Expeditious and novel synthesis of α-hydroxyesters via rhodium-NHC catalyzed arylation of ethyl glyoxalate

Article abstract of DOI:10.1016/j.tet.2012.05.129

The rhodium-NHC catalyzed arylation reaction of ethyl glyoxalate with aryl and alkyl boronic acids provides an efficient method for the synthesis of α-hydroxyesters. A wide range of α-hydroxyesters (up to 12) were prepared in good to excellent yields. KO^tBu was the base of choice, along with tert-amyl alcohol as the solvent. As far as we are aware, this is the first report of this catalytic arylation, using rhodium-NHC catalysts with this specific substrate type.

Full text of DOI:10.1016/j.tet.2012.05.129

Tetrahedron 68 (2012) 7211e7216
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expeditious and novel synthesis of a-hydroxyesters via rhodiumeNHC catalyzed
arylation of ethyl glyoxalate
*
Carolina S. Marques, Anthony J. Burke
ꢀ
ꢀ
ꢀ
~
Department of Chemistry and Chemistry Center of Evora, University of Evora, Rua Romao Ramalho 59, 7000 Evora, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 April 2012
Received in revised form 28 May 2012
Accepted 31 May 2012
Available online 12 June 2012
The rhodiumeNHC catalyzed arylation reaction of ethyl glyoxalate with aryl and alkyl boronic acids
provides an efficient method for the synthesis of a-hydroxyesters. A wide range of a-hydroxyesters (up to
12) were prepared in good to excellent yields. KOtBu was the base of choice, along with tert-amyl alcohol
as the solvent. As far as we are aware, this is the first report of this catalytic arylation, using rhodiu-
meNHC catalysts with this specific substrate type.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Catalysis
Rhodium
N-Heterocyclic carbene (NHC)
Glyoxalate
Arylboronic acids
1. Introduction
Over the last six years our group has had an interest in the de-
velopment of new efficient methods for the stereoselective syn-
The efficient synthesis of
a
-hydroxyesters is of considerable
thesis of chiral a
-hydroxyesters.1,4 As an extension of our work on
interest given that this structural moiety is found in a plethora of
the development of the catalytic arylation of activated imine sub-
strates with boronic acids and derivatives5,6 we decided to in-
vestigate the arylation of glyoxalate esters as a route to such
products. As far as we are aware, there is only one example of
a catalytic reaction with this substrate type, one that employs
a SuzukieMiyaura coupling reaction with Pd and phosphine
ligands.7
complex natural products and therapeutic molecules1 (Fig. 1), as
well as being important in the synthesis of
number of synthetic methods exist in the literature, with the re-
duction of aliphatic
-ketoesters as the most common method.3
a A
-aminoesters.2
a
2. Results and discussion
Taking into account our experience in working with conforma-
tionally locked cyclic diacetal backbone molecules,8e11 we decided
to synthesize a new family of N-heterocyclic carbene (NHC) type
ligands, based on this structural motif, using known methods from
the literature12,13 (Scheme 1). Starting with the known chiral di-
amine (2) we obtained the dibenzylated amine molecules (3aec)
by reductive amination. These products were then converted into
the mono-imidazolium type salts (4aec).
We synthesized the di-imidazolium type salt (6) in 78% yield
(Scheme 1) from the dichloride molecule (5) (obtained from
(þ)-diol (1)), using a literature method.13 The synthesis and appli-
cation of (4a) in the ruthenium catalyzed arylation of activated
imines has already been achieved by us.6
Fig. 1. Selection of biologically active molecules prepared from optically active a-oxy
functionalized carbonyl building blocks.
The method of choice was the preparation of the NHCs in situ by
* Corresponding author. E-mail address: ajb@dquim.uevora.pt (A.J. Burke).
deprotonation of the corresponding imidazolium salts.6,14 Their
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.05.129

7212
C.S. Marques, A.J. Burke / Tetrahedron 68 (2012) 7211e7216
MeO OMe
MeO
O
OMe
O
e
O
N
O
N
NH
HN
R
R
R
R
d
(3a) R= Ph
(3b) R= p-CH3OC6H4
(3c) R = 2-Naph
PF6
(4a)
(4b)
(4c)
MeO OMe
MeO OMe
MeO OMe
MeO OMe
O
O
f
O
O
a,b
c
O
O
O
O
OH
OH
Cl
Cl
N3
N3
NH2 NH2
(2)
(1)
(5)
MeO OMe
O
N
O
N
g
Cl
N
N
Cl
(6)
Scheme 1. Synthetic pathways to mono-NHC salts (4aec) and di-NHC salt (6) from (þ)-diol (1). Reagents and conditions: (a) CH3SO2Cl, NEt3, CH2Cl2, 0 ꢀC, 3 h; (b) NaN3, DMF, 60 ꢀC,
overnight; (c) Pd/C, H2, EtOH, rt, 24 h; (d) benzaldehyde, MeOH, reflux, 3 h, NaBH4, toluene, rt, 2 h; (e) HC(OEt)3, NH4PF6, 120 ꢀC, 3 h; (f) PPh3, CCl4, pyridine, CH2Cl2, rt, 24 h; (g) 1-
methylimidazole, CH3CN, 140 ꢀC, 2 days.
neutrality and capacity for two-electron-donating (
s
-donating)
To compare the efficiency of the ligands synthesized above
(Scheme 1) we conducted four test reactions using the commercial
imidazoliums (7) and (8) as NHC precursors (Table 1, entries
18e21). These ligands had already been applied with success in
arylation of aldehydes with boronic acids by Gois and co-workers.21
with negligible
p back-bonding make them notable molecules for
catalysis.15e20
Inspired by the pioneering work of Gois and co-workers,21
which concerned the arylation of aldehydes with Rh(II)eNHC
complexes and boronic acids, we decided to extend this method-
ology for the synthesis of a-hydroxyesters with Rh(I) metal cata-
Table 1
lysts and our NHC type ligands (Scheme 1). Ethyl glyoxalate (50%
solution in toluene) was the substrate chosen for the catalytic
arylation reactions. For comparative purposes, two commercial
aquiral benzimidazolium salts (7) and (8) were tested as well. The
preliminary results can be seen in Table 1.
Rh(I)eNHC catalytic arylation of ethyl glyoxalate with phenylboronic acid
Our study commenced by screening the rhodium pre-catalysts
with ligand precursor (4a) in tert-amyl alcohol at 60 ꢀC, with
KOtBu to evaluate the best rhodium catalyst for this reaction
(Table 1, entries 1e4). The best results were obtained with
[Rh(OH)COD]2 and Rh(COD)2BF4 (Table 1, entries 2 and 4, re-
spectively), giving the desired product in 97 and >99% yield, re-
spectively. Encouraged by these results, we decided to screen our
NHC-type ligands (Scheme 1). In general, the results with
Rh(COD)2BF4 were quite impressive (Table 1, entries 8e10), with
excellent yields obtained with all the NHC-type ligands tested (up
to 95% yield). It seems that the bulkiness of the ligand has a det-
rimental effect on the reaction yield (Table 1, see entries 5 and 6).
This observation would be expected from partial blockage of part
of the coordination sphere of the active catalyst formed in situ.
With regards to the [Rh(OH)COD]2 pre-catalyst, the best results
were obtained with ligand precursors (4a) (97%) (Table 1, entry 2)
and (6) (>99%) (Table 1, entry 7). Ligand (4a) (less bulky) was
screened using both the rhodium pre-catalysts described above.
The best pre-catalyst proved to be [Rh(OH)COD]2, providing the
Entrya Rh(I)
Ligand Solvent
T/ꢀC t/h Yieldb/%
1
2
[Rh(COD)Cl]2
[Rh(OH)COD]2
4a
4a
tert-Amyl alcohol 60
7
4
4
4
4
4
4
4
4
4
68
97
43
>99
73
58
>99
95
>99
>99
tert-Amyl alcohol 60
tert-Amyl alcohol 60
tert-Amyl alcohol 60
tert-Amyl alcohol 60
tert-Amyl alcohol 60
tert-Amyl alcohol 60
tert-Amyl alcohol 60
tert-Amyl alcohol 60
tert-Amyl alcohol 60
tert-Amyl alcohol rt
tert-Amyl alcohol rt
tert-Amyl alcohol
MeOH
Dioxane
DME/H2O (5/1)
DME
3
Rh(acac)(C2H4) 4a
4
Rh(COD)BF4
4a
4b
4c
6
4b
4c
6
4a
4a
4a
4a
4a
4a
4a
7
5
6
7
8
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
Rh(COD)BF4
9
Rh(COD)BF4
10
11
12
13
14
15
16
17
18
19
20
21
22
Rh(COD)BF4
[Rh(OH)COD]2
Rh(COD)BF4
0,5 >99
4
4
4
4
4
4
4
4
4
4
4
66
>99
47
90
21
>99
46
59
12
14
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
[Rh(OH)COD]2
0
60
60
60
60
tert-Amyl alcohol rt
tert-Amyl alcohol 60
tert-Amyl alcohol rt
tert-Amyl alcohol 60
tert-Amyl alcohol 60
7
8
8
d
desired a-hydroxyester in >99% yield (Table 1, entry 11) in less
than an hour. In fact, we showed that the reaction occurs at low
temperature (Table 1, entry 13) with almost total conversion of the
substrate within 4 h. Preliminary studies using phosphine ligands6
have shown that these NHC ligands provide superior ligand
acceleration.
5
a
Reaction conditions: [Rh(I)]2 (1.5 mol %) or [Rh(I)] (3 mol %), ligand precursor
(3.3 mol %), KOtBu (1 equiv), PhB(OH)2 (2 equiv), tert-amyl alcohol (1 ml).
b
Isolated yields.

C.S. Marques, A.J. Burke / Tetrahedron 68 (2012) 7211e7216
7213
The yields were lower than those obtained with NHC precursor (4a)
(Table 1, compare entry 11 with entries 18 and 20). Upon increasing
the temperature to 60ꢀ there was a slight increase in the yield
(Table 1, entries 19 and 21), showing that the NHCs resulting from
(7) and (8) were less efficient in this particular transformation. It
was the less bulky NHC ligand derived from (7), which gave better
results compared to the NHC derived from (8) (Table 1, compare
entries 18 and 19 with entries 20 and 21, respectively). We think
that specific stereochemical factors in the formation of the catalytic
active species might be the reason.
To test for possible solvent effects, we decided to use the optimal
conditions found previously with a variety of different solvents,
ranging from polar protic ones, like MeOH and H2O (Table 1, entries
14 and 16), and aprotic polar ones, like DME (Table 1, entry 16) to
non-polar ones, like 1,4-dioxane (Table 1, entry 15). In fact, the best
results were obtained using tert-amyl alcohol with [Rh(OH)COD]2
and ligand precursor (4a), allowing the formation of the ethyl
mandelate product in high yield under mild conditions, without
any water present (see Table 1, entry 11). Finally, to prove the ef-
ficiency of the NHC type ligands used in this transformation, a test
reaction in the absence of ligand was made (Table 1, entry 22). A
vestigial quantity of ethyl mandelate was only obtained.
reacting center. The aliphatic product (9l) obtained upon using
ethylboronic acid was formed in poor yield (23%, Table 2, entry 12).
Unfortunately all the a-hydroxyester products that were formed
were racemic, despite the use of chiral RheNHC catalystsdone of
which has already proved to give high levels of enantiofacial se-
lectivity for the arylation of activated imines using Ru catalysts (to
be precise, [RuCl2(h
6-p-cymene)]2).6 This was first considered to be
a racemization processes, which has already been observed for such
compounds in the presence of Rh(II) catalysts.21c,22 Key experi-
ments were performed with (R)-(ꢁ)-methyl mandelate. In one
flask, 50 mg of this compound was stirred at room temperature
with 1.5 mol % of [Rh(OH)COD]2, 3.3 mol % of ligand precursor (4a)
and KOtBu (1 equiv relative to the ligand), in 1 ml of dry tert-amyl
alcohol, during 24 h. Simultaneously, in another flask, 50 mg of (R)-
(ꢁ)-methyl mandelate was stirred at 60 ꢀC with 1.5 mol % of
[Rh(OH)COD]2, 3.3 mol % of ligand precursor (4a), 2 equiv of
PhB(OH)2 and 1 equiv of KOtBu (relative to the mandelate), in 1 ml
of dry tert-amyl alcohol, for 4 h.
No racemization was observed, thus suggesting that there may
be competing transition states in this reaction. However, in the
absence of concrete experimental evidence, the principle mecha-
nism (as pointed out by one of the referees) could be analogous to
that proposed by Nolan23 (which is based on that originally sug-
gested by Hayashi24) and perhaps the lack of any observable
enantioselectivity could be due to substitution of the NHC unit
(present in a very likely square planar complex) by the glyoxylate
substrate during the catalytic cycle (also suggested by the same
referee). If this proves to be the case, and given the fact that the
reaction yield in the absence of NHC ligand was very poor (Table 1,
entry 22dproving that there is pronounced ligand acceleration in
this reaction), then it might be safe to assume that the formation of
an NHCeRh-aryl intermediate (isolated by Nolan23 in their partic-
ular case), is the key rate determining step.
To investigate the scope and limitations of this reaction, we
screened various arylboronic acids bearing electron-donating and
electron-withdrawing substituents in the ortho, meta and para
positions of the phenyl ring, as well as aliphatic boronic acids using
the optimized catalytic system discovered above. The results can be
seen in Table 2.
Table 2
Catalytic arylation of ethyl glyoxalate, applying
substituted boronic acids
a number of aryl and alkyl
We are currently investigating this mechanism and obviously
wish to develop a system that provides high enantioselectivities.
3. Conclusion
Entrya
R
Product (9)
Yieldb/%
In summary, we have developed novel Rh(I) complexes in situ
from [Rh(OH)COD]2 and NHC-type ligands and used them in the
efficient, high yielding synthesis of a diverse range of substituted
1
2
3
4
5
6
7
8
2-Naph
4-FC6H4
a
b
c
d
e
f
g
h
i
36
>99
nr
81
>99
71
34
>99
12
72
Trace
23
3-HOC6H4
2-CH3OC6H4
3-CH3OC6H4
2-Fur
4-ClC6H4
3-CH3OC6H4
3-AcC6H4
1-Naph
a-hydroxyesters. As far as we are aware, only one example on the
use of NHCeRh(I) complexes in arylation processes has been
reported todate.23 Our chiral NHC based catalytic systems have
proved more efficacious than those derived from some commercial
achiral NHC precursors. Further investigations on an asymmetric
version are in progress, including studies directed at exploring the
full mechanism of this reaction.
9
10
11
12
j
k
l
3-NH2C6H4
CH3CH2
a
Reaction conditions: [Rh(OH)COD]2 (1.5 mol %), (4a) (3.3 mol %), KOtBu
4. Experimental section
4.1. General remarks
(1 equiv), RB(OH)2 (2 equiv), tert-amyl alcohol (1 ml).
b
Isolated yields; nr¼no reaction.
In most cases the reaction proceeded with remarkable efficiency
(up to 99% yield of isolated product (entries 2, 5 and 8, Table 2), and
between 71 and 81% yield of isolated product (entries 4, 6 and 10,
Table 2)), under mild conditions. The lower yields were observed
when certain electron-donating groups were present in the orga-
noboron reagent (Table 2, entries 1, 11 and 12). No reaction was
observed when 3-HOC6H4B(OH)2 was used (Table 1, entry 3) and
only a vestigial quantity of product (9k) was obtained, with 3-
NH2C6H4B(OH)2 (Table 2, entry 11). Moreover, electron-
withdrawing substituents in the ortho position (Table 2, entry 4)
seem to have no significant influence on the yield, which indicates
that the reaction does not suffer from steric hindrance around the
All the reagents were purchase from Aldrich, Fluka, Acros and
Alfa Aeser. The chiral diazide (precursor to diamine (2)) (2) was
obtained from ChiraTecnics Lda. The solvents used were dry under
current laboratory techniques: tert-amyl alcohol was distilled from
CaH2, as well as MeOH, toluene, CH2Cl2, CH3CN and DME (1,2-
dimethoxyethane). 1,4-Dioxane was distilled from Na and benzo-
ꢁ
phenone. Pyridine was distilled from KOH. CCl4 was kept under 4 A
molecular sieves and then distilled. The phenylboronic acid and
derivatives were used as received, as well as ethyl glyoxalate (50%
solution in toluene).
Column chromatography was carried out on silica gel (SDS,
70e200 mm). Thin layer chromatography (TLC) was carried out on

7214
C.S. Marques, A.J. Burke / Tetrahedron 68 (2012) 7211e7216
aluminium backed Kieselgel 60 F254 plates (Merck). Plates were vi-
sualized either by UV light or with phosphomolybdic acid in ethanol.
The NMR analysis were recorded on a Bruker Avance instrument
(400 MHz) using CDCl3 as solvent and the signal from the residual
CHCl3 as an internal standard. Mass spectra were recorded on a Wa-
ters-Micromass (MaldiTOF, MicroTOF, ESI) or FAB Focus (Bruker Dal-
tonics) using the TOF technique. Melting points were measured in
a Barnstead/Electrothermal 9100 instrument. Specific rotation mea-
surements were measured on a PerkineElmer 241 polarimeter.
diazepin-6-ium hexafluorophosphate (4a).12 The secondary diamine
product (3a) (0.26 mmol), NH4PF6 (0.26 mmol) and triethylortho-
formate (0.26 mmol) were added to a round bottom flask under an
inert atmosphere. The reaction mixture was stirred at 120 ꢀC for
3 h. The EtOH formed by-product was evaporated under vacuum
and the crude product was recrystallized from EtOH to give the
desired NHC precursor product (4a) (white crystals) in 57% yield. 1H
NMR analysis (CDCl3, 400 MHz)
d (ppm): 1.14 (s, 6H, CH3), 3.02 (s,
6H, OCH3), 3.20e3.28 (m, 2H, CH2N), 3.37e3.42 (m, 2H, CH2N),
3.55e3.56 (m, 2H, CHO), 4.67e4.79 (q, J¼12 Hz, 4H, CH2Ar),
7.33e7.38 (m, 10H, Ar), 8.37 (s, 1H, NH]N). 13C NMR analysis
4.2. NHC-type salts synthesis
(CDCl3, 100 MHz) d (ppm): 17.10 (CH3), 48.04 (OCH3), 51.21 (CH2Ar),
4.2.1. Synthesis of N,N0-((2R,3R,5S,6S)-5,6-dimethoxy-5,6-dimethyl-1,
4-dioxane-2,3-diyl)bis(methylene)bis(1-phenylmethanamine)(3a).13a
Diamine (2) (0.4 mmol) was added to a round bottom flask con-
taining dry MeOH (35 ml) and benzaldehyde (10 mmol). The mix-
ture was stirred under nitrogen and reflux overnight. Dry toluene
(50 ml) and NaBH4 (21 mmol, added in small portions over a 20 min
period) were added to the cooled solution (cooled to rt). The mixture
was stirred for 2 h and then the solvents were removed under vac-
uum. H2O (50 ml) and AcOEt (50 ml) were added to the crude
mixture and extracted. The organic layer was washed with brine,
dried with anhydrous MgSO4, filtered and the solvent was again
evaporated under vacuum. The crude product was purified using
column chromatography (SiO2 gel, Hexane/AcOEt (1/1)), giving the
desired diamine product (3a) (colourless oil) in 35% yield. 1H NMR
63.12 (NCH2C), 67.20 (CHO), 99.08 (CeC), 128.78 (Ar), 129.18 (Ar),
129.28 (Ar), 132.63 (AreC), 159.06 (C]N). MicroTOF MS m/z:
425.25 (Mþ), 426.26 (Mþ1), 427.26 (Mþ2). ½a 2D5
ꢁ67.8 (c 0.96, CHCl3).
ꢂ
4.2.5. Synthesis of (2R,3R,4aR,9aR)-2,3-dimethoxy-6,8-bis(4-
methoxybenzyl)-2,3-dimethyl-3,4a,5,8,9,9a-hexahydro-2H-[1,4]diox-
ino[2,3-e][1,3]diazepin-6-ium hexafluorophosphate (V) (4b). The
same procedure was applied using 0.38 mmol of the diamine (3b).
The crude product was recrystallized from EtOH to give the desire
NHC precursor product (4b) (yellowish crystals) in 59% yield. 1H
NMR analysis (CDCl3, 400 MHz)
d (ppm): 1.16 (s, 6H, CH3), 3.07 (s,
6H, OCH3), 3.18e3.26 (m, 2H, CH2N), 3.37e3.42 (m, 2H, CH2N),
3.50e3.60 (m, 2H, CHO), 3.80 (s, 6H, OCH3), 4.66 (m, 4H, CH2Ar),
6.86 (d, 4H, Ar), 7.22e7.26 (d, 4H, Ar), 8.23 (s, 1H, NH]N). 13C NMR
analysis (CDCl3, 400 MHz)
d
(ppm): 1.25 (s, 6H, CH3), 2.46 (s, 2H,
analysis (CDCl3, 100 MHz) d (ppm): 17.26 (CH3), 48.24 (OCH3), 51.22
CH2NH), 2.63 (s, 2H, CH2NH), 3.22 (s, 3H, OCH3), 3.68e3.81 (m, 6H,
(CH2), 55.43 (OCH3), 62.91 (CH2), 67.32 (CHO), 99.17 (CHO), 114.76
(Ar), 124.58 (Ar), 130.50 (Ar), 158.21 (Ar), 160.38 (C]N). (ESI) MS m/
z: 485.26 (Mþ), 486.27 (Mþ1), 487.27 (Mþ2).
CHOþCH2Ar), 5.25 (s, 2H, NH), 7.22 (m, 10H, Ar). 13C NMR analysis
(CDCl3, 100 MHz)
d (ppm): 17.30 (CH3), 47.81 (CH2N), 49.30 (OCH3),
53.54 (CH2Ar), 68.93 (CHO), 98.17 (CeO), 126.66 (Ar), 127.87 (Ar),
139.49 (Ar). ESI-TOF MS (m/z): 415.27 (Mþ1).
4.2.6. Synthesis of (2R,3R,4aR,9aR)-2,3-dimethoxy-2,3-dimethyl-6,8-
bis(naphthalen-2-ylmethyl)-3,4a,5,8,9,9a-hexahydro-2H-[1,4]dioxino
[2,3-e][1,3]diazepin-6-ium hexafluorophosphate (V) (4c). The same
procedure was applied using 0.37 mmol of the diamine (3c). The
crude product was recrystallized from EtOH to give the desired
NHC precursor product (4c) (yellow crystals) in 78% yield. 1H NMR
4.2.2. Synthesis of N,N0-((2R,3R,5S,6S)-5,6-dimethoxy-5,6-dimethyl-
1,4-dioxane-2,3-diyl)bis(methylene)bis(1-(4-methoxyphenyl)meth-
anamine) (3b). The same procedure was applied, using p-ani-
saldehyde (2.13 mmol) to 0.85 mmol of diamine (2). The crude
product was purified using column chromatography (SiO2 gel,
Hexane/AcOEt (1/1)), giving the desired diamine product (3b)
(yellow oil) in 48% yield. 1H NMR analysis (CDCl3, 400 MHz)
analysis (CDCl3, 400 MHz)
d (ppm): 1.06 (s, 6H, CH3), 2.94 (s, 6H,
OCH3), 3.27e3.35 (m, 2H, CH2N), 3.45e3.49 (m, 2H, CH2N),
3.63e3.64 (m, 2H, CHO), 4.86e4.97 (m, 4H, CH2Ar), 7.36e7.39 (m,
4H, Ar), 7.46e7.49 (m, 4H, Ar), 7.72e7.79 (m, 6H, Ar), 8.47 (s, 1H,
d
(ppm): 1.28 (s, 6H, CH3), 2.04 (s, 2H, CH2NH), 2.65e2.67 (m, 4H,
CH2NH), 3.26 (s, 3H, OCH3), 3.69e3.77 (m, 4H, CH2Ar), 3.79 (s, 6H,
OCH3), 4.08e4.16 (m, 2H, CHO), 6.83e6.86 (d, 4H, Ar), 7.20e7.23 (d,
NH]N). 13C NMR analysis (CDCl3, 100 MHz)
d (ppm): 17.15 (CH3),
48.13 (OCH3), 51.42 (CH2), 63.56 (CH2), 67.37 (CHO), 99.20 (CHO),
125.37 (Ar), 126.75 (Ar), 126.88 (Ar), 127.79 (Ar), 128.23 (Ar),
128.68 (Ar), 129.53 (Ar), 130.03 (Ar), 133.28 (Ar), 133.49
(Ar), 159.14 (C]N). (ESI) MS m/z: 525.27 (Mþ), 526.28 (Mþ1),
527.28 (Mþ2).
4H, Ar). 13C NMR analysis (CDCl3, 100 MHz)
d (ppm): 17.10 (CH3),
48.29 (CH2), 49.58 (OCH3), 53.08 (CH2), 55.42 (OCH3), 69.41 (CHO),
98.80 (CHO), 113.95 (Ar), 129.84 (Ar), 134.18 (Ar), 158.99 (Ar). ESI-
TOF MS (m/z): 475.30 (Mþ1).
4.2.3. Synthesis of N,N0-((2R,3R,5S,6S)-5,6-dimethoxy-5,6-dimethyl-
1,4-dioxane-2,3-diyl)bis(methylene)bis(1-(naphthalen-2-yl)methan-
amine) (3c). The same procedure was applied, using 2-
naphthaldehyde (2.13 mmol) to 0.85 mmol of diamine (2). The
crude product was purified using column chromatography (SiO2
gel, Hexane/AcOEt (1/1)), giving the desired diamine product (3c)
(colourless oil) in 41% yield. 1H NMR analysis (CDCl3, 400 MHz)
4.2.7. Synthesis of (2S,3S,5S,6S)-5,6-bis(chloromethyl)-2,3-
dimethoxy-2,3-dimethyl-1,4-dioxane (5).13 In a round bottom flash
under an inert atmosphere was added commercial ((2R,3R,5S,6S)-
5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2,3-diyl)dimethanol (1)
(1.38 mmol), PPh3 (5.54 mmol), dry pyridine (5.54 mmol), dry CCl4
(5.54 mmol) and dry CH2Cl2 (10 ml). The mixture was left stirring
24 h at room temperature in the dark. The solvents was evaporated
under vacuum and the crude product was purified by liquid chro-
matography (SiO2 gel, Hexane/AcOEt (1/1)), giving the desired
product (5) (as a white solid) in 99% yield (mp¼67.4e68.6 ꢀC). 1H
d
(ppm): 1.29 (s, 6H, CH3), 1.92 (s, 2H, CH2NH), 2.69e2.70 (m, 4H,
CH2NH), 3.28 (s, 3H, OCH3), 3.91e3.93 (m, 6H, CH2ArþCHO),
7.42e7.48 (m, 2H, Ar), 7.72e7.74 (m, 2H, Ar), 7.77e7.82 (m, 3H, Ar).
13C NMR analysis (CDCl3, 100 MHz)
d
(ppm): 17.78 (CH3), 48.26
NMR analysis (CDCl3, 400 MHz)
6H, OCH3), 3.55e3.67 (m, 4H, CH2eCl), 3.94e3.96 (m, 2H, CHO). 13
NMR analysis (CDCl3, 100 MHz) (ppm): 17.35 (CH3), 43.48
d (ppm): 1.33 (s, 6H, CH3), 3.29 (s,
(CH2), 49.63 (OCH3), 54.06 (CH2), 69.55 (CHO), 98.83 (CHO), 125.80
(Ar), 126.22 (Ar), 126.82 (Ar), 126.90 (Ar), 127.74 (Ar), 127.85 (Ar),
127.94 (Ar), 128.28 (Ar), 128.64 (Ar), 132.82 (Ar), 133.52 (Ar), 138.73
(Ar). ESI-TOF MS (m/z): 515.30 (Mþ1).
C
d
(CH2eCl), 48.08 (OCH3), 69.68 (CHO), 99.31 (CO). MicroTOF MS m/z:
295.05 (Mþ1). ½a D20
ꢁ196.7 (c 1.33, CHCl3).
ꢂ
4.2.4. Synthesis of (2S,3S,4aR,9aR)-6,8-dibenzyl-2,3-dimethoxy-2,3-
dimethyl-3,4a,5,8,9,9a-hexahydro-2H-[1,4]dioxino[2,3-e][1,3]
4.2.8. Synthesis of 3,30-((2R,3R,5S,6S)-5,6-dimethoxy-5,6-dimethyl-
1,4-dioxane-2,3-diyl)bis(methylene)bis(1-methyl-1H-imidazol-

C.S. Marques, A.J. Burke / Tetrahedron 68 (2012) 7211e7216
7215
3-ium) chloride (6).13 In a round bottom flask fitted with a reflux
condenser and under an inert atmosphere, was added the
dichloride compound (5) (7.32 mmol), 1-methylimidazole
(37 mmol) and dry CH3CN (50 ml). The mixture was stirred 2
days at 90 ꢀC. The solvent was evaporated under vacuum and the
crude brown oil was washed several times with pentane. The
pentane fractions were evaporated under vacuum, giving the
desired product (6) in 47% yield (colourless crystals). 1H NMR
127.50, 127.58, 128.01, 128.65, 129.56, 129.69, 136.91, 140.15, 159.08,
173.65. ESI-TOF MS (m/z): 269.13 (eOH), 287.13 (Mþ1).
4.3.7. Ethyl 2-(furan-2-yl)-2-hydroxyacetate (9f). Isolated yield
(71%). Yellow oil. 1H NMR (CDCl3, 400 MHz)
d: 1.18 (t, 3H, CH3), 3.78
(br s, 1H, OH), 4.20e4.28 (m, 2H, CH2), 5.06 (s, 1H, CH), 6.33e6.36
(m,1H, OCH), 7.31e7.42 (m, 2H, CHeCH). 13C NMR (CDCl3, 100 MHz)
d
: 14.11, 61.86, 71.36, 108.81, 110.64, 126.62, 142.89, 170.59. ESI-TOF
analysis (CDCl3, 400 MHz)
d
(ppm): 1.28 (s, 6H, CH3), 3.24 (s, 6H,
MS (m/z): 153.05 (eOH), 171.06 (Mþ1).
OCH3), 3.55e3.63 (m, 4H, CH2N), 3.65 (s, 6H, CH3), 3.90e3.91 (m,
2H, CHO), 6.84 (s, 2H, NHC), 7.01 (s, 2H, NHC), 7.39 (s, 2H, NCHN).
4.3.8. Ethyl 2-(4-chlorophenyl)-2-hydroxyacetate (9g).7 Isolated
13C NMR analysis (CDCl3, 100 MHz)
d
(ppm): 17.31 (CH3), 33.20
yield (34%). Light yellow solid. 1H NMR (CDCl3, 400 MHz)
d
: 1.20 (t,
3H, CH3), 3.61e3.69 (m, 1H, CH2), 3.73e3.78 (br s, 1H, OH),
3.81e3.89 (m, 1H, CH2), 4.93 (s, 1H, CH), 7.32e7.49 (m, 4H, Ar). 13
NMR (CDCl3, 100 MHz) : 14.12, 64.06, 71.82, 116.75, 128.02, 128.36,
128.86, 129.18, 137.11, 169.66. ESI-TOF MS (m/z): 213.11.
(CH3), 43.47 (CH2), 48.01 (OCH3), 69.56 (CHO), 99.24 (CHO), 120.02
(NC), 129.44 (NC), 137.77 (NCN). (FABþ) MS m/z: 365.0 (Mþ).
C
d
4.3. Catalytic reactions
4.3.1. General procedure. [Rh(I)]2 (1.5 mol %, 7.34ꢃ10ꢁ3 mmol) or
[Rh(I)] (3 mol %, 0.015 mmol) was added to a round bottom flask,
under an inert atmosphere. NHC precursor (3.3 mol %, 0.015 mmol),
arylboronic acid or derivative (2 equiv, 0.98 mmol), KOtBu (1 equiv,
0.49 mmol) and solvent (2 ml) were added sequentially. Finally,
4.3.9. Ethyl 2-hydroxy-2-(3-methoxyphenyl)acetate (9h). Isolated
yield (>99%). Yellow oil. 1H NMR (CDCl3, 400 MHz)
: 1.21 (t, 3H,
CH3), 3.63 (br s, 1H, OH), 3.78 (S, 3H, OCH3), 4.11e4.19 (m, 1H, CH2),
4.20e4.28 (m, 1H, CH2), 5.12 (s, 1H, CH), 6.83e6.85 (m, 1H, Ar),
6.96e6.98 (m, 2H, Ar), 7.23e7.27 (m, 1H, Ar). 13C NMR (CDCl3,
d
ethyl glyoxalate (50% in toluene, 0.49 mmol, 100
ml) was added and
100 MHz) d: 13.96, 55.29, 62.14, 72.61, 111.85, 114.32, 118.92, 129.46,
the reaction was stirred at the desired temperature, and monitored
by TLC. The crude mixture was passed through a porous ceramic
glass filter and eluted with CH2Cl2. The solvents were concentrated
under reduced pressure and the residue purified by liquid chro-
140.23, 159.73, 173.97. ESI-TOF MS (m/z): 193.09 (eOH), 211.10
(Mþ1).
4.3.10. Ethyl 2-(3-acetylphenyl)-2-hydroxyacetate (9i). Isolated
matography (SiO2 gel, Hexane/AcOEt (5/1)), yielding the desire
hydroxyester product.
a
-
yield (12%). Colourless oil. 1H NMR (CDCl3, 400 MHz)
d: 1.25 (t, 3H,
CH3), 2.62 (s, 3H, CH3 (Ac)), 4.19e4.41 (m, 2H, CH2), 5.35 (s, 1H, CH),
7.32e7.51 (m, 2H, Ar), 7.91e7.97 (m, 1H, Ar), 8.04 (s, 1H, Ar). 13C
4.3.2. Ethyl mandelate.7 Obtained in >99% isolated yield, at room
temperature in 30 min. Colourless oil. 1H NMR (CDCl3, 400 MHz)
NMR (CDCl3, 100 MHz) d: 14.03, 22.62, 62.83, 72.39, 128.41, 128.66,
d:
129.01, 131.30, 137.55, 139.17, 173.06, 198.14. ESI-TOF MS (m/z):
1.21 (t, 3H, CH3), 3.56 (br s, 1H, OH), 4.17e4.26 (m, 2H, CH2), 5.16 (s,
223.10 (Mþ1).
1H, CH), 7.34e7.42 (m, 5H, Ar). 13C NMR (CDCl3, 100 MHz)
d: 14.14,
62.33, 73.01, 126.63, 128.49, 128.66, 138.53, 173.76.
4.3.11. Ethyl 2-hydroxy-2-(naphthalen-1-yl)acetate (9j). Isolated
yield (72%). White solid. 1H NMR (CDCl3, 400 MHz)
d: 1.26 (t, 3H,
4.3.3. Ethyl 2-hydroxy-2-(naphthalen-2-yl)acetate (9a). Isolated
yield (36%). White solid. 1H NMR (CDCl3, 400 MHz)
: 1.20 (t, 3H,
CH3), 4.12e4.32 (m, 2H, CH2), 5.81 (s, 1H, CH), 7.44e7.70 (m, 4H, Ar),
d
7.84e7.96 (m, 1H, Ar), 8.11e8.18 (m, 2H, Ar). 13C NMR (CDCl3,
CH3), 3.71 (br s, 1H, OH), 4.15e4.21 (m, 1H, CH2), 4.24e4.30 (m, 1H,
CH2), 5.33 (s, 1H, CH), 7.47e7.54 (m, 3H, Ar), 7.83e7.85 (m, 3H, Ar),
100 MHz) d: 14.17, 62.06, 71.33, 123.46, 123.70, 125.13, 125.68,
125.78, 126.48, 127.84, 128.80, 129.36, 134.07, 174.48. ESI-TOF MS
7.91 (s, 1H, Ar). 13C NMR (CDCl3, 100 MHz)
d
: 14.45, 62.40, 73.08,
(m/z): 233.08 (Mþ2).
124.17, 125.90, 126.06, 126.33, 127.91, 128.34, 128.62, 133.28, 133.38,
135.89. ESI-TOF MS (m/z): 213.10 (eOH), 231.10 (Mþ1).
4.3.12. Ethyl 2-(3-aminophenyl)-2-hydroxyacetate (9k). Obtained in
vestigial quantities. Colourless oil. 1H NMR (CDCl3, 400 MHz)
d: 1.33
4.3.4. Ethyl 2-(4-fluorophenyl)-2-hydroxyacetate (9b).7 Isolated
(t, 3H, CH3), 2.17 (br s, 1H, OH), 3.92 (s, 2H, NH2), 4.17e4.27 (m, 2H,
CH2), 5.67 (s, 1H, CH), 7.32e7.37 (m, 1H, Ar), 7.42e7.43 (d, 1H, Ar),
7.52e7.54 (m, 1H, Ar), 7.69e7.72 (m, 1H, Ar).
yield (>99%). Colourless oil. 1H NMR (CDCl3, 400 MHz)
d: 1.16 (t, 3H,
CH3), 3.88 (br s, 1H, OH), 4.12e4.18 (m, 1H, CH2), 4.20e4.24 (m, 1H,
CH2), 5.11 (s, 1H, CH), 6.99e7.03 (m, 2H, Ar), 7.36e7.40 (m, 2H, Ar).
13C NMR (CDCl3, 100 MHz)
d: 14.15, 62.36, 71.47, 115.49, 115.61,
4.3.13. Ethyl 2-hydroxypentanoate (9l). Isolated yield (23%). Yellow
128.24, 134.37, 161.42, 164.06, 173.67. ESI-TOF MS (m/z): 181.07
oil. 1H NMR (CDCl3, 400 MHz)
d: 0.87e0.93 (m, 3H, CH3), 1.30e1.33
(eOH), 199.08 (Mþ1).
(m, 3H, CH3), 1.32e1.35 (m, 2H, CH2),1.37e1.41 (m, 2H, CH2), 2.07 (s,
1H, OH), 4.23e4.32 (m, 2H, CH2), 5.32e5.34 (m, 1H, CH). 13C NMR
4.3.5. Ethyl 2-hydroxy-2-(2-methoxyphenyl)acetate (9d).7 Isolated
(CDCl3, 100 MHz) d: 14.09, 14.27, 22.79, 36.42, 62.70, 73.11, 169.23.
yield (81%). Colourless oil. 1H NMR (CDCl3, 400 MHz)
d
: 1.20 (t, 3H,
ESI-TOF MS (m/z): 146.07 (Mþ).
CH3), 3.91 (s, 3H, OCH3), 4.19e4.26 (m, 2H, CH2), 5.28 (s, 1H, CH),
6.89e6.96 (m, 2H, Ar), 7.01e7.05 (m, 1H, Ar), 7.42e7.47 (m, 1H, Ar).
13C NMR (CDCl3, 100 MHz)
d
: 14.31, 55.64, 61.52, 71.45, 110.01,
Acknowledgements
121.46, 129.51, 132.60, 137.17, 164.75, 174.01. ESI-TOF MS (m/z):
193.10 (eOH), 211.10 (Mþ1).
We are grateful for the award of a PhD grant to C.S.M. (SFRH/BD/
ˇ
~
45132/2008) from the Fundac¸ ao para a Ciencia e a Tecnologia (FCT)
4.3.6. Ethyl 2-(3-(benzyloxy)phenyl)-2-hydroxyacetate
2010. Chiratecnics Lda (www.chiratecnics.com) is acknowledged
for its support and interest in this project. We acknowledge
LabRMN at FCT-UNL for the acquisition of the NMR spectra; the
NMR spectrometers are part of the National NMR Network and
were purchased within the framework of the National Programme
for Scientific Re-equipment (contract REDE/1517/RMN/2005), with
(9e). Isolated yield (>99%). Yellow oil. 1H NMR (CDCl3, 400 MHz)
d: 1.24 (t, 3H, CH3), 3.63 (br s, 1H, OH), 4.13e4.21 (m, 1H, CH2),
4.23e4.31 (m, 1H, CH2), 5.08 (s, 2H, CH2), 5.15 (s, 1H, CH), 6.94e7.10
(m, 2H, Ar), 7.27e7.36 (m, 2H, Ar), 7.40e7.46 (m, 5H, Ar). 13C NMR
(CDCl3, 100 MHz) d: 13.94, 62.43, 70.41, 72.89, 113.03, 114.92, 119.20,

7216
C.S. Marques, A.J. Burke / Tetrahedron 68 (2012) 7211e7216
991e1000; (c) Saba, S.; Brescia, A.; Kaloustian, M. K. Tetrahedron Lett. 1991, 32,
5031e5034.
13. (a) Barros, M. T.; Phillips, A. M. F. Molecules 2006, 11, 177e196; (b) Arnanz, A.;
funds from POCI 2010 (FEDER) and FCT. The University of Vigo
(Spain) is gratefully acknowledgement for MS analysis.
ꢀ
ꢀ
Gonzalez-Arellano, C.; Juan, A.; Villaverde, G.; Corma, A.; Iglesias, M.; Sanchez,
F. Chem. Commun. 2010, 3001e3003.
Supplementary data
14. For recent examples, see: (a) Buitrago, E.; Zani, L.; Adolfsson, H. Appl. Organo-
met. Chem. 2011, 25, 748e752; (b) Busetto, L.; Cassani, M. C.; Femoni, C.;
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.05.129.
€
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