Synthesis of Aminomethylene- gem-bisphosphonates Containing an Aziridine Motif: Studies of the Reaction Scope and Insight into the Mechanism

Article abstract of DOI:10.1021/acs.joc.0c02434

A broad range of N-carbamoylaziridines were obtained and then treated by the diethyl phosphonate anion to afford α-methylene-gem-bisphosphonate aziridines. Study of the reaction's scope and additional experiments indicates that the transformation proceeds via a new mechanism involving the chelation of lithium ion. This last step is crucial for the reaction to occur and disfavors the aziridine ring-opening. A phosphonate-phosphate rearrangement from a α-hydroxybisphosphonate aziridine intermediate is also proposed for the first time. This reaction provides a simple and convenient method for the synthesis of a highly functionalized phosphonylated aziridine motif.

Full text of DOI:10.1021/acs.joc.0c02434

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Synthesis of Aminomethylene-gem-bisphosphonates Containing an
Aziridine Motif: Studies of the Reaction Scope and Insight into the
Mechanism
Thomas Cheviet and Suzanne Peyrottes*
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ABSTRACT: A broad range of N-carbamoylaziridines were
obtained and then treated by the diethyl phosphonate anion to
afford α-methylene-gem-bisphosphonate aziridines. Study of the
reaction’s scope and additional experiments indicates that the
transformation proceeds via a new mechanism involving the
chelation of lithium ion. This last step is crucial for the reaction to
occur and disfavors the aziridine ring-opening. A phosphonate−
phosphate rearrangement from a α-hydroxybisphosphonate azir-
idine intermediate is also proposed for the first time. This reaction
provides a simple and convenient method for the synthesis of a
highly functionalized phosphonylated aziridine motif.
bisphosphonates, targeting enzymes of the mevalonate path-
way and exhibiting antiosteoporosis and antiproliferative
activities.12,13 For example, the incadronate (Figure 1) is an
antiosteoporosis drug with a 1-aminobisphosphonate motif.
Syntheses of 1-aminobisphosphonates (or aminomethylene-
gem-bisphosphonates) are described through numerous
methods,14 namely the condensation of ethyl orthoformates
and phosphites,15,16 the Beckmann rearrangement of ox-
imes,17,18 or the bisphosphorylation of amides,19,20 imines,21
isonitriles,22−24 or nitriles.25 To our knowledge, such
derivatives when containing an aziridine motif are not reported
in the literature. Thus, we propose an original synthetic route
involving lithiated diethylphosphite for the valorization of
these three-membered rings in phosphorus chemistry (Scheme
1). We use N-carbamoylaziridines as starting material for the
preparation of brand new phosphonylaziridine compounds,
such as aziridine α-methylene-gem-bisphosphonates (abbre-
viated AzbisPs). To investigate the scope and limitations of the
method, a library of N-carbamoylaziridines is obtained
beforehand. In addition, complementary experiments are
performed to propose a mechanism for the formation of
such derivatives.
INTRODUCTION
■
Aziridines are widely studied as key intermediates in organic
syntheses and represent a valuable source of chiral centers
because of their regio- and stereoselectivity in ring-opening
reactions. Their reactivity has recently been reviewed.1 When
combined with a phosphonate moiety (widely used in
medicinal chemistry as a bioisoster of organic phosphate and
insensitive to enzymatic cleavage), they are useful building
blocks for the synthesis of aminophosphonates that can be
considered as analogues of α-amino acids. For example, the
synthesis of aziridine-2-phosphonates and aziridin-1-yl meth-
ylphosphonates have been well described in the literature.2−5
However, the association of a chiral aziridine with several
phosphonate groups is rather limited and may lead to
promising scaffolds for obtaining biomolecules of interest.
Indeed, bisphosphonates (or BPs, Figure 1) have been
developed for their coordination abilities and their structural
analogy with inorganic pyrophosphate (the P−C−P bridge
replacing the P−O−P bonds is not sensitive to enzymatic
cleavage), making them suitable for the treatment of bone
diseases or drug delivery.6−11 N-BPs are nitrogen-containing
Received: October 14, 2020
Published: January 21, 2021
Figure 1. Structures of BPs and N-BPs clinically used or of biological
interest.
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© 2021 American Chemical Society
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an electron-withdrawing substituent, which enhances the
electrophilicity of the aziridine ring. In the case of aryl or
alkyl substituents, no byproducts are isolated.
Scheme 1. Synthesis of Aziridine α-Methylene-gem-
bisphosphonates (AzbisPs) from N-Carbamoylaziridines
As expected, we obtained better yields at higher temper-
atures (from rt to 55 °C) for derivatives 3b and 3f, whereas
some aziridines (2a, 2c, and 2k) appeared unstable upon
heating. Temperature has also an effect on the competition
between ring-opening and AzbisP formation (no byproduct is
isolated from 2f after refluxing the reaction mixture at 80 °C,
whereas the ring-opened product is recovered, in 5% and 16%
yield, respectively, at room temperature and 50 °C) indicating
that the AzbisP is the thermodynamic product of the reaction.
In addition, the studied reaction does not lead to the
epimerization of the aziridine ring, since compound 3g is not
isolated as a mixture of diastereoisomers.
RESULTS AND DISCUSSION
■
In the course of a medicinal project, we envisaged the
preparation of β-aminophosphonates through the ring-opening
of aziridines with phosphites,26 a methodology poorly reported
in the literature.27,28 When such conditions (DEP/LiHMDS in
THF) are applied to an N-Cbz-aziridine as substrate, we
observed the formation of an aziridine α-methylene-gem-
bisphosphonate (AzbisP) instead of the expected ring-opened
product. To study the scope of this reaction, we examined the
behavior of several N-Boc- or N-Cbz-protected aziridines.
With this aim, 14 substrates (Table 1, compounds 2a−n)
were synthesized starting from commercially available amino
acids and amino alcohols through protection/reduction steps
and then cyclization. Among them, nine N-carbamoylaziridines
(2a, 2d, 2e, 2f, 2g, 2i, 2j, 2l, and 2n) were hitherto unknown
compounds that may be viewed as valuable building blocks.
According to the nature of the substituents, either Mitsunobu
conditions (route A) or intramolecular substitution (route B)
is used. Likely due to interactions/steric hindrance between
the tosylate group and the phenyl moiety of the Cbz protecting
group, the one-pot cyclization of N-Cbz-aziridines usually led
to lower yields than under Mitsunobu conditions. Except in the
case of the cyclohexyl aziridine 2k (Table 1, entry 11), where
the 3D conformation of the carbocycle is supposed to reduce
the possible interactions between the two groups. We observed
lower yields for compounds 2l and 2m (obtained as
invertomers because of the high-energy barrier of the nitrogen
inversion), and this may be associated with the formation of a
highly constrained aziridine ring. In the Mitsunobu conditions,
no reactivity is observed.
The reaction does not occur on N-Boc-protected primary
amines (Table 2, side chain of the lysine derivatives 2i and 2j).
This difference of reactivity may be explained by the pKaH
values of aziridine and aliphatic amine (7−8 vs 9−11 in H2O,
respectively), which has an impact on the electrophilicity of the
carbonyl moiety. The N-carbamoylaziridine moiety is more
reactive in our conditions, thus allowing the selective
formation of the AzbisP, even in the presence of another
carbamate group. To validate this hypothesis, we examined the
behavior of few analogues of the N-carbamoylaziridine scaffold
with higher pKaH values, such as N-Cbz-azetidine (10−11), N-
Cbz-pyrrolidine (10.8), and N-Cbz-piperidine (10) derivatives
(pKaH values have been estimated using the MarvinSketch
software),33 as well as a well-known rearrangement product of
N-carbamoylaziridines in the presence of azaphilic Lewis acids,
the oxazolidine-2-one 4 (Scheme 2).34 In all cases, the pKaH of
the nitrogen is higher than that of the aziridine scaffold, and no
reactivity is observed in our conditions (DEP/LiHMDS).
The structures of bisphosphonate esters (compounds 3a,b,
3d−i, and 3k) were readily identified by analysis of the NMR
data, including bidimensional techniques, as well as mass
spectrometry, and compared to their corresponding N-
carbamoylaziridines used as starting materials (see the SI). In
all cases, 1H NMR spectra shows a triplet in the range of 2.4−
2.8 ppm with a coupling constant value of ∼18 Hz and
corresponding to a single proton. The 2D spectral data (COSY
1
1H/1H and HSQC H/13C) demonstrate that this proton is
Having established the suitable reaction conditions (data not
shown), aziridines 2a−n were treated with 6.1 equiv of diethyl
phosphite and 6 equiv of LiHMDS (1 M in THF), in
anhydrous THF, at −78 °C. Then the reaction mixture was
heated at the indicated temperature until completion of the
reaction (TLC monitoring). According to our results,
formation of AzbisPs occurs both in the presence of N-Boc
and N-Cbz protecting groups, with an enhanced reactivity of
the latter (Table 2, comparison between substrates 2b and 2c,
2i, and 2j). Three substrates did not lead to the expected
derivatives. For the bicyclic compounds 2l and 2m, the lack of
reactivity is mostly associated with the highly constrained
conformation of the aziridine-ring, and the reduced product 3l
is isolated in high yields. For the biaryl aziridine 2n, the
starting material is almost entirely recovered even after 4 days
at reflux. Thus, the high steric hindrance of the heterocycle
appears to prevent the formation of the AzbisP derivative.
Ring-opened products are observed as byproducts for a few
aziridines (2f, 2h and 2i), highlighting the competition
between the formation of aziridine α-methylene-gem-bis-
phosphonates and β-aminophosphonates in the presence of
not coupling with other protons of the molecules and is
associated with a carbon atom, whose signal is also a triplet at
∼65 ppm with a wide coupling constant of ∼150 Hz. This
observation is consistent with the proposed structure including
two phosphonate groups attached to the same carbon (P−
CH−P). For example, a detailed study of the 1D and 2D NMR
spectra (see the SI) for two AzbisPs (compounds 3d and 3g)
and their corresponding N-carbamoylaziridines (compounds
2d and 2g) highlights the characteristic signals of these
compounds and peak attribution. The aziridine structure is
clearly recognizable by the presence of 2 doublets at ∼2 ppm
1
in H NMR (corresponding to the methylene of the aziridine
1
ring) in the AzbisPs, which are also present in H NMR
spectrum of the starting material, supporting that the ring is
kept intact at the end of the reaction. In addition, COSY and
13C spectra also demonstrate the presence of the aziridine ring,
1
the two doublets in H NMR are associated with the same
carbon according to HSQC experiments. The signal of the
methylene protons is coupling only with the methyne proton
of the aziridine ring in the COSY experiment.
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Table 1. Preparation of N-Carbamoylaziridines (as Substrates) from Commercially Available Amino Acids and Amino
Alcohols
a
Reaction conditions: Mitsunobu (route A) PPh3, DEAD, THF, 0 °C to rt, overnight; one-pot cyclization (route B) p-TsCl, KOH, Et2O, reflux,
b
c
overnight. Isolated yield after purification by column chromatography. Preparation of starting material 1a, 1d, 1e, and 1i−n is available in the
Experimental Section. Commercially available.
d
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Table 2. Substrate Scope for the Formation of Aziridine α-Methylene-gem-bisphosphonates*
*
a
b
Isolated yield after purification by column chromatography. Abbreviation o.n. means overnight. Total conversion indicated by TLC. Starting
c
material recovered. Corresponding ring-opened byproduct was also isolated (from 2f, 5% at rt and 16% at 55 °C) or detected (from 2h and 2i).
Scheme 2. Synthesis of the Oxazolidine-2-one 4 from 2b Using a Previously Published Procedure34 and Its Lack of Reactivity
a
toward Nucleophilic Attack of Diethylphosphite
a
The chelation model and the proposed mechanism for the ring expansion of N-Boc-aziridines into oxazolines catalyzed by azaphilic Lewis acids is
well-known in the literature.35,36
.
We then became interested in deciphering the mechanism of
the reaction. Because the aziridine 2g does not show any
epimerization, we exclude the ring opening of the aziridine and
its subsequent ring closing. Thus, our first hypothesis consisted
in the nucleophilic attack of 1 equiv of diethyl phosphite anion
on the carbonyl group, leading to the elimination of the
alkoxide and the formation of an aziridine N-carbamoyl
phosphonate (Scheme 3A). Differences of reactivity between
N-Boc and N-Cbz substrates support this assumption as the
benzyl oxide ion may be considered as a better leaving group
than the tert-butyl oxide one. This kind of addition/elimination
occurring on a carbamate moiety has already been reported in
the literature.37 In addition, an acyl derivative of the 2-
benzylaziridine treated in our conditions (data not shown) did
not lead to the formation of the corresponding AzbisP, which
indicated the key role of the carbamoyl moiety.
This addition/elimination step may be competing with the
nucleophilic attack on the aziridine ring that is also an
electrophilic center. Here, we assumed that the chelation of the
lithium with the ester moiety enhanced the reactivity of the
carbamate, since lithium is considered as a better Lewis acid
than the other alkali ions (sodium and potassium).
Corresponding models and rules are presented in Scheme
3A. Herein, we propose a different site of chelation for the
Lewis acid (than the one drawn in Scheme 2) on the basis of
the work of Lectka et al.,36 indicating that coordination to the
carbonyl may be better at activating the substrate toward
external nucleophilic attack.
In a second step, the N-carbamoyl phosphonate inter-
mediate may be subject to a second nucleophilic attack of the
diethyl phosphite anion affording an α-hydroxybisphosphonate
derivative as a second intermediate (Scheme 3B). This scaffold
is known to undergo [1,2]-phospha-Brook rearrangement
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Scheme 3. Mechanistic Investigation. (A) Models for the Ring Opening of N-Carbamates Compared with the Addition of DEP
on the Carbamate Moiety in the Presence of Lithium Cations. (B) Second Nucleophilic Attack Leading to a Hypothetic α-
Hydroxybisphosphonate Intermediate. (C) [1,2]-Phospha-Brook Rearrangement with Lithiated Base Starting from α-
Hydroxybisphosphonate Intermediate
(phosphonate−phosphate rearrangement) in the presence of a
base, leading to the formation of a phosphate moiety (Scheme
3C).38−44
ably proceeds through lithium−proton exchange (involving the
diethyl phosphite as supposed by Ranga et al.).
To go further in the study of the impact of the lithium ion in
the proposed mechanism and rearrangement as well as the
nature of the base, we envisaged additional experiments (Table
3). Thus, various bases susceptible to deprotonate the diethyl
phosphite were tested using aziridine 2f as substrate. In the
presence of tBuOK (entry 1), only 3% of AzbisP was
The proposed mechanism (Scheme 3C) is adapted from the
work of Ranga et al.,45 who studied the n-BuLi-mediated [1,2]-
phospha-Brook rearrangement and the addition of lithiated
diethyl phosphite on acetophenone. Their conclusions
(supported by DFT calculations and 31P NMR experiments)
proved the crucial role of lithium in the stabilization of the
transition states. This rearrangement occurs right after the
formation of the intermediate I (Scheme 3C). The lithium,
conjugated to the hydroxylate, chelates the phosphonate and
induces the addition of the hydroxyl anion on the phosphorus
atom, leading to the formation of the oxaphosphirane high
energy intermediate II. The cleavage of the P−C bond of the
lithium-chelated oxaphosphirane and the subsequent creation
of the P−O bond then forms the 5-membered carbanion
containing cycle intermediate III. The rearrangement presum-
Table 3. Influence of the Nature of the Base on the
Formation of AzbisPs
yield (%)
entry
base (6 equiv)
pKa
AzbisP 3f (%)
β-aminoP (%)
1
2
3
4
tBuOK
17
30
30
35
3
0
30
0
47
9
5
NaHMDS
LiHMDS
NaH
5
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recovered, and we mainly observed the formation of ring-
opened product (47% yield). When using NaHMDS (entry 2)
or LiHMDS (entry 3) with similar pKa values, no AzbisP is
observed for NaHMDS and only 9% of the ring-opened
product is recovered. These results are in agreement with
previous data from the literature, comparing the effect of
various [M]HMDS bases on the double addition of DEP on
acid chlorides39 and the recent mechanistic study of the role of
the lithium ion in the [1,2]-phospha-Brook rearrangement.45
When a stronger base such as NaH was used (entry 4), only
traces of ring-opened product were observed.
Accordingly, the lithium is conjugated to the hydroxylate
anion generated after the second nucleophilic attack of DEP on
the acylphosphonate moiety (Scheme 3C). Lithium acts as a
Lewis acid as well as a conjugated cation. It is supposed to
chelate the phosphonate group I to facilitate the formation of
the oxaphosphirane II and to stabilize the carbanion III with
the formation of a strong ion pair. The proposed model
(Scheme 3B) is hypothesized from the mechanism of the
reverse reaction, the phosphate−phosphonate rearrangement,
in the presence of strong lithiated base,46,47 and on the basis of
the work of Ranga et al.45 This point further reinforces the
crucial role of lithium in the stabilization of the transition
states. The [1,2]-phospha-Brook rearrangement likely ends by
the lithium−proton exchange between DEP and the transition
state III.
Table 4. Influence of the Amounts of DEP/LiHMDS on the
Yield of the Reaction
entry
DEP (equiv)
LiHMDS (equiv)
time (h)
yield of 3b (%)
1
2
3
4
5
2.1
3.1
4.1
5.1
6.1
2
3
4
5
6
6
4.5
4
2.5
2
13
14
29
32
69
and 3 equiv of the reactants (Table 4, entry 1 and 2) may
suggest that the reaction requires at least 3 equiv of DEP/
LiHMDS to be in stoichiometric conditions.
CONCLUSION
■
N-Carbamoylaziridines are efficiently converted into their
corresponding methylene-gem-bisphosphonylated derivatives
in the presence of LiHMDS and DEP. To our knowledge, it
is the first time that such reaction has been reported in the
literature. This transformation preferably occurs with N-Cbz-
aziridines and competes with the aziridine ring-opening
reaction. A broad range of N-Cbz- and N-Boc-aziridines were
synthesized to study the scope of the reaction and afforded the
desired phosphonylated compounds with mild to good yield.
Influence of the nature of the base, the nature of the aziridine
protecting group, amount of reactants, and the aziridine
substituent were studied.
In the last step, we assumed that the newly formed
phosphate group may be substituted by a third equivalent of
deprotonated diethyl phosphite, still with the assistance of the
lithium as a Lewis acid, which chelates the phosphate group
and leads to the AzbisP product (Scheme 4). A similar
According to the reaction scope and additional experiments,
we proposed a mechanism and highlighted the essentiality of
the lithium ion and the basicity of the nitrogen. The latter
involved a phosphonate−phosphate rearrangement newly
described from a lithiated α-hydroxybisphosphonate species.
Scheme 4. Substitution of the phosphate Group by a Third
Nucleophilic Attack of DEP
EXPERIMENTAL SECTION
■
General Information. Reagents were from the followed suppliers:
Sigma-Aldrich, Alfa Aesar, Acros, or TCI. Anhydrous solvents (sealed
flasks and stored on molecular sieves) were from Sigma-Aldrich
(acetonitrile, MeOH, dichloromethane, THF, DMF, Et2O) or
distilled beforehand on P2O5 or CaCl2 (dichloromethane) or sodium
and benzophenone (THF), according to protocols by Armarego and
Perrin.49 Diethyl phosphite (Acros) was distilled on KOH under
reduced pressure and stored in a sealed round-bottom flask under
argon atmosphere and in the dark. Reactions that required heating
were performed in hot plate/heating block apparatus with internal
temperature control.
substitution reaction is observed by Fitch and Moedritzer on a
phosphonyl phosphate compound in the presence of PCl5.48 It
has to be specified that the diethyl phosphoester moiety (in
red, intermediate IV, Scheme 4), as well as the phosphonate
group, certainly increase the electrophilicity of the vicinal
carbon atom (in green, intermediate IV, Scheme 4), assisting
consequently the nucleophilic attack of DEP (in blue, Scheme
4) on this position. As for the previous steps, the aziridine ring
is supposed to participate in the same way because of the low
pKa value of its nitrogen atom. This last step is thought to be
fast, in order to consume quickly the rearranged phosphory-
lated compound and thus preventing the reverse reaction.
Furthermore, several attempts to isolate intermediates
during the reaction and to synthesize the N-carbamoyl
phosphonate intermediates were unsuccessful, thus demon-
strating both high reactivity and instability of these species.
When using lower equivalents of DEP/base (Table 4), total
consumption of the starting N-carbamoylaziridine is observed
but the yields of the recovered AzbisP remain below the one
obtained with 6 equiv of DEP/LiHMDS, and yet no
intermediate is isolated. The similar yields obtained for 2
Microwave conditions reactions were performed on an Anton-Paar
Monowave instrument and using sealed tubes; the reaction temper-
ature was monitored by external surface sensor.
Thin-layer chromatography (TLC) was performed on precoated
aluminum sheets of silica 60 F254 (Merck, Art. 5554). Visualization
of products was accomplished by UV absorbance (254 nm) and/or by
charring with Ninhydrin solution, “Molybden blue”, or sulfuric acid
5% (v/v) in ethanol. Flash chromatography on silica gel were
performed on the automated system Biotage Isolera 4 and silica
cartridges (Buchi Flashpure Silica or Biotage ZIP Si Cartridge).
NMR spectra were recorded in the Laboratoire de Mesures
Physiques (LMP, University of Montpellier) on Bruker Avance
̈
1
spectrometers (400, 500, or 600 MHz for H NMR spectra, 101 or
126 MHz for 13C NMR spectra, and 162 or 202 MHz for 31P NMR),
at room temperature (20 °C). Chemical shifts were reported in ppm
(parts per million) and determined according to the solvent peak used
as internal reference and relatively to the trimethylsilyl peak (TMS)
1
for H and 13C NMR and according to an external reference for 31P
NMR. Used solvents were CDCl3, D2O, MeOD-d4, and DSMO-d6
(Sigma-Aldrich). COSY (1H 2D), HSQC 1H−13C, and HMBC
1
1H−13C were obtained to interpret and confirm H and 13C NMR
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1
spectra. H NMR data are reported as follows: chemical shift (ppm),
C(CH3)3, Boc), 70.2 (s, OCH2Ph), 38.7 (s, CHAz), 37.7 (s,
CHCH2Ph), 31.5 (s, CH2, Az), 28.1 (s, 3C, CH3, Boc). HRMS (ESI/
Q-TOF) m/z: [M-H]− calcd for C21H24NO3 338.1756, found
338.1753.
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad signal), coupling constants and integration.
High-resolution mass spectra (HRMS) were recorded on a Q-TOF
Synapt-G2-S instrument using electrospray ionization (ESI) in
positive or negative ion polarity mode.
The pKa and pKaH values calculations were performed on Marvin
Sketch software (ChemAxon, version 19.13.00)33 from the compound
structures. The acidic pKa value was leveled up to 50 for the
calculations.
General Procedure for the Preparation of N-Boc- and N-
Cbz-aziridines Using the Mitsunobu Reaction (Table 1, Route
A). N-Cbz- or N-Boc-amino alcohol (1.0 equiv) was dissolved under
argon atmosphere in anhydrous THF (13.2 mL/mmol) at 0 °C.
Triphenylphosphine (1.5 equiv) was added in one portion, followed
by diethyl azodicarboxylate (1.64 equiv) dropwise, at 0 °C. The
reaction mixture was allowed to warm to room temperature and kept
stirring until completion of the reaction (TLC monitoring). Solvents
were removed in vacuum, and the crude was purified by silica gel flash
chromatography (petroleum ether/ethyl acetate) to obtain the
desired compound.
Benzyl (S)-2-(4-((tert-Butoxycarbonyl)amino)butyl)aziridine-1-
carboxylate (2i). The compound (S)-2i (900 mg, 2.59 mmol, 95%
yield) was obtained as an oil following the procedure described above
(overnight stirring) from compound 1i (1.00 g, 2.73 mmol). Rf
petroleum ether/EtOAc (7/3, v/v): 0.51. 1H NMR (600 MHz,
CDCl3): δ 7.38−7.30 (m, 5H, CHAr), 5.12 (s, 2H, OCH2Ph), 4.49
(s, 1H, NH), 3.10 (m, 2H, CH2NH), 2.46−2.38 (m, 1H, CHAz),
2.34 (d, J = 6.1 Hz, 1H, CH2, Az), 1.98 (d, J = 3.8 Hz, 1H, CH2, Az),
1.55−1.45 (m, 6H, 3CH2), 1.44 (s, 9H, 3CH3, Boc). 13C{1H} NMR
(151 MHz, CDCl3): δ 163.6 (s, C(O)Cbz), 156.1 (s, C(O)Boc),
136.0 (s, CAr), 128.7 (s, CHAr), 128.5 (s, CHAr), 128.3 (s, CHAr),
68.2 (s, OCH2Ph), 40.6 (s, CH2NH), 38.3 (s, CHAz), 32.0 (s, CH2,
Az), 31.9 (s, CH2), 28.6 (s, 3C, 3CH3, Boc), 24.2 (s, 2C, CH2).
HRMS (ESI/Q-TOF) m/z: [M + Na]+ calcd for C19H28N2O4Na
371.1947, found 371.1945.
Benzyl (2S,3S)-2,3-Diphenylaziridine-1-carboxylate (2n). The
compound (S)-2n (724 mg, 2.20 mmol, 76% yield) was obtained
as an oil following the procedure described above (overnight stirring)
from compound 1n (1.00 g, 2.88 mmol). Rf petroleum ether/EtOAc
Benzyl (S)-2-Phenylaziridine-1-carboxylate (2a). The compound
(S)-2a (1.42 g, 5.61 mmol, 76% yield) was obtained as an oil
following the procedure described above (overnight reaction) from
compound 1a (2.00 g, 7.38 mmol). Rf petroleum ether/EtOAc (7/3,
1
(7/3, v/v): 0.90. H NMR (600 MHz, CDCl3): δ 7.29−7.15 (m,
13H, CHAr), 6.94 (dd, J = 7.8, 1.6 Hz, 2H, CHAr), 4.91 (dd, J = 65.4,
12.1 Hz, 2H, OCH2Ph), 3.71 (s, 2H, CHAz). 13C{1H} NMR (151
MHz, CDCl3): δ 160.5 (s, C(O)Cbz), 135.5 (s, CAr), 129.7−125.5
(m, CHAr), 68.3 (s, OCH2Ph), 48.5 (s, CHAz). HRMS (ESI/Q-
TOF) m/z: [M + H]+ calcd for C22H20NO2 330.1494, found
330.1491.
1
v/v): 0.90. H NMR (500 MHz, CDCl3): δ 7.31−7.13 (m, 10H,
HAr), 5.07 (q, J = 12.3 Hz, 2H, CH2Ph), 3.42 (dd, J = 6.3, 3.6 Hz,
1H, CH), 2.63 (d, J = 6.3 Hz, 1H, CH2CH), 2.22 (d, J = 3.6 Hz, 1H,
CH2CH). 13C{1H} NMR (126 MHz, CDCl3): δ 163.2 (s, C(O)Cbz),
137.0 (s, CAr), 135.8 (s, CAr), 129.0−127.8 (m, CHAr), 126.3 (s,
CHAr), 68.5 (s, CH2Ph), 39.5 (s, CH), 35.3 (s, CH2CH). HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C16H16NO2 254.1181, found
254.1181.
General Procedure for the Preparation of N-Boc- and N-
Cbz-aziridines from Amino Alcohols via One-Pot Cyclization
(Table 1, Route B). N-Cbz- or N-Boc-amino alcohol (1 equiv) was
dissolved under argon atmosphere in anhydrous diethyl ether (15
mL/mmol) at room temperature. Dry p-toluenesulfonyl chloride (2.2
equiv) was added, followed by the addition of KOH grinded pellets
(9.0 equiv). A drying tube filled with calcium chloride (CaCl2) sealed
the condenser. The reaction mixture was heated to 40 °C and stirred
until completion of the reaction. Solvents were evaporated in vacuum,
and the crude was dissolved in ethyl acetate. The salts were filtered,
and the filtrate was concentrated to obtain the desired compound.
The purification step using silica gel flash chromatography (petroleum
ether/ethyl acetate gradient) was only performed for compounds 2b,
2l, and 2m.
Benzyl (S)-2-Benzylaziridine-1-carboxylate (2c). The compound
(S)-2c (626 mg, 2.34 mmol, 67% yield) was obtained as a white solid
following the procedure described above (overnight stirring) from
commercially available N-Cbz-L-phenylalanilol (1.00 g, 3.50 mmol). Rf
1
hexane/EtOAc (7/3, v/v): 0.80. H NMR (400 MHz, CDCl3): δ
7.40−7.19 (m, 10H, CHAr), 5.12 (s, 2H, OCH2Ph), 3.04−2.90 (m,
1H, CHCH2Ph), 2.77−2.64 (m, 2H, CHAz, CHCH2Ph), 2.39 (d, J =
5.9 Hz, 1H, CH2, Az), 2.10 (d, J = 3.5 Hz, 1H, CH2, Az). Data in
accordance with the literature.50
Benzyl (S)-2-((1H-Indol-3-yl)methyl)aziridine-1-carboxylate (2d).
The compound (S)-2d (550 mg, 1.80 mmol, 49% yield) was obtained
as an oil following the procedure described above (overnight stirring)
from compound 1d (1.20 g, 3.70 mmol). Rf petroleum ether/EtOAc
tert-Butyl (S)-2-Benzylaziridine-1-carboxylate (2b). The com-
pound (S)-2b (1.39 g, 5.96 mmol, 75% yield) was obtained as a pale
orange oil following the procedure described above (overnight
stirring) from commercially available N-Boc-L-phenylalanilol (2.00 g,
1
(7/3, v/v): 0.43. H NMR (500 MHz, CDCl3): δ 8.00 (s, 1H, NH),
7.58 (dd, J = 7.9, 0.8 Hz, 1H), 7.41−7.28 (m, 7H, CHAr), 7.22−7.18
(m, 1H, CHAr), 7.16−7.09 (m, 1H, CHAr), 5.13 (s, 2H, OCH2Ph),
3.14−3.04 (m, 1H, CHCH2C), 2.90 (ddd, J = 15.3, 5.8, 0.7 Hz, 1H,
CHCH2C), 2.82 (qd, J = 5.9, 3.8 Hz, 1H, CHAz), 2.40 (d, J = 6.0 Hz,
1H, CH2, Az), 2.14 (d, J = 3.7 Hz, 1H, CH2, Az). 13C{1H} NMR (126
MHz, CDCl3): δ 171.3 (s, C(O)Boc), 163.5 (s, CAr), 136.0 (s, CAr),
129.8−126.6 (m, CHAr), 122.3 (d, J = 16.6 Hz, CHAr), 119.6 (s,
CHAr), 118.9 (s, CHAr), 112.2 (s, CHAr), 111.3 (s, CHAr), 68.2 (s,
OCH2Ph), 38.3 (s, CHAz), 32.0 (s, CH2, Az), 28.2 (s, CHCH2C).
HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C19H19N2O2
307.1447, found 307.1446.
1
7.96 mmol). Rf petroleum ether/EtOAc (9/1, v/v): 0.75. H NMR
(500 MHz, CDCl3): δ 7.33−7.29 (m, 4H, CHAr), 7.23 (dt, J = 5.5,
4.2 Hz, 1H, CHAr), 2.96 (dd, J = 14.0, 5.4 Hz, 1H, CH2Ph), 2.66 (dd,
J = 18.9, 4.8 Hz, 1H, CH2Ph), 2.66−2.60 (m, 1H, CHAz), 2.31 (d, J =
5.7 Hz, 1H, CH2, Az), 2.03 (d, J = 3.5 Hz, 1H, CH2, Az), 1.44 (s, 9H,
3CH3, Boc). Data in accordance with the literature.51
tert-Butyl (S)-2-((S)-sec-Butyl)aziridine-1-carboxylate (2g). The
compound (S)-2g (891 mg, 4.47 mmol, 97% yield) was obtained as
an oil following the procedure described above (overnight stirring)
from commercially available N-Boc-L-isoleucinol (1.00 g, 4.60 mmol).
tert-Butyl (S)-2-(4-(Benzyloxy)benzyl)aziridine-1-carboxylate
(2e). The compound (S)-2e (766 mg, 2.26 mmol, 53% yield) was
obtained as an oil following the procedure described above (6h
stirring) from compound 1e (1.51 g, 4.23 mmol). Rf petroleum ether/
1
Rf hexane/EtOAc (7/3, v/v): 0.85. H NMR (600 MHz, CDCl3): δ
2.22 (d, J = 6.3 Hz, 1H, CH2, Az), 2.18−2.14 (m, 1H, CHAz), 1.90
(d, J = 3.9 Hz, 1H, CH2, Az), 1.65 (tdd, J = 14.5, 7.3, 5.0 Hz, 1H,
CH2CH3), 1.44 (s, 9H, 3CH3, Boc), 1.41−1.32 (m, 1H, CH2CH3),
1.17−1.09 (m, 1H, CHCH3), 0.97 (t, J = 7.5 Hz, 3H, CH3CH2), 0.91
(d, J = 6.8 Hz, 3H, CH3CH). 13C{1H} NMR (151 MHz, CDCl3): δ
163.0 (s, C(O)Boc), 80.9 (s, C(CH3)3, Boc), 43.5 (s, CHAz), 37.8 (s,
CHCH3), 30.7 (s, CH2, Az), 28.1 (s, 3C, 3CH3, Boc), 27.7 (s,
CH2CH3), 16.1 (s, CH3CH), 11.1 (s, CH3CH2). HRMS (ESI/Q-
TOF) m/z: [M + H]+ calcd for C11H22NO2 200.1645, found
200.1643.
1
EtOAc (9/1, v/v): 0.42. H NMR (500 MHz, CDCl3): δ 7.45−7.41
(m, 2H, CHAr), 7.41−7.35 (m, 2H, CHAr), 7.35−7.29 (m, 1H,
CHAr), 7.24−7.20 (m, 2H, CHAr), 6.95−6.90 (m, 2H, CHAr), 5.05
(s, 2H, OCH2Ph), 2.97−2.82 (m, 1H, CHCH2Ph), 2.66−2.53 (m,
2H, CHCH2Ph, CHAz), 2.29 (d, J = 5.9 Hz, 1H, CH2, Az), 2.01 (d, J
= 3.4 Hz, 1H, CH2, Az), 1.44 (s, 9H, CH3, Boc). 13C{1H} NMR (126
MHz, CDCl3): δ 162.6 (s, C(O)Boc), 157.7 (s, CAr), 137.3 (s, CAr),
131.3−126.7 (m, 9C, CHAr, CAr), 115.0 (s, CHAr), 81.2 (s,
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tert-Butyl (S)-2-(4-((tert-Butoxycarbonyl)amino)butyl)aziridine-
1-carboxylate (2j). The compound (S)-2j (284 mg, 0.90 mmol,
quantitative yield) was obtained as an oil following the procedure
described above (4h stirring) from compound 1j (300 mg, 0.90
mmol). Rf dichloromethane/MeOH (95/5, v/v): 0.70. 1H NMR (400
MHz, CDCl3): δ 4.55 (s, 1H, NH), 3.12 (dd, J = 9.0, 4.2 Hz, 2H,
CH2NH), 2.34 (dt, J = 9.8, 4.9 Hz, 1H, CHAz), 2.25 (d, J = 6.1 Hz,
1H, CH2, Az), 1.90 (d, J = 3.8 Hz, 1H, CH2, Az), 1.53 (m, 6H,
3CH2), 1.45 (s, 9H, CH3, Boc), 1.44 (s, 9H, CH3, Boc). 13C{1H}
NMR (101 MHz, CDCl3): δ 162.8 (s, C(O),Boc Az), 156.1 (s,
C(O)Boc), 81.1 (s, C(CH3)3, Boc), 79.2 (s, C(CH3)3, Boc), 40.6 (s,
CH2NH), 38.0 (s, CHAz), 32.0 (s, CH2), 31.8 (s, CH2, Az), 28.6 (s,
3C, 3CH3, Boc), 28.1 (s, 3C, 3CH3, Boc), 24.3 (s, 2C, 2CH2). Weakly
ionizable compound, molecular peak undetected in MS analysis,
neither in positive or negative mode.
p-Toluenesulfonyl chloride (2.2 equiv) was added, followed by
ground KOH pellets (6 equiv). The reaction mixture was then heated
at 45 °C and kept under stirring overnight. Volatiles were removed in
vacuo and purified by silica gel flash chromatography (petroleum
ether/ethyl acetate gradient) to obtain the title compound as an oil
(3.15 g, 9.23 mmol, 64% yield). Rf hexane/EtOAc (6/4, v/v): 0.65.
[α]D20 +23 (c 1, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ 7.80 (d, J
= 8.2 Hz, 1H, HAr, Ts), 7.35 (d, J = 8.2 Hz, 1H, HAr, Ts), 4.23−4.14
(m, 2H, CH2O), 2.45 (s, 3H, CH3,Ts), 2.43−2.38 (m, 1H, CHAz),
2.26 (d, J = 6.5 Hz, 1H, CH2, Az), 1.92 (d, J = 3.4 Hz, 1H, CH2, Az),
1.90−1.84 (m, 1H, CH2CH2O), 1.79−1.72 (m, 1H, CH2CH2O), 1.42
(s, 9H, CH3,Boc). 13C{1H} NMR (126 MHz, CDCl3): δ 161.1 (s,
NC(O)O, Boc Az), 143.9 (s, CCH3, Ts), 132.0 (s, CS, Ts), 128.9 (m,
2C, CH, Ts), 126.9 (m, 2C, CH, Ts), 80.4 (s, CCH3, Boc), 67.0 (s,
CH2O), 33.3 (s, CHAz), 30.9 (s, CH2CH2N), 30.4 (s, CH2, Az), 26.8
(s, 3C, CH3,Boc), 20.6 (s, CH3, Ts). HRMS (ESI/Q-TOF) m/z: [M
+ Na]+ calcd for C16H23NO5SNa 364.1195, found 364.1194.
Benzyl (1R,6S)-7-Azabicyclo[4.1.0]heptane-7-carboxylate (2k).
The compound (S)-2k (789 mg, 3.41 mmol, 97% yield) was obtained
as a pale orange oil following the procedure described above (5h
stirring) from compound 1k (1 g, 3.5 mmol). Rf petroleum ether/
(S)-tert-Butyl 2-(2-(1H-Benzimidazol-1-yl)ethyl)aziridine-1-car-
boxylate (2f). NaH (256 mg, 60% in oil, 1.2 equiv) was dissolved
in anhydrous THF (4.76 mL/mmol of benzimidazole) at 0 °C, under
argon atmosphere. Benzimidazole (760 mg, 6.44 mmol, 1.2 equiv)
previously dissolved in anhydrous THF (2.38 mL/mmol of
benzimidazole) was added, and the mixture was stirred for 30 min.
The mixture was warmed to room temperature, and N-Boc-tosylated
aziridine 6 (1.83 g, 5.36 mmol, 1 equiv) dissolved in anhydrous THF
(3 mL/mmol of aziridine) was added. The mixture was then heated to
60 °C and kept under stirring overnight. Volatiles were removed in
vacuo, and the crude was dissolved in ethyl acetate. After filtration
(glass filter, porosity 4), the salts were washed with ethyl acetate and
the filtrates were combined and concentrated then purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate gradient)
to obtain the title compound as a colorless oil (750 mg, 2.61 mmol,
50% yield). Thus, compound 2f was obtained in five steps with 22%
1
EtOAc (9/1, v/v): 0.50. H NMR (400 MHz, CDCl3): δ 7.40−7.28
(m, 5H, CHAr), 5.12 (s, 2H, CH2Ph), 2.71−2.59 (m, 2H, 2CHAz),
2.03−1.72 (m, 4H, 2CH2), 1.46−1.20 (m, 4H, 2CH2). Data in
accordance with the literature.32 Weakly ionizable compound,
molecular peak undetected in MS analysis, neither in positive or
negative mode.
Benzyl (1aR,6aS)-6,6a-Dihydroindeno[1,2-b]azirine-1(1aH)-car-
boxylate (Invertomers) (2l). The compound (S)-2l (150 mg, 0.57
mmol, 16% yield) was obtained as an oil following the procedure
described above (overnight stirring) from compound 1l (1.00 g, 3.53
mmol). Rf hexane/EtOAc (7/3, v/v): 0.30. 1H NMR (400 MHz,
CDCl3): δ 7.43−7.31 (m, 8H, CHAr, A,B), 7.30−7.22 (m, 5H,
CHAr, A,B), 5.15 (s, 0.68H, CH2Ph, A), 5.13 (s, 2H, CH2Ph, B), 5.10
(d, J = 2.9 Hz, 0.42H, CCHAz, A), 5.05 (d, J = 5.2 Hz, 1H, CCHAz,
B), 4.45 (t, J = 9.5 Hz, 1H, CHAzCH2, B), 4.06 (t, J = 6.7 Hz, 0.12H,
CHAzCH2, A), 3.34 (dd, J = 15.3, 8.2 Hz, 0.33H, CH2, A), 3.26 (dd, J
= 15.8, 7.2 Hz, 1H, CH2, B), 2.90 (dd, J = 15.8, 7.3 Hz, 1H, CH2, B),
2.72 (dd, J = 15.3, 9.1 Hz, 0.29H, CH2, A). HRMS (ESI/Q-TOF) m/
z: [M + H]+ calcd for C17H16NO2 266.1176, found 266.1162.
tert-Butyl (1aR,6aS)-6,6a-Dihydroindeno[1,2-b]azirine-1(1aH)-
carboxylate (invertomers) (2m). The compound (S)-2m (480 mg,
2.08 mmol, 31% yield) was obtained as an oil following the procedure
described above (2 h stirring) from compound 1m (1.67 g, 6.70
mmol). Rf hexane/EtOAc (7/3, v/v): 0.50. 1H NMR (600 MHz,
CDCl3): δ 7.42 (d, J = 7.3 Hz, 2H, CHAr, A,B), 7.32−7.19 (m, 4H,
CHAr, A,B), 5.06 (d, J = 6.2 Hz, 0.42H, CCHAz, A), 5.04 (d, J = 5.2
Hz, 1H, CCHAz, B), 4.37 (s, 1H, CHAzCH2, B), 4.08 (dd, J = 15.6,
7.9 Hz, 0.37H, CHAzCH2, A), 3.30 (dd, J = 15.2, 8.2 Hz, 0.55H, CH2,
A), 3.23 (dd, J = 15.8, 7.3 Hz, 1H, CH2, B), 2.87 (dd, J = 15.8, 7.2 Hz,
1H, CH2, B), 2.69 (dd, J = 15.2, 9.1 Hz, 0.56H, CH2, A), 1.48 (s, 5H,
CH3, Boc A), 1.47 (s, 9H, CH3, Boc B). 13C{1H} NMR (151 MHz,
CDCl3): δ 156.2 (s, C(O)Boc), 142.3 (s, CAr), 141.2 (s, CAr),
130.8−123.3 (m, CHAr), 82.1 (s, CCHAz, A), 75.0 (s, CCHAz, B),
62.0 (s, CH2CHAz, A), 54.8 (s, CH2CHAz, B), 37.0 (s, CH2, B), 36.2
(s, CH2, A), 28.5 (s, 3C, CH3, Boc). HRMS (ESI/Q-TOF) m/z: [M
+ H]+ calcd for C14H18NO2 232.1332, found 232.1329.
1
overall yield from L-aspartic acid. Rf EtOAc: 0.30. H NMR (500
MHz, CDCl3): δ 8.06 (s, 1H, NCHArN), 7.81 (dd, J = 6.7, 1.9 Hz,
1H, HAr), 7.43 (dd, J = 7.0, 2.1 Hz, 1HAr), 7.34−7.27 (m, 2H, HAr),
4.41 (dd, J = 7.8, 5.8 Hz, 2H, CH2CH2N), 2.36 (ddt, J = 8.3, 6.2, 3.8
Hz, 1H, CHN), 2.29 (d, J = 6.2 Hz, 1H, CHCH2N), 2.27−2.20 (m,
1H, CH2CH2N), 1.91 (d, J = 3.6 Hz, 1H, CHCH2N, Az), 1.72 (ddt, J
= 14.3, 8.5, 5.8 Hz, 1H, CH2CH2N), 1.48 (s, 9H, 3CH3, Boc).
13C{1H} NMR (126 MHz, CDCl3): δ 162.22 (s, C(O), Boc), 144.2
(s, CAr), 143.5 (s, C-2), 133.7 (s, CAr), 123.1 (s, CAr), 122.3 (s,
CAr), 120.7 (s, CAr), 109.7 (s, CAr), 81.9 (s, C(CH3)3,Boc), 43.1 (s,
CH2CH2N), 35.2 (s, CHN), 32.8 (s, CH2CH2N), 31.8 (s,
CHCH2N), 28.1 (s, 3C, 3CH3, Boc). HRMS (ESI/Q-TOF) m/z:
[M + H]+ calcd for C16H22N3O2 288.1712, found 288.1718.
Benzyl (R)-2-(2-(tert-Butoxy)-2-oxoethyl)aziridine-1-carboxylate
(2h). The procedure is adapted from the work of Jung et al.30 Cbz-L-
Asp(OtBu)-OH (882 mg, 2.73 mmol, 1 equiv) was dissolved in
anhydrous THF (3.2 mL/mmol) under argon atmosphere, at 0 °C.
BH3·THF (1 M in THF, 5 equiv) was added portionwise. The
mixture was stirred for 1 h at 0 °C and then allowed to warm at room
temperature and quenched by slow addition of methanol. The mixture
was concentrated in vacuo. The crude was purified on silica gel by
flash chromatography (dichloromethane/ethyl acetate gradient) to
obtain the amino alcohol30 as an oil (508 mg, 1.64 mmol, 60% yield).
For the next step, the protocol from Aaseng et al.31 was adapted. The
reduced compound (508 mg, 1.64 mmol, 1 equiv) was dissolved
under argon atmosphere in anhydrous THF (13.2 mL/mmol) at 0
°C. Triphenylphosphine (1.5 equiv) was added, followed by diethyl
azodicarboxylate (1.64 equiv) dropwise, at 0 °C. The mixture was
allowed to warm to room temperature for 2.5 h. Solvents were
evaporated in vacuo, and the crude was purified by silica gel flash
chromatography (petroleum ether/ethyl acetate gradient) to obtain
the desired compound (296 mg, 1.02 mmol, 62% yield) as an oil.
Compound 2h was obtained in two steps with 37% overall yield from
Cbz-L-Asp(OtBu)-OH. Rf petroleum ether/EtOAc (6/4, v/v): 0.90.
1H NMR (400 MHz, CDCl3): δ 7.37−7.26 (m, 5H, CHAr), 5.16−
Synthesis of Aziridine 2f.
tert-Butyl (S)-(1,4-Dihydroxybutan-2-yl)carbamate (5). The proto-
29
̈
col is adapted from the work of Jorres et al. Compound 5 was
isolated as oil (6.54 g, 31.80 mmol, 73% yield) from L-aspartic acid.
Data in accordance with the literature.29
tert-Butyl (S)-2-(2-(Tosyloxy)ethyl)aziridine-1-carboxylate (6).
The procedure is adapted from the work of Aaseng et al.52 The
compound 5 (2.96 g, 14.40 mmol, 1 equiv) was dissolved in diethyl
ether (15 mL/mmol) under argon atmosphere at room temperature.
5.09 (m, 2H, CH2Ph), 2.79 (ddd, J = 12.6, 6.0, 3.7 Hz, 1H, CHAz),
2.60 (dd, J = 16.1, 5.9 Hz, 1H, CHCH2C(O)), 2.42 (d, J = 6.1 Hz,
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1H, CH2, Az), 2.28 (dd, J = 16.1, 6.7 Hz, 1H, CHCH2C(O)), 2.07 (d,
J = 3.7 Hz, 1H, CH2, Az), 1.44 (s, 9H, 3CH3, Boc). Data in
accordance with the literature.53
in water, at 0 °C. After being stirred for 1 h 30, the reaction mixture
was filtered on a glass filter with dichloromethane. The filtrate was
concentrated, dissolved in ethyl acetate, and washed with water. The
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo. The resulting crude was purified by silica gel flash
chromatography (dichloromethane/MeOH gradient) to obtain the
title compound as an oil (1.53 g, 4.18 mmol, 80% yield). Rf
dichloromethane/MeOH (95/5, v/v): 0.40. 1H NMR (400 MHz,
CDCl3): δ 7.40−7.28 (m, 5H, CHAr), 5.10 (s, 2H, CH2Ph), 5.15−
5.01 (m, 3H), 4.57 (s, 1H), 3.74−3.54 (m, 3H), 3.22−3.13 (m, 1H),
3.12−3.01 (m, 1H), 2.46 (br s, 1H, OH), 1.67−1.57 (m, 2H), 1.53−
1.33 (m, 17H). Data in accordance with the literature.58
Di-tert-butyl (6-Hydroxyhexane-1,5-diyl)(S)-dicarbamate (1j).
The L-Nα,Nε-bisBoc-Lys-OH dicyclohexylammonium (600 mg,
1.14 mmol, 1 equiv) was dissolved in anhydrous THF (11 mL/
mmol) under argon atmosphere. N-Methylmorpholine and ethyl
chloroformate (1 equiv) were added at −10 °C, and the reaction
mixture was stirred for 30 min at −10 °C. LiAlH4 (2.0 equiv) was
then slowly added dropwise, and the reaction was allowed to warm at
room temperature. The reaction mixture was stirred overnight and
then quenched by the slow addition of a 4.5% NaOH solution in
water, at 0 °C. After being stirred for 1 h 30, the reaction mixture was
filtered on a glass filter. The filtrate was concentrated in vacuo,
dissolved in ethyl acetate, and washed with water. The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The crude
was purified by silica gel flash chromatography (dichloromethane/
MeOH gradient) to obtain the title compound as a colorless oil (300
mg, 0.90 mmol, 80% yield). Rf dichloromethane/MeOH (95/5, v/v):
0.25. 1H NMR (400 MHz, CDCl3): δ 4.77 (br s, 1H, NH), 4.58 (br s,
1H, NH), 3.72−3.46 (m, 3H, CH2, CH), 3.23−3.13 (m, 1H), 3.13−
3.05 (m, 1H), 2.69−2.43 (m, 1H, OH), 1.63−1.54 (m, 2H, CH2),
1.52−1.25 (m, 22H, 6CH3, Boc, 2CH2). Data in accordance with the
literature.59
(S)-4-Benzyloxazolidin-2-one (4). The protocol is adapted from
the work of Cardillo et al.34 The compound 2b (160 mg, 0.68 mmol,
1 equiv) was dissolved in anhydrous toluene (35.7 mL/mmol), at
room temperature under argon atmosphere, in a microwave tube. BF3·
Et2O (1 equiv) was added, and then the tube was sealed and placed
under microwave radiations (55 °C for 10 min, 100 W, and 1000
rpm). The reaction mixture was diluted with ethyl acetate and water.
The aqueous layer was extracted twice with ethyl acetate, and the
organic layers were combined, dried on MgSO4, filtered, and
concentrated in vacuo, and the crude was purified by silica gel flash
chromatography (dichloromethane/MeOH gradient) to afford the
title compound (88 mg, 0.49 mmol, 73% yield) as a white solid. Rf
dichloromethane/MeOH (95/5, v/v): 0.30. 1H NMR (500 MHz,
CDCl3): δ 7.42−7.13 (m, 5H, CHAr), 5.38 (d, J = 4.0 Hz, 1H, NH),
4.87 (dq, J = 8.0, 6.7 Hz, 1H, CH), 3.58 (t, J = 8.4 Hz, 1H, OCH2),
3.34 (dd, J = 8.5, 6.9 Hz, 1H, OCH2), 3.15 (dd, J = 14.0, 6.2 Hz, 1H,
CH2Ph), 2.95 (dd, J = 14.0, 6.8 Hz, 1H, CH2Ph). 13C{1H} NMR
(126 MHz, CDCl3): δ 159.7 (s, C(O)), 135.3 (s, CAr), 129.5 (s,
CHAr), 128.9 (s, CHAr), 127.3 (s, CHAr), 77.2 (s, CH), 45.1 (s,
OCH2), 40.7 (s, CH2Ph). HRMS (ESI/Q-TOF) m/z: [M + H]+
calcd for C10H12NO2 178.0868, found 178.0868.
Benzyl (S)-(2-Hydroxy-1-phenylethyl)carbamate (1a). The title
compound (3.76 g, 13.87 mmol, 95% yield) was obtained as a white
powder following the procedure described by Sultane et al.54 from
commercially available L-phenylglycinol (2.00 g, 14.58 mmol). Rf
petroleum ether/EtOAc (6/4, v/v): 0.26. 1H NMR (400 MHz,
CDCl3): δ 7.42−7.23 (m, 10H, CHAr), 5.47 (s, 1H, NH), 5.11 (q, J =
12.2 Hz, 2H, OCH2Ph), 4.86 (s, 1H, CH), 3.95−3.80 (m, 2H,
CH2OH). Data in accordance with the literature.54
Benzyl (S)-(1-Hydroxy-3-(1H-indol-3-yl)propan-2-yl)carbamate
(1d). The title compound (720 mg, 2.22 mmol, 42% yield) was
obtained as a white foam following the procedure from Yeung et al.55
from the commercially available L-tryptophanol (1.00 g, 5.26 mmol).
Benzyl ((1R,2R)-2-Hydroxycyclohexyl)carbamate (1k). The pro-
tocol was adapted from Luna et al.60 The (1R,2R)-trans-2-amino-
cyclohexanol hydrochloride (2.00 g, 13.19 mmol, 1 equiv) was
dissolved in distilled water (1.7 mL/mmol), and K2CO3 (1.2 equiv)
was added. Then benzyl chloroformate (CbzCl, 1.2 equiv) was added
dropwise at 0 °C. A white precipitate was formed. The reaction
mixture was allowed to warm to room temperature and stirred
overnight. Dichloromethane was added to the reaction mixture, and
the aqueous layer was extracted with dichloromethane. The organic
layers were combined, dried on MgSO4, filtered, and concentrated in
vacuo. The crude was purified on silica gel (petroleum ether/ethyl
acetate gradient) to afford the title compound (3.72 g, 13.00 mmol,
98% yield) as a white solid. Rf petroleum ether/EtOAc (7/3, v/v):
1
Rf petroleum ether/EtOAc (6/4, v/v): 0.10. H NMR (400 MHz,
CDCl3): δ 8.03 (s, 1H, NH), 7.65 (d, J = 7.5 Hz, 1H, CHAr), 7.43−
7.28 (m, 6H), 7.21 (t, J = 7.5 Hz, 1H, CHAr), 7.15−7.07 (m, 1H,
CHAr), 7.03 (s, 1H, CHAr), 5.10 (s, 2H, CH2Ph), 5.04 (br s, 1H,
NH), 4.16−3.95 (m, 1H, CH), 3.68 (ddd, J = 15.4, 9.7, 4.2 Hz, 2H,
CCH2CH), 3.03 (d, J = 6.8 Hz, 2H, CH2OH). Data in accordance
with the literature.55,56
tert-Butyl (S)-(1-(4-(Benzyloxy)phenyl)-3-hydroxypropan-2-yl)-
carbamate (1e). The protocol was adapted from Jung et al.30 Boc-
Tyr(OBn)-OH (1.00 g, 2.69 mmol, 1 equiv) was dissolved in
anhydrous THF (2.3 mL/mmol) at 0 °C under argon atmosphere.
BH3·THF (1 M in THF, 2.5 equiv) was added dropwise over 20 min
(exothermic reaction) to the solution, and the reaction mixture was
stirred for 1 h at 0 °C and then 3 h at room temperature. Methanol
was slowly added at 0 °C to quench the reaction. Volatiles were
removed in vacuo, and the crude was dissolved in methanol and then
concentrated several times. The crude was purified by flash
chromatography on silica gel (dichloromethane/MeOH gradient) to
obtain the title product as a white solid (958 mg, 2.68 mmol, 99%
1
0.20. H NMR (400 MHz, CDCl3): δ 7.40−7.28 (m, 5H, CHAr),
5.20−5.04 (m, 2H, CH2Ph), 4.72 (br s, 1H, NH), 3.40 (m, 1H, CH),
3.32 (m, 1H, CH), 2.80 (br s, 1H, OH), 2.11−1.93 (m, 2H, CH2),
1.71 (m, 2H, CH2), 1.40−1.09 (m, 4H). Data in accordance with the
literature.60
Benzyl ((1R,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-
carbamate (1l). The (1R,2R)-(−)-1-amino-2-indanol (1.00 g, 6.70
mmol, 1 equiv) was dissolved in anhydrous dichloromethane (1 mL/
mmol) at 0 °C under argon atmosphere. Benzyl chloroformate
(CbzCl, 1 equiv) was added at 0 °C, followed by pyridine (1.5 equiv),
and the reaction mixture was stirred at room temperature overnight.
The reaction was quenched by addition of brine, and water was added
to dissolve the salts. The mixture was extracted with dichloromethane,
and the resulting emulsion was filtered on a hydrophobic filter
cartridge. The prganic layers were recovered, dried on MgSO4,
filtered, and concentrated in vacuo. The crude was purified by silica
gel flash chromatography (petroleum ether/ethyl acetate gradient) to
obtain the title compound (1.20 g, 4.24 mmol, 63% yield) as a white
1
yield). Rf dichloromethane/MeOH (95/5, v/v): 0.55. H NMR (400
MHz, CDCl3): δ 7.47−7.29 (m, 5H, CHAr), 7.12 (d, J = 8.5 Hz, 2H,
CHAr), 6.92 (d, J = 8.5 Hz, 2H, CHAr), 5.05 (s, 2H, CCH2Ph), 3.82
(m, 1H, CH), 3.60 (ddd, J = 43.3, 11.3, 5.4 Hz, 2H, CHCH2Ph), 2.78
(d, J = 7.2 Hz, 2H, CH2OH), 1.42 (s, 9H, 3CH3, Boc). Data in
accordance with the literature.30,57
Benzyl tert-Butyl (6-hydroxyhexane-1,5-diyl)-(S)-dicarbamate
(1i). The L-Nα-Z,Nε-BocLys-OH (2.00 g, 5.26 mmol, 1 equiv) was
dissolved in anhydrous THF (11.0 mL/mmol) under argon
atmosphere. N-Methylmorpholine and ethyl chloroformate (1
equiv) were added at −10 °C, and the reaction mixture was stirred
for 30 min at −10 °C. LiAlH4 (2 equiv) was then slowly added
dropwise, and the reaction was allowed to warm at room temperature.
The reaction mixture was stirred overnight at room temperature. The
reaction was quenched by the slow addition of a 4.5% NaOH solution
1
solid. Rf hexane/EtOAc (66/34, v/v): 0.30. H NMR (600 MHz,
CDCl3): δ 7.39 (dd, J = 4.2, 1.8 Hz, 2H, CHAr), 7.38−7.33 (m, 1H,
CHAr), 7.29−7.17 (m, 6H, CHAr), 5.23 (s, 1H, NH), 5.19 (q, J =
12.2 Hz, 1H, OCH2Ph), 4.99 (t, J = 6.1 Hz, 1H, CHNH), 4.46 (dd, J
= 14.7, 7.4 Hz, 1H, CHOH), 3.31 (dd, J = 15.8, 7.7 Hz, 1H, CH2),
2.93 (dd, J = 15.8, 8.1 Hz, 1H, CH2). 13C{1H} NMR (151 MHz,
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CDCl3): δ 157.9 (s, C(O)Cbz), 140.3 (s, CAr), 139.1 (s, CAr), 136.1
(s, CAr), 128.7 (m, CHAr), 127.5 (s, CHAr), 125.4 (s, CHAr), 123.1
(s, CHAr), 82.2 (s, CHOH), 67.6 (s, OCH2Ph), 64.6 (s, 1C,
CHNH), 38.6 (s, CH2). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd
for C17H18NO3 284.1281, found 284.1285.
2CH2CH3), 1.18 (dt, J = 14.2, 7.1 Hz, 6H, 2CH2CH3). 13C{1H}
NMR (126 MHz, CDCl3): δ 139.3 (s, CAr), 128.2 (s, CHAr), 127.2
(s, CHAr), 126.5 (s, CHAr), 65.1 (t, J = 149.3 Hz, PCHP), 63.6 (d, J
= 7.1 Hz, 2C, CH2CH3), 63.4−63.1 (m, 2C, CH2CH3), 43.6 (d, J =
15.6 Hz, CHAz), 40.2 (d, J = 15.9 Hz, CH2, Az), 16.8−16.6 (m, 2C,
2CH2CH3), 16.4 (d, J = 6.8 Hz, 2C, 2CH2CH3). 31P{1H} NMR (162
MHz, CDCl3): δ 17.6 (d, JPP = 2.6 Hz), 17.4 (d, JPP = 2.6 Hz). HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C17H30NO6P2 406.1548,
found 406.1549.
tert-Butyl ((1R,2R)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)-
carbamate (1m). The (1R,2R)-(−)-1-amino-2-indanol (1.00 g, 6.70
mmol, 1 equiv) was dissolved in anhydrous dichloromethane (1.8
mL/mmol) at room temperature under argon atmosphere. Triethyl-
amine (Et3N, 1.5 equiv) was added, followed by Boc2O (di-tert-butyl
dicarbonate, 1.2 equiv). The reaction was stirred at room temperature
for 6 h. The reaction was quenched by addition of an aqueous
solution of saturated NaHCO3 and extracted with dichloromethane.
The emulsion was filtered on a hydrophobic filter cartridge. The
organic layer was dried over MgSO4, filtered, and concentrated in
vacuo to obtain the title compound (1.67 g, 6.7 mmol, quantitative
yield) as a white solid. Rf hexane/EtOAc (66/34, v/v): 0.50. 1H NMR
(600 MHz, CDCl3): δ 7.30−7.14 (m, 4H, CHAr), 5.06 (s, 1H, NH),
4.90 (t, J = 5.9 Hz, 1H, CHNH), 4.41 (dd, J = 14.2, 7.8 Hz, 1H,
CHOH), 4.30 (s, 1H, OH), 3.28 (dd, J = 15.8, 7.7 Hz, 1H, CH2),
2.91 (dd, J = 15.7, 8.1 Hz, 1H, CH2), 1.50 (s, 9H, CH3, Boc).
13C{1H} NMR (151 MHz, CDCl3): δ 157.6 (s, C(O)Boc), 140.3 (s,
Tetraethyl ((2-Benzylaziridin-1-yl)methylene)-(S)-bis-
(phosphonate) (3b). The title compound (264 mg, 0.63 mmol,
84% yield) was obtained as a colorless oil following the procedure
described above (overnight stirring at room temperature) from
compound 2c (200 mg, 0.75 mmol) or from compound 2b (stirring 2
h at 80 °C, 500 mg, 2.14 mmol) with 69% yield (630 mg, 1.50 mmol).
1
Rf dichloromethane/MeOH (95/5, v/v): 0.35. H NMR (500 MHz,
CDCl3): δ 7.30−7.18 (m, 5H, CHAr), 4.32−4.18 (m, 8H, CH2CH3),
3.33 (dd, J = 14.1, 3.6 Hz, 1H, CH2Ph), 2.40 (t, J = 18.1 Hz, 1H,
PCHP), 2.40 (dd, J = 13.4, 9.4 Hz, 1H, CH2Ph), 2.11−2.00 (m, 1H,
CHAz), 1.93 (d, J = 3.9 Hz, 1H, CH2, Az), 1.72 (d, J = 8.3 Hz, 1H,
CH2, Az), 1.38 (t, J = 7.1 Hz, 6H, CH2CH3), 1.35 (dt, J = 7.0, 4.4 Hz,
6H, CH2CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 138.8 (s, CAr),
129.1 (s, 2C, CHAr), 128.5 (s, 2C, CHAr), 126.4 (s, CHAr), 64.9 (t,
J = 150.1 Hz, PCHP), 63.3 (d, J = 10.6 Hz, 2C, CH2CH3), 63.1 (d, J
= 6.9 Hz, 2C, CH2CH3), 43.1 (d, J = 16.2 Hz, CHAz), 38.9 (s,
CH2Ph), 36.5 (d, J = 17.0 Hz, CH2 Az), 16.7 (d, J = 10.3 Hz, 2C,
CH2CH3), 16.6 (d, J = 10.1 Hz, 2C, CH2CH3). 31P{1H} NMR (202
MHz, CDCl3): δ 18.0 (s, 1P), 17.9 (s, 1P). HRMS (ESI/Q-TOF) m/
z: [M + H]+ calcd for C18H32NO6P2 420.1705, found 420.1709.
Tetraethyl ((2-((1H-indol-3-yl)methyl)aziridin-1-yl)methylene)-
(S)-bis(phosphonate) (3d). The title compound (53 mg, 0.11
mmol, 45% yield) was obtained as a colorless oil following the
procedure described above (4h stirring at room temperature) from
compound 2d (78 mg, 0.25 mmol).
CArCH2), 139.5 (s, CArCHNH), 128.6 (s, CH), 127.3 (s, CH),
125.3 (s, CH), 123.1 (s, CH), 82.2 (s, CHOH), 80.6 (s, C(CH3)3),
64.2 (s, CHNH), 38.5 (s, CH2), 28.6 (s, CH3, Boc). HRMS (ESI/Q-
TOF) m/z: [M + H]+ calcd for C14H20NO3 250.1437, found
250.1434.
Benzyl ((1S,2R)-2-Hydroxy-1,2-diphenylethyl)carbamate (1n).
The (1R,2S)-2-amino-1,2-diphenylethanol (2.00 g, 9.38 mmol, 1
equiv) was dissolved in anhydrous THF (2.77 mL/mmol) at 0 °C
under argon atmosphere. Solid NaHCO3 (2 equiv) was then added,
followed by benzyl chloroformate (CbzCl, 1.2 equiv) dropwise. The
mixture was stirred overnight at room temperature until completion
of the reaction (TLC monitoring). The reaction was quenched by
addition of water and extracted with ethyl acetate. The organic layers
were acidified with HCl 1 N, washed with brine, dried on MgSO4,
filtrated, and concentrated in vacuum. The crude was purified by silica
gel flash chromatography (dichloromethane/MeOH gradient) to
obtain the title compound (3.25 g, 9.38 mmol, quantitative yield) as a
Rf dichloromethane/MeOH (95/5, v/v): 0.50. 1H NMR (600
MHz, CDCl3): δ 8.46 (s, 1H, NH), 7.60 (dd, J = 7.8, 0.7 Hz, 1H,
CHAr), 7.36 (d, J = 8.1 Hz, 1H, CHAr), 7.19−7.11 (m, 1H, CHAr),
7.11−7.05 (m, 1H, CHAr), 7.02 (d, J = 2.0 Hz, 1H, NHCHArC),
4.35−4.17 (m, 8H, 4CH2CH3), 3.50 (dd, J = 14.8, 3.3 Hz, 1H,
CHCH2C), 2.55−2.47 (m, 1H, CHCH2C), 2.43 (t, J = 18.2 Hz, 1H,
PCHP), 2.19−2.13 (m, 1H, CHAz), 1.96 (d, J = 4.0 Hz, 1H, CH2,
Az), 1.72 (d, J = 7.0 Hz, 1H, CH2, Az), 1.39−1.36 (m, 6H,
2CH2CH3), 1.37−1.33 (m, 6H, 2CH2CH3). 13C{1H} NMR (151
MHz, CDCl3): δ 136.4 (s, CAr), 127.8 (s, CAr), 122.1 (s, CHAr),
121.9 (s, CHAr), 119.3 (s, CHAr), 119.1 (s, CHAr), 112.8 (s, CAr),
111.3 (s, CCHArNH), 65.1 (t, J = 150.3 Hz, PCHP), 63.4−62.7 (m,
4C, CH2CH3), 42.8 (d, J = 16.1 Hz, CHAz), 37.0 (d, J = 16.8 Hz,
CH2, Az), 28.6 (s, CHCH2C), 16.6 (s, 4C, CH2CH3). 31P{1H} NMR
(162 MHz, CDCl3): δ 18.1 (s, 2P). HRMS (ESI/Q-TOF) m/z: [M +
H]+ calcd for C20H33N2O6P2 459.1814, found 459.1814.
1
white powder. Rf petroleum ether/EtOAc (7/3, v/v): 0.50. H NMR
(400 MHz, CDCl3): δ 7.41−7.28 (m, 5H, CHAr), 7.24−7.19 (m, 6H,
CHAr), 7.04 (m, 4H, CHAr), 5.59 (br s, 1H, NH), 5.15−4.99 (m,
4H, CHOH, CHNH, CH2Ph), 2.39 (br s, 1H, OH). Data in
accordance with the literature.61
General Procedure for the Preparation of N-Methylene-
gem-bisphosphonate Aziridines from N-Carbamoylaziridines.
Freshly distilled diethyl phosphite (6.1 equiv) was dissolved in
anhydrous THF (0.5 mL/mmol of diethyl phosphite) under argon
atmosphere and cooled to −78 °C. Then LiHMDS (1 M in THF, 6
equiv) was added, and the reaction mixture was stirred for 30 min at
−78 °C. A solution of the N-carbamoylaziridine (1 equiv) in
anhydrous THF (2.8 mL/mmol of aziridine) was added dropwise to
the reaction, which was then allowed to warm to room temperature.
The reaction mixture was stirred at temperature T0 until completion
of the reaction (TLC monitoring). The reaction was quenched by
addition of a saturated aqueous solution of NH4Cl until dissolution of
the salts formed. The mixture was extracted twice with ethyl acetate.
The organic layers were dried on MgSO4, filtered, and concentrated in
vacuo, and the crude was purified by silica gel flash chromatography
(dichloromethane/MeOH gradient) to afford the desired product.
Tetraethyl ((2-Phenylaziridin-1-yl)methylene)-(S)-bis-
(phosphonate) (3a). The title compound (100 mg, 0.39 mmol,
45% yield) was obtained as a colorless oil following the procedure
described above, after being stirred for 1 h at room temperature, from
compound 2a (73 mg, 0.18 mmol). Rf dichloromethane/MeOH (95/
Tetraethyl ((2-(4-(benzyloxy)benzyl)aziridin-1-yl)methylene)(S)-
bis(phosphonate) (3e). The title compound (108 mg, 0.21 mmol,
46% yield) was obtained as a colorless oil following the procedure
described above (3h stirring at 80 °C) from compound 2e (150 mg,
0.44 mmol).
Rf dichloromethane/MeOH (95/5, v/v): 0.25. 1H NMR (500
MHz, CDCl3): δ 7.44−7.40 (m, 2H, CHAr), 7.40−7.35 (m, 2H,
CHAr), 7.34−7.29 (m, 1H, CHAr), 7.14−7.09 (m, 2H, CHAr),
6.92−6.87 (m, 2H, CHAr), 5.03 (s, 2H, OCH2Ph), 4.32−4.17 (m,
8H, 4CH2CH3), 3.26 (dd, J = 14.2, 3.6 Hz, 1H, CHCH2Ph), 2.39 (t, J
= 18.1 Hz, 1H, PCHP), 2.34 (dd, J = 14.2, 8.6 Hz, 1H, CHCH2Ph),
2.06−1.97 (m, 1H, CHAz), 1.90 (d, J = 4.0 Hz, 1H, CH2, Az), 1.70
(dd, J = 6.4, 1.1 Hz, 1H, CH2, Az), 1.37 (t, J = 7.1 Hz, 6H,
2CH2CH3), 1.36−1.33 (m, 6H, 2CH2CH3). 13C{1H} NMR (126
MHz, CDCl3): δ 157.5 (s, OCAr), 137.3 (s, CAr), 131.1 (s, CAr),
130.0 (s, 2C, CHAr), 128.7 (s, 2C, CHAr), 128.0 (s, CHAr), 127.6 (s,
2C, CHAr), 115.0 (s, 2C, CHAr), 70.1 (s, OCH2Ph), 64.91 (t, J =
150.0 Hz, 1C, PCHP), 63.5−62.9 (m, 4C, CH2CH3), 43.2 (d, J =
16.3 Hz, CHAz), 38.0 (s, CHCH2Ph), 36.4 (d, J = 16.8 Hz, CH2, Az),
16.6 (s, 4C, CH2CH3). 31P{1H} NMR (202 MHz, CDCl3): δ 18.0 (s,
1
5, v/v): 0.30. H NMR (400 MHz, CDCl3): δ 7.31−7.24 (m, 4H,
CHAr), 7.21 (m, 1H, CHAr), 4.37−4.24 (m, 4H, 2CH2CH3), 4.21−
3.98 (m, 4H, 2CH2CH3), 2.84 (ddd, J = 6.1, 4.1, 1.7 Hz, 1H, CHAz),
2.61 (t, J = 18.0 Hz, 1H, PCHP), 2.19 (d, J = 3.9 Hz, 1H, CH2, Az),
2.14 (dd, J = 6.7, 1.8 Hz, 1H, CH2, Az), 1.39 (td, J = 7.1, 4.1 Hz, 6H,
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2P). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C25H38NO7P2
526.2124, found 526.2131.
(s, 3C, 3CH2), 28.6 (s, 3C, CH3, Boc), 18.0−15.6 (m, 4C, CH2CH3).
31P{1H} NMR (162 MHz, CDCl3): δ 18 (d, JPP = 3.2 Hz), 17.9 (d,
JPP = 3.2 Hz). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
C20H43N2O8P2 501.2495, found 501.2497.
(S)-Tetraethyl ((2-(2-(1H-Benzo[d]imidazol-1-yl)ethyl)aziridin-1-
yl)methylene)bis(phosphonate) (3f). The title compound (133 mg,
0.28 mmol, 50% yield) was obtained as a colorless oil following the
procedure described above (stirring for 7h at 55 °C) from compound
2f (162 mg, 0.56 mmol). Rf dichloromethane/MeOH (95/5, v/v):
Tetraethyl (((1R,6S)-7-Azabicyclo[4.1.0]heptan-7-yl)methylene)-
bis(phosphonate) (3k). The title compound (120 mg, 0.31 mmol,
72% yield) was obtained as a colorless oil following the procedure
described above (stirring for 2 h at room temperature) from
compound 2k (100 mg, 0.43 mmol). Rf dichloromethane/MeOH
95/5 (v/v): 0.25. 1H NMR (500 MHz, CDCl3): δ 4.32−4.16 (m, 8H,
4CH2CH3), 2.39 (t, J = 18.0 Hz, 1H, PCHP), 1.94−1.87 (m, 4H,
2CH2, 2CHAz), 1.77−1.70 (m, 2H, CH2), 1.35 (td, J = 7.1, 5.9 Hz,
12H, 4CH2CH3), 1.34−1.30 (m, 2H, 2CH2), 1.20−1.11 (m, 2H,
2CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 64.7 (t, J = 149.8 Hz,
PCHP), 63.5−62.4 (m, 4C, 4CH2CH3), 41.3 (d, J = 16.4 Hz, 2C,
2CHAz), 24.1 (s, 2C, 2CH2), 20.5 (s, 2C, 2CH2), 17.0−16.3 (m, 4C,
4CH2CH3). 31P{1H} NMR (202 MHz, CDCl3): δ 18.2 (s, 2P).
HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C15H32NO6P2
384.1705, found 384.1705.
(1aR,6aS)-1,1a,6,6a-Tetrahydroindeno[1,2-b]azirine (3l). The
title compound (57.7 mg, 0.44 mmol, 97% yield) was obtained as a
solid following the procedure described above (overnight stirring at
room temperature) starting from compound 2l (N-Cbz, 120 mg, 0.45
mmol) or from compound 3m (N-Boc, 120 mg, 0.52 mmol)) with
84% yield (57 mg, 0.43 mmol). Rf dichloromethane/MeOH (95/5, v/
v): 0.50. 1H NMR (500 MHz, CDCl3): δ 7.50−7.45 (m, 1H, CHAr),
7.36−7.24 (m, 2H, CHAr), 7.22 (d, J = 7.5 Hz, 1H, CHAr), 6.84 (s,
1H, NH), 5.93 (d, J = 7.5 Hz, 1H, CH), 4.64 (t, J = 7.0 Hz, 1H, CH),
3.21 (dd, J = 17.1, 6.5 Hz, 1H, CH2), 3.03 (d, J = 17.0 Hz, 1H, CH2).
13C{1H} NMR (126 MHz, CDCl3): δ 140.9 (s, CAr), 138.4 (s, CAr),
1
0.25. H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H, NCHArN), 7.80
(dd, J = 5.9, 3.0 Hz, 1H, HAr), 7.41 (dd, J = 5.9, 2.9 Hz, 1H, HAr),
7.31−7.26 (m, 2H, HAr), 4.51−4.34 (m, 2H, CH2N), 4.31−4.15 (m,
8H, 4 CH2CH3), 2.34 (t, J = 18.1 Hz, 1H, PCHP), 2.19−1.95 (m,
1H, CH2CH2N), 1.92−1.86 (m, 1H, CH), 1.70 (dd, J = 9.6, 5.2 Hz,
2H, CHCH2N), 1.35 (t, J = 7.1 Hz, 12H, 4 CH3CH2). 13C{1H} NMR
(151 MHz, CDCl3): δ 144.0 (s, CAr), 143.3 (s, C-2), 133.8 (s, CAr),
122.9 (s, CAr), 122.2 (s, CAr), 120.6 (s, CAr), 109.8 (s, CAr), 64.9
(t, J = 150.5 Hz, PCHP), 63.4 (dd, J = 26.4, 6.4 Hz, 4C, CH2CH3),
42.8 (s, CH2CH2N), 39.3 (d, J = 20.5 Hz, CHN), 35.9 (d, J = 15.0
Hz, CHCH2N), 33.4 (d, J = 40.2 Hz, CH2CH2N), 16.7 (s, 4C,
CH3CH2). 31P{1H} NMR (162 MHz, CDCl3): δ 17.8 (s, 1P), 17.7 (s,
1P). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C20H34N3O6P2
474.1923, found 474.1932.
Tetraethyl (((S)-2-((S)-sec-Butyl)aziridin-1-yl)methylene)bis-
(phosphonate) (3g). The title compound (121 mg, 0.31 mmol,
41% yield) was obtained as a colorless oil following the procedure
described above (stirring for 2 h at 80 °C) from compound 2g (150
mg, 0.75 mmol). Rf petroleum ether/EtOAc (7/3, v/v): 0.10. 1H
NMR (500 MHz, MeOD): δ 4.31−4.15 (m, 8H, 4CH2CH3), 2.71 (t,
J = 18.8 Hz, 1H, PCHP), 1.87 (tdd, J = 6.3, 4.5, 1.7 Hz, 1H, CHAz),
1.84−1.81 (m, 1H, CH2, Az), 1.76−1.67 (m, 1H, CHCH2CH3), 1.66
(dd, J = 6.5, 1.3 Hz, 1H, CH2, Az), 1.44−1.39 (m, 1H, CHCH3), 1.37
(tdd, J = 7.1, 2.5, 1.2 Hz, 12H, 4 CH2CH3), 1.31−1.19 (m, 1H,
CHCH2CH3), 0.94 (t, J = 7.5 Hz, 3H, CH3CH2CH), 0.81 (d, J = 6.9
Hz, 3H, CH3CH). 13C{1H} NMR (126 MHz, MeOD): δ 65.0 (t, J =
152.0 Hz, PCHP), 64.6 (ddd, J = 17.5, 13.8, 6.8 Hz, 4C, CH2CH3),
47.7 (dd, J = 13.7, 5.2 Hz, CHAz), 37.9 (s, CHCH3), 35.3 (d, J = 14.6
Hz, CH2 Az), 28.6 (s, CHCH2CH3), 16.8 (dd, J = 10.8, 4.8 Hz, 4C,
CH2CH3), 14.9 (s, CHCH3), 11.9 (s, CHCH2CHy). 31P{1H} NMR
(202 MHz, MeOD): δ 18.2 (d, JPP = 5.1 Hz), 18.1 (d, JPP = 5.1 Hz).
HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C15H34NO6P2
386.1861, found 386.1860.
130.3 (s, CHAr), 127.8 (s, CHAr), 126.3 (s, CHAr), 125.7 (s,
CHAr), 84.4 (s, CHCH), 55.3 (s, CHCH), 39.6 (s, CH2). HRMS
(ESI/Q-TOF) m/z: [M + H]+ calcd for C9H10N 132.0813, found
132.0814.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02434.
tert-Butyl (S)-2-(1-(Bis(diethoxyphosphoryl)methyl)aziridin-2-yl)-
acetate (3h). The title compound (30 mg, 0.07 mmol, 20% yield) was
obtained as a colorless oil following the procedure described above
(stirring for 2 h at room temperature) from compound 2h (100 mg,
1
Copies of H, 13C, and 31P NMR spectra of all new
compounds described in the Experimental Section;
1
copies of H NMR spectra for known compounds or
1
0.34 mmol). Rf dichloromethane/MeOH 95/5 (v/v): 0.22. H NMR
intermediates (PDF)
(500 MHz, CDCl3): δ 4.30−4.16 (m, 8H, 4CH2CH3), 3.01 (dd, J =
15.9, 3.1 Hz, 1H, CH2C(O)), 2.38 (t, J = 18.1 Hz, 1H, PCHP), 2.11−
2.04 (m, 1H, CHAz), 1.98 (dd, J = 15.9, 9.3 Hz, 1H, CH2C(O)), 1.95
(d, J = 3.8 Hz, 1H, CH2, Az), 1.81 (d, J = 6.5 Hz, 1H, CH2, Az), 1.43
(s, 9H, 3CH3, tBu), 1.39−1.31 (m, 12H, 4CH2CH3). 13C{1H} NMR
(126 MHz, CDCl3): δ 170.8 (s, C(O)tBu), 80.8 (s, C(CH3)3, tBu),
66.0−63.5 (t, J = 150.3 Hz, PCHP), 63.4−63.0 (m, 4C, 4CH2CH3),
39.0 (s, CH2C(O)), 38.4 (d, J = 15.6 Hz, CHAz), 36.2 (d, J = 15.3
Hz, 2C, CH2, Az), 28.2 (s, 3C, 3CH3, tBu), 16.6 (s, 4C, 4CH2CH3).
31P{1H} NMR (162 MHz, CDCl3): δ 17.8 (d, JPP = 3.3 Hz, 1P), 17.7
NMR comparative study for compounds 2d/3d and 2g/
3g (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Suzanne Peyrottes − Team Nucleosides & Phosphorylated
Effectors, Institute for Biomolecules Max Mousseron
(IBMM), UMR 5247 CNRS, ENSCM, Univ. Montpellier,
34095 Montpellier, France; orcid.org/0000-0003-1705-
0576; Email: suzanne.peyrottes@umontpellier.fr
(d, JPP = 3.3 Hz, 1P). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for
C17H36NO8P2 444.1911, found 444.1913.
tert-Butyl (S)-(4-(1-(Bis(diethoxyphosphoryl)methyl)aziridin-2-
yl)butyl)carbamate (3i). The title compound (115 mg, 0.23 mmol,
40% yield) was obtained as colorless oil following the procedure
described above (stirring for 4 h at room temperature) from
compound 2i (200 mg, 0.58 mmol). Rf dichloromethane/MeOH
(95/5, v/v): 0.26. 1H NMR (600 MHz, CDCl3): δ 4.71 (s, 1H, NH),
4.31−4.16 (m, 8H, 4CH2CH3), 3.15−3.06 (m, 2H, NHCH2), 2.34 (t,
J = 18.2 Hz, 1H, PCHP), 1.83−1.79 (m, 1H, CHAz), 1.79 (d, J = 4.3
Hz, 1H, CH2, Az), 1.66 (d, J = 6.4 Hz, 1H, CH2, Az), 1.56−1.43 (m,
6H, 3CH2), 1.43 (s, 9H, CH3, Boc), 1.39−1.34 (m, 12H, 4CH2CH3).
13C{1H} NMR (151 MHz, CDCl3): δ 156.2 (s, C(O)Boc), 65.3 (t, J
Author
Thomas Cheviet − Team Nucleosides & Phosphorylated
Effectors, Institute for Biomolecules Max Mousseron
(IBMM), UMR 5247 CNRS, ENSCM, Univ. Montpellier,
34095 Montpellier, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02434
Notes
= 150.3 Hz, PCHP), 63.3−62.8 (m, 4C, CH2CH3), 42.0 (d, J = 15.3
Hz, CHAz), 40.7 (s, CH2NH), 36.7 (d, J = 16.3 Hz, CH2, Az), 29.9
The authors declare no competing financial interest.
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J. Org. Chem. 2021, 86, 3107−3119

The Journal of Organic Chemistry
pubs.acs.org/joc
Featured Article
Constrained Aminomethylene Gem-Diphosphonate Derivatives via
Beckmann Rearrangement. J. Org. Chem. 1994, 59 (24), 7562−7564.
(18) Wu, M.; Chen, R.; Huang, Y. Simple, Efficient and One-Pot
Method for Synthesis of Aminomethylene Gem-Diphosphonic Acid
Derivatives from Ketones via Beckmann Rearrangement. Synthesis
2004, 2004 (15), 2441−2444.
ACKNOWLEDGMENTS
■
We are grateful to the CNRS (National Scientific Research
Council) for financial support
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