Copper(I)-catalyzed asymmetric hydrosilylations of imines at ambient temperatures

Article abstract of DOI:10.1002/anie.200353294

Are you looking for an operationally simple means of preparing enantio-enriched benzylic-like centers bearing nitrogen? Consider this new and convenient alternative to asymmetric hydrogenation: CuH when ligated by an enantio-pure SEGPHOS ligand can cataly

Full text of DOI:10.1002/anie.200353294

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CuH, when coordinated by enantiopure SEGPHOS derivative, can
reduce aryl ketimines catalytically at room temperature. This conven-
ient route to enantio-enriched benzylic-like centers bearing a nitrogen
atom is economically attractive as the starting materials and catalyst
are inexpensive. For more information see the communication by B. H.
Lipshutzand H. Shimizu on the following pages.
Angew. Chem. Int. Ed. 2004, 43, 2227
DOI: 10.1002/anie.200353294
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Asymmetric Synthesis
and highly enantioselective hydrosilylation at room temper-
ature.
Copper(i)-Catalyzed Asymmetric
The diphenylphosphinyl moiety was chosen first as the
appendage on the nitrogen atom.[10] These derivatives are
very commonly used and easily constructed, being obtained as
a single (presumably E) isomer. Importantly, they can be
readily hydrolyzed to the desired amines[10,11] without erosion
of stereoechemical integrity in the newly formed product.
Moreover, the nature of the phosphinyl residue was antici-
pated to be crucial in weakening an otherwise strong
copper–nitrogen bond, the likely initial outcome from addi-
Hydrosilylations of Imines at Ambient
Temperatures**
Bruce H. Lipshutz* and Hideo Shimizu
Catalytic asymmetric hydrosilylation of aryl-ketone-derived
imines remains to this day a nontrivial, challenging reaction in
organic synthesis that is highly valued in both industrial and
academic circles.[1] Although considerably greater attention
has been paid to the analogous asymmetric hydrogenation,[2]
the use of safe and inexpensive silanes can be viewed as a
highly desirable alternative. As is the case for hydrosilylations
of aryl ketones,[3] catalysts derived from transition metals such
as Rh,[4] Ru,[5] and Ti[6] predominate, although related
chemistry based on Ir[7] has also been reported. Non-
transition-metal-based processes in which induced chirality
derives from a binaphthyl array[8] or proline derivatives[9] also
showpromise, although thus far ee values tend to be
moderate.
À
tion of the elements of Cu H across the imine prior to any
transmetalation event required for the regeneration of the
metal catalyst (see compound 1, Scheme 2).
The problems we faced in developing new methodology,
as others have noted previously, include the crucial choice of
the substituent attached to nitrogen (R in Scheme 1).
Scheme 2. Presumed pathway for addition of CuH to a phosphinyl
imine.
Initial experiments conducted at À258C in toluene by
using ligated CuH prepared in situ[12] from CuCl, NaO tBu,
À
DTBM–SEGPHOS,[13] and polymethylhydrogensiloxane
(PMHS)[14] as hydride source led to lowconversions (ca.
40%) and modest ee values (ca. 70%). Although previous
hydrosilylations with CuH that involved carbonyl systems[15]
indicated that the nature of the silane had little impact on
levels of induction,[16] changing to tetramethyldisiloxane
(TMDS)[17] dramatically increased the observed ee value
(ca. 92%), although the extent of conversion remained low.
The key observation was then made that only one equivalent
of MeOH[18] as additive and by using NaOMe in place of
Scheme 1. General reaction for asymmetric hydrosilylations of
aromatic ketimines.
Opportunities for E/Z isomerism can play a pivotal role in
the observed outcomes. Another variable of consequence can
be the silane, the source of stoichiometric hydride. A general
process that not only addresses these reaction variables but
has no special reliance on temperature control and/or
handling of imines, is efficient, and provides product amines
of high ee values, is still lacking. In this contribution we
describe unprecedented technology which relies on a base
metal, copper. When in the form of CuIH that is nonracemi-
cally ligated by a particular biaryl bisphosphane, a reagent
results which gives rise to a straightforward, very efficient,
À
NaO tBu as base drove the reaction almost to completion in
the presence of DTBM–SEGPHOS as ligand,[19] without
erosion of the enantiomeric excess. When the reaction was
warmed to room temperature, the ee value remained above
the 80% mark, which encouraged further optimization. By
switching to the 3,5-dixylyl analogue[20] of the diphenylphos-
phinyl residue on nitrogen (Scheme 3), ee values on the order
of > 95% were realized although the reactions took 2–3 days
to reach completion. Ultimately, use of 2–3.3 equivalents of
tBuOH in place of MeOH nicely improved the rates of these
hydrosilylations while maintaining high levels of enantiose-
lectivity.
[*] Prof. B. H. Lipshutz, H. Shimizu
Department of Chemistry
University of California
Santa Barbara, CA 93106 (USA)
Fax: (+1)805-893-8265
E-mail: lipshutz@chem.ucsb.edu
Table 1 illustrates representative examples studied to
date, all of which are based on DTBM–SEGPHOS-chelated
CuH thereby documenting both versatility and elements of
generality that is characteristic of this newmethod. Branching
in the alkyl residue associated with the imine carbon did not
adversely affect the ee values (compare entries 1–3). Imines
derived from 1-indanone (entry 4) and a-tetralone (entry 5)
behaved similarly, affording the corresponding nonracemic
[**] We thank the NSF (CHE 0213522) for financial support, and
Takasago for a research assistantship to H.S. We are also indebted
to Dr. Takao Saito (Takasago), Drs. Rudolf Schmid and Michel-
angelo Scalone (Roche), Drs. Hans-Ulrich Blaser and Marc Thom-
men (Solvias) for supplying the SEGPHOS, BIPHEP, and
JOSIPHOS ligands, respectively, used in this study.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353294
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products in high enantiomeric excess. Results from three
substituted aromatic imine derivatives (entries 6–8) suggest
that electronic perturbations are not significant at least
insofar as yields and ee values are concerned. Most of these
reactions were run at room temperature, although in the case
of imines 2 (entry 1) and 3 (entry 3), cooling the reaction
mixture to À258C increased the observed selectivity. Thus, it
is assumed that higher ee values might follow, in general, at
lower temperatures, a trend noted previously with aryl
ketones by using a related reagent combination.[16]
While the examples in Table 1 were conducted at 0.14m in
toluene by using a convenient 6% of each catalyst precursor
(i.e., CuCl, NaOMe, and DTBM–SEGPHOS), the level could
be lowered to 1%, although reaction times increased (ca.
24 h). Raising the concentration (from 0.14m to 0.5m) led to
an expected drop in reaction time [Eq. (1)].[21]
Scheme 3. Reagents and conditions used in these asymmetric hydrosi-
lylations.
Table 1: Asymmetric hydrosilylations of imine derivatives using
(R)-DTBM–SEGPHOS.[a]
entry
1
imine[b]
Yield [%][c]
ee [%][d]
99
94
96.2
99.3
The sense of chiral induction engendered by (R)-DTBM–
SEGPHOS was determined for all substrates by treating each
isolated product with HCl in alcoholic media.[11] Basic workup
led to the respective primary amines for which the rotation of
each was measured and compared with literature values.[22] In
all cases, the (R)-amine was clearly formed.[23]
2
3
96
97.5
90
93
94.3[f]
97.3[f]
In summary, a novel process for effecting asymmetric
hydrosilylations of aryl ketimines based on catalytic amounts
of copper hydride has been uncovered. This newtechnology
offers convenience in the form of room temperature reac-
tions, attractive economics due to reliance on catalytic
quantities of a nonprecious metal, and an inexpensive
silane. Efficiencies with regard to both chemical yields and
enantioselectivities are high, and the resulting products are
smoothly converted to their free-base forms upon mild
hydrolysis. Further assessment of the scope and limitations
of this method is underway, in particular regarding imines of
dialkyl ketones.
4
5
93
93
98.4
97.6
6
7
8
95
98
94
96.1
94.2
Experimental Section
General procedure for the asymmetric hydrosilylation of phosphinyl
imines at room temperature. (R)-N-(1-phenylethyl) bis(3,5-dimethyl-
phenyl)phosphinamide (Table 1, entry 1). CuCl (3.7 mg, 0.038 mmol),
NaOMe (2.0 mg, 0.038 mmol) and (R)-DTBM–SEGPHOS (44.3 mg,
0.038 mmol) were placed into a 25 mL round-bottomed flask (RBF).
Toluene (1.0 mL) was added to the RBFand the resulting mixture was
stirred at room temperature for 30–40 min. Meanwhile, N-(1-phenyl-
97.3[g]
[a] Reactions were all run by using 6% CuCl, 6% NaOMe, 6% R-(À)-
DTBM–SEGPHOS, 3 equiv TMDS, 3.3 equiv tBuOH in toluene at RT for
17 h unless specified otherwise. [b] R=P(O)(xylyl)2. [c] Of isolated,
chromatographically purified reduced material. [d] Determined by chiral
HPLC unless noted otherwise. [e] Run at À258C. [f] Used 6 equiv TMDS.
[g] Determined by chiral GC on the derived free amine.
ethylidene)
bis(3,5-dimethylphenyl)phosphinamide
(235 mg,
0.626 mmol), tBuOH (0.20 mL, 2.1 mmol) and toluene (1.8 mL)
were placed into a separate 5 mL pear-bottomed flask (PBF). The
RBF was charged with tetramethyldisiloxane (TMDS; 0.33 mL,
1.9 mmol). The contents of the PBF were slowly added to the RBF
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by syringe and then the PBF was washed with additional toluene
cantly belowthose obtained with DTBM–SEGPHOS. DTBM–
MeO–BIPHEP (BIPHEP = 6,6’-dimethoybiphenyl-2,2’-diyl(di-
phenylphosphane)) afforded a comparable ee value, however,
the extent of conversion was low in reactions run at À258C.
[20] Made following a standard literature method[10c] by using chloro
bis(3,5-dimethylphenyl)phosphane; T. V. RajanBabu, T. A.
Ayers, G. A. Halliday, K. K. You, J. C. Calabrese, J. Org.
Chem. 1997, 62, 6012.
(1 mL). The reaction mixture was stirred at room temperature for
17 h. MeOH (1 mL) was slowly added and after 30 min 1n NaOH in
MeOH (0.5 mL) was added. The mixture was stirred for a few hours,
filtered through a plug of silica and concentrated under vacuum.
Purification by silica gel chromatography (10% acetone in CH2Cl2)
gave the corresponding phosphinyl amine (235 mg, 99% yield).
HPLC analysis indicated 96.2% ee. (Daicel Chiralcel OD, hexane/
isopropylalcohol 90/10, 1.0 mLminÀ1
,
220 nm; Rt = 5.3 min, (R),
[21] The increased concentration was achieved by decreasing the
amount of toluene used. 1,1,3,3-tetramethyl disilazane (TMDS;
6 equiv) gave best results.
7.3 min (S)).
Supporting Information available: Procedures and spectral data
for all hydrosilylations.
[22] See Supporting Information for details.
[23] As reported for BINAP, the (S)-enantiomer of DTBM–SEG-
PHOS is available by resolution following the protocol for the
(R)-enantiomer, but with reliance on the opposite enantiomer of
dibenzoyl tartrate; see H. Takaya, K. Mashima, K. Koyano, M.
Yagi, H. Kumobayashi, T. Taketomi, S. Akutagawa, R. Noyori, J.
Org. Chem. 1986, 51, 629.
Received: November 10, 2003 [Z53294]
Published Online: February 16, 2004
Keywords: copper · hydrides · hydrosilylation · P ligands ·
.
reduction
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[19] Josiphos
(1-(2-(diphenylphosphanyl)ferrocenyl)ethyldicyclo-
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thylphospholano)benzene, and BINAP (2,2'-bis(diphenylphos-
phanyl)-1,1'-binaphthyl), all gave ee values that were signifi-
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