N-Heteroarylation of Optically Pure α-Amino Esters using the Pd-PEPPSI-IPentCl-o-picoline Pre-Catalyst

Article abstract of DOI:10.1002/chem.201603933

A robust, mild, and efficient method for the Pd-catalyzed N-heteroarylation of optically pure α-amino esters was developed. Dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](o-picoline)palladium(II) (Pd-PEPPSI-IPent^Cl-o-picoline; PEPPSI=pyridine enhanced pre-catalyst preparation, stabilization, and initiation) was shown to effectively couple a variety of amino acids as the tert-butyl ester with heteroaryl chlorides in high yields and with excellent stereoretention of the acidic proton adjacent to the ester. Control experiments revealed that racemization is base-mediated, with no evidence of Pd-mediated β-hydride elimination when using Pd-PEPPSI-IPent^Cl, and that racemization occurs only after the product is formed, that is, the non-arylated starting amino ester does not deprotonate under our reaction conditions. Studies also revealed that increasing the steric bulk of the ester moiety on the amino acid (e.g., ethyl to tert-butyl) drastically slows racemization of the product.

Full text of DOI:10.1002/chem.201603933

A Journal of
Accepted Article
Title: N-Heteroarylation of Optically Pure -Amino Esters using the Pd-PEPPSI-
IPentCl-o-picoline Pre-catalyst
Authors: Michael G Organ; Sepideh Sharif; David Mitchell; Michael Rodriguez; Jen-
nifer L. Farmer
This manuscript has been accepted after peer review and the authors have elected
to post their Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by using the Digital
Object Identifier (DOI) given below. The VoR will be published online in Early View as
soon as possible and may be different to this Accepted Article as a result of editing.
Readers should obtain the VoR from the journal website shown below when it is pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201603933
Link to VoR: http://dx.doi.org/10.1002/chem.201603933
Supported by

Chemistry - A European Journal
10.1002/chem.201603933
COMMUNICATION
N-Heteroarylation of Optically Pure α-Amino Esters using the
Pd-PEPPSI-IPentCl-o-picoline Pre-catalyst
Sepideh Sharif,[a] David Mitchell,[b] Michael J. Rodriguez,[b] Jennifer L. Farmer,[a] and Michael G.
Organ*[a,c]
Abstract: A robust, mild, and efficient method for the Pd-catalyzed
N-heteroarylation of optically pure amino esters was developed.
Pd-PEPPSI-IPentCl-o-picoline was shown to effectively couple a
variety of amino acids as the tert-butyl ester with heteroaryl
chlorides in high yields and with excellent stereoretention of the
acidic proton adjacent to the ester. Control experiments revealed
that racemization is base mediated, with no evidence of Pd-
mediated β-hydride elimination when using Pd-PEPPSI-IPentCl, and
that racemization occurs only after the product is formed, i.e., the
non-arylated starting amino ester does not deprotonate under our
reaction conditions. Studies also revealed that increasing the steric
bulk of the ester moiety on the amino acid (e.g., ethyl to tert-
butyl) drastically slows racemization of the product.
typically required. While the advent of Pd-catalyzed amination
reactions has obviated the substrate scope limitation associated
with copper-catalyst systems, there exist only a few reports on
Pd-catalyzed N-(hetero)arylation of optically pure α-amino
acids(esters).[9,14,15] However, retention of stereochemistry of the
product still remains a significant challenge with Pd catalysis, as
racemization of the α-chiral amines can occur through β-hydride
elimination (BHE) during the catalytic cycle.[8] One way to
overcome this challenge is through ligand design. Bulky
phosphine ligands, which have been reported to facilitate fast
reductive elimination (RE) and suppress BHE, have been
successfully employed in these amination reactions, coupling a
variety of (hetero)aryl halides with α-amino acids(esters) in
moderate-to-excellent yields.[9,14,15] However, these catalyst
systems generally require temperatures in excess of 90 °C to
achieve acceptable levels of conversion to product.
Primary α-amino acids(esters) (i.e., RO2CCH(NH2)R’)
have an additional selectivity concern as overarylation of the
amine can occur taking the desired monoarylation product
(RO2CCH(NHAr)R’) to the diarylated product (RO2CCH(NAr2)R’).
For example, the use of α-amino acids(esters) with relatively
less bulky alkyl groups at the α carbon (e.g., methyl and benzyl
vs. isopropyl and sec-butyl) have been shown to decrease the
efficiency of these transformations, with significant amounts of
Aromatic amines bearing a stereocenter adjacent to the nitrogen
are important building blocks for the synthesis of many bio-
medically active molecules.[1-4] Since the biological properties of
different stereoisomers can differ markedly,[5] much attention has
focused on developing enantioselective methods for the
synthesis of optically pure aromatic amines. Amongst the
numerous chiral aromatic amines, the synthesis of N-heteroaryl
α-amino acids(esters) have proven to be quite challenging. This
is a consequence of the lower pKa value of the α proton on
chiral α-amino acids(esters), relative to simpler chiral amines.
This makes the former chiral amines more prone to racemization, di-N-arylated products being reported.[9] Further, the chiral
even under mildly basic conditions. While traditional methods,
such as nucleophilic aromatic substitution (SNAr), have been
used to access N-heteroaryl α-amino acids(esters), the
substrate scope has largely been limited to activated aryl
halides.[4,6] Further, elevated temperatures (usually >100 °C) are
often required, which can lead to decomposition. More recently,
transition metal-catalyzed aminations of (hetero)aryl halides with
optically pure amines has emerged as an alternative approach
for the preparation of aromatic amines of high enantio-purity.[7-9]
Copper-catalyzed Ullmann-type reactions have, in certain cases,
proven to be effective in preparing optically enhanced
arylamines from amino acids, however the substrate scope for
the oxidative addition partners has been limited to the use of aryl
bromides and iodides with no reports on the use of heteroaryl
halides or aryl chlorides.[7,10-13] In addition, strong heating
(usually >80 °C) along with prolonged reaction times are
integrity of the α-amino acids(esters) was not preserved,
presumably due to faster rates of BHE over RE.[14] Thus, a
catalyst system that is capable of coupling aryl halides with
optically pure α-amino acids(esters) with high enantio-retention,
which is also selective for monoarylation, has yet to be
developed.
Recently, we reported Pd-PEPPSI-IPentCl (PEPPSI =
Pyridine Enhanced Pre-catalyst Preparation, Stabilization, and
Initiation) (1; Figure 1) to be a highly reactive and selective pre-
catalyst for the monoarylation of (hetero)aryl halides with
primary aliphatic amines.[16] This pre-catalyst has also
demonstrated high selectivity in the Negishi cross-coupling of
secondary organozinc reagents favouring formation of the non
rearranged product due to suppression of the BHE pathway.[17]
Putting these facts together it would seem that 1 could therefore
be used for the selective monoarylation of heteroaryl halides
with optically pure α-amino esters, while suppressing BHE that
leads to racemization, to yield N-heteroaryl α-amino esters
selectively.
[a]
[b]
[c]
S. Sharif, Dr. J. L. Farmer, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, Ontario, M3J 1P3 (Canada)
Dr. D. Mitchell, Dr. M. J. Rodriguez
Lilly Research Laboratories, A Division of Eli Lilly and Company
Indianapolis, IN 46285 (USA)
Professor Michael G. Organ, Director, Centre for Catalysis
Research and Innovation (CCRI) and Department of Chemistry,
University of Ottawa, Ottawa, Ontario, Canada,
Email: organ@uottawa.ca
Figure 1. Highly active Pd-PEPPSI pre-catalysts in C-N coupling.
Cl
Cl
Cl
Cl
N
N
N
N
Cl Pd Cl
N
Cl Pd Cl
N
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Cl
Pd-PEPPSI-IPentCl (1)
Pd-PEPPSI-IPentCl-o-picoline (2)
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Chemistry - A European Journal
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COMMUNICATION
We began our study by evaluating 1 in the coupling of 2-
chloropyridine (3) with L-phenyl alanine ethyl ester hydrochloride
(4) using the hindered and mild base sodium BHT (BHT= 2,6-di-
t-butyl-hydroxytoluene) (Table 1, entry 1). We envisioned that
the use of such a base would suppress the base-mediated
racemization pathway. The cross-coupled product was formed in
low yield (15% yield), with significant erosion of the stereocenter.
The use of less sterically encumbered phenolate bases, such as
the sodium salt of 2,4-dimethyl phenol and phenol, did not
significantly improve the yield nor the stereochemical retention
(Table 1, entries 2 and 3). Other inorganic bases, such as K3PO4
and ZnHMDS, which have previously been reported by Hartwig
and co-workers[18] to be non-racemizing bases, did not improve
the stereochemical retention of the coupled product (Table 1,
entries 4 and 5). Cesium carbonate, which has been used
extensively in other amination reactions[19-21] and is perhaps the
most mild of inorganic bases, was next investigated. Complete
conversion of the oxidative addition partner (3) was recorded at
80 °C, albeit with poor enantiomeric purity (Table 1, entry 6). It is
possible that the elevated temperature of the reaction could be
responsible in some way for the low observed enantio-retention.
To examine this possibility, Pd-PEPPSI-IPentCl-o-Picoline (2,
Figure 1), which has been previously reported by our group to
be a highly efficient pre-catalyst in room temperature aminations
of highly deactivated electrophiles, was next evaluated.[21] The
reaction temperature was lowered from 80° C to 60° C and
better enantio-retention (76% ee) was observed (Table 1, entry
7). Of note, the degree of racemization showed no dependence
on the concentration of the aryl halide in the reaction mixture
(Table 1, entry 8).
the ester moiety and the enantio-retention of the cross-coupled
product, where an increase in the steric bulk led to higher
preservation (Table 2). For example, when the methyl derivative
(6) was used instead of ethyl ester analogue 4, enantio-retention
of the cross-coupled product (8) decreased from 76% to 53%
(Table 2, entries 1 and 2). However, when the tert-butyl ester (7)
was employed, the desired mono-arylated product (9) was
obtained in high yield as a single isomer (Table 2, entry 3).
When the free base amino ester was used, the amount of
Cs2CO3 could be reduced to 1.5 equivalents and still furnish the
product in high yield while retaining the stereocenter (>99% ee).
We also recognize that the tert-butyl esters of amino acids offer
significant advantages over their ethyl and the methyl congeners.
For example, the free base tert-butyl esters of amino acids have
longer shelf lives[22] and as a protecting group, can be cleaved
readily under significantly more mild conditions.
Table 2. Influence of sterics of the ester moiety of the amino ester
on %enantio-retention.
NH2
2 (3 mol%)
Ph
O
Cs2CO3 (2.7 equiv.)
Bn
R
+
O
O
N
Cl
·HCl
DME, 60 oC, 16 h
N
N
R
H
O
3 (1.0 equiv.)
1.3 equiv.
Entry
R
% conv. of 3[a]
Product
% Yield [b]
% ee [c]
53
1
2
3
Me (6)
Et (4)
100
100
100
8
5
9
83
93
95
76
tBu (7)
98
[a] Percent conversion of 3 to coupled product was determined by 1H NMR
spectroscopic analysis of the crude reaction mixture. [b] Yields are reported on
isolated product following purification by column chromatography on silica gel.
[c] Percentage ee of product was determined by chiral HPLC analysis.
Table 1. Influence of basic additives and pre-catalysts 1 and 2 on the enantio-
retention and conversion of 2-chloropyridine (3) and L-phenyl alanine ethyl
ester hydrochloride (4) into 5.[a]
Pre-catalyst (3 mol%),
NH2
To further understand the racemization process, we
Bn
additive (3.0 equiv.),
+
Ph
OEt
OEt
N
Cl
conducted additional control experiments. When
5
was
N
N
H
Solvent (0.25 M) , 80 °C, 24 h
O
·HCl
O
subjected to the optimized reaction conditions a significant
decrease in enantio-retention was observed (Table 3, entry 1).
To ensure the stereocenter was thermally stable 5 was stirred in
DME at 80 °C for 24 hours, however no change in enantio-purity
was observed (Table 3, entry 2). When 5 was treated under
similar reaction conditions to entry 1 but this time in the absence
of the base, again no degradation of the stereocenter was
observed (Table 3, entry 3). This result confirms that Pd-
PEPPSI-IPentCl does not undergo BHE of the amine product,
just as it resists BHE with secondary alkyl cross-coupling
partners.[17] However, when 5 was treated with only base (e.g.,
Cs2CO3) and stirred at 80° C for 24 hours, enantio-purity
diminished drastically, suggesting racemization is base
dependent (Table 3, entry 4). When 9 was treated with Cs2CO3
(Table 3, entry 5), racemization did occur, however, to a lesser
extent than with 5 (Table 3, entry 4). This suggests that an
increase in steric bulk of the ester moiety helps to suppress the
3
(0.25 mmol)
4
(1.3 equiv.)
5
Pre-
catalyst
% conv.
of 3
% Yield[b]
(% ee)[c]
Entry
1
Base
Solvent
Toluene
Na-BHT
Na-2,4-dimethyl
phenolate
Na-Phenolate
K3PO4
1
20
15 (0)
2
3
Toluene
Toluene
DME
1
1
1
1
1
2
2
45
48
38 (10)
39 (13)
21 (54)
-
4
28
5
ZnHMDS
Cs2CO3
DME
10
6
DME
100
100
100
73 (58)
83 (76)
81 (76)
7[d]
8[e]
Cs2CO3
DME
Cs2CO3
DME
[a] Percent conversion of 3 to 5 was determined by 1H NMR spectroscopic
analysis of the crude reaction mixture. [b] Yields are reported on isolated
product following purification by column chromatography on silica gel. [c] The
percent ee of 5 was determined by chiral HPLC analysis. [d] Reaction was
carried out at 60°C. [e] Concentration of 3 = 0.125 M.
base-mediated
racemization
pathway.
Similar
control
experiments were carried out with 4 and the chiral integrity of the
aminoester remained intact throughout the reaction (Table 3,
entries 6-8). This study reveals that racemization only occurs to
the arylated amine product, and not the primary amine, and that
this process is mediated solely by the base.
While trying to understand the origin of the observed
racemization, a correlation was found between the steric bulk of
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COMMUNICATION
Table 3. Investigating the source of racemization.[a]
picoline (2) was developed. Using this method, a variety of N-
heteroaryl α-amino esters were prepared in high yield with
excellent enantiomeric purity. Extensive control experiments
have proven that racemization only occurs with the cross-
coupled product and is base mediated with no evidence of
catalyst-mediated BHE being observed. The use of tert-butyl
amino acid esters, which are readily accessible, is key to obtain
products possessing very high levels of enantio-purity, and
produces products that are easily converted to the
corresponding carboxylic acid.
Bn
Bn
R1
condition,
R1
O
O
R2
N
R2
N
H
DME , 80 oC, 24 h
H
O
O
Starting
Amine
Initial
%ee
Final
%ee
Entry
1[b]
R1
Ar
R2
Et
additives
2 (3 mol%),
5
84
8
Cs2CO3 (3.0 equiv.)
-
2[b]
3[b]
4b]
Ar
Ar
Ar
Ar
Et
Et
Et
5
5
5
9
84
84
84
98
84
84
8
Table 4. Scope of amination of heteroaryl halides using optically pure α-amino
2 (3 mol%)
esters.[a,b]
2 (3 mol%)
Cs2CO3 (1.5 equiv.)
Cs2CO3 (3.0 equiv.)
Cs2CO3 (3.0 equiv.)
2 (3 mol%),
NH2
R
OtBu
(Hetero)Ar
(Hetero)Ar-X
(1.0 equiv.)
OtBu
+
5[b]
tBu
61
R
N
DME , 60-80 ° C, 24 h
H
O
O
(1.3 equiv.)
6
H
Et
4
> 99
> 99
Bn
Bn
Bn
Cs2CO3 (3.0 equiv.)
2 (3 mol%)
N
OtBu
OtBu
OtBu
N
N
N
O
N
N
7
8
H
H
Et
Et
4
4
> 99
> 99
> 99
> 99
H
H
H
O
O
O
Cs2CO3 (3.0 equiv.)
12, 74% Yield, 80% ee
10, 85% Yield, 90% ee
11, 89% Yield, 90% ee
[a] Initial and final percentage ee of substrate was determined by chiral HPLC
analysis. [b] Ar = 2-pyridyl
OtBu
OtBu
N
OtBu
N
N
N
N
N
H
H
H
O
O
O
To confirm that BHE is not responsible for the observed
racemization we needed to ensure that the pre-catalyst is
activated under the reaction conditions of our control
experiments employing 2. To this end 1.0 equivalent of 3 was
reacted with 5 mol% of free base 7, in the presence of 5 mol%
Cs2CO3 and 3 mol% of 2 at 80° C (Scheme 1). These are the
cross-coupling conditions so reduction of 2 is certain. Three
hours later, 0.1 equivalents of 9 was added and after stirring for
an additional 20 hours, no apparent change was observed in
enantio-purity of 9, thus confirming that BHE is not operative.
13, 87% Yield, 99% ee
14, 95% Yield, >99% ee
15, 92% Yield, >99% ee
O
O
OtBu
OtBu
OtBu
N
N
N
N
N
N
H
O
16, 83% Yield, >99% ee
17, 85% Yield, > 99% ee
18, 76% Yield, 96% ee
OtBu
N
N
Bn
OtBu
N
N
N
N
H
H
O
O
19, 87% Yield, >99% ee
20, 89% Yield, 98% ee [c]
2 (3 mol%)
NH2
O
Cs2CO3 (5 mol%)
9 (0.1 equiv.) 98 % ee
DME, 80 °C, 20 h
O
Bn
O
Bn
Ph
OtBu
OtBu
+
N
N
N
Cl
N
OtBu
DME, 80 °C, 3 h
N
OtBu
H
N
N
O
N
N
H
H
O
3 (1.0 equiv.)
7 (5 mol %)
9 (98% ee)
O
21, 90% Yield, >99% ee
22, 96% Yield, 90% ee
Scheme 1. Determination of racemization pathway.
[a] Yields are reported on isolated product following purification by column
chromatography using silica gel. [b] Percentage ee of product was determined
by chiral HPLC analysis. [c] Ar-Br was used.
With the optimized reaction conditions in hand, we set out
to explore the substrate scope and generality of this
transformation (Table 4). A wide variety of heterocyclic chlorides
were efficiently coupled with the tert-butyl ester of L-alanine, L-
valine, L-phenylalanine, L-isoleucine, and L-proline in very high
yield as the mono-arylated product and with excellent enantio-
purity (Table 4, products 10-22). Moreover, oxidative addition
partners possessing multiple heteroatoms, including 2-
chloropyrazine (19), 5-bromopyrimidine (20), and 2-chloro-6-
methoxypyridazine (21-22) were successfully coupled with a
variety of amino esters, generating the arylated product in
excellent yield and very high enatio-purity (Table 4). We also
evaluated the scalability of the reaction by synthesizing 9 on a
10 mmol scale and the desired product was isolated in 93%
yield with excellent enantio-retention (>99% ee).
Acknowledgements
This work was supported by NSERC Canada in the form of a
CRD grant and by the Eli Lilly Research Award Program (LRAP).
We also would like to thank Professor Arturo Orellana and Dr.
Debasis Mallik for assistance with HPLC.
Keywords: N- heteroaryl α-amino esters• amination • cross-
coupling • palladium • PEPPSI
[1]
[2]
P. Maity, B. König, Org. Lett. 2008, 10, 1473.
M. Hammond, J. R. Patterson, S. Manns, T. H. Hoang, D. G. Washburn,
W. Trizna, L. Glace, E. T. Grygielko, R. Nagilla, M. Nord, H. E. Fries, D.
In conclusion, a robust, mild and efficient method for N-
heteroarylation of α-amino esters using Pd-PEPPSI-IPentCl-o-
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COMMUNICATION
J. Minick, N. J. Laping, J. D. Bray, S. K. Thompson, Bioorganic Med.
Chem. Lett. 2009, 19, 2637.
[3]
[4]
B. Xu, Y. Sun, Y. Guo, Y. Cao, T. Yu, Bioorg. Med. Chem. 2009, 17,
2767.
P. M. Chandrika, T. Yakaiah, A. R. R. Rao, B. Narsaiah, N. C. Reddy, V.
Sridhar, J. V. Rao, Eur. J. Med. Chem. 2008, 43, 846.
L. A. Nguyen, H. He, C. Pham-Huy, Int. J. Biomed. Sci. 2006, 2, 85.
M. G. Bursavich, S. Lombardi, A. M. Gilbert, Org. Lett. 2005, 7, 4113.
D. Ma, J. Yao, Tetrahedron: Asymmetry 1996, 7, 3075.
S. Wagaw, R. A. Rennels, S. L. Buchwald, J. Am. Chem. Soc., 1997,
119, 8451.
[5]
[6]
[7]
[8]
[9]
H. Hammoud, M. Schmitt, E. Blaise, F. Bihel, J. J. Bourguignon, J. Org.
Chem. 2013, 78, 7930.
[10] D. Ma, Y. Zhang, J. Yao, S. Wu, F. Tao, J. Am. Chem. Soc. 1998, 8,
12459.
[11] Z. Lu, R. J. Twieg, Tetrahedron Lett. 2005, 46, 2997.
[12] N. Narendar, S. Velmathi, Tetrahedron Lett. 2009, 50, 5159.
[13] K. K. Sharma, S. Sharma, A. Kudwal, R. Jain, Org. Biomol. Chem.
2015, 13, 4637.
[14] F. Ma, X. Xie, L. Ding, J. Gao, Z. Zhang, Tetrahedron 2011, 67, 9405.
[15] R. Surasani, D. Kalita, A. V. Dhanunjaya Rao, K. B. Chandrasekhar,
Beilstein J. Org. Chem. 2012, 8, 2004.
[16] S. Sharif, R. P. Rucker, N. Chandrasoma, D. Mitchell, M. J. Rodriguez,
R. D. J. Froese, M. G. Organ, M. G. Angew. Chem. 2015, 127, 9643;
Angew. Chem. Int. Ed. 2015, 54, 9507.
[17] M. Pompeo, R. D. J. Froese, N. Hadei, M. G. Organ, Angew. Chem.
2012, 124, 11516; Angew. Chem. Int. Ed. 2012, 51, 11354.
[18] D. Y. Lee, J. F. Hartwig, Org. Lett. 2005, 7, 1169.
[19] K. H. Hoi, S. Çalimsiz, R. D. J. Froese, A. C. Hopkinson, M. G. Organ,
Chem. Eur. J. 2011, 17, 3086.
[20] K. H. Hoi, S. Çalimsiz, R. D. J. Froese, A. C. Hopkinson, M. G. Organ,
Chem. Eur. J. 2012, 18, 145.
[21] M. Pompeo, J. L. Farmer, R. D. J. Froese, M. G. Organ, Angew. Chem.
2014, 126, 3287; Angew. Chem. Int. Ed. 2014, 53, 3223.
[22] G. W. Anderson, F. M. Callahan, J. Am. Chem. Soc. 1960, 82, 3359.
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COMMUNICATION
10.1002/chem.201603933
S. Sharif, D. Mitchell, M. J. Rodriguez, J.
L. Farmer, M. G. Organ*
Page No. – Page No.
N-Heteroarylation of Optically Pure
Amino Esters using the Pd-
PEPPSI-IPentCl-o-picoline Pre-catalyst
A robust, mild, and efficient method for the Pd-catalyzed N-heteroarylation of
optically pure amino esters was developed. Pd-PEPPSI-IPentCl-o-picoline was
shown to effectively couple a variety of amino acids as the tert-butyl ester with
heteroaryl chlorides in high yields and with excellent stereoretention of the acidic
proton adjacent to the ester. Control studies revealed that racemization is base
mediated, with no evidence of Pd-mediated βhydride elimination being observed,
and that racemization occurs only after the product is formed.
This article is protected by copyright. All rights reserved