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NEW SYNTHETIC APPROACHES TO 3-NITROAZETIDINES
PART I; NITRATION OF SALTS OF l-TERT-BUTYL-S-CYANOAZETIDINE
PART 2: REACTION OF PRIMARY AMINES WITH 2-NITROALLYL ESTERS
DISSERTATION
Presented in Partial Fulfillment of the Requirements for the Degree Doctor of
Philosophy in the Graduate School of The Ohio State University
By
Anthony F. Skufca
*****
The Ohio State University 1998
Dissertation Committee: Approved by Professor Harold Shechter, Adviser
Professor David Hart kdviser
Professor Gideon Fraenkel Department of Chemistry UMI Number: 9834065
UMI Microform 9834065 Copyright 1998, by UMI Company. All rights reserved.
This microform edition is protected against unauthorized copying under Title 17, United States Code.
UMI 300 North Zeeb Road Ann Arbor, MI 48103 ABSTRACT
l-rerr-Butyl-3,3-dinitroazetidine ( 8 ) has been synthesized from \-tert- butylazetidin-3-ol (21) as follows. Phase-transfer reactions of sodium cyanide with I- ré'rr-butyl-3-methanesulfonylazetidine (7), l-terr-butyl-3-bromoazetidine (50), and 1- rerr-butyl-3-chloroazetidine (51), respectively, yield 1 -fgrr-buty 1-3-cyanoazetidine
(44). The behavior of various bases ( NaH, potassium r-butoxide, phenylsodium, mesitylsodium, LDA, and KDA) with l-rerr-butyl-3-cyanoazetidine (44) has been studied. LDA is an effective base for deprotonating 44. Nitration of lithio \-tert- butyl-3-cyanoazetidine (59) with propyl nitrate or 2-(trifluoromethyl)-2-propyl nitrate yields l-rerr-butyl-3-cyano-3-nitroazetidine (45). Neither acetone cyanohydrin nitrate
(65) nor tetranitromethane (66) convert 59 to 45. In a one pot process I-rerr-butyl-3- cyano-3-nitroazetidine (45) is hydrolyzed with aqueous sodium hydroxide; oxidative- nitration of sodium i-terr-butyl-3-azetidinylnitronate then gives TBDNAZ ( 8 ).
Study was made of preparation of 2-nitroallyl acetate (78) by pyrolysis of 2-nitro-
1,3-propanediol diacetate (82) and by reaction of 2-nitroallyl alcohol (93) with acetyl chloride. The behavior of 2-nitroallyl alcohol (93) with electrophiles (trifluoroacetic anhydride and acetic anhydride) was also investigated. Reactions of hindered primary alkylamines (rerr-butylamine, /err-octylamine (110) and benzhydrylamine) with 2-nitroallyl acetate (78) or 2-nitroallyl trifluoroacetate (95) were studied under a variety of conditions. No l-alkyl-3-nitroazetidines were found in these reactions; intractable products were obtained.
Reactions of aromatic amines with either 2-nitroallyl acetate (78) or 2-nitroallyl trifluoroacetate (95) result in formation of stable mono or di-addition products. 3,5-
Dinitroaniline (117) reacts with 2-nitroallyl acetate (78) to give 3-(3,5- dinitrophenylamino)-2-nitro-l-propene (118) and l,3-bis(3,5-dinitrophenylamino)-2- nitropropane (119). Reaction of 2-nitroallyl trifluoroacetate (95) with 3,5- dinitroaniline (117) gives l,3-bis(3,5-dinitrophenylamino)-2-nitropropane (119). p-
Toluidine (124) reacts with 2-nitroallyl acetate (78) or 2-nitroallyl trifluoroacetate (95) to yield l,3-bis(4-methylphenylamino)-2-propane (126). o-Phenylenediamine (127) forms the seven-membered ring derivative, 3-nitro-2,3,4,5-tetrahydro-H- benzo[ 6 ][ 1,4]diazepine (129) when reacted with 2-nitroallyl acetate (78).
Ill Dedicated to my parents
IV ACKNOWLEDGEMENTS
I wish to express my sincere gratitude to Professor Harold Shechter for making me a better chemist by teaching me how to think critically about chemistry and how to evaluate new ideas. I will never forget all of the support and guidance you gave me when I joined your group.
I would like to thank Professor John Masnovi who showed me that research involved more than repeating literature preparations. His positive attitude and continued friendship over the years I have valued greatly.
Special thanks are extended to my former labmates: Drs. Chris Woltermann,
Michael Waterman, J. Kirby Kendall, and Larry Yet whose friendship made the graduate school experience even better. Deepest appreciation is extended to an honorary Shechter group member Dan Repicz, who prepared starting materials for my research, and who spent as much time in the lab as some “official” Shechter group members. I was always reminded of how lucky I was to be in graduate school and how great it would be to graduate by my good friend Kathy Weber.
Finally, thanks to Dr. James Lanter, Dr. Brian Aquilla and (soon to be Dr.) Brian
Bliss, three of the hardest working and intense individuals that I know, who inspired me to work as hard and to be as productive as they were. VITA
May I. 1969...... Bom-Wickiiffe, Ohio
1991 B.S. Chemistry - Cleveland State University
1991-1996...... Graduate Teaching Associate, The Ohio State University
1996-1998...... Research Associate, The Ohio State University
HELD OF STUDY
Major Field: Chemistry
Studies in Organic Chemistry
VI TABLE OF CONTENTS
A bstract...... ii
D edication ...... iv
Acknowledgments ...... v
V ita ...... vi
List of Tables ...... ix
List of Figures ...... x
Part I Statement of Problem ...... 1
Chapters:
1. Historical Information ...... 3
2. Results and Discussion ...... 20
Preparation of 1 -rert-Buty 1-3-cyanoazetidine ...... 21
Studies of Deprotonation of l-tert-Butyl-3-cyanoazetidine ...... 22
Nitration of Lithio-1 -rerr-Butyl-3-cyanoazetidine ...... 30
Conversion of I-/ert-Butyl-3-cyano-3-nitroazetidine to Sodium l-rerr-Butyl-3-nitroazetidine and l-rert-Butyl-3,3-dinitroazetidine ...... 33
Conclusions ...... 35
Summary: Part 1...... 35
VII Part 2: Introduction ...... 37
Chapters:
3. Historical Information ...... 39
4. Results and Discussion ...... 46
Preparation of 2-NitroaIlyI Esters ...... 46
Reactions of Bulky Primary Alkylamines With 2-Nitroallyl Esters...... 50
Reactions of Primary Aromatic Amines With 2-Nitroallyl Esters ...... 61
Reaction of Sodio N-rerr-Butylacetamide and 2-Nitroallyl Acetate ...... 6 6
Conclusions ...... 70
Summary: Part 2 ...... 70
5. Experimental Section ...... 72
List of References ...... 105
Appendix:
'H and '^C NMR Spectra ...... 108
VIII LIST OF TABLES
Table Page
2.1 Deprotonation of l-terr-butyl-3-cyanoazetidine (44) followed by
reaction with ethyl bromide...... 26
4.1 P>Tolysis of 2-nitro-1,3-propanediol diacetate (82) over CaSO^
to 2-nitroallyl acetate (78) 47
IX LIST OF FIGURES
Figure Page
1 'H NMR (200 MHz) of I-rm-Butyl-3-cyano-3-nitroazetidine (45)...... 109
2. '^C DEPT (75 MHz) of l-/err-Butyl-3-cyano-3-nitroazetidine (45)...... 110
3. ‘H NMR (200 MHz) of 2-Nitroallyl Trifluoroacetate (95) ...... 111
4. '^C NMR (75 MHz) of 2-Nitroallyl Trifluoroacetate (95) ...... 112
5. ‘H NMR (200 MHz) of 3-/e/-r-Butyl-5-/er/-butylaminomethyl-5- nitrotetrahydro-1,3-oxazine (108) ...... 113
6 . '^C DEPT (75 MHz) of 3-rer/-ButyI-5-/err-butylaminomethyl-5- uitrotetrahydro-1,3 -oxazine (108) ...... 114
7. 'H NMR (200 MHz) of N,N-Bis(2-nitroalIyl)/'er/-butylamine (113)...... 115
8 . ‘H NMR (200 MHz) of 3-(3,5-Dinitrophenylamino)-2-nitro- 1-propene (118) ...... 116
9. “C NMR (50 MHz) of 3-(3,5-Dinitrophenylamino)-2-nitro- 1-propene (118) ...... 117
10. 'H NMR (300 MHz) of l,3-Bis(3,5-dinitrophenylamino)- 2-nitropropane (119) ...... 118
11. '^C NMR (75 MHz) of l,3-Bis(3,5-dinitrophenylamino)- 2-nitropropane (119) ...... 119
12. 'H NMR (300 MHz) of l,3-Bis(4-methyIphenylamino)- 2 -nitropropane (126)...... 1 2 0
13. '^C NM R (75 MHz) o f l,3-Bis(4-methylphenylamino)- 2 -nitropropane (126)...... 121
X 14. 'H NMR (300 MHz) of 3-Nitro-2,3,4,5-tetrahydro-//-benzo[6] [l.4]diazepine (129) ...... 122
15. ‘^C NMR (75 MHz) of 3-Nitro-2,3,4,5-tetrahydro-77-benzo[6] [l,4]diazepine (129) ...... 123
16. ‘H NMR (300 MHz) of N-(fer/-butyI-2-nitroalIyl)acetamide (132)...... 124
17 '^C NMR (75 MHz) of N-(rerr-butyI-2-nitroallyI)acetamide (132)...... 125
XI PARTI
STATEMENT OF PROBLEM
1,3,3-Trinitroazetidine (TNAZ, 1) is a new energetic material of interest to U.S. military agencies and industrial companies for use in propellant and explosive formulations'.
OzK ^NOz
N
NO2 1
A number of syntheses of TNAZ (1) have been recently reported as will be discussed in the Historical Information Section. These syntheses suffer from low overall yields and/or use of expensive reagents. Key intermediates in the preparation of TNAZ (1) are I-r^rr-butyl-3-nitroazetidine (TBNAZ, 2) or I-rerr-butyl-3-hydroxymethyl-3- nitroazetidine (TBHMAZ, 3) and these compounds have as yet not been produced economically. NOg NOg HO
New and cost-effective methods for preparation of TBNAZ (2) and/or TBHMAZ (3) will be valuable and will enable the widespread use of TNAZ (1). The purpose of this research is to investigate new methods for synthesis of TBNAZ (2) and/or TBHMAZ
(3). As will be seen these investigations lead to significant questions and new areas for research and development. The results of these studies will be discussed as follows. PARTI
CH APTER 1
HISTORICAL INFORMATION
1,3,3-Trinitroazetidine (1) possesses many favorable properties: a low melting
point ( 101 °C)‘, low impact sensitivity" '’, high density (1.84 g/cm^)‘, and good
thermal stability (decomposition temperature 249 °C)'. TNAZ (1) has the following
advantages over the currently used explosives: 1,3,5-trinitro-1,3,5-triazacyclohexane
(RDX ,4) and I,3,5,7-tetraaza-I,3,5,7-tetranitrocyclooctane (HMX,5):
NOg NOg 1 r 'A /N OgN-N N-NOg
O2No ^ NOg NOg
5
I) 1 can be steam melted and cast into various shapes easily' whereas the high melting points of RDX (4, 204 °C)'^ and HMX (5 ,281 ° C f preclude their being melted and both RDX (4) and HMX (5) must be mixed with a binder^ before loading into munitions, 2) 1 (35 cm) has a lower impact sensitivity" than RDX (4, 22 cm)' and
HMX (5, 26 cm)* and 3) 1 can be reclaimed easily from obsolescent munitions and reused'. Synthesis of 1 was first reported by Archibald and Baum in 1990 (Equation 1).
H. O H CHON CH3SO0C1 -NH 2 + 01 N « H C i - Et3N
H O S O 2 C H 3 H NOg ( 1 ) NaNO-, 1 . N aO H
$ M eO H . H iO l.N a N O n . PTC Na^SiOg. K3Fe(CN)6
OgN NOg OgN NOg AciO
N 98% HNO3 N NOg 1
The starting material for their synthesis, I-re/t-butylazetidin-3-ol hydrochloride (6 ), is prepared from epichlorohydrin and rcrr-butylamine by the elegant procedure developed by Gaertner"^. Conversion of 6 to its mesylate 7 is effected by reaction with mesyl chloride and triethylamine. The key step in the overall synthesis is reaction of sodium nitrite with 7 in methanol/water using phloroglucinol as a phase transfer catalyst to give TBNAZ (2) in 8 % yield. No 2 is formed when DMSG or DMF is used as the solvent or when the mesyl group is substituted with a tosyl or a bromo group.
Oxidative-nitration of the sodium salt of TBNAZ (2) with silver nitrate/sodium nitrite” or potassium ferricyanide, sodium persulfate, and sodium nitrite'" produces I-
r
TBDNAZ (8 ) is stable at room temperature but will decompose explosively on
distillation above 120 °C. Nitrolysis of TBDNAZ ( 8 ) with acetic anhydride and 98%
nitric acid occurs with the removal of the ferr-butyl group to produce TNAZ (1) in
35% yield.
A similar series of reactions was studied using I-benzhydrylazetidin-3-ol
hydrochloride'* (9) as prepared from benzhydrylamine and epichlorohydrin (Equation
2 ).
( 2 ) NOg H J Nal. NaNO 1. NaOH. EtOH
DMF. HiO 2. NaNO,, C(NO,). PTC
10 11
© O2N, NO2 NO, O2 N NO2
// '
NO2 1
Mesylate 10 is insoluble in methanol and does not react with sodium nitrite under the
5 conditions used for 7. Heating 10 in wet DMF with sodium iodide, sodium nitrite and
phloroglucinol initially forms l-benzhydryl-3-iodoazetidine which is then displaced by
sodium nitrite to form II in 11% yield. Also recovered from the mixture is unreacted
l-benzhydryl-3-iodoazetidine (13%). Dinitroazetidine 12 is then obtained by reactions
of sodium nitrite and tetranitromethane with the sodium salt of 11. Attempts to
nitrolyze 12 give complex mixtures of products but no TNAZ (1).
Preparation of 1 starting from rerr-butylamine and epichlorohydrin has been scaled
up at the Aerojet Corporation'^. Phloroglucinol as the phase transfer catalyst in
water/methanol in the reaction of 7 with sodium nitrite was first replaced by water/
Freon 113'■* and later with toluene/water. Unfortunately after extensive attempts to optimize preparation of TBN.4Z (2) the yield was still very poor (28%)'^. Another disadvantage of this synthesis is that large amounts of waste are generated (42 pounds of waste per pound of 1 produced)'^. Equation 3 shows the percent yields and the scale (kg) in parentheses of the intermediates and TNAZ (1) produced in pilot-plant runs at Aerojet.'^ H. OH CHjCN 85% ^»3S0,C1 -NH2 + Cl (2 0 0 ) 2 EtjN N #HCI
(3) H O SO 2 CH3 H NO2 NaNO', I. NaOH 6 95% < 5 (8 ) N toluene, H?0 N (75) 2 .NaN0 2 . KjFeiCN)^, NaoSnOg
O2N NO2 0 2 N^ ^N0 2 ACnO 65% 73% ( 10) N 98% HNOi N ( 12) NO2 I
A different synthesis of TNAZ (1) has been recently developed at Los Alamos
National Laboratories by Cobum and Hiskey’^ (Equation 4) as follows:
,N02 NO, H ;0 ^ HCl _ + HO. ,0H EtOH 'OH 14 ^ .5 (4)
O2N NO2 HO 1. 3 NaOMe
DEAD 2. NaNOn. NH OH N #HCI KjFeCCNie. 5 T JHCl NaiSiOg. /K 16 17 l,3,5-Tri-fÊ’rr-butylhexahydrotriazine‘®(13) is readily obtained by condensation of formaldehyde with rgrr-butylamine. Tris(hydroxymethyl)nitromethane(14) is prepared commercially (Angus Chemical Company) by base-catalyzed condensation of nitromethane with three equivalents of formaldehyde. Reaction of three equivalents of
14 with 13 yields 3-re/t-butyl-5-hydroxymethyl-5-nitrotetrahydro-l,3-oxazine(15).
Ethanolic hydrogen chloride converts 15 to 2-rm-butylaminomethyl-2-nitro-1,3- propanediol hydrochloride'* (16). l-7err-butyl-3-hydroxymethyl-3-nitroazetidine hydrochloride (17) is then formed in 70% yield from 16 via a Mitsunobu reaction using triphenylphosphine and diethyl azodicarboxylate (DEAD).
A novel but awkward set of reactions is used to remove the tert-b\xty\ group from
TBDNAZ (8 ) and introduce the N-nitro group (Equation 5).
O2N NO2 o O 2N NO2 CHCI3 V CF 3 SO 3 H $ • oA
O)
O2N NO2 0 2 N^ ,N 0 2 ,N 0 2 I.NaHC0 3 X Ac.O
Ü.CF3SO3H N.HNO 3 Y ^ ^ ^ n HNO3 NO2 19 2 0 I Reaction of 8 with benzyl chioroformate gives l-(benzyloxycarbony!)-3,3- dinitroazetidine (18)'^ which upon treatment with trifluoromethanesulfonic acid produces 3,3-dinitroazetidinium trifluoromethanesulfonate (19). Neutralization of 19 and reaction with ammonium nitrate yield 3,3-dinitroazetidinium nitrate (20).
Reaction of 20 with acetic anhydride and 90% nitric acid as catalyzed by zinc chloride forms TNAZ (1). The Los Alamos synthesis of TNAZ (1) has been improved"® and is currently used on a pilot-plant scale.
Shaima and Shechter"* first investigated low temperature (-60 °) Swem oxidation of l-terr-butylazetidin-3-ol (21) using oxalyl chloride, DMSO and triethylamine to produce l-rerr-butyl-3-azetidinone (22) in 93% yield (Equation 6 ).
H OH 9 1. oxalyl chloride NHiOH • HCl ii.
N DMSO.-60 N NaOAc. EtOH N Z .E tjN
21 22 23
The azetidinone (22) undergoes aldol condensations readily at room temperature.
Reaction of 22 however with two equivalents of hydroxylamine at -40 “C gives l-ien- butyl-3-azetidinone oxime (23 , 8 8%), a stable product. Nitration of 23 with 95% nitric acid in dich loro methane produces TBDNAZ ( 8 , Equation 7) in 30-40% yields.
Nitrative-oxidation of 23 to 8 (possibly with N2O5) needs to be improved. OH O2K ,N 0 2 957c HNOi A A (7) N CH.CI1 N - - I NO2
Katritsky" et al after learning of The Ohio State methodology developed a similar synthesis of TNAZ (1, Equation 8 ) starting with l-benzhydrylamineazetidin-3-ol hydrochloride (9) which is oxidized with chromium trioxide/sulfuric acid or pyridine/sulfur trioxide in DMSO to l-benzhydrylazetidin-3-one (24), an unstable product.
10 H OH O CH3CN % CrO^. H2SO4 NH2 + 2i/\ < > N*HC1 or
C sH jN » SO3 DMSO EtjN
SO2C1 Pd(OH)
N • HCl H-, MeOH ' n '. H (8)
O2N ^NÜ2 NHiOH 95% HNO3
CHiCh N NO2
26 27
Immediate acidification of 24 with hydrogen chloride in ethyl ether yields I- benzhydryl-3-azetidinone hydrochloride (25), a stable solid, which upon hydrogenolysis and subsequent reaction with tosyl chloride produces 26. Reaction of
26 with hydroxylamine gives I-tosyl-3-(hydroxyimino)azetidine (27). Nitrolysis of 27 with 95% nitric acid forms 1; the overall yield of TNAZ (1) from epichlorohydrin and benzhydrylamine is only 7-11%. Attempts to nitrolyze 28 with 95% nitric acid produce I-benzhydryl-3-nitroazetidine (29, 8 %) and benzophenone (37%,Equation 9).
11 H NOz o NH-.OH 95% HNO? (9) - 6 ..APh Ph
24 28 29
The expense of benzhydrylamine and the many steps make the synthesis as in
Equation 8 uneconomical and an alternate approach was investigated starting with
benzylamine and epichlorohydrin (Equation 10)."
NHz OH pet. ether 'h ,01
( 10)
,SiM63 H 0-SIM e3 O' CH 3 CN NaOEt ,01 Et,N V EtOH
,0 H N' H. OH C 5 H 5 N NHiOH
N DMSG N
30
Unfortunately the overall yield of 30 (5%, Equation 10) is low and the failure of 1- benzhydrylamine-3-(hydroxyimino)azetidine (28, Equation 9) to nitrolyze to TNAZ
(1) render this approach unattractive.
12 Axenrod et al^ have used a slightly different method for preparing TNAZ (1) which does not involve benzhydrylamine. p-Toluenesulfonamide Is reacted with ten- butyldimethylsilyl ether derivatives of 1 ,3-dihalo-2-propanols (31a: X=C1: 31b:
X=Br) in the presence of potassium carbonate to obtain l-(p-toluenesulfonyl)-3-( tert- butyldimethylsiloxy)azetidine (32) in 50 and 6 8 % yields, respectively (Equation 11).
/TBDMS H o -^TBDMS
A y — S O 2NH2 + X, CH3CN \ / (1 1 )
31a: X= Cl 31b: X= Br
32
A variation for preparing 32 (Equation 12, 53% yield) involves reaction of 3-amino-
1 ,2 -propanediol with p-toluenesulfonyl chloride ( one equiv) followed by protection of alcohol 33 with rcrr-butyldimethylsilyl chloride (TBDMSCl) and base-promoted cyclization using lithium hydride in THF.
13 /=\ pyridine q H TBDMSCl
-^^SOsCi + Î1 ^ ^ s 02-N . J L .OH "imidazole'
H 3 3 DMF
( 12) / = , OH UH —4 /> -so 2 - n ^ J \ . otbdms ------► < > I THF N n I
32
TNAZ (1) is then synthesized (Equation 13) from 32 by removal of the TBDMS group from 32, oxidation of alcohol 34 to ketone 26, reaction with hydroxylamine to produce oxime 27 and then nitration of 27 with 95% HNO 3 in dichloromethane. The overall yield of 1 (Equations 12 and 13) starting from 2-amino-1,3-propanediol is
21%.
14 H Q-TBDIVIS H OH HOAc X CrO]
HiO H2SO4
(13) 32 34
U O2 N NO2 A NHoGH 957c HNO3 N EtOH 'V CH,CU N SO 2 SO 2 NO2
1
26 27 ,24 In a recent patent""* Dave describes methods of preparing TNAZ (1) by nitrating I- acetyl (35a) or I-nitro-3-(hydroxyimino)azetidines (35b, Equation 14).
O H OCCH3 H OH 9 ^ N aH C O j V pcc A NH.OH
N EtOH. H2O N CH2CI2 N E to n R O R R
R=CCH3,N02 hh (14) N '° " 0 2 N^ NO2 conc. HNO3
N or N R n NO2 u CHiCIi 35a: R= CCH3 " " i 35b: R= NO2
The 3-substituted-azetidines (Equation 14) used in the above synthesis are obtained
15 simply by heating the corresponding 3-substituted-l-fgrr-butylazetidines in acetic
anhydride with a catalytic amount of boron trifluoride etherate at 115 °C^ (Equation
15).
r V r V r ^ Ac-,0 (15) N BF]# EtnO N
A o
r ' = CI. 0 H : R - = H
r ' =R - = NÜ2
1-Acylazetidines are easily converted to 1-nitroazetidines by reaction with ammonium
nitrate in acetic anhydride^. This synthesis is superior to the method reported by
Archibald et al'** (Equation 14) because Dave’s method does not require hydrogenolysis of 1-benzhydrylamine-substitutedazetidines and then nitration with acetic anhydride and nitric acid.
H. ,R ^R HR Ho, HCl X H N O i (16) Pd/C N AcoO N H ” J NO2
O O R=O H , C -C H 3 , O - S - C H 3 6
Marchand et al"’ have recently developed a novel synthesis of 1 which involves electrophilic addition of dinitrogen trioxide (N 2O 3) across the strained C(3)-N bond in l-azabicyclo[ 1. 1.0 ]butane (36) and in 3-(bromomethyl)-l- azabicyclo[ 1.1,0]butane(37).
16 -Br
<î> 36 37
Azabicyclobutane 31, first synthesized by Funke** (Equation 17), is prepared from 2- amino-1,3-propanediol by the following sequence of reactions.
HOA c ^ 30% HBr. HOAc HO Y OH CHCl H Br(g) 3 NH 2 « HOAc
(17)
Aq. NaOH B r^ Br N H g. HBr distill 36
When 36 is reacted with aqueous nitrous acid l-nitroso-3-nitroazetidine (38) is formed in only 1% yield. Nitration of 38 with absolute nitric acid in trifluoroacetic anhydride gives l-nitro-3-nitroazetidine (39, 72% yield). Oxidative-nitration of 39 produces TNAZ (1, 40%; Equation 18). Unfortunately the overall yield of TNAZ (1) from 36 is 0.2%.
17 H NOg NaNO-, <5 100% HNO-, <î> HCl. HnO N TFAA I 36 N<
38 (18)
H N O ; /NO 2 1. NaOH
2 . NaNO]. N N0 2 K3Fe(CN)ô- NO2 Na^SoOg 39 1
A slightly different approach was then investigated by Marchand et al‘^ (Equation
19) starting with tris(hydroxymethyl)aminomethane which is converted to azabicyclobutane 37; reactions of 37 with aqueous nitrous acid produce 40 and 41 in only 10 and 3% yields respectively.
NH2 NH2 *HBr 1.HOAc. CHClg.EtiO NaOH Br Br 2. 30% HBr-HOAc. HBr (g) Distill Br
-Br (19) ^ \ / N 0 2 HO NO NaNO-, Br < 5 * 6 HCl, HnO N N N<. 37 '0 0
40 41
18 Nitration of 40, and then hydrolysis of the bromo group in 42 give 43 which is deformylated and oxidatively-nitrated to TNAZ (1) in an overall yield of 2% from tris(hydroxymethy)aminomethane (Equation 20). The methodology though interesting is unsatisfactory as a synthetic method for preparation of TNAZ (1).
Br 100% HNO. NaHCO,
N TFAA N Nal N, NOz DMSO
42 40 <20)
HO ,NaO H
N 2 . NaNOn N NOg KjFeCCN)^ NagSgOg 43 1
19 CHAPTER 2
RESULTS AND DISCUSSION
As has been discussed TNAZ (1) can be prepared efficiently (Equation I) by oxidative-nitration of TBNAZ (2) to TBDNAZ ( 8 ) followed by nitro-de-rerr- butylation of 8 with nitric acid in acetic anhydride. The unsatisfactory feature of this synthesis of TNAZ (1) and all of its modifications is that preparation of TBNAZ (2) is inefficient and expensive. It has become clear that a more practical and presumably different synthesis of TBNAZ (2) must be developed if TNAZ (1) is to become a widely-used energetic material. The present investigator has proposed study of preparation of TBNAZ (2) from I-terr-butylazetidin-3-ol hydrochloride ( 6 , Equation
21) by some practical sequence involving l-te/t-butyl-3-cyanoazetidine (44), conversion of 44 to l-t^rr-butyl-3-cyano-3-nitroazetidine (45), and subsequent hydrolytic-decarboxylation of 44.
2 0 H OH CH3CN lE tjN ■nh2 + Cl N 'H C l CH3 SO2 CI
6
H OSO2CH3 H. .ON ( 21 ) NaCN 1 . base
NN 2. RONOo
44
02N ^ .o n © H NO2 H H2 O or N © N OH HiO
45
In support of this proposal for synthesis of TBNAZ (2) is that, as has been discussed, i-rerr-butylazetidin-3-ol hydrochloride ( 6 ) is preparable on large scale from epichlorohydrin and re/t-butylamine. I-rerr-Butyl-3-cyanoazetidine (44) has also been synthesized previously by mesylation of 6 followed by reaction of mesylate 7 with potassium cyanide in methanol."^ Of particular importance to this proposal is that a, co-dinitriles (46; Equation 20) are dimetallated by potassium r-butoxide in THF at -50
°C, di-potassium salts 47 are efficiently nitrated by amyl nitrate, and the subsequent dipotassium dicyanodinitronate salts (48) are effectively converted upon saponification and acidification to the corresponding a, m-dinitroalkanes(49)/° This
21 nitration methodology has also been applied to ketones, aliphatic carboxylic and
phenylacetic esters, alkylsulphonate esters, activated toluenes, amides, lactams and
heterocyclic compounds.^’
2 Me^COK ^ ^ amyl nitrate NCCH-,(CH^)nCHoCN ------► NCCH(CH,)„CHCN ►
46" ' THF.-50°C 4 7
n= 2. 3. 4. 6 (22)
NOiK NOiK I. KOH II - II - 0 2 NCH2(CH2)nCH2N0 2 NCC(CH2 )nCCN 2. HOAc 48
PREPARATION of l-ferr-BUTYL-3-CYANOAZETIDINE (44)
l-tcrr-Butyl-3-cyanoazetidine (44) has been previously prepared by reaction of? in
methanol with potassium cyanide (3 equivalents) for three days?" The long reaction time makes the procedure unsuitable for large-scale synthesis. To solve the preceding problem phase-transfer methods have been presently investigated using toluene/water as solvents and tetraethylammonium bromide as the phase-transfer catalyst. Sodium cyanide has now been substituted for the more expensive potassium cyanide. Only 1.2 equivalents of sodium cyanide are required to give 44 (Equation 23) in 62% yield in less than 20 hours at 50 °C. Yields of 44 from 7 are lowered when two equivalents of sodium cyanide are used under the above phase-transfer conditions at 50 or 90 °C. A further problem is that 7 decomposes significantly at elevated temperatures. Of value is that l-rerr-butyl-3-bromoazetidine’ (50, 30%) is obtained from sodium bromide and 7 and l-re/t-butyl-3-chIoroazetidine'’^ (51) is readily prepared in good yields by
reaction of azetidinol 6 with phosphorous pentachloride. Phase-transfer displacements
of 50 and 51 with sodium cyanide in toluene/water at 50 “C have been presently found
to give 44 in 67 and 53% yields, respectively. The probable mechanism and the
overall results for synthesis of 44 from 7, 50, and 51 are summarized in equation
33.34 23.
NaCN
KN — H ?0. ^toluene <% N © ' n ' (23)
50 “C ^
44
7. Z= OSOoCHj 62%
50. Z= Br 67%
51.Z=C1 53%
It is likely that the above synthesis of 44 can be improved further. Of present
importance will be demonstration that cyanoazetidine 44 can be used for preparation
of TBNAZ (2).
STUDIES OF DEPROTONATION OF l-fe/7-BUTYL-3-
CYANOAZETIDINE(44)
Deprotonation of cyanoazetidine 44 by bases has not been studied previously. As
has been summarized earlier potassium r-butoxide deprotonates simple ni tri les and terminal dinitriles in e.xcellent yields at -50 °C. Further, phenylsodium,^^ prepared in
23 quantitative yields from sodium dispersions and chlorobenzene, is reported to deprotonate phenylacetonitrile rather than add to the cyano group/'' 3-Cyanopentane, a secondary nitrile, is also deprotonated by phenylsodium (Equation 24); the a-sodio nitrile 52 generated is alkylated on carbon by benzyl chloride in 71% yield/^
QHjNa QHgCHiCI (CH3 CH2 )2 CHCN ► (CH3 CH2 )2 CCN ► (CH3 CH2 )2 CCN (24)
52
Alpha-metallonitriles, however, may also behave as ambident reagents/^ Hindered a-metallo nitriles undergo alkylation on nitrogen to give ketenimines (53, Equation
25) along with a-alkyl derivatives (54)/*^
, Metal R x R------► R^C=C=N-R’ + RiC" (25) CN -MetalX ' CN 53 54
There are thus many questions to be answered with respect to generation and utilization of a-metallo (I-rerr-butyl-3-azetidinyl) nitriles such as 55.
M etal V.CN
55
Among these questions are: 1) how serious are ring size, ^-nitrogen, and varied
24 métallo effects on the kinetic and thermodynamic reactivities of 55 with various bases and 2) what will be the effects of the above factors in the reactions of 55 to give \-ten- butyl-3-cyano-3-nitroazetidine (45, Equation 2 1 ).
Study has now been made of the behavior of cyanoazetidine 44 with various bases.
As a measure of the “effectiveness” of these bases for deprotonating 44, the overall yields for production of l-rerr-butyl-3-cyano-3-ethylazetidine (56, Equation 26) upon reactions of ethyl bromide with the 55 generated was determined as follows:
Metal \ ,CN .CN - Metal Br y C + CiHgBr ------► < > (26) N N
55 56
The behaviors of 44 with potassium fg/Y-butoxide in THF and in toluene and subsequent treatment with ethyl bromide were investigated first. Disappointingly, potassium rert-butoxide, as summarized in Table 1, does not deprotonate nitrile 44 effectively even in re fluxing THF ( bp 67 °C) or toluene (bp 111 °C).
25 H. ,CN
base + N 2. EtBr T
44 43
base solvent temp (°C) % yield
Me^COK THF reflux 0
MejCOK toluene reflux 0
NaH THF reflux 0
n-BuLi THF -78 17
0 "N a toluene 25 17
-H 26 -78 0
toluene 25 23
LDA THF -78 73
KDA THF -78 32
Table 2.1: Deprotonation of l-rm-butyl-3-cyanoazetidine (44) followed by reaction with ethyl bromide.
2 6 No l-ferr-butyl-3-cyano-3-ethyIazetidine (56) is obtained; most of the 44 is recovered.
It is thus apparent because of ring-size and possibly P-nitrogen effects, 44 is a significantly weaker carbon acid than are primary nitriles. Sodium hydride in re fluxing THF with 44 and then exposure to ethyl bromide also fails to give any 56
(Table 2.1). Sodium hydride is poorly soluble in THF and along with potassium hydride are known to add to the cyano groups of various nitriles and then give condensation and oligomeric products.^
Phenylsodium in toluene at various temperatures when reacted with 44 and then addition of ethyl bromide does result in a-ethylation to give 56 along with \-tert- butyl-3-(phenylbenzoyl)azetidine (57, Equation 27) in 5% yield.
" ” ^ . X X ) » N 2. EtBr N N
44 56 57
The a-ethylated product 56 is not formed when the transformation of 44 is attempted at -78 °C. At-II and 25 °C 38 is converted to 56 in 26 and 17% yields along with
57. The utility of phenylsodium was not developed further for two reasons: 1) phenylsodium adds to the cyano group in 44 and 2) the difficulties in preparing phenylsodium from sodium and chlorobenzene. Phenylsodium in the present
27 experiments contained subsequential quantities of unreacted chlorobenzene. To
prepare phenylsodium in high yields the average particle size must be below 25
microns.^^ Very high speed stirring is necessary at temperatures above the melting
point of sodium (97.8 “C), and emulsifying agents such as oleic acicP^ or rgrf-butyl
hydroperoxide"*' must be added to prevent cohesion of sodium particles when the
solutions are cooled.
Mesitylsodium, a highly-hindered strong organometallic base prepared by reaction
of highly dispersed sodium (2 equivalents) with chloromesitylene (Equation 28), then
became of interest because of the addition of phenylsodium to the cyano group in 44.
H. .CN 2 Na / = \ / r ^ -N aC l N CqH9^12
(28) 44
N a ON CN
V - NaBr
58 56
Crude mesitylsodium as presently prepared by this investigator from chloromesitylene and sodium contains much unreacted chloromesitylene. The mesitylsodium suspensions prepared does react well with cyanoazetidine 44 by proton-abstraction in toluene at 25 °C and the sodio cyanoazetidine 58 generated is converted by ethyl
28 bromide to 56 as reported in Table 1. The overall conversion of chloromesitylene to mesitylsodium is 23%; the yield of 56 in reactions of 44 with mesitylsodium and then ethyl bromide is essentially quantitative. The difficulties with mesitylsodium are in its preparation, cost, and use on a large scale. For mesitylsodium to be prepared in high yield finely dispersed sodium and very high-speed stirring is required. It was thus decided to investigate the behavior of more readily-accessible stong bases with 44.
Study was then made of metallations of 44 by /i-butyllithium (/i-BuLi), lithium diisopropylamide (LDA) and potassium diisopropylamide (KDA), respectively, followed by reactions with ethyl bromide. Addition of commercial /z-butyllithium in hexane to cyanoazetidine 44 at -78 °C in THF under argon followed by ethyl bromide
(I equivalent, 3 hours) at -78 °C and chromatography yield 56 (17%, Table 1).
Lithium diisopropylamide (1.03 equivalents), prepared in siiii from diisopropylamine and commercial /z-butyllithium, behaves much better. At -78 °C under the conditions used previously , éthylation occurs to give 56 as isolated in 73% yield (Table I).
Potassium diisopropylamide (KDA)"*', prepared by a literature procedure from potassium rm-butoxide, diisopropylamine and /z-butyllithium at -78 “C, does not work as well as lithium diisopropylamide (LDA) in that in the overall procedure, 56 is produced in only 32% yield (Table 1). No attempts have been made to maximize the efficiencies of the above metallations of 58 followed by éthylation to 56. The a- lithiation of 44 is satisfactory for the present purposes. Of importance is that, for large quantities in a commercial process, lithium diisopropylamide (LDA) is produced much
29 less expensively and in much higher purity by reaction of metallic lithium with
diisopropylamine in the presence of styrene, an electron-transfer reagenf^^.
NITRATION OF LITHIO-l-fe/t-BUTYL-3-CYANOAZETIDINE (59)
Upon determining that lithio cyanoazetidine (59), as generated from cyanoazetidine
44 and LDA at -78 °C, can be ethylated by ethyl bromide to 56 in yields of at least
73% (Table 2.1), study was then initiated of possible efficient nitrative conversions of
59 to l-terr-butyl-3-cyano-3-nitroazetidine (45). As indicated previously alkyl nitrates
can be used to nitrate variously stabilized carbanions on carbon (Equation 22). The
mechanism of such nitrations involves bimolecular reaction of the delocalized
carbanionic nucleophile 60 on nitrogen of the nitrate ester 61 (possibly involving
addition to the nitro group) with displacement of alkoxide 62 to give the nitrocarbon
product 63 (Equation 28).
R , 0 0 ^ 0 f c ? © I © ,p © .c-z + N—0 “ R’ R—C ~ N t O ~ R ’ R—C-N + OR’ (29) I R 60 © ° 61 % ^ % 64 63 62
The alkyl nitrates usually used: amyl nitrate, butyl nitrate, and propyl nitrate are safe, inexpensive, and commercially available.
Reaction of cyanoazetidine 44 with LDA (1.03 equiv) in THF/hexane at -78 °C and then propyl nitrate (1.1 equiv) at -78 °C (Equation 30), allowing the mixture to warm
30 slowly to 0 °C , followed by neutralization, extraction and chromatography of the
products, give l-/err-butyl-3-cyano-3-nitroazetidine (45) in only 10% yield.
H. .CN L i. .C N O 2N CN LDA PrONO-, (30) N .78 ° c N - 78 °C to 0 °C N ^ -(/-Fr)^NH - LiOPr
44 59 45
Varying the rate of addition and the amount of propyl nitrate, the order of addition of
the reagents and the reaction time did not improve the yields of 45. Compound 45 was
also prepared independently by deformylation of 1 -rerr-buty 1-3-hydroxymethy 1-3-
nitroazetidine hydrochloride (17) with sodium hydroxide followed by oxidative-
cyanation in 8 % yield (Equation 31).
NO, NO NO2 HO' 1.3 NaOH. HoO « 6 (31) N#HCI -CH2O N 2. NaCN. KjFeCCNle, 17 Na^SoOg, 45
Acetone cyanohydrin nitrate (65) and tetranitromethane ( 6 6 ) have been used previously to nitrate stabilized carbanions advantageously.^' Reactions of 65 and of
6 6 with lithio cyanoazetidine 59 in THF at -78 °C however did not yield 45 (Equations
32 and 33). It has not been determined why these nitrating agents do not convert 59 to
45.
31 ÇH, NC-C-ONO, I CH. (32) N - CH3C(0)CH3. LiCN
59 45
M C y U C(N02)4 NC NO2
-■■/ / (33) ' n " 5 ~ LiC(N02)3
59 45
Bottaro et al'” report that 2-(trif!uoromethyl)-2-propyl nitrate (67) is an excellent nitrating agent for conversion of secondary amines (R.N-H) to secondary nitramines
(R2N-NO 2) and is a superior reagent as compared to acetone cyanohydrin nitrate (65).
2-(Trifluoromethyl)-2-propyl nitrate (67) is prepared by reaction of anhydrous nitric acid and trifluoroacetic anhydride with 2-(trifluoromethyl)-2-propanol ( 6 8 , Equation
34).
ÇH, 1007c HNO. CH3
F3C-C-OH F3 C-C-ONO 2 (34) I CH3 TFAA, 0 °C CH3 68 67
32 Addition of 67 to lithio cyanoazetidine 59 (Equation 35) at -78 °C in THF, warming the mixture to 0 °C , simple work-up, and chromatography of the reaction product is found to give 45 in at least 36% yield.
F 3 C-C-ONO 2 + < > ► < > + F3 C-C-OÜ (35)
CH 3 N -78 “C N CH;
67
59 45
The nitration of 59 is believed to be improvable. At present however 2-
(trifluoromethyl)-2-propanol ( 6 8 ) is an expensive chemical. The behavior of 59 with other non-acidic nitrating agents (N 2 O 5 , MesSiONO:, CH3CONO3, NOX/O3,
B(0 N0 :)3) has not been examined in the present study.
CONVERSION OF l-fe/7 BUTYL-3-CYANO-3-MTROAZETIDINE (45)
TO SODIUM l-fe/7-BUTYL-3-AZETIDINYLNITRONATE (69) AND
l-fe/7-BUTYL-3.3-DINITROAZETIDINE ( 8 )
Essential to the utility of cyanoazetidine 44 for preparing TNAZ (1) is that cyanonitroazetidine 45 be readily converted to l-rc/t-butyl-3-azetidinylnitronate salts such as 69. Indeed 45 has now been found to react with aqueous sodium hydroxide at
100 °C with loss of its cyano group to give 69 (Equation 36).
33 NO2 Na NC. ^NOg HnO + 2 NaOH ------A (36) N 100 °C N
45 69
Addition of bromine to an aqueous solution of 59 leads to l-rerr-butyl-3-bromo-3- nitroazetidine (70, Equation 37) in 38% yield.
NO2 Na O 2 N Br H ,0 + Br-) ------► < > (37) -NaBr N
69 70
Hydrolysis of 45 followed by oxidative-nitration of 69 with potassium ferricyanide, sodium persulfate, and sodium nitrite produce 8 in 57% yield (Equation 38).
N a ,N 0 2 m O2N, NO2 2 NaOH JL NaN02, HnO (38) N H.O. 100 “C N NanSiOg. N KjFeiCNie
45 69 8
Conversion of 45 to TBDNAZ ( 8 ) should be improvable. Hydrolysis of 45 to 69 should not require the reflux time used in the present experiments. Milder conditions may improve the yield of nitronate salt 69 and its subsequent oxidative-nitration to
TBD N AZ (8 ).
34 CONCLUSIONS
Lithio l-rerr-butyl-3-cyanoazetidine (59), prepared by 1) reaction of l-rert-butyl-3-
methanesulfonylazetidine (7) with sodium cyanide to give l-rerr-butyl-3-
cyanoazetidine (44) and 2) lithiation of 44 with LDA, can be nitrated to l-rerr-butyl-3-
cyano-3-nitroazetidine (45) which upon hydrolysis and oxidative-nitration yields
l-fgrf-butyl-3,3-dinitroazetidine ( 8 ). The methodology will be excellent for synthesis
of TNAZ (1) upon development of a satisfactory procedure for nitration of 59.
SUMMARY: PART 1
l-terr-Butyl-3,3-dinitroazetidine ( 8 ) has been synthesized from i-tert-
butylazetidin-3-ol (21) as follows. Phase-transfer reactions of sodium cyanide with 1-
ré’rr-butyl-3-methanesulfonylazetidine (7), l-rgrr-butyl-3-bromoazetidine (50), and 1-
té’rr-butyl-3-chloroazetidine (51), respectively, yield 1 -rerf-buty 1-3-cyanoazetidine
(44). The behavior of various bases ( NaH, potassium r-butoxide, phenylsodium,
mesitylsodium, LDA, and KDA) with l-tgrf-butyl-3-cyanoazetidine (44) has been studied. LDA is an effective base for deprotonating 44. Nitration of lithio l-fcrr- butyl-3-cyanoazetidine (59) with propyl nitrate or 2-(trifluoromethyl)-2-propyl nitrate yields l-tgrt-butyl-3-cyano-3-nitroazetidine (45). Neither acetone cyanohydrin nitrate
(65) nor tetranitromethane ( 6 6 ) convert 59 to 45. In a one pot process l-rerr-butyl-3-
35 cyano-3-niiroazetidine (45) is hydrolyzed with aqueous sodium hydroxide; oxidative- nitration of sodium l-rerr-butyi-3-azetidinyinitronate (83) then gives TBDNAZ ( 8 ).
The present route to 8 , with further development, can be of practical value.
36 PART 2
INTRODUCTION
As has been summarized in Chapter 2 TBDNAZ (8 ) is obtained by 1) nitration of
lithio l-fôrr-butyl-3-cyanoazetidine (59) to l-rerr-butyI-3-cyano-3-nitroazetidine (45),
2) reaction of 45 with aqueous sodium hydroxide, and 3) oxidative-nitration of sodium
l-re/t-butyl-3-azetidinylnitronate (45). At present the low yield in the nitration of 59
to 45 , although believed to be improvable, limits the usefulness of the above
synthesis. Upon evaluating the previous efforts in other laboratories, it became of
interest to attempt synthesis of TBDNAZ ( 8 ) in which the nitro group is introduced early, possibly from derivatives of nitromethane which is commercially available. In
Part 2 of this research (Equation 39) study has been made of I) addition-élimination
reactions of 2-nitroallyl esters (71) with primary amines to give l-substituted-2- nitroallylamines (72) and 2) possible ring closures of 73 to I-substituted-3- nitroazetidines (74) by addition.
37 NOg RNH. NO 2 base
= = ( ^ R’NH. A. .O 2 CR V_n„r.p-O2CR -78°C - RCO2H 72 71 (39)
H, ,N 0 2 NO2 R’NH N A- 74
The previous syntheses and the relevant literature of 2-nitroallyl esters (71) will be summarized in a subsequent section. It is important to determine if 3-nitroazetidines
74 can be prepared efficiently by mechanistic processes as summarized in Equation 39.
38 PARTI
CH APTER 3
HISTORICAL INFORMATION
AZETIDINE SYNTHESES
Azetidines have been prepared by displacement ring-closures from y-haloamines
(Equation 40), y-aminoalkyl sulfates (Equation 41), 1,3-diammonium salts (Equation
42), and 1,3-dihalides (Equation 43)/^
alkali BrCH2CH2CH2NH2 ------► < > (40) N I H
^ H H © © NaOH X OSOnOCHoCHiCHiNHiR ► < > ...... N I R
39 © © © 0 heat V ' CIHjNCHnCHiCHiNHjCl ------^ \ / (^2) N I H
H. ,H base ^ BrCHiCHiCHiCI + H2 NSO 2 —< >— ► <; > (43) N SO 2
As described previously (Equation 4), ring-closure of 2-rerr-butyIamino-2-nitro-l,3- propanediol hydrochloride (16) by triphenylphosphine and diethyl azodicarboxylate
(DEAD) occurs expensively by Mitsunobu displacement to give l-rerr-butyl-3- hydroxymethyl-3-nitroazetidine'^ (17). The mechanisms of these successful ring- closures all involve intermolecular attack of amino nucleophiles on primary carbon (C-
1 ) having appropriate leaving groups (internal Sn 2 processes).
Unfortunately, displacement reactions of 3-re/t-butylamino-2,2-dinitropropyl derivatives containing various leaving groups at C-1 (75, Equation 44) to give
TBDNAZ (8 ) do not occur."*^ Similarly, TBDNAZ ( 8 ) is not formed from 3-tert- butylamino-2,2-dinitro-1-propanol (76, Equation 45) with the Mitsunobu reagents: triphenylphosphine and DEAD.^ Further, re/t-butylamine does not react with 1,3- dibromo-2,2-dinitropropane (77, Equation 46) to give TBDNAZ ( 8 ).'*’ The failure of
75, 76, and 77 to undergo intramolecular cyclizations to TBDNAZ ( 8 ) must be due to significant steric and electronic effects arising from their 2 ,2 -dinitro moieties.
40 OgN NOg base OgN NOg
(44) NH2 X N
HCl 75 8 X=CI. Br. OMs.OTs
^N0 2 PPh3 /N O 2
- 7 4 / ------► < > (45)
NH 2 OH N#HCI DEAD T HClhc 76 8
OgN NOg V base OgN NOg
+ “ ^ N H g ------t4 / ------► < / (46) Br Br
77
2-NITROALLYL ESTERS
2-Nitroallyl acetate (78, Equation 47), the first 2-nitroallyl ester to be prepared, was synthesized by Klager"**’ by: 1) cycloaddition of anthracene and nitroethylene in o- dichlorobenzene at 145 °C to yield I l-nitro-9, lO-dihydro-9,10-ethanoanthracene (79),
2) reaction of 79 with sodium methoxide, addition of formaldehyde and acidification to yield (1 l-nitro-9,lO-dihydro-9,10-ethanoanthracen-11-yl) methanol 80), 3) conversion of 80 by acetic anhydride to acetic acid ( 11-nitro-9,10-dihydro-9,10- ethanoanthracen-11-yl) methyl ester, 81), and 4) decomposition of 81 under vacuum at
200-220 °C. The yield in the final step is only 21% and the overall synthesis of 2-
41 nitroallyl acetate (78 ) as in Equation 47 is impractical.
NO NOg o-dichlorobenzene
145 °C
79
HO AcO I. NaOM e AciO (47)
3. H 81
200-220 “C ,N O g ^
78
Two much simpler syntheses of 2-nitroallyl acetate (78) have been developed from
2-nitro-1,3-propanediol diacetate (82, Equation 48) prepared as follows:
NOg N a 5 0 % H iS O ; NaOH CH3NO2 + 2 CH2O — H-.0 HoO 83 (48) NOg NOg 2 AcCl HO. ,0 H AcO ^^ /^ n^ ^ O A g CH.CIi 84 82
I) condensation of nitromethane with formaldehyde (2 equiv) and sodium hydroxide (
1 equiv) to form sodium 1,3-dihydroxy-2-propanenitronate (83), 2) acidification of 83 with 50% sulfuric acid at 0 °C, and 3) reaction of the resulting 2-nitro-1,3-propanediol
42 (84) with acetyl chloride (2 equiv) in refluxing CH 2CI2- The yield from 84 to 82 is
90% and the overall synthesis of 84 from nitromethane has been used in the United
States on an industrial scale.
Elimination of 82 to 78 can be effected catalyticaly on small scale with sodium acetate (Equation 49) in 36% yield at temperatures at or below 100
_ ca.,NaOAc ------► AcO. (49) g_ distill “ .HOAc
The elimination of acetic acid from 82 is slow however and the method has been unsatisfactory on a laboratory scale because of fume-offs during the distillations and at higher temperatures and because of polymerization of the 82. A more satisfactory method for preparing 78 is reported to be vapor-phase decomposition of 82 at 180 °C under nitrogen over calcium phosphate as a catalyst (Equation 50).'*'' Yields of 78 of
77% have been obtained by the pyrolytic method on small scale.
Ca3(P0 4 )o (50)
82 78 -HOAc
The ability of 78 to undergo addition-elimination-addition reactions was first reported by Klager in 1961.'*’ Various calcium salts of 1,1-dinitroalkanes 85 were found to react with 78 as summarized in Equation 51 to give, after acidification,
1,1,3,5,5-pentanitro derivatives 8 6 in good yields. 2-Nitroallyl acetate (78) is therefore of interest as a reagent which undergoes overall double Michael addition reactions.
43 NÛ2 ^^02 l.CaHj, EtOH NO2 2 R - C - H + NO: ^ 85 O (51) R= CH3 , CH2 CH3 . CH2 CH2 CH3 , CH2 CH2 OCCH3
NO2
R= CH2 C - Z ; Z= CH3 . CH2 CH3 . CH2 CH2 CH3 NO2
From 1981 to 1990 Seebach et added greatly to knowledge of synthesis and the chemistry of2 -nitroallyl esters. In addition to elaboration of the behavior of 2 - nitroallyl acetate (78), preparation and various advantageous reactions of 2-nitroallyl pivalate (87) were reported. 2-Nitroallyl pivalate (87) is obtainable in 43% yield
(Equation 52) by 1) reaction of 2-nitro-1,3-propanediol (84) with pivalyl chloride (88,
3.3 equiv) in CH 2CI2 to give 2-nitro-1,3-propanediol dipivalate (89) and 2) elimination of 84 with sodium acetate in MTBE at 25
CHoC NO-, O
OH + 2
NaOAc
MTBE 87
2-Nitroallyl pivalate (87) has been found to react selectively with one equivalent of a wide variety of organolithium (Equation 53) and Grignard reagents (Equation 54) and with lithium enolates of ketones (Equation 55) to form 2-nitroallyl derivatives in good yields.^^
44 \ ° -100 “c yOz (53) RU 4- ^
R= alkyl, aryl, naphthyl
NO 2 -100 °C NO; (54) RMgX ^
R= n-octyl. n-butyl
9 \ o NOj ,7g 0(~ O NOj
r A ^ L I 4 . <55.
Of relevance to the research program presently proposed is that Seebach and
Knochel^" report two examples of addition of secondary aromatic amines to 78. N-
Methylaniline is found to react with 2-nitroallyl pivalate (78) in THF at -78 °C to form
N-methyl-N-(2-nitro-2-nitroallyl)aniline (90. Equation 56) in 8 6 % yield. Similarly, phenothiazine (91) and 78 in THF at -78 °C yield the addition-élimination product: N-
(2-nitro-2-nitroallyl)phenothiazine (92, 95%, Equation 57).
^ X - 78 II J 90
sH- h * s H - X / -78 °C 92
91
45 C H APTER 4
RESULTS AND DISCUSSION
PREPARATION OF 2-NITROALLYL ESTERS
The principal objective of this effort is investigation of reactions of primary amines
with 2-nitroallyl esters. As summarized in the Historical Information Section, 2-
nitroallyl acetate (78) has been prepared by distillation of 2-nitro-1,3,-propanediol
diacetate (82) in the presence of sodium acetate"**^ and by vapor-phase elimination of 2 -
nitro-1,3-propanediol diacetate (82) over calcium phosphate."*^ Since pyrolysis of 82
was reported to be effective on a laboratory scale, this method was initially chosen for
preparation of 2 -nitroallyl acetate (78) in the present work.
In initial efforts to eliminate di acetate 82 over calcium sulfate at 160 “C (Table 4.1)
no 2-nitroallyl acetate (78) was obtained. Much of the initial diacetate (82, 74%) was
recovered. As the nitrogen flow decreased and the pyrolysis contact time increased,
up to 48% conversions of 82 to 78 were obtained. Examination of the furnace tube revealed the presence of large amounts of charred material on the calcium sulfate catalyst. In these experiments82 was dropped as a liquid into the heated, packed pyrolysis chamber and the contact times and presumably the temperatures of elimination were difficult to control. A series of experiments was then conducted in which the amount of catalyst (100 g, Drierite) in the furnace tube was held constant
46 and the effect of the surface area of an inert heat-transfer solid, berl porcelain saddles, placed ahead of the catalyst was investigated. After each run the catalyst was discarded and oxygen was passed through the furnace tube heated by a flame until all of the black residue was removed. The presence of berl saddles has a significant effect on pyrolysis of 82. When a pyrolysis is effected over the saddles (25 g) at 160 °C and a nitrogen flow of 1.25 SLPM, 78 is formed in 54% yield with 4% 78 remaining.
Under the same conditions without the saddles, a 48% yield of 78 is obtained with
24% 82 remaining unreacted. Contact time, temperature, and the catalyst are important variables in pyrolysis of 82. Optimization studies were not made since ample supplies of 78 were obtained from the above runs. There is concern however that vapor-phase decomposition of 82 will not be a practical industrial route to 78.
Conversion Y ield 78 R ecovered Nitrogen Flow Berl Saddles 82 Tem p (°C) m (SLPH) (%) (%)
1. 190 0.75 yes 44 50 12
2. 190 1.25 yes 50 53 5
3. 160 1.25 yes 54 56 4
4. 130 1.25 yes 31 39 21
5. 160 1.75 no 0 0 74
6. 160 1.25 no 48 63 24
7. 160 0.63 no 42 63 33
Table 4 .1 : Pyrolysis of 2-nitro- 1,3-propanediol di acetate (82) over CaSO^ to 2-nitroallyl acetate (78).
47 An alternate method for preparing 78 was then investigated. Ores ko et ai report synthesis of 2-nitroallyl alcohol (93) in 26% yield by adding 60% nitric acid to a suspension of sodium l,3-dihydroxy-2-propanenitronate (83) in CHiChat -20 °C
(Equation 58).
HoJÇ,OH .60%HNO, HoJC « 8 , -NaNOj ^ -H ,0 M
It has been presently found that reaction of 83 with 40% sulfuric acid gives 93 in (>)
42% yield (Equation 59). Compound 93 can be isolated simply by evaporating the
CH 2CI2 and the resulting product is sufficiently pure for synthetic uses. Further purification may be effected by vacuum distillation but the yields of93 are lowered because of decomposition of the product during distillation. Since 83 is easily prepared on a large scale and converted simply to 93, large quantities of 93 may now be produced practically.
NO2 Na NO2
+ 60% H 2 SO , ------• (59) - NaHSO^ ^ . H ,0 ”
Further, 93 reacts with acetyl chloride (2 equiv) in CHCI3 to yield 78 (> 49%,
Equation 60).
9 -HCl 9 T ' + CH 3 CCI ------► (60)
93 78
48 Acetic anhydride however, even in large excess, is much less effective than acetyl
chloride for converting 93 to 78. The sulfuric acid/ acetyl chloride procedures for
converting 83 to 78 were not maximized but it is clear that these sequences have
excellent potential for preparing 78 in large quantities if desired without the
difficulties encountered in vapor-phase pyrolysis of 82.
Study was then made of the behavior of trifluoroacetic anhydride with 2-nitro-1,3-
propanediol (84). Reaction of trifluoroacetic anhydride (2 equiv) with 84 forms 2-
nitro-1,3-propanediol ditrifluoroacetate (94) which upon distillation (bp 78-80 °C @
4.5 mm Hg, oil bath temperature 120 °C) eliminates trifluoroacetic acid to form 2-
nitroallyl trifluoroacetate (95, Equation 61).
NOg 0 0 - 2 TFA 9 ^ ^ 2 O ^11 _ II II O N + 2 CF3COCCF 3
d istil! NOg (61) " = ( i? -TFA — OCCF 3
95
Further, when 93 is reacted with trifluoroacetic anhydride (2.4 equiv) 95 is produced in 75% yield (Equation 62). This method is satisfactory for preparing large quantities of 95.
i? ? -TFA i? „ + CF 3COCCF 3 ------► FaCCO^^t^ (62)
93 95
49 REACTIONS OF BULKY PRIMARY ALKYLAMINES
WITH 2-NITROALLYL ESTERS
As has been described previously TBNAZ (2) is an important precursor for synthesis of TNAZ (1). TBNAZ (2) has been prepared in pilot-plant quantities and is a stable molecule which can be distilled without decomposition and can be converted simply to its nitronate salts by bases. Further, TBNAZ (2) is much more stable than its self-neutralized zwitterionic tautomer 96 (Equation 63) and it does not ring-open readily to N-rerr-butyl-2-nitroallylamine (97).
© H NO2
(63) N T- r f f ' H 96
Of importance to the research objective to be described shortly is that intermolecular conjugative addition reactions of nitroolefins (98, Equation 64) with secondary amines which are not highly basic occur readily with proton-transfer to give P-aminonitro adducts (99).^^
0 H NOg NOg
RgNH + (64)
98 99
50 Even tertiary amines such as triethylamine add conjugatively to nitroethylene and 1,1- dinitroethylene (100, Equation 65) at low temperatures/^
NOg EtgN -t- (65) NOg 100
It is also emphasized that the addition reactions illustrated above frequently lead to oligomerization of the nitroolefins by continued anionic addition processes.
It thus became of interest to attempt development of a practical synthesis of nitroallylamine 97 and study its possible ring-closure to TBNAZ (2) by processes which are the reverse of that in Equation 63. Study was then initiated of reactions of rerr-butylamine with 2-nitroallyl acetate (78) in the hope that l-rer(-butyl-2- nitroallylamine (97) is formed which would then cyclize to TBNAZ (2, Equation 6 6 ) efficiently.
0 .NOg NOg -HOAc -NH; -GAc H 78 ( ) 0 66 NOa H NOg NOg
N^ n ' H
rerr-Butylamine was chosen for study because it is a bulky primary amine and might lead to efficient synthesis of TBNAZ ( 2). It was hoped that the steric bulk of the tert-
51 butyl group would prevent complicating intermolecular and oligomerization reactions
after 97 is formed and that the bulky alkyl group would facilitate ring-closure of97 to
2.
Additions of 2-nitroallyl acetate (78) to rerr-butylamine ( 1 equiv) in THF at -78 °C
result in rapid disappearance (< 30 min) of the reactants to give bright yellow
solutions. When the solutions warm to ambient temperature their colors fade.
Removal of the THF from the reaction mixtures give viscous red oils which by
GC/MS/IR analysis contain no TBNAZ (2). Vacuum distillations (0.1 mm Hg) or
heating of the viscous oils (up to 15 g) give in volatile charred products and no TBNAZ
(2). Under the above conditions TBNAZ (2) is distillable, stable and will pass through
a GC/MS/IR instrument. The above reaction products are highly polar and do not
move on varied TLC plates using CHiCh, EtOAc, acetone, or MeOH as the eluent.
Many experiments were conducted with rcrr-butylamine and 2-nitroallyl acetate
(78). Reactions were effected at -78 °C using different solvents: CH 2CI2, EtOAc, and
MeOH. The order of addition of the reagents was varied: 1) rcrr-butylamine was added to 2-nitroallyl acetate (78), 2) 2-nitroallyl acetate (78) was added to tert- butylamine and 3) both rc/t-butylamine and 78 were added simultaneously to THE at
-78 °C. The concentration of the reactants were varied greatly: dilute and concentrated. The reaction times and temperatures were varied. In all of the above experiments the reaction product was a highly polar intractable oil. No TBNAZ (2) was detected as a reaction product.
52 The behavior of 2-nitroallyl acetate (78) with additional /err-butylamine (2 equiv)
was then studied to see if the extra rerr-butylamine would lead to cyclization to
TBNAZ (2) by neutralizing the acetic acid formed in the reaction. When either 78 was
added to rerr-butylamine or rcrr-butylamine was added to 78 in THF at -78 °C, and the
solution was warmed and then worked-up, no TBNAZ (2) was detected by GC/MS/IR
analysis. The only product obtained was a viscous involatile red oil.
Triethylamine was also used as an external base to neutralize the acetic acid
liberated upon addition-élimination with 97. Further, excess triethylamine might add
to the N-rcrr-butyl-2-nitroallylamine (97) to form 109 which might give 2 by a Sn2
ring-closure displacement mechanism (Equation 71).
NOz \ \ Iff) II EtiN
H 103 -E tjN H O A c 78 (71)
Nof © NOg H NOg NOg © -EtjN + Et,N NEtg > I H H Ï 97
109 fgrf-Butylamine (1 equiv) was thus added to 2-nitroallyl acetate (78, 1 equiv) in THF at -78 °C. After the mixture warmed to room temperature, the THF was removed under vacuum and the red oily intractable residue was then dissolved in CH 2CI2.
53 Triethylamine (4 equiv) was added. The solution was stirred at room temperature for 3
h and water was added. Evaporation of the CH 2CI2 layer gave a red oily product.
GC/MS/IR analysis did not show any TBNAZ (2). Repeating the experiment with less
triethylamine (1 equiv) did not give 2. Likewise adding triethylamine (1 equiv) to 78
and fgrt-butylamine in THF at -78 °C and then warming the reaction mixture to room
temperature did not give 2. A further variation in the reaction of 78 with tert-
butylamine and triethylamine was attempted in which 2-nitroallyl acetate (78) was
added to a mixture of rert-butylamine (1 equiv) and triethylamine (1 equiv) in THF at -
78 °. After warming the reaction mixture to room temperature and removal of the
THF only an oily red product was obtained. No 2 was detected by CG/MS/IR analysis.
In all experiments with 78 and rerr-butylamine, the initial products are yellow at
-78 °C and change to intense red on warming. Many different work-ups of the
reaction products at various temperatures were used in efforts to obtain TBNAZ (2).
Of concern was that a major product might be the involatile salt 101 or 102 depending on the mole ratio of 78 and fgrt-butylamine used in the initial experiment.
-P ..P / H ^NOg
N,© 0 N —p/ H OAc
/K 1 0 2 1 0 1
Other simple products possibly formed are 97,103, and/or 104 depending on the mole ratio of rerr-butylamine and 78 used in the initial experiment.
54 " 103 0 ^ , " 104 H „
The reaction products were thus washed with 2% HOAc or with different bases: 10%
NaHCOs, 10% NaiCO], or 10% NaOH in efforts to effect their neutralization.
TBNAZ (2) was not detected by GC/MS/IR. The viscous products could not be manipulated.
Since the starting materials were consumed in all of the above experiments it was thought that the ferr-butylamine might have added to rerr-butyl-2-nitroallylamine (97) to give the 2:1 adduct, l,3-bis-di(rerr-butylamino)-2-nitropropane (106, Equation 67).
/NOa \ \ fe 11°^ -HOAc
N O , n | ^ N O ,
H H 105 H H 106 H
Furthermore if di adduct 106 is formed it is expected to convert extensively to zwitterion 105 which would make chromatography and distillation of the product very difficult. In attempts to prepare derivatives of 105 and/or 106 the product of reaction of 2-nitroallyl acetate (78) and rerr-butylamine (2 equiv) in THF at -78 °C was treated with a saturated solution of picric acid in EtOH. No crystalline picric acid derivative was obtained.
55 Attempts were then made to derivativize 105 or 106 by reactions with formaldehyde
(2 equiv) as summarized in Equation 6 8 .
,0 CH,0 NO2 CH,0 N- H H H
105 (68 ) NO [„®1 N N- I k \ H OH OH 108
Heterocycle 108 is a stable, readily chromatographable solid which is prepared simply by reaction of rert-butylamine (2 equiv) in water at 25 °C with tris(hydroxymethyl)nitromethane (14, Equation 69) or reaction of 15 with aqueous re/t-butylamine (1 equiv) at 25 °C (Equation 70).
I NO2 NO2 N HnO HO. ,0H + 2 -NHc (69) 'OH 108 14
HO HiO -NH2 (70) N. ^ 0 % 108
56 Upon treatment of the product of reaction of 2-nitroallyl acetate (78) with tert- butylamine (2 equiv) in THF at -78 °C with excess 37% aqueous formaldehyde no 108 could be detected by TLC. As will be discussed further later, reactions of 2-nitroallyl acetate (78) with rerr-butylamine under various conditions do not give TBNAZ (2) and the reaction system is complicated by various oligomeric processes which have not been controllable.
Because it has been impossible to effect reactions of 2-nitroallyl acetate (78) with re/t-butylamine to give N-rcrr-butyl-2-nitroallyl amine (97), TBNAZ (2) or 1,3- bis(fgrr-butylamino)- 2 -nitropropane (106) as isolable products, investigation was then made of the behavior of 2-nitroallyl acetate (78) with very bulky primary amines:
1,1,3,3-tetramethylbutylamine (tg/f-octylamine, 109; Equation 71) and benzhydrylamine (Equation 72) in which the objectives were synthesis of 1-terr-octyl-
3-nitroazetidine (111, Equation 71) and I-benzhydryl-3-nitroazetidine (11, Equation
72), respectively.
57 H NOg H NOg
(71)
H. NOg H NOg - HOAc ^ 6
The principle basis for this study is that because of steric factors, ring-closures of N- rcrr-octyl-2-nitroallylamine ( 110, Equation 71) and N-benzhydryl-2-nitroallylamine
(112, Equation 72) are expected to occur more readily than for l-tcrr-butyl-2- nitroallylamine (97). Further considerations are: 1) 11 is a stable molecule and 111 is also be expected to be stable, 2 ) 1 1 0 and 1 1 2 should be less prone to addition of tert- octylamine (109) and benzhydrylamine, respectively than is l-tcrr-butyl-2- nitroallylamine (97) with rcrr-butylamine, and 3) anionic polymerization of 78 by tert- octylamine (109) and benzhydrylamine should be slower than with tert-butylamine.
The facts are: reaction of rcrr-octylamine (109) and benzhydrylamine with 2- nitroallyl acetate (78), under conditions similar to that for rcrr-butylamine and 2- nitroallyl acetate (78), do not yield detectable quantities (GC/MS/IR analysis) of the
élimination-addition products 1 1 1 and 1 1 2 or their ring-closure derivatives, azetidines
11 and 111 The reaction products are highly-polar, intractable red oils presumably resulting from oligomerization processes which will be discussed shortly.
58 The behavior of rerr-butylamine with 2-nitroallyl trifluoroacetate (95) was then investigated with the hope that the leaving group ability of trifluoroacetate would lead to formation of TBNAZ (2). When 2-nitroallyl trifluoroacetate (95) is added to ten- butylamine or when rcrr-butylamine is added to 95 in THF at -78 °C, the product is however intractable material. In one experiment in which 2-nitroallyl trifluoroacetate
(95) and /crr-butylamine were added simultaneously to THF at -78 °C, the results differ in part from that obtained previously. After rapid aqueous work-up and rapid chromatography of the reaction product a yellow solid was isolated. The ’H NMR of the product showed singlets at 1.19, 3.68, 5,72 and 6.38 ppm in a ratio of 9:4:2:2, respectively and is assigned as N,N-bis(2-nitroallyl)terr-butylamine (113, 16% yield).
The bis-2-nitroallyl product 113 is very unstable, decomposing in the solid state or in solution within 30 min. Formation of 113 presumably results from addition-
élimination of 97 as an amino nucleophile to 95 (Equation 73).
NO2 THF OpN^ -NH2 + H2C=C ► \ C=CH2 CH2-O2CCF3 -78 °C - ^ N H - C H 2
95 - TFA 9 7 (73) NO2 H2C=C NO2 95 CH2-O2CCF3 \ /■ -N -TFA ' ^ 1= NO2 113
The reaction of 97 with 95 to give 113 is important in that such processes might also be occurring in reactions of 2-nitroallyl acetate (78) with terr-butylamine, ten-
59 octylamine, and benzhydrylamine.
The failure to characterize the products from the reaction of 2-nitroallyl acetate
(78) with terr-butylamine was extremely disappointing. The above results are similar to those of Ranganathan et al^’ who found that addition of amines with a pKa > 8 to nitroethylene (114) did not form the addition product but rather polymeric materials
(Equation 6 8 ).
RNHCH2CH2NO2 © / NO2 © NO2
RNH 2 + H2 C=C - : “ RNH 1 CH 1 CH ------^ (74)
114 ^ 0 NO2 NO2 RNH2CH2CH-(CH2CH2)n
The reaction of rerr-butylamine (pKa 10.5^°) with 2-nitroallyl acetate (78) behaves in a similar way to alkylamines with nitroethylene. It appears that the reaction oftert- butylamine with 2-nitroallyl acetate (78) results in the formation of oligomeric products (Equation 69).
60 - ^ N H 2 NÛ 2 -H O A c OgN ■NH2 + H 2C = C ^ ------^ \ (j—C H 2 CH2OAC - 4 —NHCH2 7» ^ 9 7 (75) NÛ2 © H2C=C^ 0 NO2 Hg) / 78 CH2OAC \ NO2 Hg) \ H Y ® / 78 \ % r 2
^ —Nue q O.N
REACTIONS OF PRIMARYAROMATIC AMINES
WITH 2-NITROALLYL ESTERS
After months of effort, control of the addition-élimination reactions of tert- butylamine, rerr-octylamine (109) and benzhydrylamine with 2-nitroallyl esters to give
N-3-alkylamino-2-nitropropenes (73) and/or their isomeric 1 -alky 1-3-nitroazetidines
(74) has been impossible. As discussed in the Historical Information Section Chapter
3, weakly basic secondary amines react with 2-nitroallyl pivalate (87) by addition-
élimination to give the corresponding N-substituted-2-nitroallylamines. Of relevance
is that primary amines which are weak bases (pK^ 2-8) do add to nitroethylene (114,
Equation 76) to give, after proton transfer, the corresponding 2-amino-1 -nitroethanes
(151) as stable products.^’ Amines which are strong bases polymerize nitroethylene.
61 © NOg (B NO? NO 2
ArNHi + H 2 C=C ^ ArNHjCHjCH ^ ------ArNHCHiCH (76)
150 ^ 151
The reactions of primary aromatic amines with 2-nitroaiiyl esters however have not been previously investigated. Study of the behavior of primary aromatic amines with
2-nitroallyl esters has now been initiated. The principle objective of this effort is to determine if the primary amines react with 2-nitroallyl esters (71, Equation 62) to give
2-nitroallylamines (73) which then cyclize to I-aryl-3-nitroazetidines (74).
o NO. r r ® X " + Ar-NHz < X \ / (77) -RCOoH N© N 71 ■ a/ H a/ H i r 115 116
3,5-Dinitroaniline (117), a weak nucleophile and a weak base, has now been found to react with 2-nitroallyl acetate (78, I equiv) at -78 °C to 25 °C (Equations 78 and 79) to give 3-(3,5-dinitrophenylamino)-2-nitro-l-propene (118, 45%) and I,3-bis(3,5- dinitrophenylamino)-2-nitropropane (119, 12%).
o NO. -78 »C ° " > = \ 1'° : (78)
78 OoN - HOAc O 2 N 117 118
NO. 118 + THF ) <” >
■HOAc O 2 N 119
6 2 In a separate experiment reaction of 117 (2 equiv) with 78 occurs in THF at -78 °C to give 119 in 67% yield. Even more impressively, 119 is formed in 63% yield by addition-elimination-addition reactions of one equivalent of 117 with 2-nitroallyl trifluoroacetate (95) in THF at -78 °C (Equation 80).
o N O , .7 8 - c
95 O2N -TFA O2N ^ 110 N O 2 117
Products 118 and 119 are handleable solids and are assigned unambiguously from their elemental analyses and spectral values. It is important to have demonstrated that 117 reacts with 78 and 118 by logical addition-élimination and addition-elimination- addition mechanisms.
Efforts were then made to ring-close 118 to I-(3,5-dinitrophenyl)-3-nitroazetidine
(153, Equation 81).
© O2N NO2 H NO2
(81 )
o , n ' " ' 118 Y NO2 0 2 N NO2
120
Refluxing 118 in THF for 7 days did not yield 120; only starting material was recovered (64%). Further, reaction with 118 with DBU occurs rapidly to give intractable products; ring-closure of 153 to 156 did not occur. The failure of 120 to ring-close is similar to the behavior reported for 2-[a(N-tert-
63 butylamino)benzyl]acrylophenone (121, Equation 82).*^’ W hen 121 is heated in either
methanol or acetonitrile no l-re/t-butyl-2-phenyl-3-benzoyIazetidine (122) is
obtained. 61
CqHs CHzBr CsHs -NHg ■ <^CgHg / / ■*- < V H COCgHs NH CHjCN N (82) or MeOH 121 122
Ring-closure of 121 to 122 (Equation 82) is however effected by reaction of HBr with
121 to form 123 which is then converted by re/t-butylamine to 122 in 80% yield. 61
CgHg O ^ C g H g O w C g H g -NHg ______HBr ^ y ^ G g H g CeHg
NH CHCI3 0 © NH2 Br N (83) Br
121 123 122
The behavior of 78 with p-toluidine (124), a primary amine more nucleophilic and
basic than 117, was then investigated. Reaction of 124 with 78 ( 1 equiv) at -78 °C in
THF does not stop at 125; the 1:2 adduct l,3-bis(4-methylphenylamino)-2- nitropropane (126, Equation 84) is obtained in 60% yield.
64 o NO2 y = \ -78 °C / = \
H 78 125 (84)
N0 2 „
126
Under the same experimental conditions as for 78 (Equation 83) 95 reacts with 124 (1 equiv) to form 126 (Equation 85) in 79% yield.
O N O 2 /=\ -78 °C /—\ /—\ _ _!i_ I . / . \ __MU ------to- —L /)— M JL N— 95 124 -TFA There was no evidence by 'H NMR for 126 as a reaction product. It is clear that as the nucleophilicity and the basicity of a primary aromatic amine increase it becomes more difficult to stop reactions of the amines with 2 -nitroallyl esters to give the initial addition-élimination products. The behavior of 2-nitroallyl acetate (78) with highly-hindered primary aromatic amines was then studied. As expected 78 reacts slowly with 2-rerr-butylaniline and with 2,4,6-trimethylaniline. With extended reaction times and forcing conditions complex mixtures of products were obtained which were not separable by chromatography. GC/MS/IR analysis of the mixtures showed no evidence for the presence of azetidines. Because of the difficulties encountered with the two hindered anilines and 78, their reactions were not studied further. 65 Investigation was then made of the behavior of o-phenylenediamine (127) with 78. Of particular interest is determination if the product of addition-élimination 128 (Equation 8 6 ) undergoes ring-closure to give the seven-membered ring derivative, 3- nitro-2,3,4,5-tertrahydro-H-benzo[6][l,4]diazepine (129). According to the Baldwin rules of ring closure, formation of 129 from 128 is a favored process (7-endo-trig).*' Indeed, reaction of 78 with 127 in THF at -78 °C occurs rapidly by addition- elimination-addition and proton transfers to yield 129 (>33%). Upon careful work-up of the reaction 128 was not found. The only product detected by TLC was 129. Cycloadduct 129 is a stable solid and its structure is assigned from its elemental analysis and its MS and NMR spectral properties. H NOg I 128 H 129 Reaction of Sodio N-tert-Butylacetamide (130) and 2-NitroalIyl Acetate (78) After the successes in the reaction of aromatic amines with 2-nitroallyl acetate (78) study was made of the behavior of sodio N-ferr-butylacetamide (131) with 2-nitroallyl acetate (78). Sodio N-rerr-butylacetamide (131) is readily prepared from N-terr- butylacetamide (130, Equation 78) and sodium hydride in refluxing THF. Reaction of 131 with 2-nitroallyl acetate (78) at -78 °C in THF and then warming the mixture to room temperature gives the mono-addition product N-(/err-butyl-(2-nitroallyl) acetamide 132 (Equation 87) in 29% yield. 6 6 ^NOg O O ^ O A c 9 J L NaH A. 78 N CH 3 (87) -N 'C H 3 - - N ^ C H a ------I — o O / " H TH F N a THF. -78“C 130 131 -NaOAc O2 N The structure of 132 was assigned by 'H and '^C NMR. The 'H NMR shows two singlets at Ô 1.44 and 2.07 ppm in the ratio of 9:3 which correspond to the rerr-butyl group and the acetyl group, respectively. The methylene group exhibits a triplet at Ô 4.43 ppm. The olefinic proton resonances appear as quartets at Ô 5.81 and 6.72 ppm. The '"’C NMR of 132 displays signals at 5 25.6 and 28.7 ppm for the methyl groups of the rerr-butyl group and on the amide nitrogen, respectively. Peaks at 6 45.3 (C) and 57.9 (CHi) are assigned based on the chemical shifts. The olefinic carbons show resonances at Ô II8.7 (C=CHi) and 155.7 (C=C(NO])H) ppm; that of the carbonyl group is at 6 171.7 ppm. As expected 132 is unstable. Compound 132 decomposes completely within one day at room temperature. The present study of the behavior of bulky primary amines with 2-nitroallyl systems merits further discussion. It has been previously reported from this laboratory^' that 2- nitroallyl acetate (78) and 2-nitroallyl pivalate (87) react at -78 °C in THF with tert- butylamine, rerr-octylamine (109) and benzhydrylamine to give, upon treatment with triethylamine atO°C, I-rerr-butyl-3-nitroazetidine (2), I-rerr-octyl-3-nitroazetidine (111) and I-benzhydry 1-3-nitroazetidine (11), respectively, in 50>80% yields. All attempts by this researcher, and the effort has been enormous, to obtain the results of 67 the previous experiments have failed . There is no evidence in the present study for reaction of a hindered primary amine with a 2-nitroallyl ester as in Equation 39 to give the corresponding l-alkyl-3-nitroazetidine (74). Other reactions occur more rapidly. Ring closure of 2-nitroallylamine 73 is presumably resisted by angle-strain in the four-membered cyclic transition state, steric resistance to delocalization at the developing nitronate center and the 1,3-repulsive effects by the bulky rerr-alkyl group within the puckered developing nitroazetidinyl ring system (133). The resistance of a 2-nitroallylamine 73 to ring closure is similar to that for other allylamines substituted at C-2 by electron-withdrawing groups. The present facts and interpretation are also consistent with theory given by Baldwin*' for the inability of the above systems to ring-close. H R NO2 133 The present results can be rationalized however by initial attack of the hindered amine (Equation 8 8 ) on a 2-nitroallyl ester (71) by a rapid “Michael-like” addition- élimination or a Sn2’ displacement mechanism to give the corresponding N-alkyl-2- nitroallylamine 73. 6 8 NO2 N0 2 R'-NHn R-NH-, FI'-HN 4 ^ HOoCR iCR 73 71 © (88) R'-HN 135 R’-HN R’-NH H o 0 R’-NH R'-HN—V p 134 ® y = N R'-HN' - H N — / O - 136 I H R’-HN Reaction of 73 with a second molecule of the hindered amine is then expected to give the “Michael adduct 134” which continues “Michael additions” to form oligomers by carbon (135) or oxygen (136) alkylation of the nitronate moieties. Oligomers resulting from oxygen alkylation are nitronic esters and are expected to be unstable. An alternate or competitive possibility, for which there is evidence from from the behavior of 2-nitroallyl trifluoroacetate (95) with ferr-butylamine, is a Michael- addition-elimination or a Sn 2’ reaction of N-rgrr-butyl-2-nitroallylamine (97) with a 2- nitroallyl ester (71) to give 137 which then undergoes amine oligomerizations. O2 N r V OgN 137 As yet the structures of the non-volatile, highly-polar products from the present 69 reactions of te/t-butylamine, /^/t-octylamine (113), and benzhydrylamine with 2- nitroallyl acetate (78) are not known. Of further interest with respect to the above facts and interpretations is that all attempts to cyclize 2-nitroallyl alcohol (93) to 3-nitrooxetane (138, Equation 89) on storage, thermally or in the presence of highly hindered bases failed. H NÜ2 (89) OH O The reaction products are oligomeric and intractable. CONCLUSIONS Reactions of hindered primary alkylamines (rm-butylamine, rm-octylamine (110) or benzhydrylamine) with either 2-nitroallyl acetate (78) or 2-nitroallyl trifluoroacetate (95) under various conditions do not give N-alkyl-3-nitroazetidines; unidentified intractable products are obtained. Aromatic amines (3,5-dinitroaniline (117) and p-toluidine (124)) react with either 78 or 95 to give addition-élimination or addition-elimination-addition products 3-(3,5- dinitrophenylamino)-2-nitro-l-propene (118), l,3-bis(3,5-dinitrophenylamino)-2- nitropropane (119) l,3-bis(4-methylphenylamino)-2-nitropropane (126) which are stable. Addition of 2-nitroallyl acetate (78) to o-phenylenediamine (127)results in ring-closure to yield the seven-membered ring derivative, 3-nitro-2,3,4,5-tetrahydro-H- 70 benzo[Z>][l,4]diazepine (129). Reaction of sodio N-rerr-butylacetamide (130) with 2- nitroallyl acetate (78) gives the mono-addition elimination product N-(rerr-butyi-(2- nitroallyOacetamide (132). SUMMARY: PART 2 Preparation of 2-nitroallyl acetate (78) by pyrolysis of 2-nitro-1,3-propanediol diacetate (82) over calcium sulfate and reaction of 2-nitroallyl alcohol (93) with acetyl chloride has been studied. The latter method is preferred for synthesis of 78 because of the simplicity of preparing 2-nitroallyl alcohol (93) from sodium l,3-dihydroxy-2- propanenitronate (83) and 40% H 1SO4. Reactions of primary alkylamines (re/t-butylamine, rerr-octylamine (110) or benzhydrylamine) with either 2-nitroallyl acetate (78) or 2-nitroallyl trifluoroacetate (95) under various conditions did not yield N-alkyl-3-nitroazetidines. Intractable products were obtained. Attempts to treat the products of 2-nitroallyl acetate (78) with terr-butylamine with either picric acid or formaldehyde to form identifiable compounds were unsuccessful. 71 CH A PTER 5 EXPERIMENTAL SECTION General Procedures Melting points of solids were determined in capillary tubes in a Thomas Hoover melting point apparatus and are uncorrected. Infrared spectra (IR, bands reported in cm ') were produced with a Perkin-Elmer (Model 1600) Fourier Transform single beam infrared spectrometer. Liquid samples were analyzed as neat, thin films between sodium chloride plates. Solid samples were analyzed as dispersions in pressed potassium bromide pellets. Nuclear magnetic resonance (NMR, peaks reported in ppm downfield from tetramethylsilane at Ô 0.00) were determined on either a Bruker AM-200 or Bruker AC-300 Fourier Transform nuclear magnetic resonance spectrometer operating at 200.133 or 300.133 MHz for ‘H spectra and at 50.323 or 75.469 MHz for '^C spectra. High resolution mass spectra were obtained from The Ohio State University Chemical Instrument Center using either a VG 70-250S or a Kratos MS-30 mass spectrometer. Reaction mixtures were analyzed using a Hewlett-Packard gas chromatograph (Model 5890, Series II) equipped with a mass spectrometer detector (Model 5970B) 72 and a Fourier Transform infrared detector (Model 5968A) (GC/MS/IR). Infrared spectra from this instrument are recorded as “gas phase”. Mass spectra are low resolution. Reaction solvents were dried and purified prior to use. Diethyl ether (Et^O) and tetrahydrofuran (THF) and benzene were distilled from sodium under argon. Other solvents were distilled from appropriate desiccants prior to use. Commercial solvents were used for recrystallization, extraction and chromatography. Solvents were removed from reaction products in vacuo on a rotary evaporator at pressures ranging from 40 to 60 mm Hg. Throughout this experimental section the following abbreviations are used: EtOAc (ethyl acetate), CH3OH (methanol), EtOH (ethanol), SG (silica gel), CH,Ch (dichloromethane) and C C I4 (carbon tetrachloride). l-rerr-Butylazetidin-3-oi Hydrochloride ( 6 ) Acetonitrile (1.67 L) was cooled (5 “C) and rerr-butylamine (907.8 g, 12.4 mol) was added followed by epichlorohydrin (1147.5 g, 12.4 mol). The cooling bath was removed and the solution heated to 35 °C . After a short time a solid formed and an exotherm occurred that caused the temperature of the mixture to rise to 50 “C. Ice bath cooling was used to keep the temperature of the reaction mixture between 35 to 45 °C for 8 h. The resulting suspension was stirred 2 days at ambient temperature. 'H NMR showed that no epichlorohydrin remained and the suspension was heated to 85 °C for 1 h. After cooling the suspension to 4 °C the solid obtained was filtered, washed with 73 cold acetonitrile, then Et,0 and pressed dry overnight to give I-rert-butylazetidin-3-ol hydrochloride ( 6 , 972.5 g, 47%); mp 144-153 “C, lit'"165-166 “C. \-tert- Butylazetidin-3-ol (21) was prepared by first dissolving 6 in excess aqueous sodium hydroxide, saturating the solution with sodium chloride and then repeated extractions with Et;0. The organic extracts were dried (MgSOJ, and the Et,0 evaporated to give l-t-butylazetidin-3-ol (21) as a clear, viscous oil which is pure enough for subsequent use. High purity 21 was prepared by distillation ( 84-85 “C @ 0.8 mm Hg) and the distillate solidified; mp 43.5-45 °C; lit 45-47 “C. 1 -te/ï-ButyI-3-methanesu Ifonylazetidine (7) Dichloromethane (CH,C1,, 350 ml), 1 -tg/-f-butyl-3-azetidin-3-ol (21, 38.83 g, 0.30 mol) and triethylamine (30.46 g, 0.31 mol) were mixed in a flask equipped with a CaCU drying tube. After cooling the solution to -12 °C (ethylene glycol/ dry ice bath) methanesulfonyl chloride (34.47 g, 0.30 mol) was added dropwise keeping the temperature between -12 to -8 “C. A precipitate of triethylammonium hydrochloride formed. After the addition had been completed the suspension was warmed to room temperature for 5 min. The suspension was filtered and the CH^Cl, layer was extracted with cold aqueous 3.5% HiSO; (2x250 mL). The acidic extracts were made basic with excess Na^COj. The solution was extracted with CH2CU( 5x100 mL) and dried (MgSO^). The majority of the CH,CL was removed on a rotary evaporator. Residual CHiCL was removed in vacuo (0.1 mm Hg). l-tert-Butyl-3- methanesulfonylazetidine (7, 62.1 1 g, 98%) was isolated as a viscous clear oil which still contained CH,Ck (4.5%): 'H NMR (CDCI 3) 5 0.97 (s, 9H), 3.01 (s, 3H), 3.28-3.36 74 (m, 2H), 3.52-3.60 (m, 2H), 5.05 (pentet, IH, J= 5.6 Hz) ppm. This product was used immediately because it decomposes slowly at room temperature. l-/^rf-Butyl-3-bromoazetidine (50)’ A rapidly stirred solution of toluene (100 mL), water (50 mL), I-rert-butyl-3- methanesulfonylazetidine (7, 17.36 g, 83.7 mmol), sodium bromide (18.50 g, 179 mmol) and tetraethylammonium bromide (2.52 g, 12 mmol) was heated to 55-60 °C in a Morton flask for 15 h. The aqueous layer was saturated with sodium chloride and separated. The 'H NMR (CDCI3) of the toluene solution (92.77g) showed 1-tert- butyl-3-bromoazetidine (50, 5.2%) to be present. Based upon ‘H NMR data the weight o f 50 was 4.81 g, (30%): 'H NMR (CDCI3): Ô 1.01 (s, 9H), 3.53-3.60 (m, 2H), 3.79-3.85 (m, 2H), 4.50 (pentet, IH, J= 5.1 Hz) ppm. l-rert-Butyl-3-chicroazetidine (51) The procedure of Gaertner^"* was followed. Purified l-rerr-butylazetidin-3-ol (21, 15.02 g, 116 mmol; distilled and dried //i vacuo over P,0;) was dissolved in dry C C I4 (250 mL; dried over CaCLand distilled) and triphenylphosphine (34.16 g, 130 mmol; recrystallized from hexanes and dried over P,0;) was added. The suspension was refluxed 60 h. The triphenylphosphine oxide precipitate was filtered and the organic layer was extracted with cold, aqueous 5% H 3SO4 (4x50 mL). The H3SO4 extracts were cooled in an ice bath and excess concentrated aqueous NaOH was added. The solution was extracted with Et,0 (4x50 mL), dried (MgS 0 4 ) and concentrated i/i vacuo to a red oil. Distillation of the red oil ( 80-83 °C (g 37 mm Hg; lit ” 60-66 °C (§ 1 75 mm Hg) gave l-/err-butyl-3-chloroazetidine (51, 11.03 g, 64%); ‘H NMR (CDClj): 5 0.93 (s, 9H), 3.22-3.31 (m, 2H), 3.56-3.64 (m, 2H), 4.38 pentet, IH, J= 5.2 Hz). Reaction of l-terr-ButyI-3-methanesulfonyIazetidine (7) with Sodium Cyanide A mixture of sodium cyanide (4.51 g, 92 mmol), water (45 mL), toluene (95 mL), l-rert-butyl-3-methanesulfonylazetidine (7, 15.74 g, 75.9 mmol) and tetraethylammonium bromide (3.77 g, 18 mmol) was stirred 2 h at 50-55 °C and then at ambient temperature for 10 h. The aqueous layer was saturated with sodium chloride and the solution was stirred vigorously. The organic layer was dried (MgSO^) and concentrated in vacuo. Distillation of the residue ( 52-55 @ 0.1 mm Hg; lit"'^ 60-61 @ 2 mm Hg ) yielded l-terr-butyl-3-cyanoazetidine (44, 6.53 g, 62%): ‘^C NMR (CDClj): Ô 16.3, 23.8, 50.2, 52.0, 120.4 ppm; FTIR (neat): 2966, 2868, 2241, 1471, 1390, 1364, 1298, 1236, 1175, 1105, 1017, 8 8 6 , 806, 703 cm '; MS (Low Res) m/e 138 (M l, 123, 94, 82, 70, 57,41. In a similar experiment with 2 equivalents of sodium cyanide, a mixture of water (100 mL), toluene (200 mL), 1 -t-buty 1-3-methanesulfbnylazetidine (7, 82.36 g, 0.39 mmol), sodium cyanide (38.95 g, 0.79) and tetraethylammonium bromide (5.75 g, 0.27 mmol) was stirred at 90 °C for 2 h. Work-up as above and distillation (55-60 °C @ 1.2 mm Hg) gave 44 (26.02 g, 47.4%). The retention time and the MS (Low Res) of this product were identical to that of an authentic sample of 44. 76 In a larger scale experiment with 1.2 equivalents of sodium cyanide and 0.07 equivalents of tetraethylammonium bromide, a solution of l-r-butyl-3- methanesulfonylazetidine (7, 134.89 g, 0.65 mmol) ,water (150 mL), toluene (250 mL sodium cyanide (38.90 g, 0.79) and tetraethylammonium bromide (1.38 g, 6.5 mmol) was stirred rapidly. An exothermic reaction caused the temperature of the mixture to rise to 38 °C . The temperature of the mixture remained at 38 °C for 4 h. The solution was then stirred for 7 h at ambient temperature. ‘H NMR (CDClj) showed approximately 50% conversion of 7 to 44 and the solution was heated at 45-50 ”C for 8 h. Work-up as above and distillation (59-62 °C @ 1.1 mm Hg) produced 44 (35.90g, 40%). GC/MS/IR analysis showed the product to be identical to that of an authentic sample o f 44. Reaction of l-t^rr-Butyl-3-bromoazetidine (50) with Sodium Cyanide A solution of l-r-butyl-3-bromoazetidine (50, 4.8 Ig, 25 mmol) in toluene (100 mL) was added to a Morton flask. Sodium cyanide (1.53 g, 31 mmol), and tetraethylammonium bromide (1.20 g, 5.7 mmol) in water (45 mL) were added and the mixture was stirred rapidly at 50-60 “C for 21 h. Work-up and distillation (36-38 “C @ 0.05 mm Hg) produced 44 (2.33 g, 67%); the retention time and MS (Low Res) of this product were identical to that of an authentic sample of 44. Reaction of l-rgrt-Butyl-3-chloroazetidine (51) with Sodium Cyanide A solution of sodium cyanide (0.40 g, 8.2 mmol), water (10 mL), toluene (20 mL), l-t-butyl-3-chloroazetidine (51, 1.00 g, 6 .8 mmol) and tetraethylammonium bromide 77 (0.34 g, 1 .6 mmol) was stirred for 20 h at 70-75 “C. After usual work-up, 44 (0.50 g, 53%) was isolated; the retention time and MS (Low Res) of this product were identical to that of an authentic sample. Reaction of l-tert-Butyl-3-cyanoazetidine (44) with Lithium Diisopropylamide A solution of LDA was prepared by reaction of diisopropylamine (0.37 g, 3.7 mmol), and «-butyllithium (3.0 mL, 1.22 M in hexane, 3.7 mmol) in THF (25 mL) under argon at -78 °C. After l-rert-butyl-3-cyanoazetidine (44, 0.50 g, 3.6 mmol) had been added the bright yellow solution was stirred at -78 °C for 1 h. Ethyl bromide (0.39 g, 3.6 mmol) in THF was added over 9 min. The mixture was then stirred for 3 h at -78 °C. After warming to room temperature the solution was poured into water (100 mL) and extracted with Et,0 (3x25 mL). The organic extracts were washed with brine (100 mL), dried (MgSO^) and evaporated to a red oil. Chromatography (SG, 4 :1 hexaneszEtOAc) gave l-terr-butyl-3-cyano-3-ethylazetidine (56, 0.44 g, 73%) as a clear liquid; 'H NMR (CDCI 3): Ô 0.90 (s, 9H), 1.02 (t, 3H, J= 7.4 Hz), 1.89 (q, 2H, J= 7.4 Hz), 3.11 (AB, 2H, J= 7.2 Hz), 3.47 (AB, 2H, J= 7.2 Hz) ppm; "C NMR (CDCI 3): Ô 9.5, 23.7, 29.1, 30.8, 51.6, 54.6, 122.8 ppm; FTIR (neat) 2967, 2868, 2235, 1684, 1540, 1472, 1363, 1244, 1088, 1011, 848, 799 cm '; HRMS (El) calcd for C.oH.sN, 166.1470, found 166.1488. Reaction of l-rerr-Butyl-3-cyanoazetidine (44) with Potassium Diisopropylamide Potassium diisopropylamide was prepared by the method of Lochmann and TrekovaF*. To an oven dried flask were added: potassium r-butoxide (0.41 g, 3.7 mmol), THF (10 mL) and diisopropylamine (0.5 mL, 3.6 mmol) under argon. The 78 solution was cooled to -78 “C and n-butyllithium (3.00 mL, 1.22 M in hexane, 3.7 mmol) then added. After 36 min l-terr-butyl-3-cyanoazetidine (44, 0.49 g, 3.5 mmol) in THF was added over 2 min. Upon stirring the mixture 15 min, ethyl bromide (0.47 g, 4.3 mmol) was added. The solution was stirred 7 min at -78 °C, warmed to room temperature and then poured into brine (50 mL). The layers were separated and the brine was extracted with CHjCT (25 mL). The organic extracts were dried (MgSO^), evaporated and chromatographed (SG; 4:1 hexanes/EtOAc) to yield 1 -rg/r-butyl-3- cyano-3-ethylazetidine (56, 0.19 g, 32%); the retention time and MS (Low Res) of the product were identical to that of an authentic sample. Reaction of 1 -fert-But) l-3-cyanoazetidine (44) with /i-Butyllithium A solution of l-re/-r-butyl-3-cyanoazetidine (44, 0.50 g, 3.6 mmol) in THF (15 mL) was cooled to -78 “C under argon. «-Butyllithium (3.00 mL, 1.22 M in hexane, 3,7 mmol) was added dropwise. After 1 h at -78 °C, ethyl bromide (0.40 g, 3.8 mmol) in THF (5 mL) was added over 30 min. The solution was stirred 3 h and warmed to ambient temperature. Work-up and chromatography as above yielded l-rm-butyl-3- cyano-3-ethylazetidine (56, 0.10 g, 17%) whose retention time and MS (Low Res) were identical to that of an authentic sample of 56. Reaction of l-t^rr-Butyl-3-cyanoazetidine (44) with Potassium rert-Butoxide Potassium hydride (0.65 g, 35% dispersion, 5.7 mmol) was washed with pentane (3x5 mL). The residual pentane was removed by a fast flow of argon. THF (10 mL) was added followed by r-butyl alcohol (0.40 g, 5.4 mmol). The solution was refluxed 79 1.5 h and then cooled to ambient temperature. Upon addition of I-rert-butyl-3- cyanoazetidine (44, 0.49 g, 3.6 mmol) in THF (5 mL) in 14 min, the mixture was refluxed for 30 min and ethyl bromide (0.50 g, 4.6 mmol) was added at 3 °C. The cooling bath was removed and the reaction mixture was stirred at room temperature for 2 h. The solution was poured into water and extracted with Et^O (3x25 mL). The organic extracts were washed with brine (25 mL) and dried (MgSO^). GC/MS/IR analysis showed only l-terr-butyl-3-cyanoazetidine (44, 0.39 g, 80% recovery) and no l-/er/-butyl-3-cyano-3-ethylazetidine(56). In a similar experiment l-t-butyl-3-cyanoazetidine (44, 0.47 g, 3.4 mmol), was refluxed in dry toluene with potassium terr-butoxide (5.5 mmol; prepared as above) for 4.25 h. The solution was cooled and treated with ethyl bromide (0.54 g, 5.0 mmol). The product after work-up was a red oil. Analysis by GC/MS/IR showed only 1 -tgrt-butyl-3-cyanoazetidine (44, 0.25 g, 53% recovery) to be present. Reaction of l-te/t-Butyl-3-cyanoazetidine (44) with Phenylsodium at 25°C Sodium (2.74 g, 0.12 mol) and dry toluene (50 mL) were added under argon to a flame dried Morton flask equipped with a wire stirrer. The suspension was heated to 105 “C and stirred vigorously for 30 min. rer/-Butyl hydroperoxide"*' (0.2 mL, 70 % aqueous solution) was then added all at once. After being stirred for 30 min, the mixture was cooled to 28 “C and dry chlorobenzene (2 mL) was added all at once. The temperature of the mixture slowly rose to 33 °C as the solution turned black. Additional chlorobenzene (3 mL, total 5 mL, 49 mmol) was added; the reaction 8 0 temperature was kept between 33-38 °C for 50 min by occasional cooling. A toluene solution (30 mL) of l-rerr-butyI-3-cyanoazetidine (44, 6.67 g, 50 mmol) was then added dropwise over 40 min; the resulting solution became dark brown. Ethyl bromide (5.45 g, 50 mmol) was added over 11 min keeping the temperature between 20-28 °C for 30 min. Upon addition of water the solution immediately turned from brown to bright yellow. Saturation of the aqueous layer with sodium chloride, separation , drying (MgSO^) and distillation (46-48 “C @ 0.05 mm Hg) yielded \-tert- butyl-3-cyano-3-ethylazetidine (56, 1.42 g, 17%); the retention time and MS (Low Res) of this product were identical to that of an authentic sample of 56. Analysis of the pot residue by TLC showed another product to be present. Chromatography (SG, EtOAc) gave l-(/e/'t-butylazetidin-3-yl) phenylmethanone'’' (122, 0.54 g, 5%) as an oil; 'H NMR (CDCI 3): Ô 0.96 (s, 9H), 3.50 (s, 2H), 3.55 (s, 2H), 4.09 (pentet, IH, J= 8.3 Hz), 7.45-7.55 (m, 2H), 7.84 (m, IH), 7.87 (m, IH) ppm; "C NMR (CDCI3): 5 24.0, 36.1, 49.0, 52.0, 128.2, 128.7, 133.2, 135.5, 198.6 ppm; HRMS (El) calcd for C^H^NO 217.1467, found 217.1446. Reaction ofl-tert-Butyl-3-cyanoazetidlne (44) with Phenylsodium at -12 "C A sodium suspension (1.22 g, 53 mmol) was prepared in dry toluene (30 mL) under argon using r-butyl hydroperoxide"*' (0.2 mL, 70% solution) as the dispersing agent. Chlorobenzene (2.5 mL, 3.0 g, 28 mmol) was added all at once to the sodium suspension. The temperature of the mixture slowly rose from 25 to 31 °C. After 81 having been stirred for 2 h, the suspension was cooled to -12 °C . l-/ert-Butyl-3- cyanoazetidine (44, 3.41 g, 25 mmol) in toluene (15 mL) was added over 5 min. The solution was stirred for 1 h and then ethyl bromide (3.01 g, 28 mmol) was added. After 4 h at -12 °C the cooling bath was removed, the mixture was warmed to room temperature, and water was added. The layers were separated. After being saturated with sodium chloride the aqueous layer was extracted with toluene (2x50mL). The organic layers were combined, dried (MgSO^) and distilled (52-54 °C @ 0.15 mm Hg) to give l-r-butyl-3-cyano-3-ethylazetidine (56, 1.84 g, 26%). The retention time and the MS (Low Res) of the product were identical to that of an authentic sample of 56. Reaction of l-rert-Butyi-3-cyanoazetidine (44) with Phenylsodium at -78 °C In an experiment similar to that described above, ethyl bromide (3.02 g, 28 mmol) was added to sodium 1 -t-butyl-3-cyanoazetidine as prepared from l-t-butyl-3- cyanoazetidine (44, 3.73 g, 27 mmol), sodium dispersion (1.32 g, 57 mmol), chlorobenzene (2.77g, 25 mmol) and tert-butyl hydroperoxide (0.2 mL, 70 % solution) in toluene (45 mL) at -78 “C. No l-ter/-butyl-3-cyano-3-ethylazetidine (56) was obtained upon work-up and distillation of the reaction mixture. Only l-/m-butyI-3- cyanoazetidine (44,1.84 g, 49% recovery; bp 62-66 °C @ 0.5 mmHg) was obtained. Acetone Cyanohydrin Nitrate (65) The procedure of Freeman and Shepard“ was used as follows. White fuming nitric acid (53 mL, 1.1 mol; prepared by addition of urea to 90% red fuming nitric acid and air sparging the solution until colorless) was added dropwise to acetic anhydride (206.5 g, 2.0 mol) at 3-7 °C. The mixture was stirred (3 °C) for 1 h and then acetone 82 cyanohydrin (42.87 g, 0.50 mol) was added slowly keeping the temperature at 3-5 “C. After the addition had been completed the cooling bath was removed. The reaction mixture was stirred for 1 h at room temperature and then poured into ice/water (1600 mL). After stirring for 90 min the solution was extracted with CHiCL (4x75 mL). The organic extracts were washed with 10% aqueous Na^COj (3x75 mL), brine (100 mL), dried (MgSO^) and distilled through a 30 cm vacuum-jacketed Vigreux column (62- 63 °C @ 5 mm Hg; lit*^ 62-65 °C @ 5 mm Hg) to give acetone cyanohydrin nitrate (45.25 g, 69%); FTIR (neat) 3005, 2938, 1660, 1469, 1393, 1374, 1301, 1230, 1199, 1140, 950, 897, 850, 750, 712 cm '. 2-(T rifluoromethyl)-2-propanol ( 68 ) This procedure is similar to that by Pierce et al"^. A solution of méthylmagnésium iodide was prepared from methyl iodide (125.4 g, 0.88 mol), magnesium turnings (66.50 g, 2.73 mol) in Et,0 (450 mL). Ethyl trifluoroacetate'’^ (50.13 g, 0.16 mol) was added to the ice-cooled solution of méthylmagnésium iodide. The solution was slowly warmed to ambient temperature, stirred overnight, filtered, poured onto ice, acidified with 10% aqueous HCl, and extracted with EtiO (6x100 mL). The Et,0 extract was washed with 10% NaHSOj (2x150 mL) and ice water (to remove any ethanol) and then dried (MgSO^). The Et^O solution was distilled through a 30 cm, vacuum-jacketed Vigreux column. The fraction boiling at 57 °C (lit ^ 76-77 °C) was collected to give 2-(trifluoromethyl)-2-propanol (18.75 g, 42%) : colorless liquid; 'H NM R ( C D C L 3 ) Ô 1.40 (s, 6 H), 2.25 (br s, IH) ppm. 83 2-(Trifluoromethyl)-2-propyl Nitrate (67) The procedure of Bottaro et al"" was used as follows. Anhydrous nitric acid (2.60 g, 41 mmol; freshly prepared by distillation of 98% nitric acid from an equal volume of concentrated sulfuric acid at ca. 30 mm Hg) was added to trifluoroacetic anhydride (9.10 g, 43 mmol) at 0 “C. The temperature was kept below 10 “C during the addition. The solution was then stirred for 35 min at 0 °C and then 2-(trifluoromethyl)-2- propanol (3.50 g, 27 mmol) was added dropwise. The mixture was stirred for 40 min at 3 “C and then at ambient temperature for 15 min. Upon dilution with CH^Ch (15 mL), the mixture was poured into ice/water and shaken vigorously. The organic layer was separated and dried (MgSO^). The CH,CL was removed at atmospheric pressure by distillation. When the oil bath reached 150 °C the distillation was stopped. The product, 2-(trifluoromethyl)-2-propyl nitrate (1.91 g, 40%) was removed from the distillation pot: ‘H NMR (CDCI 3) 5 1.77 (s) ppm; FTIR (neat) 3006, 2958, 1651, 1464, 1399, 1381, 1322, 1295, 1237, 1167, 1011,964, 8 6 8 , 838 cm '. Reaction of Lithio l-fôrt-ButyI-3-cyanoazetidine (59) with 1-Propyl Nitrate Disopropylamine (0.37 g, 3.7 mmol; distilled from KOH) and THF (25 mL) were added to a flame-dried flask. A flow of argon was started and the mixture was cooled to -78 “C at which time «-butyllithium (3.00 mL, 1.22 M in hexane, 3.7 mmol) was injected by syringe. The mixture was stirred for 18 min and then l-rerf-butyl-3- cyanoazetidine ( 44, 0.50 g, 3.6 mmol) was added dropwise over 7 min. The solution 84 turned bright yellow. After 1.75 h at -78 °C propyl nitrate (0.43 g, 4.1 mmol) in THF was added over 35 min. The solution was stirred for 3 h, warmed to ambient temperature, poured into cold, aqueous 2% HOAc (100 mL), made basic with saturated Na^COj, extracted witli CH^CL (6x50 mL), washed with brine (100 mL) and dried (MgSOJ. Chromatography (SG, 10:1 hexanes:EtOAc, visualized with diphenylamine in C^Hg followed by heating) yielded l-rert-butyl-3-cyano-3- nitroazetidine (45, 0.10 g, 15%): white solid; mp 42-43.5 “C; 'H NMR ( C D C I 3 ): 5 0.99 (s, 9H), 3.85 (AB, 2H, J= 8 .8 Hz), 4.00 (AB, 2H, J= 9.0 Hz) ppm; "C NMR (C D C I 3 ): 23.6, 52.3, 56.3, 72.2, 113.8 ppm; FTIR (neat) 2968, 2872, 1572, 1473, 1367, 1306, 1234, 1105, 1023, 860, 801, 644 cm '; HRMS (El) Calcd forCgH, 3N 3 0 3 183.1008, Found 183.0997; Anal Calcd for CgH, 3N 3 0 :: C, 52.45%; H, 7.15%. Found: C, 52.18%, H, 7.07%. Compound 45 was also prepared by oxidative-cyanation of sodium l-re/'t-butyl-3- nitrocyanoazetidine (69) as follows. A solution of water (65 mL) and l-re/*r-butyl-3- hydroxymethyl-3-nitroazetidine hydrochloride'” (12.28 g, 54.7 mmol) was cooled in an ice bath. Aqueous sodium hydroxide (6.50 g, 163 mmol) in water (65 mL) was added. The stirred mixture was warmed to room temperature for 5.5 h and then cooled to 8 “C. A chilled solution of sodium cyanide (9.96 g, 203 mmol) and potassium ferricyanide (4.75 g, 14.4 mmol) in water (190 mL) was added in one portion. Solid sodium persulfate (15.14 g, 63.6 mmol) was rapidly added. The ice bath was removed and the temperature of the mixture slowly rose to 27 °C over 30 min. The solution was stirred fcr an additional 45 min. Extraction of the aqueous layer with CHjCh 85 (3x50 mL) and washing the organic extracts with brine (lOOmL) and drying (MgSO^) yielded a red oil. Distillation ( 60 °C @ O.l mmHg) gave l-rerr-butyl-3-cyano-3- nitroazetidine (45, 0.88g, 9%) as yellow oil which solidified; mp 42-43.5 °C. The ‘H NMR and TLC of the product were identical to that of 45 prepared previously. Reaction of Lithio l-teft-Butyl-3-cyanoazetidine (59) with 1-Propyl Nitrate: Inverse Addition A V-shaped flask was charged with diisopropylamine (0.19g, 0.19 mmol) and THF (5 mL). A flow of argon was maintained as the solution was cooled to -78° C. After addition of n-butyllithium (1.50 mL, 1.22 M in hexane, 0.19 mmol) the mixture was stirred for 49 min. 1 -tgrt-Buty 1-3-cyanoazetidine (44, 0.25 g, 1.8 mmol) in THF (10 mL) was then added over 5 min. The mixture was agitated for 35 min and then cannulated into 1-propyl nitrate (1.04 g, 9.9 mmol) in THF (10 mL) at -78 °C in 4 min. The solution was warmed to 0 °C and worked-up as in the previous experiment. After chromatography 1 -terf-buty 1-3-cyano-3-nitroazetidine (45, 0.032 g, 10%) was isolated. The ‘H NMR and TLC of the product were identical with that of an authentic sample. Slow Addition of Lithio l-/ert-Butyl-3-cyanoazetidine (59) to Excess 1-Propyl Nitrate 1-Propyl nitrate (1.03 g, 5.4 mmol) in THF (7 mL) was added dropwise in 8 min to a solution of lithio ter/-butyl-3-cyanoazetidine (59, 0.25 g, 0.18 mmol; prepared fi'om diisopropylamine (0.19 g, 1.9 mmol) and /i-butyllithium (1.50 mL, 1.8 mmol, 1.22 M in hexanes)) at -78 °C . After stirring at -78 °C for 3 min the solution was warmed to 0 86 °C in 12 min and then poured into aqueous 2% HO Ac (75 mL). The reaction mixture was worked-up as above and chromatographed to yield l-terr-butyI-3-cyano-3- nitroazetidine (45, 0.032 g, 10%). The ‘H NMR and TLC of the product were identical with that of authentic sample. Reaction of Potassium l-r^rr-Butyi-3-cyanoazetidine with 1-Propyl Nitrate A solution of potassium r-butoxide (0.41 g, 3.7 mmol), diisopropylamine (0.36 g, 3.6 mol) and THF (10 mL) was prepared under argon. The mixture was cooled to -78 °C and then «-butyllithium (3.00 mL, 3.7 mmol, 1.22 M in hexane) was added. After 15 min l-terr-butyI-3-cyanoazetidine (44, 0.47 g, 3.4 mmol) in THF (5 mL) was added dropwise. The resulting bright yellow solution was stirred 15 min and then 1-propyl nitrate (0.42 g, 4.0 mmol) was added all at once. After 5 min the cooling bath was removed. The mixture was warmed to 0 °C and then poured into cold aqueous 10% HOAc (50 mL). Work-up as above and chromatography yielded 1 -tert-butyl-3-cyano- 3-nitroazetidine (45, 0.050 g, 8 %) as a clear oil which solidified upon cooling. The ‘H NMR and TLC of the solid product were identical with an authentic sample of 45. Reaction of Lithio l-te/t-Butyl-3-cyanoazetidine (59) with 2-(Trifluoromethyl)-2- p ropy I Nitrate (68 ) To a -78 °C solution of lithio 1 -t-butyl-3-cyanoazetidine (59, 0.25 g, 1.8 mol; prepared from diisopropylamine (0.21 g, 2.1 mmol and n-butyllithium (1.50 mL, 1.22 M in hexane, 1.8 mmol) in THF (10 mL)) was added all at once 2-(trifluoromethyl)-2- propyl nitrate (0.68 g, 3.9 mmol). After 4 min at -78 “C the reaction mixture was 87 warmed to 0 “C and then poured into cold, aqueous 2% HOAc (75 mL). Standard work-up and chromatography yielded 1 -tert-buty 1-3-cyano-3-nitroazetidine (45, 0.121 g, 37%). The ‘H NMR and TLC of the product were identical with an authentic sample o f 45. Reaction of Lithio l-re/t-Butyl-3-cyanoazetidine (59) with Acetone Cyanohydrin Nitrate (65) To lithio l-t-butyl-3-cyanoazetidine (59, 3.6 mmol; prepared from diisopropyl amine (3.8 mmol) and «-butyllithium (3.00 mL, 1.22 M in hexanes, 3.7 mmol) at -78 “C was added acetone cyanohydrin nitrate (0.26 g, 4.0 mmol). After 1 h the solution was warmed to ambient temperature and worked-up as usual. No l-rert-butyl-3- cyano-3-nitroazetidine (45) was obtained. Reaction of Lithio l-terr-ButyI-3-cyanoazetidine (59) with Tetranitromethane (66 ) «-Butyllithium (3.00 mL, 1.22 M in hexane, 3.7 mmol) was added to diisopropylamine (3.8 mmol) in THF (10 mL) at -78 “C under argon. l-rerr-Butyl-3- cyanoazetidine (44, 0.49 g, 3.6 mmol) in THF (5 mL) was added in 6 min. The solution was stirred for 15 min and then tetranitromethane (0.74 g, 3.7 mmol: dried over CaH,) was slowly added. The first drop caused a vigorous reaction to occur and 88 the solution changed from yellow to red. After the addition had been completed, the solution was stirred for 10 min, poured into water and worked-up as above. No \-tert- butyl-3-cyano-3-nitroazetidine (45) was obtained. l-rert-Butyl-3-bromo-3-nitroazetidine (70) A mixture of water (10 mL), 1 -tert-buty 1-3-cyano-3-nitroazetidine (45, 0.0376 g, 0.21 mmol), and sodium hydroxide (0.10 g, 2.5 mmol) was re fluxed for 45 min. After the mixture had been cooled ice bath, CH,CL (10 mL) was added followed by excess bromine. After 15 min the layers were separated, and the aqueous layer was extracted with CHiCL (10 mL), and dried (MgSO^). Evaporation of the solvent gave \-tert- butyl-3-bromo-3-nitroazetidine (70, 0.0184 g, 38%): yellow solid; mp 8 6 - 8 8 °C; ‘H NMR ( C D C L 3 ) Ô 0.97 (s, 9H), 3.79 (AB, 2H, J= 11 Hz), 4.17 (AB, 2H, J= 11 Hz) ppm; "C NMR ( C D C L 3 ) 24.0, 52.5, 61.3, 115.3 ppm. The ' H and "C NMR of 70 were identical with the literature values.** l-rerr-ButyI-3,3-dinitroazetidine (8) A mixture of sodium hydroxide (0.20 g, 5.0 mmol), water (10 mL) and l-r-butyl-3- cyano-3-nitroazetidine (45, 0.11 g, 0.60 mmol) was refluxed for 1.25 h. After cooling the mixture to 5 °C, potassium ferricyanide (0.07 g, 0.2 mmol) and sodium nitrite (0.25 g, 3.6 mmol) in ice water (lOmL) were added. Solid sodium persulfate (0.25 g) was added all at once. The solution was stirred for 5 min in the ice bath and then warmed to room temperature. After having been stirred for 1.5 h the solution was extracted with CH.CL (3x25 mL). The CH,CL extract on drying (MgSO^) and evaporation gave 89 pure l-rerr-butyI-3,3-dinitroazetidine ( 8 , 70 mg, 57%) as a yellow oil; 'H NMR (C D C I3 ) Ô 1.01 (s, 9H), 4.08 (s, 4H) ppm; FTIR(neat) 2968, 2873, 1572, 1472, 1369, 1335, 1237, 1158, 1069, 1032, 864, 838, 802 cm ', were identical to literature values.’ Sodium 2-Nitro-l,3-propanediol * 2 CHjOH (83)^’ Sodium hydroxide (176.44 g, 4.4 mol) in methanol (800 mL) was added dropwise to a mechanically stirred suspension of paraformaldehyde (241.07 g, 8.0 mol) and nitromethane (96%, 255.03 g, 4.0mol) in methanol (1.5 L). The temperature of the mixture was kept at 4-7 °C. [Caution: Adding the sodium hydroxide too quickly, and/or allowing the temperature to rise above 10 °C will cause an uncontrollable exotherm and ejection of the contents from the flask]. After the addition had been completed, the suspension was stirred for 20 min at 5 °C and then placed in a refrigerator overnight. Solid 83 was filtered, washed with cold methanol, and then dried m vaciw (797.04 g, 95.9%). The salt slowly turns yellow when at room temperature but does not when kept in a refrigerator. 2-Nitro-l,3-propanedioI (84) Acetic acid (412.41 g, 6 .8 mol) in methyl fg/ t-butyl ether (MTBE, 600 mL) was added as rapidly as possible to a mechanically stirred suspension of sodium 2 -nitro- 1,3,-propanediol* 2 CH 3OH (83, 1419.6 g, 6 .8 mol) in MTBE (600 mL) at 20 °C. Sodium acetate precipitated instantly. After the suspension had stirred at room 90 temperature for 3 h, the sodium acetate was filtered and washed with MTBE. The filtrate was treated with decolorizing carbon, filtered through Celite and concentrated until crystallization occurred. After filtration and drying the product in vacuo over P2O5 excellent 2-nitro-1,3,-propanediol (84, 635.1 g, 77%) was obtained; mp 47.5-51 °C, lit'- 53-55 °C; ‘H NMR (acetone d- 6 ): Ô 3.98 (m, 4H), 4.41 (s, 2H), 4.78 (m, IH). Diol 84 decomposes when stored at room temperature but is stable for months in a freezer. 2-Nitro-l,3-propanediol Diacetate (82) The procedure of BClager'*^ was followed. A mixture of 2-nitro-1,3-propanediol (233.67 g, 1.9 mol) and CH,C1, (1 L) was refluxed. Acetyl chloride (474.70 g, 6.0 mol) was added dropwise over 1.75 h. The solution was then re fluxed for 3 h. The resulting light brown solution was treated with decolorizing carbon and then filtered through Celite. The CH,C1, was evaporated from the product on a rotary evaporator and then at 0.2 mm Hg (50 °C). 2-Nitro-l,3-propanediol diacetate (82,387.52 g, 98%) was obtained as a light yellow liquid; ‘H NMRfCDClj): 5 2.08 (s, 6 H), 4.51 d, 4H, J= 5.9 Hz), 4.92 (pentet, IH, J= 5.8 Hz). 2-Nitroaiiyi Acetate (78) From Pyrolysis of 2-Nitro-l,3-propanediol Diacetate (82) A vertical pyrolysis apparatus consisting of a Pyrex furnace tube (2.5 cm in diameter x 26 cm in length) was packed with porcelain berl saddles (26.33 g, 6 mm in size, approximately 8 cm) and then with calcium sulfate (Drierite, 6 mesh, approximately 20 cm). A large water-cooled coil condenser was attached at the furnace outlet; its receiver flask was cooled in an ice bath. The nitrogen carrier gas 91 flow was set to 1.25 standard liters per minute (SLPM) using a Tylan Model FC-260 Mass Flow Controller. The furnace tube was heated to 160 “C and 2-nitro-1,3- propanediol diacetate (82, 50.53 g, 0.25 mol) was added dropwise in 2.3 h. The condenser was washed with CH,C1,. The condensate was dissolved in Et,0 (100 mL), washed with 10% NaHCOj (3x50 mL) and brine (100 mL), and then dried (MgSO^). Evaporation of the solvent yielded a brown oil (21.29 g). Analysis by ‘H NMR showed the product to be 74% 2-nitroallyl acetate (78, 19.1 g, 54%); 'H NMR (CDClj): 6 2.11 (s, 3H), 5.03 (s, 2H), 5.96 (s, IH), 6 .6 8 (d, IH, J= 2.1 Hz) ppm; "C NMR (CDCI3): 6 20.6, 59.6, 121.6, 152.1, 169.9 ppm. The remainder was 2-nitro- 1,3-propanediol diacetate (82, 2.2 g, 4%). The ‘H NMR of the 2-nitro-1,3-propanediol diacetate (82) was identical with that of an authentic sample of 82. Compound 78 was stored in a freezer for months without decomposition. 2-NitroaIIyI Acetate(78) from 2-NitroaIIyl Alcohol (93) and Acetyl Chloride Acetyl chloride (0.45 g, 5.7 mmol) was added all at once to 2-nitroallyl alcohol (93, 0.25 g, 2.4 mmol) in CHCI 3 (10 mL). The solution was refluxed for 2.75 h. Excess acetyl chloride and CHCI 3 were removed in vacuo to give a yellow liquid. Chromatography (SG, 2:1 CH^Ch:hexanes) yielded 2-nitroalIyl acetate (78, 0.17 g, 49%). The 'H NMR of the product was identical with that of an authentic sample. 92 2-Nitroallyl Trifluoroacetate (95) from Distillation of 2-Nitro-l,3-propanediol Ditrifluoroacetate (94) 2-Nitro-l,3-propanedioI (10.08 g, 0.11 mol) was added to trifluoroacetic anhydride (34 mL, 0.24 mol) at 3 “C. After the solution had been stirred for 3 h at 3-6 °C, the trifluoroacetic acid formed was removed in vacuo (40 mmHg). The remaining yellow liquid was distilled (bp 78-80 °C @ 4.5 mm Hg) to give 2-nitroallyl trifluoroacetate (95, 9.98 g, 44%) as a yellow liquid; ‘H NMR (CDCIJ: Ô 5.28 (s, 2H), 6.12 (s, IH), 6.83 (d, J=2.6 Hz); "C (CDCI3): Ô 62.3, 116.0, 123.6, 149.7, 156.8 ppm; FTIR (neat): 3139, 3027, 2879,1793, 1539, 1450, 1383, 1353, 1226, 1169, 960, 849, 774, 735 cm '; HRMS (El): calcd for C^H^F^NO, 199.0092, found 199.0081; Anal Calcd for C 5H 4F3NO 4: C, 30.16; H, 2.03. Found: C, 30.43; H, 2.28. 2-NitroaiIyl Trifluoroacetate (95) from 2-NitroalIyl Alcohol (93) and Trifluoroacetic Anhydride 2-Nitroallyl alcohol (93, 3.45 g, 41 mmol) was added to trifluoroacetic anhydride (20.8 g, 99 mmol) at 3-9 °C . After the solution had been stirred for 2.5 h at 5 “C, trifluoroacetic acid and the remaining trifluoroacetic anhydride were removed in vacuo. Distillation (bp 60-65 °C @ 2.5 mm Hg) to yielded 2-nitroallyl trifluoroacetate (95, 6.05 g, 75%). The ‘H NMR of the product was identical to the 95 prepared previously. 93 2-NitroallyI Alcohol This procedure as follows is similar to that by Oreshko et aT*. A suspension of 2- nitro-1,3-propanediol * 2 CH 3OH (83, 101.02 g, 0.49 mol) and CH^CU (370 mL) in a Morton flask was cooled to -18 °C . Sulfuric acid (40%, 6 6 mL) was added dropwise in 1.3 h to the suspension keeping the temperature of the mixture at -10 to -20 “C.. After having been stirred for 48 min, the suspension was poured into ice water. The aqueous layer was extracted with CH,CL (6x70 mL). The CH^CL extracts were washed with brine (75 mL) and dried (MgSOJ. Concentration of the solution yielded 2-nitroallyl alcohol (83, 20.94 g, 42%) as a light green liquid. 'H NMR (CDCI 3): 5 2.37 (s, IH), 4.56 (s, 2H), 5.92 (s, IH), 6.59 (d, IH, J= 2.0 Hz). This product is not very stable and decomposes when stored at room temperature. Distillation of 83 (71- 73 °C @ 0.9 mm Hg, lit^® 55-56 °C @ 1 mm Hg) lowers the yield because of decomposition. Compound 83 may be stored in a fi'eezer, but after 2 months the product had decomposed with evolution of nitrogen oxides. Addition of 2-NitroalIyl Acetate (78) to te/t-Butylamine (Attempted Distillation of the Products) 2-Nitroallyl acetate (78, 13.37 g, 92 mmol) and THF (100 mL) was cooled to -78 “C. /er/-Butylamine (6.81 g, 93 mmol) in THF (50 mL) was added dropwise over 1 h to the 2-nitroallyl acetate/THF solution over 1 h. The first drops of rerZ-butylamine caused the solution to turn bright yellow. After the addition had been completed the solution was slowly warmed to room temperature over 3 h and then stirred at ambient 94 temperature overnight. Upon removal of the THF under vacuum, a very dark brown residue was obtained. This product was dissolved in CH,Ch (100 mL) and the solution was washed with water (100 mL) and then with 10% NaHCOj (50 mL). The CH^CL solution was treated with decolorizing carbon and filtered through Celite. The solution was still dark brown. Upon removal of the CH,CL at reduced pressure, distillation of the residue was attempted. No volatile products were obtained and the residue charred on prolonged heating at 170 °C. Addition of r^rr-Butyiamine to 2-Nitroailyl Acetate (78) (Reverse Addition) To a solution of 2-nitroallyl acetate (78, 4.22 g, 29 mmol) in THF (ISO mL) at -78 °C was added rerr-butylamine (2.20 g, 30 mmol) in THF (50 mL) over 2.2 h. After having had been stirred for 2.5 h at -78 °C, the solution was slowly warmed to -30 °C and then poured into 3% HOAc (100 mL). The solution was extracted with CH,CL (3x50mL); the CH^CL extracts were washed with 10% NaHCOj and then with brine. After the solution extracts had been dried (MgSO^), the CH,CL was evaporated under vacuum. The remaining product was a dark red solid. 'H NMR (CDCIJ and GC/MS/IR analyses of the product did not show the presence of l-rerr-butyl-3- nitroazetidine (2). TLC analysis of the product did not show any definite spots. 2-NitroaIIyl Acetate (78) With rert-Butylamine (High Dilution) 2-Nitroallyl acetate (78, 0.60 g, 4.1 mmol) in THF (250 mL) was added dropwise in 4.5 h to /er/-butylamine (0.32 g, 4.4 mmol) in THF (500 mL) at -78 °C. After the solution had been stirred for 5 h at -78 °C and then warmed to -30 °C, 2% acetic acid 95 (50 mL) was added. The layers were separated and the aqueous layer was extracted with EtiO (50 mL). The organic extracts were dried (MgSO^) and the solvent removed to give a viscous red oil. No 1 -fert-buty 1-3-nitroazetidine (2) could be found in the red oily compound by GC/MS/IR analysis. The above experiment was repeated using MeOH as the solvent. The red oil was analyzed by CG/MS/IR analysis and no 1- terr-butyl-3-nitroazetidine (2) was present. The results were similar to that in THF. Addition of teit-Butyiamine and then Trietbylamine to 2-Nitroaiiyl Acetate (78) To 2-nitroallyl acetate (2.92 g, 20 mmol) in THF (50 mL) at -78 °C was added tert- butylamine (1.48 g, 20 mmol) in THF (15 mL) over 45 min. The first drop of tert- butylamine caused the solution to turn bright yellow. After having been stirred for 2 h at -78 °C, the mixture was warmed to -30 °C ,poured into water (100 mL), and extracted with CH^CU (3x25 mL). The CH^Cl, extracts were washed with 10% NaHCO, (25 mL), then with brine (50 mL), and dried (MgSOJ. The MgSO; was filtered and triethylamine (8.28 g, 82 mmol) was added dropwise to the filtrate at 19 “C. The first drop of triethylamine caused to solution to turn dark red. The solution was stirred at room temperature for 3.5 h, poured into water (100 mL) and then shaken vigorously. The solution was extracted with CH,CU (100 mL). The organic extracts were washed with brine (100 mL) and dried (MgSO^). Evaporation of the CH^CL and triethylamine yielded a viscous red oil. 'H NMR (acetone-i/^) showed the presence of tert-butyl groups but no signals for l-fôrt-butyl-3-nitroazetidine. 96 Addition of 2-Nitroailyl Acetate (78) to teit-Butylamine and Triethylamine 2-NitroalIyl acetate (78, 0.255 g, 1.8 mmol) was added dropwise to a solution of rert-butylam ine (0.136 g, 1.9 mmol) and triethylamine (0.186 g, 1.8 mmol) in THF (25 mL) at -78 °C. The solution was stirred for 2 h at -78 “C, poured into water, and extraced with CH^CL (3x25 mL). Evaporation of the CH,CL extracts yielded a small amount of a brown oil. GC/MS/IR and *H NMR analyses did not show the presence o f TBNAZ (2). Addition of Benzhydrylamine to 2-Nitroallyi Acetate (78) A solution of 2-nitroallyl acetate (78, 0.324 g, 2.2 mmol) in THF (5 mL) was added dropwise to benzhydrylamine (0.405 g, 2.2 mmol) in THF (30 mL) at -78 “C. After having had been stirred for 8 h at -78 °C, the reaction was warmed to - 20 °C , poured into 2% HOAc (25 mL) and then extracted with EtiO (4x25 mL). The organic extracts washed with 10% NaHCOj (2x25 mL) and then with brine (100 mL). Evaporation of the Et^O yielded a red oil which solidified. No l-benzhydryl-3-nitroazetidine (11) was detected by GC/MS/IR analysis. An experiment was conducted in which benzhydrylamine ( 1 equiv) was added to 2- nitroallyl acetate (78, 1 equiv) in THF at -78 “C and the reaction was worked-up as above. GC/MS/IR analysis showed that there was no l-benzhydryl-3-nitroazetidine in the reaction product. 97 Addition of 2-Nitroailyl acetate (78) to fôrr-octylamine (109) To of fôrr-octylamine (109, 0.46 g, 3.6 mmol) in CHjCU at -78 °C was added 2- nitroallyl acetate (78, 0.5 Ig, 3.5 mmol) in CHjCU (10 mL). After the solution having been stirred at -78 °C, the solution was warmed and poured into 10% Na,COj (25 mL). The aqueous layer was extracted with CH,CL (2x20 mL). The combined organic extracts were washed with brine (20 mL) and then dried (MgSO^). Evaporation of the solvent under vacuum yielded a red oil. No product could be separated by column chromatography using SG. GC/MS/IR analysis did not detect any l-mrr-butyl-3-nitroazetidine (11). Addition of tert-octylamine to 2-nitroallyl acetate (78) in CH^Ch at -78 ° and working-up the reaction mixture as in the previous experiment showed that no 1 -tert- butyl-3-nitroazetidine (11) was present by GC/MS/IR analysis. Reaction of 2-Nitroallyl Trifluoroacetate (95) with tert-Butylamine (Simultaneous Addition of Reagents) 2-Nitroallyl trifluoroacetate (95, 1.02 g, 5 mmol) in THF (10 mL) and tert- butylamine (0.43 g, 5.9 mmol) were added simultaneously to THF (20 mL) at -78 “C. The resulting solution was light green. The mixture was stirred for 4 h at -78 °C, warmed slowly to -30 °C, poured into 3% HOAc (50 mL), and extracted with CH,CL (3x25 mL). The CH^Ch extracts were washed with 10% NaHCO^ (25 mL) and with brine (25 mL) and dried (MgSOJ. Removal of the CH,CL to gave a yellow solid. Chromatography (SG, 4:1 hexanes: EtOAc) yielded N,N-bis(2-nitroallyl)/err- 98 butylamine (113, 0.10 g, 16%) as a yellow solid: ‘H NMR (CDClj): 5 1.19 (s, 9 H), 3.68 (s, 4 H), 5.72 (s, 2 H), 6.38 (s, 2H) ppm. The product turned brown rapidly and decomposed completely within 30 min. Attempts to repeat this experiment were unsuccessful. The products obtained were viscous red oils similar to those obtained from reaction of 2-nitroallyl acetate (78) with rerr-butylamine. Reaction of Tris(hydroxymethyl)nitromethane with rerr-But>'Iamine (2 equiv) rerr-Butylamine (2.09 g, 29 mmol) was added to tris(hydroxymethyl)nitromethane (14, 2.05 g, 14 mmol) in water (25 mL) at 23 “C. A solid formed instantly and the temperature of the solution rose from 23 “C to 30 °C. After the suspension had stirred for 2 h, the solid was filtered, dried in vacuo over and dissolved in CHiCh. The solution was treated with decolorizing carbon, filtered through Celite and concentrated to a solid. Recrystallization first from hexanes and then from EtOH gave 3-rerr-butyl- 5-/err-butylaminomethyl-5-nitrotetrahydro-l,3-oxazine (108, 1.67 g, 45%) as a white solid; mp 108-109.5 “C; 'H NMR ( C D C I 3 ) : Ô 1.02 (s, 9 H), 1.08 (s, 9 H), 2.93 (d, 2 H), 3.07 (d, 1 H), 3.48 (d, 1 H), 3.76 (d, 1 H), 4.13 (d, 1 H), 4.40 (d, 2 H) ppm; "C NMR ( C D C I 3 ): Ô 26.6 (C H 3 ), 28.9 (C H 3 ), 46.8 (CH.), 50.3 (C), 50.8 (C), 52.7 ( C H .) , 69.6 ( C H .) , 81.5 ( C H . ) , 87.8 (C-NO.) ppm; FTIR (KBr):3447,3321, 2968, 1542, 1442, 1362, 1321, 1232, 1221, 1173, 1106, 1026, 951,876, 778, 626, 573 cm '; HRMS(El) calcd for C, 3H.7 N 3 0 3 273.2052, found 273.2044; Anal Calcd for C, 3H.7 N 3 0 3 : C, 57.12; H, 9.95. Found: C, 57.23; H, 9.90. 99 Reaction of te/t-Butylamine with 3-tert-Butyl-5-Hydroxymethyi-5- Nitrotetrahydro-1,3-Oxazine (15) To of 3-rer/-butyI-5-hydroxymethyl-5-nitrotetrahydro-l,3-oxazine (15, 2.05 g, 9.4 mmol) in water (25 mL) at 22 “C was added /err-butyiamine (0.70 g, 9.5 mmol). A solid formed immediately and the suspension was stirred overnight. The solid was filtered, washed with ice water and then with cold EtOH, and then recrystalized from EtOH to give 3-/err-butyl-5-terr-butylaminomethyl-5-nitrotetrahydro-I,3-oxazine (108, 0.87 g, 34%). The 'H NMR of the product was identical to that of an authentic sample o f 108. Reaction of 2-NitroallyI Acetate (78) with 3,5-Dinitroaniline (117) 2-Nitroallyl acetate (0.88 g, 6.1 mmol) in THF (5 mL) was added dropwise to 3,5- dinitroaniline (1.10 g, 6.0 mmol) in THF at -78 °C. The solution was stirred for 2.5 h and then poured into 2% HOAc (75 mL). The solution was extracted with Et,0 (4x25 mL). The Et,0 extracts were washed with 10% NaHCOj and then with brine, dried (MgSO^), and concentrated in vacuo to a red oil. Chromatography (SG, CH^CU) and recrystallization from hexanes/ EtOAc gave 3-(3,5-dinitrophenylamino)-2-nitro-1 - propene (118, 0.72 g, 45%): yellow solid; mp 111-112 “C dec; 'H NMR (acetone-rfj: Ô 4.69 (d, 2H, J= 6.3 Hz), 6.14 (s, IH), 6.64 (s, IH), 6.87 (br s, IH), 7.95 (d, 2H, J= 2.0 Hz), 8.16 (t, IH, J= 2.0 Hz) ppm; '^C NMR (acetone-cfj; 5 41.9, 105.5, 111.5, 100 118.9, 149.4, 153.5 ppm; FTIR (KBr): 3401, 3106, 1635, 1548, 1522, 1345, 1295, 1124, 1109, 991, 960, 921, 878, 808, 733, 654 cm '; HRMS (El) calcd for 268.0443, found 268.0452; Anal Calcd for C,HgN^Og: C, 40.31; H, 3.01. Found C, 40.60; H, 3.07. Further elution (9:1 CH,CU: EtOAc) and recrystallization from nitroethane yielded l,3-bis(3,5-dinitrophenylamino)-2-nitropropane (119, 0.32 g, 12%): yellow solid; mp 169-170 “C dec; ‘H NMR (acetone-d/J 4.23 (m, 2H), 5.36 (m, IH), 6.71 (br s, 2H), 7.94 (d, 4H, 1.9 Hz), 8.14 (t, 2H, J=1.9 Hz); "C (acetone-t/J: 5 45.1, 86.5, 107.2, 113.1, 150.9, 151 ppm; FTIR (KBr): 3396,3101, 1635, 1551, 1536, 1348, 1290, 1132, 1075, 992, 920, 879, 808, 732, 654 cm '; HRMS (El) calcd for 451.0723, found 268.0411 (M- C^H^N^OJ; Anal Calcd for C„H„N;0,o: C, 39.92%; H 2.90%. Found: C, 39.78%, H, 2.98%. 2-NitroalIyI Trifluoroacetate (78) with 3,5-Dinitroaniline (117) 2-Nitroallyl trifluoroacetate (95, 0.40 g, 2.3 mmol) in THF (10 mL) was added to a solution of 3,5-dinitroaniline (117, 0.42 g, 2.3 mmol) in THF (30 mL) at -78 “C. After the mixture had been stirred at -78 “C for 2 h it was warmed and then poured into 2% HOAc (25 mL). After the solution had been extracted with Et,0 (4x25mL) the organic extracts were washed with NaHCG, (2x12 mL) and then with brine (25 mL) and dried (MgSO^). The resulting product was chromatographed (SG, 7:1 CHjCK: hexanes) and recrystallized (EtOAc/ hexanes) to give l,3-bis(3,5-dinitrophenylamino)- 2-nitropropane (119, 0.39 g, 63%): yellow solid; mp 111-112 dec. 'H NMR (acetone- d^) of this product was identical to that of an authentic sample. 101 2-NitroallyI Acetate with 3,5-Dinitroaniline (117, 2 Equivalents) 2-NitroaIlyI acetate (78, 0.53 g, 3.7 mmol) in THF (10 mL) was added to a mixture of 3,5-dinitroaniline (1.30 g, 7.1 mmol) in THF (50 mL) at -78 “C. After the solution had stirred at -78 “C for 5 h, the cooling bath was removed. The mixture was stirred overnight, diluted with Et,0 (50 mL), washed with 10% NaHCO; and with brine then dried (MgSOJ. Chromatography (SG, 3:1 hexanes:EtOAc) and recrystallization from nitromethane gave I,3-bis(3,5-dinitrophenylamino)-2-nitropropane (119, 1.07 g, 67%); mp 169-170 “C dec. 'H NMR of the product was identical with that of an authentic sample. 2-Nitroallyi Acetate (78) with /7-Toluidine (124) 2 -Nitroallyl acetate (78, 1.01 g, 7.0 mmol) in CH^Cl, (5 mL) was added to a mixture ofp-toluidine (124, 1.51 g, 14 mmol) in CHiCl, (50 mL) at -78 °C over 1 h. After the solution had been stirred for 1.2 h the cooling bath was removed. The solution was warmed to room temperature and poured into 10% NaHCO,. The organic layer was separated and dried (MgSOJ. After the CH,Chhad been removed in vacuo, the resulting solid was recrystallized from nitroethane to give l,3-bis(4- methylphenylamino)-2-nitropropane (126, 1.09 g, 52%); mp 184-185 °C dec; ‘H NMR (DMSO-i/,): Ô 2.13 (s, 6 H), 3.57 (m, 4H), 4.95 (m, IH), 5.78 (t, 2H, J= 6.4 Hz), 6.52 (d, 4H, J= 8.4 Hz), 6.89 (d, 4H, J= 8.2 Hz) ppm; ‘'C NMR (DMSO-t/J: 20.1, 44.3, 86.1, 112.43, 125.10, 129.5, 145.3 ppm; FTIR (KBr): 3399, 1613, 1543, 1523, 1445, 102 1354, 1319, 1258, 1185, 865, 809, 509 cm '; HRMS (El) calcd for 299.1634, found 299.1650; Anal Calcd for CivH^iNjO,: C, 68.20; H, 7.07. Found: C, 67.92; H, 6.95. 2-NitroaIlyi Trifluorocetate (95) with ^-Toluidine (124) To a solution ofp-toluidine (124, 0.27 g, 2.,5 mmol) in CH^CU (50 mL) at -78 “C was added 2-nitroallyl trifluoroacetate (95, 0.52 g, 2.6 mmol) in CH^CU (10 mL). After the solution had been stirred for 2 h at -78 °C the cooling bath was removed. The mixture was poured into 10% Na^HCOj (100 mL) and extracted with CHiCh (2x25 mL). The organic extracts were washed with brine (25 mL) and then dried (MgSO.,). The product was recrystallized form nitroethane to give 1,3-bis(4- methyIphenylamino)-2-nitropropane (126, 0.62 g, 79%); mp 182-184 °C. The 'H NMR (DMSO-(/J of the 126 obtained was identical with that of an authentic sample. o-Phenylenediamine (127) with 2-Nitroallyi Acetate (78) A solution ofo-phenylenediamine (127, 0.37 g, 3.4 mmol) in THF (50 mL) was cooled to -78 °C. 2-Nitroallyl acetate (78, 0.51 g, 3.4 mmol) in THF (10 mL) was added dropwise over 1 h. After stirring for 1.2 h the mixture was poured into 2% HOAc (75 mL) and then extracted with CHiCh (3x50 mL). The organic extracts were washed with 10% NaHCG, and brine (50 mL) and then dried (MgSOj). The solvent was evaporated in vacito and the solid obtained was rapidly chromatographed (SG, 2 :1 CHiChihexanes) and recrystallized (CHClj/hexanes) to give 3-nitro-2,3,4,5- tetrahydro-//-benzo[ 6 ] [l,4]diazepine (129, 0.22g, 33%); mp 147-148 “C; 'H NMR (acetone-dj: 5 3.87 (m, 2H), 3.94 (m, 2H), 4.67 (br s, 2H), 4.85 (pentet, IH, J= 5.4 103 Hz), 6.57-6.67 (m, 4H) ppm; '^C NMR (acetone-c/J: ô 48.5, 84.9, 119.5, 121.4, 140.3 ppm; HRMS (El) calcd for CgH^NjO, 193.0851, found 193.0859; Anal Calcd for CçH hN jO,: c , 55.95; H, 5.74. Found: C, 56.05; H, 5.72. Reaction of 2-Nitroaiiyl acetate (78) With Sodio N-fe/t-butyiacetamide (131) N-/err-ButyIacetamide (130, 0.39 g, 3.4 mmol) in THF (5 mL)was added to a suspension of sodium hydride (0.15 g, 3.8 mmol, 60% dispersion in oil) under argon. The mixture was refluxed 3.5 h, cooled to -78 °C and 2-nitroallyl acetate (78, 0.51 g, 3.5 mmol) in THF (5 mL) was added over 8 min. The solution was stirred for 3 h at - 78 “C and poured into 10% NaHCOj (100 mL). The aqueous layer was extracted with EtiO (3x25 mL). The organic extracts were dried (MgSO^); evaporated; and chromatographed (SG, 1.2:1.0 hexanes: ethyl acetate) to give N-(/err-butyl-2- nitroallyl)acetamide (132, 0.19 g, 29% yield) as a yellow oil; 'H NMR (CDClj): ô 1.44 (s, 9 H), 2.07 (s, 3 H), 4.43 (t, 2 H, J=1.9 Hz), 5.81 (q, 1 H, J= 2.1 Hz), 6.72 (q, 1 H, J= 2.2 Hz) ppm; "C (C D C I 3 ): 24.5, 28.7, 45.3, 57.9, 118.7, 115.7, 171.7 ppm; FTIR (neat): 2922, 2854, 1674, 1533, 1460, 1377, 1342, 1198 cm ';. Product 132 decomposes rapidly and thus it could not be analyzed by HRMS. 104 REFERENCES 1. S tec III, D.; Perez, R. Proceedings o f the Eleventh Annual Working Group Institute on Synthesis o f High Energy Materials, Picatinny Arsenal, NJ, June 1992, pp 383-6. 2. Stec III, D.; Iyer, S.; Eng, S.; Joyce, S.; Alster, J. Proceedings o f the Tenth Annual Working Group Institute on Synthesis o f High Energy Materials, Picatinny Arsenal, NJ, June 1991, p 392. 3. Impact sensitivity is determined by allowing a free-falling weight (usually 2 kg) to hit a sample of explosive (30-40 mg) placed in the depression of a small die- cup, capped with a thin brass cover, in the center of which a slotted-vented- cylindrical steel plug is placed. The weight is dropped and the height at which an “event” occurs 50% of the time (H 50) as detected by a microphone or a pressure transducer is the impact sensitivity for that explosive. LASL Explosive Property Data-, Gibbs, T. R.; Popolato, A. Eds.; University of California Press: Berkley, 1980; p 446. 4. Ref 3, pi45. 5. Ref 3, p 46. 6 . The usual binders are polymeric materials such as polybutadiene and polystryene. The polymer is dissolved in a organic solvent and the explosive is added as a water slurry. Upon agitating the suspension and removing the solvent under vacuum, the polymer is precipitated on the explosive. Kirk-Othmer Encyclopedia o f Chemical Technology, 4* ed; Wiley: New York, 1993; vol. 10, p 44. 7. R ef 3, p 150. 8 . Ref 3, p 50. 9. Archibald, T. G.; Gilardi, R.; Baum, K.; George, C. J. Org. Chem. 1990, 55, 2920. 10. Gaertner, V. R. J. Org. Chem. 1970, 22, 2972. 11. (a) Kaplan, R.B.; Shechter, H.J. Am. Chem. Soc. 1961, 83, 3535. (b) Shechter, H.; Kaplan, R. B. U. S. Patent 2,997,504 (August 22, 1961). 12. Garver, L. C.; Grakauskas, V. Baum, K. J. Org. Chem. 1985, 50, 1699. 13. Archibald, T. G.; Carlson, R. P. ref 1, p 403. 105 14. Archibald, T. G.; Carlson, R. P. ref 1, p 417. 15 Archibald, T. G.; Carlson, R. P. Proceedings o f the Twelth Annual Working Group Institute on Synthesis o f High Energy Materials, Picatinny Arsenal, NJ, June 1993, p 372. 16. Archibald, T. G.; Carlson, R. P. ref 1, p 429. 17. Hiskey, M. A.; Cobum, M. D. U. S. Patent 5,336,784 (August 9, 1994). 18. Piotrowska, H.; Urbanski, T.; Seinicki, W. Rocz. Chem. 1973, 47, 193. 19. a) Hiskey, M. A. U. S. Patent 5,395,945 March 7, 1995). b) Hiskey, M. A.; Cobum, M. D.; Mitchell, M. A.; Benicewicz, B. C.J. Heterocycl. Chem. 1992, 29, 1855. 20. Hiskey, M. A.; Cobum, M. D., private communication. 21. Sharma, P.K.; Shechter, H. ref 15, pp 385-395. 22. Katritsky, A. R.; Cundy, D. J.; Chen, J. J Heterocycl. Chem. 1994, 31, 271. 23. (a) Axenrod, T.; Watnick, C.; Yazdekhasti, H. Tetrahedron Lett. 1993, 24, 6677. (b) Axenrod, T.; Watnick, C.; Yazdekhasti, H.; Dave, P. R.J. Org. Chem. 1995, 60, 1959. 24. Dave, P. R. U. S. Patent 5,580,988 (December 3, 1996). 25. Dave, P. R. J. Org. Chem. 1996, 61, 5453. 26. Archibald, T. G.; Baum, K.; Garver, L. C. Syn. Comm. 1990, 20, 407. 27. Marchand, A. P.; Rajagopal, D.; Bott, S. G. J. Org. Chem. 1995, 60, 4943. 28. (a) Funke, W. Chem. Ber. 1969, 102, 3148. (b) Funke, W. Angew. Chem. Int. Ed. Eng. 1969, 8, 70. 29. Okutani, T; Kaneko, T.; Masuta, K. Chem. Pharm. Bull. 1974, 22, 1490. 30. Feuer, H; Savides, C. J. Am. Chem. Soc. 1959, 81, 5826. 31. Feuer, H. Chemistry o fAmino, Nitroso, and Nitro Compounds and Their Derivatives. Part 2; Patai, S. Ed.; Wiley: New York, 1982; pp 805-848. 32. Chen, T.; Sanjiki, T.; Kato, H; Ohta, M. Bull. Chem. Soc. Jpn. 1967, 40, 2401. 33. Cobum, M. D.; Buntain, G. A.; Harris, B. W.;Lee, K-Y.; Steincipher, M. M. ref 1, p 355. 34. Gaertner, V. R. J. Org. Chem. 1970, 35, 3952. 35. Nobis, J. F.; Moormeier, L. F. Ind. Eng. Chem. 1954, 46, 539. 36. O’Sullivan, W. I.; Swamer, F. W.; Humphlett, W. J. Hauser, C. R. J. Org. Chem. 1961,26,2306. 37. Rushig, H.; Fugmann, R.; Meixner, W. Angew. Chem. 1958, 70, 71. 38. Juchnovski, I. N.; Binev, I. G. J. Organomet. Chem. 1975, 99, 1. 1 0 6 39. Newman, M. S.; Fukunaga, T.; Miwa, T. J. Am. Chem. Soc. 1960, 52, 873. 40. Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React.-, Dauben, W. G. 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P. private communication. 107 APENDIX H AND "C NMR OF NEW COMPOUNDS 108 // J/ 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 Figure U\: 'H NMR (200 MHz) of l-/er/-Butyl-3-cyano-3-nitroazctidinc (45) I " ' r" 170 160 ISO HO 130 120 no 100 90 40 30 10 PPM Figure U2: '^C DEFT (75 M li/) of l-rt'rr-Bulyl-3-cyano-3-nitro‘.uctidine (45) SP 1 257 CDCL3 PPM Figure #3: 'il r ------1 . ' I ' ' I "' "^'1 '^ '' ' —r~^ I ---- I ' nr^ ’•'T^ 190 180 170 160 150 HO 130 no ICO 90 80 70 60 SO 40 30 20 PPM Figure #4: '^C NMR (75 MHz) of 2-Nitroallyl Tritluoroacetatc (95) / / y y y / V_ l l j y ii u l o « 1 \ » » \ 1 ; 1-1 ï--î j—1 ?—» -T— 1— 1— r-T— 1— T—1— 1— 1— 1— p-*t \ I t - ■U— T - A - -, ' I l » > • ' r ■ • » • •• » ---- T r T— T r- |l f , 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 PPM Figure #5: H NMR (200 MHz) of 3-/éîr/-Butyl-5-/('r/-butylaininonicthyi-5- nitrotctrahydro-1,3-oxazinc ( 108) j - hf##wA^ ^ — —1— " I "T" 170 160 150 140 130 120 no 90 70 20 10 Figure #6: ’^C DEPT (75 MHz) of 3-/t'r/-Butyl-5-/t'/Y-butylaniinoniefliyI-5- iiKrotciraliydro-1,3-oxazinc (108) 1 1 ' 1—T—|- r - T - T — r — r— r — T— Î T—J , , — I --.r* - - j--» 7 0 6 6 6 0 6 .5 6.0 A .6 A.O 3.5 3 0 2 5 2.0 1,5 1 0 PPM Figure #7; 'H NMR (200 MHz) of N,N-Bis(2-nitroallyl)/£.'/7-butylaminc (113) ON PPM Figure U8: 'H NMR (200 MHz) of 3-(3,5-I)iiutropliciiylainino)-2-nitro-l-propcnc(l 18) Il lylii 1 -1— 220 200 100 160 140 120 100 80 60 40 20 PPM Figure #9: '^C NMR (50 MHz) of 3-(3,5-l)ini(ropheiiyiainiiu))-2-nitro-l-prupcnc 1*) / A I I u 1 l - l - l -, T ■»“ 1 f -T»'f 6.0 7 .5 7 .0 5 .5 5 .0 4.5 4.0 3.5 3 0 2 5 2 0 I 5 1 0 PPM Figure #10: 'H NMR (300 MHz) of l,3-Bis(3,5-diiutrophenyliunino)-2-nitropropanc (i 1 9) 210 190 170 160 ISO 120 110 100 00 70 50 40 10 PPM Figure #11: '^CNMR (75 M il/) l,3-Bl.s(3,5-dinilr<)phenylainin())-2-nilropi()pane (H 9) 6.5 PPM Figure #12: *H NMR (300 MM/.) of l,3-Bis(4-incthylplicnylainino)-2-nitropropanc (126) w*L ' T ' 160 ISO HO 130 120 no 100 30 20 Figure #13: '^C NMR (75 MHz) of l,3-Bis(4-incthylphcnylainino)-2-nitropropanc (126) L U — I— ' 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2 .5 2.0 1.5 1 .0 PPM Figure #14: 'H NMR (300 MHz) of 3-Nitro-2,3,4,5-tctrahydro-//-benzo(Al |l,4|diazcpinc (129) WN) 130 120 no 100 90 00 ' 70 ^ Vo 50 ^ 40^ "^30 ' gg ID PPM Figure #15: "C NMR (75 MHz) of 3-Nltro-2,3,4,5-tetrahydro-//-benzol6) ll,4)dlazcpinc (129) / / 4.0 3.5 3.0 2.5 2 0 1.5 PPM Figure #16: H NMR (301) MHz) of N-(/t'r/-butyl-2-niti oallyl)acetaniicle (132) to LA '^r*' 1 70 160 130 120 90 50 30 20 PPM Figure #17: '^C NMR (75 MHz) of N-(rt'rM)uCyl-2-nltr()allyl)acctainldc (132) IMAGE EVALUATION TEST TARGET (Q A -3 ) y Y, /, % 1.0 M 2.2 2.0 l.l 1.8 1.25 1.4 1.6 150mm V f >1PPL IE D A IIWIGE . 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