Synthesis of 2-amino-3-arylpropan-1-ols and 1-(2,3-diaminopropyl)-1,2,3- triazoles and evaluation of their antimalarial activity

Article abstract of DOI:10.3762/bjoc.7.205

A variety of 2-amino-3-arylpropan-1-ols, anti-2-amino-3-aryl-3- methoxypropan-1-ols and anti-2-amino-1-arylpropan-1,3-diols were prepared selectively through elaboration of trans-4-aryl-3-chloro-β-lactams. In addition, a number of 2-(azidomethyl)-aziridines was converted into novel 2-[(1,2,3-triazol-1-yl)methyl]aziridines by Cu(I)-catalyzed azide-alkyne cycloaddition, followed by microwave-assisted, regioselective ring opening by dialkylamine towards 1-(2,3-diaminopropyl)-1,2,3-triazoles. Although most of these compounds exhibited weak antiplasmodial activity, six representatives showed moderate antiplasmodial activity against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with IC ₅₀-values of <25 μM.

Full text of DOI:10.3762/bjoc.7.205

Synthesis of 2-amino-3-arylpropan-1-ols and
1-(2,3-diaminopropyl)-1,2,3-triazoles and
evaluation of their antimalarial activity
Matthias D’hooghe*1, Stéphanie Vandekerckhove1, Karen Mollet1,§,
Karel Vervisch1, Stijn Dekeukeleire1,§, Liesbeth Lehoucq1,
Carmen Lategan2, Peter J. Smith2, Kelly Chibale3 and Norbert De Kimpe*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1745–1752.
1Department of Sustainable Organic Chemistry and Technology,
Faculty of Bioscience Engineering, Ghent University, Coupure Links
653, B-9000 Ghent, Belgium, 2Medical School, University of Cape
Town, K45, OMB, Groote Schuur Hospital, Observatory, 7925, South
Africa and 3Department of Chemistry and Institute of Infectious
Disease & Molecular Medicine, University of Cape Town,
Rondebosch 7701, South Africa
doi:10.3762/bjoc.7.205
Received: 28 September 2011
Accepted: 28 November 2011
Published: 30 December 2011
Associate Editor: J. N. Johnston
Email:
© 2011 D’hooghe et al; licensee Beilstein-Institut.
License and terms: see end of document.
Matthias D’hooghe* - matthias.dhooghe@UGent.be;
Norbert De Kimpe* - norbert.dekimpe@UGent.be
* Corresponding author
§ Aspirant of the “Research Foundation – Flanders” (FWO-Vlaan-
deren)
Keywords:
aminopropanes; antimalarial activity; aziridines; β-lactams; ring
opening
Abstract
A variety of 2-amino-3-arylpropan-1-ols, anti-2-amino-3-aryl-3-methoxypropan-1-ols and anti-2-amino-1-arylpropan-1,3-diols
were prepared selectively through elaboration of trans-4-aryl-3-chloro-β-lactams. In addition, a number of 2-(azidomethyl)-
aziridines was converted into novel 2-[(1,2,3-triazol-1-yl)methyl]aziridines by Cu(I)-catalyzed azide-alkyne cycloaddition, fol-
lowed by microwave-assisted, regioselective ring opening by dialkylamine towards 1-(2,3-diaminopropyl)-1,2,3-triazoles. Although
most of these compounds exhibited weak antiplasmodial activity, six representatives showed moderate antiplasmodial activity
against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with IC50-values of ≤25 μM.
Introduction
Malaria remains a major issue in health control, especially in [1]. Despite recent advances in the development of a vaccine
developing countries. This disease affects 40% of the global against malaria, chemotherapy remains the most viable alter-
population, causing an annual mortality of one million people native towards treatment of the disease [2]. In light of the rapid
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Beilstein J. Org. Chem. 2011, 7, 1745–1752.
emergence of multiple drug resistance to clinically established pounds with diverse synthetic and biological applications. In
antimalarial drugs, however, there is a compelling need to intro- previous works, we have elaborated the synthetic potential of
duce new chemicals that can overcome this resistance. In 2007, 3-chloroazetidin-2-ones with a focus on stereoselectivity, thus
nitrogen-analogues of glycerol, which have a long-standing providing convenient entries into, e.g., aziridines, azetidines and
tradition in medicine as β-blockers, were introduced as a novel β-aminoalcohols [28-31]. In continuation of our interest in the
class of antimalarials [3]. Prior to this, the well known use of functionalized β-lactams as synthons for further elabo-
β-blocker propranolol was shown to inhibit infection of erythro- ration, racemic trans-4-aryl-3-chloro-β-lactams 5 were prepared
cytes by P. falciparum, as well as to reduce the parasitaemia of by treatment of N-(arylmethylidene)alkylamines (synthesized in
P. berghei infections in vivo [4,5]. In light of the biological high yields through condensation of the corresponding
potential of these compounds, continuous efforts have been benzaldehydes with the appropriate primary amines in CH2Cl2
devoted to the preparation of structurally diverse analogues in the presence of anhydrous MgSO4) with 1.5 equiv of
bearing a functionalized propane skeleton [6-8]. In that respect, chloroacetyl chloride and 3 equiv of 2,6-lutidine in benzene
we have been engaged in the stereoselective synthesis of syn-2- according to a literature protocol [30]. Subsequently, β-lactams
alkoxy-3-amino-3-arylpropan-1-ols 1 by reductive ring opening 5 were subjected to LiAlH4-mediated reductive ring opening,
of the corresponding β-lactams, which were shown to be of furnishing either 2-aminopropan-1-ols 6a–c, by using two molar
great importance as novel antiplasmodial agents (Figure 1) [6]. equiv of LiAlH4 in Et2O under reflux for 20–80 h, or trans-2-
More recently, we reported 1,2,3-triaminopropanes 2 as a new aryl-3-(hydroxymethyl)aziridines 7a–h by applying milder
class of antimalarial compounds (Figure 1), prepared through reactions conditions (i.e., one molar equiv of LiAlH4 in Et2O at
microwave-assisted, regioselective ring opening of the corre- room temperature for 5–8 h) (Scheme 1) [30].
sponding 2-(aminomethyl)aziridines by diethylamine [8].
Nonetheless, a number of challenges with regard to As aziridines are known to be versatile synthetic intermediates
structure–activity relationship studies of functionalized amino- for the preparation of a variety of ring-opened and ring-
propanes remain unaddressed, especially concerning the expanded amines, the aziridines 7 were deployed as substrates
screening of structural analogues of aminopropanes 1 and 2. for the stereoselective synthesis of functionalized amino-
propanols. In accordance with a literature approach [30], the
In the present paper, the synthesis of racemic anti-2-amino- nonactivated trans-2-aryl-3-(hydroxymethyl)aziridines 7 were
propan-1-ols 3 is described as a variant of the syn-3-amino- regio- and stereoselectively converted into anti-2-amino-3-aryl-
propan-1-ols 1 synthesis (regio- and stereoisomerism with 3-methoxypropan-1-ols 8a–e through heating in methanol under
respect to the relative position of the amino group NHR2 and reflux (Scheme 1). Furthermore, in order to provide access to
the oxygen substituent OR3, Figure 1), by applying a different the class of 2-aminopropan-1,3-diols, aziridines 7 were evalu-
synthetic route. Furthermore, a new synthetic approach is ated for the first time as substrates for a water-induced aziri-
disclosed towards racemic aminopropanes 4 bearing a 1,2,3- dine ring opening in an acidic medium. Thus, treatment of
triazole moiety, as structural analogues of the previously trans-2-aryl-3-(hydroxymethyl)aziridines 7 with one equiv of
reported 1,2,4-triazoles 2 (Figure 1). Both classes of functional- para-toluenesulfonic acid in a H2O/THF (1/1) solvent system
ized aminopropanes 3 and 4 were tested for their antiplas- [32] furnished novel anti-2-amino-1-arylpropan-1,3-diols 9a–d
modial activity.
in good yields after 3 h at 40 °C, again in a regio- and stereo-
specific way (Scheme 1). The observed regio- and stereoselec-
tivity in aminopropanols 8 and 9 can be rationalized by consid-
ering the ring opening of the aziridine moiety at C2 due to
Results and Discussion
Synthesis
Within azaheterocyclic chemistry, aziridines [9-17] and benzylic stabilization of the developing carbenium ion in an
β-lactams [18-27] are extraordinary classes of strained com- SN2 fashion [30].
Figure 1: Functionalized aminopropanes as potential antimalarial agents.
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Beilstein J. Org. Chem. 2011, 7, 1745–1752.
Scheme 1: Synthesis of aminopropanols 6, 8 and 9.
As the use of imines bearing a N-tert-butyl group in combina- in this case, the observed regio- and stereoselectivity in the for-
tion with a substituent in the ortho-position of the aromatic ring mation of aminopropanols 12 can be rationalized by consid-
is known to afford the corresponding cis-4-aryl-3-chloro- ering the ring opening of the aziridine moiety at C2 due to
azetidin-2-ones as the major stereoisomers after condensation benzylic stabilization of the developing carbenium ion in an
with chloroketene in benzene [30], racemic cis-3-chloro-β- SN2 fashion [30]. The formation of the other regio- and
lactams 10a,b were prepared and converted into cis-2-aryl-3- stereoisomers was excluded based on detailed spectroscopic
(hydroxymethyl)aziridines 11a,b upon treatment with two analysis.
molar equiv of LiAlH4 in Et2O under reflux for 15 h
(Scheme 2). Next, the aziridines 11, which have previously It should be noted that both diastereomeric antipodes of the
been shown to be unreactive towards LiAlH4 and methanol and class of 1-aryl-2-aminopropan-1,3-diols, i.e., anti- and syn-
thus unable to undergo ring opening [30], were used as aminopropanols 9 and 12, can now be prepared selectively
substrates for a water-induced ring opening through initial through choice of the appropriate imine for the Staudinger syn-
protonation of the aziridine ring with p-TsOH. Although more thesis of the starting β-lactams.
drastic reaction conditions were required compared to the ring
opening of trans-2-aryl-3-(hydroxymethyl)aziridines 7 (3 equiv Given the recently disclosed antiplasmodial activities of a
p-TsOH, Δ, 30 h instead of 1 equiv p-TsOH, 40 °C, 3 h), novel number of 2,3-diamino-1-(1,2,4-triazol-1-yl)propanes [8], the
syn-aminopropanols 12a,b were obtained in a selective and con- second objective of this work was the preparation of new
venient way (Scheme 2, yields after purification), providing the analogues bearing a 1,2,3-triazole moiety instead. A powerful
first example of the ring opening of this type of aziridines. Also methodology towards the synthesis of functionalized 1,2,3-tri-
Scheme 2: Synthesis of syn-aminopropan-1,3-diols 12.
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Beilstein J. Org. Chem. 2011, 7, 1745–1752.
azoles involves the Cu(I)-catalyzed azide-alkyne Huisgen the Et2NH·HCl/Et2NH system was employed [8]. In this way,
cycloaddition (CuAAC) [33], which has gained major interest protonation of the aziridine ring provides a highly electrophilic
from the synthetic community due to its high efficiency and aziridinium intermediate, which is prone to undergo nucle-
selectivity. Eligible substrates to perform “click chemistry” [34] ophilic ring opening. In order to drive the reaction to comple-
incorporate an azide group and an aziridine ring in their struc- tion, and to avoid competition between chloride- and diethyl-
ture, for example in 2-(azidomethyl)aziridines, thus providing a amine-induced ring opening, a large excess of Et2NH·HCl
direct access to 2-[(1,2,3-triazol-1-yl)methyl]aziridines through (20 equiv) and an additional amount of diethylamine (10 equiv)
Cu-catalyzed reaction with alkynes [35].
was used. Thus, heating of the aziridines 15 at 140 °C in
CH3CN under microwave irradiation resulted in full and selec-
In this work, nonactivated N-(arylmethyl)aziridines were tive conversion to the desired new triaminopropanes 16a–e after
selected as substrates, as previous research had revealed the 2 h (Scheme 3), which were purified by column chromatog-
importance of N-benzyl, N-chlorobenzyl and N-methoxybenzyl raphy (SiO2) in order to obtain analytically pure samples.
groups in functionalized aminopropanes with regard to their Furthermore, in addition to the use of diethylamine, the intro-
antiplasmodial activity [6,8]. Thus, a number of racemic duction of a dimethylamino group was considered in order to
2-(azidomethyl)aziridines 14 was prepared by reaction of compare the contribution of this moiety to the potential
sodium azide with 2-(bromomethyl)aziridines 13 [36-38], antiplasmodial activity with that of a diethylamino group. This
employing the electrophilicity of the latter as a convenient objective was achieved by treatment of aziridines 15 with
handle for their connection to other moieties. In this way, novel 20 equiv of Me2NH·HCl in CH3CN at 140 °C for 2 h under
2-(azidomethyl)aziridines 14a–e were prepared in good yields microwave irradiation, resulting in dimethylaminopropanes
by treatment of bromides 13 with two equiv of sodium azide in 16f,g in good yields (Scheme 3). This result showed that this
DMSO at 80 °C for 16 h (CAUTION) (Scheme 3). Subse- microwave-assisted methodology for the ring opening of nonac-
quently, a CuI-catalyzed 1,3-cycloaddition of N-(arylmethyl)- tivated aziridines can be further extended towards the use of
aziridine azides 14 was evaluated for the first time by utilizing other secondary amines. In order to introduce structural diver-
one equiv of an arylacetylene in CH3CN under reflux for 16 h, sity within these molecules, different substituent patterns at the
furnishing a direct entry towards new 2-[(1,2,3-triazol-1- aromatic rings (R1, R2) in aminopropanes 16a–g were realized
yl)methyl]aziridines 15a–f in a highly efficient and selective as well.
way (Scheme 3).
In view of the biological potential of aminopropanes in general,
The final step comprised ring opening of the aziridine moiety in compounds 6, 8, 9, 12 and 16 were subsequently screened for
compounds 15 by diethylamine to afford functionalized amino- their antiplasmodial activity.
propanes as potential antimalarial agents. With the intention to
introduce a diethylamino group, a microwave-promoted ring In addition, aziridines 14 and 15 were tested against the malaria
opening of analogous aziridines by diethylamine with the aid of parasite Plasmodium falciparum, too.
Scheme 3: Synthesis of 2-[(1,2,3-triazol-1-yl)methyl]aziridines 15 and their transformation into 1,2,3-triaminopropanes 16.
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Beilstein J. Org. Chem. 2011, 7, 1745–1752.
Biological evaluation
in triplicate on one occasion. The antiplasmodial and cytotoxic-
At first, compounds 6a–c, 8a–e, 9a–d, 12a,b, 14a–e, 15a–f and ity assays were performed as described previously [8,39,40].
16a–g were screened for in vitro antiplasmodial activity. All
samples were tested in triplicate on one occasion against a The results from the biological study are summarized in
chloroquine-sensitive (CQS) strain of P. falciparum (D10). Table 1. Although most of these compounds were shown to
Those samples showing antiplasmodial activity were then tested possess weak or no antiplasmodial activity, eight of them (i.e.,
in triplicate on one occasion against a chloroquine-resistant compounds 6a, 9a,b, 15c,d, 16a,b,f) were identified as poten-
(CQR) strain of P. falciparum (Dd2) and screened for in vitro tially interesting for further study with IC50-values of ≤25 μM.
cytotoxicity against a Chinese hamster ovary (CHO) cell-line, Moreover, these compounds, with the exception of triamino-
Table 1: IC50-values of compounds 6, 8, 9, 12, 14, 15 and 16 tested for in vitro antiplasmodial activity and cytotoxicity.
Compound
R1
R2
R3
D10:
Dd2:
CHO:
RIa
SIb
IC50 (μM)
IC50 (μM)
IC50 (μM)
6a
4-Cl
4-OMe
2-F
H
Bn
iBu
n-Pr
iPr
Bn
Bn
iBu
n-Pr
Bn
Bn
Bn
4-ClBn
–
–
12.58
281.58
217.34
369.70
143.79
198.56
38.56
38.54
25.22
21.18
129.86
80.68
98.68
60.46
230.40
100.82
160.50
93.68
179.86
34.44
41.32
25.69
20.43
40.54
32.33
22.09
25.86
139.61
32.55
171.37
11.33
69.58
10.88
ND
137.90
ND
0.9
ND
ND
ND
ND
ND
0.7
0.6
0.3
0.6
ND
ND
ND
ND
2
11
6b
–
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
16.1
ND
6c
–
ND
ND
8a
–
ND
ND
8b
H
–
ND
ND
8c
4-Cl
4-OMe
2-F
4-Cl
2-Cl
4-Me
H
–
ND
ND
8d
–
25.69
21.92
8.47
13.57
ND
>530
>530
>530
>530
ND
8e
–
9a
–
9b
–
9c
–
9d
–
ND
ND
12a
12b
14a
14b
14c
14d
14e
15a
15b
15c
15d
15e
15f
16a
16b
16c
16d
16e
16f
16g
OMe
F
–
ND
ND
–
–
ND
ND
H
–
–
466.81
ND
>530
ND
4-Cl
4-OMe
2-Cl
3-Cl
H
–
–
ND
ND
ND
ND
3.1
ND
2.2
1
–
–
ND
ND
–
–
ND
ND
–
–
ND
ND
H
–
106.97
ND
>530
ND
4-Cl
4-OMe
H
H
–
H
–
55.65
20.99
ND
>530
>530
ND
Me
OMe
H
–
H
–
ND
0.8
10.5
6.8
ND
ND
ND
1.2
ND
2-Cl
H
–
25.00
231.47
176.40
ND
>530
>530
>530
ND
H
Et
Et
Et
Et
Et
Me
Me
4-Cl
4-OMe
H
H
H
Me
OMe
H
ND
ND
H
ND
ND
2-Cl
H
13.03
ND
181.83
ND
H
CQ
19.14 ng/mL
75.56 ng/mL
3.9
(n = 6)
(n = 5)
Emetine
0.27
(n = 6)
aRI (Resistance Index) = IC50 Dd2/IC50 D10; bSI (Selectivity Index) = IC50 CHO/IC50 D10; ND = not determined; n = number of data sets averaged.
The more hydrophobic samples were added to the parasites as a suspension, meaning that for these samples the reported IC50-value might be an
underestimation of the activity.
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Beilstein J. Org. Chem. 2011, 7, 1745–1752.
propanes 16a,b, also proved to be active against a chloroquine- azide-alkyne cycloaddition reactions. From a biological view-
resistant strain of P. falciparum (Dd2). In addition, the in vitro point, most of these compounds exhibited weak antiplasmodial
cytotoxicity results showed that only compounds 6a and 16f activity, although six representatives showed moderate antiplas-
have lower selectivity with SI’s of 11 and 16, respectively, modial activity against both a chloroquine-sensitive and a
whereas the other compounds did not show cytotoxicity at the chloroquine-resistant strain of P. falciparum with IC50-values
concentrations tested.
of ≤25 μM.
Although the aziridine moiety was initially only considered as a Experimental
synthetically useful entity, two 2-[(1,2,3-triazol-1-yl)methyl]- General information regarding NMR, IR, MS and elemental
aziridines (15c and 15d) were also found to exhibit weak analyses, melting point measurements, and microwave reaction
antiplasmodial activity. On the other hand, the aminopropane conditions can be found in the literature [8].
unit has again proven its value as a template for the preparation
anti-2-(N-Benzylamino)-1-(4-chlorophenyl)-
of novel antimalarial agents, as a variety of structurally different
aminopropanes were demonstrated to exhibit weak to moderate propan-1,3-diol (9a)
antiplasmodial activity. In particular, antiplasmodial assays Recrystallization from hexane/EtOAc (1:25), white crystals,
against a chloroquine-sensitive strain of P. falciparum (D10) 95%. Mp 192.3 °C; 1H NMR (300 MHz, CDCl3) δ 2.39 (s, 2H),
showed activity for 2-aminopropan-1-ol 6a, 2-aminopropan- 3.12–3.18 (m, 1H), 3.54 (dd, J = 13.0, 3.6 Hz, 1H), 3.82 (dd,
1,3-diols 9a,b and triaminopropanes 16a,b,f with IC50-values J = 13.0, 5.8 Hz, 1H), 4.27 and 4.32 (2 d, J = 13.2 Hz, 2 × 1H),
between 11.3 and 25.9 μM. Moreover, screening against a 5.24 (d, J = 2.2 Hz, 1H), 7.04–7.07, 7.19–7.36, 7.46–7.49 and
chloroquine-resistant strain of P. falciparum (Dd2) revealed 7.69–7.71 (4 m, 2H, 3H, 2H, 2H); 13C NMR (75 MHz, CDCl3)
antiplasmodial activity for 2-aminopropan-1-ol 6a, 2-amino- δ 51.0, 59.4, 62.6, 72.0, 127.2, 128.1, 128.7, 128.8, 128.9,
propan-1,3-diols 9a,b and triaminopropane 16f with IC50- 133.4, 137.0, 139.1; IR (cm−1) νmax: 3437 (OH), 3342 (NH),
values between 8.5 and 13.6 μM.
2926, 1448, 1162, 1008, 681; MS (70 eV) m/z (%): 292/4
(M+ + 1, 100); HRMS (ESI): [M + H]+ calcd for C16H19ClNO2,
From a structure–activity relationship viewpoint, the presence 292.1104; found, 292.1112.
of a chlorinated aromatic ring seems to contribute to the
syn-2-(N-tert-Butylamino)-1-(2-methoxyphen-
antiplasmodial activity of these functionalized aminopropanes,
and the introduction of a dimethylamino group at the expense of yl)propan-1,3-diol (12a)
a diethylamino moiety might provide better activities in some Rf 0.07 (EtOAc), white crystals, 30%. Mp 112.8 °C; 1H NMR
cases. It is noteworthy that these compounds were synthesized (300 MHz, CDCl3) δ 1.03 (s, 9H), 2.77 (ddd, J = 7.1, 3.0,
in racemic form, and it is conceivable that enantiomerically 3.0 Hz, 1H), 3.50–3.51 (m, 2H), 3.86 (s, 3H), 4.80 (d, J =
pure variants could deliver superior activities. It should also be 7.1 Hz, 1H), 6.87–6.89, 6.98–7.03, 7.22–7.28 and 7.47–7.50
noted that, in general, the bioactivities reported in this paper are (4 m, 4 × 1H); 13C NMR (75 MHz, CDCl3) δ 30.0, 50.8, 55.6,
less pronounced as compared to those described in literature 58.1, 63.7, 68.5, 110.4, 121.3, 127.7, 128.4, 130.5, 156.5; IR
precedents on the synthesis and evaluation of functionalized (cm−1) νmax: 3391 (NH), 3313 (OH), 3058, 3004, 2987, 2957,
aminopropanes [6,8].
2927, 2873, 2838, 1492, 1467, 1438, 1368, 1242, 1066, 1050,
1027, 755; MS (70 eV) m/z (%): 254 (M+ + 1, 100); HRMS
(ESI): [M + H]+calcd for C14H24NO3, 254.1756; found,
Conclusion
In summary, a variety of 2-amino-3-arylpropan-1-ols, anti-2- 254.1766.
amino-3-aryl-3-methoxypropan-1-ols and anti-2-amino-1-aryl-
2-Azidomethyl-1-(phenylmethyl)aziridine
propan-1,3-diols were prepared selectively through elaboration
of trans-4-aryl-3-chloro-β-lactams. Furthermore, a number of (14a)
2-(azidomethyl)aziridines were converted into novel 2-[(1,2,3- Rf 0.20 (hexane/EtOAc 4:1), yellow oil, 70%. 1H NMR
triazol-1-yl)methyl]aziridines by Cu(I)-catalyzed azide-alkyne (300 MHz, CDCl3) δ 1.51 (d, J = 6.1 Hz, 1H), 1.79 (d, J =
cycloaddition, followed by microwave-assisted, regioselective 3.3 Hz, 1H), 1.79–1.86 (m, 1H), 3.18 and 3.27 (2 dd, J = 12.9,
ring opening by diethyl- or dimethylamine towards the corre- 6.6, 4.4 Hz, 2H) 3.38 and 3.58 (2 d, J = 13.2 Hz, 2H), 7.24–7.36
sponding 1-(2,3-diaminopropyl)-1,2,3-triazoles. From a syn- (m, 5H); 13C NMR (75 MHz, CDCl3) δ 32.2, 37.9, 53.8, 64.3,
thetic viewpoint, new insights were provided concerning the 127.4, 128.3, 128.6, 138.8; IR (cm−1) νmax: 2088 (N3), 1453,
water-induced ring opening of nonactivated cis- and trans-2- 1357, 1322, 1255, 1159, 1062, 1028, 907, 732, 697; MS
aryl-3-(hydroxymethyl)aziridines and with respect to the syn- (70 eV) m/z (%): 189 (M+ + 1, 100); HRMS (ESI): [M + H]+
thesis and use of 1-arylmethyl-2-(azidomethyl)aziridines for calcd for C10H13N4, 189.1140; found, 189.1141.
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Beilstein J. Org. Chem. 2011, 7, 1745–1752.
1-Phenylmethyl-2-[(4-phenyl-1,2,3-triazol-1-
yl)methyl]aziridine (15a)
5. Harrison, T.; Samuel, B. U.; Akompong, T.; Hamm, H.; Mohandas, N.;
Lomasney, J. W.; Haldar, K. Science 2003, 301, 1734.
doi:10.1126/science.1089324
Rf 0.23 (CHCl3/MeOH 98:2), viscous light-brown oil, 61%.
1H NMR (300 MHz, CDCl3) δ 1.65 (d, J = 6.6 Hz, 1H), 1.88 (d,
J = 3.3 Hz, 1H), 2.01–2.08 (m, 1H), 3.09 and 3.67 (2 d, J =
12.9 Hz, 2H), 3.93 and 4.70 (2 dd, J = 14.3, 8.2, 3.3 Hz, 2H),
7.06–7.43 (m, 8H), 7.49 (s, 1H), 7.66–7.69 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 32.4, 38.3, 53.5, 64.5, 119.9, 125.9, 127.7,
128.1, 128.4, 128.6, 128.7, 130.8, 138.2, 147.9; IR (cm−1) νmax:
2919, 1453, 1358, 1225, 1075, 1046, 1027, 763, 731, 694; MS
(70 eV) m/z (%): 291 (M+ + 1, 100); HRMS (ESI): [M + H]+
calcd for C18H19N4, 291.1610; found, 291.1613.
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Rf 0.19 (CHCl3/MeOH 97:3), light-brown oil, 56%. 1H NMR
(300 MHz, CDCl3) δ 0.92 (t, J = 7.2 Hz, 6H), 2.26–2.52 (m,
6H), 3.05–3.13 (m, 1H), 3.74 and 3.81 (2 d, J = 13.5 Hz, 2H),
4.36 and 4.44 (2 dd, J = 14.2, 4.9, 4.7 Hz, 2H), 7.21–7.44 and
7.82–7.84 (2 m, 10H), 7.86 (s, 1H); 13C NMR (75 MHz,
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128.1, 128.2, 128.6, 128.9, 130.9, 140.2, 147.5; IR (cm−1) νmax: 16.Padwa, A.; Murphree, S. S. ARKIVOC 2006, No. iii, 6.
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Supporting Information
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Supporting Information File 1
21.Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107,
Experimental procedures and characterization data.
4437. doi:10.1021/cr0307300
[http://www.beilstein-journals.org/bjoc/content/
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Acknowledgements
The authors are indebted to the “Research Foundation – Flan-
ders” (FWO-Vlaanderen), the “Institute for the Promotion of
Innovation through Science and Technology – Flanders” (IWT-
Vlaanderen), and to Ghent University (GOA) for financial
support.
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