Palladium Catalyzed C?O Coupling of Amino Alcohols for the Synthesis of Aryl Ethers

Article abstract of DOI:10.1002/adsc.201901302

Amine containing aryl ethers are common pharmacophore motifs that continue to emerge from drug discovery efforts. As amino alcohols are readily available building blocks, practical methodologies for incorporating them into more complex structures are highly desirable. We report our efforts to explore the application of Pd-catalyzed C?O coupling methods to the arylation of 1,2- and 1,3-amino alcohols. We established general and reliable conditions, under which we explored the scope and limitations of the transformation. The insights gained have been valuable in employing this methodology within a fast-moving drug discovery environment, which we anticipate will be of general interest to the synthesis and catalysis communities.

Full text of DOI:10.1002/adsc.201901302

Title: Palladium Catalyzed C‒O Coupling of Amino Alcohols for the
Synthesis of Aryl Ethers
Authors: Malte Mikus, Carina Sanchez, Cary Fridrich, and Jay Larrow
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901302
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10.1002/adsc.201901302
Advanced Synthesis & Catalysis
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Palladium Catalyzed C‒O Coupling of Amino Alcohols for
the Synthesis of Aryl Ethers
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Malte S. Mikus , Carina Sanchez , Cary Fridrich and Jay F. Larrow *
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Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue,
Cambridge, Massachusetts 02139, United States
Corresponding author, email: jay.larrow@novartis.com; ph: +1-617-871-4008
Current address: Medicinal Chemistry, Relay Therapeutics, 399 Binney Street, Cambridge, Massachusetts
02139, United States
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†
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Received: 2019
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
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Abstract. Amine containing aryl ethers are common pharmacophore motifs that continue to emerge from drug
discovery efforts. As amino alcohols are readily available building blocks, practical methodologies for incorporating
them into more complex structures are highly desireable. We report our efforts to explore the application of Pd-
catalyzed C-O coupling methods to the arylation of 1,2- and 1,3-amino alcohols. We established general and reliable
conditions, under which we explored the scope and limitations of the transformation. The insights gained have been
valuable in employing this methodology within a fast-moving drug discovery environment, which we anticipate will
be of general interest to the synthesis and catalysis communities.
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Keywords: amino alcohols; C-O coupling; aryl alkyl ethers; bippyphos; palladium catalysis
Introduction.
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Due to their presence in a large number of biologically active natural products, amino alcohols have found
significant application as essential pharmacophores and structural motifs in modern drug design,[1] and as
highly effective stereocontrol elements in the field of asymmetric catalysis.[2] Consequently, a diverse
number of practical methodologies that render them readily accessible have been developed in addition to
chiral pool sources,[3] making them ideal building blocks to be used in the design and optimization of novel
pharmaceuticals. For example, nearly the entire class of beta-blocker drugs such as Carvedilol (Scheme 1)
contain a common 1-aminopropan-2,3-diol motif variable only in the aromatic ether of the primary
hydroxyl and the substitution on the amine. Given this historical success (Scheme 1),[4] aryl ether
derivatives of amino alcohols continue to emerge from the drug discovery process and practical
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methodologies that render them readily accessible are sought after in the pharmaceutical industry. For the
synthesis of aryl ethers, methods such as SNAr/SN2, Ullman or Mitsunobu reactions have been traditionally
employed,[5] while more efficient catalytic methods, including the Cu-[6] and Pd-catalyzed[7] coupling of
aryl halides with alcohols, continue to evolve. More recently, Ni-promoted coupling reactions, including
those utilizing photoredox catalysis, have also been shown to be effective for the synthesis of aryl ethers.[8]
While all these methods have different strengths and weaknesses, our highest priority was the expedient
development of general and reliable conditions for the scalable production of aryl ethers starting with
readily available amino alcohols in support of a swiftly moving drug discovery project.
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In this context, we rapidly found that the established Pd-catalyzed C-O coupling methdologies could be
effectively applied to amino alcohol substrates despite few precedented examples in the literature.[9]
Included among the potential reasons for the paucity of amino alcohol examples are the issue of N- vs. O-
selectivity, the relative propensity for these substrates to undergo β-hydride elimination, and the potential
for these substrates to sequester the catalyst through chelation.[10] While there have been studies of Cu-
promoted coupling reactions of amino alcohols and amino acids (e.g. derivatives of serine and threonine),[11]
to the best of our knowledge this substrate class has yet to be thoroughly explored in Pd catalysis. In this
communication, we detail our experiences exploring the Pd-catalyzed C-O coupling of this important and
under-represented class of alcohol substrates.
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Scheme 1. Selected examples of pharmaceuticals containing amino aryl ethers
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Results and Discussion. In our search for robust and scaleable conditions, we began by evaluating the
optimized conditions reported by the Beller[7f] and Buchwald[7l] groups, as well as a process group from
Merck,[7g] to the coupling of 1a and 2a (Table 1, entries 1-5). We found the bippyphos ligands L4 and L5
gave the highest yield of the desired product 3a, with L5 giving slightly better results. We further optimized
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around ligand L4 since it is more generally available in larger quantities, and, except where noted, the
differences between L4 and L5 were negligible (<5% difference in isolated yield). Variation of the
stoichiometry between the aryl halide and alcohol substrate showed no significant impact on either the yield
of the ether product or the formation of the reduced arene 4 (entries 6-10), which results from competitive
β-hydride elimination of the intermediate Pd-alkoxide followed by reductive elimination. This alternate
pathway highlights one of the main challenges in this chemistry. In order to obtain consistent results, it
was beneficial to premix the phosphine ligand, base and aryl halide in the reaction solvent with heating
until oxidative addition was observed (indicated by a distinct color change) prior to addition of the amino
alcohol substrate.[12] Following this premixing procedure, 19F-NMR spectroscopy revealed that a species
was formed with an identical CF3 chemical shift to that observed for the independently synthesized
oxidative addition complex Pd-1.[13] The performance of complex Pd-1 in the reaction was similar to that
of the in situ generated species (Table 1, entry 11).[14]
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Table 1. Evaluation of published optimal reaction conditions.[15]
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a) Values represent NMR yield determined by 19F NMR of unpurified mixtures versus 1,3,5-(CF3)3C6H3 as internal
standard. b) Values in parenthesis represent isolated yield of purified products. c) The reaction was run using complex
Pd-1 in place of ligand and Pd2(dba)3, and the alcohol was added directly without preheating.
With general reaction conditions identified, a range of common amine protecting groups were next
evaluated in order to better define the scope and limitations of the method (Table 2). As expected,
unprotected amines gave predominant formation of N-coupled products indicating that the potential for
chelation shutting down catalysis was not observed, even with 1,2 amino alcohols.[16,9] Electronic
deactivation of the amine by Boc protection effectively reversed the chemoselectivity of the reaction,
affording 3b and 3c in 66% and 68% yield respectively (entries 1-2). Boc protection proved to be the most
general, as Cbz protection resulted in cyclization to the oxazolidinone and arylation on nitrogen (entry 3).
However, switching from Cs2CO3 to the less basic CsF allowed the desired product to be isolated in 59%
yield (entry 4). The Fmoc group was rapidly deprotected under the reaction conditions with either base,
leading to a complex mixture with N-arylated species as the major products (entry 5). As with previous
examples containing tertiary amines,[9] the dibenzylamine product 3e was obtained in 80% yield (entry 6),
thereby allowing facile revelation of the primary amine by hydrogenolysis. Amide protection as the acetate
gave product 3f in moderate yield despite the potential for either direct N-coupling or dehydration to form
the oxazoline, while the trifluoroacetamide proved insufficiently stable to the reaction conditions, yielding
mixtures of N- and O-coupled products (entries 7-8 respectively). Common groups used to introduce
protected amine functionality (phthalimide and azide) were also found to be sufficiently stable to obtain
products 3g and 3h in moderate yields (entries 9-10).
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Table 2. Evaluation of substitution on nitrogen on chemoselectivity and reaction efficiency.
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b)
c)
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Ar refers to the 4-(CF3)-C6H4- fragment introduced.
Yields are for purified products.
Corrected yield after
d)
isolation as an inseparable mixture with compound 5b’. Pure product could be isolated by slurrying in heptanes.
CsF used in place of Cs2CO3. e) The N,O-diarylated species was also isolated in 19% isolated yield (5c in supporting
information). f) The reactions were run in 1,4-dioxane due to low solubility of the amide alcohols in toluene. g) The
desired O-coupled product was isolated in 11% yield as a 9:1 mixture with the N,O-diarylated species.
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Exploring the scope of aryl halides and amino alcohols, we next investigated the coupling of various aryl
bromides and chlorides with several Boc-protected 1,2- and 1,3-amino alcohols (Scheme 2). Choosing aryl
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bromide 1a as coupling partner, we compared a variety of cyclic and acyclic amino alcohols. As seen in
Table 2 (entries 1-2), the 1,2-product (3b) and 1,3-product (3c) were obtained in similar yield. This trend
was also observed in the case of cyclic amino alcohols, as products 3i and 3j were also obtained in nearly
identical yield. However, the ring size clearly plays a significant role in the efficiency of the reaction, as
the 6- and 7-membered ring substrates gave products in <60% yield (3i-j, 3m), while the 4- and 5-membered
ring substrates gave products 3k and 3l in 85% and 87% yield respectively. In addition, increasing
substitution around the reacting alcohol center had a significantly detrimental effect with acyclic substrates
(cf. 3n and 3o vs 3c), leading to N-arylation of the Boc carbamate as a competing pathway (predominant
in case of 3o). On the other hand, secondary alcohols on cyclic structures showed little detriment relative
to primary alcohols when the nitrogen was contained in the ring (cf. 3k vs 3p), suggesting secondary
alcohols are competent substrates in the absence of an NH carbamate.[16] In the case of 3q where a sterically
hindered NH carbamate is present, both O- and N-coupling are similarly impaired, yielding the desired
product in only 20% yield.[17] However, coupling ethyl 4-bromobenzoate more than doubled the yield of
the desired O-coupled product (3r), presumably due to the electronic nature of the aromatic ring facilitating
reductive elimination. Taken together, these data suggest that reduced steric congestion around the alcohol
is a crucial factor in reaction efficiency, with the geometric constraints of the cyclic systems reinforcing
these factors relative to acyclic systems. Moreover, 3a, 3k and 3q were isolated with no significant erosion
in enantio- or diastereomeric purity, highlighting the utility of the method to incorporate chiral
substrates.[16,7m]
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Varying substituents on the aryl halide partner shows that several common functional groups are amenable
to the conditions, such as nitrile (3s and 3t), ester (3r and 3w), ketone (3x), and xanthene (3y). As with the
alcohol substrates, increasing the steric bulk ortho to the halide carbon hinders the efficiency of the reaction,
as the ortho isopropyl containing 3v was isolated in only 49% yield. In addition, several electron-poor
heteroaromatics yielded products in 63-97%, including 7-bromoquinoline (3u), 2-chlorobenzoxazole (3z),
2-chloropyridine (3aa), and 2-bromo-5-methylpyrazine (3ab).
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Scheme 2. Substrate scope of amino alcohols and aryl halides. a) A mixture of O- and N-arylated products was formed
b)
(see supporting information for details).
supporting information for details).
The N-arylated carbamate product was isolated in 77% yield (see
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A common challenge in Pd promoted coupling reactions are electron rich aryl halides.[18] As shown in
Scheme 3, the formation of para methoxy 6a was not observed, rather a complex mixture of side products
was formed. We did find that the less electron rich p-OCH2CF3 6b could be isolated in 20% yield. As
described by Beller,[7f] the use of the bis(adamantyl)phosphine ligand L5 resulted in a significant increase
in reaction efficiency with electron rich substrates, as 6b was isolated in 29% yield (~50% increase in yield
over the use of L4). Similarly, m-methoxy substituted 6c was isolated in 63% yield (vs 40% when L4 was
employed). Other limitations of the current methodology include the coupling of electron-rich
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heteroaromatics such as 4-chloroquinoline, 5-bromopyrimidine, and 1-Boc-6-bromoindole, which gave
products 6d, 6h and 6f in <25% yield, while 3-bromothiophene and 2-bromofuran leading to 6i and 6j were
not stable to the reaction conditions. Further limitations around the alcohol substrate include protected
serine and threonine derivatives (acid and esters), as well as glycol type substrates with or without
protection of the pendant alcohol (6e).
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Scheme 3. Challenging substrates and limitations of the reaction. a) Conversion was assessed by LC/MS analysis.
Formation of a mixture of N-, O- and bis-arylated products was observed.
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Conclusion
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In this study, we have found that established conditions for Pd-catalyzed C-O coupling have proven reliable
to provide scalable access to 1,2- and 1,3 amino aryl ethers. While several amine protecting groups were
tolerated in the coupling reaction, Boc protection of non-tertiary amines was demonstrated as the most
general means to not only reverse the inherent chemoselectivity of the reaction, but to also prevent reaction
of the alcohol with the carbamate group. Our results showed comparable substrate scope and reactivity
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patterns as simple alcohol substrates, leading to a number of products in good to excellent yield utilizing a
variety of readily available amino alcohol building blocks. The robustness of this methodology has enabled
rapid application up to kilogram scale both internally and with external CRO partners. In addition, with a
well-defined scope, we anticipate this methodology will find ready application to parallel and library
synthesis platforms to enable access to diverse chemical space containing this historically rich
pharmacophore motif. Our current efforts are aimed towards expanding the substrate scope by developing
a deeper understanding of some of the ligand effects observed with challenging substrates.
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Experimental Section
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Under a nitrogen atmosphere, an oven-dried 50 mL two-neck flask equipped with a magnetic stir bar was charged
with cesium carbonate (977 mg, 3 mmol, 3 equiv), Pd2(dba)3 (22.9 mg, 0.025 mol, 2.5 mol %) and ligand L4 (25.3
mg, 0.05 mmol, 5 mol %). The flask was sealed with a septum and then purged by performing two vacuum-to-nitrogen
cycles with a manifold. A solution of aryl bromide in anhydrous toluene (4 mL) was added via syringe, followed by
another purge cycle with the manifold.[19] The dark red suspension was then allowed to stir at 85 °C (external) until a
color change indicating oxidative addition was observed (usually within 10-15 minutes). At this point, a solution of
the amino alcohol derivative (2 mmol) in anhydrous toluene (1 mL) was added via syringe, and the reaction allowed
to stir for 14h. The reaction mixture was allowed to cool to room temperature, and the dark suspension was filtered
through a pad of Celite and washed through with EtOAc. The filtrate was concentrated by rotary evaporation under
reduced pressure. The dark oil residue was subjected to silica gel chromatography, eluting with heptanes and EtOAc
gradients, to afford the aryl ether product after removal of solvents.
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Acknowledgements
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The authors wish to thank Dr. Peng Fu and the catalysis screening lab in our early development group for the initial screening of
our reaction of interest, which helped to narrow the scope of this work. We thank Dr. Beatrix Wagner and Philippe Piechon for
obtaining the X-ray crystal structure of Pd-1. We also thank Prof. Matt Sigman and Dr. Kian Tan for helpful discussions. Drs.
Scott Plummer, Simone Bonnazzi, Eric McNeil, and Art Cernijenko are gratefully acknowledged for assistance with reviewing this
manuscript.
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[10] For a recent study exploring catalyst sequestration in Pd catalyzed C-N coupling, see: a) N. A. Strotman, M. C.
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For further studies, see: b) ref. 6d. For studies discussing the issue of beta-hydride elimination in Pd promoted C-
O coupling, see: refs. 7b and 7m.
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[11] a) See ref. 6h; b) M. E. Khatib, G. A. Molander, Org. Lett. 2014, 16, 4944–4947; c) M. Al Masum, L. Quinones,
L. T. Cain, Int. J. Org. Chem. 2016, 6, 100–106.
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4
[12] For a discussion of the importance of premixing reagents and establishing the initial oxidative addition occured
in absence of alcohol, see: ref 7g.
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7
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[13] a) For procedures for the preparation of complex Pd-1, see: B. T. Ingoglia, S. L. Buchwald, Org. Lett. 2017, 19,
2853–2856. See supporting information for details. b) CCDC-1959277 (Pd-1) contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
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[14] Although not extensively considered for this work, a screening of typical Pd sources in our reaction of interest
revealed Pd2(dba)3 to give the best results, but most other common sources were also effective in addition to the
specific methodologies in ref. 7. For a relevant discussion, see: a) B. Schlummer, U. Scholz, Adv. Synth. Catal.,
2004, 346, 1599–1626.
[15] Not shown in the table, a comparison of typical solvents and bases confirmed best results when employing cesium
carbonate and toluene, although the differences were not substantial. In cases where one of the substrate partners
was poorly soluble in toluene and could not be added neat, 1,4-dioxane was substituted with nearly identical results.
[16] See supporting information for details.
[17] The product of β-hydride elimination of the alcohol substrate was also isolated in 26% yield, but coupling of the
secondary NH carbamate was not significantly observed. Similar results were observed in the reaction to produce
3r.
[18] R. A. Widenhoefer, S. L. Buchwald, J. Am. Chem. Soc. 1998, 120, 6504–6511
[19] In cases where the alcohol substrate was insufficiently soluble in toluene, the entire 5 mL volume was added with
the aryl bromide and the alcohol was added as a solid through the second neck. No significant differences in
reaction performance were observed, highlighting the robustness of the reaction.
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10.1002/adsc.201901302
Advanced Synthesis & Catalysis
UPDATE
Palladium Catalyzed C‒O Coupling of Amino
Alcohols for the Synthesis of Aryl Ethers
Adv. Synth. Catal. 2020, Volume, Page –
Page
Malte S. Mikus, Carina Sanchez, Cary Fridrich,
and Jay F. Larrow*
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10.1002/adsc.201901302
Advanced Synthesis & Catalysis
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