1,3-Alkyl Transposition in Allylic Alcohols Enabled by Proton-Coupled Electron Transfer

Article abstract of DOI:10.1002/anie.202105285

A method is described for the isomerization of acyclic allylic alcohols into β-functionalized ketones via 1,3-alkyl transposition. This reaction proceeds via light-driven proton-coupled electron transfer (PCET) activation of the O?H bond in the allylic al

Full text of DOI:10.1002/anie.202105285

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How to cite:
International Edition: doi.org/10.1002/anie.202105285
German Edition: doi.org/10.1002/ange.202105285
Photocatalysis
1,3-Alkyl Transposition in Allylic Alcohols Enabled by Proton-
Coupled Electron Transfer
Kuo Zhao, Gesa Seidler, and Robert R. Knowles*
Abstract: A method is described for the isomerization of
acyclic allylic alcohols into b-functionalized ketones via 1,3-
alkyl transposition. This reaction proceeds via light-driven
À
proton-coupled electron transfer (PCET) activation of the O
À
H bond in the allylic alcohol substrate, followed by C C b-
scission of the resulting alkoxy radical. The transient alkyl
radical and enone acceptor generated in the scission event
subsequently recombine via radical conjugate addition to
deliver b-functionalized ketone products. A variety of allylic
alcohol substrates bearing alkyl and acyl migratory groups
were successfully accommodated. Insights from mechanistic
studies led to a modified reaction protocol that improves
reaction performance for challenging substrates.
T
he allylic transposition of alkyl groups is an appealing
synthetic transformation, providing opportunities to recon-
À
figure C C bonds in complex carbon frameworks. While
thermal [1s,3s] alkyl shifts are forbidden by orbital symme-
try,[1] numerous alkyl 1,3-transpositions have been reported
À
that proceed via sequential C C bond-cleavage and reforma-
tion pathways.[2–5] Seeking to expand on these advances, we
recently aimed to develop general methods for the 1,3-
transposition of alkyl groups in allylic alcohol substrates
enabled by proton-coupled electron transfer (PCET) (Fig-
ure 1a).[6] In these reactions, an excited-state oxidant and
a weak Brønsted base jointly mediate the homolytic activa-
Figure 1. a) 1,3-alkyl transposition enabling useful skeletal rearrange-
À
ments. b) 1,3-transposition of allylic alcohols via O H PCET-mediated
À
C C bond cleavage.
and preliminary mechanistic investigations of these reactions
are presented herein.
The reaction design underlying the proposed allylic
isomerization is presented in Figure 2. In line with our
previous studies, we envisioned that under blue-light irradi-
À
tion of a substrate alcohol O H bond to generate a reactive
alkoxy radical intermediate.[7] These unstable oxygen-cen-
À
tered radicals then prompt the cleavage of a vicinal C C bond
via b-scission to furnish an a,b-unsaturated carbonyl and an
alkyl radical that may then recombine through radical
conjugate addition.[8,9] From a synthetic perspective, these
methods enable the products of 1,2-addition to enone
electrophiles to be selectively transposed into their corre-
sponding 1,4-isomers. Building on important precedents from
Renaud and Galatsis,[10] we recently reported that this
approach could be applied to numerous ring-expansion
reactions of cyclic alkenols.[7c] Here we demonstrate that
this protocol can be successfully adapted to enable both 1,3-
alkyl transpositions with acyclic allylic alcohol substrates, as
well as a variety of aliphatic ring isomerizations and ring
contractions (Figure 1b). The design, optimization, scope,
[*] K. Zhao, G. Seidler, Prof. R. R. Knowles
Department of Chemistry, Princeton University
Princeton, NJ 08544 (USA)
E-mail: rknowles@princeton.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202105285.
Figure 2. Reaction design for allylic transposition.
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ation the excited state of an IrIII chromophore would first
oxidize the electron-rich p-methoxyphenyl (PMP) group of
substrate 1, generating aryl radical cation intermediate I.
Next, an intramolecular PCET event would occur between
the alcohol adjacent to the radical cation I and an exogenous
Brønsted base to furnish key alkoxy radical intermediate
With these optimized conditions in hand, we examined the
generality of this 1,3-transposition protocol (Table 2) and
found that a variety of allylic alcohol substrates were
accommodated. Substrates bearing secondary and tertiary
aliphatic migratory groups (1–11) generally afforded the
desired ketone products in good to excellent yields, though
for 5 optimal results required the use of 2-methyl-2-oxazoline
as the optimal base co-catalyst. Analogous substrates bearing
primary aliphatic migratory groups proved to be inefficient,
likely due to less favorable b-scission. Unsaturated b-amino
alcohol derivatives (12–16) were also readily isomerized to
furnish g-amino aldehyde products (12a-16a), albeit requir-
ing increased loading of the photocatalyst for optimal
performance.[12] Notably, for this class of substrates, the
PMP group was not required for PCET activation, though
optimal results required the use of diphenyl phosphate as
a base in place of collidine. These reactions proceed through
an alternative PCET mechanism which we have reported
previously for non-benzylic alcohols involving a hydrogen-
bonded complex between the alcohol and the phosphate
base.[7b,c] In this class of substrates, the formation of a stabi-
II.[7a,11] Radical II would then undergo C C b-scission, leading
À
to the concurrent formation of alkyl radical intermediate III
and an a,b-unsaturated ketone. Intermolecular recombina-
tion of these scission products would then occur via radical
À
conjugate addition to deliver a new C C bond and electro-
philic a-acyl radical IV. IV would accept an electron from the
reduced IrII state of the photocatalyst and the resulting
enolate would then be protonated by the conjugate acid of the
Brønsted base to close the catalytic cycle and furnish the
desired ketone product 1a (Figure 2).
Our experimental investigations began with conditions
À
adapted from our previous reports on O H b-scission,
employing allylic alcohol 1 as the model substrate.[7c] Upon
treating 1 with 2 mol% [Ir(dF(CF3)ppy)2(5,5’-d(CF3)(bpy))]-
(PF6) and 25 mol% PBu4+CF3CO2À in PhCF3 under blue-light
irradiation for 24 hours, the desired ketone product 1a was
formed in 46% yield as judged by 1H NMR analysis (Table 1,
entry 1). Further optimization revealed that neutral 2,4,6-
collidine (entry 5) was a superior Brønsted base (entries 1–4),
and that increasing the loading of the base from 25 mol% to
300 mol% (entries 5–7) further benefitted the reaction yield.
A survey of reaction solvents (entries 7–9) affirmed PhCF3 as
the optimal reaction medium, but reactions in toluene and
dichloromethane also provided serviceable yields. Finally,
control experiments revealed that the Ir photocatalyst and
visible-light irradiation are essential for the observed reac-
tivity (entries 10, 11), while the absence of the Brønsted base
afforded a complex mixture of products and low yields of the
desired ketone product 1a (entry 12).
À
lized a-aminoalkyl radical intermediate enables the C C b-
scission step to compete effectively with non-productive back-
electron transfer.
In addition to alkyl radicals, acyl radicals also proved to be
viable migratory groups, as demonstrated by the isomer-
ization of a-hydroxy ketone 17 into 1,4-diketone 17a.
Cascade cyclization reactions can also be accomplished as
demonstrated by the reaction of norbornene derivative 18. In
this substrate, the alkyl radical intermediate formed in the b-
scission event first undergoes intramolecular addition of
À
a pendant alkene to form a new C C bond, and the resulting
alkyl radical is then captured by the ejected enone acceptor to
afford the polycyclic product 18a as a single diastereomer in
78% yield.
Further investigation revealed that derivatives of (À)-
menthol (19), metoprolol (20), D-ribose (21), gemfibrozil
(22), pregnenolone (23), and harmandianone (24) all fur-
nished the desired 1,3-transposed ketone products (19a-24a)
in synthetically useful yields, demonstrating that the method
tolerates a variety of functional groups including electron-rich
arenes (20, 22), distal olefins (23), acetals (21), and esters (24).
Notably, for 20 and 22, a combination of 3% photocatalyst
loading, acetonitrile solvent, and 2-methyl-2-oxazoline as the
base co-catalyst provided optimal results. 21a and 23a were
afforded as single diastereomers while 20a was the sole
product observed despite two potential sites for b-scission in
substrate 20—an outcome in line with the known preference
for b-scission reactions to favor the ejection of the most stable
radical intermediate.[9]
We then considered whether methylidenecycloalkanols
might be prompted to undergo allylic ring reconstruction
under these PCET conditions. As such, we were pleased to
find that a variety of methylidenecycloalkanol substrates (25–
27) rearranged readily, yielding transposed ketone (25a) or
aldehyde products (26a, 27a) in excellent yields, albeit with
a slightly higher loading of photocatalyst (3 mol%). Reac-
tions of 26 and 27 are thought to proceed through the
hydrogen-bond-mediated PCET mechanism discussed for 12–
Table 1: Optimization Studies.[a]
Entry
Brønsted Base [mol%]
Solvent
Yield[c]
+
1
2
3
4
5
6
7
8
9
PBu4 CF3CO2À (25)
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCH3
CH2Cl2
46%
68%
24%
32%
75%
85%
95%
84%
79%
PBu4 (PhO)2P(O)OÀ (25)
+
PBu4 (MeO)2P(O)OÀ (25)
+
PBu4 (n-BuO)2P(O)OÀ (25)
+
2,4,6-collidine (25)
2,4,6-collidine (100)
2,4,6-collidine (300)
2,4,6-collidine (300)
2,4,6-collidine (300)
Changes from the optimal conditions (entry 7)
no light
10
11
12
0%
0%
14%
no IrIII photocatalyst
no Brønsted base
[a] Optimization reactions were performed on 0.05 mmol scale.
[b] Internal temperature of the reaction mixture under LED irradiation
(see SI for details). [c] Yields were determined by H NMR analysis of
crude reaction mixtures relative to dimethylformamide as the internal
standard.
1
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Table 2: Scope of the allylic transposition reaction.[a][20]
[a] Reactions were run on 0.5 mmol scale. Reported yields are for isolated and purified material and are the average of two experiments.
Diastereomeric ratios were determined by 1H NMR analysis of the crude reaction mixtures. The internal reaction temperature in the reaction setup was
measured to be ꢀ458C. Details are provided in Supporting Information [b] 2-methyl-2-oxazoline (25 mol%) was used as the base. [c] 5 mol% phenyl
vinyl ketone (PVK) was added. [d] 3 mol% photocatalyst was used. [e] 5 mol% photocatalyst was used. [f] PBu4+(PhO)2P(O)OÀ (25 mol%) was used
as the base. [g] PBu4+(MeO)2P(O)OÀ (25 mol%) was used as the base. [h] PBu4+CF3CO2À (25 mol%) was used as the base. [i] in 0.1 M PhCF3. [j] in
0.2 M PhCF3. [k] in 0.05 M MeCN. [l] 2-methyl-2-oxazoline (300 mol%) was used as the base. [m] Relative configuration was determined by X-ray
crystallographic analysis. [n] 2,4,6-triisopropylbenzenethiol (5 mol%) was added as a hydrogen-atom transfer co-catalyst.
+
À
16 with PBu4 CF3CO2 as the optimal base co-catalyst.[7a,c]
Tropane 27 is particularly efficient in this rearrangement,
furnishing aldehyde 27a in 95% yield as a 1.8:1 mixture of
exo:endo diastereomers. As will be detailed in the mecha-
nistic discussion to follow, optimal yields for substrates 6, 8,
10, 17, and 22 were realized when 5 mol% of phenyl vinyl
ketone (PVK) was added to the reaction mixture.
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Next, we questioned whether allylic alcohols bearing
endocyclic olefins might afford an opportunity to develop
nÀ2 aliphatic ring contraction reactions. Indeed, under the
standard reaction conditions cycloheptenol 28 was readily
transformed into the ring-contracted cyclopentyl aldehyde
product 28a. In addition, we demonstrated analogous nÀ1
ring-contraction reactions of benzylidene tetrahydropyran
cycloalkenols (29, 30) through a formal 1,2-alkyl shift, which
take advantage of the known preference for anti-Michael
regioselectivity in alkyl radical additions to cinnamate
derivatives.[13] In this case, incorporating a catalytic amount
of a thiol hydrogen-atom transfer (HAT) co-catalyst is
necessary to assist the reduction of benzyl radical intermedi-
separation of the enone and the alkyl radical.[15] To do so,
we performed a series of crossover experiments (Scheme 1a)
wherein increasing equivalents of an exogenous acceptor
alkene, methyl 2-phenylacrylate, were added to the reaction
mixture. Upon addition of 1 equivalent of acrylate, the major
product observed was the crossover product 1b (73%) while
the 1,3-transposition product 1a was obtained in 27% yield.
Increasing amounts of added olefin further suppressed the
formation of 1a, and when 5 equivalents of acrylate acceptor
was employed, crossover product 1b was the sole product
observed with nearly quantitative recovery of PMP vinyl
ketone (PVK). These results suggest that in-cage recombina-
tion is not operative in these reactions and that the ketone and
radical intermediates formed upon b-scission diffuse apart
À
ate formed up upon C C bond formation, which cannot be
reduced directly to its corresponding carbanion by the IrII
complex.[7c] Additionally, we note that PMP ketone product
1a can be readily converted to its respective ester (31) and
amide (32) derivatives via Baeyer–Villiger oxidation and
Schmidt-type rearrangement.[14] Lastly, while these isomer-
ization reactions typically underwent full conversions within
24 hours on small scale (0.05 mmol), we observed notably
diminished rates for preparative-scale runs (0.5 mmol). In
addition to decreased photon flux for the larger reaction
vessels, we hypothesize that the slow reaction rates may be
due in part to the accumulation of a reduced and inactive state
of the Ir photocatalyst under the reaction conditions.
into the solution at a rate faster than C C bond formation.
À
This result in turn raises an interesting question related to the
apparent efficiency of these processes. Following b-scission,
the concentrations of solvent-separated olefin and radical in
solution are expected to be exceedingly low at any given time,
implying that the rate of their bimolecular union may not be
kinetically competitive with other non-productive processes
that consume the radical intermediate.
To shed light on this issue, the reaction kinetics were
1
studied by H photo-NMR.[16] In reactions of substrate 5, we
observed that a small equilibrium concentration of PVK is
established within the first 10 minutes of irradiation and
persists until the reaction reaches completion (Scheme 1b-
(I)).[17,18] While this in situ accumulation of PVK likely
In considering the mechanism of this transformation, we
sought to ascertain whether the radical recombination step
occurs within the solvent cage prior to the diffusional
À
facilitates the key C C bond-forming step, its formation
Scheme 1. Mechanistic studies and rate acceleration with additional alkene acceptor. [a] Yields were determined by 1H NMR analysis of crude
reaction mixtures. Reactions on 0.05 mmol scale. [b] PVK data points are removed for clarity [c] isolated yields with added 5 mol% PVK at
0.5 mmol scale.
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implies that a majority of the photocatalyst may have also
been converted into an inactive IrII state, thus decreasing the
overall rate of reaction. To address this issue, we investigated
reactions where small amounts of PVK were added solution
prior to the beginning of the reaction. We reasoned that
a higher olefin concentration would improve reaction perfor-
mance by increasing the efficiency of the radical conjugate
addition and thus mitigate the formation of a non-productive
state of the photocatalyst. Gratifyingly, 1H photo-NMR
analysis of the rearrangement of 5 incorporating 20 mol%
of added PVK revealed a significant rate enhancement, with
the reaction reaching full conversion after only 2 hours as
compared to 7 hours for reactions without added PVK
(Scheme 1b(II)).[19]
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Building on these NMR observations, we questioned
whether we could develop a modified protocol to improve the
yields for challenging substrates by adding small amounts of
exogenous PVK to the reaction mixture. Utilizing substrate
10 as a model, we were pleased to discover that product 10a is
formed in 72% yield with as low as 5 mol% of added PVK
compared to only 36% yield under the standard conditions
(Scheme 1c). Using this simple modification of the reaction
conditions, we were able to substantially improve the yields
for several challenging substrates (6a, 8a, 10a, 17a, and 22a)
by up to 45% (Scheme 1d). While these reactions were more
efficient with added PVK, we note they still required long
reaction times to reach completion on preparative scale.
In summary, we have developed a light-driven, PCET-
based method for the 1,3-transposition of acyclic allylic
À
alcohols through sequential C C bond dissociation and
recombination steps. In addition to the reactions of acyclic
substrates, previously unexplored ring isomerization reactions
were described, including intra-annular transpositions and
several novel ring contractions. Mechanistic studies revealed
the in situ generation of low steady-state concentrations of the
key enone acceptor, leading to a modified experimental
protocol that significantly improved the performance for
several challenging substrates. We are optimistic that these
À
methods will provide new opportunities for remodeling C C
bond connectivity in a variety of complex contexts.
Acknowledgements
Financial support was provided by the NIH (R35 GM134893).
We thank Kenji Yamashita for conducting preliminary
experiments, Phil Jeffrey for assistance with X-ray crystallo-
graphic analysis, Laura Wilson for assistance with sample
purification, and Kenith Conover for assistance with photo-
NMR experiments.
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Conflict of Interest
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The authors declare no conflict of interest.
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À
Keywords: alkoxy radicals · C C cleavage · isomerization ·
PCET · photocatalysis
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[17] The steady-state concentration of PVK in the NMR studies was
observed to be slightly higher than the loading of the photo-
catalyst, suggesting that a species in the solution other than the
alpha-acyl radical is also able to re-oxidize the IrII complex.
[18] In the NMR kinetic studies, we observed that 2-methyl-2-
oxazoline underwent partial decomposition, which complicated
the analysis. 2,4,6-collidine was thus used instead as it was found
to be equally efficient as a base co-catalyst and was stable under
the reaction conditions.
[19] The faster rates in the NMR reactions can be attributed to
increased photon flux relative to the preparative scale reactions.
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Manuscript received: April 18, 2021
Revised manuscript received: June 2, 2021
Accepted manuscript online: June 22, 2021
Version of record online: && &&, &&&&
[16] a) C. Feldmeier, H. Bartling, E. Riedle, R. M. Gschwind, J.
Magn. Reson. 2013, 232, 39 – 44; b) Y. Ji, D. A. DiRocco, C. M.
6
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These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Photocatalysis
K. Zhao, G. Seidler,
R. R. Knowles*
&&&& — &&&&
1,3-Alkyl Transposition in Allylic Alcohols
Enabled by Proton-Coupled Electron
Transfer
A method is described for the isomer-
ization of acyclic allylic alcohols into b-
functionalized ketones via 1,3-alkyl
transposition. This reaction proceeds via
light-driven proton-coupled electron
bond in an allylic alcohol substrate, fol-
À
lowed by C C b-scission of the resulting
alkoxy radical to form an enone and an
alkyl radical that may recombine via rad-
ical conjugate addition.
À
transfer (PCET) activation of the O H
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
7
These are not the final page numbers!