Desymmetrizing reductive aldol cyclizations of enethioate derivatives of 1,3-diones catalyzed by a chiral copper hydride

Article abstract of DOI:10.1039/c2ob25206f

A range of enethioate derivatives of 1,3-diones underwent reductive aldol cyclizations catalyzed by a chiral copper hydride generated in situ from 5 mol% TaniaPhos (SL-T001-1), 5 mol% Cu(OAc)₂·H₂O, 5 mol% bipyridine and 2.0 equiv. of PhSiH₃, to furnish polycyclic β-hydroxythioester products bearing three newly established contiguous stereocenters, with >98:2 dr and in up to 94% yield and 98% ee. The use of an amine such as bipyridine or 2,6-lutidine as additive results in an increase of the overall reaction rate. The major bicyclic aldol product has all substituents cis and can be rationalized by a reductively generated (Z)-enolate reacting with the dione via a cyclic transition state.

Full text of DOI:10.1039/c2ob25206f

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PAPER
Desymmetrizing reductive aldol cyclizations of enethioate derivatives of
1,3-diones catalyzed by a chiral copper hydride†‡
Jun Ou, Wing-Tak Wong and Pauline Chiu*
Received 27th January 2012, Accepted 18th April 2012
DOI: 10.1039/c2ob25206f
A range of enethioate derivatives of 1,3-diones underwent reductive aldol cyclizations catalyzed by a
chiral copper hydride generated in situ from 5 mol% TaniaPhos (SL-T001-1), 5 mol% Cu(OAc)2·H2O,
5 mol% bipyridine and 2.0 equiv. of PhSiH3, to furnish polycyclic β-hydroxythioester products bearing
three newly established contiguous stereocenters, with >98 : 2 dr and in up to 94% yield and 98% ee. The
use of an amine such as bipyridine or 2,6-lutidine as additive results in an increase of the overall reaction
rate. The major bicyclic aldol product has all substituents cis and can be rationalized by a reductively
generated (Z)-enolate reacting with the dione via a cyclic transition state.
Research by Krische, Lam, Riant, Lipshutz, Shibasaki and
Kanai, as well as other researchers, has developed asymmetric
Introduction
Asymmetric domino reactions are a challenging and highly
useful class of reactions to investigate and design.1 Their poten-
tial to provide multiple transformations and bond formations in
one step increases the complexity of the products without the
concomitant increase in length, steps, reagents or solvents
required in multi-step reactions and purifications. In all kinds of
syntheses, including the total syntheses of natural products, the
application of these reactions makes the overall sequence more
efficient, economical and environmentally sound.2,3
Copper has emerged as an attractive metal for the mediation
or catalysis of a variety of domino reactions.4 Because of the
abundance, comparatively low toxicity and costs of copper,
copper-catalyzed reactions are highly practical and desirable,
especially in the industrial setting.
Our interest in copper-mediated organic synthesis initiated our
work on stoichiometric and catalytic reductions, particularly
domino transformations, mediated by copper hydride species.5
Based on this mild and non-basic method to generate enolates
from Michael acceptors, we have developed reductive aldol
cyclizations of enediones, keto-enoates, nitroalkenones and
alkynediones.6,7
versions of the reductive intramolecular and intermolecular aldol
reactions catalysed by copper, usefully generating aldol products
with multiple functional groups and stereogenic centers with
enantioselectivity.8–10
Recently, our research interest has turned to thioesters, versa-
tile substrates which offer unique synthetic opportunities as pre-
cursors of nucleophiles as well as electrophiles.11,12 We have
reported on the use of copper ligated with BDP or dppf to effec-
tively catalyse the conjugate reduction of unsaturated thioesters
by silanes, which could proceed to completion without suffering
detrimental catalyst poisoning. Furthermore, keto–enethioates
continue on to an aldol cyclization after reduction in a domino
process under these conditions.13 We have also subsequently
reported on the first asymmetric reductive aldol cyclization of
symmetrical enethioate derivatives of 1,3-cyclopentandiones cat-
alyzed by a chiral copper complex generated in situ from Tania-
Phos, Cu(OAc)2·H2O and PhSiH3.14 Under optimal conditions,
β-hydroxythioesters with a bicyclo[4.3.0]nonane carbon frame-
work could be obtained with up to 96% ee. However, presum-
ably due to the competitive interaction between copper and
sulphur, this reductive aldol cyclization requires higher reaction
temperatures and longer completion times than their oxoester
counterpart substrates.9
Department of Chemistry, The University of Hong Kong, Pokfulam
Road, Hong Kong, P.R. China. E-mail: pchiu@hku.hk; Fax: +852 2859
8949; Tel: +852 2857 1586
†This article is part of the Organic & Biomolecular Chemistry 10th
Anniversary issue.
‡Electronic supplementary information (ESI) available: Detailed pro-
cedures, for the synthesis and reductions of 3, characterizations and
spectra of all products. CCDC 851777, 851778 and 856812. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2ob25206f
The mechanism of this reductive aldol cyclization is pro-
posed to be through the intermediacy of a chiral copper hydride
complex, as shown in Scheme 1. The chiral copper hydride
is generated in situ and induces conjugate reduction of the un-
saturated thioester to offer a chiral copper thioester enolate. The
enolate undergoes intramolecular aldol cyclization to generate
copper aldolate. Metathesis with silane at this stage completes
the catalytic cycle and regenerates chiral copper hydride.
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Scheme 1 Catalytic reductive aldol catalysed by Cu(I).
Herein we report on the results of our continued investigations
to explore the optimizations and scope of this reaction.
Results and discussion
We continued our studies to expand the scope of the enethioates
examined in this reductive reaction. A range of prochiral enethio-
ate derivatives 3 of 1,3-diones 1 were synthesized by a Wittig
reaction with stabilized thioester phosphoranes in a two or three
step sequence (Scheme 2). Generally 1,3-diones 1 were con-
verted to their homologated aldehyde intermediates, which were
then subjected to the Wittig reaction with phosphoranes 2a–h,15
to furnish the corresponding enethioate derivatives 3a–u. All
thioesters 3 were obtained predominantly or exclusively as the
(E)-olefins, with only one case of low selectivity for 3b.
Although DMAP has been reported to induce the efficient equili-
bration of unsaturated thioesters to give the more stable geo-
metric isomer,16 the treatment of an isomeric mixture of 3a with
DMAP returned only a 34% yield of pure (E)-3a along with side
products. Because E and Z isomers of 3a–h are inseparable by
chromatography, the isomeric mixtures are used as obtained
from synthesis. However, this turned out not to be a critical
issue, because the geometric isomerism of the substrates has not
been observed to have a significant effect on the reaction rate,
yields, diastereo- or enantioselectivity of this reductive aldol
reaction (vide infra).
Scheme 2 Synthesis of enethioate derivatives of 1,3-dione.
Our previous study has screened ligands L1–8 (Fig. 1) in the
copper-catalyzed reductive aldol cyclization reactions of 3a in
the presence of polymethylhydrosiloxane (PMHS), and found
that hydroxythioester 4a bearing three contiguous stereocenters
was obtained as the major product.14 Of these, TaniaPhos L8
(SL-T001-1) afforded the highest yield and enantioselectivity
(Scheme 3). We have further screened another member of the
TaniaPhos family L9 (SL-T002-1, Fig. 1) in this reaction, and
have found, surprisingly, that the reaction did not produce any
4a. It may be that, due to both the increase in electron donating
ability and steric hindrance conferred by the cyclohexyl groups,
L9 promoted 1,2-reduction instead to give alcohol 5a as a
mixture of diastereomers in 38% yield, along with 37% recov-
ered 3a.
yields. Those that have primary R2 (4a, R2 = Et; 4b, R2
=
C12H25; 4d, R2 = Bn) were reduced with higher enantioselectiv-
ities than the hindered R2 (4c, R2 = tBu; 4d, R2 = Ph), among
which 4d with R2 = Bn reacted with the highest ee.
Silanes have been among the most effective stoichiometric
reductants used in copper-catalyzed reductions, the metathesis
driven by exploiting the strong Si–O bond formation that con-
comitantly promotes copper hydride regeneration. Our screening
of several silanes revealed that phenylsilane is the most reactive
and it significantly reduced the time required for complete reac-
tion (Table 1, entry 1). Except for PhMe2SiH which appeared to
be unable to undergo effective metathesis (Table 1, entry 5), the
dr and the ee remained virtually the same regardless of the iden-
tity of the silane; only the reaction time and, to a lesser extent,
the yields were affected. This observation, together with the
The variation of the mercaptan R2 resulted in further improve-
ments in enantioselectivity (Scheme 4). All substrates bearing R2
larger than Et were reductively cyclized with 10–20% lower
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Table 1 Screening of reductants
Entry
Reductant
t (h)
Yielda
dr
eeb (%)
1
2
3
4
5
6
PhSiH3
4
83%
82%
71%
62%
NR
>98 : 2
>98 : 2
>98 : 2
>98 : 2
—
84
83
84
85
—
75
Ph2SiH2
(EtO)2MeSiH
PMHS
PhMe2SiH
PinBH
16
48
62
48
16
74%
>98 : 2
a Isolated yields. b Determined by HPLC on a CHIRACEL AY-3
column.
Table 2 Screening of amine additives
Fig. 1 Chiral bisphosphine ligands.
Entry
Additive
X
t (h)
Yielda
dr
eeb (%)
Scheme 3 Copper-catalyzed reductions of 3a.
1
2
3
4
None
Pyridine
2,6-Lutidine
2,6-Lutidine
Bipy
—
10
5
10
5
40
11
12
11
18
5
81
85
75
87
84
62
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
>98 : 2
91
90
90
90
90
90
5
6b
Phenanthroline
5
a Isolated yields. b Determined by HPLC on a CHIRACEL AY-3
column.
Scheme 4 The effect of R1 on enantioselectivity.
significant enantioselectivity in the reaction that has been
induced as a result of the ligand on copper, supports the mechan-
ism (Scheme 1) that the aldol reaction occurred via the copper
enolate intermediates, not through the silyl enol ethers, and that
the role of the silane is post-cyclization and affects the rate of the
ensuing copper hydride regeneration from the aldolate.17 This
also suggests that copper hydride regeneration, and not conjugate
reduction or aldol cyclization, is the rate limiting step in the
reduction of substrates such as 3d. We also examined pinacolbor-
ane (PinBH) as a reductant (Table 1, entry 6) in this reaction.
While the reductive aldol reaction proceeded effectively, both the
yield and the ee of 4d obtained were inferior to those obtained
using phenylsilane.
Scheme 5 Reduction of pure (E)-3d.
the reaction remained unchanged, but the reaction rates were
increased, thereby reducing the time required for complete reac-
tion. For example, the reaction of 3d requires about 40 h at
−20 °C (Table 2, entry 1), but in the presence of 5 mol% 2,6-
lutidine or bipyridine (bipy) (Table 2, entries 3 and 5), the reac-
tion could be complete in 12 and 18 h respectively, reducing the
reaction time by two-thirds to half.
There have been a number of reports of catalytic asymmetric
reactions whose enantioselectivities are increased by the addition
of achiral ligands that operate by modifying the coordination
sphere and magnifying the asymmetric environment.18 However,
when we screened several amine additives in this reaction
(Table 2), we found that the diastereo- and enantioselectivity of
Similarly, pure (E)-3d was reduced in approximately 12 h in the
presence of bipy to give an 80% yield of 4d with the same 90%
ee (Scheme 5), demonstrating that the E/Z ratio of the substrate
does not have a significant effect on the outcome of the reaction.19
At this time, we surmise that the role of the amine does not
appear to be a ligand to the copper enolate, as there has been no
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difference observed in the ee of the cyclizations, and it may be
related to post-reduction and post-cyclization events, for
example, facilitating metathesis in some way to exert its rate-
accelerating effect.
Nevertheless, the discovery of the rate enhancement of the
reductive aldol reaction of enethioates in the presence of amines
facilitates the optimization of enantioselectivity by allowing us
to carry out the reactions at lower temperatures, and completing
them in a more practical time scale. We therefore expanded and
explored the scope of enethioates that can undergo this chiral
copper-catalyzed desymmetrizing reductive aldol reaction, at
−20 °C in the presence of bipy as an additive. Table 3 shows the
Table 3 Reductive aldol cyclizations of 3 with bipyridine as additive
Entry
Enethioates 3
ta (h)
Major products
Yielda,b
dr (4 : 6)a
eea,c (%)
1
2
3
3d, Ar = Ph
3f, Ar = 4-tBuC6H4
3g, Ar = 2,4,6-Me3C6H2
18 (40)
15 (24)
15 (40)
4d,d Ar = Ph
4f, Ar = 4-tBuC6H4
4g, Ar = 2,4,6-Me3C6H2
84% (84%)
94% (75%)
93% (64%)
>98 : 2 (>98 : 2)
>98 : 2 (>98 : 2)
>98 : 2 (>98 : 2)
90 (90)
90 (91)
93 (89)
420
5
6
3i, R3 = Me
(120)
48 (120)
30 (96)
4i,d R3 = Me
(71e)
(>98 : 2)
87 : 13 (>98 : 2)
78 : 22 (81 : 19)
(96)
95/73 (95)
98/91 (97/92)
3j, R3 = CH2CHvCH2
3k, R3 = CH2(3-BrC6H4)
4j, R3 = CH2CHvCH2
4k, R3 = CH2(3-BrC6H4)
60 (54f)
65 (63)
7
8
3l, Ar = Ph
3m, Ar = 4-tBuC6H4
15 (18)
20
4l, Ar = Ph
4m, Ar = 4-tBuC6H4
72 (73)
86
>98 : 2 (88 : 12)
90 : 10
93 (85/68)
88/74
9
20
65
>98 : 2
93
10
(18)
(35g)
(>98 : 2)
(68)
11
12
18 (21)
7 (21)
56 (57)
44 (35)
>98 : 2 (>98 : 2)
>98 : 2 (>98 : 2)
27 (30)
59 (59)
a Results with no bipy/−10 °C, in parentheses. b Isolated yields. c ee determined by HPLC. d Absolute stereochemistry determined for 4d, 4i. e 13%
recovered 3i. f 18% recovered 3j. g 17% simple conjugate reduction product.
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scope of the reductive cyclizations of a spectrum of enethioates
3. Also shown in parentheses are the results of the reduction of
the same substrates at a slightly higher temperature of −10 °C in
the absence of bipy for comparison.
It can be seen that in all cases of substrates 3, the presence of
bipy resulted in an overall decrease of 15–60% in the time
required for complete reaction. The same all-cis diastereomer 4
was obtained as the major or exclusive bicyclic aldol product in
all cases. The diastereoselectivity was very high, and in many
1
reactions, no other diastereomer was observed in the H NMR
Fig. 2 Substrates that failed in reductive aldol cyclization.
spectra of the crude reaction mixtures. In the few cases where a
minor aldol diastereomer was observable (Table 3, entries 5–8),
it was determined to have the structure 6, having a cis–trans
stereochemistry as shown.
The yields of the reactions, without or with the additive, were
similar, but in some cases they were improved in the presence of
bipy, as in the reductions of enethioates 3g and 3h (Table 3,
entries 2 and 3). The dr and the ee were also approximately the
same. Only in the reductions of 3g and 3l was there a slight
increase of 4–8% in the ee in the presence of bipyridine
(Table 3, entries 3 and 7), which may be a result of conducting
the reaction at a slightly lower temperature.
Examining the scope of the substrates reveals that the copper-
catalyzed reductive aldol cyclization with L8 was most effective
for generating six-membered ring aldols. Substrates 3a–3k
underwent desymmetrizing reduction typically in the range of
90–98% ee (Table 3, entries 1–9), with the derivatives of indane-
1,3-dione giving the highest ee’s (Table 3, entries 4–6). The only
exception is the acyclic substrate 3p, which produced 4p as
product diastereoselectively, but with only 68% ee, along with
product from a simple conjugate reduction that failed to cyclize,
which was also isolated in 17% yield. Several R3 substituents are
tolerated, although groups bulkier than methyl tend to be reduc-
tively cyclized with lower yields (Table 3, entries 5, 6 and 9).
We explored the effects of substituents on the S-benzyl group by
variation of the substitution on the aromatic ring; but the enan-
tioselectivity of the reductive cyclization did not improve signifi-
cantly as a result of modifications on the ring (Table 3, entries
2–3). Overall, the copper-catalyzed reductive aldol cyclization of
enethioate substrates with L8 as ligand proceeded to give six-
membered ring aldols with up to 94% yields, excellent to exclu-
sive diastereoselectivity and up to 98% ee.
On the other hand, reductions that continue on to five-mem-
bered ring aldol formation are not efficient (Table 3, entries
11–12). Both the yields and enantioselectivities were greatly
inferior to the previous reductive cyclizations. It may be that for
this substrate type, TaniaPhos L8 is not the optimum phosphine,
and another ligand with alternative stereochemical features could
engender improved enantioselectivities.
For the analysis of ee, the corresponding racemic products
were generated by copper-catalyzed reductive cyclizations using
either bis(diphenylphosphino)benzene (BDP) or 1,1′-bis(diphe-
nylphosphino)ferrocene (dppf) as ligands. It was noted that such
reductions proceeded in much lower yields (trace to 39%), and
in some cases also with grossly reduced diastereoselectivity.
Therefore it is apparent that the chiral ligands not only conferred
enantioselectivity, but their steric bulk in the copper complex
also prevented competing reactions and stabilized the transition
state leading to the all-cis aldol diastereomer 4.
Fig. 3 Summary of nOe correlations for 4d, 4i, 4l, 6l.
Several hindered substrates failed to undergo any reductive
cyclization under these conditions (Fig. 2). Steric hindrance in
the form of α-substituents (3h), in the mercaptan (3s) and in the
cyclic scaffold (3t) retarded the reaction greatly. These exper-
iments returned unreacted enethioates in 82–84% yields; not
even the conjugate reduction was observed. For these hindered
substrates, the initial conjugate reduction has become the rate
limiting step. For substrate 3u, only simple conjugate reduction
in 76% yield occurred without cyclization, due to the ineffi-
ciency of formation of large rings.
The relative stereochemistries of the major and minor aldol
products 4 and 6 can be deduced on the basis of 2D-NMR (H–H
NOESY, COSY) spectral analysis. Four representative examples
and their informing NOE correlations are shown in Fig. 3. The
relative stereochemistry has been confirmed by an X-ray crystal
structure of ( )-4c.14
The absolute configuration of 4d has additionally been deter-
mined by conversion to aldehyde 7d by a Fukuyama reduction
in 86% yield,20 then by a Wittig reaction to afford the crystalline
8d in 89% yield (Scheme 6). X-ray crystallographic analysis of
8d indicates that the absolute configurations at the stereocenters
are 4S,8R,9R.21 This infers that its precursor is (4R,8R,9R)-4d.
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Scheme 6 Determination of absolute configuration of 4d and 8d.
Fig. 5 ORTEP plot of L8–CuBr, 9.
Fig. 4 ORTEP of 4i.
Because product 4i is a crystalline compound, it was directly
subjected to X-ray analysis and determined to be (8R,12S,13R)-
4i (Fig. 4).22
Based on the consistent absolute stereochemical outcome of
4d and 4i, the other aldol products are assumed to have the same
absolute stereochemistry by analogy, as represented by the struc-
tures in Table 3 as shown.
Scheme 7 Putative transition state in the formation of 4d.
To better understand the nature of the copper hydride and
copper enolate ligated to TaniaPhos (L8), we sought to investi-
gate the coordination at the metal center. In the literature, a Josi-
Phos–copper(I) bromide complex has been previously prepared
and its crystal structure has been elucidated.23 This monomeric
copper complex is trigonal planar, as expected for copper(I)
having three ligands occupying sp2-hybridized orbitals. There
are many differences in the steric and electronic properties
between JosiPhos (L7) and TaniaPhos (L8), so it was not clear
how L8 conferred superior enantioselectivity on the L8–copper(I)
hydride mediated reaction, compared with the JosiPhos-
ligated copper hydride which afforded a much lower ee
(Scheme 3).24 In particular, it was not clear whether the dimethyl-
amino unit in L8 was functioning as an additional ligand in any
way, in either the L8-ligated copper hydride or the copper
enolate.
molecule of MeCN. It can be seen clearly that in 9 the
dimethylamino group does not coordinate with copper,
so its function is steric in nature. Together with the ortho-disub-
stituted phenyl group, the dimethylamino group effectively
blocks the β-face of the copper complex, leaving the α-face open
for coordination and approach. It could be inferred that the
monomeric L8–copper(I) hydride complex would have similar
structural features to 9, but the state of aggregation of the copper
hydride complex in solution and in various solvents could differ
greatly.
Nevertheless, based on the absolute configuration of
(4R,8R,9R)-4d, the aldol cyclization could be rationalized as a
chiral copper (Z)-enolate 10 whose β-face is blocked by the
dimethylamino unit of (RP)-1-[(R)-α-(dimethylamino)-2-(diphe-
nylphosphino)benzyl]-2-diphenylphosphinoferrocene (TaniaPhos
L8) (Scheme 7), undergoing aldol attack from the α-face. The
L8 stereochemistry therefore directs the attack by the enolate
from its Si-face to the Re-face of the ketone.
To clarify this issue, we prepared, crystallized and character-
ized the TaniaPhos L8–copper(I) bromide complex 9.25 From the
X-ray crystallographic analysis (Fig. 5), 9 co-crystallized with a
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1 M HCl (1.0 mL). The organic layer was separated, and the
aqueous layer was back-extracted with EtOAc (3 × 5 mL). The
combined organics were dried over anhydrous MgSO4 and con-
centrated in vacuo. Flash chromatography of the residue on silica
gel using 5%–20% EtOAc in hexane afforded the aldol products.
Conclusions
In summary, twenty enethioate derivatives of various symmetri-
cal prochiral 1,3-diones have been examined in the asymmetric
reductive aldol cyclization catalyzed by copper. Using chiral
copper hydride generated from 5 mol% of each of TaniaPhos
L8, Cu(OAc)2·H2O and bipyridine, with PhSiH3 as the stoichio-
metric reductant, a range of enethioates undergo desymmetrizing
reductive cyclization to afford bicyclic or polycyclic β-hydro-
xythioester products bearing three newly generated contiguous
stereocenters diastereoselectively (>98 : 2) in up to 94% yield
and up to 98% ee. The incorporation of a catalytic amount of
bipyridine or other amines as additive accelerates the reaction
rate to allow the reaction to proceed at a lower temperature and
in less reaction time. This catalytic system generally induces the
reductive formation of six-membered ring aldol products with
good to excellent ee, but the enantioselectivity in five-membered
ring aldol formation is markedly inferior. The stereochemistry of
the major bicyclic β-hydroxythioester product is the all-cis dia-
stereomer, and the absolute configurations of the products have
been ascertained through X-ray crystallography. The crystal
structure of the monomeric L8–CuBr complex has been
obtained, which helps to postulate a transition state that rational-
izes the observed stereochemical outcome. The thioester func-
tional group has a rich chemistry, and further reactions of this
class of thioester aldol product have also been demonstrated to
offer stereodefined scalemic intermediates such as 7d and 8d for
synthesis.
Acknowledgements
We thank Solvias for the gift of chiral ligands, Mr Elvis
W. H. Ng for technical assistance, and Prof. Z.-Y. Zhou, Dr
W. T.-K. Chan, Dr L. Szeto and the Department of Applied
Biology and Chemical Technology of the Hong Kong Polytech-
nic University for X-ray crystallographic work. This research
was supported by the University of Hong Kong, and the
Research Grants Council of Hong Kong SAR, P.R. China (GRF
HKU 7017/09P, HKU1/CRF/08).
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Experimental section
General procedure for the preparation of keto–enethioates 3
The thioester-derived phosphoranes were prepared as previously
described.14,15
To a solution of 1,3-dione (1.0 equiv.) in H2O–THF (30 mL,
1 : 1) was added acrolein (2.0 equiv.). The reaction mixture was
stirred for 24–48 h. The solvent was removed in vacuo to give
the crude aldehyde, which was used in the next reaction without
further purification.
To a solution of aldehyde (1.0 equiv.) in CH2Cl2 was added
the phosphorane (1.2 equiv.). The reaction mixture was stirred at
room temperature for 12 h. The solvent was removed in vacuo,
and the residue was subjected to flash chromatography on silica
gel to give the corresponding enethioates 3 as a mixture of
(E)- and (Z)-isomers.
7 P. Chiu, C.-P. Szeto, Z. Geng and K.-F. Cheng, Org. Lett., 2001, 3, 1901;
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8 Reductive intramolecular aldol reactions: K. Agapiou, D. F. Cauble and
M. J. Krische, J. Am. Chem. Soc., 2004, 126, 4528; H. W. Lam and P.
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General procedure for asymmetric reductive aldol cyclizations
Cu(OAc)2·H2O (0.015 mmol), L8 (TaniaPhos SL-T001-1,
0.015 mmol) and bipy (0.015 mmol) were transferred into an
oven-dried 5 mL round-bottomed flask, to which anhydrous
PhMe (1.0 mL) and phenylsilane (0.75 mmol) were added under
argon. The reaction mixture was stirred at room temperature until
a characteristic greenish-yellow color was observed. The reaction
mixture was cooled to the desired reaction temperature. Substrate
3 (0.15 mmol) in PhMe (1.0 mL) was added to the reaction
mixture via a cannula. The progress of the reaction was moni-
tored by TLC. The reaction was quenched by the addition of
9 J. Deschamp and O. Riant, Org. Lett., 2009, 11, 1217; J. Deschamp,
T. Hermant and O. Riant, Tetrahedron, 2012, 68, 3457–3467.
10 Reductive intermolecular aldol reactions catalysed by copper:
J. Deschamp, O. Chuzel, J. Hannedouche and O. Riant, Angew. Chem.,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5971–5978 | 5977

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19 The results in Scheme 5 also show that the use of 5 mol% Cu(I) or Cu(II)
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monohydrate used in the reaction do not lead to a significant difference in
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20 T. Fukuyama and H. Tokuyama, Aldrichimica Acta, 2004, 37, 87.
21 Crystal data for 8d: C15H22O3S, Mw = 282.39, monoclinic, space group
P21 (#4), a = 6.8058(3) Å, b = 8.7130(4) Å, c = 13.1696(5) Å, β =
91.746(3)°, V = 780.58(6) Å3, Z = 2, Dx = 1.201 Mg m−3, μ(Mo Kα) =
0.21 mm−1, F(000) = 304, T = 296 K; crystal dimensions: 0.44 mm ×
0.22 mm × 0.04 mm. Of the 7329 reflections that were collected, 2515
reflections were unique. (Rint = 0.0291); equivalent reflections were
merged. All non-H atoms were refined anisotropically. R1 = 0.062, wR2 =
0.185. Crystallographic data for 8d have been deposited at the Cambridge
Crystallographic Data Center, CCDC 851777.
22 Crystal data for 4i: C22H22O3S, Mw = 366.46, triclinic, space group P1
(#1), a = 8.6495(6) Å, b = 8.6869(6) Å, c = 13.4401(9) Å, α = 72.062
(4)°, β = 89.472(4)°, γ = 85.803(5)°, V = 958.09(11) Å3, Z = 2, μ(Mo
Kα) = 0.19 mm−1, F(000) = 388, T = 296 K; crystal dimensions:
0.76 mm × 0.34 mm × 0.16 mm. Of the 13 175 reflections that were col-
lected, 5970 reflections were unique. (Rint = 0.0479); equivalent reflec-
tions were merged. R1 = 0.071, wR2 = 0.236. Crystallographic data for 4i
have been deposited at the Cambridge Crystallographic Data Center,
CCDC 851778.
23 F. López, S. R. Harutyunyan, A. Meetsma, A. J. Minnaard and B.
L. Feringa, Angew. Chem., Int. Ed., 2005, 44, 2752.
24 A recent theoretical study showed that an increase in the bite angle of the
bisphosphine results in a more hydridic and reactive copper hydride:
T. Gathy, O. Riant, D. Peeters and T. Leyssens, J. Organomet. Chem.,
2011, 696, 3425.
25 Crystal data for 9: (C43H39BrCuFeNP2)2–C2H3N, Mw = 1703.04, ortho-
rhombic, P212121 (#19), a = 9.3018(3) Å, b = 16.8469(5) Å, c = 25.9616
(8) Å, V = 4068.4(2) Å, Z = 2, μ(Mo Kα) = 1.971 mm−1, F(000) = 1740,
T = 296 K; crystal dimensions: 0.52mm × 0.40 mm × 0.36 mm. Of the
47 426 reflections that were collected, 8295 reflections were unique. (Rint
= 0.0634); equivalent reflections were merged. All non-H atoms, except
for those of the acetonitrile solvent molecule, were refined anisotropically.
Flack parameter = 0.044(15). R1 = 0.057, wR2 = 0.149. Crystallographic
data for 9 have been deposited at the Cambridge Crystallographic Data
Center, CCDC 856812.
16 G. E. Keck, E. P. Boden and S. A. Mabury, J. Org. Chem., 1985, 50,
709.
17 Some researchers have also proposed that a copper hydride complex
incorporating the silane reacts in some reductive reactions, see:
5978 | Org. Biomol. Chem., 2012, 10, 5971–5978
This journal is © The Royal Society of Chemistry 2012