Synthesis of 1,11,11-trimethyl-3,6-diazotricyclo [6.2.1.0 2,7]undeca-2,6-diene and 1,15,15-trimethyl-3,10-diazotetracyclo[10.2. 1.02,11.04,9]pentadeca-2,4(9),5,7,10-pentaene from camphoroquinone enantiomers

Article abstract of DOI:10.1007/s10600-007-0032-2

Optically active camphordihydro-2,3-pyrazine and camphorquinoxaline were prepared from camphoroquinone enantiomers. It was shown that (1S,4R)-(+)-camphoroquinone was formed by oxidation of (1S,3R, 4R)-(-)-3-bromocamphor and (1R,4S)-(-)-camphoroquinone from (1R,3S, 4S)-(+)-3-bromocamphor, respectively. Camphor anhydride was a side product (6-10%) of the reaction. Springer Science+Business Media, Inc. 2007.

Full text of DOI:10.1007/s10600-007-0032-2

Chemistry of Natural Compounds, Vol. 43, No. 1, 2007
SYNTHESIS OF 1,11,11-TRIMETHYL-3,6-DIAZOTRICYCLO
2,7
[6.2.1.0 ]UNDECA-2,6-DIENE AND 1,15,15-TRIMETHYL-3,10-
2,11 4,9
DIAZOTETRACYCLO[10.2.1.0 .0 ]PENTADECA-2,4(9),5,7,10-
PENTAENE FROM CAMPHOROQUINONE ENANTIOMERS
E. N. Adamenko, L. L. Frolova, M. V. Panteleeva, and A. V. Kuchin
UDC 547.599.6
Optically active camphordihydro-2,3-pyrazine and camphorquinoxaline were prepared from
S R
camphoroquinone enantiomers. It was shown that (1 ,4 )-(+)-camphoroquinone was formed by oxidation
S R R
R S
R S S
of (1 ,3 ,4 )-(-)-3-bromocamphorand(1 ,4 )-(-)-camphoroquinone from(1 ,3 ,4 )-(+)-3-bromocamphor,
respectively. Camphor anhydride was a side product (6-10%) of the reaction.
Key words: 3-
endo
-bromocamphor, camphoroquinone, camphor anhydride, camphordihydro-2,3-pyrazine,
camphorquinoxaline.
Camphor and its derivatives are used as starting chiral compounds in various syntheses [1, 2] due largely to the
availability of both enantiomers. Camphoroquinone is used not only as a simple precursor for preparing certain stereoisomeric
diols, keto- and aminoalcohols, oximes, and other derivatives but also as a ligand in asymmetric catalysis [3, 4].
Methods that use electrophilic reagents with nitrogenous functionalities are very valuable for preparing N-containing
camphor derivatives because they can immediately introduce nitrogen via an electrophilic addition reaction without forming
any intermediates. Such reagents include 1,2-diamines, which are widely used to synthesize heterocyclic systems and as
chelating agents in medicinal chemistry[5]. Moreover, their opticallyactive derivatives are important for asymmetric synthesis
of various compounds [6-8].
Many natural and synthetic biologically active molecules include a pyrazine ring. In particular, steroidal pyrazines
that were recently isolated from marine worms
have high antitumor activity [9, 10]. Several studies
Cephalodiscus gilchristi
on thesynthesisandinvestigation ofthebiologicalactivityofbenzopyrazinederivatives have been published [11-13]. Therefore,
the demand for optically active compounds containing a pyrazine moiety continues to grow.
2,7
Herein we report the synthesis of optically active 1,11,11-trimethyl-3,6-diazatricyclo[6.2.1.0 ]undeca-2,6-diene
2,11 4,9
(camphordihydro-2,3-pyrazine)and1,15,15-trimethyl-3,10-diazatetracyclo[10.2.1.0 .0 ]pentadeca-2,4(9),5,7,10-pentaene
(camphorquinoxaline) based on both enatiomers of camphoroquinone.
O
O
O
O
1
5% NaOH
1
4
O
KI, DMSO, air, 150°C
O
Br
2
COOH
COOH
O
3
O
Institute of Chemistry, Komi Scientific Center, Urals Division, Russian Academy of Sciences, 167982, Syktyvkar, ul.
Pervomaiskaya, 48, fax (8212) 43 66 77, e-mail: chemi@ksc.komisc.ru. Translated from Khimiya Prirodnykh Soedinenii,
No. 1, pp. 50-52, January-February, 2007. Original article submitted October 19, 2006.
0009-3130/07/4301-0059 ©2007 Springer Science+Business Media, Inc.
59

TABLE 1. Reaction Conditions for Camphorquinoxaline Synthesis
Solvent/catalyst
MeOH/-
MeOH/BF3 Et2O
CH3COOH
Reaction time, h
Reaction temperature, °C
Yield, %
30
15
1
65
65
118
60-70
50-65
60-70
Camphoroquinone (1) can be prepared by several methods including oxidation of camphor by selenium dioxide [14,
15] and phenylselenous acid anhydride [16] and oxidation of 3-bromocamphor (2) by air in DMSO, DMF, or HMPA in the
presence of NaI [17]. The last study confirmed that (+)-camphoroquinone was formed from (+)-3-endo-bromocamphor;
(-)-camphoroquinone, from (-)-3-endo-bromocamphor in quantitative yields.
We found that this reaction is a good method for preparing camphoroquinone but that it also forms small quantities
(6-10%) of camphor anhydride (3), which crystallizes with camphoroquinone. Compound 3 was isolated as white crystals by
column chromatography over SiO followed by crystallization from ether:hexane. Anhydrides are known to hydrolyze readily
2
in acidic or basic medium into the corresponding acids. Therefore, treatment of a mixture of 1 and 3 with NaOH solution (5%)
produced pure 1 in 74-76% yield and camphoric acid (4). The absolute configuration was determined by comparing optical
rotations of 3 and 4 with literature data [18]. During the measurement of the specific rotation of 1, it was observed that its sign
reverses, i.e., (+)-camphoroquinone formed from (-)-3-endo-bromocamphor [19] and (-)-camphoroquinone, from (+)-3-endo-
bromocamphor [19], which does not agree with previous results [17].
Reaction of camphoroquinone with ethylenediamine at a 1:2 molar ratio formed in good yield (84%) camphordihydro-
2,3-pyrazine (5) (Scheme 1). The reaction occurs at room temperature in methanol in the presence of 4 Å molecular sieves over
7 h. Performing the synthesis in boiling methanol could shorten the reaction time to 1 h.
13
14
12
11
O
O
N
H N(CH ) NH
2 2
H N(CH ) NH
2 2 2 2
N
N
2
2
1
3
7
5
9
O
N
O
5
1
1
H N
2
(+)-1S, 4R
(-)-1R,4S
H N
2
H N
2
H N
2
17
15
16
14
18
5
N
N
N
1
3
11
7
10
N
13
9
6
Scheme 1. Synthesis of camphordihydro-2,3-pyrazine (5) and camphorquinoxaline (6)
Under analogousconditions, cyclocondensation ofcamphorquinoneando-phenylenediamineat a 1:1moleratioformed
camphorquinoxaline (6) after 30 h (Scheme 1). The reaction gave complete conversion of the camphoroquinone (TLC
monitoring).
Using BF ·Et O as the catalyst shortened the reaction time to 15 h. However, the yield of camphorquionoxaline was
3
2
reduced due to the formation of side products. The optimal conditions were boiling in glacial acetic acid where acetic acid is
both the solvent and catalyst. Compound 6 was isolated by crystallization from hexane in 71% yield (Table 1).
Wefoundthat(+)-camphordihydro-2,3-pyrazineand(+)-camphorquinoxalinewereformedfrom (-)-camphoroquinone
and the (-)-forms of 5 and 6 from (+)-camphoroquinone.
The structures of 5 and 6 were confirmed by IR, NMR and mass spectroscopy and elemental analysis.
The optically active N-containing camphoroquinone derivatives are interesting as potential biologially active
compounds.
60

EXPERIMENTAL
13
PMR and C NMR spectra in CDCl were recorded on a Bruker AM-400 spectrometer (working frequency 400.13
3
and 100.61 MHz, respectively). IR spectra were recorded on a Specord M-80 instrument in KBr disks. Specific rotation was
measured using an SM-3 circular polarimeter. Mass spectra were obtained on a Finnigan SSQ-7000 GC—MS at 70 eV
ionization energyusing a DB-5MS column (30 m). GC was performed on a Kristall 2000 M instrument with a capillarycolumn
(60 m × 0.25 mm), HP-5MS phase, and He carrier gas. TLC was performed on Silufol plates with elution by
diethylether:hexane and development by bromthymol blue (0.2%) in ethanol (95%) and vanillin solution [vanillin (3 g) +
ethanol (95%, 100 mL) + conc. H SO (0.5 mL)].
2
4
20
-1
(+)-1S,4R-Camphoroquinone (1). [α]
+108° (c 1.8, toluene), mp 200°C. IRspectrum (KBr, ν, cm ): 2976, 1776,
D
1760, 1452, 1400, 1380, 1328, 1200, 1168, 1108, 1056, 1008, 1000, 972, 912.
+
+
+
Mass spectrum (m/z, I , %): 166 (20) [C H O ] , 138 (30) [M - CO] , 123 (20), 110 (10) [M - 2CO] , 95 (100)
rel
10 14 2
+
[C H ] , 83 (63), 69 (58), 67 (22), 55 (56).
7
11
PMR spectrum (400.13 MHz, CDCl , δ, ppm, J/Hz): 0.94 (3H, s, Me), 1.07 (3H, s, Me), 1.11 (3H, s, Me), 1.64 (2H,
3
13
m, H-6 , H-5
), 1.94 (1H, m, H-6
), 2.18 (1H, m, H-5 ), 2.64 (1H, d, J = 5.1, H-4). C NMR spectrum (100.62 MHz,
exo
endo
endo
exo
CDCl ): 204.7 (C-2), 202.7 (C-3), 58.5 (C-1), 57.9 (C-4), 42.5 (C-7), 29.8 (C-6), 22.2 (C-5), 21.0 (C-8), 17.3 (C-9), 8.6 (C-10).
3
20
(-)-1R,4S-Camphoroquinone. [α]
-109 (c 1.6, toluene), mp 196 C.
(+)-1S,3R-1,2,2-Trimethylcyclopentan-1,3-dicarboxlic Anhydride (3). [α]
221.5°C. IR spectrum (KBr, ν, cm ): 2980, 1812, 1768, 1460, 1400, 1392, 1376, 1326, 1316, 1282, 1252, 1224, 1214, 1184,
D
20
+0.9° (c 1.8, CHCl ), mp 221-
3
D
-1
+
+
1152, 1132, 1112, 1046, 986, 984, 948. Mass spectrum (m/z, I , %): 138 (31) [M - CO] , 123 (19), 110 (14) [M - 2CO] , 95
rel
+
(100) [C H ] , 83 (44), 69 (73), 67 (18), 55 (49).
(-)-(1S,3R)-1,2,2-Trimethylcyclopentan-1,3-dicarboxylic Acid (4). [α]
IR spectrum (KBr, ν, cm ): 3500-2500, 1704, 1464, 1414, 1398, 1384, 1286, 1246, 1168, 1128, 948.
7
11
20
-51.9° (c 4.0, EtOH), mp 181-182°C.
D
-1
20
(+)-(1R,3S)-1,2,2-Trimethylcyclopentan-1,3-dicarboxylic Acid. [α]
+50.7° (c 3.6, EtOH), mp 182°C.
D
2,7
Synthesisof(-)-1S,4R-1,11,11-Trimethyl-3,6-diazatricyclo[6.2.1.0 ]undeca-2,6-diene [(-)-camphordihydro-2,3-
pyrazine] (5). A solution of (+)-camphoroquinone (0.5 g, 0.003 mol) in methanol (10 mL) was treated with ethylenediamine
(0.4 mL, 0.006 mol) and refluxed with stirring in the presence of 4 Å molecular sieves for 1 h. After the reaction was complete,
the mixture was cooled, extracted with Et O, washed with saturated NaCl solution, and dried over K CO . Solvent was
2
2
3
20
removed. The solid was chromatographed over SiO (CHCl :CH OH, 100:1) to afford 5 (0.48 g, 84%), [α]
D
-11.6° (c 2.1,
2
3
3
-1
EtOH). IR spectrum (KBr, ν, cm ): 2968, 2856, 1656, 1480, 1448, 1396, 1376, 1340, 1234, 1212, 1116, 1084, 972, 920.
Mass spectrum (m/z, I , %): 190 (100), 175 (74), 163 (46), 148 (54), 135 (39), 120 (74), 106 (12), 91 (19), 77 (23),
rel
54 (44).
PMR spectrum (400.13 MHz, CDCl , δ, ppm, J/Hz): 0.81 (3H, s, Me), 1.00 (3H, s, Me), 1.07 (3H, s, Me), 1.51 (2H,
3
m, H-6 , H-5
), 1.82 (1H, m, H-6
), 2.04 (1H, m, H-5 ), 2.42 (1H, d, J = 4.8, H-4), 3.48 (4H, m, H-11, H-12).
endo exo
exo
13
endo
C NMR spectrum (100.62 MHz, CDCl ): 168.7 (C-2), 167.1 (C-3), 52.6 (C-4), 46.4 (C-1), 46.3 (C-7), 44.6 (C-12),
3
44.5 (C-11), 31.8 (C-6), 24.2 (C-5), 20.1 (C-8), 17.3 (C-9), 9.3 (C-10).
2,7
(+)-1R,4S-1,11,11-Trimethyl-3,6-diazatricyclo[6.2.1.0 ]undeca-2,6-diene. [(+)-Camphordihydro-2,3-pyrazine]
20
was prepared from (-)-camphoroquinone by the same method, [α]
+9.4° (c 6.8, EtOH).
D
2,11 4,9
Synthesis of (-)-1S,4R-1,15,15-Trimethyl-3,10-diazatricyclo[10.2.1.0 .0 ]pentadeca-2,4(9),5,7,10-pentaene
[(-)-camphorquinoxaline] (6). A solution of (+)-camphoroquinone (0.5 g, 0.003 mol) in glacial acetic acid (8 mL) was treated
with o-phenylenediamine (0.32 g, 0.003 mol) and refluxed for 1 h. After the reaction was complete, the mixture was cooled,
extracted with Et O, washed with saturated NaCl solution, and dried over Na SO . Solvent was removed. Recrystallization
2
2
4
20
from hexane afforded camphorquinoxaline (0.51 g, 71%), C H N , mp 69-70°C, lit. [5] mp 78°C, [α]
-32.7° (c 2.2,
EtOH). PMR spectrum (400.13 MHz, CDCl , δ, ppm, J/Hz): 0.63 (3H, s, Me), 1.12 (3H, s, Me), 1.45 (3H, s, Me), 1.43 (2H,
16 18
2
D
3
m, H-6 , H-5
), 2.06 (1H, m, H-6
), 2.30 (1H, m, H-5 ), 3.06 (1H, d, J = 4.8, H-4), 7.64 (2H, m, H-13, H-16), 8.01
endo exo
exo
endo
(2H, m, H-14, H-15).
13
C NMR spectrum (100.62 MHz, CDCl ): 165.44 (C-2), 163.68 (C-3), 141.47 (C-12), 141.26 (C-11), 128.74 (C-16),
3
128.60 (C-13), 128.00 (C-14), 127.97 (C-15), 54.14 (C-1), 53.72 (C-7), 53.23 (C-4), 31.79 (C-6), 24.57 (C-5), 20.23 (C-8),
18.46 (C-9), 9.98 (C-10).
61

2,11 4.9
(+)-1R,4S-1,15,15-Trimethyl-3,10-diazatricyclo[10.2.1.0 .0 ]pentadeca-2,4(9),5,7,10-pentaene.[(+)-Camphor-
20
quinoxaline] was prepared from (-)-camphoroquinone by the same method, [α]
+33.0° (c 2.2, EtOH).
D
ACKNOWLEDGMENT
The work was supported financially by the Russian Foundation for Basic Research (project No. 05-03-33005).
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