in order to quickly identify those that
are most appropriate for a new substrate and also to find
and overcome gaps in the existing methodologies.
that are inherently tolerated by each set of conditions. For
those that are not well tolerated, optimization of the
model reaction in the presence of the FGA generates new
conditions that are expected to perform well in substrates
containing those functional groups. This approach quick-
ly generates uniform understanding of the effect of vari-
ous FGAs, and highlights appropriate reaction conditions
for molecules containing the corresponding functional
group. Limiting the initial screen to conditions known to
have a broad scope of reactivity increases the likelihood of
effectiveness when applied to a broad range of substrates.
Glorius and co-workers have developed a “Robustness
Screen”7 designed to assess the scope of a given set of
conditions in an unbiased manner by performing a reac-
tion in the presence of an intermolecular functional group
additive (FGA). To date, this methodology has only been
applied to single reaction conditions i.e. “Will this reac-
tion work for my substrate?” and has not been used as a
comparative tool to facilitate method selection, “Which
conditions will work for my substrate?” To answer this
broader question, a variant of this protocol was conceived
where a large number of known conditions for a trans-
formation could be compared on a model reaction in the
presence of a series of FGAs. The results can thus be ex-
trapolated to substrates containing the various functional
groups, allowing preselection of different conditions for
individual family members in a synthetic library (Fig. 1).
Additionally, for FGAs that are poorly tolerated across all
conditions, it was envisaged that optimization of the
model reaction in the presence of the FGA would allow
rapid development of alternate conditions that overcome
this substrate incompatibility. Therefore, for a given li-
brary, several sets of known conditions could be “tailored”
for certain family members, while bespoke conditions
could be sought in an expedited fashion for those library
members that are deemed problematic from the initial
assessment.
The Buchwald-Hartwig amination reaction exemplifies
this problem well; it is a highly versatile method for the
conversion of aryl and vinyl halides and pseudohalides to
the corresponding amino derivatives and has become a
central tool for the construction of C-N bonds in drug
discovery. In a recent analysis of the medicinal chemistry
literature it was shown around 6% of the reactions used
in the pursuit of drug candidates were amine arylations,
making it the most popular C-N bond forming reaction
after amide formation8 and one of a limited number of
recently developed reaction types that is frequently used
in medicinal chemistry.9 Since the early reports by Buch-
wald10 and Hartwig,11 the scope of this reaction continues
to expand to encompass a wide variety of coupling part-
ners, driven by the development of new ligand classes,12
deeper understanding of reactivity12h and advances in cat-
alyst activation.13 The success of a given amination reac-
tion is dependent on many factors; the properties of the
amine and aryl halide/pseudohalide, catalyst activa-
tion/deactivation, competing side reactions, and poison-
ing from low level impurities are all possible contributors
to reaction performance.12h To overcome these hurdles,
the nature of the catalyst, solvent and base can be ad-
dressed, as well as concentration and reaction tempera-
ture. In spite of numerous significant advances, it remains
Screening several known reaction conditions against a
panel of FGAs develops a picture of the functional groups
ACS Paragon Plus Environment

Page 3 of 11
The Journal of Organic Chemistry
Reaction condition A
47 additives + 1 control
48 reactions
69 general
conditions
assessed
1
2
O
O
N
Br
3
4
5
6
+
Reaction condition B
47 additives + 1 control
48 reactions
N
H
3
96-well plate
1
2
Average yield for
control reaction = 59%
(Std Dev = 35%)
3312 reactions
7
8
9
N
N
Cl
Competitive N-H
Ph NH2
O
O
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
(29%)
(49%)
(55%)
(57%)
O
S
NH2
Ph
NH2
(15%)
(16%)
(18%)
O
O
H
N
Ph
N
Ph
Ph
O
NH2
(30%)
N
(50%)
(55%)
O
H
(26%)
(15%)
N
(15%)
S
OH
O
Ph
NH2
H
NH
(6%)
(34%)
SH
(27%)
(63%)
N
H
N
H
O
O
(11%)
(6%)
(33%)
Ph Cl
(61%)
Ph OH
(35%)
O
N
N
N
N
NH
(21%)
(6%)
N
N
H
H
O
O
O
(7%)
(9%)
(13%)
S
S
S
Heterocycles/Competitive N-H
(60%)
(47%)
(25%)
Functional Groups
O
N
S
N
N
N
Cl
O
(59%)
N
N
(32%)
(9%)
nBu
(40%)
(50%)
(12%)
Bn
N
N
N
N
N
N
O
S
N
N
nBu
Cl
S
N
(42%)
(26%)
(56%)
(58%)
(51%)
(39%)
(39%)
O
O
HO
N+
O-
O
N
(50%)
(46%)
(34%)
(15%)
Heterocycles
Figure 2. Generalized high throughput screening (HTS) protocol and summary of FGAs employed. Additives em-
ployed in HTS of model Buchwald-Hartwig amination reaction. Numbers in parentheses are the mean yield of 3 in the
various amination conditions tested in the presence of that FGA (see Supporting Information Tables S2-S70) determined
by UPLC analysis against internal standard. All reactions were performed for the length of time described in the original
publication.
difficult to rationally preselect conditions for application
to highly functionalized substrates. A recent study of the
patent literature linked the increased use of protecting
groups to the rise in application of catalytic methods, and
also revealed that the Buchwald-Hartwig amination of
both aryl bromides and chlorides were 2 of the 10 worst
performing reactions in terms of median yield.3
representing commonly occurring functional groups and
heterocycles, in a high throughput screening format (Fig.
2). Across all conditions the mean yield (determined by
UPLC analysis vs internal standard) for the model reac-
tion in the absence of any FGA was 59.6%, which reflects
that some conditions selected were not optimized for the
chosen model reaction. A number of additive classes did
not adversely affect the model reaction with average
yields close to that of the control. Bioactive molecules and
pharmaceuticals invariably contain hydrogen bond do-
nors and acceptors especially N-H groups, with 17 of the
top 25 best-selling small molecule drugs from 2013 con-
2. Results and Discussion. To combat this problem, a
study was designed to assess a number of general condi-
tions for the Buchwald-Hartwig amination reaction (Sup-
porting Information Table S1) against a matrix of 47 FGAs,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 11
taining this moiety.14 Interestingly, of the 15 worst per-
S68) and N-phenylacetamide was far more inhibitory
1
2
3
4
5
6
7
8
forming FGAs in this model reaction, 11 contain the N-H
moiety (average yield for the bottom 15 = 11.5%). Histo-
gram plots (Supporting Information Figures S3-S97) fur-
ther demonstrate the tendency for these FGAs to be clus-
tered at the lowest end of the yield range, but also facili-
tate the identification of conditions that are outliers and
could represent good starting points for further optimiza-
tion.
than N-methyl-N-phenylacetamide (Supporting Infor-
mation Fig. S46 versus S10). In neither case could the de-
gree of inhibition be fully explained by simple consump-
tion of the N-H containing additive (Supporting Infor-
mation Figs S53 and S47).
The approach described in Fig. 1 was therefore applied
to develop reaction conditions that would tolerate these
functional groups. Benzenesulfonamide was selected for
further study (Scheme 1) given that N-H sulfonamide
groups were particularly underrepresented in the litera-
ture, with only a single example15 of the group being pre-
sent as a non-reacting spectator in the various methodol-
ogy papers from which our screening conditions were
chosen (Supporting Information Table S72). The first iter-
ation was to verify the small number of conditions that
showed promise from the HTS. While the initial HTS data
were obtained as single points with no repetition and on a
small scale, the screening data translated well when re-
peated in a non-HTS setting. A few examples of reactions
where the product was formed but the sulfonamide was
degraded were also analyzed (see Supporting Information
Table S71) to add certainty to this validation.16
9
The mechanism by which different classes of FGA pre-
vent the desired reaction can be understood to some ex-
tent. Many additives prevent the desired reaction without
forming any discernible byproducts, suggesting that cata-
lyst poisoning or inhibition of active catalyst formation is
occurring. In contrast certain FGAs create strongly com-
peting side reactions. Several products of potential side
reactions were prepared as analytical standards to allow
the quantitative assessment of these competing processes
(Supporting Information Figure S2). Focusing on those
FGAs that led to the lowest average yields, we confirmed
that thiophenol, indole, indoline, aniline and 2-
phenylethanamine were all readily arylated under numer-
ous reaction conditions (see Supporting Information Ta-
bles S2-S70). Conversely, carbazole, a byproduct of the
reductive elimination in 2nd and 3rd generation Buchwald
palladacycles,13d, 13f was rarely arylated but still had a sig-
nificant detrimental effect on the yield of the model reac-
tion (Supporting Information Figure S56). This is con-
sistent with recent observations in amination reactions13g
and potentially explains the relatively poor results ob-
tained when using a 3rd generation palladacycle (Support-
ing Information Table S57).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To apply this screening data to the selection of Buch-
wald-Hartwig amination conditions for highly functional-
ized substrates, conditions could be chosen where the
yield of the model reaction is high, the additive is uncon-
sumed and the literature suggests that the coupling part-
ners are sterically and electronically compatible. This ap-
proach can be used to systematically evaluate the effect of
a given functional group on the coupling across a wide
range of conditions, but substrate specific influences such
as changes in solubility, metal chelation, steric or elec-
tronic effects caused by other groups or by the functional
group itself should also be considered when selecting
conditions for application to novel targets.7a
Figure 3. Ligands and Pd complexes that were de-
fined as hits in HTS of sulfonamide, indole and am-
ide FGAs. Ad= 1-adamantyl.
Several conditions performed well, with the AdBip-
pyphos and PEPPSI-IPent (Fig. 3) conditions described by
Hartwig17 and Organ18 respectively giving outstanding
conversion to desired target with little degradation of the
benzenesulfonamide additive. During the hit verification
reactions with PEPPSI-IPent (9), it was noticed that those
using 1,2-dimethoxyethane (DME) as solvent were some-
what capricious, giving variable conversions for all reac-
tions when repeated. Upon switching from DME to 1,4-
dioxane, these reactions became very efficient and repro-
ducible (Supporting Information Table S71). For the se-
cond iteration, the model reaction was optimized in the
presence of the FGA. Even though seemingly adequate
conditions had been identified in the first iteration, the
second iteration allows optimization in other dimensions,
for example selecting a base that might be more tolerant
of other functional groups that could be present in
2.1 Using the data to generate functional group tol-
erant conditions. Across the broad spectrum of condi-
tions studied, several FGAs caused significant inhibition
of the model reaction and certain FGAs afforded no suita-
ble hits whatsoever. The significant negative impact of
benzenesulfonamide, benzamide and indole (Supporting
Information Figures S26, S44 and S52) on the perfor-
mance of the majority of catalyst systems was striking,
particularly given the frequency with which these sub-
structures are encountered in medicinal chemistry efforts.
There were also stark differences between certain N-H
containing additives and their N-methylated derivatives.
Specifically, indole was far more inhibitory than N-
methylindole (Supporting Information Fig. S52 versus
ACS Paragon Plus Environment

Page 5 of 11
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Scheme 1. Optimization of model reaction in presence of benzenesulfonamide. Condition set a: Pd2(dba)3 (10
mol%), 4 (15 mol%), NaOtBu (1.4 eq), PhMe, 110 °C. Condition set b: [(cinnamyl)PdCl]2 (1.2 mol%), 5 (10 mol%), NaOtBu
(1.5 eq), TPGS-750-M (2% in H2O), 65 °C. Condition set c: [(allyl)PdCl]2 (1.5 mol%), 6 (6 mol%), base, Dioxane, 100 °C.
Condition set d: 7 (3 mol%), 8 (3 mol%), NaOtBu (1.5 eq), Dioxane, 110 °C. Condition set e: 9 (3 mol%), base, solvent, 80
°C.
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Optimization of model reaction in presence of indole. Condition set a: Pd2(dba)3 (10 mol%), 4 (15
mol%), NaOtBu (1.4 eq), PhMe, 110 °C. c: [(allyl)PdCl]2 (1.5 mol%), 6 (6 mol%), base, Dioxane, 100 °C. Condition set e: 9 (3
mol%), base, solvent, 80 °C. a) N-Arylation to form 10 competes.
potential library members. In instances where the first
screening hits are less successful, this second iteration is
invaluable for arriving at suitable conditions. The condi-
tions employing AdBippyphos and PEPPSI-IPent (condi-
tion sets c & e) were selected for further study, since these
conditions overlapped with successful conditions for the
other FGAs under consideration here. A simple screen of
commonly used bases for these coupling reactions12h
showed that, for both catalyst systems, cesium carbonate,
potassium tert-butoxide and lithium hexamethyldisilazide
were highly effective bases for the model reaction with
little degradation of the benzenesulfonamide additive.
reaction is the competing side product formation. Condi-
tions were selected from the HTS data where the side N-
arylation to form 10, was minimized. Notably, the AdBip-
pyphos and PEPPSI-IPent conditions (condition sets c
and e) from the previous screen were also high quality
starting points for indole. Further screening of bases in
the second iteration showed that the AdBippyphos condi-
tions favored the coupling of morpholine, but that cou-
pling of indole was a significant side reaction. Interesting-
ly, with a variety of bases PEPPSI-IPent did not afford
indole arylation to an appreciable extent.
A truncated set of conditions was assessed in an identi-
cal manner for N-phenylacetamide as the FGA. Condi-
tions that had previously tolerated benzenesulfonamide
and indole were selected preferentially and further study
Similarly, optimization was performed with indole as
the FGA (Scheme 2). One of the key differences between
the sulfonamide and indole as an additive in this model
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Optimization of model reaction in presence of N-phenylacetamide. Condition set a: Pd2(dba)3 (10
mol%), 4 (15 mol%), NaOtBu (1.4 eq), PhMe, 110 °C. Condition set c: [(allyl)PdCl]2 (1.5 mol%), 6 (6 mol%), base, Dioxane,
100 °C. Condition set Condition set e: 9 (3 mol%), base, solvent, 80 °C. a) From HTS data without repeat.
of bases identified several conditions where the additive
was tolerated and not significantly consumed (Scheme 3).
When applying these data to the selection of conditions
for use with medicinally interesting substrates, conditions
could either be individually selected for each FGA class or
a single set of conditions that was effective for all, alt-
hough perhaps not optimal for any, could be chosen. Fol-
lowing the latter of these paths, PEPPSI-IPent (9) was
selected to prepare a small library of products from cou-
pling partners containing sulfonamides, indoles and am-
ides (Fig. 4). The catalyst was paired with lithium hexa-
methyldisilazide, which is precedented to show some NH
tolerance19 in such couplings. Note that any of the suc-
cessful hits using different catalysts, bases and solvents
could similarly have been selected (Supporting Infor-
mation Table S71).
is not predicted. For example, the low yield of 15 (relative
to 11 containing the same functional group) may be due to
the formation of a stable palladacycle intermediate that
prevents catalyst turnover. Despite this, knowledge of the
conditions that tolerate a particular functional group pro-
vides excellent starting points for focused design of fol-
low-up experiments and more rapid development of con-
ditions that might overcome such challenges.
3. Conclusion
A simple and systematic approach for identifying and
optimizing reaction conditions with high functional
group tolerance is described. The application to the me-
dicinally important Buchwald-Hartwig amination demon-
strates the potential of this approach for tailoring condi-
tions to provide libraries containing desirable functional
groups without the need for protecting groups. By apply-
ing such tailored conditions an improvement in the reac-
tion success rate can be expected with concomitant im-
provements in the amount of chemical space explored.
Reducing the number of missed opportunities will result
in diverse libraries that contain molecules with more suit-
able physicochemical properties and thus a higher proba-
bility of finding drug leads or candidates.
Across a wide variety of sulfonamide, indole and amide
containing aryl bromides very good yields of desired
product were obtained in most instances and 17 of the 18
members gave useful quantities of the target compounds.
This is particularly impressive given that this library is
composed entirely of substrates bearing challenging func-
tional groups. Although optimized with a secondary alkyl
amine, primary amines and aniline derivatives were also
coupled effectively under these conditions. The coupling
of morpholine with 4-bromobenzenesulfonamide to af-
ford 11 and the coupling of N-(2-bromophenyl)acetamide
to afford 24 both delivered product under the standard
conditions, but were hindered by limited solubility of the
starting material in the reaction solvent. Performing these
reactions in dioxane at higher temperature and with al-
ternate bases resulted in substantially improved yield.
Using the first pass conditions, all compounds were
formed in sufficient yield to be considered as successful in
a parallel synthesis setting with the exception of 17. This
high success rate is in stark contrast to the 55% failure
rate described for Buchwald-Hartwig couplings of func-
tionalized substrates by the Merck group.1
This approach is equally applicable to other catalytic
and non-catalytic processes and will readily generate large
data sets, enabling chemists to select conditions prior to
experimentation, thus accessing compound libraries with
the properties required for biomedical research, rather
than those dictated by the method of synthesis. The data
can also be used to identify trends and new opportunities
to improve these methods in a manner that does not re-
quire attempted application in the rarified circumstances
of synthesizing a specific target.
Applying this approach to other commonly used and
high value transformations could have a significant im-
pact on library synthesis by allowing the identification
and development of bespoke conditions for challenging
substrates in an efficient manner prior to working with
the actual library members. Those functional groups that
cannot be improved by varying the reaction parameters
One limitation of this method is that the impact of the
proximity of the functional groups to the reacting centers
ACS Paragon Plus Environment

Page 7 of 11
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Figure 4. Application of optimized reaction conditions to functional group containing substrates. Isolated yields,
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
average of 2 runs. a) HPLC yield vs internal std. b) Cs2CO3 (2 equiv.), dioxane, 100 °C. c) KOtBu (2 equiv.), dioxane, 100 °C.
d)
reaction
performed
at
room
temperature.
e)
Reaction
performed
at
30
°C.
provide a foundation for future innovation in catalyst
design, as chemists continue to deliver syntheses that are
efficient, environmentally benign (protecting group free)
and robust (i.e. tolerant of process impurities).
screws. Reactions were monitored using a Waters Acquity
UPLC-MS. Column: Acquity UPLC HSS C18 1.7 um 2.1 x 50
mm (Part # 186002350), pH 3.5 Stock Solution: 12.6 g am-
monium formate + 7.9 mL formic acid to 1 L water; Mo-
bile Phase A: 1% pH 3.5 stock solution in H2O, Mobile
Phase B: 1% pH 3.5 stock solution in water (100 mL) +
acetonitrile (900 mL); Strong Wash: acetonitrile (1700 mL),
water (200 mL), 2-propanol (100 mL); Weak Wash: acetoni-
trile (200 mL) + water (1800 mL). The instrument was
equipped with an SQD detector with electrospray ionization
(ESCi) source in positive and negative mode. High through-
put data analysis was carried out with Virscidian Analytical
Studio™ software. Flash column chromatography was carried
out using silica gel columns with a Teledyne ISCO Com-
EXPERIMENTAL SECTION
General Methods.
All reagents purchased from commercial suppliers and used
as received. Solvents were purchased from Aldrich, anhy-
drous, sure-seal quality, and used with no further purifica-
tion. The ligands and bases were purchased from commercial
sources and stored in the glovebox. All HTS reactions were
performed inside a Vacuum Atmospheres (VAC) glovebox
operating with a N2-atmosphere (oxygen typically < 5 ppm).
All other experiments were performed in a conventional
fume cupboard. Reaction experimental design was aided by
the use of Accelrys Library Studio. 20 μmol scale reactions
for the limiting reagent were carried out in 1 mL glass vials
(Freeslate, Cat. No. S11500, 8 x 30 mm, 1mL, flat bottom)
equipped with magnetic tumble stir bars (V&P Scientific,
Cat. No. 7111D-1) in 96-well reaction plates (Analytical Sales,
Cat. No. 96960) or 24-well reaction plates (Analytical-Sales,
Cat. No. 24249). Liquid handling was done using single and
multi-channel Eppendorf pipettors (10, 100, 200, and 1000
μL). On completion of solution dosing the plates were cov-
ered by a perfluoroalkoxy alkane (PFA) mat (Analytical-Sales,
Cat. No. 96967 and 24261), followed by two silicon rubber
mats (Analytical-Sales, Cat. No. 96965 and 24262), and an
aluminum cover which was tightly and evenly sealed by 9
1
biFlash Companion system. H and 13C NMR spectra were
recorded on a Bruker AV-HD 400 spectrometer. Signal posi-
tions were recorded in δ ppm with the abbreviations s, d, t, q,
dd, dt and m denoting singlet, doublet, triplet, quartet, dou-
blet of doublets, doublet of triplets and multiplet respective-
ly. All 1H NMR chemical shifts were referenced to SiMe4 as an
13
internal standard (0.00 ppm). All C NMR chemical shifts in
CDCl3 were referenced to the residual solvent peak at 77.00
ppm. All 13C NMR chemical shifts in (CD3)2SO were refer-
enced to the residual solvent peak at 39.52 ppm. All coupling
constants, J, are quoted in Hz. Infra-red spectra were record-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
ed on a Nexus FT-IR spectrometer with Nicolet OMNI sam-
N-(4-Morpholinophenyl)methanesulfonamide (13). A 20 mL
1
2
3
4
5
6
7
8
pler using a neat sample. Melting points were obtained using
a DSC 1 STARe system and high resolution mass spectrome-
try (HRMS) data were recorded under electrospray ionisation
conditions. High performance liquid chromatography
(HPLC) purification was achieved using Gilson 333/334
pumps, a Gilson 155 dual wavelength detector and a Gilson
215 autosampler with 819-injection module, where fractiona-
tion was triggered by slope of UV response.
Microwave experiments were carried out using sealed vessels
in a Biotage Initiator Sixty microwave reactor operating at
2.45 GHz with stirring at 600 rpm and variable power output
(0-400 W), sensing temperature with an IR sensor to meas-
ure the temperature of the external surface of the glass vial.
Pressure was recorded by the cavity lid, which resisted the
deformation of the vial cap as pressure increased. Reactions
reached their target temperature within 1 minute and cooled
back to room temperature within 3 minutes upon comple-
tion.
microwave vial equipped with a stirrer bar was charged with
N-(4-bromophenyl)methanesulfonamide (400 mg, 1.58
mmol) and Pd-PEPPSI-IPent (39 mg, 3 mol%). The vial was
sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS
(1 M in THF, 5.5 mL, 5.5 mmol) and morpholine (200 µl, 2.29
mmol) were then added via a syringe and the vial purged
with a further 2x vacuum/nitrogen cycles. The mixture was
then stirred at 30 °C for 66 h. After adsorbing the reaction
mixture onto silica, purification by column chromatography
(gradient elution 0-10% MeOH in DCM) yielded the desired
product 13 as a yellow solid (Run 1 = 399 mg, 99% yield; Run
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2 = 398 mg, 99%). m.p. 184 – 188 °C; H NMR (400 MHz,
DMSO): 9.25 (s, 1H), 7.11-7.08 (m, 2H), 6.94-6.91 (m, 2H),
3.73-3.71 (m, 4H), 3.06-3.04 (m, 4H), 2.86 (s, 3H). 13C NMR
(100 MHz, MeOD): 149.4, 130.0, 123.4, 116.3, 66.5, 49.5, 37.3. IR
(neat, cm-1): 3227, 2970, 2819, 2361, 1738, 1512. HRMS (ESI)
m/z: [M+] calcd for C11H16N2O3S 256.0882 found 256.0884.
N,N-Dimethyl-2-morpholino-benzenesulfonamide (14). A 20
mL microwave vial equipped with a stirrer bar was charged
with 2-bromo-N,N-dimethylbenzenesulfonamide (500 mg,
1.86 mmol) and Pd-PEPPSI-IPent (46 mg, 3 mol%). The vial
was sealed and purged with 3 x vacuum/nitrogen cycles.
LiHMDS (1 M in THF, 6.5 mL, 6.5 mmol) and morpholine
(230 µl, 2.64 mmol) were then added via a syringe and the
vial purged with a further 2x vacuum/nitrogen cycles. The
vial was placed in a pre-heated aluminium block at 60 °C and
stirred at this temperature for 6 h. After cooling to room
temperature, the reaction mixture was adsorbed onto silica
gel and purified by column chromatography (gradient elu-
tion 0-50% EtOAc in heptane) to afford the desired product
14 as a yellow solid (Run 1 = 397 mg, 79% yield; Run 2 = 393
Synthesis of compounds prepared in Figure 4.
4-Morpholinobenzenesulfonamide (11). A 20 mL microwave
vial equipped with a stirrer bar was charged with 4-
bromobenzenesulfonamide (500 mg, 2.05 mmol), Pd-
PEPPSI-IPent (51 mg, 3 mol%) and cesium carbonate (1.34 g,
4.11 mmol). The vial was sealed and purged with 3x vacu-
um/nitrogen cycles. 1,4-dioxane (4 mL) and morpholine (250
µl, 2.87 mmol) were then added via a syringe and the vial
purged with a further 2x vacuum/nitrogen cycles. The vial
was placed in a pre-heated aluminium block at 100 °C and
stirred at this temperature for 24 h. After cooling to room
temperature, the reaction mixture was diluted with EtOAc
and filtered through a plug of silica. The silica plug was
rinsed with EtOAc, the organic filtrates combined and con-
centrated in vacuo. Purification by column chromatography
(gradient elution 0-90% EtOAc in Heptane) yielded the de-
sired product 11 as a yellowish white solid (Run 1 = 402 mg,
1
mg, 78%). m.p. 113 – 115 °C; H NMR (400 MHz, DMSO): 7.82
(dd, J= 1.6, 8.0 Hz, 1H), 7.68-7.64 (m, 1H), 7.53 (dd, J= 1.0, 8.0
Hz, 1H), 7.36-7.32 (m, 1H), 3.73-3.71 (m, 4H), 2.96-2.93 (m,
4H), 2.70 (s, 6H). 13C NMR (100 MHz, CDCl3): 152.5, 133.8,
132.9, 132.2, 124.8, 123.1, 67.0, 54.4, 38.2. IR (neat, cm-1): 3072,
2860, 1732, 1585. HRMS (ESI) m/z: [M+] calcd for C12H18N2O3S
270.1038 found 270.1038.
1
81% yield; Run 2 = 394 mg, 79%). m.p. 213 – 216 °C; H NMR
(400 MHz, DMSO): 7.63 (d, J= 9.0 Hz, 2H), 7.06-7.02 (m,
4H), 3.75-3.72 (m, 4H), 3.24-3.21 (m, 4H). 13C NMR (100 MHz,
DMSO): 153.5, 133.8, 127.5, 114.0, 66.3, 47.7. IR (neat, cm-1):
3186, 2962, 2862, 1593. HRMS (ESI) m/z: [M+] calcd for
C10H14N2O3S 242.0725 found 242.0731.
N-(2-Morpholinophenyl)methanesulfonamide (16). A 20 mL
microwave vial equipped with a stirrer bar was charged with
N-(2-bromophenyl)methanesulfonamide (611 mg, 2.52 mmol)
and Pd-PEPPSI-IPent (61 mg, 3 mol%). The vial was sealed
and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in
THF, 8.5 mL, 8.5 mmol) and morpholine (300 µl, 3.79 mmol)
were then added via a syringe and the vial purged with a
further 2x vacuum/nitrogen cycles. The vial was placed in a
pre-heated aluminium block at 60 °C and stirred at this tem-
perature for 24 h. After cooling to room temperature, the
mixture was treated with 2N HCl (8 mL) and stirred for 5
min, then neutralized with sat. aq. sodium bicarbonate (15
mL) and diluted with 2-MeTHF (50 mL). The layers were
separated and the organic layer evaporated to dryness. The
residue was dissolved in MeOH and purified on an SCX-2
column, eluting first with MeOH (5 column volumes) then
3.5N NH3 in MeOH (5 column volumes). The basic fraction
was evaporated to dryness. Purified by preparative HPLC
(Phenomenex Gemini 5 Micron 30*100mm C-18 column, 30%
to 100% MeCN in ammonium hydroxide solution, over 9
minutes at 60 mL/min, detection at 220 nm) to afford the
desired product 20 as a yellow oil (Run 1 = 127 mg, 20 % yield;
Run 2 = 146 mg, 21%). 1H NMR (400 MHz, CDCl3): 7.23 (t, J =
8.0 Hz, 1H), 6.81 (dd, J = 1.8, 2.1 Hz, 1H), 6.72 (dd, J = 2.1, 8.5,
N-Methyl-2-morpholino-benzenesulfonamide (12). A 20 mL
microwave vial equipped with a stirrer bar was charged with
2-bromo-N-methylbenzenesulfonamide (500 mg, 1.96 mmol)
and Pd-PEPPSI-IPent (50 mg, 3 mol%). The vial was sealed
and purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in
THF, 7 mL, 7 mmol) and morpholine (240 µl, 2.75 mmol)
were then added via a syringe and the vial purged with a
further 2 x vacuum/nitrogen cycles. The vial was placed in a
pre-heated aluminium block at 60 °C and stirred at this tem-
perature for 18 h. After cooling to room temperature, the
reaction mixture was adsorbed onto silica and purified by
column chromatography (gradient elution 0-5% methanol in
DCM), yielding the desired product 12 as a white solid (Run 1
= 480 mg, 96% yield; Run 2 = 438 mg, 87%). m.p. 174 – 177
1
°C; H NMR (400 MHz, CDCl3): 8.03 (dd, J= 1.6, 7.8 Hz, 1H),
7.61 (td, J= 7.8, 1.6 Hz, 1H), 7.42 (dd, J= 1.0, 8.0 Hz, 1H), 7.35
(td, J= 7.6, 1.0 Hz, 1H), 5.86 (d, J= 5.1 Hz, 1H), 3.88 (d, J= 3.9
Hz, 4H), 3.07-3.05 (m, 4H), 2.52 (d, J= 5.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3): 150.3, 134.4, 134.0, 130.7, 126.0, 123.4, 67.7,
54.2, 29.8. IR (neat, cm-1): 3337, 3097, 2964, 1587. HRMS (ESI)
m/z: [M+] calcd for C11H16N2O3S 256.0882 found 256.0887.
ACS Paragon Plus Environment

Page 9 of 11
The Journal of Organic Chemistry
1H), 6.67 (dd, J = 1.8, 8.0, 1H), 3.88-3.83 (m, 4H), 3.19-3.15 (m,
1H), 7.23-7.17 (m, 3H), 7.04 (dd, J= 2.0, 8.6 Hz, 1H), 6.77-6.71
4H), 3.00 (s, 3H). 13C NMR (100 MHz, CDCl3): 152.4, 137.4,
130.3, 112.3, 111.7. 107.7, 66.8, 48.8, 39.2. IR (neat, cm-1): 1603,
1585, 1502, 1475, 1450, 1325, 1267, 1147, 1117, 987, 771. ES/MS:
m/z 257.0 (M+H).
(m, 3H), 6.52-6.51 (m, 1H), 3.33 (s, 3H). 13C NMR (100 MHz,
CDCl3): 150.4, 142.0, 133.5, 128.8, 124.9, 121.5, 118.0, 117.4, 114.7,
111.9, 111.9, 102.8, 40.9. IR (neat, cm-1): 3404, 2870, 1738, 1595.
HRMS (ESI) m/z: [M+] calcd for C15H14N2 222.1157 found
222.1160.
1
2
3
4
5
6
7
8
9
N-Benzyl-1H-indol-5-amine (18). A 20 mL microwave vial
equipped with a stirrer bar was charged with 5-bromoindole
(500 mg, 2.52 mmol) and Pd-PEPPSI-IPent (63 mg, 3 mol%).
The vial was sealed and purged with 3x vacuum/nitrogen
cycles. LiHMDS (1 M in THF, 8.8 mL, 8.8 mmol) and benzyl-
amine (308 µl, 2.80 mmol) were then added via a syringe and
the vial purged with a further 2x vacuum/nitrogen cycles.
The vial was placed in a pre-heated aluminium block at 60 °C
and stirred at this temperature for 42 h. After cooling to
room temperature, the reaction mixture was adsorbed onto
silica and purified by column chromatography (gradient elu-
tion 0-40% EtOAc in heptane), yielding the desired product
18 as a green solid (Run 1 = 543 mg, 97 % yield; Run 2 = 535
mg, 95%). m.p. 102 – 106 °C; 1H NMR (400 MHz, CDCl3): 7.90
(s, 1H), 7.42 (d, J= 7.4 Hz, 2H), 7.35-7.32 (m, 2H), 7.28-7.24
(m, 1H), 7.19 (d, J= 8.6 Hz, 1H), 7.09 (t, J= 2.8 Hz, 1H), 6.87 (d,
J= 2.3 Hz, 1H), 6.65 (dd, J= 2.2, 8.7 Hz, 1H), 6.38-6.37 (m, 1H),
4.36 (s, 2H), 3.81 (s, 1H). 13C NMR (100 MHz, CDCl3): 142.4,
140.1, 130.6, 128.8, 128.6, 127.7, 127.1, 124.4, 112.1, 111.6, 102.3,
101.9, 49.7. IR (neat, cm-1): 3360, 3147, 2839, 1687, 1618, 1584.
HRMS (ESI) m/z: [M+] calcd for C15H14N2 222.1157 found
222.1163.
4-(1H-Indol-7-yl)morpholine (21). A 20 mL microwave vial
equipped with a stirrer bar was charged with 7-bromoindole
(500 mg, 2.52 mmol) and Pd-PEPPSI-IPent (63 mg, 3 mol%).
The vial was sealed and purged with 3x vacuum/nitrogen
cycles. LiHMDS (1 M in THF, 8.8 mL, 8.8 mmol) and mor-
pholine (308 µl, 3.53 mmol) were then added via a syringe
and the vial purged with a further 2x vacuum/nitrogen cy-
cles. The reaction was stirred at room temperature for 18 h.
After adsorbing the reaction mixture onto silica, purification
by column chromatography (gradient elution 0-30% EtOAc
in heptane) yielded the desired product 21 as a yellow solid
(Run 1 = 502 mg, 98% yield; Run 2 = 489 mg, 96%). m.p. 143 –
145 °C; 1H NMR (400 MHz, CDCl3): 8.25 (br s, 1H), 7.40 (d, J=
7.8 Hz, 1H), 7.20-7.19 (m, 1H), 7.08 (t, J= 7.7 Hz, 1H), 6.86 (d,
J= 7.0 Hz, 1H), 6.56 (dd, J= 2.1, 3.1 Hz, 1H), 3.94-3.92 (m, 4H),
3.13-3.10 (m, 4H). 13C NMR (100 MHz, CDCl3): 137.9, 130.6,
129.0, 123.7, 120.4, 116.5, 110.8, 103.5, 67.5, 52.1. IR (neat, cm-1):
3319, 2959, 2816, 2360, 1726, 1581. HRMS (ESI) m/z: [M+] calcd
for C12H14N2O 202.1106 found 202.1111.
2-Phenyl-1,3,4,9-tetrahydropyrido[3,4-b]indole (22). A 20 mL
microwave vial equipped with a stirrer bar was charged with
2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (500 mg, 2.84
mmol) and Pd-PEPPSI-IPent (71 mg, 3 mol%). The vial was
sealed and purged with 3x vacuum/nitrogen cycles. LiHMDS
(1 M in THF, 10 mL, 10 mmol) and bromobenzene (303 µL,
2.85 mmol) were then added via a syringe and the vial
purged with a further 2x vacuum/nitrogen cycles. The vial
was placed in a pre-heated aluminium block at 60 °C and
stirred at this temperature for 17 h. After cooling to room
temperature, the reaction mixture was adsorbed onto silica
gel and purified by column chromatography (gradient elu-
tion 0-50% EtOAc in heptane), yielding the desired product
22 as a yellow solid (Run 1 = 663 mg, 94% yield; Run 2 = 638
mg, 90%). m.p. 179 – 182 °C; 1H NMR (400 MHz, CDCl3): 7.78
(s, 1H), 7.50 (d, J= 7.8 Hz, 1H), 7.32-7.25 (m, 3H), 7.17-7.09 (m,
2H), 7.03-7.01 (m, 2H), 6.86 (t, J= 7.3 Hz, 1H), 4.41 (s, 2H),
3.69-3.66 (m, 2H), 2.93-2.90 (m, 2H). 13C NMR (100 MHz,
CDCl3): 150.8, 136.1, 131.4, 129.2, 127.2, 121.6, 119.6, 119.4, 118.1,
116.2, 110.8, 109.3, 48.0, 46.6, 21.4. This data matched previ-
ously reported data.20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-(1H-Indol-5-yl)morpholine (19). A 20 mL microwave vial
equipped with a stirrer bar was charged with 5-bromoindole
(500 mg, 2.52 mmol) and Pd-PEPPSI-IPent (63 mg, 3 mol%).
The vial was sealed and purged with 3x vacuum/nitrogen
cycles. LiHMDS (1 M in THF, 8.8 mL, 8.8 mmol) and mor-
pholine (308 µl, 3.53 mmol) were then added via a syringe
and the vial purged with a further 2x vacuum/nitrogen cy-
cles. The reaction was stirred at room temperature for 72 h.
After adsorbing the reaction mixture onto silica, purification
by column chromatography (gradient elution 0-50% EtOAc
in heptane) yielded the desired product 19 as a brick-red
solid (Run 1 = 479 mg, 89% yield; Run 2 = 443 mg, 82%).
1
m.p. 132 – 135 °C; H NMR (400 MHz, CDCl3): 8.09 (s, 1H),
7.30-7.24 (m, 1H), 7.16-7.14 (m, 2H), 6.95 (dd, J= 2.3, 8.8 Hz,
1H), 6.47-6.46 (m, 1H), 3.91-3.89 (m, 4H), 3.14-3.12 (m, 4H).
13C NMR (100 MHz, CDCl3): 145.9, 131.5, 128.4, 124.7, 115.3, 111.6,
107.5, 102.4, 67.3, 52.0. This data matched previously reported
data.19b
N-Methyl-N-phenyl-1H-indol-5-amine (20). A 20 mL micro-
wave vial equipped with a stirrer bar was charged with 5-
bromoindole (500 mg, 2.52 mmol) and Pd-PEPPSI-IPent (63
mg, 3 mol%). The vial was sealed and purged with 3x vacu-
um/nitrogen cycles. LiHMDS (1 M in THF, 8.8 mL, 8.8 mmol)
and N-methylaniline (670 µl, 6.12 mmol) were then added via
a syringe and the vial purged with a further 2x vacu-
um/nitrogen cycles. The vial was placed in a pre-heated al-
uminium block at 60 °C and stirred at this temperature for 24
h. After cooling to room temperature, the solvent was re-
moved in vacuo and the reaction mixture dissolved in
MeOH. A 10 g SCX-2 column was used to remove any of the
5-bromoindole starting material. The crude product was then
adsorbed onto silica and purified by column chromatography
(gradient elution 0-40% EtOAc in heptane), yielding the
desired product 20 as a yellow oil (Run 1 = 337 mg, 60 %
N-(4-Morpholinophenyl)acetamide (23). A 20 mL microwave
vial equipped with a stirrer bar was charged with 4-
bromoacetanilide (500 mg, 2.29 mmol) and Pd-PEPPSI-IPent
(57 mg, 3 mol%). The vial was sealed and purged with 3x
vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8 mL, 8.0
mmol) and morpholine (280 µl, 3.21 mmol) were then added
via a syringe and the vial purged with a further 2x vacu-
um/nitrogen cycles. The vial was placed in a pre-heated al-
uminium block at 60 °C and stirred at this temperature for 16
h. After cooling to room temperature, the reaction mixture
was adsorbed onto silica and purified by column chromatog-
raphy (gradient elution 0-100% EtOAc in Heptane), yielding
the desired product 23 as a white solid (Run 1 = 480 mg, 86%
1
yield; Run 2 = 487 mg, 87%). m.p. 209 – 211 °C; H NMR (400
MHz, CDCl3): 7.40-7.36 (m, 2H), 7.15-7.05 (m, 1H), 6.89-6.86
(m, 2H), 3.87-3.84 (m, 4H), 3.12-3.10 (m, 4H), 2.15 (s, 3H). 13C
1
yield; Run 2 = 373 mg, 66%). H NMR (400 MHz, CDCl3):
8.20-8.07 (m, 1H), 7.46 (d, J= 2.0 Hz, 1H), 7.38 (d, J= 8.6 Hz,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 11
NMR (100 MHz, CDCl3): 168.1, 148.3, 130.6, 121.526, 116.3, 66.9,
N-Methyl-2-morphilino-benzamide (27). A 20 mL microwave
49.8, 24.4. This matched previously reported data.19d
vial equipped with a stirrer bar was charged with 2-bromo-N-
methylbenzamide (500 mg, 2.29 mmol) and Pd-PEPPSI-IPent
(57 mg, 3 mol%). The vial was sealed and purged with 3x
vacuum/nitrogen cycles. LiHMDS (1 M in THF, 8 mL, 8
mmol) and morpholine (280 µl, 3.21 mmol) were then added
via a syringe and the vial purged with a further 2x vacu-
um/nitrogen cycles. The vial was placed in a pre-heated al-
uminium block at 60 °C and stirred at this temperature for 21
h. After cooling to room temperature, the reaction mixture
was adsorbed onto silica and purified by column chromatog-
raphy (gradient elution 0-5% methanol in DCM), yielding the
desired product 27 as a white solid (Run 1 = 433 mg, 86%
1
2
3
4
5
6
7
8
N-(2-Morpholinophenyl)acetamide (24). A 5 mL microwave
vial equipped with a stirrer bar was charged with 2-
bromoacetanilide (100 mg, 0.448 mmol), Pd-PEPPSI-IPent (11
mg, 3 mol%) and cesium carbonate (293 mg, 0.898 mmol).
The vial was sealed and purged with 3x vacuum/nitrogen
cycles. 1,4-dioxane (0.9 mL)and morpholine (55 µl, 0.631
mmol) were then added via a syringe and the vial purged
with a further 2x vacuum/nitrogen cycles. The vial was
placed in a pre-heated aluminium block at 100 °C and stirred
at this temperature for 20 h. After cooling to room tempera-
ture, the reaction mixture was diluted with EtOAc and fil-
tered through a plug of silica. The silica plug was rinsed with
EtOAc, the organic filtrates combined and concentrated in
vacuo. Purification by column chromatography (gradient
elution 0-60% EtOAc in Heptane) yielded the desired prod-
uct 24 as a white solid (Run 1 = 76 mg, 69% yield; Run 2 = 81
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
yield; Run 2 = 430 mg, 85% yield). m.p. 99 - 102 °C; H NMR
(400 MHz, CDCl3): 9.38 (s, 1H), 8.14 (dd, J= 1.8, 7.8 Hz, 1H),
7.44 (td, J= 7.7, 1.7 Hz, 1H), 7.27-7.16 (m, 2H), 3.87-3.85 (m,
4H), 3.03-2.99 (m, 7H). 13C NMR (100 MHz, CDCl3): 167.2,
150.5, 132.0, 131.7, 128.0, 124.9, 119.8, 67.5, 53.4, 26.0. IR (neat,
cm-1): 3283, 2999, 2361, 1649, 1593, 1548. HRMS (ESI) m/z:
[M+] calcd for C12H16N2O2 220.1212 found 220.1206.
1
mg, 74%). m.p. 86 – 88 °C. H NMR (400 MHz, CDCl3): 8.48
(s, 1H), 8.35 (d, J= 7.8 Hz, 1H), 7.17-7.14 (m, 2H), 7.09-7.05 (m,
1H), 3.88-3.86 (m, 4H), 2.88-2.86 (m, 4H), 2.21 (s, 3H). 13C
NMR (100 MHz, CDCl3): 168.0, 140.6, 133.5, 125.8, 123.8, 120.5,
119.6, 67.6, 52.6, 25.0. IR (neat, cm-1): 3343, 2964, 2845, 2360,
1739, 1674, 1587. HRMS (ESI) m/z: [M+] calcd for C12H16N2O2
220.1212 found 220.1217.
4-Phenyl-1,3-dihydroquinoxalin-2-one (28). A 20 mL micro-
wave vial equipped with a stirrer bar was charged with 3,4-
dihydro-1H-quinoxalin-2-one (500 mg, 3.21 mmol) and Pd-
PEPPSI-IPent (80 mg, 3 mol%). The vial was sealed and
purged with 3x vacuum/nitrogen cycles. LiHMDS (1 M in
THF, 11 mL, 11 mmol) and bromobenzene (341 µL, 3.20 mmol)
were then added via a syringe and the vial purged with a
further 2x vacuum/nitrogen cycles. The vial was placed in a
pre-heated aluminium block at 60 °C and stirred at this tem-
perature for 17 h. After cooling to room temperature, the
reaction mixture was adsorbed onto silica and purified by
column chromatography (gradient elution 0-70% EtOAc in
heptane), yielding the desired product 28 as a white solid
(Run 1 = 654 mg, 91% yield; Run 2 = 623 mg, 87%). m.p. 180 –
4-Morpholinobenzamide (25). A 20 mL microwave vial
equipped with
a
stirrer bar was charged with 4-
bromobenzamide (500 mg, 2.42 mmol) and Pd-PEPPSI-IPent
(61 mg, 3 mol%). The vial was sealed and purged with 3x vac-
uum/nitrogen cycles. LiHMDS (1 M in THF, 8.5 mL, 8.5
mmol) and morpholine (300 µl, 3.44 mmol) were then added
via a syringe and the vial purged with a further 2x vacu-
um/nitrogen cycles. The vial was placed in a pre-heated al-
uminium block at 60 °C and stirred at this temperature for 16
h. After cooling to room temperature, the reaction mixture
was adsorbed onto silica and purified by column chromatog-
raphy (gradient elution 0-10% methanol in DCM), yielding
the desired product 25 as a white solid (Run 1 = 420 mg, 84%
1
184 °C; H NMR (400 MHz, CDCl3): 8.51-8.44 (m, 1H), 7.40-
7.36 (m, 2H), 7.21-7.12 (m, 3H), 6.95-6.89 (m, 4H), 4.28 (s,
2H). 13C NMR (100 MHz, CDCl3): 167.2, 144.4, 133.5, 129.5,
127.3, 124.0, 123.8, 122.2, 121.0, 116.2, 116.0, 52.5. IR (neat, cm-1):
3337, 3032, 2908, 2332, 1739, 1668, 1589. HRMS (ESI) m/z:
[M+] calcd for C14H12N2O 224.0950 found 224.0949.
1
yield; Run 2 = 457 mg, 91%). m.p. 216 – 220 °C; H NMR (400
MHz, DMSO): 7.77-7.70 (m, 3H), 7.02-6.93 (m, 3H), 3.74-3.72
(m, 4H), 3.21-3.19 (m, 4H). 13C NMR (100 MHz, DMSO): 168.1,
153.4, 129.3, 124.4, 113.8, 66.4, 47.9. This matched previously
reported data.21
ASSOCIATED CONTENT
Supporting Information. Materials, general methods, HTS
data and broader analysis, experimental procedures, analyti-
cal data, literature analysis. This material is available free of
charge via the Internet at http://pubs.acs.org.
2-Morpholinobenzamide (26). A 20 mL microwave vial
equipped with
a
stirrer bar was charged with 2-
bromobenzamide (500 mg, 2.42 mmol) and Pd-PEPPSI-IPent
(61 mg, 3 mol%). The vial was sealed and purged with 3x vac-
uum/nitrogen cycles. LiHMDS (1 M in THF, 8.6 mL, 8.6
mmol) and morpholine (300 µl, 3.44 mmol) were then added
via a syringe and the vial purged with a further 2x vacu-
um/nitrogen cycles. The vial was placed in a pre-heated al-
uminium block at 60 °C and stirred at this temperature for 72
h. After cooling to room temperature, the reaction mixture
was adsorbed onto silica and purified by column chromatog-
raphy (gradient elution 0-10% methanol in DCM), yielding
the desired product 26 as a yellow solid (Run 1 = 415 mg, 82%
AUTHOR INFORMATION
Corresponding Author
* richardson_jeffery@lilly.com.
ACKNOWLEDGMENT
Funding (EL) was provided by EPSRC UCL IAA allocation.
Thanks to Iván Collado and Magnus Walter for support of
the program, Stephanos Ghilagaber, Jason Howe and Gio-
vanni Giuliano for synthesis of compounds B3, B5-B13 and
Lewis Vidler and David Evans for helpful discussions around
data analysis.
1
yield; Run 2 = 403 mg, 80%). m.p. 117 – 121 °C; H NMR (400
MHz, DMSO): 8.37 (s, 1H), 7.68 (dd, J= 1.6, 7.6 Hz, 1H), 7.50-
7.41 (m, 2H), 7.18-7.10 (m, 2H), 3.76-3.73 (m, 4H), 2.94-2.91
13
(m, 4H). C NMR (100 MHz, DMSO): 168.9, 151.1, 131.9, 130.7,
129.5, 123.5, 119.7, 66.8, 53.1. This matched previously reported
data.22
REFERENCES
ACS Paragon Plus Environment

Page 11 of 11
The Journal of Organic Chemistry
1.
Buitrago Santanilla, A.; Regalado, E. L.; Pereira, T.;
13.
(a) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S.
1
2
3
4
5
6
7
8
Shevlin, M.; Bateman, K.; Campeau, L.-C.; Schneeweis, J.;
Berritt, S.; Shi, Z.-C.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch,
C. J.; Vachal, P.; Davies, I. W.; Cernak, T.; Dreher, S. D. Science
2015, 347, 49-53.
L. Org. Lett. 2008, 10, 3505-3508; (b) Biscoe, M. R.; Fors, B. P.;
Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686-6687; (c)
Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552-13554; (d) Kinzel, T.; Zhang, Y.;
Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14073-14075; (e)
Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4,
916-920; (f) Bruno, N. C.; Niljianskul, N.; Buchwald, S. L. J.
Org. Chem. 2014, 79, 4161-4166; (g) DeAngelis, A. J.; Gildner,
P. G.; Chow, R.; Colacot, T. J. J. Org. Chem. 2015, 80, 6794-
6813.
2.
(a) Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J.
F. Angew. Chem., Int. Ed. 2010, 49, 8082-8091; (b) Nadin, A.;
Hattotuwagama, C.; Churcher, I. Angew. Chem., Int. Ed. 2012, 51,
1114-1122; (c) Hann, M. M.; Keserü, G. M. Nat. Rev. Drug
Discov. 2012, 11, 355-365.
9
3.
A.; Landrum, G. A. J. Med. Chem. 2016, 59, 4385-4402.
4. Anastas, P. T.; Warner, J. C., Green Chemistry: Theory
and Practice. Oxford University Press: New York, 1998.
Schneider, N.; Lowe, D. M.; Sayle, R. A.; Tarselli, M.
14.
McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Chem. Ed. 2010, 87, 1348-1349.
15.
Crawford, S. M.; Lavery, C. B.; Stradiotto, M. Chem.
5.
6.
7.
Trost, B. Science 1991, 254, 1471-1477.
Young, I. S.; Baran, P. S. Nat. Chem. 2009, 1, 193-205.
(a) Collins, K. D.; Glorius, F. Acc. Chem. Res. 2015, 48,
Eur. J. 2013, 19, 16760-16771.
16.
Full details of other experiments that were performed,
either to validate negative results or to test other hypotheses
around the translation of the screening data to scaled-up repeats in
Schemes 1-3 can be found in Supporting information Table S71.
619-627; (b) Collins, K. D.; Glorius, F. Tetrahedron 2013, 69,
7817-7825; (c) Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5,
597-601; (d) Gensch, T.; Glorius, F. Science 2016, 352, 294-295;
(e) Collins, K. D.; Rühling, A.; Lied, F.; Glorius, F. Chemistry – A
European Journal 2014, 20, 3800-3805.
17.
Brusoe, A. T.; Hartwig, J. F. J. Am. Chem. Soc. 2015,
137, 8460-8468.
18.
(a) Hoi, K. H.; Calimsiz, S.; Froese, R. D. J.;
8.
Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54,
Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2011, 17, 3086-
3090; (b) Hoi, K. H.; Calimsiz, S.; Froese, R. D. J.; Hopkinson, A.
C.; Organ, M. G. Chem. Eur. J. 2012, 18, 145-151.
3451-3479.
9.
10.
Chem., Int. Ed. 1995, 34, 1348-50.
11.
3609-3612.
12.
L.; Hines, C. C.; Griffin, S. T.; Rogers, R. D.; Shaughnessy, K.
H.; Grasa, G. A.; Johansson Seechurn, C. C. C.; Li, H.; Colacot,
T. J.; Chou, J.; Woltermann, C. J. J. Org. Chem. 2010, 75, 6477-
6488; (b) Raders, S. M.; Moore, J. N.; Parks, J. K.; Miller, A. D.;
Leißing, T. M.; Kelley, S. P.; Rogers, R. D.; Shaughnessy, K. H.
J. Org. Chem. 2013, 78, 4649-4664; (c) Rataboul, F.; Zapf, A.;
Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.;
Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983-2990;
(d) Shen, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109-4112; (e)
Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655; (f)
Klingensmith, L. M.; Strieter, E. R.; Barder, T. E.; Buchwald, S.
L. Organometallics 2006, 25, 82-91; (g) Valente, C.; Pompeo, M.;
Sayah, M.; Organ, M. G. Org. Process Res. Dev. 2014, 18, 180-
190; (h) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27-50.
Brown, D. G.; Boström, J. J. Med. Chem. 2015.
Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
19.
(a) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett.
2002, 4, 2885-2888; (b) Charles, M. D.; Schultz, P.; Buchwald, S.
L. Org. Lett. 2005, 7, 3965-3968; (c) Anderson, K. W.; Tundel, R.
E.; Ikawa, T.; Altman, R. A.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2006, 45, 6523-6527; (d) Urgaonkar, S.; Verkade, J. G. Adv.
Syn. Cat. 2004, 346, 611-616; (e) Henderson, J. L.; McDermott,
S. M.; Buchwald, S. L. Org. Lett. 2010, 12, 4438-4441; (f) Perez,
F.; Minatti, A. Org. Lett. 2011, 13, 1984-1987; (g) Grob, J. E.;
Dechantsreiter, M. A.; Tichkule, R. B.; Connolly, M. K.; Honda,
A.; Tomlinson, R. C.; Hamann, L. G. Org. Lett. 2012, 14, 5578-
5581; (h) Plas, A.; Martin, C.; Joubert, N.; Viaud-Massuard, M.-
C. Org. Lett. 2015, 17, 4710-4713.
Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36,
(a) Hill, L. L.; Crowell, J. L.; Tutwiler, S. L.; Massie, N.
20.
Ueda, H.; Yoshida, K.; Tokuyama, H. Org. Lett. 2014,
16, 4194-4197.
21.
Lakshminarayana, N.; Prasad, Y. R.; Gharat, L.;
Thomas, A.; Narayanan, S.; Raghuram, A.; Srinivasan, C. V.;
Gopalan, B. Eur. J. Med. Chem. 2010, 45, 3709-3718.
22.
Sun, X.; Hu, Y.; Nie, S.-z.; Yan, Y.-y.; Zhang, X.-j.;
Yan, M. Adv. Syn. Cat. 2013, 355, 2179-2184.
ACS Paragon Plus Environment