Iron-Catalyzed Intra-intermolecular Aminoazidation of Alkenes

Article abstract of DOI:10.1021/acs.oprd.9b00400

An intra-intermolecular iron-catalyzed aminoazidation of non-activated alkenes is reported for the preparation of imidazolidinone, oxazolidinone, and pyrrolidinone derivatives. The method uses cheap and abundant iron as a catalyst and commercially available TMSN₃ as an azide source. This domino process allows, in a single operating step, for a ring-closure that generates an aza-heterocycle and the introduction of an azido appendage tethered to the heterocycle. The conditions developed offer a sustainable alternative method for the preparation of unsymmetrical vicinal diamine compounds.

Full text of DOI:10.1021/acs.oprd.9b00400

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Full Paper
Iron-catalyzed intra-intermolecular aminoazidation of alkenes
Sandra Abi Fayssal, Alessandro Giungi, Farouk Berhal, and Guillaume Prestat
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00400 • Publication Date (Web): 14 Nov 2019
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Iron-catalyzed intra-intermolecular aminoazidation
of alkenes
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Sandra Abi Fayssal, Alessandro Giungi, Farouk Berhal*, Guillaume
Prestat*
Université de Paris, UMR CNRS 8601, Laboratoire de Chimie et
Biochimie Pharmacologiques et Toxicologiques, 45 rue des Saints-
Pères F-75006 Paris, France.
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Graphical Abstract TOC
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Fe(OAc)2 (cat)
Phenanthroline (cat)
TMSN3 (1.5 equiv.)
O
O
X
R1
O
X
N
NH
H
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O
N3
X = CH2 , O, NR
21 examples
22 to 90 % ; up to 98:2 dr
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ABSTRACT
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An intra-intermolecular iron-catalyzed aminoazidation of non-
activated alkenes is reported for the preparation of
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imidazolidinone, oxazolidinone and pyrrolidinone derivatives. The
method uses cheap and abundant iron as a catalyst and commercially
available TMSN3 as an azide source. This domino process allows, in
a single operating step, for a ring-closure that generates an aza-
heterocycle and the introduction of an azido appendage tethered to
the heterocycle. The conditions developed offer a sustainable
alternative method for the preparation of unsymmetrical vicinal
diamine compounds.
KEYWORDS: iron catalysis, sustainable chemistry, aminoazidation,
alkene functionalization.
INTRODUCTION
One major challenge for the modern synthetic chemistry community
is the production of complex molecules through ecologically
respectful processes. To answer this concern, the development of
new sustainable protocols based upon abundant reagents and
efficient strategies is of prime importance. Transition-metal-
catalyzed domino processes have emerged as a highly efficient
strategy to prepare complex molecules by allowing for the formation
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of multiple bonds in a single operating step. Such processes follow
the principles of green chemistry, such as atom and step economy,
but their sustainability is severely hampered by the common use of
catalysts based on rare and precious late transition-metals.
Conversely, the high concentration of iron in the earth’s crust
guarantees a sustainable access to a large variety of inexpensive
iron salts. Moreover, the low toxicity of iron makes it a catalyst
of choice, especially for the pharmaceutical industry.3 In this
context, and following our research program dedicated to one-pot
dihetero-functionalization of alkenes,4 we recently reported an
iron-catalyzed intramolecular aminoacetoxylation of alkenes
leading to functionalized imidazolidinone derivatives (figure
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1a).5
(a) Our previous work: iron-catalyzed aminoacetoxylation
OCOR
NH
O
O
[Fe]
NH
OCOR
(b) Previous work: copper-catalyzed diamination
OMe
O
O
OMe
[Cu]
NH
N
Zhdankin
reagent
N3
2017 Wang10
(c) This work: iron-catalyzed amino-azidation
OCOR
NH
O
O
[Fe]
NH
N3
TMSN3
Figure 1. From Fe-catalyzed aminoacetoxylation to Fe-catalyzed
aminoazidation
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This process was efficient for mono-, di- and tri-substituted
double bonds and also furnished versatile precursors of 1,2-amino-
alcohols. We then wondered whether this methodology could be
extended to a 1,2-diamination reaction. Indeed, vicinal 1,2-
diamines are important structural moieties found in numerous
natural products, pharmaceuticals or chiral ligands.6 Many methods
were reported to access these essential skeletons,7 and the most
straightforward route is obviously the alkene diamination
reaction.8 The processes developed so far are mostly based on the
use of two identical amino groups or a reagent with tethered
nitrogen atoms, even though the introduction of two different amino
groups is highly desirable. A breakthrough was obtained by the
group of Chemler who reported in 2010 a copper-promoted intra-
intermolecular alkene diamination.9 The process was efficient for
the formation of various nitrogen heterocycles and tolerated a
wide range of external amine sources. However, this protocol
appears to be limited to terminal alkenes and requires harsh
conditions with an excess of the copper complex to reach a large
scope of products. In the same vein, Wang very recently reported
milder reaction conditions for the intra-intermolecular copper-
catalyzed alkene aminoazidation as entry to 1,2-diamines (figure
1b).10 This strategy, which is efficient for both terminal and
internal alkenes, is highly appealing as it generates a nitrogen
heterocycle bearing an azido appendage. The azido substituent is
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one of the most versatile functional groups in organic synthesis
for constructing diverse nitrogen-containing molecules.11 On one
hand it can give easy access to amine derivatives by a simple
reduction and on the other hand, it can be used in bioorthogonal
conjugation such as in Huisgen “click” cycloaddition12 and
Staudinger ligation.13 However, this protocol suffers from the use
of the Zhdankin reagent, 1-azido-1,2-benziodoxol-3(1H)-one,14 as
an azide source which in turn has to be prepared from
azidotrimethylsilane and has been shown to be highly shock and
friction sensitive.15 Thus, as a complementary and sustainable
methodology, we report herein the development of an intra-
intermolecular alkene aminoazidation catalyzed by environmentally
benign iron salt using a commercially available azide source
(figure 1c). To the best of our knowledge, such an iron-catalyzed
orthogonal diamination reaction has not yet been reported.
RESULTS AND DISCUSSION
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In order to tackle the aminoazidation process, we hypothesized
that the introduction of an exogeneous azide source in our iron-
catalyzed aminoacetoxylation protocol, should allow it to compete
with the transfer of the benzoyl group. We focused our attention
on the use of simple azidotrimethylsilane as an azide source.
Starting from our previous work, we submitted allyl-oxy-urea
derivatives to the action of Fe(OAc)2 (10 mol %) as a catalyst and
phenanthroline (20 mol %) as a ligand in acetonitrile (table 1).
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When the reaction was conducted at room temperature with substrate
1a, only trace amounts of the target product 2a was observed after
18 h (table 1, entry 1). We were pleased to observe that the
reaction occurred smoothly when the temperature was increased to
50 °C. Product 2a was then isolated with a moderate 40 % yield
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(table
1,
entry
2).
In
our
previous
iron-catalyzed
aminoacetoxylation study, the modulation of R1 and R2 functional
groups appeared to be the critical point to reach
a
high
reactivity.5 Disappointingly, the use of substrates 1aa and 1ab,
where R2 is a 2,4-dichlorophenyl or a 3,5-ditrifluorophenyl group
instead of the phenyl group, led to a significant decrease of the
yield (29 % and 22 % respectively, table 1 entries 3 and 4).
Starting with substrate 1ac, in which the benzoate substituent was
replaced by an acetate (R2 = Me), allowed for the isolation of the
product 2a in a 50 % yield, where full conversion was observed
(table 1, entry 5). Keeping the acetate and replacing the R1 benzyl
group by a methyl substituent (substrate 1b, R1 = R2 = Me) led to,
at 50 °C, a poor 38 % yield. This resulted from an incomplete
conversion of the starting material after 18 h at this temperature
(table 1, entry 6). Increasing the temperature slightly to 70 °C
led to a complete conversion after 18 h, and the target product 2b
was then isolated in a good 71 % yield (table 1, entry 7).
Increasing the temperature to 100 °C had no impact on the
reactivity, where product 2b was obtained with the same result
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(table 1, entry 8 vs 7). The influence of the azide source was
then evaluated next. Firstly, sodium azide was tested in place of
TMSN3 under the same reaction conditions, and was found to perform
equally as well, where the product 2b was isolated in 71 % yield
(table 1, entry 9). Conversely, the use of tetrabutylammonium azide
in place of TMSN3 induced a dramatic decrease of the reaction yield
to 11 % (table 1, entry 10).
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Table 1. Optimization of the reaction conditionsa
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O
Fe(OAc)2 (10 mol %)
Phenanthroline (20 mol %)
TMSN3 (1.5 equiv.)
O
N
R1
R2
O
N
N
H
NH
R1
O
N3
18 h, T °C, ACN
1
2
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Entr
ya
Product
T °C
r.t.
Substrate
Yield (%)b
Trace
O
O
NH
Bn
O
N
N
H
N
Bn
N3
1
2
3
O
O
2a
1a
O
Bn
O
N
N
H
50 °C
50 °C
2a
40
29
1a
Cl
O
Bn
O
N
N
2a
H
O
Cl
1aa
CF3
O
Bn
O
4
50 °C
2a
2a
22
N
N
CF3
H
O
1ab
O
Bn
O
N
N
5
6
50 °C
50 °C
50
38
H
O
1ac
O
O
O
NH
N
N
N
H
N3
O
2b
1b
7
8
70 °C
100 °C
70 °C
70 °C
1b
1b
1b
1b
2b
2b
2b
2b
71
71
71
11
9c
10d
(a) Reactions were performed under Ar using substrate 1 (1
equiv.), Fe(OAc)2 (10 mol %), phenanthroline (20 mol %), TMSN3
(1.5 equiv.) in ACN for 18 h at the required temperature. (b)
Isolated yields. (c) NaN3 (1.5 equiv.) was used instead of
TMSN3. (d) TBAN3 (1.5 equiv.) was used instead of TMSN3.
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Having in hand the optimized conditions, the scope of this process
was studied for the preparation of a series of functionalized
azido-imidazolidinone products (scheme 1). Using our mild
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conditions,
the
synthesis
of
the
phenyl-substituted
imidazolidinone derivative 2c occurred efficiently with 75 % yield
and a good diastereomeric ratio (dr = 93:7, scheme 1) starting
with E-alkene substrate. On the other hand, the bicyclic azido-
cyclohexyl-imidazolidinone
product
2d
arising
from
the
corresponding Z-alkene was isolated with a modest 30 % yield, but
with an excellent dr (> 95:5). Note that both products 2c and 2d
arose from an anti-addition process. Satisfyingly, the use of
challenging trisubstituted alkenes as substrates was found to be
well tolerated. The azido-propyl-imidazolidinone 2e and the azido-
methyl-imidazolidinone 2f were obtained with a 62 % and 53 % yield
respectively.
Scheme 1. Scope for the imidazolidinone familya
O
Fe(OAc)2 (10 mol %)
O
OAc
Phenanthroline (20 mol %)
N
N
H
NH
TMSN3 (1.5 equiv.)
N
70 °C, 18 h, ACN
1
2
N3
Scope
O
N
O
O
N
NH
NH
NH
N
Ph
N3
N3
N3
2b, 71 %
2c, 75 %, dr = 93:7
2d, 30 %, dr > 95:5
O
N
O
NH
NH
N
N3
2f, 53 %
N3
2e, 62 %
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(a) Reactions were performed under Ar using substrates 1 (1
equiv.), Fe(OAc)2 (10 mol %), phenanthroline (20 mol %) in ACN for
18 h at 70 °C; Isolated yields; dr were determined by 1H NMR on
the crude mixture.
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In order to demonstrate the efficiency of our methodology, the
preparation of two other families of heterocycles was envisioned.
The access to oxazolidinone derivatives was first investigated
(scheme 2). The allyl acetoxycarbamate substrates 3 were submitted
to the reaction conditions. Gratifyingly, the unsubstituted model
product 4a was isolated with an excellent 87 % yield (scheme 2).
A series of E- cinnamyl substrates were next evaluated. The azido-
phenyl compound 4b was formed in high yield with
a
high
diastereoselectivity favoring the anti-addition mechanism (90 %
yield, dr > 98:2). Substrates bearing a phenyl ring substituted
with electron-withdrawing chloro- and nitro- substituents at the
para position reacted smoothly. The chloride product 4c was
obtained with an excellent 85 % yield as a single diastereomer,
and the nitroso product 4d with a good 75 % yield and dr = 95:5.
On the other hand substrates with an electron enriched phenyl ring
were
less
efficient.
Although
the
azido-2-methoxyphenyl
oxazolidinone product 4e was isolated as a single diastereomer (dr
> 98:2), the yield was moderate (54 %). A more dramatic decrease
in the reaction efficiency was observed for the formation of the
azido-4-methoxyphenyl oxazolidinone product 4f which was isolated
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with a poor 22 % yield and no diastereoselectivity (dr = 50:50)
while the product arising from the competitive aminoacetoxylation
was isolated in 40 % yield. Compared to aryl substituents, alkyl
functionalized alkene substrates showed moderate results. The
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azidomethyl
methyloxazolidinone
4g
and
the
azidobenzyl
methyloxazolidinone 4h were isolated with 63 % and 65 % yield
respectively, and poor diastereoselectivity (dr = 60:40 for 4h).
A complete diastereoselectivity was observed for the synthesis of
the cyclohexyl compound 4i which was isolated as a single isomer
in 50 % yield. Finally, the azido-dimethyl oxazolidinone 4j was
isolated with a moderate 43 % yield in line with the steric
hindrance of the alkene double bond.
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Scheme 2. Scope for the oxazolidinone familya
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9
Fe(OAc)2 (10 mol %)
O
O
O
Phenanthroline (20 mol %)
TMSN3 (1.5 equiv.)
OAc
N
H
O
NH
70 °C, 18 h, ACN
3
4
N3
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Scope
O
O
O
O
O
Cl
NH
NH
NH
O
Ph
N3
N3
N3
4a, 87 %
4b, 90 %, dr > 98:2
4c, 85 %, dr > 98:2
O
O
O
O
NO2
OMe
NH
NH
O
NH
O
N3
N3 OMe
N3
4d, 75 %, dr = 95:5
4e, 54 %, dr > 98:2
4f, 22 %, dr = 50:50
O
O
O
O
NH
NH
NH
O
O
Ph
N3
N3
4g, 63 %
N3
4h, 65 %, dr = 60:40
4i, 50 %, dr > 98:2
O
NH
O
N3
4j, 43 %b
(a) Reactions were performed under Ar using substrates 3 (1
equiv.), Fe(OAc)2 (10 mol %), phenanthroline (20 mol %) in ACN for
18 h at 70 °C; Isolated yields; dr were determined by 1H NMR on
the crude mixture. (b) DCM:ACN (9:1) was used as solvent.
Finally, the access to the pyrrolidinone family was explored. A
series of acetoxy-pentenamide substrates 5, devoid of any Thorpe-
Ingold bias, were engaged in the aminoazidation process (scheme
3). The unsubstituted azido-lactam 6a was formed smoothly in a
good 71 % yield. The cinnamyl substrates were found to be less
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reactive than for the other series. The azido-phenyl pyrrolidinone
6b was isolated with moderate yield and diastereoselectivity (54
% yield, dr = 70:30) whereas, the sterically demanding azido-2-
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methoxy-phenyl pyrrolidinone 6c was obtained with
a
poor
reactivity (27 % yield, dr = 75:25) along with the product arising
from the competitive aminoacetoxylation (25 % yield). In this
series, internal and terminal dialkylalkenes reacted satisfyingly.
The azidoethyl pyrrolidinone derivative 6d was isolated with a
good 76 % yield and a moderate diastereoselectivity (dr = 80:20)
while the 5-azidomethyl-5-methylpyrrolidinone 6e was obtained in
74 % yield. Finally the 5-azidomethyl-4-methylpyrrolidinone 6f was
isolated in 74 % yield with a poor diasteroselectivity in favor of
the trans diasteromer (dr = 65:35).
Scheme 3. Scope for the lactam familya
O
Fe(OAc)2 (10 mol %)
Phenanthroline (20 mol %)
TMSN3 (1.5 equiv.)
O
OAc
N
H
NH
70 °C, 18 h, ACN
5
6
N3
Scope
O
O
O
NH
Ph
NH
NH
N3
N3 OMe
N3
6a, 71 %
6b, 54 %, dr = 70:30
6c, 27 %, dr = 75:25
O
O
O
NH
N3
NH
NH
N3
N3
6d, 76 %, dr = 80:20
6e, 74 %
6f, 74 %, dr = 65:35
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(a) Reactions were performed under Ar using substrates 5 (1
equiv.), Fe(OAc)2 (10 mol %), phenanthroline (20 mol %) in ACN for
18 h at 70 °C; Isolated yields; dr were determined by 1H NMR on
the crude mixture.
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The results reported herein are in agreement with our proposed
substrate dependent mechanism for the iron-catalyzed oxyamination.
5
Oxidative addition of the N-O bond onto the iron(II) catalyst
generates an iron imido/nitrene complex. In the major path, the
complex reacts stereospecifically with the olefin to afford an
aziridine intermediate. The following SN2 opening of the aziridine
by the azide leads to the formation of the major anti isomer. In
the minor path, the iron imido/nitrene complex evolves through a
stepwise amino-cyclisation to a carbo-radical species that is
rapidly oxidized to the corresponding carbocation. The latter can
be trapped intramolecularly to generate the aziridine or directly
by the azide without stereocontrol. This path gains importance for
sterically hindered olefin, potentially leading to congested
aziridine, and for substrates leading to stabilized carboradical
or carbocation intermediates. It is noteworthy to highlight that
the trapping of the carbocation by the azide is in competition
with the trapping by the released acetate that leads to the
aminoacetoxylated product which was observed during the formation
of 4f and 6c (vide supra).
In order to demonstrate the applicability of our methodology, two
experiments were performed on a 1 gram scale, using substrate 1b
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(5.8 mmol) and 3a (6.3 mmol) with a decreased catalyst loading.
The azido imidazolidinone 2b and the azido oxazolidinone product
4a were respectively isolated in 63 and 80 % yield after 18 h using
only 2 mol % of the iron catalyst (scheme 4).
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Scheme 4. Gram-scale experiment and decrease of the catalyst
loading
Fe(OAc)2 (2 mol %)
Phenanthroline (4 mol %)
TMSN3 (1.5 equiv.)
70 °C, 18 h, ACN
O
O
OAc
X
N
NH
H
X
N3
1b (X=NMe) 1 g
3a (X=O) 1 g
2b 63 % yield, 570 mg
4a 80 % yield, 710 mg
Finally, to illustrate the versatility of the azido products
synthesized, some post-functionalization reactions were carried
out on compound 4a (scheme 5). First, the carbamate moiety was
protected with a BOC group to afford 7 in an excellent 92 % yield.
The cleavage of the oxazolidinone core in basic conditions
furnished the azido-amino-alcohol 8 in 84 % yield. From 7, the
reduction of the azide and protection of the nitrogen atoms gave
access to the di-Boc-protected oxazolidinone derivative 9 in 86 %
yield. Finally, the azide 4a was submitted to classical click
reaction conditions with ethyl propiolate, leading to the
formation of the complex oxazolidinone 10, isolated with an 83 %
yield.
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Scheme 5. Post-functionalization reactions
5
6
O
7
O
OEt
O
8
9
1 equiv.
O
O
NH
NH
N
DiPEA (2 equiv.)
Lutidine (2 equiv.)
CuI (0.1 equiv.)
ACN, 16 h, rt.
N
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N3
N
CO2Et
4a
10, 83 %
Boc2O 1.1 equiv.
DMAP 10 mol %
DCM, 2 h, rt
O
O
Boc2O 1.2 equiv.
H2, Pd/C 15 mol %
HO
NHBoc
N3
Cs2CO3 1.1 equiv.
EtOH, 1.5 h, 0 °C
O
O
NBoc
N3
NBoc
NHBoc
AcOEt, 1.5 h, rt
9, 86 %
7, 92%
8, 84 %
CONCLUSION
To conclude, we have developed mild conditions for the iron-
catalyzed intra-intermolecular aminoazidation of alkenes. Our
methodology proved to be applicable for three main families of
heterocycles: imidazolidinone, oxazolidinone and pyrrolidinone
derivatives. Moreover, we demonstrated the great potential of this
reaction for an industrial purpose, as the catalyst loading could
be decreased to 2 mol % in a scale-up experiment. Finally, the
molecules synthesized appeared as valuable building blocks for
post-functionalization reactions.
EXPERIMENTAL SECTION
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General Information:
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All reagents were purchased from chemical suppliers and used
without further purification. Reactions were performed under an
argon atmosphere. DCM was dried using a Pure Solv Micro solvent
purification system. Dry THF and acetonitrile were purchased from
chemical suppliers. Analytical thin layer chromatography was
performed on commercial silica gel plates 60F254. Flash column
chromatography was performed on silica gel 60 (40−63 μm). NMR
spectra were recorded on a 500 MHz spectrometer as specified.
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Chemical
shifts
(δ)
are
reported
in
ppm
relative
to
tetramethylsilane (δ 0.00 ppm) or the CHCl3 residual peak (δ 7.26)
or for the CH3OH residual peak (δ 3.31) for 1H NMR. Chemical shifts
of 13C NMR are reported relative to CDCl3 (δ 77.16) or CD3OD (δ
49.00). Coupling constant (J) are reported in Hertz unit (Hz).
Multiplicities
are
described
with
standard
following
abbreviations: s = singlet, br = broad, d = doublet, t = triplet,
q = quadruplet, m = multiplet. Low resolution mass spectra (LRMS)
were recorded with an ion trap mass analyzer under electrospray
ionization (ESI) in positive or negative ionization mode detection
or atmospheric pressure chemical ionization (APCI). High
resolution mass spectra (HRMS) were recorded with a TOF mass
analyzer under electrospray ionization (ESI) in positive or
negative ionization mode detection, atmospheric pressure chemical
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ionization or atmospheric pressure photoionization (APPI). Melting
points were measured on a Köfler bench. IR spectra were recorded
on a FT-IR spectrophotometer, and the wavelengths reported in cm-
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.
Typical procedure for the iron catalyzed amino-azidation:
In a sealed tube, 10 mol % of Fe(OAc)2 (5.1 mg, 0.029 mmol)and 20
mol % of phenanthroline (10.5 mg, 0.058 mmol) were placed in ACN
(1.45 mL, C = 0.2 M) under argon. The solution was stirred for 10
minutes at room temperature and then 1.0 equiv. of the desired
alkene substrate (0.29 mmol)was added followed by 1.5 equiv. of
TMSN3 (60 L, 0.44 mmol). The deep red solution was stirred at 70
°C for 18h. The reaction mixture was then diluted with a saturated
aqueous solution of NaHCO3 (10 mL) to quench the unreacted TMSN3
reagent. The aqueous layer was extracted with DCM (10 mL,3 times).
The combined organic phases were dried over MgSO4, filtered and
the solvents were removed under reduced pressure (T°C < 50°C). The
crude residue was purified by silica gel flash chromatography using
cyclohexane/AcOEt as eluent.
4-(azidomethyl)-1-methylimidazolidin-2-one (2b)
Beige solid; 32 mg,71 % Yield; m.p. 72-74 °C; 1H RMN (CDCl3, 500
MHz, ppm) δ = 5.62 (brs, 1H), 3.82-3.75 (m, 1H), 3.51 (t, J = 9
Hz, 1H), 3.42-3.32 (m, 2H), 3.14 (dd, J = 5 Hz, 9 Hz, 1H), 2.76
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(s, 3H); 13C RMN (CDCl3, 125 MHz, ppm) δ = 161.9, 55.0, 50.5, 49.1,
5
6
7
8
30.5; IR (ν = cm-1): 3274, 2930, 2868, 2103, 1697, 1502, 1275; MS
(ESI): m/z = 156.17 [M+H+]; HRMS (ESI): m/z calcd for C5H10N5O [M+H+]
156.08799, found 156.08784.
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4-(azido(phenyl)methyl)-1-methylimidazolidin-2-one (2c)
White solid; 50 mg,75 % Yield; d.r. = 93:7; m.p. 94-96 °C; major
diastereoisomer: 1H RMN (CDCl3, 500 MHz, ppm) δ = 7.46-7.38 (m,
3H), 7.35-7.30 (m, 2H), 4.42 (d, J = 8.5 Hz, 1H), 4.15 (brs, 1H),
3.77 (dt, J = 9 Hz, 5 Hz, 1H), 3.56 (t, J = 9 Hz, 1H), 3.41 (dd,
J = 5.5 Hz, 9.5 Hz, 1H), 2.78 (s, 3H); 13C RMN (CDCl3, 125 MHz,
ppm) δ = 161.2, 135.7, 129.5, 129.4, 127.8, 68.8, 53.9, 50.7, 30.5;
IR (ν = cm-1): 3212, 2096, 2924, 2853, 2101, 1691, 1274, 1244, 701;
MS (ESI): m/z = 232.25 [M+H+]; HRMS (ESI): m/z calcd for C11H14N5O
[M+H+] 232.11929, found 232.11900.
4-azido-1-methyloctahydro-2H-benzo[d]imidazol-2-one (2d)
Colourless oil; 17 mg,30 % Yield; d.r. > 95:5; 1H RMN (CDCl3, 500
MHz, ppm) δ = 5.11 (brs, 1H), 3.58-3.53 (m, 1H), 3.37-3.30 (m,
1H), 3.16 (t, J = 7.5 Hz, 1H), 2.69 (s, 3H), 2.04-1.95 (m, 2H),
1.74-1.67 (m, 1H), 1.62-1.53 (m, 1H), 1.44 (tq, J = 3 Hz, 12 Hz,
1H), 1.34 (dq, J = 3 Hz, 12 Hz, 1H); 13C RMN (CDCl3, 125 MHz, ppm)
δ = 163.1, 64.0, 57.9, 55.2, 28.5, 27.5, 24.6, 18.7; IR (ν = cm-
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1): 3241, 2069, 2940, 2864, 2099, 1702, 1444, 1433, 1256; MS (ESI):
m/z 196.3 [M+H+]; HRMS (ESI): m/z calcd for C8H14N5O [M+H+]
196.11929, found 196.12019.
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4-(2-azidopropan-2-yl)-1-methylimidazolidin-2-one (2e)
White solid; 33 mg,62 % Yield; m.p. 116-118 °C; 1H RMN (CDCl3, 500
MHz, ppm) δ = 5.62 (brs, 1H), 3.55 (dd, J = 6.5 Hz, 9.5 Hz, 1H),
3.42 (t, J = 9.5 Hz, 1H), 3.23 (dd, J = 6.5 Hz, 9.5 Hz, 1H), 2.76
(s, 3H), 1.28 (s, 3H), 1.24 (s, 3H); 13C RMN (CDCl3, 125 MHz, ppm)
δ = 162.0, 62.9, 57.3, 48.7, 30.4, 22.1, 21.5; IR (ν = cm-1): 3218,
2091, 2980, 2929, 2877, 2095, 1684, 1515, 1269; MS (ESI): m/z =
184.28 [M+H+]; HRMS (ESI): m/z calcd for C7H14N5O [M+H+] 184.11929,
found 184.11920.
4-(azidomethyl)-1,4-dimethylimidazolidin-2-one (2f)
Colourless oil; 26 mg,53 % Yield; 1H RMN (CDCl3, 500 MHz, ppm) δ =
4.90 (brs, 1H), 3.36 (d, J = 12 Hz, 1H), 3.29 (d, J = 11.5 Hz,
1H), 3.27 (d, J = 9 Hz, 1H), 3.10 (d, J = 9.5 Hz, 1H), 2.77 (s,
3H), 1.32 (s, 3H); 13C RMN (CDCl3, 125 MHz, ppm) δ = 161.0, 59.4,
56.8, 54.8, 30.5, 24.7; IR (ν = cm-1): 3262, 2973, 2931, 2867,
2103, 1698, 1502, 1297, 1261, 1032, 763; MS (ESI): m/z 170.30
[M+H+]; HRMS (ESI): m/z calcd for C6H12N5O [M+H+] 170.10364, found
170.10445.
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4-(azidomethyl)oxazolidin-2-one (4a)
7
8
9
White solid; 36 mg,87 % Yield; m.p. 68-70 °C; 1H RMN (CDCl3, 500
MHz, ppm) δ = 6.42 (brs, 1H), 4.87 (t, J = 9 Hz, 1H), 4.17 (dd, J
= 5 Hz, 9 Hz, 1H), 4.05 – 3.98 (m, 1H), 3.51 (dd, J = 5 Hz, 12.5
Hz, 1H), 3.43 (dd, J = 5.5 Hz, 12 Hz, 1H); 13C RMN (CDCl3, 125 MHz,
ppm) δ = 159.7, 67.6, 54.2, 51.8; IR (ν = cm-1): 3671, 3212, 3122,
2987, 2923, 294, 1726, 1242, 1008, 698; MS (ESI): m/z = 165.03
[M+Na+]; HRMS (ESI): m/z calcd for C4H7N4O2 [M+H+] 143.05635, found
143.05612.
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4-(azido(phenyl)methyl)oxazolidin-2-one (4b)
White solid; 57 mg, 90 % Yield; dr > 98:2; m.p. 80-82 °C; 1H RMN
(CDCl3, 500 MHz, ppm) δ = 7.48-7.40 (m, 3H), 7.36-7.31 (m, 2H),
5.18 (brs, 1H), 4.52 (d, J = 8 Hz, 1H), 4.47 (dd, J = 8 Hz, 9 Hz,
1H), 4.39 (dd, J = 5 Hz, 9 Hz, 1H), 3.98 (tdd, J = 1 Hz, 5 Hz, 8.5
Hz, 1H); 13C RMN (CDCl3, 125 MHz, ppm) δ = 158.7, 134.9, 129.8,
129.7, 127.6, 68.3, 67.7, 56.5; IR (ν = cm-1): 3232, 3136, 2926,
2105, 1731, 1241, 1033, 1024; MS (ESI): m/z = 219.25 [M+H+]; HRMS
(ESI): m/z calcd for C10H11N4O2 [M+H+] 219.08765, found 219.08745.
4-(azido(4-chlorophenyl)methyl)oxazolidin-2-one (4c)
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White solid; 58 mg, 85 % Yield; dr > 98:2; m.p. 112 °C; 1H RMN
(CDCl3, 500 MHz, ppm) δ = 7.42 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8
Hz, 2H), 5.98 (brs, 1H), 4.57 (d, J = 7.5 Hz, 1H), 4.40 (dd, J =
8.5 Hz, 9.5 Hz, 1H), 4.32 (dd, J = 4.5 Hz, 9 Hz, 1H), 4.01-3.95
(m, 1H); 13C RMN (CDCl3, 125 MHz, ppm) δ = 159.2, 135.6, 133.4,
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129.8, 128.9, 67.4, 67.2, 56.6; IR (ν = cm-1): 3403, 2987, 2915,
2102, 1784, 1750, 1212, 1017; MS (ESI): m/z = 250.92 [M-H+]; HRMS
(ESI): m/z calcd for C10H8ClN4O2 [M-H+] 251.03413, found 251.03398.
4-(azido(4-nitrophenyl)methyl)oxazolidin-2-one (4d)
Pale yellow solid; 57 mg,75 % Yield; dr = 95:5; m.p. 124-126 °C;
major diastereoisomer : 1H RMN (CDCl3, 500 MHz, ppm) δ = 8.32 (d,
J = 9 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 5.73 (brs, 1H), 4.70 (d,
J = 7 Hz, 1H), 4.45 (t, J = 9 Hz, 1Hz, 1H), 4.36 (dd, J = 3.5 Hz,
9.5 Hz, 1H), 4.07-4.00 (m, 1H); 13C RMN (CDCl3, 125 MHz, ppm) δ =
158.8, 148.8, 142.0, 128.6, 124.8, 67.4, 67.2, 56.5; IR (ν = cm-
1): 3142, 3116, 2977, 2899, 2120, 1750, 1517, 1350, 744; HRMS
(ESI): m/z calcd for C10H8N5O4 [M-H+] 262.05818, found 262.05859.
4-(azido(2-methoxyphenyl)methyl)oxazolidin-2-one (4e)
White solid; 39 mg,54 % Yield; dr > 98:2; m.p. 112-114 °C; 1H RMN
(CDCl3, 500 MHz, ppm) δ = 7.38 (td, J = 1.5 Hz, 8.5 Hz, 1H), 7.32
(dd, J = 1.5 Hz, 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.97 (d,
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J = 8 Hz, 1H), 5.04 (d, J = 7.5 Hz, 1H), 4.90 (brs, 1H), 4.43-4.34
(m, 2H), 4.18-4.12 (m, 1H), 3.87 (s, 3H); 13C RMN (CDCl3, 125 MHz,
ppm) δ = 158.8, 157.2, 130.8, 128.2, 122.8, 121.5, 111.3, 67.5,
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62.2, 55.8, 54.9; IR (ν = cm-1): 3231, 2970, 2915, 2837, 2118,
1741, 1724, 1248, 1236, 1029, 1020, 757; MS (ESI): m/z = 249.20
[M+H+]; HRMS (ESI): m/z calcd for C11H13N4O3 [M+H+] 249.09931, found
249.09782.
4-(azido(4-methoxyphenyl)methyl)oxazolidin-2-one (4f)
Sticky yellow paste; 16 mg, 22 % Yield; dr = 50:50; mixture of
diastereoisomers: 1H RMN (CDCl3, 500 MHz, ppm) δ = 7.25 (t, J = 8
Hz, 4H), 7.00-6.94 (m, 4H), 5.96 (brs, 1H), 5.35 (brs, 1H), 4.51-
4.43 (m, 3H), 4.36 (dd, J = 4.5 Hz, 9 Hz, 1H), 4.22-4.15 (m, 1H),
4.03-3.94 (m, 3H), 3.84 (s, 3H), 3.83 (s, 3H); 13C RMN (CDCl3, 125
MHz, ppm) δ = 160.7, 160.6, 158.9, 129.1, 128.9, 126.7, 126.1,
115.0, 69.0, 67.8, 67.7, 66.7, 56.7, 56.4, 55.5; IR (ν = cm-1):
3302, 2966, 2837, 2107, 1753, 1514, 1248, 1030; MS (ESI): m/z =
271.25 [M+Na+]; HRMS (ESI): m/z calcd for C11H13N4O3 [M+H+]
249.09822, found 249.09782.
4-(azidomethyl)-4-methyloxazolidin-2-one (4g)
Colourless oil; 28.5 mg,63 % Yield; 1H RMN (CDCl3, 500 MHz, ppm) δ
= 6.75 (brs, 1H), 4.25 (d, J = 9 Hz, 1H), 4.02 (d, J = 9 Hz, 1H),
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3.45 (d, J = 12.5, 1H), 3.32 (d, J = 12.5, 1H), 1.37 (s, 3H); 13C
RMN (CDCl3, 125 MHz, ppm) δ = 159.3, 73.4, 58.5, 58.1, 23.7; IR (ν
= cm-1): 3278, 2979, 2917, 2105, 1742, 1244, 1042; MS (ESI): m/z =
157.16 [M+H+]; HRMS (ESI): m/z calcd for C5H9N4O2 [M+H+] 157.07200,
found 157.07179.
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4-(azido(phenyl)methyl)-4-methyloxazolidin-2-one (4h)
White solid; 44 mg,65 % Yield; d.r. = 60:40; m.p. 96-98 °C; mixture
of diastereoisomers: 1H RMN (CDCl3, 500 MHz, ppm) δ = 7.45-7.37 (m,
5H dia maj), 7.37-7.30 (m, 3.5H dia min), 6.57 (brs, 0.7H dia min), 6.22
(brs, 1H dia maj), 4.63 (s, 1H dia maj), 4.60 (s, 0.7 dia min), 4.45 (d,
J = 9 Hz, 1H dia maj), 4.44 (d, J = 9 Hz, 0.7 dia min), 3.98 (d, J = 9
Hz, 1H dia maj), 3.89 (d, J = 9 Hz, 0.7H dia min), 1.30 (s, 2.1H dia min),
1.28 (s, 3H dia maj); 13C RMN (CDCl3, 125 MHz, ppm) δ = 158.9, 158.8,
134.3, 129.3, 129.0, 128.2, 128.1, 73.2, 72.7, 71.8, 71.5, 60.7,
60.6, 23.0, 22.6; IR (ν = cm-1): 3675, 3273, 2988, 2901, 2109,
1734, 1722, 1258, 1043, 706; MS (ESI): m/z = 233.15 [M+H+]; HRMS
(ESI): m/z calcd for C11H13N4O2 [M+H+] 233.10440, found 233.10300.
4-azidohexahydrobenzo[d]oxazol-2(3H)-one (4i)
White solid; 26 mg, 50 % Yield; d.r. > 98:2; m.p. 84 °C; 1H RMN
(CDCl3, 500 MHz, ppm) δ = 5.37 (brs, 1H), 4.73-4.68 (m, 1H), 3.44-
3.38 (m, 1H), 3.32 (dd, J = 6 Hz, 8.5 Hz, 1H), 2.27-2.20 (m, 1H),
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2.11-2.03 (m, 1H), 1.83-1.75 (m, 1H), 1,72-1.59 (m, 2H), 1.42-1.30
5
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(m, 1H); 13C RMN (CDCl3, 125 MHz, ppm) δ = 159.1, 76.6, 64.1, 57.2,
7
8
9
26.7, 26.2, 18.5; IR (ν = cm-1): 3310, 2960, 2883, 2116, 2095,
1739, 1226; MS (ESI): m/z = 183.21 [M+H+]; HRMS (ESI): m/z calcd
for C7H11N4O2 [M+H+] 183.08765, found 183.08746.
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4-(2-azidopropan-2-yl)oxazolidin-2-one (4j)
White solid; 21 mg,43 % Yield (30 % Yield in pure ACN); m.p. 80
°C; 1H RMN (CDCl3, 500 MHz, ppm) δ = 5.66 (brs, 1H), 4.42 (t, J =
9 Hz, 1H), 4.25 (dd, J = 5 Hz, 9.5 Hz, 1H), 3.72 (ddd, J = 1.5 Hz,
5 Hz, 9 Hz, 1H), 1.33 (s, 3H), 1,30 (s, 3H); 13C RMN (CDCl3, 125
MHz, ppm) δ = 159.2, 66.1, 62.5, 59.7, 21.6, 21.5; IR (ν = cm-1):
3242, 3139, 2976, 2112, 2096, 1736, 1271, 1248; MS (ESI): m/z =
171.25 [M+H+]; HRMS (ESI): m/z calcd for C6H11N4O2 [M+H+] 171.08765,
found 171.08740.
5-(azidomethyl)pyrrolidin-2-one (6a)
Pale red oil; 29 mg,71 % Yield; 1H RMN (CDCl3, 500 MHz, ppm) δ =
6.48 (brs, 1H), 3.86-3.77 (m, 1H), 3.47 (dd, J = 4.5, 12.5 Hz,
1H), 3.30 (dd, J = 7, 12.5 Hz, 1H), 2.46-2.33 (m, 2H), 2.33-2.24
(m, 1H), 1.87-1.78 (m, 1H); 13C RMN (CDCl3, 125 MHz, ppm) δ = 178.2,
56.2, 53.6, 29.7, 24.2; IR (ν = cm-1): 3659, 3229, 3101, 2972,
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2925, 2101, 1688, 1278; MS (ESI): m/z 141.3 [M+H+]; HRMS (ESI):
m/z calcd for C5H9N4O [M+H+] 141.07709, found 141.07787.
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5-(azido(phenyl)methyl)pyrrolidin-2-one (6b)
Colourless oil; 34 mg, 54
%
Yield; d.r.
=
70:30; major
diastereoisomer: 1H RMN (CDCl3, 500 MHz, ppm) δ = 7.46 – 7.36 (m,
3H), 7.35-7.29 (m, 2H), 5.91 (brs, 1H), 4.44 (d, J = 7 Hz, 1H),
3.90-3.80 (m, 1H), 2.34-2.14 (m, 3H), 2.07-1.98 (m, 1H); 13C RMN
(CDCl3, 125 MHz, ppm) δ = 178.2, 135.7, 129.3, 127.7, 69.6, 58.3,
29.5, 23.7; IR (ν = cm-1): 3214, 3090, 3028, 2926, 2102, 1693,
1250, 702; MS (ESI): m/z 217.2 [M+H+]; HRMS (ESI): m/z calcd for
C11H13N4O [M+H+] 217.10839, found 217.10947.
5-(azido(2-methoxyphenyl)methyl)pyrrolidin-2-one (6c)
Pale red oil; 19 mg, 27
%
Yield; d.r.
=
75:25; major
diastereoisomer: 1H RMN (CDCl3, 500 MHz, ppm) δ = 7.38-7.28 (m,
2H), 7.06-7.00 (m, 1H), 6.95 (d, J = 8.5 Hz, 1H), 5.93 (brs, 1H),
4.96 (d, J = 7.5 Hz, 1H), 3.94-3.88 (m, 1H), 3.86 (s, 3H), 2.43-
2.32 (m, 1H), 2.31-2.23 (m, 1H), 2.07-1.98 (m, 1H), 1.89-1.76 (m,
1H); 13C RMN (CDCl3, 125 MHz, ppm) δ = 177.9, 157.1, 130.2, 128.0,
124.0, 121.3, 111.2, 64.1, 57.5, 55.7, 29.9, 23.7; IR (ν = cm-1):
3212, 3077, 2940, 2840, 2102, 1694, 1493, 1247, 756; MS (ESI): m/z
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= 247.19 [M+H+]; HRMS (ESI): m/z calcd for C12H15N4O2 [M+H+]
247.11895, found 247.11847.
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5-(1-azidoethyl)pyrrolidin-2-one (6d)
Melting white solid; 34 mg, 76 % Yield; d.r. = 80:20; major
diastereoisomer: 1H RMN (CDCl3, 500 MHz, ppm) δ = 7.18 (brs, 1H),
3.62 (dt, J = 5 Hz, 8 Hz, 1H), 3.59-3.53 (m, 1H), 2.43-2.35 (m,
1H), 2.34-2.26 (m, 1H), 2.24-2.14 (m, 1H), 1.97-1.88 (m, 1H), 1.27
(d, J = 6.5 Hz, 3H); 13C RMN (CDCl3, 125 MHz, ppm) δ = 179.1, 61.0,
58.4, 29.8, 22.6, 15.5; IR (ν = cm-1): 3217, 2978, 2934, 2109,
1693, 1265; MS (ESI): m/z = 177.32 [M+Na+]; HRMS (ESI): m/z calcd
for C6H11N4O [M+H+] 155.09274, found 155.09250.
5-(azidomethyl)-5-methylpyrrolidin-2-one (6e)
Colourless oil; 33 mg, 74 % Yield; 1H RMN (CDCl3, 500 MHz, ppm) δ =
7.13 (brs, 1H), 3.35 (d, J = 12 Hz, 1H), 3.26 (d, J = 12.5 Hz,
1H), 2.50-2.35 (m, 2H), 2.02 (ddd, J = 5.5 Hz, 9.5 Hz, 13 Hz, 1H),
1.90-1.81 (m, 1H), 1.30 (s, 3H); 13C RMN (CDCl3, 125 MHz, ppm) δ =
177.8, 60.6, 59.7, 31.4, 30.5, 25.6.; IR (ν = cm-1): 3223, 2972,
2932, 2102, 1690, 1420, 1383, 1301, 1249; MS (ESI): m/z = 155.2
[M+H+]; HRMS (ESI): m/z calcd for C6H11N4O [M+H+] 155.09274, found
155.09238.
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5-(azidomethyl)-4-methylpyrrolidin-2-one (6f)
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8
Colourless oil; 33 mg, 74 % Yield; d.r. = 65:35; mixture of
diastereoisomers: 1H RMN (CDCl3, 500 MHz, ppm) δ = 7.16 (brs, 1.5H
dia min + dia maj), 3.69 (td, J = 4.5 Hz, 7.5 Hz, 0.5H dia min), 3.48 (dt,
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J = 4 Hz, 12 Hz, 1.5H dia min + dia maj), 3.36-3.31 (m, 1.5H
dia min + dia
maj), 3.27 (dd, J = 6.5 Hz, 12 Hz, 1H dia maj), 2.70-2.61 (m, 0.5H
dia
min), 2.56 (dd, J = 8.5 Hz, 17 Hz, 1H dia maj), 2.41 (dd, J = 8.5 Hz,
16.5 Hz, 0.5H dia min), 2.23-2.14 (m, 1H dia maj), 2.08 (dd, J = 9 Hz,
17 Hz, 0.5H dia min), 1.99 (dd, J = 6.5 Hz, 17 Hz, 1H dia maj), 1.14
(d, J = 7.5 Hz, 3H dia maj), 1.06 (d, J = 7.5 Hz, 1.5H dia min); 13C
RMN (CDCl3, 125 MHz, ppm) δ = 178.2, 177.9, 61.2, 56.5, 55.0, 52.6,
38.5, 38.1, 32.6, 31.7, 19.5, 14.6; IR (ν = cm-1): 3229, 2965,
2930, 2873, 2103, 1691, 1439, 1382, 1306, 1274; MS (ESI): m/z =
155.2 [M+H+]; HRMS (ESI): m/z calcd for C6H11N4O [M+H]+ 155.09274,
found 155.09270.
tert-butyl 4-(azidomethyl)-2-oxooxazolidine-3-carboxylate (7)
In a round bottom flask 1 equivalent of compound 4a (100 mg, 0.70
mmol) was placed in DCM (7 mL, 0.1 M) under argon. Then 1.1 equiv.
of Boc2O (0.17 mL, 0.77 mmol) and 0.1 equiv. of DMAP (8.6 mg, 0.070
mmol) were added. The solution was stirred at r.t. for 2 h. The
reaction mixture was concentrated under reduced pressure, then the
crude residue was purified by silica gel flash chromatography using
cyclohexane/ AcOEt (from 70/30 to 0/100) as eluent to obtain 7.
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