Application of 3-bromo-3-ethylazetidines and 3-ethylideneazetidines for the synthesis of functionalized azetidines

Article abstract of DOI:10.1055/s-0033-1340250

The synthetic utility of 3-bromo-3-ethylazetidines has been demonstrated by the straightforward preparation of 3-alkoxy-, 3-aryloxy-, 3-acetoxy-, 3-hydroxy-, 3-cyano-, 3-carbamoyl- and 3-amino-3-ethylazetidines. In addition, 3-bromo-3-ethylazetidines have been successfully deployed as precursors for a convenient synthesis of 3-ethylideneazetidines, which served as starting materials for the preparation of novel functionalized azetidines and spirocyclic azetidine building blocks. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340250

LETTER
▌75
lAettper plication of 3-Bromo-3-ethylazetidines and 3-Ethylideneazetidines for the
Synthesis of Functionalized Azetidines
Synthesis of Functionalized Azetidines
Sonja Stanković, Matthias D’hooghe,* Tim Vanderhaegen, Kourosch Abbaspour Tehrani,1 Norbert De Kimpe*
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653,
9000 Ghent, Belgium
E-mail: matthias.dhooghe@UGent.be; Fax +3292646221; E-mail: norbert.dekimpe@UGent.be
Received: 14.08.2013; Accepted after revision: 14.10.2013
ways toward functionalized azetidines. It should be men-
Abstract: The synthetic utility of 3-bromo-3-ethylazetidines has
tioned that the synthesis and reactivity study of
been demonstrated by the straightforward preparation of 3-alkoxy-,
structurally related 2-alkylideneazetidines, which behave
3-aryloxy-, 3-acetoxy-, 3-hydroxy-, 3-cyano-, 3-carbamoyl- and
3-amino-3-ethylazetidines. In addition, 3-bromo-3-ethylazetidines
as cyclic enamines, has been the subject of previous re-
have been successfully deployed as precursors for a convenient syn- ports.10,11 These azetidines have been shown to be eligible
thesis of 3-ethylideneazetidines, which served as starting materials
for the preparation of novel functionalized azetidines and spirocy-
clic azetidine building blocks.
substrates in various cycloaddition reactions and ring re-
arrangements.
However, it was expected that 3-alkylideneazetidines,
which can be regarded as cyclic allylamines, would
exhibit a totally different reactivity profile as compared to
2-alkylideneazetidines due to the presence of a rather in-
Key words: heterocycles, nitrogen, nucleophiles, rearrangement,
ring opening, spiro compounds
active and sterically hindered double bond. The reactivity
Aziridines and azetidines belong to an intriguing group of
of both the azetidine ring and the olefenic moiety has been
small-ring azaheterocycles with interesting properties and
assessed in this study.
a great potential from both a synthetic2 and a biological3
In accordance with the previously described synthesis of
3-bromo-3-methylazetidines, 3-bromo-3-ethylazetidines
3a,b were prepared starting from 2-bromomethyl-2-ethyl-
aziridines 2a,b, themselves obtained by a three-step
approach12 involving bromination of 2-ethylpropenal (1)
using Br2 in CH2Cl2, imination with primary N-(arylmeth-
yl)amines in the presence of TiCl4 and Et3N in Et2O, and
reduction of the corresponding α,β-dibromoimines by
means of NaBH4 in MeOH (Scheme 1). Heating aziridi-
nes 2 in MeCN under reflux for 15 hours afforded the de-
sired novel 3-bromo-3-ethylazetidines 3a,b in nearly
quantitative yields. A similar aziridine to azetidine ring
rearrangement of 2-bromomethyl-2-methylaziridines has
previously been shown to occur via intermediacy of bicy-
clic aziridinium species, which were opened at the more
hindered carbon atom to provide the corresponding 3-bro-
mo-3-methylazetidines.12
point of view. Azetidines, which have been studied to a
lesser extent than aziridines, are accessible via established
synthetic routes including ring closure of γ-haloamines
and reduction of β-lactams,2j,k,4 although other general
approaches such as addition of nucleophiles across
β-haloimines followed by ring closure5 and Mannich-type
reactions of functionalized imines6 have been designed.
3-Alkylideneazetidines are strained cyclic allylamines,
and very limited information on the reactivity of this pe-
culiar class of azetidine compounds is available in the lit-
erature.7 In most cases, the 3-alkylideneazetidine moiety
has been incorporated in the structure of more complex
molecules,8 and no special attention has been devoted to
the chemical nature and synthetic applicability of these
systems so far. The two main literature approaches to in-
troduce an alkylidene functionality at the 3-position of an
azetidine ring comprise Wittig olefination of the corre-
sponding azetidin-3-ones7b,d,e and dehydrohalogenation of
3-halo-3-(haloalkyl)azetidines.7d
In contrast to the synthesis of 1-arylmethyl-3-bromo-
3-ethylazetidines 3, obtained through rearrangement of
2-bromomethyl-2-ethylaziridines 2, the formation of 3-
bromo-1-tert-butyl-3-ethylazetidine (5) proceeded via
β,γ-dibromoamine 4, formed through consecutive treat-
ment of 2-ethylpropenal (1) with bromine, tert-butyl-
amine and sodium borohydride (Scheme 1). Heating a
solution of the β,γ-dibromoamine 4 in i-PrOH under re-
flux for 16 hours followed by basic workup induced cycli-
zation to the target 3-bromo-3-ethylazetidine 5.
In continuation of our interest in the study of 3-haloazeti-
dines as synthons in organic chemistry,9 3-bromo-3-ethyl-
azetidines were prepared in this work and evaluated as
suitable substrates to enable nucleophilic bromide dis-
placement leading to functionalized 3-ethylazetidines and
dehydrobromination as an entry to novel 3-ethylide-
neazetidines. Furthermore, the behavior of this 3-ethyl-
ideneazetidine scaffold was then assessed with respect to
different reagents in order to reveal new synthetic path-
It should be mentioned that 3-bromo-3-ethylazetidines 3
represent eligible substrates for nucleophilic bromide dis-
placements, as was the case for their structurally related
3-bromo-3-methylazetidines.9a
SYNLETT 2014, 25, 0075–0080
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DOI: 10.1055/s-0033-1340250; Art ID: ST-2013-D0780-L
© Georg Thieme Verlag Stuttgart · New York

76
S. Stanković et al.
LETTER
R
1. Br2 (1.02 equiv)
CH2Cl2, r.t., 4 h
1. Br2 (1.05 equiv), CH2Cl2
0 °C to r.t., 2.5 h
2. t-BuNH2 (5 equiv)
TiCl4 (0.6 equiv)
R
2. ArCH2NH2 (1 equiv)
TiCl4 (0.6 equiv)
Et3N (3 equiv)
MeCN, Δ
O
15 h
Et2O, 0 °C to r.t., 15 h
N
pentane, r.t., 2 h
i-PrOH
N
N
H
Br
N
H
3. NaBH4 (2 equiv)
MeOH, r.t., 1–2 d
Br
Br
Δ, 16 h
3. NaBH4 (2.5 equiv), MeOH
0 °C to r.t., 4 h
Br
Br
5 (78%)
1
2a (R = H, 87%)
2b (R = Me, 88%)
3a (R = H, 94%)
3b (R = Me, 98%)
4 (65%)
Scheme 1
For example, the reactions of 3a,b with oxygen nucleo- forded 1-tert-butyl-3-ethylideneazetidine (9) in a good
philes, such as methoxide [NaBH4 (2 equiv), MeOH, Δ, yield (Scheme 3), the synthesis of 1-arylmethyl-3-ethyli-
2 d], phenoxide [PhOH (2.2 equiv), K2CO3 (5 equiv), deneazetidines 10a,b starting from 3-bromo-3-ethylazeti-
MeCN, Δ, 1 d], sodium acetate [NaOAc (5 equiv), MeCN, dines 3a,b was not as straightforward as initially
Δ, 3–5 d] and potassium hydroxide [KOH (5 equiv), anticipated, and several attempts were performed to opti-
H2O/CH2Cl2 (7:1), Δ, 15–20 h], provided the correspond- mize the reaction conditions. Treatment of azetidine 3a
ing 3-alkoxy-, 3-aryloxy-, 3-acetoxy- and 3-hydroxy- with different bases such as t-BuOK, LDA and NaH in
3-ethylazetidines 6a–d (Nu = OMe, OPh, OAc, OH), re- THF at room temperature or under reflux gave no reac-
spectively (Scheme 2). The reaction of 3a with n-propyl- tion, and addition of t-BuOK in t-BuOH under reflux re-
amine furnished 3-propylaminoazetidine 6e [Nu = n-PrNH; sulted in a mixture of different compounds. Eventually,
n-PrNH2 (5 equiv), MeCN, Δ, 1 d], while azetidines 3a,b the use of 1.5 equivalents of t-BuOK in THF and heating
gave 3-cyanoazetidines 6f,f′ on treatment with potassium under microwave irradiation for ten minutes at 120 °C se-
cyanide [KCN (1.5 equiv), MeCN, Δ, 1 d].
lectively provided 3-ethylideneazetidines 10a,b in excel-
lent yields (Scheme 3).13
Further reaction of azetidine-3-carbonitrile 6f with KOH
(5 equiv) in EtOH/H2O (10:1) under microwave irradia- The reactivity study of 3-ethylideneazetidines was ex-
tion (10 min, 150 °C, 150 W) resulted in amide 7 as the pected to be a quite challenging task bearing in mind the
major compound (77%), accompanied by a small amount sterically hindered and poorly reactive double bond. Prior
of the corresponding amino acid 8 (19%; Scheme 2). The to evaluating the intrinsic reactivity of this olefinic moi-
formation of carboxylic acid 8 was evidenced upon neu- ety, the propensity of the azetidine ring to undergo ring
tralization of the reaction mixture to pH 7 using 1 M HCl. opening was investigated. Due to the presence of an elec-
Attempts to develop an effective synthesis of amino acid tron-donating alkyl group at nitrogen, activation of the
8 by prolonging the reaction time (up to 2 h) proved to be azetidine ring toward an azetidinium species is necessary
unsuccessful.
to effect ring-opening processes. N-Acetylation of alkyl-
ideneazetidine 10a with 1.5 equivalents of acetyl chloride
in CH2Cl2 and subsequent ring opening by the displaced
chloride ion afforded a mixture of (E)- and (Z)-allyl-
amines 12 (E = MeCO, X = Cl, E/Z = 1:1) after 15 hours
under reflux (Table 1, Scheme 3). In a similar manner, the
reaction of 10a with one equivalent of benzyl bromide in
MeCN gave the corresponding allylamines 13 (Table 1, E
= Bn, X = Br, E/Z = 3:2 or vice versa) after 15 hours under
reflux. These reactions were straightforward and resulted
in a complete conversion of the starting material, although
In summary, the above-described findings acknowledge
the suitability of 3-bromo-3-ethylazetidines as substrates
for nucleophilic substitutions by different oxygen-, nitro-
gen- and carbon-centered nucleophiles.
In the next part of our studies, the eligibility of 3-bromo-
3-ethylazetidines as substrates for the preparation of the
corresponding new 3-ethylideneazetidines was investigat-
ed. Whereas the dehydrobromination of 3-bromo-1-tert-
butylazetidine 5 utilizing t-BuOK (1.5 equiv) in THF af-
R
R
R
1) KOH (5 equiv)
EtOH–H2O (10:1)
MW, 10 min, 150 °C
KCN (1.5 equiv)
MeCN, Δ, 1 d
H
N
Nu
N
N
N
N
+
2) HCl (pH 7)
R = H
COO
8 (19%)
CN
Br
Nu
O
NH2
7 (77%)
6f (R = H, 89%)
3a (R = H, 94%)
6a (R = H, Nu = OMe, 89%)
6b (R = H, Nu = OPh, 78%)
6b' (R = Me, Nu = OPh, 80%)
6c (R = H, Nu = OAc, 75%)
6c' (R = Me, Nu = OAc, 77%)
6d (R = H, Nu = OH, 94%)
6d' (R = Me, Nu = OH, 80%)
6e (R = H, Nu = n-PrNH, 94%)
6f' (R = Me, 92%)
3b (R = Me, 98%)
Scheme 2
Synlett 2014, 25, 75–80
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Functionalized Azetidines
77
R
R
R1
E
KOt-Bu (1.5 equiv)
THF, Δ, 12 h
KOt-Bu (1.5 equiv)
E
X
N
N
N
MW, 120 °C
10 min, THF
N
Table 1
Br
R1 = t-Bu
X
3a,b (R1 = ArCH2)
5 (R1 = t-Bu)
R1 = ArCH2
10a (R = H, 92%)
10b (R = Me, 94%)
9 (77%)
11
R
O
DMF, MW
140 °C, 30 min
150 W
N
O
E
N
R
E = COOMe
X = Cl
X
16
Z/E = 1:1
(96% overall yield)
12–15
(75–100%)
Scheme 3
chromatographically inseparable E/Z-mixtures were ob- was evaluated in the next phase of this work. Attempts to
tained. In addition, treatment of azetidines 10a,b with 1.5 prepare halohydrins by treatment of azetidine 10a with
equivalents of methyl chloroformate in MeCN for 15 one equivalent of NBS in water/THF (1:1) for ten minutes
hours under reflux resulted in an E/Z-mixture of 4-amino- to two days proceeded sluggishly and gave complex mix-
but-2-enes 14 (E = COOMe, X = Cl, E/Z = 1:1). Upon tures. The outcome of this reaction was shown to be diffi-
heating this mixture under microwave irradiation (140 °C, cult to control and also dependent on the purity of NBS.
30 min, 150 W) in DMF, the corresponding new cyclic On the other hand, selective access to the functionalized
carbamates 16 were obtained through 6-exo-tet cycliza- dibrominated azetidine 17 was achieved by the reaction of
tion.14 These cyclic carbamates can be regarded as inter- azetidine 10a with two equivalents of NBS in CHCl3 or
esting compounds with a variety of applications, most CH2Cl2 under reflux for 15–24 hours. Apparently, the
notably as precursors for γ-amino alcohols,15 as chiral small amount of bromine, released from NBS, was able to
auxiliaries,16 and as the core substructure in a number of react with azetidine 10a to afford 3-bromo-3-(1-bromo-
biologically active compounds.17 When azetidine 10a was ethyl)azetidine 17 (X = Br), although in variable yields
added to a mixture of 1.3 equivalents of benzyloxy- or (30–70%) depending upon the purity of the NBS (Scheme
methoxyacetyl chloride and three equivalents of Et3N in 4). In another approach, the azetidine nitrogen atom was
CH2Cl2 and stirred at room temperature for 15 hours in an protonated by introducing gaseous HCl to the solution of
attempt to effect cycloaddition, the corresponding ring- azetidine 10a in CH2Cl2 for ten minutes, after which one
opened amides 15a,b (E = MeOCH2CO or E = equivalent of mCPBA was added. Instead of the expected
BnOCH2CO, X = Cl, E/Z = 1:1) were formed instead. Ap- spirocyclic azetidinyl epoxide 20a, 3-chloro-3-(1-chloro-
parently, the initial attack of the nucleophilic nitrogen ethyl)azetidine 18 (X = Cl) was obtained in 92% yield
atom across the ketene formed in situ and subsequent ring (Scheme 4), probably as the result of the electrophilic ad-
opening of the azetidine moiety prevailed over the desired dition of in situ formed Cl2 to the double bond.18 The vic-
cycloaddition reaction.
inal dihalogenated azetidines 17 and 18 were
subsequently subjected to reactions with benzylamine or
KCN in MeCN in the presence of a catalytic amount of
Ag2CO3 or NaI. Unfortunately, these reactions resulted in
The reactivity of 3-ethylideneazetidines 10 with respect to
electrophilic additions across the exocyclic double bond
Table 1 Activation and Ring Opening of 3-Ethylideneazetidines 10a,b toward Functionalized Allylamines
Substrate
Reaction conditions
E
X
Product (yield, E/Z)
10a
10a
10a
10b
10a
AcCl (1.5 equiv), CH2Cl2, Δ, 15 h
BnBr (1 equiv), MeCN, Δ, 15 h
MeCO
Cl
Br
Cl
Cl
Cl
12 (R = H, 100%, E/Z = 1:1)
Bn
13 (R = H, 100%, E/Z = 3:2 or vice versa)
14a (R = H, 100%, E/Z= 1:1)
14b (R = Me, 100%, E/Z = 1:1)
15a (R = H, 78%, E/Z = 1:1)
ClCOOMe (1.5 equiv), MeCN, Δ, 15 h
ClCOOMe (1.5 equiv), MeCN, Δ, 15 h
COOMe
COOMe
MeOCH2CO
MeOCH2COCl (1.3 equiv)
Et3N (3 equiv), CH2Cl2, r.t., 15 h
10a
BnOCH2COCl (1.3 equiv)
Et3N (3 equiv), CH2Cl2, r.t., 15 h
BnOCH2CO
Cl
15b (R = H, 75%, E/Z = 1:1)
Synlett 2014, 25, 75–80
© Georg Thieme Verlag Stuttgart · New York

78
S. Stanković et al.
LETTER
R
R
1. NMO (1.1 equiv)
OsO4 (5 mol%)
Me2CO–H2O (4:1)
0 °C to r.t., 4 h
NBS (2 equiv)
CHCl3, Δ, 15 h to 1 d
or
N
N
N
1. HCl (g), 10 min
CH2Cl2
2. mCPBA (1 equiv)
CH2Cl2, Δ, 1 d
3. aq NaHCO3
2. aq Na2SO3, 10 min
OH
OH
X
X
22a (R = H, 82%)
22b (R = Me, 84%)
10a,b
1. p-TsOH⋅H2O (1 equiv)
CH2Cl2, r.t., 10 min
2. mCPBA (1.5 equiv)
CH2Cl2, Δ, 15 h
17 (70%, X = Br)
18 (92%, X = Cl)
R = H
p-TsOH (1.1 equiv)
CuSO4 (5 equiv)
acetone, Δ, 1 d
R = Me
R
R
NaN3 (3 equiv)
NH4Cl (2 equiv)
NaH (1 equiv)
THF, r.t., 15 h
N
N
N
N
OH
N3
OH
OTs
Me2CO–H2O (8:1)
O
O
O
Δ, 15 h
R = Me
21 (80%)
(based on 1H NMR)
23 (96%)
20a (R = H, 95%)
20b (R = Me, 96%)
19a (R = H, 92%)
19b (R = Me, 93%)
Scheme 4
the recovery of the starting materials or gave complex moethyl)azetidine 17 and no traces of the corresponding
mixtures.
spiro compounds. Using phenyltrimethylammonium tri-
bromide (PTAB) and chloramine-T in MeCN, a complex
mixture was also obtained.25 An alternative route to the
synthesis of the spiro-fused aziridinyl azetidine core
structure could comprise the ring opening of epoxides 20
with an appropriate amine (i-PrNH2) in the presence of
BF3·OEt2, followed by subsequent ring closure of the re-
sulting amino alcohols under Mitsunobu conditions. Al-
though the epoxide ring opening was shown to be
successful, the drawback of this procedure involved the
very low stability of the β-amino alcohol thus obtained,
which underwent immediate decomposition. On the other
hand, ring opening of epoxides 20 with three equivalents
of NaN3 and two equivalents of NH4Cl in acetone/water
(8:1) did afford the corresponding azide 21 after 15 hours
under reflux (Scheme 4). However, the subsequent ring
closure of 21 utilizing Ph3P in THF gave only complex re-
action mixtures. In addition, dihydroxylation of the
double bond in azetidines 10a,b with 1.1 equivalents of
N-methylmorpholine-N-oxide (NMO) and OsO4 (5
mol%) in acetone/water (4:1) for four hours at room tem-
perature, followed by an aqueous workup, furnished dihy-
droxyazetidines 22a,b in good yields (Scheme 4). In order
to provide an entry to a different class of azaspirocyclic
building blocks, azetidine 22b was treated with 1.1 equiv-
alents of p-TsOH and five equivalents of CuSO4 in ace-
tone to afford the corresponding novel 5,7-dioxa-2-
azaspiro[3.4]octane 23 after stirring under reflux for one
day (Scheme 4). This spirocyclic core structure has been
found to be present in a number of spiro lactams, suitable
for further chemical transformations.26
In a final attempt to produce the synthetically challenging
spirocyclic azetidinyl epoxides 20, the azetidine nitrogen
atom in structures 10 was protected by addition of one
equivalent of p-TsOH in CH2Cl2. Subsequent addition of
1.5 equivalents of mCPBA and heating under reflux for 15
hours afforded highly unstable azetidin-3-ols 19a,b.
However, immediate treatment of these alcohols 19 with
one equivalent of NaH in THF for 15 hours at room tem-
perature provided the target 1-oxa-5-azaspiro[2.3]hex-
anes 20a,b in excellent yields (Scheme 4).19 These novel
strained spirocyclic systems showed a considerable stabil-
ity as they could be purified by means of column chroma-
tography on basic Al2O3 to provide analytically pure
samples. The synthesis of the spiroazetidinyl epoxide
moiety has received only very limited attention in the lit-
erature.20 However, these compounds have been shown to
be useful intermediates for the preparation of different bi-
ologically active molecules.21 In general, the synthesis
and reactivity of different azaspirocyclic scaffolds repre-
sent a challenging task for organic chemists and have late-
ly been the subject of significant interest.20a,22
Bearing in mind that a number of azaspirocyles containing
an azetidine moiety can be considered as structural surro-
gates of commonly employed saturated heterocycles with
beneficial inherent structural features, further efforts were
devoted to expand the family of novel spiroazetidine
building blocks. By analogy with the epoxidation of azeti-
dines 10, the direct aziridination of the double bond could
provide an access to novel spirocyclic 1,5-diazaspiro-
[2.3]hexanes,23 although the treatment of azetidine 10a
with NBS and Chloramine-T as nitrene precursor24 in
MeCN afforded only small amounts of 3-bromo-3-(1-bro-
In conclusion, 3-bromo-3-ethylazetidines have been
shown to undergo ready nucleophilic substitution with
Synlett 2014, 25, 75–80
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Functionalized Azetidines
79
(c) Hanessian, S.; Fu, J.-M.; Chiara, J.-L.; Di Fabio, R.
Tetrahedron Lett. 1993, 34, 4157. (d) Marehand, A. P.;
Devasagayaraj, A. J. Org. Chem. 1997, 62, 4434.
(e) Burtoloso, A. C. B.; Correia, C. R. D. Tetrahedron 2008,
64, 9928.
different nucleophiles, providing a convenient method for
the preparation of new 3-alkoxy-, 3-aryloxy-, 3-acetoxy-,
3-hydroxy-, 3-cyano-, 3-carbamoyl- and 3-amino-3-eth-
ylazetidines. Furthermore, 3-bromo-3-ethylazetidines can
be used as suitable substrates for the preparation of 3-eth-
ylideneazetidines which, in spite of the presence of a rath-
er inactive double bond, were shown to represent valuable
compounds for the preparation of novel functionalized
azetidines and spirocyclic azetidine building blocks.
(8) (a) Hanessian, S.; Fu, J.-M.; Tu, Y. Tetrahedron Lett. 1993,
34, 4153. (b) Emmer, G. Tetrahedron 1992, 48, 7165.
(c) Liang, Y.; Raju, R.; Le, T.; Taylor, C. D.; Howell, A. R.
Tetrahedron Lett. 2009, 50, 1020.
(9) (a) Stanković, S.; D’hooghe, M.; Abbaspour Tehrani, K.; De
Kimpe, N. Tetrahedron Lett. 2012, 53, 107. (b) Van
Driessche, B.; Van Brabandt, W.; D’hooghe, M.; Dejaegher,
Y.; De Kimpe, N. Tetrahedron 2006, 62, 6882.
References and Notes
(10) (a) Abbaspour Tehrani, K.; De Kimpe, N. Curr. Org. Chem.
2009, 13, 854. (b) Mangelinckx, S.; Boeykens, M.; De
Kimpe, N. Synlett 2008, 1394. (c) Lu, H.; Li, C. Org. Lett.
2006, 8, 5365. (d) Sulmon, P.; De Kimpe, N.; Schamp, N.
J. Org. Chem. 1988, 53, 4462. (e) De Kimpe, N.; Boeykens,
M. J. Org. Chem. 1994, 59, 5189. (f) De Kimpe, N.;
Boeykens, M. J. Org. Chem. 1994, 59, 5189. (g) Abbaspour
Tehrani, K.; De Kimpe, N. Tetrahedron Lett. 2000, 41, 1975.
(11) Cainelli, G.; Giacomini, D.; Gazzano, M.; Galletti, P.;
Quintavalla, A. Tetrahedron Lett. 2008, 49, 5652.
(12) (a) Stanković, S.; Goossens, H.; Catak, S.; Tezcan, M.;
Waroquier, M.; Van Speybroeck, V.; D’hooghe, M.; De
Kimpe, N. J. Org. Chem. 2012, 77, 3181. (b) Stanković, 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.
(13) 3-Ethylidene-1-(4-methylbenzyl)azetidine (10b): To an ice-
cooled solution of 3-bromo-3-ethyl-1-(4-methylbenzyl)-
azetidine (3b; 1.34 g, 5 mmol) in anhyd THF (30 mL),
t-BuOK (0.84 g, 1.5 equiv) was added and the mixture was
subjected to microwave heating (150 W) for 10 min at
120 °C. Afterwards, the reaction mixture was cooled to r.t.,
filtered, poured into H2O (20 mL) and extracted with Et2O (3
× 20 mL). The combined organic extracts were washed with
H2O (2 × 15 mL) and brine (20 mL). Drying (MgSO4),
filtration of the drying agent and evaporation of the solvent
in vacuo afforded azetidine 10b (0.88 g, 94%), which was
purified by silica gel column chromatography to obtain an
analytically pure sample; pale yellow oil; Rf 0.22 (petroleum
ether–EtOAc, 4:1); yield: 94%. 1H NMR (300 MHz,
CDCl3): δ = 1.46–1.51 (m, 3 H), 2.33 (s, 3 H), 3.68 (s, 2 H),
3.79–3.82 (m, 4 H), 5.16–5.24 (m, 1 H), 7.11–7.14, 7.18–
7.21 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ = 13.6, 21.2,
60.8, 62.2, 63.5, 115.1, 128.5, 129.1, 131.8, 135.7, 136.7. IR
(neat): 2917, 2805, 1514, 1439, 1358, 1273, 1176, 1042,
1021, 806, 780, 753 cm–1. MS: m/z (%) = 188 (100) [M+ +
1]. HRMS (ESI): m/z [M + H]+ calcd for C13H18N: 188.1434;
found: 188.1435.
(1) Present address: Department of Chemistry, Faculty of
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LETTER
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(19) 5-Benzyl-2-methyl-5-aza-1-oxaspiro[2.3]hexane (20a): To
an ice-cooled solution of 1-benzyl-3-hydroxy-3-(1-tosyl-
oxyethyl)azetidine (19a; 0.19 g, 0.5 mmol) in anhyd THF
(15 mL), NaH (60% suspension; 0.02 g, 1 equiv) was slowly
added and the mixture was stirred for 15 h at r.t. The reaction
mixture was poured into H2O (20 mL) and extracted with
Et2O (3 × 20 mL). The combined organic extracts were
washed with H2O (2 × 15 mL) and brine (20 mL). Drying
(MgSO4), filtration of the drying agent and evaporation of
the solvent in vacuo afforded spirocycle 20a (0.10 g, 95%),
which was purified by means of column chromatography on
basic alumina in order to obtain an analytically pure sample;
pale yellow oil; Rf 0.22 (petroleum ether–EtOAc, 4:1); yield:
95%. 1H NMR (300 MHz, CDCl3): δ = 1.23 (d, J = 5.5 Hz,
3 H), 3.07 (q, J = 5.5 Hz, 1 H), 3.35–3.38, 3.43–3.46 (2 × m,
2 H), 3.60–3.66 (m, 2 H), 3.76 (s, 2 H), 7.23–7.36 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 15.5, 56.2, 59.5, 60.4, 61.6,
64.1, 127.3, 128.6, 138.2. IR (neat): 2925, 2831, 1495, 1453,
1363, 1161, 826, 725, 697 cm–1. MS: m/z (%) = 190 (100)
[M+ + 1]. HRMS (ESI): m/z [M + H]+ calcd for C12H15NO:
190.1232; found: 190.1232.
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Synlett 2014, 25, 75–80
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