Facile ring cleavage of basic azetidines

Article abstract of DOI:10.1016/j.tetlet.2013.03.012

Azetidines containing a basic ring nitrogen atom have been shown to undergo facile ring cleavage to afford 3-halo-1-amino propane derivatives upon exposure to alkyl bromides and acyl chlorides under certain conditions. The rate of ring cleavage appears to be determined largely by the rate at which quaternization of the azetidine nitrogen atom occurs. Alkylation of NH azetidines to afford N-alkyl azetidines can be carried out in synthetically useful yields if reaction times are kept short. As the free base, azetidines may undergo spontaneous oligomerization with concomitant ring cleavage.

Full text of DOI:10.1016/j.tetlet.2013.03.012

Tetrahedron Letters 54 (2013) 2502–2505
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile ring cleavage of basic azetidines
⇑
Jun Xiao, Stephen W. Wright
Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Azetidines containing a basic ring nitrogen atom have been shown to undergo facile ring cleavage to
afford 3-halo-1-amino propane derivatives upon exposure to alkyl bromides and acyl chlorides under
certain conditions. The rate of ring cleavage appears to be determined largely by the rate at which
quaternization of the azetidine nitrogen atom occurs. Alkylation of NH azetidines to afford N-alkyl
azetidines can be carried out in synthetically useful yields if reaction times are kept short. As the free
base, azetidines may undergo spontaneous oligomerization with concomitant ring cleavage.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 16 February 2013
Revised 3 March 2013
Accepted 4 March 2013
Available online 13 March 2013
Keywords:
Azetidine
Heterocycle
Ring cleavage
Alkylation
Acylation
Azetidines have come to play an important role in medicinal
chemistry programs.1 Azetidines impart lower basicity, lipophilic-
ity, and molecular weight to target compounds than the corre-
sponding pyrrolidine and piperidine rings, often resulting in
more favorable pharmacokinetic properties. In addition, they often
provide an element of novelty that can be important to securing an
intellectual property position. Despite these appealing properties,
the ring strain inherent in the four membered ring cannot be over-
looked, and can contribute to undesired reactivity of the azetidine
ring. While the ring cleavage of azetidinones (b-lactams) has been
exploited for decades, the ring cleavage of all sp3 azetidine rings
has only been studied more recently. Ring cleavage by a mecha-
nism involving the intramolecular generation of an adjacent carbe-
nium ion center, followed by azetidine ring expansion to a
pyrrolidine and trapping with a halide or other nucleophile, has
been reported.2 Similarly, the ring cleavage of tertiary azetidines
by an intramolecular acid chloride has been reported.3 Recently,
the regiospecific ring cleavage of 1-alkyl-2-(trifluoromethyl)azeti-
dines by alkyl, acyl, and hydrogen halides was reported.4 In this
Letter, we wish to report the unexpectedly facile ring cleavage of
some azetidines under various intermolecular reaction conditions.
During the course of a recent medicinal chemistry program, we
sought to prepare the tertiary azetidine 2 as an intermediate for
further elaboration ( Fig. 1). Following an established procedure
for the analogous piperidine compound,5 we attempted the
preparation of 2 from the readily available6 intermediate 1a by
alkylation with methyl bromoacetate. To our surprise, the major
product of this reaction, isolated in 88% yield, was not the expected
tertiary azetidine 2 but rather the trisubstituted propane derivative
3a. The structure of 3a was plainly evident from its mass spectrum
and 1H NMR. Further evidence to confirm the structure of 3a was
its conversion into the oxazolidinone 4 upon heating, a reaction
characteristic of N-BOC amines substituted with a beta-leaving
group.7 The structure of 4 was likewise established by 1H and 13C
NMR, mass spectroscopy, IR, and elemental analyses.
Prompted by this result, we sought to explore the scope of this
reaction to determine its generality and potential synthetic utility
(Table 1). Initial efforts were focused upon the use of 1a as a
substrate for this reaction, after which additional secondary and
tertiary azetidines were examined.
From Table 1, it can be seen that reactive alkyl bromides, such
as benzyl bromides, allyl bromide, methyl bromide,and methyl
bromoacetate all afforded the products of exhaustive alkylation
and ring cleavage in moderate to good yields, while the kinetically
H
N
O
H
N
tBu
O
N
tBu
O
HN
O
O
O
OMe
1a
2
O
O
O
tBu
MeO
HN
O
Br
MeO
HN
4
O
N
O
N
MeO
MeO
O
3a
⇑
Corresponding author. Tel.: +1 860 441 5831; fax: +1 860 715 4483.
E-mail address: stephen.w.wright@pfizer.com (S.W. Wright).
Figure 1.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.012

J. Xiao, S. W. Wright / Tetrahedron Letters 54 (2013) 2502–2505
2503
Table 1
Cleavage of azetidines 1 upon alkylationa Structures of starting materials 1 and products 3 and 5 are shown above
O
O
R2
R2
MeN
X
or
N
R1
N
R3
R4
N
R3
R4
1a - g
3a - s
5a - c
Entry
Azetidine
R1
R2
Alkyl halide (equiv)
BrCH2CO2Me (2.1)
BrCH2C6H4-4-NO2 (2.1)
BrCH2C6H4-4-CN (2.1)
BrCH2Ph (2.1)
Product
R3
R4
Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1e
1e
1f
H
H
H
H
H
H
H
NHBOC
NHBOC
NHBOC
NHBOC
NHBOC
NHBOC
NMeBOC
NHBOC
NHCO2Me
NMeBOC
NMeBOC
NMeBOC
NMeBOC
OC6H4OMe
OCHPh2
3a
3b
3c
3d
3e
3f
5a
3g
3h
5b
5c
5d
5e
3i
CH2CO2Me
CH2CO2Me
88
50
49
50
CH2C6H4-4-NO2
CH2C6H4-4-CN
BrCH2Ph
CH2C6H4-4-NO2
CH2C6H4-4-CN
BrCH2Ph
BrCH3 (5)
CH3
CH3
53
BrCH2CH2CH3 (2.1)
BrCH2C6H4-4-CN (2.1)
BrCH2C6H4-4-NO2 (1.1)
BrCH2C6H4-4-CN (2.1)
BrCH2CH@CH2 (1.1)
BrCH2C6H4-4-CN (1.1)
BrCH2CH2CH3 (1.1)
CH3CHBrCH3 (1.1)
BrCH2C6H4-4-CN (2.1)
BrCH2C6H4-4-CN (1.1)
CH2CH2CH3
CH2C6H4-4-CN
CH2C6H4-4-CN
CH2C6H4-4-CN
CH2C6H4-4-NO2
CH2C6H4-4-NO2
CH2C6H4-4-NO2
CH(CH3)2
CH2CH2CH3
CH2C6H4-4-CN
CH2C6H4-4-NO2
CH2C6H4-4-CN
CH2CH@CH2
CH2C6H4-4-CN
CH2CH2CH3
CH(CH3)2
<10c
81
CH2C6H4-4-CN
H
52
56
83
77
9
10
11
12
13
14
15
CH2C6H4-4-NO2
CH2C6H4-4-NO2
CH2C6H4-4-NO2
CH2C6H4-4-NO2
H
37
<10c
59
CH2C6H4-4-CN
CH3
CH2C6H4-4-CN
CH2C6H4-4-CN
1g
Me
3j
50
a
Experiments were performed using 1 mmol of 1, the indicated alkylating agent, and 2.5 equiv of powdered K2CO3 in 7 mL of MeCN for 24 h at 20 °C while being monitored
by LCMS.
b
Isolated yields of purified product.
The product was not isolated but was present in the reaction mixture by LCMS.
c
O
less reactive 1-bromopropane afforded a lower yield during the
standard reaction time (entries 6 and 12). Similarly, 2-bromopro-
pane failed to afford a significant amount of product (entry 13),
suggesting that the overall rate of this reaction is determined lar-
gely by the rate at which alkylation of the azetidine by the alkylat-
ing agent occurs. Azetidines 1f and 1g likewise underwent
alkylation and azetidine ring cleavage (entries 14 and 15), demon-
strating that this process is not exclusive to carbamate substituted
azetidines.
O
HN
N
R
7
O
HN
O
N
H
1a
O
O
HN
O
HN
O
Br
Also of note was the propensity with which the 3-N-methyl-
N-BOC substituted azetidines 1b and 1e underwent cyclization to
the oxazolidinone derivatives 5a–5d (entries 7, 10–13). In these
experiments, LCMS monitoring of the reaction mixtures showed
the formation of 5 without the apparent intermediacy of the ring
opened products 3, suggesting that the scission of the azetidine
ring was effected by intramolecular attack of the BOC group
(Scheme 1). Indeed, a side–by side comparison of azetidines 1a
and 1b under the same reaction conditions showed that accumula-
tion of the ring–opened bromopropane product 3 was observed
with 1a but not with 1b.
N+
N
R
R
R
R
8
3c
Scheme 2. Species generated during reaction of 1a with 4-cyanobenzyl bromide 6
monitored by 1H NMR. R = 4-cyanobenzyl.
Table 2
1H NMR study of reaction of 1a with 2.2 equiv 4-cyanobenzyl bromide 6a
Time (h)
1a
6
7
8
3c
A study of the reaction using 1H NMR was undertaken to further
understand the alkylation and ring scission. Azetidine 1a was trea-
ted with 4-cyanobenzyl bromide (6) in CD3CN in the presence of
powdered K2CO3 at 20 °C (Scheme 2). Aliquots of the reaction mix-
ture were taken at intervals, filtered, and diluted with CD3CN for
immediate 1H NMR analysis. The identity of the products and
intermediates present in the mixture was established by compari-
0
0.25
1
2
4
1.0b
0
0
0
0
2.2b
1.2
0.8
0.6
0.5
0.2
0
1
0.7
0.5
0.3
0.1
0
0
0
0
0
0
0
0
0.4
0.5
0.7
0.9
21
0
a
The experiment was performed using 0.7 mmol of 1a and 1.6 mmol of 6 in 5 mL
of CD3CN containing 1.8 mmol powdered K2CO3 and monitored by 1H NMR
b
Molar equivalents of starting materials and products determined by integration
of unique resonances and normalized to 1a originally present. Assignments were
made by comparison to 1H NMR spectra of authentic samples.
O
O
O
MeN
MeN
N+
O
O
MeN
N+
O
son to the 1H NMR spectra of authentic samples of 1a, 4-cyanoben-
zyl bromide 6, the tertiary azetidine 7, and the ring cleavage
product 3c.
From the results in Table 2, it can be noted that the initial alkyl-
ation of 1a to afford 7 was quite rapid, having gone to completion
with 15 min. The subsequent quaternization of 7 by 6 was
N
R
R
R
R
R
R
H+
+
C4H8 +
Scheme 1. Proposed mechanism for intramolecular cleavage of azetidinium ion by
adjacent N(Me)BOC group.

2504
J. Xiao, S. W. Wright / Tetrahedron Letters 54 (2013) 2502–2505
considerably slower. Interestingly, no accumulation of the quater-
nary salt 8 could be observed by 1H NMR (or by UPLC–MS), suggest-
ing that cleavage of the quaternary salt 8 to afford 3c occurred at a
significantly faster rate than the quaternization of 7.
O
O
O
Cl
N
HN
N
O
NH
O
O
The 1H NMR study suggested that the tertiary azetidines that
were the original object of this investigation, such as 2, could be
prepared successfully by direct alkylation if the reaction time
was kept short. Treatment of 1a with methyl bromoacetate for
45 minutes afforded 2 in 68% isolated yield. Likewise, treatment
of 1a with 4-cyanobenzyl bromide for 45 min afforded 7 in 74%
isolated yield, identical in all regards with a sample of 7 prepared
by reductive amination of 1a with 4-cyanobenzaldehyde.
As this study progressed, we observed that the sample of 1a that
we were using slowly underwent degradation. Originally a free
flowing white solid, melting point 134–136 °C (lit. melting point
138–140 °C),6 our sample of 1a gradually transformed into a stiff
taffy–like substance after standing at ambient room temperature
in the dark for 2 years. The melting point had decreased to less than
100 °C. Trituration of this degraded material with 1-chlorobutane
returned only 16% of 1a as a white solid. Chromatography of the
mother liquor afforded an additional 20% of 1a and 35% of a colorless
glass. The 1H and 13C NMR and high resolution mass spectrum of this
substance indicated that it was a dimer of 1a, either the diazacyclo-
octane structure 9 or the tertiary azetidine 10 (Fig. 2). Acylation with
p-toluic anhydride and Et3N in THF afforded 87% of a mono-tolua-
mide 11 (Fig. 3), a result consistent with the tertiary azetidine 10.
The diazacyclooctane structure may therefore be eliminated from
consideration, in as much as no bis-toluamide was formed.
Azetidine 1g also underwent decomposition when stored as the
free base at room temperature. Originally a mobile oil, 1g trans-
formed to a stiff resin within 1 week. 1H NMR showed that 15%
of 1g remained in the resinous material; the remainder of the sam-
ple was composed of ring–opened oligomers of 1g.
H
N
H
N
O
O
O
O
O
N
H
N
H
11
12
Figure 3. Structures of products resulting from treatment of 10 with p-toluic
anhydride and p-toluoyl chloride, respectively.
O
O
Cl
N
O
O
O
N
O
O
O
O
13
14
Figure 4. Acylation and concomitant ring cleavage of a tertiary azetidine.
O
O
HN
O
HN
O
Ph
Ph
N
N
S
15
16
Acylation of the dimer 10 with p-toluoyl chloride and Et3N in
THF did not afford 11, but instead afforded 58% of 12,8 resulting
from the reaction of 10 with additional p-toluoyl chloride and ring
cleavage by chloride ion.
Figure 5. Medicinal chemistry intermediates prepared from 1a by azetidine
alkylation and ring cleavage.
Likewise, acylation of the azetidine 13 with p-toluoyl chloride
and Et3N in THF afforded 96% of the amide 14 within 10 min at
ambient temperature (Fig. 4). These results demonstrate yet again
the exceptional susceptibility of the azetedinium ion to ring cleav-
age by halide ions.
Having shown that the azetidine ring was readily cleaved by
exposure to alkyl halides and acyl halides under conditions during
which formation of an azetidinium ion was likely, we sought to
determine whether exposure to hydrogen halides would result in
a similar general ring cleavage reaction. The cleavage of azetidines
by hydrogen halides is known,9 and can cause difficulty during the
removal of a BOC group,10 but the generality of this side reaction is
not known. Surprisingly, the azetidine 1f resisted ring cleavage in a
1H NMR experiment upon exposure to D2O solutions containing
either 6 M DCl or 8 M DBr, even at 80 °C for up to 4 h. Similarly,
1f and N-BOC 1f afforded no significant amounts of ring cleavage
product upon exposure to 4 M HCl in dioxane solution.
The ring cleavage of azetidines may be used to prepare tri-
substituted propane derivatives that otherwise might require
lengthier syntheses.11 For example, we prepared rac-1512 (Fig. 5)
in 96% isolated yield in a single step from 1a by heating for 16 h
with excess benzyl bromide and K2CO3 in MeCN.
Likewise, rac-1613 was prepared in 65% yield in two-steps start-
ing from 1a: (a) alkylation with methyl bromide, followed by (b)
treatment with sodium thiophenoxide.
In conclusion, we have found that azetidines with a basic ring
nitrogen atom may be easily cleaved upon exposure to alkyl and
acyl halides. N-Unsubstituted azetidines may be successfully alkyl-
ated or acylated with appropriate selection of reaction conditions.
Azetidines, as the free base, may undergo oligomerization involv-
ing ring cleavage and the formation of dimeric and possibly other
products. The reactivity that we describe should inform the organic
chemistry community that azetidines should not be viewed simply
as lower molecular weight, less polar analogs of pyrrolidines and
piperidines. Indeed, azetidines may bring an undesirable reactivity
profile to synthetic targets. In these regards, azetidines may be
viewed similarly to aziridines.14 Finally, the ring opening of appro-
priately substituted azetidines may offer a synthetic approach for
the preparation of tri-substituted propane derivatives.
O
O
NH
HN
N
O
O
NH
HN
H
N
O
O
HN
Supplementary data
O
O
H2N
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.
012.
9
10
Figure 2. Structures of possible products of spontaneous dimerization of 1a .

J. Xiao, S. W. Wright / Tetrahedron Letters 54 (2013) 2502–2505
2505
6. Domagala, J. M.; Mich, T. F.; Nichols, J. B. U.S. Patent 5,281,612, 1994; Chem.
Abstr. 1994, 120, 270360.
References and notes
7. Curran, T. P.; Pollastri, M. P.; Abelleira, S. M.; Messier, R. J.; McCollum, T. A.;
Rowe, C. G. Tetrahedron Lett. 1994, 35, 5409.
1. See, for example: (a) Brandt, T. A.; Caron, S.; Damon, D. B.; Di Brino, J.; Ghosh,
A.; Griffith, D. A.; Kedia, S.; Ragan, J. A.; Rose, P. R.; Vanderplas, B. C.; Wei, L.
Tetrahedron 2009, 65, 3292; (b) Van Hende, E.; Verniest, G.; Deroose, F.;
Thuring, J.-W.; Macdonald, G.; De Kimpe, N. J. Org. Chem. 2009, 74, 2250; (c)
Holladay, M. W.; Decker, M. W. Adv. Med. Chem. 2000, 5, 85; (d) Mangelinckx,
8. The structures of 11 and 12 were confirmed by 1H and 13C NMR, mass
spectroscopy, IR, and elemental analyses.
9. Kaneko, C.; Kasai, K.; Katagiri, N.; Chiba, T. Chem. Pharm. Bull. 1986, 34, 3672.
See also Ref. 4.
ˇ
ˇ
S.; Zukauskaite, A.; Buinauskaite, V.; Šackus, A.; De Kimpe, N. Tetrahedron Lett.
˙
˙
10. Kelly, M. G.; Kincaid, J.; Fang, Y.; He, J.; Cao, Y.; Kaub, C.; Gowlugari, S.; Wang, Z.
U.S. Patent 7,816,371, 2010; Chem. Abstr. 2007, 147, 406702.
11. D’hooghe, M.; De Kimpe, N. Tetrahedron 2008, 64, 3275.
12. Celanire, S.; Quere, L.; Denonne, F.; Provins, L. U.S. Patent 7,943,605, 2011;
Chem. Abstr. 2007, 146, 481929.
13. Augeri, D. J.; Baumeister, S. A.; Bruncko, M.; Dickman, D. A.; Ding, H.; Dinges, J.;
Fesik, S. W.; Hajduk, P. J.; Kunzer, A. R.; McClellan, W.; Nettesheim, D. G.; Oost,
T.; Petros, A. M.; Rosenberg, S. H.; Shen, W.; Thomas, S. A.; Wang, X.; Wendt, M.
D. U.S. Patent 6,720,338, 2004; Chem. Abstr. 2002, 137, 78769.
14. Cerichelli, G.; Luchetti, L. J. J. Chem. Soc., Chem. Commun. 1985, 339.
2008, 49, 6896.
2. (a) Couty, F.; Drouillat, B.; Lemee, F. Eur. J. Org. Chem. 2011, 4, 794; (b) De Rycke,
N.; David, O.; Couty, F. B. Org. Lett. 2011, 13, 1836.
3. (a) Bartholomew, D.; Stocks, M. J. Tetrahedron Lett. 1991, 32, 4799; (b)
Wasserman, H. H.; Han, W. T.; Schaus, J. M.; Faller, J. W. Tetrahedron Lett.
1984, 25, 3111.
4. Kenis, S.; D’hooghe, M.; Verniest, G.; Dang Thi, T. A.; Pham The, C.; Van Nguyen,
T.; De Kimpe, N. J. Org. Chem. 2012, 77, 5982.
5. Youngman, M. A.; McNally, J. J.; Lovenberg, T. W.; Reitz, A. B.; Willard, N. M.;
Nepomuceno, D. H.; Wilson, S. J.; Crooke, J. J.; Rosenthal, D.; Vaidya, A. H.; Dax,
S. L. J. Med. Chem. 2000, 43, 346.