Photoredox-Induced Radical Relay toward Functionalized β-Amino Alcohol Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b03693

A radical relay strategy is described to synthesize functionalized β-amino alcohols. This strategy is enabled by photoredox-catalyzed and nitrogen-centered radical-triggered cascade reactions of styrenes (or phenylacetylenes), enol derivatives, and O-acyl hydroxylamines in DMSO. The broad synthetic application of this method is demonstrated by the reaction of structurally diverse reaction components, including complex molecular scaffolds. Multiple functional groups of the resultant highly functionalized β-amino alcohol derivatives facilitate their further transformations.

Full text of DOI:10.1021/acs.orglett.7b03693

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoredox-Induced Radical Relay toward Functionalized β‑Amino
Alcohol Derivatives
Xiao-De An, Yan-Yan Jiao, Hao Zhang, Yuxiang Gao, and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, Jiangsu Key Laboratory of Advanced Organic Materials, School of
Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
S
* Supporting Information
ABSTRACT: A radical relay strategy is described to synthesize functionalized β-amino alcohols. This strategy is enabled by
photoredox-catalyzed and nitrogen-centered radical-triggered cascade reactions of styrenes (or phenylacetylenes), enol
derivatives, and O-acyl hydroxylamines in DMSO. The broad synthetic application of this method is demonstrated by the
reaction of structurally diverse reaction components, including complex molecular scaffolds. Multiple functional groups of the
resultant highly functionalized β-amino alcohol derivatives facilitate their further transformations.
β-Amino alcohols and their derivatives are highly valuable and
found in a vast range of biologically important natural products,
pharmaceuticals, and agrochemicals.1 These compounds are also
very useful synthons in chemical synthesis.2 Although several
stepwise functional group manipulations have been established,1a
1,2-oxyamination of olefins is arguably the most direct and
efficient method for the synthesis of β-amino alcohol
derivatives.3 In this reaction, two carbon−heteroatom (N and
O) bonds are constructed across the CC bonds (Figure 1a).
Radical cascade reactions remain a challenge due to the high
reactivity of radical intermediates.6 Photoredox-catalyzed and
nitrogen-centered radical (N-radical)-involved cascade reactions
are of current research interest and have evolved into powerful
tools for the synthesis of nitrogen-containing molecules.7
Inspired by these works and our continuing interest in N-radical
chemistry,8 we propose a novel radical relay strategy for the
synthesis of functionalized amino alcohol derivatives based on
C−C and C−N bond formations (Figure 1b). These cascade
reactions are triggered by the intermolecular addition of amidyl
N-radicals to electron-rich enol ether, followed by intermolecular
C-radical trapping by another olefin (or alkyne). This method
can provide functionalized β-amino alcohol derivatives in high
regio- and chemoselectivity.
The reaction principle can be detailed by the combination of
phenylacetylene 1, benzyl vinyl ether 2a, and O-acyl hydroxyl-
amine 3. As shown in Figure 2a, electrophilic N-radical A
generated under photoredox catalysis adds to the electron-rich
enol ether 2a to give electron-rich C-radical D adjacent to the
oxygen atom. Then, nucleophilic C-radical D is trapped by
relatively electron poor alkyne 1. The resultant vinyl radical I
undergoes 1,5-hydrogen atom transfer (HAT) to give α-oxy
benzyl radical J.9 Subsequent oxidation and hydrolysis afford the
final de-O-benzyl product 4. A deuterium labeling experiment
provides evidence of the 1,5-HAT process (Figure 2b). In
addition, the isolation of aldehyde 9 provides further support for
our reaction mechanism (for more details, see the Supporting
Information). Alternatively, when styrene 5 is used instead of
phenylacetylene 1, C-radical D is trapped by styrene 5. The
Figure 1. Strategies for the synthesis of β-amino alcohols.
However, some of these established methods suffer from poor
regioselectivity.4 Intermolecular oxyamination of 1,3-dienes,
which delivers highly functionalized allyl amino alcohols, is
even more challenging. 1,4-Oxyamination can compete with its
1,2-counterpart (Figure 1a).5
Received: November 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03693
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Rationale and challenges of our multicomponent radical cascade reaction. aIsolated yield. bDetermined by 1H NMR spectroscopy.
resultant C-radical G is prone to oxidation by the highly covalent
photocatalyst to give the carbon cation H. The carbon cation H is
trapped by DMSO to give the final ketone 6 following the
Kornblum oxidation process.10
Although this radical relay strategy is designed, some
challenges still remain: C-radical D can be easily oxidized to
give oxocarbenium E, which can be trapped by the nucleophiles
to give side products, such as F.11,12 Therefore, the suppression
of this potential side reaction is crucial to the success of our
strategy. The chemoselectivity of this reaction is controlled by
Figure 3. Protecting group screening of the N-centered radical
precursors. Reaction conditions: a solution of 1a (0.2 mmol, 1.0
equiv), 2a (0.6 mmol, 3 equiv), 3 (0.6 mmol, 3 equiv), and Ir(tBuppy)3
(0.004 mmol, 2.0 mol %) in DMSO (1.8 mL) and H2O (0.2 mL) was
irradiated by white LED strips for 12 h. The yields are based on 1H NMR
analysis. aIsolated yield.
the polarity of the radical species. The amidyl N-radicals A are
electrophilic, and they will always want to react with the more
election-rich partners. So they react with enol derivatives first.
The resultant C-radicals D are adjacent to the oxygen atom and
nucleophilic. They therefore react with the relatively electron-
poor species of styrenes or alkynes instead of polymerization.
The feasibility of this strategy was first examined by the
reaction of phenylacetylene 1, benzyl vinyl ether 2a, and
hydroxylamine derivative 3 in a mixture of DMSO and water
under photoredox catalysis conditions. The N-protecting group
of hydroxylamine derivative 3 was found to play a key role in this
reaction. Therefore, a series of hydroxylamine derivatives were
synthesized and investigated (Figure 3). 2,2,2-Trifluoroethoxy
carbonyl (Tfoc) was the optimal protecting group, providing an
84% yield based on 1H NMR analysis (81% isolated yield) for the
desired α-aminomethyl cinnamyl alcohol 4a in exclusively the E-
isomer. Other protecting groups, such as Cbz, Ac, Boc, and Ts,
also worked but provided much lower yields. The ratio of the
starting materials also had a significant impact on the outcome of
this reaction. The optimal ratio of 1a/2a/3a was established to be
1:3:3 (for more details, see the SI).
satisfactory yields. Phenylacetylenes with meta- and ortho-
substitutions were efficiently transformed into the corresponding
products 4j−4n in 70−86% yields. ortho-MeO-phenylacetylene
treated with Cbz-protected hydroxylamine 3b afforded the
desired product 4j′ in acceptable yield (69%). Naphthalene-,
pyridine-, and thiophene-derived alkynes smoothly underwent
this reaction to give the desired amino alcohols 4o−4r in 49−
71% yields. Notably, the products were isolated in single E-
isomers in most cases except the reactions of phenylacetylenes
with conjugated electron-withdrawing groups (4d, 4g, 4i, and
4o), which led to lower E/Z ratios. This reaction was easily scaled
up to a Gram-scale with a comparable isolated yield (64% yield
for 4j′ on a 6 mmol scale). To our disappointment, aliphatic
alkynes could not go through this reaction.
Next, we investigated the radical relay reactions of styrenes 5
with enol ether 2 and acyl hydroxylamine 3a (Figure 5). The
optimal reaction conditions were determined after a series of
exploration on substrate ratios, catalysts, solvents, and protecting
groups (for the condition optimizations, see the SI). The reaction
of styrene 5a, enol ether 2a, and acyl hydroxylamine 3a was
achieved in DMSO using Ir(ppy)3 as the photocatalyst irradiated
by white LEDs, and the desired β-alkoxy-γ-aminoketone 6a was
With the optimized conditions in hand, we sought to explore
the generality and limitations of this radical relay reaction (Figure
4). The reaction was examined with respect to various aryl
alkynes, which gave the desired products in up to 91% yields.
Different functional groups, such as halides (4e, 84%; 4f, 91%),
cyano (4d, 63%), ester (4g, 70%), hydroxyl (4h, 46%), ketone
(4i, 56%), and amide (4l, 70%), tolerated these conditions with
B
DOI: 10.1021/acs.orglett.7b03693
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this reaction. Vinyl ether 6c bearing a bulky tert-butyl group was
converted to the corresponding product in 89% yield. Phenyl
vinyl ether also gave 6d in 82% yield. Disubstituted enol ether
was also accommodated in the reaction to give the desired ketone
6u with a quaternary carbon center in 63% yield. However, the
electronic effect had a huge impact on this transformation. Vinyl
acetate was not a suitable substrate in this reaction. Encouraged
by the successful results of the enol ethers, we explored the scope
of the reaction with respect to styrene derivatives. Styrene
derivatives bearing both electron-donating and electron-with-
drawing groups in the para position were well tolerated, giving
the corresponding products 6f−6k in good yields (60−72%).
meta-Substituted styrenes also worked well to give the
corresponding products 6l and 6n in 65% and 60% yields,
respectively. Aliphatic alkenes survived this reaction (58% yield
for 6o). Other aromatic rings, such as naphthalene (6p, 54%
yield), quinoline (6q, 63% yield), and benzofuran (6r, 41%
yield), also tolerated this reaction. Alkenes derived from
biologically important molecules smoothly underwent this
transformation to afford the corresponding ketones 6s and 6t
in 65% and 62% yields, respectively. N-Methyl hydroxylamine
derivative 3h furnished N-methyl product 6v in 69% yield. This
reaction was easily scaled up to the Gram-scale with a slightly
lower isolated yield (77% yield for 6a on a 4 mmol scale).
Aliphatic alkenes failed to undergo this reaction.
Figure 4. Scope of α-aminomethyl cinnamyl alcohols. Reaction
conditions: a solution of 1 (0.2 mmol, 1.0 equiv), 2a (0.6 mmol, 3
equiv), 3a (0.6 mmol, 3 equiv), and Ir(t-Buppy)3 (0.004 mmol, 2.0 mol
%) in a mixture of DMSO (1.8 mL) and H2O (0.2 mL) was irradiated by
white LED strips for 12 h. Isolated yield. E/Z ratios were determined by
1H NMR spectroscopy of the crude products. Unless otherwise noted,
E/Z > 20:1. aThe reaction was run on a 6 mmol scale. bE/Z = 7.0:1. cE/Z
= 11:1. dE/Z = 3.6:1. eE/Z = 3.3:1.
The synthetic potential of this method was exemplified by the
synthesis of dopamine D4 receptor ligand 14.13 As shown in
Scheme 1, hydrogenation of α-aminomethyl cinnamyl alcohol 4j′
Scheme 1. Synthesis of Dopamine Receptor D4 Ligand
followed by acetylation of the resultant amino alcohol gave
hydroxylamide 11 in 57% yield over 2 steps. Intramolecular O-
alkylation and intermolecular N-benzylation delivered amide 13
in 63% yield. Finally, reduction of amide 13 with BH3 produced
the dopamine receptor D4 ligand 14 in 78% yield.
In summary, we reported a novel radical relay strategy for the
synthesis of functionalized β-amino alcohols. This strategy was
enabled by photoredox-catalyzed and N-radical-triggered
cascade reactions of phenylacetylenes (or styrenes), enol
derivatives, and O-acyl hydroxylamines in DMSO. The broad
synthetic application of this method was demonstrated by the
reaction of structurally diverse reaction components, including
complex molecular scaffolds. The resultant α-aminomethyl
cinnamyl alcohols and β-alkoxy-γ-aminoketones are highly
functionalized molecules, which facilitate their further trans-
formations.
Figure 5. Scope of β-alkoxy-γ-aminoketones. Reaction conditions: a
solution of 5 (0.1 mmol, 1.0 equiv), 2 (0.25 mmol, 2.5 equiv), 3a (0.15
mmol, 1.5 equiv), and Ir(ppy)3 (0.001 mmol, 1.0 mol %) in DMSO (1.0
a
mL) was irradiated by white LED strips for 12 h. Isolated yield. The
reaction was run on a 4 mmol scale. bp-CF3PhCO2NMeTfoc (3h) was
used instead of 3a.
isolated in 90% yield. The generality of this reaction was then
explored (Figure 5). The reaction was first examined with respect
to various vinyl enol ethers, which gave the desired products 6a-
6e and 6u in up to 89% yields. The steric effect of the substituent
on the O-atom of the vinyl enol ether did not significantly affect
C
DOI: 10.1021/acs.orglett.7b03693
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03693.
Full experimental and characterization data for all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yushouyun@nju.edu.cn.
ORCID
Shouyun Yu: 0000-0003-4292-4714
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The financial support from the National Natural Science
Foundation of China (21472084, 21672098, and 21732003) is
acknowledged.
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