Ruthenium catalyzed C-C bond formation via transfer hydrogenation: Branch-selective reductive coupling of allenes to paraformaldehyde and higher aldehydes

Article abstract of DOI:10.1021/ol800836v

(Chemical Equation Presented) Under the conditions of ruthenium-catalyzed transfer hydrogenation employing 2-propanol as the terminal reductant, 1,1-disubstituted allenes 1a-h engage in reductive coupling to paraformaldehyde to furnish homoallylic alcohol

Full text of DOI:10.1021/ol800836v

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2705-2708
Ruthenium Catalyzed C-C Bond
Formation via Transfer Hydrogenation:
Branch-Selective Reductive Coupling of
Allenes to Paraformaldehyde and Higher
Aldehydes
Ming-Yu Ngai, Eduardas Skucas, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry,
Austin, Texas 78712
mkrische@mail.utexas.edu
Received April 11, 2008
ABSTRACT
Under the conditions of ruthenium-catalyzed transfer hydrogenation employing 2-propanol as the terminal reductant, 1,1-disubstituted allenes
1a-h engage in reductive coupling to paraformaldehyde to furnish homoallylic alcohols 2a-h. Under identical transfer hydrogenation conditions,
1,1-disubstituted allenes engage in reductive coupling to aldehydes 3a-f to furnish homoallylic alcohols 4a-n. In all cases, reductive coupling
occurs with branched regioselectivity to deliver homoallylic alcohols bearing all-carbon quaternary centers.
Although ruthenium-catalyzed transfer hydrogenation ranks
among the foremost methods for enantioselective ketone
reduction,1 reductive C-C bond formation catalyzed by
ruthenium is highly uncommon.2–4 We have developed a
family of reductive C-C bond formations employing
elemental hydrogen as the terminal reductant.5,6 More
recently, we discovered that reductive C-C bond formation
could be achieved under the conditions of iridium-catalyzed
transfer hydrogenation, wherein allenes or cyclohexadiene
are coupled to aldehydes and, remarkably, alcohols.7 In an
effort to expand the scope of such “transfer hydrogenative
(1) For selected reviews on ruthenium catalyzed transfer hydrogenation,
see: (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. ReV. 1992, 92,
1051. (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (c)
Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2001, 40, 40. (d) Noyori,
R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66, 7931. (e)
Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008. (f) Noyori, R. AdV. Synth.
Catal. 2003, 345, 15. (g) Noyori, R. Chem. Commun. 2005, 1807. (h)
Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006, 35, 226. (i) Ikariya, T.;
Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300.
(3) For ruthenium catalyzed reductive C-C bond formations beyond
alkene hydroformylation, see: (a) Tsuji, Y.; Mukai, T.; Kondo, T.; Watanabe,
Y. J. Organomet. Chem. 1989, 369, C51. (b) Kondo, T.; Ono, H.; Satake,
N.; Mitsudo, T.; Watanabe, Y. Organometallics 1995, 14, 1945. (c) Yu,
C.-M.; Lee, S.; Hong, Y.-T.; Yoon, S.-K. Tetrahedron Lett. 2004, 45, 6557
.
(4) For selected reviews of ruthenium catalyzed C-C coupling, see:
(a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101,
2067. (b) Kondo, T.; Mitsudo, T.-a. Curr. Org. Chem. 2002, 6, 1163. (c)
De´rien, S.; Monnier, F.; Dixneuf, P. H. Top. Organomet. Chem. 2004, 11,
(2) Ruthenium complexes catalyze alkene hydroformylation. For a
review, see: Kalck, P.; Peres, Y.; Jenck, J. AdV. Organomet. Chem. 1991,
32, 121.
1.
10.1021/ol800836v CCC: $40.75
Published on Web 06/06/2008
2008 American Chemical Society

C-C bond formations”, ruthenium catalysts were found to
promote the coupling of acylic 1,3-dienes or 1,3-enynes to
both aldehydes and alcohols to furnish products of carbonyl
allylation and propargylation, respectively.8 For these transfer-
hydrogenative processes, rather than using elemental hydro-
gen as reductant, hydrogen embedded in 2-propanol or an
alcoholic substrate is redistributed among reactants to gener-
ate nucleophile-electrophile pairs, enabling carbonyl addition
from the aldehyde or alcohol oxidation level (Scheme 1).8
Table 1. Optimization of Ruthenium-Catalyzed Coupling of
Paraformaldehyde to 1-Methyl-1-phenylallene (1a) via Transfer
Hydrogenationa
concn yield
entry
catalystb
ligand (mol %)
(M)
(%)
1
2
3
4
5
6
7
8
9
[Cp(p-cymene)Ru]PF6 PPh3 (15)
CpRuCl(PPh3)3
0.5
0.5
0.5
0.5 trace
0.5 18
0.5 20
0.5 55
0.5 trace
0.5 49
–
–
–
Scheme 1. Carbonyl Allylation from the Aldehyde or Alcohol
Oxidation Level via Transfer Hydrogenative C-C Coupling of
Ru3(CO)12
RuHCl(PPh3)3·toluene
[Ru(cod)Cl2]n
RuHCl(CO)(PPh3)3
[RuBr(CO)3(η3-C3H5)]
[RuBr(CO)3(η3-C3H5)]
[RuBr(CO)3(η3-C3H5)]
PPh3 (15)
PPh3 (15)
PPh3 (15)
BINAP (7.5)
Allenes
10 [RuBr(CO)3(η3-C3H5)]
11 [RuBr(CO)3(η3-C3H5)]
12 [RuBr(CO)3(η3-C3H5)]
MeC[CH2PPh2]3 (5) 0.5 trace
CatacXium A (15)
t-BuPPh2 (15)
0.5 72
0.5 81
1.0 86
13 [RuBr(CO)3(η3-C3H5)] t-BuPPh2 (15)
a Cited yields are of isolated material. b 5 mol % with respect to
ruthenium content. See the Supporting Information for detailed experimental
procedures.
As part of a continuing effort to broaden this emergent
class of C-C bond formations, we investigated the coupling
of 1,1-disubsituted allenes to paraformaldehyde and higher
aldehydes under the conditions of ruthenium catalysis. Here
we disclose that allenes 1a-1h engage in branch-selective
reductive coupling to paraformaldehyde and higher aldehydes
under the conditions of ruthenium-catalyzed transfer hydro-
genation employing 2-propanol as the terminal reductant to
furnish homoallylic alcohols 2a-h and 4a-n, respectively,
bearing all-carbon quaternary centers. Additionally, we report
isotopic labeling studies that provide further insight into key
mechanistic features of these processes.
In an initial set of experiments, structurally diverse
ruthenium complexes were assayed for their ability to
catalyze the reductive coupling of allene 1a to paraformal-
dehyde using 2-propanol as the terminal reductant (Table
1, entries 1-7). It was found that the complex prepared in
situ from [RuBr(CO)3(η3-C3H5)] (5 mol %) and PPh3 (15
mol %) in toluene (0.5 M) at 75 °C catalyzes the reductive
C-C coupling of 1a to paraformaldehyde to provide the
desired adduct 2a in 55% isolated yield along with small
quantities of the corresponding formate ester, which is
hydrolytically cleaved upon isolation (Table 1, entry 7).9
Table 2. Ruthenium-catalyzed reductive coupling of
paraformaldehyde to 1,1-disubstituted allenes 1a-h via transfer
hydrogenationa
(5) For reviews on hydrogenative C-C coupling, see: (a) Iida, H.;
Krische, M. J. Top. Curr. Chem. 2007, 279, 77. (b) Ngai, M.-Y.; Kong,
J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063. (c) Skucas, E.; Ngai,
M.-Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007, 40, 1394.
(6) For recent examples, see the following. CdX vinylation: (a) Kong,
J.-R.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718. (b)
Skucas, E.; Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 7242.
(c) Barchuk, A.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2007, 129,
8432. (d) Ngai, M.-Y.; Barchuk, A.; Krische, M. J. J. Am. Chem. Soc. 2007,
129, 12644. Aldol and Mannich addition: (e) Jung, C.-K.; Garner, S. A.;
Krische, M. J. Org. Lett. 2006, 8, 519. (f) Jung, C.-K.; Krische, M. J. J. Am.
Chem. Soc. 2006, 128, 17051. (g) Garner, S. A.; Krische, M. J. J. Org.
Chem. 2007, 72, 5843. (h) Bee, C.; Han, S. B.; Hassan, A.; Iida, H.; Krische,
M. J. J. Am. Chem. Soc. 2008, 130, 2746. CdO allylation: (i) Skucas, E.;
Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12678.
(7) (a) Bower, J. F.; Skucas, E.; Patman, R. L.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 15134. (b) Bower, J. F.; Patman, R. L.; Krische,
M. J. Org. Lett. 2008, 10, 1033.
a Cited yields are of isolated material. Standard conditions employ 1
equiv of allene and 4 equiv of paraformaldehyde. See the Supporting
Information for detailed experimental procedures.
(8) (a) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc.
2008, 130, 6338. (b) Patman, R. L.; Williams, V. M.; Bower, J. F.; Krische,
M. J. Angew. Chem., Int. Ed. 2008, 47, 6338.
(9) See the Supporting Information for detailed experimental procedures.
2706
Org. Lett., Vol. 10, No. 13, 2008

or tridentate ligands (Table 1, entries 9 and 10). Under
optimal conditions employing [RuBr(CO)3(η3-C3H5)] (5 mol
%) as precatalyst in combination with t-BuPPh2 (15 mol %)
as ligand in toluene (0.5 M) at 75 °C, the coupling product
2a is obtained in 81% isolated yield (Table 1, entry 12). By
increasing the concentration of the reaction mixture (1.0 M
in toluene), the isolated yield was increased to 86% (Table
1, entry 13). These optimized reaction conditions proved to
be quite general, as demonstrated by the coupling of
paraformaldehyde to 1,1-disubstituted allenes 1a-h to
furnish the homoallylic alcohols 2a-h (Table 2).
Table 3. Ru-Catalyzed Reductive Coupling of Aldehydes 3a-f
to 1,1-Disubstituted Allenes via Transfer Hydrogenationa
Under identical conditions, the coupling of allenes to higher
aldehydes was explored. It was found that aromatic aldehydes
(Table 3, entries 1 and 2), heteroaromatic aldehydes (Table 3,
entry 3), R,ꢀ-unsaturated aldehydes (Table 3, entry 4), and
aliphatic aldehydes (Table 3, entries 5 and 6) couple to a range
of 1,1-disubstituted allenes in good yields but with low
diastereoselectivity. Under standard conditions, electron-rich
aldehydes couple less efficiently, as demonstrated by the
coupling of allene 1a to hexanal, which occurs in 38% yield to
provide a 4:1 diastereomeric ratio of adducts.
To gain insight into the catalytic mechanism, the coupling
of paraformaldehyde and allene 1a was conducted employing
1
2-propanol-d8 as the terminal reductant. As revealed by H
NMR analysis, deuterium is incorporated solely at the vinylic
2
position (30% H). Similarly, coupling of allene 1a to p-
nitrobenzaldehyde 3a employing 2-propanol-d8 as the terminal
reductant also results in deuterium incorporation exclusively at
2
the vinylic position, but to a far greater extent (80% H).
Notably, the isolated yield of coupling products in reactions
employing 2-propanol-d8 as the terminal reductant are signifi-
cantly lower than the isolated yields obtained in the parent
reactions (Scheme 2).10
Scheme 2. Ruthenium-Catalyzed Coupling of Allene 1a to
Paraformaldehyde and p-Nitrobenzaldehyde Employing
2-Propanol-d8 as the Terminal Reductanta
aCited yields are of isolated material. See the Supporting Information
for detailed experimental procedures.
a Cited yields are of pure isolated material. See the Supporting
Information for detailed experimental procedures.
A plausible catalytic cycle accounting for the relatively
low levels of deuterium incorporation in the reaction of
Notably, only trace quantities of adduct are formed in the
absence of PPh3 (Table 1, entry 8), suggesting that appropri-
ate selection of ligand is crucial. Indeed, screening the
precatalyst [RuBr(CO)3(η3-C3H5)] against a series of phos-
phine ligands (Table 1, entries 9-13) reveals that mono-
dentate ligands promote greater conversion than bidentate
(10) Couplings employing 2-propanol-d8 as terminal reductant were
conducted twice. The isolated yields and levels of deuterium incorpora-
tion for deuterio-2a and deuterio-4a were reproducible within experi-
mental error.
Org. Lett., Vol. 10, No. 13, 2008
2707

Scheme 3. Plausible Catalytic Mechanisms As Supported by Deuterium-Labeling Studies
paraformaldehyde and allene 1a is indicated (Scheme 3).
Reaction of the precatalyst [RuBr(CO)3(η3-C3H5)] with
aldehyde in the presence of 2-propanol generates the ho-
moallylic alcohol I and active catalyst II,11 which hydro-
metallates allene 1a to furnish the allylruthenium complexes
IIIa and IIIb.12 Allyl transfer to the aldehyde delivers the
ruthenium alkoxide IV. The intermediate IV may react with
2-propanol to provide the coupling product V and ruthenium
isopropoxide VI, which upon ꢀ-hydride elimination regener-
ates the active catalyst II (cycle A). Alternatively, the
intermediate IV may react with another molecule of aldehyde
to form ruthenium complex VII,13 which delivers ester VIII
upon ꢀ-hydride elimination and regenerates the active
catalyst II (cycle B). The latter catalytic cycle suggests that
the aldehyde may serve as a hydride donor. Indeed, when
the coupling of paraformaldehyde and 1a is carried out in
the absence of 2-propanol, substantial quantities of the
formate ester VIII (R ) H) are detected. Mechanisms
involving ruthenium-catalyzed allene hydroacylation with
subsequent 2-propanol-mediated reduction of the resulting
aldehyde are inconsistent with the results of deuterium
incorporation. Upon resubjecting diastereomerically enriched
adduct 4a to standard coupling conditions, a 2:1 diastereo-
meric ratio is reestablished, suggesting redox equilibration
of the homoallylic alcohol under coupling conditions. That
is, the ratio of diastereomers appears to be thermodynami-
cally controlled.
In summary, ruthenium-catalyzed transfer hydrogenation
ranks among the most powerful methods available for the
reduction of polar functional groups, yet reductive C-C
couplings under the conditions of ruthenium catalysis are
highly uncommon. Recent studies from our laboratory are
aimed at addressing this deficiency, with the ultimate goal
of developing a broad new family of “transfer hydrogenatiVe
C-C bond formations”. In prior work, ruthenium-catalyzed
transfer hydrogenation was applied to the coupling of acyclic
1,3-dienes (butadiene, isoprene, and 2,3-dimethylbutadiene)
and 1,3-enynes to aldehydes or alcohols. Here, we demon-
strate the ruthenium-catalyzed reductive coupling of 1,1-
disubstituted allenes 1a-h to paraformaldehyde and higher
aldehydes 3a-f to furnish homoallylic alcohols 2a-h and
4a-n, respectively. Stereoselective variants of these trans-
formations and the development of new transfer hydroge-
native couplings, including imine additions from the amine
oxidation level, are currently underway.
(11) When R-phthalimidoacetaldehyde was coupled to 1 equiv of
[RuBr(CO)3(η3-C3H5)], the corresponding homoallylic alcohol and its
isomers were detected. See also ref 3b.
(12) For hydrometalation of allenes with Ru complexes, see: (a) Hill,
A. F.; Ho, C. T.; Wilton-Ely, J. D. E. T. Chem. Commun. 1997, 2207. (b)
Nakanishi, S.; Sasabe, H.; Takata, T. Chem. Lett. 2000, 1058. (c) Sasabe,
H.; Nakanishi, S.; Takata, T. Inorg. Chem. Commun. 2002, 5, 177. (d)
Sasabe, H.; Nakanishi, S.; Takata, T. Inorg. Chem. Commun. 2003, 6, 1140.
(e) Xue, P.; Bi, S.; Sung, H. H. Y.; Williams, I. D.; Lin, Z.; Jia, G.
Organometallics 2004, 23, 4735. (f) Sasabe, H.; Kihara, N.; Mizuno, K.;
Ogawa, A.; Takata, T. Chem. Lett. 2006, 35, 212. (g) Bai, T.; Zhu, J.; Xue,
P.; Sung, H. H.-Y.; Williams, I. D.; Ma, S.; Lin, Z.; Jia, G. Organometallics
2007, 26, 5581.
Acknowledgment. Acknowledgment is made to the
Robert A. Welch Foundation, the ACS-GCI Pharmaceutical
Roundtable, Merck, and the NIH-NIGMS (RO1-GM69445)
for partial support of this research.
Supporting Information Available: Experimental pro-
cedures and 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.
(13) For Ru-catalyzed oxidative transformation of alcohols and aldehydes
to esters, see: (a) Blum, Y.; Shvo, Y. Isr. J. Chem. 1984, 24, 144. (b) Blum,
Y.; Shvo, Y. J. Organomet. Chem. 1984, 263, 93. (c) Blum, Y.; Shvo, Y.
J. Organomet. Chem. 1985, 282, C7. (d) Murahashi, S. I.; Naota, T.; Ito,
K.; Maeda, Y.; Taki, H. J. Org. Chem. 1987, 52, 4319. (e) Zhang, J.; Leitus,
G.; Ben-David, Y.; Milstein, D. J. Am. Chem. Soc. 2005, 127, 10840.
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