Highly Diastereoselective Functionalization of Piperidines by Photoredox-Catalyzed α-Amino C-H Arylation and Epimerization

Article abstract of DOI:10.1021/jacs.9b13165

We report a photoredox-catalyzed α-amino C-H arylation reaction of highly substituted piperidine derivatives with electron-deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bearing multiple substituti

Full text of DOI:10.1021/jacs.9b13165

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Article
Highly Diastereoselective Functionalization of Piperidines by
Photoredox Catalyzed #-Amino C–H Arylation and Epimerization
Morgan M. Walker, Brian Koronkiewicz, Shuming Chen, K. N. Houk, James M. Mayer, and Jonathan A. Ellman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13165 • Publication Date (Web): 14 Apr 2020
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Highly Diastereoselective Functionalization of Piperidines by Photore‐
dox Catalyzed α‐Amino C–H Arylation and Epimerization
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Morgan M. Walker,† Brian Koronkiewicz,† Shuming Chen,‡ K. N. Houk,*,‡ James M. Mayer,*,† and
Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
‡Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
ABSTRACT: We report a photoredox catalyzed α-amino C–H arylation reaction of highly substituted piperidine derivatives
with electron deficient cyano(hetero)arenes. The scope and limitations of the reaction were explored, with piperidines bear-
ing multiple substitution patterns providing the arylated products in good yields and with high diastereoselectivity. In order
to probe the mechanism of the overall transformation, optical and fluorescent spectroscopic methods were used to investigate
the reaction. By employing flash-quench transient absorption spectroscopy, we were able to observe electron transfer pro-
cesses associated with radical formation beyond the initial excited state Ir(ppy)3 oxidation. Following the rapid and unselec-
tive C–H arylation reaction, a slower epimerization occurs to provide the high diastereomer ratio observed for a majority of
the products. Several stereoisomerically pure products were re-subjected to the reaction conditions, each of which converged
to the experimentally observed diastereomer ratios. The observed distribution of diastereomers corresponds to a thermody-
namic ratio of isomers based upon their calculated relative energies using density functional theory (DFT).
group provided a seminal study using a transition metal
photoredox catalyst for the synthesis of α-branched amines
via α-amino radical coupling with electron deficient cy-
ano(hetero)arene derivatives (Scheme 1A).4,5 Following
this report, many groups have developed transformations
using α-amino radicals as the reactive intermediate for ad-
ditions to alkenes and other unsaturated π-bonds,6 cross-
coupling with (hetero)arenes,7 and other coupling part-
ners.8
INTRODUCTION
Piperidines are by far the most prevalent of all heterocy-
cles found in drugs.1 For example, the piperidine substruc-
ture is present in the blockbuster antidepressant paroxe-
tine, morphine along with its congeners, many of the anti-
histamine class of drugs, and tofacitinib used in the treat-
ment of arthritis and ulcerative colitis.1 Substitution about
the piperidine scaffold is extremely common,1a and for this
reason, efficient new methods for the diastereoselective
elaboration of the piperidine framework have the potential
to greatly facilitate the discovery of new pharmaceutical
agents.
Achieving stereoselective transformations is one of the
major challenges for photoredox catalysis because radicals
serve as key reactive intermediates.9 In this regard, signifi-
cant advances have been realized for the asymmetric syn-
thesis of α-branched amines via α-amino radical intermedi-
ates using photoredox catalysts often in combination with
other modes of catalysis.10 Approaches for the diastereose-
lective synthesis of α-branched amines to produce com-
pounds that incorporate two or more stereogenic centers
via α-amino radical intermediates have also been devel-
oped.10c,11 However, the elaboration of complex molecules
incorporating stereogenic center(s) requires that diastere-
oselectivity be achieved relative to the pre-existing stereo-
genic center(s). This type of stereoselective transformation
has rarely been explored for photoredox catalyzed α-amino
radical reactions.11b,12,13
Photoredox catalysis utilizing transition metal-
polypyridyl complexes has provided a powerful strategy to
access novel reactivity manifolds.2 Although the utility of α-
amino radicals has long been appreciated,3 the MacMillan
Scheme 1. Photoredox catalyzed α‐amino C–H arylation
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Scheme 2. Highly diastereoselective two‐step synthe‐
Although the reactivity of α-amino radicals can introduce
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8
challenges for achieving stereoselective transformations,
the low inversion barrier for these radicals also provides
new opportunities for stereoselective synthesis by epimer-
ization. Pioneering studies by Bertrand and coworkers
demonstrated that a thiyl radical could mediate the racemi-
zation of benzylic amines through reversible hydrogen ab-
straction.14 Very recently, Knowles and Miller have
achieved an impressive photo-driven deracemization of cy-
clic ureas based on the use of excited-state redox events.10a
Moreover, in a photoredox catalyzed reverse polarity Pova-
rov annulation to give disubstituted tetrahydroquinolines,
an increase in diastereoselectivity to 18:1 was observed
when the initial 10:1 ratio of product diastereomers was re-
submitted to the reaction conditions.11e,15,16
sis of densely substituted piperidines
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the α-arylation, in agreement with MacMillan’s earlier re-
port.4,19 Of particular note, we were able to employ the pi-
peridine as the limiting reagent to give 2a in high yield and
with high diastereoselectivity (Table 1). For this transfor-
mation, arylation unambiguously provided the syn isomer
as determined by X-ray crystallography.
Herein, we report the development of a highly diastere-
oselective Ir(III) photoredox catalyzed reaction cascade
that proceeds by α-amino C–H arylation of densely function-
alized piperidines 1 followed by epimerization at the α-po-
sition to give the most stable stereoisomer 2 (Scheme 1B).
Notably, differentially substituted piperidine derivatives
with up to four stereogenic centers were effective sub-
strates, providing the products with generally high dia-
stereoselectivity relative to the pre-existing stereogenic
centers. We propose mechanisms for both the C–H arylation
reaction and epimerization steps based on an array of spec-
troscopic studies and time courses for product formation.
Our results are consistent with an unselective photoredox
C–H arylation followed by product epimerization leading to
the observed diastereoselectivity. The diastereomers un-
derwent oxidation with comparable rate constants, and
therefore, product oxidation kinetics were not responsible
for the epimerization diastereoselectivity. We subjected the
separate diastereomers to the photoredox-catalyzed reac-
tion conditions, and each yielded the experimentally ob-
served distribution of diastereomers suggesting that the re-
action is under thermodynamic control. The calculated rel-
ative energies of the diastereomers using density functional
theory (DFT) correlate with the observed diastereomer ra-
tios.
The optimized conditions were next applied to a number
of piperidine derivatives using DCB as the coupling partner
(Table 1). Piperidines with the strained cyclopropyl ring
(2b) and the linear propyl chain (2c) at R2 were effective
substrates in the reaction. A phenyl substituent could also
be incorporated at the R2 position to provide product 2d in
good yield and with high diastereoselectivity, although a
longer reaction time of 16 h was required.
Trisubstituted piperidines with a different substitution
pattern also provided the arylated products in high yield
and diastereoselectivity as exemplified for 2e‐2k. However,
for this substitution pattern, the anti-stereoisomer was ob-
tained, as unambiguously determined by X-ray crystallog-
raphy for 2e. Piperidines with cyclopentyl (2f), Boc pro-
tected piperidine (2g), and isopropyl (2h) at R4 were all ef-
fective substrates in the reaction. Notably, arylation of the
N-Boc piperidine in 2g does not occur under our reaction
conditions, due to the thermodynamically unfavorable oxi-
dation of electron-deficient carbamates.20 Different N-aryl
substituents were also evaluated, with products 2h‐2k each
obtained in good to high yields and with excellent diastere-
oselectivities. However, for alkyl, acyl and toluenesulfonyl
substituents on the piperidine nitrogen, no coupling was
observed (for a full list of unsuccessful reactants, see Table
S4 in the Supporting Information).
RESULTS AND DISCUSSION
Arylation of a tetrasubstituted piperidine gave the fully
substituted piperidine product 2l in high yield and with
85:15 diastereoselectivity for the anti isomer.21 A monosub-
stituted piperidine also arylated in high yield to give prod-
uct 2m with modest diastereoselectivity and with a prefer-
ence for the syn isomer.21
Efficient Preparation of Piperidine Starting Materials
1. We first developed a facile two-step route to diastereo-
merically pure, densely substituted piperidines 1 from
readily available precursors (Scheme 2). Previously, we re-
ported a Rh(I)-catalyzed C–H activation/electrocyclization
cascade to furnish highly substituted 1,2-dihydropyridines
4 from imines 3 and internal alkynes.17 Catalytic hydrogena-
tion of dihydropyridines 4 with Pd/C then provides piperi-
dines 1 (see Supporting Information for optimization Table
S1 and experimental details).18 In all cases, only the all-cis
stereoisomer was detected and was isolated in 63% average
overall yield for the two step process.
Using piperidine 1a, we explored the scope with respect
to the cyano(hetero)arene coupling partner (2n-2q). Heter-
ocycles, such as for 4-cyanopyridine, provided product 2n
in moderate yield and with high selectivity. The desired
products were also obtained in moderate to good yields for
other electron deficient cyanoarenes, including a para sub-
stituted morpholine amide (2o), phthalide (2p) and ethyl
ester (2q). Arylation with the electron-rich 4-methoxyben-
zonitrile and the electron-neutral cyanobenzene were not
successful, consistent with the redox potentials of these de-
rivatives22 and with MacMillan’s initial report on tertiary
aniline arylation.23,4 MacMillan has successfully coupled
heteroaryl chlorides with unhindered tertiary anilines;24
Optimization and Scope of C–H Arylation. To optimize
the yield and diastereoselectivity of the C–H arylation reac-
tion, we explored a variety of conditions for arylating tri-
substituted piperidine 1a (R1 = H, R2 = Me, R3 = R4 = Et) with
1,4-dicyanobenzene (DCB) to give 2a (Tables S2 and S3 in
the Supporting Information). Ir(ppy)3 (ppy = 2-phenylpyri-
dine) was determined to be the optimal photocatalyst for
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however, with our more hindered, substituted piperidines played the 3-ethyl group anti to the two other alkyl substit-
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less than 10% coupling occurred with 2-chlorobenzothia-
zole (for a full list of unsuccessful reactants, see Table S4 in
the Supporting Information). All of the cyano(het-
ereo)arene coupling partners were additionally explored
with a trisubstituted piperidine with a different substitution
pattern and provided products 2r-2u in moderate to good
yields and with excellent diastereoselectivities in all cases.
uents (for the synthesis of 5, see the Supporting Infor-
mation). Under the standard reaction conditions, product
2v was obtained in good yield and with 84:16 diastereose-
lectivity.
We further explored functional group compatibility of the
reaction by evaluating readily accessible 4-substituted pi-
peridines (Table 2). These unhindered piperidine sub-
strates are capable of over-addition, which introduces an
added challenge for obtaining high product yields. For pho-
toredox mediated arylations of unhindered tertiary ani-
lines, over-addition is typically minimized by using excess
The large majority of piperidines that we investigated for
arylation were efficiently prepared by face selective hydro-
genation of DHPs 4 to give the all-syn substituted diastere-
omer 1 (see Scheme 2). To demonstrate the potential gen-
erality of the approach to other stereoisomers, we also eval-
uated the arylation of diastereomer 5 (eq 1), which dis-
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Table 1. Substrate scopea
aIsolated yields on 0.2 mmol scale; dr was determined by 1H NMR analysis of the purified product and was within a single per-
centage point relative to the crude dr. bX-ray structure shown with anisotropic displacement ellipsoids at the 50% probability
level. The picryl sulfonate counterion and hydrogen atoms are omitted for clarity. c87:13 dr prior to isolation determined by
f
crude 1H NMR analysis. d16 h reaction time. e2 mol % Ir(ppy)3, 72 h reaction time. [Ir(dtbbpy)(ppy)2]PF6 instead of Ir(ppy)3.
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of the tertiary amine substrate.4 We instead chose to employ
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Table 2. Examining scope with 4‐substituted piperi‐
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the DCB coupling partner in a 1:1 stoichiometry because the
substituted piperidines are the more expensive of the two
inputs. Even with this stoichiometry, the acetamide substi-
tuted piperidine provided the arylated product 2w in excel-
lent yield though with modest diastereoselectivity. Prod-
ucts were also obtained in reasonable yields and modest di-
astereoselectivities for hydroxy (2x), hydroxymethyl (2y),
and methoxymethyl (2z) substituents at the 4-position.
dinesa
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aIsolated yields on 0.2 mmol scale; dr was determined by 1H
NMR analysis of the purified product and was within a single
percentage point relative to the crude dr. b1:1 dr prior to isola-
tion determined by crude H NMR analysis. 59:41 dr prior to
isolation determined by crude 1H NMR analysis.
Mechanistic Investigations. To better understand the
mechanism of product formation, we investigated the reac-
tivity of the Ir(ppy)3 photosensitizer and DCB intermediates
using optical and fluorescent spectroscopies. Upon irradia-
tion at 450 nm, the Ir complex undergoes a metal-to-ligand
charge transfer followed by rapid intersystem crossing to
give the long-lived triplet state that engages in single elec-
tron transfer.25 Based on the reduction potential of
*Ir(ppy)3 (*E1/2(Ir IV/*III) = -1.73 V vs. SCE in MeCN)26 and
DCB (DCB/DCB•– Ep = -1.61 V vs. SCE in MeCN),27 we would
expect an oxidative quenching mechanism to be operative,
generating IrIV and the DCB•– in the first step as depicted in
Figure 1A. Indeed, luminescence quenching studies re-
vealed fast electron transfer (ET) between DCB and
*Ir(ppy)3, occurring with a rate constant kquench = 2.9 x 109
M-1s-1 in N,N-dimethylacetamide (DMA). In contrast, high
concentrations of piperidine 1m caused minimal change in
the *Ir(ppy)3 lifetime (see Figure S2 in the Supporting Infor-
mation). These data, and the experimental excess of DCB,
1
c
is reduced back to Ir(ppy)3 more rapidly, consistent with pi-
peridine oxidation by Ir(ppy)3+ to form the aminium radical
cation 7m and Ir(ppy)3 (Figure 1A, S5 in the Supporting In-
formation). In agreement with this observation, increasing
concentration of piperidine 1m leads to larger residual ab-
sorbance for the DCB•– at 346 nm because the Ir(ppy)3+ that
is consumed by piperidine oxidation is unable to recombine
with DCB•– (Figure 1C, S5 in the Supporting Information). Pi-
peridine oxidation by Ir(ppy)3+ is consistent with the reduc-
tion potentials of the two species, (E1/2(Ir IV/III) = 0.77 V vs.
SCE in MeCN) for the Ir(ppy)3 catalyst,26 versus the aminium
cation (Ep = +0.71 V vs. SCE in MeCN for N,N-dimethylani-
line).29 From the piperidine concentration dependent refor-
mation of Ir(ppy)3 observed at 390 nm, we estimate a rate
constant for piperidine oxidation kox,1m = 2.4 x 107 M-1s-1 in
DMA (see Figure S6 in the Supporting Information).
+
support an initial excited state ET producing Ir(ppy)3 and
DCB•– and are also in agreement with MacMillan’s previous
observations.4
Under the conditions of our luminescence quenching and
TA measurements, the photoinduced formation of DCB•– and
the piperidine radical cation seems plausible. We did not
observe further radical coupling reactions involving the
persistent DCB•– by TA or by transient absorption IR exper-
iments, specifically searching for new CN containing photo-
products. We therefore turned to quantum yield measure-
ments to determine the plausibility of a closed-loop photo-
redox mechanism under the C–H arylation conditions. We
used Scaiano’s method30 to determine the quantum yield of
the reaction between 1a and DCB. The quantum yield was
calculated to be Φ = 0.5 at early conversions, indicating that
the photoredox catalyzed cycle is reasonable, although rad-
ical chain pathways cannot be ruled out.31
In order to examine the reactivity of these photoproducts,
we pursued the visible absorption spectra for each. We ob-
tained authentic absorption spectra for Ir(ppy)3+ from spec-
troelectrochemical oxidation of Ir(ppy)3 in DMA (see Figure
S3 in the Supporting Information), and found authentic
spectra for the DCB•– in the pulse radiolysis literature.28 We
fortuitously observed an isosbestic point for the Ir(ppy)3 to
+
Ir(ppy)3 conversion at 346 nm, very close the λmax of the
DCB•– species. This allowed us to observe absorption
changes at 346 nm that correspond only to the evolution of
DCB•–.
The reactivity of the Ir(ppy)3+ and DCB•– species is not vis-
ible in luminescence quenching studies, and so we turned to
flash-quench transient absorption spectroscopy (TA) to ob-
serve the ground state reactivity of these photogenerated
Taken together, these findings support the proposed
mechanism shown in Figure 1D, which is consistent with
MacMillan’s original hypothesis.4 IrIII is excited by blue light
to produce the excited state *IrIII, which transfers an elec-
tron to DCB to generate the IrIV species and the DCB radical
anion. ET from the piperidine 1m to the IrIV regenerates IrIII.
The formed amine radical cation 7m undergoes deprotona-
tion at the α position by either NaOAc or the piperidine
starting material or product, to deliver the α-amino radical
8m, which can undergo a radical-radical coupling with the
persistent DCB radical anion.32 Following coupling to form
+
species. In the absence of piperidine substrate, Ir(ppy)3
and DCB•– recombine at or near the diffusion limit (Figure
1C), which we can follow at 346 nm for the DCB•– decay and
at 390 nm for the Ir(ppy)3 decay (Figure 1B, S4 and S5 in
+
the Supporting Information). This recombination follows an
equal concentration bimolecular kinetic model (see Sup-
+
porting Information). With added piperidine 1m, Ir(ppy)3
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Figure 1. Mechanistic studies (A) Reactions studied by TA and luminescence spectroscopies. (B) TA data collected at 390 nm with
10 mM DCB, 40 μM Ir(ppy)3, and increasing concentrations of 1m. The laser flash leads to rapid oxidation of the Ir(ppy)3+, yielding
+
a large negative absorbance change because the Ir(ppy)3 species has a smaller ε390 than Ir(ppy)3 (Figure S3). 1m oxidation by
•–
+
+
Ir(ppy)3 is observed as a return in the absorbance at 390 nm as Ir(ppy)3 is reduced to Ir(ppy)3. Residual DCB absorbance was
observed at higher concentrations of 1m. (C) TA spectroscopy at 346 nm to monitor DCB•– reactivity. (D) Proposed photoredox cycle.
9m, extrusion of cyanide furnishes the arylated piperidine
2m and closes the catalytic cycle.
formed. Over the course of the remaining 2 h, the anti prod-
uct isomer 2a‐anti epimerizes to the observed syn diastere-
omer 2a‐syn, which is ultimately obtained in >95:5 dr.11e
Additionally, if the reaction is irradiated for 16 min followed
by stirring in the dark for the remaining 2 h, the dr is 56:46
slightly favoring 2a‐anti, indicating that epimerization is a
light driven process (see Table S5 in the Supporting Infor-
mation).
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Epimerization studies. We sought to better understand
the origins of the high diastereoselectivity observed under
the reaction conditions, especially given that our postulated
mechanism suggests that the C–C bond forming step is a
radical-radical coupling.9b Surprisingly, when monitoring
the progress of the reaction of piperidine 1a and DCB over
time, we observed that the initial reaction is not stereose-
lective (Figure 2). In fact, at 16 min, the ratio of the syn to
anti isomer is 50:50 with 75% of the product already
In an effort to elucidate the mechanism of epimerization,
we isolated the anti diastereomer 2a‐anti (>95:5 dr) and
subjected it to the reaction conditions (Table 3). Notably, we
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Table 3. Evaluating epimerization conditions
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% recovered % yield
entrya
conditions
2a‐anti
2a‐syn
Figure 2. Time course studies of the C–H arylation of 1a and
follow-up epimerization of 2a.
1
2
3
4
Standard conditions
No NaOAc
<5
85
74
21
15
obtained only the syn diastereomer 2a‐syn (>95:5 dr) in
85% yield after 2 h (Table 3, entry 1). Epimerization was
next evaluated upon removing different reaction compo-
nents. Complete epimerization to the syn diastereomer 2a‐
syn was still obtained when NaOAc was removed (Table 3,
entry 2), indicating that NaOAc does not play a significant
role in the epimerization mechanism. When DCB was re-
moved, only 21% of the product epimerized, with the unre-
acted anti isomer 2a‐anti recovered in 67% yield (Table 3,
entry 3). Similar results were obtained when both DCB and
NaOAc were removed (Table 3, entry 4). These observa-
tions suggest that significant epimerization only occurs un-
der conditions that were shown to produce Ir(ppy)3+ upon
irradiation.
<5
No DCB
67
No NaOAc, no DCB
62
No NaOAc, no DCB,
[Ir(dtbbpy)(ppy)2]PF6
5b
<5
72
aYields determined by 1H NMR spectroscopy with 2,6-di-
methoxytoluene as the external standard. b16 h reaction time.
initial ET oxidation at different rates leading to steady-state
concentrations of the diastereomers (Figure 3). To evaluate
this hypothesis, we measured the rate constants for oxida-
tion of stereoisomerically pure 2a‐syn and 2a‐anti by
+
Ir(ppy)3 using TA spectroscopy. To account for the ob-
To further explore this hypothesis, we postulated that a
more oxidizing photocatalyst could directly form the piper-
idine radical cation by excited state electron transfer, with-
out the need for initial quenching by DCB. To this end, we
employed [Ir(dtbbpy)(ppy)2]PF6 (dtbbpy = 4,4’-di-tert-bu-
tyl-2,2’-bipyridine, *E1/2(IrIII/II) = 0.66 V vs. SCE in MeCN),
whose excited state reduction potential is significantly
more positive than that of Ir(ppy)3.25,33 Indeed, subjecting
the anti diastereomer 2a‐anti to [Ir(dtbbpy)(ppy)2]PF6 un-
der blue light, and in the absence of DCB, delivers the major
diastereomer 2a‐syn as the only detectable product in 72%
yield (Table 3, Entry 5). These results are consistent with
an epimerization mechanism that proceeds through initial
product piperidine oxidation (Table 3).
served >19:1 2a‐syn:2a‐anti ratio, kinetically controlled
selectivity would require that the rate constant for 2a‐anti
oxidation (kox,anti) is at least 19 times larger than the rate
constant for 2a‐syn (kox,syn), which would lead to depletion
of 2a‐anti and enrichment of 2a‐syn under our reaction
conditions. However, we determined that kox,anti and kox,syn
were the same within error, indicating that the relative rate
constants for piperidine oxidation were not responsible for
the observed high selectivity. We can conclude that the epi-
merization is not kinetically controlled by initial oxidation
to the aminium radical cations 7a.
We therefore investigated whether or not the epimeriza-
tion reaction could be under thermodynamic control. The
proton transfer between 7a‐syn and 7a‐anti could gener-
ate an equilibrium mixture of diastereomers which controls
the observed distribution of 2a diastereomers. Such an
equilibrium should be achievable starting with either dia-
stereomer. To probe this possibility, we examined piperi-
dine 2m, which gave a quantifiable mixture of diastere-
omers under the reaction conditions (Scheme 3). We sub-
jected both 2m‐syn and 2m‐anti separately to epimeriza-
tion with the photocatalyst [Ir(dtbbpy)(ppy)2]PF6. After 90
min of irradiation of the syn diastereomer 2m-syn, a 70:30
(syn:anti) mixture of stereoisomers was obtained in 91%
yield. Furthermore, subjecting the anti diastereomer 2m‐
anti to the same conditions, gave a 78:22 (syn:anti) mixture
of isomers and 94% recovery. Taken together, these results
Based on these collective results, we propose the follow-
ing mechanism for epimerization under the optimized reac-
tion conditions with Ir(ppy)3 (see Table 3): Excited state
+
quenching by DCB gives potent oxidant Ir(ppy)3 . ET from
2a‐anti and perhaps also 2a‐syn followed by deprotona-
tion yields α-amino radical 8a. This intermediate then equil-
ibrates to the 2a‐syn isomer through subsequent reproto-
nation and ET.
We next investigated whether or not the diastereoselec-
tivity was a result of kinetic control as has been observed
for other photoredox-catalyzed isomerization reac-
tions.34,10a Specifically, one possibility for kinetic control
would require that the piperidine diastereomers undergo
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Journal of the American Chemical Society
7‐anti aminium radical cation diastereomers would be sim-
A)
1
2
3
4
5
6
7
8
Et
Et
ilarly affected by the piperidine substituents. The calculated
relative free energies of 2‐syn and 2‐anti piperidine iso-
mers correlate with the observed diastereomer ratios. For
the less substituted piperidine 2m, the 2m‐syn isomer was
calculated to be 0.6 kcal/mol lower in energy than the 2m‐
anti isomer, consistent with the modest 63:37 syn:anti dia-
stereoselectivity (Table 4, Entry 1). For piperidine 2a, the
2a‐anti isomer is calculated to be 1.3 kcal/mol higher in en-
ergy than the experimentally obtained 2a‐syn isomer (Ta-
ble 4, Entry 2). This preference is likely due to the 2a‐anti
isomer having two axial alkyl substituents in the lowest-en-
ergy conformation (ethyl at R4 and methyl at R2), while the
2a‐syn isomer only has one. For piperidine 2e, the differ-
ence in energy is more pronounced, with the 2e‐syn isomer
disfavored by 4.3 kcal/mol (Table 4, Entry 3). In this case,
the aryl substituent and the ethyl group at R4 are calculated
to be axial in the lowest energy conformation of 2e‐syn.
Typically, aryl substituents have much higher A values than
secondary alkyl carbons,35 likely causing the 2e‐anti isomer
to be significantly more favored.
Et
Ph
Et
Ph
N
N
kox,syn
Me
Me
+
Ir(ppy)3
CN
CN
2a-syn
>95:5 dr
7a-syn
Et
Et
Et
Ph
Et
Ph
kox,anti
N
N
+
Ir(ppy)3
Me
Me
9
CN
CN
10
11
12
13
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19
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22
23
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50
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60
2a-anti
>95:5 dr
7a-anti
B)
Table 4. Calculated relative energies
exptl. dr
exptl.
calculated
entrya substrate
syn/anti
ΔGanti-ΔGsyn
ΔGanti-ΔGsyn
Figure 3. A) Oxidation reactions investigated for stereoiso-
merically pure 2a diastereomers. B) Plot of observed oxida-
tion rate constant versus 2a concentration, where the slope is
kox for the respective diastereomers. kox,anti and kox,syn are
within error of each other.
1
2
3
2m
2a
63:37
>95:5
>5:95
0.3 - 0.7
>1.8
0.6
1.3
2e
<-1.8
-4.3
aLevel of theory: ωB97X-D/6-311++G(d,p), CPCM (DMA)
// ωB97X-D/6-31G(d), CPCM (DMA). Exptl. = experi-
mental.
suggest that the observed diastereoselectivity can be ap-
proached from either diastereomer, which is consistent
with a thermodynamically controlled process. However,
this result does not rule out that the observed selectivity is
due to a kinetically controlled steady state.10a
CONCLUSIONS
We have described the highly diastereoselective α-amino
C–H arylation of densely substituted piperidine derivatives.
This study represents a rare example of utilizing photore-
dox catalysis to promote diastereoselective transfor-
mations of complex molecules containing pre-existing ste-
reogenic centers. Key to the generally high selectivity was
an epimerization reaction that followed a rapid and non-se-
lective C–H arylation. The observed selectivities for the
overall transformation correlate to the calculated relative
stabilities of the diastereomers. We anticipate that epimer-
ization processes should be applicable to efficient, diastere-
oselective syntheses of many different classes of nitrogen
heterocycles. Towards this end, efforts are underway in our
labs.
Scheme 3. Equilibration of 2m‐syn and 2m‐anti dia‐
stereomersa
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental procedures, characterization data, crystallo-
graphic data, optical and fluorescence quenching studies, and
Cartesian coordinates of all computed structures.
aYields determined by 1H NMR spectroscopy with 2,6-di-
methoxytoluene as the external standard.
Further evidence for a thermodynamically controlled epi-
merization was obtained using DFT calculations to deter-
mine the relative stability of various arylated piperidine di-
astereomers (Table 4). We reasoned that the relative stabil-
ity of the 2‐syn and 2‐anti diastereomers and the 7‐syn and
AUTHOR INFORMATION
Corresponding Author
*jonathan.ellman@yale.edu
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Journal of the American Chemical Society
Page 8 of 10
*james.mayer@yale.edu
*houk@chem.ucla.edu
CoIII Complex and Ligand for Asymmetric C(sp3)–H Functional-
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Klauck, F. J. R.; Kim, J. H.; Daniliuc, C. G.; Glorius, F. Ligand-En-
abled Enantioselective Csp3–H Activation of Tetrahydroquino-
lines and Saturated Aza-Heterocycles by RhI. Angew. Chem. Int.
Ed. 2018, 57, 9950. (c) Jain, P.; Verma, P.; Xia, G.; Yu, J.-Q. Enan-
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Enantioselective Decarboxylative Arylation of α-Amino Acids
via the Merger of Photoredox and Nickel Catalysis. J. Am. Chem.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by NIH Grant R35GM122473 (to J. A.
E.), NIH Grant R01GM050422 (to J. M. M.), and NSF Grant CHE-
1764328 (to K. N. H.). B. K. thanks the NSF Graduate Research
Fellowship for funding. We thank Dr. Brandon Q. Mercado
(Yale) for solving the crystal structure of 2a, 2e, 5, 2v, and 2w
and Dr. Fabian Menges (Yale) for assistance with mass spec-
trometry. We gratefully acknowledge Dr. Eva Nichols (Yale) for
assistance with spectroelectrochemistry and transient absorp-
tion IR, Dr. Maraia Ener-Goetz (Yale) for help with fluorescence
quenching experiments and Amy Y. Chan (Yale) for the synthe-
sis of starting materials. We also thank Dr. Kazimer Skubi (Yale)
for helpful discussions and careful review of the manuscript.
Calculations were performed on the Hoffman2 cluster at the
University of California, Los Angeles, and the Extreme Science
and Engineering Discovery Environment (XSEDE), which is
supported by the National Science Foundation (Grant OCI-
1053575).
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ACS Paragon Plus Environment