Titanocene-catalyzed conjugate reduction of αβ-unsaturated carbonyl derivatives

Article abstract of DOI:10.1021/ol9024315

"Chemical Equation Presented" A titanocene-catalyzed conjugate reduction of αβ-unsaturated carbonyl derivatives has been developed. A series of carbonyl compounds including aldehydes, ketones, esters, and amides proved viable in the reduction process providing an efficient, chemoselective method for the catalytic reduction of unsaturated carbonyl derivatives.

Full text of DOI:10.1021/ol9024315

ORGANIC
LETTERS
2
010
Vol. 12, No. 1
4-47
Titanocene-Catalyzed Conjugate Reduction
of r,ꢀ-Unsaturated Carbonyl Derivatives
Andrew D. Kosal and Brandon L. Ashfeld*
4
Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556
bashfeld@nd.edu
Received October 21, 2009
ABSTRACT
A titanocene-catalyzed conjugate reduction of r,ꢀ-unsaturated carbonyl derivatives has been developed. A series of carbonyl compounds
including aldehydes, ketones, esters, and amides proved viable in the reduction process providing an efficient, chemoselective method for the
catalytic reduction of unsaturated carbonyl derivatives.
The chemoselective 1,4-reduction of R,ꢀ-unsaturated car-
bonyl derivatives is an important tactic in organic synthesis.
copper hydride complexes are quite possibly the most widely
utilized and have arguably demonstrated the greatest syn-
thetic utility. A number of alkali and lanthanide metal-based
1
6
In recent years, a number of significant advances have been
made toward the development of efficient and economical
protocols for achieving this transformation with substantial
emphasis placed on the use of transition metal catalysts. As
a result, a number of metals have been shown to facilitate
the conjugate reduction of R,ꢀ-unsaturated carbonyls, includ-
reagents have shown useful levels of reactivity, but the
7
procedures often suffer from chemoselectivity issues.
In many ways, concerns associated with synthetic inef-
ficiency, the high cost of chemical research, and the need
for hazardous reaction conditions can be alleviated through
the use of transition metals in a catalytic fashion. To the
best of our knowledge, there has yet to be discovered a
2
3
4
5
ing palladium, rhodium, magnesium, and others, of which
(
1) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. (b) Haskel, A.; Keinan, E. Palladium-catalyzed 1,4-
reduction (conjugate reduction). In Handbook of Organopalladium Chem-
istry for Organic Synthesis; Negishi, E.-i., de Meijere, A., Eds.; Wiley:
New York , 2002; Vol. 2, p 2767. (c) Shibata, I. Organomet. News 2004,
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D. S.; Scholl, M.; Fu, G. C. J. Org. Chem. 1996, 61, 6751. (c) Magnus, P.;
Waring, M. J.; Scott, D. A. Tetrahedron Lett. 2000, 41, 9731.
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Kim, D.; Park, B.-M.; Yun, J. Chem. Commun. 2005, 1755. For examples
of enantioselective conjugate reductions catalyzed by copper, see: (f)
Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 9473. (g) Moritani, Y.; Appella, D. H.;
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Lipshutz, B. H.; Servesko, J. M.; Petersen, T. B.; Papa, P. P.; Lover, A. A.
Org. Lett. 2004, 6, 1273. (n) Rainka, M. P.; Milne, J. E.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2005, 44, 6177. (o) Lipshutz, B. H.; Tanaka, N.;
Taft, B. R.; Lee, C.-T. Org. Lett. 2006, 8, 1963. (p) Llamas, T.; Array a´ s,
R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2007, 46, 3329.
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(2) (a) Four, P.; Guibe, F. Tetrahedron Lett. 1982, 23, 1825. (b) Keinan,
E.; Greenspoon, N. Tetrahedron Lett. 1985, 26, 1353. (c) Keinan, E.;
Greenspoon, N. J. Am. Chem. Soc. 1986, 108, 7314. (d) Otsuka, H.;
Shirakawa, E.; Hayashi, T. Chem. Commun. 2007, 1819. For examples of
enantioselective conjugate reductions catalyzed by palladium, see :(e)
Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8, 4851. (f)
Monguchi, D.; Beemelmanns, C.; Hashizume, D.; Hamashima, Y.; Sodeoka,
M. J. Organomet. Chem. 2008, 693, 867.
(3) (a) Evans, D. A.; Fu, G. C. J. Org. Chem. 1990, 55, 5678. (b) Wang,
Z.; Zou, G.; Tang, J. Chem. Commun. 2004, 1192. For examples of
enantioselective conjugate reductions catalyzed by rhodium, see: (c)
Kanazawa, Y.; Nishiyama, H. Synlett 2006, 3343.
(
4) (a) Youn, I. K.; Yon, G. H.; Pak, C. S. Tetrahedron Lett. 1986, 27,
2
1
409. (b) Hudlicky, T.; Sinai-Zingde, G.; Natchus, M. G. Tetrahedron Lett.
987, 28, 5287. (c) Hutchins, R. O.; Suchismita; Zipkin, R. E.; Taffer, I. M.;
Sivakumar, R.; Monaghan, A.; Elisseou, E. M. Tetrahedron Lett. 1989, 30,
5
5.
10.1021/ol9024315  2010 American Chemical Society
Published on Web 12/07/2009

catalytic, single electron transfer-type process that can enable
the conjugate reduction of carbonyl derivatives. The de-
of pinacol coupling byproducts. Various other proton sources
were examined, but it was determined that Et N·HCl provided
8
3
the best overall results. Employing manganese as the
reducing metal effectively led to longer reaction times and
was less efficient in comparison to zinc dust.
velopment of such a method would enable the controlled
Barbier-type reduction of R,ꢀ-unsaturated carbonyl deriva-
tives that can then be implemented in the context of
consecutive bond forming reaction sequences including
reductive alkylations and reductive aldol reactions.
In search of an efficient, transition metal complex to
catalyze the conjugate reduction of R,ꢀ-unsaturated carbonyl
derivatives that would proceed through metal-ketyl interme-
diate, we looked to titanocene derivatives due to their
propensity to undergo redox processes between the +3 and
With this initial result in hand, we focused on reducing
the amount of zinc dust and Et N·HCl required to achieve
3
an efficient reduction of enone 1a (Table 1, entry 1). A
decrease in the amount of zinc dust from 20 equiv to 1.1
equiv resulted in a marked drop in the yield of ketone 2a to
3
3% (entry 2). Most notably, however, was the dramatic
inefficiency of the reduction, and propensity for side reactions
to occur, that is indicated by a mere 37% yield based on
recovered starting material. The use of 2.5 equiv of zinc dust,
+
4 oxidation states. Based mainly on the elegant work by
Gans a¨ uer and co-workers, we surmised that catalytic turnover
could be achieved by the addition of a proton source and a
mild reducing metal, such as zinc. Thus, we were decidedly
in conjunction with 5 equiv of Et N·HCl, resulted in a 60%
3
yield of ketone 2a that was comparable to the original
conditions (entry 3). Attempts to reduce the amount of
9
pleased when treatment of enone 1a with Cp
), zinc dust (20 equiv), and Et N·HCl (5 equiv) provided
the 1,4-reduction product 2a in 57% yield (eq 1). It is
important to note that Cp TiCl is necessary for the reduction
2 2
TiCl (5 mol
Et N·HCl from 5.0 to 2.1 equiv led to a decrease in the yield
3
%
3
of the process (entry 4). It should be noted that in those
experiments which resulted in low yields of ketone 2a, the
major side product resulted from a pinacol coupling pro-
2
2
as performing the reaction in its absence failed to provide
the desired saturated ketone. Additionally, we found that
1
1
cess. With these results in hand, we moved forward with
the optimized conditions of 5 mol % Cp TiCl , 2.5 equiv of
zinc dust, and 5 equiv of Et N·HCl in CH Cl
2
2
Cp
combination of TiCl
yields of the reduced products and lacked reproducibility.
2
TiCl
2
provided the best catalytic source of titanium, as a
3
2
2
.
3
and zinc dust gave substantially lower
1
0
a
Table 1. Optimization Studies in the Reduction of Enone 1a
b
entry
equiv of Zn(0)
equiv of Et
3
N·HCl
yield (%)
1
2
3
4
a
20
5
5
5
2.1
57
33 (37)
60
27 (42)
c
1.1
2.5
2.5
Attempts to lower the catalyst loading resulted in increased
reaction times and lower yields, presumably a result of the
finite lifetime of in situ generated Cp TiCl. Examination of
2
other solvents found that THF also provided the reduced
product. However, the reduction proved unreliable when
applied to a number of different substrates, often resulting
in decomposition of the starting material or the emergence
c
Conditions: enone (1 mmol), Cp
2 2
TiCl (5 mol %), Zn dust, and
b c
Et
3
N·HCl in CH
on recovered starting material in parentheses.
2
2
Cl (0.05 M) at rt for 6 h. Isolated yields. Yields based
We next turned our attention toward evaluating the overall
1
2
(
7) (a) Fujita, Y.; Fukuzumi, S.; Otera, J. Tetrahedron Lett. 1997, 38,
121. (b) Davies, S. G.; Rodriguez-Solla, H.; Tamayo, J. A.; Garner, A. C.;
Smith, A. D. Chem. Commun. 2004, 2502.
8) (a) Moisan, L.; Hardouin, C.; Rousseau, B.; Doris, E. Tetrahedron
scope of the titanium-catalyzed conjugate reduction.
A
2
series of R,ꢀ-unsaturated aldehydes, ketones, esters, and
amides were examined. The yields of the 1,4-reduction
products ranged from good to excellent, and the results of
(
Lett. 2002, 43, 2013. (b) Asandei, A. D.; Chen, Y. Macromolecules 2006,
3
9, 7549.
(
9) (a) Gans a¨ uer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int. Ed.
2
002, 41, 3206. (b) Gans a¨ uer, A.; Bluhm, H.; Rinker, B.; Narayan, S.;
(11) (a) Knoop, C. A.; Studer, A. AdV. Synth. Catal. 2005, 347, 1542.
(b) Chatterjee, A.; Joshi, N. N. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 2007, 46B, 1475. (c) Hirao, T. Top. Curr. Chem. 2007, 279,
53. (d) Paradas, M.; Campana, A. G.; Estevez, R. E.; Alvarez de Cienfuegos,
L.; Jimenez, T.; Robles, R.; Cuerva, J. M.; Oltra, J. E. J. Org. Chem. 2009,
74, 3616.
Schick, M.; Lauterbach, T.; Pierobon, M. Chem.sEur. J. 2003, 9, 531. (c)
Rosales, A.; Oller-L o´ pez Juan, L.; Justicia, J.; Gans a¨ uer, A.; Oltra, J. E.;
Cuerva, J. M. Chem. Commun. 2004, 2628. (d) Gans a¨ uer, A.; Franke, D.;
Lauterbach, T.; Nieger, M. J. Am. Chem. Soc. 2005, 127, 11622. (e)
Daasbjerg, K.; Svith, H.; Grimme, S.; Gerenkamp, M.; Muck-Lichtenfeld,
C.; Gans a¨ uer, A.; Barchuk, A.; Keller, F. Angew. Chem., Int. Ed. 2006, 45,
(12) Representative procedure: 4-phenylbutan-2-one. A solution of
2
041. (f) Gans a¨ uer, A.; Barchuk, A.; Keller, F.; Schmitt, M.; Grimme, S.;
2 2
Cp TiCl (2.6 mg, 0.01 mmol, 5 mol%), zinc dust (33.5 mg, 0.51 mmol,
Gerenkamp, M.; Muck-Lichtenfeld, C.; Daasbjerg, K.; Svith, H. J. Am.
Chem. Soc. 2007, 129, 1359. (g) Gans a¨ uer, A.; Fan, C.-A.; Keller, F.;
Karbaum, P. Chem.sEur. J. 2007, 13, 8084. (h) Gans a¨ uer, A.; Fan, C.-A.;
Keller, F.; Keil, J. J. Am. Chem. Soc. 2007, 129, 3484. (i) Friedrich, J.;
Walczak, K.; Dolg, M.; Piestert, F.; Lauterbach, T.; Worgull, D.; Gans a¨ uer,
A. J. Am. Chem. Soc. 2008, 130, 1788. (j) Est e´ vez, R. E.; Justicia, J.; Bazdi,
B.; Fuentes, N.; Paradas, M.; Choquesillo-Lazarte, D.; Garc ´ı a-Ruiz, J. M.;
Robles, R.; Gans a¨ uer, A.; Cuerva, J. M.; Oltra, J. E. Chem.sEur. J. 2009,
2.5 equiv), and triethylamine hydrochloride (140 mg, 1.0 mmol, 5 equiv)
was stirred in CH Cl (1.5 mL) for 10 min or until the solution had turned
from red to green. A solution of trans-4-phenyl-3-butene-2-one (30 mg,
0.20 mmol) in CH Cl (2.5 mL) was then added via syringe. The reaction
was stirred until starting material was consumed as monitored by TLC (p-
anisaldehyde). The mixture was quenched with saturated aqueous NH Cl
(10 mL). The solution was passed through celite and extracted with Et
(3 × 10 mL), and the combined organic fractions were washed with
saturated aqueous NaCl (30 mL), dried (MgSO ), and concentrated under
2
2
2
2
4
2
O
1
5, 2774.
4
(
10) (a) Karrer, P.; Yen, Y.; Reichstein, I. HelV. Chim. Acta 1930, 13,
reduced pressure. The crude residue was purified by flash chromatography,
eluting with hexanes/EtOAc (4:1) to give 16.7 mg (55%, 57% by 400 MHz
1
308. (b) Pons, J.-M.; Santelli, M. Tetrahedron Lett. 1986, 27, 4153. (c)
1
1
Jung, M. E.; Hogan, K. T. Tetrahedron Lett. 1988, 29, 6199. (d) Moisan,
L.; Hardouin, C.; Rousseau, B.; Doris, E. Tetrahedron Lett. 2002, 43, 2013.
H NMR referenced to naphthalene) of 2a as a clear colorless oil. H NMR
13
and C NMR data are consistent with literature values: Hayes, J. F.;
(
e) Asandei, A. D.; Chen, Y. Macromolecules 2006, 39, 7549.
Shipman, M.; Twin, H. J. Org. Chem. 2002, 67, 935.
Org. Lett., Vol. 12, No. 1, 2010
45

(entries 1-4). Conjugated enones with ꢀ-aryl (entries 5-8)
and ꢀ-alkyl (entries 9-11) substitution provided the corre-
sponding saturated ketones in excellent yields. Additionally,
acylic (entries 5-9) and cyclic (entries 10 and 11) enones
performed equally well in the reduction sequence. Of
particular note, enone 1j containing a cyclopropane ring at
the ꢀ-carbon underwent reduction in 57% yield without
strain-driven ring expansion of the cyclopropane ring (entry
a
Table 2. Titanium-Catalyzed Conjugate Reduction
9
). Interestingly, when the conjugate reduction of ꢀ-alkyl-
substituted enones was performed in CH Cl , only decom-
position of the starting enone was observed. However, by
switching the solvent from CH Cl to THF, and the proton
2
2
2
2
source to collidine·HCl, an excellent yield of the desired
saturated ketones could be obtained (entries 9-11). Aromatic
enoates provided the corresponding saturated esters in good
yields (entries 12 and 13), along with unsubstituted enamides
(entry 14). Ynones also proved viable substrates providing
the corresponding fully saturated carbonyl compounds in
good yields (entries 15 and 16). In general, these results
demonstrate the ease with which an inexpensive titanocene
catalyst can facilitate the conjugate reduction of R,ꢀ-
unsaturated carbonyl derivatives.
On the basis of our observations, the following generaliza-
tions can be made. First, the efficiency of the reduction was
highly dependent upon the concentration of titanocene
catalyst. If the reactions were performed with greater than
1
0 mol % titanocene, or at reaction concentrations greater
than 1 M, substantial amounts of pinacol coupling products
were observed. Additionally, R,ꢀ-unsaturated substrates with
ꢀ
-aryl rings substituted with electron-withdrawing groups
provided the reduced products in excellent yields, whereas
those containing electron-donating substituents failed to
undergo reduction resulting in a quantitative recovery of
starting material.
To determine the chemoselectivity of the catalytic con-
jugate reduction protocol, a series of competition studies were
performed (Table 3). Treatment of a 1:1 mixture of enone
1
a and enoate 1r to catalytic Cp
zinc dust and Et N·HCl provided a 53% yield of the 1,4-
reduced enone 2a and 95% yield of the unreacted enoate 1r
2 2
TiCl in the presence of
3
(entry 1). Likewise, subjection of enal 1b and enoate 1r to
a
Table 3. Chemoselectivity in the Conjugate Reduction
a
Conditions: alkene (1 mmol), Cp
2 2
TiCl (5 mol %), Zn dust (2.5 mmol),
b
yield of yield of
III (%) II (%)
and Et
3
N·HCl (5 mmol) in CH
2
Cl (0.05 M). Yields calculated by 400
2
1
c
entry
I
II
MHz H NMR to an internal standard (naphthalene). Yields in parentheses
based on recovered starting material. THF and collidine·HCl were used
in place of CH
d
2
2
1
2
3
4
a
1a Ar ) Ph, R ) OEt (1r)
1b 1r
1b 1a
53 (2a) 95 (1r)
76 (2b) 95 (1r)
e
2
Cl
2
and Et
3
N·HCl. Cp
2
TiCl
2
(10 mol %), Zn dust (5 equiv),
and Et
3
N·HCl (10 equiv).
b
73 (2b) 91 (1a)
2
2
1i Ar ) p-MeO-C
Conditions: 1 mmol of each substrate, Cp
2.5 equiv), and Et N·HCl (5 equiv) in CH Cl (0.05 M) at rt for 6 h. Zn
6
H
4
, R ) Me (1s) 78 (2i) 87 (1s)
2
TiCl (5 mol %), Zn dust
2
our findings are summarized in Table 2. The conjugate
reduction of aryl-substituted R,ꢀ-unsaturated aldehydes
provided the corresponding reduced aldehydes in good yields
b
(
3
2
2
dust (1.5 equiv) and Et N·HCl (3 equiv).
3
46
Org. Lett., Vol. 12, No. 1, 2010

IV
the same conditions resulted in the selective 1,4-reduction
of 1b to provide the saturated aldehyde 2b in 76% yield
A second reduction of Cp
2
Ti Cl
2
with zinc dust provides
III
Cp Ti Cl and completes the catalytic cycle.
2
(entry 2). We were also able to demonstrate that 1,4-reduction
of R,ꢀ-unsaturated aldehyde 1b (73% yield) could be
achieved selectively in the presence of enone 1a (entry 3).
Finally, a chemoselective reduction of electron-deficient
enone 1i in the presence of the electron-rich enone 1s was
accomplished in 78% yield and 87% recovered 1s. Thus,
the chemoselective reduction of more electrophilic R,ꢀ-
unsaturated carbonyl derivatives can be achieved under the
titanocene-catalyzed conditions described herein.
Scheme 1. Proposed Catalytic Cycle
We next sought to examine the diastereoselectivity ober-
seved in the reduction of a chiral R,ꢀ-unsaturated ketone.
We identified enone 1t as ideally suited to examine the
stereochemical outcome of the resulting protonation event.
However, when enone 1t was subjected to the titanium-
catalyzed conjugate reduction conditions, a 1.3:1 ratio of
diastereomers was formed in which the all equatorial
substituted ketone 2t was favored. Unfortuantely, all attempts
to examine the stereoselectivity at the ꢀ-carbon of R,ꢀ-
unsaturated carbonyl substrates by reduction of the corre-
IV
1
3
2 2
In conclusion, we have demonstrated how Cp Ti Cl can
sponding tetrasubstituted olefin were unsuccessful.
be used as an efficient catalyst for the conjugate reduction
of R,ꢀ-unsaturated carbonyl derivatives. A series of R,ꢀ-
unsaturated aldehydes, ketones, esters, unsubstituted amides,
and ynones underwent chemoselective conjugate reduction
by utilizing a catalytic quantity of titanocene. The catalytic
reduction process should be amenable to an asymmetric
protocol through the installation of chiral ligands on the
titanium complex. Studies directed toward the development
of a catalytic asymmetric reduction of R,ꢀ-unsaturated
carbonyl derivatives and the exploitation of titanium-bound
intermediates for cascade carbon-carbon bond-forming
reactions are ongoing and will be reported in due course.
On the basis of Gansäuer’s reports, and our own findings,
a proposed catalytic cycle for the titanocene-catalyzed
9
j
conjugate reduction is illustrated in Scheme 1. Initial
IV
reduction of the precatalyst Cp
2
Ti Cl
2
to the active reducing
III
species Cp
zinc dust. Coordination of Cp
2
Ti Cl is accomplished by a catalytic quantity of
III
2
Ti Cl to the carbonyl moiety
in enone 1l initiates a reallocation of electron density to
provide an intermediate ketyl radical that sequesters a second
equivalent of titanocene(III) through a rapid radical-radical
annihilation to provide the bis-titanium(IV)-bound intermedi-
Acknowledgment. The authors would like to thank the
reviewers for their helpful comments and the University of
Notre Dame for financial support of this research.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
ate 3. Protonation of the titanium alkoxide and allyl motifs
IV
by Et
3
N·HCl provides the saturated ketone 2l and Cp
2
Ti Cl
2
.
(13) Reduction of 3,5-dimethyl-2-cyclohexen-1-one resulted in decom-
position and a complex mixture of products.
OL9024315
Org. Lett., Vol. 12, No. 1, 2010
47