Radical cyclizations terminated by Ir-Catalyzed hydrogen atom transfer

Article abstract of DOI:10.1021/ja109362m

A system for coupling catalytic radical cyclization and Ir-catalyzed hydrogen atom transfer (HAT) is described. It is essential that the HAT catalyst activates H2 quickly and is not a hydrogenation catalyst. Vaska's complex was found to fulfill both purpo

Full text of DOI:10.1021/ja109362m

Published on Web 12/14/2010
Radical Cyclizations Terminated by Ir-Catalyzed Hydrogen Atom Transfer
Andreas Gansa¨uer,* Matthias Otte, and Lei Shi
Kekule´-Institut fu¨r Organische Chemie und Biochemie der UniVersita¨t Bonn, Gerhard Domagk Strasse 1,
53121 Bonn, Germany
Received October 18, 2010; E-mail: andreas.gansaeuer@uni-bonn.de
Scheme 1. Concept of the Catalytic Radical Cyclization of 2
Terminated by an Ir-Catalyzed HAT
Abstract: A system for coupling catalytic radical cyclization and
Ir-catalyzed hydrogen atom transfer (HAT) is described. It is
essential that the HAT catalyst activates H2 quickly and is not a
hydrogenation catalyst. Vaska’s complex was found to fulfill both
purposes efficiently.
Radical cyclizations are highly useful for the synthesis of
complex molecular architectures due to their high selectivity and
compatibility with densely functionalized substrates.1 For synthetic
applications catalytic, sustainable methodology without stoichio-
metric amounts of toxic and expensive substances, especially
hydrogen atom donors, is highly desirable. To this end, H2O,2
alcohols,3 and H2 are especially attractive.4 A first example of a
H2-mediated, Cr-catalyzed radical cyclization was recently reported
by Norton.5 Unfortunately, the remarkable threefold task of the
catalystsH2 activation, radical generation, and radical reduction
via hydrogen atom transfer (HAT)slimits the substrate scope of
the reaction.
Scheme 2. Study of the Competing Pathways of Trapping of
Radicals Formed by 5-exo Cyclization for 2 and 4
A conceptually different and unprecedented approach to such
cyclizations is the coupling of catalytic cycles for radical generation
and for hydrogen activation and HAT. In that manner, more general
reactions become available. However, potential pitfalls for such
methodology are numerous. Most notably, the kinetics of radical
generation, cyclization, H2 activation, and HAT have to be precisely
adjusted to preclude undesired side reactions such as hydrogenation
of radical acceptors or reduction of radical intermediates by a HAT
before cyclization (Scheme 1).
We chose Vaska’s complex, IrCl(CO)(PPh3)2 (1), as HAT
catalyst to address these issues.6 It forms a stable product of
oxidative addition to H2 without free coordination sites and hence
displays low activity in the hydrogenation reactions of radical
acceptors, especially alkynes. Since premature reduction of inter-
mediate radicals must be avoided, the steric shielding of the hydrido
ligands in [IrH2Cl(CO)(PPh3)2] seems favorable.
The use of 1 also imposes limitations for a catalytic system for
radical generation. No H2 activation or ligand exchange with 1
should occur. The cyclization must take place before undesired HAT
to intermediate radicals. Finally, the radical-generating agent must
not intercept the final radical before the catalytic HAT. Titanocene-
catalyzed reductive epoxide opening7 is an attractive method for
these purposes. The titanocene complexes involved do not bind
phosphines and CO and do not activate H2.
The presence of the desired and undesired pathways can be
readily distinguished experimentally. If A is intercepted by HAT,
an undesired product will be formed. In the absence of 1 or in the
case of an inefficient HAT, B will be trapped by Cp2TiCl to give
C. From C, liberation of 3 and regeneration of Cp2TiCl2 requires
the protonation of the Ti-O and Ti-C bonds by at least 2 equiv
of Coll ·HCl. In the case of trapping of B by HAT, the formation
of 3 and regeneration of Cp2TiCl2 from D requires only the
protonation of the Ti-O bond by 1 equiv of Coll ·HCl. Subse-
quently, Cp2TiCl is re-formed by reduction with Mn. Thus, the
amount of Coll ·HCl added to the reaction provides a simple
experimental means for studying the efficiency of the Ir-catalyzed
HAT. Scheme 2 summarizes the results of the catalytic cyclizations
of 2 and 4 in the absence and in the presence of 1.
In the absence of 1, the yields of 3 and 5 are below 50%, even
with 1.5 equiv of Coll ·HCl.8 The remainder consists of starting
material. In the presence of 1 and H2 (4 atm), the isolated yields
increase by more than a factor of 2. This indicates an efficient
coupling of catalytic radical cyclization and Ir-catalyzed HAT. No
products of undesired HAT to radicals of type A were observed.
Even when taking into account that both radical and HAT reagent
are present in catalytic amounts, and therefore a bimolecular
trapping is disfavored, this is still amazing, because reactions of
radicals with M-H bonds are exothermic and can have rate
constants much higher than those of 5-exo cyclizations.9 As a reason
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416 J. AM. CHEM. SOC. 2011, 133, 416–417
10.1021/ja109362m  2011 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Radical Cyclizations to Carbocycles Terminated by
for the chemoselectivity of the HAT, we suggest that the steric
shielding of the hydrido ligands in [IrH2Cl(CO)(PPh3)2] by PPh3
retards the trapping of radicals of type A. This could be especially
relevant for the tertiary radicals employed here.
Ir-Catalyzed HAT (1.5 equiv of Coll ·HCl, 3 equiv of Mn, 0.1 M
THF, 4 atm H2)
In the case of 4, the situation is more complex. After the
cyclization, a highly reactive vinyl radical is generated that is not
trapped Cp2TiCl. Instead, its high reactivity results either in a
reduction by the Ir-catalyzed HAT or by a HAT from THF. In the
latter case, a tetrahydrofuranyl radical is generated that can be either
trapped by Cp2TiCl or reduced by an Ir-catalyzed HAT. The 80%
isolated yield of 5 obtained in the presence of 1 (37% without 1)
demonstrates that the coupling of the catalytic cycles is not affected
by the nature of the final HAT step. The identical diastereoselec-
tivity of the formation of 4 with or without 1 may suggest an initial
HAT from THF. Hydrogenation catalysts, such as Wilkinson’s
catalyst, RhCl(PPh3)3,10 are not useful, because hydrogenation,
especially of alkynes, competes with the desired coupling of the
catalytic cycles. Table 1 summarizes further examples of the
synthesis of pyrrolidines.
entry
substrate
conditions
producta
1
2
3
4
5
14b
14b
14b
16d
18f
10 mol % Cp2TiCl2, 1 mol % 1
10 mol % Cp2TiCl2, 5 mol % 1
15 mol % Cp2TiCl2, 5 mol % 1
15 mol % Cp2TiCl2, 5 mol % 1
15 mol % Cp2TiCl2, 5 mol % 1
15, 60%c
15, 71%c
15, 88%c
17, 68%e
19, 91%g
a All products can be diastereoconvergently hydrogenated to the trans
products with Crabtree’s catalyst.12 b dr ) 96:4. c dr ) 63:37. d dr )
99:1. e dr ) 85:15. f dr ) 98:2. g dr ) 67:33.
HAT with H2 as terminal reductant. It is essential that the HAT
catalyst, Vaska’s complex, is not a hydrogenation catalyst.
Table 1. Radical Cyclizations Terminated by Ir-Catalyzed HAT (1.5
equiv of Coll ·HCl, 3 equiv of Mn, 0.1 M THF, 4 atm H2)
Acknowledgment. We thank the Alexander von Humboldt-
Stiftung, Fonds der Chemischen Industrie, and DFG for support.
Supporting Information Available: Experimental details and
compound characterization. This material is available free of charge
via the Internet at http://pubs.acs.org.
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entry
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conditions
product
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2
3
4
5
6
6
8
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12
15 mol % Cp2TiCl2, 5 mol % 1
7, 72%
15 mol % Kagan’s complex, 5 mol % 1 7, 77%a
15 mol % Cp2TiCl2, 5 mol % 1
15 mol % Cp2TiCl2, 5 mol % 1
15 mol % Cp2TiCl2, 5 mol % 1
9, 76%b
11, 70%c
13, 70%d
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a er ) 63:37. b dr ) 96:4. c dr ) 91:9. d dr ) 89:11.
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are formed in much higher selectivity [(E):(Z) ) 89:11 to 96:4,
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In summary, we have devised a system of coupled catalytic
cycles for sustainable radical cyclizations terminated by Ir-catalyzed
JA109362M
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