Br?nsted acid catalyzed azlactone ring opening by nucleophiles

Article abstract of DOI:10.1016/j.tet.2013.11.037

Br?nsted acid catalyzed azlactone ring opening in the presence of different nucleophiles leading to the efficient synthesis of protected amides and amino esters is presented. Sixteen compounds were synthesized in good to excellent isolated yields. Mechani

Full text of DOI:10.1016/j.tet.2013.11.037

Tetrahedron 70 (2014) 3271e3275
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Brønsted acid catalyzed azlactone ring opening by nucleophiles
Adriane A. Pereira a, Pedro P. de Castro a, Amanda C. de Mello a, Bruno R.V. Ferreira b,
,
a,
*
Marcos N. Eberlin b , Giovanni W. Amarante
*
a Department of Chemistry, Federal University of Juiz de Fora, 36036-900 Juiz de Fora, MG, Brazil
b Institute of Chemistry, ThoMSon Mass Spectrometry Laboratory, University of CampinasdUNICAMP, Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 October 2013
Received in revised form 5 November 2013
Accepted 13 November 2013
Available online 20 November 2013
Brønsted acid catalyzed azlactone ring opening in the presence of different nucleophiles leading to the
efficient synthesis of protected amides and amino esters is presented. Sixteen compounds were syn-
thesized in good to excellent isolated yields. Mechanism investigation by using ESI(þ)-MS/MS revealed
that the CSA catalyst promotes azlactone activation for electrophilic attack facilitating therefore the at-
tack of the nucleophile that leads to ring opening and protonation.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Azlactones
Alcohols
Amines
ESI(þ)-MS/MS
Organocatalysis
Brønsted acid
1. Introduction
azlactone can also suffer nucleophile attack, as shown for instance
by Wang and co-workers, who described a Brønsted acid func-
Over the past years a major area in organic chemistry has been
the development of efficient catalytic reactions able to form bi-
ologically functional amino acids and small peptides.1 For such goal,
azlactones have been attractive since they may serve as protected
amino acids, which can be used in the synthesis of natural or
synthetic bioactive molecules.2 Our research group has explored
the potential of azlactones as pro-nucleophiles in the presence of
Michael acceptors by using an organocatalytic approach.3 The
multi-functional heterocyclic azlactone structure, however, confers
to such molecules a diverse chemistry reacting as electrophiles via
two distinct sites (Fig. 1). This structural versatility is very impor-
tant since it could be applied in peptide-type synthesis. But
tioning as a catalyst for the asymmetric dynamic kinetic resolution
following by opening of azlactone rings in the presence of a nucle-
ophile. However, only a few azlactone rings and a particular alcohol
were well tolerated in their optimized reaction condition.4 Re-
cently, Connon and Palacio showed that cinchona derivatives are
suitable organocatalysts for the highly enantioselective dynamic
kinetic resolution of azlactones by thiolysis. Moderate to high levels
of enantioselectivity were achieved by using this catalytic system.5
We envisioned therefore that the use of Brønsted acid catalysis
could be an attractive, metal-free strategy to activate azlactones
toward nucleophile attack, and that this reaction could also be
useful to prepare protected amino acid derivatives. In this com-
munication, we show that indeed (þ/ꢀ)-camphorsulfonic acid
(CSA) functions as an effective Brønsted acid catalyst for the
azlactone ring via nucleophile attack.
Electrophile sites
O
O
R1
pro-nucleophile
2. Results and discussion
N
R
Our studies initiated by reacting azlactone6 2 and octanol in the
presence of 10 mol % of CSA as catalyst. To our delight, the desired
product 6 was isolated in 88% yield (Scheme 1). After optimization
of the reaction conditions, we found that replacing octanol with
DCM as solvent provided the best reaction conditions. We also note
that no reaction was observed in the absence of the CSA catalyst.
Fig. 1. General structure of azlactones.
* Corresponding authors. E-mail addresses: eberlin@iqm.unicamp.br (M.N.
Eberlin), giovanni.amarante@ufjf.edu.br (G.W. Amarante).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.037

3272
A.A. Pereira et al. / Tetrahedron 70 (2014) 3271e3275
An ion of m/z 211 corresponding to the final product 22 [22þH]þ
O
O
H
N
CH3(CH2)7XH
10 mol% CSA
(Fig. 2A) was intercepted. Its collision-induced dissociation (CID)
showed fragment ions of m/z 176, 148, and 105, which were at-
tributed to 23, 24, and 25, respectively (Fig. 2B). In addition, another
key species of m/z 408 corresponding to the association of the
azlactone and the catalyst, that is, [2þCSAþH]þ was also inter-
cepted. Its ESI(þ)-MS/MS showed as the unique fragment an ion of
m/z 176 due to the neutral loss of CSA (Fig. 2C), which fully agrees
with the proposed H-bonded proton dimmer structure in which
protonation of 2 occurs at the most basic ring nitrogen.
H3C(H2C)7X
R
O
R
O
N
CH2Cl2, 24 h
Ph
6
7
8
9
R = Me, X = O (88%)
R = iPr, X = O (82%)
R = iBu, X = O (59%)
R = Bn, X = O (74%)
1 R = H
2 R = Me
3 R = iPr
4 R = iBu
5 R = Bn
10 R = Me, X = NH (93%)
11 R = iPr, X = NH (55%)
12 R = iBu, X= NH (64%)
13 R = Bn, X = NH (96%)
14 R = H, X = O
(78%)
Scheme 1. Opening of the azlactone ring by lipophilic alcohols and amines. Reactions
were carried out using 0.2 mmol of azlactone, 0.02 mmol of CSA (10 mol %), and
0.21 mmol of nucleophile (0.2 M in azlactone).
The reaction was also found to tolerate different azlactones
(1e5); for example, the sterically bulky azlactone 3 provided the
desired product 7 in 82% yield. Different lipophilic alcohols and
amines could also be used in this reaction condition with medium
to high yields (Schemes 1 and 2). Although no diastereoselectivity
was observed, sugar-based derivatives were also found to provide
the acyclic products in high yields. A secondary alcohol also worked
quite well and even a tertiary alcohol was well tolerated, giving the
desired product 13 in 57% isolated yield.
O
Nucleophile (Nu);
10 mol % CSA
O
H
N
Me
O
Nu
CH2Cl2, 24 h
N
Me
O
O
Ph
OH
Nu:
O
20
15 HOCH2(CH2)6CH2OH (75%)
16 C6H5NH2 (43%)
17 (CH3)2CHOH (78%)
18 t-BuOH (57%)
(72%)
O
O
O
NH2
O
O
OH
19
21
O
(91%)
O
(79%)
O
Fig. 2. (A) ESI(þ)-MS of the azlactone 2 and CD3OD reaction solution in the presence of
CSA as catalyst; (B) ESI(þ)MS/MS of the ion of m/z 211; (C) ESI(þ)-MS/MS of the ion of
m/z 408.
Scheme 2. Opening of azlactone ring by others nucleophiles. Reactions were carried
out using 0.2 mmol of azlactone, 0.02 mmol of CSA (10 mol %), and 0.21 mmol of
nucleophile (0.2 M in azlactone).
In the second experiment, D2O was used as the nucleophile. As
before, the two ions [2þCSAþH]þ of m/z 408 and [26þH]þ of m/z
195 were intercepted (Eq. 1). No H/D exchange for these two ions
was noted, which suggested that de-protonation, the last reaction
step, is also promoted by the catalyst. The mechanism seems
therefore to proceed through azlactone activation via N-pro-
tonation and CSA binding at the NHþ center (ion pairing), which
facilitates nucleophilic attack at the carbonyl carbon and then the
final CSA protonation (Scheme 3).
We then turned our attention to understanding the basics of this
reaction by investigating its mechanism. The transfer of charged
reaction intermediates directly from reaction solutions to the gas
phase by electrospray ionization (ESI) followed by (tandem) mass
spectrometry characterization ESI(þ)-MS/MS7 was therefore used
in an attempt to intercept potential intermediates involved in the
catalytic cycle. To this end, two experiments were carried out. First,
after 5 min of reaction, an aliquot was taken from the crude mixture
of azlactone 2 and CD3OD in the presence of 10 mol % of CSA, di-
luted in acetonitrile, and directly analyzed by ESI(þ)-MS (Eq. 1).
3. Conclusion
Efficient Brønsted acid catalyzed azlactone ring opening via
electrophilic attack in the presence of different nucleophiles has
been presented. Several amines and alcohols can be applied in this
reaction condition, providing protected amino esters and amides
derivatives in good to excellent yields. Mechanism investigation via
ESI(þ)-MS/MS revealed azlactone activation by the catalyst CSA to
form an ion pairing intermediate, following by nucleophilic attack.
No H/D exchange occurs when D2O is used with no deuterium in-
corporation in the final product, suggesting that CSA is responsible
for the protonation and de-protonation step. The development of
(D) no deuterium
O
CD3OD or D2O
10 mol % CSA
incorporated
O
H
N
Me
Ph
O
Eq. 1
RO
CH2Cl2
N
2
Me
O
Ph
R = -CD3; 22; m/z = 211
R = -D ; 26; m/z = 195
ð1Þ

A.A. Pereira et al. / Tetrahedron 70 (2014) 3271e3275
3273
mixture was then diluted in CH2Cl2 (10 mL) and washed with sat-
urated solution of sodium bicarbonate (5 mL). The organic phase
was dried over anhydrous Na2SO4 and concentrated under reduced
pressure. After, the crude reaction mixture was purified through
silica gel chromatography by using ethyl acetate/hexanes as sol-
vents (up to 25% ethyl acetate/hexanes). The purified products were
then fully characterized by the conventional elemental analysis.
O
O
R
O
R
(+/-)-CSA
X
N
R1
N
H
Ph
Ph
O
O
O
N
H
X
R
O
4.3. Characterization data
Ph
R1
N
Ph
R
O
S
O
O
S
H
H
4.3.1. Octyl 2-(benzamido)propanoate (6). The product was purified
by column chromatography on silica gel (elution: hexanes to hex-
anes/ethyl acetate 25%) to afford product 6 (123 mg, 88%); IR (KBr,
cmꢀ1): 3321; 2961; 2930; 2876; 2858; 1741; 1644; 1534; 1170; 1H
O
R2
O
O
R2
O
O
XHR1
R
O
NMR (300 MHz, CDCl3)
d (ppm): 7,80e7.78 (m, 2H); 7.51e7.39 (m,
Ph
R1-XH
3H); 6.88 (d, 1H, J¼6.9 Hz); 4.78 (qu, 1H, J¼7.2 Hz); 4.16e4.01 (m,
N
H
2H); 1.62e1.24 (m, 12H); 0.91e0.86 (m, 6H); 13C NMR (75 MHz,
O
R2 =
O
S
R2
O
CDCl3) d (ppm): 173.5; 166.9; 134.1; 131.8; 128.7; 127.2; 68.0; 48.7;
O
38.9; 30.4; 29.0; 23.9; 23.1; 18.8; 14.2; 11.1; HRMS: calcd for
[C18H27NO3]þ ([MþH]þ): m/z 306.2069, found 306.2075.
Scheme 3. Mechanism hypothesis for the azlactone activation following by nucleo-
philic attack.
4.3.2. Octyl 2-(benzamido)-3-methylbutanoate (7). The product was
purified by column chromatography on silica gel (elution: hexanes
to hexanes/ethyl acetate 25%) to afford product 7 (62 mg, 82%); IR
(KBr, cmꢀ1): 3313; 2960; 2927; 2873; 2856; 1737; 1647; 1526; 1191;
an enantioselective version is ongoing and will be reported in due
course.
1H NMR (300 MHz, CDCl3)
d (ppm): 7.82e7.79 (m, 2H); 7.54e7.41(m,
4. Experimental section
4.1. General remarks
3H); 6.68 (d, 1H, J¼8.7 Hz); 4.80 (dd, 1H, J¼8.7 Hz, J¼4.5 Hz);
4.14e4.02 (m, 2H); 2.34e2.23 (m, 1H); 1.60 (qu, 1H, J¼6.0 Hz);
1.43e1.24 (m, 9H); 1.02e0.86 (m, 11H); 13C NMR (75 MHz, CDCl3)
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 glassware under
a positive pressure of dry nitrogen. Analytical thin layer chroma-
tography (TLC) was performed on Merck precoated glass-backed TLC
plates (silica gel 60 F254) and visualized by UV lamp (254 nm). Yields
refer to chromatographically purified and spectroscopically pure
compounds, unless stated otherwise. 1H and 13C spectra were
recorded on a Bruker DPX-300 spectrometer. Chemical shifts are
reported in parts per million (ppm).1H NMR spectra were referenced
to CDCl3 (7.26 ppm) and 13C NMR spectra were referenced to CDCl3
(77.23 ppm). All 13C spectra were measured with complete proton
decoupling. Peak multiplicities are designated by the following ab-
breviations: s, singlet; d, doublet; dd, double doublet; t, triplet; m,
multiplet; br, broad; q, quartet; qu, quintet; and J, coupling constant
in hertz (Hz). High-resolution mass spectra as well as mechanism
investigation were acquired in the positive ion mode using a mass
spectrometer Micromass (Manchester, UK) QTof instrument of ESI-
QTof configuration with 5000 mass resolution and 50 ppm mass
accuracy in the TOF mass analyzer. The following typical operating
conditions were used: 3 kV capillary voltage, 8 V cone voltage, and
desolvation gas temperature of 100 ꢁC. Tandem ESI-MS/MS were
collected after 4e32 eV collision-induced dissociation (CID) of mass-
selected ions with argon. Mass-selection was performed by Q1 using
a unitary m/z window, and collisions were performed in the rf-only
hexapole collision cell, followed by mass analysis of product ions
by the high-resolution orthogonal reflectron TOF analyzer.
d
(ppm): 172.5; 167.4; 134.5; 131.9; 128.8; 127.2; 67.9; 57.7; 38.9;
32.0; 30.5; 29.0; 24.0; 23.0; 19.2; 18.1; 14.2; 11.2; HRMS: calcd for
[C20H31NO3]þ ([MþH]þ): m/z 334.2382, found 334.2433.
4.3.3. Octyl 2-(benzamido)-4-methylpentanoate (8). The product
was purified by column chromatography on silica gel (elution:
hexanes to hexanes/ethyl acetate 25%) to afford product 8 (142 mg,
59%); IR (KBr, cmꢀ1): 3303; 2958; 2927; 2867; 1749; 1642; 1529;
1162; 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.77 (d, 2H, J¼6.9 Hz);
7.48e7.35 (m, 3H); 6.78 (d, 1H, J¼8.4 Hz); 4.87e4.80 (m, 1H);
4.10e3.99 (m, 2H); 1.75e1.56 (m, 4H); 1.38e1.23 (m, 9H);
0.97e0.84 (m, 11H); 13C NMR (75 MHz, CDCl3)
d (ppm): 173.5;
167.2; 134.2; 131.7; 128.6; 127.2; 67.9; 51.5; 42.1; 38.9; 30.5; 29.0;
25.2; 23.9; 23.0; 22.9; 22.3; 14.1; 11.1; HRMS: calcd for
[C21H33NO3]þ ([MþH]þ): m/z 348.2539, found 348.2725.
4.3.4. Octyl 2-(benzamido)-3-phenylpropanoate (9). The product
was purified by column chromatography on silica gel (elution:
hexanes to hexanes/ethyl acetate 25%) to afford product 9 (84 mg,
74%); IR (KBr, cmꢀ1): 3330; 2960; 2927; 2873; 2852; 1740; 1644;
1534; 1210; 1H NMR (300 MHz, CDCl3)
d (ppm): 7.64e7.61 (m, 2H);
7.42e7.29 (m, 3H); 7.22e7.03 (m, 5H); 6.59 (d, 1H, J¼7.5 Hz);
5.03e4.97 (m,1H); 4.03e3.88 (m, 2H); 3.23e3.10 (m, 2H); 1.51e1.43
(m, 1H); 1.28e1.17 (m, 8H); 0.81e0.76 (m, 5H); 13C NMR (75 MHz,
CDCl3) d (ppm): 172.0; 167.0; 136.1; 134.2; 131.9; 129.5; 128.7; 127.2;
68.2; 53.8; 38.9; 38.2; 30.5; 29.0; 23.9; 23.1; 14.2; 11.1; HRMS: calcd
for [C24H31NO3]þ ([MþH]þ): m/z 382.2382, found 382.2285.
4.2. General procedure for the catalytic azlactone ring open-
ing in the presence of nucleophiles
4.3.5. N-(1-(Octylcarbamoyl)ethyl)benzamide (10). The product
was purified by column chromatography on silica gel (elution:
hexanes to hexanes/ethyl acetate 25%) to afford product 10 (219 mg,
93%); IR (KBr, cmꢀ1): 3278; 3071; 2951; 2925; 2858; 1657; 1633;
In a flamed screw cap vial and under nitrogen atmosphere,
0.2 mmol of azlactone was added. After, CH2Cl2 was cannulated at
the concentration of 0.2 M in azlactone. To this solution, 0.02 mmol
(10.0 mol %) of (þ/ꢀ)-camphorsulfonic acid was added followed by
0.21 mmol of nucleophile. The reaction mixture was kept at room
temperature and under nitrogen atmosphere for 24 h. The reaction
1546; 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.82 (d, 2H, J¼7.8 Hz);
7.68 (d, 1H, J¼7.5 Hz); 7.53e7.32 (m, 4H); 4.85 (qu, 1H, J¼7.2 Hz);
3.32e3.13 (m, 2H); 1.49e1.42 (m, 5H); 1.23e1.19 (m, 10H); 0.82 (t,
3H, J¼6.6 Hz); 13C NMR (75 MHz, CDCl3)
d (ppm): 172.7; 167.3;
134.0; 131.7; 128.5; 127.3; 49.4; 39.7; 31.9; 29.5; 29.4; 27.0; 22.7;

3274
A.A. Pereira et al. / Tetrahedron 70 (2014) 3271e3275
18.9; 14.1; HRMS: calcd for [C18H28N2O2]þ ([MþH]þ): m/z 305.2229,
hexanes to hexanes/ethyl acetate 25%) to afford product 16
found 305.2224.
(130 mg, 43%); IR (KBr, cmꢀ1): 3304; 3253; 3196; 3134; 3064; 1H
NMR (300 MHz, CDCl3)
d (ppm): 9.39 (s, 1H); 7.79e7.76 (m, 2H);
4.3.6. N-(1-(Octylcarbamoyl)-2-methylpropyl)benzamide (11). The
product was purified by column chromatography on silica gel
(elution: hexanes to hexanes/ethyl acetate 25%) to afford product
11 (40.6 mg, 55%); IR (KBr, cmꢀ1): 3286; 2960; 2927; 2853; 1648;
7.53e7.50 (m, 3H); 7.46e7.30 (m, 4H); 7.19 (t, 2H, J¼7.5 Hz);
7.03e6.98 (m, 1H); 5.01 (qu, 1H, J¼7.2 Hz); 1.50e1.48 (d, 3H,
J¼6.9 Hz); 13C NMR (75 MHz, CDCl3)
d (ppm): 171.1; 168.0; 138.2;
133.8; 132.2; 129.0; 127.4; 124.5; 120.3; 50.3; 18.7; HRMS: calcd for
1630; 1543; 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.83e7.81 (m, 2H);
[C16H16N2O2]þ ([MþH]þ): m/z 269.1290, found 269.1361.
7.53e7.39 (m, 3H); 7.15 (d, 1H, J¼8.7 Hz); 6.78e6.75 (m, 1H); 4.50 (t,
1H, J¼8.4 Hz); 3.38e3.26 (m, 1H); 3.23e3.12 (m, 1H); 2.23e2.12 (m,
1H); 1.49 (qu, 2H, J¼7.2 Hz); 1.25e1.22 (m, 10H); 0.99 (d, 6H,
4.3.12. Isopropyl 2-(benzamido)propanoate (17). The product was
purified by column chromatography on silica gel (elution: hexanes
to hexanes/ethyl acetate 25%) to afford product 17 (158 mg, 78%); IR
(KBr, cmꢀ1): 3360; 2984; 1747; 1645; 1525; 1174; NMR 1H
J¼6.6 Hz); 0.85 (t, 3H, J¼6.3 Hz); 13C NMR (75 MHz, CDCl3)
d (ppm):
171.4; 167.6; 134.3; 131.9; 128.7; 127.3; 59.3; 39.8; 32.0; 31.6; 29.9;
29.6; 29.4; 27.1; 22.8; 19.5; 18.8; 14.3; HRMS: calcd for
[C20H32N2O2]þ ([MþH]þ): m/z 333.2542, found 333.2569.
(300 MHz, CDCl3)
d (ppm): 7.76e7.73 (m, 2H); 7.44e7.30 (m, 3H);
7.06 (d, 1H, J¼7.2 Hz); 5.0 (qu, 1H, J¼6.3 Hz); 4.66 (qu, 1H, J¼7.2 Hz);
1.43 (d, 3H, J¼7.2 Hz); 1.22e1.19 (m, 6H); NMR 13C (75 MHz, CDCl3)
4.3.7. N-(1-(Octylcarbamoyl)-3-methylbutyl)benzamide (12). The
product was purified by column chromatography on silica gel
(elution: hexanes to hexanes/ethyl acetate 25%) to afford product
12 (153 mg, 64%); IR (KBr, cmꢀ1): 3333; 3244; 2957; 2927; 2853;
d (ppm): 172.8; 166.9; 134.1; 131.6; 128.5; 127.1; 69.2; 48.7; 21.8;
18.4; HRMS: calcd for [C13H17NO3]þ ([MþH]þ): m/z 236.1287, found
236.1310.
1666; 1635; 1540; 1H NMR (300 MHz, CDCl3)
d
(ppm): 7.85e7.82
4.3.13. tert-Butyl 2-(benzamido)propanoate (18). The product was
purified by column chromatography on silica gel (elution: hexanes
to hexanes/ethyl acetate 25%) to afford product 18 (203 mg, 57%); IR
(KBr, cmꢀ1): 3301; 3071; 2984; 2936; 1723; 1630; 1544; 1H NMR
(m, 2H); 7.65 (d, 1H, J¼8.4 Hz); 7.47e7.32 (m, 4H); 4.81 (q, 1H,
J¼8.1 Hz); 3.31e3.20 (m, 1H); 3.16e3.06 (m, 1H); 1.68 (d, 3H,
J¼4.8 Hz); 1.46 (qu, 2H, J¼7.2 Hz); 1.28e1.21 (m, 10H); 0.90e0.82
(m, 9H); 13C NMR (75 MHz, CDCl3)
d
(ppm): 172.6; 167.5; 134.1;
(300 MHz, CDCl3)
d (ppm): 7.77e7.74 (m, 2H); 7.45e7.32 (m, 3H);
131.7; 128.5; 127.5; 52.4; 41.5; 39.7; 31.9; 29.5; 29.4; 29.3; 27.1;
25.1; 22.9; 22.8; 22.5; 14.2; HRMS: calcd for [C21H34N2O2]þ
([MþH]þ): m/z 347.2699, found 347.2655.
6.98 (d, 1H, J¼6.3 Hz); 4.62 (qu, 1H, J¼6.6 Hz); 1.44e1.42 (m, 12H);
13C NMR (75 MHz, CDCl3)
d (ppm): 172.6; 166.8; 134.2; 131.6; 128.5;
127.1; 82.1; 49.1; 28.0; 18.7; HRMS: calcd for [C14H19NO3]þ
([MþH]þ): m/z 250.1443, found 250.1496.
4.3.8. N-(1-(Octylcarbamoyl)-2-phenylethyl)benzamide
(13). The
product was purified by column chromatography on silica gel
(elution: hexanes to hexanes/ethyl acetate 25%) to afford product
13 (218 mg, 96%); IR (KBr, cmꢀ1): 3306; 2955; 2924; 2853; 1657;
4.3.14. N-((1-(60-Deoxy-10,20:30,40-di-O-cyclohexylidene-
a-D-gal-
actopyrane-60-yl)carbamoyl)ethyl)benzamide (19). The product was
purified by column chromatography on silica gel (elution: hexanes
to hexanes/ethyl acetate 25%) to afford product 19 (81.3 mg, 79%);
IR (KBr, cmꢀ1): 3425; 3301; 2963; 2933; 2856; 1635; 1260; 1096;
1635; 1523; 1H NMR (300 MHz, CDCl3)
d (ppm): 7.78 (d, 3H,
J¼7.5 Hz); 7.49e7.33 (m, 3H); 7.21e7.09 (m, 6H); 5.06 (q, 1H,
J¼7.5 Hz); 3.29e2.99 (m, 4H); 1.37e1.18 (m, 12H); 0.87 (t, 3H,
1021; 1H NMR (300 MHz, CDCl3)
d (ppm, mixture of diastereomers):
J¼6.6 Hz); 13C NMR (75 MHz, CDCl3)
d
(ppm): 171.3; 167.4; 137.1;
7.81 (t, 2H, J¼6.3 Hz); 7.48e7.35 (m, 3H); 7.28e7.21 (m, 1H);
0
133.9; 131.7; 129.5; 128.5; 127.4; 126.8; 55.2; 39.7; 39.0; 31.9; 29.8;
29.4; 29.3; 27.0; 22.8; 14.2; HRMS: calcd for [C24H32N2O2]þ
([MþH]þ): m/z 381.2542, found 381.2653.
6.99e6.92 (m, 1H); 5.48 (d, 1H, H1, J¼4.8 Hz); 5.45 (d, 1H, H1 ,
J¼5.1 Hz); 4.73 (qu, 1H, J¼7.2 Hz); 4.60e4.56 (m,1H); 4.30e4.26 (m,
1H); 4.17 (d, 1H, J¼8.1 Hz); 3.87 (d, 1H, J¼7.5 Hz); 3.77e3.64 (m,
1H); 3.32e3.17 (m, 1H); 1.60e1.34 (m, 23H); 13C NMR (75 MHz,
4.3.9. Octyl 2-(benzamido)acetate (14). The product was purified
by column chromatography on silica gel (elution: hexanes to hex-
anes/ethyl acetate 25%) to afford product 14 (284 mg, 78%); IR (KBr,
cmꢀ1): 3335; 2958; 2930; 2873; 2859; 1750; 1650; 1540; 1H NMR
CDCl3) d (ppm, mixture of diastereomers): 172.9; 172.85; 167.1;
166.9; 134.13; 134.1; 131.7; 131.67; 128.6; 127.3; 127.28; 110.2;
110.16; 109.4; 96.0; 95.98; 71.45; 71.4; 70.6; 70.3; 66.5; 66.4; 49.3;
40.4; 40.3; 35.8; 34.4; 34.38; 34.0; 25.2; 25.1; 24.1; 24.0; 23.8; 23.6;
19.5; 18.9; HRMS: calcd for [C28H38N2O7]þ ([MþH]þ): m/z 515.2758,
found 515.2974.
(300 MHz, CDCl3)
d (ppm): 7.79e7.76 (m, 2H); 7.46e7.33 (m, 3H);
7.11e7.08 (m,1H); 4.17 (d,1H, J¼5.4 Hz); 4.04 (m, 2H); 1.57e1.51 (m,
1H); 1.36e1.24 (m, 11H); 0.84 (t, 3H, J¼7.2 Hz); 13C NMR (75 MHz,
CDCl3)
d
(ppm): 170.3; 167.6; 133.8; 131.7; 128.6; 127.2; 68.0; 41.9;
4.3.15. 10,20:30,40-Di-O-isopropilidene- -galactopyrane-60-yl-2-
a-D
38.8; 30.4; 28.9; 23.8; 23.0; 14.1; 11.0; HRMS: calcd for
(benzamido)propanoate (20). The product was purified by column
chromatography on silica gel (elution: hexanes to hexanes/ethyl
acetate 25%) to afford product 20 (298 mg, 72%); IR (KBr, cmꢀ1):
3330; 2987; 2936; 1744; 1647; 1072; 1H NMR (300 MHz, CDCl3)
[C17H25NO3]þ ([MþH]þ): m/z 292.1913, found 292.1985.
4.3.10. 8-Hydroxyoctyl 2-(benzamido)propanoate (15). The product
was purified by column chromatography on silica gel (elution:
hexanes to hexanes/ethyl acetate 25%) to afford product 15
(96.4 mg, 75%); IR (KBr, cmꢀ1): 3318; 2930; 2855; 1734; 1642; 1537;
d
(ppm, mixture of diastereomers): 7.74 (d, 2H, J¼7.2 Hz); 7.43e7.30
(m, 3H); 7.06 (dd, 1H, J¼7.5 Hz, J¼2.4 Hz); 5.48e5.44 (m, 2H, H1,
0
H1 ); 4.74 (qu, 1H, J¼7.2 Hz); 4.56e4.51 (m, 2H); 4.37e4.14 (m, 6H);
1H NMR (300 MHz, CDCl3)
d
(ppm): 7.80e7.77 (m, 2H); 7.50e7.38
4.00e3.93 (m, 1H); 3.82e3.62 (m, 3H); 1.46e1.43 (m, 8H);
1.37e1.34 (m, 8H); 1.25e1.23 (m, 12H); 13C NMR (75 MHz, CDCl3)
(m, 3H); 6.94 (d, 1H, J¼4.8 Hz); 4.76 (qu, 1H, J¼7.2 Hz); 4.14 (t, 2H,
J¼6.6 Hz); 3.59 (t, 1H, J¼6.6 Hz); 2.20 (s, 1H); 1.63 (qu, 2H,
J¼6.9 Hz); 1.57e1.48 (m, 5H); 1.30e1.23 (m, 9H); 13C NMR (75 MHz,
d
(ppm, mixture of diastereomers): 172.9; 172.8; 166.8; 133.9;
131.5; 128.4; 127.1; 109.6; 109.2; 108.7; 108.5; 96.2; 71.3; 70.9;
70.6; 70.55; 70.4; 68.2; 66.0; 65.8; 64.2; 61.8; 48.6; 48.5; 25.9;
25.88; 24.9; 24.33; 24.3; 18.4; HRMS: calcd for [C22H29NO8]þ
([MþH]þ): m/z 436.1971, found 436.1978.
CDCl3)
d (ppm): 173.5; 167.1; 134.1; 131.8; 128.7; 127.2; 65.8; 62.9;
48.7; 32.8; 29.8; 29.3; 29.2; 28.6; 25.8; 18.7; HRMS: calcd for
[C18H27NO4]þ ([MþH]þ): m/z 322.2018, found 322.2070.
4.3.11. N-(1-(Phenylcarbamoyl)ethyl)benzamide (16). The product
was purified by column chromatography on silica gel (elution:
4.3.16. Adamantan-1-yl-methyl-2-(benzamido)propanoate (21). The
product was purified by column chromatography on silica gel

A.A. Pereira et al. / Tetrahedron 70 (2014) 3271e3275
3275
2. For azlactones as substrates in catalytic reactions, see: (a) Uraguchi, D.; Ueki, Y.;
Sugiyama, A.; Ooi, T. Chem. Sci. 2013, 4, 1308; (b) Weber, M.; Frey, W.; Peters, R.
Adv. Synth. Catal. 2012, 354, 1443; (c) Weber, M.; Jautze, S.; Frey, W.; Peters, R.
Chem.dEur. J. 2012, 18, 14792; (d) Weber, M.; Peters, R. J. Org. Chem. 2012, 77,
10846; (e) Oh, J.-S.; Lee, J.-W.; Ryu, T. H.; Lee, J. H.; Song, C. E. Org. Biomol. Chem.
2012, 10, 1052; (f) Lu, G.; Birman, V. B. Org. Lett. 2011, 13, 356; (g) Han, Z.-Y.; Guo,
R.; Wang, P.-S.; Chen, D.-F.; Xiao, H.; Gong, L.-Z. Tetrahedron Lett. 2011, 52, 5963;
(h) Melhado, A. D.; Amarante, G. W.; Wang, Z. J.; Luparia, M.; Toste, F. D. J. Am.
Chem. Soc. 2011, 133, 3517; (i) Dong, S.; Liu, X.; Chen, X.; Mei, F.; Zhang, Y.; Gao,
(elution: hexanes to hexanes/ethyl acetate 25%) to afford product
21 (90 mg, 91%); IR (KBr, cmꢀ1): 3351; 2906; 2847; 1743; 1635;
1168; 1H NMR (300 MHz, CDCl3)
d (ppm): 7.80e7.77 (m, 2H);
7.50e7.37 (m, 3H); 6.95 (d, 1H, J¼7.2 Hz); 4.80 (qu, 1H, J¼7.2 Hz);
3.80 (d, 1H, J¼10.5 Hz); 3.69 (d, 1H, J¼7.2 Hz); 2.01e1.96 (m, 3H);
1.73e1.47 (m, 14H); 1.25e1.17 (m, 1H); 13C NMR (75 MHz, CDCl3)
d
(ppm): 173.5; 167.0; 134.2; 131.8; 128.7; 127.2; 75.1; 48.8; 39.3;
37.0; 33.5; 28.1; 18.9; HRMS: calcd for [C21H27NO3]þ ([MþH]þ): m/z
~
B.; Lin, L.; Feng, X. J. Am. Chem. Soc. 2010, 132, 10650; (j) Jiang, H.; Paixao, M. W.;
Monge, D.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132, 2775; (k) Alba, A.-N. R.;
342.2069, found 342.2091.
ꢀ
Companyo, X.; Valero, G.; Moyano, A.; Rios, R. Chem.dEur. J. 2010, 16, 5354; (l)
Alba, A.-N. R.; Valero, G.; Calbet, T.; Font-Bardía, M.; Moyano, A.; Rios, R. Chem.
dEur. J. 2010, 16, 9884; (m) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc.
2009, 131, 3430; (n) Uraguchi, D.; Ueki, Y.; Ooi, T. Science 2009, 326, 120.
Acknowledgements
ꢀ
3. (a) Avila, E. P.; De Mello, A. C.; Diniz, R.; Amarante, G. W. Eur. J. Org. Chem. 2013,
1881; For our recent view about organocatalytic processes, see: (b) Amarante, G.
W.; Coelho, F. Quim. Nova 2009, 32, 469; (c) Avila, E. P.; Amarante, G. W.
ChemCatChem 2012, 4, 1713.
4. Wang, C.; Luo, H.-W.; Gong, L.-Z. Synlett 2011, 992.
We are grateful to FAPEMIG, CAPES, CNPq (305489/2012-7), and
Rede Mineira de Química for financial support. The authors thank
Prof. Mauro V. de Almeida (DQ-UFJF) for helpful suggestions.
ꢀ
5. Palacio, C.; Connon, S. J. Eur. J. Org. Chem. 2013, 5398.
6. For the preparation of azlactone rings, see: Melhado, A. D.; Luparia, M.; Toste, F.
D. J. Am. Chem. Soc. 2007, 129, 12638.
Supplementary data
7. (a) Machado, A. H. L.; Milagre, H. M. S.; Eberlin, L. S.; Sabino, A. A.; Correia, C. R.
D.; Eberlin, M. N. Org. Biomol. Chem. 2013, 11, 3277; (b) Coelho, F.; Eberlin, M. N.
Angew. Chem., Int. Ed. 2011, 50, 5261; (c) Amarante, G. W.; Benassi, M.; Pascoal, R.
N.; Eberlin, M. N.; Coelho, F. Tetrahedron 2010, 66, 4370; (d) Amarante, G. W.;
Benassi, M.; Milagre, H. M. S.; Braga, A. A. C.; Maseras, F.; Eberlin, M. N.; Coelho, F.
Chem.dEur. J. 2009, 15, 12460; (e) Orth, E. S.; da Silva, P. L. F.; Mello, R. S.; Bunton,
C. A.; Milagre, H. M. S.; Eberlin, M. N.; Fiedler, H. D.; Nome, F. J. Org. Chem. 2009,
74, 5011; (f) Amarante, G. W.; Milagre, H. M. S.; Vaz, B. G.; Ferreira, B. R. V.;
Eberlin, M. N.; Coelho, F. J. Org. Chem. 2009, 74, 3031; (g) de Souza, R. O. M. A.; da
Penha, E. T.; Milagre, H. M. S.; Garden, S. J.; Esteves, P. M.; Eberlin, M. N.; Antunes,
O. A. C. Chem.dEur. J. 2009, 15, 9799; (h) Carrasco-Sanchez, V.; Simirgiotis, M. J.;
Santos, L. S. Molecules 2009, 14, 3989.
Copies of IR and NMR spectra for the prepared compounds are
available free of charge at www.sciencedirect.com. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2013.11.037.
References and notes
ꢀ
1. (a) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584; (b) Viso, A.; De la Pra-
dilla, R. F.; García, A.; Flores, A. Chem. Rev. 2005, 105, 3167.