Anti-markovnikov hydroamination of alkenes catalyzed by a two-component organic photoredox system: Direct access to phenethylamine derivatives

Article abstract of DOI:10.1002/anie.201402443

Disclosed herein is a general catalytic system for the intermolecular anti-Markovnikov hydroamination of alkenes. By using an organocatalytic photoredox system, α- and β-substituted styrenes as well as aliphatic alkenes undergo anti-Markovnikov hydroamination. Heterocyclic amines were also successfully employed as nitrogen nucleophiles, thus providing a direct route to heterocyclic motifs common in medicinal agents.

Full text of DOI:10.1002/anie.201402443

Angewandte
Chemie
DOI: 10.1002/anie.201402443
Photochemistry
anti-Markovnikov Hydroamination of Alkenes Catalyzed by a Two-
Component Organic Photoredox System: Direct Access to
Phenethylamine Derivatives**
Tien M. Nguyen, Namita Manohar, and David A. Nicewicz*
Abstract: Disclosed herein is a general catalytic system for the
intermolecular anti-Markovnikov hydroamination of alkenes.
By using an organocatalytic photoredox system, a- and b-
substituted styrenes as well as aliphatic alkenes undergo anti-
Markovnikov hydroamination. Heterocyclic amines were also
successfully employed as nitrogen nucleophiles, thus providing
a direct route to heterocyclic motifs common in medicinal
agents.
C
arbon–nitrogen bonds are ubiquitous in biologically active
compounds and appear as numerous but distinct structural
motifs.[1] A particularly prevalent class of nitrogen-containing
bioactive compounds, phenethylamine derivatives, display
wide-ranging medicinal properties from antidepressants to
fungicides (Figure 1). One of the most direct means of
accessing amine derivatives is the hydroamination reaction
of alkenes.[2] The synthetic community has developed numer-
ous methods for the hydroamination of olefins catalyzed by
late transition metals, and they generally proceed with
Markovnikov selectivity. In contrast, anti-Markovnikov-selec-
tive methods are less prevalent and often require either
a large excess of alkene, strong bases, or precious transition-
metal catalysts.[3–6] In addition, hydroboration-amination
strategies provide access to formal anti-Markovnikov hydro-
amination products, but they are indirect.[7]
Our lab recently demonstrated the intramolecular anti-
Markovnikov hydroamination of unsaturated amines employ-
ing the Fukuzumi acridinium photoredox catalyst and thio-
phenol as a hydrogen atom donor (Figure 1a).[8a] We hoped to
expand the general utility of this catalyst system to include
intermolecular examples with the goal of accessing biologi-
cally relevant amines. Herein, we report the use of a mild two-
component organic photoredox catalyst system which enables
a direct anti-Markovnikov hydroamination of alkenes to
access the important phenethylamine motif, and also allows
use of nitrogen heteroaromatic nucleophiles (Figure 1b).
Figure 1. Photoredox strategy to access phenethylamines. DCE=1,2-
dichloroethane, Ts=4-methylbenzenesulfonyl.
Beginning with our previously reported reaction condi-
tions, we tested the intermolecular reaction between b-
methylstyrene and amine nucleophiles (Table 1). By employ-
ing trifluoromethanesulfonamide (TfNH2) as the nucleophile
and thiophenol as the cocatalyst, we obtained a single
regioisomer of N-triflylamphetamine in 87% yield (entry 1).
To probe the electronic effects of the cocatalyst on the
reaction, we surveyed both electron-rich (entry 2) as well as
electron-deficient (entry 3) thiophenols. Neither offered an
improvement over thiophenol, and 4-nitrothiophenol gave
only moderate yields of the desired adduct (58%). In our
previous communication,[8a] we observed that phenyl disulfide
could be employed in place of thiophenol as the cocatalyst for
alkene hydroamination. We found that by replacing 20 mol%
thiophenol with 10 mol% phenyl disulfide, good yields could
be maintained (entry 7). Diphenyl disulfide exists as an
odorless solid and provides a practical advantage over
thiophenol, which is a pungent and highly toxic liquid.
[*] T. M. Nguyen, N. Manohar, Prof. D. A. Nicewicz
Department of Chemistry
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
E-mail: nicewicz@unc.edu
Homepage: http://www.chem.unc.edu/people/faculty/nicewicz/
[**] The project described was supported by Award No. R01 GM098340
from the National Institute of General Medical Sciences, UNC-CH,
and an Eli Lilly New Faculty Award. We also are grateful to Dr. Mark
Scott for insightful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402443.
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Table 1: Optimization of the anti-Markovnikov alkene hydroamination
Table 2: Scope of the intermolecular anti-Markovnikov hydroamination
reaction.[a]
reactions with styrenyl substrates.[a]
Entry
Ar
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
Ph
4-FC6H4
4-ClC6H4
4-tBuC6H4
2,4,6-Me3C6H2
2-naphthyl
48
48
48
72
72
72
72
96
72
72
72
72
55
69
73
76
73
84
72
77
75
43
64
63
Entry
R
Cocatalyst
mol%
Yield [%][b]
1
2
3
4
5
6
7
8
Tf
Tf
Tf
Tf
Tf
Tf
Tf
Tf
thiophenol
20
20
20
20
0
87
80
58
78
<5
35
89
40
8
<5
<5
2,6-dimethylthiophenol
4-nitrothiophenol
phenyl disulfide
–
phenyl disulfide
phenyl disulfide
phenyl disulfide
phenyl disulfide
phenyl disulfide
phenyl disulfide
5
9
10
100
10
10
10
10
11
12
9
10
11
Boc
Ts
Ns
13
14
96
57
35
[a] All reactions irradiated with a 15 W 450 nm LED flood lamp and run
on a 0.2 mmol scale. [b] Determined by 1H NMR spectroscopy using
[(H3C)3Si]2O as an internal standard. Boc=tert-butoxycarbonyl, Ns=4-
nitrobenzenesulfonyl, Tf=trifluoromethanesulfonyl.
144
[a] All reactions irradiated with a 15 W 450 nm LED flood lamp. [b] Yield
of isolated product (average of two trials).
Importantly, no reaction was observed in the absence of
a cocatalyst (entry 5). The inclusion of 25 mol% 2,6-lutidine
resulted in slightly higher product yields and cleaner crude
reaction mixtures. Attempts to use BocNH2 in place of TfNH2
were unfortunately unsuccessful (entry 9), as was the use of
other sulfonamides (Ts, Ns; entries 10 and 11).
We then began exploring the scope of the reaction with
various b-methyl-substituted styrenes as the alkene partner.
Electron-rich methoxy-substituted styrenes gave the desired
products in moderate to good yields (Table 2, entries 1–3).
These substrates demonstrated the fastest times to comple-
tion, likely because of the ease of their oxidation. Slightly less-
electron-rich methyl-substituted styrenes were obtained in
uniformly good yields, with a variation in the substitution
pattern having little effect (entries 4–6). Halogenated sty-
renes also provided the corresponding phenethylamine deriv-
atives in good yields (entries 7–9). We obtained a lower yield
for 4-tert-butyl-substituted styrene, and observed many oligo-
meric side products in the crude reaction mixture (entry 10).
Styrenes with bulky arenes were also participants in the
reaction, with 2,4,6-Me3C6H4 undergoing hydroamination in
good yield (entry 11). We were able to extend the reaction to
include bicyclic styrenes, such as naphthalene and isosafrole,
which gave the desired product in modest yields (entries 12
and 13). Heteroaromatic substitution was also tolerated, as
demonstrated by the thiophene-substituted product, albeit in
low yield and with a long reaction time (entry 14). All
substrates gave complete anti-Markovnikov regioselectivity.
We then turned our attention to styrenyl substrates
bearing different functional groups at the b-position
(Figure 2). We were pleased to find that the reaction
proceeded in good yields with esters, alcohols, and phthal-
imide-protected amines as substituents on the styrenes
Figure 2. Scope of the intermolecular anti-Markovnikov hydroamina-
tion reactions with alkenes. All reactions irradiated with a 15 W
450 nm LED flood lamp. All yields are those of the isolated products
(average of two trials). [a] E-configured styrenes employed in reaction.
[b] Diastereoselectivity determined by 1H NMR analysis of the crude
reaction mixture. [c] Used 3.0 equiv alkene. PMP=4-MeOC6H4, Tf=tri-
fluoromethanesulfonyl.
(entries 1–3). In particular, the use of allylic amines and
alcohols provided 1,2-diamine and amino alcohol products,
respectively (entries 2 and 3). The result in entry 3 should be
underscored, as it is the only example, to our knowledge, of an
alkene bearing a free alcohol undergoing a hydroamination
reaction. Perhaps most impressively, trisubstituted aliphatic
cyclic alkenes underwent hydroamination with complete
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regioselectivity, despite having oxidation potentials in the
vicinity of + 2.0 V vs. SCE (entries 5 and 6). As a result of its
volatility, 3.0 equivalents of 2-methyl-2-butene were
employed in the reaction.
In accord with our previous work in this area, we propose
that the mechanism of this transformation begins with
excitation of the mesityl acridinium catalyst 1 by l = 450 nm
light, with subsequent single-electron oxidation of the alkene
by 1* (Scheme 1). Reversible addition of triflylamide to the
Figure 3. Scope of the intermolecular anti-Markovnikov hydroamina-
tion reactions with heterocyclic amines. All reactions irradiated with
a 15 W 450 nm LED flood lamp. All yields are those of the isolated
products (average of two trials). Values within parentheses indicate the
ratio of N1 substitution to N2 substitution. [a] Used 3.0 equiv imid-
azole.
Scheme 1. Proposed mechanism for the intermolecular anti-Markovni-
kov alkene hydroamination reaction. HAT=hydrogen-atom transfer.
solubility with various solvent combinations were unsuccess-
ful (50% yield; entry 3). 1,1-Disubstituted styrenes did not
react productively with triflylamide but were reactive toward
1,2,3-triazole (entries 5 and 6). For 1,2,3-triazole, substitution
at N1 was led to the major regioisomer as expected, because
of the statistical advantage and increased electron density of
N1/N3 over N2.[13] This reaction class should be of potential
interest to the biomedical community as tool for lead-drug
candidate discovery.
less-substituted position of 2 results in the formation of
tertiary radical 3, which reacts with a hydrogen-atom donor,
presumably thiophenol, to furnish the final adduct 4. How
thiophenol is generated is less clear. One potential mecha-
À
nism involves homolysis of the S S bond, either directly by
light, or by energy transfer from 1*, thus giving rise to the thiyl
radical 5. This oxidizing radical could reset the acridinium
catalyst by oxidation of the long-lived acridine radical 6. This
process seems feasible given the thiyl radical/thiophenoxide
redox couple (Ep/2 =+ 0.16 V vs. SCE)[9] and the acridinium
redox potential (E1/2ox = À0.49 V vs. SCE),[10] thus ensuring
that the redox event would be exergonic by nearly 15 kcal
molÀ1. Subsequent protonation generates the putative hydro-
gen-atom-transfer reagent, thiophenol. In previous control
experiments, if thiophenol was employed as the cocatalyst,
varying quantities of phenyl disulfide were observed in the
crude reaction mixture, thus implicating the disulfide/thio-
phenol equilibrium.
Finally, we were able to employ heterocyclic amines as
nucleophiles in this setting, thus providing access to poten-
tially valuable nitrogen heterocycles (Figure 3).[11] We
observed good reactivity between methoxy-substituted sty-
renes and pyrazole, indazole, and 1,2,3-triazole. Indazole gave
a single N2 regioisomeric product, congruent with prior
observations of indazole alkylation selectivity under nonbasic
conditions (entry 2).[12] The addition of poorly soluble imid-
azole gave a slightly lower yield and attempts to improve its
In conclusion, we have demonstrated an anti-Markovni-
kov intermolecular hydroamination reaction of alkenes and
amines employing a novel organic photoredox catalyst
system. The broad reaction scope extends to trisubstituted
aliphatic alkenes and a- and b-substituted styrenes with
a variety of functional groups such as halides, esters, alcohols,
and protected amines. The amine coupling partner can be
triflamide or heterocyclic amines. Though extended reaction
times are required, this method expands the limited arena of
anti-Markovnikov hydroamination for the direct addition of
sulfonamides to alkenes. We are actively probing the mech-
anism of this and associated transformations as to the exact
nature of the redox cycle and involvement of phenyl disulfide
in the reaction mechanism.
Experimental Section
A magnetic stir bar, N-Me-mesityl acridinium catalyst (1, 1.0 mol%),
phenyldisulfide (10 mol%), and the amine (1.5 equiv) were added to
a flame-dried 2 dram vial. The reaction vessel was purged with
nitrogen, then 2,6-lutidine (25 mol%), the alkene (1.0 equiv), and
dichloromethane (sparged for 15 min, [0.5m]) were added. The vial
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was sealed with Teflon tape and irradiated with a blue LED lamp (l =
450 nm) at room temperature. Reactions were quenched with
a solution of TEMPO (ca. 5 mg) in dichloromethane (0.2 mL) and
concentrated in vacuo. The final products were purified by silica gel
chromatography using the conditions given in the Supporting
Information.
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Received: February 14, 2014
Revised: March 25, 2014
Published online: && &&, &&&&
Keywords: alkenes · amines · organocatalysis · photochemistry ·
.
radicals
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4
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Photochemistry
T. M. Nguyen, N. Manohar,
D. A. Nicewicz*
&&&& — &&&&
anti-Markovnikov Hydroamination of
Alkenes Catalyzed by a Two-Component
Organic Photoredox System: Direct
Access to Phenethylamine Derivatives
On the (anti)mark: Disclosed is a general
catalytic system for the intermolecular
anti-Markovnikov hydroamination of
alkenes. An organocatalytic photoredox
system tolerates a- and b-substituted
styrenes, as well as aliphatic alkenes.
Heterocyclic amines were also success-
fully employed as nitrogen nucleophiles,
thus providing a direct route to hetero-
cyclic motifs common in medicinal
agents.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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