Oxyfunctionalization of the Remote C?H Bonds of Aliphatic Amines by Decatungstate Photocatalysis

Article abstract of DOI:10.1002/anie.201707537

Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H₂O₂ or O₂ as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value-added ketone products. Lastly, NMR spectroscopy using in situ LED-irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.

Full text of DOI:10.1002/anie.201707537

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Accepted Article
Title: Oxyfunctionalization of the remote C-H bonds of aliphatic amines
via decatungstate photocatalysis
Authors: Danielle Schultz, François Lévesque, Daniel A. DiRocco,
Mikhail Reibarkh, Yining Ji, Leo A. Joyce, James F. Dropinski,
Huaming Sheng, Benjamin D. Sherry, and Ian W. Davies
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707537
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Oxyfunctionalization of the remote C–H bonds of aliphatic amines
via decatungstate photocatalysis
Danielle M. Schultz,* François Lévesque, Daniel A. DiRocco, Mikhail Reibarkh, Yining Ji, Leo A. Joyce,
James F. Dropinski, Huaming Sheng, Benjamin D. Sherry, Ian W. Davies
Abstract: Remotely oxygenated aliphatic amines represent an
important class of synthetic building blocks to which there are
currently no direct means of access. Reported here is an efficient
and scalable solution that relies upon decatungstate photocatalysis
2 2 2
under acidic conditions using either H O or O as the terminal
oxidant. Using these conditions a series of simple and unbiased
aliphatic amine starting materials can be oxidized to value added
ketone products. Lastly, in situ LED-irradiated NMR spectroscopy
was utilized to monitor the kinetics of the reaction, enabling direct
translation of the reaction in flow.
Functionalized aliphatic amines represent a common and
important class of chemical building blocks for complex molecule
synthesis. As a consequence, discovering new approaches for
accessing functionalized amine building blocks in a direct and
cost-effective manner is of considerable importance. One of the
most well-studied approaches for the direct functionalization of
Figure 1. Pharmaceuticals that contain aliphatic amines with distal
functionality.
3
[1]
aliphatic amines is through sp C–H oxidation. While the most
[
2]
As pioneered by Hill and coworkers, decatungstate anion has a
long history of performing oxidation reactions on unbiased
prevalent site of C–H oxidation is α to the nitrogen atom,
3
achieving efficient distal oxidation of unactivated sp C–H bonds
[
9]
aliphatic alkanes, with the preliminary studies focusing on the
autoxidation of cyclohexane to cyclohexanol and cyclohexanone
has proven to be considerably more challenging. Recently,
3
effective remote sp C–H hydroxylation of unprotected amines
[
10]
(
Figure 2).
Consequently, we wondered if distal oxygenation
was found to be accessible through the deactivation of the
[
3]
of aliphatic amines could be accomplished by merging the
α
amine C –H bonds via protonation, allowing the less activated
[
3,11]
[
4]
concept of remote C–H activation via amine protonation
decatungstate photocatalysis.
with
and remote C–H bonds to undergo oxidation. Despite the great
strides in amine C–H hydroxylation, the ability to convert simple
and unprotected aliphatic amines to ketone products via 4 e-
[
12-13]
Moreover, we envisioned that
this catalyst system would be less likely to yield a mixture of
alcohol and ketone products, as hydroxylated intermediates
would serve as better substrates for HAT than the starting
material. Lastly, this method would be amenable to continuous
[
5]
oxidation of a methylene remains an unsolved problem. The
value of such a transformation is most apparent in the case of
remotely oxygenated pyrrolidine, piperidine and azepane. This
important class of simple building blocks has a substitution
flow
photochemistry,
overall
making
decatungstate
6
photooxidation a scalable solution for remote amine oxygenation.
pattern prevalent in biologically relevant molecules with the
ketone functional group serving as an excellent handle to
introduce diversity (Figure 1). We hypothesized that the unique
H-atom transfer (HAT) properties of decatungstate anion (DT,
-4
[7]
[8]
[W
10
O
32] ), a polyoxometalate photocatalyst, could provide a
potential solution to this long standing problem.
[*]
Dr. D. M. Schultz, Dr. F. Lévesque, Dr. D. A. DiRocco,
Dr. M. Reibarkh, Dr. Y. Ji, Dr. L. A. Joyce, James F. Dropinski,
Dr. H. Sheng, Dr. B. D. Sherry, Dr. I. W. Davies
Department of Process Research and Development
Merck Sharp & Dohme Corp.
Rahway, NJ, 07065 (USA)
E-mail: danielle.schultz@merck.com
Figure 2. Application of decatungstate photocatalysis toward remote
oxygenation of simple and unbiased amines
Supporting information for this article is given via a link at the end of
the document.
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Pyrrolidine (1) was selected as the model system to study,
as oxidation would yield pyrrolidin-3-one (2), an important
With optimized conditions in hand we began to study the
scope of the transformation, with all reactions conducted on a >5
mmol scale (Table 1). Amine salts were shown to be viable
substrates, precluding the need for additional acid; for example,
norvaline and proline methyl ester were purchased and oxidized
[
6b]
building block present in numerous pharmaceuticals.
described reaction represents a 4 e- oxidation of pyrrolidine (to
The
[
14]
yield the kinetic product) without the formation of 2-pyrrolidone
a transformation that, to the best of our knowledge, has not
–
2 4
as their HCl and H SO salts, respectively. While the cationic
been reported to date. Initial efforts to determine suitable
reaction conditions were carried out via high-throughput
keto amine products were stable in solution, isolations were
achieved through several derivatization methods from the crude
reaction mixtures allowing Boc, Cbz, benzyloxime and
phenylhydrazone products to be isolated. To determine the
efficiency of the photooxidation, assay yields (AY) were
experimentation
(HTE)
in
which
tetrabutylammonium
decatungstate (TBADT) was screened with different oxidants,
acids, and solvents using our photochemical screening
[
15]
[18]
platform
analysis (Figure 3).
generate chlorinated products and other acids such as TFA,
PO , and MSA were found to be less effective. Gratifyingly,
after several rounds of HTE, proof of concept for remote C–H
oxygenation was demonstrated with H SO /H in acetonitrile,
and HPLC with single ion monitoring (SIM) MS for
determined prior to derivatization.
[
16]
Under certain conditions HCl tended to
[a]
Table 1. Decatungstate photocatalyzed oxidation of aliphatic amines
H
3
4
2
4
2 2
O
yielding exclusively 2 in 59% yield with no oxidation at C-2
observed.
Figure 3. Use of HTE to screen conditions for remote oxidation of pyrrolidine.
From this initial proof of concept, we established a standard
set of reactions conditions (Scheme 1) using sodium deca-
[16]
tungstate (NaDT) in place of TBADT for solubility purposes.
[
a] Reactions were performed with 1 equiv of amine on a >5 mmol scale.
1
All reactions were performed in the recently reported small-scale
integrated photoreactor that enabled enhanced photon efficiency
Assay yields (AY) were determined at end of reaction by H NMR analysis with
an internal standard. Isolated yields (IY) reported for derivatized products. [b]
H O as solvent. [c] 23% AY of RSM. [d] 3-aminopropanoic acid formed in 22%
2 2
AY. [e] 2 mol% NaDT, 4 equiv of H O and ACN as solvent.
[
17]
2
in a standardized environment.
2 2
Omission of light, H O , or
NaDT from the reaction led to trace formation of 2; however, the
exclusion of acid led to clean formation of N-hydroxypyrrolidine.
Increasing or decreasing the equivalents of H O failed to
2 2
promote higher yields or efficiency. Little to no conversion was
observed upon the bathochromic shift of the light source to 420
and 450 nm, further supporting that the decatungstate anion is
the active catalyst mediating HAT.
At the outset, we were curious if larger cyclic amines would
yield single oxidation products similar to pyrrolidine. Oxidation of
piperidine proceeded with similar efficiency as pyrrolidine,
yielding a 68% AY (34% IY of 4); however, a 2:1 mixture of γ:β
keto products was observed. In contrast, the oxidation of
azepane led exclusively to oxidation at the most remote C–H
bond in 58% AY, to give 5. This interesting result suggest that a
catalyst controlled HAT event might be operating via an ion pair
of the substrate with the catalyst. Amino acids were also
amenable to oxygenation as was observed in the oxidation of L-
pipecolic acid, (S)-proline methyl ester, and L-norvaline.
Oxidation occurred exclusively at C-4 when L-pipecolic acid and
(
S)-proline methyl ester were subjected to the decatungstate
photooxidation, affording 6 and 7, respectively. C-4 variants of
pipecolic acid and proline represent two large families of
pharmacologically active compounds, and their preparation has
Scheme 1. Optimized reaction conditions performed in photoreactor.
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[
19]
been the subject of several reviews.
Next, we turned our
the LED filament being placed inside the coaxial capillary tube to
isolate it from the reaction mixture (Figure 4B). The sample was
irradiated at 365 nm throughout the reaction course and a series
attention towards the oxidation of linear aliphatic amines that
3
have 1° sp C–H bonds available for oxidation. Expecting a
1
mixture of oxidation products we were instead surprised to find
that the oxidation of L-norvaline and butylamine yielded 8 and 9,
respectively, as single regioisomers. This observed
regioselectivity for oxygenation of distal 2° C–H bonds made us
of H NMR spectra were used to determine the kinetics of the
reaction (Figure 4C). While several different mechanistic
scenarios are likely operable, over the course of 30 h no
additional intermediates were detected, suggesting that 16 plays
a significant role in the formation of 2.
3
question if oxidation of 1° sp C–H bonds were likewise feasible.
Thus, subjection of propylamine, whose 2° C–H bonds are in
closer proximity to the protonated nitrogen yielded 22% of 1°
oxidation product 3-aminopropanoic acid; however, 2° C–H
oxygenation was still favored by the formation of 10 in 57% AY.
In turn, oxidation of amylamine, a substrate with δ 2° C–H bonds,
gave a 2:1 mixture of δ:γ ketone products 11 in 36% AY.
Organic hydroperoxides are common intermediates that
have been observed in the decatungstate photocatalyzed
3
[10, 22]
oxidation of 3° sp C–H bonds with oxygen,
as a result the
identification of 16 made us question if oxygen could be used as
our terminal oxidant. To investigate aerobic conditions, and
avoid the problems associated with scale in batch
[
23]
Long reaction times (17 hours) were required for the benzylic
oxidation of 3-phenylpropylamine to afford 12, potentially due to
the disfavorable approach of the arene ring to the anionic
photochemistry,
we decided to perform the reaction in a
[
16]
commercially available continuous flow reactor setup.
The
generation of a plug flow regime (utilizing a T-mixer) maximizes
[20]
[24]
catalyst for HAT.
N-ethylpyrrolidine, a 3° amine with both
the specific surface area between the liquid/gas phases, thus
linear and cyclic C–H bonds, afforded cyclic oxidation product 13
with no oxidation products derived from oxidation of the ethyl
group detected. Carbocyclic ring oxidation can also be accessed
with these conditions, with cyclopentanone 14 being formed in
overcoming mass transfer limitation associated with batch
processes. To our delight, oxygen served as an effective
oxidant for pyrrolidine; however, >1h residence time was
required which forced us to recycle the reaction mixture through
the reactor. Two light sources were investigated, a medium
pressure mercury lamp (150 W) and a 365 nm LED lamp (62 W
input, 16 W radiant power); however, the LED lamp provided a
faster rates and less decomposition. As shown in Figure 5A,
performing the reaction in a pressurized vessel improved
conversion and a small oxidation scale-up (5 g of pyrrolidine)
resulted in a space time yield of 15 mmol/h/mL, similar to that
observed in batch (Figure 5B).
51% AY (41% IY) from cyclopentylamine. Attempts to oxidize
bridging and smaller carbocyclic/heterocyclic amines have
proven unsuccessful to date and the presence of remote 3° C–H
bonds leads to hydroxylation (see 15). Lastly, unless otherwise
mentioned, no other products were observed during reaction
optimization (see SI) and in Table 1, overall suggesting that
light-mediated decomposition accounts for the remaining mass
balance.
Figure 4. A. Identification of intermediate 16. B. Picture of the NMR tube
setup both assembled and unassembled. C. Kinetics of pyrrolidine
photooxidation using in situ LED-irradiated NMR.
Figure 5. A. Effect of oxygen pressure on the oxygenation of 1 in flow. B. 5 g
pyrrolidine oxidation demonstration in flow.
In conclusion, through the use of decatungstate
photocatalysis in an acidic environment, we were able to effect
the direct conversion of unbiased aliphatic amines to remotely
Throughout the course of our studies we did not observe
hydroxylated products at the end of our reactions; however
halting the oxidation of 1 at 25% conversion revealed an
1
2 2 2
oxidized products using either H O or O as the terminal oxidant.
intermediate by H NMR spectroscopy that was present in a 1:4
More importantly, these conditions provide a scalable solution
for transforming simple and inexpensive aliphatic amines to
value added ketone products that are not readily available and
average >$100/g. Current efforts are underway to further expand
upon this amine oxidation methodology with the hope of
impacting other substrate classes that have eluded direct
oxidation.
ratio with 1. Detailed in situ NMR analysis coupled with direct-
infusion ESI MS/MS allowed for identification of the intermediate
as 3-hydroperoxypyrrolidine 16 (Figure 4A and SI). With this
information in hand, we studied the mechanism of the photo-
chemical oxidation by observing the growth and decay of
intermediate 16. Our studies were carried out utilizing a modified
[
21]
setup to the recently reported in situ LED-irradiated NMR, with
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Keywords: oxidation • photocatalysis • decatungstate • flow •
[
[
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Author(s), Corresponding Author(s)*
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Title
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Danielle M. Schultz,* François
Lévesque, Daniel A. DiRocco, Mikhail
Reibarkh, Yining Ji, Leo A. Joyce,
James F. Dropinski, Huaming Sheng,
Benjamin D. Sherry, Ian W. Davies
Page No. – Page No.
Decatungstate anion, a UV absorbing photocatalyst, was utilized in the conversion
of unprotected aliphatic amines to remotely oxidized ketone building blocks using
Black not Blue
2 2 2
H O or O as the terminal oxidant. LED-irradiated NMR studies aided in the
identification of a key reaction intermediate that ultimately allowed the
transformation to be translated into flow.
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