Anti-markovnikov hydroamination of alkenes catalyzed by an organic photoredox system

Article abstract of DOI:10.1021/ja4031616

Herein we report a metal-free method for the direct anti-Markovnikov hydroamination of unsaturated amines. Irradiation of the amine substrates with visible light in the presence of catalytic quantities of easily synthesized 9-mesityl-10-methylacridinium t

Full text of DOI:10.1021/ja4031616

Communication
pubs.acs.org/JACS
Anti-Markovnikov Hydroamination of Alkenes Catalyzed by an
Organic Photoredox System
Tien M. Nguyen and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
saw an opportunity to demonstrate the utility of our catalytic
ABSTRACT: Herein we report a metal-free method for
the direct anti-Markovnikov hydroamination of unsatu-
rated amines. Irradiation of the amine substrates with
visible light in the presence of catalytic quantities of easily
synthesized 9-mesityl-10-methylacridinium tetrafluorobo-
rate and thiophenol as a hydrogen-atom donor furnished
the nitrogen-containing heterocycles with complete
regiocontrol. Two examples of intermolecular anti-
Markovnikov alkene hydroamination are also disclosed.
strategy toward this end. Herein we report a metal-free anti-
Markovnikov hydroamination of unsaturated amines using 9-
mesityl-10-methylacridinium tetrafluoroborate (A) as the
catalyst and thiophenol as the H-atom donor (eq 2 in Figure 1).
In our previously reported hydroalkoxylation reaction, we
took advantage of the well-documented single-electron
oxidation of alkenes to provide unique radical cations that
give rise to anti-Markovnikov reactivity.11−13 We proposed to
apply this strategy to the hydroamination reaction, although we
anticipated some challenges associated with amine oxidation.14
Sufficiently electron-rich amines are susceptible to oxidation at
nitrogen, and numerous groups have taken advantage of this
reactivity.15While this pathway could lead to productive
hydroamination, it could also result in undesirable side
reactions stemming from amine radical cation intermediates.
Judicious selection of the amine protecting group could
circumvent these potential issues, and for this reason, we
elected first to examine the use of a sulfonyl group, as it should
be adequately electron-withdrawing to suppress amine
oxidation yet still render the amine nucleophilic.
We began our studies by submitting p-toluenesulfonyl-
protected isoprenylamine 9a to our previously reported
conditions for the anti-Markovnikov hydroalkoxylation reac-
tion. Despite the low yield obtained (16%), complete anti-
Markovnikov regioselection (>20:1) was observed in the
formation of the desired pyrrolidine product after 3 days
(Table 1, entry 1). After additional efforts at reaction
optimization (solvent, addition of organic and inorganic
bases, concentration, etc.) failed to increase the reaction
efficiency, we turned our attention to the identity of the H-
atom donor. While 9-cyanofluorene (entry 2) gave essentially
the same result as did phenylmalononitrile, the heteroatomic
hydrogen donor thiophenol provided a 2-fold increase in the
yield (entry 3).16 When the thiophenol loading was decreased
to 20 mol %, we were pleased to find that pyrrolidine 9b could
be obtained in 70% yield as a single regioisomer (entry 4). To
our knowledge, this result represents a rare example of an
intramolecular anti-Markovnikov hydroamination of a non-
activated olefin.3b,4a
he direct addition of N−H across an alkene1 provides an
Tefficient, atom-economical route to highly valuable,
biologically active nitrogen-containing compounds.2 Consid-
erable effort has been devoted to the development of catalyst
systems for alkene hydroamination, with the majority of these
strategies exhibiting preferential Markovnikov selectivity.3,4
Thus, accessing anti-Markovnikov reactivity has proven quite
challenging, and considerably fewer reports exist in this arena.
Catalytic intermolecular anti-Markovnikov olefin hydroamina-
tion reactions have been demonstrated using transition metals,5
alkaline-earth metals,5l,5 and, to a limited extent, photo-
sensitizers.6,7To our knowledge, the only intramolecular anti-
Markovnikov hydroamination of styrenes, which employs a Rh
catalyst at elevated temperatures (eq 1 in Figure 1), was
reported by the Hartwig group in 2006.8,9 Recently, our group
reported an anti-Markovnikov hydroalkoxylation reaction using
a photocatalyst/H-atom donor system.10 Given the paucity of
intramolecular anti-Markovnikov hydroamination reports, we
Control experiments revealed that thiophenol, light, and
photocatalyst were all necessary for productive reactivity
(entries 8−10). The use of thiophenol as the H-atom donor
allowed us to explore the use of alternative common protecting
groups for amines. While a benzyl protecting group afforded
Received: March 29, 2013
Figure 1. Catalytic anti-Markovnikov intramolecular hydroaminations.
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4031616 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Optimization Studies
Table 2. Scope of the Intramolecular Anti-Markovnikov
Hydroamination Reaction of Unsaturated Amines
a
b
Entry
R
H-Atom Donor
Time Yield
1
2
Ts
Ts
Ts
Ts
H
1.0 equiv of PhCH(CN)2
1.0 equiv of 9-cyanofluorene
1.0 equiv of PhSH
72 h
72 h
72 h
96 h
96 h
96 h
96 h
96 h
24 h
24 h
16%
12%
41%
70%
<5%
15%
65%
<5%
<5%
<5%
3
c
4
0.2 equiv of PhSH
5
0.2 equiv of PhSH
6
Bn
Boc
Ts
Ts
Ts
0.2 equiv of PhSH
7
0.2 equiv of PhSH
8
none
9
0.2 equiv of PhSH without photocatalyst
0.2 equiv of PhSH without light
10
a
Irradiation was performed with a 15 W, 450 nm light-emitting diode
b
c
(LED) flood lamp. Determined by 1H NMR analysis. Isolated yield.
only a small amount of the pyrrolidine adduct (15% yield; entry
6), presumably because of the formation of numerous
unidentified side products, we found that the Boc protecting
group was suitable in this context (65% yield; entry 7). This
supported our hypothesis that electron-rich amines would be
poor substrates because of their susceptibility to oxidation.
While the use of a Boc protecting group was quite appealing
because of its ease of removal, we elected to evaluate
tosylamine substrates because of their straightforward charac-
terization.
We next shifted our focus to investigate the scope of the
alkene hydroamination reaction (Table 2). Amine substrates
bearing pendant styrenes underwent smooth 5-exo cyclization
to furnish the corresponding regioisomerically pure pyrrolidines
(entries 1−6). It should be noted that similar reactivity can be
obtained with catalytic quantities of strong bases.17 The
presence of electron-releasing (OMe) and -withdrawing (F)
groups had little effect on the reaction efficiency (entries 2−5).
Substitution at the ortho position of the styrene was tolerated,
giving the desired pyrrolidine 4b in 69% yield (entry 4).
Importantly, 6-endo cyclizations of 1,1-disubstituted styrenes to
give tosylpiperidine products 7b and 8b also proceeded in good
yields with complete regiocontrol (entries 7 and 8). We
observed that geminal substitution in the backbone was not
required for reactivity, and only slight decreases in yield
compared with the dimethyl-substituted analogues were
observed, although longer reaction times were generally
required (cf. entries 3 vs 5 and 7 vs 8). For styrenyl substrates,
the major byproduct was the cyclized deprotected product.
Reprotection or deprotection of the reaction mixture could
easily convert the remainder of the mass balance as desired.
The inclusion of a stereocenter next to the amino group (10a)
gave stereocontrol during the ring-forming event, albeit at a
modest level (3:1 dr; entry 10). We were pleased to find that a
more geometrically challenging 5-endo cyclization could be
achieved with unsaturated amine 11a, which afforded the fully
saturated indole derivative 11b in 72% yield with 12:1 dr (entry
11). Furthermore, the method is not limited to tosylamines, as
the sulfamate proved to be a competent nucleophile, giving
access to a unique 6-exo cyclization (entry 12).
a
In all cases, the reaction mixture was irradiated with a 15 W, 450 nm
LED flood lamp. The reported yields are average isolated yields from
two trials. Determined by H NMR analysis of the crude reaction
mixture.
b
1
subsequent thiyl radical could serve to reoxidize the reduced
form of A. To exclude alternative mechanistic pathways, we
conducted several control experiments. We considered that
thiophenol could participate in a thiol−ene reaction catalyzed
by the acridinium catalyst,18 after which nucleophilic displace-
ment of the resultant phenylthioether could furnish the
observed products. However, this prospect seemed unlikely
because the limited number of examples of this reactivity
require either strong exogenous base or elevated temperatures.
To probe the potential involvement of this reaction pathway,
we prepared Boc-protected unsaturated amine 13 and
submitted it to the reaction conditions shown in eq 3. As we
observed only unchanged starting material and no incorpo-
ration of thiophenol into the molecule, we believe that the
thiol−ene pathway likely is not operative in this transformation.
From the beginning of our studies, we presumed that the role
of the thiophenol was to act as the H-atom donor and that the
B
dx.doi.org/10.1021/ja4031616 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
hypothesis depicted in Scheme 1. After oxidation of
unsaturated amine 9a by the excited state of the catalyst
(A*), anti-Markovnikov addition of the amine would furnish
intermediate radical cation 14. H-atom transfer from
thiophenol to 14 would furnish the desired amine heterocycle
9b after proton loss. Thiyl radical 15 formed by reduction of A*
could serve as a reductant for thiyl radical 16 derived from
thiophenol to reset catalyst A and generate thiophenoxide
anion (17). Given the known reduction potential of 16 (Epred
=
=
+0.45 V vs SCE)21 and the oxidation potential of 15 (E
ox
1/2
−0.57 V vs SCE),22 we estimate that this electron transfer
should be exergonic. 17 then should serve as a mild base to
neutralize the acid generated during the course of the reaction.
We were pleased to find that this protocol could be extended
to include examples of intermolecular alkene hydroamination
(eqs 6 and 7). Treatment of styrenyl and alkenyl substrates
We also considered the possibility that thiophenol could act
solely as a hydrogen-atom shuttle.19 In this context, we
submitted isoprenyl amine 9a to thiophenol with di-tert-butyl
peroxide or azobis(isobutyronitrile) (AIBN) as a thermal
radical initiator (conditions A or B, respectively; eq 4). No
reactivity was observed in either case, suggesting that the
formation of N-centered radical intermediates was also unlikely.
Finally, the observation of varying quantities of PhSSPh in
the crude reaction mixtures led us to question whether this
byproduct was active in the catalytic cycle. Subjection of 9a to
reaction conditions employing PhSSPh instead of PhSH
afforded the anti-Markovnikov hydroamination product in
55% yield (eq 5). While this observation is not fully understood
with 3.0 equiv of triflylamide under our standard reaction
conditions with the addition of 0.25 equiv of 2,6-lutidine gave
the desired products in modest yields as single regioisomers. To
our knowledge, this represents the first example of an
organocatalytic intermolecular anti-Markovnikov alkene hydro-
amination.
In conclusion, we have reported an intramolecular anti-
Markovnikov hydroamination method using catalytic amounts
of thiophenol and an organic photocatalyst promoted by visible
light. The reaction conditions are mild and effect a range of
cyclization modes to give important nitrogen-containing
heterocycles. We have also demonstrated that this protocol
at this time, it is conceivable that diphenyl disulfide could serve
as a reservoir of phenyl thiyl radical via oxidation of the
disulfide (Epox = +1.51 V vs SCE)20 and subsequent
fragmentation. It is possible that the phenyl thiyl radical
could then act as an oxidant for the reduced form of catalyst A
in a manner similar to the mechanism invoked in our prior
communication.10
On the basis of these experiments and the reactivity observed
in this study, we have developed the working mechanistic
Scheme 1. Working Mechanism for Direct Anti-Markovnikov Hydroamination of Alkenes
C
dx.doi.org/10.1021/ja4031616 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
A. L.; Trogler, W. C. Organometallics 1993, 12, 744. (e) Castonguay,
A.; Spasyuk, D. M.; Madern, N.; Beauchamp, A. L.; Zargarian, D.
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Organometallics 2001, 20, 1960. (g) Beller, M.; Trauthwein, H.;
can be extended to intermolecular reactions. Efforts to obtain a
better understanding of the mechanism of this transformation
are currently underway.
Eichberger, M.; Breindl, C.; Herwig, J.; Muller, T. E.; Thiel, O. R.
̈
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
Chem.Eur. J. 1999, 5, 1306. (h) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J.
Am. Chem. Soc. 2003, 125, 12584. (i) Utsunomiya, M.; Hartwig, J. F. J.
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S
AUTHOR INFORMATION
Corresponding Author
nicewicz@unc.edu
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank M. Geier for aid with cyclic voltammetry
and N. Manohar for the preparation of some of the unsaturated
amine substrates. This project was supported by Award R01
GM098340 from the National Institute of General Medical
Sciences, UNC-CH, and an Eli Lilly New Faculty Award.
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