Synthesis of 1,5-diazaspiro[2.3]hexanes, a novel diazaspirocyclic system

Article abstract of DOI:10.1016/j.tet.2013.02.065

The convenient synthesis of 1,5-diazaspiro[2.3]hexanes, as new structurally challenging strained diazaspirocyclic compounds, was developed starting from easily accessible ethyl 2-(bromomethyl)-1-tosylaziridine-2-carboxylate. The key transformations in the developed four-step sequence involved a chemoselective reduction of the functionalized ethyl 1-tosylaziridine-2-carboxylate to the corresponding β-bromo aldehyde and an aza-Payne-type rearrangement of intermediate N-tosyl 2-(aminomethyl)aziridines into N-alkyl 2-(aminomethyl) aziridines. A final base-mediated cyclization of the formed bromo amines gave efficient access to the new diazaspirocyclic system.

Full text of DOI:10.1016/j.tet.2013.02.065

Tetrahedron 69 (2013) 3437e3443
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 1,5-diazaspiro[2.3]hexanes, a novel diazaspirocyclic
system
a
,
Asta Zukauskaite b, Sven Mangelinckx a, Gert Callebaut a, Clarence Wybon a,
ꢀ
_
b
a,
*
ꢀ
ꢀ
Algirdas Sackus , Norbert De Kimpe
a Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent,
Belgium
b
_
Institute of Synthetic Chemistry, Kaunas University of Technology, Radvilenu˛ pl. 19, LT-50270 Kaunas, Lithuania
a r t i c l e i n f o
a b s t r a c t
Article history:
The convenient synthesis of 1,5-diazaspiro[2.3]hexanes, as new structurally challenging strained dia-
zaspirocyclic compounds, was developed starting from easily accessible ethyl 2-(bromomethyl)-1-
tosylaziridine-2-carboxylate. The key transformations in the developed four-step sequence involved
a chemoselective reduction of the functionalized ethyl 1-tosylaziridine-2-carboxylate to the corre-
Received 14 September 2012
Received in revised form 14 February 2013
Accepted 19 February 2013
Available online 26 February 2013
sponding b-bromo aldehyde and an aza-Payne-type rearrangement of intermediate N-tosyl 2-(amino-
methyl)aziridines into N-alkyl 2-(aminomethyl)aziridines. A final base-mediated cyclization of the
formed bromo amines gave efficient access to the new diazaspirocyclic system.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aziridines
Azetidines
Azaspirocycles
Aza-Payne rearrangement
1. Introduction
Akt inhibitors.14 Series of potent muscarinic antagonists bear 3,9-
diazaspiro[5.5]undecane, 1-oxa-4,9-diazaspiro[5.5]undecane and
Recently, there has been a growing interest in the field of spi-
rocyclic chemistry. Spirocycles comprise an interesting class of
compounds, both from a chemical and a biological point of view.
Azaspiro scaffolds are present in a number of natural products, such
as halichlorine,1 sibirine,2 nitramine,3 and families of histri-
onicotoxins.4 Heteroatom-containing azaspirocycles, in particular,
are considered to be surrogates for other saturated heterocycles,
such as piperazines, morpholines, thiomorpholines, and piperi-
dines,5 in some cases even being stable alternatives of their labile
monocyclic analogues6 with applications as valuable building
blocks in the field of drug discovery and for tuning of drugs or drug-
like structures.7 For example, 5-azaspiro[2.4]heptyl substituents
were reported to enhance the antibacterial activity of quinolone
antibiotics8 or highly potent oxazolidinone antibacterial agents.9
1,6-Diazaspiro[3.4]octanes possess (partial) agonist potencies for
nicotinic acetylcholine receptors.10 3,9-Diazaspiro[5.5]undecanes,11
3-azaspiro[5.5]undecanes,12 and 2,8-diazaspiro[4.5]decanes13 were
found to be spirocyclic nonpeptide glycoprotein IIbeIIIa antago-
nists and antiplatelet agents for inhibition of thrombus formation,
while several diazaspiro sulfonamides were described as potent
2,9-diazaspiro[5.5]undecane moieties.15 The 2,8-diazaspiro[4.5]
decane moiety was used to replace piperidine in a series of soluble,
selective neuropeptide YeY2 receptor antagonists,16 while appro-
priately substituted 2,8-diazaspiro[4.5]decanones were found to be
potent and selective T-type calcium channel antagonists.17 7-
Azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane were re-
ported as lead scaffolds for novel spirocyclic inhibitors of fatty acid
amide hydrolase.18 Several 3,9-diazaspiro[5.5]undecanes were
disclosed as chemokine receptor antagonists,19 while 1,7-
diazaspiro[4.5]decanes were used as ligands for metal complexa-
tion with ZnCl2.20
Despite the significant interest and development in this field,
some areas of this challenging chemistry are still un- or underex-
plored. Up to now, 1,5-diazaspiro[2.3]hexanes 1 (Fig. 1) are un-
known in the well documented area of spirocyclic diamines, with
the exception of some spirocyclic aziridine-azetidinones.21 In order
R1
N
N
R2
1
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 21; e-mail
address: norbert.dekimpe@UGent.be (N. De Kimpe).
Fig. 1. General structure of 1,5-diazaspiro[2.3]hexanes 1.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.065

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A. Zukauskaite et al. / Tetrahedron 69 (2013) 3437e3443
3438
to fill this important gap, the synthesis of 1,5-diazaspiro[2.3]hex-
anes 1 was investigated starting from previously reported ethyl 2-
(bromomethyl)-1-tosylaziridine-2-carboxylate 7.22
group,23 a transformation, which was foreseen to provide synthetic
access to the structurally challenging 1,5-diazaspiro[2.3]hexanes. All
initial attempts to directly form aziridine-2-carboxaldehyde 10 by
the use of DIBAL-H,24 in diethyl ether (ꢀ78 ꢁCdreflux) failed as each
time no reaction occurred. When LiAlH4 in diethyl ether at 0 ꢁC was
used, a mixture of bromo alcohol 8 and alcohol 9 was obtained, in
36% and 41% yield, respectively (Table 1, entry 1). In order to avoid
the formation of 2-methylaziridine 9, as side product resulting from
dehalogenation of aziridine 8, a smaller amount of LiAlH4 was used
and the reaction time was shortened to 15 min. However, even
under these conditions, dehalogenation could not be avoided (Table
1, entry 2). Surprisingly, when the reaction was performed at ꢀ78 ꢁC
with 1 mol equiv of LiAlH4 for 1 h, no formation of the corre-
2. Results and discussion
In view of the initially reported low yield of aziridine 7 (17% yield
over three steps),22 and the high price of the starting ethyl 2-(bro-
momethyl)acrylate 2, a new synthetic pathway for this functional-
ized aziridine was developed (Scheme 1). As the original synthesis
suffered from undesired diallylation in the amination step using N-
tosylamide, it was envisioned that this side reaction could be avoi-
ded if instead of a primary amine, an appropriate secondary amine
was used. For this reason, ethyl 2-(hydroxymethyl)acrylate 3 was
treated with BocNHTos under Mitsunobu conditions, efficiently
affording N,N-diprotected allylamine 4 in 91% yield. The carbamate
function in allylamine 4 was cleaved with TFA in CH2Cl2 at room
temperature for 1 h, yielding N-allyl-N-tosylamide 5 in 98% yield.
The low yield of 57% of the subsequent bromination, as previously
reported,22 was improved by simply prolonging the reaction time to
24 h (instead of 4.5 h). Thus, after optimizing reaction conditions,
sponding alcohol was observed and instead b-bromo aldehyde 10
was directly obtained in 88% yield (Table 1, entry 3).
As shown by several groups, halogenated aldehydes7b,25,26,27
and aldimines28 can be used as attractive substrates for the syn-
thesis of spiro derivatives. Inspired by these examples, several at-
tempts were made to access the novel class of structurally
challenging 1,5-diazaspiro[2.3]hexanes. Initially, it was expected
that the reaction of b-bromo aldehyde 10 with an amine and re-
ducing agent would give the corresponding 1,5-diazaspiro[2.3]
hexane directly via the intermediate imine.29 However, even
though treatment of bromo aldehyde 10 with benzylamine in the
presence of HOAc in methanol at 50 ꢁC for 4 h gave intermediate
and final cyclization of dibromo b-amino ester 6, ethyl 2-(bromo-
methyl)-1-tosylaziridine-2-carboxylate 7 was synthesized from
commercially available ethyl 2-(hydroxymethyl)acrylate 3 by a four-
step procedure in 79% overall yield.
Tos
1.1 equiv DIAD
1.1 equiv PPh3
Br
N
OH
Boc
1.1 equiv BocNHTos
THF, r.t., 24 h
COOEt
COOEt
4 (91%)
COOEt
2
3
TFA
Ref. 22
CH2Cl2, r.t., 1 h
17% over 3 steps
Tos
NH
Tos
NH
Br
Tos
N
1.5 equiv K2CO3
CH3CN, 60 °C, 2 h
1.1 equiv Br2
Br
COOEt
Br
CH2Cl2, r.t., 24 h
COOEt
5 (98%)
COOEt
6 (93%)
7 (95%)
Scheme 1. Synthesis of ethyl 2-(bromomethyl)-1-tosylaziridine-2-carboxylate 7.
It was envisioned that reduction of aziridine 7 with the appro-
priate reducing agent and, if necessary, subsequent oxidation of the
corresponding alcohol 8, would give b-bromo aldehyde 10. Azir-
idine-2-carboxaldehydes have recently proven to be good substrates
in reductive aminations for the introduction of an aminomethylene
imine 11a, the addition of 2 equiv of sodium cyanoborohydride did
not result in a 4-exo-tet-cyclization toward the corresponding 1,5-
diazaspiro[2.3]hexane. Instead, a ring transformation, similar to
an aza-Payne rearrangement, during which activated 2-(hydroxy-
methyl)aziridines are transformed into the corresponding epoxy
Table 1
Synthesis of 2-bromomethyl-1-tosylaziridine-2-carboxaldehyde 10
Tos
N
Tos
N
Tos
N
Tos
Reaction conditions
N
+
+
Br
Br
Br
Et2O
COOEt
OH
OH
O
H
7
8
9
10
Entry
Reducing agent
Temperature
Reaction time
Resulta,b
1
2
3
1 mol equiv LiAlH4
0.6 mol equiv LiAlH4
1 mol equiv LiAlH4
0
0
ꢁC
ꢁC
30 min
15 min
1 h
8 (36%)þ9 (41%)
7/8/9 2:2:1
10 (88%)
ꢀ78 ꢁC
a
Yields in parentheses indicate isolated yields after flash chromatography.
b
Ratio of reaction products determined by 1H NMR analysis of the crude reaction mixture.

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A. Zukauskaite et al. / Tetrahedron 69 (2013) 3437e3443
3439
amines under basic conditions,30 occurred (Scheme 2). This rear-
rangement involved regioselective ring opening of in situ formed
activated 2-(aminomethyl)aziridine 12a by intramolecular nucle-
ophilic substitution to afford aziridine 13a in 10% yield.
rearrangement involved ring opening of the intermediate 2-(ami-
nomethyl)aziridines (like 12a) by intramolecular nucleophilic sub-
stitution (Scheme 2). Subsequently, the synthesis of 1,5-diazaspiro
[2.3]hexanes 14 was completed by cyclization of the bromo amines
1) 1 equiv BnNH2
Tos
N
Tos
N
Tos
N
Tos
1 equiv HOAc
HN
=
MeOH, 50 °C, 4 h
Br
Br
Br
= NH
Br
2) 2 equiv NaCNBH3
MeOH, Δ, 15 h
O
N
Bn
N
Bn
13a (10%)
H
H
11a
Bn
H
10
12a
Scheme 2. Unexpected rearrangement of b-bromo aldehyde 10 to aziridine 13a.
Even though the desired azaspiro product was not formed, the
reaction outcome was promising, as after optimization of reaction
conditions, bromo amines 13 could be suitable substrates for
intramolecular ring closure under basic conditions. Therefore,
13 with 2 equiv of K2CO3 and heating at 60 ꢁC in acetonitrile for 24 h,
affording spiro compounds 14aed in 88e96% yield.
To further demonstrate the usefulness of the developed syn-
thetic procedure, the deprotection of the tosyl group of 1,5-
diazaspiro[2.3]hexane 14a was attempted (Scheme 4). Analogous
to the detosylation of a related 1,6-diazaspiro[3.3]heptane,6 tosyl-
amide 14a was treated with a large excess of Mg in methanol for
26 h at room temperature, leading to the formation of the desired
crude amine 15 without ring opening of the strained spirocyclic
system (LC-MS and NMR analysis). The 1H NMR spectrum of the
crude amine 15 showed the characteristic singlets for the protons of
the methylene function of the aziridine at 1.43 and 2.05 ppm, to-
gether with the partially overlapping signals of the methylene
protons of the azetidine and benzyl moiety in the range
3.16e3.71 ppm. The corresponding 13C NMR spectrum contained
signals of the aziridine methylene carbon, spiro-carbon, azetidine
methylene carbons and benzylic methylene carbon at 37.1, 40.9,
56.5, 61.4, and 59.2 ppm, respectively. Further efforts to isolate an
analytically pure product via column chromatography, or via pre-
cipitation as the corresponding oxalate salt,6 failed however.
several N-alkyl- and N-aryl-b-bromo imines 11 were prepared
through condensation of 2-bromomethyl-1-tosylaziridine-2-
carboxaldehyde 10 with 1.1e1.5 equiv of the corresponding amine
in CH2Cl2 at reflux in the presence of MgSO4 (Table 2).31 The
strategy chosen gave nearly quantitative amounts of imines 11 that
were obtained in high purity (imines 11bed). Only in case of benzyl
derivative 11a, the purity of the crude product was lower due to the
presence of excess unreacted benzylamine, which could be re-
moved in a subsequent step.
Table 2
Synthesis of (aziridin-2-yl)carboxaldimines 11
Tos
N
Tos
N
1.1-1.5 equiv RNH2
Br
Br
MgSO4, CH2Cl2, Δ, 2 h
O
N
R
H
10
H
11a-d
Bn
N
Bn
N
15 equiv Mg
Entry
R
Amine
Resulta,b
11a (97%)c
11b (95%)
10/11c 1:1
11c (96%)
11d (99%)
MeOH, 0 °C - r.t., 26 h
1
2
3
4
5
Bn
Allyl
i-Pr
i-Pr
c-Hex
1.1 equiv BnNH2
1.1 equiv allylNH2
1.1 equiv i-PrNH2
1.5 equiv i-PrNH2
1.1 equiv c-HexNH2
N
NH
Tos
a
14a
15 (89%)
a
Yield of crude product
a
Yields in parentheses indicate crude yields.
Scheme 4. Deprotection of the tosyl group of 1,5-diazaspiro[2.3]hexane 14a.
b
Ratio of reaction products determined by 1H NMR analysis of the crude reaction
mixture.
c
The crude imine 11a contained excess benzylamine.
3. Conclusion
Upon reduction of imines 11 with 1.1 equiv of NaBH4 in methanol
at reflux for 2 h, the rearranged amines 13aed were obtained in high
yields (85e90%) (Scheme 3). As discussed above, this heterocyclic
In conclusion, an efficient synthesis of 1,5-diazaspiro[2.3]hex-
anes, as new structurally challenging strained diazaspirocyclic
compounds, was developed starting from ethyl 2-(bromomethyl)-
Tos
N
R
N
R
N
2 equiv K2CO3
1.1 equiv NaBH4
Br
Br
CH3CN, 60 °C, 24 h
MeOH, Δ, 2h
N
N
R
NH
Tos
Tos
H
11a (R = Bn)
13a (90%)
13b (85%)
13c (88%)
13d (90%)
14a (88%)
11b (R = allyl)
11c (R = i-Pr)
11d (R = c-Hex)
14b (93%)
14c (96%)
14d (90%)
Scheme 3. Synthesis of 1,5-diazaspiro[2.3]hexanes 14.

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A. Zukauskaite et al. / Tetrahedron 69 (2013) 3437e3443
3440
1-tosylaziridine-2-carboxylate, the synthesis of which was opti-
mized. The key transformations in the developed short sequence
involved a chemoselective reduction of the functionalized ethyl 1-
150.7, 165.6. IR (neat, cmꢀ1):
y
y
C]O¼1726,
y
C]C¼1640,
O]S]O¼1169. MS (ES, pos. mode): m/z (%): 384 (MþHþ, 100).
tosylaziridine-2-carboxylate to the corresponding
hyde and an aza-Payne-type rearrangement occurring upon re-
duction of the subsequently formed -bromo aldimines leading to
non-activated 2-(aminomethyl)-2-(bromomethyl)aziridines. A fi-
nal base-mediated cyclization of the latter bromo amines gave ef-
ficient access to the new diazaspirocyclic system.
b
-bromo alde-
4.2.3. Synthesis of ethyl 2-{[(N-toluene-4-sulfonyl)amino]methyl}-
acrylate 5. Ethyl 2-({(N-tert-butoxycarbonyl)[N-toluene-4-sulfonyl]
amino}methyl)prop-2-enoate 4 (1935 mg, 5.1 mmol) was dissolved
in CH2Cl2 (36 mL), and trifluoroacetic acid (15 mL) was slowly added
at 0 ꢁC, and then the reaction mixture was warmed up to room
temperature. After 1 h, the reaction mixture was cooled down to
b
0
ꢁC, quenched by slowly adding aqueous saturated NaHCO3 and
4. Experimental
4.1. General
extracted with CH2Cl2 (3ꢂ15 mL). Drying of the combined organic
extracts with MgSO4, filtration of the drying agent, evaporation of
the solvent under reduced pressure and purification by flash chro-
matography on silica gel (petroleum ether/EtOAc 7:3) afforded pure
title compound 5. Note: the sufficiently pure crude product can also
be used in the next step without purification.
Flame-dried glassware was used for all non-aqueous reactions.
Commercially available solvents and reagents were purchased from
common chemical suppliers and used without further purification,
unless stated otherwise. Tetrahydrofuran and diethyl ether were
distilled from sodium and sodium benzophenone ketyl. Dichloro-
methane was distilled over calcium hydride. Methanol was dried
with magnesium and distilled. Flash chromatography was carried
out using a glass column filled with silica gel (Acros, particle size
0.035e0.070 mm, pore diameter ca. 6 nm). TLC was performed on
glass-backed silica plates (Merck Kieselgel 60 F254, precoated
0.25 mm), which were developed using standard visualization
techniques or agents: UV fluorescence (254 nm and 366 nm), col-
4.2.4. Ethyl 2-{[(N-toluene-4-sulfonyl)amino]methyl}acrylate 5. Orange
oil, yield 98%, Rf¼0.27 (petroleum ether/EtOAc 7:3). 1H NMR
(300 MHz, CDCl3):
d
1.26 (3H, t, J¼7.2 Hz), 2.43 (3H, s), 3.81 (2H, d,
J¼6.6 Hz), 4.16 (2H, q, J¼7.2 Hz), 5.02 (1H, t, J¼6.6 Hz), 5.76 (1H, d,
J¼0.7 Hz), 6.17 (1H, d, J¼0.7 Hz), 7.29 (2H, d, J¼8.3 Hz), 7.72 (2H, d,
J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 14.1, 21.5, 44.7, 61.1, 127.1, 127.7,
129.7, 135.5, 137.2, 143.5, 165.8. IR (neat, cmꢀ1): yNH¼3277,
y
C]O¼1708,
y
C]C¼1636 (weak), O]S]O¼1155. MS (ES, pos. mode):
y
m/z (%): 284 (MþHþ, 100).
oring with iodine vapor, permanganate solution/D.
1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were run with a Jeol
Eclipse FT 300 NMR spectrometer at room temperature. The com-
pounds were diluted in deuterated chloroform, quoted in parts per
4.2.5. Synthesis of ethyl 2,3-dibromo-2-[(tosylamino)methyl]prop-
anoate 6. To a solution of ethyl 2-{[(N-toluene-4-sulfonyl)amino]-
methyl}acrylate 5 (3320 mg, 11.7 mmol) in CH2Cl2 (230 mL),
a solution of Br2 (2065 mg, 0.67 mL, 12.9 mmol) in CH2Cl2 (100 mL)
was added dropwise at 0 ꢁC and the reaction mixture was left stirring
upon warming to room temperature for 24 h. Subsequently, the
resulting reaction mixture was poured into saturated NaHCO3 solu-
tion and extracted with EtOAc (3ꢂ50 mL). Drying of the combined
organic extracts with MgSO4, filtration of the drying agent, evapo-
ration of the solvent under reduced pressure and purification by flash
chromatography on silica gel (petroleum ether/EtOAc 7:3) afforded
pure title compound 6.
million (ppm) and referenced to tetramethylsilane (TMS,
d
¼0) or
the appropriate residual solvent peak. IR spectra were obtained
from a Perkin Elmer Spectrum BX spectrometer from samples in
neat form with an ATR (Attenuated Total Reflectance) accessory.
Only selected absorbances (ymax/cmꢀ1) are reported. LC-MS was
performed with Agilent 1100 Series VL (ES, 4000 V) equipment or
Agilent 1100 Series SL (ES, 4000 V) equipment, performing
electron-spray ionization at 4 kV (positive mode) or 3.5 kV (nega-
tive mode) and fragmentation at 70 eV, with only molecular ions
(MþHþ), and major peaks being reported with intensities quoted as
percentage of the base peak, using either an LC-MS coupling or
a direct inlet system. HRMS analysis was performed using an Agi-
lent 1100 series HPLC coupled to an Agilent 6220 TOF-Mass Spec-
trometer equipped with ESI/APCI-multimode source. Melting
4.2.6. Ethyl 2,3-dibromo-2-{[(toluene-4-sulfonyl)amino]methyl}prop-
anoate 6. Pink oil, yield 93%, Rf¼0.40 (petroleum ether/EtOAc 7:3).
1H NMR (300 MHz, CDCl3):
d
1.32 (3H, t, J¼7.2 Hz), 2.44 (3H, s), 3.61
(1H, dd, J¼14.3 Hz, 5.2 Hz), 3.71 (1H, dd, J¼14.3 Hz, 9.2 Hz), 3.90 (1H,
d, J¼10.3 Hz), 4.07 (1H, d, J¼10.3 Hz), 4.27 (1H, dq, J¼10.7 Hz, 7.2 Hz),
4.31 (1H, dq, J¼10.7 Hz, 7.2 Hz), 5.07 (1H, dd, J¼9.2, 5.2 Hz), 7.34 (2H,
€
points of crystalline compounds were measured with a Buchi 540
apparatus and were not corrected.
d, J¼8.3 Hz), 7.79 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 13.8,
4.2. Synthetic procedures
21.6, 33.2, 47.5, 58.7, 63.2, 127.2, 129.9, 136.5, 144.0, 167.2. IR (neat,
cmꢀ1): yNH¼3279,
y
C]O¼1735, O]S]O¼1155. MS (ES, pos. mode):
y
4.2.1. Synthesis of ethyl 2-({(N-tert-butoxycarbonyl)[N-toluene-4-
sulfonyl]amino}methyl)prop-2-enoate 4. Ethyl 2-(hydroxymethyl)-
acrylate 3 (1470 mg, 11.31 mmol), triphenylphosphine (3259 mg,
12.44 mmol) and BocNHTos (3360 mg, 12.44 mmol) were dissolved
in dry THF (110 mL). Diisopropyl azodicarboxylate (2512 mg,
12.44 mmol) was slowly added at 0 ꢁC and the reaction mixture was
stirred at room temperature for 24 h. Evaporation of the solvent
and purification by flash chromatography on silica gel (petroleum
ether/EtOAc 9:1) afforded pure compound 4.
m/z (%): 442/444/446 (MþHþ, 100).
4.2.7. Synthesis of ethyl 2-(bromomethyl)-1-(toluene-4-sulfonyl)azir-
idine-2-carboxylate 7. To a solution of ethyl 2,3-dibromo-2-[(tosyl-
amino)methyl]propanoate 6 (618 mg, 1.39 mmol) in CH3CN (30 mL)
was added powdered K2CO3 (289 mg, 2.09 mmol) and the reaction
mixture was stirred at 60 ꢁC for 2 h. Then the solvent was removed
under reduced pressure and Et2O (30 mL) was added. The resulting
solution was filtered and the filter cake was washed with small
portions of Et2O. Evaporation of the solvent under reduced pressure
and purification by flash chromatography on silica gel (petroleum
ether/Et2O 7:3) afforded pure title compound 7.
4.2.2. Ethyl 2-({(N-tert-butoxycarbonyl)[N-toluene-4-sulfonyl]amino}
methyl)prop-2-enoate 4. Colorless viscous oil, yield 91%, Rf¼0.31
(petroleum ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3):
d 1.31 (3H,
t, J¼7.2 Hz), 1.35 (9H, s), 2.45 (3H, s), 4.24 (2H, q, J¼7.2 Hz), 4.72 (2H,
dd, J¼1.7, 1.7 Hz), 5.75 (1H, t, J¼1.7 Hz), 6.37 (1H, t, J¼1.7 Hz), 7.31
(2H, d, J¼8.3 Hz), 7.81 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
4.2.8. Ethyl 2-(bromomethyl)-1-(toluene-4-sulfonyl)aziridine-2-
carboxylate 7. Yellow oil, yield 95%, Rf¼0.52 (petroleum ether/
EtOAc 7:3). 1H NMR (300 MHz, CDCl3):
(3H, s), 2.75 (1H, s), 3.19 (1H, d, J¼1.1 Hz), 3.70 (1H, d, J¼10.5 Hz),
d
1.34 (3H, t, J¼7.2 Hz), 2.45
d
14.3, 21.8, 27.9, 47.3, 61.1, 84.7,124.9,128.3,129.4,136.4,137.1,144.6,

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A. Zukauskaite et al. / Tetrahedron 69 (2013) 3437e3443
3441
4.23 (1H, dd, J¼10.5 Hz, 1.1 Hz), 4.30 (2H, q, J¼7.2 Hz), 7.34 (2H, d,
representative. To a slurry of MgSO4 (480 mg) in CH2Cl2 (10 mL) was
added benzylamine (57 mg, 0.53 mmol) followed by 2-bromomethyl-
1-(p-toluene-4-sulfonyl)aziridine-2-carboxaldehyde 10 (154 mg,
0.48 mmol). The resulting suspension was refluxed for 2 h and cooled
to room temperature. Then, the reaction mixture was filtered and the
filter cake was washed with small portions of CH2Cl2. The solvent was
evaporated under reduced pressure to afford the title compound 11a,
which was used in the next step without further purification.
J¼8.3 Hz), 7.83 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 14.0,
21.8, 29.3, 38.9, 49.9, 63.0, 127.9, 129.8, 136.1, 145.1, 165.5. IR (neat,
cmꢀ1):
y
C]O¼1740, O]S]O¼1162. MS (ES, pos. mode): m/z (%):
y
362/364 (MþHþ, 100).
4.2.9. Synthesis of [2-bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-
yl]-methanol 8 and [2-methyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-
methanol 9. Ethyl 2-bromomethyl-1-(toluene-4-sulfonyl)aziridine-
2-carboxylate 7 (140 mg, 0.39 mmol) was dissolved in dry Et2O (5 mL),
after which LiAlH4 (15 mg, 0.39 mmol) was added in small portions at
0 ꢁC. The resulting mixture was stirred at 0 ꢁC for 30 min. Afterward,
water was added dropwise and the quenched reaction mixture was
extracted with Et2O (3ꢂ10 mL). Drying of the combined organic ex-
tracts with MgSO4, filtration of the drying agent, evaporation of the
solvent under reduced pressure and purification by flash chroma-
tography on silica gel (petroleum ether/EtOAc 3:1e1:1) afforded pure
4.2.15. [2-Bromomethyl-1-(toluene-4-sulfonyl)-aziridin-2-ylmethylene]-
benzylamine 11a. Light yellow oil, yield 97% (75% purity), Rf¼0.33
(petroleum ether/EtOAc 4:1) 1H NMR (300 MHz, CDCl3):
d 2.44 (3H,
s), 2.79 (1H, s), 3.19 (1H, s), 3.58 (1H, d, J¼10.5 Hz), 4.11 (1H, d,
J¼10.5 Hz), 4.78 (1H, d, J¼14.3 Hz), 4.79 (1H, d, J¼14.3 Hz), 7.25e7.38
(7H, m), 7.81 (2H, d, J¼8.3 Hz), 7.83 (1H, s).13C NMR (75 MHz, CDCl3):
d
21.8, 31.5, 40.4, 52.0, 64.4, 127.2, 127.8, 128.0, 128.6, 129.8, 136.0,
138.3,144.9,158.0. IR (neat, cmꢀ1):
y
CH]N¼1659, O]S]O¼1160. MS
y
[2-bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-methanol
8
(ES, pos. mode): m/z (%): 407/409 (MþHþ, 100).
and [2-methyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-methanol 9.
Caution: strict safety measurements have to be applied for LiAlH4-
promoted reactions to avoid risk of violent reactions or explosions.
4.2.16. [2-Bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-ylmethylene]-
allylamine 11b. Yellow oil, yield 95%, Rf¼0.63 (petroleum ether/
EtOAc 1:1). 1H NMR (300 MHz, CDCl3):
d 2.45 (3H, s), 2.77 (1H, s),
4.2.10. [2-Bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-metha-
3.16 (1H, s), 3.58 (1H, d, J¼10.5 Hz), 4.09 (1H, d, J¼10.5 Hz),
4.12e4.28 (2H, m), 5.17 (1H, dq, J¼10.5, 1.7 Hz), 5.24 (1H, dq, J¼17.1,
1.7 Hz), 6.00 (1H, ddt, J¼17.1, 10.5, 5.5 Hz), 7.34 (2H, d, J¼8.3 Hz),
nol 8. White crystals (mp¼126.4e126.6 ꢁC), yield 36%, Rf¼0.52
(petroleum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3):
d 2.46 (3H,
s), 2.50 (1H, s), 2.72 (1H, dd, J¼9.9, 5.0 Hz), 2.85 (1H, s), 3.27 (1H, dd,
J¼10.5,1.1 Hz), 4.00 (1H, ddd, J¼13.2, 5.0,1.1 Hz), 4.13 (1H, dd, J¼10.5,
1.1 Hz), 4.39 (1H, dd, J¼13.2, 9.9 Hz), 7.35 (2H, d, J¼8.3 Hz), 7.83 (2H,
7.71 (1H, s), 7.82 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 21.8,
31.4, 40.4, 52.0, 62.7, 116.6, 127.8, 129.8, 134.8, 136.1, 144.9, 158.0. IR
(neat, cmꢀ1):
y
CH]N¼1660,
y
C]C¼1642, O]S]O¼1161. MS (ES,
y
d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d
21.8, 32.4, 39.3, 54.0, 61.1,
pos. mode): m/z (%): 357/359 (MþHþ, 100).
127.6,129.9,136.4,144.9. IR (neat, cmꢀ1): yOH¼3526,
O]S]O¼1154.
y
MS (ES, pos. mode): m/z (%): 320/322 (MþHþ, 100). HRMS Calcd for
C11H14BrNO3S: 319.9951 [MþH]þ. Found: 319.9954 [MþH]þ.
4.2.17. [2-Bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-ylmethylene]-
isopropylamine 11c. Yellow oil, yield 96%, Rf¼0.36 (petroleum ether/
EtOAc 4:1) 1H NMR (300 MHz, CDCl3):
d
1.20 (6H, d, J¼6.1 Hz), 2.44
4.2.11. [2-Methyl-1-(toluene-4-sulfonyl)aziridin-2-yl]-methanol
9. Yellow oil, yield 41%, Rf¼0.31 (petroleum ether/EtOAc 1:1). All
spectroscopic data were in good agreement with reported data.32 IR
(3H, s), 2.73 (1H, s), 3.14 (1H, s), 3.53 (1H, d, J¼10.5 Hz), 3.55 (1H,
sept, J¼6.1 Hz), 4.08 (1H, d, J¼10.5 Hz), 7.33 (2H, d, J¼8.3 Hz), 7.71
(1H, s), 7.82 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 21.8, 23.6,
(neat, cmꢀ1): yOH¼3501,
yO]S]O¼1154. MS (ES, pos. mode): m/z
23.7, 31.9, 40.3, 52.0, 61.2, 127.7, 129.8, 136.3, 144.8, 153.8. IR (neat,
(%): 242 (MþHþ, 100).
cmꢀ1):
y
CH]N¼1656, O]S]O¼1161. MS (ES, pos. mode): m/z (%):
y
359/361 (MþHþ, 100).
4.2.12. Synthesis of 2-bromomethyl-1-(toluene-4-sulfonyl)aziridine-
2-carboxaldehyde 10. Ethyl 2-bromomethyl-1-(toluene-4-sulfonyl)-
aziridine-2-carboxylate 7 (400 mg, 1.1 mmol) was dissolved in dry
Et2O (40 mL), after which LiAlH4 (42 mg, 1.1 mmol) was added in
small portions at ꢀ78 ꢁC. The resulting mixture was stirred at
ꢀ78 ꢁC for 1 h. Afterward, water was added dropwise and the
quenched reaction mixture was extracted with Et2O (3ꢂ20 mL).
Drying of the combined organic extracts with MgSO4, filtration of
the drying agent, evaporation of the solvent in vacuo and purifi-
cation of the residue by flash chromatography on silica gel (pe-
troleum ether/EtOAc 3:2) afforded pure title compound 10.
Caution: strict safety measurements have to be applied for LiAlH4-
promoted reactions to avoid risk of violent reactions or explosions.
4.2.18. [2-Bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-ylmethylene]-
cyclohexylamine 11d. Yellow oil, yield 99%, Rf¼0.63 (petroleum
ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3):
d 1.14e1.86 (10H, m),
2.44 (3H, s), 2.73 (1H, s), 3.15 (1H, s), 3.17e3.30 (1H, m), 3.52 (1H, d,
J¼10.5 Hz), 4.08 (1H, d, J¼10.5 Hz), 7.33 (2H, d, J¼8.3 Hz), 7.73 (1H,
s), 7.82 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 21.8, 24.5, 25.7,
32.0, 33.7, 33.9, 40.3, 52.1, 69.0, 127.7, 129.8, 136.4, 144.8, 154.0. IR
(neat, cmꢀ1):
y
CH]N¼1656, O]S]O¼1161. MS (ES, pos. mode): m/z
y
(%): 399/401 (MþHþ, 100).
4.2.19. Synthesis of rearranged aziridines 13. The synthesis of N-[1-
benzyl-2-(bromomethyl)aziridin-2-ylmethyl]-4-methylbenzenesul-
fonamide 13a is representative. [2-Bromomethyl-1-(toluene-4-
sulfonyl)aziridin-2-ylmethylene]benzylamine 11a (197 mg, 0.48
mmol), dissolved in MeOH (10 mL) and cooled down to 0 ꢁC, was
treated with NaBH4 (20 mg, 0.53 mmol) in small portions, and the
resulting reaction mixture was stirred at reflux for 2 h. The reaction
mixture was then cooled to room temperature and concentrated to 2/
3 of the initial volume. Ice was added and the product was extracted
with CH2Cl2 (3ꢂ10 mL). The combined organic extracts were dried
with MgSO4, filtered and evaporated in vacuo. The residue was pu-
rified by flash chromatography on silica gel (petroleum ether/EtOAc
3:1e2:1) to afford pure compound 13a.
4.2.13. 2-Bromomethyl-1-(toluene-4-sulfonyl)aziridine-2-carboxalde-
hyde 10. White crystals (mp¼112.9e113.1 ꢁC), yield 88%, Rf¼0.45
(petroleum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3):
d 2.47 (3H,
s), 2.91 (1H, s), 3.37 (1H, s), 3.65 (1H, d, J¼11.0 Hz), 3.83 (1H, d,
J¼11.0 Hz), 7.38 (2H, d, J¼8.3 Hz), 7.86 (2H, d, J¼8.3 Hz), 9.38 (1H, s).
13C NMR (75 MHz, CDCl3):
d 21.8, 27.0, 40.0, 54.4, 127.9, 130.0, 135.3,
145.5, 191.7. IR (neat, cmꢀ1):
y
C]O¼1726, O]S]O¼1162. MS (ES,
y
pos. mode): m/z (%): 318/320 (MþHþ, 100). HRMS Calcd for
C11H12BrNO3S: 317.9794 [MþH]þ. Found: 317.9801 [MþH]þ.
4.2.14. Synthesis of 2-bromomethyl-1-(toluene-4-sulfonyl)aziridin-2-
yl-carboxaldimines 11. The synthesis of N-benzyl 2-bromomethyl-1-
4.2.20. N-(1-Benzyl-2-(bromomethyl)aziridin-2-ylmethyl)-4-methyl-
(p-toluene-4-sulfonyl)aziridin-2-yl-carboxaldimine
11a
is
benzenesulfonamide 13a. Yellow oil, yield 90%, Rf¼0.15 (petroleum

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A. Zukauskaite et al. / Tetrahedron 69 (2013) 3437e3443
3442
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3):
d
1.53 (1H, s), 2.12 (1H,
59.4, 127.2, 127.4, 128.5, 128.6, 130.0, 131.4, 138.3, 144.3. IR (neat,
s), 2.42 (3H, s), 3.11 (1H, dd, J¼12.9, 3.9 Hz), 3.24 (1H, dd, J¼12.9,
7.2 Hz), 3.41 (1H, d, J¼13.2 Hz), 3.51 (1H, d, J¼11.3 Hz), 3.76 (1H, d,
J¼11.3 Hz), 4.01 (1H, d, J¼13.2 Hz), 5.00 (1H, br s), 7.17e7.40 (7H, m),
cmꢀ1):
y
O]S]O¼1156. MS (ES, pos. mode): m/z (%): 329 (MþHþ,
100). HRMS Calcd for C18H20N2O2S: 329.1318 [MþH]þ. Found:
329.1332 [MþH]þ.
7.72 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 21.7, 32.6, 39.2,
41.8, 46.4, 56.1, 127.2, 127.5, 127.9, 128.7, 129.9, 136.7, 138.7, 143.6. IR
4.2.26. 1-Allyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane
(neat, cmꢀ1): yNH¼3279,
yO]S]O¼1157. MS (ES, pos. mode): m/z
14b. Light yellow crystals (56.0e56.2 ꢁC), yield 93%, Rf¼0.25 (Et2O
(%): 409/411 (MþHþ, 100).
100%). 1H NMR (300 MHz, CDCl3):
d 1.23 (1H, s), 1.92 (1H, s), 2.48
(3H, s), 2.66 (1H, dd, J¼14.9, 5.0 Hz), 2.75 (1H, ddt, J¼14.9, 5.0,
1.7 Hz), 3.93 (1H, d, J¼8.8 Hz), 3.97 (1H, d, J¼8.8 Hz), 4.04 (1H, d,
J¼8.8 Hz), 4.06 (1H, d, J¼8.8 Hz), 4.97 (1H, dq, J¼10.5, 1.7 Hz), 5.06
(1H, dq, J¼17.8, 1.7 Hz), 5.72 (1H, ddt, J¼17.8, 10.5, 5.0 Hz), 7.39 (2H,
4.2.21. N-(1-Allyl-2-(bromomethyl)aziridin-2-ylmethyl)-4-methyl-
benzenesulfonamide 13b. Colorless oil, yield 85%, Rf¼0.44 (petro-
leum ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3):
d 1.40 (1H, s),
2.07 (1H, s), 2.43 (3H, s), 2.87 (1H, dd, J¼14.3, 6.1 Hz), 3.09 (1H, dd,
J¼13.2, 4.4 Hz), 3.22 (1H, dd, J¼13.2, 7.2 Hz), 3.46 (1H, dd, J¼14.3,
5.5 Hz), 3.51 (1H, d, J¼11.6 Hz), 3.71 (1H, d, J¼11.6 Hz), 5.00e5.28
(3H, m), 5.81e5.95 (1H, m), 7.31 (2H, d, J¼8.3 Hz), 7.74 (2H, d,
d, J¼8.3 Hz), 7.76 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 21.7,
36.0, 38.0, 54.1, 57.3, 59.4, 116.3, 128.6, 129.9, 131.5, 134.5, 144.4. IR
(neat, cmꢀ1):
y
C]C¼1643, O]S]O¼1159. MS (ES, pos. mode): m/z
y
(%): 279 (MþHþ, 100). HRMS Calcd for C14H18N2O2S: 279.1162
J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 21.6, 32.4, 38.8, 41.6, 46.5,
[MþH]þ. Found: 279.1172 [MþH]þ.
54.8, 116.8, 127.2, 129.9, 135.0, 136.8, 143.6. IR (neat, cmꢀ1):
yNH¼3276,
y
C]C¼1644,
y
O]S]O¼1156. MS (ES, pos. mode): m/z (%):
4.2.27. 1-Isopropyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane
359/361 (MþHþ, 100).
14c. Light yellow amorphous solid, yield 96%, Rf¼0.25 (Et2O 100%).
1H NMR (300 MHz, CDCl3):
d
0.83 (3H, d, J¼6.1 Hz), 1.01 (3H, d,
4.2.22. N-(2-Bromomethyl-1-isopropylaziridin-2-ylmethyl)-4-methyl-
J¼6.1 Hz),1.18 (1H, s), 1.46 (1H, sept, J¼6.1 Hz), 1.84 (1H, s), 2.46 (3H,
s), 3.91 (1H, d, J¼8.8 Hz), 3.95 (1H, d, J¼8.8 Hz), 4.05 (2H, s), 7.40
(2H, d, J¼8.3 Hz), 7.78 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
benzenesulfonamide 13c. Yellow oil, yield 88%, Rf¼0.40 (petroleum
ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3):
d 1.08 (3H, d,
J¼6.1 Hz), 1.09 (3H, d, J¼6.1 Hz), 1.40 (1H, s), 1.91 (1H, s), 2.24 (1H,
sept, J¼6.1 Hz), 2.43 (3H, s), 2.88 (1H, dd, J¼12.7, 5.0 Hz), 3.31
(1H, dd, J¼12.7, 5.5 Hz), 3.48 (1H, d, J¼11.0 Hz), 3.71 (1H, d,
J¼11.0 Hz), 4.94 (1H, br s), 7.31 (2H, d, J¼7.7 Hz), 7.74 (2H, d,
d 21.7, 22.1, 22.4, 35.1, 38.0, 54.1, 55.1, 59.9, 128.6, 129.9, 131.3, 144.4.
IR (neat, cmꢀ1):
y
O]S]O¼1155. MS (ES, pos. mode): m/z (%): 281
(MþHþ, 100). HRMS Calcd for C14H20N2O2S: 281.1318 [MþH]þ.
Found: 281.1324 [MþH]þ.
J¼7.7 Hz). 13C NMR (75 MHz, CDCl3):
d 21.6, 22.6, 23.6, 31.8, 37.7,
43.0, 47.0, 52.5, 127.2, 129.8, 136.8, 143.6. IR (neat, cmꢀ1):
4.2.28. 1-Cyclohexyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hex-
yNH¼3284,
y
O]S]O¼1157. MS (ES, pos. mode): m/z (%): 361/363
ane 14d. Yellow oil, yield 90%, Rf¼0.11 (petroleum ether/EtOAc 1:1).
(MþHþ, 100).
1H NMR (300 MHz, CDCl3):
d 0.80e1.75 (11H, m), 1.17 (1H, s), 1.82
(1H, s), 2.47 (3H, s), 3.93 (1H, d, J¼8.8 Hz), 3.96 (1H, d, J¼8.8 Hz),
4.2.23. N-(2-Bromomethyl-1-cyclohexylaziridin-2-ylmethyl)-4-methyl-
4.00 (1H, d, J¼8.8 Hz), 4.05 (1H, d, J¼8.8 Hz), 7.39 (2H, d, J¼8.3 Hz),
benzenesulfonamide 13d. Yellow oil, yield 90%, Rf¼0.31 (petroleum
7.78 (2H, d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d 21.7, 24.3, 24.6,
25.8, 32.1, 33.2, 34.3, 37.5, 54.2, 60.1, 62.7, 128.7, 129.9, 131.3, 144.4.
ether/EtOAc 1:1). 1H NMR (300 MHz, CDCl3):
d
1.09e1.37 (4H,
m), 1.42 (1H, s), 1.52e1.88 (7H, m), 1.90 (1H, s), 2.43 (3H, s),
2.84 (1H, dd, J¼12.7, 5.5 Hz), 3.33 (1H, dd, J¼12.7, 6.1 Hz), 3.46
(1H, d, J¼11.0 Hz), 3.72 (1H, d, J¼11.0 Hz), 4.88 (1H, br s), 7.31
(2H, d, J¼8.3 Hz), 7.74 (2H, d, J¼8.3 Hz). 13C NMR
IR (neat, cmꢀ1):
y
O]S]O¼1160. MS (ES, pos. mode): m/z (%): 321
(MþHþ, 100). HRMS Calcd for C17H24N2O2S: 321.1631 [MþH]þ.
Found: 321.1636 [MþH]þ.
(75 MHz, CDCl3):
d
21.6, 24.5, 24.8, 25.8, 32.0, 32.8, 34.2,
4.2.29. Detosylation of 1,5-diazaspiro[2.3]hexane 14a. A mixture of
magnesium powder (74 mg, 3.0 mmol) in dry MeOH (1 mL) was
stirred at room temperature for 10 min. The reaction mixture was
cooled down to 0 ꢁC and a solution of 1-benzyl-5-(toluene-4-
sulfonyl)-1,5-diazaspiro[2.3]hexane 14a (100 mg, 0.3 mmol) in
dry MeOH (0.6 mL) was added dropwise. Subsequently, the
resulting suspension was allowed to warm slowly to room tem-
perature. The reaction was monitored by LC-MS and after 22 h,
a second portion of magnesium powder (37 mg, 1.5 mmol) was
added. The suspension was stirred for another 4 h at room
temperature. Subsequently, the reaction mixture was concentrated
under reduced pressure to afford a gray suspension. This was
suspended in CH2Cl2 (10 mL), filtered and the filter cake was
washed with small portions of CH2Cl2. The solvent was evaporated
under reduced pressure to afford the detosylated compound 15.
Caution: strict safety measurements have to be applied for Mg-
promoted reactions to avoid risk of violent reactions, fires or
explosions.
37.3, 42.5, 47.0, 60.3, 127.2, 129.8, 136.8, 143.6. IR (neat,
cmꢀ1): yNH¼3280,
O]S]O¼1157. MS (ES, pos. mode): m/z (%):
y
401/403 (MþHþ, 100).
4.2.24. Synthesis of 1,5-diazaspiro[2.3]hexanes 14. The synthesis of
1-benzyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane 14a is
representative. To a solution of N-(1-benzyl-2-(bromomethyl)azir-
idin-2-ylmethyl)-4-methylbenzenesulfonamide 13a (90 mg,
0.22 mmol) in CH3CN (9 mL) was added powdered K2CO3 (46 mg,
0.33 mmol). The reaction mixture was stirred at 60 ꢁC for 24 h. Then
the solvent was removed under reduced pressure and Et2O (10 mL)
was added. The mixture was filtered and the filter cake was washed
with small portions of Et2O. The combined filtrates were evapo-
rated under reduced pressure and the residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc 4:1e1:1) to
afford compound 14a.
4.2.25. 1-Benzyl-5-(toluene-4-sulfonyl)-1,5-diazaspiro[2.3]hexane
14a. Yellow solid (120.6e120.8 ꢁC), yield 88%, Rf¼0.09 (petroleum
4.2.30. 1-Benzyl-1,5-diazaspiro[2.3]hexane 15. Colorless oil, yield of
crude product 89%, Rf¼0.40 (CH2Cl2/MeOH 9:1). All spectroscopic
data were obtained from the crude product. 1H NMR (300 MHz,
ether/EtOAc 4:1). 1H NMR (300 MHz, CDCl3):
d 1.36 (1H, s), 1.97 (1H,
s), 2.46 (3H, s), 3.18 (1H, d, J¼13.8 Hz), 3.36 (1H, d, J¼13.8 Hz), 3.95
(1H, d, J¼8.8 Hz), 4.00 (1H, d, J¼8.8 Hz), 4.07 (1H, d, J¼8.8 Hz), 4.12
(1H, d, J¼8.8 Hz), 7.15e7.30 (5H, m), 7.33 (2H, d, J¼8.3 Hz), 7.72 (2H,
CDCl3):
J¼13.8 Hz), 3.46e3.55 (3H, m), 3.66e3.71 (2H, m), 7.20e7.40 (5H,
m). 13C NMR (75 MHz, CDCl3):
37.1, 40.9, 56.5, 59.2, 61.4, 126.9,
d 1.43 (1H, s), 1.81 (1H, br s), 2.05 (1H, s), 3.18 (1H, d,
d, J¼8.3 Hz). 13C NMR (75 MHz, CDCl3):
d
21.8, 36.4, 38.6, 54.3, 58.9,
d

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A. Zukauskaite et al. / Tetrahedron 69 (2013) 3437e3443
3443
127.7, 128.4, 139.4. IR (neat, cmꢀ1): yNH¼3365. MS (ES, pos. mode):
m/z (%): 175 (MþHþ, 100).
10. Sippy, K. B.; Anderson, D. J.; Bunnelle, W. H.; Hutchins, C. W.; Schrimpf, M. R.
Bioorg. Med. Chem. Lett. 2009, 19, 1682e1685.
11. Smyth, M. S.; Rose, J.; Mehrotra, M. M.; Heath, J.; Ruhter, G.; Schotten, T.;
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Acknowledgements
The authors are indebted to the Research Foundation-Flanders
(FWO-Flanders), Ghent University (BOF), the Lithuanian State
Studies Foundation, the Research Council of Lithuania and Kaunas
University of Technology for financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.02.065.
These data include MOL files and Intake’s of the most important
compounds described in this article.
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