Ruthenium catalyzed hydroaminoalkylation of isoprene via transfer hydrogenation: Byproduct-free prenylation of hydantoins

Article abstract of DOI:10.1039/c3cc43463j

The ruthenium catalyst derived from Ru₃(CO)₁₂ and triphos [Ph₂P(CH₂CH₂PPh₂) ₂] promotes the direct C-C coupling of isoprene with aryl substituted hydantoins 1a-1f at the diene C4-position to furnish products of n-prenylation 2a-2f. A mechanism involving hydantoin dehydrogenation followed by diene-imine oxidative coupling to furnish a transient aza-ruthencyclopentene is proposed.

Full text of DOI:10.1039/c3cc43463j

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Ruthenium catalyzed hydroaminoalkylation of
isoprene via transfer hydrogenation: byproduct-free
prenylation of hydantoins†
Cite this: DOI: 10.1039/c3cc43463j
Received 9th May 2013,
Accepted 23rd May 2013
Daniel C. Schmitt, Jungyong Lee, Anne-Marie R. Dechert-Schmitt, Eiji Yamaguchi
and Michael J. Krische*
DOI: 10.1039/c3cc43463j
www.rsc.org/chemcomm
The ruthenium catalyst derived from Ru3(CO)12 and triphos
[Ph2P(CH2CH2PPh2)2] promotes the direct C–C coupling of isoprene
with aryl substituted hydantoins 1a–1f at the diene C4-position to
furnish products of n-prenylation 2a–2f. A mechanism involving
hydantoin dehydrogenation followed by diene-imine oxidative
coupling to furnish a transient aza-ruthencyclopentene is proposed.
Metal catalyzed hydroaminoalkylation1 was discovered by Maspero2a
and Nugent2b in the early 1980’s. These processes were ineffi-
cient and it was not until 2007 that the first high-yielding
hydroaminoalkylations were reported by Hartwig, who employed
a tantalum-based catalyst.3 Subsequently, other efficient early
transition metal catalysts based on tantalum,3 titanium4 and
niobium5 were developed. These early transition metal catalyzed
hydroaminoalkylations largely focused on olefin partners, and
withstanding one recent report of titanium catalyzed diene hydro-
aminoalkylation,4h hydroaminoalkylations of other p-unsaturated
reactants are unknown. For early transition metal catalysts, func-
Scheme 1 Overcoming the requirement of directing groups in late transition
metal catalyzed hydroaminoalkylation. Triphos = [Ph2P(CH2CH2PPh2)2].
tional group compatibility and sensitivity to adventitious moisture these data suggested the feasibility of isoprene mediated prenyla-
pose serious limitations. Hence, it would be desirable to develop tions of a-amino acid derivatives catalyzed by zero-valent ruthenium
less sensitive late transition metal catalysts for hydroaminoalkyla- complexes. Toward this end, a diverse set of N-protected phenyl-
tion. However, existing ruthenium6 and iridium7 based catalysts glycine esters were exposed to isoprene in the presence of Ru3CO12
for hydroaminoalkylation require pyridyl directing groups and and tricyclohexylphosphine, PCy3, in toluene solvent at 130 1C.
only have been applied to olefins. In this account, a ruthenium However, the anticipated products of prenylation were not observed.
catalyst for diene hydroaminoalkylation is reported that does not It was reasoned that the steric demand posed by formation of a fully
require directing groups and employs hydantoins as aminoalkyl substituted carbon center rendered the rate of C–C coupling prohi-
donors (Scheme 1).
bitively slow. Such steric effects are potentially mitigated for the
Our initial experiments were inspired by two separate accounts N-benzyl hydantoin 1a derived from phenylglycine. As hydantoin 1a
in the literature. The first is Jun’s report of the Ru3CO12 catalyzed is sparingly soluble in toluene, THF solutions of hydantoin 1a and
hydroaminoalkylation of olefins employing 3-methyl-2-(N-benzyl- isoprene were exposed to substoichiometric amounts of Ru3CO12 in
amino)pyridine (Scheme 1, top).6a The second is our own report the presence of various phosphine ligands. Ultimately, it was found
of the Ru3CO12 catalyzed hydrohydroxyalkylation of isoprene and that exposure of hydantoin 1a (100 mol%) to isoprene (300 mol%)
myrcene employing substituted mandelic esters.8 Taken together, in the presence of the ruthenium(0) catalyst derived from Ru3CO12
(3 mol%) and triphos [Ph2P(CH2CH2PPh2)2] (12 mol%) at 140 1C in
THF solvent (2 M) provides the prenylated adduct 3a in 87% yield as
determined by H NMR analysis using 1,3,5-trimethoxybenzene as
an internal standard (Table 1).
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin,
TX 78712, USA. E-mail: mkrische@mail.utexas.edu; Fax: +1 613 9418447;
Tel: +1 512 2325892
1
These conditions were applied to C–C coupling of isoprene
† Electronic supplementary information (ESI) available: Characterization data for
all new compounds (1H NMR, 13C NMR, IR, LRMS). See DOI: 10.1039/c3cc43463j with aryl substituted hydantoins 1a–1f. Due to the poor solubility
c
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Table 1 Selected optimization experiments in the hydroaminoalkylation of
isoprene 2 with hydantoin 1a to form the prenylated adduct 3a
Table
2
Ruthenium catalyzed hydroaminoalkylation of isoprene 2 with
hydantoin 1a–1f to form prenylated adducts 3a–3fa
Ru3(CO)12
Entry (mol%)
2
T
Time NMR yield
1a, Ar = Ph
1d, Ar = 4-MeO-Ph
1b, Ar = 4-i-Pr-Ph
1e, Ar = piperonyl
1c, Ar = 4-F-Ph
1f, Ar = 3-pyridyl
Ligand
(mol%) (1C) (h)
(%)
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
2
2
Pcy3
400
400
400
400
150 72
150 72
150 72
150 72
150 72
140 72
140 72
140 48
140 48
140 48
9
20
26
26
37
72
81
70
77
87
iPrPPh2
Ph2PCH2PPh2
Cy2P(CH2)2PCy2
PhP(CH2CH2PPh)2 400
PhP(CH2CH2PPh)2 400
PhP(CH2CH2PPh)2 600
PhP(CH2CH2PPh)2 600
PhP(CH2CH2PPh)2 600
PhP(CH2CH2PPh)2 600
2.5
3
of the prenylated adducts 3a–3f, the yields determined by 1H NMR
analysis were significantly higher than the corresponding isolated
yields due to loss of material in the course of purification by flash
silica gel chromatography. Nevertheless, the products of prenyla-
tation 3a–3f could be obtained in 58–76% yield. Both electron
deficient and electron rich aryl substituents are tolerated. The
reactions did prove to be somewhat sensitive to moisture, perhaps
due to hydration of the transient dehydro-hydantoins (vida supra),
which necessitated drying THF solvent via distillation from
sodium-benzophenone ketyl and the drying of isoprene over
molecular sieves. Under this initial set of conditions, alkyl sub-
stituted hydantoins are recovered unchanged from the reaction
mixtures (Table 2). The products of hydroaminoalkylation offer
several possibilities for further elaboration. For example, upon
exposure of adduct 3a to substoichiometric quantities of triflic
acid, the product of hydroamination 4a is formed in good yield
(eqn (1)).9 Exposure of adduct 3a to lithium aluminum hydride
provides the vicinal diamine 5a (eqn (2)).10
a
Yields determined by 1H NMR analysis employed 1,3,5-trimethoxy-
benzene as an internal standard. See ESI for further details.
b-Hydride elimination releases dehydro-1a and delivers the
alkylruthenium hydride IV,15 which upon C–H reductive
elimination generates the product of hydroaminoalkylation
and returns ruthenium to its zero-valent form (Scheme 2).
In summary, we report a ruthenium catalyst for diene hydro-
aminoalkylation that does not require directing groups and
(1)
(2)
With regard to the catalytic mechanism, exposure of
Ru3(CO)12 to chelating phosphine ligands is known to provide
discrete, monometallic complexes.11 Oxidative coupling of iso-
prene 2 and dehydro-1a to form metallacycle I finds precedent
in the work of Chatani and Murai on Pauson–Khand type
reactions of 1,2-diones,12 and studies from our laboratory.8,13,14
Isomerization of metallacycle I to metallacycle II, the presum-
ably more stable primary s-allyl haptomer, followed by protono-
lysis of metallacycle II by hydantoin 1a provides complex III.
Scheme 2 Proposed mechanism for ruthenium(0) catalyzed hydroamino-
alkylation via transfer hydrogenation.
c
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Organometallics, 2011, 30, 921; (b) A. L. Reznichenko and K. C. Hultzsch,
J. Am. Chem. Soc., 2012, 134, 3300.
6 For ruthenium catalyzed hydroaminoalkylation, see: (a) C.-H. Jun,
D.-C. Hwang and S.-J. Na, Chem. Commun., 1998, 1405; (b) N. Chatani,
T. Asaumi, S. Yorimitsu, T. Ikeda, F. Kakiuchi and S. Murai, J. Am.
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7 For iridium catalyzed hydroaminoalkylation, see: (a) K. Tsuchikama,
M. Kasagawa, K. Endo and T. Shibata, Org. Lett., 2009, 11, 1821;
(b) S. Pan, K. Endo and T. Shibata, Org. Lett., 2011, 13, 4692.
8 J. C. Leung, L. M. Geary, T.-Y. Chen, J. R. Zbieg and M. J. Krische,
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employs hydantoins as aminoalkyl donors. This process may be
viewed as a formal imine addition from the amine oxidation
level, representing a novel addition to the growing family of C–C
bond forming transfer hydrogenations.16 Future studies will
focus on the development of related hydroaminoalkylations
catalyzed by late transition metals.
Acknowledgment is made to the Robert A. Welch Foundation
(F-0038) and the NIH-NIGMS (RO1-GM069445) for partial support
of this research.
Notes and references
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L. L. Schafer, Pure Appl. Chem., 2010, 82, 1503.
2 For initial reports of metal catalyzed hydroaminoalkylation, see:
provides Ru(CO)3(dppe): R. A. Sanchez-Delgado, J. S. Bradley and
G. Wilkinson, J. Chem. Soc., Dalton Trans., 1976, 399.
(a) M. G. Clerici and F. Maspero, Synthesis, 1980, 305; (b) W. A. Nugent, 12 (a) N. Chatani, M. Tobisu, T. Asaumi, Y. Fukumoto and S. Murai,
D. W. Ovenall and S. J. Holmes, Organometallics, 1983, 2, 161.
3 For tantalum catalyzed hydroaminoalkylation, see: (a) S. Herzon and
J. F. Hartwig, J. Am. Chem. Soc., 2007, 129, 6690; (b) S. Herzon and
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J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 14940; (c) P. Eisenberger, 13 (a) J. C. Leung, L. M. Geary, T.-Y. Chen, J. R. Zbieg and M. J. Krische,
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coupling pathways: J.-R. Kong, C.-W. Cho and M. J. Krische, J. Am.
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P. Eisenberger, D. C. Leitch, P. R. Payne and L. L. Schafer, J. Am.
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finds abundant precedent in the context of amine racemization.
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¨
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¨
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c
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Chem. Commun.