Ligand-Enabled γ-C(sp3)–H Acetoxylation of Triflyl-Protected Amines

Article abstract of DOI:10.1002/ejoc.201800891

A palladium-catalyzed γ-C(sp³)–H acetoxylation of triflyl-protected amines has been achieved. The use of pyridine or 2-alkoxyquinoline-type ligands is key to the success of this transformation. The reaction is highly diastereoselective and easily scalable, and constitutes a direct approach for the synthesis of γ-hydroxy-α-amino acids and β,γ-dihydroxy amines, which are not readily accessible by other routes.

Full text of DOI:10.1002/ejoc.201800891

A Journal of
Accepted Article
Title: Ligand-Enabled γ-C(sp3)-H Acetoxylation of Triflyl-Protected
Amines
Authors: Wen-Liang Jia and Maria Ángeles Fernández-Ibáñez
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
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using the Digital Object Identifier (DOI) given below. The VoR will be
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800891
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800891
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201800891
COMMUNICATION
3
Ligand-Enabled γ-C(sp )–H Acetoxylation of Triflyl-Protected
Amines
Wen-Liang Jia and M. Ángeles Fernández-Ibáñez*
3
Abstract: Palladium-catalyzed -C(sp )–H acetoxylation of triflyl-
protected amines has been achieved for the first time. The use of
pyridine or 2-alkoxyquinoline-type ligands is key to the success of
this transformation. The reaction is highly diastereoselective and
easily scalable and constitutes a direct approach for the synthesis of
γ-hydroxy-α-amino acids and β,γ-dihydroxy amines, which are not
readily accessible by other routes.
palladium catalyst and PhI(OAc)
2
as the oxidant, in 1,2-
dichloroethane (0.1 M) at 110 C. Under these conditions, only
̊
trace amount of acetoxylated product 2a were detected after 20
h (Table 1).
3
Table 1. Screening of ligands for the -C(sp )–H acetoxylation of N-triflyl-L-
valinate.[a,b]
Introduction
In
the
past
decades,
palladium-catalyzed
C–H
functionalization reactions have attracted substantial attention
from organic chemists.[1] The ability to install functionalities into
molecules directly from inert C–H bonds can streamline and
shorten substantially the synthesis of target compounds. A
common practice to increase both the reactivity and selectivity of
these processes is the use of directing groups.[2] In the case of
3
less reactive C(sp )–H bonds, generally, a bidentate directing
group is needed in order to achieve good reactivity.[3] Recently,
3
the direct and selective functionalization of C(sp )–H bonds has
been achieved combining monodentate directing groups and
ligands.[4-6] In these transformations, the selectivity is controlled
by the directing group and the ligand plays a pivotal role in
3
increasing the reactivity of the inert C(sp )–H bond. For example,
triflyl- or nosyl-protected amines can be efficiently -arylated or -
alkylated in the presence of mono-protected-amino acid or -
aminomethyl oxazoline ligands.[4] Since amines are ubiquitous
subunits in organic molecules, the development of new
methodologies that permit their direct functionalization are of
great interest.[7] For instance, γ-hydroxy-α-amino acids widely
exist in many peptide-based drugs and can be used for native
[
2
a] Reaction conditions: 1a (0.1 mmol, 1.0 equiv), Pd(OAc) (0.01 mmol, 10
mol%), ligand (0.02 mmol, 20 mol%), PhI(OAc)
(
crude mixture using CH Br as internal standard.
2 2
2
(0.25 mmol, 2.5 equiv), DCE
1.0 mL), 110 °C, 20 h. [b] Yields were determined by 1H NMR analysis of the
3
In order to increase the reactivity of the C(sp )–H bond, we
decided to evaluate different ligands in this transformation. Thus,
under the standard reaction conditions, the addition of 1-
methylpyrazole (L1, 20 mol%) provided the desired acetoxylated
product 2a in 29% yield, together with trace amount of
diacetoxylated product 2a’. Encouraged by this result, other
protected 1-methylpyrazole-type ligands were tested. The 5-
methyl substituted ligand L2, exhibited similar behaviour (30%
yield) than L1. When the 5-position of the pyrazole ligand
beared a methoxy group, only 21% yield of the desired product
was detected, while the unprotected 5-hydroxy-1-methylpyrazole
[8]
chemical ligation (NCL). Although several examples of direct γ-
3
C(sp )–H acetoxylation of α-amino acids have been reported,
they all rely on the use of a bidentate directing group to achieve
good reactivity.[9] In our group, we are interested in the
development of new ligands capable of promoting CH
[
10]
functionalization reactions. Herein, we report the first example
3
of Pd-catalyzed γ-C(sp )–H acetoxylation of triflyl-protected
amines assisted by pyridine-based ligands.[11]
(
L4) completely inhibited the reaction. Pyridine-type ligands are
Results and Discussion
known to be effective ligands in CH functionalization
reactions.[ Therefore, we evaluated their effect in the C(sp )–H
acetoxylation reaction. The model reaction in the presence of
pyridine (L5) furnished 2a in 11% yield. The electron-deficient 3-
nitropyridine ligand (L6) provided improved results compared
with pyridine, giving 2a in 24% yield. We also tested different 2-
substituted pyridine ligands. The use of 2-picoline (L7) improved
the yield of 2a up to 40%. The introduction of a methoxy group in
the pyridine ring (L8) showed once more negative effects in the
reaction (20% yield). Very low conversion was also observed
when 2-(trifluoromethyl)pyridine (L9) was employed as ligand,
but the reaction in the presence of 2,6-lutidine (L10) gave 2a in
12]
3
We started our investigations using methyl N-triflyl-L-valinate
(
2
1a) as the model substrate, Pd(OAc) (10 mol%) as the
[
a]
Wen-Liang Jia, Prof. M. Ángeles Fernández-Ibáñez
Van’t Hoff Institute for Molecular Sciences
University of Amsterdam
Science Park 904, 1098 XH, Amsterdam, the Netherlands
E-mail: m.a.fernandezibanez@uva.nl
http://www.fernandezibanezgroup.com/
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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European Journal of Organic Chemistry
10.1002/ejoc.201800891
COMMUNICATION
41% yield. It is worth mentioning that the reaction proceeds
of reaction conditions. Different palladium sources were
cleanly and mainly the acetoxylated product and starting
material were detected in the crude mixture. Finally, we also
tried the reaction using a mono-protected amino acid ligand,
Boc-L-isoleucine (L11), which was an efficient ligand in the
evaluated (entries 10-13), and only Pd(OPiv)
2
furnished slightly
and 1
better yield than Pd(OAc) . The reaction using Pd(OPiv)
2
2
equiv. of AgOAc furnished the acetoxylated products in 63%
total isolated yield (56% monoacetoxylated product 2a and 7%
diacetoxylated product 2a’, entry 14). We performed a control
experiment in the absence of palladium-catalyst and, as
expected, no conversion to the desired product was observed
3
C(sp )–H -arylation and -alkylation of triflyl- or nosyl-protected
amines.[
4a-b]
However, under our reaction conditions, no
acetoxylated product was detected.
(
2
entry 15). Finally, we executed the reaction in the absence of
,6-lutidine (L10) under the optimal reaction conditions and only
Table 2. Optimization of reaction conditions.
17% yield was detected, which highlights the crucial role of the
ligand in this transformation (entry 16). Important features of the
3
2
,6-lutidine enabled C(sp )–H -acetoxylation of methyl N-triflyl-
L-valinate (1a) are that the monoacetoxylated product was
obtained with very high diastereoselectivity (dr
= 13:1;
1
determined by H-NMR) and that no-gemdiacetoxylated product
was observed. The synthetic utility of our methodology was
highlighted in a scale-up of the reaction to a 1.0 mmol of 1a,
providing the acetoxylated products in comparable yields than to
the original value (Table 3).
Entry
Variations from standard reaction conditions
Yield[a] (2a + 2a‘)
41% + traces
42% + traces
26 % + traces
21% + traces
< 10%
1
2
3
4
5
6
7
8
9
None
DCM as solvent
Toluene as solvent
CH
3
CN as solvent
With the optimized reaction conditions in hand, we sought to
explore the substrate scope and limitations of this transformation
AcOH/Ac O (9:1, v/v) as solvent
2
DCM (0.5M)
42% + 3%
traces
(
Table 3). First, we tested different alkyl N-triflyl amino esters.
PhCO
3
tBu (2.0 equiv.), DCM (0.5M)
The reaction with ethyl (1b) or benzyl (1c) N-triflyl-L-valinate
provided the desired monoacetoxylated product in 56% and 49%
yield, respectively, with very high diastereoselectivity. However,
only trace amount of product was detected when tert-butyl N-
triflyl-L-valinate (1d) was used. The reaction with the more
conformationally flexible methyl N-triflyl-L-homoalaninate (1e)
provided the corresponding -acetoxylated product in moderate
yield (36%). The reaction with N-triflyl isoleucine and
alloisoleucine derivatives showed a very different reactivity
profile in agreement with the high stereoselectivity observed in
the reaction with N-triflyl-L-valinates. While the reaction with the
isoleucine derivative 1f provided the acetoxylated product 2f in
AgOAc (2.0 equiv.), DCM (0.5M)
(2.0 equiv.), DCM (0.5M)
, AgOAc (2.0 equiv.), DCM (0.5M)
PdCl , AgOAc (2.0 equiv.), DCM (0.5M)
Pd(TFA) , AgOAc (2.0 equiv.), DCM (0.5M)
Pd(OPiv) , AgOAc (2.0 equiv.), DCM (0.5M)
Pd(OPiv) , AgOAc (1.0 equiv.), DCM
58% + 5%
53% + 6%
32% + 2%
25% + traces
41% + 2%
62% + 7%
60% + 7%
2 2 8
K S O
10
11
12
13
14
PdCl
Na
2
2
4
2
2
2
[
b]
(
0.5M)
No Pd-catalyst, AgOAc (1.0 equiv.), DCM
0.5M)
No ligand, AgOAc (1.0 equiv.), DCM (0.5M)
(56% + 7%)
1
5
6
0%
(
1
17% + traces
a] The yield was determined by 1H NMR analysis of the crude mixture using
CH Br as internal standard. [b] Isolated yield.
39%
isolated yield, the diastereoisomeric alloisoleuceine
[
2
2
derivative 1g furnished the acetoxylated product 2g in 87%
isolated yield. The difference in reactivity between the two
diastereoisomers can be attributed to the greater accessibility of
the C(sp )–H bond in the palladation step. Indeed, this behaviour
has
With a suitable ligand in hand, other reaction conditions were
evaluated (Table 2). A systematic screening of solvents revealed
that dichloromethane (DCM) gave similar yield (42%) than 1,2-
dichloroethane (entries 1-2). Other solvents such as toluene or
acetonitrile provided the monoacetoxylated product 2a in lower
yields (26% and 21% yield, respectively; entries 3-4). When
using AcOH as solvent, almost no conversion was obtained
3
3
been
previously
observed
in
other
C(sp )–H
[3e,h]
functionalization reactions of amino acid derivatives.
Taking
into consideration the outcome of the reaction of N-triflyl
isoleucine 1f and alloisoleucine 1g, we propose that the -
acetoxylation of valine derivatives 1a-c occurs mainly at the pro-
R methyl group.
(
entry 5). When the reaction was performed at higher
concentration (0.5M DCM) similar yield for 2a was obtained
entry 6). Having identified the best solvent, we tested other co-
oxidants in the reaction. Although the use of PhCO t
Bu
completely inhibited the reaction (entry 7), the conversion was
improved to 63% and 59% when AgOAc and K were
t
The reaction with the O- Bu threonine derivative 1h, under
(
optimized reaction conditions, provided the -acetoxylated
product 2h in 45% isolated yield. When the reaction was
performed with the O-TBS protected threonine derivative 1i the
product 2i was obtained in lower yield (23%). Nevertheless,
when the reaction was carried out with O-TBS allothreonine
derivative 1j, the acetoxylated product was formed in higher
yield (49%). Finally, we evaluated if amino alcohols were
suitable substrates for this transformation. When we performed
the reaction of O-acetyl-N-triflyl-L-tert-leucinol (1k) under the
optimized reaction conditions, only 20% 1H-NMR yield was
3
2
2 8
S O
employed, respectively (entries 8-9). We further screened other
pyridine and 2-alkoxyquinoline-type ligands using DCM as
solvent and AgOAc as co-oxidant (see Supporting Information,
Table S4). We found out that some 2-alkoxyquinoline ligands
(
2
L21–L23) provided comparable yields of acetoxylated products
a and 2a’ than 2,6-lutidine. Given that 2,6-lutidine is easily
accessible, we used it as the optimal ligand for further screening
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European Journal of Organic Chemistry
10.1002/ejoc.201800891
COMMUNICATION
obtained. Fortunately, the use of the 2-alkoxyquinoline ligand
L22, which had proved equally efficient than 2,6-lutidine in the
CH acetoxylation of amino acid derivatives (see supporting
information, Table S10), provided the acetoxylated products in
47% isolated yield. Similarly, the reaction of O-acetyl-N-triflyl-L-
valinol (1l), using L22 as external ligand, provided 38% total
yield of acetoxylated products, being the monoacetoxylated
product 2l obtained with high diastereoselectivity (dr = 17:1;
determined by H-NMR).[13]
1
Table 3. Substrate scope.[a,b]
Conclusions
In summary, we have developed the first palladium-
3
catalyzed -C(sp )–H acetoxylation of N-trifyl protected amines.
Key to the success of this transformation is use of pyridine or 2-
alkoxyquinoline-type ligands.
The reaction
is
highly
diastereoselective and takes place with a variety of amino acid
and amino alcohol derivatives in moderate to good yields. This
protocol is easily scalable and constitutes a direct approach for
the synthesis of γ-hydroxy-α-amino acids and β,γ-dihydroxy
amines, which are not readily accessible by other routes. Future
efforts will focus on improving the efficiency of these
transformations by ligand design.
Acknowledgements
We acknowledge financial support from NWO through a VIDI
grant (723.013.006). Wen-Liang Jia gratefully acknowledges the
financial support from China Scholarship Council (CSC).
Keywords: C–H activation • amines • ligand design • palladium •
[
a] See supporting information for detailed reaction conditions. [b] Isolated
1
yields. [c] The reaction was performed on a 1.0 mmol scale. [d] From H NMR
analysis of the crude mixture, the conversion to diacetoxylated product was ca
acetoxylation
5
%. The diacetoxylated product could not be isolated pure by column
chromatography. [e] 20 mol% of Pd(OPiv) and 40 mol% of ligand were used.
f] L22 was used instead of 2,6-lutidine.
[
1]
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2
to form organopalladium(IV) complex. This
palladium(IV) complex can then undergo a CO bond reductive
elimination to form the acetoxylated product and the
palladium(II) catalyst.
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European Journal of Organic Chemistry
10.1002/ejoc.201800891
COMMUNICATION
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Accepted
(DOI:
10.1002/cctc.201701973R1).
2
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3
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800891
COMMUNICATION
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201800891
COMMUNICATION
COMMUNICATION
CH activation*
Wen-Liang Jia and M. Ángeles
Fernández-Ibáñez*
Page No. – Page No.
3
Ligand-Enabled γ-C(sp )–H
Acetoxylation of Triflyl-Protected
Amines
3
Palladium-catalyzed -C(sp )–H acetoxylation of triflyl-protected amines has been
achieved for the first time. The use of pyridine or 2-alkoxyquinoline-type ligands is
key to the success of this transformation. The reaction is highly diastereoselective
and easily scalable and constitutes a direct approach for the synthesis of γ-hydroxy-
α-amino acids and β,γ-dihydroxy amines.
*Direct -functionalization amines
This article is protected by copyright. All rights reserved.