Hyphenating the curtius rearrangement with morita-baylis-hillman adducts: Synthesis of biologically active acyloins and vicinal aminoalcohols

Article abstract of DOI:10.1590/S0103-50532011000800022

Using Morita-Baylis-Hillman adducts as substrates, the Curtius rearrangement was performed in a sequence that allowed the synthesis of several hydroxy-ketones (acyloins) with great structural diversity and in good overall yields. These acyloins in turn were easily transformed into 1,2-anti aminoalcohols through a highly diastereoselective reductive amination step. The synthetic utility of these approaches was exemplified by performing the syntheses of (±)-bupropion, a drug used to treat the abstinence syndrome of smoker and (±)-spisulosine, a potent anti-tumoral compound originally isolated form a marine source.

Full text of DOI:10.1590/S0103-50532011000800022

J. Braz. Chem. Soc., Vol. 22, No. 8, 1568-1584, 2011.
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Article
A
Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts:
Synthesis of Biologically Active Acyloins and Vicinal Aminoalcohols
Giovanni W. Amarante, Mayra Cavallaro and Fernando Coelho*
Laboratório de Síntese de Produtos Naturais e Fármacos, Instituto de Química,
Universidade de Campinas, 13083-970 Campinas-SP, Brazil
Um rearranjo de Curtius, utilizando adutos de Morita-Baylis-Hillman como substrato, foi
realizado em uma sequência que permitiu a síntese de várias hidroxi-cetonas (aciloínas) com
uma grande diversidade estrutural e com bons rendimentos globais. Por sua vez, essas aciloínas
foram transformadas em 1,2-amino-alcoóis de configuração relativa anti, através de uma etapa
de aminação redutiva altamente diastereosseletiva. A utilidade sintética dessas abordagens foi
demonstrada através das sínteses totais da (±)-bupropiona, fármaco utilizado no tratamento na
síndrome de abstinência de fumantes e da (±)-espisulosina, um potente agente anti-tumoral isolado
inicialmente de uma fonte marinha.
Using Morita-Baylis-Hillman adducts as substrates, the Curtius rearrangement was performed
in a sequence that allowed the synthesis of several hydroxy-ketones (acyloins) with great structural
diversity and in good overall yields. These acyloins in turn were easily transformed into 1,2-anti
aminoalcohols through a highly diastereoselective reductive amination step. The synthetic utility
of these approaches was exemplified by performing the syntheses of (±)-bupropion, a drug used
to treat the abstinence syndrome of smoker and (±)-spisulosine, a potent anti-tumoral compound
originally isolated from a marine source.
Keywords: Curtius rearrangement, Morita-Baylis-Hillman, drugs, aminoalcohols, acyloins
Introduction
has limited the industrial use of this transformation until
recently, whenAm Ende et al. reported a new experimental
8
The formation of new C–N bonds by incorporation
of a nitrogen atom into a molecule is a fundamental
transformation in organic chemistry, since it allows
protocol, which enabled the use of this reaction under safer
conditions even when conducted on a large scale. This and
other protocols have revived interest in this rearrangement,
1
9
accessing many valuable compounds. Basically, this can
particularly for industrial purposes.
be achieved by nucleophilic substitution reactions or by
electrophilic amination reactions.
Regarding the potential of this rearrangement, our group
has recently reported the preparation of some carbamates
2
1
0
A C–N bond can also be built through rearrangement
from Morita-Baylis-Hillman (MBH) adducts. Curtius
rearrangement would be the best way to achieve our target,
since the carboxyl group in this structure is needed to
perform this rearrangement. Thus, when an acid derived
from a MBH adduct was treated with sodium azide,
heated at reflux and treated subsequently with t-butanol,
the corresponding ene-carbamate was formed in good
overall yield. However, in some examples it was observed
the occurrence of a byproduct (ca. 12-15%) which was
characterized as being an acyloin (Scheme 1).
3
4
5
reactions. For instance, Lossen, Beckman, Schmidt and
6
Curtius rearrangements are processes which allow the
efficient formation of a new C–N bond from carbonyl
containing derivative compounds.
The Curtius rearrangement is a thermal decomposition
of a carbonyl azide leading to an isocyanate. This
stereospecific rearrangement provides carbamates or amines
in good overall yields and selectivities. Unfortunately, this
rearrangement has the drawback that low molar mass acyl
7
azides present an explosion hazard. This safety issue
The acyloin formation was easily explained by the
presence of water (tiny amount) in the t-BuOH used
to transform the intermediate ene-isocyanate into the
*
e-mail: coelho@iqm.unicamp.br

Vol. 22, No. 8, 2011
Amarante et al.
1569
OTBS
OTBS
OH
CO2Me
CO2H
O2N
O2N
1) Curtius
OTBS
OTBS
OTBS
anhydrous
humid
t-BuOH
O
t-BuOH
NHBoc
ene-carbamate
NCO
O2N
O2N
O2N
acyloin
Scheme 1. Curtius rearrangement using Morita-Baylis-Hillman adduct as substrate.
corresponding ene-carbamate. This undesirable side
reaction caught our attention, since a-hydroxyketones
active compounds. They are also part of several chiral
catalysts and new materials.
(
acyloins) are structural motifs present in several
Thebiologicalandsyntheticimportancesofthisstructural
motif have stimulated the development of several methods
to synthesize it, both in racemic and enantiomerically
biologically active compounds, in which the activity is
closely associated with the presence of this structural
pattern. Due to the synthetic and biological relevance
of acyloins, several synthetic approaches have already
been developed in order to prepare them. Conventionally,
a-hydroxy ketones are prepared by the acyloin condensation
reaction, oxidation of enolates or double bonds, or
reduction of a-diketones or esters. Recently, a method
based on ketohydroxylation of alkenes was developed
1
9
pure forms. Classically, syn-1,2-aminoalcohols can be
prepared in their racemic or asymmetric versions using the
20
aminohydroxylation strategy developed by Sharplesset al.
Another efficient way to prepare vicinal aminoalcohols
is by the opening of an epoxide ring with a suitable
nitrogen source, such as amines or azide ions, to provide
1
1
12
13
21,22
aminoalcohols or azidoalcohols, respectively.
1
4
to give acyloins. Alternatively, radical oxidation of a
,3-dicarbonyl compound with cerium salts could also
By using simple chemical transformations,
1
a-hydroxyketones (acyloins) can also be used as substrates
15
23
be used for the preparation of acyloins. Most recently, a
skeletal rearrangement of symmetrically a,a-disubstituted
a-amino aldehyde has been reported as a new strategy for
for the stereoselective preparation of 1,2-aminoalcohols.
Spisulosine (2, Figure 1) is a sphingoid-type base
which presents a long unsaturated alkyl chain (C ) and
1
5
16
24
preparing acyloins.
a 1,2-aminoalcohol motif in an anti relationship. This
Beyond its biological importance, a-hydroxyketones
are also an interesting synthetic platform that allows further
chemical transformations. For instance, a a-hydroxyketone
can be easily transformed into a a-aminoketone. This
structural pattern is present in some commercial drugs, such
as bupropion [(±)-a-t-butylamino-3-chloropropiophenone]
compound was isolated from extracts obtained from the
clam Spisula polynyma and exhibits a promising activity
25
against prostate cancer.
In a research program directed towards the total
2
6
synthesis of drugs from Morita-Baylis-Hillman adducts,
we describe herein the synthesis of a-hydroxyketones
and their diastereoselective transformations into
anti-1,2-aminoalcohols. To exemplify the synthetic utility
of this approach, we also describe the syntheses of the drugs
(+/-)-bupropion and (+/-)-spisulosine.
(
1, Figure 1), a potent synthetic inhibitor of dopamine
17
reuptake with subtle noradrenergic reuptake. Bupropion
is an atypical antidepressant, which has been licensed by
18
FDA to treat the abstinence syndrome of smokers.
O
Results and Discussion
OH
N
H
NH2
The present work began by preparing the MBH
adducts, according to a procedure previously developed in
our laboratory. The strategy provides the corresponding
adducts in good to high yields. The results are summarized
in Table 1.
Cl
± ±)-bupruꢀron(1±
(
(± ±)ꢁuꢀꢁblrꢁꢀoꢂn(2±
27
Figure 1. Molecular structures of bupropion and spisulosine.
Vicinal aminoalcohols (or 1,2-aminoalcohols) are
structural units that currently occur in several biologically
Initially, the Curtius rearrangement without protection
of the secondary hydroxyl group was of interesting in this

1
570
Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
Table 1. Morita-Baylis-Hillman adducts
yields. Soon after, ester hydrolysis was carried out with
LiOH, in an acetonitrile:H O mixture at 60 °C to produce
acids 23-32 in excellent yields. The results of these steps
are summarized in Table 2.
2
a
Entry
Aldehyde
2-nitrobenzaldehyde
3-chlorobenzaldehyde
benzaldehyde
MBH adduct, yield / %
1
2
3
4
5
6
7
8
9
3, 92
4, 89
5, 75
6, 77
7, 60
8, 90
9, 95
10, 80
11, 76
The Curtius rearrangement was initiated using
2
8
diphenylphosphoryl azide (DPPA). This reagent is
supposed to react with a carboxylic acid to provide an
isocyanate in a single step. A solution of silyl-acid 23 in
toluene was therefore treated with DPPA at reflux for 20 h.
Unfortunately, it was unable to isolate any isocyanate.
Instead, a complete destruction of the silylated acid was
observed.
4-methoxybenzaldehyde
3,4,5-trimethoxybenzaldehyde
thiophenecarboxaldehyde
2-fluorobenzaldehyde
propanaldehyde
b
hexanaldehyde
c
Because of this result, it was decided to perform the
Curtius rearrangement by using a classical experimental
protocol. Thus, an acetone solution of silylated acids
was treated with ethyl chloroformate in the presence of
triethylamine at 0 °C for 5 min. After that, sodium azide
was added to the reaction mixture and this mixture was
vigorously stirred for 2 h. The crude products were refluxed
in dry toluene for 2 h to give the corresponding isocyanates,
which finally were refluxed in water to furnish a set of
acyloins in good overall yield (ranging from 35 to 50% for
3 steps). The results are summarized in Table 3.
Acyloins were obtained in good overall yield in three
steps from Morita-Baylis-Hillman adducts. The strategy
is simple and requires no special conditions such as low
temperature, dry solvents or special catalysts. Moreover, it
uses reagents which are routinely found in organic synthesis
laboratories.
1
0
hexadecanaldehyde
12, 60
a
b
Yields refer to isolated and purified products; MBH reaction was
performed with excess of methyl acrylate in the presence of [bmim]PF6
at 0 °C; prepared by oxidation of commercial hexadecanol with PCC in
c
refluxing dichloromethane in 95% yield.
work. So, adduct 3 was hydrolysed in the presence of LiOH
in an acetonitrile:H O (1:1) mixture to give a hydroxyacid
2
in almost quantitative yield (> 98%). When this acid was
treated with ethyl chloroformate, extensive degradation of
our starting material was observed by TLC analysis.
In an attempt to circumvent this issue, the secondary
hydroxyl group of the MBH adducts was protected, before
ester hydrolysis. Thus, adducts 3-12 were treated with
TBSCl or TBSOTf in DMF or dichloromethane, in the
presence of imidazole or triethylamine, respectively. The
silylated adducts (13-22) were obtained in good to excellent
Table 2. Silylation and hydrolysis of Morita-Baylis-Hillman adducts
OR1
O
OR1
O
OH
O
TBSCl or TBSOTf
LiOH
R
O
R
O
R
OH
DCM, imidazole
or NEt3
CH CN:H O, 1:1
3
2
o
50-60 C
MBH adducts
R = aryl or alkyl
sylilated adducts
sylilated acids
1
1
R = TBS
R = TBS
(23-32)
(
3-12)
(13-22)
a
a
Entry
MBH adducts
Silylated adducts, yield / %
Silylated acids, yield / %
1
2
3
4
5
6
7
8
9
3
4
13, 97
14, 99
15, 99
16, 99
17, 99
18, 90
19, 85
20, 85
21, 99
22, 70
23, 97
24, 99
25, 99
26, 98
27, 99
28, 99
29, 99
30, 99
31, 98
5
6
7
8
9
10
11
b
1
0
12
32, 99
a
b
Yields refer to isolated and purified products; methanol used as solvent and NaOH used as base instead of LiOH.

Vol. 22, No. 8, 2011
Amarante et al.
1571
Table 3. Acyloins from Morita-Baylis-Hillman adducts
synthetic versatility explains the frequent use of acyloins
as building blocks for the synthesis of pharmaceutical
compounds.
A ketone carbonyl group can be promptly transformed
into an amine by a reductive amination reaction.
Applications of this reaction are widespread in the
pharmaceutical, agrochemical and chemical industries, and
29
o
OR1
O
i) ClCO2Et, acetone, 5 C, 5 min
OR1
ii) NaN3, r.t., 2 h
O
R
OH
R
iii) toluene, reflux, 2 h
iv) H2O, reflux, 2 h
1
R = TBS
acyloins
3
3-42
23-32
3
0-32
in materials science and biotechnology.
a,b
Entry
R
2-nitrophenyl
3-chlorophenyl
phenyl
Acyloin
Yield / %
46
3
3
Recently, Cabral et al. have developed a simple
method to perform a reductive amination, based on in situ
formation of an iminium, followed by reduction with
1
2
3
4
5
6
7
8
9
33
34
35
36
37
38
39
40
41
42
45
50
LiBH . Thus, this was viewed in the present work as an
4
4-methoxyphenyl
3,4,5-trimethoxyphenyl
thienyl
48
attractive opportunity to test this method to prepare vicinal
aminoalcohols from our acyloins.
42
44
A methanol solution of 35 was treated with LiBH in the
4
2-fluorophenyl
ethyl
41
presence of an excess of benzylamine (3 equiv.) at −72 °C
to give aminoalcohol 46 in 83% yield and excellent 1,2-anti
diastereoselectivity(97:3d.r.,anti:syn).Thissimplesequence
has allowed the development of a highly diastereoselective
synthesis of several different aminoalcohols in good yields.
The results are summarized in Table 4.
46
hexyl
42
10
hexadecanyl
40
a
b
Yields refer to isolated and purified products; overall yield (3 steps
from silyl esters).
For all cases examined, the vicinal aminoalcohols
were obtained in good yields and with excellent
diastereoselectivities. To confirm the 1,2-anti relative
stereochemistry, the silyl protecting group of aminoalcohol
44 was removed by treatment with TBAF. The unprotected
vicinal aminoalcohol 55 was reacted with triphosgene to
The bifunctional identity (one eletrophilic group and
another nucleophilic) makes acyloins an important building
block in organic synthesis. They can be converted into
several different functional groups, such as alcohols, diols,
epoxides, amines, hydroxylamines and haloketones. This
Table 4. Vicinal aminoalcohols from acyloins
OTBS
1
OTBS
R NH2, LiBH4, MeOH
O
R
R
–
78 °C to r.t., 13 h
NHR1
acyloins
4-35, 37-40
3
(+/-)-anti-
vicinal aminoalcohols (43-54)
1
a
b
Entry
Acyloin (R)
Amine (R )
phenethyl
benzyl
Yield / %
43, 79
44, 77
45, 85
46, 83
47, 82
48, 80
49, 81
50, 80
51, 82
52, 78
53, 73
d.r.
1
2
3
4
5
6
7
8
9
34, 3-chlorophenyl
34, 3-chlorophenyl
35, phenyl
96:4
92:8
phenethyl
benzyl
> 95:5
97:3
35, phenyl
35, phenyl
allyl
98:2
35, phenyl
cyclohexyl
phenethyl
allyl
93:7
37, 3,4,5-trimethoxyphenyl
37, 3,4,5-trimethoxyphenyl
38, thienyl
> 95:5
87:13
91:9
phenethyl
phenethyl
phenethyl
decyl
1
0
1
2
39, 2-fluorophenyl
40, ethyl
> 95:5
> 95:5
> 95:5
1
1
40, ethyl
54, 71
a
b
1
Yields refer to isolated and purified products; diastereoisomeric ratio was determined by analysis of the H NMR spectra of the crude reaction mixture.
The carbinolic proton shows a doublet with a coupling constant of 5 Hz for the anti relationship, while the syn product shows a coupling constant of 8.2 Hz.

1
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Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
O
OTBS
OH
O
NBn
Hb
TBAF, MeOH, r.t.
Cl3CCOCCl3
Ha
NHBn
NHBn
2
h, 80%
CH2Cl2, r.t., 12 h,
70%
8.2 Hz
Cl
Cl
Cl
(+/-)-44
(+/-)-55
(+/-)-56
Scheme 2. Relative stereochemistry assignment of the 1,2-anti aminoalcohol derivatives.
OH
OH
OTBS
O
2 2 2
Ph(CH ) NH
O
TBAF, MeOH, r.t.
h, 80%
NH(CH2)2Ph
2
LiBH , MeOH
4
–78 °C to r.t., 13 h, 70%
(+/-)-57
(+/-)-58
anti:syn, 87:13
(+/-)-35
Scheme 3. Silyl protecting group and diastereoselectivity.
afford oxazolidinone 56, in 70% yield (Scheme 2). The
less hindered side. The oxygen atom attached to the silicon
of the TBS group has a low basicity, however it is still able
to establish intramolecular hydrogen bonds in order to
coupling constant between hydrogens H and H was found
a
b
to be 8.2 Hz, which it is in agreement with typical coupling
35
constants for a cis relationship in oxazolidinones formed
control stereoselectivities of reactions.
34
from a 1,2-anti aminoalcohol (Scheme 2).
The Curtius rearrangement carried out with MBH
adducts has allowed the development of a new approach
to prepare a-hydroxyketones, which have been used to
prepare diastereoselective 1,2-anti vicinal aminoalcohols.
Searching to demonstrate the synthetic utility of these
approaches, the total synthesis of two pharmacologically
active compounds is now described. (±)-Bupropion
The presence of a bulky protecting group on the
secondary hydroxyl group might play an important role in
the iminium reduction step. Most likely the hydride attack
occurs at the opposite side from the protecting group. To
experimentally validate this hypothesis, silylated acyloin
3
5
5 was treated with TBAF in methanol to provide acyloin
7 in 80% yield. A methanol solution of 57 at −72 °C was
3
6
(1, Figure 1) is an aminoketone acting on CNS. This
compound is commmercialized in its racemic form, since
it racemizes very quickly in the body when administered in
its enantiomerically pure form. Our target compound could
be prepared from acyloin 34 (Figure 3). A 1,2-carbonyl
transposition reaction is required to provide 59, which can
treated with LiBH to afford aminoalcohol 58 in 70% yield
4
and moderate diastereoselectivity (87:13 d.r.; anti:syn)
(
Scheme 3).
This result shows the effect of the silyl protecting
group on the diastereoselectivity of the reduction step.
Besides, the lithium atom could be complexed both with
the nitrogen and the oxygen lone pairs (Figure 2). This
arrangement allows the hydride to approach only from the
37
be converted uneventfully to (±)-1.
A direct way to perform the required 1,2-carbonyl
transposition was using the Lobry-de Bruyn-van Ekenstein
38
transformation. Thisreaction,currentlyusedincarbohydrate
chemistry, is essentially an enolization of a sugar having a
hydrogen at the a-carbon to the carbonyl group and proceeds
via an enediol intermediate. Some acyloins rearrange with
positions exchanged under the influence of base in this
transformation. To test this alternative, the TBS group of
acyloin34wasremovedbytreatmentwithTBAFinmethanol
for 12 h to give the corresponding unprotected acyloin in
H
H
TBS
O
Li
H C
3
N
R1
R
Figure 2. Rationalizing the diastereoselectivity.
C=O
transposition
OTBS
O
O
O
H
N
OH
Cl
Cl
(+/-)-59
Cl
(+/-)-bupropion (1)
(
+/-)-34
Figure 3. Synthesis of (±)-bupropion from acyloin 34.

Vol. 22, No. 8, 2011
Amarante et al.
1573
7
5% yield. A methanol solution of this acyloin was reacted
direct sequence. Reductive amination of acyloin (±)-42 was
performed with an excess of benzylamine to give vicinal
aminoalcohol (±)-62, with high anti diastereoselectivity
(> 95:5, anti:syn), in 68% yield (Scheme 6). To quickly
finish the synthesis, it was only necessary to remove the
protecting groups (TBS and benzyl). For thus, a solution
of (±)-62 in methanol was acidified with some drops
of concentrated HCl and the mixture was poured into
a hydrogenating bottle containing 10% Pd on charcoal
(10 mol%). To our surprise, after several hours at 60 psi,
neither of the protecting groups was removed. Perhaps,
the long carbon chain favoured the formation of mycelles,
which could interact with the solid catalyst.
with a 30% solution of NaOH at room temperature. As a
result, an extensive acyloin degradation was observed even
at lower temperatures (−5 and −10 °C). We also tested the
Voight amination (formation of ketoamine by treatment of
an acyloin with P O in the presence of a primary amine),
2
5
39
however this reaction also failed.
Due to these results, the synthetic approach towards the
synthesis of bupropion was changed. As an alternative, the
required transposition could be done in three steps. Thus,
carbonyl reduction of the acyloin (±)-34 directly led to a
monoprotected diol (±)-60 in almost quantitative yield. TBS
removal was performed in the presence of TBAF to afford
diol (±)-61 in 97% yield, as a mixture of diastereoisomers.
Selective benzylic oxidation of (±)-61 with IBX in DMSO
expectedly led to the 1,2-carbonyl transposition product
To solve this unexpected issue, a mixture of solvents for
the hydrogenation reaction was used. Thus, a mixture of
(±)-62 in dichloromethane:acetic acid (1.5:1) in the presence
of 10% Pd/C at 60 psi and 50 °C was shaken for 20 h to
furnish the debenzylated aminoalcohol (±)-63 in 87% yield.
Finally, the TBS group of (±)-63 was removed by
the treatment with concentrated HCl (0.1 mL) in a
solution of dichoromethane:methanol (1:1; 1 mL) to give
(±)-spisulosine (2) in 98% yield. All spectroscopic and
physical data are identical to those described in literature
(±)-59, as the sole product, in 85% yield (3 steps, 81%
overall yield, Scheme 4).
Bupropion, in its racemic version, was obtained in 7
steps from Morita-Baylis-Hillman 4, in 27% overall yield.
The sequence is facile to execute and can be scaled-up
without problems.
The synthetic methods described in this paper can be
combined in order to synthesize spisulosine (2, Figure 1)
as a racemate. This natural anti-tumoral compound can
be prepared from acyloin 42, using a diastereoselective
reductive amination step (Scheme 5).
2
4,40
for natural and synthetic spisulosine (Scheme 6).
Spisulosine was synthetized in 7 steps from hexadecanal
with an overall yield of 10%. The strategy is very simple
and requires no special conditions such as low temperature
or dry solvents. If the sequence begins with adduct 12
in its enantiomerically pure form, it would allow the
The diastereoselective total synthesis of spisulosine was
accomplished from acyloin (±)-42 using a very simple and
OTBS
OH
OTBS
OH
TBAF,
THF
O
OH
NaBH4, MeOH
r.t., 10 min, 99%
r.t., 2 h,
9
7%
Cl
Cl
Cl
(
+/-)-34
(+/-)-60
(+/-)-61
IBX, DMSO
r.t., 30 h, 85%
i) Tf2O,CH2Cl2
O
H
N
O
2
,6-lutidine
o
OH
–
40 C, 30 min
Cl
ii) t-BuNH2
12 h, 75%
Cl
(
+/-)-bupropion (1)
(+/-)-59
Scheme 4. Racemic total synthesis of bupropion from an acyloin.
OTBS
OH
O
13
NH2
(± ±)ꢁaculpie(42±
(
± ±)-sp-ꢀul-pine(2±
Scheme 5. Retrosynthesis of spisulosine (2).

1
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Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
OTBS
OTBS
BiNH2,nCH2Cy2
O
l
1
3
N-BH3CN,n40n C
n20nh,n68%
13
NHBi
antin>n95:5
± ±)(62±
(
± ±)-acyloin(42±
(
AaOH,nCH2Cy2,n10%nPd/C
l
H2n,n60npso,n50n C,n87%
OH
OTBS
CH2Cy2,nMeOH
1
3
l
NH2
HCy,n50n C
0nh,n98%
antin>n95:5
1
3
NH2
2
(
± ±)sposꢀylsoien(2±
(± ±)(63±
Scheme 6. Diastereoselective total synthesis of (+/-)-spisulosine from acyloin.
enantioselective synthesis of spisulosine. By using this
strategy, spisulosine derivatives can also be synthesized
using the sequence described herein.
detected by spraying with 5% ethanolic phosphomolybdic
acid and heating. All the Morita-Baylis-Hillman reactions
were sonicated in an ultrasonic cleaner (81 W, 40 MHz).
Conclusions
General procedure for the synthesis of the Morita-Baylis-
Hillman adducts
In summary, the Curtius rearrangement coupled with
Morita-Baylis-Hillman adducts as substrate has proven to
be an alternative for the preparation of interesting building
blocks for organic syntheses. This combination allowed
the synthesis of a set of acyloins in good overall yields for
three steps. Reductive amination of these acyloins gave
vicinal aminoalcohols in good overall yields and with
high diastereoselectivities, in favor of the 1,2-anti isomer.
Moreover, we have demonstrated that these methods can
be used in the synthesis of important pharmacologically
active compounds. Thus, (±)-bupropion was prepared in
A mixture of aldehyde (3-10 mmol), methyl acrylate
(excess, ca. 5 equiv.) and DABCO (0.65 equiv.) was
sonicated in an ultrasound bath at 30 °C. Reaction evolution
was followed by TLC analysis. For the preparation of
the MBH adducts 10 and 12 the reaction was carried
out using methyl acrylate (10 equiv.), ionic liquid
o
([bmim]BF ; 5 drops) as an additive, at 50 C with stirring.
4
The excess of methyl acrylate was removed under vaccum.
The crude residue was diluted in ethyl acetate (25 mL). The
organic layer was washed with distilled water (15 mL),
brine (2 × 15 mL), dried over anhydrous Na SO and the
7
steps from a MBH adduct, in 27% overall yield. Using
2
4
this strategy we also showed a highly diastereoselective
total synthesis of (±)-spisulosine which was accomplished
in 7 steps from hexadecanal with an overall yield of 10%.
solvent was removed under vacuum. The residue was
purified by flash silica gel column chromatography (ethyl
acetate:hexanes, up to 30:70) to provide the MBH adducts
in good to high yields.
Experimental
(
±)-Methyl 2-[hydroxy(2-nitrophenyl)methyl]prop-
General procedure
2-enoate (3): 92% yield, pale yellow oil; IR (film)
nmax/cm : 3469, 1716, 1630, 1528, 1352; H NMR
-
1
1
1
13
The H and C NMR spectra were recorded on a Bruker
at 250 and 62.5 MHz, respectively, or on an Inova instrument
at 500 and 125 MHz, respectively. High resolution mass
(500 MHz, CDCl ): d 7.94 (dd, J 1.2/8.2 Hz, 1H), 7.78 (d,
3
1H, J 7.9 Hz), 7.61-7.67 (m, 1H), 7.41-7.48 (m, 1H), 6.36
(s, 1H), 6.20 (s, 1H), 5.72 (s, 1H), 3.73 (s, 3H), 3.08 (s,
13
(HRMS) spectra were recorded using a Q-TOF Micromass
1H, OH); C NMR (125 MHz, CDCl ): d 166.3, 148.2,
3
equipment (Waters, UK). Manipulations and reactions were
not performed under dry atmospheres or employing dry
solvents, unless otherwise specified. In those cases CH Cl ,
140.7, 136.0, 133.4, 128.8, 128.6, 126.4, 124.5, 67.6,
+
52.1; HRMS (ESI TOF) Calcd. for C H NO [M + Na ]:
11
11
5
260.0529. Found: 260.0530.
2
2
DMF and triethylamine were dried over CaH and distilled.
2
Purification and separations by column chromatography
were performed on silica gel, using normal or flash
chromatography. Thin layer chromatography (TLC) was
(±)-Methyl 2-[(3-chlorophenyl)(hydroxy)methyl]
prop-2-enoate (4): 89% yield, colorless oil; IR (film)
-1
1
nmax/cm : 3452, 1711, 1433, 1282, 1151, 1041; H NMR

Vol. 22, No. 8, 2011
Amarante et al.
1575
(
250 MHz, CDCl ): d 7.36 (s, 1H), 7.21-7.26 (m, 3H), 6.34
MHz, CDCl ): d 166.7, 160.0 (d, J 245.5 Hz), 140.9, 129.4
3
3
(
1
1
s, 1H), 5.84 (s, 1H), 5.49 (s, 1H), 3.71 (s, 3H), 3.16 (s,
(d, J 8.2 Hz), 128.4, 128.1 (d, J 3.7 Hz), 126.3, 124.1 (d, J
3.5 Hz), 115.3 (d, J 21.5 Hz), 66.7, 52.0; HRMS (ESI TOF)
1
3
H, OH); C NMR (62.5 MHz, CDCl ): d 166.6, 143.4,
3
+
41.4, 134.3, 129.7, 127.9, 126.7, 124.8, 72.6, 52.1; HRMS
Calcd. for C H FO [M + H] : 211.0765. Found: 211.0762.
11
12
3
+
(ESI TOF) Calcd. for C H O Cl [M + Na ]: 249.0294.
11
11
3
Found: 249.0318.
(±)-Methyl 3-hydroxy-2-methylenepentanoate (10):
-1
8
0% yield; colorless oil; IR (film) n /cm : 3454, 2928,
max
1
(
±)-Methyl 2-[hydroxy(phenyl)methyl]prop-2-enoate
2853, 1705, 1287, 1157; H NMR (250 MHz, CDCl ):
3
-
1
(5): 75% yield, oil; IR (film) n /cm : 3448, 2949, 1711,
d 6.15 (s, 1H), 5.74 (s, 1H), 4.27 (q, 1H, J 5.7 Hz), 3.69 (s,
3H), 3.00 (d, 1H, J 5.7 Hz), 1.45-1.71 (m, 2H), 0.86 (t, 3H,
max
1
1
446, 1270, 1155, 1041; H NMR (250 MHz, CDCl ):
3
13
d 7.21-7.37 (m, 5H), 6.31 (s, 1H), 5.86 (s, 1H), 5.52 (s,
J 7.4 Hz); C NMR (62.5 MHz, CDCl ): d 167.0, 142.3,
3
1
3
1H), 3.65 (s, 3H), 3.45 (s, 1H, OH); C NMR (62.5 MHz,
124.9, 72.4, 51.7, 29.0, 9.9; HRMS (ESI TOF) Calcd. for
+
CDCl ): d 166.7, 142.1, 141.4, 128.4, 127.8, 126.7,
C H O [M + H] : 145.0859. Found: 145.0856.
3
7
13
3
1
25.8, 72.8, 51.9; HRMS (ESI TOF) Calcd. for C H O
11 12 3
+
[M + Na ]: 215.0684. Found: 215.0811.
(±)-Methyl 3-hydroxy-2-methylenenonanoate (11):
6% yield; amorphous solid; mp 131-132 ºC; IR (KBr)
nmax/cm : 3452, 2929, 2855, 1707, 1290, 1155; H NMR
7
-1
1
(±)-Methyl 2-[hydroxy(4-methoxyphenyl)methyl]prop-
2
-enoate (6): 73% yield; amorphous solid; mp 70-72 °C;
(500 MHz, CDCl ): d 6.20 (s, 1H), 5.78 (s, 1H), 4.37 (t,
3
-1
IR (KBr) n /cm : 3465, 1714, 1611, 1512, 1465, 1034;
1H, J 6.7 Hz), 3.77 (s, 3H), 1.54-1.71 (m, 2H), 1.19-1.50
max
1
13
H NMR (250 MHz, CDCl ): d 7.29 (d, 2H, J 8.5 Hz),
(m, 8H), 0.86 (t, 3H, J 6.7 Hz); C NMR (125 MHz,
3
6
1
.87 (d, 2H, J 8.5 Hz), 6.32 (s, 1H), 5.85 (s, 1H), 5.53 (s,
H), 3.80 (s, 3H), 3.72 (s, 3H), 2.43 (s, 1H, OH); C NMR
CDCl ): d 167.0, 142.5, 124.9, 71.7, 51.8, 36.2, 31.7, 29.0,
3
1
3
25.7, 22.5, 14.0; HRMS (ESI TOF) Calcd. for C H O
3
1
1
21
+
(62.5 MHz, CDCl ): d 166.8, 159.2, 142.1, 133.4, 127.9,
[M + H] : 201.1485. Found: 201.1483.
3
1
25.7, 113.8, 72.8, 55.2, 51.9; HRMS (ESI TOF) Calcd. for
+
C H O [M + Na ]: 245.0784. Found: 245.0780.
(±)-Methyl-3-hydroxy-2-methyleneoctadecanoate
1
2
14
4
(
12): 60% yield; amorphous solid; mp 43-45 °C; IR (film)
-1
(±)-Methyl 2-[hydroxy(3,4,5-trimethoxyphenyl)methyl]
n
/cm : 3465, 2984, 2929, 2856, 1742, 1374, 1242, 1048;
max
1
prop-2-enoate (7): 60% yield; amorphous solid; mp 121-
H NMR (250 MHz, CDCl ): d 6.21 (s, 1H), 5.79 (t, 1H,
3
-
1
1
1
(
3
(
1
23 ºC; IR (KBr) n /cm : 3464, 1712, 1613, 1514, 1463,
J 1.0 Hz), 4.37 (q, 1H, J 6.5 Hz), 3.77 (s, 3H), 2.59 (d, 1H,
J 6.5 Hz), 1.55-1.70 (m, 2H), 1.18-1.50 (m, 26H), 0.87 (t,
max
1
036; H NMR (250 MHz, CDCl ): d 6.54 (s, 2H), 6.27
s, 1H), 5.81 (s, 1H), 5.44 (d, 1H, J 5.0 Hz), 3.78 (s, 6H),
.77 (s, 3H), 3.69 (s, 3H), 3.35 (d, 1H, J 5.0 Hz); C NMR
62.5 MHz, CDCl ): d 166.8, 153.1, 141.9, 137.2, 137.0,
25.9, 103.5, 72.9, 60.7, 55.9, 52.0;HRMS(ESITOF)Calcd.
for C H O Cl [M + Na ]: 305.0996. Found: 305.0989.
3
13
3H, J 6.9 Hz); C NMR (62.5 MHz, CDCl ): d 167, 142.5,
3
13
124.9, 71.8, 51.8, 36.2, 31.9, 29.7, 29.63, 29.6, 29.5, 29.4,
29.3, 25.8, 22.7, 14.1; HRMS (ESI) Calcd. for C H O
3
20 39
3
+
[M + H] 327.2894; Found 327.2877.
+
11
11
3
General procedure for the silylation of Morita-Baylis-
Hillman adducts
(
±)-Methyl 2-[hydroxy(thiophen-2-yl)methyl]prop-
-1
2
3
(
(
(
-enoate (8): 90% yield; pale yellow oil; IR (film) nmax/cm :
445, 2952, 1715, 1632; H NMR (250 MHz, CDCl ): d 7.21
dd, 1H, J2.5/3.8 Hz), 6.90-6.93 (m, 2H), 6.32 (s, 1H), 5.95
s, 1H), 5.73 (d, 1H, J 6,2 Hz), 3.73 (d, 1H, J 6.2 Hz), 3.70
s, 3H); C NMR (62.5 MHz, CDCl ): d 166.5, 145.8, 141.5,
26.8, 126.0, 125.2, 124.8, 69.1, 52.0; HRMS (ESI TOF)
Calcd. for C H O S [M + H] : 199.0423. Found: 199.0417.
1
A mixture of MBH adduct (1-3 mmol), imidazole
(2.5 equiv.), TBSCl (1.5 equiv.) and a few drops of DMSO
(to facilitate stirring), under argon atmosphere, was stirred
at room temperature. After 2-4 h, the crude residue was
diluted in ethyl acetate (25 mL). The organic layer was
washed with distilled water (15 mL), brine (2 × 15 mL),
dried over anhydrous Na SO and the solvent was removed
3
13
3
1
+
9
11
3
2
4
(
±)-Methyl 2-[(2-fluorophenyl)(hydroxy)methyl]prop-
under vacuum. The crude mixture was filtered through silica
gel (ethyl acetate:hexanes, 30:70) to provide the silylated
compounds in good to excellent yields.
-1
2
3
-enoate (9): 95% yield; colorless oil; IR (film) nmax/cm :
437, 1721; H NMR (250 MHz, CDCl ): d 7.42 (dt, 1H,
1
3
J1.9/7.5 Hz), 7.21-7.28 (m, 1H), 7.10 (dt, 1H, J1.2/7.5 Hz),
.97-7.05 (m, 1H), 6.31 (s, 1H), 5.85 (d, 1H, J 5.5 Hz), 5.76
6
(±)-Methyl 2-{[(tert-butyldimethylsilyl)oxy](2-fluoro-
phenyl)methyl}prop-2-enoate (13): 97% yield; pale yellow
13
(s, 1H), 3.69 (s, 3H), 3.62 (d, 1H, J 5.5 Hz); C NMR (62.5

1
576
Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
-
1
oil; IR (film) nmax/cm : 2949, 2929, 2851, 1728, 1531, 1352,
51.6, 25.6, 18.1, −4.9, −5.1; HRMS (ESI TOF) Calcd. for
1
+
1
1
7
1
249, 1090, 837; H NMR (250 MHz, CDCl ): d 7.78 (d,
C H O Si [M + Na ]: 419.1860. Found: 419.1855.
3
20 32
6
H, J 8.0 Hz), 7.68 (d, 1H, J 8.0 Hz), 7.56 (t, 1H, J 7.5 Hz),
.37 (t, 1H, J 7.5 Hz), 6.34 (s, 1H), 6.29 (s, 1H), 5.97 (s,
H), 3.64 (s, 3H), 0.88 (s, 9H), 0.13 (s, 3H), −0.06 (s, 3H);
C NMR (62.5 MHz, CDCl ): d 165.2, 148.2, 143.1, 137.5,
32.6, 129.6, 128.1, 125.0, 123.9, 66.7, 51.8, 25.7, 18.1,
(±)-Methyl 2-{[(tert-butyldimethylsilyl)oxy](thiophen-
2-yl)methyl}prop-2-enoate (18): 90% yield; colorless
13
-1
oil; IR (film) n /cm : 2954, 2930, 2857, 1723, 1632,
3
max
1
1
−
1256, 1082; H NMR (250 MHz, CDCl ): d 7.18 (dd, 1H,
3
+
5.1. HRMS (ESI TOF) Calcd. for C H NO Si [M + Na ]:
74.1394. Found: 374.1389.
J5.0/1.3 Hz), 6.83-6.98 (m, 2H), 6.28 (t, 1H, J 1.1 Hz), 6.12
(t, 1H, J 1.5 Hz), 5.89 (s, 1H), 3.73 (s, 3H), 0.90 (s, 9H),
17
25
5
3
13
0
.08 (s, 3H), −0.003 (s, 3H); C NMR (62.5 MHz, CDCl ):
3
(
±)-Methyl 2-{[(tert-butyldimethylsilyl)oxy](3-chloro-
d 166.2, 147.3, 143.5, 126.3, 124.6, 124.4, 124.2, 68.4,
phenyl)methyl}prop-2-enoate (14): > 99% yield; pale
51.7, 25.7, 18.2, −5.1, −5.14; HRMS (ESI TOF) Calcd.
-1
+
yellow oil; IR (film) n /cm : 2949, 2929, 2855, 1707,
for C H O SSi [M + Na ]: 335.1108. Found: 335.1107.
max
15 24
3
1
1
061, 841, 780; H NMR (250 MHz, CDCl ): d 7.35 (s,
3
1
H), 7.17-7.32 (m, 3H), 6.28 (s, 1H), 6.10 (s, 1H), 5.58
(±)-Methyl 2-{[(tert-butyldimethylsilyl)oxy](2-fluoro-
(
s, 1H), 3.69 (s, 3H), 0.88 (s, 9H), 0.06 (s, 3H), −0.08 (s,
phenyl)methyl}prop-2-enoate (19): 85% yield; colorless
1
3
-1
1
3
1
1
H); C NMR (75.5 MHz, CDCl ): d 166.1, 144.8, 143.4,
oil; IR (film) nmax/cm : 1723; H NMR (250 MHz, CDCl ):
3
3
33.9, 129.3, 127.5, 127.0, 125.2, 124.4, 72.1, 51.7, 25.7,
8.1, −5.0; HRMS (ESI TOF) Calcd. for C H ClO Si
d 7.35 (dt, 1H, J1.5/7.5 Hz), 7.16-7.28 (m, 1H), 6.95-7.14
(m, 2H), 6.34 (s, 1H), 6.07 (s, 1H), 5.95 (s, 1H), 3.66 (s,
1
7
25
3
+
13
[
M + Na ]: 363.1154. Found: 363.1150.
3H), 0.87 (s, 9H), 0.08 (s, 3H), −0.09 (s, 3H); C NMR
(
62.5 MHz, CDCl ): d 166.0, 159.8 (d, J 245.7 Hz), 142.7,
3
(
±)-Methyl 2-{[(tert-butyldimethylsilyl)oxy](phenyl)
129.5 (d, J 13.5 Hz), 129.1, 129.0 (d, J 6.8 Hz), 128.8,
124.8, 123.9 (d, J 3.5 Hz), 115.2 (d, J 22.2 Hz), 65.8, 51.6,
25.7, 18.1, −5.2, −5.3.
methyl}prop-2-enoate (15): > 99% yield; colorless oil; IR
film) nmax/cm : 2949, 2851, 1458, 1258, 1082; H NMR
-1
1
(
(
250 MHz, CDCl ): d 7.17-7.41 (m, 5H), 6.25 (s, 1H), 6.08
3
(
s, 1H), 5.61 (s, 1H), 3.68 (s, 3H), 0.88 (s, 9H), 0.06 (s,
(± )-Methyl 3-[(tert-butyldimethylsilyl)oxy]-
1
3
3
1
1
H), −0.11 (s, 3H); C NMR (62.5 MHz, CDCl ): d 166.4,
2-methylidenepentanoate (20): 85% yield; colorless oil;
3
-1
1
43.9, 142.6, 128.0, 127.3, 127.0, 123.8, 72.7, 51.6, 25.7,
8.1, −4.9; HRMS (ESI TOF) Calcd. for C H O Si [M +
IR (film) nmax/cm : 2930, 2845, 1721; H NMR (250 MHz,
CDCl ): d 6.20-6.23 (m, 1H), 5.86-5.89 (m, 1H), 4.50-4.59
17
26
3
3
+
Na ]: 329.1543. Found: 329.1537.
(m, 1H), 3.74 (s, 3H), 1.35-1.75 (m, 2H), 0.90 (s, 9H), 0.85
13
(
t, 3H, J 7.4 Hz), 0.05 (s, 3H), −0.02 (s, 3H); C NMR
(
± )-Methyl 2-{[(tert-butyldimethylsilyl)oxy]
(62.5 MHz, CDCl ): d 166.8, 143.6, 124.5, 71.0, 51.6,
3
(
4-methoxyphenyl)methyl}prop-2-enoate (16): > 99%
30.3, 25.8, 18.1, 9.0, −4.8, –5.1; HRMS (ESI TOF) Calcd.
-1
+
yield; amorphous solid; mp 112-114 ºC; IR (KBr) nmax/cm :
2
for C H FO Si [M + Na ]: 347.1449 Found: 347.1445.
17
25
3
1
949, 2929, 2851, 1715, 1507, 1245, 1047, 833, 771; H
NMR (250 MHz, CDCl ): d 7.27 (d, 2H, J 7.0 Hz), 6.82 (d,
(± )-Methyl 3-[(tert-butyldimethylsilyl)oxy]-
3
2
H, J 7.0 Hz), 6.22 (s, 1H), 6.06 (s, 1H), 5.56 (s, 1H), 3.78
2-methylidenenonanoate (21): > 99% yield; amorphous
-
1
(
s, 3H), 3.67 (s, 3H), 0.87 (s, 9H), 0.06 (s, 3H), −0.11 (s,
solid; mp 102-103 ºC; IR (film) n /cm : 2929, 2859,
max
1
3
1
3
1
−
H); C NMR (125 MHz, CDCl ): d 166.4, 158.8, 144.1,
1719, 1249, 1090, 837; H NMR (250 MHz, CDCl ):
3
3
34.8, 128.2, 123.3, 113.4, 72.3, 55.1, 51.6, 25.7, 18.1,
d 6.17-6.21 (m, 1H), 5.87-5.90 (m, 1H), 4.52-4.61 (m,
+
4.9; HRMS (ESI TOF) Calcd. for C H O Si [M + Na ]:
1H), 3.72 (s, 3H), 1.18-1.65 (m, 10H), 0.78-0.92 (m, 12H),
18
28
4
13
3
59.1649. Found: 359.1647.
0.04 (s, 3H), −0.04 (s, 3H); C NMR (62.5 MHz, CDCl ):
3
d 166.7, 144.1, 124.2, 70.2, 51.5, 37.8, 31.8, 29.1, 25.7,
(
± )-Methyl 2-{[(tert-butyldimethylsilyl)oxy]
24.9, 22.6, 18.1, 14.0, −4.8, −5.1; HRMS (ESI TOF) Calcd.
+
(
3,4,5-trimethoxyphenyl)methyl}prop-2-enoate (17): 80%
yield; colorless oil; IR (film) nmax/cm : 2950, 2927, 2854,
718, 1505, 1246, 1051; H NMR (250 MHz, CDCl ):
for C H O Si [M + Na ]: 337.2169. Found: 337.2168.
17
34
3
-1
1
1
(± )-Methyl-3-[(tert-butyldimethylsilyl)oxy]-
3
d 6.56 (s, 2H), 6.18 (t, 1H, J 1.1 Hz), 5.95 (t, 1H, J 1.5 Hz),
2-methyleneoctadecanoate (22): 70% yield; viscous
-1
5
3
1
.53 (s, 1H), 3.78 (s, 6H), 3.67 (s, 3H), 0.85 (s, 9H), 0.03 (s,
colorless oil; IR (film) n /cm : 2926, 2855, 1722, 1463,
max
1
3
1
H), −0.10 (s, 3H); C NMR (62.5 MHz, CDCl ): d 166.5,
1257, 1092; H NMR (250 MHz, CDCl ): d 6.19-6.21 (m,
3
3
52.8, 143.9, 138.3, 137.0, 123.9, 103.7, 72.4, 60.7, 55.9,
1H), 5.90 (t, 1H, J 1.6 Hz), 4.56-4.61 (m, 1H), 3.75 (s, 3H),

Vol. 22, No. 8, 2011
Amarante et al.
1577
-
1
1
.18-1.63 (m, 28H), 0.81-0.93 (m, 12H), 0.05 (s, 3H), −0.02
colorless oil; IR (film) nmax/cm : 2953, 2925, 2847, 1691,
13
1
(s, 3H); C NMR (62.5 MHz, CDCl ): d 166.7, 144.2, 124.2,
1507, 1245, 1074, 837, 775; H NMR (250 MHz, CDCl ):
3
3
70.2, 51.6, 37.9, 31.9, 29.7, 29.63, 29.6, 29.55, 29.5, 29.3,
d 7.25 (d, 2H, J 7.0 Hz), 6.82 (d, 2H, J 7.0 Hz), 6.35 (s,
2
5.8, 22.7, 18.1, 14.1, −4.8, −5.1; HRMS (ESI TOF) Calcd.
1H), 6.11 (s, 1H), 5.52 (s, 1H), 3.79 (s, 3H), 0.89 (s, 9H),
+
13
for C H O Si [M + Na] : 463.3578. Found: 463.3572.
0.09 (s, 3H), -0.06 (s, 3H); C NMR (125 MHz, CDCl ):
26
52
3
3
d 170.1, 158.9, 143.1, 134.2, 128.1, 126.0, 113.5, 72.4,
General procedure for hydrolysis of silylated esters
55.2, 25.7, 18.1, −4.9, −5.1; HRMS (ESI TOF) Calcd. for
+
C H O Si [M + Na ]: 345.1493. Found: 345.1490.
17
26
4
To a solution of silylated MBH adduct (1-3 mmol)
in a mixture of water:acetonitrile (1:1) was added LiOH
(±)-2-{[(tert-Butyldimethylsilyl)oxy](3,4,5-trimethoxy-
(
5
10 equiv.). The resulting solution was stirred for 4 h at
0-60 C. Then, the solvents were removed under reduced
phenyl)methyl}prop-2-enoic acid (27): 99% yield; viscous
o
-1
oil; IR (film) n /cm : 2955, 2923, 2849, 1692, 1509, 1243,
max
1
pressure and the crude mixture was extracted with ethyl
1077; H NMR (250 MHz, CDCl ): d 6.58 (s, 2H), 6.37 (s,
3
acetate. The organic layer was dried over anhydrous Na SO4
1H), 6.08 (s, 1H), 5.53 (s, 1H), 3.81 (s, 9H), 0.89 (s, 9H),
2
13
and the solvent was removed under vacuum. The residue
was filtered through silica gel (ethyl acetate as solvent)
to provide the corresponding carboxylic acids in almost
quantitative yields, for most cases > 99%.
0.06 (s, 3H), −0.05 (s, 3H); C NMR (62.5 MHz, CDCl ):
3
d 170.9, 152.8, 143.3, 137.9, 137.1, 126.4, 103.7, 72.3,
60.8, 56.0, 25.7, 18.2, −4.9, −5.1; HRMS (ESI TOF)
+
Calcd. for C H O Si [M + Na ]: 405.1709. Found:
1
9
30
6
4
05.1566.
(
±)-2-{[(tert-Butyldimethylsilyl)oxy](2-nitrophenyl)
methyl}prop-2-enoic acid (23): 97% yield; viscous pale
(±)-2-{[(tert-Butyldimethylsilyl)oxy](thiophen-3-yl)
-1
yellow oil; IR(film)n /cm : 2945, 2864, 2353, 1703, 1531,
methyl}prop-2-enoic acid (28): 99% yield; viscous
max
1
-1
1
1
7
0
258, 1090, 837; H NMR (250 MHz, CDCl ): d 7.81 (d,
colorless oil; IR (film) nmax/cm : 2959, 2931, 2857, 1691,
3
1
H, J 8.0 Hz), 7.71 (d, 1H, J 8.0 Hz), 7.57 (t, 1H, J 7.5 Hz),
.38 (t, 1H, J 7.5 Hz), 6.40 (s, 1H), 6.34 (s, 1H), 6.04 (s, 1H),
.90 (s, 9H), 0.13 (s, 3H), 0.05 (s, 3H); C NMR (62.5 MHz,
1459, 1259, 1074, 837; H NMR (250 MHz, CDCl ):
3
d 7.20 (dd, 1H, J 5.0/1.3 Hz), 6.85-6.97 (m, 2H), 6.45 (t,
1H, J 1.0 Hz), 6.23 (t, 1H, J 1.3 Hz), 5.87 (s, 1H), 0.92
13
13
CDCl ): d 170.4, 148.1, 142.4, 137.3, 132.7, 129.5, 128.2,
(s, 9H), 0.10 (s, 3H), 0.02 (s, 3H); C NMR (62.5 MHz,
3
1
27.2, 124.0, 66.6, 25.7, 18.1, −4.9;HRMS(ESITOF)Calcd.
CDCl ): d 170.8, 146.9, 142.8, 126.9, 126.4, 124.8, 124.5,
3
+
for C H NO Si [M + Na ]: 360.1238. Found: 360.1237.
68.3, 25.7, 18.2, −5.1, −5.14; HRMS (ESI TOF) Calcd.
16
23
5
+
for C H O SSi [M + Na ]: 321.0957. Found: 321.0883.
14
22
3
(
±)-2-{[(tert-Butyldimethylsilyl)oxy](3-chlorophenyl)
methyl}prop-2-enoic acid (24): 99% yield; viscous colorless
(±)-2-{[(tert-Butyldimethylsilyl)oxy](2-fluorophenyl)
methyl}prop-2-enoic acid (29): 99% yield; colorless oil;
-1
oil; IR (film) n /cm : 2949, 2929, 2851, 1691, 1437, 1254,
max
1
-1
1
7
0
074, 833, 780; H NMR (250 MHz, CDCl ): d 7.34 (s, 1H),
IR (film) n /cm : 2951, 2928, 2850, 1692, 1072, 832, 782;
3
max
1
.18-7.29 (m, 3H), 6.43 (s, 1H), 6.19 (s, 1H), 5.54 (s, 1H),
.88 (s, 9H), 0.06 (s, 3H), −0.07 (s, 3H); C NMR (62.5
H NMR (250 MHz, CDCl ): d 10.44 (s, 1H, COOH), 7.34
3
13
(dt, 1H, J 1.8/7.5 Hz), 7.18-7.29 (m, 1H), 6.95-7.15 (m,
MHz, CDCl ): d 170.1, 144.4, 142.6, 134.0, 129.4, 127.7,
2H), 6.47 (s, 1H), 6.16 (s, 1H), 5.92 (s, 1H), 0.87 (s, 9H),
3
13
1
27.0, 125.1, 71.9, 25.7, 18.1, −5.0;HRMS(ESITOF)Calcd.
0.09 (s, 3H), −0.08 (s, 3H); C NMR (62.5 MHz, CDCl ):
3
+
for C H O ClSi [M + Na ]: 349.0918. Found: 349.1003.
d 171.0, 159.8 (d, J 246.1 Hz), 142.1, 129.3 (d, J 3.0 Hz),
16
23
3
1
29.1 (d, J 2.1 Hz), 128.8 (d, J 3.8 Hz), 127.3, 123.9 (d,
(
±)-2-{[(tert-Butyldimethylsilyl)oxy](phenyl)methyl}
J 3.5 Hz), 115.3 (d, J 22.0 Hz), 65.7, 51.6, 25.7, 18.1,
1
prop-2-enoic acid (25): 99% yield; yellowish oil; H NMR
250 MHz, CDCl ): d 7.20-7.41 (m, 5H), 6.39 (s, 1H), 6.13
−5.2, −5.24; HRMS (ESI TOF) Calcd. for C H O FSi
1
6
23
3
+
(
[M + Na ]: 333.1298. Found: 333.1207.
3
(
3
s, 1H), 5.58 (s, 1H), 0.88 (s, 9H), 0.07 (s, 3H), −0.07 (s,
13
H); C NMR (62.5 MHz, CDCl ): d 169.8, 142.9, 141.9,
(±)-3-[(tert-Butyldimethylsilyl)oxy]-2-methylidene-
3
-
1
1
28.1, 127.6, 126.8, 126.4, 72.8, 25.7, 18.2, −5.0; HRMS
pentanoic acid (30): fluid oil; 99% yield; IR (film) n /cm :
max
+
1
(ESI TOF) Calcd. for C H O Si [M + Na ]: 315.1393.
2923, 2854, 1691, 1253, 1084; H NMR (250 MHz, CDCl ):
16
24
3
3
Found: 315.1338.
d 11.60 (s, 1H, COOH), 6.41 (d, 1H, J 1.2 Hz), 6.00 (t,
1
H, J 1.5 Hz), 4.55 (t, 1H, J 5.4 Hz), 1.41-1.80 (m, 2H),
13
(±)-2-{[(tert-Butyldimethylsilyl)oxy](4-methoxyphenyl)
0.78-1.00 (m, 12H), 0.08 (s, 3H), 0.01 (s, 3H); C NMR
methyl}prop-2-enoic acid (26): 98% yield; viscous
(62.5 MHz, CDCl ): d 171.6, 142.9, 127.2, 71.2, 30.3, 29.1,
3

1
578
Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
-
1
2
5.7, 18.1, 9.1, −4.9, −5.1; HRMS (ESI TOF) Calcd. for
nmax/cm : 2953, 2933, 2851, 1728, 1527, 1343, 1254,
+
1
C H O Si [M + H ]: 245.1573. Found: 245.1554.
1102, 833; H NMR (250 MHz, CDCl ): d 7.97-8.03 (m,
1
2
24
3
3
1
H), 7.58-7.77 (m, 2H), 7.42-7.51 (m, 1H), 5.72 (s, 1H),
(
±)-3-[(tert-Butyldimethylsilyl)oxy]-2-methylidene-
2.31 (s, 3H), 0.91 (s, 9H), 0.16 (s, 3H), −0.07 (s, 3H);
-1
13
nonanoic acid (31): 98% yield; fluid oil; IR (film) n /cm :
925, 2859, 1691, 1254, 1086, 833, 649; H NMR
250 MHz, CDCl ): d 6.37 (s, 1H), 5.92 (s, 1H), 4.51-4.59
m, 1H), 1.20-1.40 (m, 10H), 0.82-0.93 (m, 12H), 0.08
C NMR (62.5 MHz, CDCl ): d 205.8, 147.7, 135.0,
max
3
1
2
133.2, 129.2, 128.8, 124.8, 26.3, 25.6, 18.1, −5.0; HRMS
+
(
(
(
(ESI TOF) Calcd. for C H O NSi [M + H ]: 310.1475.
3
15 23
4
Found: 310.1600.
13
s, 3H), 0.02 (s, 3H); C NMR (62.5 MHz, CDCl ), d:
3
1
1
70.6, 142.9, 126.9, 71.2, 37.7, 31.7, 29.1, 25.7, 25.0, 22.6,
(±)-1-[(tert-Butyldimethylsilyl)oxy]-1-(3-chlorophenyl)
8.1, 14.1, −5.0; HRMS (ESI TOF) Calcd. for C H O Si
propan-2-one (34): 45% yield; colorless oil; IR (film)
16
32
3
+
-1
[
M + H ]: 301.2199. Found: 301.2232.
n
/cm : 2953, 2929, 2864, 1719, 1470, 1258, 1111, 775;
max
1
H NMR (250 MHz, CDCl ): d 7.43 (s, 1H), 7.23-7.33
3
(
±)-3-[(tert-Butyldimethylsilyl)oxy]-2-methylene-
(m, 3H), 5.00 (s, 1H), 2.12 (s, 3H), 0.96 (s, 9H), 0.09 (s,
13
octadecanoic acid (32): 99% yield; white solid; mp
5-47 °C; IR (film) nmax/cm : 2918, 2851, 1681, 1623, 1472,
090, 838; HNMR(250MHz, CDCl ):d6.34-6.36(m, 1H),
.86-5.88 (m, 1H), 4.53 (t, 1H, J 5.6 Hz), 1.45-1.63 (m, 2H),
.18-1.39 (m, 26H), 0.83-0.93 (m, 12H), 0.1 (s, 3H), 0.03 (s,
H); C NMR (62.5 MHz, CDCl ): d 169.7, 142.5, 126.8,
1.8, 37.6, 31.9, 29.7, 29.64, 29.6, 29.5, 29.5, 29.4, 29.3,
5.8, 25.1, 22.7, 18.1, 14.1, −4.8, −5.0; HRMS (ESI TOF)
3H), 0.02 (s, 3H); C NMR (62.5 MHz, CDCl ): d 208.5,
3
-1
4
1
5
1
3
7
2
140.7, 134.5, 129.8, 128.2, 125.9, 123.9, 80.6, 25.7, 23.9,
18.2, −4.9; HRMS (ESI TOF) Calcd. for C H O ClSi
1
3
15 23
2
+
[M + Na ]: 321.1053. Found: 321.1056
13
(±)-1-[(tert-Butyldimethylsilyl)oxy]-1-phenylpropan-
3
-
1
2-one (35): 50% yield; pale yellow oil; IR (film) n /cm :
max
1
2949, 2929, 2855, 1711, 1258, 1102, 865, 837; H NMR
+
Calcd. for C H O Si [M + H] : 427.3607. Found: 427.3599.
(250 MHz, CDCl ): d 7.25-7.45 (m, 5H), 5.04 (s, 1H),
25
50
3
3
2
.11 (s, 3H), 0.96 (s, 9H), 0.10 (s, 3H), 0.01 (s, 3H);
1
3
General procedure for the preparation of a-hydroxyketones
acyloins)
C NMR (125 MHz, CDCl ): d 209.1, 199.5, 138.6, 128.5,
3
(
128.0, 125.8, 81.2, 25.7, 23.9, 18.2, −4.9, −5.2; HRMS
+
(
ESI TOF) Calcd. for C H O Si [M + H ]: 265.1624.
1
5
24
2
-1
To a stirred 0.2 mol L solution of carboxylic acid in
Found: 265.1685.
acetone at 0 ºC was added triethylamine (2 equiv.) and
ethyl chloroformate (1.5 equiv.). The mixture was stirred at
(±)-1-[(tert-Butyldimethylsilyl)oxy]-1-(4-methoxy-
0
5
ºC and carbonate formation was observed by TLC after
phenyl)propan-2-one (36): 48% yield; pale yellow oil;
-1
min.After that, NaN was added (2.5 equiv.). The resulting
IR (film) n /cm : 2949, 2855, 1715, 1511, 1090, 841,
3
max
1
mixture was vigorously stirred for 2 h until the formation
of a slightly apolar layer (acylazide formation). Then, the
crude mixture was diluted in cold dichloromethane and
washed with cold water. The organic layer was dried over
anhydrous Na SO and the solvent was removed under
784; H NMR (250 MHz, CDCl ): d 7.30 (d, 2H, J 6.7 Hz),
3
6.87 (d, 2H, J 6.7 Hz), 4.99 (s, 1H), 3.80 (s, 3H), 2.11 (s,
13
3H), 0.94 (s, 9H), 0.08 (s, 3H), −0.01 (s, 3H); C NMR
(62.5 MHz, CDCl ): d 209.2, 159.4, 130.7, 127.1, 113.9,
3
80.8, 55.2, 25.7, 23.8, 18.2, −5.0; HRMS (ESI TOF) Calcd.
2
4
+
vacuum. To this crude material, under an argon atmosphere,
for C H O Si [M + Na ]: 317.1549. Found: 317.1505.
16
26
3
-1
dry toluene (0.1 mol L ) was added and the mixture was
refluxedfor2h.Thesolventwasthenremovedunderreduced
pressure and the resulting product was diluted in water. The
mixture was refluxed for 12 h. Then, the reaction mixture
was coolled to room temperature and extracted with ethyl
(± )-1-[(tert-Butyldimethylsilyl)oxy]-1-(3,4,5-
trimethoxyphenyl)propan-2-one (37): 42% yield; colorless
-
1
oil; IR (film) n /cm : 2947, 2853, 1714, 1512, 1089, 843;
max
1
H NMR (250 MHz, CDCl ): d 6.65 (s, 2H), 4.95 (s, 1H),
3
acetate. The organic layer was dried over anhydrous Na SO4
and the solvent was removed under vacuum. The residue
was purified by flash silica gel column chromatography
3.75-3.88 (m, 9H), 2.10 (s, 3H), 0.95 (s, 9H), 0.07 (s, 3H),
2
13
0.03 (s, 3H); C NMR (62.5 MHz, CDCl ): d 208.8, 153.3,
3
137.5, 134.0, 102.4, 80.9, 60.8, 56.0, 25.7, 23.7, 18.2, −4.9,
+
(ethyl acetate:hexanes, up to 25:75) to provide the required
−5.1; HRMS (ESI TOF) Calcd. for C H O Si [M + Na ]:
18
30
5
acyloins. Yields refer to 3 steps from MBH adducts.
377.1760. Found: 377.1657.
(
±)-1-[(tert-Butyldimethylsilyl)oxy]-1-(2-nitrophenyl)
(±)-1-[(tert-Butyldimethylsilyl)oxy]-1-(thiophen-2-yl)
propan-2-one (33): 46% yield; pale yellow oil; IR (film)
propan-2-one (38): 44% yield; pale yellow oil; IR (film)

Vol. 22, No. 8, 2011
Amarante et al.
1579
-
1
1
nmax/cm : 2949, 2851, 1712, 1091; H NMR (250 MHz,
vigorously stirred at room temperature for 1 h. After, the
o
CDCl ): d 7.22-7.28 (m, 1H), 6.96-7.01 (m, 2H), 5.24 (s,
solution was cooled to −78 C and LiBH (1.2 equiv.)
3
4
1
H), 2.20 (s, 3H), 0.95 (s, 9H), 0.10 (s, 3H), 0.05 (s, 3H);
was added. The mixture was then warmed to room
temperature and stirred for 12 h. Then, the medium was
diluted with ethyl acetate (15 mL) and the organic phase
was washed with water (5 × 7 mL), brine (10 mL), dried
over anhydrous Na SO and the solvent was removed
13
C NMR (62.5 MHz, CDCl ): d 207.7, 153.3, 142.6, 127.1,
3
125.2, 124.3, 77.8, 25.6, 23.7, 18.2, −5.1, −5.2; HRMS
+
(ESI TOF) Calcd. for C H O SSi [M + Na ]: 293.1007.
13
22
2
Found: 293.0922.
2
4
under vacuum. The residue was purified through silica gel
(solvent: hexanes:ethyl acetate, up to 65:35) to provide the
corresponding vicinal aminoalcohols, in good yields and
in high diastereoselectivities.
(
±)-1-[(tert-Butyldimethylsilyl)oxy]-1-(2-fluorophenyl)
propan-2-one (39): 41% yield; colorless oil; IR (film)
nmax/cm : 2951, 1720, 1471, 1256, 1109; H NMR
-
1
1
(
250 MHz, CDCl ): d 7.47 (dt, 1H, J1.8/7.5 Hz), 7.23-7.35
3
(m, 1H), 7.15 (dt, 1H, J 1.2/7.5 Hz), 7.00-7.09 (m, 1H),
(±)-1,2-anti-1-[(tert-Butyldimethylsilyl)oxy]-1-
5
.34 (s, 1H), 2.18 (s, 3H), 0.92 (s, 9H), 0.11 (s, 3H), −0.05
(3-chlorophenyl)propan-2-yl](2-phenylethyl)amine (43):
1
3
-1
(s, 3H); C NMR (62.5 MHz, CDCl ): d 207.1, 159.8 (d,
79% yield; yellowish oil; IR (film) n /cm : 2955, 2929,
3
max
1
J 245.4 Hz), 129.8 (d, J 8.1 Hz), 128.2 (d, J 3.8 Hz), 126.6
d, J 14.3 Hz), 124.3 (d, J 3.5 Hz), 115.4 (d, J 21.5 Hz),
2857, 1471, 1254, 1075, 836; H NMR (250 MHz, CDCl ):
3
(
d 7.08-7.32 (m, 9H), 4.55 (d, 1H, J 4.7 Hz), 2.62-2.99 (m,
5H), 0.98 (d, 3H, J 6.4 Hz), 0.86 (s, 9H), −0.003 (s, 3H),
74.9, 25.6, 24.9, 18.1, −5.1, −5.2; HRMS (ESI TOF) Calcd.
+
13
for C H O FSi [M + Na ]: 305.1349. Found: 305.1284.
−0.20 (s, 3H); C NMR (62.5 MHz, CDCl ): d 145.1, 139.9,
1
5
23
2
3
1
33.9, 129.2, 128.6, 128.4, 127.3, 126.8, 126.1, 124.8,
(
±)-3-[(tert-Butyldimethylsilyl)oxy]pentan-2-one (40):
77.0, 59.7, 48.6, 36.5, 25.8, 18.1, 14.9, −4.6, −5.1; HRMS
+
(ESI TOF) Calcd. for C H ClNOSi [M + H ]: 404.2177.
23 34
1
4
6% yield; colorless oil; H NMR (250 MHz, CDCl ):
3
d 3.90 (dd, 1H, J 5.6/6.5 Hz), 2.13 (s, 3H), 1.50-1.71
m, 2H), 0.77-0.93 (m, 12H), 0.04 (s, 3H), 0.03 (s, 3H);
Found: 404.1996.
(
1
3
C NMR (62.5 MHz, CDCl ): d 212.5, 79.9, 27.8, 25.3,
(±)-1,2-anti-Benzyl-[1-[(tert-butyldimethylsilyl)oxy]-
3
1
8.0, 9.1, −5.0, −5.1; HRMS (ESI TOF) Calcd. for
1-(3-chlorophenyl)propan-2-yl]amine (44): 77% yield;
+
-1
C H O Si [M + H ]: 217.1624. Found: 217.1608.
yellowish oil. IR (film) n /cm : 2929, 2857, 1471, 1255,
1
1
24
2
max
1
1
075, 836; H NMR (250 MHz, CDCl ): d 7.12-7.37 (m,
3
(
±)-3-[(tert-Butyldimethylsilyl)oxy]nonan-2-one (41):
9H), 4.63 (d, 1H, J 4.8 Hz), 3.82 (d, 1H, J 13.5 Hz), 3.71
(d, 1H, J 13.5 Hz), 2.77 (dq, 1H, J 4.8/6.4 Hz), 1.02 (d,
3H, J 6.4 Hz), 0.89 (s, 9H), 0.05 (s, 3H), −0.16 (s, 3H);
1
4
2% yield; pale yellow oil; H NMR (250 MHz, CDCl ):
d 3.92-4.03 (m, 1H), 2.15 (s, 3H), 1.18-1.45 (m, 10H), 0.82-
.09 (m, 12H), 0.05 (s, 6H); C NMR (62.5 MHz, CDCl ):
3
13
13
1
C NMR (62.5 MHz, CDCl ): d 145.2, 140.4, 133.9, 129.2,
3
3
d 212.8, 79.0, 34.8, 31.7, 29.2, 25.7, 25.2, 24.7, 22.6, 18.1,
4.1, −4.9; HRMS (ESI TOF) Calcd. for C H O Si [M +
Na ]: 295.4887. Found: 295.4849.
128.3, 127.8, 127.3, 127.0, 126.8, 125.0, 77.1, 58.6, 51.0,
25.8, 18.1, 15.1, −4.6, −4.9; HRMS (ESI TOF) Calcd. for
1
15
32
2
+
+
C H ONClSi [M + H ]: 390.2020. Found: 370.1797.
22
32
(
±)-3-[(tert-Butyldimethylsilyl)oxy]octadecan-2-one
(±)-1,2-anti-{1-[(tert-Butyldimethylsilyl)oxy]-
-1
(
2
42): 40% yield; colorless viscous oil; IR (film) n /cm :
926, 2855, 1719, 1465, 1253, 1104; H NMR (250 MHz,
CDCl ): d 3.97 (dd, 1H, J 5.3/6.9 Hz), 2.15 (s, 3H), 1.46-
1-phenylpropan-2-yl}(2-phenylethyl)amine (45): 85%
max
1
-1
yield; yellowish oil; IR (film) n /cm : 2928, 2857, 1453,
max
1
1255, 1063, 836; H NMR (250 MHz, CDCl ): d 7.09-7.32
3
3
1
.55 (m, 2H), 1.17-1.40 (m, 26H), 0.83-0.97 (m, 12H), 0.06
(m, 10H), 4.58 (d, 1H, J 5.0 Hz), 2.61-2.99 (m, 5H), 1.02
(d, 3H, J 6.4 Hz), 0.86 (s, 9H), −0.001 (s, 3H), −0.22 (s,
13
(s, 3H), 0.05 (s, 3H); C NMR (62.5 MHz, CDCl ): d 212.7,
3
13
7
2
9.0, 34.8, 31.9, 29.7, 29.64, 29.6, 29.5, 29.4, 29.3, 25.7,
3H); C NMR (62.5 MHz, CDCl ): d 142.9, 140.0, 128.6,
3
5.2, 24.7, 22.7, 18.1, 14.1, −5.0; HRMS (ESI TOF) Calcd.
128.4, 127.9, 127.1, 126.7, 126.0, 77.6, 59.8, 48.7, 36.6,
25.8, 18.1, 15.1, −4.6, −5.1; HRMS (ESI TOF) Calcd. for
+
for C H O Si [M + Na ]: 421.3478. Found: 421.3453.
2
4
50
2
+
C H ONSi [M + H ]: 370.2566. Found: 370.2747.
23
35
General procedure for the diastereoselective preparation
of vicinal alcohols
(±)-1,2-anti-Benzyl({1-[(tert-butyldimethylsilyl)oxy]-
1
-phenylpropan-2-yl})amine (46): 83% yield; yellowish oil;
-1
-1
To a 0.2 mol L methanolic solution of acyloins was
added an amine (3 equiv.). The resulting solution was
IR (film) n /cm : 2956, 2929, 2857, 1493, 1254, 1063,
1028, 836; H NMR (250 MHz, CDCl ): d 7.12-7.38 (m,
max
1
3

1
580
Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
1
0H), 4.64 (d, 1H, J 5.1 Hz), 3.81 (d, 1H, J13.5 Hz), 3.72
2H), 4.55 (d, 1H, J 5.0 Hz), 3.84 (s, 9H), 3.10-3.37 (m, 2H),
2.80 (dq, 1H, J 5.0/6.3 Hz), 1.03 (d, 3H, J 6.3 Hz), 0.91
(s, 9H), 0.06 (s, 3H), −0.14 (s, 3H); C NMR (62.5 MHz,
(
d, 1H, J13.5 Hz), 2.80 (dq, 1H, J5.1/6.4 Hz), 1.05 (d, 3H,
13
13
J 6.4 Hz), 0.90 (s, 9H), 0.05 (s, 3H), −0.18 (s, 3H); C NMR
62.5 MHz, CDCl ): d 142.9, 140.6, 128.3, 127.9, 127.8,
(
CDCl ): d 152.8, 138.7, 136.9, 136.8, 115.4, 103.4, 77.6,
3
3
1
−
27.1, 126.9, 126.7, 77.8, 58.7, 51.0, 25.8, 18.2, 15.4, −4.5,
60.9, 59.0, 56.0, 49.6, 25.8, 18.2, 15.1, −4.5, −5.0; HRMS
+
+
5.0; HRMS (ESI TOF) Calcd. for C H ONSi [M + H ]:
(ESI TOF) Calcd. for C H O NSi [M + H ]: 396.2570.
22
33
21 37
4
3
56.2410. Found: 356.2561.
Found: 396.2693.
(
±)-1,2-anti-{1-[(tert-Butyldimethylsilyl)oxy]-
(±)-1,2-anti-{1-[(tert-Butyldimethylsilyl)oxy]-
1
-phenylpropan-2-yl}(prop-2-en-1-yl)amine (47): 82%
1-(thiophen-2-yl)propan-2-yl}(2-phenylethyl)amine (51):
-1
-1
yield; yellowish oil; IR (film) nmax/cm : 2956, 2929, 2857,
1
82% yield; yellowish oil; IR (film) n /cm : 2955, 2929,
max
1
1
471, 1255, 1063, 867, 837; H NMR (250 MHz, CDCl ):
2857, 1471, 1253, 1075, 836; H NMR (250 MHz, CDCl ):
3
3
d 7.17-7.42 (m, 5H), 5.73-5.95 (m, 1H), 5.00-5.21 (m, 2H),
.65 (d, 1H, J 4.8 Hz), 3.12-3.39 (m, 2H), 2.80 (dq, 1H,
J4.8/6.4 Hz), 0.99 (d, 3H, J 6.4 Hz), 0.90 (s, 9H), 0.05 (s,
d 7.09-7.27 (m, 6H), 6.80-6.93 (m, 2H), 4.76 (d, J 5.6 Hz,
1H), 2.63-2.99 (m, 5H), 1.08 (d, 3H, J 6.3 Hz), 0.85 (s, 9H),
4
13
0.02 (s, 3H), −0.15 (s, 3H); C NMR (62.5 MHz, CDCl ):
3
1
3
3
1
2
H), −0.19 (s, 3H); C NMR (62.5 MHz, CDCl ): d 142.9,
37.0, 128.3, 127.9, 127.1, 126.7, 115.4, 77.3, 58.9, 49.6,
d 146.9, 140.0, 128.6, 128.4, 126.002, 126.0, 124.5, 124.3,
3
74.7, 60.1, 48.7, 36.5, 25.7, 18.1, 15.9, −4.6, −5.1; HRMS
+
5.8, 18.2, 14.9, −4.5, −5.0; HRMS (ESI TOF) Calcd. for
(ESI TOF) Calcd. for C H ONSSi [M + H ]: 376.2130.
21
33
+
C H ONSi [M + H ]: 306.2253. Found: 306.2394.
Found: 376.2141.
1
8
31
(
±)-1,2-anti-N-{1-[(tert-Butyldimethylsilyl)oxy]-
(±)-1,2-anti-{1-[(tert-Butyldimethylsilyl)oxy]-1-(2-
1
-phenylpropan-2-yl}cyclohexanamine (48): 80% yield;
fluorophenyl)propan-2-yl}(2-phenylethyl)amine (52): 78%
-1
-1
yellowish oil; IR (film) n /cm : 2928, 2855, 1451, 1255,
1
yield; yellowish oil; IR (film) n /cm : 2857, 1486, 1254,
max
max
1
1
066, 862, 836; H NMR (250 MHz, CDCl ): d 7.15-7.40
1033, 837; H NMR (250 MHz, CDCl ): d 7.43 (dt, 1H,
3
3
(m, 5H), 4.61 (d, 1H, J 4.7 Hz), 2.89 (dq, 1H, J4.7/6.3 Hz),
J 1.8, J 7.5 Hz), 7.05-7.35 (m, 8H), 6.90-7.01 (m, 1H),
1
2
2
0
3
7
1
.41-2.60 (m, 1H), 1.50-1.92 (m, 6H), 1.09-1.35 (m, 4H),
5.07 (d, 1H, J 3.9 Hz), 2.62-2.99 (m, 5H), 0.97 (d, 3H,
J 6.5 Hz), 0.87 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); C NMR
13
.97 (d, 3H, J 6.3 Hz), 0.90 (s, 9H), 0.04 (s, 3H), −0.20 (s,
1
3
H); C NMR (62.5 MHz, CDCl ): d 143.3, 127.8, 127.0,
(62.5 MHz, CDCl ): d 159.4 (d, J 242.8 Hz), 140.2, 130.0
3
3
7.5, 55.8, 52.9, 34.1, 33.1, 26.2, 25.6, 25.0, 24.9, 18.2,
5.5, −4.5, −5.0; HRMS (ESI TOF) Calcd. for C H ONSi
(d, J 13.3 Hz), 128.8 (m, C-Ar), 128.4 (m, C-Ar), 126.0,
123.7 (d, J 3.4 Hz), 114.8 (d, J 22.0 Hz), 70.0, 58.3, 48.7,
36.7, 25.8, 18.1, 14.8, −4.8, −5.2; HRMS (ESI TOF) Calcd.
21
37
+
[
M + H ]: 348.2723. Found: 348.2834.
+
for C H ONFSi [M + H ]: 388.2472. Found: 388.2512.
23
34
(
±)-1,2-anti-{1-[(tert-Butyldimethylsilyl)oxy]-1-
(
3,4,5-trimethoxyphenyl)propan-2-yl}(2-phenylethyl)
(±)-1,2-anti-{3-[(tert-Butyldimethylsilyl)oxy]pentan-
amine (49): 81% yield; colorless oil; IR (film) n
cm : 2933, 1592, 1455, 1321, 1128, 836, 776; H
/
2-yl}(2-phenylethyl)amine (53): 73% yield; yellowish oil;
max
1
-
1
-1
IR (film) n /cm : 2958, 2930, 2857, 1470, 1254, 1007,
max
1
NMR (250 MHz, CDCl ): d 7.05-7.27 (m, 5H),
835; H NMR (250 MHz, CDCl ): d 7.12-7.37 (m, 5H),
3
3
6
3
.48 (s, 2H), 4.45 (d, 1H, J 5.4 Hz), 3.84 (s, 3H),
.81 (s, 6H), 2.62-3.00 (m, 5H), 1.05 (d, 3H,
3.49-3.60 (m, 1H), 2.60-2.99 (m, 5H), 1.38-1.52 (m, 2H),
0.98 (d, 3H, J 6.5 Hz), 0.78-0.90 (m, 12H), 0.03 (s, 3H),
13
J 6.1 Hz), 0.86 (s, 9H), 0.01 (s, 3H), −0.19 (s, 3H);
−0.01 (s, 3H); C RMN (62.5 MHz, CDCl ): d 140.2, 128.7,
3
1
3
C NMR (62.5 MHz, CDCl ): d 152.8, 139.8, 138.6,
128.4, 126.1, 76.6, 56.9, 49.3, 36.9, 25.8, 25.3, 18.0, 15.0,
10.4, −4.4, −4.5; HRMS (ESI TOF) Calcd. for C H ONSi
3
1
4
36.8, 128.5, 128.4, 126.1, 103.4, 77.9, 60.9, 59.9, 56.0,
19
35
+
8.6, 36.4, 25.8, 18.1, 15.3, −4.5, −5.1; HRMS (ESI TOF)
[M + H ]: 322.2566. Found: 322.2550.
+
Calcd. for C H O NSi [M + H ]: 460.2805. Found:
2
6
41
4
4
60.2871.
(±)-1,2-anti-{3-[(tert-Butyldimethylsilyl)oxy]pentan-
2
-yl}(decyl)amine (54): 71% yield; yellowish oil; IR (film)
-1
1
(±)-1,2-anti-{1-[(tert-Butyldimethylsilyl)oxy]-1-(3,4,5-
nmax/cm : 2958, 2928, 2855, 1463, 1254, 836; H NMR
trimethoxyphenyl)propan-2-yl}(prop-2-en-1-yl)amine (50):
(250 MHz, CDCl ): d 3.50-3.61 (m, 1H), 2.54-2.71 (m,
2H), 2.38-2.51 (m, 1H), 1.38-1.60 (m, 6H), 1.26 (br, 16H),
3
-1
8
1
0% yield; colorless oil; IR (film) n /cm : 2930, 2857,
592, 1420, 1330, 1130, 869, 837; H NMR (250 MHz,
max
1
0.96 (d, 3H, J 6.5 Hz), 0.81-0.91 (m, 12H), 0.05 (s, 6H);
13
CDCl ): d 6.54 (s, 2H), 5.75-5.92 (m, 1H), 5.01-5.17 (m,
C NMR (62.5 MHz, CDCl ): d 76.6, 56.9, 47.8, 31.9, 30.4,
3
3

Vol. 22, No. 8, 2011
Amarante et al.
1581
2
1
9.6, 29.5, 29.3, 27.5, 25.8, 25.2, 22.6, 18.1, 15.1, 14.1,
0.5, −4.4, −4.42; HRMS (ESITOF) Calcd. for C H NOSi
Synthesis of (±)-1-(3-chlorophenyl)-2-hydroxypropan-
1-one (59)
21
47
+
[M + H ]: 358.3505. Found: 358.3428.
To a solution of diol (±)-61 (70 mg, 0.38 mmol) in
DMSO (1 mL) was slowly added 45% IBX (236.4 mg,
0.38 mmol) at room temperature. Caution: addition
time 15 h, faster addition will give a diketone product.
The mixture was stirred for 30 h. After that, the reaction
medium was diluted with water (5 mL) and ethyl acetate
(15 mL). The organic phase was separated, washed with
brine (5 mL), dried over anhydrous Na SO and the solvent
Synthesis of (±)-1-[(tert-Butyldimethylsilyl)oxy]-
1-(3-chlorophenyl)propan-2-ol (60)
To a solution of acyloin 34 (170 mg, 0.57 mmol) in
anhydrous methanol (10 mL), under argon atmosphere
o
and at 0 C was added NaBH (108.3 mg, 2.85 mmol).
4
The resulting mixture was stirred for 10 min, after that
2
4
1
mL of water was added and the solvent was removed
was removed under vacuum. The residue was purified by
silica gel column chromatography (solvent: hexanes:ethyl
acetate, up to 60:40) to provide the acyloin (±)-59, in 85%
under reduced pressure. The residue was diluted with ethyl
acetate (15 mL) and the organic phase was washed with
brine (5 mL), dried over anhydrous Na SO and the solvent
-1
yield.Yellowish oil; IR (film) nmax/cm : 3436, 2982, 2921,
2
4
1
was removed under vacuum to provide the alcohol 60, in
2843, 1687, 1569, 1262, 1123, 1070, 1033, 739; H NMR
almost quantitative yield. Thus, it was used to the next step
(250 MHz, CDCl ): d 7.91 (s, 1H), 7.77-7.82 (m, 1H),
3
-1
without purification. Colorless oil; IR (film) nmax/cm : 3448,
7.57-7.62 (m, 1H), 7.46 (t, 1H, J 7.9 Hz), 5.12 (q, 1H,
1
13
2
949, 2933, 2851, 1462, 1254, 1070, 833, 775; H NMR
J 7.0 Hz, CH), 1.45 (d, 3H, J 7.0 Hz, CH ); C NMR
3
(
(
(
(
(
250 MHz, CDCl ): d (mixture of diastereomers) 7.12-7.35
(75.4 MHz, CDCl ): d 201.3, 135.3, 134.9, 133.9, 130.2,
3
3
’
m, 6H), 4.52 (d, J 4.7 Hz, H ), 4.28 (d, J 6.5 Hz, H ), 3.80
128.7, 126.6, 77.2, 69.5, 22.1; HRMS (ESI TOF) Calcd. for
a
a
’
+
q, J 4.7 Hz, H ), 3.70 (q, J 6.5 Hz, H ), 2.36 (s, 1H), 1.06
C H O Cl [M + Na ]: 207.6093. Found: 207.6075.
b
b
9
9
2
’
d3H,, J 6.5 Hz, CH ), 1.00, (d, 3H, J 6.5 Hz, CH ), 0.89
s, 9H), 0.05 (s, 3H), −0.12 (s, 3H); C NMR (75.4 MHz,
3
3
13
Synthesis of (±)-2-(tert-butylamino)-1-(3-chlorophenyl)
CDCl ): d (diastereomeric mixture) 143.7, 143.3, 134.1,
propan-1-one (bupropion) (1)
3
133.9, 129.5, 129.3, 127.9, 127.7, 127.1, 125.2, 125.1, 80.0,
7
8.2, 72.4, 71.9, 25.8, 18.2, 18.1, 17.9, 17.6, −4.9; HRMS
To a solution of acyloin (±)-59 (30 mg, 0.16 mmol) in
+
(ESI TOF) Calcd. for C H ClO Si [M + H ]: 301.1391.
3 mL of anhydrous CH Cl , at −78 ˚C, was added triflic
15
25
2
2
2
Found: 301.1577.
anhydride (50 mg, 0.177 mmol, 29.81 mL) and 2,6-lutidine
(
26 mg, 0.24 mmol, 28.26 mL). The resulting mixture
o
Synthesis of (±)-1-(3-chlorophenyl)propane-1,2-diol (61)
To a solution of alcohol (±)-60 (100 mg, 0.34 mmol) in
was cooled to −40 C and stirred for 30 min. After that,
the organic phase was washed with brine (5 mL), dried
over anhydrous Na SO and the solvent was removed
2
4
o
THF (6 mL) at 0 C was added a solution ofTBAF (0.41 mL,
1
under vacuum. The residue was immediately dissolved
-1
o
mol L in toluene). The mixture was stirred for 5 min and
in dry CH Cl and the solution was cooled to −40 C.
2
2
was warmed to room temperature. After 2 h, a mixture of
water (5 mL) and ethyl acetate (15 mL) was added to the
reaction medium. The organic phase was separated, washed
with brine (5 mL), dried over anhydrous Na SO and the
Then tert-butylamine (29.6 mg, 0.41 mmol, 42.5 mL) was
o
added. The mixture was stirred for 2 h at −40 C, warmed
o
to 0 C and kept at this final temperature for 12 h. After,
the reaction medium was diluted with dichloromethane
(10 mL). The organic phase was separated, washed
with sodium bicarbonate (5 mL), water (5 mL), brine
(5 mL), dried over anhydrous Na SO and the solvent
2
4
solvent was removed under vacuum. The residue was
filtered through silica gel (solvent: ethyl acetate) to provide
the diol (±)-61, in 97% yield. Colorless oil; IR (film)
2
4
-
1
nmax/cm : 3395, 2978, 2876, 1569, 1426, 1082, 1037,
was removed under reduced pressure. The residue
was purified through silica gel (solvent: hexanes:ethyl
acetate, up to 60:40) to provide (±)-1 as a white solid,
1
7
80, 694; H NMR (250 MHz, CDCl ): d (diastereomeric
3
’
mixture) 7.16-7.39 (m, 6H), 4.67 (d, J 4.0 Hz, H ), 4.33 (d,
a
’
b
41
J 7.1 Hz, H ), 3.92-4.07 (m, H ), 3.81 (q, J 7.1 Hz, H ), 2.62
in 75% yield; mp 233-234 °C (as hydrochloride;
a
b
13
1
(
s, 3H, OH), 1.00-1.13 (m, 5H, CH ); C NMR (62.5 MHz,
233-234 °C); H NMR (250 MHz, CDCl ): d 7.83-7.90
3
3
CDCl ): d (diastereomeric mixture) 143.1, 142.4, 134.4,
(m, 1H), 8.03-8.11 (m, 1H), 7.97-7.99 (m, 1H), 6.11
3
1
29.7, 129.5, 128.2, 127.8, 127.0, 126.7, 125.1, 124.8, 78.6,
(q, 1H, J 7.0 Hz, CH), 4.65 (s, 1H, NH), 1.67 (t, 3H,
J 7.0 Hz, CH ), 1.44 (s, 9H); C NMR (62.5 MHz, CDCl ):
3 3
d 195.7, 136.0, 135.2, 133.5, 130.1, 128.6, 126.5, 71.9,
13
77.2, 71.9, 71.0, 18.7, 16.9; HRMS (ESI TOF) Calcd. for
+
C H O Cl [M + Na ]: 209.6252. Found: 209.6223.
9
11
2

1
582
Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
5
8.1, 30.3, 17.0; HRMS (ESI TOF) Calcd. for C H OClN
d 3.45-3.60 (m, 1H), 2.85-2.99 (m, 1H), 1.10-1.45 (m, 28H),
1.01 (d, 3H, J 6.6 Hz), 0.80-0.91 (m, 12H), 0.0-0.10 (m, 6H);
13
18
+
[
M + Na ]: 262.7309. Found: 262.7299.
13
C NMR (62.5 MHz, CDCl ): d 77.2, 56.3, 50.8, 31.9, 31.6,
3
Synthesis of (± )-1,2-anti-benzyl({3-[(tert-
butyldimethylsilyl)oxy]octadecan-2-yl})amine (62)
29.8, 29.7, 29.6, 29.3, 25.9, 25.7, 22.7, 18.1, 17.9, 14.1, −4.3,
+
−4.4; HRMS (ESI TOF) Calcd. for C H NOSi [M + H] :
24
53
400.3964. Found: 400.3960.
Toastirredmixtureofacyloin(±)-42(0.2g, 0.502mmol)
and molecular sieves (4 Å) in anhydrous dichloromethane
Synthesis of (±)-1,2-anti-2-aminooctadecan-3-ol
(
3 mL), under an argon atmosphere, was added distilled
(spisulosine) (2)
benzylamine (0.268 g, 0.27 mL, 2.51 mmol). The resulting
mixture was kept at 40 °C for 7 h. Then, the reaction was
To a stirred solution of aminoalcohol (±)-63 (0.01 g,
0.025 mmol) in a mixture of dichloromethane (0.5 mL) and
methanol (0.5 mL) was added a solution of concentrated
hydrochloric acid (0.1 mL). The resulting mixture was
warmed to 50 °C and stirred for 20 h. Then, the solvents
were removed under reduced pressure and the residue
was dissolved in dichloromethane (5 mL). To the stirred
organic phase was added a saturated sodium bicarbonate
solution (5 mL) and the resulting mixture was vigorously
stirred for 30 min. The organic phase was separated, dried
over anhydrous sodium sulfate and removed under reduced
pressure. The crude residue was filtered over a plug of
Florisil® to provide (±)-spisulosine (1, 7 mg), as a white
cooled to 0 °C and NaBH CN (0.038 g, 0.6 mmol) was
3
added in three small portions at 40 min. intervals. The
reaction was warmed to room temperature and stirred for
12 h. The solvent was removed under reduced pressure and
the residue was dissolved with ethyl acetate. The organic
phase was filtered, washed with distilled water (3 × 10 mL),
brine (15 mL), dried over anhydrous sodium sulfate and
evaporated. The crude residue was purified by silica gel
column chromatography (ethyl acetate:hexane, 25:75)
to provide anti aminoalcohol 62 (0.19 g), as a viscous
-
1
colorless oil, in 70% yield; IR (film) nmax/cm : 2925,
1
2
854, 1463, 1254, 1030; H NMR (250 MHz, CDCl ):
3
-
1
d 7.22-7.32 (m, 5H), 3.89 (d, 1H, J13.2 Hz), 3.67 (d, 1H,
J 13.2 Hz), 3.54 (q, 1H, J 4.6 Hz), 2.69 (q, 1H, J 6.0 Hz),
solid, in 98% yield; mp 58-59 °C; IR (film) n /cm :
max
1
3348,3297,2955,2919,2851,1607,1471; HNMR(250MHz,
1
.32-1.48 (m, 2H), 1.17-1.35 (m, 26H), 1.02 (d, 3H,
CDCl ):d3.39-3.47(m,1H),2.88-3.06(m,1H),1.64-1.88(bs,
3
J 6.5 Hz), 0.82-0.92 (m, 12H), 0.04 (s, 3H), −0.02 (s, 3H);
3H), 1.20-1.40 (m, 28H), 1.01 (d, 3H, J 6.5 Hz), 0.88 (t, 3H,
1
3
13
C NMR (62.5 MHz, CDCl ): d 140.6, 128.3, 128.14,
J 7.0 Hz); C NMR (62.5 MHz, CDCl ): d 74.7, 50.3, 32.4,
3
3
1
2
−
28.1, 126.8, 75.4, 56.3, 51.5, 32.1, 31.9, 29.8, 29.7,
31.9, 29.8, 29.7, 29.6, 29.3, 26.2, 22.7, 16.8, 14.1; HRMS
+
9.65, 29.6, 29.4, 26.1, 25.9, 22.7, 18.1, 15.2, 14.1, −4.3,
(ESI TOF) Calcd. for C H NO [M + H] : 286.3110;
1
8
40
+
4.4; HRMS (ESI TOF) Calcd. for C H NOSi [M + H] :
Found 286.3088.
31
59
4
90.4439. Found: 490.4434.
Supplementary Information
Synthesis of (±)-1,2-anti-[(2-aminooctadecan-3-yl)oxy]
(
tert-butyl)dimethylsilane (63)
All the spectra of the synthesized compounds in this
paper are available as supplementary file and are free of
charge at http/jbcs.sbq.org.br as pdf file.
To a stirred solution of aminoalcohol (±)-62 (0.025 g,
0.05 mmol) in a mixture of dichloromethane (1.5 mL) and
acetic acid (1.0 mL) was added 10% Pd/C (0.006 g). The
resulting suspension was purged twice with hydrogen gas
and kept under a hydrogen atmosphere. Then, the reaction
was warmed at 50 °C and stirred for 20 h under hydrogen
atmosphere. After that time, the reaction mixture was
diluted with dichloromethane (10 mL) and the organic
phase was washed with a saturated solution of NaHCO3
Acknowledgments
Authors thank Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq) and Fundação deAmparo
à Pesquisa do Estado de São Paulo (FAPESP) for financial
support. G. W.A. and M. C. thank FAPESP for fellowships.
The authors are grateful to Prof. C. H. Collins for English
revision of this text.
(
8 mL), dried over anhydrous sodium sulfate and evaporated.
The crude residue was filtered over a plug of silica gel
dichloromethane:methanol, 97:3, as eluent) to provide
silylated aminoalcohol (±)-63 (0.018 g), as a viscous
(
References
-1
colorless oil, in 90% yield; IR (film) nmax/cm : 3409, 2926,
1. Ikariya, T.; Gridnev, I. D.; Top. Catal. 2010, 53, 894; Krüger, K.;
Tillack, A.; Beller, M.; ChemSusChem 2009, 2, 715; Narasaka,
1
2
855, 1682, 1465, 1255, 1084; H NMR (250 MHz, CDCl ):
3

Vol. 22, No. 8, 2011
Amarante et al.
1583
K.; Kitamura, M.; Eur. J. Org. Chem. 2005, 4505; Dembech,
8. Am Ende, D. J.; De Vries, K. M.; Clifford, P. J.; Brenek, S. J.;
Org. Process Res. Dev. 1998, 2, 382.
P.; Seconi, G.; Ricci, A.; Chem. Eur. J. 2000, 6, 1281. For some
examples of formation of C–N bond catalyzed by transition
metals, see: Surry, D. S.; Buchwald, S. L.; Angew. Chem. Int. Ed.
9. Lebel, H.; Leogane, O.; Org. Lett. 2006, 8, 5717; Lebel, H.;
Leogane, O.; Org. Lett. 2005, 7, 4107; Yao, R.-S.; Wu, S.-H.;
Jiang, L.; Deng, S.-S.; Yu, S.-X.; Res. Chem. Intermed. 2010,
36, 523.
2008, 47, 6338; Buchwald, S. L.; Jiang, L. In Metal-Catalyzed
Cross-Coupling Reactions; deMeijere, A.; Diederich, F., eds.;
Wiley-VCH:Weinheim, 2004, p. 699; Hartwig, J. F.; Acc. Chem.
Res. 2008, 41, 1534; Marion, N.; Nolan, S. P.; Acc. Chem. Res.
10. Mateus, C. R.; Coelho, F.; J. Braz. Chem. Soc. 2005, 16,
386. For reviews about Morita-Baylis-Hillman reaction, see:
Basavaiah, D., Reddy, B. S.; Badsara, S. S.; Chem. Rev. 2010,
110, 5447; Carrasco-Sanchez, V.; Simirgiotis, M. J.; Santos,
L. S.; Molecules 2009, 14, 3989; Basavaiah, D.; Rao, K. V.;
Reddy, R. J.; Chem. Soc. Rev. 2007, 36, 1581; Almeida, W. P.;
Coelho, F.; Quim. Nova 2000, 23, 98.
2008, 41, 1440; Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola,S.;Chem.Rev.2007,107,5318;Ackerman,L.;Born,
R.; Spatz, J. H.;Althammer,A.; Gschrei, C. J.; PureAppl. Chem.
2006, 78, 209; Lakshman, M. K.; Curr. Org. Synth. 2005, 2, 83.
2
. For a complete and recent review regarding electrophilic
amination, see: Ciganek, E.; Org. React. 2008, 72, 1; Amador-
Bedolla, C.; Salomón-Ferrer, R.; Lester Jr., W. A.; Vázquez-
Martínez, J. A.; Aspuru-Guzik, A.; J. Chem. Phys. 2007, 126,
11. Schräpler, U.; Rühlmann, K.; Chem. Ber. 1964, 97, 1983; Mori,
K.; Nakahara, T.; Nozaki, H.; Can. J. Chem. 1969, 47, 3266. For
an example of a benzoin type reaction catalyzed by nucleophilic
carbene for the preparation of cyclic acyloin, see: Enders, D.;
Niemeier, O.; Synlett 2004, 2111; Heck, R.; Henderson, A. P.;
Köhler,B.;Rétey,J.;Golding,B.T.;Eur.J.Org.Chem.2001,2623.
12. For a comprehensive review on a-hydroxylations, see: Davis,
F. A.; Chen, B.-C. In Houben-Weyl: Stereoselective Synthesis,
vol. E 21; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.;
Schaumann, E., eds.; Thieme Stuttgart: New York, 1996,
p. 4497; Zhou, P.; Chen, B. A.; Davies, F. A. In Asymmetric
Oxidation Reactions; Katsuki, T., ed.; Oxford University Press:
Oxford, 2001, p. 128; Plietker, B.; Tetrahedron: Asymmetry
2005, 16, 3453.
2
04308.
3
. For some reviews, see: Yale, H. L.; Chem. Rev. 1943, 33, 209;
Bauer, L.; Exner, O.; Angew. Chem. Int. Ed. Eng. 1974, 13, 376.
For recent references concerning the Lossen rearrangement,
see: Dubé, P.; Fine Nathel, N. F.; Vetelino, M.; Couturier, M.;
Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M.;
Org. Lett. 2009, 11, 5622 and references cited therein;Vasantha,
B.; Hemantha, H. P.; Sureshbabu, V. V.; Synthesis 2010, 2990;
Ramon, F.; Prié, G.; Lecornué, F.; Papot, S.; Tetrahedron Lett.
2
009, 50, 6800; Marzoni, G.; Varney, M. D.; Org. Process Res.
Dev. 1997, 1, 81.
4
. Gawley, R. E.; Org. React. 1988, 35, 14; Hoelderich, W. F.;
Catal. Today 2000, 62, 115. For some recent examples about
Beckman rarrangement, see: Song; L.; Chen, X.; Zhang, S.;
Zhang, H.; Li, P.; Luo, G.; Liu, W.; Duan, W.; Wang, W.; Org.
Lett. 2008, 10, 5489; Hashimoto, M.; Obora,Y.; Sakaguchi, S.;
Ishii, Y.; J. Org. Chem. 2008, 73, 2894; Ramalingan, C.; Park,
Y.-T.; J. Org. Chem. 2007, 72, 4536;Yamabe, S.; Tsuchida, N.;
Yamazaki, S.; J. Org. Chem. 2005, 70, 10638; Chandrasekar,
S.; Gopalaiah, K.; Tetrahedron Lett. 2003, 44, 755; de Luca, L.;
Giacomelli, G.; Porcheddu, A.; J. Org. Chem. 2002, 67, 6272;
Sharghi, H.; Hosseini, M.; Synthesis 2002, 1057.
13. Khan, F. A.; Dash, J.; Sahu, N.; Gupta, S.; Org. Lett. 2002, 4,
1015 and references cited therein; Hayakawa, R.; Sahara, T.;
Shimizu, M.; Tetrahedron Lett. 2000, 41, 7939; Bornemann,
S.; Crout, D. H. G.; Dalton, H.; Kren, V.; Lobell, M.; Dean, G.;
Thomson, N.;Turner, M. M.; J. Chem. Soc., PerkinTrans. 1 1996,
425; Kawai,Y.; Hida, K.; Tsujimoto, M.; Kondo, S.; Kitano, K.;
Nakamura, K.; Ohno, A.; Bull. Chem. Soc. Jpn. 1999, 72, 99.
14. Plietker, B.; Org. Lett. 2004, 6, 289; Plietker, B.; J. Org. Chem.
2004, 69, 8287; Zhang,Y.; Shen, Z.; Tasng, J.; Zhang,Y.; King,
L.; Zhang, Y.; Org. Biomol. Chem. 2004, 4, 1478.
15. Christoffers, J.; Werner, T.; Under, S.; Frey, W.; Eur. J. Org.
Chem. 2003, 425.
th
5
. Li, J. J.; Named Reactions, 4 ed., Springer-Verlag: Berlin, 2009,
p. 490 (doi: 10.1007/978-3-642-01053-8_229); Grecian, S.;
Aubé, J. In Organic Azides: Synthesis and Applications; Bräsé,
S.; Banert, K., eds.; WILEY-VCH Verlag GmbH & Co. KgaA:
Weinheim, 2010, chapter 7 (doi: 10.1002/9780470682517.ch7).
For some recent examples of this reaction, see: Gorin, D. J.;
Davies, N. R.; Toste, F. D.; J. Am. Chem. Soc. 2005, 127, 11260;
Yao, L.; Aubé, J.; J. Am. Chem. Soc. 2007, 129, 2766.
16. Ooi, T.; Ohmatsu, K.; Maruoka, K.; J. Am. Chem. Soc. 2007,
129, 2410; Ooi, T.; Sasito, A.; Maruoka, K.; J. Am. Chem. Soc.
2003, 125, 3220.
17. Dir, A.; Kulkarni, S. K.; Eur. J. Pharmacol. 2007, 568, 177.
18. Mooney, M. E.; Sofuoglu, M.; Expert Rev. Neurother. 2006, 6,
965.
19. Lohray, B. B.; Thombare, P. S.; Bhushan, V.; PINSA-A 2002,
68, 391 (CA 139:84775).
6
7
. For a recent review, see: Caron, S.; Dugger, R. W.; Gut Ruggeri,
S.; Ragan, J. A.; Brown Rippin, D. H.; Chem. Rev. 2006, 106,
20. Demko, Z. P.; Bartsch, M.; Sharpless, K. B.; Org. Lett., 2000,
2, 2221; O´Brien, P.; Angew. Chem. Int. Ed. 1999, 38, 326; Tao,
B.; Schlingloff, G.; Sharpless, K. B.; Tetrahedron Lett., 1998,
39, 2507.
2
943.
. Bräse, S.; Gil, C.; Knepper, K.; Zimmermann,V.; Angew. Chem.
Int. Ed. 2005, 44, 5188.

1
584
Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
2
2
1. For a review, see: Bergmeier, S. C.; Tetrahedron 2000, 56, 2561.
2. For some recent examples for the preparation of
,2-aminoalcohols, see: Shivani, B. P.; Chakaborti, A. J.;
Stetsenko, D. A.; Gait, M. J.; Oretskaya, T. S.; Bioconjugate
Chem. 2005, 16, 471; Antos, J. M.; Francis, M. B.; Curr. Opin.
Chem. Biol. 2006, 10, 253.
1
J. Org. Chem. 2007, 72, 3713; Azizi, N.; Saidi, M. R.; Org.
Lett. 2005, 7, 3649; Heydari, A.; Mehrdad, M.; Maleki, A.;
Ahmadi N.; Synthesis 2004, 1557; Azoulay, S.; Manabe, K.;
Kobayashi, S.; Org. Lett. 2005, 7, 4593; Cepanec, I.; Litvic,
M.; Mikuldas, H.; Bartolincic, A.; Vinkovic, V.; Tetrahedron
31. For reviews on enzymatic reductive amination, see: Wildeman,
S. D.; Sonke, T.; Schoemaker, H. E.; May, O.; Acc. Chem. Res.
2007, 40, 1260; Höhne, M.; Bornscheuer, U. T.; ChemCatChem
2009, 1, 42.
32. For an outstanding example concerning a homogeneous
reductive amination reaction, see: Wang, C.; Pettman, A.;
Basca, J.; Xiao, J.; Angew. Chem. Int. Ed. 2010, 49, 7548 and
references cited therein.
2
003, 59, 2435; Chakraborti, A. K.; Rudrawar, S.; Kondaskar,
A.; Org. Biomol. Chem. 2004, 2, 1277; Kim, H. Y.; Talukdar,
A.; Cushman, M.; Org. Lett. 2006, 8, 1085; Shivarkar, A. B.;
Gupte, S. P.; Chaudhari, R.V.; Synlett 2006, 1374; Donohoe, T.
J.; Johnson, P. D.; Pye, R. J.; Org. Biomol. Chem. 2003, 1, 2025.
3. Amarante, G. W.; Cavallaro, M.; Coelho, F.; Tetrahedron Lett.
33. Cabral, S.; Hulin, B.; Kawal, M.; Tetrahedron Lett. 2007, 48,
7134.
2
2
34. Futagawa, S.; Inui, T.; Shiba, T.; Bull. Chem. Soc. Jpn 1973,
46, 3308; Dias, L. C.; Fattori, J.; Perez, C. C.; de Oliveira, V.
M.; Aguilar, A. M.; Tetrahedron 2008, 64, 5891.
2
010, 51, 2597.
4. Rinehart, K. L.; Fregeau, N. L.; Warwick, R. A.; Gravalos,
D. G.; Avila, J.; Faircloth, G. T.; WO Patent 9952521A 1999
35. Dias, L. C.; Ferreira, M. A. B.; Tormena, C. F.; J. Phys. Chem.
A 2008, 112, 232.
(CA 131:295576); Aceña, J. L.; Adrio, J.; Cuevas, C.; Gallego,
P.; Manzanares, I.; Munt, S.; Rodriguez, I.; WO Patent 0194357
A1 2001 (CA 136:19976).
36. For some examples of total synthesis of bupropion, see: Kelley,
J. L.; Musso, D. L.; Boswell, G. E.; Soroko, F. E.; Cooper, B.
R.; J. Med. Chem. 1996, 39, 347; Musso, D. L.; Mehth, N. B.;
Soroko, F. E.; Ferris, R. M.; Hollingsworth, E. B.; Kenney, B. T.;
Chirality 1993, 5, 495; Musso, D. L.; Mehth, N. B.; Soroko,
F. E.; Bioorg. Med. Chem. Lett. 1997, 7, 1; Fang, Q. K.; Han,
Z.; Grover, P.; Kessler, D.; Senanayake, C. H.; Wald, S. A.;
Tetrahedron: Asymmetry 2000, 11, 3659; Amarante, G. W.;
Rezende, P.; Cavallaro, M.; Coelho, F.; Tetrahedron Lett. 2008,
49, 3744.
2
2
5. Sanchez, A. M.; Malagarie-Cazenave, S.; Olea, N.; Vara, D.;
Cuevas, C.; Diaz-Laviada, I.; Eur. J. Pharmacol. 2008, 584,
2
37.
6. For some examples concerning the synthetic usage of Morita-
Baylis-Hillman adducts, see: Resende, P.; Paioti, P. H. S.;
Coelho, F.; Synth. Commun. 2011, 41, 227; Trazzi, G.; André,
M. F.; Coelho, F.; J. Braz. Chem. Soc. 2010, 21, 2327;Amarante,
G. W.; Coelho, F.; Tetrahedron, 2010, 66, 6749; Rodrigues Jr.,
M. T.; Gomes, J. C.; Smith, J.; Coelho, F.; Tetrahedron Lett.
37. Bernardelli, P.; Moradei, O. M.; Friedrich, D.;Yang, J.; Gallou,
F.; Dyck, B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. O.;
J. Am. Chem. Soc. 2001, 123, 9021.
2
010, 51, 4988; Pirovani, R. V.; Ferreira, B. R. V.; Coelho, F.;
Synlett 2009, 2333; Fournier, J. F.; Reddy, B.V. S.; Corey, E. J.;
Org. Lett. 2005, 7, 2699.
38. Miljkovic, M. In Carbohydrates: Synthesis, Mechanisms and
Stereoeletronic Effects; Springer Science: New York, 2010,
p. 108.
2
7. Almeida, W. P.; Coelho, F.; Tetrahedron Lett. 1998, 39, 8609;
Coelho, F.; Almeida, W. P.; Mateus C. R.; Veronese, D.;
Lopes, E. C. S.; Silveira, G. P. C.; Rossi, R. C.; Pavam, C. H.;
Tetrahedron 2002, 58, 7437.
39. Lawrence, S. A.; Amines: Synthesis, Properties and
Applications; Cambrigde University Press: Cambridge, 2004.
40. Yun, J. M.; Sim, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J.;
J. Org. Chem. 2003, 68, 7675; Seguin, C.; Ferreira, F.; Botuha,
C.; Chemla, F.; Perez-Luna, A.; J. Org. Chem. 2009, 74, 6986;
Allepuz, A. C.; Badorrey, R.; Diaz-de-Villegas, M. D.; Galvez,
J. A.; Eur. J. Org. Chem. 2009, 35, 6172.
2
2
8. Liang, H.; Synlett 2008, 2554; Shioiri, T.; Ninomiya, K.;
Yamada, S.; J. Am. Chem. Soc. 1972, 94, 6203; Chan, B. K.;
Ciufolini, M. A.; J. Org. Chem. 2007, 72, 8489.
9. Winkler, C. K.; Stueckler, C.; Mueller, N. J.; Pressnitz, D.;
Faber, K.; Eur. J. Org. Chem. 2010, 6354; Patel, R. N.; Curr.
Org. Chem. 2006, 10, 1289; Demir, A. S.; Ayhan, P.; Sopaci,
S. B.; Clean 2007, 35, 406; Adam, W.; Lazarus, M.; Saha-
Möller, C. R.; Schreier, P.; Acc. Chem. Res. 1999, 32, 837.
0. For recent reviews, see: Gomez, S.; Peters, J. A.; Maschmeyer,
T.; Adv. Synth. Catal. 2002, 344, 1037; Tararov, V. I.; Börner,
A.; Synlett 2005, 203;Abdel-Magid,A. F.; Mehrman, S. J.; Org.
Process Res. Dev. 2006, 10, 971; Nugent, T. C.; El-Shazly, M.;
Adv. Synth. Catal. 2010, 352, 753; Tripathi, R. P.; Verma, S. S.;
Pandey, J.; Tiwari, V. K.; Curr. Org. Chem. 2008, 12, 1093;
Hayes, K. S.; Appl. Catal., A 2001, 221, 187; Zatsepin, T. S.;
41. Perrine, D. M.; Ross, J. T.; Nervi, S. J.; Zimmerman, R. H.;
J. Chem. Educ. 2000, 77, 1479; Reddy, Y. T.; Reddy, P. N.;
Reddy, M. N.; Rajitha, B.; Crooks, P. A.; Synth. Commun.
2010, 40, 1566.
3
Submitted: February 8, 2011
Published online: May 17, 2011
FAPESP has sponsored the publication of this article.

J. Braz. Chem. Soc., Vol. 22, No. 8, S1-S65, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
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Supplementary Information
SI
Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts:
Synthesis of Biologically Active Acyloins and Vicinal Aminoalcohols
Giovanni W. Amarante, Mayra Cavallaro and Fernando Coelho*
Laboratório de Síntese de Produtos Naturais e Fármacos, Instituto de Química,
Universidade de Campinas, 13083-970 Campinas-SP, Brazil
General
1
13
1
13
The H and C spectra were recorded on Bruker at 250 MHz and 62.5 MHz respectively. The H and C spectra were
also recorded on Inova instrument at 500 MHz and 125 MHz, respectively. The high resolution mass spectra were recorded
using a Q-TOF Micromass equipment (Waters, UK).
1
Figure S1. H NMR (CDCl , 500 MHz) of MBH adduct 3.
3
*e-mail: coelho@iqm.unicamp.br

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Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
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Figure S2. C NMR (CDCl , 125 MHz) of MBH adduct 3.
3
1
Figure S3. H NMR (CDCl , 250 MHz) of MBH adduct 4.
3

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Figure S4. C NMR (CDCl , 62.5 MHz) of MBH adduct 4.
3
1
Figure S5. H NMR (CDCl , 250 MHz) of MBH adduct 5.
3

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Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
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Figure S6. C NMR (CDCl , 62.5 MHz) of MBH adduct 5.
3
1
Figure S7. H NMR (CDCl , 250 MHz) of MBH adduct 6.
3

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Figure S8. C NMR (CDCl , 62.5 MHz) of MBH adduct 6.
3
1
Figure S9. H RMN (CDCl , 250 MHz) of MBH adduct 7.
3

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Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
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Figure S10. C NMR (CDCl , 62.5 MHz) of MBH adduct 7.
3
1
Figure S11. H NMR (CDCl , 250 MHz) of MBH adduct 8.
3

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Figure S12. C NMR (CDCl , 62.5 MHz) of MBH adduct 8.
3
1
Figure S13. H NMR (CDCl , 250 MHz) of MBH adduct 9.
3

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Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
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Figure S14. C NMR (CDCl , 62.5 MHz) of MBH adduct 9.
3
1
Figure S15. H NMR (CDCl , 250 MHz) of MBH adduct 10.
3

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Figure S16. C NMR (CDCl , 62.5 MHz) of MBH adduct 10.
3
1
Figure S17. H NMR (CDCl , 250 MHz) of MBH adduct 11.
3

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Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
J. Braz. Chem. Soc.
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Figure S18. C NMR (CDCl , 125 MHz) of MBH adduct 11.
3
1
Figure S19. H NMR (CDCl , 250 MHz) of MBH adduct 12.
3

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Figure S20. C NMR (CDCl , 125 MHz) of MBH adduct 12.
3
1
Figure S21. H NMR (CDCl , 250 MHz) of silylated MBH adduct 13.
3

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Hyphenating the Curtius Rearrangement with Morita-Baylis-Hillman Adducts
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Figure S22. C RMN (CDCl , 62.5 MHz) of silylated MBH adduct 13.
3
1
Figure S23. H NMR (CDCl , 250 MHz) of silylated MBH adduct 14.
3

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Figure S24. C NMR (CDCl , 62.5 MHz) of silylated MBH adduct 14.
3
1
Figure S25. H NMR (CDCl , 250 MHz) of silylated MBH adduct 15.
3