A direct link between the Passerini reaction and α-lactams

Article abstract of DOI:10.1016/j.tet.2003.11.067

α-Lactams (aziridinones) can function to replace two of the three reactants, the oxo-compound and the isonitrile, in the Passerini reaction. Four α-lactams (5a-d) were reacted with mono- and dicarboxylic acids of positive pK_a values to give 2-acyloxycarboxamides (4) and bis-2-acyloxycarboxamide products 12 and 13, respectively. The same compounds were also prepared via the Passerini reaction. Acids with a negative pK _a decarbonylate α-lactams to give immonium salts. The main path of the reaction depends on the pK_a of the acid component, the reactivity of the α-lactam, and the reaction conditions.

Full text of DOI:10.1016/j.tet.2003.11.067

Tetrahedron 60 (2004) 1107–1124
A direct link between the Passerini reaction and a-lactamsq
a
Istvan Lengyel, Victor Cesare and Tony Taldone
a
b
,
*
´
aDepartment of Chemistry, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
bDepartment of Pharmaceutical Sciences, St. John’s University, 8000 Utopia Parkway, Jamaica, NY 11439, USA
Received 10 September 2003; revised 21 November 2003; accepted 21 November 2003
Abstract—a-Lactams (aziridinones) can function to replace two of the three reactants, the oxo-compound and the isonitrile, in the Passerini
reaction. Four a-lactams (5a-d) were reacted with mono- and dicarboxylic acids of positive pKa values to give 2-acyloxycarboxamides (4)
and bis-2-acyloxycarboxamide products 12 and 13, respectively. The same compounds were also prepared via the Passerini reaction. Acids
with a negative pKa decarbonylate a-lactams to give immonium salts. The main path of the reaction depends on the pKa of the acid
component, the reactivity of the a-lactam, and the reaction conditions.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
derivatives (6), while non-ionic protic nucleophiles, such as
water, tert-butyl alcohol, benzylamine, glycine ethyl ester,
a-toluenethiol, etc. cause ring-opening with cleavage of the
1–3 bond, to yield a-substituted carboxamides (7)10
(Scheme 2). There are, however, a number of published
reports,13–16 which contradict the above general rule of ring-
opening of stable a-lactams. The reactions of a-lactams
with amines appear to be especially complicated, the
products often being mixtures derived from competing
modes of ring-opening. The factors governing regioselec-
tivity in nucleophilic ring-opening of stable a-lactams have
not been fully enumerated to date, although substantial
progress has been made.17,18 While unsubstituted aziri-
dinone itself is still unknown, and appears to be unstable, the
structural prerequisites that lend stability to this class of
compounds are a tertiary alkyl substituent in position 1 and
a tertiary alkyl or aryl substituent in position 3.
In 1921, Mario Passerini reported2 that the one-pot, three-
component reaction between a carboxylic acid (1), an
aldehyde or ketone (2), and an isonitrile (3) yields a-
acyloxycarboxamides (4) (Scheme 1). The yields of type 4
products reported by Passerini himself varied between 143
and 87%,4 depending on the substituents in the reactants.
Since then, this reaction, named the Passerini reaction, has
been used widely, as documented in several extensive
reviews5–8
.
About 40 years later, the synthesis of a-lactams (aziri-
dinones) (5) has been achieved, and their reactions studied9.
a-Lactams are the first stable representatives of three-
membered ring carbonyl compounds to have been isolated
in pure state. As summarized in a 1968 review9 and in later
published reports, ionic aprotic nucleophiles, such as tert-
butoxide,10 phenyl magnesium bromide,11 or lithium
aluminum hydride12 effect ring-opening with cleavage of
the lactam bond (the 1–2 bond), to give a-amino acid
The predominant general path of thermal decomposition of
most stable a-lactams prepared to date is fragmentation into
an aldehyde or ketone (2) and an isonitrile (3), via the
Scheme 1. The Passerini reaction.
q See Ref. 1.
Keywords: Aziridinones; Maleic anhydride; Mono- and dicarboxylic acids; Nucleophilic substitution; Passerini reaction.
*
Corresponding author. Tel.: þ1-718-990-6291; fax: þ1-718-990-1876; e-mail address: cesarev@stjohns.edu
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.067

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I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
Scheme 2. Nucleophilic ring cleavage of a-lactams, and their thermal, photolytic, and electron bombardment induced decomposition.
imino-oxirane intermediate 819 (Scheme 2). This thermal
decomposition path of a-lactams is in sharp contrast with
their electron impact-induced fragmentation,20–22 ultra-
violet photolysis,23 and reaction with strong, non-aqueous
mineral acids (e.g., HCl in ether24), all of which lead to
Schiff bases (9) or their salts (10), and carbon monoxide
(Scheme 2). An imino-oxirane intermediate (8) has also
been postulated in the oxidation of ketenimines (11) with
peracids,25,26 which yields oxo-compounds (2) and iso-
nitriles (3), along with minor amounts (,20%) of a-acyl-
oxycarboxamides (4) (Scheme 3).
aziridinone (5c),20 and 1,3-di-tert-butylaziridinone (5d)29
and five monocarboxylic acids, viz. acetic acid (1a), pivalic
acid (1b), benzoic acid (1c), trans-cinnamic acid (1d), and
trifluoroacetic acid (1e), as well as hydrofluoric acid.
We have found that a-lactams readily react with carboxylic
acids (1) to give a-acyloxycarboxamides (4) (Scheme 4),
that is, a-lactams are capable of replacing two of the three
reactants in the Passerini reaction (the aldehyde or ketone
and the isonitrile), and the yields are comparable. An
important advantage of this new synthesis of a-acyloxy-
carboxamides (4) is that it obviates the necessity of working
with the repulsive-smelling isonitriles. Naturally, all the
reactions have to be performed under sufficiently mild
conditions to preclude the concurrent spontaneous
decomposition of the a-lactam. The yields of products (4)
from the reaction of a-lactams 5a-d with monocarboxylic
acids 1a-e and from the Passerini reaction are listed in
Table 1.
2. Results and discussion
2.1. Reaction of a-lactams with monocarboxylic acids
Heretofore, it went unnoticed that there is a connection
between a-lactams and the Passerini reaction.27
2.2. Reaction of a-lactams with dicarboxylic acids
For this study, we have chosen four a-lactams for their
greatly varying thermal stability and reactivity, viz. 1-tert-
butyl-3,3-dimethylaziridinone (5a),10 1-(1-adamantyl)-3,3-
dimethylaziridinone (5b),28 1-(1-adamantyl)-3-tert-butyl-
The reaction described above can also be extended to
dicarboxylic acids. Thus, a-lactams 5a and 5b with maleic
Scheme 3. The oxidation of ketenimines with peracids.

I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1109
Scheme 4. The reaction of a-lactams with monocarboxylic acids.
acid, and a-lactams 5a-d with succinic acid gave bis-
Passerini products 12 and 13, respectively. The same
compounds can also readily be prepared by the Passerini
reaction (Scheme 5).
mono- and dicarboxylic acids react with a-lactams to give
the Passerini product, while strong non-aqueous mineral
acids, such as hydrochloric acid, hydrobromic acid, and
p-toluenesulfonic acid cause decarbonylation with the
formation of immonium salts (Scheme 7). If water is
present, the immonium salts are hydrolyzed to an aldehyde
or ketone and an amine.24
We reported earlier30 that treatment of 1-(1-adamantyl)-3-
tert-butylaziridinone (5c) with maleic acid in dioxane
solution yields di-(N-1-adamantylneopentylidenimmonium)
maleate (14), mp 191 8C (dec.), along with carbon
monoxide, rather than a bis-Passerini product (Scheme 6).
Whether the reaction of a-lactams with acids yields a
Passerini product or an immonium salt depends on three
factors: (1) the pKa of the acid, (2) the relative reactivity of
the a-lactam, (3) the reaction conditions. Of these, the first
factor is the most determining one.
We concur with the observation of Bott,24b that even though
ordinary amide-resonance is diminished in a-lactams
because of the small-ring strain, it still contributes signi-
ficantly to their stability. If N-protonation suppresses this
amide-resonance, a-lactams decompose immediately and
quantitatively, even at room temperature (Scheme 7).
According to the evidence presented in this paper, the
protonating power of carboxylic acids with a positive pKa is
Ordinary saturated or unsaturated aliphatic and aromatic
Table 1. The yields of products from the reaction of a-lactams
R1
R2
R3
R4
Yielda (%)
37
66
67
84
66
81
74
75
60
41
63
36
58
74
Yieldb (%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
CH3
t-C4H9
C6H5
C6H5CHvCH
CF3
CH3
t-C4H9
C6H5
C6H5CHvCH
CF3
CH3
t-C4H9
C6H5
C6H5CHvCH
CF3
CH3
t-C4H9
C6H5
C6H5CHvCH
CF3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
t-C4H9
t-C4H9
t-C4H9
t-C4H9
t-C4H9
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
1-Ad
t-C4H9
t-C4H9
t-C4H9
t-C4H9
t-C4H9
66
45
76
54
47
50
29
32
23
75
57
54
68
75
70
42
81
45
33
72
CH3
CH3
t-C4H9
t-C4H9
t-C4H9
t-C4H9
t-C4H9
t-C4H9
t-C4H9
t-C4H9
t-C4H9
t-C4H9
Decarbonylates
67
80
38
65
Decarbonylates
4t
H
a
Monocarboxylic acids.
Passerini reaction.
b

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I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
Scheme 5. The reaction of a-lactams with dicarboxylic acids and the corresponding Passerini reactions.
Scheme 6. Reaction of 1-(1-adamantyl)-3-t-butylaziridinone (5c) with maleic acid.
Scheme 7. Dependence of the product on the pKa of the acid (see also Table 2).
insufficient to lead to decarbonylation, instead it leads to a
Passerini product by nucleophilic substitution at C-3
(Scheme 7). Thus, while a-lactam 5b reacts with hydro-
fluoric acid at room temperature to give 2-fluoro-2-methyl-
N-(1-adamantyl)propanamide (4u) in good yield (Scheme
8), treatment of a-lactam 5c with aqueous hydrobromic acid
at room temperature leads to decarbonylation and a good
yield of pivalaldehyde, isolated as the semicarbazone, and a
nearly quantitative yield of 1-adamantanamine (Scheme 9).
It appears that the acid-strength where the turning point in
the reaction path occurs is around a pKa of zero. So, the acids
in the left column of Table 2 will give a Passerini product
with a-lactams, while those in the right-side column will
Table 2. The pKa values of selected acids31
‘Weak acid’
pKa
‘Strong acid’
pKa
Pivalic acid
Acetic acid
trans-Cinnamic acid
Benzoic acid
Succinic acid
Formic acid
Phthalic acid
Hydrofluoric acid
Maleic acid
Trifluoroacetic acid
5.03
4.8
4.44
4.2
4.16, 5.61
3.8
3.51, 4.82
3.2
Benzenesulfonic acid
Methanesulfonic acid
Sulfuric acid
p-Toluenesulfonic acid
Hydrochloric acid
Hydrobromic acid
Hydroiodic acid
20.6
21.2
25.0
26.6
27
29
210
1.83, 6.07
0.2
Scheme 8. Reaction of a-lactam 5b with hydrofluoric acid.

I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1111
Scheme 9. Reaction of a-lactam 5c with hydrobromic acid.
cause decarbonylation as the predominant reaction path.
Trifluoroacetic acid (1e), the pKa of which is at or near the
turning point, gives both, depending on the relative
reactivity of the a-lactam. Thus, the two more reactive
a-lactams (5a, 5b) give Passerini products (4e, 4j),
while the two less reactive ones (5c, 5d) decarbonylate
upon treatment with trifluoroacetic acid to immonium
trifluoroacetates 10c-d. After work-up, 1-adamantan
ammonium trifluoroacetate (15c) was isolated from 5c
and tert-butyl ammonium trifluoroacetate (15d) or N-tert-
butyl-2,2-dimethyl-1-(trifluoroacetyl)oxypropan-1-aminium
trifluoroacetate (16) was isolated from 5d, in excellent yield.
2.3. Reaction of a-lactams with maleic anhydride
It has been reported32 that maleic anhydride is an excellent
‘dipolarophile’ in 1,3-dipolar cycloaddition reactions. We
found indeed that a-lactam 5a undergoes smooth and rapid
reaction with maleic anhydride, even at 0 8C in CHCl3.
However, the product isolated after chromatography on
alumina is not a 3þ2¼5 type cycloadduct (17 or 18), but the
bis-Passerini product di(2-methyl-N-tert-butylpropana-
mido-2-)maleate (12a), representing a 2:1 addition without
decarbonylation, even if the two reactants are applied in an
equimolar ratio (Scheme 11). It should be noted that this
product is obtained even when freshly vacuum-sublimed
maleic anhydride is used. This same product was also
readily obtained from a-lactam 5a and maleic acid, and
by the Passerini reaction from maleic acid, acetone, and
tert-butyl isonitrile (Scheme 5), cf. Section 4. This result is
the more surprising since a-lactam 5a has been reported to
undergo successful 1,3-dipolar cycloaddition reaction with
three different ‘dipolarophiles’, viz. phenylisocyanate,33
diphenylketene,34 and N,N-dimethylformamide.35
In separate experiments, both hydrolysis products, pival-
aldehyde and 1-adamantanamine, were isolated from 5c, the
former as its semicarbazone. Pivalaldehyde semicarbazone
was also isolated from the reaction of 5d with CF3COOH
and subsequent hydrolysis of the intermediate salt 10d
(Scheme 10). Because of the low boiling point of tert-
butylamine (bp 44–46 8C), it was removed with the solvent
upon evaporation.
Scheme 10. Reactions of a-lactams 5a-d with trifluoroacetic acid.

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I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
Scheme 11. The reaction of a-lactam 5a with maleic anhydride.
We include these results here because they represent a
striking example of an a-lactam leading to a bis-Passerini
product, even though no mechanistic investigation was
undertaken to date to fully account for the reaction. It is
evident, however, that the absence of a strong acid preserves
the a-lactam ring from decarbonylation so that it can
undergo nucleophilic ring-opening. Under comparable
conditions (0–25 8C, in CHCl3 or CCl4 solution), a-lactams
5b-d do not react with maleic anhydride. When a 2:1
mixture of a-lactam 5b and maleic anhydride is heated to
70 8C for 10 min in carbon tetrachloride solution, the
characteristic a-lactam carbonyl band in the IR at
,1840 cm21 completely disappears. However, under
these forced conditions, several parallel reactions occur
simultaneously and concurrently:
has been proposed.30 Control experiments on 5a-d with
benzoic and succinic anhydride under comparable con-
ditions (0–25 8C, in CHCl3 or CCl4 solution) led to no
detectable reaction.
3. Conclusions
a-Lactams 5a-d react with ordinary aliphatic and aromatic
mono- and dicarboxylic acids and hydrofluoric acid to give
Passerini products 4 and 12-13, whereas reaction with
stronger acids leads to immonium salts, for example, 10
with concomitant decarbonylation, in agreement with an
earlier report.24 The major path of the reaction depends on a
combination of three factors:
(a) Passerini reaction, leading to a low yield (17%) of the
bis-Passerini product (12b),
(b) spontaneous thermal decomposition of the a-lactam,
leading to acetone (not isolated) and 1-adamantyl
isonitrile (26%),
(c) formation of a bright purple dye (,51%) which stays at
the top of the silica gel column during chromatography
and was not investigated further.
(1) the pKa of the acid: a positive pKa favors Passerini
product formation, while a negative pKa leads to
decarbonylation.
(2) the relative reactivity of the a-lactam: higher reactivity
favors Passerini product.
(3) the reaction conditions: milder reaction conditions
favor Passerini product.
As we reported earlier,30 a-lactam 5c also reacts with
maleic anhydride, but only at 80 8C, and under the more
severe conditions required for this reaction, decarbonyl-
ation occurs and the products are N-(1-adamantyl)
maleamic acid (19), pivalaldehyde (20), and carbon
monoxide (Scheme 12). The details of this complicated
reaction have been studied, and a four-step mechanism,
based on acid-catalyzed decarbonylation and hydrolysis,
An advantage of this synthesis of a-acyloxycarboxamides
from a-lactams is that it obviates the necessity of working
with the repulsive-smelling isonitriles.
a-Lactams 5a and 5b also react with maleic anhydride to
give the bis-Passerini product 12a and 12b, respectively,
rather than a cycloadduct (17 or 18).
Scheme 12. The reaction of a-lactam 5c with maleic anhydride.

I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1113
4. Experimental
0.004 mol) was cooled to 0 8C and 2 equiv. of benzoic acid
(0.98 g, 0.008 mol) dissolved in toluene (2 mL) was added
dropwise. After stirring for 1 h, the reaction mixture was
washed with 5% sodium bicarbonate and twice with water
(20 mL). The organic layer was dried with sodium sulfate and
the solvent removed under reduced pressure to afford crude
product 4c (0.81 g, 77.0%) with mp 88–89 8C. After
recrystallization from n-heptane (1.5 mL), 0.70 g (66.5%) of
a white solid with mp 89–90 8C was obtained. TLC (80% n-
hexane/20% ethyl acetate) Rf¼0.52. IR (CCl4) n: 3435, 3050,
Melting points were determined on a Thomas Hoover
1
Capillary Melting Point Apparatus and are uncorrected. H
and 13C NMR spectra were recorded on a 500 MHz Bruker
instrument with tetramethylsilane as internal standard.
Chemical shifts are reported in ppm (d). IR spectra were
measured on a Perkin–Elmer Spectrum 1000 FT-IR.
Microanalyses were preformed by Atlantic Microlab Inc.,
Norcross, GA. Mass spectra (MS) were recorded on a
Hewlett–Packard GC–MS GCD system. For column
chromatography, JT Baker Silica gel (40 mm) was used.
Thin layer chromatography (TLC) was preformed with
Analtech silica gel glass backed plates (250 mm). The
aziridinones were prepared by the method of Scrimin et al.36
except where noted otherwise.
1
2955, 1722, 1680, 1505 cm21. H NMR (CDCl3) d 1.35 (s,
9H), 1.72(s, 6H),5.89(s, 1H), and7.44(t, 2H, J¼7.7 Hz), 7.56
(t, 1H, J¼7.5 Hz), 7.97 (d, 2H, J¼7.5 Hz). 13C NMR (CDCl3)
d 24.7, 28.8, 51.2, 82.5, 128.7, 129.6, 130.7, 133.4, 164.9, and
172.3. MS: m/z 263, 205, 191, 164, 146, 123, 105 (base peak),
77, 59, 57. Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N,
5.32. Found: C, 68.26; H, 8.00; N, 5.22.
4.1. Reactions of a-lactams with carboxylic acids
4.1.4. Reaction of 1-tert-butyl-3,3-dimethylaziridinone
(5a) with trans-cinnamic acid. N-tert-Butyl-2-methyl-2-
4.1.1. Reaction of 1-tert-butyl-3,3-dimethylaziridinone
(5a) with acetic acid. N-tert-Butyl-2-acetoxy-2-methyl-
propanamide (4a). The toluene solution of the a-lactam 1-
tert-butyl-3,3-dimethylaziridinone10 (5a) (0.565 g, 0.004 mol)
was cooled to 0 8C and 2 equiv. of acetic acid (0.48 g,
0.008 mol) dissolved in toluene (2 mL) was added drop-
wise. After stirring for 1 h, the reaction mixture was washed
with 5% sodium bicarbonate and twice with water (20 mL).
The organic layer was dried with sodium sulfate and the
solvent removed under reduced pressure to afford crude
product 4a (0.430 g, 53.4%). After recrystallization from
3 mL of n-heptane, a white solid 4a (0.30 g, 37%) with mp
78–79 8C was obtained. TLC (80% n-hexane/20% ethyl
acetate) Rf¼0.45. IR (CCl4) n: 3430, 2955, 1739, 1680, and
1505 cm21. 1H NMR (CDCl3) d 1.30 (s, 9H), 1.55 (s, 6H),
2.02 (s, 3H), and 5.78 (s, 1H). 13C NMR (CDCl3) d 22.1,
24.4, 51.1, 81.8, 169.2, 172.2. MS: m/z 201, 186, 158, 144,
129, 115, 102, 101, 88, 86, 61, 59, 58, 57, 43 (base peak).
(trans-3-phenylacryloyloxy)propanamide (4d). To
a
solution of crude 1-tert-butyl-3,3-dimethylaziridinone
(0.318 g, 2.25 mmol) in 25 mL of toluene at 0 8C was
added 1.00 g (6.75 mmol) of trans-cinnamic acid in 10 mL
of anhydrous toluene. The solution was stirred overnight
slowly coming to rt for 18.5 h then was washed with
4£35 mL of 5% NaHCO3 and 2£35 mL of distilled water,
dried with Na2SO4, filtered and rotary-evaporated to give
0.60 g of a yellow solid. After flash chromatography (90%
n-hexane/10% ethyl acetate), 0.55 g (84%) of a white
solid (4d) with mp 102–104 8C was obtained. TLC (80%
n-hexane/20% ethyl acetate) Rf¼0.50. IR (CCl4) n: 3447,
1
3030, 2975, 1722, 1688, 1637 cm21. H NMR (CDCl3): d
1.38 (s, 9H), 1.68 (s, 6H), 5.87 (s, 1H, exchangeable in
D2O), 6.43 (d, 1H, J¼16.0 Hz), 7.41 (q, 3H, J¼2.6 Hz),
7.54 (quintuplet, 2H, J¼2.6 Hz), 7.68 (d, 1H, J¼16.0 Hz).
13C NMR (CDCl3): d 24.5, 28.6, 51.0, 81.9, 118.3, 128.1,
129.0, 130.5, 134.2, 145.4, 165.1, 172.2. MS: m/z 231, 217,
190, 175, 172, 145, 131 (base peak), 103, 77, 59, 57, 51, 41.
Anal. Calcd for C17H23NO3: C, 70.56; H, 8.01; N, 4.84.
Found: C, 70.32; H, 7.94; N, 4.83.
4.1.2. Reaction of 1-tert-butyl-3,3-dimethylaziridinone
(5a) with pivalic acid. N-tert-Butyl-2-(2,2-dimethyl-
propanoyloxy)-2-methylpropanamide (4b). To a solution
of crude 1-tert-butyl-3,3-dimethylaziridinone (0.318 g,
2.25 mmol) in 25 mL of toluene at 0 8C was added
0.689 g (6.75 mmol) of pivalic acid in 10 mL of anhydrous
toluene. The solution was stirred overnight slowly coming
to rt for 20 h then was washed with 4£35 mL of 5%
NaHCO3 and 2£35 mL of distilled water, dried with
Na2SO4, filtered and rotary evaporated to give 0.46 g of a
white solid. After flash chromatography (95% n-hexane/5%
ethyl acetate), 0.36 g (66%) of a solid (4b) with mp 49–
50 8C was obtained. TLC (90% n-hexane/10% ethyl acetate)
4.1.5. Reaction of 1-tert-butyl-3,3-dimethylaziridinone
(5a) with trifluoroacetic acid. N-tert-Butyl-2-methyl-2-
trifluoroacetoxypropanamide (4e). 1-tert-Butyl-3,3-
dimethylaziridinone (5a) (0.565 g, 0.004 mol) was dis-
solved in toluene (30 mL). A solution of trifluoroacetic
acid (0.92 g, 0.008 mol) in toluene (2 mL) was added
dropwise at 0 8C. After stirring for 1 h, the reaction mixture
was washed with 5% NaHCO3 (30 mL) and twice with
distilled water (20 mL). The organic layer was dried with
Na2SO4 and the toluene was removed under reduced
pressure to afford 0.47 g (83%) of an oil which partially
solidified after 2 days. 0.37 g (65.5%) of pure 4e was
obtained by sublimation (40–50 8C, 11 mm), mp 46–47 8C.
TLC (90% n-hexane/10% isopropyl alcohol) Rf¼0.45. IR
(CCl4) n: 3454, 2970, 1793, 1690 cm21. 1H NMR (CDCl3):
d 1.35 (s, 9H), 1.70 (s, 6H), 5.85 (s, 1H). 13C NMR (CDCl3):
d 23.7, 28.5, 51.5, 87.0, 114.3 (q, J¼286.5 Hz), 155.0 (q,
J¼42.0 Hz), 169.9. MS: m/z 255, 240, 184, 155, 126, 114,
98, 86, 69, 57 (base peak), 41. Anal. Calcd for
C10H16NO3F3: C, 47.06; H, 6.32; N, 5.49. Found: C,
47.32; H, 6.51; N, 5.57.
Rf¼0.35. IR (CCl4) n: 3446, 2973, 2935, 1739, 1687 cm21
.
1H NMR (CDCl3): d 1.22 (s, 9H), 1.35 (s, 9H), 1.59 (s, 6H),
5.86 (bs, 1H). 13C NMR (CDCl3): d 24.1, 27.1, 28.6, 39.1,
50.8, 81.6, 172.4, 176.3. MS: m/z 243, 228, 186, 185, 171,
158, 144, 114, 103, 102, 86, 85, 59, 58, 57 (base peak), 41.
Anal. Calcd for C13H25NO3: C, 64.16; H, 10.36; N, 5.76.
Found: C, 64.28; H, 10.47; N, 5.78.
4.1.3. Reaction of 1-tert-butyl-3,3-dimethylaziridinone
(5a) with benzoic acid. N-tert-Butyl-2-benzoyloxy-2-
methylpropanamide (4c). The toluene solution of the
a-lactam 1-tert-butyl-3,3-dimethylaziridinone (5a) (0.565 g,

1114
I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
4.1.6. Reaction of 1-(1-adamantyl)-3,3-dimethylaziridi-
none (5b) with acetic acid. N-(1-Adamantyl)-2-acetoxy-
2-methylpropanamide (4f). To a solution of crude 1-(1-
adamantyl)-3,3-dimethylaziridinone28 (0.493 g, 1.67 mmol)
in 25 mL of benzene at rt was added 0.502 g (8.35 mmol) of
acetic acid. The solution was stirred for 2.5 h then was
washed with 3£10 mL of distilled water, dried with
Na2SO4, filtered and rotary evaporated to give 0.51 g of a
white solid. After flash chromatography (90% n-hexane/
10% ethyl acetate), 0.38 g (81%) of a white solid (4f) with
mp 157–158 8C was obtained. TLC (90% n-hexane/10%
ethyl acetate) Rf¼0.20. IR (CCl4) n: 3439, 2910, 2848,
1750, 1685 cm21. 1H NMR (CDCl3): d 1.59 (s, 6H), 1.69 (s,
6H), 2.00 (s, 6H), 2.07 (s, 6H), 5.67 (bs, 1H). 13C NMR
(CDCl3): d 22.0, 24.3, 29.5, 36.4, 41.4, 51.6, 81.7, 169.1,
171.9. MS: m/z 279, 236, 222, 219, 178, 176, 150, 135 (base
peak), 102, 93, 79, 59, 43, 41. Anal. Calcd for C16H25NO3:
C, 68.79; H, 9.02; N, 5.01. Found: C, 69.05; H, 9.16; N,
4.91.
4.1.9. Reaction of 1-(1-adamantyl)-3,3-dimethylaziri-
dinone (5b) with trans-cinnamic acid. N-(1-Adamantyl)-
2-methyl-2-(trans-3-phenylacryloyloxy)propanamide
(4i). To a solution of crude 1-(1-adamantyl)-3,3-dimethyl-
aziridinone (0.493 g, 1.67 mmol) in 25 mL of benzene at rt
was added 1.24 g (8.35 mmol) of trans-cinnamic acid in
10 mL of benzene. The solution was stirred for 5 h then was
washed with 4£40 mL of 5% NaHCO3 and 2£40 mL of
distilled water, dried with Na2SO4, filtered and rotary
evaporated to give 0.60 g of a light yellow solid. After flash
chromatography (90% n-hexane/10% ethyl acetate), 0.37 g
(60%) of a white solid (4i) with mp 125–126 8C was
obtained. TLC (85% n-hexane/15% ethyl acetate) Rf¼0.39.
IR (CCl4) n: 3438, 3064, 3029, 2910, 2851, 1722, 1686,
1637 cm21. 1H NMR (CDCl3): d 1.68 (s, 12H), 2.03 (s, 6H),
2.08 (s, 3H), 5.74 (bs, 1H, exchangeable in D2O), 6.42 (d,
1H, J¼16.0 Hz), 7.40 (s, 3H), 7.53 (s, 2H), 7.68 (d, 1H,
J¼16.0 Hz). 13C NMR (CDCl3): d 25.0, 29.8, 36.7, 41.8,
52.0, 82.2, 118.7, 128.5, 129.3, 130.9, 134.6, 145.7, 165.5,
172.3. MS: m/z 367, 309, 238, 219, 190, 175, 150, 145, 135
(base peak), 131, 107, 103, 93, 91, 79, 77, 59, 41. Anal.
Calcd for C23H29NO3: C, 75.17; H, 7.95; N, 3.81. Found: C,
75.21; H, 8.13; N, 3.71.
4.1.7. Reaction of 1-(1-adamantyl)-3,3-dimethylaziri-
dinone (5b) with pivalic acid. N-(1-Adamantyl)-2-(2,2-
dimethylpropanoyloxy)-2-methylpropanamide (4g). To a
solution of crude 1-(1-adamantyl)-3,3-dimethylaziridinone
(0.493 g, 1.67 mmol) in 25 mL of benzene at rt was added
0.853 g (8.35 mmol) of pivalic acid. The solution was
stirred for 4 h then was washed with 4£40 mL of 5%
NaHCO3 and 2£40 mL of distilled water, dried with
Na2SO4, filtered and rotary evaporated to give 0.88 g of
an oil. After flash chromatography (92.5% n-hexane/7.5%
ethyl acetate), 0.40 g (74%) of a white solid (4g) with mp
65–67 8C was obtained. TLC (90% n-hexane/10% ethyl
acetate) Rf¼0.41. IR (CCl4) n: 3438, 2910, 2852, 1739,
1685 cm21. 1H NMR (CDCl3): d 1.22 (s, 9H), 1.59 (s, 6H),
1.69 (s, 6H), 1.99 (s, 6H), 2.08 (s, 3H), 5.75 (bs, 1H,
exchangeable in D2O). 13C NMR (CDCl3): d 24.1, 27.2,
29.5, 36.4, 39.1, 41.5, 51.4, 81.6, 172.2, 176.3. MS: m/z 321,
306, 263, 236, 219, 220, 192, 163, 150, 144, 135 (base
peak), 107, 103, 93, 85, 79, 67, 59, 57, 41. Anal. Calcd for
C19H31NO3: C, 70.99; H, 9.72; N, 4.36. Found: C, 71.01; H,
9.94; N, 4.29.
4.1.10. Reaction of 1-(1-adamantyl)-3,3-dimethylaziridi-
none (5b) with trifluoroacetic acid. N-(1-Adamantyl)-2-
methyl-2-trifluoroacetoxypropanamide (4j). To a solution
of 1-(1-adamantyl)-3,3-dimethylaziridinone (5b) (0.89 g,
0.004 mol) in 10 mL of ether at 0 8C, trifluoroacetic acid
(0.570 g, 0.005 mol) was added. The solution was stirred for
3 h. The ether was removed under reduced pressure to afford
crude N-(1-adamantyl)-2-methyl-2-trifluoroacetoxypropan-
amide 4j (81.9%). After flash chromatography (70%
n-hexane/30% ethyl acetate), 0.54 g (40.6%) of a white solid
with mp 100–102 8C was obtained. TLC (90% n-hexane/10%
ethyl acetate) Rf¼0.42. IR (CCl4) n: 3445, 2920, 2860, 1795,
1693 cm21. 1H NMR (CDCl3): d 1.67 (t, J¼2.7 Hz, 6H), 1.70
(s, 6H), 1.97 (d, J¼2.7 Hz, 6H), 2.08 (s, 3H), 5.68 (s, 1H). 13C
NMR (CDCl3): d 23.9, 29.6, 36.4, 41.5, 52.2, 87.0, 114.4 (q,
J¼287.0 Hz), 155.4 (q, J¼42.4 Hz), 169.7. MS: m/z 333, 219,
192, 176, 155,135(base peak), 107, 93, 69, 41. Anal. Calcdfor
C16H22NF3O3: C, 57.65; H, 6.65; N, 4.20. Found: C, 57.79; H,
6.67; N, 4.02.
4.1.8. Reaction of 1-(1-adamantyl)-3,3-dimethylaziridi-
none (5b) with benzoic acid. N-(1-Adamantyl)-2-benzoyl-
oxy-2-methylpropanamide (4h). To a solution of crude 1-
(1-adamantyl)-3,3-dimethylaziridinone (0.493 g, 1.67 mmol)
in 25 mL of benzene at rt was added 1.02 g (8.35 mmol) of
benzoic acid in 10 mL of benzene. The solution was stirred
for 3 h then was washed with 4£40 mL of 5% NaHCO3 and
2£40 mL of distilled water, dried with Na2SO4, filtered and
rotary evaporated to give 0.54 g of a white solid. After flash
chromatography (90% n-hexane/10% ethyl acetate), 0.43 g
(75%) of a white solid (4h) with mp 105–106 8C was
obtained. TLC (90% n-hexane/10% ethyl acetate) Rf¼0.24.
IR (CCl4) n: 3441, 2910, 2852, 1730, 1686 cm21. 1H NMR
(CDCl3): d 1.68 (s, 6H), 1.73 (s, 6H), 2.02 (s, 6H), 2.08 (s,
3H), 5.78 (bs, 1H, exchangeable in D2O), 7.47 (t, 2H, J¼7.0,
8.0 Hz), 7.59 (t, 1H, J¼7.0 Hz), 8.00 (d, 2H, J¼8.0 Hz). 13C
NMR (CDCl3): d 24.6, 29.5, 36.4, 41.5, 51.7, 82.3, 128.5,
129.5, 130.7, 133.2, 164.8, 171.9. MS: m/z 341, 283, 240,
219, 193, 192, 191, 164, 135 (base peak), 105, 77, 59. Anal.
Calcd for C21H27NO3: C, 73.87; H, 7.97; N, 4.10. Found: C,
74.02; H, 8.03; N, 4.04.
4.1.11. Reaction of 1-(1-adamantyl)-3-tert-butylaziridi-
none (5c) with acetic acid. N-(1-Adamantyl)-2-acetoxy-
3,3-dimethylbutanamide (4k). 1-(1-Adamantyl)-3-tert-
butylaziridinone (5c)20 (0.990 g, 0.004 mol) was dissolved
in benzene (30 mL). Acetic acid (0.480 g, 0.008 mol) was
added and the reaction refluxed for 2 h. After cooling to rt,
the reaction mixture was washed with 5% Na2CO3 (30 mL)
and twice with distilled water (20 mL). The organic layer
was dried with Na2SO4 and the benzene was removed under
reduced pressure to afford crude 4k (88%). After flash
chromatography (90% n-hexane/10% ethyl acetate), pure
N-(1-adamantyl)-2-acetoxy-3,3-dimethylbutanamide
was
obtained (63%), mp 138–140 8C. TLC (90% n-hexane/10%
ethyl acetate) Rf¼0.33. IR (CCl4) n: 3435, 3092, 3037, 2910,
2852, 1752, 1691 cm21. 1H NMR (CDCl3) d 1.01(s, 9H), 1.67
(s, 6H), 1.99 (s, 6H), 2.07 (s, 3H), 2.14 (s, 3H), 4.56 (s, 1H),
5.45 (bs, 1H). 13C NMR (CDCl3) d 26.7, 29.8, 32.0, 34.4, 36.7,
42.0, 52.3, 81.5, 167.6, 170.1. MS: m/z 307, 251, 232, 207,
178, 150, 135 (base peak), 120, 93, 79, 57, 43. Anal. Calcd for

I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1115
C18H29NO3: C, 70.32; H, 9.51; N, 4.56. Found: C, 70.10; H,
9.53; N, 4.66.
(CDCl3) d 1.07 (s, 9H), 1.67 (s, 6H), 2.00 (s, 6H), 2.07 (s,
3H), 4.82 (s, 1H), 5.54 (bs, 1H), 6.50 (d, J¼16.0 Hz, 1H),
7.44 (m, 3H), 7.55 (dd, J¼3.7 Hz, 2H), 7.76 (d, J¼16.0 Hz,
1H). 13C NMR (CDCl3) d 26.4, 29.4, 34.2, 36.3, 41.6, 52.0,
81.1, 117.2, 128.3, 129.1, 130.7, 134.1, 146.0, 165.7, 167.3.
MS (ES): m/z 417.9 (Mþ23), 395.8, 380.9, 313.1, 245.0.
Anal. Calcd for C25H33NO3: C, 75.91; H, 8.41; N, 3.54.
Found: C, 75.95; H, 8.39; N, 3.33.
4.1.12. Reaction of 1-(1-adamantyl)-3-tert-butylaziri-
dinone (5c) with pivalic acid. N-(1-Adamantyl)-3,3-
dimethyl-2-(2,2-dimethylpropanoyloxy)butanamide
(4l). 1-(1-Adamantyl)-3-tert-butylaziridinone (5c) (0.75 g,
0.003 mol) was dissolved in benzene (30 mL). Pivalic acid
was added (0.61 g, 0.006 mol) and the reaction was refluxed
for 2 h. The reaction mixture was then washed with 5%
NaHCO3 (30 mL), and twice with H2O (20 mL). The
organic layer was dried with Na2SO4, and the solvent was
removed under reduced pressure, to give a crude oil which
solidified (0.95 g, 90.5%). Crude 4 l was flash chromato-
graphed (90% n-hexane/10% ethyl acetate) to obtain pure
N-(1-adamantyl)-2-(2,2-dimethylpropanoyloxy)-3,3-dimethyl-
butanamide (0.38 g, 36.2%), mp 90–92 8C. TLC (80% n-
hexane/20% ethyl acetate): Rf¼0.64. IR (CCl4) n: 3437,
4.1.15. Reaction of 1,3-di-tert-butylaziridinone (5d) with
acetic acid. N-tert-Butyl-2-acetoxy-3,3-dimethylbutana-
mide (4p). 1,3-di-tert-Butylaziridinone29 (5d) (0.68 g,
0.004 mol) was dissolved in benzene (30 mL). Acetic acid
(0.48 g, 0.008 mol) was added and the reaction refluxed for
2 h. After cooling to rt, the reaction mixture was washed
with 5% NaHCO3 (30 mL) and twice with distilled water
(20 mL). The organic layer was dried with Na2SO4 and the
benzene was removed under reduced pressure to afford
crude 4p (0.90 g, 98.1%) as an oil which solidified
overnight. After recrystallization from 1 mL of n-hexane,
0.61 g (66.5%) of a white solid was obtained, mp 62–63 8C.
TLC (80% n-hexane/20% ethyl acetate) Rf¼0.44. IR (CCl4)
n: 3440, 2965, 1738, 1683, 1505 cm21. 1H NMR (CDCl3) d
0.98 (s, 9H), 2.11 (s, 3H), 4.64 (s, 1H), 5.57 (s, 1H). 13C
NMR (CDCl3) d 21.0, 26.4, 28.8, 34.2, 51.4, 81.2, 167.7,
169.9. MS: m/z 229, 214, 186, 173, 157, 131, 129, 87, 75, 57
(base peak), 43.
1
2910, 1742, 1687 cm21. H NMR (CDCl3) d 1.02 (s, 9H),
1.26 (s, 9H), 1.67 (s, 6H), 1.98 (s, 6H), 2.07 (s, 3H), 4.68 (s,
1H), 5.48 (s, 1H). 13C NMR (CDCl3) d 26.4, 27.2, 29.4,
34.2, 36.3, 38.9, 41.6, 51.8, 80.6, 167.6, 176.5. MS: m/z 349,
293, 249, 232, 208, 172, 163, 135 (base peak), 117, 85, 70,
57. Anal. Calcd for C21H35NO3: C, 72.17; H, 10.09; N, 4.01.
Found: C, 72.26; H, 10.15; N, 4.05.
4.1.13. Reaction of 1-(1-adamantyl)-3-tert-butylaziridinone
(5c) with benzoic acid. N-(1-Adamantyl)-2-benzoyloxy-3,3-
dimethylbutanamide (4m). 1-(1-Adamantyl)-3-tert-butylaziri-
dinone (5c) (0.75 g, 0.003 mol) was dissolved in benzene
(30 mL). Benzoic acid (0.73 g, 0.006 mol) was added and the
reaction refluxed for 2 h. After cooling to rt, the reaction mixture
was washed with 5% NaHCO3 (30 mL) and twice with distilled
water (20 mL). The organic layer was dried with Na2SO4 and
the benzene was removed under reduced pressure to afford
crude 4m (0.86 g, 77.5%). After flash chromatography
(95% n-hexane/5% ethyl acetate), pure 4m (0.645 g, 58.2%)
was obtained, mp 163–165 8C. TLC (80% n-hexane/20%
ethyl acetate): Rf¼0.67. IR (CCl4) n: 3436, 2911, 2852,
4.1.16. Reaction of 1,3-di-tert-butylaziridinone (5d) with
pivalic acid. N-tert-Butyl-3,3-dimethyl-2-(2,2-dimethyl-
propanoyloxy)butanamide (4q). 1,3-di-tert-Butylaziridi-
none (5d) (0.68 g, 0.004 mol) was dissolved in benzene
(30 mL). Pivalic acid (0.817 g, 0.008 mol) was added and the
reaction refluxed for 30 min. After cooling to rt, the reaction
mixture was washed with 5% NaHCO3 (30 mL) and twice
with distilled water (20 mL). The organic layer was dried with
Na2SO4 and the benzene was removed under reduced pressure
to afford crude 4q (0.91 g, 83.8%). Crude 4q was flash
chromatographed (95% n-hexane/5% ethyl acetate) to obtain
pure N-tert-butyl-2-(2,2-dimethylpropanoyloxy)-3,3-dimethyl-
butanamide (4q) (0.869 g, 80%), mp 87–88 8C. TLC (90% n-
hexane/10% ethyl acetate) Rf¼0.48. IR (CCl4) n: 3427, 3370,
1
1734, 1688, 1513 cm21. H NMR (CDCl3) d 1.14 (s, 9H),
1.66 (s, 6H), 1.99 (s, 6H), 2.06 (s, 3H), 4.93 (s, 1H), 5.55 (s,
1H), 7.48 (m, 2H), 7.63 (m, 1H), 8.10 (m, 2H). 13C NMR
(CDCl3) d 26.5, 29.4, 34.4, 36.3, 41.6, 52.0, 81.5, 128.7,
133.4, 165.2, 167.2. MS: m/z 369, 313, 283, 269, 240, 208,
192, 177, 135 (base peak), 105, 79, 77, 70. Anal. Calcd for
C23H31NO3: C, 74.76; H, 8.46; N, 3.79. Found: C, 74.79; H,
8.62; N, 3.69.
1
2955, 2860, 1735, 1667, 1505 cm21. H NMR (CDCl3) d
0.99 (s, 9H), 1.24 (s, 9H), 1.30 (s, 9H), 4.66 (s, 1H), and 5.59
(s, 1H). 13C NMR (CDCl3) d 26.5, 27.3, 28.8, 34.4, 39.0,
51.3, 80.8, 167.8, and 176.7. MS: m/z 271, 256, 215, 199,
172, 157, 143, 130, 102, 85, 71, 57 (base peak), 41.
4.1.14. Reaction of 1-(1-adamantyl)-3-tert-butylaziridi-
none (5c) with trans-cinnamic acid. N-(1-Adamantyl)-
3,3-dimethyl-2-(trans-3-phenylacryloyloxy)butanamide
(4n). 1-(1-Adamantyl)-3-tert-butylaziridinone (5c) (0.75 g,
0.003 mol) was dissolved in benzene (30 mL). trans-
Cinnamic acid (0.89 g, 0.006 mol) was added and the
reaction refluxed for 2 h. After cooling to rt, the reaction
mixture was washed with 5% NaHCO3 (30 mL) and twice
with distilled water (20 mL). The organic layer was dried
with Na2SO4 and the benzene was removed under reduced
pressure to afford crude 4n (1.04 g, 100%). After recrys-
tallization from 6 mL hot n-heptane, a white solid (0.77 g,
74.0%) with mp 122–123 8C was obtained. TLC (80% n-
hexane/20% ethyl acetate) Rf¼0.52. IR (CCl4) n: 3429,
3060, 2910, 1732, 1687, 1638, 1549, 1512 cm21. 1H NMR
4.1.17. Reaction of 1,3-di-tert-butylaziridinone (5d) with
benzoic acid. N-tert-Butyl-2-benzoyloxy-3,3-dimethyl-
butanamide (4r). 1,3-di-tert-Butylaziridinone (5d) (0.68 g,
0.004 mol) was dissolved in benzene (30 mL). Benzoic acid
(0.98 g, 0.008 mol) was added and the reaction refluxed for
2 h. After cooling to rt, the reaction mixture was washed
with 5% NaHCO3 (30 mL) and twice with distilled water
(20 mL). The organic layer was dried with Na2SO4 and the
benzene was removed under reduced pressure to afford crude
4r (0.92 g, 79%). After recrystallization from n-heptane/ethyl
acetate (5 mL/2 mL), 0.44 g (37.6%) of a white solid with
mp 128–129 8C was obtained. TLC (90% n-hexane/10%
ethyl acetate) Rf¼0.68. IR (CCl4) n: 3440, 3380, 3060,
2965, 2870, 1720, 1685, 1598, 1505 cm21 1H NMR
.
(CDCl3) d 1.10 (s, 9H), 1.32 (s, 9H), 4.91 (s, 1H), 5.70 (s,

1116
I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1H), 7.47 (m, 2H), 7.59 (m, 1H), 8.09 (m, 2H). 13C NMR
(CDCl3) d 26.6, 28.8, 34.6, 51.4, 81.7, 128.8, 129.8, 133.6,
165.4, 167.6. MS: m/z 291, 276, 253, 235, 219, 192, 177,
143, 130, 105 (base peak), 87, 77, 70, 57, 41.
of ice–cold water to give 0.200 g of crude pivalaldehyde
semicarbazone which was recrystallized from 5 mL of hot
water to give 0.160 g (77%) of pure product, mp 186–188 8C
(reported37 mp 191 8C). TLC, IR, and MS were identical with
those of an authentic sample prepared from pivalaldehyde and
semicarbazide hydrochloride.
4.1.18. Reaction of 1,3-di-tert-butylaziridinone (5d) with
trans-cinnamic acid. N-tert-Butyl-3,3-dimethyl-2-(trans-
3-phenylacryloyloxy)butanamide (4s). 1,3-di-tert-Butyl-
aziridinone (5d) (0.68 g, 0.004 mol) was dissolved in
benzene (30 mL). trans-Cinnamic acid (1.19 g, 0.008 mol)
was added and the reaction refluxed for 2 h. After cooling to
rt, the reaction mixture was washed with 5% NaHCO3
(30 mL) and twice with distilled water (20 mL). The organic
layer was dried with Na2SO4 and the benzene was removed
under reduced pressure to afford crude 4s (1.22 g, 96.2%).
After recrystallization from methylene chloride/n-heptane
(1 mL:3 mL), 0.83 g (65.4%) of a white solid was
obtained, mp 97–98 8C. TLC (80% n-hexane/20% ethyl
acetate) Rf¼0.46. IR (CCl4) n: 3440, 2960, 2868, 1715,
To the filtrate was added NaHCO3 until pH¼8 and stirred
for 1 h at 0 8C. It was then filtered to give 0.135 g (61%) of
pure adamantanamine, mp 203–205 8C. TLC, IR, and MS
were identical with those of an authentic sample of
adamantanamine (Aldrich).
4.1.21. Reaction of 1,3-di-tert-butylaziridinone (5d) with
1 equiv. of trifluoroacetic acid. tert-Butyl ammonium
trifluoroacetate (15d). Dropwise over a period of 5 min, a
solution of trifluoroacetic acid (0.650 g, 5.7 mmol) in 5 mL
of THF was added to a solution of 1,3-di-tert-butylaziri-
dinone (5d) (0.96 g, 5.7 mmol) in 15 mL of THF at 0 8C.
The solution stirred for 3 h slowly reaching a temperature of
10 8C and then the THF was removed under reduced
pressure to give 1.22 g of a white solid. It was recrystallized
from hot n-heptane/isopropyl alcohol (3 mL/1 mL) to give
0.87 g (82%) of tert-butyl ammonium trifluoroacetate (15d),
mp 185–187 8C. 1H NMR (DMSO-d6) d 1.26 (s, 9H), 8.04
(bs, 3H). 13C NMR (DMSO-d6) d 27.0, 50.8, 117.1 (q,
J¼299.0 Hz), 158.6 (q, J¼31.6 Hz). MS: m/z 97, 69, 58, 45.
Anal. Calcd for C6H12F3NO2: C, 38.50; H, 6.42; F, 30.48;
N, 7.49. Found: C, 38.67; H, 6.49; F, 30.75; N, 7.47.
1
1680, 1633, 1505 cm21. H NMR (CDCl3) d 1.06 (s, 9H),
1.33 (s, 9H), 4.81 (s, 1H), 5.70 (s, 1H), 6.50 (d, 1H,
J¼16.0 Hz), 7.38 (m, 3H), 7.54 (m, 2H), 7.74 (d, 1H,
J¼16.0 Hz). 13C NMR (CDCl3) d 26.6, 28.8, 34.4, 51.4, 81.2,
117.3,128.4,129.1,130.8,134.2,146.2,165.8,167.7.MS:m/z
317, 261, 245, 231, 218, 175, 162, 149, 131 (base peak), 103,
77, 70, 57, 41.
4.1.19. Reaction of 1-(1-adamantyl)-3-tert-butylaziri-
dinone (5c) with 1 equiv. of trifluoroacetic acid.
1-Adamantan ammonium trifluoroacetate (15c). Drop-
wise, over a period of 5 min, a solution of trifluoroacetic
acid (0.659 g, 5.78 mmol) in 5 mL of THF was added to a
solution of 1-(1-adamantyl)-3-tert-butylaziridinone (5c)
(1.43 g, 5.78 mmol) in 20 mL of THF at 0 8C. The solution
stirred for 3 h slowly reaching a temperature of 10 8C and
then the THF was removed under reduced pressure to
give 1.77 g of a white solid. It was recrystallized from hot
n-heptane/isopropyl alcohol (15 mL:5 mL) to give 1.26 g
(82%) of 1-adamantan ammonium trifluoroacetate (15c),
mp 298–300 8C. IR (KBr) n: 2914, 1668, 1541, 1455,
4.1.22. tert-Butyl ammonium trifluoroacetate (15d). To a
solution of tert-butylamine (1.76 g, 0.024 mol) in 27 mL of
THF is added trifluoroacetic acid (2.96 g, 0.026 mol) in one
portion at rt. It is stirred for 17 h then evaporated to dryness
to give 3.8 g of a white solid. It was recrystallized from n-
heptane/isopropyl alcohol (24 mL/7 mL) to give 3.2 g
1
(71%) of a white solid (15d), mp 187–189 8C. H NMR
(DMSO-d6) d 1.26 (s, 9H), 8.04 (bs, 3H). 13C NMR
(DMSO-d6) d 27.0, 50.8, 117.1 (q, J¼299.0 Hz), 158.6 (q,
J¼31.6 Hz). MS: m/z. 97, 69, 58, 45.
1365 cm21
.
1H NMR (DMSO-d6) d 1.59 (dd, 6H,
J¼10.0 Hz), 1.77 (s, 6H), 2.06 (s, 3H), 8.03 (bs, 3H,
exchanges in D2O). 13C NMR (DMSO-d6) d 28.4, 35.2,
50.9, 117.1 (q, J¼299.0 Hz), 158.6 (q, J¼31.0 Hz). Anal.
Calcd for C12H18F3NO2: C, 54.33; H, 6.84; N, 5.28. Found:
C, 54.35; H, 6.76; N, 5.27.
4.1.23. Reaction of 1,3-di-tert-butylaziridinone (5d) with
2 equiv. of trifluoroacetic acid. N-tert-Butyl-2,2-
dimethyl-1-(trifluoroacetyloxy)propan-1-aminium tri-
fluoroacetate (16). Dropwise, a solution of trifluoroacetic
acid (0.91 g, 0.008 mol) in 10 mL of benzene was added to a
solution of 1,3-di-tert-butylaziridinone (5d) (0.68 g,
0.004 mol) in 5 mL of benzene at 10 8C. The resulting
mixture was stirred overnight and then filtered to yield pure
16 (74%), mp 119–120 8C. IR (KBr) n: 2990, 1785, 1691,
1485 cm21. 1H NMR (CDCl3) d 1.17 (s, 9H), 1.36 (s, 9H),
4.78 (s, 1H), 8.33 (s, 2H, exchangeable in D2O). 13C NMR
(CDCl3) d 23.8, 25.5, 36.4, 51.0, 60.9, 115.1 (q,
J¼291.0 Hz), 161.3 (q, J¼36.0 Hz), 182.9. Anal. Calcd
for C13H21F6NO4: C, 42.28; H, 5.73; F, 30.87; N, 3.79; O,
17.33. Found: C, 42.42; H, 5.73; N, 3.77.
4.1.20. Reaction of 1-(1-adamantyl)-3-tert-butylaziridi-
none (5c) with trifluoroacetic acid followed by hydroly-
sis. To 0.36 g (1.46 mmol) of 1-(1-adamantyl)-3-tert-
butylaziridinone in 10 mL of benzene was added a solution
of trifluoroacetic acid (0.347 g, 3.04 mmol) in 5 mL of
benzene and it stirred at rt for 66 h (immediately upon
addition of trifluoroacetic acid gas evolution was observed).
The benzene was removed under reduced pressure to yield a
solid to which 9 mL of hexane was added and the mixture
was stored at 220 8C for several hours. It was then filtered
to give 0.481 g of a white solid, which was added to a
solutionofsemicarbazide hydrochloride (0.186 g,1.67 mmol)
and sodium acetate (0.151 g, 1.84 mmol) in 10 mL of water
and stirred at rt for 7.5 h. It was then cooled down in an ice-
bath for 15 min. The reaction mixture was filtered over a
sintered disc Bu¨chner funnel and the solid washed with 5 mL
4.1.24. Reaction of 1,3-di-tert-butylaziridinone (5d) with
trifluoroacetic acid followed by hydrolysis. To 0.611 g
(3.6 mmol) of 1,3-di-tert-butylaziridinone in 20 mL of
benzene is added a solution of trifluoroacetic acid (0.912 g,
8 mmol) in 10 mL of benzene and is stirred at rt for 3 days
(immediately upon addition of trifluoroacetic acid gas

I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1117
evolution was observed). The benzene was removed under
reduced pressure to yield a solid to which 6 mL of hexane
was added and the mixture was stored at 220 8C for
overnight. The precipitate was then filtered to give 0.97 g of
a white solid, which was subsequently added to a solution
of semicarbazide hydrochloride (0.491 g, 4.4 mmol) and
sodium acetate (0.397 g, 4.84 mmol) in 20 mL of water and
stirred at rt for 2 days. It was then cooled down in an ice-
bath for 15 min. The reaction mixture was filtered over a
sintered disc Bu¨chner funnel and the solid washed with
5 mL of ice–cold water to give 0.270 g (52%) of pure
pivalaldehyde semicarbazone, mp 186–188 8C. TLC, IR,
and MS were identical with those of an authentic sample
prepared directly from authentic pivalaldehyde and semi-
carbazide hydrochloride. No effort was made to isolate the
other hydrolysis product, tert-butylamine.
butyl-3,3-dimethylaziridinone (0.317 g, 2.25 mmol) in
25 mL of toluene at 0 8C was added 0.133 g (1.12 mmol)
of succinic acid in 6 mL of THF. The solution was stirred
overnight slowly coming to rt for 19 h then was washed with
4£35 mL of 5% NaHCO3 and 2£35 mL of distilled water,
dried with Na2SO4, filtered and rotary evaporated to give
0.40 g of an oil which crystallized upon standing. After flash
chromatography (65% n-hexane/35% ethyl acetate), 0.29 g
(65%) of a white solid (13a) with mp 106–108 8C was
obtained. TLC (60% n-hexane/40% ethyl acetate) Rf¼0.34.
IR (CCl4) n: 3446, 3402, 2966, 2929, 1745, 1686,
1
1637 cm21. H NMR (CDCl3): d 1.35 (s, 18H), 1.59 (s,
12H), 2.62 (s, 4H), 5.94 (bs, 2H). 13C NMR (CDCl3): d 24.5,
28.6, 29.7, 51.1, 82.2, 170.6, 171.9. MS: m/z 401, 385, 345,
301, 242, 228, 215, 187, 160, 142, 114, 101, 86, 69, 59, 58,
57, 41. Anal. Calcd for C20H36N2O6: C, 59.98; H, 9.06; N,
6.99. Found: C, 60.03; H, 9.08; N, 6.90.
4.1.25. Reaction of 1-tert-butyl-3,3-dimethylaziridinone
(5a) with maleic acid. Di(2-methyl-N-tert-butylpropana-
mido-2-)maleate (12a). To a solution of crude 1-tert-butyl-
3,3-dimethylaziridinone (0.317 g, 2.25 mmol) in 17 mL of
toluene at 0 8C was added 0.130 g (1.125 mmol) of maleic
acid in 15 mL of THF. The solution was stirred for 15 h
slowly coming to rt. The solvents were evaporated under
reduced pressure and the residue was taken up into 50 mL of
methylene chloride and washed with 3£30 mL of 5%
NaHCO3 and 2£30 mL of distilled water, dried with
Na2SO4, filtered and rotary evaporated to give 0.36 g of a
white solid. After flash chromatography (60% n-hexane/
40% ethyl acetate), 0.33 g (73%) of a white solid (12a) with
mp 148–149 8C was obtained. TLC (60% n-hexane/40%
ethyl acetate) Rf¼0.36. IR (CCl4) n: 3448, 3401, 2973,
1731, 1687, 1642 cm21. 1H NMR (CDCl3): d 1.36 (s, 18H),
1.61 (s, 12H), 6.26 (s, 2H), 6.30 (bs, 2H, exchangeable in
TFD). 13C NMR (CDCl3): d 24.6, 28.6, 51.2, 83.2, 130.2,
163.4, 171.3. MS: m/z 398, 383, 343, 326, 299, 256, 228,
160, 143 (base peak), 114, 87, 58, 57, 41.
4.1.28. Reaction of 1-(1-adamantyl)-3,3-dimethylaziridi-
none (5b) and succinic acid. Di[2-methyl-1-(1-adaman-
tyl)propanamido-2-]succinate (13b). To a solution of 1-(1-
adamantyl)-3,3-dimethylaziridinone (5b) (0.48 g, 0.002 mol)
in 15 mL of THF at 0 8C, succinic acid (0.12 g, 0.001 mol)
was added. The solution stirred for 7.5 h. THF was removed
under reduced pressure. The residue was dissolved in
methylene chloride (30 mL) and washed with 5% NaHCO3
(15 mL) and distilled water (2£15 mL). The organic
layer was dried with Na2SO4 and the methylene chloride
was removed under reduced pressure to afford crude
di[2-methyl-1-(1-adamantyl)propanamido-2]succinate (13b)
(68.5%). After washing with hot n-heptane and ethyl
acetate, a white solid with mp 216–218 8C was obtained.
TLC (70% n-hexane/30% ethyl acetate) Rf¼0.34. IR (CCl4)
n: 3420, 2900, 2838, 1735, 1678 cm21. (KBr) n: 3390,
2900, 2840, 1730, 1663 cm21. 1H NMR (CDCl3) d 1.55 (s,
12H), 1.64 (s, 12H), 1.97 (s, 12H), 2.04 (s, 6H), 2.58 (s, 4H),
and 5.76 (s, 2H). 13C NMR (CDCl3) d 24.7, 29.6, 29.8, 36.5,
41.4, 51.9, 82.2, 170.7, 171.8. Anal. Calcd for C32H48N2O6:
C, 69.04; H, 8.69; N, 5.03. Found: C, 68.90; H, 8.80; N,
5.15.
4.1.26. Reaction of 1-(1-adamantyl)-3,3-dimethylaziridi-
none (5b) with maleic acid. Di[2-methyl-N-(1-adamantyl)
propanamido-2-]maleate (12b). To a solution of crude 1-(1-
adamantyl)-3,3-dimethylaziridinone (0.366 g, 1.67 mmol) in
25 mL of benzene at rt was added 0.097 g (0.835 mmol) of
maleic acid in 8 mL of THF. The solution was stirred for
20 h and the solvents were evaporated under reduced
pressure to give an oil which was taken up into 60 mL of
benzene and washed with 3£30 mL of 5% NaHCO3 and
2£30 mL of distilled water, dried with Na2SO4, filtered and
rotary evaporated to give 0.47 g of a white solid. After flash
chromatography (75% n-hexane/25% ethyl acetate), 0.39 g
(84%) of a white solid (12b) with mp 205–206 8C was
obtained. TLC (70% n-hexane/30% ethyl acetate) Rf¼0.33.
IR (CCl4) n: 3439, 3394, 2910, 2852, 1732, 1684,
4.1.29. Reaction of 1-(1-adamantyl)-3-tert-butylaziri-
dinone with succinic acid. Di[3,3-dimethyl-1-(1-adaman-
tyl)butanamido-2-]succinate (13c). To a solution of 1-(1-
adamantyl)-3-tert-butylaziridinone (5c) (1.63 g, 0.0066 mol)
in 20 mL of dioxane succinic acid (0.35 g, 0.003 mol) was
added. The solution was refluxed for 10 h. Dioxane was
removed under reduced pressure and the residue was taken
up into 25 mL of ethyl acetate and washed with 5%
NaHCO3 (20 mL) and distilled water (2£15 mL). The
organic layer was dried with Na2SO4 and the ethyl acetate
was removed under reduced pressure to afford 0.81 g (44%)
of crude 13c which was recrystallized twice from isopropyl
alcohol (17 and 11 mL) to give 0.22 g (12.0%) of a white
solid (13c) with mp 244–246 8C. TLC (70% n-hexane/30%
ethyl acetate) Rf¼0.58. IR (CCl4) n: 3420, 2900, 2840,
1735, 1675 cm21. 1H NMR (CDCl3) d 1.0 (s, 18H), 1.7 and
2.0 (s, 30H), 2.65 (s, 4H), and 4.65 (s, 2H). 13C NMR
(CDCl3) d 26.5, 29.1, 29.6, 34.1, 36.5, 41.6, 52.2, 81.8,
167.0, 171.3. High resolution MS: m/z 612, 556, 500, 435,
379, 347, 321, 264, 209, 135 (base peak), 107, 79, 57. Anal.
Calcd for C36H56N2O6: C, 70.55; H, 9.21; N, 4.57. Found:
C, 70.34; H, 9.27; N, 4.39.
1
1635 cm21. H NMR (CDCl3): d 1.61 (s, 12H), 1.68 (s,
12H), 2.02 (s, 12H), 2.07 (s, 6H), 6.16 (s, 2H, exchangeable
in D2O), 6.24 (s, 2H). 13C NMR (CDCl3): d 24.7, 29.5, 36.4,
41.3, 52.0, 83.1, 130.2, 163.3, 171.1. Anal. Calcd for
C32H46N2O6: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.26;
H, 8.27; N, 4.93.
4.1.27. Reaction of 1-tert-butyl-3,3-dimethylaziridinone
with succinic acid. Di(2-methyl-N-tert-butylpropana-
mido-2-)succinate (13a). To a solution of crude 1-tert-

1118
I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
4.1.30. Reaction of 1,3-di-tert-butylaziridinone with
succinic acid. Di(3,3-dimethyl-1-tert-butylbutanamido-
2-)succinate (13d). To a solution of 1,3-di-tert-butylaziri-
dinone (5d) (2.99 g, 0.0177 mol) in 30 mL of THF, succinic
acid (0.95 g, 0.008 mol) was added. The solution was
refluxed for 6 h. Dioxane was removed under reduced
pressure and the residue was taken up into 40 mL of ethyl
acetate and washed with 5% NaHCO3 (30 mL) and distilled
water (2£25 mL). The organic layer was dried with Na2SO4
and the ethyl acetate was removed under reduced pressure to
afford 1.89 g (51.8%) of crude 13d which was recrystallized
from 12 mL of hexane/ethyl acetate. It was filtered and the
filtrate was evaporated to give 1.35 g of a sticky solid which
was recrystallized twice from n-heptane to give 0.89 g
(24.4%) of solid 13d with mp 156–157 8C. TLC (70%
n-hexane/30% ethyl acetate) Rf¼0.35. IR (CCl4) n: 3443,
C13H25NO3: C, 64.16; H, 10.35; N, 5.76. Found: C, 64.34;
H, 10.48; N, 5.76.
4.2.3. Passerini reaction between benzoic acid, acetone,
and tert-butyl isonitrile. N-tert-Butyl-2-benzoyloxy-2-
methylpropanamide (4c). A solution of tert-butyl isonitrile
(1.66 g, 0.02 mol), benzoic acid (2.44 g, 0.02 mol), and a
catalytic amount of p-toluene sulfonic acid in 10 mL of
acetone was stirred overnight at room temperature. The
excess acetone was removed under reduced pressure and the
remaining residue was dissolved in 30 mL of ethyl acetate.
This solution was washed with 5% NaHCO3 (30 mL) and
distilled water (2£20 mL). The organic layer was dried with
Na2SO4 and the ethyl acetate was removed under reduced
pressure to afford crude 4c (5.27 g, 100%). After recrys-
tallization from 5 mL of carbon tetrachloride, a white solid
(1.63 g, 30.9%) with mp 88–89 8C was obtained. The
mother liquor was evaporated to yield 2.40 g (45.5%) of
a nearly pure second crop with mp 80–84 8C. TLC (80%
n-hexane/20% ethyl acetate) Rf¼0.52. IR (CCl4) n: 3435,
3050, 2955, 1722, 1680, 1505 cm21. 1H NMR (CDCl3) d 1.35
(s, 9H), 1.72 (s, 6H), 5.89 (s, 1H), 7.44 (t, 2H, J¼7.7 Hz), 7.56
(t, 1H, J¼7.5 Hz), 7.97 (d, 2H, J¼7.5 Hz). 13C NMR (CDCl3)
d 24.7, 28.8, 51.2, 82.5, 128.7, 129.6, 130.7, 133.4, 164.9, and
172.3. MS: m/z 263, 205, 191, 164, 146, 123, 105 (base peak),
77, 59, 57. Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N,
5.32. Found: C, 68.37; H, 7.98; N, 5.27.
1
2967, 2876, 1746, 1686 cm21. H NMR (CDCl3) d 1.0 (s,
18H), 1.32 (s,18H), 2.7 (s, 4H), 4.6 (s, 2H), and 5.65 (s, 2H).
4.2. Passerini reactions
4.2.1. Passerini reaction between acetic acid, acetone,
and tert-butyl isonitrile. N-tert-Butyl-2-acetoxy-2-
methylpropanamide (4a). To a solution of acetic acid
(1.80 g, 0.03 mol) in acetone (10 mL), tert-butyl isonitrile
(2.49 g, 0.03 mol) was added. The solution was seeded with
p-toluene sulfonic acid and sat overnight. The excess
acetone was removed under reduced pressure. The residue
was dissolved in ethyl acetate (30 mL) and washed with 5%
NaHCO3 (30 mL) and distilled water (2£20 mL). The
organic layer was dried with Na2SO4 and the ethyl acetate
removed under reduced pressure to afford crude 4a (3.03 g,
75.2%). After recrystallization from 10 mL n-heptane, a
white solid (2.66 g, 66%) with mp 78–79 8C was obtained.
TLC (80% n-hexane/20% ethyl acetate) Rf¼0.42. IR (CCl4)
n: 3430, 2955, 1739, 1680, 1505 cm21. 1H NMR (CDCl3) d
4.2.4. Passerini reaction between trans-cinnamic acid,
acetone, and tert-butyl isonitrile. N-tert-Butyl-2-methyl-
2-(trans-3-phenylacryloyloxy)propanamide (4d). To a
solution of trans-cinnamic acid (1.00 g, 0.00675 mol) in
an excess amount of acetone (10 mL), tert-butyl isonitrile
(0.561 g, 0.00675 mol) dissolved in 2 mL of acetone was
added dropwise at room temperature. The reaction mixture
was stirred for 6 days. The excess acetone and unreacted
tert-butylisonitrile were removed under reduced pressure.
The residue was dissolved in 30 mL of methylene chloride,
washed with 2£30 mL of 5% NaHCO3, 3£50 mL of
distilled water, the organic layer dried with Na2SO4, and
the methylene chloride was removed under pressure to yield
1.06 g (54.3%) of 4d, mp 96–98 8C. TLC (80% n-hexane/
20% ethyl acetate) Rf¼0.52. IR (CCl4): 3446, 3085, 3064,
3030, 2950, 1720, 1693, 1635. 1H NMR (CDCl3): d 1.37 (s,
9H), 1.68 (s, 6H), 5.86 (bs, 1H), 6.42 (d, J¼16.0 Hz, 1H),
7.40–7.53 (m, 5H), 7.67 (d, J¼16.0 Hz, 1H). 13C NMR
(CDCl3): d 24.5, 28.7, 51.0, 81.9, 118.3, 128.2, 129.0, 130.5,
134.2, 145.4, 165.1, 172.2. MS: m/z 231, 217, 190, 175, 172,
145, 131 (base peak), 103, 77, 59, 57, 51, 41.
1.30 (s, 9H), 1.55 (s, 6H), 2.02 (s, 3H), and 5.78 (s, 1H). 13
C
NMR (CDCl3) d 22.1, 24.4, 51.1, 81.8, 169.2, 172.2. MS: m/z
201, 186, 158, 144, 129, 115, 102, 101, 88, 86, 61, 59, 58,
57, 43 (base peak). Anal. Calcd for C10H19NO3: C, 59.68; H,
9.52; N, 6.96. Found: C, 59.76; H, 9.53; N, 6.96.
4.2.2. Passerini reaction between pivalic acid, acetone,
and tert-butyl isonitrile. N-tert-Butyl-2-(2,2-dimethyl-
propanoyloxy)-2-methylpropanamide (4b). A solution
of tert-butyl isonitrile (1.66 g, 0.02 mol), pivalic acid
(2.04 g, 0.02 mol), and a catalytic amount of p-toluene
sulfonic acid in 10 mL of acetone was stirred overnight at
room temperature. The excess acetone was removed under
reduced pressure and the remaining residue was dissolved in
20 mL of methylene chloride. This solution was washed
with 5% NaHCO3 (20 mL) and distilled water (2£20 mL).
The organic layer was dried with Na2SO4 and the methylene
chloride was removed under reduced pressure to afford crude
4b (2.20 g, 45.2%), a light yellow oil which crystallized upon
standing. After recrystallization from 3.5 mL of n-heptane,
a white solid with mp 50–51 8C was obtained. TLC (90%
n-hexane/10% ethyl acetate) Rf¼0.40. IR (CCl4) n: 3430,
2960, 1730, 1680, 1505 cm21. 1H NMR (CDCl3) d 1.18 (s,
9H), 1.31 (s, 9H), 1.55 (s, 6H), 5.82 (s, 1H). 13C NMR
(CDCl3): d 24.1, 27.1, 28.6, 39.1, 50.8, 81.6, 172.4, 176.3.
MS: m/z 243, 228, 186, 185, 171, 158, 144, 114, 103, 102,
86, 85, 59, 58, 57 (base peak), 41. Anal. Calcd for
4.2.5. Passerini reaction between trifluoroacetic acid,
acetone, and tert-butyl isonitrile. N-tert-Butyl-2-methyl-
2-trifluoroacetoxypropanamide (4e). A solution of tert-
butyl isonitrile (1.66 g, 0.02 mol) in 5 mL of acetone was
added dropwise to a solution of trifluoroacetic acid (3.42 g,
0.03 mol) in 10 mL of acetone at 210 8C over a period of
10 min. The ice-bath was then removed and the solution
stirred at rt for 2 days. Excess acetone was evaporated under
reduced pressure to yield 6.36 g of a light yellow oil which
was taken up into 30 mL of ethyl acetate and washed with
30 mL of 5% NaHCO3, 2£20 mL of distilled water, dried
with Na2SO4, filtered and rotary evaporated to give 3.30 g
(64.7%) of a light yellow oil which solidified after 3 days. It

I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1119
was purified by vacuum sublimation (40–50 8C at 11 mm)
to give 2.4 g (47%) of a white solid 4e, mp 45–46 8C. TLC
(90% n-hexane/10% isopropyl alcohol) Rf¼0.45. IR (CCl4)
n: 3454, 2970, 1793, 1690 cm21. 1H NMR (CDCl3): d 1.35
(s, 9H), 1.70 (s, 6H), 5.85 (s, 1H). 13C NMR (CDCl3): d
23.7, 28.5, 51.5, 87.0, 114.3 (q, J¼286.5 Hz), 155.0 (q,
J¼42.0 Hz), 169.9. MS: m/z 255, 240, 184, 155, 126, 114,
98, 86, 69, 57 (base peak), 41. Anal. Calcd for
C10H16F3NO3: C, 47.06; H, 6.32; N, 5.49. Found: C,
47.32; H, 6.51; N, 5.57.
acetone was removed under reduced pressure and the
residue was dissolved in 30 mL of ethyl acetate, washed
with 5% NaHCO3 (30 mL) and distilled water (2£20 mL),
dried with Na2SO4 and the ethyl acetate was removed under
reduced pressure to afford 0.87 g (68.5%) of a white solid. It
was flash chromatographed (90% n-hexane/10% ethyl
acetate) to give 0.41 g (32.3%) of a white solid (4h), mp
101–103 8C. TLC (90% n-hexane/10% ethyl acetate)
1
Rf¼0.24. IR (CCl4): n¼3441, 2910, 2852, 1730, 1686. H
NMR (CDCl3): d 1.68 (s, 6H), 1.73 (s, 6H), 2.02 (s, 6H),
2.08 (s, 3H), 5.78 (bs, 1H, exchangeable in D2O), 7.47 (t,
2H, J¼7.0 Hz, 8.0 Hz), 7.59 (t, 1H, J¼7.0 Hz), 8.00 (d, 2H,
J¼8.0 Hz). 13C NMR (CDCl3): d 24.6, 29.5, 36.4, 41.5,
51.7, 82.3, 128.5, 129.5, 130.7, 133.2, 164.8, 171.9. MS: m/z
341, 283, 240, 219, 193, 192, 191, 164, 135 (base peak),
105, 77, 59.
4.2.6. Passerini reaction between acetic acid, acetone and
adamantyl isonitrile. N-(1-Adamantyl)-2-acetoxy-2-
methylpropanamide (4f). To a solution of acetic acid
(0.405 g, 0.00675 mol) in an excess amount of acetone
(10 mL), adamantyl isonitrile (1.09 g, 0.00675 mol) dis-
solved in 10 mL of acetone was added dropwise at room
temperature. The reaction mixture was stirred for 5 days.
The excess acetone was removed under reduced pressure.
The residue was dissolved in 30 mL of methylene chloride,
washed with 2£30 mL of 5% NaHCO3, 3£50 mL of
distilled water, the organic layer dried with Na2SO4, and
the methylene chloride was removed under reduced
pressure to yield 0.93 g (49.5%) of pure 4f, mp 154–156.
TLC (90% ethyl acetate/10% hexane) Rf¼0.20. IR (CCl4):
3403, 2920, 2854, 1750, 1688. 1H NMR (CDCl3): d 1.59 (s,
6H), 1.69 (s, 6H), 2.00 (s, 6H), 2.07 (s, 6H), 5.67 (bs, 1H).
13C NMR (CDCl3): d 22.0, 24.3, 29.5, 36.4, 41.4, 51.6, 81.7,
169.1, 171.9. MS: m/z 279, 236, 222, 219, 178, 176, 150,
135 (base peak), 102, 93, 79, 59, 43, 41.
4.2.9. Passerini reaction between trans-cinnamic acid,
acetone, and adamantyl isonitrile. N-(1-Adamantyl)-2-
methyl-2-(trans-3-phenylacryloyloxy)propanamide (4i).
To a solution of trans-cinnamic acid (0.919 g, 0.0062 mol)
in an excess amount of acetone (25 mL), adamantyl
isonitrile (1.00 g, 0.0062 mol) in 25 mL of acetone was
added dropwise over a period of 10 min at room
temperature. A catalytic amount of p-toluenesulfonic acid
was added and the reaction mixture was stirred for 7 days.
The excess acetone was removed under reduced pressure
and the residue was dissolved in 90 mL of methylene
chloride, washed with 3£40 mL of 5% NaHCO3, 2£30 mL
of distilled water. The organic layer was dried with Na2SO4
and the methylene chloride was removed under reduced
pressure to yield 1.36 g of crude 4i. After flash chromatog-
raphy (90% n-hexane/10% ethyl acetate), 0.52 g (22.8%) of
a white solid (4i) with mp 124–125 8C was obtained. 0.30 g
of pure unreacted adamantyl isonitrile was also recovered.
TLC (85% n-hexane/15% ethyl acetate) Rf¼0.39. IR (CCl4)
4.2.7. Passerini reaction between pivalic acid, acetone,
and adamantyl isonitrile. N-(1-Adamantyl)-2-(2,2-
dimethylpropanoyloxy)-2-methylpropanamide (4g). To
a solution of pivalic acid (0.633 g, 0.0062 mol) in an excess
amount of acetone (20 mL), adamantyl isonitrile (1.00 g,
0.0062 mol) dissolved in 10 mL of acetone was added
dropwise at room temperature over a period of 10 min. A
catalytic amount of p-toluenesulfonic acid was added and
the reaction was stirred for 7 days. The excess acetone was
removed under reduced pressure. The residue was dissolved
in 50 mL of methylene chloride, washed with 4£30 mL of
5% NaHCO3, 3£30 mL of distilled water, dried with
Na2SO4, and the methylene chloride was removed under
reduced pressure to yield 1.14 g of a yellow solid. It was
flash chromatographed (92.5% n-hexane/7.5% ethyl acetate)
to give a white solid (4g) 0.57 g (28.6%), mp 63–65 8C.
TLC (90% n-hexane/10% ethyl acetate) Rf¼0.32. IR (CCl4)
n: 3438, 2910, 2852, 1739, 1685 cm21. 1H NMR (CDCl3): d
1.22 (s, 9H), 1.59 (s, 6H), 1.69 (s, 6H), 1.99 (s, 6H), 2.08 (s,
3H), 5.75 (bs, 1H, exchangeable in D2O). 13C NMR
(CDCl3): d 24.1, 27.2, 29.5, 36.4, 39.1, 41.5, 51.4, 81.6,
172.2, 176.3. MS: m/z 321, 306, 263, 236, 219, 220, 192,
163, 150, 144, 135 (base peak), 107, 103, 93, 85, 79, 67, 59,
57, 41.
n: 3438, 3064, 3029, 2910, 2851, 1722, 1686, 1637 cm21
.
1H NMR (CDCl3): d 1.68 (s, 12H), 2.03 (s, 6H), 2.08 (s,
3H), 5.74 (bs, 1H, exchangeable in D2O), 6.42 (d, 1H,
J¼16.0 Hz), 7.40 (s, 3H), 7.53 (s, 2H), 7.68 (d, 1H,
J¼16.0 Hz). 13C NMR (CDCl3): d 25.0, 29.8, 36.7, 41.8,
52.0, 82.2, 118.7, 128.5, 129.3, 130.9, 134.6, 145.7, 165.5,
172.3. MS: m/z 367, 309, 238, 219, 190, 175, 150, 145, 135
(base peak), 131, 107, 103, 93, 91, 79, 77, 59, 41.
4.2.10. Passerini reaction between trifluoroacetic acid,
acetone, and adamantyl isonitrile. N-(1-Adamantyl)-2-
methyl-2-trifluoroacetoxypropanamide (4j). Dropwise, a
solution of adamantyl isonitrile (1.61 g, 0.01 mL) in 20 mL
of methylene chloride was added to a solution of trifluoro-
acetic acid (1.14 g, 0.01 mol) in 5 mL of acetone. The
solution was stirred overnight. Methylene chloride and
excess acetone was removed under reduced pressure. The
residue was taken up in methylene chloride, washed with
5% NaHCO3 (40 mL) and distilled water (2£20 mL). The
organic layer was dried with Na2SO4, and the methylene
chloride was removed under reduced pressure to afford 4j
(2.51 g, 75.4%). An analytical sample was obtained by
vacuum sublimation (50–60 8C at 0.5 mm), mp 98–99 8C.
TLC (90% n-hexane/10% ethyl acetate) Rf¼0.42. IR (CCl4)
n: 3445, 2911, 2852, 1792, 1690 cm21. 1H NMR (CDCl3): d
1.67 (t, 6H, J¼2.7 Hz), 1.70 (s, 6H), 1.97 (d, 6H, J¼2.7 Hz),
2.08 (s, 3H), 5.68 (s, 1H). 13C NMR (CDCl3): d 23.9, 29.6,
4.2.8. Passerini reaction between benzoic acid, acetone,
and adamantyl isonitrile. N-(1-Adamantyl)-2-benzoyl-
oxy-2-methylpropanamide (4h). To a solution of 0.460 g
(0.00377 mol) benzoic acid in an excess of acetone (3 mL),
0.600 g (0.00372 mol) of adamantyl isonitrile dissolved in
2 mL of acetone was added dropwise at room temperature.
The reaction mixture was stirred for 4 days. The excess

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I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
36.4, 41.5, 52.2, 87.0, 114.4 (q, J¼287.0 Hz), 155.4 (q,
J¼42.4 Hz) 169.7. MS: m/z 333, 219, 192, 176, 155, 135
(base peak), 107, 93, 69, 41. Anal. Calcd for C16H22F3NO3:
C, 57.65; H, 6.65; N, 4.20. Found: C, 57.43; H, 6.67; N,
4.28.
0.01 mol) in 20 mL of CH2Cl2 at rt and stirred for 2 days.
The solution was washed with 5% NaHCO3 (25 mL) and
distilled water (2£25 mL). The organic layer was dried with
Na2SO4 and the CH2Cl2 was removed under reduced
pressure to afford crude 4m (2.80 g, 75.7%). Recrystalliza-
tion from n-heptane/ethyl acetate (20 mL/3 mL) yielded
2.50 g (67.6%) of pure 4m, mp 166–168 8C. TLC (80%
n-hexane/20% ethyl acetate) Rf¼0.67. IR (CCl4) n: 3436,
4.2.11. Passerini reaction between acetic acid, pivalalde-
hyde, and adamantyl isonitrile. N-(1-Adamantyl)-2-
acetoxy-3,3-dimethylbutanamide (4k). Dropwise, at
0 8C, a solution of adamantyl isonitrile (1.61 g, 0.01 mol)
in 15 mL of THF was added to a solution of acetic acid
(0.600 g, 0.01 mol) and pivalaldehyde (0.861 g, 0.01 mol)
in 20 mL of THF. After the addition of the isonitrile, the ice
bath was removed and the solution was stirred for 5 days at
rt. THF was removed under reduced pressure and the
resulting residue was dissolved in 35 mL of ethyl acetate.
The solution was washed with 5% NaHCO3 (15 mL) and
distilled water (15 mL). The organic layer was dried with
Na2SO4 and the ethyl acetate was removed under reduced
pressure to afford crude 4k (2.74 g, 89.3%). Purification by
flash chromatography (90% n-hexane/10% ethyl acetate)
yielded pure 4k (1.76 g, 57.3%), mp 140–141 8C. TLC
(90% n-hexane/10% ethyl acetate) Rf¼0.25. IR (CCl4) n:
1
2911, 2852, 1734, 1688, 1513 cm21. H NMR (CDCl3) d
1.14 (s, 9H), 1.66 (s, 6H), 1.99 (s, 6H), 2.06 (s, 3H), 4.93 (s,
1H), 5.55 (s, 1H), 7.48 (m, 2H), 7.63 (m, 1H), 8.10 (m, 2H).
13C NMR (CDCl3) d 26.5, 29.4, 34.4, 36.3, 41.6, 52.0, 81.5,
128.7, 133.4, 165.2, 167.2. MS: m/z 369, 313, 283, 269, 240,
208, 192, 177, 135 (base peak), 105, 79, 77, 70. Anal. Calcd
for C23H31NO3: C, 74.76; H, 8.46; N, 3.79. Found: C, 74.66;
H, 8.49; N, 3.77.
4.2.14. Passerini reaction between trans-cinnamic acid,
pivalaldehyde, and adamantyl isonitrile. N-(1-Adaman-
tyl)-3,3-dimethyl-2-(trans-3-phenylacryloyloxy)butan-
amide (4n). Dropwise, at 0 8C, a solution of adamantyl
isonitrile (1.61 g, 0.01 mol) in 20 mL of THF was added to a
solution of trans-cinnamic acid (1.48 g, 0.01 mol) and
pivalaldehyde (0.861 g, 0.01 mol) in 20 mL of THF. After
the addition of the isonitrile, the ice bath was removed and
the solution was stirred for 6 days. THF was removed under
reduced pressure and the resulting residue was dissolved in
25 mL of methylene chloride. The solution was washed with
5% NaHCO3 (15 mL) and distilled water (2£10 mL). The
organic layer was dried with Na2SO4 and the methylene
chloride was removed under reduced pressure to afford
crude 4n (3.54 g, 89.4%). After recrystallization from
22 mL of n-hexane, 2.97 g (75%) of a white solid with mp
122–123 8C was obtained. TLC (80% n-hexane/20% ethyl
acetate) Rf¼0.52. IR (CCl4) n: 3429, 3060, 2910, 1732,
1687, 1638, 1549, 1512 cm21. 1H NMR (CDCl3) d 1.07 (s,
9H), 1.67 (s, 6H), 2.00 (s, 6H), 2.07 (s, 3H), 4.82 (s, 1H),
5.54 (bs, 1H), 6.50 (d, J¼16.0 Hz, 1H), 7.44 (m, 3H), 7.55
(dd, J¼3.7 Hz, 2H), 7.76 (d, J¼16.0 Hz, 1H). 13C NMR
(CDCl3) d 26.4, 29.4, 34.2, 36.3, 41.6, 52.0, 81.1, 117.2,
128.3, 129.1, 130.7, 134.1, 146.0, 165.7, 167.3. MS (ES): m/
z 417.9 (Mþ23), 395.8, 380.9, 313.1, 245.0. Anal. Calcd for
C25H33NO3: C, 75.91; H, 8.41; N, 3.54. Found: C, 75.75; H,
8.40; N, 3.52.
3437, 2911, 2852, 1752, 1691, 1513 cm21 1H NMR
.
(CDCl3) d 0.98 (s, 9H), 1.64 (m, 6H), 1.97 (m, 6H), 2.04
(s, 3H), 2.11 (s, 3H), 4.63 (s, 1H), and 5.43 (s, 1H). 13C
NMR (CDCl3) d 26.7, 29.8, 32.0, 34.4, 36.7, 42.0, 52.3,
81.5, 167.6, 170.1. MS: m/z 307, 251, 232, 207, 178, 150,
135 (base peak), 120, 93, 79, 57, 43. Anal. Calcd for
C18H29NO3: C, 70.32; H, 9.51; N, 4.56. Found: C, 70.39; H,
9.55; N, 4.51.
4.2.12. Passerini reaction between pivalic acid, pivalal-
dehyde, and adamantyl isonitrile. N-(1-Adamantyl)-3,3-
dimethyl-2-(2,2-dimethylpropanoyloxy)butanamide (4l).
Dropwise, at 0 8C, a solution of adamantyl isonitrile
(0.806 g, 0.005 mol) in 10 mL of THF was added to a
solution of pivalic acid (0.511 g, 0.005 mol) and pivalalde-
hyde (0.431 g, 0.005 mol) in 10 mL of THF. After the
addition of the isonitrile, the ice bath was removed and the
solution was stirred for 6 days at rt. THF was removed under
reduced pressure and the resulting residue was dissolved in
15 mL of methylene chloride. The solution was washed with
5% NaHCO3 (15 mL) and distilled water (2£10 mL). The
organic layer was dried with Na2SO4 and the methylene
chloride was removed under reduced pressure to afford
crude 4l (1.30 g, 74.3%). After recrystallization from 8 mL
of n-hexane, 0.95 g (54.4%) of a white solid with mp 88–
89 8C was obtained. TLC (80% n-hexane/20% ethyl acetate)
4.2.15. Passerini reaction between trifluoroacetic acid,
pivalaldehyde, and adamantyl isonitrile. N-(1-Adaman-
tyl)-3,3-dimethyl-2-trifluoroacetoxybutanamide (4o). A
solution of pivaldehyde (0.43 g, 0.005 mol) in 2 mL of
methylene chloride was added to a solution of trifuoroacetic
acid (0.57 g, 0.005 mol) in 10 mL of methylene chloride
dropwise. A solution of adamantyl isonitrile (0.805 g,
0.005 mol) was added dropwise, to the mixture at 210 8C.
The solution stirred for 4 days and the mixture was filtered.
It was washed with 30 mL of 5% NaHCO3, 2£20 mL H2O,
dried with Na2SO4, and evaporated under reduced pressure
to give an oil (1.42 g, 79%) which solidified upon standing.
Crude 4o was recrystallized from 2 mL n-heptane to give
1.26 g (69.6%) of pure 4o, mp 108–111 8C. TLC (90%
n-hexane/10% ethyl acetate): Rf¼0.78. IR (CCl4) n: 3437,
2912, 1796, 1693 cm21. 1H NMR (CDCl3) d 0.96 and 1.04
(s, 9H), 1.66 (s, 12H), 1.99 (s, 3H), 4.82 (s, 1H), 5.46 (s, 1H,
exchanges in TFD). 13C NMR (CDCl3) d 26.1, 29.5, 34.5,
Rf¼0.63. IR (CCl4) n: 3437, 2910, 1743, 1689, 1505 cm21
.
1H NMR (CDCl3) d 1.02 (s, 9H), 1.26 (s, 9H), 1.67 (s, 6H),
1.98 (s, 6H), 2.07 (s, 3H), 4.68 (s, 1H), 5.48 (s, 1H). 13C
NMR (CDCl3) d 26.4, 27.2, 29.4, 34.2, 36.3, 38.9, 41.6,
51.8, 80.6, 167.6, 176.5. MS: m/z 349, 293, 249, 232, 208,
172, 163, 135 (base peak), 117, 85, 70, 57. Anal. Calcd for
C21H35NO3: C, 72.17; H, 10.09; N, 4.01. Found: C, 72.28;
H, 10.15; N, 3.93.
4.2.13. Passerini reaction between benzoic acid, pival-
aldehyde, and adamantyl isonitrile. N-(1-Adamantyl)-2-
benzoyloxy-3,3-dimethylbutanamide (4m). Adamantyl iso-
nitrile (1.61 g, 0.01 mol) was added to a solution of benzoic
acid (1.22 g, 0.01 mol) and pivalaldehyde (0.861 g,

I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1121
36.4, 41.6, 52.8, 84.5, 115.0 (q, J¼287.0 Hz), 156.4 (q,
J¼43.0 Hz), 165.4. MS: m/z 361, 343, 305, 292, 268, 232,
208, 193, 176, 135 (base peak), 107, 79, 69, 41. Anal. Calcd
for C18H26F3NO3: C, 59.82; H, 7.25; N, 3.88. Found: C,
59.58; H, 7.30; N, 3.90.
128–129 8C was obtained. The mother liquor was evapor-
ated to yield an additional 0.742 g (12.7%) of a solid with
mp 126–127 8C. TLC (90% n-hexane/10% ethyl acetate)
Rf¼0.68. IR (CCl4) n: 3440, 3380, 3060, 2965, 2870, 1720,
1
1685, 1598, 1505 cm21. H NMR (CDCl3) d 1.10 (s, 9H),
1.32 (s, 9H), 4.91 (s, 1H), 5.70 (s, 1H), 7.47 (m, 2H), 7.59
(m, 1H), 8.09 (m, 2H). 13C NMR (CDCl3) d 26.6, 28.8, 34.6,
51.4, 81.7, 128.8, 129.8, 133.6, 165.4, 167.6. MS: m/z 291,
276, 253, 235, 219, 192, 177, 143, 130, 105 (base peak), 87,
77, 70, 57, 41. Anal. Calcd for C17H25NO3: C, 70.07; H,
8.65; N, 4.81. Found: C, 70.27; H, 8.64; N, 4.74.
4.2.16. Passerini reaction between acetic acid, pivalalde-
hyde, and tert-butyl isonitrile. N-tert-Butyl-2-acetoxy-
3,3-dimethylbutanamide (4p). Dropwise, at 215 8C, a
solution of tert-butyl isonitrile (1.66 g, 0.02 mol) in 10 mL
of methylene chloride was added dropwise to a solution of
acetic acid (1.20 g, 0.02 mol) and pivalaldehyde (1.72 g,
0.02 mol) in 25 mL of methylene chloride over a period of
5 min. After the addition, the ice-bath was removed and the
solution stirred overnight at rt. The reaction mixture was
washed with 5% NaHCO3 (2£20 mL) and distilled water
(20 mL). The organic layer was dried with Na2SO4 and the
methylene chloride was removed under reduced pressure to
afford crude 4p (2.75 g, 60.0%). After recrystallization from
3 mL of n-hexane, a white solid (1.92 g, 41.9%) with mp
62–63 8C was obtained. TLC (80% n-hexane/20% ethyl
acetate) Rf¼0.44. IR (CCl4) n: 3440, 2965, 1738, 1683,
1505 cm21. 1H NMR (CDCl3) d 0.98 (s, 9H), 2.11 (s, 3H),
4.64 (s, 1H), 5.57 (s, 1H). 13C NMR (CDCl3) d 21.0, 26.4,
28.8, 34.2, 51.4, 81.2, 167.7, 169.9. MS: m/z 229, 214, 186,
173, 157, 131, 129, 87, 75, 57 (base peak), 43. Anal. Calcd
for C12H23NO3: C, 62.88; H, 10.04; N, 6.11. Found: C,
62.78; H, 10.02; N, 6.21.
4.2.19. Passerini reaction between trans-cinnamic acid,
pivalaldehyde, and tert-butyl isonitrile. N-tert-Butyl-3,3-
dimethyl-2-(trans-3-phenylacryloyloxy)butanamide (4s).
A solution of tert-butyl isonitrile (1.66 g, 0.02 mol) in
10 mL of methylene chloride was added dropwise to a
solution of trans-cinnamic acid (2.96 g, 0.02 mol) and
pivalaldehyde (1.72 g, 0.02 mol) in 30 mL of methylene
chloride at 215 8C over a period of 10 min. The ice-bath
was then removed and the solution stirred overnight at rt.
The reaction mixture was washed with 5% NaHCO3
(2£20 mL) and distilled water (2£15 mL). The organic
layer was dried with Na2SO4 and the methylene chloride
was removed under reduced pressure to yield crude 4s
(4.89 g, 77.1%). After recrystallization from n-heptane/
methylene chloride (10 mL/2 mL), a white solid (2.08 g,
32.8%)withmp97–98 8Cwasobtained. TLC(80%n-hexane/
20% ethyl acetate) Rf¼0.46. IR (CCl4) n: 3440, 2960, 2868,
1
4.2.17. Passerini reaction between pivalic acid,
pivalaldehyde, and tert-butyl isonitrile. N-tert-Butyl-
3,3-dimethyl-2-(2,2-dimethylpropanoyloxy)butanamide
(4q). A solution of tert-butyl isonitrile (1.66 g, 0.02 mol) in
5 mL of methylene chloride was added dropwise to a solution
of pivalic acid (2.04 g, 0.02 mol) and pivalaldehyde (1.72 g,
0.02 mol)in20 mLofmethylenechloride. Thesolutionstirred
overnight. The reaction mixture was washed with 5%
NaHCO3 (2£25 mL) and distilled water (25 mL). The organic
layer was dried with Na2SO4 and the methylene chloride was
removedunderreducedpressuretoafford4.39 g(81%)ofpure
4q, mp 87–88 8C. TLC (90% n-hexane/10% ethyl acetate)
Rf¼0.48. IR (CCl4) n: 3427, 3370, 2955, 2860, 1735, 1667,
1505 cm21. 1H NMR (CDCl3) d 0.99 (s, 9H), 1.24 (s, 9H),
1.30 (s, 9H), 4.66 (s, 1H), and 5.59 (s, 1H). 13C NMR
(CDCl3) d 26.5, 27.3, 28.8, 34.4, 39.0, 51.3, 80.8, 167.8, and
176.7. MS: m/z 271, 256, 215, 199, 172, 157, 143, 130, 102,
85, 71, 57 (base peak), 41. Anal. Calcd for C15H29NO3: C,
66.38; H, 10.77; N, 5.16. Found: C, 66.26; H, 10.67; N, 5.24.
1715, 1680, 1633, 1505 cm21. H NMR (CDCl3) d 1.06 (s,
9H), 1.33 (s, 9H), 4.81 (s, 1H), 5.70 (s, 1H), 6.50 (d, 1H,
J¼16.0 Hz), 7.38 (m, 3H), 7.54 (m, 2H), 7.74 (d, 1H,
J¼16.0 Hz). 13C NMR (CDCl3) d 26.6, 28.8, 34.4, 51.4,
81.2, 117.3, 128.4, 129.1, 130.8, 134.2, 146.2, 165.8, 167.7.
MS: m/z 317, 261, 245, 231, 218, 175, 162, 149, 131 (base
peak), 103, 77, 70, 57, 41. Anal. Calcd for C19H27NO3: C,
71.92; H, 8.52; N, 4.42. Found: C, 71.77; H, 8.47; N, 4.38.
4.2.20. Passerini reaction between trifluoroacetic acid,
pivalaldehyde, and tert-butyl isonitrile. N-tert-Butyl-3,3-
dimethyl-2-trifluoroacetoxybutanamide (4t). A solution
of tert-butyl isonitrile (1.25 g, 0.015 mol) in 15 mL of
CH2Cl2 was added dropwise to a solution of pivaladehyde
(1.29 g, 0.015 mol) and trifluoroacetic acid (1.71 g,
0.015 mol) in 30 mL of CH2Cl2 at 0 8C over a period of
15 min. The ice-bath was then removed and the solution
stirred at rt for 4 days. The solvents were evaporated under
reduced pressure to yield 3.92 g of a white solid which was
recrystallized from 20 mL of hot n-heptane to give 3.06 g
(72%) of a white solid (4t), mp 120–121 8C. IR (CCl4) n:
3446, 2968, 1796, 1693 cm21. 1H NMR (CDCl3): d 1.08 (s,
9H), 1.37 (s, 9H), 4.86 (s, 1H), 5.56 (bs, 1H, exchangeable
in TFD). 13C NMR (CDCl3): d 26.4, 29.0, 34.7, 52.2, 84.9,
114.9 (q, J¼285.7 Hz), 156.6 (q, J¼42.7 Hz), 165.6. MS: m/
z 283, 268, 227, 214, 183, 171, 154, 130, 114, 84, 74, 69, 58,
57, 41. Anal. Calcd for C12H20F3NO3: C, 50.88; H, 7.12; N,
4.94. Found: C, 51.16; H, 7.18; N, 4.97.
4.2.18. Passerini reaction between benzoic acid, pival-
aldehyde, and tert-butyl isonitrile. N-tert-Butyl-2-
benzoyloxy-3,3-dimethylbutanamide (4r). A solution of
tert-butyl isonitrile (1.66 g, 0.02 mol) in 10 mL of methyl-
ene chloride was added to a solution of benzoic acid (2.44 g,
0.02 mol) and pivalaldehyde (1.72 g, 0.02 mol) in 25 mL of
methylene chloride dropwise at 215 8C. After the addition,
the ice-bath was removed and the solution stirred overnight
at rt. The reaction mixture was washed with 5% NaHCO3
(2£15 mL) and distilled water (2£15 mL). The organic
layer was dried with Na2SO4 and the methylene chloride
was removed under reduced pressure to afford crude 4r
(2.86 g, 49.1%). After recrystallization from 15 mL of
carbon tetrachloride, a white solid (1.88 g, 32.3%) with mp
4.2.21. Passerini reaction between maleic acid, acetone,
and tert-butyl isonitrile. Di(2-methyl-N-tert-butylpro-
panamido-2-)maleate (12a). To a solution of maleic acid
(4.06 g, 0.035 mol) in acetone (70 mL), tert-butyl isonitrile
(5.82 g, 0.07 mol) was added in one portion at rt. The

1122
I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
solution was seeded with a few crystals of p-toluene sulfonic
acid and stirred for 3 days. It was then evaporated to dryness
under reduced pressure and the residue taken up into 75 mL
of CH2Cl2 and washed with 3£50 mL of 5% NaHCO3 and
70 mL of H2O, dried with Na2SO4, filtered and evaporated
under reduced pressure to give 5.20 g of a brown solid. It
was recrystallized from 40 mL of hot n-heptane and 1 mL of
acetonitrile (to which 0.3 g of activated charcoal was added)
to give 3.70 g of a yellow solid, mp 100–120 8C. After flash
chromatography (60% n-hexane/40% ethyl acetate), 3.23 g
(23%) of a white solid, pure 12a with mp 148–149 8C was
obtained. TLC (60% n-hexane/40% ethyl acetate) Rf¼0.41.
IR (CCl4) n: 3448, 3401, 2973, 1731, 1687, 1642 cm21. 1H
NMR (CDCl3): d 1.36 (s, 18H), 1.61 (s, 12H), 6.26 (s, 2H),
6.30 (bs, 2H, exchangeable in TFD). 13C NMR (CDCl3): d
24.6, 28.6, 51.2, 83.2, 130.2, 163.4, 171.3. MS: m/z 398,
383, 343, 326, 299, 256, 228, 160, 143 (base peak), 114, 87,
58, 57, 41. Anal. Calcd for C20H34N2O6: C, 60.27; H, 8.60;
N, 7.03. Found: C, 60.28; H, 8.87; N, 7.08.
4.2.24. Passerini reaction between succinic acid, acetone,
and adamantyl isonitrile. Di[2-methyl-1-(1-adamantyl)-
propanamido-2-]succinate (13b). To a solution of succinic
acid (1.18 g, 0.01 mol) in acetone (20 mL) and 5 mL of
THF, adamantylisonitrile (3.23 g, 0.02 mol) was added at rt.
The solution was seeded with p-toluene sulfonic acid and
stirred for 5 days. The excess acetone and THF were
removed under reduced pressure. The residue was dissolved
in methylene chloride (50 mL) and washed with 5%
NaHCO3 (20 mL) and distilled water (2£25 mL). The
organic layer was dried with Na2SO4 and methylene
chloride removed under reduced pressure to afford crude
product 13b (5.22 g, 93.7%). It was recrystallized twice,
first from hot carbon tetrachloride/ acetonitrile (20 mL/
10 mL) and then from hot n-heptane/acetonitrile (18 mL/
27 mL) to give 1.28 g (23.0%) of a solid with mp 218–
221 8C. TLC (70% n-hexane/30% ethyl acetate) Rf¼0.35.
IR (CCl4) n: 3420, 2900, 2838, 1737, 1680 cm21. 1H NMR
(CDCl3) d 1.55 (s, 12H), 1.64 (s, 12H), 1.97 (s, 12H), 2.04
(s, 6H), 2.58 (s, 4H), 5.76 (s, 2H). 13C NMR (CDCl3) d 24.7,
29.6, 29.8, 36.5, 41.4, 51.9, 82.2, 170.7, 171.8.
4.2.22. Passerini reaction between maleic acid, acetone,
and adamantyl isonitrile. Di[2-methyl-N-(1-adamantyl)-
propanamido-2-]maleate (12b). To a solution of maleic
acid (0.360 g, 0.0031 mol) in acetone (20 mL), adamantyl
isonitrile (1.00 g, 0.0062 mol) in 10 mL of acetone was
added dropwise over a period of 10 min at rt. The solution
was seeded with a few crystals of p-toluene sulfonic acid
and stirred for 5 days. It was then evaporated to dryness
under reduced pressure and the residue taken up into
60 mL of CH2Cl2 and washed with 3£25 mL of 5%
NaHCO3 and 2£25 mL of H2O, dried with Na2SO4,
filtered and evaporated under reduced pressure to give a
yellow oil that was flash chromatographed (75% n-
hexane/25% ethyl acetate) to give 0.40 g (23.3%) of a
white solid (12b) with mp 205–206 8C was obtained.
TLC (70% n-hexane/30% ethyl acetate) Rf¼0.36. IR
(CCl4) n: 3439, 3394, 2910, 2852, 1732, 1684,
4.2.25. Passerini reaction between succinic acid, pival-
aldehyde, and adamantyl isonitrile. Di[3,3-dimethyl-1-
(1-adamantyl)butanamido-2-]succinate (13c). To a sol-
ution of succinic acid (0.59 g, 0.005 mol) and pivalaldehyde
(0.86 g, 0.01 mol) in methylene chloride (40 mL) and
10 mL of THF, adamantyl isonitrile (1.61 g, 0.01 mol)
was added. The solution was stirred for 5 days. It was then
evaporated to dryness under reduced pressure to give a
residue which was taken up into 40 mL of methylene
chloride. It was washed with 25 mL of 5% NaHCO3,
2£25 mL of H2O dried with Na2SO4 and evaporated under
reduced pressure to afford 2.46 g (80.4%) of a dark oil
which slowly crystallized. It was flash chromatographed
(70% n-hexane/30% ethyl acetate) to yield 1.26 g (41.2%)
of a solid (13c) with mp 243–245 8C. TLC (70% n-hexane/
30% ethyl acetate) Rf¼0.58. IR (CCl4) n: 3420, 2900, 2840,
1735, 1670 cm21. 1H NMR (CDCl3) d 1.0 (s, 18H), 1.7 and
2.0 (s, 30H), 2.65 (s, 4H), and 4.65 (s, 2H). 13C NMR
(CDCl3) d 26.5, 29.1, 29.6, 34.1, 36.5, 41.6, 52.2, 81.8,
167.0, 171.3. High resolution MS: m/z 612, 556, 500, 435,
379, 347, 321, 264, 209, 135 (base peak), 107, 79, 57. Anal.
Calcd for C36H56N2O6: C, 70.55; H, 9.21; N, 4.57. Found:
C, 70.73; H, 9.27; N, 4.60.
1
1635 cm21. H NMR (CDCl3): d 1.61 (s, 12H), 1.68 (s,
12H), 2.02 (s, 12H), 2.07 (s, 6H), 6.16 (s, 2H, exchange-
able in D2O), 6.24 (s, 2H). 13C NMR (CDCl3): d 24.7,
29.5, 36.4, 41.3, 52.0, 83.1, 130.2, 163.3, 171.1.
4.2.23. Passerini reaction between succinic acid, acetone,
and tert-butyl isonitrile. Di(2-methyl-N-tert-butylpro-
panamido-2-)succinate (13a). To a solution of succinic
acid (2.84 g, 0.002 mol) in acetone (100 mL), tert-butyl
isonitrile (4.00 g, 0.004 mol) was added in one portion at rt.
The solution was seeded with a few crystals of p-toluene
sulfonic acid and stirred for 3 days. It was then evaporated to
dryness under reduced pressure and the residue taken up into
75 mL of CH2Cl2 and washed with 3£50 mL of 5%
NaHCO3 and 70 mL of H2O, dried with Na2SO4, filtered
and evaporated under reduced pressure to give 1.60 g of a
white solid mp 88–97 8C. After flash chromatography (60%
n-hexane/40% ethyl acetate), 1.35 g (14%) of a white solid
(13a) mp 106–108 8C was obtained. TLC (60% n-hexane/
4.2.26. Passerini reaction between succinic acid, pival-
aldehyde, and tert-butyl isonitrile. Di(3,3-dimethyl-N-
tert-butylbutanamido-2-]succinate (13d). To a solution of
succinic acid (2.36 g, 0.02 mol) and pivalaldehyde (3.44 g,
0.04 mol) in methylene chloride (55 mL), tert-butyl iso-
nitrile (3.32 g, 0.04 mol) was added at 0 8C. It was seeded
with a crystal of p-toluene sulfonic acid and stirred for 4
days at rt. It was washed with 40 mL of 5% NaHCO3,
2£25 mL of H2O, dried with Na2SO4 and evaporated
under reduced pressure to afford 7.77 g (85.1%) of an oil
which slowly crystallized. It was recrystallized twice from
n-heptane/ethyl acetate to give 2.3 g (25.2%) of a solid (13d)
with mp 161–162 8C. TLC (70% n-hexane/30% ethyl acetate)
Rf¼0.35. IR (CCl4) n: 3443, 2967, 2872, 1744, 1687 cm21. 1H
NMR (CDCl3) d 1.0 (s, 18H), 1.32 (s,18H), 2.7 (s, 4H), 4.6 (s,
2H), and 5.65 (s, 2H). Anal. Calcd for C24H44N2O6: C, 63.13;
H, 9.71; N, 6.13. Found: C, 63.22; H, 9.68; N, 6.27.
1
40% ethyl acetate) Rf¼0.46. H NMR (CDCl3): d 1.35 (s,
18H), 1.59 (s, 12H), 2.62 (s, 4H), 5.94 (bs, 2H). 13C NMR
(CDCl3): d 24.5, 28.6, 29.7, 51.1, 82.2, 170.6, 171.9. MS:
m/z 401, 385, 345, 328, 301, 260, 242, 228, 215, 187, 160,
142, 114, 101, 86, 69, 59, 58, 57, 41. Anal. Calcd for
C20H36N2O6: C, 59.98; H, 9.06; N, 6.99. Found: C, 60.14;
H, 9.10; N, 6.97.

I. Lengyel et al. / Tetrahedron 60 (2004) 1107–1124
1123
4.3. Reactions of a-lactams with maleic anhydride
organic layer was dried with Na2SO4 and the benzene
was removed under reduced pressure to afford crude N-
(1-adamantyl)-2-fluoro-2-methylpropanamide (4u) (0.55 g,
67.6%). After column chromatography, pure 4u was
obtained (0.42 g, 51.6%), mp 42–44 8C. TLC (80%
n-hexane/20% ethyl acetate) Rf¼0.65. IR (CCl4) n: 3420,
2960, 2900, 2840, 1680 cm21. 1H NMR (CDCl3) d 1.51 (s,
6H), 1.65 (s, 6H), 1.98 (d, J¼2.7 Hz, 6H), 2.05 (s, 3H), 6.03
(s, 1H). 13C NMR (CDCl3) d 25.1 (d, J¼23.8 Hz), 29.6,
36.5, 41.6, 51.7, 96.3 (d, J¼181.6 Hz), 172.3 (d,
J¼19.2 Hz). MS: m/z 239, 196, 182, 162, 135 (base peak),
120, 107, 93, 79, 61, 41. Anal. Calcd for C14H22NOF: C,
70.26; H, 9.27; N, 5.85. Found: C, 70.26; H, 9.29; N, 5.94.
4.3.1. Reaction of 1-tert-butyl-3,3-dimethylaziridinone
(5a) with maleic anhydride. Di(2-methyl-N-tert-butyl-
propanamido-2-)maleate (12a). 1-tert-Butyl-3,3-dimethyl-
aziridinone (5a) (1.41 g, 0.010 mol) was dissolved in 10 mL
of chloroform, a solution of freshly sublimed, powdered
maleic anhydride (0.98 g, 0.010 mol) in 10 mL of chloro-
form was added at 0 8C, and the reaction mixture was stirred
at 0 8C for 20 h. After evaporation of the solvent on a rotary
evaporator, the solid residue was chromatographed on
neutral alumina, Woelm, activity grade one, further deacti-
vated by the addition of water (3 mL of water/100 g of
alumina) with benzene–methylene chloride as eluent, to
afford 1.07 g (53%) of di(2-methyl-N-tert-butylpropan-
amido-2-)maleate (12a), mp 150–151 8C. IR (CCl4) n:
3425, 3370, 1730, 1678, 1525 cm21. UV: lmax (ethanol)¼
200 nm, log 1¼4.37. lmax (ethanol) of dimethyl maleate¼
192.5 nm, log 1¼4.34.37 1H NMR (CDCl3) d 1.39 (s, 18H),
1.65s, (12H), 4.80 (s, 1H), 6.39 (s, 2H). 13C NMR (CDCl3):
d 24.6, 28.6, 51.2, 83.2, 130.2, 163.4, 171.3. MS: m/z 398,
383, 343, 326, 299, 256, 228, 160, 143 (base peak), 114, 87,
58, 57, 41. Anal. Calcd for C20H34N2O6: C, 60.27; H, 8.60;
N, 7.03. Found: C, 60.18; H, 8.41; N, 7.16.
4.4.2. Reaction of 1-(1-adamantyl)-3-tert-butylaziridi-
none (5c) with aqueous hydrogenbromide. A solution of
9.3 mL (0.093 mol) of 48% (aq) HBr with 20 mL of distilled
water was added to 1.21 g (0.0055 mol) of 1-(1-adamantyl)-
3-tert-butylaziridinone (5c). The reaction mixture was
stirred for 1 h at room temperature, then approximately
20 mL of liquid over a period of 1 h was distilled over into a
receiving flask containing 0.736 g (0.0066 mol) of semi-
carbazide hydrochloride, 0.591 g (0.0072 mol) of sodium
acetate, and 5 mL of distilled water, immersed in an ice/
water bath. The receiving flask was then removed from the
ice bath and stirred for an additional 45 min at room
temperature. The reaction mixture was filtered on Bu¨chner
funnel and the solid washed with ice–cold water to afford
0.46 g (65.3%) of pure pivalaldehyde semicarbazone38 with
mp 188–191 8C (rep.38 mp 191 8C). TLC (100% ethyl
acetate) Rf¼0.50. MS: m/z 143, 128, 111, 100, 86 (base
peak), 84, 68, 57, 41.
Using a relative ratio of 4 equiv. of a-lactam to 1 equiv. of
maleic anhydride, and a reaction time of 48 h at room
temperature, increased the isolated yield of 12a, after
chromatography, to 87%.
4.3.2. Reaction of 1-(1-adamantyl)-3,3-dimethylaziri-
dinone (5b) with maleic anhydride. Di[2-methyl-N-(1-
adamantyl)propanamido-2-]maleate (12b). A solution of
1-(1-adamantyl)-3,3-dimethylaziridinone (5b) (1.15 g,
5.25 mmol) and freshly sublimed maleic anhydride (0.515 g,
5.25 mmol) in 25 mL of carbon tetrachloride was heated to
70 8C for 10 min. It was then washed with 2£25 mL of 2 N
HCl, 2£25 mL of H2O, dried with Na2SO4, filtered over
Celite, and rotary evaporated to give 1.28 g of a purple
solid, which was flash chromatographed (75% n-hexane/
25% ethyl acetate) to give 0.25 g (17.1%) of di[2-methyl-N-
(1-adamantyl)propanamido-2-]maleate (12b), mp 204–
206 8C. TLC (70% n-hexane/30% ethyl acetate) Rf¼0.36.
IR (CCl4) n: 3439, 3394, 2910, 2852, 1732, 1684,
The residue remaining in the distilling flask was washed
with 15% Na2CO3 until the solution was basic. A solid
precipitated and was collected on a Bu¨chner funnel. It was
dried and washed with 10 mL of ice cold ether and again
filtered on a Bu¨chner funnel to afford 0.69 g (95.0%) crude
1-adamantanamine. After recrystallization from acetone/
methanol pure adamantanamine was obtained (mp 203–
205 8C). TLC, IR, and MS were identical to an authentic
sample (Aldrich) [TLC (100% ethanol) Rf¼0.18. MS: m/z
151, 136, 108, 94 (base peak), 77, 57, 41].
1
1635 cm21. H NMR (CDCl3): d 1.61 (s, 12H), 1.68 (s,
4.4.3. Preparation of authentic pivalaldehyde semicarb-
azide. To a solution of pivalaldehyde (Lancaster, 0.86 g,
0.01 mol) in 35 mL of distilled water was added 1.22 g
(0.011 mol) of semicarbazide hydrochloride and 0.984 g
(0.012 mol) of sodium acetate. The solution was stirred for
1 h. The precipitate was collected on a Bu¨chner funnel and
washed with ice–cold water to afford 1.18 g (82.5%) of
pure pivalaldehyde semicarbazone,38 mp 191 8C (rep.38 mp
191 8C). TLC (100% ethyl acetate) Rf¼0.50. IR (CCl4) n:
3460, 3030, 2970, 1683 cm21 (KBr) n: 3460, 3300, 3180,
3040, 2940, 1690, 1645, 1625, 1600, 1500 cm21. MS: m/z
143, 128, 111, 100, 86 (base peak), 84, 68, 57, 41.
12H), 2.02 (s, 12H), 2.07 (s, 6H), 6.16 (s, 2H, exchangeable
in D2O), 6.24 (s, 2H). 13C NMR (CDCl3): d 24.7, 29.5, 36.4,
41.3, 52.0, 83.1, 130.2, 163.3, 171.1.
0.22 g (26%) of pure adamantyl isonitrile was also isolated
from the reaction and approximately 51% of a purple dye
remained on the column.
4.4. Reactions of a-lactams with mineral acids
4.4.1. Reaction of 1-(1-adamantyl)-3,3-dimethylaziridi-
none (5b) with hydrofluoric acid. N-(1-Adamantyl)-2-
fluoro-2-methylpropanamide (4u). To a solution of 1-(1-
adamantyl)-3,3-dimethylaziridinone (0.737 g, 0.0034 mol)
in 45 mL of benzene at 7 8C, 5 mL (0.175 mol) of HF/
pyridine complex was added. The solution was stirred for
1.5 h, then washed with distilled water (2£25 mL), 2 N HCl
(10 mL), and again with distilled water (2£25 mL). The
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1124
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