Catalytic hydrogen atom transfer (HAT) for sustainable and diastereoselective radical reduction

Article abstract of DOI:10.1002/anie.201202818

Going cyclic! A catalytic cycle and cyclic transition states enable a novel sustainable and catalytic hydrogen atom transfer (HAT) for highly diastereoselective radical reductions. Readily available nontoxic silanes are the terminal reductants for epoxides that are opened by bifunctional titanocene(III) hydride catalysts. Copyright

Full text of DOI:10.1002/anie.201202818

Angewandte
Chemie
DOI: 10.1002/anie.201202818
Radical Chemistry
Catalytic Hydrogen Atom Transfer (HAT) for Sustainable and
Diastereoselective Radical Reduction**
Andreas Gansꢀuer,* Max Klatte, Gerhard M. Brꢀndle, and Joachim Friedrich*
Radical reduction by HAT (hydrogen atom transfer) is an
essential step in numerous radical reactions.[1] While transi-
tion-metal hydrides are in principle excellent reagents for this
purpose because of their low bond dissociation energies,[2]
their use in such reactions is attractive only when they serve as
catalysts.[2d] The ideal catalyst for such a process should be
able to activate a readily available, nontoxic terminal
reductant to form the transition-metal hydride, act as
a radical-generating agent, and reduce the radical through
HAT. A system matching the requirements is the reductive
epoxide opening catalyzed by [Cp2TiH] (1; Scheme 1).
titanocene(III) reagents.[5] Radical reduction can subse-
quently take place through an intramolecular HAT from the
weak TiIV H bond to the radical center in 2. The active
À
catalyst 1 is regenerated from 3 by s-bond metathesis.[6] The
intramolecular HAT in this cycle is an appealing step not only
because it enables catalysis. First, it should occur with radicals
that are otherwise difficult to reduce. Second, it should enable
unprecedented catalytic and stereoselective HATs[7] via
conformationally well-defined cyclic transition states.
The realization of our catalytic cycle with 4 is summarized
in Table 1. Silane 5 was chosen as the terminal reductant
because it has been shown to generate titanocene(III)
hydrides from dimethyl titanocenes and was used in the
preparation of [(Cp2TiOC2H5)2].[4] While method A provides
slightly higher yields than B it should be noted that method B
is more convenient, because [Cp2TiIV(CH3)2] is commercially
available as a solution in toluene and somewhat easier to
handle than [(Cp2TiOC2H5)2]. For both methods, the catalyst
loading can be reduced to 1 mol% under reflux without
lowering the yield of 6. Our novel method requires only
a small excess of 5 instead of an equimolar amount of the acid
(Coll·HCl; Coll = 2,4,6-trimethylpyridine) and large excesses
of Mn or Zn and 1,4-cyclohexadiene.[8]
Table 1: Catalytic reduction of 4 in the presence of 5 (1m 4/THF, RT,
desilylation with aq K2CO3) .
Scheme 1. Catalytic radical reduction featuring intramolecular HAT.
Method
Amount of Ti [mol%]
Precatalyst
t [h]
6 [%]
The active catalyst
1
can be generated from
A
A
B
B
5
1
5
1
[(Cp2TiOC2H5)2]
[(Cp2TiOC2H5)2]
[Cp2Ti(CH3)2]
[Cp2Ti(CH3)2]
14
16
14
24
84
[Cp2TiIIIOC2H5], which is formed by dissociation of the
dimer[3] or formed in situ from [Cp2TiIV(CH3)2] and silanes.[4]
Furthermore, 1 should be able to open epoxides through
electron transfer with a regioselectivity similar to that of other
86[a]
77
78[a]
[a] Reflux.
[*] Prof. Dr. A. Gansꢀuer, M. Klatte, G. M. Brꢀndle
Kekulꢁ-Institut fꢂr Organische Chemie und Biochemie der
Universitꢀt Bonn
The scope of the catalytic radical reduction was further
explored with aryl-substituted epoxides and 1-dodecene oxide
(Table 2). Both types of substrates usually give low yields in
titanocene-catalyzed and -mediated epoxide openings.[8]
Monosubstituted epoxides mainly give olefins under the
previous conditions. Aryl-substituted epoxides are not only
prone to nucleophilic ring opening under acidic conditions
but also the resulting benzylic radicals are difficult to reduce
in general.[1a–c,8]
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
E-mail: andreas.gansaeuer@uni-bonn.de
Prof. Dr. J. Friedrich
Institut fꢂr Chemie, Technische Universitꢀt Chemnitz
Strasse der Nationen 62, 09111 Chemnitz (Germany)
E-mail: joachim.friedrich@chemie.tu-chemnitz.de
[**] We are grateful to support from the Deutsche Forschungsgemein-
schaft and computer time of the Chemnitzer Hochleistungs-Linux-
Cluster (CHIC).
Our method conducted under neutral conditions gives
excellent results for both types of substrates (Table 2).
Tertiary benzylic radicals (entries 1–3) are reduced in yields
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202818.
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Table 2: Catalytic reduction of aryl- and monosubstituted epoxides
(conditions unless otherwise noted: [Cp2Ti(CH3)2] (5 mol%),
(CH3)PhSiH2 /1.5 equiv), 1m epoxide/THF, reflux, desilylation with aq
K2CO3).
Entry
Substrate
Product
t [h]
Yield [%]
1
16
83
2
3
14
36
79
82
4
5
6
7
16
18
16
18
65
68
81[a]
79[b]
[a] 78:22 mixture of 1- and 2-dodecanol. [b] RT, 80:20 mixture of 1- and 2-
dodecanol, [(tBuC5H4)2Ti(CH3)2].
Scheme 2. Reduction of cyclohexyl radicals by syn- or anti-selective
HAT. For computational details see the Supporting Information.
of ca. 80%. Secondary benzylic radicals (entries 4 and 5) give
slightly lower yields. 1-Dodecene oxide (entry 6) is opened in
81% yield with [Cp2Ti(CH3)2] as the precatalyst. In reactions
with [Cp2Ti(CH3)2] heating is necessary for reasonable
reaction times. Gratifyingly, the reaction can be carried out
at room temperature with [(tBuC5H4)2Ti(CH3)2] with essen-
tially identical results (entry 7). Thus, bulky catalysts are also
tolerated by our system and can even lead to improved results.
With an operating catalytic system in hand, we turned our
attention to the diastereoselective reduction of epoxide-
derived radicals. The postulated intramolecular HAT should
result in ordered cyclic transition states. For cyclic radicals this
leads to an unprecedented and highly selective catalytic
formation of trans products by means of a syn-selective
radical reduction[9] as verified by both computational and
synthetic results (Scheme 2).
Table 3: Catalytic diastereoselective reduction of substituted cyclohex-
ene oxides ([Cp2Ti(CH3)2] (5 mol%), 1.5 equiv (CH3)PhSiH2, in THF,
desilylation with aq K2CO3).
Entry Substrate
Product
d.r.
t [h] Yield [%]
1
96:4 22
96:4 16
80[a]
86[b]
76[b]
81[b]
2
3
4
96:4
4
94:6 16
[a] [(Cp2TiOC2H5)2] (2.5 mol%), RT, 0.17m epoxide. [b] Reflux, 1m
The computational study (Scheme 2, top) demonstrates
that the transition state for the syn HAT is lower in energy
than the transition state for anti HAT by 3.1 kcalmolÀ1. This
prediction is in excellent agreement with the synthetic
diastereoselectivity of radical reduction (syn/anti = 97:3;
Scheme 2, middle). With an external HAT reagent, such as
1,4-C6H8 (1,4-cyclohexadiene), the cis product is predomi-
nantly obtained by an anti-selective HAT. However, the
selectivity is disappointingly low (35:65; Scheme 2, bottom) in
agreement with the results of Giese et al.[7b] Thus, our concept
of an intramolecular syn-selective HAT through binding of
the HAT catalyst to the radical provides a unique opportunity
for controlling the diastereoselectivity of radical reduction.
The examples in Table 3 highlight the validity of our concept.
In reactions with aliphatic as well as aromatic substituents at
the radical center high yields and diastereoselectivities are
obtained, in the latter case, even at elevated temperatures. A
silyl protecting group (TBS) was tolerated.
epoxide.
merically pure or as 1:1 mixture of cis and trans isomers as
a substrate to investigate the influence of the syn-selective
HAT on this issue (Scheme 3). The [Cp2Ti(CH3)2]-derived
catalyst gave only a moderate diastereoselectivity of 85:15.
Introduction of bulky substituents resulted in higher selec-
tivity. With [(tBuC5H4)2Ti(CH3)2] as the precatalyst an
excellent selectivity of 97:3 was obtained even in refluxing
THF. Gratifyingly, with this system the highest yield of 10 was
obtained (82%), too. Moreover, our process is diastereocon-
vergent as exemplified in the reaction of 9 as 1:1 mixture of
diastereomers. The diastereoselectivity in the formation of 10
was the same as that observed for pure trans-9. This finding
demonstrates that after epoxide opening the intramolecular
À
HAT is slower than rotation around the C C bond adjacent to
the radical center. As an explanation for the high diastereo-
selectivity (Figure 1), we suggest that in transition state A the
interactions between the cyclopentadienyl ligands and the
An even greater challenge is the diastereoselective
reduction of acyclic radicals. We chose 9 either diastereo-
2
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selective HAT with cyclic and acyclic radicals. In the latter
case the reaction can even be conducted stereoconvergently.
The experimental results are in agreement with a preliminary
computational study of the proposed mechanism.
Experimental Section
[(Cp2TiOC2H5)2] (11.2 mg, 25.0 mmol, 1 mol% [Ti]) and 5 (917 mg,
7.50 mmol, 1.50 equiv) were dissolved in THF (5 mL) under Ar. After
the mixture had been stirred for 5 min, 4 (811 mg, 5.0 mmol,
1.0 equiv) was added and the mixture was heated at reflux for 16 h.
The solution was added to acetone (5 mL) and aq K2CO3 (25 wt% in
H2O, 100 mL, and stirred for 16 h. The organic solvents were
concentrated under reduced pressure and the remaining solution
was extracted with Et2O (1 ꢀ 100 mL). The organic phase was washed
with sat. NaCl solution (1 ꢀ 20 mL) and dried over MgSO4, and the
solvent was removed under reduced pressure. Chromatography
(SiO2, eluent cyclohexane/ethyl acetate 9:1) gave 706 mg
(4.30 mmol, 86%) of 6.
Scheme 3. Diastereoselective reduction of acyclic radicals by reductive
opening of 9.
Received: April 12, 2012
Published online: && &&, &&&&
Keywords: homogeneous catalysis · hydrogen atom transfer ·
.
radicals · stereoselectivity · titanium
[1] a) G. J. Rowlands, Tetrahedron 2009, 65, 8603 – 8655; b) B. C.
Gilbert, A. F. Parsons, J. Chem. Soc. Perkin Trans. 2 2002, 367 –
387; c) A. Studer, S. Amrein, Synthesis 2002, 835 – 849; d) D.
Pozzi, E. M. Scanlan, P. Renaud, J. Am. Chem. Soc. 2005, 127,
14204 – 14205; e) A. F. Barrero, J. E. Oltra, J. M. Cuerva, A.
Rosales, J. Org. Chem. 2002, 67, 2566 – 2571; f) J. M. Cuerva,
A. G. CampaÇa, J. Justicia, A. Rosales, J. L. Oller-Lꢁpez, R.
Robles, D. J. Cꢂrdenas, E. BuÇuel, J. E. Oltra, Angew. Chem.
2006, 118, 5648 – 5652; Angew. Chem. Int. Ed. 2006, 45, 5522 –
5526; g) S.-H. Ueng, M. M. Brahmi, E. Derat, L. Fensterbank, E.
Lacꢃte, M. Malacria, D. P. Curran, J. Am. Chem. Soc. 2008, 130,
10082 – 10083; h) J. C. Walton, M. M. Brahmi, L. Fensterbank, E.
Lacꢃte, M. Malacria, Q. Chu, S.-H. Ueng, A. Solovyev, D. P.
Curran, J. Am. Chem. Soc. 2010, 132, 2350 – 2358; i) M. Paradas,
A. G. CampaÇa, T. Jimꢄnez, R. Robles, J. E. Oltra, E. BuÇuel, J.
Justicia, D. J. Cꢂrdenas, J. M. Cuerva, J. Am. Chem. Soc. 2010,
132, 12748 – 12756.
[2] a) D. M. Smith, M. E. Pulling, J. R. Norton, J. Am. Chem. Soc.
2007, 129, 770 – 771; b) A. Gansꢅuer, C.-A. Fan, F. Piestert, J.
Am. Chem. Soc. 2008, 130, 6916 – 6917; c) A. Gansꢅuer, M. Otte,
L. Shi, J. Am. Chem. Soc. 2011, 133, 416 – 417; d) A. Gansꢅuer, S.
Lei, M. Otte, I. Huth, A. Rosales, I. Sancho-Sanz, N. M. Padial,
J. E. Oltra, Top. Curr. Chem. 2012, 320, 93 – 120.
[3] a) E. Samuel, J. F. Harrod, D. Gourier, Y. Dromzee, F. Robert, Y.
Jeannin, Inorg. Chem. 1992, 31, 3252 – 3259; b) R. Shu, J. F.
Harrod, A.-M. Lebuis, Can. J. Chem. 2002, 80, 489 – 495.
[4] a) S. Xin, J. F. Harrod, E. Samuel, J. Am. Chem. Soc. 1994, 116,
11562 – 11563; b) M. B. Carter, B. Schiøtt, A. Gutiꢄrrez, S. L.
Buchwald, J. Am. Chem. Soc. 1994, 116, 11667 – 11670; c) J. F.
Harrod, Coord. Chem. Rev. 2000, 206, 493 – 531.
Figure 1. Transition states for radical reduction through syn-selective
HAT after ring opening of 9.
methyl group at the radical center are substantially weaker
than the interactions between the cyclopentadienyl ligands
and the phenyl group in B. This will be even more pronounced
with the (tBuC5H4)2Ti-bound radical.
Thus, our catalytic system featuring the catalytic intra-
molecular syn-selective HAT is also suitable for unprece-
dented and highly selective reductions of acyclic radicals. It
should be noted that in related studies the opposite diaste-
reoselectivity was observed by Giese et al. for intermolecular
anti-selective HAT from TTMSS (tris(trimethylsilyl)si-
lane).[10]
In summary, we have devised a novel, sustainable, and
highly efficient catalytic system for the activation of readily
available, nontoxic (CH3)PhSiH2 towards reduction of epox-
ide-derived radicals. The catalytically active species,
a titanocene(III) hydride, serves a dual role as a radical-
generating species and as a HAT catalyst for the radical
formed. The crucial HAT proceeds in an intramolecular
manner and is therefore syn-selective. This unprecedented
catalyst control of radical reduction allows highly diastereo-
[5] a) A. Gansꢅuer, A. Barchuk, F. Keller, M. Schmitt, S. Grimme,
M. Gerenkamp, C. Mꢆck-Lichtenfeld, K. Daasbjerg, H. Svith, J.
Am. Chem. Soc. 2007, 129, 1359 – 1371; b) A. Gansꢅuer, C.-A.
Fan, F. Keller, J. Keil, J. Am. Chem. Soc. 2007, 129, 3484 – 3485;
c) A. Gansꢅuer, C.-A. Fan, F. Keller, P. Karbaum, Chem. Eur. J.
2007, 13, 8084 – 8090; d) A. Gansꢅuer, S. Lei, M. Otte, J. Am.
Chem. Soc. 2010, 132, 11858 – 11859.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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.
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[6] a) H.-G. Woo, T. D. Tilley, J. Am. Chem. Soc. 1989, 111, 3757 –
3758; b) H.-G. Woo, T. D. Tilley, J. Am. Chem. Soc. 1989, 111,
8043 – 8044.
[7] a) D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of
Radical Reactions, Wiley-VCH, Weinheim, 1996; b) W. Damm,
B. Giese, J. Hartung, T. Hasskerl, K. N. Houk, H. Zipse, J. Am.
Chem. Soc. 1992, 114, 4067 – 4079.
[8] a) T. V. RajanBabu, W. A. Nugent, J. Am. Chem. Soc. 1994, 116,
986 – 997; b) A. Gansꢅuer, H. Bluhm, M. Pierobon, J. Am. Chem.
Soc. 1998, 120, 12849 – 12859; c) A. Gansꢅuer, T. Lauterbach, S.
Narayan, Angew. Chem. 2003, 115, 5714 – 5731; Angew. Chem.
Int. Ed. 2003, 42, 5556 – 5573; d) J. M. Cuerva, J. Justicia, J. L.
Oller-Lꢁpez, J. E. Oltra, Top. Curr. Chem. 2006, 264, 63 – 92;
e) A. Gansꢅuer, J. Justicia, C.-A. Fan, D. Worgull, F. Piestert,
Top. Curr. Chem. 2007, 279, 25 – 52; f) A. Gansꢅuer, A.
Fleckhaus, M. Alejandre Lafont, A. Okkel, K. Kotsis, AA.
Anoop, F. Neese, J. Am. Chem. Soc. 2009, 131, 16989 – 16999.
[9] For a stoichiometric system with ligands as HAT reagents: T.
Kawaji, N. Shohji, K. Miyashita, S. Okamoto, Chem. Commun.
2011, 47, 7857 – 7859.
[10] B. Giese, M. Bulliard, J. Dickhaut, R. Hallbach, C. Hassler, U.
Hoffmann, B. Hinzen, M. Senn, Synlett 1995, 116 – 118.
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Radical Chemistry
Going cyclic! A catalytic cycle and cyclic
transition states warrant a novel sustain-
able and catalytic HAT for highly diaste-
reoselective radical reductions. Readily
available nontoxic silanes are the terminal
reductants for epoxides that are opened
by bifunctional titanocene(III) hydride
catalysts.
A. Gansꢁuer,* M. Klatte, G. M. Brꢁndle,
J. Friedrich*
&&&& — &&&&
Catalytic Hydrogen Atom Transfer (HAT)
for Sustainable and Diastereoselective
Radical Reduction
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!