Amplification of anti-diastereoselectivity via Curtin-Hammett effects in ruthenium-catalyzed hydrohydroxyalkylation of 1,1-disubstituted allenes: Diastereoselective formation of all-carbon quaternary centers

Article abstract of DOI:10.1021/ja1104156

Under the conditions of ruthenium-catalyzed transfer hydrogenation, 1,1-disubstituted allenes la-c and alcohols 2a-g engage in redox-triggered generation of allylruthenium-aldehyde pairs to form products of hydrohydroxyalkylation 3a-g, 4a-g, and 5a-g with complete branched regioselectivity. By exploiting Curtin-Hammett effects, good to excellent levels of anti-diastereoselectivity (4:1 to >20:1) are obtained. Thus, all carbon quaternary centers are formed in a diastereoselective fashion upon carbonyl addition from the alcohol oxidation level in the absence of premetalated nucleophiles or stoichiometric byproducts. Exposure of allene lb to equimolar quantities of alcohol 2a and aldehyde 6b under standard reaction conditions delivers adducts 4a and 4b in a 1:1 ratio. Similarly, exposure of allene lb to equimolar quantities of aldehyde 6a and alcohol 2b provides adducts 4a and 4b in an identical equimolar ratio. Exposure of allene lb to d₂-p- nitrobenzyl alcohol, deuterio-2a, under standard reaction conditions delivers the product of hydrohydroxyalkylation, deuterioAa, which incorporates deuterium at the carbinol position (>95% ²H) and the interior vinylic position (34% H). Competition experiments involving exposure of allene lb to equimolar quantities of benzylic alcohols 2a and deuterio-2a reveal no significant kinetic effect. The collective data corroborate rapid, reversible alcohol dehydrogenation, allene hydrometalation, and (E)-, (Z)-isomerization of the transient allylruthenium in advance of turnover-limiting carbonyl addition. Notably, analogous allene-aldehyde reductive C-C couplings employing 2-propanol as the terminal reductant display poor levels of anti-diastereoselectivity, suggesting that carbonyl addition is not turnover-limiting in reactions conducted from the aldehyde oxidation level.

Full text of DOI:10.1021/ja1104156

ARTICLE
pubs.acs.org/JACS
Amplification of Anti-Diastereoselectivity via Curtin-Hammett
Effects in Ruthenium-Catalyzed Hydrohydroxyalkylation of
1,1-Disubstituted Allenes: Diastereoselective Formation of
All-Carbon Quaternary Centers
Jason R. Zbieg, Emma L. McInturff, Joyce C. Leung, and Michael J. Krische*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
S Supporting Information
b
ABSTRACT: Under the conditions of ruthenium-catalyzed
transfer hydrogenation, 1,1-disubstituted allenes 1a-c and
alcohols 2a-g engage in redox-triggered generation of allyl-
ruthenium-aldehyde pairs to form products of hydrohydroxy-
alkylation 3a-g, 4a-g, and 5a-g with complete branched
regioselectivity. By exploiting Curtin-Hammett effects, good
to excellent levels of anti-diastereoselectivity (4:1 to >20:1) are
obtained. Thus, all carbon quaternary centers are formed in a
diastereoselective fashion upon carbonyl addition from the
alcohol oxidation level in the absence of premetalated nucleophiles or stoichiometric byproducts. Exposure of allene 1b to equimolar
quantities of alcohol 2a and aldehyde 6b under standard reaction conditions delivers adducts 4a and 4b in a 1:1 ratio. Similarly, exposure
of allene 1b to equimolar quantities of aldehyde 6a and alcohol 2b provides adducts 4a and 4b in an identical equimolar ratio. Exposure of
allene 1b to d2-p-nitrobenzyl alcohol, deuterio-2a, under standard reaction conditions delivers the product of hydrohydroxyalkylation,
deuterio-4a, which incorporates deuterium at the carbinol position (>95% 2H) and the interior vinylic position (34% 2H). Competition
experiments involving exposure of allene 1b to equimolar quantities of benzylic alcohols 2a and deuterio-2a reveal no significant kinetic
effect. The collective data corroborate rapid, reversible alcohol dehydrogenation, allene hydrometalation, and (E)-, (Z)-isomerization of
the transient allylruthenium in advance of turnover-limiting carbonyl addition. Notably, analogous allene-aldehyde reductive C-C
couplings employing 2-propanol as the terminal reductant display poor levels of anti-diastereoselectivity, suggesting that carbonyl
addition is not turnover-limiting in reactions conducted from the aldehyde oxidation level.
’ INTRODUCTION
steric differentiation of hydrogen and the sterically demanding
NR1R2 moiety.2f,4 Exclusive carbonyl addition from the (E)-σ-
allylruthenium through a chairlike transition structure accounts
for the observed anti-diastereoselectivity.
In the course of exploring C-C bond forming hydrogenations
beyond hydroformylation,1 it was found that ruthenium2- and
iridium3-based catalysts promote direct hydrohydroxyalkylation
of π-unsaturated reactants.1-3 In such processes, primary alcohols
engage π-unsaturated reactants as redox partners, whereupon
hydrogen exchange triggers generation of electrophile-nucleophile
pairs en route to products of C-C coupling. In this way, carbonyl
addition is achieved directly from the alcohol oxidation level in the
absence of premetalated nucleophiles or stoichiometric by-
products. In nearly all systems studied, identical products of
carbonyl addition may be formed from the aldehyde oxidation
level under transfer hydrogenation conditions employing 2-propa-
nol or formic acid as terminal reductant.1-3
While control of relative and absolute stereochemistry has
been achieved in iridium-catalyzed hydrohydroxyalkylations,3
stereoselective ruthenium-catalyzed processes have proven elu-
sive. Indeed, under the conditions of ruthenium catalysis, high
diastereoselectivities only have been observed in couplings of un-
substituted allenamides, where complete partitioning of (Z)- and
(E)-σ-allylruthenium intermediates is achieved readily through
The energetic bias required for partitioning trisubstituted (Z)-
and (E)-σ-allylruthenium intermediates derived upon hydro-
metalation of 1,1-disubstituted allenes is far more difficult to
achieve. Studies on stoichiometric hydrometalation of 1,1-disubstituted
Received: December 1, 2010
Published: December 22, 2010
r
2010 American Chemical Society
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allenes or dienes employing HXRu(CO)(PR3)3 (X = Cl, Br) re-
veal that the resulting π-allylruthenium complexes Ru(η3-allyl)-
(X)(CO)(PR3)2 are highly fluxional.5,6 Rapid interconversion
of π-allyl- and σ-allylruthenium complexes precludes kinetically
controlled partitioning of (Z)- and (E)-σ-allylruthenium isomers
via stereoselective hydrometalation. Therefore, it was postulated
that crowding at the ruthenium center might result in energetic
differentiation of the transient (Z)- and (E)-σ-allylruthenium iso-
mers or perhaps manifest in a Curtin-Hammett scenario, where-
in a given σ-allyl isomer preferentially participates in carbonyl
addition. However, while the feasibility of enacting Curtin-
Hammett effects by virtue of configurationally dynamic allylme-
tal intermediates is suggested by stereoconvergence observed in
the addition of γ-monosubstituted allylchromium reagents,7a,b
γ,γ-disubstituted allylchromium reagents were found to act
stereospecifically.7c Here, we report that exceptional levels of
anti-diastereoselectivity may be obtained in the hydrohydrox-
yalkylation of 1,1-disubstituted allenes through exploitation of
Curtin-Hammett effects. This method, which combines oxidation-
construction events, enables diastereoselective formation of all-
carbon quaternary centers under catalytic conditions in the absence
of premetalated nucleophiles or stoichiometric byproducts.8,9
Table 1. Ruthenium-Catalyzed Hydrohydroxyalkylation of
1,1-Disubstituted Allenes 1a-1c employing alcohols 2a-2ga
’ RESULTS AND DISCUSSION
In an initial experiment, 1,1-disubstituted allene 1a was exposed
to p-nitrobenzyl alcohol 2a in the presence of a ruthenium catalyst
derived upon the combination of HClRu(CO)(PPh3)3 and dippf
[dippf = bis(diisopropylphosphino)ferrocene] in THF solvent at
50 °C. Although the desired hydrohydroxyalkylation product 3a
was isolated in excellent yield with complete branched regioselec-
tivity, a modest 2:1 diastereoselectivity was observed. On the basis
of the aforementioned line of reasoning, an assay of counterion
was undertaken. Complexes HXRu(CO)(dippf)(PPh3)n are con-
veniently prepared in situ through the acid-base reaction of
H2Ru(CO)(PPh3)3 and HX (eq 1).10
a Yields are of isolated material. Diastereoselectivity was determined via
1H NMR analysis of crude reaction mixtures. See Supporting Informa-
tion for further experimental details. b Ligands: A = dippf (5 mol %), B =
dCypf, (5 mol %), and C = PPh2Cy (15 mol %). c Three equivalents of
allene. d 48 h.
for the phthalimido-substituted allene 1c. The assignment of re-
lative stereochemistry for adducts 3a-g, 4a-g, and 5a-g is
made in analogy to that determined for compound 5a, which was
established via single crystal X-ray diffraction analysis, and com-
pound 3c, which is reported in the literature (Table 1).8b
Under identical reaction conditions, a given allene can display
substantially different levels of diastereoselectivity in response to
the structure of its transient aldehyde partner. This observation
suggests that the relative thermodynamic stabilities of the (Z)-
and (E)-σ-allylruthenium intermediates do not alone determine
diastereocontrol. Rather, it appears that a Curtin-Hammett sce-
nario is operative, wherein the transient aldehyde influences ener-
getic partitioning of the diastereomeric transition structures. Kinet-
ically controlled diastereoselection is suggested by the fact that the
diastereomeric ratio does not change over the course of the reaction.
This observation is significant, as reversible carbonyl addition or
product oxidation could potentially occur. However, although
secondary alcohol oxidation is in general thermodynamically
It was found for the specific combination of allene 1a and
p-nitrobenzyl alcohol 2a that the ruthenium mesitylenesulfonate
complex enforced complete levels of anti-diastereoselectivity. En-
couraged by these results, the hydrohydroxyalkylation of 1,1-disub-
stituted allenes 1a-c employing alcohols 2a-g were explored. In
many cases, the chloride counterion provided the highest levels
of anti-diastereoselectivity. However, in other cases, for example
allene 1b, the BINOL-modified phosphate counterion was most
effective in promoting anti-diastereoselectivity.11 Finally, whereas
dippf was the ligand of choice for allenes 1a and 1b, alternate ligands
were required to achieved optimal levels of anti-diastereoselectivity
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Table 2. Oxidation Level Dependent Anti-Diastereoselectiv-
ity in Ruthenium-Catalyzed Couplings of Allene 1ca
Table 3. Concentration-Dependent Anti-Diastereoselectivity
in Ruthenium-Catalyzed Couplings of Allene 1ca
entry alcohol
X
T, °C THF concn, M
% yield (dr)
1
2
3
4
5
6
2a
2a
2a
2d
2d
2d
Cl
95
95
95
85
85
85
1.0 M
0.5 M
0.2 M
0.5 M
0.2 M
0.1 M
5a, 87 (6:1)
5a, 83 (10:1)
5a, 55 (>20:1)
5d, 72 (2:1)
5d, 79 (4:1)
5d, 82 (5:1)
Cl
entry oxidation level
R
ligand
% yield (dr)
Cl
1
2
3
4
alcohol, 2a
aldehyde, 6a
alcohol, 2c
aldehyde, 6c
p-NO2Ph CyPPh2 (15 mol %) 5a, 83 (10:1)
p-NO2Ph CyPPh2 (15 mol %) 5a, 99 (1:1)
O3S-camphor
O3S-camphor
O3S-camphor
Ph
Ph
dCypf (5 mol %)
dCypf (5 mol %)
5c, 99 (8:1)
5c, 72 (1:1)
a As described in Table 1.
a As described in Table 1.
more favorable than primary alcohol oxidation, further oxidation
of the coupling product is not observed. Our collective studies2
suggest that coordination of the homoallylic olefin to the catalyst
provides a hexa-coordinate, 18-electron complex, suppressing
β-hydride elimination through occupation of all available coordi-
nation sites. Indeed, in ruthenium-catalyzed diene-carbonyl C-C
couplings, coordinative saturation of the catalyst could be varied to
partition formation of secondary alcohol and ketone products.2b In
the present case, resubjecting adduct 3a tostandardcouplingcondi-
tions in the presence of allene 1a, which may serve as a hydrogen
acceptor, does not result in any oxidation or erosion diastereomeric
purity of recovered 3a, corroborating kinetically controlled carbonyl
addition (eq 2).
Scheme 1. Competition Experiments Corroborating Rapid,
Reversible Dehydrogenation in Advance of C-C Couplinga
a As described in Table 1. Ar1 = p-NO2Ph, Ar2 = p-CF3Ph. Products 4a
and 4b are obtained as 1:1.5 (syn:anti) diastereomeric mixtures.
replenished via isomerization of the remaining (Z)-σ-allylruthe-
nium isomer (Table 3).
To assess whether primary alcohol dehydrogenation is indeed
more rapid than carbonyl addition, the following competition
experiment was performed. Allene 1b was exposed to equimolar
quantities of alcohol 2a and aldehyde 6b under standard condi-
tions employing the ruthenium catalyst generated in situ from
H2Ru(CO)(PPh3)3, dippf, and rac-BINOL-PO2H at 75 °C in
THF solvent (1.0 M). The C-C coupling products 4a and 4b
were produced in a 1:1 ratio. Under identical conditions employ-
ing equimolar quantities of aldehyde 6a and alcohol 2b, a nearly
identical ratio of coupling products 4a and 4b is observed. These
data are consistent with rapid, reversible primary alcohol dehy-
drogenation in advance of turnover-limiting carbonyl addition
(Scheme 1).12
Notably, when the allene coupling is conducted from the
aldehyde oxidation level, diastereoselectivity is essentially absent.
For example, whereas 10:1 and 8:1 anti-diastereoselectivities are
observed in the coupling of allene 1c to alcohols 2a and 2c, respec-
tively, corresponding couplings of aldehydes 6a and 6c employing
2-propanol as terminal reductant under otherwise identical condi-
tions are not diastereoselective (Table 2). These data suggest that
carbonyl addition is no longer turnover-limiting in couplings con-
ducted from the aldehyde oxidation level. There are two probable
explanations for this. In reactions conducted from the aldehyde
oxidation level, aldehyde concentration is higher throughout the
course of the reaction, which should accelerate carbonyl addition.
Alternatively, for such sterically congested ruthenium complexes,
dehydrogenation of 2-propanol, a secondary alcohol, may be slower
than primary alcohol dehydrogenation. In either case, Curtin-
Hammett effects can no longer be exploited to amplify diaster-
eoselectivity. Consistent with this interpretation, in reactions
conducted from the alcohol oxidation level, diastereoselectivity
is found to be highly concentration-dependent. Presumably,
at lower concentration, carbonyl addition is sufficiently slow
that the (E)-σ-allylruthenium consumed upon addition may be
Further insight into the catalytic mechanism is provided
by deuterium labeling and competition kinetics experiments
(Scheme 2).13 Exposure of allene 1b to d2-p-nitrobenzyl alcohol
under standard coupling conditions delivers deuterio-4a, which
incorporates deuterium at the carbinol methine (>99% 2H) and
2
1
at the interior vinylic position (34% H), as determined by H
and 2H NMR analyses. Complete retention of deuterium at the
carbinol methine, along with kinetically controlled anti-diaste-
reoselectivity (vida supra), corroborates resistance of the coupling
products toward reversible dehydrogenation. Incomplete deu-
terium incorporation at the interior vinylic position suggests that
β-hydride elimination of the π-allylruthenium intermediate
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Scheme 2. Deuterium Labeling and Competition Kinetics
Experimentsa
(2) For ruthenium-catalyzed alcohol-unsaturate C-C coupling, see
the following. (a) Dienes: Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am.
Chem. Soc. 2008, 130, 6338. (b) Shibahara, F.; Bower, J. F.; Krische, M. J.
qJ. Am. Chem. Soc. 2008, 130, 14120. (c) Han, H.; Krische, M. J. Org. Lett.
2010, 12, 2844. (d) Alkynes: Patman, R. L.; Chaulagain, M. R.; Williams,
V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066. (e) Williams,
V. M.; Leung, J. C.; Patman, R. L.; Krische, M. J. Tetrahedron 2009, 65,
5024. (f) Allenes: Zbieg, J. R.; McInturff, E. L. Org. Lett. 2010, 12, 2514.
(3) For iridium-catalyzed alcohol-allene C-C coupling, see: (a) Han,
S. B.; Kim, I.-S.; Han, H.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 6916.
For related couplings of dienes and allylic carboxylates see ref 1.
(4) Skucas, E.; Zbieg, J. R.; Krische, M. J. J. Am. Chem. Soc. 2009, 131,
5054.
(5) For leading references on the stoichiometric reaction of HXRu-
(CO)(PR3)3 (X = Cl, Br) with allenes or dienes to furnish π-allylruthe-
nium complexes, see: (a) Hiraki, K.; Ochi, N.; Sasada, Y.; Hayashida, H.;
Fuchita, Y.; Yamanaka, S. J. Chem. Soc., Dalton Trans. 1985, 873. (b) Hill,
A. F.; Ho, C. T.; Wilton-Ely, D. E. T. Chem. Commun. 1997, 2207.
(c) Xue, P.; Bi, S.; Sung, H. H. Y.; Williams, I. D.; Lin, Z.; Jia, G.
Organometallics 2004, 23, 4735.
a As described in Table 1. Ar = p-NO2Ph,
occurs to furnish diene byproducts. Such byproducts were
identified in the crude reaction mixture and may account for the
requirement of superstoichiometric loadings of allene. Competi-
tion kinetic experiments involving exposure of allene 1b to equi-
molar quantities of p-nitrobenzyl alcohol and d2-p-nitrobenzyl
alcohol reveal no significant kinetic effect (kH/kD = 1.06), within
the error limits of the experiment, suggesting that alcohol oxida-
tion is not the turnover-limiting event. If carbonyl addition was the
turnover-limiting event, an inverse secondary isotope effect would
be anticipated. Given the error limits of the experiment, the absence
of such an effect is inconclusive.
(6) For studies involving π-allylruthenium complexes of the type
Ru(η3-allyl)(X)(CO)(PR3)2, see: (a) Barnard, C. F. J.; Daniels, B. J. A.;
Holland, P. R.; Mawby, R. J. J. Chem. Soc., Dalton Trans. 1980, 2418.
(b) Hiraki, K.; Matsunaga, T.; Kawano, H. Organometallics 1994, 13,
1878. (c) Sasabe, H.; Nakanishi, S.; Takata, T. Inorg. Chem. Commun.
2002, 5, 177. (d) Cadierno, V.; Crochet, P.; Diez, J.; Garcia-Garrido,
S. E.; Gimeno, J. Organometallics 2003, 22, 5226.
(7) (a) Hiyama, T.; Okude, Y.; Kimura, K.; Nozaki, H. Bull. Chem.
Soc. Jpn. 1982, 55, 561.(b) Roush, W. R. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon:
Oxford, 1991; Vol. 2, pp 1-53.(c) Jubert, C.; Nowotny, S.; Kornemann,
D.; Antes, I.; Tucker, C. E.; Knochel, P. J. Org. Chem. 1992, 57, 6384.
(8) For selected examples of stereoselective carbonyl allylmetalation
to furnish secondary neopentyl homoallylic alcohols, see ref 7c and the
following: (a) Sato, M.; Yamamoto, Y.; Hara, S.; Suzuki, A. Tetrahedron
Lett. 1993, 34, 7071. (b) Habaue, S.; Yasue, K.; Yanagisawa, A.;
Yamamoto, H. Synlett 1993, 788. (c) Nishigaichi, Y.; Takuwa, A.
Tetrahedron Lett. 1999, 40, 109. (d) Denmark, S. E.; Fu, J. J. Am. Chem.
Soc. 2001, 123, 9488. (e) Denmark, S. E.; Fu, J. Org. Lett. 2002, 4, 1951.
(f) Ely, R. J.; Morken, J. P. J. Am. Chem. Soc. 2010, 132, 2534.
(9) As described in ref 2c, ruthenium-catalyzed C-C coupling of
ethanol and 2-substituted dienes delivers anti-configured neopentyl
homoallylic alcohols. However, incomplete regio- and diastereoselec-
tivities are observed.
’ CONCLUSION
In summary, by taking advantage of Curtin-Hammett effects
in ruthenium-catalyzed alcohol-allene C-C coupling, one by-
passes the need to partition trisubstituted σ-allylmetal species in
the ground state. Rather, from an equilibrating mixture of tran-
sient (Z)- and (E)-σ-allylruthenium isomers, preferential selec-
tion of the (E)-σ-allylruthenium species occurs upon energetic
partitioning in the transition state for carbonyl addition. Such
Curtin-Hammett effects provide a basis for diastereoselective
carbonyl allylation to furnish secondary neopentyl homoallylic
alcohols, which possess all carbon quaternary centers, thus set-
ting the stage for development of related diastereo- and enantio-
selective processes.
(10) Dobson, A.; Robinson, S. R.; Uttley, M. F. J. Chem. Soc., Dalton
Trans. 1974, 370.
’ ASSOCIATED CONTENT
(11) Chiral counterions may prove effective in enantioselective
C-C couplings of this type. For example, using the ruthenium catalyst
generated in situ from H2Ru(CO)(PPh3)3, dippf, and enantiomerically
pure [(S)-BINOL]PO2H, allene 1b couples to alcohol 2a to deliver the
secondary neopentyl alcohol 4a in 16% enantiomeric excess.
(12) For a related competition experiment, see: Bower, J. F.; Skucas,
E.; Patman, R. L.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 15134.
(13) For selected examples of kinetic isotope effects in ruthenium-
catalyzed transfer hydrogenation, see: (a) Casey, C. P.; Johnson, J. B.
J. Org. Chem. 2003, 68, 1998. (b) Sandoval, C. A.; Ohkuma, T.; Muniz,
K.; Noyori, R. J. Am. Chem. Soc. 2003, 125, 13490. (c) Pannetier, N.;
Sortais, J.-B.; Dieng, P. S.; Barloy, L.; Sirlin, C.; Pfeffer, M. Organome-
tallics 2008, 27, 5852.
S
Supporting Information. Experimental procedures and
b
spectral data for all new compounds (1H NMR, 13C NMR, IR,
HRMS). This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
mkrische@mail.utexas.edu
’ ACKNOWLEDGMENT
Acknowledgment is made to the Robert A. Welch Foundation
(F-0038) and the NIH-NIGMS (RO1-GM069445).
’ REFERENCES
(1) For selected reviews on C-C bond forming hydrogenation and
transfer hydrogenation, see: (a) Bower, J. F.; Kim, I. S.; Patman, R. L.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34. (b) Han, S. B.; Kim,
I. S.; Krische, M. J. Chem. Commun. 2009, 7278.
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