Full characterization and some reactions of 1-(2-adamantyl)-3-(1-adamantyl) aziridin-2-one

Article abstract of DOI:10.1002/jhet.5570450327

(Chemical Equation Presented) We found that 1-(2-adamantyl)-3-tert- butylaziridin-2-one (5a) is unstable. It slowly decomposes at room temperature, although detectable by IR spectroscopy (1840 cm^-1 band in CCl ₄). On the other hand, a closely related analogue, 1-(2-adamantyl)-3-(1-adamantyl)aziridin-2-one (5b), is very stable, in concurrence with an earlier report [1]. We fully characterized aziridinone 5b, identified its thermal decomposition products (7 and 8) and reacted it with two aprotic ionic (tBuO^- and HO^-) and one protic non-ionic nucleophile (benzylamine). All three products (9b, 10, and 11) result from exclusive cleavage of the lactam (1-2) bond.

Full text of DOI:10.1002/jhet.5570450327

May-Jun 2008
Full Characterization and Some Reactions of 1-(2-Adamantyl)-3-(1-
adamantyl)aziridin-2-one
803
István Lengyel*, Tony Taldone, Theresa Lyons and Victor Cesare
Department of Chemistry, St. John’s University, 8000 Utopia Parkway, Jamaica, New York 11439 USA
e-mail: tonytaldone@yahoo.com
Received September 5, 2007
O
C
H
1
-Ad
CH
COOtBu
O
KOtBu
tBuO-
1
-Ad
CH
Br
NH-2-Ad
1-Ad
NH-2-Ad
THF
0°C
0
°C
9b
4b
N
2-Ad
5b
C
6
H
-
5
C
O
T
H
H
°
C
H
5
F
,
2 N
2
H
2
,
2
5
e
n
a
°
C
diox
O
C
1
-Ad
CH
NH-2-Ad
COOH
1
-Ad
CH
NH-2-Ad
NHCH C H
2 6 5
10
11
We found that 1-(2-adamantyl)-3-tert-butylaziridin-2-one (5a) is unstable. It slowly decomposes at
-1
room temperature, although detectable by IR spectroscopy (1840 cm band in CCl ). On the other hand, a
4
closely related analogue, 1-(2-adamantyl)-3-(1-adamantyl)aziridin-2-one (5b), is very stable, in
concurrence with an earlier report [1]. We fully characterized aziridinone 5b, identified its thermal
-
-
decomposition products (7 and 8) and reacted it with two aprotic ionic (tBuO and HO ) and one protic
non-ionic nucleophile (benzylamine). All three products (9b, 10, and 11) result from exclusive cleavage of
the lactam (1-2) bond.
J. Heterocyclic Chem., 45, 803 (2008).
INTRODUCTION
Recently we attempted the synthesis of 1-(2-adamantyl)-
satisfactory synthesis of α-lactam 5a from α-bromoamide
4
a (Scheme 1).
Four different published procedures were examined: (1)
3
-tert-butylaziridin-2-one (5a), a new α-lactam having a
The dehydrobromination of α-bromoamide 4a with 1
equivalent of KOtBu in dry THF at 0°C [3], (2) Varying
amounts (1-3 equivalents) of NaOtBu in ether at 0°C or
THF at 25°C [2], (3) Excess KOH, in conjunction with
particularly bulky secondary cycloalkyl substituent on the
nitrogen. We devoted a substantial study to finding a
Scheme 1. Attempted synthesis of α-lactam 5a.
1
8-crown-6 ether as phase transfer catalyst (PTC), in
O
O
benzene at 25°C or toluene at 0°C [4], (4) Three
equivalents of NaH in the presence of 15-crown-5 ether as
PTC, in CH Cl at room temperature [5].
Et N
3
+
2-Ad-NH2
NH-2-Ad
Cl
CH Cl2
2
2
2
Br
25°C
Br
α-Lactam 5a is readily detectable in the IR (an 1840
3
a
4a
-1
cm band in CCl solution), but decomposes at room
4
b.p. [2] 72°C/19 mm
m.p. 205-207°C
temperature because the bases react with it faster than
with the α-bromoamide, which precludes its isolation.
Nonetheless, we isolated, purified and characterized one
of the follow-up products (9a) resulting from reaction of
the α-lactam with tert-butoxide. The formation of such
α-aminoacid tert-butyl esters had been observed before,
both from stable and unstable α-lactams [3, 6].
Next we conducted a comprehensive literature search,
which revealed only one short communication [1]
reporting a stable α-lactam with a secondary alkyl
substituent on the nitrogen, 1-(2-adamantyl)-3-(1-
various
(
-HBr)
bases
-25°C
0
O
O
KOtBu
THF, 0°C
O
N
1
.5 hrs
NH-2-Ad
2
-Ad
9
a
5
a
unstable at rt

8
04
I. Lengyel, T. Taldone, T. Lyons and V. Cesare
Vol 45
adamantyl)aziridin-2-one (5b). Alas, the characterization
of α-lactam 5b [1] is incomplete: there is no elemental
analysis, no mass spectrum, no C-NMR and APT, no
decomposition of only a very small fraction of the
α-lactam. Even refluxing in n-octane (b.p. 125-127°C)
for one hour results in incomplete decomposition. Only
refluxing in n-nonane (b.p. 151°C) for one hour brought
about complete spontaneous thermal decomposition by
quantitative fragmentation into 1-adamantyl aldehyde (7)
[6] and 2-adamantyl isocyanide (8) [9] (Scheme 3),
presumably via the imino-oxirane intermediate 6 [10].
1
3
yield, no TLC R , the thermal decomposition products are
f
not identified, the experimental details of the synthesis are
insufficient, the amount of base used, the reaction time
and the exact method of isolation are not described, and
no reactions of 5b are reported.
The present investigation was undertaken, prompted by
the apparent uniqueness of α-lactam 5b, with the
following aims: 1. Work out a synthesis of α-lactam 5b.
Isolate, purify and characterize it fully. 2. Determine the
limit of its thermal stability, identify and characterize its
thermal decomposition products. 3. Carry out three
reactions on it, two with aprotic ionic nucleophiles and
one with a protic non-ionic nucleophile. Identify the
reaction products and determine their physical and
spectral properties.
Scheme 3. The thermal decomposition of α-lactam 5b.
1-Ad
O
O
n-nonane
N
1-Ad
boil, 151°C, 1hr
N
2
-Ad
2
-Ad
5b
6
1
-Ad-CHO
+
2-Ad-NC
8
RESULTS AND DISCUSSION
7
m.p. 139-141°C
m.p. 178-180°C
1
. Synthesis of α-Lactam 5b. Accordingly, we synthe-
(lit. [6] 139-141°C) (lit. [9] 178-180°C)
sized the precursor, N-(2-adamantyl)-2-(1-adamantyl)-2-
bromoacetamide (4b), from commercially available 1-
adamantaneacetic acid (1) in three steps (Scheme 2),
following published procedures [7,8], and subjected it to
Characterization of the products was achieved by FT-IR
and GC-MS. The IR, MS and retention times of the two
thermal decomposition products were identical with those
of authentic samples prepared for comparison by
independent synthesis (c.f. Experimental).
3. Some Reactions of α-Lactam 5b. In general,
stability and reactivity are correlated: the most stable α-
lactams show very low reactivity. Even though 5b is the
highest-melting of all α-lactams known to date - about 60
compounds in all - it is at the same time also very
reactive. It reacts under mild conditions readily and
promptly with all common nucleophiles. What is so
astounding is not its high chemical reactivity but the high
thermal stability. To date we are unable to account for
this antinomy.
Molecular models and computer drawings indicate that 1.
in the most stable configuration the two adamantyl
substituents are trans to one another. 2. the extent of steric
hindrance around the 1-adamantyl group is the same in all
rotamers. 3. the extent of steric hindrance generated and
imparted on the ring by the 2-adamantyl substituent varies
greatly from one rotamer to another. As can be seen from
Figure 1, even in the most stable rotamer the ring is largely
1
,3-dehydrobromination by KOtBu [3]. α-Lactam 5b
forms readily and promptly, although in low yield. Our
efforts to increase the yield by adding more base, stirring
longer and/or varying the temperature, were not
successful because the α-lactam readily reacts with tert-
butoxide under the reaction conditions, to give ester 9b.
Scheme 2. Synthesis of α-lactam 5b (NBS = N-bromosuccinimide).
O
O
O
SOCl2
heat
NBS 1-Ad
1-Ad
1
-Ad
Cl
Cl
OH
CCl4
warm
Br
1
2
3
b
b.p. 117-118°C/0.8 mm
Et N NH -2-Ad
3
2
O
1-Ad
O
1
equiv. KOtBu
1-Ad
NH-2-Ad
N
-Ad
open to nucleophilic attack either at C or C .
THF, 0°C, 1 hr
2
3
Br
2
We chose to carry out three reactions on α-lactam 5b:
(-HBr)
-
-
5
b
4b
with the aprotic ionic nucleophiles tBuO and OH , and
the non-ionic protic nucleophile benzylamine (Scheme 4).
Benzylamine was chosen because it is known to
react with all α-lactams at room temperature readily
and completely [11]. According to two comprehensive
reviews [12,13], the general path of ring-opening with
ionic nucleophiles occurs via 1-2 bond cleavage, while the
m.p. 236-239°C
m.p. 226-228°C
2
.
The Thermal Decomposition of α-Lactam 5b.
Refluxing α-lactam 5b for one hour in n-hexane (b.p. 68-
0°C) causes no decomposition whatsoever. Refluxing in
n-heptane (b.p. 98°C) for one hour results in
7

May-Jun 2008
Full Characterization and Some Reactions of 1-(2-Adamantyl)-3-(1-adamantyl)aziridin-2-one
805
uncorrected. IR spectra were measured on a Perkin-Elmer
Spectrum 1000 FT-IR instrument. Mass spectra (MS) were
recorded either on a Hewlett-Packard GC-MS GCD system or a
Shimadzu GC-17A gas chromatograph equipped with a GCMS-
QP5050A mass spectrometer with direct injection into the EI ion
1
13
source. H-NMR and C-NMR spectra were recorded on a 400
MHz Bruker instrument with tetramethylsilane as internal
standard. Chemical shifts are reported in ppm (δ). 2-
Adamantylamine hydrochloride, 1-adamantaneacetic acid, 1-
adamantanemethanol, sodium hydride, 15-crown-5 ether and
pyridinium chlorochromate (PCC) were purchased from Aldrich
(Milwaukee, WI). KOtBu and N-bromosuccinimide (NBS) were
purchased from Lancaster (Windham, NH). 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). Microanalyses
were performed by Atlantic Microlab Inc., Norcross, GA.
Molecular modeling was performed with SYBYL version 7.2
[18] on a Dell Precision 470n workstation with RHEL 4.0
operating system. The energy minimization of the compound
was carried out using steepest descent followed by conjugate
gradient method which gives the local minimum conformation
of the compound by Tripos force field (empirical) based
geometry optimization.
Figure 1. Molecular model of α-lactam 5b in the most stable
conformation.
general path of ring-opening with non-ionic protic
nucleophiles proceeds via cleavage of the 1-3 bond,
although exceptions have been reported [12-15].
Aminoacid ester 9b and aminoacid 10 are the expected
-
-
products of these reactions with tBuO and HO ,
respectively. Similar derivatives have been isolated from
reactions of other α-lactams with these reagents
N-(2-Adamantyl)-2-bromo-3,3-dimethylbutanamide (4a).
The procedure of Lengyel and Aaronson [8] was followed. To a
solution of 2-adamantylamine hydrochloride (2.29 g, 0.0122
mol) in 60 mL of water was added 10.6 mL of 20% aqueous
NaOH (0.05 mol). The mixture was stirred at room temperature
for 5 minutes, cooled in an ice-water bath, filtered, and washed
three times with 10 mL water. The product was dissolved in 100
mL CH Cl , dried over Na SO and filtered. To the clear CH Cl
[
3,6,12,16]. On the other hand, the product of the
benzylamine reaction (11, Scheme 4) was less predictable.
Even though considerable effort has been expended in
trying to determine the factors governing the product of
the benzylamine reaction [11], it is not known to date why
2
2
2
4
2
2
sometimes C -N bond cleavage occurs leading to α-
2
solution was added 1.23 g (0.0122 mol) Et N. A solution of the
3
α-bromoacid chloride 3a [2] (2.59 g, 0.0122 mol) in 20 mL of
Scheme 4. Some reactions of α-lactam 5b.
CH Cl was added dropwise over a period of 20 minutes. Then
2
2
the reaction mixture was stirred at room temperature overnight.
Next day the CH Cl solution was washed with 25 mL of water,
O
O
1
-Ad
O
2
2
1
-Ad
1-Ad
then with 20 mL of 1 N HCl solution, then again with 25 mL
-OH
-OtBu
0°C
OH
NH-2-Ad
N
O
water. The organic layer was dried over Na SO , filtered and
2
4
dioxane
2
-Ad
NH-2-Ad
evaporated to dryness under reduced pressure to yield 3.86 g (97
%) of a solid. It was recrystallized from n-hexane: ethyl acetate
(9: 1) to yield pure 4a as a white solid (3.43 g, 89 %), mp 205-
2
5°C
1
0
5b
9b
m.p. 246-247°C
m.p. 236-239°C
NH CH C H
2 6 5
m.p. 180-182°C
2
07°C. TLC (90 % n-hexane: 10 % ethyl acetate): R = 0.41.
f
O
2
IR (CCl ): 3431 (N-H of secondary amide); 2910 and 2855
(aliphatic C-H); 1670 (amide C=O) cm . H-NMR (CDCl ) δ =
3
2
5°C, 6hrs
4
1
-Ad
-
1
1
NH-2-Ad
O
1
.16 (s, 9H, protons on the tert-butyl group); 1.60-1.95 (m, 14H,
NH
1
-Ad
protons of the adamantyl moiety); 4.04 (d, J = 8.1 Hz, 1H, C2-
CH2
NH CH2
proton of the 2-adamantyl moiety); 4.18 (s, 1H, Br-CH-C=O
NH-2-Ad
1
3
proton); 6.49 (bs, 1H, N-H proton).
C-NMR (CDCl ),
3
1
1
interpreted with the aid of APT: The molecule contains 13
different carbons (Figure 2).
m.p. 205-206°C
1
2 (not observed)
+
+
MS: m/z 327/329 (M , C H BrNO); 312/314 (M – CH ·) ;
1
6
26
3
+
+
2
C
71/273 (M – C H ) ; 248 base peak, (M – Br·) ; 192 (M – Br· –
) ; 178 Ad-N H=C=O; 150 Ad-NH ; 135 C10
C H ; 79 C H ; 67 C H ; 41 C H . Anal.: Calcd for
4
8
+
+
+
+
alkylamino-N-benzylamides (like 11), while at other
times the C -N bond breaks, with formation of α-benzyl-
4
H
8
H
15 ; 93
+
+
+
+
7
9
6
7
5
7
3
5
3
C H BrNO: C 58.54; H 7.98; Br 24.34; N 4.27. Found: C
1
6
26
aminoamides (like 12) [17].
5
8.72; H 8.05; Br 24.47; N 4.36.
Attempted Synthesis of 1-(2-Adamantyl)-3-tert-butyl-
EXPERIMENTAL
aziridin-2-one (5a). A mixture of dichloromethane (45 mL),
sodium hydride (0.18 g, 0.00457 mol) and 15-crown-5 ether
(0.084 g, 0.00038 mol) was stirred at room temperature for 20
minutes, after which N-(2-adamantyl)-2-bromo-3,3-dimethyl-
General Remarks. Melting points were determined on a
Thomas Hoover Capillary Melting Point Apparatus and are

8
06
I. Lengyel, T. Taldone, T. Lyons and V. Cesare
Vol 45
a
c
O
m
i
O
o
c
c
*
APT:
d
k
c
h
a
a
c
l
m
*APT:
n
CH , CH:
N
H
k
g
f
O
3
a
c
g
j
b
N
H
Br
e
CH , CH:
3
CH2 ,
C
, C=O:
l
h
4a
CH2 ,
h
C
, C=O:
9
different
carbons
f
i
j
g
d
b
*
#
APT
"
Carbon
!
Interpretation
e
a
b
c
d
e
f
27.08
27.19
27.69
31.72
31.95
31.98
32.1
One CH-carbon in Ad
One CH-carbon in Ad
9
different
carbons
"
9a
"
CH3 -carbons of tert-butyl
One CH-carbon in Ad
*
#
"
APT Carbon
!
Interpretation
"
One CH-carbon in Ad
"
"
"
"
#
#
#
"
#
#
#
"
"
#
#
a
b
c
d
e
f
27.09
28.05
28.43
31.02
31.31
31.72
34.15
34.73
37.27
37.95
38.22
60.84
Three CH3-carbons in C-t -Bu
#
One CH 2 -carbon in Ad
Two CH 2 -carbons in Ad
One CH-carbon in Ad
#
g
h
i
Three CH -carbons in O-t -Bu
3
#
35.04
37.04
37.49
53.83
Quaternary carbon in tert-butyl
One CH 2 -carbon in Ad
One CH-carbon in Ad
#
One CH -carbon in Ad
2
#
j
One CH 2 -carbon in Ad
One CH -carbon in Ad
2
"
k
CH-carbon in Ad attached to N
g
h
i
One CH -carbon in Ad
2
"
#
l
65.08
166.8
CH-carbon attached to Br
Carbonyl carbon
Two CH-carbons in Ad
m
One CH -carbon in Ad
2
j
One CH -carbon in Ad
2
1
3
Figure 2. The interpretation of the C-NMR spectrum of α-bromo-
amide 4a. Ad = adamantyl
k
l
Quaternary carbon in C-t -Bu
#
CH-carbon in Ad attached to N
m
n
o
68.42 CH-carbon between NH and C=O
butanamide (4a) (0.5 g, 0.00152 mol) was added. The reaction
mixture was monitored by IR. The maximum amount of α-
lactam detected was 32 %, based on comparison of the carbonyl
stretching frequency of the α-lactam (1840 cm ) and the starting
amide (1670 cm ), after 3 hours. To date, all attempts to isolate
α-lactam (5a) were unsuccessful.
80.61
t -Bu-carbon attached to O
175.22
Carbonyl carbon
-1
13
Figure 3. The interpretation of the C-NMR spectrum of α-amino-
acid tert-butyl ester 9a. Ad = adamantyl
-
1
#
tert-Butyl 2-(2-adamantyl)amino-3,3-dimethylbutanoate
(
9a). 0.500 g (0.00152 mol) of 4a was dissolved in 25 ml of dry
THF at 0°C. To this solution was added 0.597 g (0.00532 mol,
.5 equivalents) of KOtBu. It was stirred at 0°C for 1.5 hour.
2-Bromoadamantaneacetyl Chloride (3b) [7]. The general
procedure of Lengyel et al. [7] was followed. A solution of 1-
adamantaneacetic acid (1) (12.85 g, 0.066 mol) in 7 mL carbon
tetrachloride was treated with 31.50 g (0.265 mol) of thionyl
chloride, then NBS (14.13 g, 0.0794 mol) and 4 drops of 48%
aqueous HBr. After the succinimide byproduct was filtered off
3
The THF was evaporated to give a solid residue which was flash
chromatographed (100 % n-hexane) to give 0.39 g (80 %) of 9a,
as an oil. TLC (95 % n-hexane: 5 % ethyl acetate): R = 0.60.
f
IR (CCl ): 2905 and 2843 (aliphatic C-H); 1724 (ester C=O)
cm . The absence of a pronounced N-H type band in the IR
(m.p. 121°C) and the CCl was removed on the rotary evaporator,
4
the residual oil was vacuum distilled, b.p. 117-118°C/0.8 mm Hg
(lit. [7] b.p. 105-107°C/0.7 mm Hg), to give 17.0 g (88 %) of pure
4
-
1
spectra of α-alkylamino tert-butyl esters has been observed
1
previously [3]. H-NMR (CDCl ) δ = 0.97 (s, 9H, C-tert-butyl);
3b. IR (CCl
4
): 2908 and 2850 (aliphatic C-H); 1797 (C=O of acid
3
-1
1
.46 (s, 9H, O-tert-butyl); 1.56-1.88 (m, 13H, ten CH -protons
2
chloride) with shoulder at 1765 (weak overtone vibration) cm .
1
in Ad, two CH-protons in Ad and the N-H proton, exchanges in
H-NMR (CCl ) δ = 1.60-1.80 (m, 12H, CH -protons of the
4 2
D O); 2.12 (d, 2H, CH-protons in Ad in β-position to the NH);
adamantyl moiety); 2.05 (s, 3H, the CH-protons of the adamantyl
moiety); 4.25 (s, 1H, Br-CH-C=O proton).
2
2
.53 (s, 1H, C -proton in Ad attached to N); 2.80 (s, 1H, CH-
2
1
3
proton between nitrogen and carbonyl).
C-NMR (CDCl ),
N-(2-Adamantyl)-2-bromo-1-adamantaneacetamide (4b)
[1]. The procedure of Lengyel and Aaronson [8] was followed.
To a solution of 2-adamantylamine hydrochloride (4.93 g,
0.0263 mol) in 60 mL of water was added 10.6 mL of 20%
aqueous NaOH (0.05 mol). The mixture was stirred at room
temperature for 5 minutes, cooled in an ice-water bath, filtered,
and washed three times with 10 mL water. The product was
dissolved in 100 mL CH Cl , dried over Na SO and filtered. To
3
interpreted with the aid of APT: The molecule contains 15
different carbons (Figure 3).
+
+
+
MS: m/z 322 (M + 1) ; 321 M ; 320 (M – H·) ; 306 (M –
+
+
+
CH ·) ; 264 (M – C H ·) ; 250 [(CH ) C CH(NHAd)(COOH)];
3
4
9
3 2
+
+
2
20 (base peak, [(CH ) CCH=N HAd)]; 208 [AdN H=
3 3
CHCOOH]; 162 [AdN=CH ]; 150 AdNH ; 107 C H ; 93
C H NH ; 91 C H ; 86 [(CH ) CCH=N H ]; 79 C H ; 67
C H . Anal.: Calcd for C H NO : C 74.72; H 10.97; N 4.36.
+
+
+
8
11
+
+
+
+
6
5
2
7
7
3
3
2
6
7
2
2
2
4
+
the clear CH Cl solution was added 2.63 g (0.026 mol) Et N. A
5
7
20 35
2
2
2
3
Found: C 74.64; H 11.09; N 4.51.
solution of the α-bromoacid chloride 3b (7.29 g, 0.025 mol) in

May-Jun 2008
Full Characterization and Some Reactions of 1-(2-Adamantyl)-3-(1-adamantyl)aziridin-2-one
807
+
+
6
0 mL of CH Cl was added dropwise over a period of 20
MS: m/z 405/407 (M ); 326 (base peak, (M – Br·) , Ad-
2
2
+
+
minutes. Then the reaction mixture was stirred at room
temperature overnight. Next day the clear CH Cl solution was
C HCONH-Ad); 192 (326 – C H , CH CONHAd); 150 C H
10 14 2 10 15
+
+
+
+
+
+
NH ; 135 C H ; 119 C H ; 108 C H ; 93 C H ; 91 C H ;
2
2
10 15
9
11
+
8
12
7
9
7
7
+
+
washed with three 50 mL portions of water, then with 50 mL of
N HCl solution, then again with 50 mL water. The organic layer
was dried over Na SO , filtered and evaporated to dryness under
79 C H ; 68 C H ; 41 C H . Anal.: Calcd for C H BrNO: C
6 7 5 8 3 5 22 32
1
65.02; H 7.94; N 3.45; Br 19.66. Found: C 64.85; H 8.01; N
3.39; Br 19.57.
2
4
reduced pressure to yield a white solid, 10.16 g (100 %), mp 225-
27°C (no decomposition). TLC (90 % n-hexane-10 % ethyl
Synthesis of 1-(2-Adamantyl)-3-(1-adamantyl)aziridin-2-
one (5b). A variation of the procedure of Sheehan and Lengyel
[3] was used. 0.610 g (0.0015 mol) of α-bromoamide 4b was
dissolved in 30 mL of dry THF. To this solution was added
0.168 g (0.0015 mol, 1 equivalent) of KOtBu in one portion at
0°C and stirred vigorously for 1 hour. The mixture was then
filtered and the filtrate was evaporated to dryness. The residue
was taken up into 50 mL of EtOAc and washed with cold
phosphate buffer (0.01 M, pH 7.4, 3 x 50 mL). The organic
layer was dried with Na SO , filtered and evaporated under
2
acetate): R = 0.38, essentially single spot. This product was
f
recrystallized from a mixture of 50 mL n-heptane, 70 mL
acetonitrile, and 50 mL isopropyl alcohol, boiling on the steam
bath, cooling to room temperature for 2 hours, then kept in an ice-
water bath for 2 hours. The crystalline precipitate was collected
on a sintered-disk funnel, washed with 3 x 20 mL n-hexane and
dried in a vacuum desiccator, to give 8.2 g (80.7%) of pure 4b as
white crystals, mp 226-228°C (no decomposition) (lit. [1] m.p.
2
4
2
37.5-240.0°C [decomposition]). TLC (90 % n-hexane: 10 %
reduced pressure to give 0.40 g of a white solid which was then
flash chromatographed (95 % n-hexane: 5 % ethyl acetate) to
give 0.088 g (18 %) of α-lactam 5b, as a white solid with m.p.
236-239°C (decomposition) (lit. [1] m.p. ≈ 226°C). 0.150 g of
unreacted α-bromoamide 4b was recovered from the column.
Subtracting this increases the yield of α-lactam 5b to 24 %.
TLC (90 % n-hexane: 10 % ethyl acetate): R = 0.41. IR (CCl ):
ethyl acetate): R = 0.40. IR (CCl ): 3430 (N-H of secondary
amide); 2914 and 2853 (aliphatic C-H); 1669 (amide C=O); and
1
2
f
4
-1
1
525 (amide II band) cm . H-NMR (CDCl ) δ = 1.62-1.89 (m,
3
2H, the 11 CH -groups of the two adamantyl moieties); 1.94-2.03
2
(s, 7H, seven of the eight CH-protons of the two adamantyl
moieties); 4.04 (d, 1H, the C -proton of the 2-adamantyl moiety,
J= 8Hz); 4.07 (s, 1H, Br-CH-C=O proton); 6.45 (bs, 1H, the N-H
proton, exchangeable in CDCl /CF COOD). C-NMR (CDCl3),
interpreted with the aid of APT: The molecule contains 15
2
f
4
-
1
1
2908 and 2852 (aliphatic C-H); 1838 (lactam C=O) cm . H-
13
NMR (CDCl ) δ = 1.5-2.4 (m, 29H); 2.53 (s, 1H, C -proton of 2-
3
3
3
2
1
3
adamantyl); 3.15 (s, 1H, CH-proton of lactam).
C-NMR
different carbons. There are six non-equivalent CH -carbons in
(CDCl ), interpreted with the aid of APT: The molecule contains
2
3
the two adamantyl groups combined, four of them in the 2-
adamantyl group (e, g, j, k). The reason for this is that the O=C-
N-H group is magnetically strongly anisotropic (Figure 4).
c
j
k
j
l
c
k
O
n
c
h
*APT:
CH:
o
i
O
o
g
j
c
*
APT:
CH:
k
h
N
i
d
c
i
l
a
n
m
N
H
m
j
e
4
different
carbons
d
d
c
h
i
k
g
Br
b
CH2 ,
C , C=O:
h
f
CH2 ,
C
,
C=O:
g
f
9 different
carbons
4
different
carbons
a
4b
b
9
different
carbons
e
5
b
*
#
APT Carbon
!
Interpretation
*
#
!
"
"
"
"
#
"
#
#
#
#
#
#
"
"
#
a
b
c
d
e
f
27.08
27.19
28.42
31.7
One CH-carbon in 2-Ad
One CH-carbon in 2-Ad
APT
Carbon
Interpretation
"
"
"
"
#
#
#
#
#
#
#
#
"
"
#
a
b
c
d
e
f
27.25
27.51
28.29
31.95
32.1
One CH-carbon in 2-Ad
One CH-carbon in 2-Ad
Three CH-carbons in 1-Ad
One CH-carbon in 2-Ad
Three CH-carbons in 1-Ad
Two CH-carbons in 2-Ad
31.96
31.99
32.11
36.07
36.56
37.02
37.49
39.74
One CH -carbon in 2-Ad
2
One CH -carbon in 2-Ad
2
One CH-carbon in 2-Ad
32.27
33.73
36.61
36.76
36.86
37.55
40.19
One CH -carbon in 2-Ad
2
g
h
i
Two CH -carbons in 2-Ad
2
g
h
i
One CH -carbon in 2-Ad
2
Three CH -carbons in 1-Ad
2
One CH -carbon in 2-Ad
2
Three CH -carbons in 1-Ad
2
One CH -carbon in 2-Ad
2
j
One CH -carbon in 2-Ad
2
j
Three CH -carbons in 1-Ad
2
k
l
One CH -carbon in 2-Ad
2
k
l
Three CH -carbons in 1-Ad
2
C -carbon in 1-Ad
1
C1
-carbon in 1-Ad
m
n
o
53.84 CH-carbon attached to N in 2-Ad
66.32 CH-carbon attached to Br and C=O
m
n
o
57.76 CH-carbon attached to N in 2-Ad
67.36
CH-carbon of lactam
Carbonyl carbon
166.15
Carbonyl carbon
163.18
13
13
Figure 4. The interpretation of the C-NMR spectrum of α-
bromoamide 4b. Ad = adamantly.
Figure 5. The interpretation of the C-NMR spectrum of α-lactam
5b. Ad = adamantyl
#
#

8
08
I. Lengyel, T. Taldone, T. Lyons and V. Cesare
Vol 45
1
5 different carbons. There are four in the 1-adamantyl group
b
j
h
j
and nine in the 2-adamantyl group (Figure 5).
O
c
+
+
+
h
MS: m/z 325 M ; 297 (M – CO) ; 162 (Ad-CHN) ; 135
m
b
c
*
APT:
o
+
+
+
+
+
C H ; 93 C H NH and/or C H ; 91 C H ; 79 C H ; 77
C H ; 67 C H . Anal.: Calcd for C H NO: C 81.18; H 9.60;
q
p
10
15
+
6
5
2
7
9
7
7
6
7
O
c
+
h
b
6
5
5
7
22 31
CH , CH:
3
j
N
H
N 4.30. Found: C 80.98; H 9.75; N 4.29.
The Thermal Decomposition of α-Lactam 5b. 0.100 g
4
different
carbons
n
CH2 ,
C
, C=O:
g
i
(
0.000307 mol) of α-lactam 5b was dissolved in 20 mL of n-
nonane (b.p. 151°C) and refluxed for 1 hour. Then the mixture
was cooled to room temperature and subjected to analysis by
FT-IR and GC-MS. The reaction yielded 1-adamantyl aldehyde
f
l
k
a
f
d
e
(
7) and 2-adamantyl isocyanide (8) as the only products, in
9
b
9 different
carbons
agreement with prior observations [10, 12, 16]; IR (nonane):
1
-1
-1
725 cm (aldehyde C=O); 2129 cm (N≡C); GC-MS: two
components; first peak molecular ion at m/z 164 (1-adamantyl
aldehyde), second peak molecular ion at m/z 161 (2-adamantyl
isocyanide).
The IR and GC-MS of the two thermal decomposition
products were identical with those of authentic 7 and 8. 7 was
synthesized by the oxidation of 1-adamantanemethanol with
PCC [19] and had m.p. 139-141°C (lit. [6] m.p. 139-141°C). 8
was synthesized by a modified Hofmann carbylamine synthesis
*
#
Carbon
!
Interpretation
One CH-carbon in 2-Ad
Three CH-carbons in 1-Ad
APT
"
a
b
c
d
e
f
28.06
28.5
"
"
28.81
30.89
31.28
31.74
34.78
35.94
37.23
37.41
37.93
38.22
39.42
60.67
69.28
80.57
174.69
Three CH -carbons in t -Bu
3
"
One CH-carbon in 2-Ad
#
One CH -carbon in 2-Ad
2
[9] from 2-adamantylamine and had m.p. 178-180°C (lit. [9]
#
Two CH -carbons in 2-Ad
2
m.p. 178-180°C).
"
g
h
i
One CH-carbon in 2-Ad
Reactions of α-Lactam 5b.
#
Three CH -carbons in 1-Ad
2
a. Reaction with KOtBu. 0.100 g (0.000307 mol) of α-
lactam 5b was dissolved in 20 mL of dry THF. To this solution
was added 0.103 g (0.000922 mol, 3.0 equivalents) of powdered
KOtBu in one portion and stirred vigorously at room
temperature. After five hours the THF was removed under
reduced pressure, the residue taken up in 50 mL of CH Cl and
"
One CH-carbon in 2-Ad
#
j
Three CH -carbons in 1-Ad
2
#
k
l
One CH -carbon in 2-Ad
2
#
One CH -carbon in 2-Ad
2
#
m
n
o
p
q
C -carbon in 1-Ad
2
2
1
washed with water (3 x 25 mL). The organic layer was dried
over Na SO , filtered and the filtrate evaporated to dryness
"
CH-carbon in 2-Ad attached to N
CH carbon adjacent to C=O
2
4
"
under reduced pressure. The residue was flash chromatographed
#
(CH ) CO
(
(
100 % n-hexane), to give 0.105 g (86 %) of pure tert-butyl 2-
2-adamantyl)amino-1-adamantaneacetate (9b), m.p. 180-182°C.
3 3
#
Carbonyl carbon
TLC: (95 % n-hexane: 5 % ethyl acetate) R = 0.56. IR (CCl ):
f
4
-1
2
906 and 2849 (aliphatic C-H); 1720 (ester C=O) cm . The
13
Figure 6. The interpretation of the C-NMR spectrum of
#
absence of a pronounced N-H type band in the IR spectra of α-
α-aminoacid tert-butyl ester 9b. Ad = adamantyl
alkylamino tert-butyl esters has been observed previously [3].
1
H-NMR (CDCl ) δ = 1.46 (s, 9H, O-tert-butyl); 1.48-1.84 (m,
3
2
1
2H, the eleven CH - groups in the two adamantyl moieties);
.96 (s, 3H, CH-protons in the 1-adamantyl group); 2.12 (d, 5H,
filtered and evaporated to dryness under reduced pressure to
give 0.091 g of a white crystalline residue. This was flash
chromatographed on silica gel with 65% EtOAc: 35% n-hexane
2
the five CH-protons in the 2-adamantyl moiety); 2.51 (s, 1H,
amine N-H, exchangeable in D O); 2.66 (s, 1H, HN-CHC=O,
as mobile phase, to give 0.075 g (71 %) of 2-(2-
2
1
3
CH proton attached to nitrogen and carbonyl).
C-NMR
adamantyl)amino-1-adamantaneacetic acid (10) as a white solid,
m.p. 246-247°C (no decomposition). The compound readily
sublimes undecomposed. TLC (70% n-hexane: 30% ethyl
(
CDCl ): The molecule has 17 different carbons; four in the 1-
3
adamantyl group and nine in the 2-adamantyl group (Figure 6).
+
+
MS: m/z 399 M ; 342 (M − C H ·) ; 298 (base peak, (M –
acetate): R = 0.23. IR (KBr): 3416 (broad band); 2908 and
4
9
f
+
+
+
COOC H ·) , [AdCH=N HAd]); 240 (AdCH=N HC H ); 236
2853 (aliphatic C-H); 1719 (carbonyl of the carboxylic acid)
4
9
6
5
+
+
+
+
-1
1
(
7
7
M – AdCHNH·) ; 164 (298 – C H ) ; 135 C H ; 93 C H ;
cm . H-NMR (CD OD) δ = 1.62-2.10 (m, 29H, all eleven
1
0
14
10 15
7
9
3
+
7
+
+
9 C H ; 67 C H ; 41 C H . Anal.: Calcd for C H NO : C
CH -groups and seven of the eight C-H protons of the two
6
5
7
3
5
26 41
2
2
8.15; H 10.34; N 3.51. Found: C 78.24; H 10.41; N 3.54.
adamantyl moieties); 2.14 (d, 1H, CH-proton in the 2-adamantyl
moiety adjacent to the nitrogen); 2.27 (s, 1H, amine N-H,
b. Reaction with KOH. 0.100 g (0.000307 mol) of α-lactam
b was dissolved in 25 mL of dioxane and to this solution 0.172
5
exchangeable in D O); 3.13 (s, 1H, methine proton adjacent to
2
g (0.00307 mol, 10 equivalents) of finely powdered KOH was
added. The resulting suspension was stirred vigorously for 18
hours at room temperature. The dioxane was removed under
reduced pressure, the residue taken up in 100 mL of CH Cl and
the carbonyl, N-CH-C=O); the carboxyl proton is absent,
1
3
because of exchange with the solvent, CD OD.
C-NMR
+
3
+
(CD OD) (Figure 7). MS: m/z 343 (M ); 342 (M − H·) ; 298 (M
3
+
+
+
− COOH·) ; 208 (M − C H ·) ; 176 (1-Ad-CH=C=O) ; 164 (1-
Ad-CH=NH ) ; 162 (2-AdNHC) ; 135 (C H , 162 − HCN) ;
2 10 15
107 (C H , 135 − C H ); 93 C H ; 91 C H ; 79 C H ; 67
2
2
10 15
+
+
+
+
washed with 1N HCl (2 x 25 mL) followed by water (4 x 50
mL). The organic layer was dried over anhydrous Na SO ,
+
+
+
+
2
4
8
11
2
4
7
9
7
7
6
7

May-Jun 2008
Full Characterization and Some Reactions of 1-(2-Adamantyl)-3-(1-adamantyl)aziridin-2-one
809
+
C H . Anal.: Calcd for C H NO •1/8 H O: C 76.42; H 9.71; N
4
protons; 7.29-7.32 (m, 5H, aromatic protons); 7.43 (s, 1H, N-H
5
7
22 23
2
2
1
3
.05. Found: C 76.40; H 9.67; N 4.04.
proton of amide).
C-NMR (CDCl ): There are 21 different
3
carbons in the molecule, four in the 1-adamantyl group, ten in
the 2-adamantyl group (Figure 8).
c
i
h
i
O
p
h
c
m
c
n
i
j
O
u
*
APT:
CH:
OH
s
s
r
4
different
h
i
c
i
j
m
c
n
carbons
p
t
N
H
NH
CH2
q
c
j
4
different
carbons
*APT:
CH:
i
g
N
e
o
d
r
k
CH2 ,
C
,
C=O:
H
o
d
l
g
a
h
l
k
a
f
11
b
CH
2
,
C
,
C=O:
e
b
f
j
1
0 different carbons
1
0
10 different
carbons
*
#
APT Carbon
!
Interpretation
*
#
!
"
"
"
"
#
#
"
#
#
#
#
#
#
#
"
"
"
"
"
#
#
a
b
c
d
e
f
27.57
27.77
28.72
30.25
31.81
31.91
34.56
35.65
37.16
37.64
37.9
One CH-carbon in 2-Ad
One CH-carbon in 2-Ad
APT Carbon
Interpretation
"
"
"
"
"
#
#
#
#
#
#
#
#
"
"
#
a
b
c
d
e
f
27.25
27.44
28.72
29.78
30.35
30.83
30.97
35.27
36.64
36.99
37.07
37.23
38.43
65.17
72.4
One CH-carbon in 2-Ad
One CH-carbon in 2-Ad
Three CH-carbons in 1-Ad
One CH-carbon in 2-Ad
One CH-carbon in 2-Ad
Three CH-carbons in 1-Ad
One CH-carbon in 2-Ad
One CH -carbon in 2-Ad
2
One CH -carbon in 2-Ad
2
g
h
i
One CH-carbon in 2-Ad
One CH -carbon in 2-Ad
One CH -carbon in 2-Ad
2
2
Three CH -carbons in 1-Ad
2
g
h
i
One CH -carbon in 2-Ad
2
j
Three CH -carbons in 1-Ad
2
Three CH -carbons in 1-Ad
2
k
l
One CH -carbon in 2-Ad
2
Three CH -carbons in 1-Ad
2
38.02
39.86
43.19
One CH -carbon in 2-Ad
2
j
One CH -carbon in 2-Ad
2
m
n
o
p
q
r
C -carbon in 1-Ad
1
k
l
One CH -carbon in 2-Ad
Benzylic CH -carbon
2
2
One CH -carbon in 2-Ad
60.85 C -carbon attached to N in 2-Ad
2
2
71.24
127.47
128.01
128.75
139.09
173.29
CH-carbon attached to carbonyl
para -carbon in phenyl ring
meta-carbons in phenyl ring
ortho -carbons in phenyl ring
m
n
o
p
C -carbon in 1-Ad
1
CH carbon adjacent to COOH
CH-carbon in 2-Ad attached to N
Carbonyl carbon
s
170.98
t
C -carbon of phenyl group
1
u
Carbonyl carbon
13
Figure 7. The interpretation of the C-NMR spectrum of α-amino acid
0. Ad = adamantyl
#
1
13
Figure 8. The interpretation of the C-NMR spectrum of α-alkylamino-
N-benzylamide 11. Ad = adamantyl
#
c. Reaction with Benzylamine. 0.100 g (0.000307 mol) of
+
+
α-lactam 5b was dissolved in 20 mL of dry THF. To this
solution was added 0.132 g (0.00123 mol, 4 equivalents) of
freshly distilled benzylamine and stirred at room temperature.
After six hours the THF was distilled off under reduced
pressure. The residue was flash chromatographed (90% n-
hexane: 10% ethyl acetate), to give 0.113 g (85 %) of pure N-
MS: m/z 432 (M ); 431 (M – H·) ; 298 (base peak, 1-Ad-
+
+
+
CH=N H-2-Ad); 164 (298 – C H ) ; 162 (C H CHN) ; 150
1
0
14
10 15
+
+
+
+
(C H NH) ; 135 C H ; 106 (C H CH NH ); 91 C H ; 79
1
0
15
+
10 15
6
5
2
7
7
+
C H ; 67 C H . Anal.: Calcd for C H N O: C 80.51; H 9.32;
N 6.47. Found: C 80.34; H 9.37; N 6.41.
6
7
5
7
29 40
2
benzyl-2-(2-adamantyl)amino-1-adamantaneacetamide
m.p. 205-206°C. TLC: (90% n-hexane: 10% ethyl acetate) R =
(11),
REFERENCES AND NOTES
f
0
3
.28. IR (CCl ): 3448 (N-H of amide); 3363 (N-H of amine),
4
[
1] Talaty, E. R.; Madden, J. P.; Stekoll, L. H. Angew. Chem.
030 (aromatic CH); 2909, 2851 (aliphatic CH); 1674 (amide
1
971, 83, 848; also Angew. Chem. Internat. Ed. Engl. 1971, 10, 753.
2] Lengyel, I.; Cesare, V.; Karram, H.; Taldone, T. J.
-
1
1
carbonyl); 1525 (amide II) cm . H-NMR (CDCl ) δ = 1.26 (s,
1
Ad, plus 10 CH -protons and 4 CH-protons in 2-Ad); 1.99 (s,
3
3
[
H, N-H proton of 2-Ad); 1.5-1.9 (m, 26H, 12 CH -protons of 1-
2
Heterocycl. Chem. 2001, 38, 997.
2
[3] Sheehan, J. C.; Lengyel, I. J. Am. Chem. Soc. 1964, 86, 1356.
[4] Scrimin, P.; D’Angeli, F.; Veronese, A. C. Synthesis 1982,
586.
H, CH-protons in 1-Ad); 2.42 (s, 1H, C -proton in 2-Ad); 2.77
2
(s, 1H, CH-proton adjacent to C=O); 4.37 (dd, 1H, J = 14.5, 5.1
Hz) and 4.56 (dd, 1H, J = 14.4, 6.3 Hz) diastereotopic benzylic
[5] Cesare, V.; Lyons, T. M.; Lengyel, I. Synthesis 2002, 1716.

8
10
I. Lengyel, T. Taldone, T. Lyons and V. Cesare
Vol 45
[
6] Bott, K. Liebigs Ann. Chem. 1972, 755, 58.
[14] Talaty, E. R.; Dupuy, Jr., A. E.; Utermohlen, C. M. Chem.
Commun. 1971, 16.
[7] Lengyel, I.; Cesare, V.; Adam, I.; Taldone, T. Heterocycles
2
1
2
002, 57, 73.
8] Lengyel, I.; Aaronson, M. J. Can. J. Spectroscopy 1974, 19, 95.
9] Sasaki, T.; Eguchi, S.; Katada, T. J. Org. Chem. 1974, 39,
[15] Yusoff, M. M.; Talaty, E. R. Tetrahedron Lett. 1996, 48,
8695.
[16] Lengyel, I.; Cesare, V.; Taldone, T.; Uliss, D. Synth.
Commun. 2001, 31, 3671.
[17] The empirically deduced correlations [11] based on structural
parameters, relative stability and reactivity, substitution pattern and the
rate of reaction, may be used to predict the actual product with a high
degree of accuracy.
[18] SYBYL 7.2, Tripos Inc., 1699 South Hanley Rd., St. Louis,
Missouri, 63144.
[
[
239.
[
[
10] Sheehan, J. C.; Lengyel, I. J. Am. Chem. Soc. 1964, 86, 746.
11] Lengyel, I.; Cesare, V.; Chen, S.; Taldone, T. Heterocycles
002, 57, 677.
12] Lengyel, I.; Sheehan, J. C. Angew. Chem. 1968, 80, 27; also
Angew. Chem., Internat. Ed. Engl. 1968, 7, 25.
13] Backes, J. Houben-Weyl, Methoden der Organischen
[
[
Chemie, Vierte Auflage, Band E16b, Georg Thieme Verlag, Stuttgart,
New York, 1991, p. 1.
[19] Farooq, O.; Marcelli, M.; Prakash, G. K. S.; Olah, G. A. J.
Am. Chem. Soc. 1988, 110, 864.