The synthesis, physical, and spectral properties, and some reactions of a new stable bis-α-lactam (aziridinone) with a terpene skeleton

Article abstract of DOI:10.1081/SCC-100107018

A synthesis of a new stable bis-α-lactam, cis-1,1′(p-menth-1,8-ylene) bis(3-tert-butyl-2-azirididone) (4), derived from p-menthane, is described. Complete spontaneous thermal decomposition required lh of reflux in boiling n-decane (b.p. 174°C) and the products are 2,2-dimethylpropanal (pivalaldehyde) (6) and 1,8-diisocyano-p-menthane (7). Reaction with benzylamine yielded the unexpected bis-benzylamide (13a), while reaction with sodium methoxide gave the bisα-amino acid ester (14).

Full text of DOI:10.1081/SCC-100107018

This article was downloaded by: [Tufts University]
On: 04 November 2014, At: 08:25
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
THE SYNTHESIS, PHYSICAL, AND SPECTRAL
PROPERTIES, AND SOME REACTIONS OF A NEW
STABLE bis-α-LACTAM (AZIRIDINONE) WITH A
TERPENE SKELETON
Istvan Lengyel a , Victor Cesare a , Tony Taldone a & David Uliss a
a Department of Chemistry , St. John's University , Jamaica, New York, 11439, U.S.A.
Published online: 16 Aug 2006.
To cite this article: Istvan Lengyel , Victor Cesare , Tony Taldone & David Uliss (2001) THE SYNTHESIS, PHYSICAL, AND
SPECTRAL PROPERTIES, AND SOME REACTIONS OF A NEW STABLE bis-α-LACTAM (AZIRIDINONE) WITH A TERPENE SKELETON,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:23,
3671-3683, DOI: 10.1081/SCC-100107018
To link to this article: http://dx.doi.org/10.1081/SCC-100107018
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(23), 3671–3683 (2001)
THE SYNTHESIS, PHYSICAL,
AND SPECTRAL PROPERTIES,
AND SOME REACTIONS OF
A NEW STABLE bis-a-LACTAM
(AZIRIDINONE) WITH A
TERPENE SKELETON
Istvan Lengyel,* Victor Cesare,
TonyTaldone, and David Uliss
Department of Chemistry, St. John’s University,
Jamaica, New York 11439, USA
ABSTRACT
A synthesis of a new stable bis-a-lactam, cis-1,10(p-menth-
1,8-ylene) bis(3-tert-butyl-2-azirididone) (4), derived from
p-menthane, is described. Complete spontaneous thermal
decomposition required 1h of reflux in boiling n-decane
(b.p. 174ꢀC) and the products are 2,2-dimethylpropanal (piva-
laldehyde) (6) and 1,8-diisocyano-p-menthane (7). Reaction
with benzylamine yielded the unexpected bis-benzylamide
(13a), while reaction with sodium methoxide gave the bis-
a-amino acid ester (14).
* Corresponding author.
3671
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

ORDER
REPRINTS
3672
LENGYEL ET AL.
INTRODUCTION
Whereas the physical and chemical properties of b-lactams have been
extensively studied,1 less is known about a-lactams (aziridiones), especially
bis-a-lactams. The sole previously reported2,3 stable bis-a-lactam, 3,30-(1,3-
adamantylene)bis(1-tert-butyl-2-aziridinone), has a plane of symmetry and
the two aziridinone moieties are connected by the entirely rigid, unflexible
1,3-adamantylene linkage. We are unaware of any other published report
concerning bis-a-lactams. In addition, no reactions of that bis-a-lactam have
been reported.
Here we report the synthesis, key thermal and chemical reactions,
physical and spectroscopic properties of a new stable unsymmetrically sub-
stituted bis-a-lactam, 1,10( p-menth-1,8-ylene)bis(3-tert-butyl-2-aziridinone)
(4), containing the flexible p-menthane skeleton, the one most common in
natural products of the monoterpene class, as the connecting link between
the two aziridinone functions.
DISCUSSION
1. Synthesis
Our synthesis of the precursor, cis-(N,N0-p-menth-1,8-ylene)bis(2-
bromo-3,3-dimethylbutanamide) (3) followed the standard general
published route,4 acylation of cis-1,8-diamino-p-menthane (1) with
2-bromo-3,3-dimethylbutanoyl chloride (2) in 1,2-dichloroethane and 20%
aqueous sodium hydroxide5 (Scheme 1). For the cyclization of diamide 3, we
used the phase-transfer-catalysis procedure of Scrimin et al.6 in benzene at
15ꢀC. Under these conditions the dehydrohalogenation was essentially
quantitative, as attested to by the IR spectrum: a strong 1833 cmÀ1 band
indicated the presence of an a-lactam4 with the complete disappearance of
the starting amide bands at 3328 cmÀ1 (N-H) and 1654 cmÀ1 (C¼O). The
initially oily bis-aziridinone (4) crystallized after purification by column
chromatography, m.p. 66–68ꢀC. The high resolution NMR (1H and 13C)
(c.f. Experimental) confirms the structure, as does the mass spectrum (vide
infra) with the molecular ion present at m/z 362. Under the conditions of the
phase-transfer-catalysis synthesis, part of the a-lactam already formed is
hydrolyzed by the large excess KOH present to (N,N0-p-menth-1,8-ylene)-
bis(2-amino-3,3-dimethylbutanioc acid) (5) (identified by IR and GC-MS),
which reduced the yield of the a-lactam to 56%.

ORDER
REPRINTS
BIS-a-LACTAM
3673
Scheme 1. The synthesis of a new bis-a-lactam, cis-(1,10-p-menth-1,8-ylene)bis(3-tert-
butyl-2-aziridinone) (4).
2. Thermolysis
Refluxing bis-aziridinone 4 in n-heptane (b.p. 98ꢀC) for 1h caused no
decomposition at all: starting material was fully recovered, while refluxing in
n-octane (b.p. 126ꢀC) or n-nonane (b.p. 151ꢀC) for 1h caused only partial
decomposition. Only refluxing in n-decane (b.p. 174ꢀC) for 1h brought
about complete spontaneous thermal decomposition by quantitative
fragmentation into 2,2-dimethylpropanal (pivalaldehyde) (6) and 1,8-diiso-
cyano-p-menthane (7)7 (Scheme 2), reflecting an uncommonly high thermal
stability.
It was found that under the conditions required to achieve complete thermal
decomposition, most of the initially formed 1,8-diisocyano-p-menthane (7)

ORDER
REPRINTS
3674
LENGYEL ET AL.
Scheme 2. The thermal decomposition of bis-a-lactam 4.
isomerized to the more stable 1,8-dicyano-p-menthane8 (8), which was iden-
tified by IR and GC-MS (c.f. Experimental). A similar observation was
made by Sheehan and Beeson9 when they heated 1,3-di-tert-butylaziridinone
to 175ꢀC: the initially formed tert-butyl isonitrile rearranged to tert-butyl
nitrile.
This is the most frequently observed path of thermal decomposition of
a-lactams and was first reported by Sheehan and Lengyel.10,11 These authors
were also the first to propose10 an imino-oxirane intermediate like 9 as a
probable intermediate in this thermal fragmentation.
The 2,2-dimethylpropanal (6) was isolated as its semicarbazone deri-
vative12 and identified by direct comparison with a sample independently
synthesized by their m.p. IR, MS, and GC retention times. The 1,8-diiso-
cyano-p-menthane was identified by direct comparison with a sample we
synthesized specifically for this purpose from 1,8-diamino-p-menthane,
chloroform, and KOH by a modified7 A. W. Hofmann ‘‘Carbylamine’’
synthesis.13 The m.p. IR, NMR, and MS, as well as the GC-retention
time of the thermal fragmentation product and the synthetic compound
were identical.

ORDER
REPRINTS
BIS-a-LACTAM
3675
3. Chemical Reactions
Although some exceptions are known,4 the predominant pathway of
ring-opening of monofunctional a-lactams (10) with protic non-ionic
nucleophiles of the type HZ is to yield a-substituted N-alkylamides (11),
while with aprotic ionic nucleophiles of the type ZÀ, a-N-alkylamino acid
derivatives are the main products (12), Scheme 3.
Scheme 3. The major ring-opening pathways of aziridinones with protic and aprotic
nucleophiles.
bis-a-Lactam 4 is not only thermally very stable, it also exhibits an
astonishingly low reactivity towards certain nucleophiles. For example, a
solution of 4 in methanol at room temperature remained completely
unchanged after 120 h. Only refluxing 4 in methanol for 100 h effected
complete reaction, yielding a mixture of four products (TLC) which were
not separated or further investigated.
Reaction of 4 with benzylamine gave an essentially quantitative
yield of the unexpected (N,N0-p-menth-1,8-ylene)bis(2-amino-N-benzyl-3,-
3-dimethylbutanamide (13a), (Scheme 4), while reaction with sodium
methoxide yielded (N,N0-p-menth-1,8-ylene)bis(methyl 2-amino-3,3-di-
methylbutanoate) (14), (Scheme 5). Products 13a and 14 correspond to 12
in Scheme 3.
The reaction of 4 with benzylamine could theoretically yield either 13a
of 13b (Scheme 4). The evidence in favor of 13a includes NMR and MS. The
benzylic methylene protons in structures like 13a give a signal around
4.1–4.5 d,14 while the benzylic methylene signal for structures like 13b
appears at 3.7–3.9 d.11 Further evidence for structure 13a is found in the
mass spectrum. While all other fragment ions are compatible with both
structures 13a and 13b, ion m/z 442 (M-C6H5CH2NHCO)þ conclusively
establishes the structure of the benzylamine reaction product as 13a, i.e.
an ion of this mass cannot be derived from 13b.

ORDER
REPRINTS
3676
LENGYEL ET AL.
Scheme 4. Reaction of bis-a-lactam 4 with benzylamine.
Scheme 5. Reaction of bis-a-lactam 4 with sodium methoxide.
CONCLUSION
The synthesis of a second bis-a-lactam is reported, which has a flexible
1,8-p-menthylene connecting link between the two aziridinone functions,

ORDER
REPRINTS
BIS-a-LACTAM
3677
and a high thermal stability. At about 174ꢀC, it fragments into an
aldehyde (6) and a bis-isonitrile (7), in close analogy with the published4
thermal decomposition path of monoaziridinones. At the tempera-
ture required to achieve complete thermal decomposition (174ꢀC), the
initially formed bis-isonitrile (7) largely rearranges to the more stable
bis-nitrile (8).
bis-a-Lactam 4 is stable to methanolysis at 25ꢀC. On the other hand,
reaction with benzylamine at room temperature brings about ring-opening
with cleavage of the C2-N bond, as does sodium methoxide, leading to
bis-benzylamide (13a) and a-aminoester (14) type products. More work is
necessary concerning the benzylamine reaction, before the factors governing
product formation can be understood.
In contrast to the behavior of monoaziridinones15,16 and the only
other known bis-aziridinone,2 the major electron impact-induced fragmen-
tation of compound 4 is triggered by simple C-N bond cleavage rather than
CO ejections.
EXPERIMENTAL
Melting points were determined on a Thomas Hoover Capillary
1
Melting Point Apparatus and are uncorrected. H and 13C NMR spectra
were recorded on a 500MHz 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
performed by Atlantic Microlab Inc., Norcross, GA. Mass spectra (MS)
were recorded on a Hewlett–Packard GC-MS GCD system or a Finnigan
LCQ quadrupole ion trap mass spectrometer at The Scripps Research
Institute, La Jolla, CA. For column chromatography, JT Baker Silica gel
(40 microns) was used. Thin layer chromatography (TLC) was performed
with Analtech Silica gel glass backed plates (250 microns) cis-1,8-Diamino-
p-menthane (1) was purchased from Sigma-Aldrich Co., Milwaukee,
WI and used without further purification because it was found homoge-
neous by GC.
2-Bromo-3,3-dimethylbutanoyl chloride (2).17 The general procedure
of Harpp18 et al. was followed. 3,3-Dimethylbutyric acid (23.23 g, 0.2 mol)
and thionyl chloride (94.18 g, 0.8 mol) in 20 mL of carbon tetrachloride
was stirred at 65ꢀC for 30 min. After cooling the reaction mixture to
room temperature, N-bromosuccinimide (42.72 g, 0.24 mol), 100 mL of
carbon tetrachloride, and concentrated hydrobromic acid (7 drops)
were successively added. The reaction mixture was heated at 70ꢀC for
10 min and then at 77ꢀC for 90 min. The solvent was removed under reduced

ORDER
REPRINTS
3678
LENGYEL ET AL.
pressure and 50 mL of carbon tetrachloride was added to the remaining
black residue. The by-product, succinimide, was collected and washed
with carbon tetrachloride. The filtrate was vacuum distilled to give 39.61 g
(93%) of 2: b.p. 72ꢀC (19mm), lit. 17 b.p. 93–97ꢀC (37 mm).
cis-(N,N 0-p-Menth-1,8-ylene)bis(2-bromo-3,3-dimethylbutanamide) (3).
The general procedure of Schlesinger and Prill5 was followed. To a solution
of cis-1,8-diamino-p-menthane (1) (10.0 g, 0.059mol) in 100 mL, of
1,2-dichloroethane cooled to 10 to 15ꢀC was dropwise added, simul-
taneously and separately, with stirring 3,3-dimethylbutanoyl chloride (2)
(25.19g, 0.118 mol) and 20% aqueous sodium hydroxide (23.6 mL,
0.118 mol). The reaction mixture was allowed to warm to room temperature
overnight and filtered. The solid was washed on a sintered glass fritted
disk Buchner funnel with distilled water (750 mL). The remaining
solid was 25.06g (81%) of pure 3, m.p. 240–241ꢀC. TLC (80%
n-hexane : 20% ethyl acetate) Rf ¼ 0.48. IR (KBr): 3328 (N-H), 2962 (C-
1
H), 2869(C-H), 1654 (amide C ¼O), and 1537 cmÀ1 (amide II). H-NMR
(CDCl3): d ¼ 1.15 (18H, s, tert-butyl), 1.21 and 1.27 (9H, s, methyl protons
at C7, C9, and C10), 1.5–2.4 (9H, m, protons attached to C2, C3, C4, C5, and
C6), 4.00 and 4.07 (2H, s, CH-Br), 5.71 and 5.78 (2H, broad s, N-H,
exchanged for deuterium in CDCl3/CF3COOD). 13C-NMR (CDCl3):
d ¼ 22.72 (C9 and C10 carbons), 24.22 (methyl carbons in tert-butyl
groups), 27.15 (C7 methyl carbon), 27.85 (methylene carbons at C3 and
C5), 35.12 (quaternary carbon in tert-butyl groups), 37.24 (methylene car-
bons at C2 and C6), 43.71 (methane carbon at C4), 53.65 (C8 in menthane
moiety), 57.19(C in menthane moiety), 65.30 and 66.04 (CH-Br), 167.12
1
and 167.20 (carbonyl carbon atoms). MS: m/z 522/524/526, Mþ,
C22H40Br2N2O2þ; 507/509/511, (M-CH3)þ, C21H37Br2N2O2þ; 479/481/483,
(M-43)þ; 466/468/470, (M-C4H8)þ, C18H32Br2N2O2; 443/455, (M-Br)þ,
C22H40BrN2O2; 472/429, (M-CH3-HBr)þ, C21H36BrN2O2; 386/388, (M-
C4H8-Br)þ, C18H32BrN2O2; 373/375, (M-C5H10Br)þ, C17H30BrN2O2; 330/
332, (M-C6H11BrNO)þ, C16H29BrNO; 329/331, (M-C6H12BrNO)þ,
C16H28BrNO; 314/316, (329/331-CH3)þ, C15H25BrNO; 288/290, (330/332-
C3H6)þ; 250, (329/331-Br)þ, C16H28NOþ; 234/236, (329/331-C7H11)þ, also
(M-C13H23BrNO)þ, by fission of the C4-C8 bond, C9H17BrNO; 210, (M-Br-
C9H16BrNO)þ , C13H24NO; 194/196, (330/332-C10H16)þ, C6H13BrNO; 155,
(329/331-C7H11Br)þ, C9H17NOþ; 136, (329/331-C6H12BrNO)þ; C10H16þ
(69%); 121, (136-CH3)þ , C9H13þ; 95, C7H11þ; 84, C4H6NO (80%),
C5H10N (20%); 69, C4H5O and/or C5Hþ9 ; 58, base peak, C3H8Nþ. Ions
containing two bromine atoms are triplets, those containing one bromine
atom are doublets, and bromine-free ions are singlets. Anal. Calcd for
C22H40Br2N2O2: C 50.39; H 7.69; N 5.34; Br 30.48; found: C 50.21, H
7.80; N 5.35; Br 30.58.

ORDER
REPRINTS
BIS-a-LACTAM
3679
cis-(1,10-p-Menth-1,8-ylene)bis(3-tert-butyl-2-aziridinone) (4). The gen-
eral procedure of Scrimin et al 6 was followed. To a solution of a-bromoa-
mide 3 (1.50 g, 0.00286 mol) in 85 mL of anhydrous benzene at room
temperature was added 18-crown-6 (0.226 g, 0.000855 mol) and powdered
potassium hydroxide (1.18 g, 0.021 mol). After stirring for 7 days, the ben-
zene was removed under reduced pressure to yield an oil. Flash chromato-
graphy, using 80:20% n-hexane-ethyl acetate as eluent, gave 0.58g (56.0%)
of an oil which crystallized upon standing to give pure 4, m.p. 66–68ꢀC.
TLC (80% n-hexane : 20% ethyl acetate) Rf ¼ 0.37. IR (KBr): 2961 (C-H),
1
2867 (C-H), and 1833 cmÀ1 (a-lactam C¼O). H-NMR (CDCl3): d ¼ 0.97
and 1.03 (18H, s, tert-butyl), 1.08 and 1.12 (9H, s, the methyl protons at C7,
C9, and C10), 1.34–1.89, (8H, m, the methylene protons attached C2, C3, C5,
and C6), 2.15–2.18 (1H, m, methine proton attached to C4), 2.72 and 2.74,
(2H, s, two CH protons in aziridinone rings). 13C-NMR (CDCl3): d ¼ 21.81
and 22.38 (C9 and C10 methyl carbons, non-equivalent because of vicinity of
aziridinone function attached to C8), 23.48 (methyl carbons in tert-butyl
groups), 25.81 and 25.88 (C7 methyl carbon), 27.45–27.48 (methylene-car-
bons at C3 and C5), 31.78–31.86 (quaternary carbons in tert-butyl groups),
36.86–37.51 (methylene-carbons at C2 and C6), 46.26–46.43 (methine-
carbon at C4), 54.53 (C8 in menthane moiety), 59.03 (C1 in menthane
moiety), 62.10–62.18 (methine carbon atoms in aziridinone rings), 160.61
and 160.81 (carbonyl carbon atoms in the aziridinone rings, slightly magne-
tically non-equivalent, as would be expected on stereochemical ground).
MS: m/z 362, Mþ, C22H38N2O2; 334 (M-CO)þ, C21H38N2O; 319, (M-CO-
CH3)þ, C20H35N2O; 306, (M-2CO)þ, C20H38N2; 277, (M-CO-C4H9)þ,
C17H29N2O; 250, (M-C6H10NO)þ, C16H28NO; 222, (M-C6H10NO-CO)þ,
C15H28N; 180, (M-C6H10NO-CO-C3H6)þ, C12H22N (64%), C11H18NO
(36%); 164, (M-C6H10NO-C5H10O)þ, C11H18N; 154, (M-CO-C12H22N)þ,
C9H16NO; 137, (M-C6H10NO-C6H11NO)þ, C10H17, also (250-C5H10-
HNCOþ; 126, (M-CO-C12H22N-CO)þ, C8H16N; 114, (250-C10H16)þ,
C6H12NO; 95, (137-C3H6)þ, C7H11, 86 (M-CO-C16H28N2)þ, C5H10O (50%),
C5H12N (50%); 81, base peak, (137-C4H8)þ, C6Hþ9 ; 71, (137-C5H6)þ, C5H11
(95%), C4H7O (5%); 69C 4H5O; 58, C3H8N; 43, C3H7 (46%), C2H3O
(46%), CHNO (5%), C2H5N (3%); 41, C3Hþ5 . Anal. Calcd for
C22H38N2O2: C 72.88; H 10.56; N 7.73; found: C 72.65; H 10.63; N 7.78.
(N,N 0-p-Menth-1,8-ylene)bis(2-amino-3,3-dimethylbutanoic acid) (5).
The excess KOH/H2O present during the synthesis of bis-aziridinone 4
hydrolyzed part of this bis-aziridinone to 5, which was identified
by IR and GC-MS. IR (CCl4): 3600–3300 (O-H), 2950–2900 (C-H),
and 1727cmÀ1 (carboxyl C¼O). MS: m/z 397 (M-H)þ; 383 (M-CH3)þ;
339(M-CH -CO2)þ; 327 (M-CH2-C4H8)þ. McLafferty rearrangement ion,
3
238 (M-C4H9CH COOH-COOH)þ, 200 (base peak), 86 (pivalaldehyde).

ORDER
REPRINTS
3680
LENGYEL ET AL.
Thermal Decomposition of a-lactam 4
A mixture of cis-(1,10-p-menth-1,8-ylene)bis(3-tert-butyl-2-aziridinone)
(4) (0.250 g, 0.000689mol) in 20 mL of n-decane (bp 174ꢀC) was refluxed for
1h. During the reflux, pivalaldehyde was distilled into a receiving flask
which contained a solution of semicarbazide hydrochloride (0.169g,
0.00152 mol) and sodium acetate (0.137 g, 0.00167 mol) in 5 mL of distilled
water to give 0.155 g (78.7%) of pivalaldehyde semicarbazone, m.p.
189–190ꢀC (Lit.12 191ꢀC). TLC (100% ethyl acetate) Rf ¼ 0.35. MS: m/z
143, Mþ, C6H13N3O; 86, (pivalaldehyde), base peak; 57, (C4Hþ9 ); 41 (C3H5)þ.
The solvent from the reaction mixture was removed under vacuum to
yield 0.100 g (76.3%) of a mixture of 1,8-diisocyano-p-menthane (7) and 1,8-
dicyano-p-menthane (8) in a ratio of 10 and 90%, respectively, as deter-
mined by GC. IR (CCl4): 2258, 2243 (-CN, nitrile bands) and 2125 cmÀ1
(-NC, isonitrile band). The MS of isonitrile 7 is identical with that of
an analytical sample.7 In addition, their GC retention times are identical.
MS (7): m/z 175, (M-CH3)þ; 164 (M-CN)þ; 148 (M-C3H6N)þ; 122
(M-C4H6N)þ; 107 (122-CH3); 95 (122-HCN), base peak; 81 (107-C2H2);
69(95-C 2H2); 41, C3H5þ. MS (8): m/z 175, (M-CH3)þ; 122 (M-C4H6N)þ;
95 (122-HCN), base peak; 69 (95-C2H2); 41, C3Hþ5 .
Reaction of 4 with Benzylamine
To a solution of (1,10-p-menth-1,8-ylene)bis(3-tert-butyl-2-aziridinone)
(4) (0.0783 g, 0.000216 mol) in 1 mL of tetradydrofuran was added a sol-
ution of benzylamine (0.2315 g, 0.00216 mol) in 1 mL of tetrahydrofuran
and the reaction mixture stirred for 16 days at room temperature. The
tetrahydrofuran and excess benzylamine were removed under reduced press-
ure (0.5 mm) to yield crude (N,N0-p-menth-1,8-yelen)bis(2-amino-N-benzyl-
3,3-dimethylbutanamide) (13a) which was flash chromatographed under N2
stream using 80% n-hexane : 20% ethyl acetate as eluent, to give a quanti-
tative yield of pure 13a, mp ¼ 90–91ꢀC. TLC (60% n-hexane : 40% ethyl
acetate) Rf ¼ 0.42. IR (CCl4): 3449(amide N-H, 3354 (amine N-H), 3031
1
(aromatic C-H), 2960 (aliphatic C-H), and 1674 cmÀ1 (amide C¼O). H-
NMR (CDCl3): d ¼ 0.88 (doublet, C7 methyl protons, 3H), 0.91–094 (d,
C9 and C10 methyl protons, 6H), 1.05 (s, tert-butyl protons, 18H),
1.25–1.55 (m, methylene protons attached to C2, C3, C5, and C6 in the
menthane moiety, 8H), 1.60–1.70 (m, methine proton attached to C4 in
the menthane moiety, 1H), 2.76–2.92 (d, amine NH-protons, exchange for
deuterium in CDCl3/CF3COOD, 2H), 4.24–4.29(m, C- H protons adjacent
to the carbonyl group, 2H), 4.36–4.56 (m, benzylic methylene protons, 4H),

ORDER
REPRINTS
BIS-a-LACTAM
3681
6.87 (d, amide NH-protons, exchange for deuterium in CDCl3/CF3COOD,
2H), and 7.28 (s, aromatic protons, 10H). 13C-NMR (CDCl3): interpreted
with the aid of the APT-test, d ¼ 24.22 and 24.27 (C9 and C10-methyl
carbons in the menthane moiety), 27.74–27.91 (methyl carbons in the tert-
butyl groups), 28.88 (C7-methyl carbon in the menthane moiety), 34.17
and 34.36 (quaternary carbons in tert-butyl groups), 35.52 and 36.18
(C3 and C5 methylene carbons in the menthane moiety), 39.73 and 40.20
(C2 and C6 methylene carbons in the menthane moiety), 43.53 and 43.65
(benzylic methylene carbons), 48.56 and 48.70 (C4 methine carbon in
menthane moiety), 51.41 and 51.42 (C8 carbon in menthane moiety),
55.36 and 55.42 (C1 carbon in menthane moiety), 65.45–65.60 (methine
carbons adjacent to carbonyl carbons), 127.55 and 127.63 (p-carbon in
phenyl groups), 128.35 and 128.45 (m-carbons in phenyl groups), 128.78
and 128.85 (o-carbons in phenyl groups), 138.61–138.71 (phenyl carbons
attached to CH2), 175.01–175.27 (C¼O, carbonyl carbons). MS: exhibits
an abundant (40% relative abundance) (MH)þ ion at m/z 577. Important
fragment ions are at m/z 442 (M-C6H5CH2NHCO)þ, 357 (base peak) (M-
NHCH[C(CH3)3]CONHCH2 C6H5)þ, and 221 (357-C10H16)þ.Anal. Calcd.
for C36H56N4O2: C 74.96; H 9.78; N 9.71. Found: C 74.93; H 9.89; N 9.52.
Reaction of 4 with Sodium Methoxide
To a solution of (1,10-p-menth-1,8-ylene)bis(3-tert-butyl-2-aziridinone)
(4) (0.500 g, 0.00138 mol) in 50 mL of methanol was added sodium methox-
ide (0.596 g, 0.01104 mol) and the reaction mixture stirred for 24 h at room
temperature. The methanol was removed under reduced pressure to yield an
oily residue which was taken up in 300 mL of ethyl acetate, washed four
times with distilled water (25 mL), and dried with sodium sulfate. The ethyl
acetate was removed under reduced pressure to yield 0.59g (100%) of a
colorless oil. Flash chromatography, using 95% n-hexane : 5% methanol
as eluent, gave 0.49g (83.2%) of a colorless oil, ( N,N0-p-menth-1,8-ylene)-
bis(methyl 2-amino-3,3-dimethylbutanoate) (14). TLC (95% n-hexane : 5%
methanol) Rf ¼ 0.68. IR (CCl4): 2952 (C-H), 2871 (C-H) and 1731 cmÀ1
(ester C¼O), no pronounced N-H type absorption band19 in the
1
3200–3500cmÀ1 region. H-NMR (CDCl3): d ¼ 0.88 (s, tert-butyl sprotons,
18H), 0.91 (s, the C7, C9, and C10 methyl protons, 9H), 1.22 (m, methane
proton attached to C4,1H), 1.44 and 1.50 (m, the methylene protons
attached to C2, C3, C5, and C6 of the menthane moiety, 8H), 1.72 (m,
protons attached to the carbon atoms bearing the tert-butyl groups, 2H),
2.87 and 2.92 (s, NH-protons, exchanges for deuterium in CDCl3/
CF3COOD,2H), and 3.64 (s, O-CH3, methyl ester protons, 6H).

ORDER
REPRINTS
3682
LENGYEL ET AL.
13C-NMR (CDCl3): interpreted with the aid of the APT-test, d ¼ 23.95 and
25.33 (C9 and C10-methyl carbons), 26.76 and 27.03 (methyl carbons in the
tert-butyl groups), 29.44 (C7-methyl carbon), 34.75 (quaternary carbon in
tert-butyl groups), 36.13 (methylene carbons at C3 and C5), 40.77 (methy-
lene carbons at C2 and C6), 48.25 (methine carbon at C4), 51.15 (C8-carbon
in menthane moiety), 51.31 (O-CH3), 54.82 (C1-carbon in menthane
moiety), 63.08 (the two carbons adjacent to the tert-butyl groups), 177.89
and 177.93 (C¼O, the two ester carbonyl carbons). MS/MS: exhibits a
robust (MþH)þ ion at m/z 427 with 45% relative abundance. Fragment
ions are at m/z 367 (M-COOCH3), 282 (base peak), M-NHCH[C(CH3)3]
COOCHþ3 , and 146 (282-C10H16)þ. Anal. Calcd. for C24H46N2O4: C 67.57;
H 10.87; N 6.57. Found: C 67.71; H 10.91; N 6.44.
ACKNOWLEDGMENT
We thank Professor Klaus Biemann, Department of Chemistry,
Massachusetts Institute of Technology, for the high resolution mass spectra.
REFERENCES
1. Backes, J. 2-Oxoazetidine (b-Lactame), in Houben-Weyl, Methoden der
Organischen Chemie, Vierte Auflage, Band E16b, Georg Thieme
Verlag, Stuttgart, New York, 1991, pp. 31–867.
2. Lengyel, I.; Uliss, D.B.; Mark, R.V. J. Org. Chem. 1970, 35,
4077–4084.
3. Talaty, E.R.; Dupuy, Jr., A.E. J. Med. Chem. 1970, 13, 1021–1022.
4. A review: Lengyel, I.; Sheehan, J.C. Angew. Chem. Internat. Ed. Engl.
1968, 7, 25–36.
5. Schlesinger, A.H.; Prill, E.J. J. Am. Chem. Soc. 1956, 78, 6123–6127.
6. Scrimin, P.; D’Angeli, F.; Veronsese, A.C. Synthesis 1982, 586–587.
7. Cesare, V.; Lengyel, I.; Hagigeorgiou, M. Manuscript in preparation.
8. German Patent No. DE 3136580, 1983.
9. Sheehan, J.C.; Beeson, J.H. J. Am. Chem. Soc. 1967, 89, 362–366.
10. Sheehan, J.C.; Lengyel, I. J. Am. Chem. Soc. 1964, 86, 746.
11. Sheehan, J.C.; Lengyel, I. J. Am. Chem. Soc. 1964, 86, 1356–1359.
12. Daniloff, S.; Venus-Danilova, E. Ber. dtsch. chem. Ges. 1926, 59,
377–386.
13. (a) Hofmann, A.W. Ann. 1867, 144, 144–120; (b) Hofmann, A.W.
Ann. 1868, 146, 107–119; (c) Hofmann, A.W. Ber. 1870, 3, 761–772.
14. Shimazu, M.; Endo, Y.; Shudo, K. Heterocycles 1997, 45, 735–744.

ORDER
REPRINTS
BIS-a-LACTAM
15. Lengyel, I.; Uliss, D.B. Chem. Commun. 1968, 1621–1622.
3683
16. Lengyel, I.; Uliss, D.B.; Nafissi-V, M.M.; Sheehan, J.C. Org. Mass
Spectrum. 1969, 2, 1239–1255.
17. Homeyer, A.H.; Withmore, F.C.; Wallingford, V.H. J. Am. Chem.
Soc. 1933, 55, 4209–4214.
18. Harpp, D.N.; Bao, L.Q.; Black, C.J.; Gleason, J.G.; Smith, R.A. J. Org.
Chem. 1975, 40, 3420–3427.
19. A similar observation was made earlier by Sheehan and Lengyel11 with
regards to t-butyl 2-t-butylaminopropionate and t-butyl 2-t-butyl-
amino-2-methylpropionate.
Received in the USA February 9, 2001

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request
Permission/Reprints Here" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
(AAP) website for guidelines on Fair Use in the Classroom.
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our Website
User Agreement for more details.
Order now!
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC100107018