Ruthenium-catalyzed C-C coupling of amino alcohols with dienes via transfer hydrogenation: Redox-triggered imine addition and related hydroaminoalkylations

Article abstract of DOI:10.1021/ja5130258

Ruthenium-catalyzed hydrogen transfer from 4-aminobutanol to butadiene results in the pairwise generation of 3,4-dihydro-2H-pyrrole and an allylruthenium complex, which combine to form products of imine anti-crotylation. In couplings of 1-substituted-1,3-dienes, novel C2 regioselectivity is observed. As corroborated by deuterium labeling studies, kinetically preferred hydrometalation of the terminal olefin of the 1-substituted-1,3-diene delivers a 1,1-disubstituted π-allylruthenium complex that isomerizes to a thermodynamically more stable monosubstituted π-allylruthenium complex, which undergoes imine addition with allylic inversion through a closed transition structure. Direct ruthenium-catalyzed diene hydroaminoalkylations with pyrrolidine also are described.

Full text of DOI:10.1021/ja5130258

Communication
pubs.acs.org/JACS
Ruthenium-Catalyzed C−C Coupling of Amino Alcohols with Dienes
via Transfer Hydrogenation: Redox-Triggered Imine Addition and
Related Hydroaminoalkylations
Te-Yu Chen, Ryosuke Tsutsumi, T. Patrick Montgomery, Ivan Volchkov, and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: Ruthenium-catalyzed hydrogen transfer
from 4-aminobutanol to butadiene results in the pairwise
generation of 3,4-dihydro-2H-pyrrole and an allylruthe-
nium complex, which combine to form products of imine
anti-crotylation. In couplings of 1-substituted-1,3-dienes,
novel C2 regioselectivity is observed. As corroborated by
deuterium labeling studies, kinetically preferred hydro-
metalation of the terminal olefin of the 1-substituted-1,3-
diene delivers a 1,1-disubstituted π-allylruthenium complex
that isomerizes to a thermodynamically more stable
monosubstituted π-allylruthenium complex, which under-
goes imine addition with allylic inversion through a closed
transition structure. Direct ruthenium-catalyzed diene
hydroaminoalkylations with pyrrolidine also are described.
lthough several early transition metal-based catalysts for
A
hydroaminoalkylation have been described,1 the develop-
ment of related late transition metal-catalyzed amine C−H
functionalizations has proven challenging.1−3 Indeed, with the
exception of the ruthenium(0)-catalyzed C−C coupling of
hydantoins with dienes,3 all other late-transition-metal catalysts
for hydroaminoalkylation require pyridyl directing groups in
combination with mono-olefin reactants.2 Our laboratory has
developed a suite of redox-triggered carbonyl additions wherein
hydrogen transfer from alcohols to π-unsaturated reactants
delivers transient carbonyl−organometal pairs that combine to
furnish products of formal alcohol C−H functionalization or
“hydrohydroxyalkylation”.4 Accordingly, we envisioned a proto-
col for formal late transition metal-catalyzed hydroaminoalkyla-
tion wherein dehydrogenation of 4-aminobutanol at oxygen
would initiate intramolecular Schiff base formation5 and
hydrometalation of exogenous diene. The resulting imine−
allylruthenium pair would then combine to form products of
formal hydroaminoalkylation (Figure 1, bottom). Here, we
report that the ruthenium catalyst generated from HClRu(CO)-
(PPh3)3 and 1,3-bis(dicyclohexylphosphino)propane (dCypp)
promotes the formal hydroaminoalkylation of 4-aminobutanol
with butadiene and higher conjugated dienes to form 2-
substituted pyrrolidines with complete levels of branched
regioselectivity and good to excellent levels of anti-diastereose-
lectivity.6,7 Further, we report preliminary studies on direct
ruthenium-catalyzed hydroaminoalkylation, as exemplified by
the coupling of pyrrolidine with butadiene and isoprene.
Figure 1. Redox-triggered carbonyl and imine addition catalyzed by
ruthenium involving diene pronucleophiles.
conditions similar to those employed in related C−C couplings
of primary alcohols with dienes (Figure 1, top).8 In initial
experiments, catalysts generated in situ from HClRu(CO)-
(PPh3)3 (5 mol %) and various phosphine ligands were evaluated
(Table 1). To facilitate isolation of the reaction products, the
crude reaction mixtures were subjected directly to N-tosylation
conditions. Among chelating phosphine ligands, 1,3-bis-
(diphenylphosphino)propane (dppp) was quite effective,
providing the desired imine addition product 4a in 80% yield
but with modest levels of anti-diastereoselectivity (Table 1, entry
7). This result led us to evaluate the catalyst modified by dCypp
(Table 1, entry 9), which provided adduct 4a in 54% yield with
complete levels of anti-diastereoselectivity, as determined by 1H
NMR analysis of the crude reaction mixture. Through further
To probe the feasibility of redox-triggered imine addition,
butadiene (1a) was exposed to 4-aminobutanol (2a) under
Received: December 22, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja5130258
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Journal of the American Chemical Society
Communication
the coupling of 1,3-pentadiene (1d), C−C coupling occurs at the
diene 2-position to furnish the adduct 4d with complete levels of
anti-diastereoselectivity. Similarly, the 1-cyclohexyl-substituted
diene 1e and 1-(4-tetrahydropyranyl)-substituted diene 1f
engage in C−C coupling at the diene 2-position to furnish
adducts 4e and 4f, respectively, with complete levels of anti-
diastereoselectivity. As will be discussed (vide infra), coupling to
the diene 2-position, exemplified by the formation of 4d−4f,
suggests reversible diene hydrometalation in advance of imine
addition. Reversible hydrometalation enables nonconjugated
dienes, such as 1,4-pentadiene (1g), to serve as conjugated diene
equivalents, as shown in the formation of 4d (eq 1). Whereas
Table 1. Selected Optimization Experiments in the
Ruthenium-Catalyzed Coupling of Butadiene (1a) with 4-
a
Aminobutanol (2a)
a
b
Yields are of material isolated by silica gel chromatography. PCy3
c
(10 mol%). Average isolated yield from four experiments. See the
Supporting Information for further details.
variation of temperature and reaction time, optimal conditions
for the highly diastereoselective (>20:1 dr) coupling of 1a with
2a to form 4a in 75% yield were identified (Table 1, entry 13).
With these conditions in hand, the coupling of 2a with various
conjugated dienes 1a−1f was explored (Table 2). As illustrated
in the couplings of 1a, isoprene (1b), and myrcene (1c), a
gradual decline in anti-diastereoselectivity with increasing size of
the diene 2-substituent due to allylic 1,2-strain is observed.8c In
attempted reactions of 1a with 5-aminopentanol failed to provide
the corresponding 2-substituted piperidine, it was found that the
more highly substituted 4-aminobutanols 2b and 2c participate
in redox-triggered imine addition to form adducts 4g (eq 2) and
4h (eq 3), respectively, with complete levels of anti-
1
Table 2. Regio- and Diastereoselective Ruthenium-Catalyzed
diastereoselectivity, as determined by H NMR spectroscopy.
a
C−C Coupling of Conjugated Dienes 1a−1f with 2a
Functionalized dienes, such as chloroprene or alkoxy-substituted
dienes, do not participate in C−C coupling under these
conditions.
In the couplings of 2a with conjugated dienes 1a−1f, alcohol
dehydrogenation triggers pairwise generation of an imine
electrophile, 3,4-dihydro-2H-pyrrole, and a ruthenium hydride
that hydrometalates the diene to form a nucleophilic
allylruthenium complex. It was reasoned that such nucleo-
phile−electrophile pairs could be generated through the redox-
triggered coupling of dienes with pyrrolidine itself, constituting a
rare example of late transition metal-catalyzed hydroaminoalky-
lation in the absence of a directing group.2,3 However, as
observed empirically in the present couplings of 2a, alcohol
dehydrogenation occurs in preference to amine dehydrogen-
ation, suggesting that such processes would pose significant
challenges, which proved to be the case. Nevertheless, after
screening of various ruthenium complexes, it was found that the
catalyst generated in situ through the acid−base reaction of
H2Ru(CO)(PPh3)(dppp) and ferrocene carboxylic acid or
C7F15CO2H promotes the hydroaminoalkylation of conjugated
dienes 1a and 1b with pyrrolidine (3a) to form adducts 4a and
4b, respectively, in good yields with good levels of anti-
diastereoselectivity (Scheme 1, eq 4). Finally, with the trimeric
imine derived from pyrrolidine, dehydro-3a, 2-propanol-medi-
ated reductive coupling to form N-Cbz-4a could be achieved,
a
b
Yields are of material isolated by silica gel chromatography. 1a (500
c
mol%). dCype was used as the ligand. Diastereoselectivities were
determined by H NMR analysis of crude reaction mixtures. See the
Supporting Information for further details.
1
B
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Journal of the American Chemical Society
Communication
Scheme 1. Ruthenium-Catalyzed Hydroaminoalkylation of
Conjugated Dienes 1a and 1b with Pyrrolidine and the
Related 2-Propanol-Mediated Reductive Coupling of dehydro-
Scheme 2. Rationale for the C2 Regioselectivity Observed in
the Formation of Adducts 4d−4f and Deuterium Labeling
Studies Corroborating Reversible Diene Hydrometalation
a
3a
a
Yields are of material isolated by silica gel chromatography. For the
reaction of 1a, R2CO2H = ferrocene carboxylic acid. For the reaction
of 1b, R2CO2H = C7F15CO2H.
corroborating intervention of the imine in catalytic couplings of
2a or 3a (Scheme 1, eq 5).
emphasize the highly reversible nature of diene hydrometalation
events under the present conditions for the reaction of 1-
substituted dienes with 2a (Scheme 2).
The regioselectivity and anti-diastereoselectivity observed in
the formation of adducts 4a−4h can be understood on the basis
of stereochemical models A−D (Scheme 3). Imine addition is
Coupling at the diene 2-position, as illustrated by the
formation of adducts 4d−4f, represents a regioselectivity that
has not been reported in intermolecular metal-catalyzed carbonyl
or imine reductive coupling.6−13 Olefin coordination is a prelude
to hydrometalation, and the stability of late-transition-metal−
olefin π-complexes decreases with increasing degree of olefin
substitution.14 As observed in the stoichiometric reaction of
HClRu(CO)(PPh3)3 with 1,3-pentadiene to provide the 1,3-
dimethyl-substituted π-allylruthenium isomer,15 hydrometala-
tion of 1-substituted-1,3-dienes at the less substituted olefin to
form the π-allylruthenium complex I is kinetically preferred.14
However, the resulting terminally disubstituted π-allyl I is less
stable than the isomeric monosubstituted π-allylruthenium
complex II.16 Thus, if hydrometalation is reversible, the initially
formed disubstituted π-allyl I may isomerize8b,17 to form the π-
allylruthenium complex II, which can engage in imine addition
by way of the (E)-σ-allylruthenium haptomer to deliver the
observed reaction products 4d−4f (Scheme 2).
Scheme 3. Stereochemical Models A−D for Imine Addition
To determine whether diene hydrometalation is reversible,
deuterio-2a was subjected to the standard conditions for
ruthenium-catalyzed C−C coupling with 1a (Scheme 2).
Significant levels of deuterium incorporation were observed at
all of the vinylic positions (Hc, Hd, and Hd′), the allylic position
(Hb), and the methyl group (He), corroborating reversible diene
hydrometalation. Notably, deuterium was completely retained at
the methine adjacent to nitrogen (Ha), suggesting that alcohol
dehydrogenation is not reversible because of rapid capture of the
resulting aldehyde via imine formation. Retention of deuterium
at Ha also suggests that the transient imine is not subject to
hydrogenation−dehydrogenation and that the amine product
derived upon C−C coupling is kinetically inert with respect to
dehydrogenation−hydrogenation, likely as a result of coordina-
tion of the homoallylic olefin to ruthenium, which blocks an
otherwise vacant coordination site required for β-hydride
elimination. The incorporation of deuterium across all of the
diene-derived carbon atoms of deuterio-4a differs dramatically
from the pattern of deuterium incorporation observed in the
previously reported reaction of deuterio-2d with 1b, which was
conducted under similar conditions.8a These data further
postulated to occur by way of the primary σ-allylruthenium
haptomer with allylic inversion through a closed transition
structure. As stereochemical models A and B would generate syn-
diastereomers, these pathways are excluded. The stereochemical
model D requires intervention of the (Z)-σ-allylruthenium
isomer, which is unlikely as the deuterium labeling studies
corroborated thermodynamic control in the formation of the
allylruthenium intermediate. Thus, stereochemical model C,
wherein imine addition occurs through a chairlike transition
structure by way of the (E)-σ-allylruthenium isomer, is preferred.
With regard to scope, attempts were made to develop an
enantioselective variant of the present diene−amino alcohol C−
C couplings. Numerous chiral ligands were evaluated, but high
levels of enantiomeric enrichment could be achieved only in the
formation of the minor diastereomeric reaction products.
Attempts also were made to utilize α-olefins and styrenes as
coupling partners, but these reactions failed entirely.
In summary, we have reported the first redox-triggered
additions of dienes to unactivated imines, as illustrated in the
C
DOI: 10.1021/ja5130258
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Journal of the American Chemical Society
Communication
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formal hydroaminoalkylation of conjugated dienes 1a−1f using
amino alcohols 2a−2c to deliver adducts 4a−4h. The present
protocol for redox-triggered imine addition bypasses the
stoichiometric use of premetalated carbanions and hence, the
generation of stoichiometric metallic byproducts, as required in
conventional methods for imine addition. In the present
transformations, water is the sole stoichiometric byproduct.
Furthermore, as illustrated in the reaction of dienes 1a and 1b
with 3a, preliminary studies of direct amine C−H functionaliza-
tion have been described, constituting a rare example of late
transition metal-catalyzed hydroaminoalkylation in the absence
of directing groups.2,3 Future studies will focus on the
development of improved second-generation catalysts for
amine C−H functionalization via redox-triggered imine addition.
(7) Zhu, S.; Lu, X.; Luo, Y.; Zhang, W.; Jiang, H.; Yan, M.; Zeng, W.
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ASSOCIATED CONTENT
■
(8) For ruthenium(II)-catalyzed reactions of dienes with primary
alcohols to deliver branched products of C−C coupling, see:
(a) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 6338. (b) Smejkal, T.; Han, H.; Breit, B.; Krische, M. J. J. Am. Chem.
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Chem. Soc. 2011, 133, 10582. (d) Zbieg, J. R.; Yamaguchi, E.; McInturff,
E. L.; Krische, M. J. Science 2012, 336, 324. (e) McInturff, E. L.;
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S
* Supporting Information
Experimental procedures and spectral data for new compounds,
1
including scanned images of H and 13C NMR spectra, and
single-crystal X-ray diffraction data for 4a and 4h (CIF). This
material is available free of charge via the Internet at http://pubs.
acs.org.
(f) Kopfer, A.; Sam, B.; Breit, B.; Krische, M. J. Chem. Sci. 2013, 4, 1876.
̈
AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
Notes
■
(9) For ruthenium(0)-catalyzed reactions of dienes with secondary
alcohols to deliver linear products of C−C coupling, see: (a) Leung, J.
C.; Geary, L. M.; Chen, T.-Y.; Zbieg, J. R.; Krische, M. J. J. Am. Chem. Soc.
2012, 134, 15700. (b) Chen, T.-Y.; Krische, M. J. Org. Lett. 2013, 15,
2994.
The authors declare no competing financial interest.
(10) For iridium-catalyzed transfer hydrogenative coupling of primary
alcohols to dienes to form secondary alcohols, see: (a) Bower, J. F.;
Patman, R. L.; Krische, M. J. Org. Lett. 2008, 10, 1033. (b) Zbieg, J. R.;
Fukuzumi, T.; Krische, M. J. Adv. Synth. Catal. 2010, 352, 2416.
(11) For nickel-catalyzed intermolecular diene−aldehyde reductive
coupling, see: (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am.
Chem. Soc. 1998, 120, 4033. (b) Takimoto, M.; Hiraga, Y.; Sato, Y.;
Mori, M. Tetrahedron Lett. 1998, 39, 4543. (c) Kimura, M.; Fujimatsu,
H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.; Tamaru, Y.
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coupling, see: (a) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. Angew.
Chem., Int. Ed. 2003, 42, 4074. (b) Kimura, M.; Nojiri, D.; Fukushima,
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ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NSF (CHE-
1265504), the Center for Green Chemistry and Catalysis, and
the Uehara Memorial Foundation postdoctoral fellowship
program (R.T.) are acknowledged for partial support of this
research.
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DOI: 10.1021/ja5130258
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