One-pot synthesis of N-substituted pantolactams from pantolactone

Article abstract of DOI:10.1016/S0040-4020(03)00156-X

Rac-N-substituted pantolactams (5) are readily obtained in medium to good yields by reaction of rac-pantolactone (1) with primary amines under acid catalysis, whether at 250°C in a pressure reactor or under microwave irradiation. It appears that the amine can react with pantolactone at the carbonyl carbon atom to give a hydroxyamide (3) in a reversible way and at the methylene carbon atom to give a γ-amino acid (4). The last one on dehydration would give the corresponding pantolactam (5).

Full text of DOI:10.1016/S0040-4020(03)00156-X

Tetrahedron 59 (2003) 1971–1979
One-pot synthesis of N-substituted pantolactams
from pantolactone
b
a
Ivana Barrios,a Pelayo Camps,a Mauro Comes-Franchini, Diego Mun˜oz-Torrero,
,
*
Alfredo Riccib and Laura Sanchez
a
,
*
´
a
´ ` `
Laboratori de Quımica Farmaceutica (Unitat Associada al CSIC), Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal 643,
E-08028-Barcelona, Spain
bDepartment of Organic Chemistry “A. Mangini”, University of Bologna, Viale Risorgimento 4, I-40136 Bologna, Italy
Received 28 October 2002; revised 17 December 2002; accepted 22 January 2003
Abstract—Rac-N-substituted pantolactams (5) are readily obtained in medium to good yields by reaction of rac-pantolactone (1) with
primary amines under acid catalysis, whether at 2508C in a pressure reactor or under microwave irradiation. It appears that the amine can
react with pantolactone at the carbonyl carbon atom to give a hydroxyamide (3) in a reversible way and at the methylene carbon atom to give
a g-amino acid (4). The last one on dehydration would give the corresponding pantolactam (5). q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
through alternative and general procedures, starting from
pantolactone and primary amines.
Several years ago we published the enzymatic resolution of
4,4-dimethyl-3-hydroxy-1-phenylpyrrolidin-2-one (rac-N-
phenylpantolactam, 5a)1 and the application of the
corresponding enantiomers as chiral auxiliaries in the
asymmetric synthesis of several a-substituted carboxylic
acids.2–6 Later on, we described an efficient enantio-
selective preparation of both enantiomers of 5a by oxidation
of rac-5a to the corresponding ketolactam, followed by
enantioselective reduction with (2)- or (þ)-B-chlorodiiso-
pinocamphenylborane [(2)- or (þ)-DIP-Chloride].7 The
starting rac-5a used in these works was obtained in good
yield (82%) as described by reaction of rac-pantolactone
with an excess of aniline [about 13 equiv.] in the presence of
a catalytic amount of p-TsOH (0.02 equiv.) under reflux
(about 1808C) for 12 h.8
2. Results and discussion
The easiest way to prepare the required rac-pantolactams 5
would be the direct reaction of pantolactone (1) with
primary amines. However, there are many references to
reactions of aliphatic and aromatic primary amines with 1
leading to the corresponding hydroxyamides 3 in good
yields.9–14 Moreover, the only additional pantolactams 5
described till now correspond to the unsubstituted (5g),15
the N-methyl (5d),16 and the N-(p-carboxyphenyl)
derivatives.8
Pantolactams 5d and 5g are obtained by reaction of 1 with
aqueous methylamine or ammonium hydroxide at high
temperature in a closed vessel, while the N-(p-carboxy-
phenyl)pantolactam is prepared by a procedure similar to
the above mentioned for the preparation of 5a. Recently, the
preparation in low yield of O-benzylpantolactam by
reaction of O-benzylpantolactone with aqueous ammonia
in a closed vessel at 2308C has also been described.17
Pantolactam 5g has also been prepared by dehydration of
the corresponding g-amino acid.15
The excellent results obtained with 5a prompted us to search
for other N-substituted pantolactams with some added
values such as: (a) pantolactams 5 having an amino
substituent which would facilitate the separation and
recovery of the chiral auxiliary through acid–base wash-
ings, and (b) pantolactams 5 having a substituent, such as
hydroxyl, that would allow the chiral auxiliary to be
anchored to a polymeric support. Herein we report the
synthesis of several racemic N-substituted pantolactams,
several of which bear additional amino or hydroxy groups,
Initial attempts to prepare new pantolactams 5 were carried
out starting from benzylamine. Reaction of 1 with excess
benzylamine (2c, about 15 equiv.) in the presence of
p-TsOH (0.05 equiv.) under reflux for 22 h in a similar
manner to that used to prepare 5a allowed us to obtain pure
Keywords: pantolactone; pantolactam; microwave.
*
Corresponding authors. Tel.: þ34-93-4024536; fax: þ34-93-4035941;
camps@farmacia.far.ub.es; ricci@ms.fci.unibo.it
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00156-X

1972
I. Barrios et al. / Tetrahedron 59 (2003) 1971–1979
5c in 42% yield (Table 1, entry 12). When the reaction was
carried out under microwave irradiation using a much lower
excess of the amine (2 equiv.) and p-TsOH (0.1 equiv.), 5c
was obtained in good yield (59%) with a very short reaction
time (5 min) (Table 1, entry 10). Also, lactam 5c was
obtained in 73% yield by reacting 1 with 2c (1.5 equiv.)
catalyzed by p-TsOH (0.05 equiv.) in diglyme under reflux
for 22 h (Table 1, entry 11).
Curiously, reaction of 1 with excess n-heptylamine (2b,
14 equiv.) catalyzed by p-TsOH (0.02 equiv.) under reflux
gave the known hydroxyamide 3b9 in only 22% yield, no
pantolactam 5b being observed (Table 1, entry 8). Also,
when 3b was heated in diglyme under reflux using p-TsOH
as catalyst, a mixture of starting 3b and pantolactone was
obtained (Table 1, entry 7). However, 5b was isolated in
76% yield on reaction of 1 with 2b (2 equiv.) catalyzed by
p-TsOH (0.1 equiv.) under microwave irradiation in a
sealed reactor for 10 min (Table 1, entry 6).
Moreover, the known hydroxyamide 3c10 was prepared
quantitatively by reaction of 1 with 2c (1.4 equiv.) in
refluxing methanol for 24 h. To gain insight into the
mechanism of formation of 5c, hydroxyamide 3c was
dissolved in diglyme and heated under reflux in the presence
of p-TsOH (0.1 equiv.) to give 5c in 69% yield, some
pantolactone (about 14%) being also formed (Table 1, entry
13).
Moreover, pantolactam 5b was obtained in 49% yield
(Table 1, entry 5) when 1 was reacted with n-heptylamine
(2b, 2.1 equiv.) in methanol solution under p-TsOH
catalysis (0.1 equiv.) using more forcing reaction conditions
(pressure reactor, 2508C, 4 h: standard conditions). Simi-
larly, reaction of 1 with benzylamine (2c) under these
conditions gave 5c in 59% yield (Table 1, entry 9).
Similarly, the new hydroxyamide 3a, obtained in 59% yield
by reaction of 1 with the lithium derivative of aniline (2a,
4 equiv.) in anhydrous THF, heated in refluxing diglyme
under p-TsOH catalysis for 15 h, gave 5a (40% yield) and 1
(53% yield), after column chromatography separation of the
reaction mixture (Table 1, entry 3).
These results pointed to a mechanism for the pantolactam
formation like that shown in Scheme 1. As expected, the
reaction of 1 with a primary amine (2) would take place
faster at the carbonyl function, probably through the
addition–elimination mechanism,9–14 than at the hindered
Table 1. Products and yields from the reactions of pantolactone 1 and amines 2, or hydroxyamides 3, with p-TsOH under different reaction conditions
Entry
Starting compounds
Conditionsa (time/power)
Products (yields)b
1
2
3
4
5
6
7
8
1þ2a
1þ2a
3a
1þ2a
1þ2b
1þ2b
3b
1þ2b
1þ2c
1þ2c
1þ2c
1þ2c
3c
A (4 h)
5a (93%)
5a (76%)
B (10 min/75 W)
C (15 h)
D (12 h)
1 (53%)cþ5a (40%)c
5a (82%)1
5b (49%)
A (4 h)
B (10 min/75 W)
C (15 h)
D (15 h)
5b (76%)
1 (41%)þ3b (15%)
3b (22%)
5c (59%)
9
A (4 h)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
B (5 min/90 W)
C (22 h)
D (22 h)
C (5 h)
A (4 h)
A (4 h)
A (4 h)
A (8 h)
A (24 h)
B (30 min/30 W)
A (4 h)
B (5 min/120 W)
A (4 h)
A (4 h)
5c (59%)
5c (73%)
5c (42%)
1 (14%)cþ5c (69%)
1þ2d
5d (42%)
5d (39%)
3d
1þ2e
1þ2e
1þ2e
1þ2e
1þ2f
1þ2f
1þ2g
3g
1þ2h
1þ2i
1þ2i
3i
1þ2j
1þ2j
1þ2k
1þ2k
1þ2l
1þ2l
1þ2l
5e (10.5%)
5e (16%)
5e (14%)
5e (11%)
5f (52%)
5f (59%)
3gþ5g (19%þ19%)c
1 (40%)þ3gþ5g (9%þ9%)c
5h (24%)
A (4 h)
A (4 h)
5i (34%)
3i (72%)
1 (67%)
5j (14%)
5j (5.5%)
5k (23%)
5k (46%)
5l (37%)
A (4 h)d
C (15 h)
A (4 h)
A (8 h)
A (4 h)
B (10 min/150 W)
A (4 h)
Ae (4 h)
7 (24%)
7 (25%)
Be (25 min/90 W)
a
Procedure A: 1, 2 (2.1 equiv.) (or 3) and p-TsOH·H2O (0.1 equiv.) in MeOH (2 mL/g 1 or 3) or ethanol (2 mL/g of 3), 2508C, pressure reactor. Procedure B:
1, 2 (2 equiv.) and p-TsOH·H2O (0.1 equiv.), microwave, sealed pyrex vessel. Procedure C: 1, 2 (1.5 equiv.) (or 3) and p-TsOH·H2O (0.05 equiv.) in diglyme
(4–13 mL/g 1 or 3), reflux. Procedure D: 1, 2 (about 15 equiv.) and p-TsOH·H2O (0.05 equiv.), reflux.
Except where otherwise stated, yields refer to isolated products.
b
c
d
e
Yield calculated from the 1H NMR integration.
This reaction was carried out at 1808C.
In this case, 0.5 equiv. of the amine were used.

I. Barrios et al. / Tetrahedron 59 (2003) 1971–1979
1973
neopentyl-type methylene group, although it is known that
several better nucleophiles such as the phthalimide15 and the
azide18 anions react with 1 by attack at the methylene
position to give the expected substitution products. Under
acid catalysis and at high temperatures, formation of the
hydroxyamide 3 could become an easily reversible reaction,
as it was recently shown by Pansare and Jain.19 On the
contrary, if the reaction of the primary amine with 1 under
acid catalysis at high temperature took place at the hindered
methylene group, a g-amino acid (4) would be formed,
whose dehydration to 5 could be essentially irreversible.15
The different behavior observed in the reaction of 1 with
n-heptylamine vs aniline and benzylamine may be partly
due to the lower boiling point (about 308C) of the first amine
(bp 1558C) compared with the other two (bp 1848C). The
proposed mechanism is supported by the formation of
pantolactone from hydroxyamides 3a and 3c under
conditions in which 5a and 5c were also formed.
reaction (Table 1, entry 17). Under standard conditions
(4 h), the yield was only 10.5% (Table 1, entry 16), and on
prolonged heating (24 h), the yield decreased slightly (Table
1, entry 18). In the reactions with t-butylamine, the
formation of lactam 5g, probably formed by dealkylation
of lactam 5e, was observed, a fact that could explain the
slight decrease of the yield of this reaction at longer reaction
times. Comparable yields of 5e and 5f (Table 1, entries 19
and 21, respectively) were obtained when these reactions
were performed under microwave irradiation, although in
these cases, the reaction times were much shorter.
Reaction of pantolactone with a methanolic solution of
ammonia in a pressure reactor under the standard conditions
gave a mixture of the corresponding hydroxyamide 3g and
lactam 5g in low yield which could not be separated by
column chromatography or crystallization (Table 1, entry
22). Worthy of note, when hydroxyamide 3g was submitted
to the standard conditions to prepare pantolactams, after
column chromatography of the reaction mixture, panto-
lactone and a mixture of 3g and 5g were obtained (Table 1,
entry 23).
Alternatively, pantolactone could be formed from hydroxy-
amides 3 by acid-catalyzed intramolecular nucleophilic
substitution of the hydroxyl group by the amide oxygen
atom, followed by hydrolysis of the resulting iminolactones
6 (Scheme 1). Although the formation of pantolactams 5
from hydroxyamides 3 by a similar mechanism cannot be
excluded, the low nucleophilic character of the amide
nitrogen atom makes this mechanism less likely.
Then, the reaction was studied with primary aliphatic
amines having an extra functionality (an amino or hydroxy
group). Thus, reaction of pantolactone with 2-aminoethanol
under the standard pressure reactor conditions gave the
expected pantolactam 5h in a low 24% yield (Table 1, entry
24). Apparently, 2-aminoethanol was partially decomposed
under these conditions. Similarly, reaction of pantolactone
with 3-(dimethylamino)propylamine, 2i, gave pantolactam
5i in a moderate 34% yield (Table 1, entry 25). Worthy of
note, when the last reaction was carried out under less
forcing conditions (1808C), only hydroxyamide 3i was
isolated in high yield (Table 1, entry 26). Moreover, heating
hydroxyamide 3i in the presence of p-TsOH in diglyme
under reflux, 5i was not observed, pantolactone 1 being
formed instead in high yield (Table 1, entry 27). These
results parallel those described above in the case of
n-heptylamine, and confirmed the need of using forcing
conditions to obtain the pantolactams 5.
To study the scope of this method, the reactions of 1 with
different primary amines were carried out, the results being
collected in Table 1. First, the reaction of pantolactone with
primary amines in which the amino group is connected to a
primary, secondary or tertiary alkyl group was studied.
Under these conditions, reaction of pantolactone with a
methanolic solution of methylamine gave the expected
pantolactam 5d in 42% yield (Table 1, entry 14). Similarly,
when hydroxyamide 3d was submitted to the same reaction
conditions, 5d was obtained in a similar 39% yield (Table 1,
entry 15). The more hindered cyclohexylamine, 2f, gave
lactam 5f in 52% yield (Table 1, entry 20), while
t-butylamine, 2e, gave 5e in only 16% yield, after 8 h
Finally, the reaction was studied with aromatic amines other
than aniline. Reaction of 1 with 2-aminopyridine, 2j, under
standard pressure reactor conditions gave lactam 5j in only
14% yield (Table 1, entry 28). Increasing the reaction time
to 8 h, resulted in a decreased yield of 5.5% (Table 1, entry
29). The low yield of this reaction may be related to the
presence of two nucleophilic centers in the 2-aminopyridine
and the low nucleophilic character of its primary amino
group.
Somewhat better results were obtained in the reaction of 1
with p-aminophenol, 2k. Under the standard pressure
reactor conditions, lactam 5k was obtained in a moderate
23% yield (Table 1, entry 30). However, the yield of this
reaction performed under microwave irradiation was much
higher (46%, Table 1, entry 31).
Worthy of note, the reaction of 1 with p-phenylenediamine,
2l, gave different products, depending on the pantolactone/
diamine ratio. Under the standard pressure reactor con-
ditions (ratio of pantolactone/amine of 1:2), the only
Scheme 1. Possible pathways for the formation of pantolactams 5 from
pantolactone 1 and amines 2, or from hydroxyamides 3.

1974
I. Barrios et al. / Tetrahedron 59 (2003) 1971–1979
crystallization, while pure for synthesis solvents were used
in the reactions, extractions and column chromatography.
´
NMR spectra were performed at the Serveis Cientıfico-
Tecnics of the University of Barcelona, while elemental
`
analyses were carried out at the Mycroanalysis Service of
the IIQAB (CSIC, Barcelona, Spain).
Figure 1. Structure of the bislactam 7.
isolated product (37% yield) was the monoreaction lactam
5l (Table 1, entry 32). However, carrying out the reaction
with a ratio pantolactone/amine of 2:1, the only isolated
product (24% yield) was product 7, derived from the
reaction of each primary amino group of 2l with
pantolactone (Fig. 1, and Table 1, entry 33). A similar
result was obtained, when the last reaction was performed
under microwave irradiation (Table 1, entry 34). The highly
selective formation of 5l in the reaction of 1 with 2l in the
ratio of 1:2 is in accord with the expected greater
nucleophilicity of the p-phenylenediamine as compared
with its monoacylated derivative 5l.
4.1.1. 2,4-Dihydroxy-N-phenyl-3,3-dimethylbutyramide
(3a). A solution of freshly distilled aniline (2.0 mL, 2.04 g,
21.9 mmol, 5.2 equiv.) in anhydrous THF (10 mL) was
cooled at 2788C, and 1.6 M n-BuLi in hexanes (11.0 mL,
17.6 mmol, 4.2 equiv.) was added dropwise for 50 min. The
mixture was warmed to 08C and was stirred at this
temperature for 3 h. To the resulting solution, a cooled
solution (2788C) of pantolactone, 1 (550 mg, 4.23 mmol) in
anhydrous THF (1 mL) was added. The reaction mixture
was allowed to warm up, was stirred at room temperature
for 12 h, and was concentrated in vacuo, to give a black
solid residue, which was diluted with water (30 mL) and
extracted with AcOEt (3£30 mL). The combined organic
extracts were dried over Na2SO4, and evaporated at reduced
pressure, to give pure hydroxyamide 3a (556 mg, 59%
yield) as a light pink solid: mp 106–1078C (Et2O); Rf 0.21
(SiO2, hexane/AcOEt 1:1); IR (KBr) 3326, 3282, 1662,
1652; 1H NMR (300 MHz, CDCl3) d 0.99 (s, 3H) and 1.11
(s, 3H) [3-(CH3)2], 2.86 (broad s, 1H, 4-OH), 3.55 (broad d,
J<11.0 Hz, 1H) and 3.65 (broad d, J<11.0 Hz, 1H) (4-H2),
4.00 (d, J¼4.5 Hz, 1H, 2-OH), 4.19 (d, J¼0 4.5 Hz, 1H, 2-H),
7.130 (tt, J¼7.5 Hz, J0¼1.2 Hz, 1H, 4 -H), 7.34 [ddm,
J<J <8.0 Hz, 2H, 30(50)-H], 7.56 [dm, J¼8.8 Hz, 2H,
20(60)-H], 8.61 (broad s, 1H, CONH); 13C NMR
(75.4 MHz, CDCl3) d 20.4 (CH3) and 21.0 (CH3)
[3-(CH3)2], 39.5 (C, C3), 71.4 (CH2, C4), 77.7 (CH, C2),
120.1 [CH, C20(60)], 124.7 (CH, C40), 129.0 [CH, C30(50)],
136.8 (C, C10), 171.4 (C, C1). Anal. calcd for
C12H17NO3·1/5H2O: C, 63.53; H, 7.73; N, 6.17. Found: C,
63.64; H, 7.68; N, 6.17.
3. Conclusion
We have developed two alternative one-pot procedures for
the preparation of N-substituted pantolactams in low to
medium yields starting from pantolactone and primary
amines under acid catalysis. In one procedure the reaction is
performed in a pressure reactor at 2508C for 4 h, while in the
other one the reaction takes place in minutes under
microwave irradiation. Work is in progress to convert
several of the herein described new racemic pantolactams
into the corresponding enantiopure compounds, to study
their possible use as chiral auxiliaries suitable to be
anchored to a polymeric support or easily recoverable
through acid–base washings.
4. Experimental
4.1. General
4.2. General procedure for the preparation of
hydroxyamides 3 from pantolactone, 1
To a solution of pantolactone, 1, (1 mmol) in MeOH
(0.35 mL) at 08C was added the amine (1.3 equiv.), and the
reaction mixture was stirred at room temperature until total
conversion of the starting pantolactone was achieved as
monitored by TLC (SiO2). The resulting solution was
evaporated at reduced pressure, to give a residue, which
consisted of hydroxyamide 3, pure or slightly impurified by
the starting pantolactone, or by the amine, in the cases of the
least volatile amines. Purification was carried out as
indicated in each example.
Melting points were determined in open capillary tubes with
a MFB 595010M Gallenkamp melting point apparatus.
1
300 MHz H NMR and 75.4 MHz 13C NMR spectra were
recorded on a Varian Gemini 300 spectrometer and
200 MHz 1H NMR spectra on a Varian Gemini 200
spectrometer. The chemical shifts are reported in ppm (d
scale) relative to internal TMS, and coupling constants are
reported in Hertz (Hz). For the different compounds, the
terms Ha or Hb are assigned to hydrogen atoms which are
cis or trans relative to the hydroxyl substituent, respectively.
IR spectra were run on a FT/IR Perkin-Elmer model 1600
spectrophotometer. Absorption values are expressed as
wave-numbers (cm21); only significant absorption bands
are given. Column chromatography was performed on silica
gel 60 AC.C (70–200 mesh, SDS, ref 2100027). Thin-layer
chromatography (TLC) was performed with aluminum-
backed sheets with silica gel 60 F254 (Merck, ref 1.05554),
and the spots were visualized with UV light and 1% aqueous
solution of KMnO4. Pantolactone and all of the hydroxy-
amides and lactams prepared in this work are racemic.
Commercial pantolactone was dried at 258C/30 Torr for
12 h prior to its use. Analytical grade solvents were used for
4.2.1. N-Heptyl-2,4-dihydroxy-3,3-dimethylbutyramide
(3b).9 This compound was prepared following the above
general procedure, from a solution of pantolactone, 1
(550 mg, 4.23 mmol) in MeOH (1.5 mL) and n-heptylamine
(0.75 mL, 583 mg, 5.06 mmol) with a reaction time of 20 h.
The colorless oil obtained by evaporation of the reaction
mixture consisted of pure hydroxyamide 3b (1.05 g,
quantitative yield): Rf 0.14 (SiO2, hexane/AcOEt 1:1); IR
1
(NaCl) 3336, 1650; H NMR (300 MHz, CDCl3) d 0.88 (t,
J¼6.9 Hz, 3H, 70-H3), 0.91 (s, 3H) and 1.00 (s, 3H)
[3-(CH3)2], 1.22–1.36 (complex signal, 8H, 30-H2, 40-H2,

I. Barrios et al. / Tetrahedron 59 (2003) 1971–1979
1975
50-H2 and 60-H2), 1.52 (m, 2H, 20-H2), 3.15–3.37 (complex
signal, 2H, 10-H2), 3.49 (s, 2H, 4-H2), 3.92 (broad s, 1H) and
4.37 (broad s, 1H) (2-OH and 4-OH), 4.01 (s, 1H, 2-H), 6.92
(dd, J<J0<5.7 Hz, 1H, CONH); 13C NMR (75.4 MHz,
CDCl3) d 14.1 (CH3, C70), 20.1 (CH3) and 21.4 (CH3)
[3-(CH3)2], 22.6 (CH2, C60), 26.9 (CH2), 28.9 (CH2), 29.5
(CH2) and 31.7 (CH2) (C20, C30, C40 and C50), 39.1 (CH2,
C10), 39.3 (C, C3), 71.2 (CH2, C4), 77.4 (CH, C2), 173.1 (C,
C1).
triturated with CHCl3 (5 mL), to afford pure hydroxyamide
3g (2.84 g, 84% yield) as a white solid: mp 125–1278C
(distilled at 140–1508C/0.5 Torr) (described 128–1308C);13
Rf 0.14 (SiO2, AcOEt); IR (KBr) 3436, 3397, 3306, 3179,
1683; 1H NMR (300 MHz, CD3OD) d 0.94 [s, 6H,
3-(CH3)2], 3.39 (d, J¼11.1 Hz, 1H) and 3.48 (d,
J¼11.1 Hz, 1H) (4-H2), 3.89 (s, 1H, 2-H), 4.89 (s, 2-OH,
4-OH and CONH2); 13C NMR (75.4 MHz, CD3OD) d 20.8
(CH3) and 21.3 (CH3) [3-(CH3)2], 40.1 (C, C3), 70.3 (CH2,
C4), 77.1 (CH, C2), 179.0 (C, C1).
4.2.2. N-Benzyl-2,4-dihydroxy-3,3-dimethylbutyramide
(3c).10 This compound was prepared following the above
general procedure, from a solution of pantolactone, 1
(260 mg, 2.00 mmol) in MeOH (0.6 mL) and freshly
distilled benzylamine (0.3 mL, 294 mg, 2.74 mmol,
1.4 equiv.) with a reaction time of 24 h. Evaporation of
the reaction mixture afforded a yellowish oil, which
solidified on standing, consisting of pure hydroxyamide 3c
(475 mg, quantitative yield): mp 78–798C (Et2O/hexane
5:3) [described 101–1048C (tert-butyl methyl ether/
hexane)]10; Rf 0.14 (SiO2, hexane/AcOEt 1:1); IR (KBr)
3379, 3340, 3258, 1642; 1H NMR (200 MHz, CDCl3) d 0.93
(s, 3H) and 1.03 (s, 3H) [3-(CH3)2], 3.48 (d, J¼11.4 Hz, 1H)
and 3.55 (d, J<11.4 Hz, 1H) (4-H2), 3.1–3.4 (broad signal,
1H) and 3.6–3.9 (broad signal, 1H) (2-OH and 4-OH), 4.09
(s, 1H, 2-H), 4.420(dd, J<14.6 Hz,0J0¼5.8 Hz, 1H) and 4.52
(dd, J¼14.6 Hz, J ¼5.8 Hz, 1H) (1 -H2), 7.11 (broad signal,
1H, CONH), 7.22–7.40 (complex signal, 5H, Ar-H); 13C
NMR (75.4 MHz, CDCl3) d 20.3 (CH3) and 21.2 (CH3)
[3-(CH3)2], 39.4 (C, C3), 43.1 (CH2, C10), 71.2 (CH2, C4),
77.4 (CH, C2), 127.4 (CH, C400), 127.6 [CH, C200(600)], 128.6
[CH, C300(500)], 137.7 (C, C100), 173.3 (C, C1).
4.2.5. N-[3-(Dimethylamino)propyl]-2,4-dihydroxy-3,3-
dimethylbutyramide (3i). This compound was prepared
following the above general procedure, from pantolactone,
1 (520 mg, 4.00 mmol) and 3-(dimethylamino)propylamine
(0.6 mL, 487 mg, 4.77 mmol), but in refluxing dioxane
(5.5 mL) for 5 h. The white solid obtained by evaporation of
the reaction mixture consisted of pure hydroxyamide 3i
(892 mg, 96% yield): mp 68–698C (Et2O); Rf 0.18 (SiO2,
AcOEt/MeOH/25% aqueous solution of NH4OH
1
50:50:0.4); IR (KBr) 3400, 3310, 3084, 1632; H NMR
(300 MHz, CDCl3) d 0.91 (s, 3H) and 1.00 (s, 3H)
[3-(CH3)2], 1.70 (dddd, J<J0<J00<J000<6.9 Hz, 2H, 20-H2),
2.24 [s, 6H, N(CH3)2], 2.37 (dd, J<J0<6.9 Hz, 2H, 30-H2),
3.25–3.41 (complex signal, 2H, 10-H2), 3.47 (s, 2H, 4-H2),
3.96 (s, 1H, 2-H), 4.10–5.6 (broad signal, 2H, 2-OH and
4-OH), 7.65 (dd, J<J <5.7 Hz, 1H, CONH); 13C NMR
(75.4 MHz, CDCl3) d 20.2 (CH3) and 21.6 (CH3)
[3-(CH3)2], 26.7 (CH2, C20), 37.6 (CH2, C30), 39.3 (C,
C3), 45.2 [CH3, N(CH3)2], 57.3 (CH2, C10), 71.0 (CH2, C4),
77.4 (CH, C2), 173.7 (C, C1). Anal. calcd for
C11H24N2O3·3/4H2O: C, 53.74; H, 10.46; N, 11.39.
Found: C, 53.74; H, 10.45; N, 11.22.
Note. When the same reaction was carried out in refluxing
diglyme (2 mL) for 22 h, hydroxyamide 3c was obtained in
86% yield.
4.3. General procedure A for the preparation of lactams
5 from pantolactone, 1, or from hydroxyamides 3, under
pressure
4.2.3. 2,4-Dihydroxy-3,3,N-trimethylbutyramide (3d).11
This compound was prepared following the above general
procedure, from a solution of pantolactone, 1 (1.00 g,
7.69 mmol) in MeOH (3 mL) and 40% aqueous solution of
MeNH2 (0.80 mL, 0.32 g, 10.3 mmol) with a reaction time
of 3 h. The white solid obtained by evaporation of the
reaction mixture consisted of pure hydroxyamide 3d
(1.24 g, quantitative yield): mp 81–828C (AcOEt); Rf 0.40
(SiO2, AcOEt/MeOH 9:1); IR (KBr) 3495, 3334, 3230,
1636; 1H NMR (300 MHz, CDCl3) d 0.92 (s, 3H) and 1.04
(s, 3H) [3-(CH3)2], 2.86 (d, J¼5.1 Hz, 3H, NH–CH3), 3.49
(d, J¼11.4 Hz, 1H) and 3.55 (d, J¼11.4 Hz, 1H) (4-H2),
3.0–3.4 (broad signal, 1H) and 3.64 (broad signal, 1H)
(2-OH and 4-OH), 4.05 (s, 1H, 2-H), 6.77 (broad s, 1H,
NH–CH3); 13C NMR (75.4 MHz, CDCl3) d 20.2 (CH3) and
21.2 (CH3) [3-(CH3)2], 25.7 (CH3, NH–CH3), 39.3 (C, C3),
71.1 (CH2, C4), 77.3 (CH, C2), 174.2 (C, C1); Anal. calcd
for C7H15NO3: C, 52.16; H, 9.38; N, 8.69. Found: C, 52.25;
H, 9.43; N, 8.73.
All the reactions were carried out in a pressure reactor from
a solution of pantolactone, 1 (2.00 g, 15.4 mmol), amine 2
(2.1 equiv.) and p-TsOH·H2O (0.29 g, 1.52 mmol,
0.1 equiv.) in MeOH (4 mL) or from a solution of
hydroxyamide 3 (12.4–13.6 mmol) and p-TsOH·H2O
(0.1 equiv.) in MeOH or EtOH (4 mL). The reaction
mixture is heated at 2508C for 4 h (reaching an internal
pressure of 9.5–15 atm), then it is allowed to cool to room
temperature and is concentrated in vacuo. Purification of the
resulting oily residue through column chromatography
(SiO2, hexane/AcOEt/MeOH mixtures) affords the
lactams 5.
4.4. General procedure B for the preparation of lactams
5 from pantolactone, 1, under microwave irradiation
All the reactions were performed in a sealed cylindrical
pyrex vessel using pantolactone, 1 (260 mg, 2.00 mmol), the
amine (2 equiv.) and p-TsOH·H2O (34.0 mg, 0.2 mmol,
0.1 equiv.). The mixture is introduced into the monomode
reactor, Synthwave 402 Prolabo focused MW 2.45 GHz, at
the powers and times indicated in each example. At the end
of the reaction, after cooling down the mixture is extracted
with AcOEt (3£20 mL), washed with 1 M HCl (2£20 mL),
and dried over Na2SO4. Removal of the solvent and
4.2.4. 2,4-Dihydroxy-3,3-dimethylbutyramide (3g).13
This compound was prepared following the above general
procedure, from a solution of pantolactone, 1 (3.00 g,
23.1 mmol) in MeOH (9 mL) and 25% aqueous solution of
NH3 (4.2 mL, 61.8 mmol, 2.7 equiv.) with a reaction time of
14 h. The resulting transparent oily residue (3.00 g) was

1976
I. Barrios et al. / Tetrahedron 59 (2003) 1971–1979
purification by column chromatography affords the corre-
sponding lactams 5.
graphy (SiO2, hexane/AcOEt mixtures). On elution with
hexane/AcOEt 70:30, pantolactone, 1 (49.0 mg, 41% yield;
47% yield based on unrecovered 3b), and starting 3b
(33.4 mg) were successively isolated.
4.4.1. 3-Hydroxy-4,4-dimethyl-1-phenylpyrrolidin-2-one
(5a).8 Method 1. This compound was prepared according to
the general procedure A. The resulting brown solid residue
(5.10 g) was taken up in CH2Cl2 (90 mL) and was washed
successively with 5N HCl (2£30 mL), saturated aqueous
solution of NaHCO3 (3£20 mL), and water (25 mL). The
organic phase was dried over Na2SO4 and evaporated at
reduced pressure, to afford pure lactam 5a (2.95 g, 93%
yield), as a light brown solid: mp 118–1198C (EtOH); Rf
0.33 (SiO2, hexane/AcOEt 1:1).
Method 4. Attempted preparation of 5b from pantolactone in
refluxing n-heptylamine. A solution of pantolactone, 1
(260 mg, 2.00 mmol) and p-TsOH·H2O (8.0 mg, 42.1 mmol,
0.02 equiv.) in n-heptylamine (4.2 mL, 3.26 g, 28.3 mmol,
14 equiv.) was heated under reflux for 15 h, was allowed to
cool to room temperature, diluted with CH2Cl2 (2 mL), and
washed successively with 4N HCl (3£1.5 mL) and with
saturated aqueous solution of NaHCO3 (3£1.5 mL). The
organic phase was dried over Na2SO4 and evaporated at
reduced pressure, to give hydroxyamide 3b (110 mg, 22%
yield).
Method 2. This compound was prepared according to the
general procedure B, at a power of 75 W and with a reaction
time of 10 min. On elution with AcOEt/petroleum ether 2:1,
pure lactam 5a (312 mg, 76% yield) was isolated.
4.4.3. 1-Benzyl-3-hydroxy-4,4-dimethylpyrrolidin-2-one
(5c). Method 1. This compound was prepared according to
the general procedure A. On elution with hexane/AcOEt
40:60, pure lactam 5c (2.00 g, 59% yield) was isolated as a
yellowish solid: mp 82–838C (distilled at 818C/0.4 Torr); Rf
0.38 (SiO2, AcOEt); IR (KBr) 3317, 1684; 1H NMR
(300 MHz, CDCl3) d 0.96 (s, 3H, 4a-CH3), 1.17 (s, 3H,
4b-CH3), 2.85 (d, J¼9.9 Hz, 1H, 5a-H), 2.96 (d, J¼9.9 Hz,
1H, 5b-H), 3.2–3.8 (broad signal, 1H, 3-OH), 4.04 (s, 1H,
3-0H), 4.37 (d, J¼14.4 Hz, 1H) and 4.52 (d, J<14.4 Hz, 1H)
(1 -H2), 7.20–7.37 (complex signal, 5H, Ar-H); 13C NMR
(75.4 MHz, CDCl3) d 20.1 (CH3, 4a-CH3), 24.8 (CH3,
4b-CH3), 38.5 (C, C4), 46.8 (CH2, benzyl CH2), 56.3 (CH2,
C5), 77.8 (CH, C3), 127.7 (CH, Ar–C4), 128.2 [CH,
Ar–C2(6)], 128.6 [CH, Ar–C3(5)], 135.6 (C, Ar–C1),
174.6 (C, C2). Anal. calcd for C13H17NO2: C, 71.21; H,
7.81; N, 6.39. Found: C, 71.33; H, 7.97; N, 6.50.
Method 3. From hydroxyamide 3a in diglyme under reflux.
A solution of hydroxyamide 3a (150 mg, 0.67 mmol) and
p-TsOH·H2O (9.0 mg, 47.3 mmol, 0.07 equiv.) in diglyme
(1 mL) was heated under reflux for 15 h, was allowed to
cool to room temperature, and was submitted to column
chromatography (SiO2, hexane/AcOEt mixtures). On
elution with hexane/AcOEt 90:10, a mixture of lactam 5a
and pantolactone, 1, in an approximate ratio of 43:57 (1H
NMR) was isolated (54.5 mg of 5a, 40% yield; 46.5 mg of
1, 53% yield).
4.4.2. 1-Heptyl-3-hydroxy-4,4-dimethylpyrrolidin-2-one
(5b). Method 1. This compound was prepared according to
the general procedure A. On elution with AcOEt, pure
lactam 5b (1.72 g, 49% yield) was isolated as a yellowish
solid: mp 66–688C (distilled at 808C/0.5 Torr); Rf 0.36
1
(SiO2, AcOEt); IR (KBr) 3260, 1670; H NMR (300 MHz,
Method 2. This compound was prepared according to the
general procedure B, at a power of 90 W and with a reaction
time of 5 min. On elution with AcOEt/petroleum ether 2:1,
pure lactam 5c (258 mg, 59% yield) was isolated.
CDCl3) d 0.88 (t, J¼6.9 Hz, 3H, 70-H3), 1.03 (s, 3H, 4a-
CH3), 1.22 (s, 3H, 4b-CH3), 1.23–1.34 (complex signal,
8H, 30-H2, 40-H2, 50-H2 and 60-H2), 1.49 (m, 2H, 20-H2), 2.96
(d, J¼9.6 Hz, 1H, 5a-H0), 30.008 (d, J¼9.6 Hz, 1H, 5b-H),
3.23 (ddd, J<13.8 Hz, J <J <7.20Hz, 1H) and 3.29 (ddd,
J<13.8 Hz, J0<J00<6.9 Hz, 1H) (1 -H2), 3.98 (s, 1H, 3-H),
4.07 (broad s, 01H, 3-OH); 13C NMR (75.4 MHz, CDCl3) d
14.1 (CH3, C7 ), 20.2 (CH3, 4a-CH3), 22.6 (CH2, C60), 24.9
(CH3, 4b-CH3), 26.7 (CH2), 27.1 (CH2) and 28.9 (CH2)
(C20, C30 and C40), 31.7 (CH2, C50), 38.7 (C, C4), 42.8 (CH2,
C10), 57.0 (CH2, C5), 77.8 (CH, C3), 174.3 (C, C2). Anal.
calcd for C13H25NO2: C, 68.68; H, 11.08; N, 6.16. Found: C,
69.01; H, 11.42; N, 6.23.
Method 3. By reaction of pantolactone with benzylamine
under reflux. A solution of pantolactone, 1 (240 mg,
1.85 mmol) and p-TsOH·H2O (17.2 mg, 0.09 mmol,
0.05 equiv.) in freshly distilled n-benzylamine (3 mL,
2.94 g, 27.4 mmol, 14.8 equiv.) was heated under reflux
for 22 h, was allowed to cool to room temperature, was
diluted with CH2Cl2 (10 mL), and washed successively with
5N HCl (3£5 mL) and saturated aqueous solution of
NaHCO3 (3£5 mL). The organic layer was dried over
Na2SO4 and evaporated at reduced pressure, to give a
yellow oil (450 mg), which consisted of lactam 5c
impurified with starting benzylamine (1H NMR). This
residue was taken up in AcOEt (15 mL) and was washed
successively with 2N HCl (3£10 mL) and water (10 mL).
The organic phase was dried over Na2SO4 and evaporated at
reduced pressure, affording pure lactam 5c (170 mg, 42%
yield).
Method 2. This compound was prepared according to the
general procedure B, at a power of 75 W and with a reaction
time of 10 min. On elution with AcOEt/petroleum ether 3:1,
pure lactam 5b (345 mg, 76% yield) was isolated.
Method 3. Attempted preparation of 5b from hydroxyamide
3b. This reaction was carried out as described for the
preparation of 5a (Method 3), from a solution of hydroxy-
amide 3b (228 mg, 0.93 mmol) and p-TsOH·H2O (9.0 mg,
47.3 mmol, 0.05 equiv.) in diglyme (1 mL). After removal
of the solvent by distillation at 758C/2 Torr, the remaining
oily residue (220 mg), consisting mainly of hydroxyamide
3b and pantolactone was submitted to column chromato-
Method 4. By reaction of pantolactone with benzylamine in
diglyme under reflux. A solution of pantolactone, 1 (260 mg,
2.00 mmol), freshly distilled benzylamine (0.3 mL, 294 mg,
2.74 mmol, 1.48 equiv.), and p-TsOH·H2O (19.0 mg,
0.10 mmol, 0.05 equiv.) in diglyme (2 mL) was heated

I. Barrios et al. / Tetrahedron 59 (2003) 1971–1979
1977
under reflux for 22 h, was allowed to cool to room
temperature, was diluted with water (5 mL), and was
extracted with AcOEt (3£10 mL). The combined organic
extracts were washed successively with 5N HCl (2£5 mL)
and water (2£5 mL), dried over Na2SO4, and evaporated at
reduced pressure, to give pure lactam 5c (318 mg, 73%
yield).
AcOEt/petroleum ether 2:1, pure lactam 5e (40.7 mg, 11%
yield) was isolated.
4.4.6. 1-Cyclohexyl-3-hydroxy-4,4-dimethylpyrrolidin-
2-one (5f). Method 1. This compound was prepared
according to the general procedure A. After addition of
CH2Cl2 (10 mL) to the resulting brown oily residue (4.43 g),
pure lactam 5f (0.95 g) precipitated as a light brown solid,
which was separated by filtration in vacuo. The filtrate was
evaporated at reduced pressure and the resulting residue was
submitted to column chromatography (SiO2, AcOEt),
affording an additional crop of 5f (0.76 g, 52% total yield)
as a yellowish solid: mp 174–1758C (sublimed at
1108C/0.5 Torr); Rf 0.31 (SiO2, AcOEt); IR (KBr) 3267,
1662; 1H NMR (300 MHz, CD3OD) d 0.95 (s, 3H, 4a-CH3),
1.15 (s, 3H, 4b-CH3), 1.28–1.53 (complex signal, 5H),
1.58–1.72 (complex0 signal, 3H) and 1.75–1.86 (complex
signal, 2H) (20-H2, 3 -H2, 40-H2, 50-H2 and 60-H2), 3.03 (d,
J¼9.9 Hz, 1H, 5a-H), 3.07 (d, J¼9.9 Hz, 1H, 5b-H), 3.82
(m, 1H, 10-H), 3.90 (s, 1H, 3-H), 4.89 (s, OH); 13C NMR
(75.4 MHz, CD3OD) d 20.3 (CH3, 4a-CH3), 24.7 (CH3, 4b-
CH3), 26.4 (2CH2) and 26.6 (CH2) (C30, C40 and C50), 30.5
(CH2) and 31.1 (CH2) (C20 and C60), 39.7 (C, C4), 52.1 (CH,
C10), 53.6 (CH2, C5), 79.5 (CH, C3), 175.2 (C, C2). Anal.
calcd for C12H21NO2: C, 68.21; H, 10.02; N, 6.63. Found: C,
68.08; H, 10.08; N, 6.63.
Method 5. From hydroxyamide 3c in diglyme under reflux.
Lactam 5c was alternatively obtained as described for 5a
(Method 3), from a solution of hydroxyamide 3c (77.8 mg,
0.33 mmol) and p-TsOH·H2O (6.3 mg, 33.1 mmol,
0.1 equiv.) in diglyme (1 mL) for 5 h. After distillation of
the reaction mixture at 608C/2 Torr, the remaining yellow
oily residue (75 mg), consisting of a mixture of lactam
5c/pantolactone/diglyme in an approximate ratio of
76:12:12 (1H NMR), was submitted to column chromato-
graphy (SiO2, hexane/AcOEt mixtures). On elution with
hexane/AcOEt 50:50, pure lactam 5c (50 mg, 69% yield)
was isolated.
4.4.4. 3-Hydroxy-4,4,N-trimethylpyrrolidin-2-one (5d).16
Method 1. This compound was prepared according to the
general procedure A. On elution with AcOEt, pure lactam
5d (0.93 g, 42% yield) was isolated as a yellowish solid: mp
86–878C (AcOEt/pentane 1:1) [described 758C (AcOEt/
petroleum ether)];16 Rf 0.20 (SiO2, AcOEt); IR (KBr) 3318,
1700; 1H NMR (300 MHz, CDCl3) d 1.03 (s, 3H, 4a-CH3),
1.22 (s, 3H, 4b-CH3), 2.87 (broad s, 3H, N–CH3), 2.96 (d,
J¼9.9 Hz, 1H, 5a-H), 3.12 (d, J¼9.9 Hz, 1H, 5b-H), 3.4–
3.9 (broad signal, 1H, 3-OH), 3.96 (d, J¼0.6 Hz, 1H, 3-H);
13C NMR (75.4 MHz, CDCl3) d 20.3 (CH3, 4a-CH3), 24.9
(CH3, 4b-CH3), 30.0 (CH3, N–CH3), 38.4 (C, C4), 59.4
(CH2, C5), 77.4 (CH, C3), 174.8 (C, C2). Anal. calcd for
C7H13NO2: C, 58.72; H, 9.15; N, 9.78. Found: C, 58.68; H,
9.28; N, 9.76.
Method 2. This compound was prepared according to the
general procedure B, at a power of 120 W and with a
reaction time of 5 min. On elution with AcOEt/petroleum
ether 2:1, pure lactam 5f (249 mg, 59% yield) was isolated.
4.4.7. 3-Hydroxy-4,4-dimethylpyrrolidin-2-one (5g).15
Method 1. This compound was prepared according to the
general procedure A. On elution with AcOEt, a mixture of
lactam 5g and hydroxyamide 3g in an approximate ratio of
1:1 (1H NMR) [0.80 g; 374 mg of 5g, 19% yield; 426 mg of
3g, 19% yield] was isolated as a yellowish solid. Spectro-
scopic data of 5g, deduced from the spectra of the mixture
with 3g: 1H NMR (200 MHz, DMSO-d6) d 0.85 (s, 3H, 4a-
CH3), 1.03 (s, 3H, 4b-CH3), 2.76–2.94 (complex signal,
2H, 5a-H and 5b-H), 3.63 (m, 1H, 3-H), 5.30 (m, 1H,
3-OH), 7.54 (broad s, 1H, 1-H); 13C NMR (50.3 MHz,
DMSO-d6) d 20.4 (CH3, 4a-CH3), 25.0 (CH3, 4b-CH3),
40.0 (C, C4), 51.0 (CH2, C5), 76.8 (CH, C3), 175.8 (C, C2).
Method 2. Lactam 5d was alternatively prepared through the
general procedure A, starting from a solution of hydroxy-
amide 3d (2.00 g, 12.4 mmol) and p-TsOH·H2O (0.24 g,
1.26 mmol, 0.1 equiv.) in EtOH (4 mL). On elution with
AcOEt, pure lactam 5d (0.70 g, 39% yield) was isolated as a
yellowish solid.
4.4.5. 1-tert-Butyl-3-hydroxy-4,4-dimethylpyrrolidin-2-
one (5e). Method 1. This compound was prepared according
to the general procedure A with a reaction time of 8 h. On
elution with AcOEt, pure lactam 5e (0.45 g, 16% yield) was
isolated as a yellowish solid: mp 117–1198C (AcOEt); Rf
0.47 (SiO2, AcOEt); IR (KBr) 3332, 1674; 1H NMR
(300 MHz, CDCl3) d 0.96 (s, 3H, 4a-CH3), 1.20 (s, 3H,
4b-CH3), 1.38 [s, 9H, N–C(CH3)3], 2.90 (broad s, 1H,
3-OH), 3.06 (d, J¼9.6 Hz, 1H, 5a-H), 3.10 (d, J<9.6 Hz,
1H, 5b-H), 3.84 (s, 1H, 3-H); 13C NMR (75.4 MHz, CDCl3)
d 19.6 (CH3, 4a-CH3), 24.6 (CH3, 4b-CH3), 27.5 [CH3,
N–C(CH3)3], 38.2 (C, C4), 54.0 [C, N–C(CH3)3], 55.0
(CH2, C5), 78.2 (CH, C3), 174.3 (C, C2). Anal. calcd for
C10H19NO2·0.1H2O: C, 64.21; H, 10.35; N, 7.49. Found: C,
64.12; H, 10.67; N, 7.49.
Method 2. Lactam 5g was alternatively prepared through the
general procedure A, starting from a solution of hydro-
xyamide 3g (2.00 g, 13.6 mmol) and p-TsOH·H2O (0.27 g,
1.42 mmol, 0.1 equiv.) in MeOH (4 mL). On elution with
AcOEt, pantolactone, 1 (0.71 g, 40% yield), and a mixture
of lactam 5g and starting 3g in an approximate ratio of 1:1
(1H NMR) [340 mg; 159 mg of 5g, 9% yield] were
successively isolated.
4.4.8. 3-Hydroxy-1-(2-hydroxyethyl)-4,4-dimethylpyrro-
lidin-2-one (5h). This compound was prepared according to
the general procedure A. On elution with AcOEt/MeOH
98:2, pure lactam 5h (0.63 g, 24% yield) was isolated as a
yellowish solid: mp 76–798C (distilled at 1258C/0.5 Torr);
Rf 0.15 (SiO2, AcOEt/MeOH 3:2); IR (KBr) 3392, 1684; 1H
NMR (300 MHz, CDCl3) d 1.05 (s, 3H, 4a-CH3), 1.23 (s,
3H, 4b-CH3), 1.84 (broad signal, 1H, 20-OH), 3.07 (d,
Method 2. This compound was prepared according to the
general method B, at a power of 30 W, with a reaction time
of 30 min, and using 8 equiv. of amine. On elution with

1978
I. Barrios et al. / Tetrahedron 59 (2003) 1971–1979
J<9.9 Hz, 1H, 5a-H), 3.020 3 (d, J<9.9 Hz, 1H, 5b-H), 3.40
(ddd, J¼14.20Hz, J0¼J ¼5.4 Hz, 10H) and 3.46 (ddd,
J¼14.2 Hz, J ¼J00¼5.1 Hz, 1H) (1 -H2), superimposed
3.36–3.50 (1H, 3-OH), 3.77 (broad dd, J<J0<5.2 Hz, 2H,
20-H2), 4.00 (s, 1H, 3-H); 13C NMR (75.4 MHz, CDCl3) d
20.2 (CH3, 4a-CH3), 24.8 (CH3, 4b-CH3), 38.9 (C, C4),
46.2 (CH2, C10), 58.3 (CH2, C5), 59.9 (CH2, C20), 77.8 (CH,
C3), 175.6 (C, C2). Anal. calcd for C8H15NO3: C, 55.47; H,
8.73; N, 8.09. Found: C, 55.40; H, 8.94; N, 8.42.
for C11H14N2O2: C, 64.06; H, 6.85; N, 13.58. Found: C,
63.83; H, 7.03; N, 13.26.
4.4.11. 3-Hydroxy-1-(4-hydroxyphenyl)-4,4-dimethyl-
pyrrolidin-2-one (5k). Method 1. This compound was
prepared according to the general procedure A. On elution
with AcOEt, a mixture of lactam 5k and starting
pantolactone (2.40 g) in an approximate ratio of 3:1 (1H
NMR) was isolated. This mixture was taken up in MeOH
(75 mL), heated under reflux, treated with active charcoal,
and filtered through a short pad of Celitee. The resulting
filtrate was evaporated under reduced pressure to give a
solid residue (1.67 g), which was triturated with CHCl3
(9 mL), affording pure lactam 5k (0.77 g, 23% yield) as a
light brown solid: mp 185–1868C (acetonitrile); Rf 0.46
4.4.9. 1-[3-(Dimethylamino)propyl]-3-hydroxy-4,4-
dimethylpyrrolidin-2-one (5i). Method 1. This compound
was prepared according to the general procedure A. On
elution with AcOEt/MeOH/25% aqueous solution of
NH4OH 80:20:0.7, pure lactam 5i (1.11 g, 34% yield),
was isolated as a brown oil: Rf 0.14 (SiO2, AcOEt/
MeOH/25% aqueous solution of NH4OH 5:5:0.04); IR
(NaCl) 3336, 1687; 1H NMR (300 MHz, CDCl3) d 1.03 (s,
3H, 4a-CH3), 1.21 (s, 3H, 4b-CH3), 1.68 (m, 2H, 20-H2),
2.19–2.29 (m, 2H, 30-H2), 2.21 [s, 6H, N(CH3)2], 2.99 (d,
J¼9.6 Hz, 1H, 5a-H), 3.09 0(d, J¼9.6 Hz, 1H, 5b-H), 3.31
(dd, J<J0<7.2 Hz, 2H, 1 -H2), 3.5–4.0 (broad signal,
3-OH), 3.94 (s, 1H, 3-H); 13C NMR (75.4 MHz, CDCl3) d
20.2 (CH3, 4a-CH3), 24.9 (CH3, 4b-CH3), 25.4 (CH2, C20),
38.7 (C, C4), 41.0 (CH2, C30), 45.4 [CH3, N(CH3)2], 56.9
(CH2) and 57.1 (CH2) (C5 and C10), 77.8 (CH, C3), 174.3
(C, C2). Anal. calcd for C11H22N2O2·1/5H2O: C, 60.63; H,
10.36; N, 12.86. Found: C, 60.68; H, 10.42; N, 13.16.
1
(SiO2, AcOEt); IR (KBr) 3308, 3265, 1666 (CvO st); H
NMR (300 MHz, CD3OD) d 1.06 (s, 3H, 4a-CH3), 1.24 (s,
3H, 4b-CH3), 3.38 (d, J<9.9 Hz, 1H, 5a-H), 3.55 (d,
J<9.9 Hz, 1H, 5b-H), 4.06 (s, 1H, 3-H), 4.88 (s, 3-OH and
40-OH), 6.78 [dm, J<9.0 Hz, 2H, 30(50)-H], 7.35 [dm,
J<9.0 Hz, 2H, 20(60)-H]; 13C NMR (75.4 MHz, CD3OD) d
20.3 (CH3, 4a-CH3), 24.6 (CH3, 4b-CH3), 39.5 (C, C4),
59.5 (CH2, C5), 79.5 (CH, C3), 116.3 [CH, C30(50)], 123.5
[CH, C20(60)], 132.5 (C, C10), 156.2 (C, C40), 174.9 (C, C2).
Anal. calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33.
Found: C, 65.31; H, 7.00; N, 6.47.
Method 2. This compound was prepared according to the
general procedure B, at a power of 150 W, with a reaction
time of 10 min, and using 3 equiv. of amine in xylene
(8 mL). On elution with AcOEt/petroleum ether 1:1, pure
lactam 5k (203 mg, 46% yield) was isolated.
Note. When the above reaction was carried out heating at
1808C, hydroxyamide 3i (2.56 g, 72% yield) was obtained
instead of lactam 5i.
Method 2. Attempted preparation of 5i from hydroxyamide
3i in diglyme under reflux. In an attempted synthesis of
lactam 5i from a solution of hydroxyamide 3i (1.00 g,
4.31 mmol) and p-TsOH·H2O (84.0 mg, 0.44 mmol,
0.1 equiv.) in diglyme (7 mL) in a similar way to that
described for 5a (Method 3), pantolactone, 1 (373 mg, 67%
yield) was obtained instead.
4.4.12. 1-(4-Aminophenyl)-3-hydroxy-4,4-dimethylpyr-
rolidin-2-one (5l). This compound was prepared according
to the general procedure A. On elution with AcOEt, pure
lactam 5l (1.25 g, 37% yield) was isolated as a light brown
solid: mp 206–2078C (sublimed at 1858C/1 Torr); Rf 0.45
(SiO2, AcOEt); IR (KBr) 3446, 3360, 1684; 1H NMR
(300 MHz, CD3OD) d 1.05 (s, 3H, 4a-CH3), 1.24 (s, 3H,
4b-CH3), 3.35 (d, J¼9.6 Hz, 1H, 5a-H), 3.53 (d, J<9.6 Hz,
1H, 5b-H), 4.05 (s, 1H, 3-H), 4.89 (s, OH and NH2), 6.72
[dm, J<9.0 Hz, 2H, 30(50)-H], 7.25 [dm, J<9.0 Hz, 2H,
20(60)-H]; 13C NMR (75.4 MHz, CD3OD) d 20.4 (CH3, 4a-
CH3), 24.6 (CH3, 4b-CH3), 39.5 (C, C4), 59.6 (CH2, C5),
79.5 (CH, C3), 116.4 [CH, C30(50)], 123.4 [CH, C20(60)],
131.2 (C, C10), 146.7 (C, C40), 174.8 (C, C2). Anal. calcd for
C12H16N2O2: C, 65.43; H, 7.32; N, 12.72. Found: C, 65.28;
H, 7.44; N, 12.91.
4.4.10. 3-Hydroxy-4,4-dimethyl-1-(2-pyridyl)pyrrolidin-
2-one (5j). This compound was prepared according to the
general procedure A. On elution with AcOEt, a mixture of
lactam 5j, pantolactone and starting 2-aminopyridine in an
approximate ratio of 3:1:0.7 (1H NMR) (0.54 g) was
isolated, from which pantolactone and 2-aminopyridine
were mostly removed by distillation at 70–808C/1 Torr. The
residue, consisting of almost pure lactam 5j (0.43 g, 14%
yield) was obtained as a yellowish solid: mp 110–1118C
(isopropanol); Rf 0.52 (SiO2, AcOEt); IR (KBr) 3365, 1690;
1H NMR (300 MHz, CDCl3) d 1.07 (s, 3H, 4a-CH3), 1.34
(s, 3H, 4b-CH3), 2.83 (broad d, J<2.4 Hz, 1H, 3-OH), 3.56
(dd, J¼11.1 Hz, J0<0.5 Hz, 1H, 5a-H), 4.00 (d, J¼11.1 Hz,
1H, 5b-H), 0 4.16 (d, J¼2.4 Hz, 1H, 3-H), 7.07 (ddd,
J¼7.2 Hz, J ¼4.8 Hz, J00¼0.9 Hz, 1H,0 50-H), 7.72 (ddd,
J¼8.4 Hz, J0¼7.2 Hz, J00¼2.0 0Hz, 1H, 4 -H), superimpose0d
in part 8.36 (ddd, J¼4.8 Hz, 0J ¼2.0 Hz, J00¼0.9 H0z, 1H, 6 -
H), 8.38 (ddd, J¼8.4 Hz, J ¼J00¼0.9 Hz, 1H, 3 -H); 13C
NMR (75.4 MHz, CDCl3) d 19.9 (CH3, 4a-CH3), 24.5
(CH3, 4b-CH3), 37.8 (C, C4), 55.7 (CH2, C5), 79.0 (CH,
C3), 114.7 (CH, C30), 119.8 (CH, C50), 137.8 (CH, C40),
147.5 (CH, C60), 151.2 (C, C20), 174.4 (C, C2). Anal. calcd
4.4.13. Stereoisomeric mixture of (1)-, (2)-, and meso-3-
hydroxy-1-[4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-
1-yl)phenyl]-4,4-dimethylpyrrolidin-2-one (7). Method 1.
This compound was prepared according to the general
procedure A, but with 0.5 equiv. of the amine. On elution
with AcOEt, pure bis-lactam 7 (0.62 g, 24% yield) was
isolated as a light brown solid: mp 253–2548C (aceto-
nitrile); Rf 0.28 (SiO2, AcOEt); IR (KBr) 3458, 3384, 3326,
1
1712, 1689, 1666; H NMR (300 MHz, DMSO-d6) d 0.92
(s, 6H, 4a-CH3), 1.16 (s, 6H, 4b-CH3), 3.40 (broad d,
J¼9.3 Hz, 2H, 5a-H), 3.51 (broad d, J¼9.3 Hz, 2H, 5b-H),
3.96 (d, J¼5.7 Hz, 2H, 3-H), 5.71 (d, J¼5.7 Hz, 3-OH),
7.63 (s, 4H, Ar-H); 13C NMR (75.4 MHz, DMSO-d6) d 20.3

I. Barrios et al. / Tetrahedron 59 (2003) 1971–1979
1979
´
4. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asymmetry
1998, 9, 2065–2079.
´
5. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asymmetry
1999, 10, 493–509.
´
6. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asymmetry
1997, 8, 1877–1894.
(CH3, 4a-CH3), 24.3 (CH3, 4b-CH3), 37.6 (C, C4), 56.6
(CH2, C5), 77.6 (CH, C3), 119.4 (CH, Ar–CH), 135.8 (C,
Ar–C), 173.3 (C, C2). Anal. calcd for C18H24N2O4·1/2H2O:
C, 63.33; H, 7.38; N, 8.21. Found: C, 63.35; H, 7.31; N,
8.32.
´
7. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron Lett. 1999,
40, 6853–6856.
Method 2. This compound was prepared according to the
general procedure B, at a power of 90 W, with a reaction
time of 25 min, and using 0.5 equiv. of amine in DMF
(10 mL). On elution with AcOEt, pure bis-lactam 7
(83.0 mg, 25% yield) was isolated.
8. Marieva, T. D.; Kopelevich, V. M.; Torosyan, Zh. K.; Gunar,
V. I. J. Gen. Chem. USSR 1979, 49, 191–194.
9. For the synthesis of 3b, see: Shive, W.; Snell, E. E. J. Biol.
Chem. 1945, 160, 287–292.
10. For the synthesis of 3c, see: Szabo, A.; Ku¨nzle, N.; Mallat, T.;
Baiker, A. Tetrahedron: Asymmetry 1999, 10, 61–76.
11. For the synthesis of 3d, see: Baukov, Y. I.; Shipov, A. G.;
Kramarova, E. P.; Mamaeva, E. A.; Zamyshlyaeva, O. A.;
Anisimova, N. A.; Negrebetskii, V. V. Russ. J. Org. Chem.
1996, 32, 1216–1228.
Acknowledgements
´
Financial support from the Direccion General de Investiga-
´
´
cion of Ministerio de Ciencia y Tecnologıa (project
QUI1999-0512) and Comissionat per a Universitats i
Recerca of the Generalitat de Catalunya (project 2001-
SGR-00085) is gratefully acknowledged. We thank the
12. For the synthesis of 3f, see Ref. 10 and: (a) Arris, J.; Baddiley,
J.; Buchanan, J. G.; Thain, E. M. J. Chem. Soc. 1956,
4968–4973. (b) Wiley, R. H.; Kennedy, J. E. J. Med. Chem.
1967, 10, 117–118.
´
Serveis Cientıfico-Tecnics of the University of Barcelona
for NMR facilities and Ms P. Domenech from the IIQAB
`
`
13. For the synthesis of 3g, see: (a) Aquino, F.; Pauling, H.;
Walther, W.; Plattner, D. A.; Bonrath, W. Synthesis 2000,
731–737. (b) Sakuragi, K. J. Am. Chem. Soc. 1956, 78, 838.
14. For the synthesis of 3h, see: Nagase, O.; Tagawa, H.; Shimizu,
M. Chem. Pharm. Bull. 1968, 16, 977–983.
(CSIC, Barcelona, Spain) for carrying out the elemental
´
analyses. We are indebted with Dr J. Castan˜e for a generous
gift of pantolactone.
15. Kopelevich, V. M.; Bulanova, L. N.; Gunar, V. I. Chem. Nat.
Compd 1982, 18, 215–219.
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´