A multifunctional reagent designed for the site-selective amination of pyridines

Article abstract of DOI:10.1021/jacs.0c03537

We report the development of a multifunctional reagent for the direct conversion of pyridines to Boc-protected 2-aminopyridines with exquisite site selectivity and chemoselectivity. The novel reagent was prepared on 200-g scale in a single step, reacts in the title reaction under mild conditions without precautions toward air or moisture, and is tolerant of nearly all common functionality. Experimental and in situ spectroscopic monitoring techniques provide detailed insights and unexpected findings for the unique reaction mechanism.

Full text of DOI:10.1021/jacs.0c03537

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Communication
A Multifunctional Reagent Designed for
the Site-Selective Amination of Pyridines
Patrick S. Fier, Suhong Kim, and Ryan D. Cohen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03537 • Publication Date (Web): 23 Apr 2020
Downloaded from pubs.acs.org on April 23, 2020
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Journal of the American Chemical Society
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A Multifunctional Reagent Designed for the Site-Selective Amination
of Pyridines
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Patrick S. Fier,* Suhong Kim, and Ryan D. Cohen
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
Supporting Information Placeholder
O
F
F
ABSTRACT: We report the development of a multifunctional
reagent for the direct conversion of pyridines to Boc-protected 2-
aminopyridines with exquisite site- and chemoselectivity. The
novel reagent was prepared on 200 gram-scale in a single step,
reacts in the title reaction under mild conditions without
precautions towards air or moisture, and is tolerant of nearly all
common functionality. Experimental and in-situ spectroscopic
monitoring techniques provide detailed insights and unexpected
findings for the unique reaction mechanism.
Me
N
Me
O
F
O
O
N
N
N
H
N
N
F
H
H
F
N
Dayvigo
(Lemborexant)
Reyvow
(Lasmiditan)
Me
O
Cl
NH
N
N
N
CF3
N
O
HN
H
N
NH
N
N
O
F3C
Turalio
(Pexidartinib)
Ubrelvy
(Ubrogepant)
Pyridines are privileged heterocycles as key components of
hundreds of pharmaceuticals and agrochemicals, and thousands of
natural products.1 As such, several methods for the modification of
pyridines have been developed that have expanded access to
pyridine-containing compounds and their derivatives.2 For
example, Minisci-type radical addition reactions are commonplace
for the introduction of carbon-bound fragments,3,4 and numerous
methods have been developed for installing carbon- or heteroatom-
based fragments from pyridine N-oxides or related N-activated
pyridinium species.5,6 However, to avoid the strong oxidants and
activating agents in pyridine N-oxide chemistry, and override
inherent site-selectivity in radical reactions, we sought to develop
a new approach for site-selective functionalization of pyridines.
Me
Ph
Figure 1. Selected Examples of Pharmaceuticals Containing 2-
Aminopyridine Motifs that were Approved by the FDA in 2019.
With the above considerations in mind, we set out to develop a
general method for the conversion of pyridines to 2-
aminopyridines. Initially, we investigated reactions with our
recently reported bifunctional reagent, 1.11 The bifunctional reagent
acts as both an activator for the pyridine ring and as a mild two-
electron oxidant through N-O bond cleavage. Though hundreds of
reaction conditions were investigated with a diverse set of nitrogen-
based nucleophiles and a library of bifunctional reagents, the
targeted products were not detected in any instance. In general,
attack of the nucleophile at the oxime carbon and/or ring-opening
of putative aminal intermediates occurred (Figure 2A).12 To
circumvent these undesired pathways, we designed and tested
several new reagents that would i) react with pyridine to form a
reactive pyridinium salt, ii) provide intramolecular delivery of a
nitrogen nucleophile, thereby iii) directing functionality
exclusively to C-2, iv) prevent ring opening, and ultimately v)
promote 2-electron oxidation/rearomatization through N-O bond
cleavage.
Among the extensive pyridine-containing biologically active
compounds known, 2-aminopyridines play a central role as
privileged pharmacophores found in compounds across all
therapeutic areas.7a In fact, of the small-molecule-based therapetics
that were approved by the FDA in 2019, 8 of 32 (25%) contained a
2-aminopyridine (5 of 32) or 2-aminodiazine (3 of 32) motif (for
examples, see Figure 1).7b Thus, given the importance of 2-
aminopyridines, the challenges associated with pyridine N-oxide
and related chemistry,8 and the extreme conditions and narrow
utility of the Chichibabin reaction,9 we aimed to develop conditions
for the direct conversion of pyridines to 2-aminopyridines that
would be applicable towards the functionalization of drug-like
molecules. Specifically, the target reaction would need to occur
with exquisite site-selectivity, work directly on pyridines without
pre-activation, be tolerant of the protic and Lewis-basic
functionalities found in drug-like molecules, be able to be
conducted on the benchtop without special precautions towards air
or moisture, generate minimal waste, allow for simple purification,
and employ only simple and readily available reagents.10
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A.
1
Attempted Extension of to C-N Bond Formation
BocHN
(1.5 equiv)
ii)
Zn0
(5 equiv)
i) 2
1
2
3
4
(1)
NHBoc
2-electron
NC
NC
N
N+
O-
BSA (3 equiv)
oxidant
HNR2
a
pyridine +
nucleophiles
OMs
dioxane
80°C, 3 h
AcOH
rt, 3 h
N
N
R NH
N
2
activating
group
N+
b
N
11
see ref.
3a
4a
93%
Me
Cl
OMs
tentative structure
1
Me
N
5
a
b
6
7
8
9
Me
N
Having demonstrated the ability of reagent 2 to convert pyridine
to 2-NHBoc pyridine, 200 grams of the reagent were prepared in a
single step (eq 2) from commercially available 5,6-
dichloropyrazine-2,3-dicarbonitrile ($1.35/mmol) and N-Boc
OMs
N
NR2
NR2
N
N
+
OMs
OMs
R2N
B.
Me
N
Me
N
hydroxylamine ($0.05/mmol).14 Purified
2
is crystalline,
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C.
Unsuccessful Designs for Reagents
with Pendent Nitrogen Nucleophiles
Polyfunctional Reagent for
this work
indefinitely stable in air, not shock-sensitive, and is thermally
C-2 Amination (
)
stable in the solid state to 126 °C based on DSC analysis.15
activating group
2-electron
oxidant
O
O
S
2
NC
NC
N
N
Cl
Cl
NC
NC
N
N
Cl
O
NC
NC
N
Cl
O
H
Et3N
THF
OMs
Cl
+
H
NHR
N
N
N
N
HO
Boc
(2)
Boc
NHBoc
N
2
RHN
R
Cl
>200 grams prepared
crystalline, bench-stable
$1.35/mmol
$0.05/mmol
35%
activating
group
pendent
nucleophile
pendent
nucleophile
2-electron pendent
oxidant nucleophile
D.
2
Mechanistic Hypothesis in the Development of for Pyridine Amination
With bulk quantities of reagent 2, the substrate scope was
investigated with respect to the electronic properties of the
substrates and the tolerance of common functional groups (Scheme
1). The reaction sequence allows for the direct functionalization of
pyridines spanning a range of electronically disparate substrates.
The functional group tolerance encompasses protic and
nucleophilic functionality such as alcohols, carboxylic acids, N-H
bearing sulfonamides, amides and indoles, and unprotected
phenols. This is significant, as such functional groups are reactive
towards activating agents used in many pyridine functionalization
methods. The tolerance of such functional groups in this work may
be attributed, in part, to the capping action of the BSA, masking the
functionality as inert silyl derivatives. By design, as a relatively
inert N-O bond is used as the terminal oxidant, the reaction is
tolerant of thioethers and aldehydes, functional groups that are
reactive towards the oxidants used in pyridine N-oxide chemistry.
Cl-
N
Cl
N+
NHBoc
NC
NC
N
N
N
O
NC
NC
N
N
H
:B
Boc
NC
NC
N
N
HCl
N
O
NHBoc
O
BocHN
NC
NC
N
N+
O-
pyrazine cleavage
NHBoc
N
N
Figure 2. Pyridine Functionalization Strategies with
Multifunctional Reagents
Several reagents based on the original bifunctional reagent
design were prepared and tested (Figure 2B), but were either
unstable, due to the presence of a nucleophile and electrophile in
the same molecule, or did not promote the desired reaction. Finally,
we evolved the design by changing the activating group from an
oximoyl chloride to an electron-deficient chloropyrazine, and
transposing the 2-electron oxidant to the nucleophilic nitrogen,
ultimately leading to reagent 2 (Figure 2C).13 The tentative
mechanism that guided the reagent design and reaction
development is shown in Figure 2D, consisting of pyridine
activation, intramolecular delivery of the nitrogen nucleophile,
rearomatization through N-O bond cleavage and tautomerization,
and eventual cleavage of the pyrazine fragment.
Scheme 1. Representative Substrate Scope with
Multifunctional Reagent 2a
With pyridine as a model substrate, conditions were investigated
for C-2 amination by carrying out reactions of 2 in the presence of
HCl scavengers. While typical inorganic or organic bases led to the
decomposition of 2, N,O-bis(trimethylsilyl)acetamide (BSA)
promoted the desired reaction by scavenging HCl through the
generation of TMSCl. Reactions of pyridine with 1.5 equiv of 2 and
3 equiv of BSA in dioxane at 80°C formed the presumed (vide
infra) pyrazine-bound product in nearly quantitative yield after 3 h.
An extensive set of experiments were carried out to investigate
cleavage of the adducts to reveal the 2-aminopyridine product.
Initially, SNAr reactions with a diverse set of nucleophiles were
investigated, but were generally low-yielding. Acid-mediated
hydrolysis could cleave the adducts with removal of the Boc group
under forcing condition (6M HCl, reflux), but the harsh conditions
were deemed impractical. Finally, we discovered that mild
reducing conditions (Zn + AcOH) promote the cleavage at ambient
temperature to reveal the 2-NHBoc pyridine product in high yield
(eq 1).
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Journal of the American Chemical Society
i) BSA (3 equiv)
dioxane
80°C, 3 h
reacted to form 1-NHBoc quinoline exclusively. These selectivity
trends are analogous to known pyridine C-2 functionalization
reactions, including those with pyridine N-oxides,3 cyanation
reactions with 1,11 and fluorination with AgF2.16 Contrasteric
reactions that form the more hindered product may be rationalized
by the increased reactivity of the C-2 carbon relative to the C-6
carbon from inductive or resonance effects, and the relief of
eclipsing interactions during rehybridization in the nucleophilic
addition step.
NC
N
N
Cl
NHBoc
O
1
2
R
R
+
ii) cool to rt
Zn0 (5 equiv)
AcOH, 3 h
H
NHBoc
N
N
4
NC
3
4
3
2
, 1.5 equiv
Me
O
NH2
HO
HO
O
5
6
7
8
9
NHBoc
N
NHBoc
N
NHBoc
NHBoc
, 85%
N
N
b
4a
, 93%
b
4d
, 90%
4b
4c
, 71%
HO
In most cases, reactions were carried out with 0.5 mmol of the
pyridine substrate. The reaction carried out with 4-phenylpyridine
formed the product in the same yield and with the same reaction
profile on both 0.5 and 5.0 mmol scales, in line with expectations
for a homogeneous, air- and moisture-tolerant, thermally-driven
reaction that forms stable products. Furthermore, variants of
reagent 2 containing Cbz or Ts groups in place of Boc were also
prepared on gram-scale and promoted C-2 functionalization of
pyridine under the standard conditions in high yields (eq 3).
CO2Me
O
O
S
HN
NH
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11
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I
N
N
Boc
N
O
NHBoc
N
4e
, 40%
NHBoc
N
O
4f
NHBoc
, 64%
N
4g
, 46%
H
SMe
O
OMe
NC
NC
N
N
Cl
Cl
NC
NC
N
N
Cl
O
NHBoc
, 83%
N
NHBoc
, 82%
(3)
N
N
Et3N
THF
H
4h
NHBoc
, 73%
NHBoc
N
N
N
standard
conditions
NHR
5 mmol scale
N
4k
R
4i
4j
, 77%
+
H
2b
2c
, R = Cbz (41%)
, R = Ts (36%)
R = Cbz (91%)
R = Ts (82%)
F
HO
Br
N
OMe
Cl
R
HO
NHBoc
N
NHBoc
N
NHBoc
N
4o
b
To gain additional insight into the reaction mechanism,
mechanistic and spectroscopic experiments were carried out. First,
a competition reaction was conducted between pyridine and 4-
CO2Me pyridine. Analyzing the reaction after approximately 20%
conversion revealed that only pyridine had reacted with 2 to form
the pyridine-pyrazine adduct, with none of the product formed from
4-CO2Me pyridine (eq 4). This observation is consistent with the
fact that poorly nucleophilic pyridines react slower than more
4m, 68%b
(76:24)
4n
, 83%
(61:39)
b
NHBoc
N
, 91%
(>10:1)
c
4l
, 81%
CF3
F
CO2Me
Ph
F
O
O
BocHN
BocHN
N
N
BocHN
N
b
4p
(>10:1)
, 41%
4q
, 82%
(8:1 ratio)
4r
, 79%
(79:21)
O
NH
N
O
Cl
Cl
nucleophilic pyridines. Next,
a reaction with 2-deuterio-4-
NH2
phenylpyridine was carried out under the standard conditions to
measure the intramolecular KIE (eq 5). At the end of the reaction,
equimolar amounts of the product resulting from C-H and C-D
functionalization were observed.17
NHBoc
BocHN
NHBoc
N
N
b
4u
4t
, 42%
from
Roflumilast
, 89%
4s
, 79%
(>10:1)
H
CO2Me
H
CO2Me
standard
aIsolated yields shown for reactions carried out with 0.5 mmol
of 3 unless otherwise noted. Ratios in brackets refer to the ratio of
the major product (drawn) and the minor isomeric product at the
end of the reaction. bThe yield was determined with a UPLC
instrument calibrated against authentic standards. cThe ketone
group of 3 was reduced to the secondary alcohol in quantitative
yield in the second step.
conditions
(4)
(5)
+
stopped at
~20% conv.
NHBoc
NHBoc
N
N
N
N
exclusive product
Ph
not formed
Ph
Ph
standard
conditions
+
During the investigation of the scope for the pyridine amination
reaction with 2, some limitations became evident that we would
like to disclose. First, 2-substituted pyridines reacted in low yield
due to their significantly reduced nucleophilicity compared to
analogous 3- or 4-substituted pyridines. Similarly, diazine
substrates reacted to form less than 10% of the target products;
attempts to force the reaction were unsuccessful. While the mild
reducing conditions used to cleave the pyrazine-containing product
adducts generally showed broad generality and tolerated aldehyde,
aryl iodide, and 1,2,4-oxadiazole groups, the diaryl ketone in
substrate 4l was reduced to the secondary alcohol in quantitative
yield during the reduction step.
H
D
H
NHBoc
BocHN
D
N
N
N
1.0 : 1.0
ratio
To build on the experimental results, a series of NMR
spectroscopy experiments were carried in dioxane-d8 out to observe
and characterize the intermediates that are formed throughout the
reaction. First, the reaction was monitored at ambient temperature
to observe short-lived reaction intermediates. Within the first 10
minutes, the originally proposed dihydropyridine species 5 was
observed as a major species in the reaction mixture (COSY, HSQC,
HMBC), along with unreacted pyridine. The pyridinium adduct
that results from displacement of the chloride in 2 by pyridine
(Figure 2D) was not observed, consistent with rapid intramolecular
attack of the pendent NHBoc group at the electrophilic C-2 position
occurring as the pyridinium adduct forms. At room temperature,
dihydropyridine 5 reacted further through base-mediated cleavage
of the N-O bond, reaching full conversion after approximately 90
minutes. The originally proposed zwitterionic structure was found
Reactions carried out with 3-substituted pyridines revealed that
functionalization can occur with selectivity to form either the 2,3-
or 2,5-disubstituted products. Pyridine substrates bearing 3-fluoro,
3-bromo, or 3-methoxy substituents formed the 2,3-disubsituted
products preferentially. Larger functional groups such as
(hetero)aryl, methoxycarbonyl, and trifluoromethyl directed
functionalization primarily to the less-hindered carbon. Quinoline
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to be incorrect, with the actual structure (6) containing an OTMS
1
2
3
4
5
6
7
8
group and a deprotonated N-H Boc group on the pyridine. The
structure was unambiguously assigned through COSY, HSQC,
HMBC, LR-HSQMBC,19 NOESY, and 1H/15N HMBC
experiments.
N
+ BSA
dioxane-d8
NC
NC
N
N
Cl
NHBoc
NC
N
N
N
O
H
N
Boc
O
NC
TMSCl
AcNHTMS
In a separate experiment, the final species formed under the
standard reaction conditions after 3 h at 80°C was characterized and
determined to be different than the final species, 6, formed at room
temperature.18 LC/MS analysis of reactions carried out at room
temperature and 80°C clearly showed that the species formed prior
to Zn-mediated reduction were different, suggesting that
isomerization occurs at elevated temperatures. Indeed, the species
observed after heating at 80°C was found to be an isomer of 6 that
results from a net displacement of the pyridine nitrogen with the
Boc-protected nitrogen, forming 7.20 The structure was
unambiguously assigned through COSY, HSQC, HMBC, LR-
HSQMBC,19 NOESY, and 1H/15N HMBC experiments. The
isomerization process was unexpected, and demonstrates the value
of detailed 2D NMR spectroscopy experiments, inculding LR-
HSQMBC19 that provided key long-range correlations of the
proton-deficient molecules, as the structural assignments of 6 and
5,
Major species at rt
during first ~90 min
byproducts
characterized
Boc
N
Boc
9
Rearrangment
at 80°C
N
NC
NC
N
N
NC
NC
N
N
N
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11
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13
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60
N
O
OTMS
TMS
Major species at end of reaction
under standard conditons (80°C)
7,
6
, Major species at rt
after ~90 min
Zn0 (5 equiv)
AcOD-d4, rt, 3 h
H
N
D
NC
H/D
pyrazine-derived
byproduct
Boc
+
N
N
1
NC
N
H
O
7 were ambiguous based on typical H and 13C experiments and
H/D
mass spectrometry.
4a
8
Finally, the reaction mixture was subjected to the Zn-mediated
reduction step in acetic acid-d4. After reduction, the reaction
mixture contained 4a as the only observable pyridine-derived
compound by NMR spectroscopy.21 The structure of the pyrazine
fragment was characterized by the above-mentiond 2D NMR
Figure 3. Reaction Monitoring by NMR Spectroscopy
In summary, we have developed a novel, multifunctional reagent
for the conversion of pyridines to Boc-protected 2-aminopyridines.
A series of mechanistic and spectroscopic experiments demonstrate
that the multifunctional reagent effects the C-2 amination of
pyridines by activating pyridine as a pyridinium salt, directing the
spectroscopy experiments, including
LR-HSQMBC, and
determined to be compound 8.
The combination of experimental observations and
characterization of intermediates allows for a detailed mechanism
to be proposed. The attack of the pyridine substrates at the
chloropyrazine is product determining (eq 4) and the adduct is
quickly trapped by the pendent NHBoc group. The HCl that is
formally generated in this step reacts with BSA to generate TMSCl
and AcNHTMS (characterized in situ). Based on the results shown
in eq 5, dihydropyridine formation is irreversible. The N-O bond
cleavage occurs with rapid silylation of the liberated oxygen anion,
and the initially formed species undergoes an isomerization to
generate a more stable intermediate. The Zn-mediated reduction
likely proceeds by donation of electrons to the electrophilic
pyrazine, with extrusion of the Boc-protected aminopyridine as
from a putative aminal intermediate, followed by further reduction
to 8.
rapid intramolecular delivery of
a nitrogen nucleophile,
rearomatizing an intermediate dihydropyridine through N-O bond
cleavage, which is then thermally isomerized to a more stable
product before Zn-mediated reduction. Given the utility and scope
of the reaction, the availability of the reagent in bulk quantities in
a single step, and the straightforward reaction set-up, we are
confident this new method will be valuable for pyridine
functionalization. Building upon the concepts and observations
reported here, the invention of new multifunctional reagents to
carry-out synthetically useful reactions is the focus of several
ongoing projects in our lab.
ASSOCIATED CONTENT
Supporting Information
Experimental details and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: patrick.fier@merck.com
ACKNOWLEDGMENT
We would like to thank our Merck colleagues L.C. Campeau, Ben
Sherry, and Kevin Maloney for their helpful feedback. We thank
Ralph Zhao and Don Bachert of Merck for carrying out the physical
safety assessment of 2. S.K. would like to thank the Merck & Co.,
Inc., Rahway, NJ, USA internship program.
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(14) Prices based on Combi-blocks online catalog at the time of
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(15) No decomposition or loss of activity was observed over 6 months
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precautions towards air or moisture. For additional details on the thermal
stability and safety assessment of 2, see the Supporting Information.
(16) (a) Fier, P. S.; Hartwig, J. F. Selective C-H Fluorination of Pyridines
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appreciable rates.
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imidation of arenes and heteroarenes via visible light induced
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(21) Intermediate 6 also reacts with Zn + AcOH to form product 4a.
(7) 2-aminopyridines are often utilized as stable, non-genotoxic isosteres
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