Oxidative intramolecular cyclization of diketoximes: Synthesis of 1,5-dinitro-cis-bicyclo[3.3.0]octane

Full text of DOI:10.1021/jo950596m

J . Org. Chem. 1996, 61, 3545-3547
3545
resentative examples which employ the oxidative cycliza-
tion of the appropriate dioxime precursor as the key step
for generating the vicinal dinitro groups8a,b (vide infra).
Oxid a tive In tr a m olecu la r Cycliza tion of
Dik etoxim es: Syn th esis of
1,5-Din itr o-cis-bicyclo[3.3.0]octa n e1
Walter W. Zajac, J r.,* Gary J . Speier,
J ohn H. Buzby, and Thomas R. Walters
Department of Chemistry, Villanova University,
Villanova, PA 19085-1699
Received March 27, 1995
The publication of two recent communications9,10 re-
garding the transannular cyclization of dioximes has
prompted us to report our related findings. Our interest
in the use of diketoximes as precursors for polycyclic
vicinal dinitro compounds was stimulated by an earlier
observation that the reaction of 1-sodio-3,5-dichloro-1,3,5-
triazine-2,4,6(1H,3H,5H)-trione (NaDCTT) with the di-
oxime of bicyclo[3.3.1]nonane-3,7-dione (1) resulted in the
formation of not only the isomeric bis-geminal chloronitro
compounds expected from the oxidative chlorination but
also provided 3,7-dinitronoradamantane (2) in 20% yield.11
It was subsequently determined that the oxidative cy-
clization of dioxime 1 to 2 could be accomplished more
efficiently (65%) using 3-chloroperoxybenzoic acid (MCP-
BA) in refluxing acetonitrile containing urea and dibasic
In tr od u ction
Strained polycyclic molecules possessing multiple nitro
groups are of particular interest because of there poten-
tial use as high-energy density materials. A review of
the synthesis of this class of molecules indicates that one
of the most successful strategies for the introduction of
the nitro group is the oxidation of the corresponding
amine precursor.2 While this strategy has proven effec-
tive for isolated amino groups, attempts to extend it to
vicinal diamines, in order to generate the corresponding
vicinal dinitro compounds, have thus far proven unsuc-
cessful.3 The problem with the oxidation of vicinal
diamines appears to result from the cleavage of the bond
connecting the nitrogen-substituted carbons.4 It is pos-
tulated that the cleavage occurs as the stepwise oxidation
proceeds via either a Grob-type fragmentation5 or a
“push-pull” mechanism.6
sodium phosphate.8,9
The utility of the MCPBA-mediated
cyclization was further demonstrated by the cyclization
of the dioxime of 9,9-dimethoxybicyclo[3.3.1]nonane-3,7-
dione (3) to 9,9-dimethoxy-3,7-dinitronoradamantane (4)
in 75% yield.12 These results suggested that oxidative
cyclizations might be feasible in other related systems.
This problem has limited the number of polycyclic
vicinal dinitro compounds which have been synthesized
to date.7,8 Most of the successful syntheses generate the
key vicinal dinitro function through either the oxidative
cyclization of dioximes or the coupling of carbons already
bearing nitro substituents. The dioxime strategy was
deemed to be more generally applicable because many
of the synthetic sequences used to assemble the polycyclic
framework often result in the integration of carbonyls
into the carbon skeleton and thus obviate the need for
the independent synthesis of the requisite dinitro precur-
sor. The syntheses of 2,3-dinitrohexacyclo[5.4.1.02,6.03,10
.
04,8.09,12]dodecane and its 2,6,9-trinitro analog are rep-
(1) Presented at the 27th Middle Atlantic Reginal Meeting of the
American Chemical Society, Hofstra University, Hemstead, NY, J une
2-4, 1993.
(2) Marchand, A. P. Tetrahedron 1988, 24, 2377.
(3) Eaton, P. E.; Xiong, R.; Gilardi, R. J . Am. Chem. Soc. 1993, 115,
10195.
Resu lts a n d Discu ssion
The reactions of cyclooctane-1,5-dione dioxime13 (5)
were investigated because of the structural homology
between 1 and 5, with 5 representing the less conforma-
tionally restricted desmethylene analog of the bicyclic 1,
and the fact that transannular reactions are well prece-
(4) Zajac, W. W., J r.; Gagnon, J . L. Tetrahedron Lett. 1995, 36, 1803.
(5) (a) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535. (b)
Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967, 6, 1.
(6) If the bond scission is the result of a Grob fragmentation, then
it is likely to occur when one, or both, of the nitrogen atoms is oxidized
to the hydroxylamino oxidation state wherein the hydroxyl function
may serve as an effective leaving group. The “push-pull” mechanism
is postulated to become operational when electron pair donation from
a less oxidized nitrogen (e.g., amino or hydroxylamino) provides “the
push” toward a more highly oxidized nitrogen, “the pull” (e.g., nitroso
or nitro) which facilitates the bond scission process. Theoretical aspects
of the latter mechanism are considered in the following: (a) Murray,
J . S.; Concha, M.; Seminario, J . M.; Politzer, P. J . Phys. Chem. 1991,
95, 1601. (b) Murray, J . S.; Seminario, J . M.; Politzer, P. Struct. Chem.
1991, 2, 153.
(9) Camps, P.; Munoz-Torrero, D. Tetrahedron Lett. 1994, 35, 3187.
This reference reports a 59% yield for the 1 to 2 conversion.
(10) Dave, P. R.; Forohar, F.; Axenrod, T.; Qi, L.; Watnick, C.;
Yazdekhasti, H. Tetrahedron Lett. 1994, 35, 8965.
(11) Walters, T. R.; Zajac, W. W., J r.; Woods, J . M. J . Org. Chem.
1991, 56, 316.
(12) U.S. Patent 5,105,301, Zajac, W. W., J r., 1992.
(7) (a) Methyl 3,9-dinitro-exo-10-methoxypentacyclo[5.3.0.02,5.03,9.04,8]-
decane-8-carboxylate: Marchand, A. P.; J in, P.-W.; Flippen-Anderson,
J . L.; Gilardi, R.; George, C. J . Chem. Soc., Chem. Commun. 1987,
1108. (b) 1,2,2-Trinitroadamantane: Dave, P. R.; Axenrod, T.; Qi, L.;
Bracuti, A. J . Org. Chem. 1995, 60, 1895.
(13) Micheli, R.; Hojas, Z.; Cohen, N.; Paritosh, D.; Portland, L.;
Sciamanna, W.; Scott, M.; Wehrli, P. J . Org. Chem. 1975, 40, 675.
(14) For example: 1,5-diamino-3,3,7,7-tetracarbethoxy-cis-bicyclo-
[3.3.0]octane is formed by reductive cyclization of the dioxime of
3,3,7,7-tetracarbethoxycyclooctane-1,5-dione: Cope, A. C.; Kagan, F.
J . Am. Chem. Soc. 1958, 80, 5499. Bicyclo[3.3.0]octane-1-carboxalde-
hyde is formed by the acid-catalyzed cyclization of the enol form of
5-methylenecyclooctanecarboxaldehyde: Graham, S. H.; J onas, D. A.
J . Chem. Soc., Chem. Commun. 1968, 1091.
(8) (a) Shen, C.-C.; Paquette, L. A. J . Org. Chem. 1989, 54, 3324.
(b) Waykole, L. M.; Shen, C.-C.; Paquette, L. A. J . Org. Chem. 1988,
53, 4969. (c) Paquette, L. A.; Nakamura, K.; Engel, P. Chem. Ber. 1986,
119, 3782.
S0022-3263(95)00596-2 CCC: $12.00 © 1996 American Chemical Society

3546 J . Org. Chem., Vol. 61, No. 10, 1996
Notes
dented in the cyclooctane system.12 It was found that
when 5 was reacted with either MCPBA6 or with
NaDCTT,9 the same product was isolated in 57% and 51%
yields, respectively. Although the 13C NMR spectrum of
the product was in accordance with that expected for 1,5-
dintro-cis-bicyclo[3.3.0]octane (6), the structure was con-
clusively proven by X-ray crystallography.26
afforded the serendipitous opportunity to investigate an
alternative cyclization strategy. This method is based
upon a recent report detailing the ferricyanide-mediated
intramolecular coupling of acyclic 1,5-dinitronates to
yield vicinal dinitrocyclopentanes.16 The dl/ meso-2,6-
dinitroheptane was successfully cyclized to a mixture of
isomeric 1,2-dimethyl-1,2-dinitrocyclopentanes, in ac-
cordance with the published report.16b However, this
method did not result in cyclization for any of the other
substrates obtained from the above dioxime oxidations.
The attempt to extend the dinitronate cyclization to
the cyclooctane system required the synthesis of the
requisite precursor, 1,5-dinitrocyclooctane (7). Several
strategies for the synthesis of 7 were evaluated. The
reductive dehalogenation22 of 1,5-dichloro-1,5-dinitrocy-
clooctane (10), prepared by oxidative chlorination of
dioxime 5, was not viable due to the competitive cycliza-
tion which occurs during the oxidative chlorination of the
dioxime and precludes the formation of 10. The ozonoly-
sis of phosphine imines, available from the reaction of
the appropriate azide with a phosphine, was also inves-
tigated.23 Although 1,5-diazidocyclooctane was available
from the ditosylate and a vigorous exothermic reaction
of the diazide with tri-n-butylphosphine was observed,
no phosphine imine could be isolated. Furthermore, the
attempted ozonolysis of the crude product without isola-
tion of the putative bis-phosphine imine also failed to
yield 7.
It should be noted that this result is consistent with a
recent communication which reports related ring closures
for the dioximes of 1,5-diazacyclooctane-3,7-diones which
lead to 1,5-dinitro-3,7-diaza-cis-bicyclo[3.3.0]octanes un-
der similar conditions.10
The scope of the oxidative cyclization was further
investigated using a number of readily available di-
oximes. It was determined that the dioximes of cis-
bicyclo[3.3.0]octane-3,7-dione,9 2,6-heptanedione, 1,4-
cyclohexanedione,15 and 2,5-hexanedione were oxidized
but failed to cyclize and yielded instead the corresponding
dinitro compounds 3,7-dinitro-cis-bicyclo[3.3.0]octane,9
dl/ meso 2,6-dinitroheptane,16b 1,4-dinitrocyclohexane,15
and dl/ meso-2,5-dinitrohexane16b in 51%, 50%, 50%, and
10% yields, respectively. The yields of the oxime oxida-
tions were modest due to the formation of significant
amounts of ketone and/or lactone byproducts. The
generation of the ketones17 may result from simple
hydrolysis of the oxime or oxidative cleavage of the
oximino group via an aci-nitro intermediate. Subsequent
peracid-mediated Baeyer-Villiger reactions of the ke-
tones yields the corresponding lactones.
Finally, the dioximes of two polycyclic cage diketones,
pentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione18 (8) and
tetracyclo[6.3.0.04,11.05,9]undecane-2,8-dione19 (9), were
subjected to the oxidative cyclization reaction conditions.
A successful strategy for the synthesis of dinitro
derivative 7 involved the initial reduction of dioxime 5
to what is presumably the dihydroxylamine 11 and
subsequent ozone-mediated oxidation to the requisite 7.
The crucial step proved to be the 5 to 11 transformation
which required a modification24 of the standard condi-
tions for affecting the sodium cyanoborohydride-mediated
reduction of oximes.25 The oxidation of the crude reduc-
tion mixture with ozone permitted the isolation of 7 as a
mixture of stereoisomers in 40% yield from 5. It was
determined that the major loss of yield was associated
A very complex reaction mixture was obtained in each
case, and the 1H and 13C NMR spectra of the crude
product contained no peaks consistent with the presence
of the cyclized vicinal dinitro compound. The prominent
peaks in the spectra were again consistent with the
presence of both ketone and lactone byproducts (vide
supra).8c,20
1
with the reduction step. The H and 13C NMR spectra
of the crude reduction products indicated mixtures
containing two major components whose relative ratios
were observed to vary with the reaction conditions.
Ozonolysis of the crude reduction mixtures resulted in
the formation of 7 and 5-nitrocyclooctanone in ratios
consistant with those observed for the two major reduc-
The availability of the uncyclized dinitro derivatives
from a number of the oxime oxidations (vide supra)
(22) Kornblum, N.; Singh, H.; Kelly, W. J . Org. Chem. 1983, 48,
332.
(23) Corey, E. J .; Samuelsson, B.; Luzzio, F. J . Am. Chem. Soc. 1984,
106, 3682.
(24) Gribble, G. J . Org. Chem. 1972, 37, 1833.
(25) Borsch, R.; Bernstein, M.; Durst, F. J . Am. Chem. Soc. 1971,
93, 2897.
(26) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(15) Nielsen, A. T. J . Org. Chem. 1962, 27, 1993.
(16) (a) Bowman, W. R.; J ackson, S. W. Tetrahedron Lett. 1989,
1857. (b) Bowman, W. R.; J ackson, S. W. Tetrahedron 1990, 46, 7313.
(17) Olah, G. A.; Ramaiah, P.; Lee, C.-S.; Prakash, G. K. S. Synlett
1992, 337.
(18) Sasaki,T.; Egushi, S.; Kiriyama, T.; Hiroaki, O. Tetrahedron
1974, 30, 2707.
(19) Wenkert, E.; Yoder, J . E. J . Org. Chem. 1970, 35, 2986.
(20) ) Surapaneni, C. R.; Gilardi, R. J . Org. Chem. 1986, 51, 2382.
(21) Barnes, M. W.; Patterson, J . M. J . Org. Chem. 1976, 41, 733.

Notes
J . Org. Chem., Vol. 61, No. 10, 1996 3547
(1 g, 5.8 mmol) in glacial HOAc (10 mL) which had been cooled
to 0 °C, under N2. After 3 h, the HOAc was removed in vacuo.
The residue was suspended in H2O (3 mL), and the pH was
adjusted to 11 with 6 N KOH followed by saturation with NaCl.
The mixture was extracted with EtOAc (2 × 75 mL) and CH2-
Cl2 (2 × 75 mL). The combined organic phases were dried (Na2-
SO4), the solvent was removed in vacuo to afford a white solid
which was dissolved in EtOAc (70 mL) and cooled to -78 °C,
and an O3/O2 steam was passed through the soluton for 30 min
until a blue color persisted. The solution was allowed to warm
to rt over an hour while a flow of oxygen was maintained. The
solvent was removed in vacuo, and the residue was subjected to
PLC. Two compounds were isolated: 5-nitrocyclooctanone as a
yellow oil (397 mg, 40%), Rf ) 0.50 (CH2Cl2) [1H NMR (CDCl3)
δ 4.2-4.4 (pentet, 1H), 2.5-2.8 (m, 4H), 1.9-2.4 (m, 4H) 1.79
(m, 4H); 13C NMR (CDCl3) δ 215.0, 85.6, 41.5, 32.3, 22.8; IR (thin
film) 1550 (s), 1700 (s)], and a mixture of cis- and trans-1,5-
dinitrocyclooctane (7) as a colorless oil (469 mg, 40%), Rf ) 0.70
(CH2Cl2) [1H NMR (CDCl3) δ 4.4-4.6 (m, 2H). 1.8-2.4 (m, 8H),
1.5-1.8 (m, 4H); 13C NMR (CDCl3) δ 86.5, 85.7, 30.9, 30.5, 21.2,
20.0; IR (thin film) 1548 (s), 1383 (m)]. A solution of 7 (320 mg,
1.6 mmol) in H2O/MeOH (8 mL, 1:1) was added dropwise, under
N2, to a vigorously stirred biphasic pentane/H2O mixture (35 mL/
20 mL) containing K3Fe(CN)6 (5.4 g, 16 mmol) and NaOH (200
mg, 7.2 mmol). The reaction mixture was stirred for an
additional 3 h after which time the layers were separated. The
aqueous layer was saturated with NaCl and extracted with
pentane (4 × 25 mL). The combined pentane layers were dried
(Na2SO4), the solvent was removed in vacuo, and the solid
residue was subjected to PLC to provide 6 (260 mg, 80%).
3,7-Din itr on or a d a m a n ta n e (2).11 The bisoxime of bicyclo-
[3.3.1]nonane-3,7-dione was subjected to the reaction conditions
of method A (vide supra). A 65% yield of 2 was obtained
following PLC (Rf ) 0.66; silica gel, CHCl3).
9,9-Dim et h oxy-3,7-d in it r on or a d a m a n t a n e (4).12 The
bisoxime of 9,9-dimethoxybicyclo[3.3.1]nonane-3,7-dione was
subjected to the reaction conditions of method A (vide supra). A
75% yield of 4 was obtained following PLC (Rf ) 0.76; silica gel,
CHCl3): 1H NMR (CDCl3) δ 2.3-2.8 (m, 8H), 3.2 (s, 6H), 3.4-
3.6 (m, 2H); 13C NMR (CDCl3) δ 99.94, 55.8, 42.89, 40.2, 15.2;
IR (thin film) 1549 (s).
3,7-Din itr o-cis-bicyclo[3.3.0]octa n e.9 The bisoxime of cis-
bicyclo[3.3.0]octane-3,7-dione was subjected to the reaction
conditions of method A (vide supra). A 51% yield of 3,7-dinitro-
cis-bicyclo[3.3.0]octane, as a mixture of exo-exo, exo-endo, and
endo-endo stereoisomers, was obtained following PLC (Rf ) 0.90;
silica gel, CHCl3).
1,4-Din itr ocycloh exa n e.15 The bisoxime of 1,4-cyclohex-
anedione was subjected to the reaction conditions of method A
(vide supra). A 65% yield of 1,4-dinitrocyclohexane, as a mixture
of cis and trans stereoisomers, was obtained following PLC (Rf
) 0.78; silica gel, CHCl3)
tion products. One was assigned the structure of dihy-
droxylamine 11, based on spectroscopic data and ozonol-
ysis behavior, while the other remains unidentified but
was observed to yield 5-nitrocyclooctanone upon subse-
quent oxidation by ozone.
The same facility with which the cyclization of the
acyclic 1,5-dinitronate took place to generate the cyclo-
pentane derivatives16 was manifested in the ferricyanide-
mediated intramolecular coupling reaction of 7 which
lead to the expected product 6 in 80% yield. Although
the yield from the cyclization of the dinitronate is
superior to that obtained from the direct oxidative
cyclization of dioxime 5, the modest yield obtained for
the synthesis of requisite precursor 7 makes the overall
transformation less efficient (32% versus >50% overall
from 5).
In summary, the reactivities of the substrates were
observed to fall into three distinct reactivity categories
in which both, neither, or only one of cyclization methods
was successful. Both methods were successful in gener-
ating 1,5-dinitro-cis-bicyclo[3.3.0]octane from the ap-
propriate cyclooctane precursor. The dl/ meso-2,6-dini-
troheptanes16b could be successfully cyclized to a mixture
of stereoisomeric 1,2-dimethyl-1,2-dinitrocyclopentanes
while the corresponding dioxime strategy failed. Neither
method was successful for the majority of the substrates
examined. Studies to elucidate the reasons for these
differences in reactivity are continuing.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H NMR
and 13C NMR spectra were determined in CDCl3 solutions at
200 and 53.3 MHz, respectively. Infrared spectra were obtained
on an Analect FX-6160 FT-IR spectrophotometer. Preparative
layer chromatography (PLC) was carried out on 0.1 × 20 × 20
cm silica gel 60 F254 plates (Merck). Microanalyses were
performed by Galbraith Laboratories, Knoxville, TN.
1,5-Din itr o-cis-bicyclo[3.3.0]octa n e (6). Meth od A. A
mixture of the bisoxime of 1,5-cyclooctanedione (5) (150 mg, 0.96
mmol), anhydrous dibasic sodium phosphate (2.0 g, 14 mmol),
crushed urea (530 mg, 9 mmol), and dry acetonitrile (30 mL)
was refluxed for 0.5 h under nitrogen. Portions (six) of MCPBA
(1.1 g, 3.0 mmol) were then added at 15 min intervals. Reflux
was maintained for 2 h following the addition and the reaction
mixture allowed to cool to room temperature. The yellow-green
solution was decanted from the white precipitate and the residue
was washed with cold acetonitrile (100 mL). The combined
organic fractions were concentrated to a solid residue which was
dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed
with saturated aqueous NaHCO3 (50 mL) containing NaHSO3
(5 g), saturated aqueous NaHCO3 (3 × 50 mL), water (50 mL)
and dried (Na2SO4). Following the removal of the solvent in
vacuo, the resultant yellow solid was purified by PLC. Isolation
of the band at Rf ) 0.78 (CHCl3) yielded 1,5-dinitro-cis-bicyclo-
[3.3.0]octane (6) (100 mg, 57%) as a white amorphous solid, mp
170-181 °C dec: 1H NMR (CDCl3) δ 2.6-3.0 (m, 4H), 2.0-2.4
(m, 4H), 1.6-2.0 (m, 4H); 13C NMR (CDCl3) δ 102.6, 38.8, 22.5.
Anal. Calcd for C8H12N2O4: C, 48.00; H, 6.04; N, 13.99.
Found: C, 47.98; H, 5.98; N, 13.88.
Meth od B. A mixture of the bisoxime of 1,5-cyclooctanedione
(5) (800 mg, 4.7 mmol), NaHCO3 (10 g), H2O (100 mL) and
EtOAc (100 mL), was stirred at room temperature for 5 min,
and 1-sodio-3,5-dichloro-1,3,5-triazine-2,4,6(1H,3H,5H)-trione
(10.75 g 47 mmol) was added portionwise (six at 5 min intervals).
The reaction mixture was stirred vigorously for 24 h. The
organic layer was separated, and the aqueous layer was ex-
tracted with EtOAc (3 × 100 mL). The combined organic layers
were washed sequentially with NaOH (0.2 N, 100mL), H2O (3
× 50 mL), and brine (100 mL) and dried (Na2SO4). The removal
of the solvent in vacuo and PLC afforded 6 (480 mg, 51%).
Meth od C. A single portion of Na(CN)BH3 (500 mg, 8.3
mmol) was added to a vigorously stirred solution of bisoxime 5
2,5-Din itr oh exa n e.16b The bisoxime of 2,5-hexanedione was
subjected to the reaction conditions of method A (vide supra). A
10% yield of 2,5-dinitrohexane, as a mixture of dl and meso
stereoisomers was obtained following PLC (Rf ) 0.88; silica gel,
CHCl3).
Ack n ow led gm en t. The authors thank Dr. Richard
Gilardi of the Laboratory for the Structure of Matter,
Naval Research Laboratory, Washington, DC, for the
X-ray crystallographic analysis of compound 6 and his
attendant support for this endeavour from the Office of
Naval Research, Mechanics Division. Additional support
was provided by GEO-CENTERS, INC. (AMCCOM
Contract DAAA21-89-C-0012).
Su p p or tin g In for m a tion Ava ila ble: NMR data (13C) for
compounds 7 and 5-nitrocyclooctanone (2 pages). This mate-
rial is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal,
and can be ordered from the ACS; see any current masthead
page for ordering information.
J O950596M