Organic Process Research & Development
Communication
General. 1-tert-Butyl-3-hydroxymethyl-3-nitroazetidine (1)
was obtained from Parish Chemical Company (Vineyard, UT)
in ≥98% purity.
AUTHOR INFORMATION
■
1
-tert-Butyl-3,3-dinitroazetidine (2). A solution of
distilled water (1470 mL) and sodium hydroxide (71.2 g,
780 mmol) at 20−25 °C was treated with 1 (97.6 g, 519
Notes
1
The authors declare no competing financial interest.
mmol) over a period of 1 min. The mixture was stirred at
ambient conditions for 1−2 h. The nitronate solution was
chilled to 10 °C, and a solution of potassium ferricyanide (17.2
g, 52 mmol) and sodium nitrite (143.2 g, 2075 mmol) in water
ACKNOWLEDGMENTS
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The bioactivity and therapeutic application of the compounds
Dr. Robert B. Wardle (ATK) and Dr. Mark D. Bednarski
(RadioRx) for their pioneering ideas concerning the use of
cyclic nitro species as pharmaceuticals. Dr. Michael Kramer, Dr.
Ping Li, Dr. Michael Killpack, Paul Illum, Kieth Nielsen, Roger
Sorensen, and Bart Weber, all of ATK, are acknowledged for
their technical and analytical contributions to this work. Dr.
Kirstin Warner and Clint Nelson are also acknowledged for
their technical participation in this project. Thanks to Dr. Jan
Scicinski of RadioRx for his input in preparing this article.
(
400 mL) was added. With the solution at 10−15 °C, sodium
persulfate (173.2 g, 727 mmol) was introduced over a period of
min. The reaction temperature initially dropped and then
2
increased by 10−15 °C. Once the exotherm began to subside,
the reaction was warmed to 20−25 °C over 1 h and held for 16
h. The resulting orange/brown emulsion was extracted with
CH Cl (3 × 450 mL). The combined yellow/orange organic
2
2
extracts were dried (Na SO ) and then concentrated to ∼450
2
4
mL. For quantification and identification purposes, a small
sample of the solution was brought to dryness in vacuo,
yielding yellow/brown oil. (CAUTION: solvent-free com-
pound may undergo rapid energetic decomposition if
6
29
sufficiently heated! ) Yields were consistently >99%, 6spectral
REFERENCES
■
and analytical data matched those previously reported.
(
1) Bednarski, M. D.; Oehler, L. M.; Knox, S.; Cannizzo, L.; Warner,
K.; Wardle, R.; Velarde, S.; Ning, S. U.S. Patent 7,507,842 B2, 2009;
Chem. Abstr. 2009, 150, 345497.
1-Bromoacetyl-3,3-dinitroazetidine (3). Under a blanket
of N , the CH Cl solution of 2 (described earlier) was treated
2
2
2
with BF ·OEt (6.37 mL, 52 mmol) followed by bromoacetyl
3
2
(2) Ning, S.; Bednarski, M.; Oronsky, B.; Scicinski, J.; Saul, G.; Knox,
S. J. Dintroazetidines are a Novel Class of Anticancer Agents and
Hypoxia-activated Radiation Sensitizers Developed from Highly
Energetic Materials. Cancer Res., in press.
(3) Subsequent to the preparation of this article, RadioRx (see ref 2)
employed a contracting organization to produce kilo quantities of 3 for
clinical trials using the methods described here. Batch size = 6 kg of 1;
average yield of 3 = 85%.
4) Marchand, A. P.; Rajagopal, D.; Bott, S. G. J. Org. Chem. 1995, 60,
943−4946.
5) Axenrod, T.; Watnick, C.; Yazdekhasti, H.; Dave, P. R. J. Org.
Chem. 1995, 60, 1959−1964.
(6) Archibald, T. G.; Gilardi, R.; Baum, K.; George, C. J. Org. Chem.
bromide (33.77 mL, 388 mmol). The N purge was stopped,
2
and the vessel sealed and fitted with a small pressure-release
vent. The mixture was heated to a mild reflux and held for 6 h.
Heating was stopped, and CH Cl (1000 mL) and distilled
2
2
water (800 mL) were added in that order. The two-phase
system was stirred vigorously for 16 h. The aqueous phase was
removed and the organic layer washed with additional distilled
water (4 × 500 mL). The organic solution was dried (Na SO )
(
4
(
2
4
and concentrated to approximately half its initial volume
followed by addition of EtOH (250 mL). The remaining
CH Cl was removed at 25−30 °C, causing a precipitate to
2
2
form. The slurry was chilled in an ice bath (30 min), and the
1
990, 55, 2920−2924.
(7) Hiskey, M. A.; Coburn, M. D.; Mitchell, M. A.; Benicewicz, B. C.
J. Heterocycl. Chem. 1992, 29, 1855−1856.
(8) Katritzky, A. R.; Cundy, D. J.; Chen, J. J. Heterocycl. Chem. 1994,
solid was collected by filtration, rinsed with cold EtOH (5 ×
2
6
1
50 mL), and air-dried to afford pure 3 (56.04 g, 81% yield )
−1
as colorless crystals: mp 127−129 °C. IR (neat, cm ): 3013,
677, 1586, 1567, 1446, 1368, 1338. H NMR (400 MHz,
1
3
(
1, 271−275.
9) Sikder, N.; Sikder, A. K.; Bulakh, N. R.; Gandhe, B. R. J. Hazard.
Mater. 2004, 113, 35−43.
10) Hiskey, M. A.; Johnson, M. C.; Chavez, D. E. J. Energ. Mater.
999, 17, 233−254.
11) Hiskey, M. A.; Stinecipher, M. M.; Brown, J. E. J. Energ. Mater.
993, 11, 157−166.
12) Gaertner, V. R. Tetrahedron Lett. 1966, 39, 4691−4694.
(13) Gaertner, V. R. J. Org. Chem. 1967, 32, 2972−2976.
(14) Anderson, A. G. Jr.; Lok, R. J. Org. Chem. 1972, 37, 3953−3955.
(15) Hiskey, M. A. Coburn, M. D. U.S. Patent 5,336,784, 1994;
Chem. Abstr. 1994, 121, 300750.
16) Coburn, M. D.; Hiskey, M. A.; Archibald, T. G. Waste Manage.
997, 17, 143−146.
17) Kornblum, N.; Singh, H. K.; Kelly, W. J. J. Org. Chem. 1983, 48,
32−337.
18) Garver, L. C.; Grakauskas, V.; Baum, K. J. Org. Chem. 1985, 50,
1
acetone-d , δ): 4.0 (s, 2H, −CH Br), 4.9 (br s, 2H, ring
6
2
1
3
−
CH −), 5.3 (br s, 2H, ring −CH −); C NMR (acetone-d ,
δ): 25.5, 58.5, 60.5, 107.6, 167.4. Anal. Calcd for C H BrN O :
2
2
6
(
1
(
1
5
6
3
5
C, 22.41; H, 2.26; N, 15.68. Found: C, 22.52; H, 1.89; N, 15.60.
Flash Precipitation of 3. A quantity of 3 was dissolved in
EtOAc (mass of 3 in grams × 6 = mL of EtOAc). This solution
was rapidly added to a beaker of stirring (500 rpm) heptane
(
(
mass of 3 in grams × 18 = mL of heptane), immediately
resulting in a white precipitate. The suspension was stirred for 5
min, and the solid was collected by vacuum filtration and rinsed
with heptane. To ensure thorough solvent removal, air was
pulled through the solid on the filter for 16 h. Analytical data
matched that described previously for 3.
(
1
(
3
(
ASSOCIATED CONTENT
1699−1702.
■
(
(
19) See Supporting Information for specific calorimetry conditions.
*
S
Supporting Information
H and 13C NMR spectra of 2 and 3; FT-IR spectrum of 3;
20) Cichra, D. A.; Adolph, H. G. J. Org. Chem. 1982, 47, 2474−
1
2
476.
(21) Bhat, R. G.; Ghosh, Y.; Chandrasekaran, S. Tetrahedron Lett.
2004, 45, 7983−7985.
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dx.doi.org/10.1021/op2003216 | Org. Process Res. Dev. 2012, 16, 512−517