Thermally accelerated asymmetric hydrosilylations using ligated copper hydride

Article abstract of DOI:10.1139/v05-083

Exposure of a variety of prochiral substrates to [(R)-(-)-DTBM-SEGPHOS]CuH + PMHS under microwave or conventionally heated conditions reduces reaction times for these hydrosilylations from hours to minutes without significant erosion in ee in most cases.

Full text of DOI:10.1139/v05-083

606
Thermally accelerated asymmetric hydrosilylations
using ligated copper hydride1
Bruce H. Lipshutz, Bryan A. Frieman, John B. Unger, and Danielle M. Nihan
Abstract: Exposure of a variety of prochiral substrates to [(R)-(–)-DTBM-SEGPHOS]CuH + PMHS under microwave
or conventionally heated conditions reduces reaction times for these hydrosilylations from hours to minutes without sig-
nificant erosion in ee in most cases.
Key words: asymmetric hydrosilylation, copper hydride, microwave irradiation.
Résumé : Lorsqu’on soumet une variété de substrats prochiraux à l’effet combiné de [(R)-(–)-DTBM-SEGPHOS]CuH
et du PMHS, dans des conditions de chauffage conventionnel oui par micro-ondes, on observe une réduction des temps
de réaction de ces hydrosilylations qui passe d’heures à minutes sans érosion significative des ee, dans la plupart des
cas.
Mots clés : hydrosilylation asymétrique, hydrure de cuivre, irradiation micro-onde.
[Traduit par la Rédaction] Lipshutz et al. 614
Introduction
Copper hydride (CuH) is notoriously heat sensitive (1).
Complexation by ligands, usually phosphines (2), has al-
lowed for its extensive use in synthesis at room temperature
or below for effecting both 1,2- and 1,4-reductions of unsat-
urated carbonyl compounds (3). Since the advent of
“Stryker’s reagent”, [(Ph3P)CuH]6, in 1988 as an especially
useful reductant in synthesis (4a), many variations that alter
the nature of the chelating phosphine (4b, 4c) have provided
opportunities for utilizing CuH in an asymmetric context.
Ligands such as Roche’s 3,5-xylyl-MeO-BIPHEP (5) 1 and
Solvias’ JOSIPHOS analog (6) 2 and, in particular,
Takasago’s DTBM-SEGPHOS (7) 3 have spawned new tech-
nologies for controlling chirality in 1,2-reductions of aryl
ketones (8a) and imines (8b), as well as 1,4-additions of hy-
dride to acyclic (8c) and cyclic ketones (8d), enoates (8e),
and unsaturated lactones (8e).
The innate bias of these ligands is remarkable, as is the
reactivity they impart to CuH. In some cases, substrate-to-
ligand (S:L) ratios over a hundred thousand to one have been
documented (8a, 8d). In all cases reported to date, lower re-
action temperatures have led to higher selectivities. De-
pending upon the substrate, reaction times with S:L ratios in
the more convenient thousands to one range may still require
Me
H
MeO
MeO
P
P
2
2
P(t-Bu)2
PPh2
Fe
1
2
(R)-(S)-PPF-P(t-Bu)2
(R )-3,5-xyl-MeO-BIPHEP
Roche
Solvias
OMe
O
O
P
P
2
O
O
OMe
2
3
(R)-(–)-DTBM-SEGPHOS
Received 7 December 2004. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 11 June 2005.
Takasago
Dedicated with warmth, admiration, and tremendous respect
to Professor Howard Alper, the PI’s former (undergraduate)
mentor at SUNY Binghamton.
hours for consumption of educt. One potential approach to
increasing reaction rates is to take advantage of microwave
irradiation (9). Given that this technique involves a mainly
thermal component, its application to asymmetric CuH-
based hydrosilylations seems counter-intuitive as the ob-
served ees would be expected to drop. Moreover, elevated
temperatures might be expected to decompose CuH at an in-
creased pace and (or) alter ligand composition via oxidative
B.H. Lipshutz,2 B.A. Frieman, J.B. Unger, and
D.M. Nihan. Department of Chemistry and Biochemistry,
University of California, Santa Barbara, CA 93106 USA.
1This article is part of a Special Issue dedicated to Professor
Howard Alper.
2Corresponding author (e-mail: lipshutz@chem.ucsb.edu).
Can. J. Chem. 83: 606–614 (2005)
doi: 10.1139/V05-083
© 2005 NRC Canada

Lipshutz et al.
607
processes due to adventitious oxygen. Notwithstanding these
potential pitfalls, it seemed plausible that the overriding bias
of ligands 1–3 and the rapidity of microwave heating could
lead to fast and efficient hydrosilylations. We now report
that, indeed, such ligand-accelerated reactions can be carried
out in minutes under the influence of mild heating, employ-
ing either microwave irradiation or conventional means,
without significant compromise in enantioselectivities.
nonracemic adduct 5 drops significantly above 80 °C
presumably because of loss of reagent (decomposition is ev-
ident). Interestingly, good selectivity even at the highest
temperature remains. It is noteworthy that at 60 °C, a reac-
tion that normally requires 3 h at room temperature can be
carried out in 10 min with comparable ee. Other solvents
tested at 80 °C include CH2Cl2 and THF. Surprisingly, the
former led to only 10% conversion after 10 min (86.2% ee),
while in THF the reaction was 70% complete. Extending the
time of exposure to microwaves to 15 min afforded com-
plete conversion to the product ketone in 98.0% ee.
O
O
As noted above, these reactions were run at an S:L ratio
of 1000:1. We have tested the same asymmetric hydrosilyl-
ation on isophorone at the 100 000 : 1 level as well (eq. [1]).
Thus, while conventionally the reduction requires ca. 18 h at
room temperature to reach completion, at 60 °C in the mi-
crowave, 95% conversion is achieved within 30 min at simi-
lar concentrations. Allowing another 30 min reaction time
ensures full consumption of educt. At this temperature, the
ee remained at 98%.
R
R
*
cat (L*)CuH
NR
NR
PMHS, solvent
Ar
Ar
*
O
microwaves
O
RO
RO
R
R
*
1% Cu(OAc) •H O
2
O
O
2
0.001% DTBM-SEGPHOS
Table 1. Effect of temperature on asymmetric hydrosilylations
with CuH.
2PMHS, toluene
O
O
cat (DTBM-SEGPHOS)CuH
PMHS
at rt for 18 h:
100% conversion; 99% ee
95% conversion; 98% ee
100% conversion; 98% ee
[1]
at 60 °C + µW for 30 min:
at 60 °C + µW for 60 min:
µW, x °C, 10 min
4
5
Temperature (°C) Conversion (%)
ee (%)
:
S L = 100 000 : 1
60
80
100
120
100
100
73
98.9
97.5
97.2
96.5
Using a microwave temperature limit of 60 °C, other sub-
strates such as enoates, enones, an unsaturated lactone, and
aryl imines were treated with cat. (DTBM-SEGPHOS)CuH–
PMHS. Table 2 summarizes our observations, comparing re-
action times and ees vs. those obtained previously under
conventional conditions (where known). Modest erosion in
observed ees at this higher temperature appears to be a con-
sistent trend, independent of whether the nature of the addi-
tion of hydride is in the 1,4- (entries 1–4) or 1,2- (entry 5)
mode. The option to switch solvents from toluene to more
polar, lower boiling THF is worthy of mention and was, in
fact, needed in the case of an unsaturated lactone (entry 3).
Limited solubility and, hence, incomplete reaction were
averted by employing ethereal media along with an 80 °C
reaction temperature. This combination led smoothly and
quickly to the desired nonracemic lactone in 98.6% ee, a re-
sult that compares remarkably well with the previously ob-
served level of induction (99%) realized under conventional
conditions at 0 °C (8e). Enone A (entry 4) was surprisingly
unreactive to (DTBM-SEGPHOS)CuH–PMHS, returning
only starting material in two separate experiments. Although
WALPHOS 12 gave rise to complete conversion to keto
product B, the ee was not particularly high. Much better re-
sults were obtained using the JOSIPHOS analog 2 as ligand
for CuH (ee 93.5%). The absolute stereochemistry is indi-
toluene
65
80
10
86.2
CH Cl
2
2
80
80
70
100
98.0
98.0
a
THF
Note: Reactions were run at an S:L ratio of 1000:1.
aRun for 15 min.
Results
Initial experiments were conducted on isophorone 4
employing our recently developed “Copper hydride in a
Bottle”,3 where (R)-DTBM-SEGPHOS-chelated CuH is pre-
sumed to function as the catalytically active species. These
trials were aimed at establishing a temperature at which the
enone is quickly consumed. Along with this determination
would also come the evaluation of reagent lifetime and the
potential cost in ee. Temperatures ranging from 60 °C to
120 °C at 20° intervals were examined using a Personal
Chemistry (now Biotage) Emry’s Optimizer microwave in-
strument (Table 1). The data clearly indicate that in toluene,
with increasing temperature, the extent of conversion to
3 The experimental procedure for the preparation of “CuH in a Bottle” is available in the experimental section; B.H. Lipshutz and B.A.
Frieman. Submitted.
© 2005 NRC Canada

608
Can. J. Chem. Vol. 83, 2005
Table 2. Asymmetric hydrosilylations with (L*)CuH under µW irradiation at 60 °C for ≤30 min (L* = a nonracemic ligand).
Microwave reactions
Conventional reactions
a
Yield (%) ee (%)
Entry
Substrate
Product
Ligand
Temp (°C), time (h) ee (%)
O
O
b
1
3
88
97.7
rt, 5
91.0
EtO
EtO
H
Ph
Ph
O
O
O
b
b
3
2
92
31
90.9
89.6
91.6
90.0
98.0
0, 4
0, 6
Ph
Ph
2
3
EtO
EtO
H
c
12
68
O
d
b
O
O
3
94
98.6
0, 3
99.0
Ph
Ph
H
O
O
12
2
91
87
84.5
93.5
4
5
H
Ph
Ph
A
B
O
O
Ar
Ar
P
P
e
HN
92
95.7
rt, 17
97.3
3
N
F3C
F3C
Note: Run in toluene using PMHS (2 equiv.) as stoichiometric source of hydride. All were worked up using aqueous base to hydrolyze
residual silane. t-BuOH (1–2 equiv.) was used in each reaction to enhance the rate of (L*)CuH regeneration.
aIsolated, chromatographically purified materials.
bcf. Reference 8e.
cConversion was 71%.
dRun in THF.
ecf. Reference 8b.
cated for known products shown in entries 1–3 and 5, while
that for B was tentatively assigned on the basis of previous
data on related enones (8c).
O
P
6% CuCl, 6% NaO-t-Bu
Acetophenone-derived imine 6 (eq. [2]), which, using mi-
crowave conditions at 60 °C, gave product 7 possessing
an ee of 91.3%, was examined by conventional heating at
60 °C. Thus, the premixed catalyst–silane was added to a
round-bottom flask, to which was added the imine immedi-
ately prior to placement in a preheated oil bath at 60 °C. Af-
ter the same 30 min interval, workup and analysis by chiral
HPLC indicated that the reaction had gone to completion
and that the ee was 90.5%. Thus, as had been noted previ-
ously by Leadbeater and Marco (10), rapid conventional
heating of reaction mixtures can on occasion give essentially
the same results observed under microwave irradiation. Such
appears to be the case with these asymmetric hydrosilyl-
ations when run in toluene.
6% DTBM-SEGPHOS
N
2TMDS, toluene
6
[2]
O
P
Ar
Ar
HN
7
µW, 30 min
60 °C, 30 min
91.3% ee
90.5% ee
Test reactions on cinnamate 8 (Table 3) were performed to
assess the background reaction using Stryker’s reagent as the
source of CuH, rather than the in situ procedures based on
© 2005 NRC Canada

Lipshutz et al.
609
Table 3. Impact of Ph3P on asymmetric hydrosilylations with CuH.
Table 4. Asymmetric hydrosilylations using CuH chelated by
various ligands.
cat source of CuH
O
O
DTBM-SEGPHOS
EtO
EtO
cat Cu(OAc) •H O, L*
2
2
PMHS, toluene, t-BuOH
µW, 60 °C, 20 min
H
Ph
Ph
PMHS, toluene, t-BuOH
µW, 60 °C, 20 min
O
O
O
MeO
MeO
8
9
10
source of CuH
Cu(OAc) •H O
CuH : ligand : substrate
ee (%)
H
H
1 : 1 : 1000
1 : 1 : 1000
10 : 1 : 1000
97.7
96.2
84.5
2
2
*
*
[(Ph P)CuH]
3
6
6
[(Ph P)CuH]
3
O
O
OH
MeO
11
ee (%)
C
either CuCl + NaO-t-Bu (11) or Cu(OAc)2·H2O (12), which
do not contain Ph3P in solution. As illustrated, a 60 °C reac-
tion temperature at an S:L ratio of 1000:1 causes an increase
in the extent to which achiral (Ph3P)CuH competes for sub-
strate, with the ee of product ester 9 dropping from 97.7 to
96.2. Using 1% rather than 0.1% of Stryker’s reagent (i.e.,
an S:L = 100:1) causes a significant loss in selectivity (ee =
84.5%). Thus, as the temperature at which these asymmetric
reductions are run goes up, the presence of Ph3P should be
avoided.
Other combinations of copper hydride and nonracemic
ligands were also tested using coumarin derivative 10 (Ta-
ble 4). This substitution pattern for an enoate has not previ-
ously been examined within the context of CuH-based
asymmetric hydrosilylation chemistry. On first inspection, it
was anticipated from prior art (8e) that its Z-cinnamate-like
structure dictates that DTBM-SEGPHOS (3) would be the
ligand of choice. When the reaction of 10 was run under
conventional conditions using CuH ligated by this ligand at
ambient temperature, the unexpected product of over-
reduction, 11, was obtained in 94% ee. In addition to
DTBM-SEGPHOS, JOSIPHOS analog 2 and WALPHOS
(12)4 were screened, as were Sannicolo and co-workers’s
BITIANP (13) (13) and Boaz et al.’s BOPHOZ (14) (14) lig-
ands. Unexpectedly, microwave experiments indicated that
the ferrocenyl backbone common to 2 and 12 imparted the
greatest enantioselectivities, significantly exceeding that ob-
served with ligand 3. The sense of induction for ligands 2
and 3 is the same, presumably affording the S-isomer from
this Z-configured educt, while ligands 12–14 led to the
enantiomeric product, as indicated by chiral capillary GC
analyses.
Ligand (L*)
(R)-(S)-PPF-P(t-Bu)
(2)
(3)
(12)
(13)
(14)
96.7
90.0
94.6
85.3
6.0
2
(R)-DTBM-SEGPHOS
WALPHOS
BITIANP
BOPHOZ
conventional reaction:
cat (DTBM-SEGPHOS)CuH
rt, 7-8 h; 94% ee
CF3
Me
S
H
Ph P
2
P
CF3
Fe
Ph2P
12 (R)-(R)-WALPHOS
2
PPh
2
S
13 S-(–)-BITIANP
Me
Me
H
N
PPh2
Fe
PPh2
14 (R)-( )-BoPhoz
S
contain only trace amounts of the reactive catalyst relative to
substrate.
Discussion
Given the history of copper hydride itself, dating back to
Wurtz’ report in 1844 (1a), it is not surprising that applica-
tions of ligated CuH at elevated temperatures have not previ-
ously been considered. Chelation by modern nonracemic
bidentate phosphine ligands appears to induce not only an
extreme stereochemical bias in reactions of CuH, but adds
an unexpected element of stability such that mild heating of
reaction mixtures is well tolerated, including those that may
Our approach to heating these reactions, at least initially,
was to utilize microwave irradiation. This special, highly
controlled technique, when applied within the confines of
the Biotage instrument,5 was anticipated to allow for reac-
tion temperatures above the boiling point of the solvents to
be used, along with the associated elevation in pressures.
From the outset, however, as illustrated by the data in Ta-
ble 1, it was clear that heating beyond 80 °C, which is well
4 (R)-(R)-Ph2PPhFcCHCH3P(3,5-CF3Ph)2; Available from Solvias, Basel Switzerland (SL-W001–1; CAS Reg. No. 387868–06–6; cf. http://
www.solvias.com.
5 The Personal Chemistry Emrys Optimizer has been replaced by the Biotage Initiator; cf. http://www.biotagedcg.com/
DynPage.aspx?id=4193&mn1=919&mn2=1149.
© 2005 NRC Canada

610
Can. J. Chem. Vol. 83, 2005
below the boiling point of the reaction solvent toluene, was
not viable. Nonetheless, in going from even room tempera-
ture to 60–80 °C, normal accelerations in rates were ob-
served, while the intrinsic stereochemical bias imposed by
the chelating phosphine ligand was not significantly com-
promised. The fact that essentially the same results (i.e., ex-
tent of conversion and observed ee; cf. eq. [2]) could be
obtained by conventional heating strongly suggest that in
this case, although far more convenient, microwave irradia-
tion adds little to the chemistry. It is appreciated, however,
that toluene is not likely to be the universal solvent for all
substrate types. The switch to lower boiling THF would rely
on the controlled temperature and pressure found under mi-
crowave conditions (cf. Table 1, last entries, and Table 2,
entry 3). Although CH2Cl2 was surprisingly ineffective, re-
actions run in several other solvents that are lower boiling
than toluene (bp 110 °C) can easily be envisioned to benefit
from a microwave environment.
The interplay between substrate and the choice of ligand
on CuH, especially under the influence of applied heat, could
not have been predicted. Thus, while educt 10 had not previ-
ously been subjected to copper-hydride-based asymmetric
hydrosilylation, all prior efforts on cinnamate enoates (8e,
15) pointed to DTBM-SEGPHOS 3 as the ligand that consis-
tently affords extremely high levels of induction. JOSIPHOS
analog 2 is also quite selective in such cases (8e) but typi-
cally is best utilized for β,β-dialkyl-substituted enoates.
Thus, it was interesting to observe that both ferrocenyl-
based ligand systems 2 and WALPHOS 12 led to signifi-
cantly higher levels of enantioselectivity than did 3 (cf. Ta-
ble 4). Curiously, the inverse of this observation, that a
β,β-dialkyl-substituted enoate would best be reduced by
(DTBM-SEGPHOS)CuH, as opposed to PPF-P(t-Bu)2 2 (cf.
Table 2, entries 2 and 3), is also unexpected. These cross-
over results may reflect subtle changes in the degree of asso-
ciation of the ligand with CuH at varying temperatures, po-
tential aggregation state issues, and (or) the likely impact of
both steric and stereoelectronic factors in (L* = a nonracemic
ligand)CuH that may be influential even when differences
between educts are otherwise structurally quite small. Sec-
ond-stage reduction, in this case of the initially formed
lactone C, has not been observed previously with enoates or
unsaturated lactones (8e, 15). Presumably this results from
rapid quenching of the copper enolate by t-BuOH, followed
by 1,2-reduction. None of the intermediate lactone was ob-
served in the course of this asymmetric hydrosilylation.
What can be claimed from this study, in general, is that
the increase in reaction rates gained upon mild heating to ca.
60 °C reduces the times for these asymmetric hydrosilyl-
ations to well under an hour, even where S:L ratios are in the
thousands-to-one category. Several commonly studied sub-
strate types successfully participate, and ees remain well
within the synthetically useful range.
or [(R)-(S)-PPF-P(t-Bu)2]CuH via either microwave or
conventional means can be tolerated and that a variety of
synthetically useful 1,2- and 1,4-reductions can be realized
in both good yields and excellent levels of stereoinduction.
Experimental section
General
Reactions were performed in oven-dried glassware under
an argon atmosphere containing a Teflon coated stir bar and
dry septum. Toluene, dichloromethane, and THF were used
as is from an Innovative Technology, Inc. solvent filtration
system. All commercially available reagents were distilled
either from CaH2 or molecular sieves under an inert atmo-
sphere before use. CuCl, NaO-t-Bu, NaOMe, PPh3, iso-
phorone, and acetophenone oxime were purchased from
Aldrich. Other oximes were prepared from the correspond-
ing ketones following a literature procedure (2). Chloro
bis(3,5-dimethylphenyl)phosphine was prepared according
to a literature procedure (3). Phosphinylimines were pre-
pared from the corresponding oximes by modification of a
literature procedure (4). Cu(OAc)2·H2O, was purchased from
Acros. Tetramethyldisiloxane was purchased from Alfa
Aesar. Poly(methylhydrosiloxane) was purchased from Lan-
caster. Stryker’s reagent was prepared by the general proce-
dure (4). (R)-(–)-DTBM-SEGPHOS was generously supplied
by Takasago International Corp. All microwave experiments
were performed using Personal Chemistry Emry’s Optimizer
in 0.5–2 mL or 2–5 mL Pyrex reaction vessels that were
flame dried under an argon atmosphere. Each reaction vessel
contained a Teflon stir bar and a Teflon coated reaction ves-
sel cap. Optical rotations were measured on a PerkinElmer
341 Polarimeter. HPLC analyses were performed on a
Rainan Dynamax UV-1 with an HPXL solvent delivery
system. GC analyses were performed on a Hewlett-Packard
6890 Series GC. GC analyses were carried out using an HP-
5 capillary column (0.25 µm × 30 m; cross-linked 5% PH
ME siloxane) and a time program beginning with 5 min at
50 °C, followed by a 20 °C/min ramp to 280 °C, then
20 min at this temperature. Column chromatography was
performed using Davisil Grade 633 Type 60A silica gel.
TLC analyses were performed on commercial Kieselgel
60 F254 silica gel plates. NMR spectra were obtained on
Varian Inova systems using CDCl3 or C6D6 as solvent, with
proton and carbon resonances at 400 MHz and 100 MHz, re-
spectively. FT-IR spectra were obtained on an ATI Mattson
Infinity series spectrometer neat on NaCl plates or KBR pel-
lets and are reported in cm–1. Mass spectral data were ac-
quired on a VF Autospec or an analytical VG-70-250 HF
instrument.
Preparation of [(R)-(–)-DTBM-SEGPHOS]CuH in a
Bottle (0.001 mol/L)
An oven-dried poly-coated amber glass bottle equipped
with stir bar was purged under argon and brought into the
glove box. Cu(OAc)2·H2O (10 mg, 0.05 mmol) and (R)-
DTBM-SEGPHOS (3, 59 mg, 0.05 mmol) were added, fol-
lowed by dry toluene (44 mL), and the mixture was allowed
to stir for 2 h at room temperature (rt). PMHS (6 mL) was
added dropwise, and the mixture was allowed to stir for
Conclusions and summary
The first study on the potential for microwave irradiation
to be used to accelerate rates of asymmetric hydrosilylations
by catalytic amounts of nonracemically ligated CuH is de-
scribed. The results indicate that mild heating of reactions
containing either complex [(R)-(–)-DTBM-SEGPHOS)]CuH
© 2005 NRC Canada

Lipshutz et al.
611
30 min. The amber bottle was then sealed using a standard
“sure–seal cap” and stored at 4 °C or rt.
reaction was quenched by diluting with THF (5 mL), fol-
lowed by aqueous NaOH (5 mL, 3 mol/L), and was allowed
to stir at rt for 2 h. The reaction was analyzed by GC to con-
tain only product without any isophorone or byproducts;
Chiral GC using a Chiraldex B-DM column with 75 °C iso-
therm showed 98% ee, Rt = 41.47 (minor) and 44.94 (ma-
jor). The product spectral data matched previously reported
spectral data (8d).
(R)-3,3,5-Trimethylcyclohexanone (5; Table 1, entry 1)
To a 2–5 mL Emry’s Optimizer glass vessel, flame dried
and purged with argon, was added (DTBM-SEGPHOS)CuH
in a Bottle (2 mL, 0.001 mol/L, 0.002 mmol). Isophorone
(300 µL, 2 mmol) was added neat, and the reaction was im-
mediately taken to the Emry’s Optimizer. The following con-
ditions were applied: temperature, 60 °C; time, 600 s; fixed
hold time, on; sample absorption, normal; pre-stirring, 10 s.
The reaction was quenched by diluting the reaction with
THF (5 mL), followed by aqueous NaOH (5 mL, 3 mol/L),
and the reaction was allowed to stir at rt for 2 h. The product
was isolated as a colorless liquid; Chiral GC using a
Chiraldex B-DM column with 75 °C isotherm showed
98.9% ee, Rt = 41.47 (minor) and 44.94 (major). The prod-
uct spectral data matched previously reported spectral data
(8d).
(R)-N-(1-Phenylethyl) bis(3,5-
dimethylphenyl)phosphinamide (7; eq. [2])
CuCl (3.6 mg, 0.036 mmol), NaOMe (2.0 mg,
0.038 mmol), and (R)-DTBM-SEGPHOS (3, 42.6 mg,
0.036 mmol) were placed into a flame-dried, argon-purged
round-bottom flask (RBF). Toluene (1.5 mL) was added to
the RBF, and the resulting mixture was stirred at rt for
30–40 min. Meanwhile, N-(1-phenylethylidene) bis(3,5-
dimethylphenyl)phosphinamide (75.1 mg, 0.200 mmol) was
added to a 0.5–2.0 mL Emry’s Optimizer glass vessel, which
had been flame dried and purged with argon. t-BuOH
(50 µL, 0.55 mmol) and toluene (450 µL) were added and
allowed to stir for 5 min until the solution became homoge-
neous. The RBF was charged with tetramethyldisiloxane
(TMDS; 0.318 mL, 1.6 mmol) and allowed to stir for
10 min. After this time, the CuH mixture (618 µL) was
slowly added to the glass vessel via syringe, and the reaction
was immediately taken to the Emry’s Optimizer. The follow-
ing conditions were applied: temperature, 60 °C; time,
1800 s; fixed hold time, on; sample absorption, normal.
MeOH (1 mL) was slowly added, and after 30 min, 1 mol/L
NaOH in MeOH (0.5 mL) was added. The mixture was
stirred for 2–3 h, filtered through a plug of silica, and con-
centrated under vacuum. Purification by silica gel chroma-
tography (10% acetone–CH2Cl2) gave the corresponding
phosphinylamine (71 mg, 94% yield) as a white solid. HPLC
analysis indicated 91.3% ee. (Daicel Chiralcel OD, hexane :
isopropyl alcohol, 90:10, 1.0 mL/min, 220 nm; Rt = 5.3 min
(R), 6.7 min (S)). The product spectral data matched previ-
ously reported spectral data (8b).
(R)-3,3,5-Trimethylcyclohexanone (temperature study;
Table 1)
To a 2–5 mL Emry’s Optimizer glass vessel that had been
flame dried and purged with argon was added (DTBM-
SEGPHOS)CuH in
a Bottle (2 mL, 0.001 mol/L,
0.002 mmol). Isophorone (300 µL, 2 mmol) was added neat,
and the reaction was immediately submitted to the Emry’s
Optimizer. The following conditions were applied: tempera-
ture, 60–120 °C; time, 600 s; fixed hold time, on; sample ab-
sorption, normal; pre-stirring, 10 s. Upon completion, the
reaction was quenched by diluting with THF (5 mL) fol-
lowed by aqueous NaOH (5 mL, 3 mol/L) and then allowed
to stir at rt for 2 h. The product was analyzed by GC to de-
termine the conversion; Chiral GC using a Chiraldex B-DM
column with 75 °C isotherm was used to determine the ee.
For the cases with dichloromethane and THF, the same pro-
tocol was used to prepare the CuH in a Bottle.
(R)-3,3,5-Trimethylcyclohexanone (100 000 : 1; eq. [1])
(a)
(R)-N-(1-Phenylethyl) bis(3,5-dimethyl-
To a flame-dried, 500 mL, round-bottom flask equipped
with stir bar and purged with argon was added CuCl
(167.9 mg, 1.69 mmol), NaO-t-Bu (163 mg, 1.69 mmol),
and (R)-DTBM-SEGPHOS (3, 2 mg, 1.695 × 10–3 mmol),
followed by toluene (100 mL). The reaction was allowed to
stir for 30 min at rt. PMHS (20.35 mL, 339.12 mmol H–)
was added dropwise via syringe and allowed to stir for
10 min. Isophorone (25.47 mL, 169.5 mmol) was then added
dropwise, and the reaction was monitored by TLC. The reac-
tion was complete in 18 h at rt, as indicated by TLC and
GC.
phenyl)phosphinamide, conventional heating (7; eq. [2])
CuCl (3.6 mg, 0.036 mmol), NaOMe (2.0 mg,
0.038 mmol), and (R)-DTBM-SEGPHOS (3, 42.6 mg,
0.036 mmol) were placed into a flame-dried, argon-purged
round-bottom flask (RBF). Toluene (1.5 mL) was added to
the RBF, and the resulting mixture was stirred at rt for 30–
40 min. Meanwhile, N-(1-phenylethylidene) bis(3,5-
dimethylphenyl)phosphinamide (75.1 mg, 0.200 mmol) was
added to a 10 mL RBF, flame dried and purged with argon.
t-BuOH (50 µL, 0.55 mmol) and toluene (450 µL) were
added and allowed to stir for 5 min until the solution became
homogeneous. The RBF was charged with tetramethyl-
disiloxane (TMDS; 0.318 mL, 1.6 mmol) and allowed to stir
for 10 min. After this time, the CuH mixture (618 µL) was
slowly added to the RBF via syringe, and the reaction was
immediately placed into a preheated oil bath at 60 °C. After
30 min, MeOH (1 mL) was slowly added, and after 30 min,
1 mol/L NaOH in MeOH (0.5 mL) was added. The mixture
was stirred for 2–3 h, filtered through a plug of silica, and
concentrated under vacuum. Purification by silica gel chro-
(b)
As soon as the isophorone was added, 2 mL from the
above reaction was syringed into a 2–5 mL Emry’s
Optimizer dry glass vessel under argon. The vessel was
quickly introduced into the Emry’s Optimizer, where the fol-
lowing reaction conditions were applied: temperature, 60 °C;
time, 3600 s; fixed hold time, on; sample absorption, nor-
mal; pre-stirring, 10 s. After the 60 min reaction period, the
© 2005 NRC Canada

612
Can. J. Chem. Vol. 83, 2005
matography (10% acetone–CH2Cl2) gave the corresponding
phosphinylamines (70 mg, 93% yield) as a white solid.
HPLC analysis indicated 90.5% ee. (Daicel Chiralcel OD,
hexane : isopropyl alcohol, 90:10, 1.0 mL/min, 220 nm; Rt =
5.3 min (R), 6.7 min (S)). The product spectral data matched
previously reported spectral data.
(7.6 mL) and stirred at rt for 0.5 h. PMHS (2.4 mL,
40 mmol) was then added dropwise to the mixture via sy-
ringe. To a 2–5 mL Emry’s Optimizer glass vessel, flame
dried and purged with argon, was added 4-phenylfuran-
2(5H)-one (80 mg, 0.50 mmol), CuH catalyst solution
(0.5 mL), and t-BuOH (0.06 mL, 0.60 mmol). This solution
was immediately transferred to the microwave and heated at
80 °C for 30 min. The reaction was quenched by diluting
with ether (3 mL), followed by aqueous NaHCO3 (3 mL),
and then allowed to stir at rt for 0.5 h. The product lactone
(75 mg, 93%) was isolated as a white solid; Chiral GC using
a Chiraldex G-TA column with 160 °C isotherm showed
98.6% ee, Rt = 74.01 (minor) and 75.00 (major). The prod-
uct matched previously reported spectral data (8e).
(S)-Ethyl 3-phenylbutanoate (9; Table 2, entry 1)
To a 2–5 mL Emry’s Optimizer glass vessel, flame dried
and purged with argon, was added (E)-ethyl 3-methyl-5-
phenylpent-2-enoate (neat, 0.380 mg, 2 mmol). (DTBM-
SEGPHOS)CuH in
a Bottle (2 mL, 0.001 mol/L,
0.002 mmol) was added via syringe followed by t-BuOH
(230 µL, 2.4 mmol), and the reaction was immediately taken
to the Emry’s Optimizer. The following conditions were ap-
plied: temperature, 60 °C; time, 1200 s; fixed hold time, on;
sample absorption, normal. The TLC (9:1, hexanes:Et2O)
showed complete consumption of starting material. The re-
action was quenched by diluting with THF (3 mL), followed
by aqueous NaOH (2 mL, 3 mol/L), and was allowed to stir
at rt for 2 h. The residue was purified by column chromatog-
raphy and isolated (338 mg, 88% yield) as a clear oil; Chiral
GC using a Chiraldex G-TA column with 100 °C isotherm
showed 97.2% ee, Rt = 77.79 (minor) and 78.70 (major).
The product spectral data matched previously reported spec-
tral data (8e).
4-Phenylpentan-2-one (B, Table 2, entry 4)
To a 25 mL round-bottom flask, flame dried and purged
under argon, was added CuCl (10 mg, 0.10 mmol), NaO-t-
Bu (9.7 mg, 0.10 mmol), and (R,S)-PPF-P(t-Bu)2 JOSIPHOS
(5.2 mg, 0.01 mmol) under an argon atmosphere. The flask
was sealed with a rubber septum and toluene (8.7 mL, dried
through a column of alumina and degassed via 3 freeze–
thaw cycles) was added with a dry glass syringe. The solu-
tion was stirred at rt for 45 min, at which point PMHS
(1.3 mL, 0.73 mmol) was added. After 15 min of stirring,
0.87 mL of the solution was transferred via syringe to an
Emry’s Optimizer glass vessel (sealed and under argon) con-
taining a dry stir bar and 4-phenylpent-3-en-2-one (A,
140 mg, 0.87 mmol). t-BuOH (0.1 mL, 1.05 mmol) was
added, and the vial was immediately taken to the Emry’s
Optimizer. The following conditions were applied: tempera-
ture, 60 °C; time, 1500 s; fixed hold time, on. Upon ejection
of the reaction vial from the optimizer, the septum was re-
moved, and the reaction mixture poured into sat. NaHCO3
(15 mL), where it was stirred for 3 h. The organic layer was
extracted with diethyl ether (3 × 15 mL), washed with brine
(1 × 15 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. Purification via silica gel
chromatography (20 g, 5% Et2O in hexanes) yielded a clear
oil (124 mg, 87% yield). Chiral GC using a Chiraldex G-TA
column with 100 °C isotherm showed 93.5% ee, Rt = 51.40
(minor) and 53.00 (major). IR (neat) (cm–1): 3035, 2964,
2927, 1716, 1495, 1358, 760, 700. 1H NMR (400 MHz,
CDCl3) δ: 7.28–7.35 (m, 2H), 7.18–7.25 (m, 3H), 3.27–3.38
(m, 1H), 2.68 and 2.76 (dd, J = 6.4 Hz, 2H), 2.08 (s, 3H),
1.28 (d, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ:
22.17, 30.75, 35.58, 52.13, 126.48, 126.92, 128.71, 146.44,
208.08. EI-MS m/z (%): 162 ([M]+, 52), 147(81), 119(16),
105(100), 91(47), 77(29), 51(17). HR-EI-MS calcd. for
C11H14O: 162.1044; found 162.1051.
(S)-Ethyl 3-methyl-5-phenylpentanoate (Table 2, entry 2)
To a 25 mL round-bottom flask, flame dried and purged
under argon, was added CuCl (4.2 mg, 0.042 mmol), NaO-t-
Bu (3.7 mg, 0.039 mmol), and (R)-DTBM-SEGPHOS (3,
4.7 mg, 0.004 mmol) under an argon atmosphere. The flask
was sealed with a rubber septum, and toluene (3.5 mL, dried
through a column of alumina and degassed via 3 freeze–
thaw cycles) was added with a dry glass syringe. The solu-
tion was stirred at rt for 45 min, at which point PMHS
(0.5 mL, 0.279 mmol) was added. After 15 min of stirring,
1 mL of the solution was transferred via syringe to an
Emry’s Optimizer glass vial (sealed and argon purged) con-
taining a dry stir bar and ethyl 3-methyl-5-phenylpent-2-
enoate (218 mg, 1.0 mmol). t-BuOH (0.11 mL, 1.2 mmol)
was added, and the vial was immediately taken to the
Emry’s Optimizer. The following conditions were applied:
temperature, 60 °C; time, 1500 s; fixed hold time, on. Upon
ejection of the reaction vial from the optimizer, the septum
was removed and the reaction mixture poured into sat.
NaHCO3 (15 mL), where it was stirred for 4 h. The organic
layer was extracted with diethyl ether (3 × 15 mL), washed
with brine (1 × 15 mL), dried over anhydrous Na2SO4, and
then concentrated under reduced pressure. Purification via
silica gel chromatography (10 g, 2.5% Et2O in hexanes)
yielded a clear oil (206 mg, 93.6% yield). Chiral GC using a
Chiraldex G-TA column with 95 °C isotherm showed 94.6%
ee, Rt = 277.00 (minor) and 279.46 (major). The product
spectra matched previously reported spectral data (8e).
(R)-N-(1-(4-Trifluoromethylphenyl)ethyl) bis(3,5-
dimethylphenyl)phosphinamide (Table 2, entry 5)
CuCl (3.6 mg, 0.036 mmol), NaOMe (2.0 mg,
0.038 mmol), and (R)-DTBM-SEGPHOS (3, 42.6 mg,
0.036 mmol) were placed into a flame-dried, argon-purged
round-bottom flask (RBF). Toluene (1.5 mL) was added to
the RBF, and the resulting mixture was stirred at rt for 30–
40 min. Meanwhile, N-(1-(4-trifluoromethylphenyl)ethyl-
idene) bis(3,5-dimethylphenyl)phosphinamide (88.6 mg,
0.20 mmol) was added to a 0.5–2.0 mL Emry’s Optimizer
(R)-Dihydro-4-phenyl-(3H)-furan-2-one (Table 2, entry 3)
A
standard solution of (R)-(DTBM-SEGPHOS)CuH
(10 mL, 0.001 mol/L) was prepared as follows:
Cu(OAc)2·H2O (2.0 mg, 0.010 mmol) and (R)-DTBM-
SEGPHOS (11.8 mg, 0.010 mmol) were dissolved in THF
© 2005 NRC Canada

Lipshutz et al.
613
glass vessel, flame dried, and purged with argon. t-BuOH
(50 µL, 0.55 mmol) and toluene (450 µL) were added and
allowed to stir for 5 min until the solution became homoge-
neous. The RBF was charged with tetramethyldisiloxane
(TMDS; 0.318 mL, 1.60 mmol) and was allowed to stir for
10 min. After 10 min, the CuH mixture (618 µL) was slowly
added to the glass vessel via syringe, and the reaction was
immediately taken to the Emry’s Optimizer. The following
conditions were applied: temperature: 60 °C; time, 1800 s;
fixed hold time, on; sample absorption, normal. MeOH
(1 mL) was slowly added and after 30 min 1 mol/L NaOH in
MeOH (0.5 mL) was added. The mixture was stirred for 2–
3 h, filtered through a plug of silica, and concentrated under
vacuum. Purification by silica gel chromatography (10%
acetone–CH2Cl2) gave the corresponding phosphinylamines
(82 mg, 92% yield) as a white solid. To a solution of the
phosphinyl amine was added methanol (2 mL), followed by
HCl (0.5 mL, 5 mol/L in IPA) at rt, and this was allowed to
stir overnight. The mixture was extracted with Et2O (3 ×
10 mL) and washed with H2O (3 × 10 mL). To the aqueous
layer containing the ammonium salt was then added NaOH
(10 mL, 5 mol/L), and the product was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were
dried over anhydrous Na2SO4 and evaporated in vacuo. The
amine was analyzed to be 95.7% ee by Chiral GC using a
Chiraldex-GTA column with 90 °C isotherm, Rt = 14.75 (S)
and 15.21 (R). The product matched previously reported
spectral data (8b).
(1.75 mL). The mixture was allowed to stir for 30 min, fol-
lowed by dropwise addition of PMHS (240 µL, 4 mmol H–),
and the reaction was then stirred for 20 min. The CuH was
transferred via cannula into the enoate, followed by addition
of t-BuOH (230 µL, 2.4 mmol). The reaction vessel was im-
mediately introduced into the Emry’s Optimizer. The fol-
lowing conditions were applied: temperature, 60 °C; time,
1200 s; fixed hold time, on; sample absorption, normal. The
reaction was quenched by diluting with THF (3 mL), fol-
lowed by aqueous NaHCO3 (2 mL), and was allowed to stir
at rt for 2 h. The reaction mixture was pushed through a
plug of silica to discard the ligand. Chiral GC using a
Chiraldex G-TA column with 100 °C isotherm showed the
titled product to have 84.5% ee, Rt = 77.79 (minor) and
78.70 (major).
(S)-3,4-Dihydro-7-methoxy-4-methylchromen-2-one (11);
ligand study (Table 4)
To a 2–5 mL Emry’s Optimizer glass vessel, flame dried
and purged with argon, was added 7-methoxy-4-methyl-
coumarin (neat, 190.2 mg, 1 mmol). Toluene (3 mL) was
added to the coumarin followed by (R)-(DTBM-
SEGPHOS)CuH in a Bottle (1 mL, 0.001 mol/L in PhMe,
0.001 mmol). The corresponding reagents from ligands 2,
12, 13, or 14 were made as described above, followed by ad-
dition of t-BuOH (115 µL, 1.2 mmol). The reaction vessel
was immediately taken to the Emry’s Optimizer. The follow-
ing conditions were applied: temperature, 60 °C; time, 1200 s;
fixed hold time, on; sample absorption, normal. Each reaction
(all of which went to completion) was quenched by diluting
with THF (3 mL), followed by aqueous NaHCO3 (2 mL),
and was allowed to stir at rt for 2 h. The residue was pushed
through a plug of silica and analyzed by chiral GC, and the
product showed the ees listed in Table 4, which were found
using a Chiraldex-GTA column with 120 °C isotherm, Rt =
114.85 (minor) and 115.31 (major). Product 11 is extremely
unstable and is a mixture of cis and trans isomers at rt, as
(S)-Ethyl 3-phenylbutanoate (9) using 0.1% Stryker’s
catalyst (Table 3, entry 2)
To a 2–5 mL Emry’s Optimizer glass vessel, flame dried
and purged with argon, was added the (E)-ethyl 3-methyl-5-
phenylpent-2-enoate (neat, 0.380 mg, 2 mmol). To a 10 mL
round-bottom flask (RBF), flame dried and purged with
argon was added (R)-DTBM-SEGPHOS (3, 2.3 mg,
0.002 mmol) and Stryker’s reagent (0.6 mg, 0.002 mmol),
followed by toluene (1.75 mL). The mixture was allowed to
stir for 30 min. Following dropwise addition of PMHS
(240 µL, 4 mmol H–), the reaction was stirred for 20 min.
The CuH was transferred via cannula into the enoate, fol-
lowed by addition of t-BuOH (230 µL, 2.4 mmol). The reac-
tion vessel was immediately taken to the Emry’s Optimizer.
The following conditions were applied: temperature, 60 °C;
time, 1200 s; fixed hold time, on; sample absorption, nor-
mal. The reaction was quenched by diluting with THF
(3 mL), followed by aqueous NaHCO3 (2 mL), and was al-
lowed to stir at rt for 2 h. The reaction mixture was pushed
through a plug of silica to discard the ligand. Chiral GC us-
ing a Chiraldex G-TA column with 100 °C isotherm showed
the titled product to have 96.2% ee, Rt = 77.79 (minor) and
78.70 (major).
1
described by Goldsmith et al. (16). H NMR (400 MHz,
C6D6) δ: 6.99–6.97 (m, 1H), 6.68–6.63 (m, 1H), 6.60–6.56
(m, 1H), 5.24 (dt, J = 2.5, 6.8 Hz, 1H), 3.34 (s, 3H), 3.01
(tq, J = 6.8, 7.1 Hz, 1H), 2.43 (d, J = 7.1 Hz, 2H), 1.05 (d,
J = 6.8 Hz, 3H). 13C NMR (100 MHz, C6D6) δ: 160.50,
153.52, 108.25, 108.08, 102.76, 102.56, 92.07, 55.16, 36.51,
24.16, 20.81. EI-MS m/z (%): 194 ([M]+, 40), 179(21),
177(73), 151(100), 89(58), 61(54), 43(48). HR-EI-MS m/z
calcd. for C11H14O3: 194.0941; found: 194.0943.
Acknowledgements
We are indebted to Biotage, Amgen, the National Science
Foundation (NSF), and the University of California, Santa
Barbara (UCSB) for financial assistance in making our pur-
chase of an Emry’s Optimizer possible. We warmly thank
the NSF for financial support and Takasago, Solvias, and
Roche for their most generous gifts of their ligands used in
this study.
(S)-Ethyl 3-phenylbutanoate (9) using 1% Stryker’s
catalyst (Table 3, entry 3)
To a 2–5 mL Emry’s Optimizer glass vessel, flame dried
and purged with argon, was added the (E)-ethyl 3-methyl-5-
phenylpent-2-enoate (neat, 0.380 mg, 2 mmol). To a 10 mL
RBF, flame dried and purged with argon, was added (R)-
DTBM-SEGPHOS (3, 2.3 mg, 0.002 mmol) and Stryker’s
reagent (6.3 mg, 0.020 mmol), followed by toluene
References
1. (a) A. Wurtz. Ann. Chim. Phys. 11, 250 (1844); (b) H. Muller
and A.J. Bradley. J. Chem. Soc. 1669 (1926).
© 2005 NRC Canada

614
2. J.A. Dilts and D.F. Shriver. J. Am. Chem. Soc. 91, 4088
Can. J. Chem. Vol. 83, 2005
Shimizu. Angew. Chem. Int. Ed. 42, 2227 (2004); (c) B.H.
Lipshutz and J.M. Servesko. Angew. Chem. Int. Ed. 41, 4789
(2003); (d) B.H. Lipshutz, J.M. Servesko, T.B. Peterson, P.P.
Papa, and A.L. Lover. Organic Lett. 6, 1273 (2004); (e) B.H.
Lipshutz, J.M. Servesko, and B.R. Taft. J. Am. Chem. Soc.
126, 8352 (2004).
(1969); more recently, NH carbene ligands have been found to
stabilize CuH for use in synthesis, cf.: H. Kaur, F.K. Zinn,
E.D. Stevens, and S.P. Nolan. Organometallics, 23, 1157
(2004); V. Jurkauskas, J.P. Sadighi, and S.L. Buchwald. Or-
ganic Lett. 5, 2417 (2003); see also: N.P. Mankad, D.S. Laitar,
and J.P. Sadighi. Organometallics, 23, 3369 (2004).
9. (a) J.P. Tierney and P. Lidstrom (Editors). Microwave assisted
organic synthesis. Blackwell Publishing, Uppsala, Sweden.
2005; (b) A.K. Bose, M.S. Manhas, S.N. Ganguly, A.H.
Sharma, and B.K. Banik. Synthesis, 1578 (2002).
10. N.E. Leadbeater and M. Marco. J. Org. Chem. 68, 888 (2003).
11. D.H. Appella, Y. Moritani, R. Shintani, E.M. Ferreira, and S.L.
Buchwald. J. Am. Chem. Soc. 121, 9473 (1999).
12. (a) D. Lee and J. Yun. Tetrahedron Lett. 45, 5415 (2004);
(b) M.P. Rainka, Y. Aye, and S.L. Buchwald. Proc. Natl. Acad.
Sci. U.S.A. 101, 5821 (2004).
13. (a) T. Benincori, E. Cesarotti, O. Piccolo, and F. Sannicolo. J.
Org. Chem. 65, 2043 (2000); (b) T. Benincori, E. Brenna, F.
Sannicolo, L. Trimarco, P. Antognazza, E. Cesarotti, F.
Demartin, and T. Pilati. J. Org. Chem. 61, 6244 (1996).
14. N.W. Boaz, S.D. Dedenham, E.B. Mackenzie, and S.E. Large.
Org. Lett. 4, 2421 (2002).
3. B.H. Lipshutz. In Modern organocopper chemistry. Edited by
N. Krause. Wiley-VCH, Weinheim. 2002. pp. 167–187.
4. (a) W.S. Mahoney, D.M. Brestensky, and J.M. Stryker. J. Am.
Chem. Soc. 110, 291 (1988); P. Chiu. Synthesis, 13, 2210
(2004); (b) J.-X. Chen, J.F. Daeuble, and J.M. Stryker. Tetra-
hedron, 56, 2789 (2000); (c) J.-X. Chen, J.F. Daeuble, D.M.
Brestensky, and J.M. Stryker. Tetrahedron, 56, 2153 (2000);
(d) J.M. Stryker, W.S. Mahoney, J.F. Daeuble, and D.M.
Brestensky. In Catalysis in organic synthesis. Edited by W.E.
Pascoe. Marcel Dekker, New York. 1992. pp. 29–44.
5. (a) R. Schmid, E.A. Broger, M. Cereghetti, Y. Crameri, J.
Foricher, M. Lalonde, R.K. Muller, M. Scalone, G. Schoettel,
and U. Zutter. Pure. Appl. Chem. 68, 131 (1996); (b) R.
Schmid, J. Foricher, M. Cereghetti, and P. Schonholzer. Helv.
Chim. Acta, 74, 370 (1991).
6. H.-U. Blaser, W. Brieden, B. Pugin, F. Spindler, M. Studer,
15. (a) D.H. Appella, Y. Moritani, R. Shintani, E.M. Ferreira, and
S.L. Buchwald. J. Am. Chem. Soc. 121, 9473 (1999); (b) G.
Hughes, M. Kimura, and S.L. Buchwald. J. Am. Chem. Soc.
125, 11 253 (2003).
and A. Togni. Top. Catal. 19, 3 (2002).
7. T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T.
Miura, and H. Kumobayashi. Adv. Synth. Catal. 343, 264
(2001).
16. D.J. Goldsmith, D.C. Liotta, M. Volmer, W. Hoekstra, and L.
8. (a) B.H. Lipshutz, K. Noson, W. Chrisman, and A. Lower. J.
Am. Chem. Soc. 125, 8779 (2003); (b) B.H. Lipshutz and H.
Waykole. Tetrahedron, 41, 4873 (1985).
© 2005 NRC Canada