Acylative dealkylation of N-tert-butyl-3-substituted azetidines: Facile access to [1.1.0]azabicyclobutane, 3-hydroxyazetidinium hydrochloride, and 3-azetidinones

Article abstract of DOI:10.1021/jo9602579

A novel acylative dealkylation of N-tert-butylazetidines and its application to the facile high-yield syntheses of [1.1.0]azabicyclobutane, 3-hydroxyazetidinium hydrochloride, and 3-azetidinones is described.

Full text of DOI:10.1021/jo9602579

J . Org. Chem. 1996, 61, 5453-5455
5453
Acyla tive Dea lk yla tion of N-ter t-Bu tyl-3-su bstitu ted Azetid in es:
F a cile Access to [1.1.0]Aza bicyclobu ta n e, 3-Hyd r oxya zetid in iu m
Hyd r och lor id e, a n d 3-Azetid in on es
Paritosh R. Dave
GEO-CENTERS, INC. at ARDEC, Building 3028, Picatinny Arsenal, New J ersey 07806-5000
Received February 7, 1996
A novel acylative dealkylation of N-tert-butylazetidines and its application to the facile high-yield
syntheses of [1.1.0]azabicyclobutane, 3-hydroxyazetidinium hydrochloride, and 3-azetidinones is
described.
In tr od u ction
Since the first report of the synthesis and chemistry
of azabicyclobutane in 1969,1 the potential of this theo-
retically interesting small strained bicyclic heterocyclic
system incorporating a reactive C-N bond has remained
largely unexplored. The lack of exploitation of this highly
reactive system is directly linked to the poor yields for
the preparation of azabicyclobutane. This difficulty
notwithstanding, the versatility of additions across the
central C-N σ bond of the azabicyclobutane system has
been elegantly demonstrated recently by Marchand et al.2
Ready availability of azabicyclobutane is sure to fuel
research activity in this area. In our work in the area of
3-substituted azetidines, an interesting development has
led to a facile high-yield synthesis of azabicyclobutane,
in addition to other important azetidines.
Resu lts a n d Discu ssion
Treatment of N-tert-butyl-3-chloroazetidine, 1,3 with
acetic anhydride at 115 °C in the presence of a catalytic
amount of boron trifluoride etherate gave N-acetyl-3-
chloroazetidine, 2, in 82% yield. On the basis of the
reported quantitative conversion of 3-phenyl-3-halo-
azetidines to 3-phenylazabicyclobutane,4 hydrolysis of the
amide group under basic conditions was attempted.
Indeed, treatment of 2 with KOH in D2O in an NMR tube
showed facile quantitative conversion to azabicyclo-
butane, as depicted in Figure 1.
F igu r e 1. (A) 1H NMR (D2O) of 2. (B) KOH added to sample
A and heated at 80 °C for 3 h, showing complete conversion to
3 and KOAc.
Sch em e 1
In a separate experiment, 2 was heated with aqueous
alkali in a distillation apparatus under water aspirator
vacuum. Azabicyclobutane distilled out along with wa-
ter. Extraction with organic solvent followed by treat-
ment with ethyl chloroformate gave the adduct 4 in 50%
overall yield.If it is assumed that the reaction of aza-
bicyclobutane with ethyl chloroformate is quantitative,
then this result represents a minimum yield, since
azabicyclobutane is appreciably water soluble and there-
fore cannot be completely extracted. This method pro-
vides a way for obtaining organic solutions of aza-
bicyclobutane in a reasonable yield for further reactions.
Additionally, the C-H coupling constant of the tertiary
carbon in azabicyclobutane was determined to be 206 Hz,
consistent with that for the carbon analog.5
Similarly, when N-tert-butyl-3-hydroxyazetidine, 5,6
was treated with acetic anhydride in the presence of a
catalytic amount of boron trifluoride etherate for 6 h,
N-acetyl-3-acetoxyazetidine, 6, was obtained in 95% yield
and could be isolated simply by vacuum distillation. The
spectral characteristics of the product match those
reported earlier.7 Compound 6 was treated with 5%
aqueous HCl under reflux to give 3-hydroxyazetidine
hydrochloride, 7, in quantitative yield.8 Compound 7 has
found application in the synthesis of Charamin9 and can
be functionalized at the 1- and 3-positions.
Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) Funke, W. Angew. Chem., Int. Ed. Engl. 1969, 8, 70. Funke, W.
Chem. Ber. 1969, 102, 3148.
(2) (a) Marchand, A. P.; Rajagopal, D.; Bott, S. G.; Archibald, T. G.
J . Org. Chem. 1995, 60, 4943; (b) 1994, 59, 1608; (c) 1994, 59, 5499.
(3) Gaertner, V. R. J . Org. Chem.1970, 35,3952.
(4) Hortmann, A. G.; Robertson, D. A. J . Am. Chem. Soc. 1972, 94,
2758.
(5) Wutrich, K.; Meiboom, S.; Snyder, L. C. J . Chem. Phys. 1970,
52, 230.
(6) Gaertner, V. R. J . Org. Chem. 1967, 32, 2972.
(7) Baumann, H. Diss. ETH Nr. 7932, 1985.
(8) Chatterjee, S. S.; Triggle, D. J . J . Chem. Soc., Chem. Commun.
1968, 93.
S0022-3263(96)00257-5 CCC: $12.00 © 1996 American Chemical Society

5454 J . Org. Chem., Vol. 61, No. 16, 1996
Dave
Sch em e 2
Sch em e 3
This acylative dealkylation is especially interesting in
light of the fact that 3-acetoxy-N-tert-butylazetidine
reportedly undergoes ring opening upon acetolysis.3
Additionally, various 2- and 3-substituted N-alkyl-
azetidines suffer ring opening on treatment with acetic
anhydride.10 One other example of dealkylation of 3,3-
dinitro-N-tert-butylazetidine with chloroformate has been
reported.11 However, no study of the generalization of
this reaction has been reported.
Sch em e 4
The acylative dealkylation offers easy access to a
number of other 3-substituted azetidines (vide infra). The
3-substituted azetidine unit is present in a wide range
of compounds having importance as drugs and pharma-
ceuticals,12 natural products,13 plant growth regulatory
agents,14 and potential new fuels and energetic
materials.2a,15
3-azetidinone, 9. Compound 9 offers the potential for
further functionalization of the azetidine ring system. It
has been identified as a suitable precursor to polyoximic
acid, an amino acid constituent of polyoxin A.18 Treat-
ment of 9 with hydroxylamine led to the smooth forma-
tion of its derived oxime, 9a .
Additionally, the acetyl group in 6 is quite labile and
is easily nitrolized with concd nitric acid to N-nitro-3-
acetoxyazetidine, 10. Compound 10 was hydrolyzed to
N-nitro-3-azetidinol, 11, which was oxidized with PCC
to give N-nitro-3-azetidinone, 12, whose spectral data
match that reported for this compound.2c 3-Azetidinones
are important intermediates for further functionalization
of the azetidine ring. However, not many 3-azetidinones
are known because of the difficulties inherent in obtain-
ing the corresponding 3-azetidinols or appropriate diazo-
ketones that can be cyclized.19
The acylative dealkylation appears to be quite general.
N-tert-Butyl-3,3-dinitroazetidine, 13,15a reacted with ace-
tic anhydride under Lewis acid catalysis to give N-acetyl-
3,3-dinitroazetidine, 14, in 90% yield. The structure of
the product was determined by the NMR spectral char-
acteristics and additionally confirmed by X-ray crystal-
lography.20
In conclusion, a novel, simple and efficient method for
the acylative dealkylation of N-tert-butylazetidines has
been developed. As a result, such key intermediates as
azabicyclobutane, 3-hydroxyazetidine hydrochloride, and
3-azetidinones are now readily accessible.
To date, the best method of synthesizing the 3-substi-
tuted azetidine ring structure remains the reaction of
bulky amines with epichlorohydrin based on Gaertner’s
work.3 A major limitation of this method is that the
reaction is successful only with highly hindered amines
like tert-butylamine and benzhydrylamine. The yields
fall precipitously with smaller amines, and the reaction
fails with amides and sulfonamides.16 For this reason,
several researchers have employed benzhydrylamine to
achieve ring cyclization, followed by hydrogenolytic re-
moval of the N-blocking group to synthesize N-unsub-
stituted azetidines, which can then be functionalized.7,17
The Lewis acid-catalyzed acylative dealkylation of the
N-tert-butyl group on azetidines offers several advan-
tages. Cost and atom economy principles favor the tert-
butyl group over the benzhydryl group. The reaction of
the tert-butyl group with epichlorohydrin proceeds faster
and in better yield than that of benzhydryl amine. This
would also be advantageous in special cases, where
hydrogenolysis may not be feasible because of the pres-
ence of other groups, e.g., nitro. Utilization of 6 in the
synthesis of various important azetidines is reported.
Compound 6 was selectively hydrolyzed by aqueous
K2CO3 as reported7 to give the 3-hydroxy derivative, 8,
which was oxidized with pyridinium dichromate in re-
fluxing dichloroethane to give hitherto unknown N-acetyl-
(9) Anthoni, U.; Nielsen, P. H.; Smith-Hansen, L.; Wium-Anderson,
S.; Christophersen, C. J . Org. Chem. 1987, 52, 694.
(10) Testa, E.; Fontanella, L.; Aresi, V. Liebigs. Ann. Chem. 1964,
676, 160.
(11) Hiskey, M. A.; Coburn, M. D.; Mitchell, M. A.; Benicewicz, B.
C. J . Heterocycl. Chem. 1992, 29, 1855.
(12) E.g., Dezinamide: Teng, L. C. U.S. Patent 4571393, 1986.
(13) E.g., Polyoximic acid: Hanessian, S.; Fu, J .-M.; Tu, Y.; Isono,
K. Tetrahedron Lett. 1993, 34, 4153. Hanessian, S.; Fu, J .-M.; Chiara,
J .-L.; Di Fabio, R. Ibid. 1993, 34, 4157.
(14) Hsu, F. C.; Kleier, D. A. Weed Sci. 1990, 38, 315.
(15) (a) Archibald, T. G.; Gilardi, R.; Baum, K.; George, C. J . Org.
Chem. 1990, 55, 2920. (b) Axenrod, T. A.; Watnick, C.; Yazdekhasti,
H.; Dave, P. R. J . Org. Chem. 1995, 60, 1959. (c) Katritzky, A. R.;
Cundy, D. J .; Chen, J . J . Heterocycl. Chem. 1994, 31, 271. (d) Hiskey,
M. A.; Coburn, M. D. U.S. Patent 5,336,784; Chem. Abstr. 1994, 121,
300750s.
Exp er im en ta l Section
All yields are unoptimized. Melting points are uncorrected.
Elemental microanalysis was performed by Galbraith Labo-
ratories, Inc., Knoxville, TN. N-tert-Butyl-3-chloroazetidine,
1,3 N-tert-butylazetidinol, 5,6 and N-tert-butyl-3,3-dinitro-
azetidine, 13,15a were prepared by literature precedents. The
spectral data for 3,1 6,7 7,8 8,7 and 122c were identical to that
reported in the literature.
N-Acetyl-3-ch lor oa zetid in e, 2. To a solution of N-tert-
butyl-3-chloroazetidine, (10 g, 67.7 mmol) in acetic anhydride
(30 mL) was added boron trifluoride etherate (1mL). The
(18) Baumann, H.; Duthaler, R. O. Helv. Chim. Acta 1988, 71, 1035.
(19) Pusino, A.; Saba, A.; Desole, G.; Rosnati, V. Gazz. Chim. Ital.
1985, 115, 33.
(16) Paudler, W. W.; Gapski, G. R.; Barton, J . M. J . Org. Chem.
1966, 31, 277.
(17) Anderson, A. G., J r.; Lok, R. J . Org. Chem. 1972, 37, 3953.
(20) Ammon, H. L.; Dave, P. R. To be submitted.

Dealkylation of N-tert-Butyl-3-substituted Azetidines
J . Org. Chem., Vol. 61, No. 16, 1996 5455
resulting solution was heated at 115 °C for 4 h. The reaction
mixture was cooled to room temperature and vacuum distilled
to give N-acetyl-3-chloroazetidine (7.4 g, 82%) as a viscous
oil: bp 110-115 °C, 2.5 mm; 1H NMR (CDCl3) δ1.6 (s, 3H),
4.1-4.6 (m, 5H); 13C NMR (CDCl3) δ 18.8, 44.2, 58.4, 60.6,
170.6; HRMS (FAB) m/z 134.0373 [(M + H)+, calcd for C5H9-
NOCl 134.0373].
59.44, 146.16, 146.19, 170.82, 170.91; HRMS (FAB) m/z
129.0666 [(M + H)+, calcd for C5H9N2O2 129.0664]. Anal.
Calcd for C5H8N2O2: C, 46.87; H, 6.29; N, 21.86. Found: C,
46.68; H, 6.81; N, 21.36.
N-Nitr o-3-acetoxyazetidin e, 10. To a mixture of N-acetyl-
3-acetoxyazetidine (12 g, 76 mmol) in acetic anhydride (30 mL)
was added ammonium nitrate (8 g, 100 mmol). The resulting
suspension was slowly heated in an oil bath at 75 °C.
CAUTION: Higher temperatures lead to a vigorous exotherm.
The mixture was heated overnight. The cooled mixture was
then vacuum distilled to give pure 10 (11 g, 90%) boiling at
95-100 °C at 2 mm pressure. The compound solidifies in the
condenser. Recrystallization from acetone/hexanes afforded
Aza b icyclob u t a n e, 3,1 a n d 3-Ch lor o-N-ca r b et h oxy-
a zetid in e, 4. To a solution of aqueous KOH (10%, 50 mL)
heated at 80 °C in a distillation apparatus was added 2 (1.4
g, 10 mmol) in one portion. Water aspirator vacuum was
applied and the distillate collected for 1 h. The aqueous
distillate was extracted with CDCl3 (3 × 10 mL). The organic
extracts were combined and dried over MgSO4. 1H and 13C
NMR spectra of this solution were identical to that reported
for azabicyclobutane. In order to determine the yield, excess
ethyl chloroformate was added to the solution. An immediate
exothermic reaction occurred. The mixture was stirred for 1
additional h and then concentrated in vacuo to give 3-chloro-
N-carbethoxyazetidine, 4 (0.87 g, 50%): 1H NMR (CDCl3) δ
1.25 (t, 3H), 4.0-4.6 (m, 7H); 13C NMR (CDCl3) δ 14.5, 45.0,
59.6, 61.2, 156.2.
1
needles: mp 61-63 °C; H NMR (CDCl3) δ 2.1 (s, 3H), 4.3-
4.75 (m, 4H), 5.1 (s, 1H); 13C NMR (CDCl3) δ 20.9, 60.6, 63.8,
170.6; HRMS (FAB) m/z 161.0554 [(M + H)+, calcd for
C5H9N2O4 161.0562]. Anal. Calcd for C5H8N2O4: C, 37.50; H,
5.04; N, 17.49. Found: C, 37.61, H, 5.40, N, 17.15.
N-Nitr o-3-a zetid in ol, 11. To N-nitro-3-acetoxyazetidine
(10 g, 62.5 mmol) was added aqueous HCl (5%, 200 mL). The
resulting solution was heated under reflux for 2 h. The cooled
mixture was then concentrated under reduced pressure to give
N-nitro-3-azetidinol (6.5 g, 100%) as a colorless waxy solid:
1H NMR (CDCl3) δ 3.8 (s, 1H), 4.2 (m, 2H), 4.5 (m, 3H); 13C
NMR (CDCl3) δ 58.7, 66.8; HRMS (FAB) m/z 119.0460 [(M +
H)+, calcd for C3H7N2O3 119.0457].
N-Nitr o-3-a zetid in on e, 12.2c To a suspension of PCC (1.5
g, 7 mmol) and sodium acetate trihydrate (0.5 g, 3.7 mmol) in
methylene chloride (10 mL) was added N-nitro-3-azetidinol (0.5
g, 4.2 mmol). The resulting mixture was heated under reflux
for 2 h. The reaction mixture was cooled, and ether (20 mL)
was added. The supernatant liquid was passed through a
short pad of Florisil. The residue was washed with two
portions of ether (10 mL). The combined organics were
concentrated, and the residue was chromatographed on silica
gel, eluting with 40% acetone/hexanes to obtain 12 as a
colorless solid, with spectral characteristics identical to those
reported (0.25 g, 50%): mp 60-61 °C (lit.2c mp 61-62 °C); 1H
NMR (CDCl3) δ 5.2 (s, 4H); 13C NMR (CDCl3) δ 77.3, 190.6.
N-Acetyl-3-a cetoxya zetid in e, 6.7 To ice-cooled acetic
anhydride (190 mL) in a round-bottom flask equipped with a
drying tube was added in portions N-tert-butyl-3-azetidinol (50
g, 387 mmol). Boron trifluoride etherate (5 mL) was injected
dropwise. A refluxing condenser was attached and the reac-
tion mixture was heated at 115 °C overnight. The reaction
mixture was then fractionally distilled under vacuum to obtain
6 as a colorless oil (58 g, 95%): bp 120-25 °C (∼2 mm) (lit.7
bp 90 °C/0.05 mm); 1H NMR (CDCl3) δ 1.9 (s, 3H), 2.1 (s, 3H),
3.9-4.5 (m, 4H), 5.2 (m, 1H); 13C NMR (CDCl3) δ 19.2, 20.9,
54.9, 57.7, 63.0, 170.5, 170.7.
3-Hyd r oxya zetid in e Hyd r och lor id e, 7.8 To 2 (7 g, 44.6
mmol) was added 5% aqueous HCl (100 mL), and the resulting
solution was heated under reflux for 4 h. The cooled reaction
mixture was concentrated on a rotary evaporator connected
to a vacuum pump. Toluene (25 mL) was added to the residue
and again concentrated to yield 3-hydroxyazetidine hydro-
chloride (4.9 g, 100%) as a colorless solid. A small sample was
recrystallized from methanol/acetone to give 7 as colorless
needles: mp 90-91 °C (lit.8 mp 91-92 °C).
N-Acet yl-3,3-d in it r oa zet id in e, 14. To N-tert-butyl-3,3-
dinitroazetidine, 13 (31 g, 147.7 mmol), was carefully added
acetic anhydride (60 mL) followed by boron trifluoride etherate
(2 mL) via syringe. The mixture was heated at 115 °C
overnight under nitrogen atmosphere. Excess acetic anhydride
was removed by vacuum distillation, and the residue was
poured into ice-water. A dark colored solid separated, which
was purified by passing through a short column of silica gel
eluting with 20% acetone in hexanes. The eluent was con-
centrated, and the residue was recrystallized from methylene
chloride/hexanes to give pure 14 (25 g, 90%): mp 111-112 °C;
1H NMR (CDCl3) δ 2.0 (s, 3H), 4.8 (bs, 2H), 5.0 (bs, 2H); 13C
NMR (CDCl3) δ 19.5, 57.4, 59.0, 105.7, 170.9; HRMS (FAB)
m/z 190.0462 [(M + H)+, calcd for C5H8N3O5 190.0464]. Anal.
Calcd for C5H7N3O5: C, 31.75; H, 3.73; N, 22.22. Found: C,
31.90; H, 3.88; N, 21.81.
N-Acetyl-3-h yd r oxya zetid in e, 8.7 To 6 (10 g, 63.7 mmol)
were added 100% aqueous potassium carbonate (100 mL), and
methanol (100 mL) and the mixture was heated under reflux
for 1 h. The cooled reaction mixture was concentrated in
vacuo, and the residue was extracted with methylene chloride
(3 × 50 mL). The combined organics were dried over magne-
sium sulfate and concentrated under reduced pressure to give
8 as a viscous oil that solidified in the freezer overnight (7 g,
95%): 1H NMR (CDCl3) δ1.9(s, 3H), 3.8-4.3 (m, 4H), 4.6 (m,
1H); 13C NMR (CDCl3) δ18.6, 57.4, 59.8, 59.9, 170.8.
N-Acetyl-3-a zetid in on e, 9. To a solution of 8 (2 g, 17.4
mmol) in 1,2-dichloroethane was added pyridinium dichromate
(9 g, 23.4 mmol) under dry atmosphere. The resulting suspen-
sion was heated under reflux overnight. The cooled reaction
mixture was passed through a short column of Florisil, and
the residue was washed through with acetone. The combined
organics were concentrated under reduced pressure, and the
residue was chromatographed on silica gel, eluting with 40%
acetone in hexanes. The relevant fractions were combined and
concentrated in vacuo to give pure 9 as a colorless oil (1.2 gm,
61%): 1H NMR (CDCl3) δ 2.1 (s, 3H), 4.8 (bs, 2H), 4.9 (bs, 2H);
13C NMR (CDCl3) δ 20.8, 70.4, 71.4, 170.8, 194.8; HRMS (FAB)
m/z 114.0554 [(M + H)+, calcd for C5H8NO2 114.0555].
N-Acetyl-3-oxim id oa zetid in e, 9a . To a solution of 9 (1
g, 8.8 mmol) in absolute ethanol (20 mL) was added hydroxyl-
amine hydrochloride (0.7 g, 10 mmol) and sodium acetate
trihydrate (2.4 g, 17.6 mmol), and the resulting suspension
was heated under reflux for 3 h. The reaction mixture was
then concentrated under reduced pressure. Ice-cold water (1
mL) was added, and the mixture was filtered to provide 9a as
a colorless solid (0.65 gm, 57%). Recrystallization from acetone
afforded 9a as a colorless micrcocrystalline solid: mp 220-21
Ack n ow led gm en t. Financial support for this work
was provided by ARDEC. Drs. Rao Surapaneni,
Thomas DeAngelis, Daniel Stec, III, and Thomas
Archibald are thanked for their support and technical
discussions. Special thanks to Prof. Theodore Axenrod
for his assistance in mass spectral acquisition.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
compounds 2, 4, 6, 9, 9a , 10, 11, and 14 (8 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
1
°C dec; H NMR (CD3COCD3) δ 1.9 (s, 3H), 4.5 (m, 2H), 4.8
(m, 2H); 13C NMR (CD3COCD3) δ 20.28, 56.95, 57.09, 59.39,
J O9602579