An efficient synthesis of azetidines with (2-bromoethyl)sulfonium triflate

Article abstract of DOI:10.1055/s-0031-1290951

Easily accessible arylglycine derivatives were cyclized to azetidines by using commercially available (2-bromoethyl)sulfonium triflate in a simple and mild procedure. The high-yielding reaction has a relatively broad scope and was extended to the synthesi

Full text of DOI:10.1055/s-0031-1290951

1584▌
PAPER
paper
An Efficient Synthesis of Azetidines with (2-Bromoethyl)sulfonium Triflate
Efficient Synthesis of Azetidines
Sven P. Fritz, Juan F. Moya, Matthew G. Unthank, Eoghan M. McGarrigle,* Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Fax +44(117)9277985; E-mail: v.aggarwal@bristol.ac.uk; E-mail: eoghan.mcgarrigle@bristol.ac.uk
Received: 17.01.2012; Accepted after revision: 19.03.2012
We have previously reported on the use of (2-bromoeth-
Abstract: Easily accessible arylglycine derivatives were cyclized
yl)sulfonium triflate (1) in the synthesis of five-, six-, and
to azetidines by using commercially available (2-bromoethyl)sulfo-
seven-membered heterocycles.7,8 We therefore examined
nium triflate in a simple and mild procedure. The high-yielding re-
the possibility of extending this methodology to the syn-
thesis of strained four-membered heterocycles, such as
azetidines.
action has a relatively broad scope and was extended to the
synthesis of an oxetane.
Key words: annulations, cyclizations, heterocycles, sulfur, ylides
Scheme 2 shows our proposed annulation reaction mech-
anism, which is based on an analogous reaction of amino
alcohols.7c Nucleophilic addition of ester 3 to the vinylsul-
fonium salt 2, generated in situ from (2-bromoethyl)sulfo-
nium triflate (1) and base, gives the ylide intermediate 4,
which after proton transfer forms enolate 5. Subsequent
intramolecular nucleophilic attack displaces the Ph2S
leaving group to give the four-membered product 6.9
Here, we report the successful application of this method
in the synthesis of azetidines from readily available amino
ester derivatives such as aryl glycines.
Azetidines are important N-heterocycles, not only be-
cause of their biological importance1 and their increasing
use in medicinal chemistry,2 but also because they are
valuable synthetic intermediates3 that have found applica-
tion in asymmetric synthesis.4 In particular, certain types
of azetidines have been used in the modulation and fine-
tuning of the pharmacokinetic properties of potentially
bioactive molecules.2 However, because of the inherent
ring strain in azetidines, the synthesis of these compounds
is not always straightforward.2a,b,5,6 Scheme 1 shows some
approaches commonly used in the syntheses of 2-substi-
tuted azetidines; however, these approaches often suffer
from limitations in the scope of suitable precursors or in
the conditions required for cyclization. New synthetic
methods for preparing these heterocycles are therefore
needed.
SPh2
1
CO2R2
H
CO2R2
R1
H
R1
OTf
Br
X
X
SPh2
OTf
SPh2
3
4
2
base
in situ
X = NTs if R1 = Ar or EWG
X = O if R1 = EWG
R1
LG
LG
intramolecular
substitution
or
OR2
R2O2C
R1
NHR2
LG
R1
NHR2
O
R1
X
6
X
SPh2
5
double
substitution
+
R2NH2
R1
R2
Scheme 2 Proposed mechanism for the formation of four-membered
rings; EWG = electron-withdrawing group
R1
LG
N
Initial investigations showed that the reaction of amino es-
ter 7a10 with (2-bromoethyl)sulfonium triflate 1 in dichlo-
romethane containing 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) as a base gave a good yield of azetidine 8a
(Table 1, entry 1). Heating improved the yield and short-
ened the reaction time (entry 2). Switching to a higher-
boiling solvent led to a slight reduction in yield, due to
some decomposition of the salt (entry 3). Other bases
were not as effective for this transformation (entries 4–6).
R1
NR2
intramolecular
alkylation
LG
if R1 = EWG
R1
R2N
azetidin-2-one
reduction
O
Scheme 1 Methods for the synthesis of 2-substituted azetidines. LG
= leaving group; EWG = electron-withdrawing group
We then explored the scope of this annulation with regard
to the choice of substrate (Table 2). A change from a
methyl ester to an ethyl ester11 increased the yield slightly
(entry 2), but the use of the bulkier tert-butyl ester resulted
in no additional improvement (entry 3). The use of a
SYNTHESIS 2012, 44, 1584–1590
Advanced online publication: 26.04.2012
DOI: 10.1055/s-0031-1290951; Art ID: SS-2012-N0057-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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Efficient Synthesis of Azetidines
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Pd(CF3CO2)2 (5 mol%)
Table 1 Optimization of the Reaction Conditions
Ts
TsNCO
+
2,2'-bipyridine (6 mol%)
HN
base
CO2Me
Ph
Ph
Ts
CO2Me
+
SPh2
(3.5 equiv)
toluene, reflux, 3 h
then ArB(OH)2, 24 h
Ar
CO2Et
HC(O)CO2Et
9
NH
solvent
(0.07 M)
N
30–75%
Br
OTf
Ts
Scheme 3 Preparation of 2-arylglycine ethyl esters11
7a
1
8a
Yielda (%)
Time (h)
Entry
Base
Temp
Solvent
Table 3 shows the results of the annulation reactions of
these aryl glycines. The method was readily extended to
electron-rich and electron-deficient aryl substituents (en-
tries 2 and 3, respectively). Sterically bulky (entry 4) or
heteroaromatic (entry 5) substituents also gave good
yields. Replacing the aryl substituent with a second ester
group was also possible, giving azetidine 10f. However,
attempted annulations with alkyl-substituted substrates15
such as 9g were unsuccessful (entry 7). Evidently, the
acidity of the proton in the position α to the ester is impor-
tant to the success of the reaction.
1
2
3
4
5
6
DBU
DBU
DBU
Et3N
r.t.
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
24
3
62
72
reflux
reflux
reflux
reflux
r.t.
64b
1.5
3
3
3
trace
trace
n.r.
DIPEA
NaH
a Isolated yield.
b Some decomposition was observed.
Table 3 Substrate Scope of the Annulation Reaction
DBU
CO2Et
nitrile12 instead of an ester gave a much lower yield (entry
4), possibly as a result of competing elimination of the to-
syl group with concomitant formation of an imine. The
use of N-benzyloxycarbonyl glycine esters was also much
less effective in the annulation compared with N-tosyl es-
ters (entries 5 and 6). As might be expected from our pro-
posed mechanism, the enantiomerically enriched amines
8a and 8c gave racemic products.13
R
R
CO2Et
+
SPh2
OTf
(3.5 equiv)
NH
N
CH2Cl2
(0.07 M)
reflux, 3 h
Br
Ts
Ts
7b, 9b–g
2
8b,10b–g
Yielda (%)
Entry
R
Product
1
Ph
8b
10b
10c
10d
10e
10f
82
88
62
83
38
78
n.r.
2
4-ClC6H4
4-MeOC6H4
1-naphthyl
3-furyl
Table 2 Optimization of the Substrate Properties
3
DBU
EWG
Ph
Ph
EWG
+
SPh2
OTf
(3.5 equiv)
4
NH
CH2Cl2
(0.07 M)
reflux, 3 h
N
5
Br
PG
7a–f
PG
1
8a–f
6
CO2Et
Yielda (%)
Entry
Product
PG
EWG
7
Me
10g
a Isolated yield.
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
Ts
CO2Me
CO2Et
72
82
80
32
38
n.r.
Ts
We also attempted to extend the annulation to the synthe-
sis of oxetanes by using α-hydroxy esters. Although initial
experiments with the phenyl-substituted ester 11a16 were
unsuccessful, we found that by increasing the acidity of
the α-proton by using diester 11b17 the oxetane 12b was
obtainable in good yield (Scheme 4).18
Ts
CO2-t-Bu
CN
Ts
Cbz
Cbz
CO2Me
CO2-t-Bu
a Isolated yield.
DBU
CO2Et
R
SPh2
OTf
R
CO2Et
(3.5 equiv)
+
CH2Cl2
(0.07 M)
reflux, 3 h
OH
O
We therefore focused on the use of ethyl esters of N-to-
syl(2-aryl)glycines.14 These were easily prepared using
the method developed by Lu and co-workers (Scheme
3),11 in which a simple three-component palladium-cata-
lyzed reaction between ethyl glyoxylate, tosyl isocyanate,
and an aryl boronic ester gives the corresponding aryl gly-
cines 9 in moderate-to-good yields.
Br
11
1
12
12a R = Ph, no reaction
12b R = CO2Et, 68%
Scheme 4 Exploration of the synthesis of oxetanes
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1584–1590

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S. P. Fritz et al.
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO4S+: 362.1421;
found: 362.1425.
Finally, we report that substrate 10f can be conveniently
decarboxylated to give the monoacid 13f, which provides
access to azetidine-2-carboxylic acids (Scheme 5).19
Ethyl Esters 7b and 9b–e; General Method
According to the method of Lu and co-workers,11 a Schlenk tube
was charged with toluene (2 mL) then TsOCN (0.71 mmol, 1
equiv), ethyl glyoxylate (0.71 mmol, 1 equiv), Pd(O2CCF3)2 (5
mol%), and 2,2′-bipyridine (6 mol%) were added and the mixture
was refluxed for 3 h, under argon. The appropriate arylboronic acid
(1.42 mmol, 2 equiv) was added and the mixture was refluxed for a
further 24 h. The mixture was then cooled to r.t. and diluted with
EtOAc (10 mL). The organic layer was washed with brine (10 mL)
and the aqueous layer was extracted with EtOAc (3 × 30 mL). The
combined organic layers were dried (MgSO4), filtered, and concen-
trated under reduced pressure. The residue was purified by flash
column chromatography (EtOAc–PE or EtOAc–pentane).
CO2Et 1) KOH, EtOH
reflux, 2 h
HO2C
Ts
EtO2C
Ts
N
N
2) HCl (6 M)
reflux, 5 h
10f
74% over 2 steps
13f
Scheme 5 Monodecarboxylation of 10f to azetidine-2-carboxylic
acid 13f
In conclusion, we have demonstrated a synthesis of sever-
al substituted azetidines and an oxetane in high yields un-
der mild conditions by a simple method starting from Ethyl (±)-Phenyl(tosylamino)acetate (7b)
The product was prepared by the general method from phenylbo-
readily available materials.
ronic acid (173 mg, 1.42 mmol) to give an amorphous white solid;
yield: 163 mg (70%); mp 86–88 °C (Lit.11 90–91 °C).
Reactions were performed under a positive pressure of dry N2 in dry
glassware with magnetic stirring. Dry solvents and freshly distilled
DBU were transferred by syringe or cannula into the reaction ves-
sels through rubber septa. Reagents of the highest commercial qual-
ity available were purchased and used as received, with the
exception of DBU, which was distilled from CaH2. Anhyd solvents
(CH2Cl2, toluene, and MeCN) were purified on a column of activat-
ed alumina (A-2). Flash chromatography was performed on silica
gel (Merck Kieselgel 60 F254 230–400 mesh). TLC was performed
on aluminum-backed silica plates (0.2 mm, 60 F254), which were vi-
sualized by standard techniques: UV fluorescence (254 and 366
nm), I2 staining, or ninhydrin/heat. The 40–60 °C boiling fraction of
1H NMR (400 MHz, CDCl3): δ = 7.59–7.69 (m, 2 H, ArH), 7.21–
7.28 (m, 5 H, ArH), 7.18 (m, 2 H, ArH), 5.98 (d, J = 8.5 Hz, 1 H,
CH), 5.06 (d, J = 8.5 Hz, 1 H, NH), 3.86–4.12 (m, 2 H, CH2), 2.37
(s, 3 H, ArCH3), 1.08 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 169.9 (CO), 143.3 (C), 136.8 (C),
135.3 (C), 129.3 (CH), 128.6 (CH), 128.3 (CH), 127.1 (CH), 126.9
(CH), 62.0 (CH2), 59.3 (CH), 21.3 (CH3), 13.7 (CH3).
The spectroscopic data were consistent with those reported in the
literature.11
Ethyl (±)-(4-Chlorophenyl)(tosylamino)acetate (9b)
1
The product was prepared by the general method from (4-chloro-
phenyl)boronic acid (222 mg, 1.42 mmol) to give an amorphous
white solid; yield: 172 mg (66%); mp 87–89 °C (Lit.11 86–87 °C).
PE was used. H NMR spectra were recorded at either 300 or 400
MHz on Jeol Delta GX or Eclipse ECP/400 instruments, respective-
ly. 13C NMR spectra were recorded at 75 or 100 MHz using the
same instruments. Chemical shifts (δH and δC) are quoted in parts
per million (ppm), referenced to the appropriate NMR solvent
peak(s). Low- and high-resolution mass spectra were recorded on a
Bruker Daltronics Apex 4e 7.0T FT-MS (ESI) spectrometer. Melt-
ing points were measured on a Kofler hotstage melting point appa-
ratus and are uncorrected. Infrared spectra were recorded on the
neat compounds using an ATR sampling accessory on a Perkin-
Elmer (Spectrum One) FT-IR spectrophotometer. Only strong and
selected absorbances (max) are reported. Optical rotations were
measured using a Perkin-Elmer 241 MC polarimeter.
1H NMR (400 MHz, CDCl3): δ = 7.58–7.64 (m, 2 H, ArH), 7.14–
7.23 (m, 6 H, ArH), 5.96 (d, J = 8.0 Hz, 1 H, CH), 5.02 (d, J = 8.0
Hz, 1 H, NH), 3.90–4.11 (m, 2 H, CH2), 2.39 (s, 3 H, ArCH3), 1.09
(t, J = 7.1 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 169.5 (CO), 143.6 (C), 136.8 (C),
134.4 (C), 133.9 (C), 129.4 (CH), 128.8 (CH), 128.5 (CH), 127.1
(CH), 62.4 (CH2), 58.7 (CH), 21.4 (ArCH3), 13.7 (CH3).
The spectroscopic data were consistent with those reported in the
literature.11
(2-Bromoethyl)diphenylsulfonium trifluoromethanesulfonate (1),7c
methyl (2R)-(tosylamino)(phenyl)acetate 7a,10 and (±)-N-[cy-
ano(phenyl)methyl]-4-toluenesulfonamide (7d)12 were prepared
according to the published procedures.
Ethyl (±)-(4-Methoxyphenyl)(tosylamino)acetate (9c)
The product was prepared by the general method from (4-methoxy-
phenyl)boronic acid (222 mg, 1.42 mmol) to give an amorphous
white solid; yield: 160 mg (62%); mp 88–90 °C (Lit.11 87–89 °C).
1H NMR (400 MHz, CDCl3): δ = 7.49–7.64 (m, 2 H, ArH), 7.12 (d,
J = 8.0 Hz, 2 H, ArH), 6.98–7.09 (m, 2 H, ArH), 6.59–6.81 (m, 2 H,
ArH), 5.69 (d, J = 8.0 Hz, 1 H, CH), 4.91 (d, J = 8.0 Hz, 1 H, NH),
3.79–4.10 (m, 2 H, CH2), 3.68 (s, 3 H, OCH3), 2.30 (s, 3 H, ArCH3),
1.01 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 170.2 (CO), 159.7 (C), 143.4 (C),
137.0 (C), 129.4 (CH), 128.3 (CH), 127.5 (CH), 127.2 (CH), 114.1
(C), 62.1 (CH2), 58.8 (CH), 55.3 (CH3), 21.4 (ArCH3), 13.8 (CH3).
tert-Butyl (2R)-(Tosylamino)(phenyl)acetate (7c)
A soln of tert-butyl (2R)-amino(phenyl)acetate (100 mg, 0.48
mmol, 1 equiv) in CH2Cl2 (4.8 mL; 0.1 M) was treated with Et3N
(0.18 mL, 1.1 mmol, 2.2 equiv). TsCl (92 mg, 0.48 mmol, 1.0 equiv)
was added and the mixture was stirred for 18 h. The reaction was
then quenched with sat. aq NaHCO3 (10 mL) and the mixture was
extracted with CH2Cl2 (3 × 30 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo to provide a crude
product that was purified by flash chromatography [silica gel, EtO-
Ac–PE (3:7)] to give transparent crystals; yield: 142 mg (82%); mp
The spectroscopic data were consistent with those reported in the
literature.11
22
138–140 °C (CH2Cl2–pentane); Rf = 0.5 (EtOAc–PE, 3:7); [α]D
–78.0 (c 0.02, CHCl3).
Ethyl (±)-(2-Naphthyl)(tosylamino)acetate (9d)
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.5 Hz, 2 H, ArH),
7.17–7.33 (m, 7 H, ArH), 5.75 (d, J = 8.0 Hz, 1 H, CH), 4.95 (d,
J = 8.0 Hz, 1 H, NH), 2.39 (s, 3 H, ArCH3), 1.26 (s, 9 H, 3 × CH3).
The product was prepared by the general method from 2-naphthyl-
boronic acid (222 mg, 1.42 mmol to give an amorphous white solid;
yield: 84 mg (31%); mp 111–113 °C (Lit.11 115–116 °C).
13C NMR (100 MHz, CDCl3): δ = 169.0 (CO), 143.3 (C), 137.0 (C),
135.9 (C), 129.4 (CH), 128.5 (CH), 128.1 (CH), 127.2 (CH), 126.9
(CH), 83.0 (C), 59.7 (CH), 27.5 (CH3), 21.4 (ArCH3).
1H NMR (400 MHz, CDCl3): δ = 7.76–7.82 (m, 1 H, ArH), 7.68–
7.76 (m, 2 H, ArH), 7.63–7.68 (m, 1 H, ArH), 7.57–7.63 (m, 2 H,
ArH), 7.44–7.52 (m, 2 H, ArH), 7.31 (dd, J = 8.5, 2.0 Hz, 1 H,
Synthesis 2012, 44, 1584–1590
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Efficient Synthesis of Azetidines
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ArH), 7.04–7.11 (m, 2 H, ArH), 5.81 (d, J = 7.0 Hz, 1 H, CH), 5.22
(d, J = 7.0 Hz, 1 H, NH), 3.95–4.15 (m, 2 H, CH2), 2.27 (s, 3 H,
ArCH3), 1.11 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 170.0 (CO), 143.4 (C), 137.0 (C),
133.0 (C), 133.0 (C), 132.5 (C), 129.3 (CH), 128.7 (CH), 128.0
(CH), 127.5 (CH), 127.1 (CH), 126.7 (CH), 126.5 (CH), 126.4
(CH), 124.4 (CH), 62.3 (CH2), 59.5 (CH), 21.3 (CH3), 13.8 (CH3).
Methyl (±)-2-Phenyl-1-tosylazetidine-2-carboxylate (8a)
The racemic product was prepared according to the general method
from methyl (2R)-phenyl(tosylamino)acetate (100 mg, 0.31 mmol)
to give the racemic product as a clear oil; yield: 74 mg (72%); Rf =
0.5 (EtOAc–PE, 3:7); [α]D20 0.0 (c 1.0, CHCl3).
FTIR (neat): 3272, 3092, 2959, 1741, 1331 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.55–7.63 (m, 2 H, ArH), 7.39–
7.46 (m, 2 H, ArH), 7.30–7.38 (m, 3 H, ArH), 7.21–7.28 (m, 2 H,
ArH), 4.20 (ddd, J = 9.2, 7.0, 7.0 Hz, 1 H, CHH), 3.86 (ddd, J = 9.2,
7.0, 4.9 Hz, 1 H, CHH), 3.73 (s, 3 H, COCH3), 2.94 (ddd, J = 11.2,
9.2, 4.9 Hz, 1 H, CHH), 2.55 (ddd, J = 11.2, 9.2, 7.0 Hz, 1 H, CHH),
2.42 (s, 3 H, ArCH3).
13C NMR (100 MHz, CDCl3): δ = 170.9 (CO), 143.3 (C), 139.0 (C),
136.4 (C), 129.3 (CH), 128.3 (CH), 128.0 (CH), 127.4 (CH), 126.0
(CH), 77.2 (C), 52.8 (CH3), 47.4 (CH2), 29.6 (CH2), 21.5 (CH3).
The spectroscopic data were consistent with those reported in the
literature.11
Ethyl (±)-(3-Furyl)(tosylamino)acetate (9e)
The product was prepared by the general method from 3-furylbo-
ronic acid (159 mg, 1.42 mmol) as an amorphous yellow–white sol-
id of sufficient purity for use in the next step; yield: 92 mg (40%);
mp 68–70 °C; Rf = 0.25 (EtOAc–pentane, 2:8).
FTIR (neat): 3288, 3092, 2956, 1744, 1366 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C18H19NNaO4S+: 368.0927;
found: 368.0926.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.3 Hz, 2 H, ArH),
7.07–7.29 (m, 3 H, ArH), 6.08–6.33 (m, 2 H, ArH), 5.56 (d, J = 8.5
Hz, 1 H, CH), 5.09 (d, J = 8.5 Hz, 1 H, NH), 3.87–4.24 (m, 2 H,
CH2), 2.32 (s, 3 H, ArCH3), 1.07 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 167.9 (CO), 147.7 (C), 143.5 (C),
143.0 (CH), 136.9 (C), 129.5 (CH), 127.1 (CH), 110.5 (CH), 109.1
(CH), 62.5 (CH2), 53.6 (CH), 21.5 (CH3), 13.8 (CH3).
Ethyl (±)-2-Phenyl-1-tosylazetidine-2-carboxylate (8b)
The product was prepared according to the general method from
ethyl phenyl(tosylamino)acetate (57 mg, 0.17 mmol, 1 equiv) to
give a clear oil; yield: 50 mg (82%) Rf = 0.3 (EtOAc–pentane, 2:8).
FTIR (neat): 3265, 2968, 1724, 1336, 1156 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.56–7.62 (m, 2 H, ArH), 7.40–
7.47 (m, 2 H, ArH), 7.29–7.39 (m, 3 H, ArH), 7.21–7.26 (m, 2 H,
ArH), 4.13–4.30 (m, 3 H, CH2 and CHH), 3.83 (ddd, J = 9.0, 7.0,
5.0 Hz, 1 H, CHH), 2.91 (ddd, J = 11.0, 9.0, 5.0 Hz, 1 H, CHH),
2.58 (ddd, J = 11.0, 9.0, 7.0 Hz, 1 H, CHH), 2.41 (s, 3 H, ArCH3),
1.28 (t, J = 7.0 Hz, 3 H, CH3).
MS (ESI+): m/z (%) = 341.1 (100) [M + NH4]+, 324.1 (10), [M +
H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H17NNaO5S+: 346.0724;
found: 346.0719.
Diethyl (Tosylamino)malonate (9f)
13C NMR (75 MHz, CDCl3): δ = 170.6 (C), 143.2 (C), 139.1 (C),
136.7 (C), 129.3 (CH), 128.2 (CH), 128.0 (CH), 127.3 (CH), 126.2
(CH), 77.4 (C), 62.1 (OCH2), 47.3 (CH2), 29.2 (CH2), 21.4
(ArCH3), 13.9 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C19H21NNaO4S: 382.1083;
found: 382.1083.
Diethyl aminomalonate (211 mg, 1 mmol, 1 equiv) was treated with
TsCl (210 mg, 1.1 mmol, 1.1 equiv) and Et3N (0.42 mL, 3.0 mmol,
3.0 equiv) in CH2Cl2 (0.1 M) for 15 h at r.t. The reaction was
quenched with sat. aq NaHCO3 (5 mL) and the mixture was extract-
ed with CH2Cl2 (3 × 10 mL). The combined organic phases were
dried (MgSO4) and concentrated in vacuo. The crude product was
purified by flash chromatography [EtOAc–pentane (2:8)] to give a
gummy white solid; yield: 205 mg (62%); mp 60–62 °C (CH2Cl2–
pentane); Rf = 0.4 (EtOAc–pentane, 2:8).
tert-Butyl (±)-2-Phenyl-1-tosylazetidine-2-carboxylate (8c)
The racemic product was prepared according to the general method
from tert-butyl (2R)-phenyl(tosylamino)acetate (43.0 mg, 0.12
mmol, 1 equiv) to give a clear oil; yield: 37 mg (80%); Rf = 0.15
(EtOAc–PE, 3:7); [α]D23 0.0 (c 0.11, CHCl3).
FTIR (neat): 3276, 2944, 1748, 1339 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.5 Hz, 2 H, ArH),
7.22 (d, J = 8.5 Hz, 2 H, ArH), 5.74 (d, J = 7.0 Hz, 1 H, CH), 4.58
(d, J = 7.0 Hz, 1 H, NH), 4.06 (dq, J = 11.0, 7.0 Hz, 2 H, 2 × CHH),
4.03 (dq, J = 11.0, 7.0 Hz, 2 H, 2 × CHH), 2.34 (s, 3 H, ArCH3),
1.12 (t, J = 7.0 Hz, 6 H, 2 × CH3).
13C NMR (100 MHz, CDCl3): δ = 165.5 (C), 143.8 (C), 136.4 (C),
129.5 (CH), 127.2 (CH), 62.7 (CH2), 58.6 (CH), 21.4 (ArCH3), 13.7
(CH3).
FTIR (neat): 3260, 2961, 1721, 1339, 1152 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.63 (m, 2 H, ArH), 7.38–
7.46 (m, 2 H, ArH), 7.27–7.37 (m, 3 H, ArH), 7.17–7.25 (m, 2 H,
ArH), 4.27 (ddd, J = 9.1, 6.9, 6.9 Hz, 1 H, NCHH), 3.70 (ddd,
J = 9.1, 6.9, 4.8 Hz, 1 H, NCHH), 2.83 (ddd, J = 11.2, 9.1, 4.8 Hz,
1 H, CHH), 2.61 (ddd, J = 11.2, 9.1, 6.9 Hz, 1 H, CHH), 2.40 (s, 3
H, ArCH3) 1.55 (s, 9 H, 3 × CH3).
13C NMR (100 MHz, CDCl3): δ = 170.0 (CO), 143.0 (C), 139.4 (C),
137.5 (C), 129.3 (CH), 128.0 (CH), 127.8 (CH), 127.1 (CH), 126.5
(CH), 83.0 (C), 77.8 (C), 47.1 (CH2), 28.7 (CH2), 27.8 (CH3), 21.4
(ArCH3).
MS (ESI): m/z = 330 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H19NNaO6S: 352.0837;
found: 352.0825.
Azetidines: General Method
HRMS (ESI): m/z [M + Na]+ calcd for C21H25NaNO4S+: 410.1410;
found: 410.1397.
(2-Bromoethyl)sulfonium triflate (1; 93 mg, 0.21 mmol, 1.25 equiv)
was added to a soln of the appropriate N-protected arylglycine ester
(0.167 mmol, 1 equiv) in CH2Cl2 (2.3 mL, 0.07 M). DBU (87 µL,
0.58 mmol, 3.5 equiv) was added to the stirred soln, and the mixture
was refluxed for 3 h. The mixture was then cooled to r.t. and the re-
action was quenched with sat. aq NaHCO3 (5 mL). The mixture was
extracted with CH2Cl2 (3 × 30 mL) and the combined organic phas-
es were dried (MgSO4) and concentrated in vacuo. The product was
purified by flash chromatography (silica gel, EtOAc–PE or EtOAc–
pentane).
(±)-2-Phenyl-1-tosylazetidine-2-carbonitrile (8d)
The product was prepared according to the general method from
phenyl(tosylamino)acetonitrile (30.0 mg, 0.10 mmol, 1 equiv) to
give a clear oil; yield: 10.5 mg (32%); Rf = 0.3 (EtOAc–PE, 2:8).
FTIR (neat): 3253, 3011, 2981, 1742, 1330, 1155 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.2 Hz, 2 H, ArH),
7.62–7.69 (m, 2 H, ArH), 7.37–7.48 (m, 3 H, ArH), 7.33 (d, J = 7.9
Hz, 2 H, ArH), 4.10 (ddd, J = 8.5, 8.5, 7.0 Hz, 1 H, NCHH), 3.98
(ddd, J = 8.5, 7.0, 4.0 Hz, 1 H, NCHH), 2.83 (ddd, J = 11.0, 8.5, 4.0
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Hz, 1 H, CHH), 2.66 (ddd, J = 11.0, 8.5, 8.5 Hz, 1 H, CHH), 2.45
(s, 3 H, ArCH3).
HRMS (ESI): m/z [M + Na]+ calcd for C23H23NNaO4S+: 432.1230;
found: 432.1240.
13C NMR (100 MHz, CDCl3): δ = 144.6 (C), 136.6 (C), 129.63 (C),
129.57 (CH), 129.0 (CH), 128.4 (CH), 128.1 (CH), 125.6 (CH),
117.2 (CN), 66.0 (C), 47.0 (CH2), 33.6 (CH2), 21.6 (ArCH3).
Ethyl (±)-2-(3-Furyl)-1-tosylazetidine-2-carboxylate (10e)
The product was prepared according to the general method from
ethyl (3-furyl)(tosylamino)acetate (45 mg, 0.14 mmol, 1 equiv) to
give a clear oil; yield: 19 mg (38%); Rf = 0.2 (EtOAc–pentane, 2:8).
HRMS (ESI): m/z [M + Na]+ calcd for C17H16N2NaO2S+: 335.0825;
FTIR (neat): 3279, 2927, 1721, 1683, 1321 cm–1.
found: 335.0832.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.39 (m, 2 H, ArH), 7.20 (dd,
J = 2.0, 0.5 Hz, 1 H, ArH), 7.11 (d, J = 8.0 Hz, 2 H, ArH), 6.47 (dd,
J = 3.5, 0.5 Hz, 1 H, ArH), 6.29 (dd, J = 3.5, 2.0 Hz, 1 H, ArH),
4.20–4.30 (m, 2 H, CH2), 3.93–4.02 (m, 1 H, CHH), 3.85–3.92 (m,
1 H, CHH), 2.72–2.84 (m, 1 H, CHH), 2.61–2.70 (m, 1 H, CHH),
2.32 (s, 3 H, CH3), 1.27 (t, J = 7.0 H Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 169.4 (C), 142.9 (C), 142.6 (C),
129.3 (CH), 129.2 (CH), 127.3 (CH), 127.1 (C), 110.8 (CH), 110.7
(CH), 70.4 (C), 62.2 (CH2), 46.9 (CH2), 27.3 (CH2), 21.4 (ArCH3),
14.0 (CH3).
Ethyl (±)-2-(4-Chlorophenyl)-1-tosylazetidine-2-carboxylate
(10b)
The product was prepared according to the general method from
ethyl (4-chlorophenyl)(tosylamino)acetate (61 mg, 0.17 mmol, 1
equiv) to give a clear oil; yield: 58 mg (88%); Rf = 0.4 (EtOAc–pen-
tane, 2:8).
FTIR (neat): 3212, 2986, 1729, 1339, 1156 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.57–7.63 (m, 2 H, ArH), 7.22–
7.42 (m, 6 H, ArH), 4.21 (m, 3 H, OCH2 and NCHH), 3.83 (ddd,
J = 9.0, 7.0, 5.0 Hz, 1 H, NCHH), 2.89 (ddd, J = 11.0, 9.0, 5.0 Hz,
1 H, CHH), 2.52 (ddd, J = 11.0, 9.0, 7.0 Hz, 1 H, CHH), 2.42 (s, 3
H, ArCH3), 1.27 (t, J = 7.0 Hz, 3 H, CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C17H19NNaO5S+: 372.0876;
found: 372.0871.
13C NMR (100 MHz, CDCl3): δ = 170.2 (CO), 143.5 (C), 137.9 (C),
136.6 (C), 134.0 (C), 129.4 (CH), 128.3 (CH), 127.7 (CH), 127.3
(CH), 77.1 (C), 62.3 (CH2) 47.4 (CH2), 29.2 (CH2), 21.5 (ArCH3),
13.8 (CH3).
MS(ESI+): m/z = 418.1 [M + Na, 37Cl]+, 416.1 [M + Na, 35Cl]+.
HRMS (ESI): m/z [M + Na]+ calcd for C19H20ClNaNO4S+:
Diethyl 1-Tosylazetidine-2,2-dicarboxylate (10f)
The product was prepared according to the general method from di-
ethyl (tosylamino)malonate (56 mg, 0.17 mmol, 1 equiv) to give a
clear oil; yield: 47 mg (78%); Rf = 0.25 (EtOAc–pentane, 2:8).
FTIR (neat): 2982, 1737, 1340, 1159 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, 2 H, ArH),
7.21 (d, J = 8.0 Hz, 2 H, ArH), 4.22 (q, J = 7.0 Hz, 4 H, 2 × CH2),
3.97 (t, J = 7.5 Hz, 2 H, CH2), 2.55 (t, J = 7.5 Hz, 2 H, CH2), 2.34
(s, 3 H, ArCH3), 1.24 (t, J = 7.0 Hz, 6 H, 2 × CH3).
13C NMR (75 MHz, CDCl3): δ = 168.3 (CO), 143.4 (C), 137.9 (C),
129.2 (CH), 127.4 (CH), 62.3 (CH2), 47.5 (NCH2), 24.4 (CH2), 21.5
(ArCH3), 13.9 (CH3).
416.0692; found: 416.0694.
Ethyl (±)-2-(4-Methoxyphenyl)-1-tosylazetidine-2-carboxylate
(10c)
The product was prepared according to the general method from
ethyl (4-methoxyphenyl)(tosylamino)acetate (62 mg, 0.17 mmol, 1
equiv) to give a clear oil; yield: 41 mg (62%); Rf = 0.17 (EtOAc–
pentane, 2:8).
HRMS (ESI): m/z [M + Na]+ calcd for C16H21NNaO6S: 378.0984;
found: 378.0982.
FTIR (neat): 2979, 1731, 1339, 1157 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.48–7.59 (m, 2 H, ArH), 7.30–
7.40 (m, 2 H, ArH), 7.22 (d, J = 8.0 Hz, 2 H, ArH), 6.80–6.92 (m, 2
H, ArH), 4.09–4.35 (m, 3 H, OCH2 and CHH), 3.73–3.92 (m, 4 H,
OCH3 and CHH), 2.85 (ddd, J = 11.5, 9.0, 5.0 Hz, 1 H, CHH), 2.60
(ddd, J = 11.5, 9.0, 7.0 Hz, 1 H, CHH), 2.41 (s, 3 H, ArCH3), 1.28
(t, J = 7.0 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 171.0 (CO), 159.3 (C), 143.1 (C),
136.9 (C), 130.8 (C), 129.2 (CH), 127.8 (CH), 127.3 (CH), 113.6
(CH), 76.6 (C), 62.0 (CH2), 55.3 (OCH3), 47.1 (CH2), 29.1 (CH2),
21.5 (ArCH3), 13.9 (CH3).
1-Benzyl 2-Methyl (±)-2-phenylazetidine-1,2-dicarboxylate (8e)
The product was prepared according to the general method from
methyl [(benzyloxycarbonyl)amino](phenyl)acetate (51 mg, 0.17
mmol, 1 equiv; prepared by the method of Kashima et al.20) to give
a clear oil; yield: 21 mg (38%).
FTIR (neat): 3337, 3034, 2946, 1702, 1509, 1354, 1215 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.52 (m, 10 H, ArH), 5.40
(d, J = 12.0 Hz, 1 H, CHHPh), 5.30 (d, J = 12.0 Hz, 1 H, CHHPh)
4.30 (ddd, J = 11.0, 9.0, 3.5 Hz, 1 H, NCHH), 4.16 (ddd, J = 11.0,
6.5, 4.0 Hz, 1 H, NCHH), 3.71 (s, 3 H, OCH3), 2.76 (ddd, J = 14.0,
6.5, 3.5 Hz, 1 H, CHH), 2.03 (ddd, J = 14.0, 9.0, 4.0 Hz, 1 H, CHH).
13C NMR (100 MHz, CDCl3): δ = 173.9 (CO), 152.7 (CO), 142.6
(C), 136.3 (C), 128.4 (CH), 128.4 (CH), 128.1 (CH), 128.0 (CH),
127.5 (CH), 125.6 (CH), 69.2 (CH2), 64.4 (CH2), 63.3 (C), 52.8
(CH3), 32.0 (CH2).
HRMS (ESI): m/z [M + Na]+ calcd for C20H23NNaO5S+: 412.1195;
found: 412.1189.
Ethyl (±)-2-(2-Naphthyl)-1-tosylazetidine-2-carboxylate (10d)
The product was prepared according to the general method from
ethyl (2-naphthyl)(tosylamino)acetate (65 mg, 0.17 mmol, 1 equiv)
to give a clear oil; yield: 58 mg (83%); Rf = 0.2 (EtOAc–pentane,
2:8).
HRMS (ESI): m/z [M + Na]+ calcd for C19H19NNaO4: 348.1205;
found: 348.1206.
FTIR (neat): 2979, 1732, 1339, 1157 cm–1.
Diethyl Oxetane-2,2-dicarboxylate (12b)
1H NMR (400 MHz, CDCl3): δ = 7.78–7.86 (m, 3 H, ArH), 7.69–
7.77 (m, 1 H, ArH), 7.56–7.63 (m. ArH), 2 H, 7.43–7.53 (m, 3 H,
ArH), 7.18 (dd, J = 8.5, 0.5 Hz, 2 H, ArH), 4.15–4.43 (m, 3 H,
OCH2 and CHH), 3.92 (ddd, J = 9.0, 7.0, 5.0 Hz, 1 H, CHH), 2.99
(ddd, J = 11.0, 9.0, 5.0 Hz, 1 H, CHH), 2.64 (ddd, J = 11.0, 9.0, 7.0
Hz, 1 H, CHH), 2.38 (s, 3 H, ArCH3), 1.30 (t, J = 7.0 Hz, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 170.6 (CO), 143.3 (C), 136.8 (C),
136.4 (C), 132.8 (C), 131.0 (C), 129.3 (CH), 128.3 (CH), 128.0
(CH), 127.5 (CH), 127.3 (CH), 126.4 (CH), 126.2 (CH), 125.3
(CH), 124.1 (CH), 77.3 (C), 62.2 (CH2), 47.5 (CH2), 29.2 (CH2),
21.4 (ArCH3), 13.9 (CH3).
Diethyl hydroxymalonate (60 mg, 0.34 mmol, 1 equiv; prepared ac-
cording to the method of Cohen et al.16) was dissolved in CH2Cl2
(4.5 mL, 0.07 M). (2-Bromoethyl)sulfonium triflate (1; 185 mg,
0.42 mmol, 1.25 equiv) and DBU (175 µL, 1.16 mmol, 3.5 equiv)
were added sequentially and the mixture was refluxed for 3 h.
Workup according to the general procedure to give a clear oil; yield:
47 mg (68%); Rf = 0.5 (EtOAc–pentane, 2:8).
FTIR (neat): 3337, 2946, 1701, 1509, 1366 cm–1.
Synthesis 2012, 44, 1584–1590
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PAPER
Efficient Synthesis of Azetidines
1589
1H NMR (400 MHz, CDCl3): δ = 4.67 (t, J = 8.0 Hz, 2 H, CH2), 4.31
(q, J = 7.0 Hz, 4 H, OCH2CH3), 3.09 (t, J = 8.0 Hz, 2 H, CH2), 1.31
(t, J = 7.0 Hz, 6 H, 2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 168.7 (CO), 84.4 (C), 67.9 (CH2),
62.1 (CH2), 28.4 (CH2), 14.0 (CH3).
5861. (d) Banide, E.; de Talancé, V. L.; Schmidt, G.; Lubin,
H.; Comesse, S.; Dechoux, L.; Hamon, L.; Kadouri-Puchot,
C. Eur. J. Org. Chem. 2007, 4517. (e) Almens, J.; Foubelo,
F.; Yus, M. Tetrahedron 1994, 50, 5775.
(4) (a) Zi, G. F.; Liu, R. C.; Bai, X. M.; Zhang, Z. B. Appl.
Organomet. Chem. 2008, 22, 671. (b) Couty, F.; Prim, D.
Tetrahedron: Asymmetry 2002, 13, 2619. (c) Guanti, G.;
Riva, R. Tetrahedron: Asymmetry 2001, 12, 605.
MS (ESI+): m/z = 225.1 [M + Na]+, 203.1 [M + H]+.
+
HRMS (ESI): m/z [M + Na]+ calcd for C9H14NaO5 : 225.0735;
found: 225.0733.
(d) Hermsen, P. J.; Cremers, J. G. O.; Thijs, L.; Zwanenburg,
B. Tetrahedron Lett. 2001, 42, 4243. (e) Doyle, M. P.;
Davies, S. B.; Hu, W. Chem. Commun. 2000, 867.
(f) Starmans, W. A. J.; Walgers, R. W. A.; Thijs, L.; de
Gelder, R.; Smits, J. M. M.; Zwanenburg, B. Tetrahedron
1998, 54, 4991.
(±)-1-Tosylazetidine-2-carboxylic Acid (13f)
A 2 M soln of KOH in EtOH (4 mL) was added to diethyl 1-tosyl-
azetidine-2,2-dicarboxylate (10f; 100 mg, 0.28 mmol, 1 equiv) and
the mixture was refluxed for 2 h with vigorous stirring, then cooled.
The resulting mixture was acidified with 2 M aq HCl and extracted
with EtOAc (3 × 30 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. (LC/MS at this stage showed
complete conversion into the dicarboxylic acid.) The resulting
crude mixture was treated with 6 M aq HCl (4 mL), refluxed with
stirring for 5 h, and cooled to r.t. H2O was added (10 mL) and the
mixture was extracted with EtOAc (3 × 30 mL). The combined or-
ganic phases were washed with brine (10 mL), dried (MgSO4), and
concentrated in vacuo to give a white coating on the flask; yield: 53
mg (74%).
(5) For a recent example, see: Medjahdi, M.; González-Gámez,
J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2009, 74, 7859.
(6) For reviews on synthetic methods for azetidines, see:
(a) Couty, F.; Evano, G. Synlett 2009, 3053. (b) Brandi, A.;
Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988.
(7) For the direct use of (2-bromoethyl)sulfonium triflate in
annulation reactions, see: (a) McGarrigle, E. M.; Fritz, S. P.;
Favereau, L.; Yar, M.; Aggarwal, V. K. Org. Lett. 2011, 13,
3060. (b) Fritz, S. P.; Mumtaz, A.; Yar, M.; McGarrigle, E.
M.; Aggarwal, V. K. Eur. J. Org. Chem. 2011, 3156. (c) Yar,
M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11,
257.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.5 Hz, 2 H, ArH),
7.33 (d, J = 8.5 Hz, 2 H, ArH), 4.34–4.50 (m, 1 H, CH), 4.18 (ddd,
J = 11.5, 9.5, 5.5 Hz, 1 H, NCHH), 3.81–3.97 (m, 1 H, NCHH),
2.64–2.79 (m, 1 H, CHH), 2.43 (s, 3 H, ArCH3), 2.28 (dddd,
J = 13.0, 11.5, 11.5, 9.0 Hz, 1 H, CHH).
13C NMR (100 MHz, CDCl3): δ = 174.1 (COOH), 144.4 (C), 135.8
(C), 130.1 (CH), 127.4 (CH), 66.2 (CH2), 51.9 (CH), 31.5 (CH2),
21.7 (ArCH3).
(8) For related work on the applications of vinyl sulfonium salts
in synthesis, see: (a) Yar, M.; Fritz, S. P.; McGarrigle, E. M.;
Aggarwal, V. K. Eur. J. Org. Chem. 2012, 160. (b) Chen, J.
R.; An, J.; Chang, N. J.; Song, L. D.; Jin, Y. Q.; Ma, Y.;
Xiao, W. J. Chem. Commun. 2011, 47, 1869. (c) Yar, M.;
McGarrigle, E. M.; Unthank, M. G.; Aggarwal, V. K.
Chem.–Asian J. 2011, 6, 372. (d) Xie, C. S.; Han, D. Y.; Hu,
Y.; Liu, J. H.; Xie, T. A. Tetrahedron Lett. 2010, 51, 5238.
(e) Maeda, R.; Ooyama, K.; Anno, R.; Shiosaki, M.; Azema,
T.; Hanamoto, T. Org. Lett. 2010, 12, 2548. (f) Catalán-
Muñoz, S.; Müller, C. A.; Ley, S. V. Eur. J. Org. Chem.
2010, 183. (g) Bornholdt, J.; Felding, J.; Kristensen, J. L.
J. Org. Chem. 2010, 75, 7454. (h) Xie, C. S.; Han, D. Y.;
Liu, J. H.; Xie, T. Synlett 2009, 3155. (i) Unthank, M. G.;
Tavassoli, B.; Aggarwal, V. K. Org. Lett. 2008, 10, 1501.
(j) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew.
Chem. Int. Ed. 2008, 47, 3784. (k) Kokotos, C. G.;
McGarrigle, E. M.; Aggarwal, V. K. Synlett 2008, 2191.
(l) Hansch, M.; Illa, O.; McGarrigle, E. M.; Aggarwal, V. K.
Chem.–Asian J. 2008, 3, 1657. (m) Unthank, M. G.;
Hussain, N.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2006,
45, 7066. (n) Yamanaka, H.; Matsuo, J.; Kawana, A.;
Mukaiyama, T. ARKIVOC 2004, (iii), 42. (o) Yamanaka, H.;
Matsuo, J.; Kawana, A.; Mukaiyama, T. Chem. Lett. 2003,
32, 626. (p) Matsuo, J.; Yamanaka, H.; Kawana, A.;
Mukaiyama, T. Chem. Lett. 2003, 32, 392. (q) Kim, K. H.;
Jimenez, L. S. Tetrahedron: Asymmetry 2001, 12, 999.
(r) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. In
Encyclopaedia of Reagents for Organic Synthesis; Paquette,
L. A.; Crich, D.; Fuchs, P. L.; Molander, G. A., Eds.; Wiley:
Hoboken, 2012, in press, DOI: 10.1002/047084289X.
(s) Fritz, S. P. Synlett 2012, 23, 480.
The spectroscopic data were consistent with those reported in the
literature.21
Acknowledgment
S.P.F. thanks the Engineering and Physical Sciences Research
Council (EPSRC) for a scholarship. J.F.M. thanks the Junta de An-
dalucía (C.E.I.y C.) for a predoctoral fellowship. V.K.A. thanks the
Royal Society for a Wolfson Research Merit Award, the EPSRC for
a Senior Research Fellowship, and Merck for research support.
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© Georg Thieme Verlag Stuttgart · New York
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PAPER
(17) Cohen, S. G.; Khedouri, E. J. Am. Chem. Soc. 1961, 83,
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Soc. 2008, 130, 4153. (c) Kawabata, T.; Matsuda, S.;
Kawakami, S.; Monguchi, D.; Moriyama, K. J. Am. Chem.
Soc. 2006, 128, 15394.
4228.
(18) For descriptions of the importance of oxetanes, see:
(a) Rogers-Evans, M.; Burkhard, J. A.; Wuitschik, G.;
Muller, K.; Carreira, E. M. Angew. Chem. Int. Ed. 2010, 49,
9052. (b) Carreira, E. M.; Wuitschik, G.; Wagner, B.;
Fischer, H.; Parrilla, I.; Schuler, F.; Rogers-Evans, M.;
Muller, K. J. Med. Chem. 2010, 53, 3227.
(14) Although the conventional approach is the Strecker
synthesis, many other methods are available. For reviews,
see: (a) Sansano, J. M.; Najera, C. Chem. Rev. 2007, 107,
4584. (b) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992,
92, 889.
(15) Zareef, M.; Iqbal, R.; De Dominguez, N. G.; Rodrigues, J.;
Zaidi, J. H.; Arfan, M.; Supuran, C. T. J. Enzym. Inhib. Med.
Chem. 2007, 22, 301.
(19) (a) Azetidine-2-carboxylic acid is the four-membered-ring
analogue of the amino acid proline and causes protein
misconstruction when used to replace proline. For its first
isolation, see: Fowden, L. Nature 1955, 176, 347. (b) For
previous syntheses, see ref. 6b and: Couty, F.; Evano, G.;
Vargas-Sanchez, M.; Bouzas, G. J. Org. Chem. 2005, 70,
9028; and references therein.
(20) Kashima, C.; Tsuruoka, S.; Mizuhara, S. Tetrahedron 1998,
54, 14679.
(21) Zwanenburg, B.; Starmans, W. A. J.; Thijs, L. Tetrahedron
1998, 54, 629.
(16) This compound is commercially available and can be found
by searching on the CAS Registry Number [774-40-3].
Synthesis 2012, 44, 1584–1590
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