Published on Web 03/20/2007
Radical Transfer Hydroamination with Aminated
Cyclohexadienes Using Polarity Reversal Catalysis: Scope
and Limitations
Joyram Guin,†,‡ Christian Mu¨ck-Lichtenfeld,† Stefan Grimme,*,† and Armido Studer*,†
Contribution from the Fachbereich Chemie, Organisch-Chemisches Institut, Westfa¨lische
Wilhelms-UniVersita¨t, Corrensstrasse 40, 48149 Mu¨nster, and NRW Graduate School of
Chemistry, Westfa¨lische Wilhelms-UniVersita¨t, Corrensstrasse 36, 48149 Mu¨nster
Received December 23, 2006; E-mail: studer@uni-muenster.de
Abstract: The synthesis of various new 1-aminated-2,5-cyclohexadienes is described. These reagents
can be used in radical transfer hydroaminations of unactivated and electron-rich double bonds. With thiols
as polarity reversal catalysts good yields are obtained. The radical hydroamination occurs with good to
excellent anti-Markovnikov selectivity. Many functional groups such as alcohols, silyl ethers, phosphonates,
arylbromides, imides, amides, and also acidic protons are tolerated under the reaction conditions. DFT
calculations provide insights into the aromatization of silyl, alkyl, and aminyl substituted cyclohexadienyl
radicals to generate the corresponding C-, Si-, and N-centered radicals.
Introduction
and have to be prepared in situ. Moreover, the N-halo and N-SPh
reagents can also react as electrophiles with alkenes which may
The hydroamination of olefins has been intensively investi-
gated during the past few years. Most of the hydroaminations
successfully conducted are using transition metals as catalysts.
Despite the great achievements in this field most of the methods
developed are limited to activated olefins.1 Moreover not many
functional groups are tolerated under the conditions applied.
This is certainly an important issue for possible applications of
the hydroamination in complex natural product synthesis. In
terms of functional group compatibility, radical chemistry offers
advantages over ionic and transition metal mediated reactions:
most of the functional groups are tolerated under radical reaction
conditions which makes these processes highly useful in
complex natural product synthesis.2
However, the radical hydroamination of unactivated olefins
is not established. Whereas the addition of N-radicals to alkenes
is well-known,3,4 the H-transfer from N- to C-radicals is not an
efficient process. It is the reverse reaction, H-transfer from C
to N, occurring in the Hoffmann-Lo¨ffler-Freytag reaction
which is the favored process.5 Therefore, the direct radical
hydroamination via H-transfer reactions using NH compounds
is not feasible. N-Radicals are generated via N-halo, N-PTOC
(PTOC ) N-hydroxypyridine-2(1H)thione), N-nitroso, and
N-SPh derivatives either photochemically or by using a core-
ducing reagent.3 However, most of these precursors are unstable
lead to the formation of unwanted side products. Recently,
o-iodoxybenzoic acid (IBX) has been used for the generation
of N-centered radicals.6
The group of Walton and we have successfully used
substituted 1,4-cyclohexadienes as clean sources for C- and Si-
centered radicals.7 In these reagents the cyclohexadiene moiety
also acts as reducing agent. Hence no additional coreducing
reagent is necessary to conduct reductive C-radical or Si-radical
additions onto olefins using functionalized 1,4-cyclohexadienes.7
Herein, we present in full detail8 that aminated 1,4-cyclohexa-
(3) Reviews: Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337. Zard, S.
Z. Synlett 1996, 1148. Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53,
17543. Stella L. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, p 407. Amidyl radicals from
N-chloroamides: Mackiewicz, P.; Furstoss, R.; Waegell, B.; Cote, R.;
Lessard, J. J. Org. Chem. 1978, 43, 3746. Lessard, J.; Cote, R.; Mackiewicz,
P.; Furstoss, R.; Waegell, B. J. Org. Chem. 1978, 43, 3750. Go¨ttlich, R.
Synthesis 2000, 1561. Heuger, G.; Kalsow, S.; Go¨ttlich, R. Eur. J. Org.
Chem. 2002, 1848. Schulte-Wu¨lwer, I. A.; Helaja, J.; Go¨ttlich, R. Synthesis
2003, 1886. Amidyl radicals from sulfenamides: Esker, J. L.; Newcomb,
M. Tetrahedron Lett. 1993, 34, 6877. Amidyl radicals from PTOC-
derivatives: Newcomb, M.; Esker, J. L. Tetrahedron Lett. 1991, 32, 1035.
Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1992, 33, 5913. Esker, J. L.;
Newcomb, M. J. Org. Chem. 1993, 58, 4933. Esker, J. L.; Newcomb, M.
J. Org. Chem. 1994, 59, 2779. For other amidyl radical precursors, see:
Hoang-Cong, X.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40,
2125. Lin, X.; Stien, D.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 2333.
Gagosz, F.; Moutrille, C.; Zard, S. Z. Org. Lett. 2002, 4, 2707. Moutrille,
C.; Zard, S. Z. Chem. Commun. 2004, 1848.
(4) Recent examples on intermolecular addition of N-centered radicals:
Tsuritani, T.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2003, 68, 3246.
Kitagawa, O.; Miyaji, S.; Yamada, Y.; Fujiwara, H.; Taguchi, T. J. Org.
Chem. 2003, 68, 3184. Kitagawa, O.; Yamada, Y.; Fujiwara, H.; Taguchi,
T. Angew. Chem., Int. Ed. 2001, 40, 3865.
† Organisch-Chemisches Institut.
‡ NRW Graduate School of Chemistry.
(1) Mu¨ller, T. E.; Beller, M. Chem. ReV. 1998, 98, 675. Beller, M.; Breindl,
C.; Eichberger, M.; Hartung, C. G.; Seayad, J.; Thiel, O. R.; Tillack, A.;
Trauthwein, H. Synlett 2002, 1579. For a review of hydroaminations of
alkynes, see: Doye, S. Synlett 2004, 1653.
(5) Mackiewicz, P.; Furstoss, R. Tetrahedron 1978, 34, 3241.
(6) Nicolaou, K. C.; Baran, P. S.; Kranich, R.; Zhong, Y.-L.; Sugita, K.; Zou,
N. Angew. Chem., Int. Ed. 2001, 40, 202. Nicolaou, K. C.; Baran, P. S.;
Zhong, Y.-L.; Barluenga, S.; Hunt, K. W.; Kranich, R.; Vega, J. A. J. Am.
Chem. Soc. 2002, 124, 2233. Janza, B.; Studer, A. J. Org. Chem. 2005,
70, 6991. Reviews: Wirth, T. Angew. Chem., Int. Ed. 2001, 40, 2812.
Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523.
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Hart, D. J. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
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J. AM. CHEM. SOC. 2007, 129, 4498-4503
10.1021/ja0692581 CCC: $37.00 © 2007 American Chemical Society