Chemoselective Reduction of Azlactones Using Schwartz's Reagent

Article abstract of DOI:10.1021/acs.joc.7b00820

Highly chemoselective addition of Schwartz's reagent to widely available azlactones is described. This method allows the preparation of challenged functionalized α-amino aldehydes, in good to high isolated yields at room temperature, after only 2 min reaction. The presence of sensitive functionalities or electronic factors does not compromise the potential of the method. The use of an excess of the reducing reagent gave a very functionalized allylic alcohol derivative in 86% yield.

Full text of DOI:10.1021/acs.joc.7b00820

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Note
Chemoselective Reduction of Azlactones Using Schwartz´s Reagent
Danielle L. J. Pinheiro, Eloah P. Ávila, Gabriel M. F. Batista, and Giovanni Wilson Amarante
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 11 May 2017
Downloaded from http://pubs.acs.org on May 12, 2017
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Chemoselective Reduction of Azlactones Using
Schwartz´s Reagent
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Danielle L. J. Pinheiro, Eloah P. Ávila, Gabriel M. F. Batista, and Giovanni W.
Amarante*
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Chemistry Department, Federal University of Juiz de Fora, Cidade Universitária, São
Pedro, Juiz de Fora, MG, CEP 36036ꢀ900, Brazil
*Eꢀmail: giovanni.amarante@ufjf.edu.br
TOC graphics
Abstract
Highly chemoselective addition of Schwartz’s reagent to widely available
azlactones is described. This method allows the preparation of challenged
functionalized αꢀamino aldehydes, in good to high isolated yields at room
temperature, after only two minutes reaction. The presence of sensitive
functionalities or electronic factors do not compromise the potential of the
method. The use of an excess of the reducing reagent gave a very
functionalized allylic alcohol derivative in 86% yield.
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Synthesis of nonꢀnatural amino acids and their precursors is essential.
Peptides built from nonꢀnatural amino acids are less prone to degradation and
excretion.¹ αꢀAmino aldehydes are versatile nonꢀnatural amino acid precursors
which can be transformed into useful 1,2ꢀamino alcohols and other building
blocks.²
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Daoust et al showed a new method to synthesize αꢀnitrogenated γ,δꢀ
unsaturated aldehydes in threeꢀstep sequence. The strategy involves two
copper coupling reactions and a Claisen rearrangement. The products were
obtained with excellent yields and selectivities. However the preparation of αꢀ
amino α,βꢀunsaturated aldehydes is not demonstrated.³ Synthesis involving
those functionalized aldehydes is more scarcer in the literature due the
synthetic challenge.
In the present study we demonstrate a practical and selective synthesis
of αꢀamino α,βꢀunsaturated aldehydes and αꢀamino aldehydes through the
reduction of azlactones4 using Schwartz´s reagent5 (Figure 1). Reactions using
this zirconocene complex allow the reduction of carbonyl bonds, which
represent important tool to prepare various builting blocks. Reduction of
nitriles6, esters, ketones7, thioketones8, aldehydes9, imines, nitro groups,
phosphine oxides and sulfides10, as well as secondary amides11 are some
important transformations in which this reducing agent has been adopted.
Figure 1. Selective reactions using Schwartz´s reagent
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A route to Nꢀformamides was developed by Langer et al through the
highly chemoselective nucleophilic addition of the in situ generated Schwartz’s
reagent to reduce isocyanates. Products with uniformly high yields, full retention
of the steric information and high chemoselectivity were obtained.12
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An investigation of the hydrozirconation of tertiary amides with the
Schwartz reagent also was reported by Georg et al. The authors have
demonstrated that hydrozirconation is one of the most general method for the
formation of aldehydes from amides with the highest functional group tolerance
reported.13
Therefore, Schwartz’s reagent was chose to reduce selectively
azlactones to aldehydes. Moreover, this selective reduction of azlactones to
aldehydes has not been described in the literature.
We began our investigation using NaBH4 to investigate the selectivity of
azlactone core reduction. However, this reagent afforded a mixture of products.
To our delight, the use of Cp2ZrHCl (1.2 equiv.) in CH2Cl2, at room temperature,
2 minutes reaction, the selectivity was dramatically improved (Table 1ꢀ entry 2).
Nevertheless, the conversion was far away from optimal, even in the presence
of different solvents, temperatures, concentration or longer reaction times
(Table 1ꢀ entries 4, 5 and 6). Further improvement could be observed by carried
out the reaction using 2 equiv. of Cp2ZrHCl in CH2Cl2 (Table 1ꢀ entry 8).
ꢀ1
Concentration at 0.2 mol L
entry 13).
gave the highest level of conversion (Table 1ꢀ
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Table 1. Reduction of azlactones to aldehydes: optimization
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Entry
Reducing agent
(equiv.)
Solvent
Conc.
Temp. (°C)/time Conversion
(min)
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(mol L-1)
(%)[a]
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2
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4
5
6
7
8
NaBH4 (1.0)
THF
0.1
0.1
0.1
0.1
0.1
0.3
0.2
0.1
0.1
0.1
0.1
0.1
0.2
0.3
0.1
0/30
r.t./2
Mix of products
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4
Cp2ZrHCl[b] (1.2)
Cp2ZrHCl (1.2)
Cp2ZrHCl (1.2)
Cp2ZrHCl (1.2)
Cp2ZrHCl (1.2)
Cp2ZrHCl (1.2)
Cp2ZrHCl (2.0)
Cp2ZrHCl (2.0)
Cp2ZrHCl (2.0)
Cp2ZrHCl (2.0)
Cp2ZrHCl (2.0)
Cp2ZrHCl (2.0)
Cp2ZrHCl (2.0)
Cp2ZrHCl (3.0)
CH2Cl2
CH3CN
CH3CN
THF
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
r.t./120
60/120
60/120
r.t./2
r.t./10
r.t./2
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71
1
83
79
86
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18
96
83
86
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0/2
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15
r.t./60
r.t./120
60/120
r.t./2
r.t./2
r.t./2
CH2Cl2
CH2Cl2
CH2Cl2
[a] Measured by ¹H NMR spectroscopy analysis of the crude reaction mixture. [b] Schwartz’s reagent
To demonstrate the scope and potential of the method, a serie of
different functionalized azlactones were tested (table 2 and 3). Substitution on
the aromatic ring does not adversely influence the reaction outcome. Electronꢀ
withdrawing functionalities such as both halogens in para and meta position
gave the corresponding products (2b, 2c, 2d and 2e) with high yield. Acetoxy
substituent also was able to be used to obtain aldehyde (2f) in 63% yield.
Electronꢀdonating groups such as piperonal derivatives (2g and 2h) tolerated
the reaction condition, affording products with 78% and 70% yield. The use of
methoxy in meta position was possible and the corresponding product 2i was
isolated in 62% yield. It is important to mention, the stereochemistry Z of the
double bond is maintained.14
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Table 2. Scope of α−amino α,β-unsaturated aldehydes [a]
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_____________________________________________________________________________
[a] Reactions were carried out using 0.2 mol Lꢀ1 solution of 1a-j in CH2Cl2 and 2 equivalents of Cp2ZrHCl. [b] Reaction
time was 8 minutes.
This protocol was also effective when applied to saturated azlactones.
Aldehydes derived from simple protected amino acids could be obtained in
good yields (Table 3). For example, a very interesting αꢀamino aldehyde
derivative from allylglycine could synthesized in 50% yield. Again, all the
corresponding products were obtained with total control of the chemoselectivity.
Table 3. Scope of protected α−amino aldehydes[a]
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____________________________________________________________________________
[a] Reactions were carried out using 0.2 mol Lꢀ1 solution of 3a-j in CH2Cl2 and 2 equivalents of Cp2ZrHCl. [b]
Concentration of 0.1 mol Lꢀ1. [c] Concentration of 0.1 mol Lꢀ1 and 6 minutes of reaction. [d] 3 equivalents of Cp2ZrHCl
used.
A plausible mechanism was also proposed. The presence of a seemingly
stable intermediate is evident in this reaction, since the optimized reduction
condition did not provide the alcohol. Aldehydes are known compounds for
reduction by Schwartz’s reagent and any aldehyde formed before the work up
was prospective to be reduced to alcohol.13 This observation led to our working
hypothesis, which the azlactone ring could be incorporated by the zirconium
reagent to form an sp3ꢀhybridized, 18ꢀelectron complexe (Scheme 1ꢀꢀ
intermediate II). Presence of water would then react with II and release the
product III.13
Scheme 1. Mechanism proposal for azlactone reduction using Schwartz’s
reagent.
The following reactions were carried out to demonstrate the versatile of
this method. First, the addition of 4 equivalents of Schwartz’s reagent to
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azlactone 1i, gave a very interesting allylic alcohol 5 in 86% yield (Scheme 2). It
is important to mention the corresponding highly chemoselective additions in
the carbonyl groups to both azlactone and in the forming aldehyde intermediate.
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Scheme 2. Reduction of azlactone 1i to allylic alcohol 5.
We then prepared a trichloromethyl carbinol derivative, which is generally
used to render αꢀsubstituted carboxylic acid derivatives.15 The reaction of 2a
with potassium trichloroacetate salt in DMSO, provided a product 6 in 70% yield
as a mixture of diastereomers (Scheme 3).
Scheme 3. Synthesis of trichloromethyl carbinol derivative 6.
In summary, a route to αꢀamino aldehydes through the highly
chemoselective nucleophilic addition of Schwartz’s reagent to widely available
azlactones has been developed. Under the optimized reaction condition the
corresponding protected αꢀamino aldehydes were isolated in good to high
yields. Besides, the Z stereochemistry of the double bond were maintained. For
the first time, the use of Schwartz reagent to selectively reduce azlactones to
aldehydes was demonstrated. We also demonstrated the preparation of a allylic
alcohol by using excess of Schwartz reagent. Finally, a new CꢀC bond formation
was also possible by addition of trichloromethyl group into to one of those
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aldehydes. The corresponding trichloromethyl carbinol derivative was
synthetized in 70% yield.
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Experimental Section
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1. General information
Unless otherwise noted, all reagents were obtained commercially and used
without further purification. Unless otherwise noted, all reaction mixtures were carried
out in flame-dried flask under a positive pressure of dry nitrogen. Analytical thin layer
chromatography (TLC) was performed on precoated glass-backed TLC plates (silica gel
60 F254) and visualized by UV lamp (254 nm). Yields refer to chromatographically
purified or by recrystallization and spectroscopically pure compounds, unless stated
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otherwise. H and 13C spectra were recorded on a 500 MHz spectrometer. Chemical
1
shifts are reported in ppm. H NMR spectra were referenced to CDCl3 (7.26 ppm) and
13C NMR spectra were referenced to CDCl3 (77.0 ppm). All 13C spectra were measured
with complete proton decoupling. Peak multiplicities are designated by the following
abbreviations: s, singlet; d, doublet; dd, double doublet; t, triplet; m, multiplet; br,
broad; and J, coupling constant in Hz. High-resolution mass spectra were acquired in
the positive ion mode using a mass spectrometer equipped with an electrospray
ionization source HRMS (ESI-QTOF).
2. General procedure and characterization data for the α,β-unsaturated α-amino
aldehydes
To a solution of Erlenmeyer azlactone (0.12 mmol) in dichloromethane (0.6 mL, 0.2
mol L-1) was added the Schwartz reagent (61.7mg, 0.24 mmol, 2 equiv.) at room
temperature for 2 min. After reaction completion, the solvent was evaporated under
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reduced pressure. The product was obtained after purification through chromatography
column (elution: ethyl acetate/ hexanes, 3:1).
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(Z)-N-(3-oxo-1-phenylprop-1-en-2-yl)benzamide. The product 2a was obtained as a
yellow oil (27.7 mg, 92 %). IR (KBr, cm-1): 3272, 3059,2923, 2853, 1691, 1653, 1635,
1509, 1478, 1276, 751, 690. 1H NMR (500 MHz, CDCl3) δ: 9.53 (s, 1H), 8.10 (s, 1H),
7.94-7.92 (m, 2H), 7.61 (tt, 1H, J = 7.4 Hz, J =1.3 Hz), 7.55-7.51 (m, 4H), 7.41-7.39
(m, 3H), 7.12 (s, 1H). 13C{1H}NMR (125 MHz) δ: 189.9, 164.7, 139.2, 139.1, 134.1,
133.5, 132.5, 132.4, 130.4, 129.0, 128.5, 127.7. HRMS (ESI-QTOF) m/z: [M + Na]+
Calcd for C16H13NO2Na 274.0844, found 274.0839.
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(Z)-N-(1-(4-chlorophenyl)-3-oxoprop-1-en-2-yl)benzamide. The product 2b was
obtained as a white solid (28.0 mg, 82 %). IR (KBr, cm-1): 3380, 2950, 2918, 2851,
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1692, 1667, 1587, 1514, 1477, 1274, 1092, 754. H NMR (500 MHz, CDCl3) δ: 9.50
(s, 1H), 8.18 (s, 1H), 7.93 (d, 2H, J = 7.4 Hz), 7.64-7.61 (m, 1H), 7.55-7.52 (m, 2H),
7.46-7.44 (m, 2H), 7.38-7.35 (m, 2H), 7.04 (s, 1H). 13C{1H}NMR (125 MHz) δ:
189.8, 164.5, 137.4, 136.2, 133.3, 132.7, 132.6, 132.4, 131.5, 129.0, 128.8, 127.6.
HRMS (ESI-QTOF) m/z: [M - H]- Calcd for C16H11ClNO2 284.0478, found 284.0470.
(Z)-N-(1-(4-bromophenyl)-3-oxoprop-1-en-2-yl)benzamide. The product 2c was
obtained as a white solid (36.4 mg, 92 %). IR (KBr, cm-1): 3271, 3062, 2915, 2851,
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1692, 1666, 1636, 1580, 1580, 1510, 1476, 1269, 1169, 754. H NMR (500 MHz,
CDCl3) δ: 9.49 (s, 1H), 8.20 (s, 1H), 7.92-7.63 (m, 2H), 7.62 (tt, 1H, J =7.4 Hz, J = 1.2
Hz), 7.54-7.520 (m, 4H), 7.37-7.35 (m, 2H), 7.01 (s, 1H). 13C{1H}NMR (125 MHz) δ:
189.8, 164.6, 137.4, 133.3, 133.1, 132.6, 132.5, 131.7, 131.6, 129.0, 127.6, 124.7.
HRMS (ESI-QTOF) m/z: [M - H]- Calcd for C16H11BrNO2 327.9973, found 327.9965.
(Z)-N-(1-(4-fluorophenyl)-3-oxoprop-1-en-2-yl)benzamide. The product 2d was
obtained as a yellow oil (29.1 mg, 90 %). IR (KBr, cm-1): 3271, 3072, 2921, 2852,
1688, 1647, 1603, 1505, 1477, 1279, 1234, 1158, 7550.1H NMR (500 MHz, CDCl3) δ:
9.50 (s, 1H), 8.15 (s, 1H), 7.94-7.92 (m, 2H), 7.62 (tt, 1H, J = 7.5 Hz, J = 1.5 Hz), 7.55-
7.51 (m, 4H), 7.10-7.07 (m, 3H). 13C{1H}NMR (125 MHz) δ: 189.8, 164.5, 163.3 (d,
1F, J = 270.3 Hz), 138.0, 133.4, 132.6 (d, 1F, J = 9.0 Hz), 132.0, 130.4 (d, 1F, J = 3.4
Hz), 128.9, 127.6, 115.7 (d, 1F, J = 21.8 Hz). HRMS (ESI-QTOF) m/z: [M - H]-
Calcd for C16H11FNO2 268.0774, found 268.0779.
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(Z)-N-(1-(3-chlorophenyl)-3-oxoprop-1-en-2-yl)benzamide. The product 2e was
obtained as a yellow oil (29.1 mg, 85%). IR (KBr, cm-1): 3280, 3065, 3007, 2988,
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2916, 1849, 1674, 1654, 1638, 1601, 1508, 1478, 1276, 749. H NMR (500 MHz,
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CDCl3) δ: 9.51 (s, 1H), 8.18 (s, 1H), 7.92-7.90 (m, 2H), 7.61 (tt, 1H, J = 7.5 Hz, J = 1.3
Hz), 7.54-7.50 (m, 3H), 7.40 (dt, 1H, J = 7.40 Hz, J = 1.4 Hz), 7.36-7.30 (m, 2H), 7.01
(s, 1H). 13C{1H}NMR (125 MHz) δ: 189.7, 164.6, 136.8, 136.7, 136.0, 134.4, 133.3,
133.0, 132.6, 130.1, 129.6, 128.9, 128.0, 127.6. HRMS (ESI-QTOF) m/z: [M - H]-
Calcd for C16H11ClNO2 284.0478, found 248.0477.
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(Z)-4-(2-benzamido-3-oxoprop-1-en-1-yl)phenyl acetate. The product 2f was
obtained as a yellow oil (23.4 mg, 63 %) IR (KBr, cm-1): 3290, 3064, 2958, 2925,
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2846, 1768, 1691, 1653, 1600, 1503, 1479, 1277, 1198, 1172, 1011. H NMR (500
MHz, CDCl3) δ: 9.51 (s, 1H), 8.11 (s, 1H), 7.94-7.92 (m, 2H), 7.61 (tt, 1H, J = 7.5 Hz,
J = 1.3 Hz), 7.57-7.52 (m, 4H), 7.16-7.13 (m, 2H), 7.08 (s, 1H), 2.32 (s, 3H).
13C{1H}NMR (125 MHz) δ: 189.8, 169.0, 164.8, 151.9, 138.0, 133.4, 132.6, 132.3,
131.7, 129.0, 128.9, 127.6, 121.7, 21.2. HRMS (ESI-QTOF) m/z: [M - H]- Calcd for
C18H14NO4 308.0923, found 308.0928.
(Z)-N-(1-(benzo[d][1,3]dioxol-5-yl)-3-oxoprop-1-en-2-yl)benzamide. The product 2g
was obtained as a yellow solid (27.6 mg, 78%) using the general methodology for 8
min. IR (KBr, cm-1): 3297, 2954, 2920, 2852, 1687, 1657, 1601, 1510, 1484, 1258,
1
1038. H NMR (500 MHz, CDCl3) δ: 9.45 (s, 1H), 8.07 (s, 1H), 7.95-7.93 (m, 2H),
7.61 (tt, 1H, J = 7.5 Hz, J = 1.2 Hz), 7.54-7.51 (m, 2H), 7.11 (dd, 1H, J = 8.2 Hz, J =
1.6 Hz), 7.05 (d, 1H, J = 1.6 Hz), 7.04 (s, 1H), 6.84 (d, 1H, J = 8.2 Hz), 6.01 (s, 2H).
13C{1H}NMR (125 MHz) δ: 189.8, 165.0, 149.7, 147.9, 140.0, 133.5, 132.4, 131.0,
128.9, 128.3, 127.6, 127.0, 109.6, 108.4, 101.6. HRMS (ESI-QTOF) m/z: [M + Na]+
Calcd for C17H13NO4Na 318.0742, found 318.0740.
(Z)-N-(3-oxo-1-(3,4,5-trimethoxyphenyl)prop-1-en-2-yl)benzamide. The product 2h
was obtained as a yellow oil (31.9 mg, 78%) using the general methodology for 8 min.
IR (KBr, cm-1): 3297, 3004, 2940, 2835, 1654, 1577, 1503, 1331, 1245, 1124, 1003,
710. 1H NMR (500 MHz, CDCl3) δ: 9.49 (s, 1H), 8.07 (s, 1H), 7.95-7.93 (m, 2H), 7.60
(tt, 1H, J = 7.8 Hz, J = 1.2 Hz), 7.53-7.50 (m, 2H), 7.06 (s, 1H), 6.83 (s, 2H), 3.90 (s,
3H), 3.73 (s, 6H). 13C{1H}NMR (125 MHz) δ: 189.8, 165.0, 152.9, 140.1, 140.0,
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133.4, 132.6, 129.1, 129.0, 127.5, 108.0, 60.9, 56.0. HRMS (ESI-QTOF) m/z: [M -
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5
H]- Calcd for C19H18NO5 340.1185, found 340.1187.
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(Z)-N-(3-oxo-1-(3-trimethoxyphenyl)prop-1-en-2-yl)benzamide. The product 2i was
obtained as a yellow oil (20.9 mg, 62%) using the general procedure for 8 min. IR
(KBr, cm-1): 3366, 3006, 2958, 2919, 2850, 1722, 1652, 1600, 1486, 1277, 1260, 1157,
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1041, 764, 745. H NMR (500 MHz, CDCl3) d: 9.52 (s, 1H), 8.08 (s, 1H), 7.94-7.92
(m, 2H), 7.61 (tt, 1H, J = 7.4 Hz, J = 1.3 Hz), 7.54-7.50 (m, 2H), 7.30 (t, 1H, J = 8.0
Hz), 7.16-7.14 (m, 1H), 7.10 (s, 1H), 7.09-7.08 (m, 1H), 6.94 (ddd, 1H, J = 8.0 Hz, J
=2.6 Hz, J = 1.0 Hz), 3.73 (s, 3H). 13C{1H}NMR (125 MHz) δ: 189.9, 164.9, 159.9,
139.1, 135.2, 133.5, 132.6, 132.5, 129.5, 128.9, 127.6, 123.0, 116.6, 115.1, 55.1.
HRMS (ESI-QTOF) m/z: [M - H]- Calcd for C17H14NO3 280.0974, found 280.0977.
3. General procedure and characterization data for the α,β-saturated α-amino
aldehydes
To a solution of azlactone (0.2 mmol) in dichloromethane (1 mL, 0.2 mol L-1) was
added the Schwartz Reagent (102.8 mg, 0.4 mmol, 2 equiv.) for 2 min. After reaction
completion, the solvent was evaporated under reduced pressure. The product was
obtained after purification through chromatography column (ethyl acetate/ hexanes,
3:1).
(1-oxopropan-2-yl)benzamide. The product 4a was obtained as a white oil (13.6 mg,
64%). IR (KBr, cm-1): 3433, 2988, 2916, 2850, 1653, 1636, 1617, 1276, 1260, 763,
1
747. H NMR (500 MHz, CDCl3) δ: 9.69 (s, 1H), 7.86-7.84 (m, 2H), 7.58-7.54 (m,
1H), 7.50-7.47 (m, 2H), 6.85 (s, 1H), 4.78 (q, 1H, J = 7.4 Hz), 1.54 (d, 3H, J = 7.5 Hz).
13C{1H}NMR (125 MHz) δ: 198.9, 167.1, 133.7, 132.0, 128.8, 128.7, 128.5, 128.1,
127.1. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C10H12NO2 178.0868, found
178.0869.16
N-(4-methyl-1-oxopentan-2-yl)benzamide. The product 4b was obtained as a yellow
oil (17.1 mg, 65 %) using the general procedure with concentration of 0.1 mol L-1 of
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azlactone in dichloromethane. IR (KBr, cm-1): 3331, 3065, 2955, 2928, 2868, 1725,
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1640, 1602, 1580, 1275,762, 751, 712. H NMR (500 MHz, CDCl3) δ: 9.71 (s, 1H),
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7.85-7.83 (m, 2H), 7.55 (tt, 1H, J = 7.6 Hz, J = 1.3 Hz), 7.49-7.46 (m, 2H), 6,68 (s, 1H),
4.85-4.80 (m, 1H), 1.89-1.84 (m, 2H), 1.64-1.56 (m, 1H), 1,04 (d, 3H, J = 6.2 Hz), 1.02
(d, 3H, J = 6.3 Hz). 13C{1H}NMR (125 MHz) δ: 199.6, 167.5, 152.9, 133.8, 131.9,
128.7, 127.1, 57.8, 38.2, 25.0, 23.1, 22.2. HRMS (ESI-QTOF) m/z: [M - H]- Calcd for
C13H16NO2 218.1181, found 218.1178.
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(1-oxo-3-phenylpropan-2-yl)benzamide. The product 4c was obtained as a white
solid (20.0 mg, 66%) using the general procedure with concentration of 0.1 mol L-1 of
azlactone in dichloromethane for 6 min. IR (KBr, cm-1): 3332, 3058, 3024, 2914, 2830,
1
1735, 1627, 1538, 1601, 1278, 1253, 752, 694. H NMR (500 MHz, CDCl3) δ: 9.76 (s,
1H), 7.77-7.75 (m, 2H), 7.55 (tt, 1H, J = 7.4 Hz, J = 1.1 Hz), 7.47-7.44 (m, 2H), 7.35-
7.30 (m, 3H), 7.23-7.21 (m, 2H), 6.73 (s, 1H), 4.96 (q, 1H, J = 6.8 Hz), 3.37 (dd, 1H, J
= 14.1 Hz, J = 6.8 Hz), 3.30 (dd, 1H, J = 14.1 Hz, J = 6.8 Hz). 13C{1H}NMR (125
MHz) δ: 198.8, 167.3, 135.5, 133.6, 132.0, 129.4, 128.9, 128.7, 127.3, 127.0, 60.2, 35.2.
HRMS (ESI-QTOF) m/z: [M - H]- Calcd for C16H14NO2 252.1025, found 252.1024.17
N-(1-oxopent-4-en-2-yl)benzamide-(1-oxopent-4-en-2-yl)benzamide. The product
4d was obtained as a white solid (31.9 mg, 78%) using the general procedure in the
presence of 3 equiv. of Cp2ZrHCl. IR (KBr, cm-1): 3300, 3068, 2005, 2917, 2849,
1
1734, 1638, 1533, 1489, 1273, 1260, 765, 748. H NMR (500 MHz, CDCl3) δ: 9.73 (s,
1H), 7.83-7.82 (m, 2H), 7.58-7.55 (m, 1H), 7.50-7.47 (m, 2H), 6.78 (s, 1H), 5.84-5.76
(m, 1H), 5.26-5.22 (m, 2H), 4.83 (q, 1H, J = 6.2 Hz), 2.83-2.78 (m, 1H), 2.75-2.70 (m,
1H) 13C{1H}NMR (125 MHz) δ: 198.9,167.3, 133.7, 132.0, 131.8, 128.7, 127.1,
119.1, 58.3, 33.5. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C12H14NO2 204.1025,
found 204.1027.
N-(4-(methylthio)-1-oxobutan-2-yl)benzamide. The product 4e was obtained as a
white oil (15.4 mg, 54%). IR (KBr, cm-1): 3297, 3005, 2959, 2922, 2851, 1730, 1646,
1
1646, 1601, 1532, 1275, 1259, 766, 749. H NMR (500 MHz, CDCl3) δ: 9.77 (s, 1H),
7.90-7.86 (m, 2H), 7.59-7.56 (m, 1H), 7.51-7.47 (m, 2H), 7.06 (s, 1H), 4.84 (q, 1H, J =
6.2 Hz), 2.72-2.58 (m, 2H), 2.49-2.41 (m, 1H), 2.23-2.18 (m, 1H), 2.14 (s, 3H).
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13C{1H}NMR (125 MHz) δ: 198.5, 167.4, 133.4, 132.1, 128.7, 127.1, 58.7, 29.7,
28.4, 15.5. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C12H16NO2S 238.0902,
found 238.0903.
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4. Procedure and characterization data for allylic alcohol
To a solution of Erlenmeyer azlactone (0.12 mmol) in dichloromethane (1.2 mL, 0.1
mol L-1) was added the Schwartz reagent (123.3 mg, 0.48 mmol, 4.0 equiv.). The
mixture reaction was stirred until completion of reaction (monitored by TLC) the
solvent was evaporated under reduced pressure. The product was obtained after
purification through chromatography column (elution: ethyl acetate/ hexanes, 2:1).
(Z)-N-(3-hydroxy-1-(3,4,5-trimethoxyphenyl)prop-1-en-2-yl)benzamide.
The
product 5 was obtained as a yellow solid (35.0 mg, 86 %). IR (KBr, cm-1): 3410, 3001,
2923, 2849, 1648, 1582, 1508, 1239, 1126, 1001, 712. 1H NMR (500 MHz, CDCl3) d:
8.37 (s, 1H), 7.76-7.75 (m, 2H), 7.59-7.56 (m, 1H), 7.49-7.46 (m, 2H), 6.57 (s, 2H),
6.03 (s, 1H), 4.76 (t, 1H, J = 7.3 Hz), 4.51 (d, 2H, J = 7.3 Hz), 3.90 (s, 3H), 3.81 (s,
6H). 13C{1H}NMR (125 MHz) δ: 165.3, 153.9, 137.5, 136.5, 133.4, 132.5, 130.2,
129.0, 127.0, 116.0, 105.4, 105.3, 64.2, 56.2, 56.1. HRMS (ESI-QTOF) m/z: [M - H]-
Calcd for C19H20NO5 342.1341, found 342.1338.
5. Procedure and characterization data for the allylic trichloromethyl alcohol
In a round-bottom flask 4c (15.1 mg, 0.06 mmol) was added DMSO (0.3 mL),
potassium trichloroacetate (36.2 mg, 0.18 mmol, 3 equiv.) and then stirred until
completion of reaction (monitored by TLC). After completion, the mixture was diluted
in dichloromethane (10 mL) and extracted with H2O (5 x 10 mL). The organic phases
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were combined and dried over anhydrous sodium sulfate and the solvent was removed
under reduced pressure.
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(Z)-N-(3-hydroxy-1-(3,4,5-trimethoxyphenyl)prop-1-en-2-yl)benzamide.
The
product 6 was obtained as a mixture of diastereomers as a yellow oil (14.8. mg, 70 %).
IR (KBr, cm-1): 3439, 3196, 2962, 2920, 2851, 1662, 1459, 1402, 1382, 700. 1H NMR
(500 MHz, CDCl3) d: 7.73-7.71 (m, 2H), 7.60-7.58 (m, 2H), 7.53-7.50 (m, 2H), 7.46-
7.40 (m, 5H), 7.35-7.31 (m, 6H), 7.27-7.24 (m, 3H), 6.74 (d, 1H, J = 8.2 Hz), 6.40 (d,
1H’, J = 7.5 Hz), 4.97 (s, 1H), 4.93-4.88 (m, 1H), 4.71-4.66 (m, 2H), 4.58 (s, 1H), 4.20
(s, 1H), 3.45 (dd, 1H J = 14.3 Hz, J = 3.8 Hz), 3.35 (dd, 1H, J = 13.6 Hz, J = 6.9 Hz),
3.23 (dd, 1H, J = 14.3 Hz, J = 10.9 Hz), 3.03 (dd, 1H, J = 13.7 Hz, J = 8.5 Hz).
13C{1H}NMR (125 MHz): d: 168.4, 168.0, 138.0, 137.1, 134.1, 133.8, 132.0, 131.9,
129.4, 129.2, 128.8, 128.7, 128.6, 127.1, 127.0, 126.9, 102.1, 101.3, 83.9, 81.2, 55.2,
52.5, 39.2, 34.8.HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C17H17Cl3NO2
372.0325, found 372.0324.
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Acknowledgments
The authors are grateful to the Fundação de Amparo a Pesquisa do Estado de Minas
Gerais (FAPEMIG), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES), the Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq), and the Rede Mineira de Química for financial support. We thank Prof. Adão
A. Sabino at Federal University of Minas Gerais for HRMS analyses.
Supporting Information
Copies of 1H and 13C NMR spectra for the final products.
Dedication
This work is dedicated to Professor Ronaldo Aloise Pilli in recognition of his
outstanding contributions to Brazilian chemistry.
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Chem. 2016, 3, 459ꢀ 462. (b) De Castro, P. P.; Dos Santos, I. F.; Amarante, G. W.
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