β-Functionalization of Saturated Aza-Heterocycles Enabled by Organic Photoredox Catalysis

Article abstract of DOI:10.1021/acscatal.1c00099

The direct β-functionalization of saturated aza-heterocycles has remained a synthetic challenge because of the remote and unactivated nature of β-C-H bonds in these motifs. Herein, we demonstrate the β-functionalization of saturated aza-heterocycles enabl

Full text of DOI:10.1021/acscatal.1c00099

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Letter
β‑Functionalization of Saturated Aza-Heterocycles Enabled by
Organic Photoredox Catalysis
Natalie Holmberg-Douglas, Younggi Choi, Brian Aquila, Hoan Huynh, and David A. Nicewicz*
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ABSTRACT: The direct β-functionalization of saturated aza-
heterocycles has remained a synthetic challenge because of the
remote and unactivated nature of β-C−H bonds in these motifs.
Herein, we demonstrate the β-functionalization of saturated aza-
heterocycles enabled by a two-step organic photoredox catalysis
approach. Initially, a photoredox-catalyzed copper-mediated de-
hydrogenation of saturated aza-heterocycles produces ene-carba-
mates. This is followed by an anti-Markovnikov hydrofunctionaliza-
tion of the ene-carbamates with a range of heteroatom-containing nucleophiles furnishing an array of C−C, C−O, and C−N aza-
heterocycles at the β-position.
KEYWORDS: photoredox, organic, catalysis, heterocycle, dehydrogenation, anti-Markovnikov
aturated heterocycles adorn many small-molecule ther-
apeutics and agrochemicals. In particular, piperidine and
ation and hydrogen atom transfer processes (Scheme 1a).33−36
Recently, MacMillan and co-workers developed a C−H
trifluoromethylation of aza-heterocycles via dual hydrogen
atom transfer and copper catalysis, which affords β-
trifluoromethylated pyrrolidines or γ-trifluoromethylated pi-
peridines.16 During the preparation of this manuscript, β-
alkylation of piperidines was demonstrated via a three-step
sequence with bromoacetates via ene-carbamate intermediates
(Scheme 1b).37 Despite these advances, approaches to the
direct installation of heteroatoms are far less developed.
To our knowledge, the only example of direct β-
functionalization to form a heterosubstituted aza-heterocycle
is the oxidative β-sulfonylation using N-iodosuccinimide (NIS)
and sulfinite salts to produce enaminyl sulfones.38 While this is
a versatile synthetic intermediate, this methodology is still
limited by the types of coupling partners in this transformation.
Herein, we report one of the only examples of β-
heterofunctionalization of aza-heterocycles. This approach
relies on two key steps enabled by organic photoredox
catalysis: (1) a copper-mediated dehydrogenation followed by
(2) an anti-Markovnikov alkene hydrofunctionalization.39,40
Each step utilizes an acridinium catalyst as a multipurpose
oxidizing agent via photoinduced electron transfer (Scheme
1c).
S
pyrrolidine are ranked as the first and fifth most common
heterocycles in FDA-approved pharmaceuticals, respectively
(Scheme 1).1 As such, C−H functionalization of these and
other saturated aza-heterocycles would present an attractive
strategy to rapidly synthesize and modify these motifs.
Numerous methods have been developed for the α-
functionalization of aza-heterocycles,2−6 with some strategies
relying on α-lithiation7 or catalytic methods involving
transition metal8,9 or photoredox catalysis.10−13 Direct C−H
functionalization of piperidines at C-4 remains limited, but
some recent work employing transition metal and photoredox
strategies have been communicated for the activation of these
typically unreactive C−H bonds.14−17 Remote functionaliza-
tion of unactivated sp3 C−H bonds, particularly the C-3, or β-
position, in saturated aza-heterocycles, remains a significant
challenge.
A conventional approach to the synthesis of β-functionalized
piperidines typically relies on nucleophilic substitution of the
sulfonate ester from the corresponding 3-hydroxypiperidine.
However, this strategy is severely limited by the minimal
commercial availability of prefunctionalized 3-hydroxypiper-
idines, which are required for the synthesis of more complex
piperidine scaffolds. To circumvent this limitation, it is
common to install the functionality through SNAr reactions
of more decorated pyridiniums followed by exhaustive
hydrogenation to afford the desired saturated heterocycle.18−26
More recently, catalytic approaches to β-substituted aza-
heterocycles commonly rely on transition metal cataly-
sis.15,27−32 For example, β-alkylation of piperidines was
accomplished via ruthenium/NHC catalysis to couple
piperidines with aldehyde or alcohol partners via dehydrogen-
Received: January 8, 2021
Revised: February 12, 2021
Published: February 24, 2021
https://dx.doi.org/10.1021/acscatal.1c00099
© 2021 American Chemical Society
ACS Catal. 2021, 11, 3153−3158
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Letter
Scheme 1. Examples of Bioactive C-3-Substituted Aza-
Table 1. Optimization of Piperidine Dehydrogenation
Heterocycles and Methods for C−H Functionalization at C-
3 through (a) Ruthenium Catalysis,34−36 (b)
Electrochemical Methods,37 or (c) Organic Photoredox
Catalysis
entry
Cu (equiv)
LiNO3 (equiv)
yield
a
1
1.5
1.5
1.5
1.5
1.0
0.50
0.25
0.50
0.25
n/a
1.50
1.50
1.50
1.50
1.50
1.50
1.25
n/a
45%
n/a
62%
80%
84%
48%
86%
81%
a
2
ab
,
3
4
5
6
7
8
c
9
1.25
a
b
c
0.2 M. DCE, TFE, or DCM as the solvent. t-BuOOH (1.0 equiv)
as an additive.
solvent screening was undertaken, but reactivity was only
observed in acetonitrile with a lithium nitrate additive (entry
3). Increasing the reaction concentration from 0.2 to 0.5 M
increased yields up to 62%, and decreasing copper loading to
0.50 equiv improved the yields up to 84% (entries 4−6).
Decreased copper loading to 0.25 equiv was found to maintain
high yields in combination with a terminal oxidant (tert-butyl
peroxide) to facilitate copper(I) reoxidation but failed to
improve the reaction yields beyond 81% (entry 9). The
optimal conditions were found to be 0.50 equiv of Cu(II) with
1.25 equiv of lithium nitrate as a hydrogen-atom-abstracting
reagent in acetonitrile (entry 8).
Having identified the optimal conditions, we explored the
scope of the photoredox-catalyzed dehydrogenation with
various piperidines (Chart 1). Boc- and acyl-protected
piperidines produced the desired unsaturated products 1a
and 1b in good yields. Other piperidine protecting groups,
including Cbz and benzoyl (Bz), produced the desaturated
products 1c and 1d, respectively, albeit in lower yields. Alkyl
substitution at various positions was tolerated, yielding the
We first sought to develop a robust photoredox-catalyzed
dehydrogenation of piperidines to afford the unsaturated 2,3-
ene carbamate starting materials required for the β-
functionalization procedure. The synthesis of enamides and
enecarbamates has been accomplished through an anodic
methoxylation and elimination sequence of the corresponding
amine by Shono and co-workers.41,42 Recently, Marsden
utilized an analogous approach for the synthesis of 2,3-
unsaturated aza-heterocycles,37 but despite these advances, the
synthesis of enecarbamates has remained relatively unex-
plored.43 Our lab has previously established that α-carbamyl
radicals of pyrrolidines, piperidines, and piperazines can be
produced by photoxidation and deprotonation of the parent
saturated heterocycle. Thus, we sought to develop a method to
intercept these radicals with a terminal oxidant to effect
unsaturation.11,12 Our initial aim was to accomplish the
dehydrogenation through hydrogen evolution with cobaloxime
catalysis;44 however, the alkene was only observed in low yield.
We then turned to copper(II) salts, which have been shown to
function as single electron oxidants45,46 that can oxidize α-
amino radicals formed via a Kochi decarboxylation of amino
acids to produce 2,3-unsaturated enamides.47
‡
Chart 1. Dehydrogenation Scope
Reaction optimization was initiated using conditions
resembling Tunge’s conditions with copper(II) acetate as a
terminal oxidant with N-Boc piperidine as a model substrate.47
Lithium nitrate was found to be crucial as an additive in order
to help facilitate the formation of the α-amino radical by
hydrogen atom transfer, which successfully produced the
desired product in 45% yield (Table 1, entry 2).48 Additional
‡
a
Average isolated yields are reported (0.200 mmol, n = 2). Yield
1
determined by H NMR using (Me3Si)2O as an internal standard.
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Chart 2. Aza-Heterocycle β-Functionalization via anti-Markovnikov Hydrofunctionalization: (a) Substrate Scope, (b)
Nucleophile Scope, (c) Application to Pharmaceuticals and (d) Synthesis of Orexin Antagonists
a
b
c
d
Phenylmalononitrile instead of thiophenol. Without NaOAc. 5.0 equiv of nucleophile. Average isolated yields are reported (0.200 mmol, n =
2).
desaturated ene-carbamates 1e−1k in good to moderate yield.
Selective desaturation of 2-methyl piperidines afforded the
products 1e and 1f from oxidation at the less-hindered carbon
center with no loss of stereochemistry with the enantiopure
(S)-2-methylpiperidine. By contrast, 3-methyl piperidines 1g
and 1h afforded a 1:1 mixture of regioisomeric ene-carbamate
products, likely because of unselective 2- vs 6-hydrogen atom
abstraction. Azepane, 1l, undergoes desaturation, albeit in poor
yield (12%), while piperazines and the more strained 5-
membered pyrrolidine were unfortunately unreactive under
these conditions.
piperidines, a synthetic sequence which we anticipated could
be valuable to medicinal chemists.
Our laboratory has established a program for anti-
Markovnikov addition of a range of nucleophiles to simple
olefins via the intermediacy of alkene cation radicals.49 By
comparison, ene-carbamates have been relatively understudied
as potential substrates for this hydrofunctionalization manifold,
with the exception of a single example from our lab,40 but
would accomplish our goal of 3-selective functionalization of
aza-heterocycles. Reaction optimization was started with the
Cbz-piperidinyl ene-carbamate 1c as a model substrate, which
has been shown to undergo β-functionalization with acetic acid
as a nucleophile.40 The optimal conditions were determined to
be with 2.5 equiv of nucleophile with 2.5 mol % Mes-Acr-BF4
With a route to access 2,3-unsaturated ene-carbamates, we
turned our attention to developing a β-functionalization
method that would produce a range of 3-substituted
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Letter
and 20 mol % thiophenol as a hydrogen atom donor in DCE,
furnishing the desired addition product in good yields (see S9
for full optimization details).
trans diastereomer was isolated and carried through a three-
step sequence to give the final orexin antagonist, 5c.
Though preliminary, we propose that the mechanism for
dehydrogenation commences with a photoinduced electron
transfer event (PET) between nitrate anion (Eox= +1.97 V vs
SCE)48,52 and Mes-Acr-BF4* (+ 2.10 V vs SCE), leading to
the formation of nitryl radical.53 The radical then abstracts a
hydrogen atom from the α-piperidinyl C−H position. Either
an inner sphere or outer sphere oxidation of the α-amino
radical by Cu(II) affords the desired ene-carbamate. The
reduced catalyst, Mes-Acr•, is oxidized by an additional
equivalent of Cu(II) acetate to turn over the catalytic cycle and
produce Cu(I). Substoichiometric use of copper acetate was
found to be optimal in these reactions. Disproportionation of
Cu(I) to Cu(0) and Cu(II) or by oxidation of Cu(I) by Mes-
Acr-BF4* could be the mechanism whereby the required
Cu(II) species is regenerated.54 The hydrofunctionalization
begins by an oxidation of the ene-carbamate from Mes-Acr-
BF4*. We have studied the mechanism of alkene anti-
Markovnikov hydrofunctionalization and invoke a similar
mechanism in this instance.39,55 Since both transformations
utilize the same photooxidation catalyst, we attempted a one-
pot direct C−H functionalization; however, only α-substituted
adducts were observed. We believe this is likely attributed to a
copper-mediated coupling of the nucleophile with the α-radical
that is formed. Studies to achieve this one-pot transformation
are ongoing.
In conclusion, we have developed a two-step protocol for the
synthesis of β-functionalized aza-heterocycles using an
acridinium salt as the photooxidant. First, a copper-mediated
photoredox-catalyzed dehydrogenation of saturated aza-hetero-
cycles provides access to an array of ene-carbamates. A
subsequent photoredox-catalyzed hydrofunctionalization of the
ene-carbamates produces a range of C−O, C−C, and C−N β-
substituted aza-heterocycles. We anticipate this route will
greatly simplify the synthesis of hetero β-substituted aza-
heterocycles, which we hope will find utility for the rapid
synthesis of bioactive molecules.
Examining the scope of this transformation, we observed
that both N-Cbz and N-Boc ene-carbamates yielded the
acetylated products 2a and 2b in moderate to good yields
(Chart 2). In addition to piperidine, the corresponding
pyrrolidine and azepine ene-carbamates produced the desired
acetylated products 2c and 2d, respectively. Alkylated
piperidines substituted at positions 2−4 yielded the benzoy-
lated products 2e−2h as a mixture of diastereomers with little
relative stereocontrol. Interestingly, 5-methyl-3,4-dihydropyr-
idine afforded the quaternary β-functionalized piperidine 2h,
despite this being the more substituted position of the alkene,
albeit in lower yield.
A variety of oxygen, nitrogen, and carbon nucleophiles were
also assessed in this reaction (Chart 2). Cyanide and azide
nucleophiles (TMSCN and TMSN3, respectively) produced
the desired β-cyano or azido aza-heterocycles 3a and 3b in
good and moderate yields, respectively. The β-trifluormethy-
lated adduct, 3c, was isolated in 45% yield using the Langlois
reagent; however, some α-functionalization was also observed
(22% yield). Carboxylic acids such as benzoic acid and N-Boc
phenylalanine were also found to be suitable nucleophilic
partners, affording 3d−3e in good yields. Azole-derived
nucleophiles gave the heterocyclic products 3f−3h in 31−
36% yields. Primary amines were effective reaction partners,
producing the β-aminated products, 3i and 3j, in modest
yields. Amino acids such as phenylalanine can add either via N-
or O- simply by selection of the protecting groups, furnishing
either the aminated or acetylated products, 3j and 3e, but
unfortunately, the resident amino acid chirality does not
control stereoselectivity in the addition step. The direct β-
amine product, 3k, can be synthesized using ammonium
carbamate as the source of amine. Trifluoromethyl and methyl
sulfonamide derivatives were also competent nucleophiles
giving the desired products 3l and 3m in moderate yields.
Finally, pharmaceutical-derived nucleophiles successfully
underwent the β-amination and acetylation with Rimantidine
and Gabapentin derivatives 3n and 3o, respectively. With this
methodology, a besifloxacin precursor, 3p, was formed from
the azepine with ammonium carbamate in good yield.
With a two-step procedure for the β-functionalization of
saturated aza-heterocycles defined, we sought to demonstrate
the utility of this sequence for the synthesis of active
pharmaceutical intermediates. A 2016 patent from Merck
examined orexin antagonists synthesized via nucleophilic
substitution of 3-hydroxypiperidines which gave access to β-
pyrazole substituted benzoyl piperidine derivatives.50,51 The
synthesis of these derivatives would be greatly simplified using
the two-step dehydrogenation and β-functionalization se-
quence, which would begin with the simple methyl substituted
piperidine rather than the prefunctionalized 2-methyl-3-
hydroxypiperidine. Subjecting (R)-(2-methylpiperidin-1-yl)-
(phenyl)methanone to the copper mediated dehydrogenation
gave the desired ene-carbamate, 4a, in 25% yield. The
photoredox-catalyzed hydrofunctionalization of the ene-
carbamate with 2-(1H-pyrazol-4-yl)propan-2-ol as the nucle-
ophile gave the desired product, 4b, as a mixture of 2:1 trans:cis
diastereomers in two steps. A related orexin antagonist, 5c, was
prepared in five steps through hydrofunctionalization of 5a
with methyl 1H-pyrazole-4-carboxylate which gave a 2:1
mixture of trans:cis diastereomers of 5b in 63% yield. The
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c00099.
1
Experimental procedures and supporting H and 13C
NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
David A. Nicewicz − Department of Chemistry, University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599-3290, United States; orcid.org/0000-0003-1199-
9879; Email: nicewicz@unc.edu
Authors
Natalie Holmberg-Douglas − Department of Chemistry,
University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States
Younggi Choi − Alkermes, Inc, Waltham, Massachusetts
02451-1420, United States
Brian Aquila − Alkermes, Inc, Waltham, Massachusetts
02451-1420, United States
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Hoan Huynh − Alkermes, Inc, Waltham, Massachusetts
02451-1420, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c00099
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by Alkermes, Inc. as well as grant from
NIGMS (1R35GM136330-01 to D.A.N.). We thank the
University of North Carolina’s Department of Chemistry
Mass Spectrometry Core Laboratory, especially Diane Weath-
erspoon, for their assistance with mass spectrometry analysis.
The authors would additionally like to thank Markus
Haeberlein, Alexander Jacobine, Qing Le, Jonathan Lehmann,
Daljit Matharu, Johannah Medeiros, Roman Valiulin, James
Wood, Jim Horstick, Jeff Cataloni, Jun Hu, and Nilesh Gajipara
for their support on this project.
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