Synthesis and Characterization of 5-Substituted 1,3-Diazacyclohexane Derivatives

Article abstract of DOI:10.1021/jo991524o

Three synthetic routes to 5-substituted 1,3-diazacyclohexane derivatives 1 are reported. The first method involves treatment of 1,3-diaminopropan-2-ol 2 with paraformaldehyde to yield 5-hydroxy-1,3-diazacyclohexane 3. A second method is based on the condensation of 2-bromo-2-nitro-1,3-propanediol with tert-butylamine and formaldehyde to yield 1,3-di-tert-butyl-5-bromo-5-nitro-1,3-diazacyclohexane 22. The third method relies on the cycloalkylation of methylenebisacetamide with 3-chloro-2-chloromethyl-2-propene to provide 5-exomethylene-1,3-diacetyl-1,3-diazacyclohexane 28. Functional group manipulations of 3, 22, and 28 provide a number of novel 1,3-diazacyclohexanes functionalized at the 5-position.

Full text of DOI:10.1021/jo991524o

1200
J . Org. Chem. 2000, 65, 1200-1206
Syn th esis a n d Ch a r a cter iza tion of 5-Su bstitu ted
1,3-Dia za cycloh exa n e Der iva tives
Theodore Axenrod,* J ianguang Sun, and Kajal K. Das
Department of Chemistry, The City College of CUNY, New York, New York 10031
Paritosh R. Dave,* Farhad Forohar, and Mira Kaselj
GEO-CENTERS, INC. at ARDEC, Bldg. 3028, Picatinny Arsenal, New J ersey 07806
Nirupam J . Trivedi*
Energetic Materials and Technology Department, Naval Surface Warfare Center - Indian Head Division,
101 Strauss Avenue, Indian Head, Maryland 20640
Richard D. Gilardi and J udith L. Flippen-Anderson
Laboratory for the Structure of Matter, Naval Research Laboratory, 4555 Overlook Avenue, SW,
Washington DC 20375
Received September 28, 1999
Three synthetic routes to 5-substituted 1,3-diazacyclohexane derivatives 1 are reported. The first
method involves treatment of 1,3-diaminopropan-2-ol 2 with paraformaldehyde to yield 5-hydroxy-
1,3-diazacyclohexane 3. A second method is based on the condensation of 2-bromo-2-nitro-1,3-
propanediol with tert-butylamine and formaldehyde to yield 1,3-di-tert-butyl-5-bromo-5-nitro-1,3-
diazacyclohexane 22. The third method relies on the cycloalkylation of methylenebisacetamide with
3-chloro-2-chloromethyl-2-propene to provide 5-exomethylene-1,3-diacetyl-1,3-diazacyclohexane 28.
Functional group manipulations of 3, 22, and 28 provide a number of novel 1,3-diazacyclohexanes
functionalized at the 5-position.
In tr od u ction
1,3-dialkyl-1,3-diazacyclohexane11 have been reported,
general methods for the syntheses of 1,3-diazacyclohex-
anes derivatives that have been functionalized at the
5-position with other than C-nitro groups are lacking. In
this paper, we describe three such approaches to 5-sub-
stituted 1,3-diazacyclohexanes that allow for the incor-
poration of various substituents at the 1-, 3-, and
5-positions, including access to the heretofore unknown
1,3-disubstituted 1,3-diazacyclohexan-5-ones, which are
key intermediates for the introduction of a variety of
substituents at the 5-position. Additionally, the facile
synthesis of a new energetic material, 1,3-dinitro-5-
nitrato-1,3-diazacyclohexane 17, as well as the chemistry
leading to a number of related 5-substituted derivatives
of this ring system are described.
The design and synthesis of small-1 and medium-ring2
nitrogen-containing heterocycles have been investigated
in these laboratories as part of a continuing program to
prepare novel high-density energetic materials with
improved sensitivity properties.3 The chemistry of 1,3-
diazacyclohexanes has attracted considerable interest in
recent years, since appropriately functionalized com-
pounds of this ring system either serve as crucial
synthetic precursors or are themselves important mem-
bers of this class of heterocycles. Examples include 1,3,5-
trinitro-1,3-diazacyclohexane and 1,3,5,5-tetranitro-1,3-
diazacyclohexane, whose syntheses were achieved by the
nitrolysis of the Mannich condensation product from
nitromethane, formaldehyde, and tert-butylamine4-7 as
well as by the cyclocondensation of a nitroguanidine.8
While the parent 1,3-diazacyclohexane,9 5-hydroxy-1,3-
diazacyclohex-1-ene,10 and more recently 5-exomethylene-
Resu lts a n d Discu ssion
The construction of the 1,3-diazacyclohexane ring
system has been achieved by three pathways. These
approaches are depicted in Scheme 1.
(1) Axenrod, T.; Watnick, C.; Yazdekhasti, H.; Dave, P. R. J . Org
Chem. 1995, 60, 1959.
In our first method, the ring-closure reaction of 2,2-
disubstituted 1,3-diaminopropane with formaldehyde
gave the 5,5-disubstituted 1,3-diazacyclohexane ring,
which was further derivatized in the 1,3-positions by a
variety of reagents. The second method involved the
(2) Dave, P. R.; Forohar, F.; Axenrod, T.; Das, K.; Qi, L.; Watnick,
C.; Yazdekhasti, H. J . Org Chem. 1996, 61, 8897.
(3) Miller, R. S. In Research on New Energetic Materials, in
Decomposition, Combustion and Detonation Chemistry of Energetic
Materials; Brill, T. B., Russel, T. P., Tao, W. C., Wardle, R. B., Eds.;
Materials Research Society Symposium Proceedings: Pittsburgh, PA,
1996; Vol. 418, pp 3-14.
(4) Levins, D. A.; Bedford, C. D.; Staats, S. J . Propellants, Explos.
Pyrotech. 1983, 8, 74.
(9) Brown, D. J . In Pyrimidines and Their benzo Derivatives;
Boulton, A. J ., McKillop, A., Eds. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: New
York, 1984; Vol. 3, Part 2B.
(5) Cichra, D. A.; Adolph, H. G. J . Org Chem. 1982, 47, 2474.
(6) Boileau, J .; Piteau, M.; J acob, G. Propellants, Explos. Pyrotech.
1990, 15, 38.
(7) Ritter, H.; Licht, H. H. Propellants, Explos. Pyrotech. 1985, 10,
147.
(8) Yao, G.; Xu, Q.; Wan, D.; Yu, Y. Kogyo Kayaku 1982, 43, 2.
(10) Spry, D. O.; Aaron, H. S. J . Org Chem. 1966, 31, 3838.
(11) Barluenga, J .; Canteli, R. M.; Florez, J . J . Org Chem. 1996,
61, 3646.
10.1021/jo991524o CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/26/2000

Synthesis of 5-Substituted 1,3-Diazacyclohexane Derivatives
J . Org. Chem., Vol. 65, No. 4, 2000 1201
Sch em e 1
Sch em e 3
butoxycarbonyl derivatives make them in some instances
preferable to the acetyl derivatives as reactants. The
reaction of 3 with p-toluenesulfonyl chloride in the
presence of potassium carbonate gave 1,3-ditosyl-5-
hydroxy-1,3-diazacyclohexane 7 in excellent yield. Analo-
gous reaction of 3 with methanesulfonyl chloride gave
the corresponding 1,3-di(methanesulfonyl)-5-hydroxy-1,3-
diazacyclohexane, 8. 1,3-Diamino-2-propanol 2 was also
conveniently acetylated in refluxing ethyl acetate to give
1,3-diacetaminopropan-2-ol 9. The latter on treatment
with formaldehyde in acetic acid containing sulfuric acid
undergoes a Mannich ring-closure to also produce 10,
albeit in rather poor yield.13 Selective hydrolysis of 10
by aqueous potassium carbonate also readily affords 4.
With 5-hydroxy-1,3-diazacyclohexane 3 and related
compounds readily available, the synthesis of 5-keto
derivatives was investigated as a route to potential key
intermediates for the further functionalization of the 1,3-
diazacyclohexane ring system at the 5-position. However,
attempts to transform the 5-hydroxyl group in either 4
or 5 to the corresponding ketone by various oxidation
procedures were unsatisfactory. In our hands, when these
materials were subjected to PCC, J ones reagent, Swern
oxidation conditions, and acetyl nitrate supported on
montmorillonite,14 the corresponding ketone could not be
isolated. The failure of the oxidations was attributed to
the solubility of the starting materials/products in water,
which led to the hydrolysis of the aminal group leading
to water-soluble ring-opened products. This view is at
least partially strengthened by the finding, outlined in
Scheme 3, that 1,3-ditosyl- and 1,3-dimesyl-1,3-diazacy-
clohexane-5-ol derivatives 7 and 8, water-insoluble ma-
terials, were readily converted by oxidation with J ones
reagent to the corresponding ketones 14 and 15. Al-
though ketones 14 and 15 were found to readily form
stable hydrates, the ketone forms were easily recovered
by dehydration of the hydrate using azeotropic distilla-
tion with benzene or toluene. Reaction of ketone 14 with
ethylene glycol in the presence of acid readily converted
it to the ketal derivative 1,4-dioxa-7,9-ditosyl-7,9-diaza-
spiro[4.5]decane 16.
Sch em e 2
reaction of readily available 2-bromo-2-nitropropane-1,3-
diol with tert-butylamine and formaldehyde to give the
1,3-diazacyclohexane ring in one step. The reaction of
methylenebisacetamide with 3-chloro-2-chloromethyl-2-
propene 27 was the basis of our third method to construct
the 1,3-diazacyclohexane ring structure.
The synthesis of 5-substituted 1,3-diazacyclohexanes
by method A described above is elaborated in Scheme 2.
Treatment of 1,3-diaminopropan-2-ol 2 with paraform-
aldehyde in methanol solution affords 5-hydroxy-1,3-
diazacyclohexane 3 in 88% yield as a water-soluble
hygroscopic colorless crystalline solid.12 In refluxing 1,2-
dichloroethane, 3 reacts with acetic anhydride to yield
the completely acetylated derivative 10 or with acetic
anhydride in potassium carbonate to yield the selectively
diacetylated 1,3-derivative 4. Similarly, propionic anhy-
dride and di-tert-butyl dicarbonate convert 3 to the
corresponding dipropionyl and di-BOC derivatives, 5 and
6, respectively. Reduced water solubility and ease of
isolation of products derived from the propionyl and
We now report that the Dess-Martin procedure15
cleanly oxidizes diacylated 5-hydroxy-1,3-diazacyclohex-
anes to ketones in excellent yields using the preformed
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one pe-
(13) Vail, S. L.; Moran, C. M.; Moore, H. B. J . Org Chem. 1962, 27,
2067.
(14) de Oliveira Filho, A. P.; Moreira, B. G.; Moran, Paulo J . S.;
Rodrigues, J . Augusto R. Tetrahedron Lett. 1996, 37, 5029.
(15) a) Ireland, R. E.; Liu, L. J . Org Chem. 1993, 58, 2899. (b) Dess,
D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(12) In the presence of excess formalin, 1,3-diaminopropan-2-ol is
reported to give 1-formyl-5-hydroxy-3-methylhexahydropyrimidine,
which presumably arises from an intramolecular hydride-transfer
process involving a methyleneamino intermediate. See: Bagga, M. M.;
Everatt, B.; Hinton, I. G. J . Chem Soc., Chem. Commun. 1987, 259.

1202 J . Org. Chem., Vol. 65, No. 4, 2000
Axenrod et al.
Sch em e 4
Sch em e 5
F igu r e 1. ORTEP diagram of 17 showing the numbering
scheme and an edge-on view of the molecular structure.19 The
figure was drawn using experimentally determined coordinates
and thermal ellipsoids represented at the 20% probability
level.
riodinane reagent in methylene chloride solution. To
avoid hydrate formation, product isolation was simplified
by a nonaqueous workup. Addition of ethyl ether to the
reaction mixture precipitated the iodobenzoic acid, and
the organic layer was passed through a short column of
silica gel. Elution with ethyl acetate afforded the corre-
sponding ketones 11 and 12 and the di-BOC derivative
13 in yields of 87%, 83%, and 100%, respectively.
A second pathway (method B, Scheme 1) to access this
ring system, based on the condensation of 2-bromo-2-
nitro-1,3-propanediol 21 with tert-butylamine and form-
aldehyde to yield 1,3-di-tert-butyl-5-bromo-5-nitro-1,3-
diazacyclohexane 22, was examined and is shown in
Scheme 5.
Compound 22 was obtained in 81% yield as a pale
yellow crystalline solid. The nitrolysis of 22 with 100%
nitric acid gave a 54% yield of 1,3,5-trinitro-5-bromo-1,3-
diazacyclohexane 23. Further transformations involving
acylative dealkylation of 22 by reaction with acetic
anhydride and BF3‚etherate to afford the corresponding
1-acetyl-3-tert-butyl-5-bromo-5-nitro-1,3-diazacyclohex-
ane 24 and 1,3-diacetyl-5-bromo-5-nitro-1,3-diazacyclo-
hexane 25 have been successfully carried out.17 The
details of this chemistry are reported in the accompany-
ing paper.17
It is well-established that cyclic polynitramines are
important energetic materials.16 With reasonable quanti-
ties of these acylated ketones and related 5-hydroxy-1,3-
diazacyclohexane compounds in hand, attention turned
toward further functionalization of the ring system to
prepare new high energy density materials. 5-Hydroxy-
1,3-diazacyclohexane 3, when treated with 100% HNO3
and P2O5, produces the 1,3-dinitro-5-nitrato-1,3-diazacy-
clohexane 17, in 80% yield. X-ray crystallographic analy-
sis confirms this structure, and the crystal density is
found to be 1.76 g/cm3. The ORTEP diagram for 17 is
shown in Figure 1.
When compound 10 was subjected to nitrolysis using
either nitric acid and trifluoroacetic anhydride in meth-
ylene chloride or nitric acid and P2O5, the N-acetyl groups
were replaced by nitro groups to give the dinitramino
acetate 18. Hydrolysis of 18 with 5% HCl readily fur-
nished the dinitramino alcohol 19. Attempts to oxidize
the dinitramino alcohol 19 to the desired dinitramino
ketone 20 were unsuccessful (J ones, Dess-Martin),
perhaps due to the instability of the product during the
workup, but the dinitramino ketone 20 could be prepared
from the 1,3-dipropionyl ketone 12. Thus, treatment of
the 1,3-dipropionyl ketone 12 with nitric acid and tri-
fluoroacetic anhydride in methylene chloride furnished
the desired nitrolysis product, 1,3-dinitro-1,3-diazacyclo-
hexan-5-one 20. These transformations are summarized
in Scheme 4.
The third general approach (method C, Scheme 1) to
the 5-substituted 1,3-diazacyclohexane system is outlined
in Scheme 6.
The treatment of the readily available methylenebi-
sacetamide 26 with 2 equiv of sodium hydride in THF
followed by alkylation with 3-chloro-2-chloromethyl-2-
propene 27 resulted in the formation of 5-exomethylene-
1,3-diacetyl-1,3-diazacyclohexane 28. Hydrolysis of the
amide functions was achieved by treatment with aqueous
alkali to give 5-exomethylene-1,3-diazacyclohexane 29.
The same product was also obtained by the treatment of
3-amino-2-aminomethyl-2-propene 30 with formaldehyde.
Alkylation and acylation of the amine functions of 29
provides a general method for the synthesis of 1,3-
disubstituted 5-exomethylene-1,3-diazacyclohexanes. This
(16) Nielsen, A. T.; Chafin, A. P.; Christian, S. L.; Moore, D. W.;
Nadler, M. P.; Nissan, R. A.; Vanderah, D. J .; Gilardi, R. D.; George,
C. F.; Flippen-Anderson, J . L. Tetrahedron 1998, 54, 11793.
(17) 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. J . Org. Chem.
2000, 65, 1207.

Synthesis of 5-Substituted 1,3-Diazacyclohexane Derivatives
J . Org. Chem., Vol. 65, No. 4, 2000 1203
Sch em e 6
taken up in methylene chloride and dried over magnesium
sulfate. Removal of the solvent gave 6.43 g (83%) of a solid.
Recrystallization from ethyl acetate afforded 4 as a colorless
crystalline solid, mp 102.5-104.5 °C. The molecular structure
of 4 was confirmed by an X-ray structure determination:18 1H
NMR (CDCl3) δ 2.13 (s, 3H), 2.27 (s, 3H), 3.42 (dd, J ) 13.73
Hz, 2.29 Hz, 1H), 3.57 (dd, J ) 13.73 Hz, 2.75 Hz, 1H), 3.70
(dd, J ) 13.73 Hz, 4.58 Hz, 1H), 3.88 (m, 1 H), 3.99 (s, br,
1H), 4.09 (dd, J ) 13.73 Hz, 4.58 Hz, 1H), 4.54 (d, J ) 12.82
Hz, 1H), 5.59 (d, J ) 12.81 Hz, 1H); 13C NMR (CDCl3) δ 21.0,
21.2, 47.7, 51.9, 56.4, 63.9, 170.5, 171.0. HRMS (FAB) calcd
for C8H14N2O3 (MH+) 187.1084, found m/z 187.1083.
Meth od 2. F r om h yd r olysis of 10. A solution of 10 (63
mg, 0.28 mmol) dissolved in ethanol (2.5 mL) containing 10%
potassium carbonate (2.5 mL) was heated under reflux for 1.5
h followed by removal of the solvent in a vacuum. The residue
was taken up in methylene chloride and dried over magnesium
sulfate. Removal of the solvent gave 29 mg (56%) of a colorless
solid that was identical with that isolated from the acetylation
of 3 described above.
is exemplified by acylations with acetic anhydride to give
28 as well as with trifluoroacetic anhydride to provide
31. To synthesize the 1,3-diazacyclohexan-5-one system,
ozonation of the exomethylene unit in 28 was investi-
gated. Ozonolysis of 28 under various conditions followed
by workup with dimethyl sulfide failed to afford isolable
product. But, ozonation in methanol followed by catalytic
hydrogenation to decompose the ozonide provided 1,3-
diacetyl-1,3-diazacyclohexan-5-one 11 in modest yield
(50%). It was necessary to monitor the hydrogenation
because prolonged exposure to hydrogen resulted in the
reduction of the carbonyl function to afford alcohol 4
(Scheme 2). Conversion of 11 to the corresponding oxime
32 was accomplished by treatment with hydroxylamine
hydrochloride/sodium acetate.
In conclusion, three general approaches to the synthe-
sis of 5-keto-1,3-diazacyclohexane and related 1,3-diaza-
cyclohexanes, all versatile intermediates for further
functionalization of the 1,3-diazacyclohexane ring system
at the 5-position, have been developed. A number of
5-substituted 1,3-diazacyclohexanes including new en-
ergetic materials have been prepared.
1,3-Dip r op ion yl-5-h yd r oxy-1,3-d ia za cycloh exa n e (5).
To a stirred solution of 3 (3.25 g, 31.9 mmol) and potassium
carbonate (13.89 g, 100.5 mmol) in water (50 mL) maintained
at 0 °C was added propionic anhydride dropwise. Upon
completion of the addition, the reaction mixture was stirred
at room temperature overnight and then concentrated under
reduced pressure. The residue was taken up in methylene
chloride and dried over magnesium sulfate. Removal of the
solvent gave a colorless solid (6.10 g, 89%), which after
recrystallization from ethyl acetate afforded 5 as a colorless
crystalline solid, mp 141-143 °C. The molecular structure of
5 was confirmed by an X-ray structure determination:18 1H
NMR (CDCl3) δ 1.12 (q, 6H), 2.67-2.71 (m, 4H), 3.65 (m, 3H),
3.88(m, 2H), 4.26 (s, 1H) 4.80 (d, J ) 13.73 Hz, 1H), 5.37 (d,
J ) 13.73 Hz, 1H); 13C NMR (CDCl3) δ 9.0, 9.2, 26.0, 26.3,
48.0, 51.0, 55.6, 63.8, 173.4, 174.1; HRMS (FAB) calcd for
Exp er im en ta l Section
Melting points are uncorrected. 1,3-Diaminopropan-2-ol was
used as obtained from Aldrich Chemical Co. The 1H and 13C
NMR spectra were recorded at 300 and 75 MHz, respectively,
in either deuteriochloroform or deuterioacetone solution with
tetramethylsilane as the internal reference. In the case of
spectra measured in D2O solution, an external capillary of
tetramethylsilane was used as the reference.
WAR NING: Although no problems were encountered in
this work, compound 17 is potentially an energetic material
and appropriate precautions should be taken in the handling
of this material.
C
10H19N2O3 (MH+) 215.1396, found m/z 215.1394.
1,3-Di(ter t-bu toxyca r bon yl)-5-h yd r oxy-1,3-d ia za cyclo-
h exa n e (6). To a stirred solution of 3 (0.61 g, 5.98 mmol) and
potassium carbonate (2.50 g, 18.1 mmol) in water (30 mL)
maintained at 0 °C was added dropwise a solution of di-tert-
butyl dicarbonate in tetrahydrofuran (20 mL). On completion
of the addition, the reaction mixture was stirred at room
temperature overnight. The separated aqueous layer was
extracted with methylene chloride (2 × 30 mL) and the
combined organic layers were washed with water and dried
over magnesium sulfate. Removal of the solvent gave a
colorless solid (1.54 g, 85%), which after recrystallization from
5-Hyd r oxy-1,3-d ia za cycloh exa n e (3). A solution of 1,3-
diaminopropan-2-ol (2) (0.64 g, 7.10 mmol) and paraformal-
dehyde (0.2 g, 6.67 mmol) in methanol (10 mL) was heated
under reflux for 48 h followed by removal of the solvent in a
vacuum. The resulting solid residue was recrystallized from
acetonitrile to afford 0.60 g (88%) of pure 3 as a colorless
crystalline solid: mp 99-102 °C; 1H NMR (D2O) δ 1.93 (dd, J
) 13.27 Hz, 7.78 Hz, 2H), 2.40 (dd, J ) 13.27 Hz, 3.66 Hz,
2H), 2.78 (d, J ) 12.82 Hz, 1H), 2.90 (m, 1 H), 2.98 (d, J )
12.82 Hz, 1H); 13C NMR (D2O) δ 49.5, 59.2, 63.9. HRMS (FAB)
calcd for C4H11N2O (MH+) 103.0871, found m/z 103.0871.
1,3-Dia cet yl-5-h yd r oxy-1,3-d ia za cycloh exa n e
(4).
(18) X-ray crystallographic analysis and ORTEP diagrams are
included in the Supporting Information for this paper. Crystallographic
data (including structure factors) for the structures reported in this
paper have been deposited with the Cambridge Crystallographic
Centre. Copies of available material can be obtained, free of charge,
on application to the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44-(0)1223-
336033; e-mail: deposit@ccdc.cam.ac.uk).
Meth od 1. F r om th e Acetyla tion of 3. Acetic anhydride was
added dropwise to a stirred solution of 3 (4.26 g, 41.8 mmol)
and potassium carbonate (11.7 g, 85.3 mmol) in water (50 mL)
maintained at 0 °C. Upon completion of the addition, the
reaction mixture was stirred at room temperature for 4 h and
then concentrated under reduced pressure. The residue was

1204 J . Org. Chem., Vol. 65, No. 4, 2000
Axenrod et al.
ethyl acetate and hexanes afforded 6 as a colorless crystalline
solid: mp 127-129 °C; 1H NMR (CDCl3) δ 1.47 (s, 18H), 3.24
(m, br, 3H), 3.77 (m, br, 3H), 4.90 (m, br, 2H); 13C NMR (CDCl3)
δ 28.3, 49.3, 57.0, 63.3, 80.6, 154.3. Anal. Calcd for C14H26N2O5:
C, 55.61; H, 8.67; N, 9.26. Found: C, 55.68; H, 8.84; N, 9.13.
1,3-Di(p-tolu en esu lfon yl)-5-h ydr oxy-1,3-diazacycloh ex-
a n e (7). To a stirred solution of 3 (1.00 g, 9.80 mmol) in water
(10 mL) containing potassium carbonate (2.70 g, 20 mmol) was
added a solution of tosyl chloride (3.74 g, 20 mmol) in THF
(10 mL). The reaction mixture was stirred at room temperature
for 3 h and then concentrated under reduced pressure. The
residue was taken up in chloroform (100 mL), washed with
saturated sodium bicarbonate solution, and dried over mag-
nesium sulfate. Removal of the solvent gave a colorless solid,
which after recrystallization from ethanol afforded 2.95 g (73%)
taken up in methylene chloride (50 mL), and the organic layer
was washed successively with water, saturated sodium bicar-
bonate, and water and then dried over magnesium sulfate.
Removal of the solvent afforded 80 mg (2%) of a clear oil that
solidified on standing. This material, much of which was likely
lost due to its water solubility, was identical with that isolated
from method described above.
1,3-Dia cetyl-1,3-d ia za cycloh exa n -5-on e (11). Meth od 1.
From the alcohol 4 (0.51 g, 2.74 mmol) using the same
procedure as that employed to prepare 12 there was obtained
0.44 g (87%) of 11 as a colorless oil. Recrystallization from
acetone-hexanes afforded a colorless solid: HRMS (FAB)
calcd for C8H13N2O3 (MH+) 185.0926, found m/z 185.0923.
Meth od 2. F r om Ozon olysis of 28. Compound 27 (2.5 g,
13.7 mmol) was dissolved in methanol (250 mL) and cooled to
-78 °C. A mixture of ozone in oxygen was bubbled into the
solution for 1 h, and then oxygen was run into it until the blue
color completely disappeared. The solution was then flushed
with nitrogen gas while slowly warming to room temperature.
The solution was then treated with Pd(10%/C) and hydrogen
gas overnight, to destroy the ozonide,. The suspension was
then filtered, and the filtrate was concentrated to get a
colorless oil. The oil was dissolved in THF (10 mL) and then
slowly poured into ethyl ether (50 mL). The 1,3-diacetyl-1,3-
diazacyclohexan-5-one was collected (1.9 g, 75% yield) as a
precipitate. The precipitate is hygroscopic and was kept in a
desiccator: 1H NMR (CDCl3), δ 5.24 (s, 2H), 4.40 (s, 2H), 4.20
(s, 2H), 2.32 (s, 3H), 2.12 (s, 3H); 13C NMR (CDCl3), δ 199.0,
169.5, 169.2, 55.5, 54.9, 52.3, 21.2; HRMS (EI) calcd for
C8H12N2O3 (M+) 184.0848, found m/z 184.0846.
1
of 7 as a crystalline solid: mp 182-183 °C; H NMR (CDCl3)
δ 1.94 (d, J ) 8.2 Hz, 1H), 2.44 (s, 6H), 3.18 (dd, J ) 13.28
Hz, 5.49 Hz, 2H), 3.25 (dd, J ) 13.28 Hz, 3.66 Hz, 2H), 3.53
(m, 1H), 4.48 (d, J ) 12.36 Hz, 1H), 4.78 (d, J ) 12.36 Hz,
1H), 7.34 (d, J ) 8.24 Hz, 4H), 7.73 (d, J ) 8.24 Hz, 4H); 13C
NMR (CDCl3) δ 21.5, 50.8, 60.6, 62.0, 127.6, 129.9, 135.1, 144.3;
HRMS (FAB) calcd for C18H22N2O5S2 (MH+) 411.1048, found
m/z 411.1058.
1,3-Dim esyl-5-h yd r oxy-1,3-d ia za cycloh exa n e (8). To a
stirred solution of 3 (0.34 g, 3.33 mmol) in water (10 mL)
containing potassium carbonate (1.33 g, 9.62 mmol) was added
methanesulfonyl chloride (0.88 g, 7.68 mmol) dropwise. The
reaction mixture was stirred at room temperature overnight
and then concentrated under reduced pressure. The residue
was taken up in acetone (100 mL), washed with saturated
sodium bicarbonate solution, and dried over magnesium
sulfate. Removal of the solvent gave a colorless semisolid,
which after recrystallization from acetone/hexanes afforded 8
as a colorless crystalline solid (0.50 g, 58%) of 8, mp 156-157
°C. The molecular structure of 8 was confirmed by an X-ray
structure determination:18 1H NMR (acetone-d6) δ 3.04 (s, 6H),
3.46 (dd, J ) 13.73 Hz, 5.50 Hz, 2H), 3.58 (dd, J ) 13.73 Hz,
3.21 Hz, 2H), 3.95 (m, 1H),4.71 (d, J ) 13.27 Hz, 1H), 4.90 (d,
J ) 13.28 Hz, 1H); 13C NMR (acetone-d6) δ 39.2, 51.4, 60.3,
62.9; HRMS (FAB) calcd for C6H15N2O5S2 (MH+) 259.0422,
found m/z 259.0420.
1,3-Dia ceta m in op r op a n -2-ol (9). A solution of 1,3-diami-
nopropan-2-ol 2 (10.50 g, 116.5 mmol) in ethyl acetate (50 mL)
was heated under reflux for 48 h. Removal of the solvent in a
vacuum afforded 17.33 g (85%) of an oil that solidified on
standing. Recrystallization from ethyl acetate-hexanes gave
a colorless solid: mp 92-94 °C; 1H NMR (CDCl3) δ 2.02 (s,
6H), 3.31 (m, 4H), 3.77 (m, 1H),), 4.75 (s, br, 1H), 6.86 (t, br,
2H); 13C NMR (CDCl3) δ 23.1, 43.0, 70.3, 171.9; HRMS (FAB)
calcd for C7H15N2O3 (MH+) 175.1083, found m/z 175.1082.
Alternatively, the dangerous ozonide can be destroyed by
addition of dimethyl sulfide. However, the byproduct is DMSO
that remains with the product, and cannot be separated easily.
1,3-Dip r op ion yl-1,3-d ia za cycloh exa n -5-on e (12). To a
stirred solution of alcohol 5 (0.55 g, 2.57 mmol) in methylene
chloride (20 mL) was added the preformed 1,1,1-triacetoxy-
1,1-dihydro-1,2-benziodoxol-3(1H)-one Dess-Martin periodi-
nane reagent15 (3.47 g, 8.18 mmol), and the resulting mixture
was stirred at room temperature for 5 h. Ethyl ether (100 mL)
was added, and the resulting solid was removed by filtration.
The filtrate was passed through a short silica gel column, and
the product was eluted with ethyl acetate. Removal of the
solvent gave a yellow oil (0.45 g, 83%). Recrystallization from
acetone-hexanes afforded a colorless solid: mp 95-97 °C; 1H
NMR (CDCl3) δ 1.14 (t, 6H), 2.32 (q, 2H), 2.58 (q, 2H), 4.21 (s,
2H) 4.38 (s, 2H), 5.27 (s, 2H); 13C NMR (CDCl3) δ 8.7, 8.9, 26.4,
52.5, 54.4, 54.7, 172.4, 172.8, 199.8; HRMS (FAB) calcd for
C
10H17N2O3 (MH+) 213.1239, found m/z 213.1239.
1,3-D i(t er t -b u t o x y c a r b o n y l)-1,3-d ia za c y c lo h e x a n -
5-on e (13). A solution of the di-BOC derivative 6 (0.87 g, 2.88
mmol) and the preformed 1,1,1-triacetoxy-1,1-dihydro-1,2-
benziodoxol-3(1H)-one Dess-Martin periodinane reagent (2.04
g, 4.81 mmol) in methylene chloride (30 mL) was stirred at
room temperature overnight. The mixture was diluted with
ethyl ether (100 mL), poured into a saturated aqueous sodium
bicarbonate solution containing excess sodium thiosulfate, and
stirred for 15 min. The separated organic layer was treated
successively with 5% sodium bicarbonate and water and finally
dried over magnesium sulfate. Removal of the solvent gave a
viscous colorless oil (0.86 g, 100%) that solidified on standing:
1,3-Dia cet yl-5-a cet oxy-1,3-d ia za cycloh exa n e
(10).
Meth od 1. F r om th e Acetyla tion of 3. Acetic anhydride (5.0
mL, 53 mmol) was added dropwise to a stirred solution of
5-hydroxy-1,3-diazacyclohexane (3) (1.06 g, 10.4 mmol) in 1,2-
dichloroethane (30 mL) while the temperature was maintained
at 0 °C. Upon completion of the addition, the reaction mixture
was heated under reflux for 48 h followed by removal of the
excess acetic anhydride in a vacuum. The residue, a clear oil,
slowly solidified on standing and was recrystallized from
methylene chloride-ether to give 1.74 g (73%) of pure 10 as
colorless cubic crystalline material, mp 87-89 °C. The molec-
ular structure of 10 was confirmed by an X-ray structure
determination:18 1H NMR (CDCl3) δ 2.05 (s, 3H), 2.09 (s, 3H),
2.28 (s, 3H), 3.35 (dd, J ) 14.19 Hz, 2.29 Hz, 1H), 3.68 (dd, J
) 14.19 Hz, 2.29 Hz, 1H), 3.84 (m, 1 H), 4.40 (m, 1 H), 4.46 (d,
J ) 13.27 Hz, 1H), 4.84 (m, 1 H), 5.77 (m, 1H); 13C NMR
(CDCl3) δ 20.8, 21.2, 44.3, 49.3, 56.2, 65.7, 169.7, 169.9, 170.0.
HRMS (FAB) calcd for C10H16N2O4 (MH+) 229.1188, found m/z
229.1186.
1
mp 65-66 °C; H NMR (CDCl3) δ1.49 (s, 18Η), 4.11 (s, 4Η),
5.03 (s, 2H); 13C NMR (CDCl3) δ 28.3, 53.0, 55.9, 81.5, 153.5,
201.7.
1,3-Di(p -t olu en esu lfon yl)-1,3-d ia za cycloh exa n -5-on e
(14). To a stirred solution of 7 (2.02 g, 4.93 mmol) in acetone
(50 mL) maintained at 0 °C was added dropwise a mixture of
CrO3 (1.20 g, 12.0 mmol) in water (3 mL) containing concen-
trated sulfuric acid (1.5 mL). After the addition was complete,
the reaction mixture was stirred vigorously at room temper-
ature for 2.5 h. Water was added to dissolve precipitated salts
and the solution was extracted with methylene chloride (3 ×
30 mL). The combined organic layers were washed with
saturated sodium bicarbonate solution and water and dried
over magnesium sulfate. Removal of the solvent in a vacuum
afforded 1.52 g (76%) of a colorless solid that was recrystallized
Meth od 2. F r om th e Ma n n ich Con d en sa tion of 9 w ith
F or m a ld eh yd e. A solution of 1,3-diacetaminopropan-2-ol 9
(2.84 g, 16.3 mmol) and 37% aqueous formaldehyde (1.33 g,
16.4 mmol) in acetic acid (20 mL) containing three drops of
concentrated sulfuric acid was heated at 100 °C for 20 h. After
removal of the solvent at reduced pressure, the residue was

Synthesis of 5-Substituted 1,3-Diazacyclohexane Derivatives
J . Org. Chem., Vol. 65, No. 4, 2000 1205
from acetone-hexanes to give pure 14: mp 148 °C dec; 1H
NMR (CDCl3) δ 2.44 (s, 6H), 3.65 (s, 4H), 4.89 (s, 2H), 7.34 (d,
J ) 8.24 Hz, 4H), 7.68 (d, J ) 8.24 Hz, 4H); 13C NMR (CDCl3)
δ 21.6, 53.7, 59.3, 127.7, 130.1, 134.0, 144.9, 196.9; HRMS
(FAB) calcd for C18H20N2O5S2 (MH+) 409.0898, found m/z
409.0892.
under reflux for 4 h. Removal of the solvent under reduced
pressure gave a colorless solid (0.29 g, 98%) that was recrys-
tallized from ethyl acetate and hexanes to furnish 19 as a
colorless crystalline solid, mp 102.5-104.5 °C. The molecular
structure of 19 was confirmed by an X-ray structure determi-
nation.18 1H NMR (acetone-d6) δ 4.06 (dd, J ) 14.20 Hz, 2.29
Hz, 2H), 4.24-4.35 (m, 3H), 4.79 (m, 1H), 5.68 (d, J ) 14.64
Hz, 1H), 6.31 (d, J ) 14.64 Hz, 1H); 13C NMR (acetone-d6) δ
53.3, 61.2, 63.5. Anal. Calcd for C4H8N4O5: C, 25.01; H, 4.20;
N, 29.16. Found: C, 25.21; H, 4.30; N, 28.79.
1,3-Din itr o-1,3-d ia za cycloh exa n -5-on e (20). To a stirred
solution of trifluoroacetic anhydride (16 mL, 113 mmol) in
methylene chloride (50 mL) was added dropwise 100% nitric
acid (4.5 mL, 109 mmol) at -5 to 0 °C, and the mixture was
stirred at this temperature for 20 min. To this mixture was
added ketone 12 (1.57 g, 7.41 mmol) in small portions, and
stirring was continued at 0 °C for 4 h. The reaction mixture
1,3-Dim esyl-1,3-d ia za cycloh exa n -5-on e (15). To a stirred
solution of 8 (0.26 g, 1.01 mmol) in acetone (10 mL) maintained
at 0 °C was added dropwise a mixture of CrO3 (0.35 g, 3.5
mmol) in water (0.75 mL) containing concentrated sulfuric acid
(0.75 g). After the addition was complete, the reaction mixture
was stirred vigorously at room temperature for 4 h. Solid
sodium bicarbonate was added, and the mixture was stirred
for 30 min. The solution was passed through a short silica gel
column, and the product was eluted with acetone. Removal of
the solvent in a vacuum afforded a colorless solid (1.52 g, 76%)
that was recrystallized from acetone-hexanes to give pure
1
15: mp 139 °C dec; H NMR (acetone-d6) δ 3.05 (s, 6H), 3.47
was poured into excess hexane and stored in
a freezer
(s, 4H), 4.82 (s, 2H); 13C NMR (acetone-d6) δ 39.5, 55.2, 60.1,
198.4 (ketone); δ38.5, 54.9, 59.1, 89.1 (ketone monohydrate);
HRMS (FAB) calcd for C6H13N2O5S2 (MH+) 257.0266, found
m/z 257.0264.
overnight. The resulting precipitate was collected by filtration
to afford the product 20 (0.91 g, 65%) as a colorless solid: mp
90 °C; 1H NMR (acetone-d6) δ4.81 (s, 4H), 6.22 (s, 2H); 13C
NMR (acetone-d6) δ57.3, 61.1, 195.7.
1,4-Dioxa -7,9-d itosyl-7,9-d ia za sp ir o[4.5]d eca n e (16). A
mixture of ketone 14 (1.15 g, 2.82 mmol), ethylene glycol (0.55
g, 8.87 mmol), and p-toluenesulfonic acid monohydrate (∼0.1
g) in benzene (50 mL) was heated under reflux for 20 h using
a Dean-Stark apparatus to remove water. After cooling, the
solution was washed with saturated sodium bicarbonate
solution and water and dried over magnesium sulfate. Removal
of the solvent afforded 1.15 g (90%) of a colorless solid that
was recrystallized from acetone-hexanes to give pure 16 as a
1,3-Di(ter t-b u t yl)-5-b r om o-5-n it r o-1,3-d ia za cycloh ex-
a n e (22). To a stirred solution of 2-bromo-2-nitro-1,3-pro-
panediol 21 (18.26 g, 91.3 mmol) in 100 mL of methanol at 0
°C was added tert-butylamine (13.40 g, 183 mmol) dropwise
over 30 min. The mixture was stirred at this temperature for
an additional 30 min followed by the addition of 37% aqueous
formaldehyde (07.46 g, 92.0 mmol) in one portion. The result-
ing mixture was stirred at ambient temperature for 48 h and
cooled to 0 °C, and water (150 mL) was added. The resulting
precipitate was collected by filtration and washed with water
to yield give after recrystallization from ethanol-water 23.92
g of 22 as a pale yellow solid (81%), mp 93-94 °C. The
molecular structure of 22 was confirmed by an X-ray structure
determination:18 HRMS (FAB) calcd for C12H25BrN3O3 (MH+)
1
crystalline solid: mp 210 °C dec; H NMR (CDCl3) δ 2.43 (s,
6H), 3.13 (s, 4H), 3.79 (s, 4H), 4.63 (s, 2H), 7.30 (d, J ) 8.24
Hz, 4H), 7.70 (d, J ) 8.24 Hz, 4H); 13C NMR (CDCl3) δ 21.6,
51.2, 60.0, 65.0, 101.5, 127.7, 129.6, 135.5, 143.8; HRMS (FAB)
calcd for C20H24N2O6S2 (MH+) 453.1154, found m/z 453.1166.
1,3-Din itr o-5-n itr ato-1,3-diazacycloh exan e (17). To 100%
nitric acid (5.0 mL) maintained between -5 and 0 °C was
added P2O5 (∼0.5 g) portionwise, and after the mixture was
stirred for 20 min at this temperature, 5-hydroxy-1,3-diaza-
cyclohexane 3 (0.270 g, 2.65 mmol) was added cautiously in
small portions. The resulting solution was stirred at 0 °C for
4 h and then poured on to ice (50 g) to give a precipitate that
was collected by vacuum filtration, dried, and recrystallized
from ethanol-water to afford a white solid (0.50 g, 80%), mp
124-125.5 °C. The molecular structure of 17 was confirmed
by an X-ray structure determination:18 1H NMR (acetone-d6)
δ4.24 (d, J ) 15.56 Hz, 2H), 5.04 (dd, J ) 15.56, ∼1.5 Hz, 2H),
5.30 (d, J ) 14.65 Hz, 1H), 5.64 (m, 1H), 6.97 (dd, J ) 14.65,
∼1.5 Hz, 1H); 13C NMR (acetone-d6) δ 49.0, 61.8, 76.0. Anal.
Calcd for C4H7N5O7: C, 20.26; H, 2.98; N, 29.53. Found: C,
20.23; H, 3.08; N, 29.46.
5-Acetoxy-1,3-d in itr o-1,3-d ia za cycloh exa n e (18). To a
stirred solution of trifluoroacetic anhydride (2.4 mL, 17 mmol)
in methylene chloride (20 mL) was added 100% nitric acid (1.13
g, 18 mmol) at -5 °C, and the mixture was stirred at this
temperature for 0.5 h. A solution of 10 (0.36 g, 1.6 mmol) in
methylene chloride (5 mL) was added dropwise. The reaction
mixture was allowed to warm to room temperature, and
stirring was continued overnight. The solution was poured into
cold water (50 mL), and the layers were separated. The
aqueous layer was extracted with methylene chloride (3 × 30
mL), and the combined organic layers were treated succes-
sively with water, 5% sodium bicarbonate, and water and
finally dried over magnesium sulfate. Removal of the solvent
under reduced pressure gave a colorless solid (0.37 g, 100%)
that was recrystallized from ethyl acetate and hexanes to
furnish 18 as a colorless crystalline solid: mp 118-119 °C;
1H NMR (CDCl3) δ 2.04 (s, 3H), 3.70 (m, 2H), 4.85 (m, 2H),
4.96 (d, J ) 14.65 Hz, 1H), 5.10 (m, 1H), 6.91 (m, 1H); 13C
NMR (CDCl3) δ 20.4, 49.6, 60.7, 65.0, 169.6. Anal. calcd for
C6H10N4O6: C, 30.78; H, 4.30; N, 23.93. Found: C, 30.75; H,
4.58; N, 23.88.
1
322.1130, found m/z 322.1132; H NMR (CDCl3) δ 1.10 (s, 18
H), 2.70 (d, J ) 11.9 Hz, 2H), 2.79 (d, J ) 9.16 Hz, 1H), 4.16
(m, 3H); 13C NMR (CDCl3) δ 26.4, 53.9, 56.1, 63.3, 86.8.
1,3,5-Tr in itr o-5-br om o-1,3-d ia za cycloh exa n e(23). Com-
pound 22 (5.55 g, 17.2 mmol) was cautiously added in small
portions during about 1 h to a stirred solution of 65 mL of
100% nitric acid at 0 °C. During the addition, the temperature
of the reaction mixture was always maintained lower than 5
°C. On completion of the addition, the reaction mixture was
allowed to warm to room temperature stirred overnight and
then poured onto 500 g of ice. The resulting precipitate was
collected by filtration, washed thoroughly with water, and
dried to give 2.78 g (54%) of 23, mp 158-159 °C. The molecular
structure of 23 was confirmed by an X-ray structure determi-
nation:18 1H NMR (acetone-d6) δ5.01 (d, J ) 15.0 Hz, 2H), 5.40
(d, 14.7 Hz, 2H) 6.10 (d, J ) 14.6 Hz, 1H) 6.29 (d, 14.6 Hz,
1H); 13C NMR (acetone-d6) δ55.2, 60.3, 83.1.
1-Acet yl-3-ter t-b u t yl-5-b r om o-5-n it r o-1,3-d ia za cyclo-
h exa n e (24a /b). To a solution of 22 (0.41 g, 1.27 mmol) in
acetic anhydride (5 mL) was added boron trifluoride diethyl
etherate (0.4 mL) with stirring. The reaction mixture was
stirred at room temperature for 24 h, after which time excess
acetic anhydride was removed in a vacuum and methylene
chloride (50 mL) was added to the residue. The solution was
washed successively with water (3 × 20 mL) and brine (20
mL) and finally dried over anhydrous magnesium sulfate.
Removal of the solvent gave 0.32 g (81%) of a solid, which was
recrystallized from ethanol-water, mp 152-154d °C. The
molecular structure of 24 was confirmed by an X-ray structure
determination:18 HRMS (FAB) calcd for C10H19 BrN3O3 (MH+)
308.0610, found m/z 308.0607. The NMR solution spectra of
24 shows it to be an equilibrium mixture of a major 24a and
minor 24b rotomer in the ratio 2.5:1.
Major rotomer 24a : 1H NMR (CDCl3) δ 1.12 (s, 9H), 2.25
(s, 3H), 2.92 (d, J ) 12.81 Hz, 1H), 3.18 (d, J ) 10.98 Hz, 1H),
3.65 (d, J ) 14.65 Hz, 1H), 4.23-4.28 (m, 1H), 4.88-4.94 (m,
1H), 5.53-5.56 (m, 1H); 13C NMR (CDCl3) δ 20.8, 26.4, 49.9,
54.2, 57.1, 57.4, 84.6, 168.5.
1,3-Din itr o-5-h ydr oxy-1,3-diazacycloh exan e (19). A mix-
ture of 18 (0.36 g, 1.54 mmol) and 5% HCl (20 mL) was heated

1206 J . Org. Chem., Vol. 65, No. 4, 2000
Axenrod et al.
Minor rotomer 24b: 1H NMR (CDCl3) δ 1.12 (s, 9H), 2.09
(s, 3H), 2.98 (d, J ) 12.82 Hz, 1H), 3.31 (d, J ) 13.65 Hz, 1H),
3.72 (d, J ) 10.99 Hz, 1H), 4.17-4.23 (m, 1H), 4.66-4.71 (m,
1H), 5.55-5.61 (m, 1H); 13C NMR (CDCl3) δ 21.0, 26.4, 49.9,
54.6, 62.2, 84.9, 167.9.
reaction mixture was cooled to room temperature, and excess
solid NaOH was added, followed by methylene chloride (25
mL). The layers were separated, and the organic layer was
dried over solid sodium hydroxide/sodium sulfate. A small
portion was concentrated under reduced pressure at room
temperature to obtain 5-exomethylene-1,3-diazacyclohexane,
while the major portion was reacted further to obtain 31: 1H
NMR (CDCl3) δ 3.47 (s, 1H), 3.58 (s, 2H), 4.67 (s, 2H). The
free amine 29 has limited stability and therefore further
characterization was not possible.
1,3-Di(a cet yl)-5-b r om o-5-n it r o-1,3-d ia za cycloh exa n e
(25). To a solution of 22 (0.30 g, 9.32 mmol) in acetic anhydride
(5 mL) was added boron trifluoride dietherate (0.5 mL), and
the mixture was stirred at 100 0 °C for 3.5 h. Excess acetic
anhydride was removed in a vacuum, and the residue was
taken up in methylene chloride, washed with water, and dried
over magnesium sulfate. Removal of the solvent gave a brown
oil, which was purified by passage through a short column of
silica gel using ethyl acetate to elute the material. The solvent
was concentrated in a vacuum, and a colorless oil (0.20 g, 73%)
obtained. Recrystallization from ethyl acetate/hexanes gave
pure 1,3-di(acetyl)-5-bromo-5-nitro-1,3-diazacyclohexane 25 as
a colorless solid, mp 116-118 °C. The molecular structure of
25 was confirmed by an X-ray structure determination:18
HRMS (FAB) calcd for C8H13 BrN3O4 (MH+) 294.0089, found
m/z 294.0081; 1H NMR (CDCl3) δ 2.23 (s, 2H), 2.25 (s, 3H),
3.99 (d, J ) 14.65 Hz, 1H), 4.13 (d, J ) 14.65 Hz, 1H),4.69 (d,
J ) 13.27 Hz, 1H), 4.77 (d, J ) 14.65 Hz, 1H), 5.15 (d, J )
14.19 Hz, 1H), 5.61 (d, J ) 13.28 Hz, 1H); 13C NMR (CDCl3) δ
20.3, 20.9, 50.2, 54.9, 55.1, 83.6, 168.4, 168.9.
1,3-Dia m in o-(2-m eth ylen e)p r op a n e (30). This compound
was prepared according to the literature procedure.21
1,3-Bis(t r iflu or oa cet yl)-5-exom et h ylen e-1,3-d ia za cy-
cloh exa n e (31). To the bulk of the above solution of 29 was
added trifluoroacetic anhydride (2 mL) and the mixture stirred
at room temperature overnight. The mixture was then con-
centrated under reduced pressure, and the residue was chro-
matographed on silica gel eluting with 40% acetone/hexane
to give 31 as a pale yellow oil. The NMR spectra indicated it
to be a mixture of conformers with the major conformer having
the trifluoroacetamide groups anti to each other: 1H NMR
(CDCl3) δ 4.32 (br s, 4H); 5.21-5.35 (m, 4H); 13C NMR (CDCl3)
δ 49.32, 50.76, 55.38 CF3 quartet 110.61, 114.41, 118.22, 122.05
J ) 286 Hz; CF3 quartet 110.77, 114.58, 118.39, 122.20 J )
286 Hz, 118.0, 133.4, 155.8 (q), 156.3 (q); HRMS (EI) calcd for
C9H8N2O2F6 (M+) 290.0490, found m/z 290.0503.
1,3-Dia cetyl-1,3-d ia za cycloh exa n -5-on e oxim e (32). To
a solution of 1,3-diacetyl-1,3-diazacyclohexan-5-one (1.0 g, 5.4
mmol) in absolute ethanol (75 mL) was added hydroxylamine
hydrochloride (0.8 g, 11.8 mmol) and sodium acetate trihydrate
(4.8 g, 35.0 mmol). The mixture was stirred at room temper-
ature overnight and filtered, and the filtrate was concentrated
in vacuo. The residue was subjected to continuous Soxhlet
extraction using refluxing chloroform. The chloroform solution
was concentrated under reduced pressure to obtain a yellow
oil (0.8 g), which was chromatographed on silica gel eluting
with acetone/hexanes (gradient elution with 50% to 100%
acetone). The relevant fractions were combined and dissolved
in chloroform from which solid oxime 34 (0.5 g, 46%) deposited
on standing: mp 85-95 °C; HRMS (EI) calcd for C8H13N3O3
(M+) 199.0957, found m/z 199.0958; 1H NMR (mixture of
geometric isomers, CDCl3) δ 5.15 (s, 1H), 5.10 (s, 1H), 4.65 (s,
1H), 4.53 (s, 1H), 4.34 (s, 1H), 4.20 (s, 1H), 2.25 (s, 6H), 2.17
(s, 3H), 2.12 (s, 3H).
Meth ylen ebisa ceta m id e (26). A literature procedure20
was slightly modified. A mixture of acetamide (71.2 g, 1.2 mol),
paraformaldehyde (18.0 g, 0.6 mol), and acetic acid (14.4 g)
was refluxed overnight. When cooled to room temperature, a
solid was formed that was collected by filtration and washed
with acetone to give the product as a white solid (36.1 g): 1H
NMR (CDCl3) δ 6.9 (br, 2H), 4.58 (t, 2H), 2.0 (s, 6H). The
acetone wash after 3 days gave another 3.6 g of the product
(total yield 51%). The product was identical to the one reported
in the literature.20
5-Exom eth ylen e-1,3-diacetyl-1,3-diazacycloh exan e (28).
To a suspension of sodium hydride (4.4 g, 183.2 mmol) in
freshly dried THF (700 mL) was added methylenebisacetamide
(10.0 g, 77.0 mmol). The suspension was stirred at room
temperature under nitrogen for 30 min. A solution of 3-chloro-
2-chloromethyl-1-propene, 27 (10.0 g, 80 mmol) in THF (50
mL) was slowly added to the suspension in 2 h. The resulting
mixture was heated under reflux for 72 h. The reaction mixture
was cooled to room temperature and the formed solid was
removed by filtration and discarded. The filtrate was concen-
trated, and the residue dissolved in methylene chloride (400
mL) and extracted with water (300 mL). The organic layer was
dried over sodium sulfate and concentrated under reduced
pressure to give 28 (13.8 g, 98% yield) as a yellow oil: 1H NMR
(CDCl3) δ 5.12 (s,1H), 5.10 (s, 2H), 5.08 (s, 1H), 4.24 (s, 2H),
4.13 (s, 2H), 2.3 (s, 3H), 2.10 (s, 3H); 13C NMR (CDCl3) δ
169.30, 169.36, 136.36, 114.31, 54.72, 51.63, 47.45, 21.44,
21.06; LRMS (CI) 183 (MH+).
Ack n ow led gm en t . We thank the Office of Naval
Research, Mechanics Division, for financial support of
this work.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H and
1
13C NMR spectra of 3-10, 12-20, and 22-25 and H spectra
of 11, 28, 29, 31, and 32. Tables of X-ray data and figures for
4, 5, 7, 10, 17, 19, and 22-25. This material is available free
of charge via the Internet at http://pubs.acs.org.
5-Exom eth ylen e-1,3-d ia za cyloh exa n e (29). A mixture of
28 (0.97 g, 5.3 mmol), NaOH (1 g, 25 mmol), and water (5 mL)
was heated overnight in an oil bath maintained at 110 °C. The
J O991524O
(19) Sheldrick, G. M. SHELXTL Version 5 Software Reference
Manual (1994 Release); Siemens Energy and Automation, Inc.: Madi-
son, WI.
(21) Schulze, V. K.; Winkler, G.; Dietrich, W.; Muhlstadt, M. J .
Prakt. Chem. 1977, 463.
(20) Noyes, W. A.; Forman, D. B., J . Am. Chem. Soc. 1933, 55, 3493.