Unusual acid-induced heterocyclisation of caryophyllene-type a-amino oximes:
X-ray structure of (1
S
,2
S
,5
R
,8
S
)-1,4,4,8-tetramethyl-8-morpholin-4-yl-11-oxa-
10-azatricyclo[7.2.2.0
2,5
]tridec-9-ene
Alexey V. Tkachev,*
a
Alexander M. Agafontsev,
a
Tatyana V. Rybalova
b
and Yury V. Gatilov
b
a
Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russian Federation
b
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
630090 Novosibirsk, Russian Federation. Fax: +7 3832 34 4752; e-mail: atkachev@nioch.nsc.ru
10.1070/MC2000v010n06ABEH001361
The acid-catalysed cyclisation of caryophyllene-type a-amino oximes results in the formation of new bridged heterocycles with
the 5,6-dihydro-4H-[1,2]oxazine moiety.
Caryophyllene {(1R,4E,9S)-4,11,11-trimethyl-8-methylenebicyclo-
[7.2.0]undec-4-ene} is a unique sesquiterpenoid because it can
undergo various rearrangements of the carbon skeleton. Caryo-
phyllene and its derivatives are extremely sensitive to acidic
agents and undergo different cyclisations, isomerisations and
rearrangements.
1,2
We report here on the new unusual acid-
catalysed heterocyclisation of caryophyllene derivatives with the
retention of the carbon frame.
Amino oximes 1a,b (prepared from caryophyllene by the
addition of NOCl followed by the treatment with an amine
3
)
were found to react with concentrated H
2
SO
4
at room tempe-
rature
†
without forming any tarry products to afford hetero-
cyclisation products 2a
‡
and 2b
§
in very good yields. The NMR
spectra of these compounds (signal assignments were carried
out using 2D H– H COSY, 2D C–H COSY and 2D-NOESY)
proved both compounds to belong to the same structural type
with the same configuration of the 5,6-dihydro-4H-[1,2]oxazine
moiety.
¶
The stereochemistry of these compounds was deter-
mined by single-crystal X-ray diffraction analysis of morpho-
lino derivative 2b
††
(Figure 1). The oxazine ring bonds C(8)–
O(1) [1.453(3) Å ] and O(1)–N(1 ) [1.441(2) Å ] are elongated as
compared to the average values 1.437(13) and 1.409(15) Å ,
respectively, for eight 5,6-dihydro-4H-[1,2]oxazine structures from
the Cambridge Crystallography Database.
4
The oxazine ring
adopts a distorted twist–boat shape. The conformation of the
nine-membered heterocycle [C(1)–C(2 )–C( 3)–C (4)– C(5)=N(1)–
O(1)–C( 8)–C(9) ] is almost the same as that of the nine-mem-
bered carbocycle in caryophyllene nitrosite and dinitrocaryo-
phyllene,
5
as well as in caryophyllene nitrosochloride
6
(the dif-
ferences in endocyclic torsion angles are less than 20°).
†
Concentrated H
2
SO
4
(1.5 ml) was added to a stirred solution of caryo-
phyllene-type
a
-amino (
E
)-oxime
1a
or
1b
(1.08 mmol) in CHCl
3
(10 ml).
The mixture was vigorously stirred at room temperature for 30 min, and
then pH was adjusted to 10–1 1 by the addition of concentrated aqueous
ammonia (ice-cold bath). The organic phase was separated, dried over
MgSO
4
and concentrated at reduced pressure to leave a yellowish solid
(0.290 g), which was percolated through SiO
2
(eluent Bu
t
OMe) followed
by crystallisation of the crude product from an appropriate solvent to
afford cyclisation products
2a
or
2b
in good yields.
‡
(1
S
,2
S
,5
R
,8
S
)-1,4,4,8-Tetramethyl-8-dimethylamino-11-oxa-10-aza-
tricyclo[7.2.2.0
2,5
]tridec-9-ene
2a
: yield 72%, white crystals, mp 122–
123 °C (hexane), [
a]
22
578
–37 ( c 11 mg cm
–3
, CHCl
3
). IR (KBr, n
max
/cm
–
1
): 1625 (C=N), 895 (N–O) . MS, m/z (%): 278.23568 (10, M
+
, calc. for
C
17
H
30
N
2
O 278.23581), 263 (11), 235 (100), 218 (34), 203 (32), 192
(8), 179 (8), 177 (8), 166 (15), 148 (29), 147 (36), 138 (6), 124 (15), 123
(15), 109 (21), 98 (16), 97 (18), 85 (28), 70 (30), 56 (43), 44 (11), 41
(26).
§
(1S,2S,5R,8S)-1,4,4,8-Tetramethyl-8-morpholin-4-yl-11-oxa-10-aza-
tricyclo[7.2.2.0
2,5
]tridec-9-ene 2b: yield 75%, white crystals, mp 174–
176 °C (MeCN), [a]
22
578
–70 ( c 3mgcm
–3
, CHCl
3
). IR (KBr, n
max
/cm
–1
):
1640 (C=N), 1130 (C– O), 895 (N– O). MS, m/z (%): 320.24639 (2, M
+
,
calc. for C
19
H
32
N
2
O
2
320.24636), 305 (3), 266 (1), 235 (100), 218 (37),
203 (38), 192 (7), 178 (7), 166 (8), 162 (12), 161 (13), 148 (35), 147
(37), 133 (10), 124 (14), 123 (13), 112 (8), 109 (11), 95 (16), 86 (12), 81
(13), 69 (17), 55 (23), 41 (26).
Scheme 1
R
2
N
H
H
N
OH
11
8
7
5
4
15
14
19
13
NR
2
H
H
N
O
12
H
2
SO
4
(98%)– CHCl
3
72–7 5%
a
NR
2
= dimethylamino
b
NR
2
= 4-morpholino
1a,b 2a,b
30 min, room temperature
¶
NMR spectra were measured on a Bruker DRX-500 (500 MHz for
1
H,
125 MHz for
13
C) at 25–27 °C. Chemical shifts in square brackets were
taken from the 2D carbon–p roton shift correlation spectra.
For 2a (60 mg cm
–3
in CDCl
3
–C
6
D
6
1:1, v/v):
1
HNMR, d: 2.20 (ddd,
9-H, J 10.9, 10.9 and 8.3 Hz), 2.16 (s, 6H, NMe
2
), 1.99 (dd, 3-H
a
, J 15.0
and 7.4 Hz), [1.85, 1.84] (7-H), [1.76, 1.66] (6-H), 1.45 (dd, 10-H
a
, J
10.1 and 8.3 Hz), 1.42 (ddd, 2-H
a
, J 15.0, 11.5 and 9.0 Hz), 1.01 (13-H),
1.00 (dd, 1-H, 2-H
b
, J 15.0, 10.9, 9.0 and 7.4 Hz), 0.99 (dd, 3-H
b
, J 15.0
and 11.5 Hz), 0.88 (dd, 10-H
b
, J 10.9 and 10.1 Hz), 0.86 (14-H), 0.83
(15-H), 0.78 (12-H).
13
CNMR, d: 170.98 (C-5), 77.16 (C-8), 64.63
(C-4), 54.33 (C-1, J 128.6 Hz), 47.78 (C-9, J 133.9 Hz), 39.97 (C-3, J
128.1, 123.8 and 6× 4.0 Hz), 38.83 (NMe
2
), 36.03 (C-10, J 133.0, 128.5
and 7× 4.9 Hz), 35.35 (C-11), 30.28 (C-7, J 133.7, 129.0, 6.7, 6.7 and
4.1 Hz), 29.44 (C-14, J 3× 123.8 and 5× 5.2 Hz), 23.19 (C-13, J 3× 127.0
and 4.0 Hz), 22.19 (C-2, J 123.1 and 123.1 Hz), 20.66 (C-15, J 3× 125.1
and 6× 4.9 Hz), 19.88 (C-6, J 130, 130, 5.6 and 5.6 Hz), 12.96 (C-12, J
3× 126.3 and 1.0 Hz).
For 2b (65mgcm
–3
in CDCl
3
):
1
HNMR, d: 3.72 and 3.63 (2ddd,
NCH
2
CH
2
O, J 11.0, 6.5 and 2.8 Hz), 2.63 and 2.42 (2ddd, NCH
2
CH
2
O,
J 10.8, 6.5 and 2.8 Hz), 2.19 (dd, 3-H
a
, J 15.6 and 7.3 Hz), [2.13] (9-H),
[2.10, 2.08] (7-H), [2.14, 1.99] (6-H), 1.53 (dd, 10-H
a
, J 10.3 and
8.3 Hz), 1.43 (ddd, 2-H
a
, J 14.9, 11.2 and 8.9 Hz), 1.22 (dd, 3-H
b
, J 15.6
and 11.2 Hz), 1.165 (dd, 1-H, J 10.6 and 8.9 Hz), 1.160 (dd, 2-H
b
, J 14.9
and 7.3 Hz), 1.06 (13-H), 1.04 (12-H), 1.00 (dd, 10-H
b
, J 11.2 and
10.3 Hz), 0.88 (15-H), 0.86 (14-H).
13
CNMR, d: 171.15 (C-5), 77.21
(C-8), 67.32 (NCH
2
CH
2
O), 64.91 (C-4), 54.51 (C-1), 48.01 (C-9), 46.82
(NCH
2
CH
2
O), 39.29 (C-3), 36.26 (C-10), 35.70 (C-11), 30.45 (C-7),
29.72 (C-14), 23.29 (C-13), 22.17 (C-2), 20.87 (C-15), 20.50 (C-6),
15.69 (C-12).
††
1801 independent reflections were measured on a Bruker P4 diffracto-
meter with graphite-monochromated MoK
a
radiation using q/2q scans
with q < 25° . The crystal system of compound 2b is monoclinic, space
group P2
1
, a = 11.429(1), b = 6.3262(7), c = 13.868(1) Å, b = 111.814(5)°,
V = 930.89(2) Å
3
, C
19
H
32
N
2
O
2
, M = 320.47, Z =2, d
calc
=1.143gcm
–3
,
m =0.074mm
–1
, F(000) = 352, crystal size 0.22× 0.35× 1.20 mm. The
structure was solved by the direct methods (SHELXS-97) and refined in
the anisotropic– isotropic approximation using SHELXL-97 to wR
2
=
= 0.1074, S = 1.065 for all reflections (R = 0.0377 for 1699 F >4s). The
absorption correction was applied using an integration method. The
positions of hydrogen atoms were calculated using a riding model.
Atomic coordinates, bond lengths, bond angles and thermal parameters
have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details, see ‘Notice to Authors’, Mendeleev Commun.,
Issue 1, 2000. Any request to the CCDC for data should quote the full
literature citation and the reference number 1135/74.
Mendeleev Commun., 2000, 10(6), 211–212
– 211 –