About the First Stable α-Lactam with a Secondary Alkyl Substituent in Position Three: 3-Isopropyl-1-triphenylmethylaziridinone

Article abstract of DOI:10.1002/jhet.3359

A three-step synthesis, characterization, pyrolysis, the thermal decomposition products, and three reactions of 3-isopropyl-1-triphenylmethylaziridinone are described. This is the first stable α-lactam with a secondary alkyl substituent in position three.

Full text of DOI:10.1002/jhet.3359

Month 2018
About the First Stable α-Lactam with a Secondary Alkyl Substituent in
Position Three: 3-Isopropyl-1-triphenylmethylaziridinone
*
Michael Benitez, Yun Dan Wang, Istvan Lengyel, Matthew Fitzsimmons, and Victor Cesare
Department of Chemistry, St. John’s University, Jamaica, NY, USA
*E-mail: cesarev@stjohns.edu
Received June 23, 2018
DOI 10.1002/jhet.3359
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A three-step synthesis, characterization, pyrolysis, the thermal decomposition products, and three reac-
tions of 3-isopropyl-1-triphenylmethylaziridinone are described. This is the first stable α-lactam with a sec-
ondary alkyl substituent in position three.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
butylaziridinone
butylaziridinone
(4a)
(4b)
[7],
[8],
1-(1-adamantyl)-3-tert-
and 3-tert-butyl-1-
triphenylmethylaziridinone (4c) [9].
The structure and stability of α-lactams.
α-Lactams
(aziridinones) are three-membered heterocyclic carbonyl
compounds of structure 1 (Fig. 1). The exploration of α-
lactams continues because of their potential synthetic
value as reactive starting reagents and because of their
similarity in structure to β-lactams, which are found in
the well-known penicillin antibiotics.
The first stable α-lactam was prepared in 1962 by
Baumgarten [1]. While the unsubstituted parent
compound (R1═R2═R3═H) is still unknown and appears
to be unstable, more than 60 stable α-lactams have been
reported [2] to date. With one exception, all stable, pure,
isolable, α-lactams have a tertiary alkyl or cycloalkyl
group attached to the nitrogen (e.g., tert-butyl, 1-
adamantyl, trityl). The single exception is 1-(2-
adamantyl)-3-(1-adamantyl)-aziridinone (2) [3,4], which
has a highly bulky secondary cycloalkyl substituent on
the nitrogen (Fig. 2).
1. Compound 4a, a liquid, requires 87 h in refluxing
methanol (bp 65°C) to complete solvolysis. It does not
begin decomposing until heated to 140°C. Complete
thermal decomposition is achieved only after 12 h of
heating at 175°C in a sealed tube [7].
2. Compound 4b, mp 78–79°C, undergoes complete sol-
volysis in methanol (bp 65°C) only after 48 h of
refluxing. Its complete thermal decomposition requires
90 h of refluxing in toluene (bp 111°C) [8].
3. Compound 4c, mp 103–104°C, undergoes complete
solvolysis in methanol (bp 65°C) after 3.7 h of
refluxing. Its complete thermal decomposition requires
3 h of refluxing in n-octane (bp 126°C) [9].
All three are easily synthesized in high yield by the
common α-lactam synthetic methods. Their relative
stability order is 4a > 4b > 4c.
An additional prerequisite of stability is the presence of
a tertiary alky or aryl group at C-3. Two α-lactams with
geminal dimethyl groups at C-3 have also been prepared
[5,6] in pure state, but these are relatively less stable
(Fig. 3).
RESULTS AND DISCUSSION
As we have just seen, α-lactams 4a–c exhibit an
astonishingly high thermal stability and strong resistance
to nucleophilic attack. We reckoned with the possibility
that replacement of the tert-butyl group by the isopropyl
group would still preserve some of the stability of
compounds 4a–c. Accordingly, we decided to synthesize
During the preparation for this study, we surveyed the
substituents known to have
a particularly strong
stabilizing effect on α-lactams. These are the tert-butyl,
adamantyl, and triphenylmethyl substituents. In Figure 4,
there is one representative of each: di-tert-
© 2018 Wiley Periodicals, Inc.

M. Benitez, Y. D. Wang, I. Lengyel, M. Fitzsimmons, and V. Cesare
Vol 000
the latter with tert-butylamine, 1-adamantylamine, and
tritylamine [11], respectively, gave the corresponding N-
alkylamides 5a–c. Ring-closure to the α-lactams 8a–c
was attempted by (1) sodium tert-butoxide, (2) potassium
Figure 1. The structure of α-lactams (1).
tert-butoxide,
sodium
hydride/15-crown-5
ether
(Scheme 1).
To our satisfaction, α-lactam 8c (3-isopropyl-1-
triphenylmethylaziridinone) could be synthesized,
purified, and isolated in pure state at room temperature,
and it showed the expected high thermal stability yet
easily underwent ring-opening reactions with both ionic
and non-ionic nucleophiles, for example, sodium
benzyloxide, methanol, and benzylamine (see in the next
Discussion and Experimental section).
Figure 2. 1-(2-Adamantyl)-3-(1-adamantyl)-aziridinone (2).
α-Lactams 8a and 8b, however, although readily
detectable by IR (1840 cmÀ1 carbonyl band), could not
be isolated in pure form. One probable reason is that
these α-lactams, once formed, react with the base faster
than the α-chloroamide precursors.
Trying to rationalize these findings, we reasoned that the
trityl group, due to its bulkiness, efficiently blocks
approach of nucleophiles both at C-2 and C-3 of the ring.
On the other hand, the tert-butyl group and the 1-
adamantyl group have a smaller space-filling capacity at
these locations in 8a and 8b.
Figure 3. Two stable α-lactams with geminal dimethyl groups at C-3 (3a
and 3b).
Pyrolysis. Refluxing a 0.1 g sample of α-lactam 8c for
1 h in n-heptane (bp 98°C) or n-octane (bp 125–127°C) led
to no or only partial thermal decomposition. Only boiling
8c in n-nonane (bp 151°C) for 1 h caused complete
thermal decomposition, and the products were
isobutyraldehyde (10) (bp 63–64°C) and trityl isonitrile
(11), identified by direct comparison with authentic
samples by GC–MS and IR (Scheme 2). The
isobutyraldehyde used for identification was purchased
Figure 4. Aziridinones (4a–c) containing substituents with the strongest
stabilizing effect.
the three α-chloroamides containing the isopropyl
substituent, 5a–c (Figure 5).
Synthesis. Our starting material was the commercially
available isovaleryl chloride (3-methylbutanoyl chloride)
(6). This was converted by N-chlorosuccinimide to 2-
chloro-3-methyl butanoyl chloride (7) [10]. Treatment of
Scheme 2. The thermal decomposition of α-lactam 8c.
Figure 5. N-tert-Butyl-2-chloro-3-methylbutanamide (5a), N-(1-
adamantyl)-2-chloro-3-methylbutanamide (5b), and N-triphenylmethyl-
2-chloro-3-methylbutanamide (5c).
Scheme 1. Attempted synthesis of α-lactams 8a–c.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
About the First Stable α-Lactam with a Secondary Alkyl Substituent in
Position Three
from Sigma-Aldrich (Milwaukee, WI). The trityl isonitrile
was synthesized by a published procedure [12]. This type
of thermal decomposition, via an iminooxirane
intermediate (e.g., 9), has been observed and reported
first by Sheehan and Lengyel [13].
The non-ionic nucleophile [5] benzylamine and
methanol and the ionic nucleophile sodium benzyloxide
(in benzyl alcohol) were chosen for this study. The
reactions with benzylamine and sodium benzyloxide
proceeded readily and fast at room temperature, while the
methanol solvolysis required 45 min of refluxing (bp
65°C) (Scheme 5). The progress of the reactions was
monitored by IR: The disappearance of the 1840 cmÀ1
α-lactam band signaled the completion of the reactions.
The sodium benzyloxide and methanol reactions gave
single products, 17 and 18, respectively, in good yield
(see Experimental section). However, to our surprise, the
reaction of benzylamine with α-lactam 8c resulted in
isolation of both the C3─N bond cleavage product 15
and the C2─N bond cleavage product 16 in a combined
yield of 75.2% with an approximately 1:1 ratio of each
product. The two products were isolated using column
chromatography. All structures for the ring opening
Nucleophilic cleavage. α-Lactams undergo two types of
ring-opening reactions: non-ionic protic nucleophiles
(HZ), such as mineral acids, water, alcohols, thiols, and
amines usually open the ring with C3─N bond cleavage,
while ionic aprotic nucleophiles, for example, HOÀ,
CH3OÀ, (CH3)3COÀ effect C2─N cleavage [14]
(Scheme 3). However, the factors governing the
regioselectivity in nucleophilic ring-opening of stable
α-lactams are not well understood. There are numerous
unexplained exceptions reported [14–17]. Those room-
temperature reactions, which yield two products resulting
from both C2─N and C3─N cleavage, are particularly
baffling and disturbing. For example, the reaction of 3-(1-
adamantyl)-1-tritylaziridinone (12) [11] with benzylamine
gives a mixture of two products (13 and 14) in a
combined yield of 72% [18], in a 2:1 ratio (Scheme 4).
1
products 15–18 were determined from the IR, H NMR,
13C NMR, and mass spectra. Correct elemental analysis
was obtained for all new compounds.
CONCLUSION
Scheme 3. Nucleophilic ring-opening of α-lactams (1).
The synthesis of a remarkably stable α-lactam, 3-
isopropyl-1-triphenylmethylaziridinone
(8c),
was
accomplished. This is the first report of a stable α-lactam
with a secondary isopropyl group at position 3. Only
boiling 8c in n-nonane (bp 151°C) for 1 hour caused
complete thermal decomposition. Even though 8c is
thermally very stable, it was demonstrated that it easily
reacts under mild conditions with various nucleophiles to
obtain C2─N and/or C3─N ring-opening products.
Scheme 4. The reaction of 3-(1-adamantyl)-1-tritylaziridinone (12) with
benzylamine.
EXPERIMENTAL
Melting points are uncorrected and were measured on a
SRS Digimelt MPA 160 melting point apparatus (Stanford
Research Systems, Sunnyvale, CA). Thin layer
chromatography (TLC) was performed with Analtech
Scheme 5. The reactions of α-lactam 8c with benzylamine, sodium benzyloxide, and methanol.
Journal of Heterocyclic Chemistry
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M. Benitez, Y. D. Wang, I. Lengyel, M. Fitzsimmons, and V. Cesare
Vol 000
The
(Newark, DE) silica gel glass-backed plates (250 microns)
and recorded in terms of Rf values. Flash chromatographic
separations were performed using silica gel (JT Baker,
40 μm) as the stationary phase. Infrared spectra (IR) were
recorded using a Perkin Elmer Fourier Transform (FTIR)
Spectrum 2 Spectrophotometer (Waltham, MA) with a
Pike MIRacle ATR attachment (Pike Technologies,
Fitchburg, WI). NMR spectra (1H and 13C) were obtained
on a 400 MHz Bruker UltraShield Spectrometer (Bruker
BioSpin North America, Billerica, MA) with
tetramethylsilane as the internal standard and peak
positions are given in ppm as δ values. Elemental
analyses were performed by Atlantic Microlab, Inc.
(Norcross, GA, USA). Gas chromatography–mass
spectrometry (GC–MS) studies were performed on a
Shimadzu (Somerset, NJ) GCMS 7820A System.
The reagents 1-adamantylamine, tert-butylamine,
tritylamine, triethylamine, benzylamine, sodium hydride,
sodium benzyloxide, thionyl chloride, isovaleryl chloride,
N-chlorosuccinimide, and 15-crown-5 ether and the
solvents tetrahydrofuran, pentane, octane, nonane,
deuterated chloroform (CDCl3), and carbon tetrachloride
were obtained from Sigma-Aldrich (Milwaukee, WI,
USA). Ethyl acetate, methylene chloride, n-heptane,
hydrochloric acid, and sodium sulfate were purchased
from J.T. Baker (Phillipsburg, NJ, USA). Hexane was
obtained from VWR Scientific Products (New York, NY,
USA). Methanol was obtained from Fisher Scientific
(Fair Lawn, NJ, USA).
N-tert-Butyl-2-chloro-3-methylbutanamide (5a).
general procedure of Lengyel and Aaronsen [19] was
followed. To a solution of tert-butylamine (2.31 g,
0.0316 mol, 2.2 eq) in dichloromethane (80 mL), a
solution of 2-chloro-3-methylbutanoyl chloride (7)
(2.23 g, 0.0144 mol) dissolved in dichloromethane
(20 mL) was added dropwise at 0°C. After the addition
was complete, the reaction mixture stirred at RT overnight
and then washed twice with 50 mL of 0.1 M HCl, three
times with distilled water (80 mL), and then the organic
layer was dried with Na2SO4. The organic layer was
decanted, and the solvent was removed under reduced
pressure to yield 2.46 g (89%) of nearly pure 5a.
Recrystallization from n-heptane (25 mL) produced
analytically pure 5a (mp
=
105–106°C. TLC
[n-hexane/ethyl acetate: 90/10] Rf = 0.40. IR: 3421, 2966,
1
2927, 1677 cmÀ1. H NMR (CDCl3): δ = 0.92 (d, 3H,
J = 6.4 Hz); 1.06 (d, 3H, J = 6.4 Hz); 1.38 (s, 9H); 2.56
(m, 1H); 4.20 (d, 1H, J = 3.6 Hz); 6.46 (s, 1H). 13C NMR
(CDCl3): δ = 16.33, 20.20, 28.46, 32.18, 51.61, 68.76,
167.50. MS: m/z 191 (M+); 176, 149, 57 (base peak).
Anal. Calcd for C9H18NOCl: C, 56.39; H, 9.46; N, 7.31;
Cl, 18.49. Found: C, 56.65; H, 9.49; N, 7.36; Cl, 18.24.
N-(1-Adamantyl)-2-chloro-3-methylbutanamide (5b). The
general procedure of Lengyel and Aaronsen [19] was
followed. To a solution of 1-adamantylamine (2.927 g,
0.019 mol, 1.5 eq) and Et3N (1.96 g, 2.7 mL, 0.019 mol,
1.5 eq) in 50 mL of CH2Cl2, a solution of 2-chloro-3-
methylbutanoyl chloride (7) (2.00 g, 0.013 mol) in
15 mL of CH2Cl2 was added dropwise at 0°C. After the
addition was complete, the reaction mixture stirred at RT
overnight and then was washed twice with 25 mL of
0.1 M HCl, three times with distilled water (40 mL), and
then the organic layer was dried with Na2SO4. The
organic layer was decanted, and the solvent was removed
under reduced pressure to yield crude (5b) (4.895 g,
97.9%). After recrystallization from hexane (15 mL), the
solid was purified via column chromatography
(hexane/ethyl acetate: 90/10), giving analytically pure 5b
(2.987 g, 59.7%, mp 141–142°C). TLC (hexane/ethyl
acetate: 90/10) Rf = 0.56. IR: 3271, 2969, 2908, 2852,
2-Chloro-3-methylbutanoyl chloride (7).
The general
procedure of Harpp et al. [10] was followed. Isovaleryl
chloride (6), (6.03 g, 6.10 mL, 0.050 mol) thionyl
chloride (41 g, 25 mL, 0.3446 mol), finely powdered N-
chlorosuccinimide (16.67 g, 0.125 mol, 2.5 equivalents),
and concentrated HCl (8 drops) were stirred and refluxed
for 90 min. The reaction was monitored by 1H NMR:
The disappearance of the CH2 signal of starting acid
chloride (δ = 2.71, d) and the appearance of the CHCl
signal for the α-chloroacid chloride product (δ = 4.49, d).
After cooling to room temperature, carbon tetrachloride
(CCl4) (50 mL) was added to the reaction mixture, and it
was then kept at 0°C overnight. The reaction mixture was
then filtered through a sintered funnel to remove the
succinimide, the solid was washed with 10 mL CCl4, and
the filtrate was rotary evaporated to remove the SOCl2
1659 cmÀ1 1H NMR (CDCl3): δ = 0.92 (d, 3H,
.
J = 6.8 Hz); 1.06 (d, 3H, J = 6.8 Hz); 1.69 (s, 6H); 2.02
(s, 6H); 2.09 (s, 3H); 2.54 (m, 1H); 4.18 (d, 1H,
J = 3.5 Hz); 6.32 (s, 1H). 13C NMR (CDCl3): δ = 16.35,
20.19, 29.39, 32.18, 36.28, 41.24, 52.27, 68.70, 167.20.
MS: m/z 269 (M+); 234, 212, 135 (base peak). Anal.
Calcd for C15H24NOCl: C, 66.77; H, 8.97; N, 5.19; Cl,
13.14. Found: C, 66.86; H, 9.04; N, 5.30; Cl, 12.98.
N-Triphenylmethyl-2-chloro-3-methylbutanamide (5c).
The general procedure of Lengyel and Aaronsen [19] was
followed. To a solution of tritylamine (10.49, 0.040 mol,
1.1 eq) and triethylamine (4.13 g, 5.7 mL, 0.0408 mol,
1.1 eq) in dichloromethane (CH2Cl2) (300 mL), a
and CCl4. The remaining
crude
2-chloro-3-
methylbutanoyl chloride (7) was then vacuum distilled to
yield nearly pure 7 (6.19 g, 79.9%, bp = 70–76°C,
121 mmHg), which was used without further purification.
IR (CCl4): 2974, 1800 cmÀ1 1H NMR (CDCl3):
.
δ = 1.05 (d, 3H, J = 5.6 Hz, CH3); δ = 1.12 (d, 3H,
J = 6.8 Hz, CH3); δ = 2.57 (m, 1H, CH); δ = 4.45 (d,
1H, J = 6.4 Hz, CHCl). 13C NMR (CDCl3): δ = 16.94,
19.53, 32.32, 71.72, 170.27.
Journal of Heterocyclic Chemistry
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Month 2018
About the First Stable α-Lactam with a Secondary Alkyl Substituent in
Position Three
solution of 2-chloro-3-methylbutanoyl chloride (7) (6.19 g,
0.0368 mol) dissolved in dichloromethane (30 mL) was
added dropwise at RT. After the addition was complete,
the reaction mixture stirred at RT for 16 h and then was
washed with 1 M HCl (40 mL), distilled water
(3 × 50 mL), and then the organic layer was dried with
Na2SO4. The organic layer was decanted, and the solvent
was removed under reduced pressure to yield crude 5c.
After purification via column chromatography (hexane/
ethyl acetate: 90/10), analytically pure 5c (13.22 g,
94.9%, mp = 114–116°C) was obtained. TLC (hexane/
ethyl acetate: 90/10) Rf = 0.44. IR: 3314, 3055, 2963,
1.04 mmol) was then added and the reaction mixture
stirred for an additional 2.5 h. The progress of the
reaction was monitored via IR every 30 min, looking for
the disappearance of the α-haloamide C═O band at
~1680 cmÀ1 and the appearance of the α-lactam C═O
band at ~1840 cmÀ1. After the reaction proceeded for
2.5 h, approximately 20% of the starting amide 5a was
cyclized to α-lactam 8a. However, increased reaction
times or the addition of more NaH and 15-crown-5-ether
decreased the yield. All attempts to isolate pure 8a,
including changing the base from NaH to sodium tert-
butoxide or potassium tert-butoxide, were unsuccessful.
1
2922, 1667, 1598 cmÀ1. H NMR (CDCl3): δ = 0.91 (d,
Attempted
synthesis
of
1-(1-adamantyl)-3-
3H, J = 6.8 Hz); 1.02 (d, 3H, J = 6.8 Hz); 2.56 (m, 1H);
4.31(d, 1H, J = 3.6 Hz); 7.26 (m, 15 H); 7.92 (s, 1H).
13C NMR (CDCl3): δ = 16.75, 20.31, 32.07, 69.11,
70.68, 127.21, 128.07, 128.58, 144.25, 167.26. MS: m/z
377 (M+); 342, 243, 182, 165 (base peak), 104, 77, 55.
Anal: Calcd for C24H24NOCl: C, 76.28; H, 6.40; N, 3.71;
Cl, 9.38. Found: C, 76.41; H, 6.31; N, 3.74; Cl, 9.37.
isopropylaziridinone (8b).
The general procedure of
Cesare et al. [20] was followed. A suspension of 60%
NaH in mineral oil (0.5142 g, 12.85 mmol, 3 eq) and 15-
crown-5-ether (212 μL, 235.9 mg, 1.07 mmol, 0.25 eq)
in 15 mL dichloromethane was stirred at RT for 20 min.
N-(1-adamantyl)-2-chloro-3-methylbutanamide
(5b)
(1.156 g, 4.29 mmol) was then added and the reaction
mixture stirred for an additional 3.5 h. The progress of
the reaction was monitored via IR every 30 min, looking
for the disappearance of the α-haloamide C═O band at
~1680 cmÀ1 and the appearance of the α-lactam C═O
band at ~1840 cmÀ1. After the reaction proceeded for
3.5 h, approximately 45% of the starting amide 5b was
cyclized to α-lactam 8b. However, increased reaction
times or the addition of more NaH and 15-crown-5-ether
had minimal effects upon improving yield. All attempts
to isolate pure 8b were unsuccessful.
3-iso-Propyl-1-triphenylmethylaziridinone
(8c).
The
general procedure of Cesare et al. [20] was followed. A
suspension of 60% NaH in mineral oil (63 mg,
1.587 mmol, 3 eq) and 15-crown-5-ether (26 μL,
29.13 mg, 0.132 mmol, 0.25 eq) in 15 mL
dichloromethane was stirred at RT for 20 min. N-
triphenylmethyl-2-chloro-3-methylbutanamide (5c) (0.2 g,
0.529 mmol) was then added, and the reaction mixture
stirred for an additional 2.5 h. The progress of the
reaction was monitored by IR (the disappearance of the
α-haloamide C═O band at ~1680 cmÀ1 and the
appearance of the α-lactam C═O band at ~1840 cmÀ1).
The reaction mixture was then washed with distilled
water (3 × 50 mL) and dried with anhydrous Na2SO4.
The organic layer was decanted, and the dichloromethane
was then removed under reduced pressure. The resulting
oil was then taken up in pentane, cooled overnight at 0°,
and the resulting white crystals (0.150 g, 83.05%,
mp = 89–92°C) were filtered. IR: 3090, 3063, 3027,
Thermal
stability
of
3-iso-propyl-1-
triphenylmethylaziridinone (8c).
α-Lactam 8c (0.10 g,
mol.) was dissolved in 4 mL of nonane (bp = 151°C) and
refluxed for 1 h. The reaction mixture was then cooled to
RT and subjected to analysis by FTIR and GC–MS. The
reaction yielded isobytyraldehyde and trityl isonitrile as
the only products, which is in agreement with prior
observations [2].
Reaction of 3-iso-propyl-1-triphenylmethylaziridinone (8c)
with benzylamine. The procedure of Lengyel et al. [18]
1
2963, 2932, 2919, 2874, 1844 cmÀ1. H NMR: (CDCl3):
was followed. Tetrahydrofuran (6 mL), 3-iso-propyl-1-
triphenylmethylaziridinone (8c) (0.15 g, 0.44 mmol), and
benzylamine (0.1883 g, 0.192 mL, 1.757 mmol, 4 eq.)
were stirred at RT for 13 h. The solvent was removed
under reduced pressure, and the remaining oil was
purified by column chromatography (90% hexane/ethyl
acetate: 90/10). Two products were isolated,
2-(benzylamino)-3-methyl-N-(triphenylmethyl)
δ = 0.95 (d, 3H, J = 6.4 Hz); 0.96 (d, 3H, J = 6.4 Hz);
2.18 (m, 1H); 2.41 (d, 1H, J = 4.1 Hz); 7.30 (m, 15 H).
13C NMR: (CDCl3): δ = 18.92, 20.36, 28.84, 51.85,
77.57, 127.65, 128.15, 128.68, 142.57, 159.81 ppm. MS:
m/z 341 (M+); 165 (base peak). Anal: Calcd for
C24H23NO: C, 84.42; H, 6.79; N, 4.10; O, 4.69. Found:
C, 84.16; H, 6.88; N, 4.12.
Attempted synthesis of 1-tert-butyl-3-isopropylaziridinone
(8a). The general procedure of Cesare et al. [20] was
butanamide (15) (0.0791 g, 40.13%) and N-benzyl-3-
followed. A suspension of 60% NaH in mineral oil
(125 mg, 3.130 mmol, 3 eq) and 15-crown-5-ether
(58 μL, 59 mg, 0.261 mmol, 0.25 eq) in 15 mL
dichloromethane was stirred at RT for 20 min. N-tert-
methyl-2-[(triphenylmethyl)amino]
(0.0691 g, 35.06%).
Data for 15: mp = 141–142°C. TLC (hexane/EtOAc):
butanamide
(16)
90/10: Rf = 0.17. IR: 3323, 3232, 3084, 3058, 3026,
butyl-2-chloro-3-methylbutanamide
(5a)
(0.2
g,
2963, 2926, 2842, 1675 cmÀ1 1H NMR: (CDCl3):
.
Journal of Heterocyclic Chemistry
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M. Benitez, Y. D. Wang, I. Lengyel, M. Fitzsimmons, and V. Cesare
Vol 000
δ = 0.89 (d, 3H, J = 7.2 Hz); 0.99 (d, 3H, J = 7.2 Hz); 1.68
(s, 1H); 2.25 (m, 1H); 2.98 (d, 1H, J = 4.0 Hz); 3.75 (s,
2H); 7.22 (m, 20H); 9.00 (s, 1H) ppm. 13C NMR:
(CDCl3): δ = 17.68, 20.00, 31.24, 54.35, 68.42, 70.01,
127.00, 127.44, 127.95, 128.46, 128.62, 128.86, 139.46,
145.12, 172.44 ppm. MS: m/z 448 (M+); 207 (base peak);
162. Anal. Calcd for C31H32N2O: C, 83.00; H, 7.19; N,
6.24; O, 3.57. Found: C, 82.96; H, 7.17; N, 6.19.
triphenylmethylaziridinone (8c) (0.394 g, 1.15 mmol)
was added, and the solution was refluxed for 45 min. The
excess methanol was then removed under reduced
pressure, and the crude product (18) was purified via
column chromatography (90% hexanes/10% ethyl
acetate) leaving a clear oil. This oil was taken up in hot
hexane, left overnight at RT, and after filtration, pure
N-triphenylmethyl-2-methoxy-3-methylbutanamide (18)
(0.312 g, 72.4%, mp = 96–98°C) was obtained. TLC (90/
10 hexane/EtOAc): Rf = 0.15. IR: 3401, 3067, 3023,
Data for 16: mp
= 169–170.5°C. TLC (90/10
hexane/EtOAc): Rf = 0.28. IR: 3340, 3287, 3084, 3055,
1
3029, 2955, 2923, 2885, 1649 cmÀ1. H NMR: (CDCl3):
2960, 2931, 2895, 1689 cmÀ1 1H NMR: (CDCl3):
.
δ = 0.93 (d, 3H, J = 1.2 Hz); 0.95 (d, 3H, J = 0.8 Hz);
1.78 (m, 1H); 3.14 (d, 1H, J = 4.0 Hz); 3.83 (dd, 1H);
4.01 (dd, 1H); 6.35 (t, 1H); 7.25 (m, 15H); 7.35 (m, 5H)
ppm. 13C NMR: (CDCl3): δ = 17.72, 20.40, 34.00, 43.42,
62.46, 71.72, 126.81, 127.31, 127.91, 127.93, 127.98,
128.60, 129.05, 138.42, 145.79, 172.91 ppm. MS: m/z
448 (M+); 315, 207 (base peak). Anal. Calcd for
C31H32N2O: C, 83.00; H, 7.19; N, 6.24; O, 3.57. Found:
C, 83.05; H, 7.17; N, 6.20.
δ = 0.89 (d, 3H, J = 6.8 Hz); 0.95 (d, 3H, J = 6.8 Hz);
2.08 (m, 1H, J = 3.6 Hz); 3.37 (d, 1H, J = 4.0 Hz); 3.47
(s, 3H); 7.26 (m, 15H); 7.79 (s, 1H) ppm. 13C NMR:
(CDCl3): δ = 17.21, 19.15, 31.56, 59.82, 69.87, 88.05,
127.03, 127.97, 128.65, 144.77, 171.14 ppm. MS: m/z
373 (M+); 342, 243 (base peak); 165. Anal. Calcd for
C25H27NO2: C, 80.40; H, 7.29; N, 3.75; O, 8.56. Found:
C, 79.79; H, 7.28; N, 3.75.
Reaction of 3-iso-propyl-1-triphenylmethylaziridinone (8c)
REFERENCES AND NOTES
with sodium benzyloxide.
The general procedure of
Lengyel et al. [11] was followed. A 1.0 M solution of
sodium benzyloxide in benzyl alcohol (1 mL) and 3-iso-
propyl-1-triphenylmethylaziridinone (8c) (0.100 g,
0.293 mmol) was stirred at RT for 1 h. Dichloromethane
(25 mL) was added to the reaction, and it was washed
three times with distilled water (15 mL). The organic
layer was dried with anhydrous Na2SO4, filtered, and
then the dichloromethane was removed under reduced
pressure. The resulting oil, crude 17, was purified using
column chromatography (hexane/ethyl acetate: 90/10) to
obtain analytically pure benzyl 2-(triphenylmethylamino)-
3-methylbutanoate (17) (0.118 g, 89.4%, mp = 113–
115°C).
[1] Baumgarten, H. E. J. Am Chem Soc 1962, 84, 4975.
[2] Hoffman, R. V.; Cesare, V. In Science of Synthesis, Houben-
Weyl Methods of Molecular Transformations, Vol. 21, Chapter 8;
Shinkai, I.; Weinreb, S. Eds.; Georg Thieme Verlag: Stuttgart, 2005.
[3] Talaty, E. R.; Madden, J. P.; Stekoll, L. H. Angew Chem 1971,
83, 848 see also Angew Chem Internat Ed Engl, 1971, 10, 753.
[4] Lengyel, I.; Taldone, T.; Lyons, T.; Cesare, V. J Heterocyclic
Chem 2008, 45, 803.
[5] Sheehan, J. C.; Lengyel, I. J. Am Chem Soc 1964, 86, 1356.
[6] Setter, H.; Mayska, P.; Wiebner, U. Forelurngsbericht des
Landes Nordrhein- Westfalen Nr. 3095; Westdentscher Verlag: Opladen,
Germany, 1982.
[7] Sheehan, J. C.; Beeson, J. H. J. Am Chem Soc 1967, 89, 362.
[8] Lengyel, I.; Uliss, D. B. Chem Commun 1968 1621.
[9] Lengyel, I.; Cesare, V.; Karram, H.; Taldone, T. J Heterocyclic
Chem 2001, 38, 997.
[10] Harpp, D. N.; Bao, L. Q.; Black, C. L.; Gleason, J. G.; Smith,
R. A. J. Org Chem 1975, 40, 3420.
TLC (90/10 hexane/EtOAc): Rf = 0.53. IR: 3320, 3032,
2959, 2873, 1733, 1596 cmÀ1 1H NMR: (CDCl3):
.
[11] Lengyel, I.; Cesare, V.; Adam, I.; Taldone, T. Heterocycles
2002, 57, 73.
δ = 0.93 (3H, d, J = 7 Hz); 0.99 (3H, d, J = 7 Hz); 2.18
(1H, m); 2.70 (1H, d, J = 10 Hz); 3.315 (1H, dd, 5 Hz);
4.29 (1H, d, 12 Hz); 4.59 (1H, d, 12 Hz); 7.24 (15H, m);
7.53 (5H, m). 13C NMR: (CDCl3): δ = 17.96, 19.74,
33.93, 50.98, 60.68, 66.24, 70.99, 126.37, 127.77,
128.09, 128.27, 128.43, 128.96, 135.61, 146.15,
173.52 ppm. MS: m/z 373 (M+); 342, 314, 243 (base
peak); 165, 77. Anal. Calcd for C31H31NO2: C, 82.82; H,
6.95; N, 3.12; O, 7.12. Found: C, 82.93; H, 7.00; N, 3.04.
[12] Alexandron, N. E. J. Org Chem 1965, 30, 1335.
[13] Sheehan, J. C.; Lengyel, I. J. Am Chem Soc 1964, 86, 746.
[14] Lengyel, I.; Sheehan, J. C. Angew Chem 1968, 80, 27 see also
Angew. Chem. Internal. Ed in English, 1968, 7, 25–36.
[15] Backes, J. Houben-Weyl, Methoden der Organischen Chemie,
Vierte Auflage, Band E16b; Georg Thieme Verlag: Stuttgart, New York,
1991, pp. 1–30.
[16] Talaty, E. R.; Dupuy, A. E. Jr.; Utermoehlem, C. M. Chem
Commun 1971 16.
[17] Yusoff, M. M.; Talaty, E. R. Tetrahedron Lett 1996, 48, 8695.
[18] Lengyel, I.; Cesare, V.; Chen, S.; Taldone, T. Heterocycles
2002, 57, 677.
Reaction of 3-iso-propyl-1-triphenylmethylaziridinone (8c)
with methanol. The procedure of Lengyel et al. [11] was
followed. To methanol (10 mL), 3-iso-propyl-1-
[19] Lengyel, I.; Aaronson, M. J. Can J Spectroscopy 1974, 19, 95.
[20] Cesare, V.; Lyons, T. M.; Lengyel, I. Synthesis 2002 1716.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet