Synthesis of 3-functionalized 3-methylazetidines

Article abstract of DOI:10.1016/j.tetlet.2011.10.097

1-t-Butyl- and 1-(4-methylbenzyl)-3-bromo-3-methylazetidines were prepared from the corresponding N-(2,3-dibromo-2-methylpropylidene)alkylamines and their propensity to undergo nucleophilic substitution at the 3-position by different nucleophiles was asse

Full text of DOI:10.1016/j.tetlet.2011.10.097

Tetrahedron Letters 53 (2012) 107–110
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3-functionalized 3-methylazetidines
⇑
⇑
´
Sonja Stankovic, Matthias D’hooghe , Kourosch Abbaspour Tehrani , Norbert De Kimpe
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
1-t-Butyl- and 1-(4-methylbenzyl)-3-bromo-3-methylazetidines were prepared from the corresponding
N-(2,3-dibromo-2-methylpropylidene)alkylamines and their propensity to undergo nucleophilic substitu-
tion at the 3-position by different nucleophiles was assessed, providing a convenient access to novel 3-alk-
oxy-, 3-aryloxy-, 3-hydroxy-, 3-cyano-, 3-carboxy-, 3-(aminomethyl)- and 3-(hydroxymethyl)azetidines.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 6 October 2011
Accepted 17 October 2011
Available online 29 October 2011
Keywords:
Aziridines
Azetidines
Aziridinium salts
Imines
Substitution
Within azaheterocyclic chemistry, azetidines represent a valu-
able class of strained nitrogen-containing compounds from both
a biological1 and a synthetic point of view.2 In particular, 3-substi-
tuted azetidines have attracted considerable interest because of
the diverse biological activities associated to this type of com-
pounds. For example, 3-alkoxy- and 3-aryloxyazetidines have been
described as G-protein coupled receptor agonists,3 inhibitors of
stearoyl-coenzyme d-9 desaturase,4 and antibacterial agents.5
Moreover, 3-haloazetidines (without an additional alkyl group at
the 3-position) are generally recognized as good substrates in or-
ganic chemistry for the preparation of other 3-functionalized
azetidines.6
2-(halomethyl)aziridines to 3-haloazetidines had been observed
in the literature in only two specific cases.10
In general, the reactivity profile of 3-bromo-3-methylazetidines
as useful synthons in organic chemistry has not been studied so far.
In this Letter, the synthesis of 3-bromo-3-methyl-1-(4-methylben-
zyl)azetidine and 3-bromo-1-t-butyl-3-methylazetidine will be
covered, as well as their propensity to undergo nucleophilic substi-
tution at the 3-position to access a window of novel 3-functional-
ized azetidines.
The synthesis of 3-bromo-3-methyl-1-(4-methylbenzyl)azeti-
dine 9 was performed via thermal ring expansion of 2-bromo-
methyl-2-methylaziridine 8 upon heating in acetonitrile under
reflux according to a literature protocol (Scheme 2).7 Aziridine 8
Recently, the convenient synthesis of 3-methoxy-3-methylaz-
etidines
methylaziridines 2, obtained by NaBH4-mediated reduction of the
corresponding ,b-dibromo imines 1, upon treatment with NaBH4
3
through ring rearrangement of 2-bromomethyl-2-
was prepared by reductive cyclization of a,b-dibromoaldimine 7a
(R = 4-MeC6H4CH2), obtained via bromination of 2-methylpropenal
5 and subsequent condensation with 4-methylbenzylamine in the
presence of titanium(IV) chloride and triethylamine.7 In the same
work, it has been shown that 3-methoxy-3-methylazetidines 3
a
in methanol under reflux has been described by us.7 The same
azetidines 3 have also been prepared via a different route through
NaBH4-mediated cyclization of N-alkylidene-(3-bromo-2-meth-
oxy-2-methylpropyl)amines.8 In general, halogenated imines com-
prise useful intermediates for the preparation of azaheterocyclic
compounds such as aziridines and azetidines.9
Ar
N
NaBH4
MeOH, Δ
Ar
H
Furthermore, if aziridines 2 were heated in acetonitrile under
reflux, 3-bromoazetidines 4 were obtained as the thermodynamic
products (Scheme 1).7 Until then, the peculiar rearrangement of
OMe
Ar
NaBH4
N
3
N
MeOH, r.t.
Br
Br
Br
Ar
2
N
1
CH3CN, Δ
⇑
Corresponding authors.
E-mail addresses: matthias.dhooghe@UGent.be (M. D’hooghe), norbert.dekimpe
@UGent.be (N. De Kimpe).
Br
Ref. 7
4
Present address: Department of Chemistry, Faculty of Science, University of
Antwerp, Middelheimcampus, G.V.211, Groenenborgerlaan 171, 2020 Antwerpen,
Belgium.
Scheme 1. Reactivity of 2-bromomethyl-2-methylaziridines 2.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.097

´
108
S. Stankovic et al. / Tetrahedron Letters 53 (2012) 107–110
O
O
1.05 equiv Br2
Br
H
H
CH2Cl2, r.t., 2.5 h
Br
5
6 (98%)
1 equiv
4-MeC6H4CH2NH2
or tBuNH2
0.6 equiv TiCl4
3 equiv Et3N
→
Et2O, 0°C
r.t., 4 h
NaBH4
R
N
2.5 equiv
NaBH4
MeOH, r.t., 36 h
CH3CN
15 h,
Br
N
H
N
Br
Br
H
or LiAlH4
Et2O, Δ, 18 h
N
Δ
MeOH, r.t., 4 h
Br
Br
10 (93%)
Br
9 (62%)
7a (R = 4-MeC6H4CH2, 64%)
7b (R = tBu, 69%)
8 (82-85%)
1 equiv LiAlH4
Et2O, Δ, 18 h
75%
MeOH or EtOH
Δ, 12 h
(R1 = Me) 11/12a = 84 : 16
(R1 = Et) 11/12b = 80 : 20
(R1 = iPr) 11/12c = 100 : 0
N
N
or
+
iPrOH, Δ, 16 h
OR1
12
Br
11
83%
Scheme 2. Synthesis of 3-bromo-3-methylazetidines 9 and 11.
were obtained upon treatment of imines 7 (R = CH2Ar) with so-
dium borohydride in methanol under reflux. Considering this
smooth imine 7 (R = CH2Ar) to azetidine 3 transformation, different
reaction conditions were evaluated to obtain 3-bromoazetidine 9
directly from imine 7a. The reaction of imine 7a with 1 molar equiv
of LiAlH4 in diethyl ether for 18 h under reflux resulted only in azi-
ridine 8, while the same reaction in tetrahydrofuran for a pro-
longed reaction time (5 days) gave a mixture of ring-opened
amines derived from the hydride-induced ring opening of aziridine
8.11 The reduction of imine 7a, either with 1 molar equiv of LiAlH4
in dioxane for 15 h under reflux or with 2 molar equiv of NaBH4 in
isopropanol for 15–24 h under reflux, gave complex reaction mix-
tures, in which no 3-bromoazetidine 9 could be detected. There-
fore, the most efficient synthesis of azetidine 9 was shown to
occur via thermal rearrangement of aziridine 8.
Contrary to the reactivity of N-(arylmethyl)imine 7a, treatment
of N-t-butylimine 7b with 2.5 molar equiv of NaBH4 in methanol
for 4 h at room temperature selectively provided amine 10 instead
of 2-bromomethyl-1-t-butyl-2-methylaziridine (Scheme 2). These
observations are in accordance with the NaBH4-mediated reduc-
tion of chlorinated imines toward the synthesis of different 1-al-
kyl-2-chloromethyl-2-methylaziridines, except in the case of the
1-t-butyl derivative where the formation of the corresponding azi-
ridine was also never observed.12 When amine 10 was further
heated in methanol or ethanol for 12 h under reflux, a mixture of
azetidines 11 and 12a,b (as their hydrobromic salt) was obtained.
It should be noted that even if the corresponding 2-bromo-
methyl-2-methylaziridine was formed in this step, it immediately
rearranged into azetidines 11 and 12 as the thermodynamically
preferred products. Heating of amine 10 in a less nucleophilic sol-
vent such as isopropanol for 16 h under reflux provided only 3-bro-
moazetidine hydrobromide 11, which was then isolated as a
neutral compound upon treatment with a sodium hydroxide
solution in 83% yield. In addition, treatment of imine 7b with 1 -
molar equiv of LiAlH4 in diethyl ether for 18 h under reflux gave
3-bromoazetidine 11 as the major product (75%), together with
some non-identified side products (Scheme 2). Again, no traces of
2-bromomethyl-1-t-butyl-2-methylaziridine were observed.
The formation of 3-alkoxyazetidines 12a,b from amine 10 is
proposed to occur via nucleophilic attack of the solvent molecule
(methanol or ethanol) at the more-substituted carbon atom of
the intermediate bicyclic aziridinium ion 13 (Scheme 3). This
strained intermediate 13 is most probably formed via intramolec-
ular nucleophilic displacement of bromide in the initially formed
3-bromoazetidine 11. The proposed pathway concurs with the pre-
viously reported synthesis of 3-methoxy-3-methylazetidines 3
(R1 = CH2Ar, R2 = Me, Scheme 3) comprising the smooth ring
expansion of 2-bromomethyl-2-methylaziridines 2 via bicyclic
aziridinium intermediates 14 upon heating in methanol in the
presence of NaBH4.7 In the same study, it has been shown that 3-
methoxy-3-methylazetidines 3 can also be obtained starting from
3-bromoazetidines
(NaBH4, MeOH, ).
4 applying the same reaction conditions
D
It should be noted that bicyclic aziridinium ions such as 13 have
previously been shown to be considerably more stable than the
corresponding open-ring tertiary carbenium ions by means of high
Ar
Ar
N
R1
MeOH or
EtOH, Δ
Br
N
N
N
NaBH4
MeOH, Δ
N
2
OR2
HOMe
HOR2
Br
Ar
N
12a,b (R1 = tBu
R
11
13
14
Ref. 7
2 = Me, Et)
3 (R1 = CH2Ar
2 = Me)
Br
4
R
Scheme 3. Synthesis of 3-alkoxy-3-methylazetidines 12.

´
109
S. Stankovic et al. / Tetrahedron Letters 53 (2012) 107–110
OH
1-2.2
equiv
R
R3
R1OH
Δ, 24-72 h
N
R
R2
N
N
R3
R2
2-5 equiv K2CO3
THF or CH3CN
(R = 4-MeC6H4CH2) Δ, 4 h - 2 d
O
OR1
Br
9
12a (R1 = Me, 89%)
12b (R1 = Et, 90%)
12c (R1 = iPr, 75%)
11 (R = tBu)
15a (R = tBu, R2 = H
3 = OMe, 63%)
15b (R = tBu, R2 = Et
3 = H, 71%)
15c (R = tBu, R2 = Ph
3 = H, 67%)
5 equiv KOH, H2O/CH2Cl2 (9/1)
or 2 equiv K2CO3, H2O
Δ, 10-24 h
R
R
R
N
R
15d (R = 4-MeC6H4CH2
R2 = H, R3 = H, 96%)
OH
16a (R = tBu, 63-85%)
16b (R = 4-MeC6H4CH2, 96%)
Scheme 4. Reactivity of 3-bromo-3-methylazetidines 9 and 11 toward oxygen nucleophiles.
2 equiv LiAlH4
R
R
1.5 equiv KCN
N
N
N
N
5 equiv KOH
Et2O, r.t., 3 h
DMSO, 100 °C
EtOH, Δ, 120 h
Br
COOH
18 (23%)
CN
or MeCN, Δ, 13-15 h
OH
19 (90%)
17a (R = tBu, 91%)
9 (R = 4-MeC6H4CH2)
11 (R = tBu)
17b (R = 4-MeC6H4CH2, 94%)
5 equiv KOH
2 equiv LiAlH4, Et2O
0 °C, 3h + r.t., 14 h
EtOH/H2O 5/1
MW, 150 °C
15 min
Dowex H+
(NH4OH, 1N)
N
H
N
N
85%
COO
21 (95%)
COO
22
NH2
20 (97%)
NH4
Scheme 5. Synthesis and reactivity of 3-methylazetidine-3-carbonitriles 17a,b.
level computational studies,7 pointing to a double SN2 reaction
mechanism for the conversion of bromides 11 into ethers 12.
The latter transformation served as a starting point to thor-
oughly investigate the synthetic potential of 3-bromo-3-methylaz-
etidines for the preparation of novel 3-substituted azetidines. For
this purpose, 3-bromo-3-methyl-1-(4-methylbenzyl)azetidine 9
and 3-bromo-1-t-butyl-3-methylazetidine 11 were selected as eli-
gible substrates for reactions with different nucleophiles.
Upon heating of 3-bromo-1-t-butylazetidine 11 (R = tBu) in dif-
ferent alcohols (MeOH, EtOH, iPrOH) for 24–72 h under reflux, the
corresponding 3-alkoxyazetidines 12a–c were formed in pure form
after basic work-up (Scheme 4). Furthermore, the reactions of
azetidines 9 and 11 with 1–2.2 equiv of different phenols and 2–
5 equiv of K2CO3 in tetrahydrofuran or acetonitrile for 4–48 h un-
der reflux provided the corresponding 3-aryloxyazetidines 15a–d
in good yields, which were purified by means of column chroma-
tography on silica gel in order to obtain analytically pure sam-
ples.13 When substrates 9 and 11 were heated in water or water/
CH2Cl2 (9/1) for 10–24 h under reflux in the presence of 5 equiv
of KOH or 2 equiv of K2CO3, 1-t-butyl-3-methyl-3-azetidinol 16a
and 3-methyl-1-(4-methylbenzyl)-3-azetidinol 16b were obtained
in high yields (Scheme 4).14 The above-described findings support
the suitability of 3-bromo-3-methylazetidines as substrates for
9 and 11 were also shown to be good substrates for the synthesis of
azetidine-3-carbonitriles 17a,b upon treatment with 1.5 equiv of
KCN in dimethylsulfoxide (100 °C) or acetonitrile (reflux) for 13–
22 h (Scheme 5). Azetidine 17a was purified via distillation and
azetidine 17b by means of column chromatography on silica gel,
which were then used for further derivatization.
The hydrolysis of the cyano group in azetidines 17 can provide
an access toward cyclic amino acids which can be considered as
analogues of azetidine-2-carboxylic acid, a natural molecule iso-
lated from Convallaria majalis (lily-of-the-valley) and endowed
with impressive biological activities such as the inhibition of the
proliferation of Escherichia coli, alteration of the structure of colla-
gen, keratin and hemoglobin in human proteins, and teratogenic
effects and various malformations in animals.1e Thus, the reaction
of azetidine 17a with 5 equiv of KOH in ethanol under reflux re-
sulted in the corresponding new amino acid 1-t-butyl-3-methylaz-
etidine-3-carboxylic acid 18 (23% after purification on a Dowex
column) after a prolonged reaction time (120 h) and without traces
of the corresponding amide. The carboxy group in azetidine 18 was
then successfully reduced using 2 molar equiv of LiAlH4 in diethyl
ether for 3 h at room temperature to form 3-(hydroxymethyl)azeti-
dine 19 in 90% yield. Furthermore, 3-(aminomethyl)azetidine 20
was obtained after reduction of the cyano group with 2 molar
equiv of LiAlH4 in diethyl ether for 14 h at room temperature.16
A number of experiments were also performed concerning the
hydrolysis of the cyano group in 1-(4-methylbenzyl)azetidine-3-
carbonitrile 17b. The treatment of azetidine 17b with 5 equiv of
KOH in EtOH/H2O (5/1) under microwave irradiation (150 °C,
nucleophilic
nucleophiles.
substitutions
by
different
oxygen-centered
In the literature, it is known that azetidine-3-carbonitriles can
be prepared via nucleophilic substitution of 3-mesyloxy- and 3-
tosyloxyazetidines.15 In that respect, 3-bromo-3-methylazetidines

´
110
S. Stankovic et al. / Tetrahedron Letters 53 (2012) 107–110
7. Stankovic´, S.; Catak, S.; D’hooghe, M.; Goossens, H.; Abbaspour Tehrani, K.;
Bogaert, P.; Waroquier, M.; Van Speybroeck, V.; De Kimpe, N. J. Org. Chem. 2011,
76, 2157–2167.
CH3CN, Δ
iPrOH, Δ
8. De Kimpe, N.; De Smaele, D. Tetrahedron 1995, 51, 5465–5478.
9. (a) De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc., Chem. Commun. 1994,
1221–1222; (b) D’hooghe, M.; Waterinckx, A.; De Kimpe, N. J. Org. Chem. 2005,
70, 227–232; (c) Sulmon, P.; De Kimpe, N.; Schamp, N.; Tinant, B.; Declercq, J.-P.
Tetrahedron 1988, 44, 3653–3670.
N
R
R
Br
N
N
8
X
Br
ˇ
ˇ
10. (a) Mangelinckx, S.; Zukauskaite, A.; Buinauskaite, V.; Šackus, A.; De Kimpe, N.
˙
˙
23
Br
N
9 (R = 4-MeC6H4CH2)
11 (R = tBu)
Tetrahedron Lett. 2008, 49, 6896; (b) Gaertner, V. R. J. Org. Chem. 1970, 35,
H
X = OR, OAr, OH, CN
COOH, CH2NH2
CH2OH
Br
ˇ
ˇ
3952–3959; (c) Zukauskaite, A.; Mangelinckx, S.; Buinauskaite, V.; Šackus, A.;
˙
˙
10
De Kimpe, N. Amino Acids 2011, 41, 541–558.
11. (a) Stankovic´, S.; D’hooghe, M.; De Kimpe, N. Org. Biomol. Chem. 2010, 8, 4266–
4273; (b) De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N. J. Org. Chem. 1981,
46, 2079–2081; (c) De Kimpe, N.; Verhé, R.; De Buyck, L.; Schamp, N. Bull. Soc.
Chim. Belg. 1983, 92, 233–239; (d) Vilhelmsen, M. H.; Ostergaard, L. F.; Nielsen,
M. B.; Hammerum, S. Org. Biomol. Chem. 2008, 6, 1773–1778.
Scheme 6. 3-Bromo-3-methylazetidines
preparation of 3-substituted 3-methylazetidines 23.
9
and 11 as building blocks for the
15 min, 150 W) and subsequent neutralization with a solution of
hydrochloric acid (1 M) gave the corresponding new amino acid
21. Interestingly, two isomeric structures (ratio 3/2) of azetidine
21 were observed upon NMR analysis (CD3OD), which can be
attributed to the zwitterionic nature of this compound providing
two diastereomeric counterparts. The purification of amino acid
21 on Dowex H+ (NH4OH) afforded ammonium 3-methyl-1-(4-
methylbenzyl)azetidine-3-carboxylate 22 as a single isomer in
pure form.17 These observations further support the synthetic util-
ity of 3-bromo-3-methylazetidines as substrates for nucleophilic
displacements, for example, toward the synthesis of versatile 3-
methylazetidine-3-carbonitriles.
In conclusion, efficient syntheses of 3-bromo-3-methylazeti-
dines 9 and 11 were disclosed starting from 2-bromomethyl-2-
methylaziridine 8 and b,c-dibrominated amine 10, respectively.
Through a number of examples, the azetidines 9 and 11 were
shown to easily undergo nucleophilic substitution with different
nucleophiles, providing a convenient method for the preparation
of new synthetically and biologically attractive 3-substituted azeti-
dines 23 such as 3-alkoxy-, 3-aryloxy-, 3-hydroxy-, 3-cyano-, 3-
carboxy-, 3-(aminomethyl)-, and 3-(hydroxymethyl)azetidines
(Scheme 6).
12. Stankovic´, S.; D’hooghe, M.; Dewulf, J.; Bogaert, P.; Jolie, R.; De Kimpe, N.
Tetrahedron Lett. 2011, 52, 4529–4532.
13. As a representative example, the synthesis of 1-t-butyl-3-(4-ethylphenoxy)-3-
methylazetidine 15b is described here. 3-Bromo-1-t-butyl-3-methylazetidine
11 (1.03 g, 5 mmol) was dissolved in THF (10 mL), after which 4-ethylphenol
(0.61 g, 1 equiv) and K2CO3 (1.38 g, 2 equiv) were added, and the mixture was
stirred for 48 h under reflux. The reaction mixture was poured into an aqueous
sodium hydroxide solution (1 M, 15 mL) and extracted with CH2Cl2
(3 Â 15 mL). The combined organic extracts were washed with H2O
(2 Â 15 mL) and brine (15 mL). Drying (MgSO4), filtration of the drying agent
and evaporation of the solvent afforded 1-t-butyl-3-(4-ethylphenoxy)-3-
methylazetidine 15b (0.88 g, 71%), which was purified by column
chromatography (CH2Cl2/MeOH 96/4, Rf = 0.15) in order to obtain an
analytically pure sample. 1-t-Butyl-3-(4-ethylphenoxy)-3-methylazetidine
15b: Yield 71%; 1H NMR (270 MHz, CDCl3)
d 0.97 (9H, s), 1.21 (3H, t,
J = 7.6 Hz), 1.68 (3H, s), 2.58 (2H, q, J = 7.6 Hz), 3.32 (2H, d  d, J = 6.9, 1.6 Hz),
3.45 (2H, d, J = 6.9), 6.64–7.07 (4H, m). 13C NMR (67.8 MHz, CDCl3) d 15.8, 22.0,
24.2, 27.9, 52.0, 58.8, 72.1, 116.7, 128.6, 136.5, 153.2. IR (NaCl, cmÀ1
m
)
max = 2958, 1602, 1503, 1356, 1310, 1228, 828. MS (70 eV) m/z (%) 247 (M+,
5), 232 (16), 163 (15), 162 (100), 147 (12), 133 (36), 122 (21), 120 (14), 119
(57), 107 (44), 86 (28), 70 (30), 57 (18), 55 (14).
14. As a representative example, the synthesis of 3-methyl-1-(4-methylbenzyl)-3-
azetidinol
16b
is
described
here.
3-Bromo-3-methyl-1-(4-
methylbenzyl)azetidine 9 (1.27 g, 5 mmol) was added to a two-phase solvent
system (H2O/CH2Cl2 9/1, 15 mL), after which KOH (1.40 g, 5 equiv) was added,
and the mixture was stirred for 10 h under reflux. The reaction mixture was
poured into water (15 mL) and extracted with CH2Cl2 (3 Â 15 mL). The
combined organic extracts were washed with H2O (2 Â 15 mL) and brine
(15 mL). Drying (MgSO4), filtration of the drying agent and evaporation of the
solvent afforded 3-methyl-1-(4-methylbenzyl)-3-azetidinol 16b as white
crystals (0.92 g, purity >95% based on NMR analysis). 3-Methyl-1-(4-
methylbenzyl)-3-azetidinol 16b: White crystals; Mp = 85.3 °C. Yield 96%; 1H
NMR (300 MHz, CDCl3) d 1.40 (3H, s), 2.25 (3H, s), 2.99, and 3.20 (4H, 2 Â d,
J = 6.9 Hz), 3.53 (3H, s), 7.02–7.10 (4H, m). 13C NMR (75 MHz, ref = CDCl3) d
Acknowledgments
This work was supported by the Research Foundation-Flanders
(FWO-Vlaanderen) and the Research Board of Ghent University
(BOF-GOA).
21.2, 26.1, 63.2, 68.0, 68.9, 128.6, 128.8, 134.9, 136.8. IR (neat, cmÀ1
OH = 3359. MS (70 eV) m/z (%) 192 (M++1, 100).
)
m
15. (a) Okutani, T.; Kaneko, K.; Masuda, K. Chem. Pharm. Bull. 1974, 22, 1490–1497;
(b) Okutani, T.; Masuda, K. Chem. Pharm. Bull. 1974, 22, 1498–1505; (c) Higgins,
R. H.; Doomes, N. H.; Cromwell, N. H. J. Heterocycl. Chem. 1971, 8, 1063–1067.
16. Synthesis of 3-aminomethyl-1-t-butyl-3-methylazetidine 20. To an ice-cooled
solution of 1-t-butyl-3-methylazetidine-3-carbonitrile 17a (0.76 g, 5 mmol) in
dry diethyl ether (10 mL), LiAlH4 (0.38 g, 2 equiv) was slowly added, and the
reaction mixture was stirred first for 3 h at 0 °C, and then for 14 h at room
temperature. The resulting mixture was poured cautiously into water (15 mL)
and extracted with Et2O (3 Â 15 mL). The combined organic extracts were
washed with H2O (2 Â 15 mL) and brine (15 mL). Drying (MgSO4), filtration of
the drying agent and evaporation of the solvent afforded 3-aminomethyl-1-t-
butyl-3-methylazetidine 20 (0.76 g, 97%) in high purity (purity >95% based on
References and notes
1. (a) Cromwell, N. H.; Phillips, B. Chem. Rev. 1979, 79, 331–358; (b) Moore, J. A.;
Ayers, R. S. In Chemistry of Heterocyclic Compounds-Small Ring Heterocycles;
Hassner, A., Ed.; Wiley: New York, NY, 1983; pp 1–217. Part 2; (c) Davies, D. E.;
Storr, R. C. In Comprehensive Heterocyclic Chemistry; Lwowski, W., Ed.;
Pergamon: Oxford, 1984; Vol. 7, pp 237–284. Part 5; (d) Singh, G. S.;
D’hooghe, M.; De Kimpe, N. Azetidines, Azetines, and Azetes: Monocyclic In
Comprehensive Heterocyclic Chemistry III, a review of the literature 1995–2007;
Katritzky, A., Ramsden, C., Scriven, E., Taylor, R., Eds.; Elsevier: Oxford, 2008;
Vol. 2, pp 1–110; (e) Couty, F.; Evano, G. Org. Prep. Proced. Int. 2006, 38, 427–
465; (f) Ferraris, D.; Belyakov, S.; Li, W. X.; Oliver, E.; Ko, Y. S.; Calvin, D.; Lautar,
S.; Thomas, B.; Rojas, C. Curr. Top. Med. Chem. 2007, 7, 597–608.
2. (a) Bagal, S. K.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.; Scott, P. M.;
Thomson, J. E. Org. Lett. 2010, 12, 136–139; (b) Feula, A.; Male, L.; Fossey, J. S. Org.
Lett. 2010, 12, 5044–5047; (c) Brown, M. J.; Clarkson, G. J.; Inglis, G. G.; Shipman,
M. Org. Lett. 2011, 13, 1686–1689; (d) Couty, F.; Durrat, F.; Prim, D. Tetrahedron
Lett. 2003, 44, 5209–5212; (e) Couty, F.; Evano, G. Synlett 2009, 3053–3064; (f)
Couty, F. Sci. Synth. 2009, 773–817; (g) Couty, F.; Durrat, F.; Evano, G. Targets
Heterocycl. Syst. 2005, 9, 186–210; (h) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem.
Rev. 2008, 108, 3988–4035; (i) Couty, F.; Evano, G.; Prim, D. Mini-Rev. Org. Chem.
2004, 1, 133–148;(j)Couty, F.;David, O.;Durrat, F.; Evano, G.; Lakhdar, S.; Marrot,
J.; Vargas-Sanchez, M. Eur. J. Org. Chem. 2006, 3479–3490.
NMR analysis). 3-Aminomethyl-1-t-butyl-3-methylazetidine 20: Yield 97%; 1
H
NMR (270 MHz, CDCl3) d 0.94 (9H, s), 1.18 (3H, s), 1.63 (2H, br s), 2.78 (2H, s),
2.91, and 3.03 (4H, 2 Â d, J = 7.3 Hz). 13C NMR (67.8 MHz, CDCl3) d 22.7, 24.1,
33.4, 50.9, 51.6, 55.2. IR (NaCl, cmÀ1
) mNH2 = 3680–3000. MS (70 eV) m/z (%) no
M+, 141 (M+–Me, 58), 84 (36), 72 (72), 70 (100), 57 (69), 55 (47), 49 (35).
17. Synthesis of ammonium 3-methyl-1-(4-methylbenzyl)azetidine-3-carboxylate
22. 1-(4-Methylbenzyl)azetidine-3-carbonitrile 17b (0.20 g, 1 mmol) was
dissolved in EtOH/H2O (5/1, 5 mL), after which KOH (0.28 g, 5 equiv) was
added. The mixture was placed in a 6-mL sealed glass vessel, provided with an
appropriate stirring bar and subjected to microwave conditions (150 °C,
15 min, 150 W). The reaction mixture was neutralized with a solution of
hydrochloric acid (1 M) to pH = 7 and water was evaporated under high
vacuum. Purification of amino acid 21 (two isomeric forms confirmed by NMR
analysis) by means of ion-exchange chromatography on Dowex H+ (50 Â 8-
3. Fyfe, M. C. T.; Gattrell, W.; Rasamison, C. M. PCT Int. Appl. 2007, WO
2007116230 Al; Chem. Abstr. 2007, 147, 469218.
4. Isabel, E.; Oballa, R.; Powell, D.; Robichaud, J. PCT Int. Appl. 2007, WO
2007143823 Al; Chem. Abstr. 2007, 148, 78872.
5. Josyula, V. P. V. N.; Renslo, A. R. PCT Int. Appl. 2007, WO 2007004049 Al; Chem.
Abstr. 2007, 146, 142631.
6. Van Brabandt, W.; Mangelinckx, S.; D’hooghe, M.; Van Driessche, B.; De Kimpe,
N. Curr. Org. Chem. 2009, 13, 829–853.
100)
afforded
ammonium
3-methyl-1-(4-methylbenzyl)azetidine-3-
carboxylate 22 (0.20 g, 85%). White crystals; Mp >350 °C. Yield 85%; 1H NMR
(300 MHz, CD3OD) d 1.41 (3H, s), 2.24 (3H, s), 3.73, and 4.20 (4H, 2 Â d,
J = 10.7 Hz), 4.20 (2H, s), 7.16–7.27 (4H, m). 13C NMR (75 MHz, CD3OD) d 21.3,
23.3, 42.3, 59.4, 63.7, 128.6, 131.0, 131.1, 141.2, 180.5. IR (neat, cmÀ1
)
m
CO = 1603. MS (70 eV) m/z (%) 218 (M++1, 100).