Synthesis of 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine (TNFX), a diversified energetic heterocycle

Article abstract of DOI:10.1016/S0040-4039(01)00260-X

The syntheses of new 3,3-dinitro derivatives of the 1,5-diazocine ring system are described. Highly deactivated precursor ketones hexahydro-7,7-dinitro-1,5-bis(2- and 4-nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-ones (18) have been difluoraminated to the co

Full text of DOI:10.1016/S0040-4039(01)00260-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2621–2623
Synthesis of
3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine
(TNFX), a diversified energetic heterocycle
Theodore Axenrod,a,* Xiao-Pei Guan,a Jianguang Sun,a Lida Qi,a Robert D. Chapmanb,* and
Richard D. Gilardic
aDepartment of Chemistry, The City College of the City University of New York, New York, NY 10031, USA
bNaval Aviation Science and Technology Office (Code 4T4200D), Naval Air Warfare Center Weapons Division, China Lake,
CA 93555, USA
cLaboratory for the Structure of Matter (Code 6030), Naval Research Laboratory, 4555 Overlook Avenue SW, Washington,
DC 20375, USA
Received 25 December 2000; revised 13 February 2001; accepted 14 February 2001
Abstract—The syntheses of new 3,3-dinitro derivatives of the 1,5-diazocine ring system are described. Highly deactivated precursor
ketones hexahydro-7,7-dinitro-1,5-bis(2- and 4-nitrobenzenesulfonyl)-1,5-diazocin-3(2H)-ones (18) have been difluoraminated to
the corresponding gem-bis(difluoramino)diazocines (19). The 1,5-bis(4-nitrobenzenesulfonyl)diazocine derivative undergoes N-
nitrolysis with the protonitronium reagent formed in the nitric acid–trifluoromethanesulfonic acid–antimony pentafluoride system
to produce 3,3-bis(difluoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine 2 (TNFX), containing nitramine, gem-dinitro, and
gem-bis(difluoramino) structural components. © 2001 Elsevier Science Ltd. All rights reserved.
As first proposed by Zheng et al.1 and by Baum and
co-workers,2 gem-bis(difluoramino)-substituted hetero-
cyclic nitramines, such as structures 1 and 2, are of
interest because of their potentially high density, high
energy, and superior properties as solid propellant oxi-
dizers.3 A superior synthesis of compound 1 (HNFX)
was recently reported,4,5 and, in this communication,
we report the first synthesis of a gem-dinitro-substituted
analog, 2 (TNFX). Although the symmetric analogs,
HNFX and octahydro-1,3,3,5,7,7-hexanitro-1,5-diazo-
cine,6 have been reported, the asymmetric derivative 2,
incorporating both difluoramino and C-nitro sub-
stituents in addition to nitramine, may offer potentially
superior propellant performance in certain formula-
tions, based either on arguments involving qualitative
chemical features of the ingredient2 or on computa-
tional estimates of its thermodynamic properties.7 Of
course, the asymmetric functionalization of the C3 and
C7 carbons of the 1,5-diazocine system required devel-
opment of a judicious protection strategy, as we
describe here.
F2N NF2
NF2
N
F2N
O2N N
O2N N
O2N
NO2
N
NO2
F2N NF2
N
O2
1
2
The introduction of two geminal difluoramino groups
generally requires strongly acidic conditions (e.g. anhy-
drous H2SO4) starting from precursor ketones or cer-
tain gem-bromonitro intermediates.8 This severe
synthetic constraint limits the types of functional
groups that will survive this treatment. In this report,
we detail two approaches affording important new
gem-dinitro-1,5-diazocine derivatives that have been
successfully developed as difluoramination precursors
to 2.
With a view toward subsequent hydrolysis of the O-
acetyl group to the alcohol followed by oxidation to the
corresponding ketone, several unsuccessful attempts to
prepare the analogous gem-dinitro compound from
oxime 3 were carried out. Oxime 3, available from
on-going related studies, was made by ozonolysis of
3-acetoxy-1,5-diacetyloctahydro-7-methylene-1,5-diazo-
cine9 followed by oximation of the intermediate ketone.
* Corresponding authors. E-mail: thacc@scisun.sci.ccny.cuny.edu;
chapmanrd@navair.navy.mil
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00260-X

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T. Axenrod et al. / Tetrahedron Letters 42 (2001) 2621–2623
As outlined in Scheme 1, the conventional oxidation
methods10 for the conversion of oximes to the gem-dini-
tro group that were investigated included ꢀ100%
HNO3, N-bromosuccinimide and m-chloroperbenzoic
acid. In each case transannular bridging intervened and
only the 3,7-diacetyl-5-nitro-9-oxa-3,7-diazabicyclo-
[3.3.1]nonane derivative 4 was obtained.
In the first approach (Scheme 2), ketone 5, the precur-
sor to oxime 3, was subjected to the sequence of
transformations shown, to arrive at oxime 8. 1,3-Dioxo-
lane protection of the keto function in the latter oxime
was employed to avoid transannular reactions and,
under these conditions, smooth conversion of the oxime
8 to the corresponding gem-dinitro compound 9 took
place. However, under a variety of conditions, depro-
tection of 9 to the corresponding ketone proved impos-
sible in our hands.
OAc
a
O
Ac
N
N
Ac
b
c
Ac
N
N
Ac
In the alternative strategy, outlined in Scheme 3, a
commercially available starting material, 1,3-
diaminopropan-2-ol (10),12 was N-protected by o-
nitrobenzenesulfonyl or p-nitrobenzenesulfonyl groups,
followed by chromic acid oxidation to ketone 12, and
the latter carbonyl function was protected through
reaction with ethylene glycol to form its 1,3-dioxolane
derivative 13. Cycloalkylation of 13 with methallyl
dibromide13 followed by ozonolysis of the readily
formed exo-methylene-1,5-diazocine intermediate 14
afforded the monoprotected 1,5-diazocin-3(2H)-one 15.
Oximation followed by HNO3 oxidation of 16 afforded
the gem-dinitro derivative 17, and hydrolysis of the
latter produced the desired hexahydro-7,7-dinitro-1,5-
diazocin-3(2H)-one derivative 18.
NO2
NOH
3
4
Scheme 1. Reagents and conditions (yield): (a) HNO3,
NH4NO3, urea, CH2Cl2, reflux (29%); (b) NBS, NaHCO3,
dioxane–H2O, rt (40%); (c) m-CPBA, Na2HPO4, urea,
MeCN, reflux (49%).
These findings substantiate previously observed
difficulties in this eight-membered ring system.2b,11 The
marked propensity for transannular bridging to occur
leads to stable 9-oxa-3,7-diazabicyclo[3.3.1]nonanes.4,11c
Thus, satisfactory methodologies that circumvent
bridging are needed for the preparation of asymmetric
saturated gem-dinitro-1,5-diazocine precursors that will
undergo difluoramination reactions.
As shown in Scheme 4, the gem-bis(difluoramino)
derivative 19 was obtained by
a
modified
difluoramination4 of ketone 18 with difluoramine–
OAc
OAc
O
NOH
O2N
N
NO2
N Ac
g
e,f
d
h
Ac
Ac
Ac
Ac
N
Ac
N
Ac
Ac N
N
N
N
Ac
N
Ac
N
O
O
O
O
O
O
O
O
O
6
7
8
5
9
Scheme 2. Reagents and conditions (yield): (d) ethylene glycol, p-TsOH, benzene (69%); (e) K2CO3, MeOH–H2O, rt (86%); (f)
Jones reagent, 0°C (69%); (g) NH2OH·HCl, NaOAc, MeOH, reflux (97%); (h) HNO3, NH4NO3, urea (36%).
Ns
Ns
Ns
Ns
Ns
Ns
NH HN
NH HN
NH2
NH HN
NH2
j
i
k
l
Ns
N
N Ns
o-Ns, 80%
p-Ns, 95%
o-Ns, 90%
p-Ns, 91%
o-Ns, 89%
p-Ns, 90%
o-Ns, 86%
p-Ns, 76%
O
O
OH
O
OH
10
O
O
11
12
13
14
O
NOH
O2N NO2
O2N NO2
p
o
m
n
Ns
N
N
Ns
Ns
N
N Ns
Ns N
Ns
N
N Ns
N Ns
o-Ns, 98%
p-Ns, 95%
o-Ns, 97%
p-Ns, 91%
o-Ns, 46%
p-Ns, 33%
o-Ns, 87%
p-Ns, 92%
O
O
O
O
O
O
O
15
16
17
18
Scheme 3. Reagents and conditions: (i) 2- or 4-nitrobenzenesulfonyl chloride, THF–H2O, K2CO3, rt; (j) CrO3, H2SO4, acetone,
rt; (k) ethylene glycol, p-TsOH, toluene; (l) CH2ꢀC(CH2Br)2, K2CO3, acetone, reflux; (m) (1) O3, CH2Cl2, −78°C, (2) Me2S; (n)
NH2OH·HCl, NaOAc, EtOH, reflux; (o) HNO3, NH4NO3, urea; (p) conc. H2SO4, rt.

T. Axenrod et al. / Tetrahedron Letters 42 (2001) 2621–2623
2623
Research (Drs. Richard S. Miller and Judah Goldwasser,
program officers) is gratefully acknowledged.
O2N NO2
N
O2N NO2
O2N
N
O2
q
Ns
r
Ns
Ns
N
N
Ns
N
O2N
N
N
NO2
o-Ns, 65%
p-Ns, 90%
(p-Ns)
F2N NF2
F2N NF2
References
O
18
19
2
1. Zheng, Y.; Huang, T.; Zhang, M.; Wang, X. Proceed-
ings of the International Symposium on Pyrotechnics and
Explosives, Beijing, China, Oct. 1987; China Academic
Publishers: Beijing, 1987; pp. 234–240.
Scheme 4. Reagents and conditions: (q) HNF2–F2NSO3H–
H2SO4–CFCl3, −15°C; (r) HNO3–CF3SO3H–SbF5, rt.
2. (a) Chapman, R. D.; Archibald, T. G.; Baum, K.
Research in Energetic Compounds. Report ONR-7-1
(Interim); Fluorochem: Azusa, CA, 1989; DIALOG
Accession Number 1429659; NTIS Accession Number
AD-A214106; available from the National Technical
Information Service, US Department of Commerce,
Springfield, VA 22161; (b) Research in Energetic Com-
pounds. Report ONR-7-1; Fluorochem: Azusa, CA,
1991; final report to the Office of Naval Research
(Arlington, VA) on Contract N00014-88-C-0536.
3. Miller, R. S. Mater. Res. Soc. Symp. Proc. 1996, 418, 3.
4. Chapman, R. D.; Welker, M. F.; Kreutzberger, C. B. J.
Org. Chem. 1998, 63, 1566.
5. Chapman, R. D.; Gilardi, R. D.; Welker, M. F.;
Kreutzberger, C. B. J. Org. Chem. 1999, 64, 960.
6. (a) Cichra, D. A.; Adolph, H. G. Synthesis 1983, 830;
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8. (a) Baum, K. Intra-Sci. Chem. Rep. 1971, 5, 69; (b)
Fokin, A. V.; Kosyrev, Yu. M.; Shevchenko, V. I. Bull.
Acad. Sci. USSR, Div. Chem. Sci. 1982, 1626.
9. Dave, P. R.; Kumar, K. A.; Duddu, R.; Axenrod, T.;
Dai, R.; Das, K. K.; Guan, X.-P.; Sun, J.; Trivedi, N.
J.; Gilardi, R. D. J. Org. Chem. 2000, 65, 1207.
10. For a recent review of oxime to gem-dinitro conver-
sions, see: Honey, P. J.; Millar, R. W.; Coombes, R. G.
Am. Chem. Soc. Symp. Ser. 1996, 623, 134.
11. (a) Paudler, W. W.; Gapski, G. R.; Barton, J. M. J.
Org. Chem. 1966, 31, 277; (b) Dave, P. R.; Forohar, F.;
Axenrod, T.; Das, K. K.; Qi, L.; Watnick, C.;
Yazdekhasti, H. J. Org. Chem. 1996, 61, 8897; (c) Axen-
rod, T.; Qi, L., unpublished results.
difluorosulfamic acid in sulfuric acid. N-Nitrolysis of
dinosyldiazocine 19 proved remarkably difficult. This
could be anticipated for reasons elaborated in the previ-
ous report on the synthesis of HNFX by N-nitrolysis of
a dinosyldiazocine precursor.5 Sterically hindered and
electronegatively substituted protected amines are espe-
cially resistant to N-nitrolysis, and diazocine 19 incorpo-
rates both of these features. A b,b-bis(difluoramino)alkyl
plus a b,b-dinitroalkyl substituent impart even more
electron-withdrawing character than the two bis(difluor-
amino)alkyl substituents of the HNFX precursor; for
example, Taft’s |*(NO2)=4.7214 versus |*(NF2):
4.13.15 Thus, even extended nitrolysis (14 days) of 19 with
the system nitric acid–trifluoromethanesulfonic acid, a
source of the strongly nitrating species protonitronium
(NO2H2+),16 at elevated temperature (55°C) produced
predominantly only the corresponding mononitramine.
Only by addition of a strong Lewis acid, SbF5, to the
nitrating system—in order to generate a higher concen-
tration of protonitronium17—followed by further nitrol-
ysis (2 days) was 2 (TNFX) formed by a clean conversion
as the major product, although thus far in an
unquantified yield. Therefore, the second nitrolysis step
of Scheme 4 may well be the most difficult N-nitrolysis
ever successfully achieved, since the second nitrolysis step
producing HNFX was complete in HNO3–HOTf (with-
out Lewis acid) in only ꢀ40 h.5 Also, only the p-nosyl
isomer of 19 was useful for formation of TNFX because
the o-nosyl derivative underwent para-C-nitration, and
the resulting 2,4-dinitrobenzenesulfonyl derivative was
not effectively nitrolyzed. The product (2) was identified
by multinuclear NMR spectroscopy as well as X-ray
crystallography. CAUTION: TNFX (2) is expected to be
a relatively sensitive high explosive and should be pre-
pared and handled only by qualified personnel!
12. Benoist, E.; Loussouarn, A.; Remaud, P.; Chatal, J.-F.;
Gestin, J.-F. Synthesis 1998, 1113.
In summary, the first successful synthesis of 3,3-bis(difl-
13. Axenrod, T.; Yazdekhasti, H.; Dave, P. R.; Das, K. K.;
Stern, A. G. Org. Prep. Proc. Int. 1997, 29, 358.
14. (a) Cherkasov, A. R.; Galkin, V. I.; Cherkasov, R. A.
Russ. Chem. Rev. 1996, 65, 641; (b) Cherkasov, A. R.;
Galkin, V. I.; Sibgatullin, I. M.; Cherkasov, R. A. Russ.
J. Org. Chem. 1997, 33, 1243.
uoramino)octahydro-1,5,7,7-tetranitro-1,5-diazocine
2
(TNFX) has been realized. All compounds and interme-
diates described here have been fully characterized (1H,
13C NMR, HRMS, and/or X-ray crystallography), and
a complete report of the synthetic details and interesting
crystallographic properties of TNFX will be published
elsewhere.
15. Baum, K. J. Org. Chem. 1970, 35, 1203.
16. (a) Olah, G. A.; Laali, K. K.; Sandford, G. Proc. Nat.
Acad. Sci. USA 1992, 89, 6670; (b) Olah, G. A.; Rasul,
G.; Aniszfeld, R.; Prakash, G. K. S. J. Am. Chem. Soc.
1992, 114, 5608.
Acknowledgements
17. Prakash, G. K. S.; Rasul, G.; Burrichter, A.; Olah, G. A.
Am. Chem. Soc. Symp. Ser. 1996, 623, 10.
Financial support of this work by the Office of Naval
.
.