Copper catalyzed tandem conjugated borylation-aldol reaction

Article abstract of DOI:10.1016/j.tet.2011.07.062

We investigated the tandem conjugated borylation-aldol reaction catalyzed by copper complexes. After identification and optimisation of the catalytic system, the scope of the reaction was evaluated and the diastereoselectivity was studied on both linear a

Full text of DOI:10.1016/j.tet.2011.07.062

Tetrahedron 68 (2012) 3435e3443
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper catalyzed tandem conjugated borylationealdol reaction
*
Alexandre Welle, Virginie Cirriez, Olivier Riant
ꢀ
Universite catholique de Louvain, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2011
Received in revised form 18 July 2011
Accepted 21 July 2011
Available online 26 July 2011
We investigated the tandem conjugated borylationealdol reaction catalyzed by copper complexes. After
identification and optimisation of the catalytic system, the scope of the reaction was evaluated and the
diastereoselectivity was studied on both linear and cyclic activated alkenes. Finally, the use of some
selected borylated aldol adducts in two classical transformations was investigated.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Domino reaction
Copper
Aldol reaction
Boron
Catalysis
1. Introduction
Domino reactions are processes in which several bonds are
formed in one step without isolating intermediates, change the
conditions of reaction or add reagents.1 These reactions are eco-
logically and economically favourable because work, time and
materials are spared. Amongst domino reaction, reductive aldol has
been developed as an efficient alternative one pot procedure for the
production of aldol derivatives without the need to generate
a metal enolate prior to the condensation with an aldehyde or
a ketone. Versions based on various transition metals catalysts2
were reported, in particular with copper.3 Since the pioneering
work of Maruoka4 and Chiu,5 intramolecular racemic5,6 and enan-
tioselective7 as well as intermolecular racemic8 and enantiose-
lective9 methods were developed based on this metal. These
reactions are proposed to proceed by the in situ formation of
a metal enolate through the conjugated reduction of a metal hy-
dride species onto the Michael acceptor (Scheme 1). Then, the
generated nucleophile is trapped by the electrophile to form the
aldol-type adduct after final reaction with the hydride source.
We recently reported a modified version of this reaction using
silylboranes as pronucleophiles and (meth)acryloyloxazolidinones
as Michael acceptors leading to stereocontrolled aldol adducts.10
Since the first reports of copper catalyzed conjugated addition of
boronic esters on activated olefins by Hosomi and Miyaura, nu-
merous improvements were achieved by addition of alcohol
Scheme 1. General reductive aldol.
additives.11 Additions to alkynes and recently to 1,3-enynes were
then developed.12 Enantioselective versions followed with appli-
cations to
a,b-unsaturated esters, nitriles, amides and ketones
based on various ligands.13 However, only few examples, always
based on cyclic substrates, involve the use of such catalytic systems
in tandem reactions. Therefore, we were attracted by using this
methodology in tandem borylationealdol reaction.
2. Results and discussion
We started our investigations by the identification of the most
effective catalytic system (Table 1) on a model reaction between
methyl acrylate 1, benzaldehyde 2 and bis-(pinacolato)-diboron 3.
We first envisioned the use of the previously described catalyst
based on N-heterocyclic carbenes8 6 (entry 1) but no activity was
observed in toluene for this complex. As polar solvents can have
a strong influence on reaction outcomes by activation/stabilisation
of key catalytic intermediates in copper (I) chemistry, we were in-
spired by the work of Sawamura et al.14 Therefore, we tried DMF as
a co-solvent (entry 2) and obtained a complete conversion of the
starting acrylate, but the desired product 4 was only observed as the
minor product in the crude 1H NMR spectra along with the major
product 5, which arises from a formal hydroboration of the Michael
* Corresponding author. Tel.: þ32 (0) 10 472740; fax: þ32 (0) 10 474168; e-mail
address: Olivier.riant@uclouvain.be (O. Riant).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.062

3436
A. Welle et al. / Tetrahedron 68 (2012) 3435e3443
Table 1
First optimisation of the catalytic systema
Entry Catalytic system
Solvent 4/5b
1
2
3
4
5
IMESCuDBM (1 mol %)
Toluene No reaction
Scheme 2. Postulated catalytic cycle.
DMF
THF
THF
1/1.6
1/2.3
1/1.5
IMesCuCl, t-BuOK (1 mol %)
CuCl, t-BuOK, (rac)-BINAP (5 mol %)
[(Ph3P)3CuF$2MeOH] 8 (1 mol %), (rac)-BINAP Toluene 20/1
(2 mol %)
identified soft transition metal in the literature (such as Rh(I), Pd(II)
and Ni(II)),18 and it has been shown in most cases that such species
are actually C-bonded metal enolates. The nucleophilic in-
termediate species involved in our mechanism can then be either
an O- or a C-bonded enolate (both species can also be considered as
formed and in equilibrium of the two tautomers). This information
is of course of high importance as the control of the geometry of an
O-enolate is known to have a profound influence on the stereo-
chemical outcome of the aldol process. However, the possible for-
mation of a C-bonded enolate would involve the formation of
a chiral metal bonded carbon centre and the stereochemical out-
come of the aldol process with such species is still far from obvious
with the lack of information on such intermediates in the literature.
Furthermore, the reaction of the copper enolate with the electro-
phile could occur through an open or a closed TS and there are still
no proof in the literature that copper bonded enolates favour one
pathway over the other.19 Finally, a fast transmetallation of the
copper enolate with the diboron 3 can also be postulated to give
rise to the formation of a boron enolate. In that case, the stereo-
chemical outcome of the aldol condensation will be mainly driven
by control of the Z/E geometry of the boron enolate.20 We have not
been so far able to isolate or identify such an intermediate in our
experiments but this hypothesis cannot still be ruled out in our
postulated mechanistic cycle.
We then evaluated the scope of the reaction, by varying the
aldol electrophilic carbonyl partners. As we found that primary
boronate derivatives, such as 4 are rather unstable on silica gel,
reaction products were isolated after oxidation of the boronic
moiety under mild conditions.11c THF was also used as solvent
because of the poor miscibility, required for the oxidation step, of
toluene with water. This reaction proved quite versatile regarding
the electrophilic counterpart and the results are summarized in
Table 2. We observed a better reproducibility for our reaction when
the catalyst loading was raised to 2 mol %. The reaction between
methyl acrylate and benzaldehyde (entry 1) led to the formation of
corresponding diol with an excellent isolated yield. The di-
astereomeric ratio measured by NMR was 1 to 1 and this lack of
diastereoselectivity was observed with every other electrophiles.
When using electron poor aromatic aldehydes (entries 2 and 3),
yields were slightly lower. Using para-anisaldehyde as an electron
rich aromatic aldehyde (entry 4) led to a similar yield. The reaction
with a heteroaromatic aldehyde, 2-furyl carboxaldehyde (entry 5),
gave also a good isolated yield. With a primary aliphatic aldehyde
(entry 6), the yield was slightly decreased but with cyclo-
hexanecarboxaldehyde (entry 7), an excellent result was obtained.
a
All reactions were carried out at 21 ꢀC under an oxygen-free argon atmosphere
containing 1 (1 equiv), 2 (1 equiv) and 3 (1.2 equiv) at 0.2 M and concentrated under
reduced pressure after 16 h before NMR analysis.
b
Determined by NMR analysis.
acceptor. As our NHC based precatalyst does not seem to be activated
by the diboron derivative in non polar solvents, we turned to a well
described catalytic system developed by Nolan for the hydro-
silylation of hindered ketones.15 Using IMesCuCl 7 activated by po-
tassium tert-butoxide in THF (entry 3) however gave a decreased
selectivity for the formation of the domino adduct 4. We then fo-
cused on the use of diphosphine ligands and first tried the in situ
catalytic system formed with copper(I) chloride, potassium tert-
butoxide and (rac)-BINAP16 as ligand (entry 4). Using those reaction
conditions, we still observed the simple addition adduct 5 as the
major product. Fortunately, when using [(Ph3P)3CuF$2MeOH]17 8 as
the copper source in combinationwith (rac)-BINAP in toluene (entry
5), we obtained an excellent 20 to 1 ratio in favour of the desired
product. From the observations summarized in Table 1, it appears
that the presence of salts, i.e., KCl, is detrimental to the formation of
the domino adduct 4 and favours the simple addition adduct 5. It
might be postulated that the presence of such salts lead to a non-
negligible amount of retro-aldol reaction, leading to boronic ester
5 and benzaldehyde 1.
The suggested catalytic cycle (Scheme 2) starts with the gen-
eration of the active coppereboron 9 species from precatalyst 10
and bis(pinacolato)diboron 3. After conjugated addition of the
boronate moiety on the electrophilic double bond of methyl acry-
late 2, the resulting copper enolate 10 reacts then with benzalde-
hyde 1 to give the copper alkoxide 11. This last intermediate
undergoes s-bond metathesis with the diboron 3 to regenerate the
active catalyst 9 and a boronate ester, which yields, after hydrolysis,
the expected aldol adduct 4. We also noticed that no competitive
addition of the boronate nucleophile occurs directly on the alde-
hyde, contrasting with this common side reaction encountered
when using hydrosilanes.8,9e
However, care should be taken when drawing such a catalytic
cycle, while there is an ever increasing number of studies that in-
volve copper enolate intermediates, the true nature of such in-
termediates still remain elusive and thus care should be taken
when trying to extrapolate classical hard metal(oid) enolate
chemistry (such as Li, Ti and boron) to very soft transition metal
enolates such as Cu(I). Indeed, there are still few examples of well

A. Welle et al. / Tetrahedron 68 (2012) 3435e3443
3437
Table 2
acrylonitrile as Michael acceptor (entry 5) conducted to the cor-
responding product with a slightly improved yield. With Weinreb
acrylamide, the expected adduct was isolated with a good yield and
with a diastereomeric ratio of 2 to 1 in favour of syn isomer.
For this adduct the relative configuration of the major di-
astereoisomer was determined after treatment of diol 27 with 2,2-
dimethoxypropane in the presence of a catalytic amount of PTSA
(Scheme 3). Dioxolane 28 was obtained in quantitative yield and
NMR analysis showed unambiguously a trans relationship between
the amide and the phenyl for the major adduct.
Scope of the reaction with electrophilesa
Entry
R
R0
Yieldb,c (%)
Product
1
2
3
4
5
6
7
8
9
10
Ph
H
H
H
H
H
H
H
H
91
68
73
74
77
67
92
70
76
89
12
13
14
15
16
17
18
19
20
21
p-ClePh
p-CF3ePh
p-OMeePh
2-Furyl
PheCH2eCH2e
Cy
t-Bu
Ph
e(CH2)5e
Me
a
All reactions were carried out at 21 ꢀC under an oxygen-free argon atmosphere
containing the electrophile (1 equiv), 2 (1 equiv) and 3 (1.2 equiv) at 0.2 M.
b
Isolated yield.
c
Scheme 3. Determination of the relative configuration of 27.
Products were isolated as 1 to 1 diastereoisomeric ratio.
As a low diastereoselectivity was achieved with benzaldehyde,
we ran out a new set of experiments with a more reactive and
sterically demanding aldehyde (Table 4). When using cyclo-
hexanecarboxaldehyde with a representative set of Michael ac-
ceptors, we were pleased to observe that a good reactivity was
retained as the corresponding adducts were isolated with good
overall yields and that modest, albeit significant diaster-
eoselectivities were obtained with this aldehyde.
Even the reaction with pivaldehyde (entry 8) gave an interesting
yield. Moderate to very good yields were obtained with ketones
(entries 9 and 10), showing the high reactivity of the copper enolate
intermediate.
We then evaluated the scope with different electron-deficient
olefins using benzaldehyde as a model electrophile (Table 3).
We first examined the effect of the substituents around the
double bond. When methyl methacrylate (entry 1) was used, the
desired product was isolated with a good yield, showing of the
possibility of building chiral quaternary carbon centre through an
Table 4
Scope of the reaction with cyclohexanecarboxaldehydea
a
substitution on the Michael acceptor. On the other hands, the
introduction of substituent at the -position (entry 2) led to a di-
b
minished catalytic activity as monitored by TLC. The diaster-
eoselectivity was very low as the four possible diastereoisomers
were detected by NMR impeding us to isolate and characterize the
product. When a
action occurred, showing the major importance of
substitution. Replacing an -unsaturated ester by an enone
b
disubstituted ester was used (entry 3), no re-
b
- compared to
a
a,b
Entry
EWG
R1
Yieldb (%)
syn/antic,d
Product
(entry 4), afforded the desired aldol adduct with a good yield. Using
1
2
3
4
CO2Et
C(O)Me
CN
Me
H
H
87
77
87
73
2/1
60/40
3/1
29
30
31
32
Table 3
Scope of the reaction with electrodeficient olefinsa
C(O)N(Me)OMe
H
3/1
a
All reactions were carried out at 21 ꢀC under an oxygen-free argon atmosphere
containing cyclohexanecarboxaldehyde (1 equiv), Michael acceptor (1 equiv) and 3
(1.2 equiv) at 0.2 molarity unless otherwise stated.
b
Isolated yield.
c
Diastereoisomeric ratio determined by 1H NMR.
d
Relative configuration determined by 1H NMR after cyclisation as the corre-
sponding dioxolane.
Indeed, ethyl methacrylate (entry 1) led to an excellent yield and
a 2 to 1 syn/anti ratio, while methyl vinylketone (entry 2) gave
a lowered selectivity as well as a slightly lower yield. Using acry-
lonitrile (entry 3), a very good yield was achieved and an interesting
3 to 1 ratio in favour of anti isomer was obtained. Weinreb acryl-
amide (entry 4) gave a comparable yield and an improved dia-
stereoselectivity. Relative configurations were determined using
the same methodology as for compound 27.
As we observed modest, albeit significant diastereoselectivities
with the Weinreb acrylamide, we first retained this Michael ac-
ceptor and carried out a preliminary substrate scope with two ar-
omatic aldehydes. The domino reaction was then carried out using
the standard catalytic system with p-anisaldehyde and 2-furyl
Entry
EWG
R1
R2
R3
Yieldb (%)
Product
1
2
3
4
5
6
CO2Me
CO2Me
CO2Me
C(O)Me
CN
Me
H
H
H
H
H
H
H
Me
H
H
79
22
23
24
25
26
27
Me
Me
H
H
H
dc
dd
69
76
C(O)N(Me)OMe
H
H
72 (2/1)e
a
All reactions were carried out at 21 ꢀC under an oxygen-free argon atmosphere
containing benzaldehyde (1 equiv), Michael acceptor (1 equiv) and 3 (1.2 equiv) at
0.2 M unless otherwise stated.
b
Isolated yield.
c
1H NMR analysis showed a 1/1/0.8/0.5 diastereoisomeric ratio.
d
No reaction after 36 h.
Diastereoisomeric ratio determined by NMR.
e

3438
A. Welle et al. / Tetrahedron 68 (2012) 3435e3443
carboxaldehyde. While the isolated yields for adducts 33e34 after
oxidation remained quite modest, we were able to confirm a 3/1
syn/anti ratio for both electrophiles (Scheme 4). Those observations
are quite promising as they might be a good starting point for
further optimisations and development of an enantioselective re-
action based on the use of a proper chiral ligand. Such adducts are
particularly promising as transformations can be carried out on
both the amide group and on the boronate using well known
methodologies (vide supra).
that the absolute configuration of three new centres is controlled
(Scheme 6). As the oxidation of the boronate ester was not possible
for cyclopentenone, we have not yet been able to isolate the pure
adduct and confirm the stereochemistry of the newly formed chiral
carbon centres.
Scheme 6. Tandem reaction using enantiopure cyclic enone.
As stated earlier, all the optimisations and isolated yields of the
domino adducts were carried out on the diols resulting from the
perborate oxidation of the crude boronate ester. As we observed
that the crude 1H NMR spectrum of the boronate esters taken after
simple evaporation of the reaction mixture were usually very clean,
we decided to carry out some attempts to isolate those function-
alised boron derivatives and our choice focussed naturally on the
preparation of stable and versatile trifluoroborate salts,23 which
can be easily obtained by reaction of alkylboronate esters with
potassium bifluoride. Our choice was strongly motivated by two
reports from the groups of Molander23c and Yun13e who reported
Scheme 4. Tandem reaction using Weinreb acrylamide.
While modest diastereoselectivities were observed with acyclic
Michael acceptors, we also decided to check the reactivity of simple
cyclic enones as models. As the true nature of the enolate in-
termediate that will react with the aldehyde has still not been
established (Scheme 2) as well as the transition state involved in
the aldol process between the metal enolate and the aldehyde,
previsions on the stereochemical outcome of cyclic substrates are
not straightforward, although a recent study by the group of Hov-
eyda gave one example of a highly diastereoselective tandem
conjugated additionealdol reaction on cyclohexenone using a chi-
ral NHCecopper(I) complex.21 Furthermore, an early study of tan-
dem conjugated additionealdol reaction with hydroboranes and
Stryker’s reagents as the catalyst was reported to yield high dia-
stereoslectivities in favour of the anti-aldol adduct on cyclo-
alkenones with the intervention of an intermediate E-boron
enolate. We then tested cyclohexenone and cyclopentenone as
model substrates and found different behaviour depending on the
ring size of the Michael acceptor. In all cases, the boron ester arising
from the tandem process was identified in the crude reaction
mixture by 1H NMR but was not isolated and was directly oxidised
to the corresponding diol, which was then protected as a dioxolane
(Scheme 5) in a one pot sequence for relative configuration
determination.
the preparation of potassium b-trifluoroborato amides and esters
via the copper catalyzed addition of diboron 3 on Michael acceptors
followed by treatment with KHF2. However, the reported procedure
proved troublesome in our hand (Scheme 7) and a full character-
isation of salts 39 and 40 was impossible due to the low solubility of
those salts in various solvents.
Scheme 7. Attempts at isolation of aldol adducts as trifluoroborate salts.
Organoboronate derivatives are versatile intermediates in or-
ganic synthesis and their main application is found in the Suzuki
cross-coupling reaction. We carried out a one pot experiment to
avoid the isolation of the boronate ester and to keep the hydroxyl
group of the crude adduct protected as a borate ester to avoid po-
tential retro-aldol reaction with the base required for the cross-
coupling reaction. Thus, after condensation of benzaldehyde 1,
methyl acrylate 2 and diboron 3 using the standard catalytic con-
ditions, the solvent was evaporated from the crude reaction mix-
ture without any work-up and replaced by DMF. The Suzuki
reaction was then directly carried out with iodobenzene using
Pd(PPh3)4 as a catalyst and caesium carbonate as a base using an
optimised protocol from the literature.24 We were pleased to ob-
serve that the corresponding adduct 41 could be isolated as a sep-
arable mixture of syn/anti diastereoisomers in an excellent 89%
yield for the two steps (Scheme 8). This preliminary experiment
shows that it is potentially possible to have access to structural
diversity on this family of adducts by simple variation of the al-
dehyde electrophile and Suzuki coupling electrophilic partner.
Scheme 5. Tandem reaction using cyclic enones.
Although the unoptimised yield with cyclohexenone is modest,
only one diastereoisomer was detected in the crude reaction mix-
ture prior to oxidation. In contrast, we were disappointed by the
spontaneous dehydration after boronic ester oxidation when using
cyclopentenone, although diastereocontrol was very good. In this
case, every attempt to prevent water elimination failed.
We also investigated the use of a functionalised chiral Michael
acceptor and focussed on the enantiopure enone 37, which was
easily prepared from D
-ribose using a protocol from the literature.22
After reaction in the standard catalytic conditions, the desired ad-
duct 38 was obtained as the major product and only one di-
astereoisomer was detected in the crude reaction mixture, meaning

A. Welle et al. / Tetrahedron 68 (2012) 3435e3443
3439
1) [(Ph3P)3CuF.2MeOH] 8 (2 mol%)
(rac)-BINAP (2 mol%)
500 spectrometer. Tetramethylsilane was used as internal standard
for 1H and 13C. Chemical shift are given in part per million (ppm),
and multiplicity given as follows: singlet (s), doublet (d), triplet (t),
quadruplet (q), multiplet (m) and broad (br). Coupling constant J
are given in Hertz (Hz). Mass spectra were obtained using a Ther-
moFinnigan LCQ Quantum spectrometer for electrospray ionization
(ESI) and atmospheric pressure chemical ionization (APCI) or using
a FinniganMat TSQ7000 for chemical ionization (CI). High resolu-
tion mass spectrometry (HMRS) was performed by Dr. Lisa D. Harris
at the Mass Spectrometry Facility of the University College of
London. Infrared spectra (IR) were recorded on a Shimadzu FTIR-
8400S spectrometer. Wave numbers a given in cmꢁ1. Solvents are
of analytical grade or distilled before use: toluene was distilled on
sodium under an argon atmosphere. THF was distilled on sodium/
benzophenone under an argon atmosphere. Commercial reagents
were purchased by Acros, SigmaeAdrich, ABCR, TCI or Apolo sci-
entific and used as received unless stated otherwise. Aldehydes
were distilled before used. Flash column chromatography was
OH
3
PinB-BPin (1.2 equiv.)
O
CO2Me
CO2Me
Ph
THF, RT, 16 h
+
Ph
Ph
2) [(Ph3P)4Pd] (10 mol%), PhI (2 equiv.)
CsF (4 equiv.), DMF, 100 °C,
overnight
1
2
41
89 %
Scheme 8. Domino borylationealdoleSuzuki coupling.
In order to go further in the synthetic versatility of three com-
ponent adducts, we finally checked the transformation of a model
adduct bearing a Weinreb amide group. The condensation of
benzaldehyde, Weinreb acrylamide and diboron 3 was carried out
with a 2 mol % of the copper(I) catalytic system to deliver the in-
termediate borate ester 42. The intermediate bearing a temporary
protection on the hydroxyl group was not isolated and directly
reacted with a large excess of methyl lithium to carry out the
transformation of the amide group into the corresponding methyl
ketone 43 (Scheme 9). Final oxidation of the boronate ester by
sodium perborate delivered the desired keto-diol 24 in a 48%
overall yield for the three steps and a 3/1 syn/anti ratio.
performed on ROCC 60 (40e63 mm) silica gel. Thin layer chroma-
tography (TLC) was carried out on commercially available MERCK
5179, 250 mesh with fluorescent indicator 60 PF254, and revealed
under UV at 254 nm and with a solution of para-anisaldehyde in
ethanol (10% w/v) or a basic solution of KMnO4. IMesCuDBM,8
IMesCuCl,15 [(Ph3P)3CuF$2MeOH],17 Weinreb acrylamide25 and
cyclopentenone 3818 were prepared according to protocols from
the literature.
1)[(Ph3P)3CuF.2MeOH] 8 (2 mol%)
(rac)-BINAP (2 mol%)
O
PinB-BPin 3 (1.2 equiv.)
OH
O
O
OMe
THF, RT, 16 h
+
N
Ph
Me
Ph
2) CH3Li (5 equiv.), -78°C->25°C, 1h
3) NaBO3 (5 equiv.), H2O, 15 h
OH
25
4.2. General procedure for tandem reaction
48%, sy n/ anti : 3:1
borylationealdolisation
O
B
O
B
O
O
O
O
O
O
A dried flask was loaded with [(Ph3P)3CuF$2MeOH] (9.3 mg,
0.01 mmol, 0.02 equiv) and (rac)-BINAP (6.2 mg, 0.01 mmol,
0.02 equiv). The system was closed with a septum and after 3 vac-
uum/argon cycles, the solvent (2.5 mL) was added by syringe. After
dissolution of the solids, the Michael acceptor (0.5 mmol, 1 equiv)
and the electrophile (0.5 mmol, 1 equiv) were added. Bis(pinaco-
lato)diboron (152 mg, 0.6 mmol, 1.2 equiv) was added, and the
mixture was stirred overnight. Water (2.5 mL) and NaBO3$H2O
(249 mg, 2.5 mmol, 5 equiv) were added and the biphasic mixture
was stirred for a further 3 h. EtOAc (5 mL) was added, the aqueous
phase was saturated with NaCl and the phases were separated. The
aqueous phase was extracted with EtOAc (3ꢂ5 mL) and the com-
bined organic phases were dried over Na2SO4 and concentrated
under reduced pressure. The product was finally purified by flash
chromatography on silica gel. As pinacol is a common byproduct
found in some analytical samples, a distillation under vacuum lead
to the pure aldol adducts. Unless otherwise stated, the products
were isolated as mixture of unseparable syn/anti isomers. N.B.
When toluene was used as solvent, MeOH (2 mL) was added to the
mixture for the oxidation step.
OMe
Ph
O
N
Ph
O
Me
B
O
B
O
42
43
Scheme 9. One-pot post transformation of a Weinreb amide.
3. Conclusions
We developed an efficient procedure for the tandem bor-
ylationealdol reaction based on copper catalysis. The best condi-
tions are the use of the air-stable copper fluoride complex 8 in
combination with a commercially available diphosphine and the
reaction is very fast at room temperature. A wide variety of alde-
hydes as well as ketones may be used and leads to good to excellent
yields. Regarding the Michael acceptor, the catalytic systemtolerates
a
substitution but is sensitive to b-substitution. Different types of
electronwithdrawing groups on the Michael acceptor may be
employed and low level diastereoselection are observed with linear
substrates. The use of cyclic substrates increases dramatically the
diastereoselectivity and enantiopure substrates lead to the control
the absolute configuration of three new contiguous centres. Al-
though the isolation of products as trifluoroborate salts is trouble-
some, it is possible to combine our protocol with Suzuki coupling.
We are currently working on the development of a chiral ligand
based enantioselective version of this reaction studying the scope
of the transformation of the boronic esters with a focus on the
Weinreb amides.
4.2.1. Methyl 3-hydroxy-2-(hydroxymethyl)-3-phenylpropanoate
12. The product was isolated using the general procedure as a col-
ourless oil (91%) after flash chromatography on silica gel using P.E./
EtOAc as eluent (65/35). 1H NMR (300 MHz, CDCl3):
d 2.48 (br s,
0.5H, OH), 2.80e2.91 (dd, J¼5.7 and 4.5 Hz, 0.5H, HCO2Me),
2.91e2.97 (dt, J¼7.2 and 2.1 Hz, 0.5H, HCO2Me), 3.01 (br s, 0.5H,
OH), 3.34 (d, J¼4.5 Hz, 0.5H, CH2OH), 3.63 (d, J¼5.7 Hz, 1H, CH2OH),
3.66 and 3.71 (s, 3H, CH3O), 3.75 (br s, 0.5H, OH), 3.95 (d, J¼2.1 Hz,
1H, CH2OH), 5.04 (dd, J¼7.2 and 4.5 Hz, 0.5H, CHOH), 5.27 (t,
J¼4.5 Hz, 0.5H, CHOH), 7.27e7.35 (m, 5H, CHar.). 13C NMR (75 MHz,
4. Experimental section
CDCl3):
d 52.2 (CHCO2Me), 53.4 (OCH3), 54.6 (OCH3), 60.9 (OCH2),
4.1. General experimental methods
61.6 (OCH2), 73.1 (CHOH), 74.1 (CHOH), 125.9 (CHar.), 126.3 (CHar.),
127.9 (CHar.), 128.2 (CHar.), 128.6 (CHar.), 128.7 (CHar.), 141.4 (Car.),
141.4 (Car.), 173.6 (CO2Me), 174.3 (CO2Me). LRMS (APCI) m/z: 103.1
(35%), 131.1 (100%), 163.1 (45%). IR (film, cmꢁ1): 3419, 2952, 1720,
Nuclear magnetic resonance spectra (NMR) of proton (1H) and
carbon (13C) were recorded on Bruker-250, Bruker-300 and Bruker-

3440
A. Welle et al. / Tetrahedron 68 (2012) 3435e3443
1436, 1197, 1026, 702. HRMS (ESI) calculated for C11H14O4Na
m/z: 200.8 (100%),182.8 (45%),154.9 (35%),152.8 (65%),138.8 (85%).
HRMS (CI) calculated for C9H13O5 [MþH]þ: 201.07630, found:
201.07644 (0.70 ppm). IR (film, cmꢁ1): 3419, 2952, 1728, 1436, 1325,
1261, 1168, 1010, 746.
([MþNa]þ) 233.0790, found 233.0800 (4.3 ppm).
4.2.2. Methyl
3-(4-chlorophenyl)-3-hydroxy-2-(hydroxymethyl)
propanoate 13. The product was isolated using the general pro-
cedure as a colourless oil (68%) after flash chromatography on silica
gel using P.E./i-PrOH as eluent (90/10). 1H NMR (300 MHz, CDCl3):
4.2.6. Methyl 3-hydroxy-2-(hydroxymethyl)-5-phenylpentanoate
17. The product was isolated using the general procedure as a col-
ourless oil (67%) after flash chromatography on silica gel using P.E./i-
d
2.79e2.94 (m, 1H, HCO2Me), 3.64 and 3.67 (s, 3H, CH3O),
3.80e3.90 (m, 2H, CH2OH), 5.13 (d, J¼6.5 Hz, 0.5H, CHOH), 5.30 (d,
PrOH as eluent (90/10). 1H NMR (300 MHz, CDCl3):
d 1.80e2.00 (m,
J¼5.6 Hz, 0.5H, CHOH), 7.45 (d, J¼7.5 Hz, 2H, CHar.), 7.57 (d,
2H, CH2CHOH), 2.50e2.75 (m, 2H, CH2Ph), 2.80e2.90 (m, 1H,
HCO2Me), 3.19 (br s, 2H, OH), 3.73 (s, 3H, CH3O), 3.87e4.17 (m, 3H,
CH2OH and CHOH), 7.18e7.32 (m, 5H, CHar.). 13C NMR (75 MHz,
J¼7.5 Hz, 2H, CHar.) 13C NMR (75 MHz, CDCl3):
d 51.0 (CHCO2Me),
51.9 (CHCO2Me), 52.3 (OCH3), 61.1 (OCH2), 61.6 (OCH2), 67.0
(CHOH), 68.3 (CHOH), 107.1 (CHar.), 107.5 (CHar.), 110.4 (CHar.),
142.3 (Car.), 142.5 (Car.), 153.8 (ClCar.), 154.2 (ClCar.), 173.1 (CO2Me),
173.7 (CO2Me). LRMS (CI) m/z: 244.9 (35%), 226.8 (20%), 212.8 (15%),
196.8 (100%). HRMS (CI) calculated for C11H14O345Cl [MþH]þ:
245.05806, found: 245.05882 (3.1 ppm). IR (film, cmꢁ1): 3369,
2952, 1728, 1436, 1325, 1261, 1195, 1164, 1120, 1066, 1014, 835, 723.
CDCl3):
d 32.1 (CH2Ph), 32.2 (CH2Ph), 36.9 (CH2CHOH), 37.1
(CH2CHOH), 51.9 (CHCO2Me), 52.0 (CHCO2Me), 52.1 (OCH3), 52.2
(OCH3), 61.0 (OCH2), 62.2 (OCH2), 70.7 (CHOH), 70.9 (CHOH), 125.9
(CHar.), 128.5 (CHar.), 132.0 (CHar.), 132.2 (CHar.), 141.7 (two peaks)
(Car.), 174.0 (CO2Me), 174.1 (CO2Me). LRMS (CI) m/z: 238.9 (20%),
188.8 (45%), 170.8 (25%), 142.8 (100%). HRMS (CI) calculated for
C13H19O4 [MþH]þ: 239.12833, found: 239.12782 (2.13 ppm). IR (film,
cmꢁ1): 3417, 2950, 1731, 1436, 1336, 1263, 1193, 1068, 1029, 698.
4.2.3. Methyl 3-hydroxy-2-(hydroxymethyl)-3-(4-(trifluoromethyl)
phenyl)propanoate 14. The product was isolated using the general
procedure as a colourless oil (73%) after flash chromatography on
silica gel using P.E./i-PrOH as eluent (90/10). 1H NMR (300 MHz,
4.2.7. Methyl 3-cyclohexyl-3-hydroxy-2-(hydroxymethyl)propanoate
18. The product was isolated using the general procedure as a col-
ourless oil (92%) after flash chromatography on silica gel using P.E./
EtOAc as eluent (65/35). 1H NMR (300 MHz, CDCl3): major isomer
CDCl3):
d
2.82 (q, J¼4.5 Hz, 0.5H, HCO2Me), 2.93 (q, J¼5.4 Hz, 0.5H,
HCO2Me), 3.66 (s, 1.5H, CH3O), 3.68 (s, 1.5H, CH3O), 3.80e3.98 (m,
2H, CH2OH), 5.15 (d, J¼6.6 Hz, 0.5H, CHOH), 5.30 (d, J¼5.7 Hz, 0.5H,
CHOH), 7.47 (d, J¼6.9 Hz, 2H, CHar.), 7.60 (d, J¼8.1 Hz, 2H, CHar.). 13C
d
0.8e2.1 (m, 11H, CHcy.), 2.73 (q, J¼4.2 Hz, 1H, HCO2Me), 3.77 (s,
3H, CH3O), 3.84 (dd, J1¼7.5 Hz, J2¼4.2 Hz, 1H, CH2OH), 4.03 (d,
0.8e2.1 (m, 11H,
NMR (75 MHz, CDCl3):
d
52.2 (CHCO2Me), 53.6 (CHCO2Me), 54.2
J¼3.6 Hz, 2H, CH2OH and CHOH). Minor isomer:
d
(OCH3), 60.9 (OCH2), 61.3 (OCH2), 72.2 (CHOH), 73.3 (CHOH), 118.7,
122.3, 125.9, 129.5 (q, JCeF¼270.6 Hz, CF3), 125.4 (CHar.), 125.8
(CHar.), 126.4 (CHar.), 126.6 (CHar.), 128.6 (CHar.), 128.8 (CHar.),
129.9 (q, JCeF¼32 Hz, CCF3), 130.0 (q, JCeF¼32 Hz, CCF3), 131.9
(CHar.), 132.1 (CHar.), 132.2 (CHar.), 132.3 (CHar.), 145.6 (Car.), 145.7
(Car.), 173.0 (CO2Me), 173.6 (CO2Me). LRMS (CI) m/z: 278.9 (100%),
230.8 (10%). HRMS (CI) calculated for C12H14O4F3 [MþH]þ:
279.08440, found: 279.08445 (0.02 ppm). IR (film, cmꢁ1): 3369,
2952, 1730, 1325, 1249, 1166, 1120, 1016, 833.
CHcy.), 2.83 (q, J¼5 Hz, 1H, HCO2Me), 3.56 (dd, J1¼7.7 Hz, J2¼3.5 Hz,
1H, CH2OH), 3.76 (s, 3H, CH3O), 3.97 (t, J¼5.5 Hz, 2H, CH2OH and
CHOH). 13C NMR (75 MHz, CDCl3): major isomer
d 25.9 (CH2cy.),
26.4 (CH2cy.), 29.4 (CH2cy.), 41.2 (CHcy.), 48.3 (CHCO2Me), 52.2
(OCH3), 61.0 (OCH2), 76.7 (CHOH), 174.9 (CO2Me). Minor isomer:
d
25.9 (CH2cy.), 26.1 (CH2cy.), 29.6 (CH2cy.), 42.0 (CHcy.), 48.7
(CHCO2Me), 52.0 (OCH3), 63.6 (OCH2), 76.5 (CHOH), 174.5 (CO2Me).
LRMS (APCI) m/z: 216.8 (100%),198.5 (75%),100.8 (25%). HRMS (ESI)
calculated for C11H20O4Na ([MþNa]þ) 239.1259, found 239.1256
(1.2 ppm). IR (film, cmꢁ1): 3419, 2925, 2852, 1731, 1436, 1259, 1172,
1118, 723, 696.
4.2.4. Methy 3-hydroxy-2-(hydroxymethyl)-3-(4-methoxyphenyl)pr-
opanoate 15. The product was isolated using the general procedure
as a colourless oil (74%) after flash chromatography on silica gel
using P.E./i-PrOH as eluent (90/10). 1H NMR (300 MHz, CDCl3):
4.2.8. Methyl 3-hydroxy-2-(hydroxymethyl)-4,4-dimethylpentanoate
19. The product was isolated using the general procedure as a col-
ourless oil (70%) after flash chromatography on silica gel using P.E./
d
2.78e2.92 (m, 1H, HCO2Me), 3.60 and 3.68 (s, 3H, CH3OC(O)), 3.75
(s, 3H, CH3OPh), 3.55e3.99 (m, 2H, CH2OH), 4.95 (d, J¼7.7 Hz, 0.5H,
i-PrOH as eluent (90/10). 1H NMR (300 MHz, CDCl3):
d 0.90 and 0.91
CHOH), 5.13 (d, J¼7.3 Hz, 0.5H, CHOH), 6.84 (d, J¼8.2 Hz, 2H, CHar.),
(s, 9H, (CH3)3C), 2.70e2.90 (m, 1H, HCO2Me), 3.05 (br s, 0.5H, OH),
3.20 (br s, 0.5H, OH), 3.70 and 3.71 (s, 3H, CH3O), 3.85e4.10 (m, 3H,
7.23 (d, J¼7.2 Hz, 2H, CHar.) 13C NMR (75 MHz, CDCl3):
d 52.0
(CHCO2Me), 52.1 (CHCO2Me), 54.1 (OCH3), 54.8 (CH3OPh), 55.3
(CH3OPh), 61.2 (OCH2), 61.3 (OCH2), 72.5 (CHOH), 73.6 (CHOH),
113.8 (CHar.), 113.9 (CHar.), 127.2 (CHar.), 127.5 (CHar.), 133.5 (Car.),
133.7 (Car.), 159.1 (MeOCar.), 159.3 (MeOCar.), 173.3 (CO2Me), 174.4
(CO2Me). LRMS (CI) m/z: 240.9 (55%), 192.8 (55%), 160.8 (100%),
128.2 (25%), 137.1 (60%). HRMS (CI) calculated for C12H17O5
[MþH]þ: 241.10760, found: 241.10776 (0.66 ppm). IR (film, cmꢁ1):
3421, 2952, 1728, 1514, 1247, 1174, 1029, 833.
CH2OH and CHOH). 13C NMR (75 MHz, CDCl3):
d 25.9 (CH3C), 26.2
(CH3C), 29.4 (CH3C), 29.8 (CH3C), 46.9 (CHCO2Me), 48.4 (CHCO2Me),
52.2 (OCH3), 62.6 (OCH2), 64.6 (OCH2), 78.7 (CHOH), 79.1 (CHOH),
174.9 (CO2Me), 175.7 (CO2Me). LRMS (CI) m/z: 191.1 (100%), 173.0
(95%), 155.1 (99%), 141.1 (48%). HRMS (CI) calculated for C9H19O4
[MþH]þ: 191.12833, found: 191.12834 (0.05 ppm). IR (film, cmꢁ1):
3444, 2954, 1733, 1436, 1166, 723.
4.2.9. Methyl 3-hydroxy-2-(hydroxymethyl)-3-phenylbutanoate
20. The product was isolated using the general procedure as a col-
ourless oil (76%) after flash chromatography on silica gel using P.E./
EtOAc as eluent (65/35). 1H NMR (300 MHz, CDCl3): first isomer:
4.2.5. Methyl
3-(furan-2-yl)-3-hydroxy-2-(hydroxymethyl)prop-
anoate 16. The product was isolated using the general procedure as
a colourless oil (77%) after flash chromatography on silica gel using
P.E./i-PrOH as eluent (90/10). 1H NMR (300 MHz, CDCl3):
d
1.60 (s, 3H, CH3C), 2.46 (br t, J¼5.9 Hz, 1H, HCO2Me), 2.95 (dd,
d
3.01e3.17 (m,1H, HCO2Me), 3.71 and 3.74 (s, 3H, CH3O), 3.76e4.01
J1¼5.2 and 4.2 Hz, 1H, CH2OH), 3.64e3.72 (m, 2H, CH2OH and OH),
(m, 2H, CH2OH), 5.07 (d, J¼6.6 Hz, 0.5H, CHOH), 5.25 (d, J¼5.6 Hz,
3.81 (s, 3H, CH3O), 4.21 (s, 1H, OH), 7.26e7.42 (m, 5H, CHar.). Second
0.5H, CHOH), 6.30e6.32 (m, 2H, CHar.), 7.36 (d, J¼0.6 Hz, 1H, CHar.).
isomer:
(dd, J1¼6 Hz, J2¼4 Hz,1H, CH2OH), 3.52 (s, 3H, CH3O), 4.01e4.08 (m,
1H, CH2OH), 4.21e4.25 (m, 2H, OH), 7.26e7.40 (m, 5H, CHar.). 13
NMR (75 MHz, CDCl3): first isomer: 30.2 (CCH3), 52.3 (OCH3), 56.1
(CHCO2Me), 62.2 (CH2OH), 75.6 (COH), 124.6 (CHar.), 127.2 (CHar.),
d
1.57 (s, 3H, CH3C), 2.62 (br t, J¼5.3 Hz, 1H, HCO2Me), 3.12
13C NMR (75 MHz, CDCl3):
d 51.0 (CHCO2Me), 51.9 (CHCO2Me), 52.3
(OCH3), 61.1 (OCH2), 61.5 (OCH2), 67.0 (CHOH), 68.3 (CHOH), 107.1
(CHar.), 107.5 (CHar.), 110.4 (CHar.), 142.3 (CHar.), 142.5 (CHar.),
153.8 (Car.), 154.2 (Car.), 173.1 (CO2Me), 173.7 (CO2Me). LRMS (CI)
C
d

A. Welle et al. / Tetrahedron 68 (2012) 3435e3443
3441
128.6 (CHar.), 145.0 (Car.), 175.1 (CO2Me). Second isomer:
d
28.1
(3.0 ppm). IR (film, cmꢁ1): 3369, 2246, 1436, 1338, 1149, 1120, 1070,
(CCH3), 52.1 (OCH3), 55.7 (CHCO2Me), 61.7 (CH2OH), 75.6 (COH),
124.4 (CHar.), 127.2 (CHar.), 128.4 (CHar.), 147.0 (Car.), 174.7
(CO2Me). LRMS (CI) m/z: 117.2 (25%), 107.2 (50%), 105.7 (25%), 89
(30%), 70.9 (100%). HRMS (ESI) calculated for C12H16O4Na
([MþNa]þ): 247.0946, found 247.0943 (1.2 ppm). IR (film, cmꢁ1):
3419, 2952, 1720, 1436, 1197, 1026, 702.
910, 723, 694.
4.2.14. 3-Hydroxy-2-(hydroxymethyl)-N-methoxy-N-methyl-3-
phenylpropanamide 27. The product was isolated using the general
procedure as a colourless oil (73%) after flash chromatography on
silica gel using P.E./i-PrOH as eluent (85/15). 1H NMR (300 MHz,
CDCl3):
d 3.14 (s, 3H, CH3N), 3.20 (br s, 1H, OH), 3.57 (s, 3H, CH3O),
4.2.10. Methyl 3-hydroxy-2-(1-hydroxycyclohexyl)propanoate 21.
The product was isolated using the general procedure as a colour-
less oil (89%) after flash chromatography on silica gel using P.E./
3.68e3.75 (m, 1H, CHC(O)), 4.60e4.80 (m, 3H, CH2OH and OH), 5.07
(d, J¼5.2 Hz,1H, CHOH), 7.27e7.45 (m, 5H, CHar.). 13C NMR (75 MHz,
CDCl3):
d 32.2 (NCH3), 46.4 (HCC(O)), 61.7 (CH2OH), 65.9 (OCH3),
EtOAc as eluent (65/35). 1H NMR (300 MHz, CDCl3):
d
1.10e1.80 (m,
72.6 (CHOH), 126.0 (CHar.), 128.3 (CHar.), 128.7 (CHar.), 140.5 (Car.),
174.5 (C(O)). LRMS (CI) m/z: 240.3 (100%), 229.2 (15%), 101.1 (15%),
100.2 (45%). HRMS (ESI) calculated for C12H17NO4Na ([MþNa]þ)
262.1055, found 262.1047 (3.0 ppm). IR (film, cmꢁ1): 3350, 2923,
2850, 1633, 1448, 1419, 1384, 1178, 1110, 989.
10H, CHcy.), 2.64 (dd, J¼6.2 and 4.1 Hz, 1H, HCO2Me), 3.40 (br s, 1H,
OH), 3.76 (s, 3H, CH3O), 3.96 (dd, J¼11.3 and 4.1 Hz, 1H, CH2O), 4.12
(dd, J¼11.3 and 6.2 Hz, 1H, CH2O). 13C NMR (75 MHz, CDCl3):
d 21.7
(CH2cy.), 25.6 (CH2cy.), 35.3 (CH2cy.), 37.0 (CH2cy.), 52.0 (OCH3),
55.0 (CHCO2Me), 60.9 (OCH2), 72.6 (HOC), 175.0 (CO2Me). LRMS (CI)
m/z: 202.3 (20%), 185.3 (100%), 167.3 (65%), 103.9 (30%), 99.0 (30%).
IR (film, cmꢁ1): 3415, 2931, 2860, 1716, 1436, 1359, 1257, 1197, 1170,
1149, 1037, 1020. HRMS (ESI) calculated for C10H18O4Na ([MþNa]þ)
225.1103, found 225.1103 (0 ppm).
4.2.15. Ethyl 3-cyclohexyl-3-hydroxy-2-(hydroxymethyl)-2-
methylpropanoate 29. The product was isolated using the general
procedure as a colourless oil (89%) after flash chromatography on
silica gel using P.E./EtOAc as eluent (65/35). 1H NMR (300 MHz,
CDCl3):
OH), 3.50e3.55 (m, 1H, CHOH), 3.65e3.85 (m, 2H, CH2OH),
4.10e4.25 (m, 2H, CH3CH2). 13C NMR (75 MHz, CDCl3):
15.4
(CH3CH2), 17.9 (CH3CH2), 20.1 (CH3C), 26.1 (CH2cy.), 26.3 (CH2cy.),
26.6 (CH2cy.), 26.7 (CH2cy.), 31.3 (CH2cy.), 31.6 (CH2cy.), 40.3
(CHcy.), 40.5 (CHcy.), 50.4 (CCO2Et), 51.4 (CCO2Et), 61.1 (CH2OH),
67.7 (CH3CH2), 68.8 (CH3CH2), 79.0 (CHOH), 80.4 (CHOH), 176.5
(CO2Et), 176.6 (CO2Et). LRMS (APCI) m/z: 287.0 (100%), 286.0 (55%).
IR (film, cmꢁ1): 3440, 2923, 2852, 1722, 1448, 1413, 1247, 1103, 1027,
985.
d 1.10e1.95 (m, 17H, CHcy., CH3CH2 and CH3C), 3.16 (br s, 1H,
4.2.11. Methyl 3-hydroxy-2-(hydroxymethyl)-2-methyl-3-phenylpro-
panoate 22. The product was isolated using the general pro-
cedure as a colourless oil (79%) after flash chromatography on silica
gel using P.E./EtOAc as eluent (65/35). 1H NMR (300 MHz, CDCl3):
d
d
0.93 (s, 1.5H, CH3C), 1.08 (s, 1.5H, CH3C), 3.40 (br s, 2H, OH), 3.51 (d,
J¼11.3 Hz, 0.5H, CH2OH), 3.67e3.85 (m, 4.5H, CH2OH and CH3O),
5.11 (s, 0.5H, CHOH), 5.13 (s, 0.5H, CHOH), 5.28e5.40 (m, 5H, CHar.).
13C NMR (75 MHz, CDCl3):
d 15.1 (CCH3), 17.1 (CCH3), 52.1 (OCH3),
52.3 (OCH3), 52.4 (CCH3), 52.8 (CCH3), 65.9 (OCH2), 67.1 (OCH2), 76.5
(OCH), 78.8 (OCH), 126.3 (CHar.), 127.0 (CHar.), 127.4 (CHar.), 127.9
(CHar.), 128.0 (CHar.), 128.1 (CHar.), 139.3 (Car.), 139.7 (Car.), 176.6
(CO2Me), 176.7 (CO2Me). LRMS (APCI) m/z: 225.2 (32%), 207.1 (11%),
177.2 (100%). HRMS (ESI) calculated for C12H16O4Na ([MþNa]þ)
247.0946, found 247.0945 (0.4 ppm). IR (film, cmꢁ1): 3394, 2950,
1716, 1454, 1234, 1118, 1039, 732, 703.
4.2.16. 4-Cyclohexyl-4-hydroxy-3-(hydroxymethyl)butan-2-one
30. The product was isolated using the general procedure as a col-
ourless oil (77%) after flash chromatography on silica gel using P.E./
EtOAc as eluent (65/35). 1H NMR (300 MHz, CDCl3):
d 0.85e2.05 (m,
11H, CHcy.), 2.27 and 2.28 (s, 3H, CH3CO), 2.72 (q, J¼3.5 Hz, 0.5H,
CHCO), 2.96 (q, J¼4.7 Hz, 0.5H, CHCO), 3.53 (dd, J¼7.0 and 4.1 HZ,
0.5H, CH2OH), 3.50e4.10 (m, 2.5H, CH2OH and CHOH). 13C NMR
4.2.12. 4-Hhydroxy-3-(hydroxymethyl)-4-phenylbutan-2-one
25. The product was isolated using the general procedure as a col-
ourless oil (69%) after flash chromatography on silica gel using P.E./
(75 MHz, CDCl3):
d 24.9 (CH2cy.), 25.9 (CH2cy.), 26.1 (CH2cy.), 26.2
(CH2cy.), 26.4 (CH2cy.), 29.2 (CH3CO), 29.3 (CH2cy.), 29.5 (CH2cy.),
32.0 (CH3CO), 41.2 (CHcy.), 41.9 (CHcy.), 54.9 (CHCO), 55.0 (CHCO),
60.6 (CH2OH), 63.4 (CH2OH), 76.1 (CHOH), 77.4 (CHOH), 207.9 (C]
O), 211.7 (C]O). LRMS (CI) m/z: 201.0 (30%), 183.0 (20%), 70.8
(100%). IR (film, cmꢁ1): 3409, 2925, 1701, 1421, 1353, 1261, 1174,
1118, 1026, 800, 721, 694.
i-PrOH as eluent (85/15). 1H NMR (300 MHz, CDCl3):
d 1.95 (s, 1.5H,
CH3), 2.13 (s,1.5H, CH3), 2.87e2.94 (m, 0.5H, CHC(O)), 3.00e3.08 (m,
0.5H, CHC(O)), 3.56 (d, J¼5.7 Hz, 1H, CH2OH), 3.86 (d, J¼4.4 Hz, 1H,
CH2OH), 4.91 (d, J¼7.5 Hz, 0.5H, CHOH), 5.10 (d, J¼6.4 Hz, 0.5H,
CHOH), 7.27e7.55 (m, 5H, CHar.). 13C NMR (75 MHz, CDCl3):
d 30.6
(CH3), 32.3 (CH3), 60.7 (CHC(O)), 60.8 (CHC(O)), 61.1 (OCH2), 61.3
(OCH2), 73.0 (CHOH), 73.7 (CHOH),126.0 (CHar.),126.1 (CHar.),127.6
(CHar.), 127.8 (CHar.), 128.4 (CHar.), 128.5 (CHar.), 130.9 (Car.), 132.3
(Car.), 210.5 (C]O), 213.2 (C]O). LRMS (CI) m/z: 195.1 (0.7%), 117.1
(100%), 107.0 (46%), 70.8 (31%). HRMS (ESI) calculated for
C11H14O3Na ([MþNa]þ) 217.0841, found 217.0842 (0.4 ppm). IR
(film, cmꢁ1): 3386, 1701, 1436, 1357, 1164, 1056, 912, 721, 694.
4.2.17. 3-Cyclohexyl-3-hydroxy-2-(hydroxymethyl)propanenitrile
31. The product was isolated using the general procedure as a col-
ourless oil (87%) after flash chromatography on silica gel using P.E./
EtOAc as eluent (65/35). 1H NMR (300 MHz, CDCl3):
d
0.90e2.05 (m,
11H, CHcy.), 2.85e3.00 (m, 1H, CHCN), 3.50e4.10 (m, 5H, CH2OH,
CHOH and OH). 13C NMR (75 MHz, CDCl3):
25.6 (CH2cy.), 25.9
d
(CH2cy.), 26.2 (CH2cy.), 29.0 (CH2cy.), 29.9 (CH2cy.), 37.7 (CHCN),
38.2 (CHCN), 41.1 (CHcy.), 42.0 (CHcy.), 60.1 (CH2OH), 61.5 (CH2OH),
73.5 (CHOH), 74.0 (CHOH), 118.9 (CN), 119.9 (CN). LRMS (APCI) m/z:
183.9 (40%), 165.9 (100%). IR (film, cmꢁ1): 3398, 2925, 2852, 2244,
1448, 1062, 1047, 725.
4.2.13. 3-Hydroxy-2-(hydroxymethyl)-3-phenylpropanenitrile
26. The product was isolated using the general procedure as a col-
ourless oil (76%) after flash chromatography on silica gel using P.E./
i-PrOH as eluent (90/10). N.B. Due to interaction in solution, peaks
are widely broadened. 1H NMR (300 MHz, CDCl3):
d
2.95 (br s, 1H,
HCN), 3.84e4.20 (br m, 2.5H, CH2OH and CHOH), 5.04 (br m, 0.5H,
CHOH), 7.30e7.60 (m, 5H, CHar.). 13C NMR (75 MHz, CDCl3):
42.7
4.2.18. 3-Cyclohexyl-3-hydroxy-2-(hydroxymethyl)-N-methoxy-N-
methylpropanamide 32. The product was isolated using the general
procedure as a colourless oil (73%) after flash chromatography on
silica gel using P.E./EtOAc as eluent (55/45). 1H NMR (300 MHz,
d
(CHCN), 43.7(CHCN), 60.3 (OCH2), 60.9 (OCH2), 71.1 (OCH), 72.2
(OCH), 126.0 (CHar.), 126.5 (CHar.), 128.5 (CHar.), 128.8 (CHar.),
132.1(CHar.), 132.6 (CHar.), 140.3 (Car.), 140.6 (Car.). LRMS (CI) m/z:
178.1 (3%), 130.1 (18%), 107.0 (51%), 101.0 (100%). HRMS (ESI) cal-
culated for C10H11NO2Na ([MþNa]þ) 200.0687, found 200.0681
CDCl3):
CHC(O)), 3.60e3.80 (m, 4H, CH3O and CHOH), 3.92e4.10 (m, 2H,
CH2OH). 13C NMR (75 MHz, CDCl3):
26.0 (CH2cy.), 26.2 (CH2cy.),
d 0.85e2.10 (m, 11H, CHcy.), 3.18e3.25 (m, 4H, CH3N and
d

3442
A. Welle et al. / Tetrahedron 68 (2012) 3435e3443
26.5 (CH2cy.), 28.8 (CH2cy.), 29.6 (CH2cy.), 34.2 (NCH3), 41.1 (CHcy.),
43.8 (HCC(O)), 61.3 (CH2OH), 61.7 (OCH3), 76.3 (CHOH), 174.5 (C(O)).
LRMS (CI) m/z: 246.0 (60%), 228.0 (100%), 209.8 (75%), 198.2 (35%).
IR (film, cmꢁ1): 3438, 2923, 2852, 1631, 1390, 1176, 1101, 1022, 798.
loaded with [(Ph3P)3CuF$2MeOH] (9.3 mg, 0.01 mmol, 0.02 equiv)
and (rac)-BINAP (6.2 mg, 0.01 mmol, 0.02 equiv). The system was
closed with a septum and after 3 vacuum/argon cycles, THF (2.5 mL)
was added by syringe. After dissolution of the solids, methyl acry-
late (45 mL, 0.5 mmol, 1 equiv) and benzaldehyde (50 mL, 0.5 mmol,
4.2.19. 3-Hydroxy-2-(hydroxymethyl)-N-methoxy-3-(4-methoxy-
phenyl)-N-methylpropanamide 33. The product was isolated using
the general procedure as a colourless oil (48%) after flash chro-
matography on silica gel using P.E./i-PrOH as eluent (80/20). 1H
1 equiv) were added. Bis(pinacolato)diboron (152 mg, 0.6 mmol,
1.2 equiv) was then added, and the mixture was stirred for 1 h. The
solvent was removed under reduced pressure and tetrakis(-
triphenylphosphine) palladium (57 mg, 0.05 mmol, 0.1 equiv) and
caesium fluoride (303 mg, 2 mmol, 4 equiv) were introduced in the
flask. The system was closed and after 3 vacuum/argon cycles, DMF
NMR (300 MHz, CDCl3):
d 3.11 (s, 3H, CH3N), 3.27 (m, 1H, CHC(O)),
3.52 (s, 3H, CH3ON), 3.79 (s, 3H, CH3OAr), 3.93e4.02 (m, 2H,
CH2OH), 5.17 (d, J¼5.9 Hz, 1H, CHOH), 6.87 (m, 2H, CHAr), 7.30 (m,
(5 mL) and iodobenzene (111 mL, 1 mmol, 2 equiv) were added by
2H, CHAr). 13C NMR (75 MHz, CDCl3):
d
31.9 (NCH3), 49.5 (HCC(O)),
syringe. The solution was heated at 100 ꢀC overnight and the
product was isolated as separable diastereoisomers as an uncol-
oured foam (89%) after flash chromatography. 1H NMR (300 MHz,
55.4 (CH2OH), 61.6 (COCH3), 62.2 (NOCH3), 73.1 (CHOH), 113.9
(CHAr), 127.3 (CHAr), 134.1 (CCOH), 159.2 (COCH3), 174.5 (C(O)).
HRMS (CI) calculated for C13H20NO5 ([MþH]þ) 270.13415, found
270.13472 (2.11 ppm). IR (film, cmꢁ1): 3402, 2922, 2853, 1720, 1629,
1512, 1461, 1247, 1176, 835.
CDCl3):
d first fraction: 2.97e3.09 (br m, 4H, CH2Ph HCO2Me and
OH), 3.43 (s, 3H, CH3O), 5.05 (d, J¼4.8 Hz, 1H, CHOH), 7.10e7.45 (m,
10H, CHar.) Second fraction: 2.73 (dd, J¼13.5 and 5.8 Hz,1H, CH2Ph),
2.90 (dd, J¼13.5 and 9.7 Hz, 1H, CH2Ph), 3.04e3.10 (m, 2H, HCO2Me
and OH), 3.53 (s, 3H, CH3O), 4.82 (d, J¼6.9 Hz, 1H, CHOH), 7.10e7.50
(m, 10H, CHar.). Spectral data are identical those found in the
literature.26
4.2.20. 3-Hydroxy-2-(hydroxymethyl)-N-methoxy-N-methyl-3-(thi-
ophen-2-yl)propanamide 34. The product was isolated using the
general procedure as a colourless oil (55%) after flash chromatog-
raphy on silica gel using P.E./i-PrOH as eluent (90/10). 1H NMR
(300 MHz, CDCl3): d 3.13 (s, 3H, CH3N), 3.32 (m, 1H, CHC(O)), 3.53 (s,
4.5. Modification of the Weinreb amide
3H, CH3O), 3.97e4.02 (m, 2H, CH2OH), 5.46 (d, J¼6.8 Hz, 1H, CHOH),
6.94e7.02 (m, 2H, CHAr), 7.21e7.23 (m, 1H, CHS). 13C NMR (75 MHz,
4.5.1. 4-Hydroxy-3-(hydroxymethyl)-4-phenylbutan-2-one 25. The
general procedure for the coupling of benzaldehyde (53 mg,
0.5 mmol), Weinreb acrylamide (57 mg, 0.5 mmol, 1 equiv) and
diboron 3 (152 mg, 0.6 mmol, 1.2 equiv) was carried out in 3 mL of
THF for 5 h. The flask was cooled to ꢁ78 ꢀC and 1.56 mL of a 1.6 M
methyl lithium solution in diethyl ether (2.5 mmol, 5 equiv) was
added dropwise at this temperature. The reaction was stirred at this
temperature for 1 h and the cooling bath was removed. 250 mg of
sodium perborate (2 mmol, 4 equiv) and 3 mL water were added
and the biphasic mixture was stirred at room temperature over-
night. After ether extraction and standard work up, the crude re-
action mixture was purified by flash chromatography on silica gel
using P.E./i-PrOH as eluent (90/10). The desired keto-diol 25 was
isolated as a light yellow oil in a 48% yield.
CDCl3):
d 32.1 (NCH3), 49.8 (HCC(O)), 62.0 (CH2OH), 69.8 (OCH3),
70.9 (CHOH), 124.5 (CHAr), 125.0 (CHAr), 127.0 (CHAr), 146.2
(CCOH), 174.5 (C(O)). HRMS (CI) calculated for C10H16NSO4
([MþH]þ) 246.08000, found 246.07938 (2.52 ppm). IR (film, cmꢁ1):
3332, 2953, 1628, 1437, 1391, 1307, 1180, 1059, 986, 748.
4.3. Determination of relative configurations
The diol (0.5 mmol,
1 equiv) was dissolved in 2,2-
dimethoxypropane (2 mL, 16.2 mmol, 32.4 equiv). A catalytic
amount of PTSA was added and the solution was stirred overnight.
Then, solid anhydrous K2CO3 (500 mg) was added and the reaction
was stirred for 1 h. The solids were filtered, and the product was
concentrated under reduced pressure.
4.3.1. Acetonide 28. The product was isolated as a 2/1 trans/cis
mixture as a colourless oil (quantitative) after chromatography
using P.E./EtOAc as eluent (90/10). 1H NMR (300 MHz, CDCl3):
Acknowledgements
ꢀ
This work was supported by the Universite catholique de Lou-
d
trans: 1.53 (s, 3H, CH3C), 1.65 (s, 3H, CH3C), 2.99 (s, 3H, NCH3), 3.14
vain and F.N.R.S.
(s, 3H, OCH3), 3.27e3.42 (m, 1H, CHC(O)N), 3.96 (dd, J¼11.4 and
5.1 Hz, 1H, CH2OH), 4.20 (t, J¼11.4 Hz, 1H, CH2OH), 5.23 (d,
J¼10.4 Hz, 1H, CHOH) 7.19e7.45 (m, 5H, CHar.). Full spectral data of
the cis isomer could not be determined.
References and notes
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NMR (300 MHz, CDCl3):
d 1.49 (s, 3H, CH3C), 1.57 (s, 3H, CH3C),
1.81e2.30 (m, 6H, CH2cy.), 2.77 (dd, J¼10.5 and 10.4 Hz, 1H, CHC]
O), 3.95 (dt, J¼10.7 and 3.7 Hz, 1H, CHO), 5.13 (d, J¼10.3 Hz, 1H,
PhCHO), 7.20e7.51 (m, 5H, CHar.). 13C NMR (75 MHz, CDCl3): 19.7
(CCH3), 22.1 (CH2cy.), 30.1 (CCH3), 31.9 (CH2cy.), 42.1 (COCH2cy.),
60.3 (CHC]O), 71.3 (CHO), 73.4 (PhCHO), 99.3 (C(CH3)2), 128.0
(CHar.), 128.4 (CHar.), 128.6 (CHar.), 140.5 (Car.), 207.7 (C]O). LRMS
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1261, 1199, 1090, 1026, 752, 698.
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fied procedure from the literature was used.24 A Schlenk tube was

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3443
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