Pd-catalyzed arylation of linear and angular spirodiamine salts under aerobic conditions

Article abstract of DOI:10.1016/j.tetlet.2016.12.063

Application of Buchwald-Hartwig catalysis for development of biologically relevant arylspirodiamine compounds is reported. This synthetic methodology requires no inert atmosphere and affords yields up to 93% in just 20?min. Linear and sterically hindered angular spirodiamines in salt and free-base form are coupled with electron-rich and -withdrawing aryl chlorides, demonstrating a broad scope and applicability of this protocol.

Full text of DOI:10.1016/j.tetlet.2016.12.063

Accepted Manuscript
Pd-catalyzed arylation of linear and angular spirodiamine salts under aerobic
conditions
Sean W. Reilly, Nikaela W. Bryan, Robert H. Mach
PII:
S0040-4039(16)31718-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.063
TETL 48475
Reference:
Tetrahedron Letters
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20 December 2016
21 December 2016
Please cite this article as: Reilly, S.W., Bryan, N.W., Mach, R.H., Pd-catalyzed arylation of linear and angular
spirodiamine salts under aerobic conditions, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.12.063
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Pd-catalyzed arylation of linear and angular
spirodiamine salts under aerobic conditions
Sean W. Reillya Nikaela W. Bryanb Robert H. Macha, 
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1
Tetrahedron Letters
Pd-catalyzed arylation of linear and angular spirodiamine salts under aerobic
conditions
Sean W. Reillya Nikaela W. Bryanb Robert H. Macha, 
aDepartment of Radiology, Perelman School of Medicine, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA 19104, USA
bDepartment of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 19104, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Application of Buchwald-Hartwig catalysis for development of biologically relevant
arylspirodiamine compounds is reported. This synthetic methodology requires no inert
atmosphere and affords yields up to 93% in just 20 min. Linear and sterically hindered angular
spirodiamines in salt and free-base form are coupled with electron-rich and -withdrawing aryl
chlorides, demonstrating a broad scope and applicability of this protocol.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Pd cross-coupling
C-N cross-coupling
Arylation
Spirodiamine
RuPhos
Introduction
Spirocylic scaffolds are structurally diverse compounds with
broad applications throughout drug discovery,1 chiral ligand
development,2 and organocatalysts for asymmetric synthesis.3
Reports containing these privileged structures have grown
exponentially in the past 10 years alone due to the advantageous
structural and pharmacological properties of these motiffs.4 The
unique three-dimensional complexity of these compounds,
measured by Fsp3 (fraction of sp3 carbon hybridization),
correlates to increased physiochemical and biological properties,
due to the enhanced selectivity of targeted proteins.5 Thus,
spirodiamine cores, most notably arylspiroalkanes (Figure 1), are
present in many biologically active compounds6 with reported
antipsychotic,7 anti-insomnia,8 age-related macular degeneration
(AMD),9 and anti-viral10 properties, among others.1d, 9, 11
Despite the many examples of biologically active compounds
containing arylspirodiamine scaffolds, reports illustrating the
synthesis thereof are exceedingly rare. One attractive approach is
the Hartwig-Buchwald amination, a powerful synthetic tool in C–
N bond formation, thereby providing a direct approach to aryl
amines.12 However, to our knowledge, the only report applying
this catalysis to a broad scope of spirodiamine compounds was
disclosed by Carreira and co-workers in 2008, which entailed
Figure 1. Arylspirodiamine scaffolds in compounds with pharmacological
properties.
anaerobic conditions and extended reaction times up to 46 h.13
A
Previous work by Buchwald and co-workers illustrated highly
active Pd catalysts bearing biarylphosphine ligands in C–N cross-
coupling of aryl halides and secondary amines.14 Inspired by
these reports, we developed an aerobic piperazine arlyation
protocol using precatalyst system Pd2(dba)3 and air- and
protocol that does not necessitate prolonged reactions times or an
inert atmosphere would undoubtedly assist in furthering the
development of arylspirodiamine stuctures.
———
 Corresponding author. Tel.: +1 215 746-8233; e-mail: rhmach@mail.med.upenn.edu (R.H. Mach)

2
Tetrahedron
moisture-stable biarylphosphine ligand RuPhos.15 This bench-
substrates containing electron-donating substituents, traditionally
less reactive substrates, in the ortho position (1a-b and 1d). We
then examined if 1k-l would also result in a decrease in activity
after affording excellent yields with analogous para-substituted
aryl chlorides 1g-h. Indeed, reaction yields dropped to 74% and
76% for 2k and 2l, respectively, demonstrating a consistent trend
in diminished cross-coupling activity with aryl chlorides
containing ortho-substituted electron-withdrawing groups.
Nonetheless, this method provides a more efficient route to 2l,
compared to the 38% yield obtained in 24 h reaction time
reported by Petrukhin and co-workers.9 Arylspirodiamine
chlorides 2m-o accessed using reported conditions further
demonstrates the synthetic versatility of this protocol with di- and
tri-chloro aryl substrates. A higher yield of 2o was achieved by
increasing the Pd/Ruphos loading to 2 mol% and 4 mol%,
respectively, and using 1o in slight excess.
top method affords excellent yields of the mono-arylated product
in just 10 min and eliminates the need for an inert atmosphere
and anhydrous solvents. More impressively, we found this Pd-
ligand system to be highly efficient in coupling notoriously
unreactive electron-rich aryl chlorides in short reaction times as
well. Described herein is an extension of this methodology to
include arylation of commercially available linear and angular
spirodiamine salt and free-base compounds A-H (Figure 2).
Scheme 1 Arylation of A with aryl chloridesa
Figure 2. Spirodiamine compounds examined.
Currently, we have been examining A as a potential surrogate
for piperazine due to the unique structural space the diamine can
populate owing to the distinctive spirocyclic framework (Figure
3). Furthermore, pharmacokinetic properties, such as lipophilicity
and metabolic stability of biologically relevant compounds can
be advantageously modified by incorporation of A, along with
analogous spiro[3.3]heptane structures, thus, providing an
attractive alternative to piperazine, piperidines, and morpholine
parent compounds.16 In order to develop a library of arylated
spirodiamine A compounds in an efficient and practical time-
scale, we applied modified reaction conditions from our previous
Pd-catalyzed C–N cross-coupling report outlined in Scheme 1.
Figure 3 Structural comparison of piperazine and 2,6-
diazaspiro[3.3]heptane (A).
We began our investigation by examining 1a halide
derivatives to determine if the outlined one-pot reaction
conditions could be expanded beyond aryl chlorides. Amination
of 1a substrates proceeded smoothly in each trial run, affording
comparable 2a yields to previous Pd-catalyzed arylation report in
which a higher catalyst loading, along with 21 h reaction time,
were required.13 Sterically congested and electron-rich 1b was
efficiently coupled with A to afford 2b at 74%. Reaction
conditions were tolerable for trifluoromethoxy functional group,
1c, providing a synthetically useful 44% yield. Substrates 2-
chloro and 2-bromo anisole were both examined, with 2-
chloroanisol providing a higher 2d product yield. Impressive C–
N cross-coupling activity was also observed with extremely
electron-rich 1f, yielding 64% in just 20 min.
aConditions: Pd2(dba)3 (1 mol %), RuPhos (2 mol %), aryl chloride (0.5
mmol), A (0.55 mmol), NaOt-Bu (3.0 equiv), and dioxane (1.5 mL), 20 min.
Isolated yields. Reaction monitored by LCMS. b2.5 equiv of NaOt-Bu was
used. cPd2(dba)3 (2 mol %), RuPhos (4 mol %), 1o (1.1 mmol), A (1.0 mmol),
NaOt-Bu (3.0 equiv), and dioxane (3.0 mL), 20 min.
We next investigated if conditions would be tolerable with N-
aryl chlorides due to the prevalence of nitrogen heterocycles
biologically active compounds (Scheme 2). The coupling of 2-
chloropyrazine was met with modest activity, yielding 62% of
the desired product 4a. A comparable yield of 4b was obtained at
a faster rate and lower catalyst loading than those previously
As expected, para-substituted electron-deficient aryl chlorides
provided excellent yields including NO2 substituted 1i. However,
a noticeable decrease in C–N cross-coupling activity was
observed with ortho-substituted electron-withdrawing functional
groups. For example, only 39% of the desired product 2j was
afforded when compared to the higher yields obtained with

3
reported by Carreira under anaerobic conditions.13 Electron-rich
and –poor pyridine chlorides were also well tolerated, as good
yields were afforded for both products, 4c-d. Screening
continued with bicyclic N-aryl chlorides quinolone and
quinoxaline, obtaining 4e-f in excellent yields. Efficient coupling
continued with benzothiazole and benzooxazxole substrates, 3g-
h, compounds with known anti-cancer17 and antipsychotic
properties18, respectively. We briefly examined 5-membered
heterocycle rings with the chloro and bromo variants of 3i,
affording respectable yields for the aminated thiazole product.
resulted with substrate 1e, yielding only 40% of desired product
6l.
Scheme 3 Arylation of B-Ha
Scheme 2 Arylation of A with N-aryl chloridesa
aConditions: Pd2(dba)3 (1 mol %), RuPhos (2 mol %), aryl chloride (1.0
mmol), B-H (1.1 mmol), NaOt-Bu (3.0 equiv), and dioxane (3.0 mL), 20 min.
Isolated yields. Reaction monitored by LCMS.
Catalytic activity was considerably lower with sterically
hindered F, affording low yields for 6m-o. We postulated the
reduced product formation of 6m-o, compared to higher yields
afforded with angular spirodiamine B, could be a result of
increased steric congestion illustrated in Figure 4. A decrease in
bond distance is observed when comparing the bond distance
between carbon (C1) in F and aryl carbon (C2) in the coupled
arene ring, compared to the analogous atoms of angular
spirodiamine B. This increase in steric crowding could provide
an unfavorable environment for the active catalyst, resulting in
the poor yields observed for 6m-o.
aConditions: Pd2(dba)3 (1 mol %), RuPhos (2 mol %), aryl chloride (0.5
mmol), A (0.55 mmol), NaOt-Bu (3.0 equiv), and dioxane (1.5 mL), 20 min.
Isolated yields. Reaction monitored by LCMS. b3.0 equiv of Cs2CO3 used
instead of NaOt-Bu
With reports outlining synthetic methods of spirodiamine
cores increasing over the past few years,1a, 4, 16, 19 we sought to
apply this protocol to other structurally diverse spirodiamine
compounds. We expanded the scope to include examples of C–N
cross-coupling with B-H (outlined in Figure 2) and aryl chlorides
1a, 1e, and 1g (Scheme 3). These aryl substrates were selected to
examine how sterics and electronics affect catalytic C–N
coupling with linear and angular spirodiamine compounds B-H.
Excellent cross-coupling activity was observed with B and 1a
yielding 6a at 87%. Electron-rich 1e proved to be an unfavorable
coupling partner, affording 6b at 32% yield. Reaction conditions
were more tolerable with 1g, as product yield of 6i occurred at
77%. High yields were obtained with 1a and 1g when coupled
with B, however only modest reactivity was again observed with
1e yielding 6e at 54%. Sluggish reactivity was observed with D
and aryl substrates 1a and 1e resulting in modest yields, although
product yield improved slightly with 1g. Compound E, a
common core in molecular scaffolds with applications in type 2
diabetes mellitus (T2DM) and obesity,20 was coupled with 1a and
1e affording good yields of 6j-k. Decreased activity, however,
Figure 4 Comparison of C–C bond distances of sipirodiamine F and B.21
Excellent reactivity was observed with G, yielding >80% for
both 6p and 6q, and a respectable 67% for 6r. Reaction
conditions were also tolerable for H, a common core found in
biologically active compounds with application in thrombotic
disease, pain and inflammation, and inhibition of GPIIb-IIIa.21

4
Tetrahedron
8.
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Conclusion
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In summary, Pd/Ruphos catalyst system has been shown to be
highly active in arylation of linear and angular spirodiamines in
salt and free-base form. This extension of our previous work is a
rare example of C–N bond formation that does not require an
inert atmosphere or extended reaction times. Finally, reactions
with activated and deactivated aryl chlorides were afforded at
moderate to excellent yield at a constant catalyst loading in just
20 min.
10.
11.
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Acknowledgments
We are grateful for the financial support of National Institute
on Drug Abuse [(R01 DA29840-07 R.H.M.) and (R01 DA23957-
06 R.R. Luedtke)]. N.W.B. is supported by the National Institutes
of Health training grant T32GM008076 (J.A. Blendy, PI).
13.
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Supplementary Material
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Electronic Supplementary Information (ESI) available:
Experimental procedure, NMR and mass spectral data of the
isolated product (PDF). See DOI: 10.1039/x0xx00000x.
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5
Highlights



Efficient arylation of sterically congested spirodiamine compounds is demonstrated.
Protocol does not require anhydrous solvents or inert atmosphere.
Good to modest yields obtained with electron rich aryl halides in just 20 minutes.