Copper hydride-catalyzed tandem 1,4-reduction/alkylation reactions

Article abstract of DOI:10.1016/S0040-4020(00)00132-0

Exposure of an enone to a catalytic quantity of [CuH(PPh₃)]₆ in the presence of one of several silyl hydrides (PhMe₂SiH, PMHS, HMe₂SiOSiMe₂H) leads to conjugate reduction with concomitant formation of the corresponding silyl enol ether. Without isolation, treatment of these intermediates with a Lewis acid at low temperatures in the presence of an aldehyde, or with fluoride ion together with an activated halide, affords good yields of the product of 3-component coupling (3-CC) in a single reaction flask. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00132-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2779±2788
Copper Hydride-Catalyzed Tandem
1,4-Reduction/Alkylation Reactions
*
Bruce H. Lipshutz, Will Chrisman, Kevin Noson, Patrick Papa, Joseph A. Sclafani,
Randall W. Vivian and John M. Keith
Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA 93106, USA
Received 30 November 1999; revised 22 December 1999; accepted 23 December 1999
AbstractÐExposure of an enone to a catalytic quantity of [CuH(PPh3)]6 in the presence of one of several silyl hydrides (PhMe2SiH, PMHS,
HMe2SiOSiMe2H) leads to conjugate reduction with concomitant formation of the corresponding silyl enol ether. Without isolation,
treatment of these intermediates with a Lewis acid at low temperatures in the presence of an aldehyde, or with ¯uoride ion together with
an activated halide, affords good yields of the product of 3-component coupling (3-CC) in a single reaction ¯ask. q 2000 Elsevier Science
Ltd. All rights reserved.
Introduction
Results and Discussion
Conjugate reductions
Dimethylphenylsilane (Me2PhSiH), popularized as
precursor to silyl higher order cyanocuprates (e.g. (PhMe2-
Si)2Cu(CN)Li2),5 is commercially available and relatively
inexpensive. Importantly, it can serve the same role as
PhSiH3 in the presence of [CuH(PPh3)]6 to ef®ciently reduce
a,b-unsaturated ketones in the desired 1,4-sense affording
isolable silyl enol ethers (Eq. (2)). Related work by Mori has
shown6 that an excess of this silane is effective for this
purpose in the presence of half an equivalent of either
CuF(PPh3)´2EtOH or CuCl/PPh3/TBAF in N,N-dimethyl-
acetamide (DMA).
One approach to site-speci®c a-alkylations of ketones is to
rely on a chemospeci®c conjugate reduction followed by
trapping of the resulting enolate or equivalent with an
electrophile. While several methods for effecting 1,4-reduc-
tions exist,1 transition metal-catalyzed processes offer
convenience and ef®ciency, as well as prospects for subse-
quent use of an in situ generated reactive intermediate. In an
earlier report from these laboratories,2 we described an
expedient process for effecting such reductions which
utilized #5 mol% of Stryker's reagent, [CuH(PPh3)]6,3,4
together with stoichiometric amounts of phenylsilane
(PhSiH3). By switching to other silyl hydrides, such as
dimethylphenylsilane (PhMe2SiH), tetramethyldisiloxane
(HMe2SiOSiMe2H), or polymethylhydrosiloxane (PMHS),
a far more economical process results. In the case of the
latter two reagents, a remarkable rate enhancement is noted
thus allowing for reduction in the amount of copper to
1 mol% or less with selected substrates. The intermediate
silyl enol ethers generated can be utilized in C±C bond
formations, all in a one-pot process. We now describe the
details surrounding this facile sequence (Eq. (1)).
a
ꢀ2†
Reactions were initially run under argon using 5 mol%
[CuH(PPh3)]6 at concentrations of ca. 0.5 M in substrate,
and tended to require between one and two hours to reach
the initial stage of completion (i.e. formation of the silyl
enol ether). TLC analysis of these clean reactions using
[CuH(PPh3)]6/PhMe2SiH in toluene at ambient tempera-
tures indicates, in addition to the desired silyl enol
ether, small amounts (,5% by GCMS integration) of
the 1,4-reduced ketone product may be produced. Also
seen is residual silane, which is employed in slight excess
ꢀ1†
Keywords: conjugate reduction; copper hydride; silyl hydrides.
* Corresponding author. Tel.: 805-893-2521; fax: 805-893-8265; e-mail:
lipshutz@chem.ucsb.edu
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00132-0

2780
B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
Scheme 1.
(1.2±1.5 equiv.). The variation in time was found to be
dependent upon the quality of the silane, and especially
that of the catalyst (vide infra).
that is needed for consumption of enone within a few
hours time. The intermediate bis-enol ethers 1 could readily
be isolated and characterized. Conversion to the derived
ketones, typi®ed by the one case studied (Eq. (5)), occurs
readily upon treatment with ¯uoride ion.
Although use of Me2PhSiH is an advance with respect to
ꢀ4†
ꢀ5†
reagent cost and stability (vs. PhSiH3) of the resulting enol
ether, it was recognized that there are other commercially
available silanes that are less expensive. More reactive
silanes could enhance the rate of copper hydride regenera-
tion, thus creating opportunities for decreasing the amount
of catalyst and/or silane required. Upon switching to tetra-
methyldisiloxane (HMe2SiOSiMe2H), reactions that usually
took hours occurred in minutes. With this more reactive silyl
hydride, the b,b-disubstituted 3-methylcyclohexenone
could be converted to its silyl enol ether in 85% isolated
yield (Eq. (3)).
With unhindered enones, PMHS appears to be even more
effective than HMe2SiOSiMe2H as a hydride donor to
copper(I). Cryptone was reduced to its enol ether within
10 min using only 0.7 mol% of [CuH(PPh3)]6 (Scheme 1),
while catalyst levels as low as 0.2 mol% can be used but
take several hours to consume enone. Under a standard set
of conditions, side-by-side comparisons of four sources of
hydride clearly indicated that PMHS offers the fastest rate of
1,4-reduction (Table 1).
Conjugate reduction/alkylation reactions
Once a conjugate reduction of an a,b-unsaturated ketone is
complete, cooling the reaction mixture to 2788C is
followed by introduction of the electrophile, e.g., an alde-
hyde (1.25 equiv.). Subsequent slow addition of BF3´OEt2
or TiCl4 (1.0 M in CH2Cl2; 1.25 equiv.)7 leads to the desired
aldol process. The overall isolated yields employing this
protocol tend to be good, although considerable care is
needed to ensure that secondary processes do not over-
shadow the desired aldol pathway (e.g. partial dehydration,
polymerization, retro-aldol, etc.). Listed in Table 2 are
several examples of representative enone±aldehyde combi-
nations which participate in this process.8 The unusual enol
silanes generated using tetramethyldisiloxane (cf. Eq. (3))
react readily in Lewis acid-induced aldol reactions leading
to products of 3-CC (entries 2 and 7). Also, as previously
ꢀ3†
Most noteworthy is the observation that both hydrides
within this silane are available for use, thereby reducing
the net amount of this hydride source to half the stoichio-
metric level. A few examples of products derived from this
especially ef®cient, mild, and economical method for conju-
gate reduction are shown above, involving educts cryptone,
4,4-dimethyl-2-cyclohexenone, and carvone, respectively
(Eq. (4)). Moreover, usually 1 mol% [CuH(PPh3)]6 is all

B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
2781
Table 1. Comparison of silyl hydrides under standard reduction conditions (reaction conditions: 2 mol% 1/6[Cu(PPh3)]6, 1.25 equiv. silane, 0.5 M in PhCH3,
room temperature)
observed,2 both cyclic and acyclic educts can be viewed as
Michael acceptors. Additional points concerning this conju-
gate reduction/alkylation sequence include: (1) diastereo-
meric products were formed in all cases,9 with
chromatographic separation and complete characterization
carried out for each isomer where possible. In some cases,
however, there was no choice but to conduct analyses on
mixtures of isomers, although the con¯uence of GCMS, 1H
and 13C NMR, and high resolution mass spectral data led to
unequivocal identi®cation of the products formed; (2)
placement of an aldehyde in the reaction ¯ask along with
the enone prior to introduction of the [CuH(PPh3)]6/silane
ultimately afforded reduced aldehyde at the expense of the
conjugate addition/aldol product(s). Since the silane itself is
Table 2. 3-Component couplings: 1,4-reduction/aldol reactions
a
Refers to 1/6[CuH(PPh3)]6.
AˆPhMeSiH; BˆMe2HSi-O-SiHMe2; CˆPhSiH3.
b
c
BF3ˆBF3´Et2O.
d
Isolated, chromatographically pure materials.

2782
B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
Scheme 2.
not capable of effecting 1,2-addition to aldehydes, the
presence of a Cu(I) species, even a copper(I) hydride,
provides enough Lewis acidity to induce competitive
hydride delivery; (3) chalcone (entry 8) was very sluggish
toward reduction using Me2PhSiH. The 1,4-reduction/aldol
sequence was therefore successfully tested using PhSiH3,
which had not been examined in our previous study;2 (4)
treatment of a crude product resulting from a 3-CC under
acidic conditions is suf®cient to force dehydration, typi®ed
by the example illustrated in Eq. (6).
meric nature of this silane. Nonetheless, while these enol
derivatives cannot be readily isolated, they can be utilized
directly in a 3-CC. As illustrated below (Scheme 3), treat-
ment of an in situ derived species 2, following the same
protocol as used for enol ethers derived from Me2PhSiH
or HMe2SiOSiMe2H, affords the product of 3-CC (3) in
good yield.
Another option for these in situ-derived silyl enol ethers is
their ¯uoride ion-induced alkylation, which can be initiated
using DeShong's tetrabutylammonium (triphenylsilyl)-
di¯uorosilicate (TBAT)11 in the presence of a reactive
halide (Eq. (7)).6
(6)
ꢀ7†
With this aldehyde, essentially a single isomer of E stereo-
chemistry was obtained; and (5) for certain synthetic
situations, it may be necessary to increase the amount of
catalyst signi®cantly in order to drive a conjugate reduction
to completion. In questioning the presence of greater
amounts of copper(I) in the medium on the subsequent
aldol event, an enone was carried through the sequence
employing 18 mol% [CuH(PPh3)]6. Notwithstanding the
known tendency of copper enolates to function poorly as
nucleophiles toward aldehydes,10 and to the extent that such
enolates may be involved in this chemistry, the reactions
proceeded to give the anticipated products via routes (a) and
(b) in good isolated yields (Scheme 2).
Lastly, a comment with regard to the key ingredient in this
sequence, the [CuH(PPh3)]6 complex. This reagent is a
well-known source of hydride used mainly for stoichio-
metric conjugate reductions,3 and continues to be sold
commercially. During the course of our study we had the
opportunity to utilize different samples of this complex, and
noticed that the quality of the commercially supplied
material varies considerably as evidenced by their 1H
NMR spectra taken in distilled (Na/benzophenone) and
degassed benzene-d6 (Fig. 1). The ®rst sample of com-
mercial [CuH(PPh3)]6 (spectrum A) had a dark brown,
heterogeneous appearance in benzene and did not function
in our conjugate reduction catalytic cycle to any signi®cant
extent. The second sample, which led to spectrum B, was
also noticeably dark brown±red and heterogeneous in
Intermediates formed from 1,4-reductions employing
PMHS are not discrete species, as expected given the poly-
Scheme 3.

B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
2783
Figure 1. 1H NMR spectra of [CuH(PPh3)]6 from: A, Aldrich, 1st sample; B, Aldrich, 2nd sample; C, freshly made according to the Stryker literature method;
* denotes impurities in the [CuH(PPh3)]6.
benzene. It was to some degree catalytically active, but only
when used in amounts in considerable excess to that even-
tually needed to consume starting materials in reasonable
timeframes (ca. 6 times the `usual' amount). On the other
hand, a sample of red, powdery material which fully
dissolved in benzene (spectrum C) allowed for continuation
of the work reported herein. Comparison of these spectra
reveals that the sample giving rise to spectrum A contains
virtually none of the active hydride, a signal for which
would appear at 3.52 ppm (see inserts). It is comprised of
essentially all impurities (cf. peaks labeled by an asterisk).
The second commercial sample (spectrum B) shows
evidence of the Stryker reagent but consists mainly of the
same impurities. This accounts for the limited reactivity
observed and the required excess reagent. The third sample
of [CuH(PPh3)]6 was prepared on a multi-gram scale in a
straightforward manner following the Stryker protocol.3
This route provided nearly pure material (spectrum C)12
which was used for optimum results in our conjugate
reductions and 3-CC sequences.
and costs only pennies per gram, is noteworthy in its effec-
tiveness. Indeed, the combination of 1±2% [CuH(PPh3)]6
together with a slight excess of PMHS represents a method
which may be one of the most user-friendly, economical
and ef®cient processes known for carrying out conjugate
reductions of enones.1,3,13 Subsequent C±C bond formations
from intermediate silyl enol ethers (which may be isolated
when using Me2PhSiH or HMe2SiOSiMe2H, if desired) can
be effected via Mukaiyama aldols, or ¯uoride-induced
alkylations with activated halides.
Experimental
General. Reactions were performed using standard Schlenk
techniques in oven-dried glassware under an argon
atmosphere with Te¯on coated stir bars and double septa
tops. All solvents were freshly distilled from sodium benzo-
phenone ketyl or CaH2 under argon before use. The copper
hydride hexamer [CuH(PPh3)]6 was stored and weighed out
as a red powder in an inert atmosphere (e.g. glovebox) using
a Te¯on-coated spatula. All commercially obtained reagents
were distilled either from CaH2 or molecular sieves under an
inert atmosphere before use. Melting points were measured
on a Mel-Temp II and are uncorrected. Products were puri-
®ed by chromatography on 200±425 g mesh Fisher brand
silica gel pretreated with either 2% triethylamine or
pyridine, or which had been deactivated with 2% aqueous
acetone. TLC analyses were performed on commercial
Kieselgel 60 F254 silica gel plates. NMR spectra were
obtained on Varian Inova systems using CDCl3 or C6D6
solvents with proton and carbon resonance at 400 or
Summary and Conclusions
In summary, a mild and ef®cient method for the single-¯ask
conjugate reduction±alkylation of an a,b-unsaturated
ketone has been developed. It relies on the catalytic use of
Stryker's reagent [CuH(PPh3)]6, presumed to be the species
delivering the hydride, together with stoichiometric
amounts of either of three inexpensive silanes (Me2PhSiH,
HMe2SiOSiMe2H, or PMHS). The latter reagent, PMHS,
which is used without further handling out of the bottle

2784
B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
500 MHz and 100 or 125 MHz, respectively; the d scale
was referenced to CDCl3 or C6D6 based on residual lines
at d 7.27 and 7.15 ppm, respectively, or to 2% TMS as an
additive. FTIR spectra were obtained on an ATI Mattson
In®nity Series spectrometer neat on NaCl plates or as KBr
pellets, and are reported in cm21. Mass spectral data were
acquired on a VF Autospec or an analytical VG-70-250 HF
instrument.
0.5 equiv.), and 4-isopropyl-2-cyclohexenone (0.30 mL,
2.04 mmol). The solution was stirred at room temperature
for 1 h. Puri®cation by ¯ash chromatography (1:20 Et2O/
PE) afforded the bis-enol ether as a colorless oil (0.415 g,
99%). Rfˆ0.81 (1:10 EtOAc/PE); IR (thin ®lm) 2958, 2922,
2873, 2842, 1674, 1465, 1441, 1376, 1259, 1216, 1194,
1
1071, 894, 856, 802; H NMR (400 MHz, CDCl3) d 4.93
(dt, Jˆ5.6, 2.0 Hz, 2H), 2.11 (m, 2H), 2.02 (m, 4H), 1.77
(m, 4H), 1.27 (m, 4H), 0.90 (d, Jˆ4 Hz, 6H), 0.89 (d,
Jˆ4 Hz, 6H), 0.177 (s, 12H); 13C NMR (100 MHz,
CDCl3) d 149.7, 104.5, 40.2, 32.2, 30.3, 27.5, 26.7, 20.3,
20.1, 20.24, 20.28; LREIMS (m/z, rel. int.) 410(15),
395(5), 287(12), 271(78), 255(20), 227(55), 200(30),
149(100), 133(79), 122(19), 81(35), 69(38), 55(20),
43(33); HREIMS calcd for C22H42O3Si2 410.2673, found
410.2675.
General procedure I for the 1,4-reduction of a,b-
unsaturated ketones: (4-isopropyl-1-cyclohexenyloxy)-
dimethylphenylsilane (Eq. (2)). To a homogeneous red
solution of copper hydride [CuH(PPh3)]6 (18.7 mg,
0.01 mmol, 5.6 mol% Cu) in toluene (1.5 mL) was added
dropwise dimethylphenylsilane (0.23 mL, 1.5 mmol,
1.5 equiv.) and the solution stirred at room temperature
for approximately 3±5 min. To the resulting red solution,
dropwise 4-isopropyl-2-cyclohexen-1-one was added
(0.15 mL, 1.0 mmol). After 5±7 min the color of the solu-
tion had darkened to a heterogeneous brown/black. After
2 h, the reaction mixture was ®ltered through a pad of
sand/Celite/charcoal with excess washing using toluene.
The solvent was removed in vacuo and the crude product
puri®ed by Kugelrohr distillation (205±2108C, 1.5 Torr)
affording the corresponding silyl enol ether as a colorless
oil (0.273 g, 99%). Rfˆ0.83 (1:10 EtOAc/hexanes); IR (thin
®lm) 3413, 3069, 2959, 2873, 1716, 1674, 1593, 1428,
1,3-Bis(4,4-dimethyl-1-cyclohexenyloxy)tetramethyldisil-
oxane (Eq. (4), second entry). General method I was
employed using the following quantities: copper hydride
[CuH(PPh3)]6 (6.8 mg, 0.0034 mmol, 1 mol% Cu), toluene
(4.0 mL), tetramethyldisiloxane (0.18 mL, 0.99 mmol,
0.50 equiv.), and 4,4-dimethyl-2-cyclohexenone (0.26 mL,
1.98 mmol). The solution was stirred at room temperature
for 2 h. Puri®cation by ¯ash chromatography (1:20 Et2O/
PE) afforded bis-enol ether as a colorless oil (0.351 g,
93%). Rfˆ0.80 (1:10 EtOAc/PE); IR (thin ®lm) 2952,
2919, 2872, 2835, 1672, 1459, 1367, 1260, 1200, 1170,
1
1371, 1254, 1182, 1119, 1061, 884, 832, 789, 701; H
1
NMR (400 MHz, CDCl3) d 7.66 (m, 3H), 7.43 (m, 1H),
4.89 (dt, Jˆ2.8, 2.0 Hz, 1H), 2.06 (m, 2H), 1.78 (m, 2H),
1.49 (m, 1H), 1.30 (m, 2H), 0.92 (dd, Jˆ4.0, 3.0 Hz), 0.49
(s, 6H); 13C NMR (100 MHz, CDCl3) d 150.4, 138.3, 133.5,
133.2, 129.8, 129.4, 128.0, 127.9, 104.4, 40.1, 32.1, 30.4,
27.5, 26.6, 20.3, 20.1, 1.06, 20.80; LREI (m/z, rel. int.)
341(7), 277(15), 275(10), 135(100), 111(12), 95(18),
83(36), 69(48), 55(55); HRFABMS (NBA) (M1H) calcd
for C17H26OSi 275.1831, found 275.1826.
1070, 898, 803; H NMR (400 MHz, CDCl3) d 4.86 (tt,
Jˆ4.0, 1.6 Hz, 2H), 2.03 (tq, Jˆ6.6, 2.4, 1.6 Hz, 4H),
1.81 (dt, Jˆ4.0, 2.4 Hz, 4H), 1.41 (t, Jˆ6.6 Hz, 4H), 0.93
(s, 12H), 0.18 (s, 12H); 13C NMR (100 MHz, CDCl3) d
148.7, 103.8, 38.1, 36.1, 28.8, 28.2, 27.5, 20.31; LREIMS
(m/z, rel. int.) 382(11), 367(5), 273(8), 257(93), 239(62),
229(15), 200(96), 185(14), 149(75), 133(100), 109(34),
91(8), 81(10), 67(32), 53(39), 43(19); HREIMS calcd for
C20H38O3Si2 382.2360, found 382.2362.
(3-Methyl-1-cyclohexenyloxy)-tetramethyldisiloxane (Eq.
(3)). General method I was employed using the following
quantities: copper hydride [CuH(PPh3)]6 (16.0 mg,
0.008 mmol, 5 mol% Cu) in toluene (2.0 mL), tetramethyl-
disiloxane (0.27 mL, 1.5 mmol, 1.5 equiv.), 3-methyl-2-
cyclohexenone (0.11 mL, 1.0 mmol). The solution was stir-
red at room temperature for 24 h. Puri®cation by Kugelrohr
distillation (68±708C, 1.5 Torr) afforded the corresponding
silyl enol ether as a colorless liquid (0.207 g, 85%). Rfˆ0.81
(1:10 EtOAc/hexanes); IR (thin ®lm) 2957, 2866, 2128,
1,3-Bis(S-5-isopropenyl-2-methyl-1-cyclohexenyloxy)-
tetramethyldisiloxane (Eq. (4), third entry). General
method I was employed using the following quantities:
copper hydride [CuH(PPh3)]6 (17 mg, 0.009 mmol,
5 mol% Cu), toluene (2.0 mL), tetramethyldisiloxane
(0.10 mL, 0.55 mmol, 0.55 equiv.), and (S)-(1)-carvone
(0.16 mL, 1.03 mmol). The solution was stirred at room
temperature for 14 h. Puri®cation by ¯ash chromatography
(1:20 Et2O/PE) afforded the bis-enol ether as a colorless oil
(0.202 g, 91%). Rfˆ0.87 (1:10 EtOAc/PE); IR (thin ®lm)
2964, 2920, 2856, 2835, 1693, 1644, 1439, 1260, 1183,
1
1666, 1454, 1369, 1258, 1190, 1063, 906, 838; H NMR
1
(400 MHz, CDCl3) d 4.83 (m, 1H), 4.73 (sept, Jˆ2.8 Hz,
1H), 2.25 (m, 1H), 1.99 (m, 2H), 1.74 (m, 3H), 1.57 (m, 1H),
0.96 (d, Jˆ6.8 Hz, 3H), 0.21 (m, 12H); 13C NMR
(100 MHz, CDCl3) d 149.5, 111.6, 31.3, 29.8, 29.7, 22.6,
22.0, 0.85, 20.29, 20.43, 20.46; LREIMS (m/z, rel. int.)
281(9), 244(7), 229(4), 207(9), 149(100), 133(65), 119(7),
95(28), 81(90), 55(17); HREIMS calcd for C11H24O2Si2
244.1314, found 244.1323.
1063, 938, 888, 846, 802; H NMR (400 MHz, CDCl3) d
4.72 (m, 4H), 2.24 (m, 2H), 2.05 (m, 8H), 1.74 (m, 2H), 1.73
(br s, 6H), 1.58 (br s, 6H), 1.40 (qd, Jˆ12.4, 5.6 Hz, 2H),
0.18 (m, 12H); 13C NMR (100 MHz, CDCl3) d 149.5, 141.9,
111.6, 108.9, 42.6, 35.6, 30.3, 28.1, 21.0, 16.3, 0.13, 0.11;
LREIMS (m/z, rel. int.) 434(14), 282(99), 267(13), 239(35),
215(14), 149(100), 133(67), 119(31), 107(28), 93(49),
74(36), 59(61), 43(19); HREIMS calcd for C24H4203Si2
434.2673, found 434.2669.
1,3-Bis(4-isopropyl-1-cyclohexenyloxy)tetramethyldi-
siloxane (Eq. (4), ®rst entry). General method I was
employed using the following quantities: copper hydride
[CuH(PPh3)]6 (7.0 mg, 0.0035 mmol, 1 mol% Cu), toluene
(4.0 mL), tetramethyldisiloxane (0.18 mL, 1.02 mmol,
4-Phenyl-2-butanone (Eq. (5)). General method I was
employed using the following quantities: copper
hydride [CuH(PPh3)]6 (7 mg, 0.0035 mmol, 2 mol% Cu)
in toluene (2.0 mL), tetramethyldisiloxane (0.10 mL,

B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
2785
0.55 mmol, 0.55 equiv.), trans-4-phenyl-3-buten-2-one
(0.146 g, 1.0 mmol), and the solution stirred at room
temperature for 3 h. MeOH (5 mL) was added, followed
by TBAF´3H2O (0.946 g, 3 mmol) dissolved in 5 mL
MeOH. The solution was allowed to stir for 30 min and
the solvent was removed in vacuo affording a yellow oil.
Puri®cation by ¯ash chromatography (1:10 Et2O/PE)
afforded benzyl acetone as a colorless liquid (0.12 g,
82%), whose spectroscopic properties matched literature
data.14
(m/z, rel. int.) 283(0.03), 277(0.4), 270(0.20), 192(3),
147(100), 91(42); HRFABMS (NBA) calcd for
C17H18NO3 (M1H) 284.1287, found 284.1295.
Representative procedure A for a conjugate reduction-
aldol 3-CC: 2-(1-hydroxy-3-methylbutyl)-4-isopropyl-
cyclohexanone (Table 2, entry 4). To a homogeneous
red solution of copper hydride [CuH(PPh3)]6 (12.2 mg,
0.006 mmol, 3.2 mol% Cu) in toluene (2.4 mL) was added
dropwise dimethylphenylsilane (0.45 mL, 2.9 mmol,
2.5 equiv.) and the solution stirred at room temperature
for ca. 5 min. To the resulting homogenous red solution
2-(5-Benzyloxy-2-bromobenzylidene)-cyclohexanone
(Eq. (6)). General method I was employed using the follow-
ing quantities: copper hydride [CuH(PPh3)]6 (22 mg,
0.012 mmol, 5 mol% Cu), dimethylphenylsilane (0.34 mL,
2.2 mmol, 1.5 equiv.), 2-cyclohexenone (0.16, 1.5 mmol),
2-bromo-5-benzyloxybenzaldehyde (0.65 g, 2.2 mmol,
1.5 equiv.), and BF3´Et2O (0.25 mL, 2.0 mmol, 1.3 equiv.).
The crude aldol products were taken up into 40 mL of dry
benzene to which was added 20 mg of TsOH. The mixture
was then heated under a Dean-Stark trap at re¯ux for
90 min. The solvent was removed in vacuo and the crude
elimination product taken up in 50 mL of Et2O and
extracted with saturated NH4Cl solution (2£25 mL), washed
with brine (2£25 mL), and then dried over anhydrous
Na2SO4. Puri®cation by ¯ash chromatography (1:3
EtOAc/hexane) afforded a single (E)-alkene as a light
yellow solid (0.43 g, 77%). mpˆ100±1028C; Rfˆ0.34; IR
(KBr) 3065, 3029, 2943, 2862, 1672, 1586, 1231, 1006, 741,
was
added
dropwise
4-isopropyl-2-cyclohexenone
(0.17 mL, 1.17 mmol) and the solution was stirred at room
temperature. After ca. 7 min the solution had darkened to a
heterogeneous brown/black color. Monitoring of the reac-
tion by TLC showed that the enone was consumed after 3 h,
and a high Rf spot corresponding to the silyl enol±ether was
observed. The solution was diluted with CH2Cl2 (12.0 mL)
and cooled to 2788C followed by dropwise addition of neat
isovaleraldehyde (0.17 mL, 1.58 mmol, 1.4 equiv.), then
neat BF3´Et2O (0.16 mL, 1.50 mmol, 1.3 equiv.). Stirring
was continued for 40 min and the reaction was then
quenched by pouring into 9.0 mL of ice cold saturated
NaHCO3 solution followed by extraction with diethyl
ether (3£25 mL). The combined organic portions were
washed with brine (2£50 mL), dried over anhydrous
Na2SO4, and ®ltered through a plug of Celite. The solvent
was removed in vacuo to afford a light yellow oil. Flash
chromatography (1:10 EtOAc/PE) afforded aldol diastereo-
mers as a colorless oil (0.24 g, 89%). Rfˆ0.18±0.23; IR
1
695; H NMR (500 MHz, DMSO-d6) d 7.49 (d, Jˆ8.5 Hz,
1H), 7.40 (m, 5H), 7.34 (m, 1H), 6.83 (m, 2H), 5.07 (s, 2H),
2.54 (m, 4H), 1.92 (p, Jˆ6.6 Hz, 2H), 1.71 (p, Jˆ6.6 Hz,
2H); 13C NMR (125 MHz, CDCl3) d 202.0, 157.5, 139.0,
136.8, 136.6, 134.2, 133.6, 128.9, 128.4, 127.5, 117.4,
116.7, 116.0, 70.5, 40.9, 29.0, 24.1, 23.9; LREIMS (m/z,
rel. int.) 372(1), 370(1), 292(2), 291 (2), 291(13), 115(1),
102(2), 92(6), 91(100), 65(4), 63(1), 55(1), 51(1),
43(1); HREIMS calcd for C20H19O2Br 370.0568, found
370.0563.
1
(thin ®lm) 3530, 2933, 2871, 1704; H NMR (400 MHz,
CDCl3) [Note: integrations are not given for combined
diastereomers as signals overlap] d 4.14 (m), 3.72 (m),
3.41 (brs), 2.64 (br s), 2.30 (m), 1.95 (m), 1.80 (m), 1.56
(m), 1.42 (m), 1.17 (m), 0.96 (m), 0.86 (m); 13C NMR
(100 MHz, CDCl3) d 215.7, 67.1, 54.5, 42.8, 42.1, 32.4,
30.3, 29.5, 24.8, 23.7, 22.2, 20.2, 19.9; LRCIMS (CH4)
(m/z, rel. int.) 227(2), 209(21), 191(25), 169(11), 153(16),
141(55), 123(68), 109(11), 95(16), 81(27), 69(88), 57(36),
43(100); HRCIMS (CH4) calcd for C14H27O2 (M1H)
227.2011, found 227.2011.
3-(4-Nitrobenzyl)-4-phenyl-2-butanone (Eq. (7)). General
method I was employed using the following quantities:
copper hydride [CuH(PPh3)]6 (7 mg, 0.0035 mmol,
2 mol% Cu), toluene (2.0 mL), tetramethyldisiloxane
(0.10 mL, 0.55 mmol, 0.55 equiv.), and trans-4-phenyl-3-
buten-2-one (0.15 g, 1.0 mmol). The solution was stirred
at room temperature for 3 h. To the resulting dark solution
was added CH2Cl2 (5.0 mL) followed by solid 4-nitrobenzyl
bromide (1.08 g, 5.0 mmol, 5 equiv.) in one portion. TBAT
(1.19 g, 2.2 mmol, 2.2 equiv.) was dissolved in 5.0 mL
CH2Cl2 and cannulated into the reaction. The resulting
bright pink solution was allowed to stir at rt for 3 h, after
which the solvent was removed in vacuo affording a pink
residue. Puri®cation by ¯ash chromatography (1:10 EtOAc/
PE) afforded the alkylated product as a light yellow oil
(0.161 g, 57%). Rfˆ0.18; IR (thin ®lm) 3063, 3028, 2924,
2854, 1711, 1602, 1517, 1346, 1161, 1110, 851, 751, 700;
1H NMR (400 MHz, CDCl3) d 8.13 (m, 2H); 7.28 (m, 5H);
7.18 (m, 2H); 3.18 (m, 1H); 3.05 (dd, Jˆ10 Hz, 1H); 2.97
(dd, Jˆ8 Hz, 14 Hz, 1H); 2.79 (dd, Jˆ5 Hz, 14 Hz, 1H);
2.73 (dd, Jˆ7 Hz, 14 Hz, 1H); 1.84 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 211.0, 147.6, 146.8, 138.6, 129.9,
129.0, 128.9, 126.9, 123.9, 56.1, 38.6, 37.4, 31.6; LREIMS
Representative procedure B for the conjugate reduction-
aldol 3-CC: 2-{hydroxy-[1-(toluene-4-sulfonyl)-1H-
indol-3-yl]-methyl}-4,4-dimethylcyclohexanone (Table
2, entry 1). To a homogeneous red solution of copper
hydride [CuH(PPh3)]6 (16.0 mg, 0.008 mmol, 5 mol% Cu)
in toluene (2.0 mL) was added dropwise dimethylphenyl-
silane (0.23 mL, 1.5 mmol, 1.5 equiv.) and the solution stir-
red at room temperature for ca. 5 min. To the resulting red
solution was added dropwise 4,4-dimethylcylohexenone
(0.13 mL, 1.0 mmol) and the solution was stirred at room
temperature. After ca. 7 min the solution darkened to a
heterogeneous brown/black. Monitoring of the reaction by
TLC showed that the enone was consumed after 3 h to
form the corresponding silyl enol ether. The solution was
diluted with CH2Cl2 (5.0 mL) and added via cannula to a
solution of N-tosyl-indole-3-carboxaldehyde (0.45 g,
1.5 mmol, 1.5 equiv.) and TiCl4 (1.5 mL of 1.0 M solution
in CH2Cl2, 1 equiv.), in CH2Cl2 (7.0 mL) at 2788C. Stirring
was continued for 1 h and the reaction was quenched with
saturated NaHCO3 solution (6.0 mL) at 2788C, and allowed

2786
B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
to warm to room temperature. A blue precipitate was ®ltered
using a Buchner funnel, and the aqueous layer was extracted
with diethyl ether (3£25 mL). The combined organic
portions were washed with brine (2£50 mL), dried over
anhydrous Na2SO4, and the solvent was removed in
vacuo. Purifcation by ¯ash chromatography (1:9 EtOAc/
PE to 1:4 EtOAc/PE) afforded diastereomers as a yellow
oil (combined yield 0.35 g, 82%). Rfˆ0.19; IR (thin ®lm)
3523, 2956, 2928, 2864, 1700, 1447, 1369, 1173, 1121, 733;
1H NMR (400 MHz, CDCl3) [Note: integrations are not
given for combined diastereomers as signals overlap] d
8.00 (dd, Jˆ11.6, 8.4 Hz, 1H), 7.74 (d, Jˆ8.0 Hz, 2H),
7.67 (d, Jˆ8.0 Hz), 7.55 (s), 7.50 (s), 7.41 (d, Jˆ8.0 Hz,
1H), 7.25 (m), 5.65 (s), 5.02 (dd, Jˆ8.4, 2.4 Hz), 4.14 (d,
Jˆ2.8 Hz), 3.19 (d, Jˆ3.2 Hz), 3.02 (m), 2.85 (m), 2.55 (m),
2.35 (m), 2.31 (s), 2.30 (s), 1.70 (m), 1.28 (m), 1.17 (m),
0.94 (dd, Jˆ28.1, 10.4 Hz, 6H); 13C NMR (100 MHz,
CDCl3) d 216.0, 214.7, 145.1, 144.9, 135.6, 135.3, 130.0,
129.9, 129.2, 128.7, 126.9, 126.8, 125.0, 124.8, 124.3,
123.9, 123.5, 123.4, 123.2, 122.3, 120.8, 119.6, 114.1,
113.8, 68.7, 65.8, 51.5, 50.7, 43.4, 39.8, 39.8, 38.9, 38.7,
38.6, 31.5, 31.3, 30.6, 30.4, 24.3, 24.2, 21.6; LRFABMS
(NBA) (m/z, rel. int.) 425(11), 408(98), 380(10),
300(100), 284(39), 254(11), 154(46), 130(25); HRFABMS
(NBA) calcd for C24H27O4NS (M1H) 425.1660, found
425.1663.
2H), 5.50 (s, 1H), 4.91 (d, Jˆ8.0 Hz, 1H), 4.81 (br s, 1H),
3.18 (br s, 1H), 2.62 (m), 2.51 (m), 2.39 (m), 2.13 (m), 1.86
(m), 1.64 (m), 1.41 (m); 13C NMR (100 MHz, CDCl3) d
214.3, 149.3, 128.0, 126.8, 123.8, 74.3, 70.3, 57.4, 42.9,
31.0, 28.1, 26.1, 25.0; LRCIMS (CH4) (M±H2O) (m/z, rel.
int.) 231(6), 214(13), 184(3), 150(64), 128(2), 116(5),
98(100), 77(52), 55(67); HRFABMS (NBA) (M1H) calcd
for C13H15NO4 250.1079, found 250.1081.
2-[2-(2-Chloroethoxy)-1-hydroxyethyl]-4-isopropylcyclo-
hexanone (Table 2, entry 5). General method A was
employed using the following quantities: copper hydride
[CuH(PPh3)]6 (25 mg, 0.013 mmol, 5 mol% Cu), dimethyl-
phenylsilane (0.35 mL, 2.25 mmol, 1.5 equiv.), cryptone
(0.22 mL, 1.5 mmol), (2-chloroethoxy)-acetaldehyde (0.24 g,
2.0 mmol, 1.3 equiv.), and BF3´Et2O (0.25 mL, 2.0 mmol,
1.3 equiv.). Puri®cation by ¯ash chromatography (1:3
EtOAc/hexane) afforded aldol diastereomers as a colorless
oil (combined yield 0.34 g, 87%). Rfˆ0.19±0.27; IR (thin
®lm) 3497, 2959, 2872, 1706, 1129, 747, 665; Rfˆ0.19±
1
0.23; H NMR (500 MHz, CDCl3) [Note: integrations are
not given for combined diastereomers as signals overlap] d
4.26 (m), 4.20 (m), 3.75 (m), 3.64 (m), 3.56 (m), 3.48 (dd,
Jˆ14.1, 6.7 Hz), 2.69 (bd, Jˆ4.3 Hz), 2.56 (dt, Jˆ13.1,
5.4 Hz), 2.38 (m), 2.17 (m), 2.05 (m), 1.63 (m), 1.44 (m),
1.21 (dd, Jˆ7.1, 3.0 Hz), 0.93 (dd, Jˆ7.1 Hz, 2H); 13C
NMR (125 MHz, CDCl3) d 215.6, 215.2, 214.1, 213.8,
72.9, 72.6, 72.5, 72.3, 71.6, 71.5, 71.4, 71.2, 71.1, 71.0,
68.9, 68.4, 68.1, 68.0, 63.7, 51.5, 51.4, 50.2, 49.4, 43.1,
43.0, 42.9, 42.8, 42.7, 42.5, 42.0, 41.9, 39.4, 39.2, 38.9,
38.5, 31.2, 32.1, 32.0, 31.4, 30.7, 30.3, 29.7, 29.4, 29.0,
28.8, 28.6, 20.5, 20.4, 20.0, 19.8; LRCIMS (CH4) (m/z,
rel. int.) 263(14), 245(35), 227(3), 203(11), 183(33),
165(100), 149(3), 141(56), 123(67), 107(30), 93(37),
70(4), 63(53), 55(20); HRFABMS calcd for (M1H)
C13H24O3Cl 263.1414, found 263.1415; HREIMS (CH4)
calcd for (M±H2O) C13H21O2Cl 244.1230, found 244.1240.
2-(1-Hydroxyhexyl)-3-methylcyclohexanone (Table 2,
entry 2). General method B was employed using the
following quantities: copper hydride [CuH(PPh3)]6
(16.0 mg, 0.008 mmol, 5 mol% Cu), tetramethyldisiloxane
(0.27 mL, 1.5 mmol, 1.5 equiv.), 3-methyl-2-cyclohexenone
(0.11 mL, 1.0 mmol, 1.0 equiv.), 1-hexanal (0.18 mL,
1.5 mmol, 1.5 equiv.), and 1.0 M TiCl4 (1.50 mL,
1.5 mmol, 1.5 equiv.). Puri®cation by ¯ash chromatography
(1:9 EtOAc/PE) afforded aldol diastereomers as a colorless
oil (combined yield 0.15 g, 72%). Rfˆ0.25; IR (thin ®lm)
1
3426, 2953, 2928, 2862, 1700, 1460; H NMR (400 MHz,
CDCl3) [Note: integrations are not given for combined
diastereomers as signals overlap] d 3.70 (m), 2.82 (s, 3H),
2.80 (s, 3H), 2.36 (m), 2.10 (m), 1.90 (m), 1.72 (m), 1.47
(m), 1.28 (m), 1.12 (s), 1.11 (s), 0.89 (t, 3H); 13C NMR
(100 MHz, CDCl3) d 212.7, 68.2, 67.8, 54.5, 42.5, 42.1,
34.4, 34.2, 33.8, 31.5, 30.3, 29.5, 24.8, 23.7, 22.2, 20.2,
19.9; LRFABMS (NBA) (m/z, rel. int.) 213(33), 195(100),
191(14), 177(13), 141(14), 113(83), 97(18), 95(48), 43(8);
HRFABMS (NBA) calcd for C13H24O2Na (M1Na)
235.1674, found 235.1670.
2-(E-1-Hydroxy-3-tributylstannanyl-2-butenyl)-4-iso-
propylcyclohexanone (Tabel 2, entry 6). General method
A was employed using the following quantities: copper
hydride [CuH(PPh3)]6 (24 mg, 0.012 mmol, 5 mol% Cu),
dimethylphenylsilane (0.34 mL, 2.2 mmol, 1.5 equiv.),
cryptone (0.22 mL, 1.5 mmol), E-3-tributylstannanyl-2-
butenal (0.70 g, 2.0 mmol, 1.3 equiv.), and BF3´Et2O
(0.25 mL, 2.0 mmol, 1.3 equiv.). Puri®cation by ¯ash
chromatography (1:10 Et2O/hexane) afforded two separable
aldol diastereomers as a colorless oil (combined yield
0.57 g, 76%). Diastereomer 1: Rfˆ0.23; IR (thin ®lm)
1
2-(4-Nitrobenzylhydroxy)-cyclohexanone (Table 2, entry
3). General method A was employed using the following
quantities: copper hydride [CuH(PPh3)]6 (21.7 mg,
0.01 mmol, 3 mol% Cu), dimethylphenylsilane (0.46 mL,
3.0 mmol, 1.5 equiv.), 2-cyclohexenone (0.20 mL, 2.0 mmol),
4-nitrobenzaldehyde (0.36 g, 2.4 mmol, 1.2 equiv.), and neat
BF3´Et2O (0.30 mL, 2.4 mmol, 1.2 equiv.). Puri®cation by
¯ash chromatography (1:5 EtOAc/hexane) afforded two
aldol diastereomers as a yellow solid (combined yield
0.36 g, 73%). Rfˆ0.10±0.17; IR (thin ®lm) 3428, 2945,
2867, 2362, 2255, 1699, 1605, 1523, 1349, 1096, 909,
3461, 2956, 2926, 2871, 1704, 1463; H NMR (400 MHz,
CDCl3) d 4.97 (m), 4.73 (dt, Jˆ8.4, 2.8 Hz, 1H), 2.21 (m),
1.89 (m), 1.48 (m), 1.31 (h, Jˆ7.2 Hz), 0.96 (t, Jˆ6.8 Hz),
0.91 (m); 13C NMR (100 MHz, CDCl3) d 216.5, 142.5,
140.1, 128.1, 66.4, 42.8, 39.3, 39.2, 29.3, 28.6, 28.4, 27.6,
27.6, 20.1, 13.9, 9.4. Diastereomer 2: Rfˆ0.10; IR (thin
®lm) 3417, 2956, 2926, 2872, 1705, 1462; 1H NMR
(400 MHz, CDCl3) d 5.44 (mq, Jˆ33.0, 8.8, 1.8 Hz, 1H),
4.81 (bt, Jˆ9.0 Hz, 1H), 2.90 (bs, 1H), 2.41 (m, 6H), 1.94
(dd, Jˆ22.1, 1.9 Hz, 3H), 1.76 (bm, 5H), 1.48 (bm, 8H),
1.32 (m, 8H), 0.91 (mt, Jˆ7.3, 6.8 Hz, 15H); 13C NMR
(100 MHz, CDCl3) d 215.9, 144.4, 139.9, 67.2, 53.5, 39.2,
39.1, 31.4, 29.6, 29.4, 29.3, 27.6, 20.8, 20.4, 20.3, 13.9,
9.4; LREIMS (m/z, rel. int.) 443(1), 425(3), 304(12),
1
734, 650; H NMR (400 MHz, CDCl3) [Note: integrations
are not given for combined diastereomers as signals overlap]
d 8.22 (dd, Jˆ2.5, 9.5 Hz, 2H), 7.50 (dd, Jˆ2.0, 9.0 Hz,

B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
2787
248(5), 201(2), 192(2), 177(35), 159(18), 140(28), 121(50),
107(9), 97(23), 84(30), 70(66), 55(70); HREIMS calcd for
(M±Bu, 116Sn) C21H39O2Sn 439.1967, found 439.1953.
49(100), 45(9), 43(31); HREIMS calcd for (M1H)
C20H25O2 297.1854, found 297.1850.
2-(3-Cyclohexenyl-hydroxymethyl)-4,4-dimethylcyclo-
hexanone [Scheme 2, (a)]. General method A was
employed using the following quantities: copper hydride
[CuH(PPh3)]6 (88.0 mg, 0.045 mmol, 18 mol% Cu),
dimethylphenylsilane (0.34 mL, 2.22 mmol, 1.5 equiv.), 4,4-
dimethyl-2-cyclohexenone (0.20 mL, 1.5 mmol), (1,2,3,6)-
tetrahydrobenzaldehyde (0.94 mL, 1.7 mmol, 1.1 equiv.),
and neat BF3´Et2O (0.24 mL, 1.7 mmol, 1.1 equiv.). Puri®ca-
tion by ¯ash chromatography (1:8 Et2O/hexane) afforded two
separable aldol diastereomers as white solids (combined
yield 0.28 g, 80%). IR (neat) 3512, 3455, 3021, 2925,
6-Benzyloxy-4-ethyl-5-hydroxy-3-hexanone (Table 2,
entry 7). General method B was employed using the follow-
ing quantities: toluene (2.5 mL), copper hydride
[CuH(PPh3)]6 (8.0 mg, 0.004 mmol, 2.5 mol% Cu), tetra-
methyldisiloxane (0.25 mL, 1.4 mmol, 1.2 equiv.), trans-
4-hexen-3-one (0.13 mL, 1.17 mmol), benzyloxyacetalde-
hyde (0.20 mL, 1.4 mmol, 1.2 equiv.), and 1.0 M TiCl4
(1.4 mL, 1.4 mmol, 1.2 equiv.). Flash chromatography
(8:2 hexanes/EtOAc) afforded a colorless oil (combined
yield 0.23 g, 79%). IR (thin ®lm) 3466, 2968, 2935, 2875,
1708, 1497, 1456, 1377, 1092, 737, 699. Diastereomer 1: 1H
NMR (400 MHz, CDCl3) d 7.34 (m, 5H), 4.55 (d,
Jˆ11.6 Hz, 1H), 4.52 (d, Jˆ11.6 Hz, 1H), 3.92 (p,
Jˆ5.7 Hz, 1H), 3.51 (dd, Jˆ9.7, 4.4 Hz, 1H), 3.49 (dd,
Jˆ9.7, 5.5 Hz, 1H), 3.11 (d, Jˆ7.0 Hz, 1H), 2.69 (dt,
Jˆ8.6, 5.9 Hz, 1H), 2.52 (m, 2H), 1.62 (m, 3H), 1.00 (t,
Jˆ7.3 Hz, 3H), 0.90 (t, Jˆ7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 216.5, 137.7, 128.7, 128.1, 128.0,
73.8, 73.0, 71.9, 54.8, 38.2, 22.6, 12.1, 7.4. Diastereomer
1
1703. Diastereomer 1: Rfˆ0.11; mpˆ62±638C; H NMR
(500 MHz, CDCl3) d 5.69 (m, 2H), 3.66 (p, Jˆ7.5 Hz,
1H), 3.51 (d, Jˆ4.1 Hz, 1H), 2.61 (p, Jˆ7.5 Hz, 1H), 2.50
(dt, Jˆ14.1, 6.3 Hz, 1H), 2.28 (dq, Jˆ14.3, 2.7, 2.0 Hz, 1H),
2.09 (bm, 4H), 1.86 (bd, Jˆ17.1 Hz, 1H), 1.96 (bm, 5H),
1.42 (t, Jˆ13.3 Hz, 1H), 1.23 (s, 3H), 1.03 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 217.2, 127.2, 126.6, 75.0, 49.0, 43.1,
40.0, 39.3, 35.1, 31.6, 30.8, 26.7, 25.9, 24.7, 24.3.
1
Diastereomer 2: Rfˆ0.05 (mixture of diastereomers); H
1
2: H NMR (400 MHz, CDCl3) d 7.34 (m, 5H), 4.52 (d,
NMR (500 MHz, CDCl3) d 5.66 (m, 2H), 3.93 (d,
Jˆ3.3 Hz, 1H), 3.86 (d, Jˆ3.3 Hz, 1H), 2.71 (dd, Jˆ12.8,
3.3 Hz, 1H), 2.64 (dd, Jˆ12.8, 5.6 Hz, 1H), 2.51(m, 4H),
2.35 (bd, Jˆ17.8 Hz, 1H), 2.25 (m, 1H), 2.05 (bs, 2H), 1.85
(m, 1H), 1.69 (m, 2H), 1.55 (m, 1H), 2.21 (s, 3H), 1.04 (s,
3H); 13C NMR (125 MHz, CDCl3) d 216.0, 128.2, 126.8,
126.2, 125.3, 72.4, 72.3, 48.0, 47.8, 39.8, 38.9, 38.2, 34.8,
34.6, 31.7, 30.5, 29.0, 27.6, 25.7, 24.8, 24.7, 24.6, 24.4;
LRCIMS (CH4) combined diastereomers (m/z, rel. int.)
237(3), 219(29), 201(14.8), 167(4), 155(10), 139(20),
127(100), 109(45), 93(77), 81(18), 59(22); HRCIMS
(CH4) calcd for C15H25O2 237.1854, found 237.1864.
Jˆ12.0 Hz, 1H), 4.51 (d, Jˆ12.0 Hz), 3.97 (p, Jˆ3.3 Hz,
1H), 3.50 (m, 1H), 3.39 (m, 1H), 3.15 (d, Jˆ7 Hz, 1H), 2.75
(m, 1H), 2.50 (m, 2H), 1.62 (m, 3H), 1.01 (t, Jˆ7.3 Hz, 3H),
0.88 (t, Jˆ7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
214.8, 137.6, 128.7, 128.1, 128.0, 73.7, 72.2, 70.9, 55.6,
38.1, 21.3, 12.1, 7.5; LRFABMS (NBA) 251(33), 233(11),
143(100), 115(18), 107(16); HRFABMS (NBA) calcd for
C15H23O (M1H) 251.1647, found 251.1648.
2-Benzyl-3-hydroxy-5-methyl-1-phenyl-1-hexanone
(Table 2, entry 8). General method A was employed using
the following quantities: copper hydride [CuH(PPh3)]6
(24 mg, 0.012 mmol, 5 mol% Cu), phenylsilane (0.20 mL,
1.6 mmol, 1.1 equiv.), trans-chalcone (0.31 g, 1.5 mmol),
isovaleraldehyde (0.26 g, 2.4 mmol, 1.6 equiv.), neat
BF3´Et2O (0.30 mL, 2.4 mmol, 1.6 equiv.). Puri®cation by
¯ash chromatography (1:10 Et2O/hexane) afforded two
separable aldol diastereomers (combined yield 0.317 g,
73%). Diastereomer 1: Rfˆ0.27, colorless oil; IR (thin
®lm) 3481, 3063, 3028, 2955, 2869, 1676; 1H NMR
(500 MHz, CDCl3) d 7.82 (dd, Jˆ7.9, 1.1 Hz, 2H), 7.56
(bt, Jˆ7.2 Hz, 1H), 7.43 (t, Jˆ7.5 Hz, 2H), 7.23 (m, 4H),
7.16 (m, 1H), 3.87 (h, Jˆ4.1 Hz, 1H), 3.74 (h, Jˆ3.9 Hz,
1H), 3.20 (d, Jˆ9.2 Hz, 1H), 3.11 (dd, Jˆ7.5, 4.6 Hz, 2H),
1.8 (m, 1H), 1.44 (m, 1H), 1.19 (m, 1H), 0.83 (dd, Jˆ18.8,
6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 206.7, 139.2,
137.7, 133.7, 129.3, 128.9, 128.7, 128.4, 126.6, 70.8, 52.7,
45.3, 36.6, 25.0, 23.6, 22.0. Diastereomer 2: Rfˆ0.20; white
solid, mpˆ64±668C; IR (KBr) 3460, 3062, 3078, 2956,
2869, 1673; 1H NMR (500 MHz, CDCl3) d 7.97 (dd,
Jˆ8.2, 1.0 Hz, 2H), 7.59 (t, Jˆ7.6 Hz, 1H), 7.44 (t,
Jˆ7.8 Hz, 2H), 7.25 (dd, Jˆ11.9, 7.2 Hz, 4H), 7.19 (m,
1H), 4.14 (h, Jˆ3.4 Hz, 1H), 3.89 (p, Jˆ4.3 Hz, 1H), 3.25
(m, 2H), 2.86 (d, Jˆ33.2 Hz, 1H), 1.95 (h, Jˆ5.8 Hz, 1H),
1.72 (m, 1H), 1.39 (m, 1H), 1.03 (dd, Jˆ8.7, 6.7 Hz, 6H);
13C NMR (125 MHz, CDCl3) d 205.3, 139.2, 139.8, 137.6,
133.4, 129.2, 129.2, 128.7, 128.6, 128.5, 126.3, 70.3, 53.8,
44.1, 33.8, 24.9, 23.7, 22.0; LRCIMS (CH4) (m/z, rel. int.)
279(10), 211(39), 119(8), 105(35), 91(30), 69(23), 51(32),
2-(4-Nitrobenzylhydroxy)-4,4-dimethylcyclohexanone
[Scheme 2, (b)]. General method A was employed using
the following quantities: copper hydride [CuH(PPh3)]6
(98.0 mg, 0.05 mmol, 18 mol% Cu), dimethylphenylsilane
(0.35 ml, 2.28 mmol, 1.5 equiv.), 4,4-dimethyl-2-cyclo-
hexenone (0.19 mL, 1.5 mmol), 4-nitrobenzaldehyde
(0.34 g, 2.2 mmol, 1.5 equiv.), and neat BF3´Et2O
(0.23 mL, 1.8 mmol, 1.2 equiv.). Puri®cation by ¯ash
chromatography (1:2 Et2O/hexane) afforded two separable
aldol diastereomers as white solids (combined yield 0.98 g,
68%); IR (KBr) 3406, 3109, 3056, 2952, 2857, 1693, 1515,
1349. Diastereomer 1: Rfˆ0.17, mpˆ144±1468C; 1H NMR
(500 MHz, DMSO-d6) d 8.18 (d, Jˆ8.4 Hz, 2H), 7.60 (d,
Jˆ8.4 Hz, 2H), 5.46 (d, Jˆ4.67 Hz, 1H), 5.31 (bt,
Jˆ3.9 Hz, 1H), 3.53 (s, 1H), 2.81 (ddd, Jˆ13.2, 5.5,
2.1 Hz, 1H), 2.49 (m, 1H), 2.14 (dt, Jˆ15.3, 3.8 Hz, 1H),
1.65 (t, Jˆ13.5 Hz, 1H), 1.59 (m, 1H), 1.26 (ddd, Jˆ13.1,
5.8, 2.7 Hz, 1H), 1.00 (s, 3H), 0.93 (s, 3H); 13C NMR
(125 MHz, DMSO-d6) d 210.1, 153.2, 146.2, 127.1,
127.2, 122.9, 68.3, 52.0, 38.2, 37.7, 37.4, 31.6, 29.8, 24.1.
Diastereomer 2: Rfˆ0.11, mpˆ146±1488C; 1H NMR
(500 MHz, DMSO-d6) d 8.18 (d, Jˆ8.4 Hz, 2H), 7.60 (d,
Jˆ8.4 Hz, 2H), 5.48 (1H), 1.60 (m, 1H), 1.43 (dt, Jˆ13.6,
4.7 Hz, 1H), 1.30 (dd, Jˆ13.2, 5.0 Hz, 1H), 5.07 (bt,
Jˆ4.9 Hz, 1H), 2.97 (dt, Jˆ13.7, 5.5 Hz, 1H), 2.57 (td,
Jˆ14.1, 5.5 Hz, 1H), 2.07 (dd, Jˆ14.3, 5.2 Hz, 1H), 1.12
(s, 3H), 0.85 (s, 3H); 13C NMR (125 MHz, DMSO-d6) d

2788
B. H. Lipshutz et al. / Tetrahedron 56 (2000) 2779±2788
Tetrahedron Lett. 1998, 39, 3951; Miura, K.; Sato, H.; Tamaki,
K.; Ito, H.; Hosomi, A. Tetrahedron Lett. 1998, 39, 2585; Ito, H.;
Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett.
1998, 38, 8887; Ravasio, N.; Antenori, M.; Gargano, M.;
Mastrorilli, P. Tetrahedron Lett. 1996, 37, 3529; Evans, D.A.;
Fu, G.C. J. Org. Chem. 1990, 55, 5678.
211.0, 151.6, 146.4, 128.1, 122.9, 69.9, 52.5, 42.1, 38.2,
31.2, 30.3, 24.2; LRCIMS (CH4) (m/z, rel. int.) 237(3),
219(29), 201(15), 167(4), 155(10), 139(20), 127(100),
109(45), 93(77), 81(18), 59(22); HRCIMS (CH4) calcd for
(M1H) C15H20O4N 278.1392, found 278.1388.
3-Benzyl-5-benzyloxy-4-hydroxy-2-pentanone (Scheme
3). General method B was employed using the following
quantities; copper hydride [CuH(PPh3)]6 (7.2 mg,
0.004 mmol, 2.2 mol% Cu), polymethylhydroxysilane
(PMHS; 0.08 mL, 1.25 mmol, 1.25 equiv.), trans-4-phenyl-
3-buten-2-one (0.148 g, 1.0 mmol), benzyloxyacetaldehyde
(0.18 mL, 1.3 mmol, 1.3 equiv.), and 1.0 M TiCl4 (1.3 mL,
1.3 mmol, 1.3 equiv.). Puri®cation by ¯ash chromatography
(1:4 EtOAc/hexanes) afforded aldol diastereomers as a
yellow oil (combined yield 0.24 g, 81%). Rfˆ0.20; IR
(thin ®lm) 3438, 3032, 2923, 2866, 2253, 1703, 1643,
1454, 1362, 1102, 909, 732, 650; 1H NMR (400 MHz,
CDCl3) [Note: integrations not given for combined
diastereomers as signals overlap] d 7.30 (m), 7.15 (m),
4.51 (m), 4.02 (m, 1H), 3.89 (m, 1H), 3.52 (m), 3.44 (m),
3.27 (bm, 1H), 3.08 (m, 3H), 2.88 (m, 3H), 2.75 (bm, 1H),
1.93 (s, 3H), 1.86 (s, 3H); 13C NMR (100 MHz, CDCl3) d
213.9, 212.3, 139.4, 138.8, 137.8, 129.1, 128.8, 128.0,
126.7, 126.6, 73.7, 72.8, 71.8, 71.0, 56.9, 55.5, 35.6, 34.5,
32.8; LRFAB (NBA) (m/z, rel. int.) 299(52), 281(8),
219(10), 191(50), 165(10), 115(22); HRFAB (NBA)
(M1H) calcd for C19H22O3 299.3762, found 299.1648.
2. Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett.
1998, 39, 4627.
3. Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291; See also Mahoney, W. S.; Stryker,
J. M. J. Am. Chem. Soc. 1989, 111, 8818; Brestensky, D. M.;
Stryker, J. M. Tetrahedron Lett. 1989, 30, 5677; Stryker, J. M.,
Mahoney, W. S., Daeuble, J. F., Brestensky, D. M. In Catalysis in
Organic Synthesis; Pascoe, W. E., Ed.; Marcel Dekker: New York,
1992; pp 29±44.
4. The amount of catalyst is based on copper for 1/6[CuH(PPh3)]6.
5. Fleming, I. Organocopper Reagents; Taylor, R. J. K., Ed.;
Oxford University Press: Oxford, 1994, pp 257±292.
6. Mori, A.; Fujita, A.; Kajiro, H.; Nishihara, Y.; Hiyama, T.
Tetrahedron 1999, 55, 4573.
7. Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc.
1974, 96, 7503.
8. For an example of an intramolecular conjugate reduction/aldol
sequence of reactions with stoichiometric [CuH(PPh3)]6, see Chiu,
P.; Chen, B.; Cheng, K.F. Tetrahedron Lett. 1998, 39, 9229. See
also Kiyooka, S.; Shimizu, A.; Torii, S. Tetrahedron Lett. 1998, 39,
5237.
9. Heathcock, C. H.; Davidsen, S. K.; Hug, K. T.; Flippin, L. A.
J. Org. Chem. 1986, 51, 3027.
10. Chapdelaine, M. J.; Hulce, M. Org. React. (NY) 1990, 38,
227.
Acknowledgements
We warmly thank the NSF (CHE 97-34813) for support of
our programs, and Prof. Jeff Stryker (University of Alberta)
for his invaluable advice during the course of this study.
11. Pilcher, A. S.; Ammon, H. L.; DeShong, P. J. Am. Chem. Soc.
1995, 117, 5166.
12. This sample still contains unknown impurities, one of which
may be triphenylphosphine oxide, possibly the major contaminant
in the Aldrich samples. This material can be removed by an
additional recrystallization, although this was unnecessary for
our purposes; Stryker, J. M. Personal communication.
13. Curiously, all attempts at conjugate reduction of an a,b-
unsaturated ester or lactone (e.g. methyl cinnamate and coumarin)
were fruitless, as no reaction was observed irrespective of catalyst
amount or silyl hydride.
References
1. For representative methods, see Barrero, A. F.; Alvarez-
Manzaneda, E. J.; Chahboun, R.; Meneses, R. Synlett 1999,
1663; Ikeno, T.; Kimura, T.; Ohtsuka, Y.; Yamada, T. Synlett
1999, 96; Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira,
E. M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473;
Boudjouk, P.; Choi, S.-B.; Hauck, B. J.; Rajkumar, A. B.
14. Cortese, N. A.; Heck, R. F. J. Org. Chem. 1978, 43, 3985.