Remote C(sp3)-H Oxygenation of Protonated Aliphatic Amines with Potassium Persulfate

Article abstract of DOI:10.1021/acs.orglett.6b03731

This letter describes the development of a method for selective remote C(sp³)-H oxygenation of protonated aliphatic amines using aqueous potassium persulfate. Protonation serves to deactivate the proximal C(sp³)-H bonds of the amine substrates and also renders the amines soluble in the aqueous medium. These reactions proceed under relatively mild conditions (within 2 h at 80 °C with amine as limiting reagent) and do not require a transition metal catalyst. This method is applicable to a variety of types of C(sp³)-H bonds, including 3°, 2°, and benzylic C-H sites in primary, secondary, and tertiary amine substrates.

Full text of DOI:10.1021/acs.orglett.6b03731

Letter
pubs.acs.org/OrgLett
Remote C(sp3)−H Oxygenation of Protonated Aliphatic Amines with
Potassium Persulfate
Melissa Lee and Melanie S. Sanford*
University of Michigan, Department of Chemistry, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: This letter describes the development of a method for
selective remote C(sp3)−H oxygenation of protonated aliphatic
amines using aqueous potassium persulfate. Protonation serves to
deactivate the proximal C(sp3)−H bonds of the amine substrates and
also renders the amines soluble in the aqueous medium. These
reactions proceed under relatively mild conditions (within 2 h at 80
°C with amine as limiting reagent) and do not require a transition
metal catalyst. This method is applicable to a variety of types of
C(sp3)−H bonds, including 3°, 2°, and benzylic C−H sites in primary, secondary, and tertiary amine substrates.
liphatic amines appear in a wide variety of pharmaceuticals
substrates. We report herein a new method that uses aqueous
solutions of inexpensive K2S2O8 for this transformation. This
system is effective for the oxygenation of tertiary and benzylic
C(sp3)−H bonds as well as secondary C(sp3)−H sites.
Furthermore, both alcohol and ketone products can be
accessed from the latter, depending on the reaction conditions.
We further demonstrate that this method can be applied to the
C−H oxidation of unprotected amino acids and other amine-
containing bioactive molecules.
Our initial studies focused on the hydroxylation of the
tertiary C−H bond in 4-methylpiperidine (1) using commer-
cially available and inexpensive K2S2O8 as the oxidant (Table
1).16 Water was selected as the solvent for two reasons. First,
unlike most organic solvents, water lacks C−H bonds that
could undergo competitive oxidation. Second, both K2S2O8 and
the protonated amine substrate are highly soluble in water,
A
and agrochemicals.1 As such, methods for the selective C−
H functionalization of aliphatic amines would be valuable for
the synthesis and late-stage modification of many biologically
active molecules.2 Numerous methods have been developed for
the functionalization of the weak C(sp3)−H bonds α to
nitrogen in these substrates.2b,3 In contrast, it remains much
more challenging to selectively functionalize less activated
C(sp3)−H bonds that are remote from nitrogen.4,5 The
incorporation of various nitrogen protecting groups including
carbamates,6 amides,6b,7 imides,2a,8 and sulfonamides3f,9 has
been used to deactivate the α-C−H bonds and enable C(sp3)−
H functionalization at alternate sites. Similarly, directing groups
have been appended to nitrogen to enforce remote C(sp3)−H
functionalization.2c,10 However, these strategies both require
the additional steps of protecting group installation and
removal. Furthermore, they are only applicable to 1° and/or
2° amine substrates.
Table 1. Remote Hydroxylation of Protonated 4-
Methylpiperidine with K2S2O8
An attractive alternative approach involves the in situ
protonation of unprotected aliphatic amines.2d,11 Protonation
of the nitrogen reversibly converts it into a strong electron-
withdrawing group,12 thereby deactivating the α-C−H bonds.13
We2d,11b and others2a,11a have utilized this protonation strategy
to achieve several different types of amine C(sp3)−H
functionalization reactions. However, existing methods have
significant limitations. For instance, the earliest reported
example of this approach exhibited a small substrate scope
and required the relatively impractical oxidant methyl(trifluoro-
methyl)dioxirane (TFDO).11a,14 More recent approaches have
utilized transition metal catalysts,2a,d,11b which can be expensive
and also difficult to separate from the products. Finally, in most
reported examples, the scope is largely restricted to the
oxygenation of remote primary,11b tertiary,2a or benzylic2d
C(sp3)−H bonds.
K2S2O8
(equiv)
D2SO4
(equiv)
time
(h)
entry
conv 1 (%) yield 2 (%)
1
2
3
4
5
6
1
1
2
2
2
2
1.1
2
4
2
2
2
75
76
47
51
53
75
75
1.1
1.1
>99
>99
>99
50
2.2
3.3
none
2
1
<5
15
a
Yields and conversions determined by H NMR spectroscopy.
We sought to address these limitations by developing an
operationally simple remote C(sp3)−H oxygenation of
protonated amines that is applicable to a broad range of
Received: December 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Hydroxylation of Remote Tertiary C(sp3)−H
Bonds in a Variety of Amine Substrates
while the unprotonated amine is not. As such, these conditions
were expected to enable selective reaction of the protonated
amine.15
In the event, the combination of 1 equiv of 1 and 1.1 equiv of
D2SO4 at room temperature, followed by the addition of 1
equiv of K2S2O8 and heating at 80 °C for 2 h, afforded the 3°
1
alcohol product 2 in 47% yield as determined by H NMR
spectroscopy. A significant quantity of starting material (25%)
remained under these conditions, and increasing the reaction
time to 4 h did not lead to further conversion (entry 2). This
result suggests that the oxidant is consumed within 2 h and thus
that additional oxidant is required to increase the conversion/
yield. Indeed, the use of 2 equiv of K2S2O8 in conjunction with
2.2 equiv of H2SO4 under otherwise identical conditions
resulted in complete consumption of the starting material and
the formation of the 2 in 75% yield (entry 4). Importantly, the
addition of acid is crucial for accessing product 2. As shown in
entry 6, in the absence of acid, <5% of the 3° hydroxylation
product 2 was detected.
Overall, this represents an inexpensive and operationally
simple method for the selective C−H hydroxylation of 1.17
Furthermore, this method is highly complementary to our
recently reported Pt-catalyzed oxidation of protonated
amines.11b As shown in eq 1, the Pt-catalyzed reaction of 1
a
2.2 equiv of H2SO4, 2 equiv of K2S2O8, 80 °C, followed by protection
b
with BzCl. 1.1 equiv of H2SO4, 2 equiv of K2S2O8, 65 °C, followed by
c
protection with BzCl. 2.2 equiv of H2SO4, 2 equiv of K2S2O8, 80 °C.
d
1.1 equiv of H2SO4, 2 equiv of K2S2O8, 65 °C.
We next probed the feasibility of secondary C(sp3)−H
oxidation in the absence of competing tertiary C−H sites.
Initial studies utilized aliphatic amines containing secondary
benzylic C−H bonds. Under our standard reaction conditions
these substrates afforded mixtures of alcohol and ketone
products. For example, 4-ethyl benzylamine reacted to form a
0.94:1 mixture of alcohol 18-OH to ketone 18-O (61% overall
yield of C−H oxygenated products). This ratio could be shifted
toward the alcohol by simply adding less oxidant. For example,
the use of 1 equiv of K2S2O8 under otherwise identical
conditions afforded a 1:0.48 ratio of 18-OH:18-O (55% yield).
The alcohol product was also favored when the benzylic C−H
bonds were closer to the protonated amine. For example,
phenethylamine afforded benzylic alcohol 19-OH as the major
product (19-OH:19-O = 1:0.28) under our standard
conditions. Oxidation of the alcohol is likely slowed due to
the proximity of the electron withdrawing ammonium center.
This transformation also afforded secondary alcohol products
with the nonbenzylic substrate butylamine. Under the standard
conditions, butylamine reacted to form a 1:0.29 ratio of the γ:β-
hydroxylated products (23-OH-a:23-OH-b) in moderate 32%
isolated yield.
leads to selective functionalization at the least hindered primary
C(sp3)−H bond of 1 (to form 3), while the current method
affords tertiary C(sp3)−H hydroxylation with high selectivity.
We next applied this method to the hydroxylation of tertiary
C(sp3)−H bonds in a variety of different amine substrates to
form products 4−17. Notably, the products derived from
primary and secondary amine substrates were subsequently
converted to amides to facilitate isolation (Scheme 1, top),
while the tertiary amine products were isolated directly
(Scheme 1, bottom). In all cases, we observed hydroxylation
at a remote tertiary C−H site. However, the yield and
selectivity varied as a function of substrate. In general, the
highest yields and selectivities were obtained when the tertiary
C−H bond is two or three carbons from the protonated
nitrogen (e.g, forming products 4, 5, 8−10, and 14−16).18 In
systems with longer alkyl chains between the protonated
nitrogen and the tertiary C−H site (e.g., 11, 12), side products
derived from oxidation of secondary C−H bonds along the
chain were detected. This resulted in lower isolated yields of
the major tertiary C−H oxidation product. These secondary
C−H oxidation side reactions could be limited by lowering the
reaction temperature to 65 °C. Notably, small quantities of
related ring oxidation side products were also observed in
systems containing nitrogen heterocycles (13−17).
The results in Scheme 2 show several marked contrasts with
other recently reported systems for the remote C(sp3)−H
oxygenation of protonated amines. For instance, our Pt/Cu
system selectively afforded primary C(sp3)−H hydroxylation
products with substrates such as butylamine.11b White’s
Fe(PDP)/H2O2 system provided ketone products selectively
B
DOI: 10.1021/acs.orglett.6b03731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of protonated amines. This method uses an inexpensive and
safe oxidant (potassium persulfate) and proceeds in water
under relatively mild conditions. We demonstrate that this
transformation is complementary to several recently reported
C−H oxidation reactions of protonated amines, and that it is
applicable to bioactive substrates. As such, we anticipate that
this method will prove useful in medicinal chemistry, for the
late-stage derivatization of amine-containing drug targets.
Scheme 2. Substrate Scope Containing Amines with 2°-
C(sp3)−H Bonds
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03731.
Crystallographic data for 25 (CIF)
Optimization data, experimental data, complete charac-
terization data for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mssanfor@umich.edu.
ORCID
Melanie S. Sanford: 0000-0001-9342-9436
Notes
and was only reported to be effective for oxygenation of
C(sp3)−H bonds that were ≥3 carbons from nitrogen.2a
Meanwhile, our FeCl3/TBHP system only oxidized benzylic
C−H bonds and selectively provided ketone products.2d
Furthermore, no reactivity was observed when the benzylic
C−H sites were <3 carbons from the amine. Overall, these
comparisons highlight the complementarity of the current
method to those reported in the literature.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from NIH NIGMS
(GM073836). M.L. thanks the NSF and Rackham Graduate
School for graduate fellowships. We also thank Jeff Kampf
(University of Michigan) for an X-ray structure determination
and Pablo Cabrera (University of Michigan) for assistance with
obtaining the data shown in Table 1 as well as the TEMPO and
1,4-dinitrobenzene experiments discussed in ref 17.
A final set of studies focused on applying this transformation
to several amine-containing biologically active molecules. As
shown in eq 2, under our standard conditions the Alzheimer’s
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D
DOI: 10.1021/acs.orglett.6b03731
Org. Lett. XXXX, XXX, XXX−XXX