Ligand-enabled β-C-H arylation of α-amino acids using a simple and practical auxiliary

Article abstract of DOI:10.1021/ja512690x

Pd-catalyzed β-C-H functionalizations of carboxylic acid derivatives using an auxiliary as a directing group have been extensively explored in the past decade. In comparison to the most widely used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for C-H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary to direct β-C-H activation, albeit this system was not compatible with carboxylic acids containing α-hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this limitation of the N-methoxyamide auxiliary, leading to a significant improvement of β-arylation of carboxylic acid derivatives, especially α-amino acids. The arylation using this practical auxiliary is applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules, and chiral bis(oxazoline) ligands.

Full text of DOI:10.1021/ja512690x

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Article
Ligand-Enabled #-C–H Arylation of Alpha-Amino
Acids Using a Simple and Practical Auxiliary
Gang Chen, Toshihiko Shigenari, Pankaj Jain, Zhipeng Zhang, Zhong Jin, Jian He, Suhua Li,
Claudio Mapelli, Michael M. Miller, Michael A Poss, Paul M. Scola, Kap-Sun Yeung, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 19 Feb 2015
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Ligand-Enabled -C–H Arylation of Alpha-Amino
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Acids Using a Simple and Practical Auxiliary
Gang Chen,† Toshihiko Shigenari,† Pankaj Jain,† Zhipeng Zhang,† Zhong Jin,† Jian He,† Suhua Li,†
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Claudio Mapelli,§ Michael M. Miller,§ Michael A. Poss,§ Paul M. Scola,§ Kap-Sun Yeung,§ Jin-Quan
Yu*†
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla,
California 92037, United States
§Bristol-Myers Squibb Co, Route 206, Province Line Road, Princeton, New Jersey 08543, United States
yu200@scripps.edu
Abstract. Pd-catalyzed -C–H functionalizations of carboxylic acid derivatives using an auxiliary as a
directing group have been extensively explored in the past decade. In comparison to the most widely
used auxiliaries in asymmetric synthesis, the simplicity and practicality of the auxiliaries developed for
C–H activation remains to be improved. We previously developed a simple N-methoxyamide auxiliary
to direct -C–H activation, albeit this system was not compatible with carboxylic acids containing -
hydrogen atoms. Herein we report the development of a pyridine-type ligand that overcomes this
limitation of the N-methoxyamide auxiliary, leading to a significant improvement of -arylation of
carboxylic acid derivatives, especially -amino acids. The arylation using this practical auxiliary is
applied to the gram-scale syntheses of unnatural amino acids, bioactive molecules and chiral
bis(oxazoline) ligands.
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1. Background
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Aliphatic acids belong to an important class of useful building blocks due to their availability and
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the diverse reactivity of the carboxyl group. Among many methods for the preparation of - or -
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substituted carboxylic acids, -enolate chemistry using chiral auxiliaries1 and asymmetric conjugate
additions2 are the most powerful tools (Eqs 1-2). To seek an alternative synthetic disconnection, we
initiated a research program centered on the -C–H activation and subsequent carbon–carbon bond and
carbon–heteroatom bond forming reactions in 2002 (Eq 3). Our early studies employed an oxazoline
auxiliary as a directing group3 to investigate the reactivity and mechanism of -C–H insertion by Pd(II)
(Figure 1). We utilized the stereochemistry obtained in the C–H insertion step to deduce the pre-
transition state structure of directed C–H insertions using chiral oxazoline auxiliaries. With hindsight
and recent in-depth computational and kinetic studies,4 the primitive, but important insights we obtained
from these studies regarding the conformation and structure of the C–H insertion precursors paved the
way for our subsequent design of more efficient auxiliaries (Figure 1). In the past decade, while
Daugulis’ bidentate 8-aminoquinoline auxiliary has emerged as a powerful directing group,5 we have
focused on the development of mono-dendate simple amide auxiliaries, hoping to achieve ligand-
accelerated and -controlled -C–H functionalization reactions.
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Due to the moderate reactivity of sodium or potassium carboxylates in -C–H arylation,6 we
developed an N-methoxyamide auxiliary to mimic the carboxylate while allowing improved
coordination with Pd(II).7 The simple rationale behind this design was to best mimic the conformation
of the coordination structure of Pd(II) with carboxylates while at the same time slightly increase the
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binding strength. This new auxiliary (CONHOMe) displayed excellent efficiency in directing -C–H
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activation (Figure 1). For example, -arylation of the amide derived from pivalic acid with Ph–I using
this auxiliary proceeds at room temperature. We have also successfully exploited this reactivity to
accomplish an unprecedented coupling of -C–H bonds with alkyl boronic acids.7a Numerous
applications of this powerful auxiliary in directed C(sp2)–H activation have also been reported with
Pd(II), Rh(III), and Ru(II) catalysts.8 Unfortunately, C(sp3)–H activation of aliphatic acids using this
auxiliary has been limited to substrates containing -quaternary centers under current conditions. Apart
from the known Thorpe-Ingold effect in cyclopalladation, we suspected that the acidic -hydrogen of
aliphatic acid substrates could be responsible for the lack of reactivity. This reasoning has led us to
develop another acidic amide auxiliary (CONHArF, ArF = p-CF3C6F4) that is compatible with aliphatic
acid substrates containing -hydrogen atoms (Figure 1).9 Despite the broad utility of this new directing
group, the simplicity of CONHOMe10 in terms of installation and removal prompted us to develop new
conditions that may overcome the limitation of this potentially broadly useful auxiliary. Our recent
collaboration with Bristol-Myers Squibb to establish a robust and scalable method for the preparation of
a wide range of unnatural amino acids through C–H functionalization of readily available amino acids
such as alanine provided a further incentive for this endeavor.
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Figure 1. Advantages and disadvantages of different directing groups developed in our laboratory
Herein we report the development of pyridine-type ligands that promote selective mono- and di--
arylation of a broad range of carboxylic acids using a simple N-methoxyamide auxiliary as the directing
group. 2-Picoline ligand (L7) promotes the selective mono-arylation of primary C(sp3)–H bonds and
2,6-lutidine ligand (L13) enables the subsequent arylation of secondary C(sp3)–H bonds in one pot.
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Sequential arylation of alanine derivatives with two different aryl iodides using these ligands enables the
introduction of two distinct aryl groups to produce a variety of -Ar--Ar'--amino acids with excellent
levels of diastereoselectivity. Arylation of the N-methoxyamide derived from alanine with a variety of
heterocyclic aryl iodides on gram scales to make various unnatural amino acids was also demonstrated.
These unnatural amino acid intermediates were further transformed to drug molecules such as a human
kynurenine aminotransferase (KAT) II inhibitor11 and Doxanthrine,12 as well as chiral hydroxamic acid
ligands13 and a variety of new chiral pyridine-2,6-bis(oxazolines) (PyBOX) ligands14 (Figure 2).
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Figure 2. Synthetic applications
2. Results and Discussion
2.1. -Mono-arylation directed by N-methoxyamide
-C–H functionalizations of amino acid derivatives using various auxiliaries have been extensively
studied since the first report from the Corey group.15,16 It was established in this early study that the use
of the phthalimide protecting group was crucial for achieving -C–H activation.15a Recently, we have
discovered that pyridine- and quinoline-based ligands promote activation of the C(sp3)–H bonds in
alanine using CONHArF (ArF = p-CF3C6F4) auxiliary as the directing group.17 While the precise
mechanistic origin of the ligand effects remains to be elucidated, a recent computational study suggests
that the ligand is involved in every step of the catalytic cycle including the C–H activation step.18 This
new development encouraged us to revisit whether a simpler N-methoxyamide auxiliary, with the
assistance of a ligand, can accommodate substrates derived from carboxylic acids containing -
hydrogen atoms. Thus, phthaloyl alanine amide 1 was reacted with 1.5 equiv. of p-Tol–I using
Pd(OAc)2 and ligand L1 under various conditions. We found that the mono-arylation proceeded under
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the conditions shown in Scheme 1 to give the arylated products as a mixture of amide 2a and the
corresponding ester in 45% yield. A substantial amount of the starting material was converted to
corresponding unreactive ester. The conversion of the N-methoxyamide to the corresponding ester via a
radical process is known to be promoted by silver salts.10 A control experiment showed that ligand L1
was required for the formation of the arylated product.
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Scheme 1. Preliminary Discovery for Ligand-Promoted C–H Arylation
Prior to undertaking further ligand screening, we needed to identify conditions under which the
known decomposition of the N-methoxyamide to the unreactive ester via a radical process10a-c was
minimized (Table 1). The use of (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) to inhibit the radical
process led to a slight drop in product yield (Table 1, entry 2). The reaction did not proceed at a lower
temperature of 60 oC (Table 1, entry 3). Switching to a range of commonly used solvents did not reduce
the decomposition or improve the yields (Table 1, entries 4-8). We were pleased to find that the
decomposition of the N-methoxyamide was effectively prevented by using acidic solvents, such as
2,2,2-trifluoroethanol (CF3CH2OH) or hexafluoro-2-propanol (HFIP) (Table 1, entries 9-10). Arylation
proceeded in HFIP to give the mono-arylated product in 76% yield and the di-arylated product in 10%
yield (Table 1, entry 10). Running the reaction in 1,2-dichloroethene (DCE) in the presence of 20 mol%
trifluoroacetic acid (TFA) also significantly improved the yield to 75% (Table 1, entry 11).
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Table 1. Evaluation of Reaction Conditionsa
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a
Conditions: Substrate 1 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), p-Tol–I (0.15 mmol), Ligand L1 (20
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mol%), solvent (1.0 mL), 75 °C, 24 h. Determined by HNMR analysis of the crude product using CH2Br2 as an internal
standard, and the yield is based on the amide and ester. c Reaction run at 60 °C. d Combined 76% mono- and 10% di-arylated
products determined by crude 1HNMR.
While further ligand screening using DCE/TFA solvent system did not provide noticeable
improvement, dramatic ligand effects were observed for this reaction in HFIP (Table 2). A variety of
quinoline-based ligands (L2-L4) afforded moderate to good yields (up to 83%). Further optimizations of
quinoline-based ligands were not fruitful. We found a wide range of pyridines as suitable ligands for
this reaction. 2-Picoline ligand (L7) was found to be highly effective affording both excellent yield
(90%) and mono-selectivity (99%). Replacing the 2-methyl group by other substituents in 2-substituted
pyridines (L8-L12) resulted in lower yields. Among the di-substituted and tri-substituted pyridines
(L13-L18), L16 and L17 containing a 2-methyl group performed well with good yields (84% and 83%)
and mono-selectivity. Interestingly, the use of 2,6-lutidine (L13) resulted in some loss of mono-
selectivity affording the mono-arylated product 2a in 70% yield and the di-arylated product 3r in 10%
yield. Arylation in the absence of ligand under these new conditions gave the desired product in 36%
yield, thus confirming the significant ligand acceleration effect. Mechanistically, the comparison of the
most effective ligand L7 with the less effective ligands L10 and L11 is informative. The decrease in
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binding strength of the ligands via either electronic or steric effects reduces the efficiency of the
catalysts.
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Table 2. Ligand Screeninga,b
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a Conditions: Substrate 1 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), p-Tol–I (0.15 mmol), Ligand (20 mol%),
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HFIP (1.0 mL), 75 °C, 24 h. The yields were determined by H NMR analysis of the crude product using CH2Br2 as an
internal standard. The mono:di ratio was determined by 1H NMR.
A broad range of variously substituted aryl iodides are compatible with this ligand-promoted -C–H
arylation reaction (Table 3). Aryl iodides containing methyl, phenyl and methoxy groups react with
substrate 1 under the standard conditions to give the desired products in good to excellent yields (2a-f).
Fluoro, chloro, bromo and iodo substituents are all tolerated and moderate to good yields are obtained
(2g-k). Aryl iodides containing highly electron-withdrawing groups including acetyl and
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methoxycarbonyl are excellent coupling partners affording the arylation products in 71-82% yields (2l-
p). Di- and tri-substituted aryl iodides display similar reactivity to the mono-substituted ones (2q-t).
Most importantly, aryl iodides containing well-known directing groups such as acetamide, phosphonate
and hydroxyls are also reactive coupling partners (2u-x), thus overcoming some limitations of previous
protocols.16,17 These unnatural amino acids have been widely used as building blocks for the preparation
of bioactive peptides.19,20 For example, the corresponding amino acid of 2v was used to replace tyrosine
in a peptide to afford an improved β2 adrenergic receptor19 while a tetrapeptide containing the
corresponding amino acid of 2w has been evaluated as a tyrosine kinase inhibitor.20
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Table 3. Substrate Scope of Aryl Iodides of Mono-Arylationa,b
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mol%), HFIP (1.0 mL), 75 °C, 24 h. Isolated yields are shown. Ar–I (0.3 mmol). After C–H activation, the reaction
mixture was subjected to PhI(OAc)2 (0.1 mmol), MeOH (1 mL), 80 °C, 3 h. Yields for two steps.
2.2. Arylation with heteroaryl iodides
Heteroatoms in heterocycles coordinate strongly to Pd(II) catalysts and result in catalyst poisoning.
This detrimental effect often prevents the use of heteroaryl iodides as coupling partners in C–H
activation reactions. We reasoned that the acidic solvent HFIP used in our new protocol could weaken
the coordinating ability of the heterocycles. Furthermore, the pyridine-type ligand picoline could
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potentially also outcompete the coordination of the heteroaryl iodides. We thus proceeded to investigate
the reactivity of a wide range of heterocyclic iodides under the standard conditions. We found that aryl
iodides containing dioxane and chromonyl moieties were coupled with alanine substrate 1 successfully
to give the desired products 4a and 4b in 76% and 70% yields respectively (Table 4). Tosyl-protected
indolyl and indazolyl iodides also afforded 4c-f in synthetically useful yields (58-65%). These unnatural
amino acids containing heteroaryls are not readily accessible via other methods21 and are often desirable
in medicinal chemistry.
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Table 4. Scope of Heteroaryl Iodidesa,b
a Conditions: Substrate 1 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar–I (0.15 mmol), 2-picoline (20 mol%),
HFIP (1.0 mL), 80 °C, 24 h. b Isolated yields are shown. c Pd(OAc)2 (15 mol %), 2-picoline (30 mol%). d Yields based on the
amide and ester.
However, arylation with the more coordinative pyridyl iodide gave poor yields (less than 10%).
Considering that a halogen substituent at the 2-position of a pyridine can be readily removed or
transformed to other functional groups, we tested the reactivity of 2-fluoro, 2-chloro and 2-
bromopyridyl iodides. These coupling partners reacted with substrate 1 to give the desired products in
approximately 20% yields under the standard conditions. Through further ligand screening, 2,6-lutidine
was identified as a more efficient ligand. Thus, arylation with a range of pyridyl iodides were carried
out under the optimized conditions (Table 5). Although 4-pyridyl iodide gave poor yield (4g'), all 2-
halo-pyridyl iodides afford synthetically useful yields (4h'-4m'). The arylated products were obtained as
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a mixture of amides and esters which are treated with PhI(OAc)2 in one pot to give the pure esters as the
isolated products. Arylation with pyridyl iodides containing 2-CF3, 2-Me and 2-OMe substituents
proceeded to give the desired products in 42-66% yields. The presence of 3-CH2OH group reduced the
yield to 32% (4r'). Various quinolinyl and quinoxalinyl iodides are also compatible with protocol
affording heterocycle-containing amino acids (4s'-4v') in moderate yields.
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Table 5. Expanding the Scope of Heteroaryl Iodidesa,b
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HFIP (1.0 mL), 85 °C, 36 h, and then PhI(OAc)2 (0.1 mmol), MeOH (1 mL), 80 °C, 3h. Isolated yields are shown.
Substrate 1 (0.2 mmol), Ar–I (0.1 mmol), yield based on the Ar–I. d Lactone was first formed, then was converted to 4r' with
MeSO3H. For details, see supporting information.
2.3. Removal of the auxiliary
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Since N-alkoxyamides are used as masked esters, a number of deprotection procedures based on
radical pathways have been developed (Eq 4).10, 22 N, N-Bis-heteroatom-substituted amides formed from
N-alkoxyamides can thermally decompose to give the corresponding esters. A wide range of metal
oxidants including silver oxide (Ag2O), nickel(IV) peroxide hydrate (NiO2•H2O), ceric ammonium
nitrate (CAN), and lead(IV) acetate [Pb(OAc)4] have been used to convert N-alkoxyamides into esters.10
One-step conversion of N-alkoxyamides to esters by reacting with N-bromosuccinimide (NBS) in
toluene has also been reported.22 N-Chlorohydroxamates generated from N-alkoxyamides can be
converted to the esters by treating with sodium azide via Heron rearrangement (Eq 5).23 However, all of
these protocols convert the amino acid-derived amides to esters in only moderate yields. We found that
reacting N-methoxyamides with iodosobenzene diacetate [PhI(OAc)2] in methanol at 80 °C afforded
esters in excellent yields excluding indole-containing amides (4c, 4d) which suffered from partial
intramolecular radical lactamization. Lewis acid boron trifluoride diethyl etherate (Et2O•BF3) was also
identified as an efficient reagent to convert N-methoxyamides into esters in methanol at 90 °C. This
latter protocol is also compatible with the indole-containing amides. Importantly, no racemization of the
α-chiral center was observed during the C–H arylation and the subsequent removal of the auxiliary
(Scheme 2).
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Scheme 2. Removal of the Directing Group
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2.4. Arylation of methylene C–H bonds
Following the development of mono-arylation of the primary C(sp3)–H bonds directed by N-
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methoxyamide, we began to search for ligands that would promote further arylation of the methylene C–
H bonds. The formation of 10% of the di-arylated product with the quinoline ligand L1 (Table 1) led us
to investigate whether these conditions can be optimized for arylation of methylene C–H bonds (Table
6). Considering the previously observed significant effects of inorganic bases on the -C–H
functionalizations of N-methoxyamides,7a we investigated the arylation with a wide range of base
additives. Among the various potassium, sodium and lithium salts, monohydrogen phosphate (Table 6,
entries 5 and 8) and dihydrogen phosphate (Table 6, entries 6, 9-11) significantly improved the yields of
the arylation. Sodium dihydrogen phosphate was especially effective, affording the arylated product in
50% yield (Table 6, entries 9, 10). Increasing the amount of sodium dihydrogen phosphate monohydrate
(NaH2PO4•H2O) to three equivalents improved the yield to 72% (Table 6, entry 15).
6
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Table 6. Additive Screening in the Arylation of Phenylalaninea,b
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a
Conditions: Substrate 2' (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), p-Tol–I (0.3 mmol), L1 (20 mol%),
HFIP (1.0 mL), 100 °C, 36 h. b Determined by 1H NMR analysis of the crude product using CH2Br2 as an internal standard.
With this promising result in hand, we began to further improve the arylation of phenylalanine 2' by
screening ligands (Table 7). The dependence of this reaction on ligand was confirmed by the complete
loss of reactivity in the absence of a ligand. While other quinoline-based ligands (L2, L3, L19) were all
inferior to L1, 2,6-lutidine (L13) and 2,4,6-trimethylpyridine (L18) proved to be superior ligands,
affording the desired product in 92% and 86% yields respectively.
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Table 7. Ligand Screeninga,b
a Conditions: Substrate 2' (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), p-Tol–I (0.3 mmol), Ligand (20 mol%),
HFIP (1.0 mL), 100 °C, 36 h. b Determined by 1H NMR analysis of the crude product using CH2Br2 as an internal standard.
The scope of this newly developed methylene C–H arylation was examined with a board range of
electron-rich and electron-poor aryl iodides (Table 8). Aryl iodides containing electron-donating
substituents at the ortho-, meta- and para-positions served as efficient coupling partners, affording the
-arylated phenylalanine products in good to excellent yields (3a-f). Arylation of 2' with fluoro- and
chloro-substituted aryl iodides proceeded to afford the desired products in 70-75% yields (3g-i). This
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reaction is also compatible with aryl iodides containing electron-withdrawing groups (3j-m). Arylation
with naphthalene iodide and di-substitued aryl iodides also afforded synthetically useful yields (3n-p).
In all cases, this arylation reaction affords excellent diastereoselectivity which can be explained by a
previously isolated C–H cleavage intermediate from a related amide substrate.17
1
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9
Table 8. Substrate Scope of Aryl Iodides in the Arylation of Phenylalaninea,b
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a Conditions: Substrate 2' (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar–I (0.3 mmol), 2,6-lutidine (20 mol%),
NaH2PO4•H2O (0.3 mmol), HFIP (1.0 mL), 100 °C, 36 h. b Isolated yields are shown.
1
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9
The removal of the auxiliary from the β-diaryl alanine products using PhI(OAc)2 resulted in the
formation of a substantial amount of a lactamization side product. The use of Lewis acid Et2O•BF3
proved to be effective in removing the auxiliary in high yields. Importantly, the enantiopurity of the α-
chiral center was retained during both the C–H arylation step and the subsequent conversion of the
amide to the corresponding ester (Scheme 3).
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Scheme 3. Removal of the Directing Group
2.5. Homo-diarylation of alanine
The recently identified 2,6-lutidine ligand was also applied to the arylation of alanine substrate 1 to
obtain homo-diarylation products in one pot (Table 9). Various β-diaryl-α-amino acids (3q-t) were
synthesized in 63-75% yields. Considering the steric hindrance on the -carbon of these diarylated
amino acids, we anticipate that the corresponding chiral amino alcohols are highly valuable for the
synthesis of bulky chiral bis(oxazoline) ligands.
Table 9. Homo-Diarylation of Alanine Substratea,b
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a
Conditions: Substrate 1 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar–I (0.3 mmol), 2,6-lutidine (20 mol%),
NaH2PO4•H2O (0.3 mmol), HFIP (1.0 mL), 100 °C, 36 h. b Isolated yields are shown.
1
2
3
4
2.6. One-Pot Sequential Hetero-diarylation of Alanine
5
6
7
8
The exclusive mono-selectivity of 2-picoline-promoted -arylation of primary C–H bonds provides
a possibility for achieving sequential arylation of alanine substrate 1 with two different aryl iodides in
one pot. Thus, 1 was subjected to the mono-arylation conditions with 1.2 equiv. of 4-iodotoluene. After
1 was completely arylated as shown by thin layer chromatography (TLC), 3 equiv. of phenyl iodide
(Ph–I) as well as other reagents (2,6-lutidine, AgOAc, NaH2PO4•H2O) required for the methylene C–H
activation were added to the reaction to initiate the second arylation (Table 10). This one-pot procedure
afforded the hetero-diarylated product 3u in 71% yield. The formation of homo-arylated product with 4-
iodotoluene was not observed suggesting that the remaining aryl iodide from the first step was
outcompeted by the excess phenyl iodide introduced in the second step. This protocol is also compatible
with other combinations of a variety of aryl iodides, affording diverse range of hetero-diarylated
products in 43-71% yields with excellent diastereoselectivity (3u-ab). The switching of the arylation
order to access different diastereomers was also demonstrated with the preparation of 3w and 3x. Given
the availability of both enantiomers of the starting amino acids, all four diasteromeric products can be
obtained by switching the order of addition of the two different aryl iodides. Overall, this protocol offers
a highly versatile approach for the preparation of chiral β-Ar-β-Ar'-α-amino acids. A sequential hetero-
diarylation using a strongly coordinating bidentate directing group has also been demonstrated,16a
although the mono-arylated product needs to be isolated and subjected to different conditions to perform
the second arylation. A recent report24 on an improved synthesis of differentially substituted dehydro-
β,β-diarylalanine derivatives and subsequent asymmetric hydrogenation also speaks to the need for
efficient methods for preparing chiral β-Ar-β-Ar'-α-amino acids.
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Table 10. Hetero-Diarylation of Alanine Substratea,b
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a
Conditions: Substrate 1 (0.1 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar1–I (0.12 mmol), 2-picoline (20 mol%),
HFIP (1.0 mL), 75 °C, 24 h. Then Pd(OAc)2 (10 mol%), AgOAc (0.2 mmol), Ar2–I (0.3 mmol), 2,6-lutidine (20 mol%),
NaH2PO4•H2O (0.3 mmol), 100 °C, 36 h. b Isolated yields are shown.
2.7. Arylation of Other Carboxylic Acids
To demonstrate the generality of N-methoxyamide as a directing group for the arylation of C(sp3)–H
bond, we also examined the arylation of other aliphatic acid substrates. Under the conditions for the -
arylation of primary C–H bonds using 2-picoline as the ligand, amides derived from 2-methyl butyric
acid, β-hydroxy acid, β-amino acid, and 2-aminoisobutyric acid afforded the arylated products in 53-
72% yields (Table 11, 6a-d). Interestingly, arylation of the cyclobutyl C–H bonds in the amide substrate
derived from 1-aminocyclobutane-1-carboxylic acid afforded 86% yield under these conditions (6g). As
expected, -arylation of amide substrates derived from tyrosine and L-2-aminobutyric acid only
proceeded under the conditions developed for methylene C–H bonds (6e-f). To our surprise,
cyclopropyl C–H bond in 5h is less reactive under these conditions and requires the use of ligand L1 to
allow the arylation to proceed in moderate yield (45%).
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Table 11. Arylation of Other Amino Acids and Carboxylic Acidsa
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a
b
Isolated yields are shown. Conditions: Substrate (0.2 mmol), Pd(OAc)2 (10 mol%), AgOAc (0.4 mmol), p-Tol–I (0.3
c
mmol), 2-picoline (20 mol%), HFIP (2.0 mL), 80 °C, 24 h. Conditions: Substrate (0.1 mmol), Pd(OAc)2 (10 mol%),
AgOAc (0.2 mmol), p-Tol–I (0.3 mmol), 2,6-lutidine (20 mol%), NaH2PO4•H2O (0.3 mmol), HFIP (1.0 mL), 90 °C, 36 h.
Substrate (0.1 mmol), Pd(OAc)2 (15 mol%), AgOAc (0.2 mmol), p-Tol–I (0.3 mmol), L1 (30 mol %), TFA (20 mol %),
DCE (1.0 mL), 85 °C, 36 h.
d
2.8. Gram-scale syntheses of unnatural amino acids
The use of N-methoxyamide auxiliary has important advantages for gram-scale preparation of
unnatural amino acids. Firstly, methoxyamine hydrochloride is inexpensive and has a low molecular
weight. Secondly, the installation involves treatment of carboxylic acid with oxalyl chloride and
methoxyamine hydrochloride at room temperature to afford the N-methoxyamides in nearly quantitative
yields. Notably, the installation of other amide directing groups such as CONHArF (ArF = p-CF3C6F4)
often requires refluxing conditions or proceeds in low yields. Furthermore, the removal of this auxiliary
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using Et2O•BF3 or PhI(OAc)2 is highly reliable and high yielding with retention of stereochemistry at
the acidic -carbon center.
1
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8
In response to needs for bioactive peptides from Bristol-Myers Squibb, alanine substrate 1 was
coupled with fluorinated and trifluoromethylated aryl iodides (20 mmol scale) using 2-picoline as the
ligand to give the mono-arylated products in excellent yields (Scheme 4). The resulting crude products
were treated with PhI(OAc)2 in methanol to afford the esters in 85-98% yields over two steps. The
phthalimide group was removed in presence of ethylenediamine to generate the free amines that were
subsequently converted to Fmoc-protected amino esters. Finally, the esters were hydrolyzed in presence
of lithium hydroxide to give 7.5-9.0 grams of the desired amino acids (7-9) in 50-55% overall yields.
The less reactive heteroaryl iodides and trifluoro-aryl iodide were also successfully coupled with alanine
1 using 2,6-lutidine. Following a similar procedure, 1.1-6.0 grams of these desired Fmoc-protected
amino acids were prepared (10-13) (Scheme 5, for details, see supporting information).
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Scheme 4. Gram-Scale Synthesis of Unnatural Amino Acids 7-9
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Scheme 5. Gram-Scale Synthesis of Unnatural amino Amino Acids 10-13
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2.9. Diverse Synthetic Applications
The practical advantage of the N-methoxyamide auxiliary is further demonstrated by its versatile
transformations to various biologically active compounds (Scheme 6). Radical cyclization of 2e with
[bis(trifluoroacetoxy)iodo]benzene (PIFA) led to a lactam25 and subsequent deprotection of the
phthalamide using ethylenediamine afforded 14 as a key intermediate for the synthesis of glycogen
phosphorylase inhibitors.26 Conversion of 2e to carboxylic acid and subsequent treatment with oxalyl
chloride and aluminum trichloride gave the 2-amino-1-indanone 15,27 a key intermediate of α1-
adrenoceptor antagonists.28 The amino ester 16 derived from 2e was readily converted to Fmoc-
protected unnatural amino acid 17 as a useful building block for peptide synthesis. Through the Pictet-
Spengler reaction, 16 could be also converted to a chiral tetrahydroisoquinoline 18, a known N-methyl-
D-aspartate (NMDA) agonist.29 A chiral bioactive indoline 1930 could also be synthesized via our
previously developed intramolecular C–H amination reaction of sulfonyl protected 16.31
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Scheme 6. Application to Synthesis of a Variety of Biologically Active Compounds
The N-methoxyamide auxiliary also gives access to N-hydroxy-3-amino-3,4-dihydroquinolinone
class of compounds. First reported by Davis and co-workers over thirty years ago, they were shown to
exhibit antibacterial activity.32 More recently, similar scaffolds have been identified as potent inhibitors
of KAT II, an enzyme currently being investigated as a therapeutic target for cognitive impairment
associated with schizophrenia, among other disorders.11 Using the above protocols, arylation followed
by a known radical cyclization, medicinally important analogues of N-methoxy-3-amino-3,4-
dihydroquinolines 14' and 20-22 were prepared in a straightforward manner (Table 12).
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Table 12. Lactamization of Different Substratesa,b
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a Conditions for cyclization: Substrate, PIFA (2 equiv.), DCM, 0 °C to r.t. b Isolated yields are shown.
Chiral amino alcohols derived from chiral amino acids are essential building blocks for the
preparation of chiral ligands. For example, the sterically hindered chiral amino alcohol derived from
tert-leucine is a key precursor for the synthesis of one of the most effective chiral oxazoline ligands in
asymmetric catalysis. β-Ar-β-Ar'-α-amino acids prepared via the recently developed procedure can be
readily reduced to the corresponding chiral amino alcohols containing two chiral centers that are
previously difficult to make (Scheme 7). Thus, employing our hetero-diarylation protocol above, 3z was
obtained in moderate yields via a two steps, one-pot procedure on a 10 mmol scale. Hydrolysis of the
amide group to ester followed by removal of the phthalimide protecting group led to the amino ester 24
which was reduced to the amino alcohol 25 in 75% yield. From this common intermediate 25, PyBox
ligand 26 and Box ligand 27 were successfully prepared.33 We anticipate that these novel chiral
bis(oxazoline) ligands will display interesting and useful properties in asymmetric catalysis. The
potential impact of the additional chiral centers of ligands 26 and 27 on asymmetric catalysis is also
intriguing.
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Scheme 7. Synthesis of PyBOX and BOX Ligands
3. Conclusion
During the past decade-long efforts to develop a simple and practical auxiliary or directing group for
-C–H fucntionalizations of carboxylic acids, we have focused on the use of relatively weak
coordination from the substrates to direct metalation and match this weak coordination with ligand
development to enhance the reactivity. The simple N-methoxyamide group, initially used as a masked
ester, has been reinvented as a broadly useful directing group for -C–H arylation with the assistance of
two pyridine-type ligands. 2-Picoline promotes the mono-selective arylation of primary C(sp3)–H bonds
while 2,6-lutidine enables the subsequent arylation of secondary C(sp3)–H bonds in one pot. This new
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method is extensively applied to gram-scale synthesis of novel, unnatural amino acids, as well as
bioactive compounds and chiral bis(oxazoline) ligands.
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4. Experimental Section
9
4.1 General procedure for monoarylation with aryl iodides (Table 3):
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The starting material 1 (0.1 mmol, 24.8 mg), Pd(OAc)2 (10 mol%, 2.2 mg), and AgOAc (0.2 mmol,
33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the
reaction mixture, aryl iodide (0.15 mmol), 2-picoline (20 mol%, 2 μL), HFIP (1.0 mL) were added. The
reaction mixture was first stirred at room temperature for 10 min and then heated to 75 °C for 24 hours
under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, filtered
with celite and washed with DCM. The solvents were removed under reduced pressure and the resulting
mixture was purified by a silica gel-packed flash chromatography column using DCM/EtOAc (1/0 to
4/1 to 2/1) as the eluent.
4.2 General procedure for monoarylation with heterocyclic iodides (Table 4 and 5):
Method A (Table 4). The starting material 1 (0.1 mmol, 24.8 mg), Pd(OAc)2 (10 mol%, 2.2 mg),
and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a
magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol), 2-picoline (20 mol%, 2 μL), HFIP
(1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 min and then
heated to 80 °C for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled
to room temperature, filtered with celite and washed with DCM. The solvents were removed under
reduced pressure and the resulting mixture was purified by a silica gel-packed flash chromatography
column using DCM/EtOAc (1/0 to 4/1 to 2/1) as the eluent.
Method B (Table 5). The starting material 1 (0.1 mmol, 24.8 mg), Pd(OAc)2 (15 mol%, 3.3 mg),
and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a
magnetic stir bar. To the reaction mixture, aryl iodide (0.15 mmol), 2,6-lutidine (30 mol%, 3 μL), HFIP
(1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 min and then
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heated to 80 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled
to room temperature, filtered with celite and washed with DCM. The solvents were removed under
reduced pressure and the resulting mixture was added PhI(OAc)2 (0.1 mmol, 32.2 mg) and MeOH (1
mL) in a sealed tube (10 mL) with a magnetic stir bar, The reaction mixture was heated to 80 °C for 3
hours, Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and
washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was
purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as
the eluent.
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Method C (Table 5). The starting material 1 (0.2 mmol, 49.6 mg), Pd(OAc)2 (15 mol%, 3.3 mg),
and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a
magnetic stir bar. To the reaction mixture, aryl iodide (0.1 mmol), 2,6-lutidine (30 mol%, 3 μL), HFIP
(1.0 mL) were added. The reaction mixture was first stirred at room temperature for 10 min and then
heated to 80 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled
to room temperature, filtered with celite and washed with DCM. The solvents were removed under
reduced pressure and the resulting mixture was added PhI(OAc)2 (0.1 mmol, 32.2 mg) and MeOH (1
mL) in a sealed tube (10 mL) with a magnetic stir bar. The reaction mixture was heated to 80 °C for 3
hours. Upon completion, the reaction mixture was cooled to room temperature, filtered with celite and
washed with DCM. The solvents were removed under reduced pressure and the resulting mixture was
purified by a silica gel-packed flash chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as
the eluent.
4.3 General procedure for arylation of phenylalanine (Table 8):
The substrate 2' (0.1mmol, 32.4 mg), Pd(OAc)2 (10 mol%, 2.2 mg), NaH2PO4•H2O (0.3 mmol, 42
mg) and AgOAc (0.2 mmol, 33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a
magnetic stir bar. To the reaction mixture, aryl iodide (0.3 mmol), 2,6-lutidine (20 mol%, 2 μL), HFIP
(1 mL) were added. The reaction mixture was first stirred at room temperature for 10 min and then
heated to 100 °C for 36 hours under vigorous stirring. Upon completion, the reaction mixture was
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cooled to room temperature, filtered with celite and washed with DCM. The solvents were removed
under reduced pressure and the resulting mixture was purified by a silica gel-packed flash
chromatography column using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent.
1
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4.4 General procedure for large scale of mono-arylation step:
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The starting material 1 (10.0 mmol, 2.48 g), Pd(OAc)2 (1.50 mmol, 337 mg), and AgOAc (20.0
mmol, 3.34 g) were weighed in air and placed in a sealed tube (350 mL) with a magnetic stir bar. To the
reaction mixture, aryl iodide (15 mmol), ligand (3.00 mmol), and HFIP (100 mL) were added. The
reaction mixture was first stirred at room temperature for 10 min and then heated to 90 °C for 36 hours
under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature. The
solvents were removed under reduced pressure and recovered for next time use. The resulting mixture
was added PhI(OAc)2 (10 mmol, 3.22 g) and MeOH (100 mL) in a sealed tube (350 mL) with a
magnetic stir bar. The reaction mixture was heated to 80 °C for 3 hours. Upon completion, the reaction
mixture was cooled to room temperature, filtered with celite and washed with DCM. The solvents were
removed under reduced pressure and the resulting mixture was purified by a silica gel-packed flash
chromatography column using hexanes/EtOAc (5/1 to 4/1 to 2/1) as the eluent.
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4.5 General procedure for one pot synthesis of β-Ar-β-Ar'-α-amino acids (Table 10):
The starting material (0.1 mmol, 24.8 mg), Pd(OAc)2 (10 mol%, 2.2 mg), and AgOAc (0.2 mmol,
33.4 mg) were weighed in air and placed in a sealed tube (10 mL) with a magnetic stir bar. To the
reaction mixture, the first aryl iodide (0.12 mmol), 2-picoline (20 mol%, 2 μL), HFIP (1.0 mL) were
added. The reaction mixture was first stirred at room temperature for 10 min and then heated to 75 °C
for 24 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room
temperature, to the reaction mixture, Pd(OAc)2 (0.01 mmol, 2.2 mg), NaH2PO4•H2O (0.3 mmol, 42 mg),
AgOAc (0.2 mmol, 33.4 mg), the second aryl iodide (0.3 mmol) and 2,6-lutidine (0.2 mmol, 2 μL), were
added. The reaction mixture was first stirred at room temperature for 10 min and then heated to 100 °C
for 36 hours under vigorous stirring. Upon completion, the reaction mixture was cooled to room
temperature, filtered with celite and washed with DCM. The solvents were removed under reduced
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pressure and the resulting mixture was purified by a silica gel-packed flash chromatography column
using hexanes/EtOAc (5/1 to 3/1 to 2/1) as the eluent.
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Acknowledgements. We gratefully acknowledge The Scripps Research Institute (TSRI) and the
NIH (NIH (NIGMS, 2R01GM084019) for financial support. We thank SIOC, Zhejiang Medicine and
Pharmaron (fellowships to G.C.). We thank Drs Joel Barrish, John Kadow and Percy Carter for helpful
discussions on the amino acid synthesis.
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Supporting Information Avialable. Detailed experimental procedures, characterization of new
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
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