The Deazidoalkoxylation: Sequential Nucleophilic Substitutions with Diazidated Diethyl Malonate

Article abstract of DOI:10.1021/acs.joc.8b02969

Diazidated malonamides derived from amines and diazidated diethyl malonate react with lithiated alcohols through nucleophilic substitution reactions where azide acts as an unconventional leaving group. This deazidoalkoxylation leads to the formal construction of N,O-acetals, and the remaining azide functionality is a useful entry point for further functionalizations through, for example, standard cycloaddition chemistry. Thus, the presented chemistry provides an easy route toward densely functionalized molecules: Amines, alcohols, and alkynes can be attached onto the small malonate core unit in a sequential manner.

Full text of DOI:10.1021/acs.joc.8b02969

Note
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
The Deazidoalkoxylation: Sequential Nucleophilic Substitutions
with Diazidated Diethyl Malonate
Phillip Biallas, Tobias M. Mensak, Kevin-Alexander Kunz, and Stefan F. Kirsch*
̈
Organic Chemistry, Bergische Universitat Wuppertal, Gaußstr. 20, 42119 Wuppertal, Germany
S
* Supporting Information
ABSTRACT: Diazidated malonamides derived from amines and diazidated
diethyl malonate react with lithiated alcohols through nucleophilic substitution
reactions where azide acts as an unconventional leaving group. This
deazidoalkoxylation leads to the formal construction of N,O-acetals, and the
remaining azide functionality is a useful entry point for further functionaliza-
tions through, for example, standard cycloaddition chemistry. Thus, the
presented chemistry provides an easy route toward densely functionalized
molecules: Amines, alcohols, and alkynes can be attached onto the small
malonate core unit in a sequential manner.
Scheme 1. Substitution of Geminal Diazides 1a and 3
rganic azides have a rich reactivity with a plethora of
1,2 The current playground mainly
Ochemical applications.
consists of using azides in cycloaddition reactions, a field that
has rapidly evolved over the last decades.3,4 The pseudohalo-
genic character of azide, though known for a long period of
time,5 has found markedly less uses in organic reaction
development: While the azides are naturally employed as
excellent nucleophiles in all kinds of nucleophilic substitu-
tions,1,6 their value as potential leaving groups is somewhat
unrecognized. As an exception, acyl azides are widely used as
effective acylating agents, particularly in the acylation of
amines.7 The azide anion is the leaving group in this type of
substitution proceeding through an addition−elimination
mechanism.8 To our surprise, however, our literature search
revealed only a singular example where the nucleophilic
substitution with aliphatic azides was reported. In this specific
reaction, 3-azidopropanoic acid was transformed into aza
heterocycles, and the azide group was proposed to formally act
as a leaving group in an intramolecular substitution.9 We now
report the first example of an intermolecular substitution at a
tetrahedral carbon that is based on azide acting as the leaving
group.
corresponds to the product of a nucleophilic substitution
where methanol is the formal external nucleophile and azide
acts as the leaving group. After careful optimization, excellent
yields of 2a were achieved using 1.1 equiv of n-butyllithium
and 1.1 equiv of methanol in THF at room temperature. We
point out that the lithium alkoxide (i.e., LiOMe) is the actual
nucleophilic species under the conditions. The reaction with
sodium methoxide (derived from NaH and methanol) proved
to have a diminished efficacy, resulting in 2a in 44% yield, and
the experimental procedure was slightly more demanding. We
note that the use of amine bases (as NEt3) did not result in
product formation. The use of the inorganic salt K2CO3, on the
other hand, was successful and gave the product of substitution
in 80% yield. When subjecting lithium methoxide to diazido
diethyl malonate 3, the substitution of the azide was not
We recently launched a research program aimed at the
synthesis10 and reactivity11 of small molecules having a geminal
diazido unit. When we investigated the reaction of geminal
diazides with nucleophilic amines, we realized that the diazido
moiety was capable to trigger a range of uncommon reactions
including fragmentations with concomitant acyl transfer, most
of which did not proceed with related oxygen nucleophiles.12
However, it was observed that diazidated malonamides (such
as 1a) were smoothly transformed into N,O-acetal 2a by
simply adding an excess of n-butyllithium to a solution of 1a in
methanol (Scheme 1). The newly formed N,O-acetal
Received: November 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02969
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The Journal of Organic Chemistry
Note
observed; instead, transesterification led to the traces of the
mixed ester 4, accompanied by a range of unidentified
decomposition products. We conclude that the amide moiety
is of primary importance to make the substitution possible.
However, we currently cannot clarify whether the amide
moieties are mandatory for simply stabilizing the starting
diazide 1a, or whether the amide NH has an active effect on
the substitution; diazidated malonamides derived from
secondary amines were not accessible to us for testings,
despite heavy experimentations.
Scheme 4. Sequential Substitutions with Diazido Malonate 3
Preliminary experiments showed that the unique N,O-acetals
containing azide groups are capable of allowing new reactions:
for example, azide 2a provides the primary amine 5 upon
standard hydrogenation conditions with H2 over palladium on
charcoal (Scheme 2).13 When using PPh3 under aqueous
conditions,14 the imine 6 was formed, demonstrating that the
degree of reduction is easily controlled by the choice of
reaction conditions.
with primary amines 9.16 The diazidated malonamides are then
prone to the new deazidoalkoxylation with alcohol 10, thus
leading to the installation of the building block 2. Of
importance, this key reaction leaves one azide moiety
untouched. The smooth introduction of additional function-
alities via alkyne 11 and classical cycloaddition chemistry is
now possible, i.e., the Cu(I)-catalyzed azide-alkyne cyclo-
addition (CuAAC).17 The overall sequence consists of the
sequential connection of (i) nucleophilic amines, (ii)
nucleophilic alcohols, and (iii) alkynes to the central malonate
unit, and the coupling of three functional modules is
accomplished through formation of the final assembly 12.
To this end, we began to study how to convert best the
diethyl malonate 3 into the corresponding amides 1 using
primary amines 9. Typically, the direct reactions of malonic
acid esters with amines require harsh conditions with
temperatures > 100 °C.18 Those temperatures appeared not
applicable to malonate 3 since the diazide compound may
suffer from thermal decomposition. Gratifyingly, it was found
that milder conditions at lowered temperatures are possible for
the conversion of diazide 3: As summarized in Table 1, a broad
range of amides 1 were formed with aliphatic and benzylic
amines 9 at room temperature in THF; typically, no additional
reagents were employed. Only in a few cases, NEt3 was added
to expedite the reaction. Anilines did not react under the
conditions. Of primary importance, we did not observe any
side products or decomposition in the course of the amidation
reactions. The reactions with sufficiently nucleophilic amines
were usually high-yielding after 12 h (entries 1−9, 11−13).
Sterically more demanding amines led to reduced yields after
12 h, mostly due to incomplete conversion (entries 10 + 14).
The ease of forming malonamides 1 from malonic diester 3
with simple primary amines was evidence for the capability of
the diazido moiety to activate the adjacent ester groups for a
nucleophilic attack.16 The succeeding step of our planned
series of substitutions, the deazidoalkoxylation of 1, was again
based on the enhanced electrophilicity induced by the azide
groups: This time, the carbonyl remained untouched since the
newly formed amide carbonyl was deactivated toward oxygen
nucleophiles, and alcohol nucleophiles were aimed at replacing
one azide of the tetrahedral carbon center.
Scheme 2. Controlled Reduction of 2a
Sulfur nucleophiles were also briefly studied regarding their
tendency to trigger an azide substitution with malonamide 1a.
As summarized in Scheme 3, it was found that, for example,
Scheme 3. Substitution with S- and N-Nucleophiles
thiophenol leads to the substitution product 7 in an excellent
yield of 84%, when triethylamine was the base additive. In
striking contrast, the use of n-BuLi resulted in the exclusive
formation of disulfide 8.15 We also observed the disulfide 8 in
81% yield when using not more than 50 mol % of the diazide
1a. In this reaction, the fate of the diazidated malonamide was
unequivocally determined since imine 6 was isolated in 83%
yield. We therefore assumed that 6 was obtained via the
initially formed N,S-acetal 7 that may undergo substitution
with an excess of PhSH to give 8 and 6, accompanied by a loss
of nitrogen. This assumption was supported by the smooth
transformation of 7 into 8, through simple treatment of 7 with
PhSH.
To test the general use of the deazidoalkoxylation, we began
with the substitution of selected diazides (i.e., 1a, 1d, 1f, 1g, 1i,
and 1j), following the exact conditions illustrated in Scheme 1.
As summarized in Scheme 5, methanol was successfully
introduced in all examples with yields ranging from 69% to
95%, leaving a single unreacted azide in place. Most
importantly, this small survey did not identify any structural
limitations with regard to the newly formed amide moieties.
We then applied this azide substitution to the sequential
modification of diazidated diethyl malonate 3 (Scheme 4), a
compound that was the ideal starting point for the synthesis of
a range of malonamides 1 through the direct transamidation
B
DOI: 10.1021/acs.joc.8b02969
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The Journal of Organic Chemistry
Note
a
Table 1. Reactions of Malonate 3 with Amines
a
b
c
Conditions: 3, 9 (2.5 equiv), room temperature, THF. Isolated yields after 12 h. Conditions: 3, 9 (3.0 equiv), NEt3 (3.0 equiv), room
temperature, THF.
albeit with somewhat lowered yields, providing the desired
N,O-acetals. We note that phenols, and derivatives thereof, do
not react under the conditions.
Scheme 5. Scope of the Substitutions with Methanol
With the goal of creating additional linkages to functional
units through click chemistry,3a,17 we next investigated the
reaction of a selection of the monoazides 2 with alkynes 11
(Scheme 7). Using catalytic amounts of CuSO4 and sodium
ascorbate at room temperature in aqueous tBuOH or DMF,
the monoazides underwent clean cycloaddition, leading to the
formation of the triazoles 12. As one would expect for this
classical reaction, a range of linkages with complex alkynes
could be easily installed, and the nature of the substituents R1
and R2 had only minor influence on the late-stage
functionalization with R3.
Scheme 6 shows a broad variety of alcohols 10a−j that were
successfully coupled to the malonate core through deazidoal-
Scheme 6. Reactions of 1a with Alcohols
In summary, the diazidated diethyl malonate 3 is an
excellent tool for providing a linkage between a nucleophilic
amine and a nucleophilic alcohol. Our few experiments show
an order of reactivity of 3 toward nucleophiles where the
carbonyls react more easily than the tetrahedral carbon.
Through sequential substitutions, amines are attached first to
the connector molecule, followed by alcohols through
subsequent deazidoalkoxylation under basic conditions. The
remaining azide functionality is a simple handle for an
additional linkage to alkynes using click chemistry. The overall
concept adds synthetic value to diethyl 2,2-diazidomalonate 3
because the reagent is a versatile hub for creating multiple links
between (nucleophilic) molecules, and the rapid and simple
connection of functional molecules is of ongoing importance,
from biology to materials applications.19 We also demonstrated
that the somewhat unique substitution of an azide attached to
a tetrahedral carbon is not limited to alcohol nucleophiles:
sulfur nucleophiles were also used in a successful manner,
albeit with lower efficacy. We therefore conclude that the
substitution of azides at saturated carbons may become a
general mode of reaction, and studies with other classes of
nucleophiles are currently ongoing.
koxylation. The reaction with the alcohols proceeded
smoothly: when 1.1 equiv of the given alcohol and of n-BuLi
were employed to treat the diazide 1a in THF at room
temperature, the monosubstituted products 2 were formed in
yields ranging from 36% to 89%, leaving a single unreacted
azide in place. Reactions of diazide 1a with a selection of
secondary and tertiary alcohols proceeded equally reliably,
C
DOI: 10.1021/acs.joc.8b02969
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The Journal of Organic Chemistry
Note
was then concentrated under reduced pressure. Column chromato-
graphic purification afforded the corresponding 2,2-diazido malona-
mides 1.
Scheme 7. Modifications of Monoazides with Alkynes
General Procedure C for the Substitution Reaction of 2,2-
Diazido Malonamides 1 with Alcoholates 10. n-Butyllithium (2.5 M
in hexane, 1.1 equiv) was added to a solution containing the
corresponding alcohol (1.1 equiv) 10 in dry THF (0.15 M) under a
nitrogen atmosphere at room temperature. After stirring for 10 min at
this temperature, the 2,2-diazido malonamide (1.0 equiv) 1 was
added, and the reaction mixture was allowed to stir overnight. The
crude mixture was diluted with ethyl acetate (10 mL) and washed
with water (2 × 5 mL). The aqueous phase was extracted with ethyl
acetate (3 × 10 mL). The combined organic layer was washed with
brine (10 mL), dried over Na2SO4, filtered, and evaporated under
reduced pressure. Column chromatographic purification afforded the
substituted azides 2.
General Procedure D for CuAAc of Azides 2 with Alkynes 11.
The azide (1.0 equiv) 2 and the alkyne (1.1 equiv) 11 were dissolved
in H2O/t-BuOH (1:1, 0.15 M) or DMF (0.15 M). Sodium ascorbate
(0.4 equiv) and copper(II) sulfate pentahydrate (0.2 equiv) were
added. The reaction mixture was stirred overnight at room
temperature. The crude mixture was diluted with ethyl acetate (10
mL) and washed with saturated aqueous EDTA-solution (15 mL) and
water (2 × 5 mL). The aqueous phase was extracted with ethyl acetate
(3 × 10 mL). The combined organic layer was washed with brine (10
mL), dried over Na2SO4, filtered, and evaporated under reduced
pressure. Column chromatographic purification afforded the corre-
sponding triazoles 12.
Synthesis of Geminal Diazide 3. The synthesis of geminal diazide
3 was published recently.10d
2,2-Diazido-N1,N3-dibenzylmalonamide (1a). According to gen-
eral procedure A using (100 mg, 0.41 mmol) diethyl 2,2-
diazidomalonate (3), 2,2-diazido-N1,N3-dibenzylmalonamide (1a)
was obtained as a colorless solid after purification by column
chromatography (EA:PE 15:85). Yield: 139 mg, 0.38 mmol, 92%.
TLC: Rf = 0.51 (EA:PE 2:8) [Cl2]. IR (ATR): 3308, 2118, 1689,
1
1516, 1240, 1062, 693 cm−1. H NMR (400 MHz, CDCl3): δ 7.44−
7.30 (m, 8 H), 7.30−7.24 (m, 4 H), 4.50 (d, J = 5.8 Hz, 4 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ 163.5, 136.7, 129.0, 128.0,
127.7, 81.8, 44.3 ppm. LRMS (ESI) m/z: 365.1 (100) [M + H]+,
387.1 (12) [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
EXPERIMENTAL SECTION
■
General Remarks. All reactions, where it is not explicitly
mentioned, were operated under air and no measures were taken to
exclude water. The commercially available compounds and solvents
were used as received. TLC was conducted with aluminum sheets
(TLC silica gel 60 F254) and visualized by exposure to UV light (254
nm), stained with ceric ammonium molybdate (CAM) or basic
potassium permanganate (KMnO4) and subsequent heating. Flash
column chromatography was performed on silica gel (40−60 μm);
the eluent used is reported in the particular experiments. IR spectra
were measured using the ATR technique in the range of 400−4000
+
C17H16N8O2Na1 387.1288; Found 387.1272.
2,2-Diazido-N1,N3-bis(4-methoxybenzyl)malonamide (1b). Ac-
cording to general procedure A using (70 mg, 0.29 mmol) diethyl
2,2-diazidomalonate (3), 2,2-diazido-N1,N3-bis(4-methoxybenzyl)-
malonamide (1b) was obtained as a colorless solid after purification
by column chromatography (EA:PE 1:9 → 1:1). Yield: 115 mg, 0.27
mmol, 94%. TLC: Rf = 0.43 (EA:PE 2:8) [Cl2]. IR (ATR): 3288,
2112, 1678, 1511, 1225, 1032 cm−1. 1H NMR (600 MHz, CDCl3): δ
7.26 (br. s., 2 H), 7.20−7.12 (m, J = 9.0 Hz, 4 H), 6.90−6.80 (m, 4
H), 4.40 (d, J = 6.0 Hz, 4 H), 3.79 (s, 6 H) ppm. 13C{1H} NMR (151
MHz, CDCl3): δ 163.4, 159.5, 129.2, 128.8, 114.4, 81.6, 55.4, 43.9
ppm. LRMS (ESI) m/z: 425.2 (100) [M + H]+, 447.2 (9) [M + Na]+.
cm−1 1H NMR spectra were recorded at 400 or 600 MHz
.
spectrometers, 13C NMR at 101 or 151 MHz. Chemical shifts are
reported as δ values in ppm, coupling constants J in Hz. Multiplicities
were defined by standard abbreviations. Low-resolution mass spectra
(LRMS) were recorded using a LC/MS-combination (ESI). High-
resolution mass spectra (HRMS) were obtained using ESI ionization
methods on a MicroTOF.
+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H20N8O4Na1
447.1500; Found 447.1500.
2,2-Diazido-N1,N3-bis(4-(trifluoromethyl)benzyl)malonamide
(1c). According to general procedure A using (70 mg, 0.29 mmol)
diethyl 2,2-diazidomalonate (3), 2,2-diazido-N1,N3-bis(4-(trifluoro-
methyl)benzyl)malonamide (1c) was obtained as a colorless solid
after purification by column chromatography (EA:PE 1:9 → 25:75).
Yield: 108 mg, 0.22 mmol, 75%. TLC: Rf = 0.58 (EA:PE 2:8) [Cl2].
IR (ATR): 3301, 2132, 1690, 1521, 1323, 1257, 1111, 1065 cm−1. 1H
NMR (400 MHz, CDCl3): δ 7.64−7.54 (m, 4 H), 7.51−7.39 (m, 2
H), 7.39−7.30 (m, 4 H), 4.53 (d, J = 6.1 Hz, 4 H) ppm. 13C{1H}
NMR (101 MHz, CDCl3): δ 163.7, 140.7, 130.4 (q, J = 32.9 Hz),
127.9, 126.0 (q, J = 3.7 Hz), 124.1 (q, J = 271.5 Hz), 82.1, 43.8 ppm.
LRMS (ESI) m/z: 501.1 (55) [M + H]+, 523.1 (11) [M + Na]+.
Caution! Geminal diazides are potentially hazardous and should be
handled with care.
General Procedures. General Procedure A for the Synthesis of
2,2-Diazido Malonamides 1. Diethyl 2,2-diazidomalonate (1.0
equiv) (3) was dissolved in THF (1.00 M), and the amine 9 (2.5
equiv) was added. The reaction mixture was stirred overnight at room
temperature, and the solvent was then concentrated under reduced
pressure. Column chromatographic purification afforded the corre-
sponding 2,2-diazido malonamides 1.
General Procedure B for the Synthesis of 2,2-Diazido
Malonamides 1. Diethyl 2,2-diazidomalonate (1.0 equiv) (3) was
dissolved in THF (0.50−1.00 M); the amine 9 (3.0 equiv) and
triethylamine (3.0 equiv) were sequentially added. The reaction
mixture was stirred overnight at room temperature, and the solvent
+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H14F6N8O2Na1
523.1036; Found 523.1022.
D
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The Journal of Organic Chemistry
Note
2,2-Diazido-N1,N3-bis(4-iodobenzyl)malonamide (1d). According
to general procedure B using (250 mg, 1.03 mmol) diethyl 2,2-
diazidomalonate (3), 2,2-diazido-N1,N3-bis(4-iodobenzyl)-
malonamide (1d) was obtained as a colorless solid after purification
by column chromatography (EA:PE 3:7). Yield: 468 mg, 0.76 mmol,
74%. TLC: Rf = 0.61 (EA:PE 3:7) [CAM]. IR (ATR): 3301, 2113,
1.13 mmol, 91%. TLC: Rf = 0.67 (EA:PE 1:1) [CAM]. IR (ATR):
3367, 2112, 1619, 1509, 1226, 740 cm−1. 1H NMR (400 MHz,
CDCl3): δ 8.15 (br. s., 2 H), 7.60 (d, J = 7.8 Hz, 2 H), 7.35 (d, J = 8.1
Hz, 2 H), 7.22 (dt, J = 1.3, 7.6 Hz, 2 H), 7.19−7.12 (m, 2 H), 7.04 (t,
J = 5.4 Hz, 2 H), 6.96 (d, J = 2.3 Hz, 2 H), 3.59 (q, J = 6.7 Hz, 4 H),
2.97 (t, J = 6.7 Hz, 4 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ
163.5, 136.5, 127.1, 122.4, 122.3, 119.6, 118.6, 112.0, 111.5, 81.2,
40.6, 25.1 ppm. LRMS (ESI) m/z: 471.2 (100) [M + H]+, 493.2 (14)
[M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
1
1682, 1670, 1509, 1240, 807 cm−1. H NMR (400 MHz, CDCl3): δ
7.71−7.62 (m, 4 H), 7.30 (br. s., 2 H), 7.01−6.95 (m, 4 H), 4.41 (d, J
= 6.1 Hz, 4 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 163.5,
138.2, 136.4, 129.7, 93.6, 81.7, 43.9 ppm. LRMS (ESI) m/z: 617.0
(46) [M + H]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
C23H22N10O2Na1 493.1819; Found 493.1824.
2,2-Diazido-N1,N3-bis((R)-1-(naphthalen-2-yl)ethyl)malonamide
(1j). According to general procedure B using (300 mg, 1.24 mmol)
diethyl 2,2-diazidomalonate (3), 2,2-diazido-N1,N3-bis((R)-1-(naph-
thalen-2-yl)ethyl)malonamide (1j) was obtained as a colorless solid
after purification by column chromatography (EA:PE 1:9). Yield: 248
mg, 0.50 mmol, 41%. TLC: Rf = 0.27 (EA:PE 1:9) [CAM]. IR
+
C17H14I2N8O2Na1 638.9221; Found 638.9226.
2,2-Diazido-N1,N3-diphenethylmalonamide (1e). According to
general procedure A using (70 mg, 0.29 mmol) diethyl 2,2-
diazidomalonate (3), 2,2-diazido-N1,N3-diphenethylmalonamide
(1e) was obtained as a colorless solid after purification by column
chromatography (EA:PE 1:9 → 2:8). Yield: 106 mg, 0.27 mmol, 93%.
TLC: Rf = 0.86 (EA:PE 2:8) [Cl2]. IR (ATR): 3318, 2114, 1673,
1
(ATR): 3372, 2117, 1688, 1517, 1215, 745 cm−1. H NMR (400
MHz, CDCl3): δ 7.77−7.62 (m, 8 H), 7.48−7.41 (m, 4 H), 7.35 (d, J
= 7.8 Hz, 2 H), 7.30−7.24 (m, 2 H), 5.23 (quin, J = 7.1 Hz, 2 H),
1.62 (d, J = 6.8 Hz, 6 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ
162.9, 139.2, 133.4, 133.0, 128.9, 128.1, 127.8, 126.6, 126.2, 124.7,
124.1, 81.3, 50.4, 21.9 ppm. LRMS (ESI) m/z: 493.2 (31) [M + H]+,
515.2 (3) [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
1
1520, 1211, 644 cm−1. H NMR (400 MHz, CDCl3): δ 7.39−7.31
(m, 4 H), 7.31−7.24 (m, 2 H), 7.24−7.18 (m, 4 H), 7.02 (br. s., 2 H),
3.66−3.46 (m, 4 H), 2.85 (t, J = 7.1 Hz, 4 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ 163.5, 138.1, 128.8, 128.8, 126.9, 81.3, 41.6,
35.5 ppm. LRMS (ESI) m/z: 393.2 (33) [M + H]+, 415.2 (21) [M +
Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C19H20-
+
C27H24N8O2Na1 515.1914; Found 515.1919.
2,2-Diazido-N1,N3-di(prop-2-yn-1-yl)malonamide (1k). Accord-
ing to general procedure A using (70 mg, 0.29 mmol) diethyl 2,2-
diazidomalonate (3), 2,2-diazido-N1,N3-di(prop-2-yn-1-yl)-
malonamide (1k) was obtained as a colorless solid after purification
by column chromatography (EA:PE 15:85 → 3:7). Yield: 59 mg, 0.20
mmol, 69%. TLC: Rf = 0.29 (EA:PE 2:8) [Cl2]. IR (ATR): 3292,
2151, 2135, 1689, 1505, 1258 cm−1. 1H NMR (400 MHz, CDCl3): δ
7.20 (br. s., 2 H), 4.08 (dd, J = 2.5, 5.3 Hz, 4 H), 2.29 (t, J = 2.5 Hz, 2
H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 163.2, 81.0, 77.8,
73.0, 30.2 ppm. LRMS (ESI) m/z: 283.1 (100) [M + Na]+. HRMS
+
N8O2Na1 415.1601; Found 415.1585.
2,2-Diazido-N1,N3-dioctylmalonamide (1f). According to general
procedure A (2.1 eq. amine) using (70 mg, 0.29 mmol) diethyl 2,2-
diazidomalonate (3), 2,2-diazido-N1,N3-dioctylmalonamide (1f) was
obtained as a colorless solid after purification by column
chromatography (EA:PE 5:95 → 2:8). Yield: 107 mg, 0.26 mmol,
91%. TLC: Rf = 0.45 (EA:PE 1:9) [Cl2]. IR (ATR): 3308, 2918,
2850, 2127, 1685, 1521, 1246 cm−1. 1H NMR (400 MHz, CDCl3): δ
7.00 (br. s., 2 H), 3.38−3.18 (m, 4 H), 1.52 (quin, J = 7.1 Hz, 4 H),
1.37−1.22 (m, 20 H), 0.90−0.84 (m, 6 H) ppm. 13C{1H} NMR (101
MHz, CDCl3): δ 163.6, 81.5, 40.5, 31.9, 29.3, 29.3, 26.9, 22.7, 14.2
ppm. LRMS (ESI) m/z: 409.3 (100) [M + H]+. HRMS (ESI-TOF)
+
(ESI-TOF) m/z: [M + Na]+ Calcd for C9H8N8O2Na1 283.0662;
Found 283.0662.
+
m/z: [M + Na]+ Calcd for C19H36N8O2Na1 431.2853; Found
2,2-Diazido-N1,N3-diisobutylmalonamide (1l). According to
general procedure A using (100 mg, 0.41 mmol) diethyl 2,2-
diazidomalonate (3), 2,2-diazido-N1,N3-diisobutylmalonamide (1l)
was obtained as a colorless solid after purification by column
chromatography (EA:PE 15:85 → 2:8). Yield: 112 mg, 0.38 mmol,
92%. TLC: Rf = 0.73 (EA:PE 2:8) [Cl2]. IR (ATR): 3326, 2960,
431.2841.
2,2-Diazido-N1,N3-bis(3,3-diethoxypropyl)malonamide (1g). Ac-
cording to general procedure A using (100 mg, 0.41 mmol) diethyl
2,2-diazidomalonate (3), 2,2-diazido-N1,N3-bis(3,3-diethoxypropyl)-
malonamide (1g) was obtained as a yellow oil after purification by
column chromatography (EA:PE 15:85 → 4:6). Yield: 172 mg, 0.39
mmol, 94%. TLC: Rf = 0.24 (EA:PE 2:8) [Cl2]. IR (ATR): 3350,
2976, 2880, 2131, 2111, 1698, 1510, 1054 cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.62 (br. s., 2 H), 4.56 (t, J = 5.1 Hz, 2 H), 3.68 (qd, J =
7.2, 9.1 Hz, 4 H), 3.51 (qd, J = 7.1, 9.1 Hz, 4 H), 3.44−3.36 (m, 4 H),
1.91−1.79 (m, 4 H), 1.23 (t, J = 7.1 Hz, 12 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ 163.2, 102.4, 81.6, 62.4, 36.4, 32.7, 15.4 ppm.
LRMS (ESI) m/z: 354.2 (14) [M - 2(C2H5O)−]+, 399.2 (63) [M −
(C2H5O)−]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
1
2112, 1682, 1522, 1157 cm−1. H NMR (600 MHz, CDCl3): δ 7.05
(br. s., 2 H), 3.12 (t, J = 6.6 Hz, 4 H), 1.90−1.76 (m, 2 H), 0.90 (d, J
= 6.8 Hz, 12 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ 163.7,
81.8, 47.6, 28.5, 20.0 ppm. LRMS (ESI) m/z: 297.2 (100) [M + H]+,
319.2 (82) [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
C11H20N8O2Na1 319.1601; Found 319.1604.
Di-tert-butyl (((2,2-Diazidomalonyl)bis(azanediyl))bis(pentane-
5,1-diyl))dicarbamate (1m). According to general procedure A
using (86 mg, 0.36 mmol) diethyl 2,2-diazidomalonate (3), di-tert-
butyl (((2,2-diazidomalonyl)bis(azanediyl))bis(pentane-5,1-diyl))-
dicarbamate (1m) was obtained as a colorless solid after purification
by column chromatography (EA:PE 3:7 → 1:1). Yield: 160 mg, 0.29
mmol, 81%. TLC: Rf = 0.68 (EA:PE 1:1) [Cl2]. IR (ATR): 3319,
2130, 1682, 1535, 1251, 1172 cm−1. 1H NMR (600 MHz, CDCl3): δ
7.03 (br. s., 2 H), 4.59 (br. s., 2 H), 3.32−3.23 (m, 4 H), 3.15−3.03
(m, 4 H), 1.55 (quin, J = 7.4 Hz, 4 H), 1.49 (quin, J = 7.3 Hz, 4 H),
1.43 (s, 18 H), 1.36−1.29 (m, 4 H) ppm. 13C{1H} NMR (151 MHz,
CDCl3): δ 163.6, 156.2, 81.6, 79.2, 40.4, 40.3, 29.7, 29.0, 28.6, 24.0
ppm. LRMS (ESI) m/z: 577.0 (100) [M + Na]+. HRMS (ESI-TOF)
+
C17H32N8O6Na1 467.2337; Found 467.2337.
N1,N3-Bis(3-(1H-imidazol-1-yl)propyl)-2,2-diazidomalonamide
(1h). According to general procedure A using (70 mg, 0.29 mmol)
diethyl 2,2-diazidomalonate (3), N1,N3-bis(3-(1H-imidazol-1-yl)-
propyl)-2,2-diazidomalonamide (1h) was obtained as a yellow oil
after purification by column chromatography (DCM:MeOH 9:1 →
8:2). Yield: 112 mg, 0.28 mmol, 97%. TLC: Rf = 0.10 (DCM:MeOH
8:2) [Cl2]. IR (ATR): 2938, 2113, 1676, 1505, 1228 cm−1. 1H NMR
(400 MHz, CDCl3): δ 7.84 (s, 2 H), 7.47 (s, 2 H), 7.01 (s, 2 H), 6.90
(s, 2 H), 3.95 (t, J = 6.8 Hz, 4 H), 3.26 (q, J = 6.6 Hz, 4 H), 2.00
(quin, J = 6.8 Hz, 4 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ
164.0, 137.2, 129.5, 119.0, 81.8, 44.2, 37.4, 30.6 ppm. LRMS (ESI)
m/z: 401.2 (100) [M + H]+. HRMS (ESI-TOF) m/z: [M]+ Calcd for
+
m/z: [M + Na]+ Calcd for C23H42N10O6Na1 577.3181; Found
577.3182.
2,2-Diazido-N1,N3-bis(1-hydroxy-2-methylpropan-2-yl)-
malonamide (1n). According to general procedure A using (70 mg,
0.29 mmol) diethyl 2,2-diazidomalonate (3), 2,2-diazido-N1,N3-bis(1-
hydroxy-2-methylpropan-2-yl)malonamide (1n) was obtained as a
colorless oil after purification by column chromatography (EA:PE
85:15 → 9:1). Yield: 37 mg, 0.11 mmol, 39%. TLC: Rf = 0.47 (EA:PE
9:1) [Cl2]. IR (ATR): 3368, 2114, 1698, 1510, 1217 cm−1. 1H NMR
+
C15H21N12O2 401.1905; Found 401.1905.
N1,N3-Bis(2-(1H-indol-3-yl)ethyl)-2,2-diazidomalonamide (1i).
According to general procedure B using (300 mg, 1.24 mmol)
diethyl 2,2-diazidomalonate (3), N1,N3-bis(2-(1H-indol-3-yl)ethyl)-
2,2-diazidomalonamide (1i) was obtained as a pale brown solid after
purification by column chromatography (EA:PE 1:1). Yield: 532 mg,
E
DOI: 10.1021/acs.joc.8b02969
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(400 MHz, CDCl3): δ 6.91 (br. s., 2 H), 3.61 (s, 4 H), 3.38 (br. s., 2
H), 1.33 (s, 12 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 163.7,
81.8, 47.7, 28.5, 20.0 ppm. LRMS (ESI) m/z: 329.2 (100) [M + H]+,
351.2 (7) [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
dried over Na2SO4, and concentrated in vacuo. After purification by
flash chromatography, (PE:EA 70:30), 23 mg (0.11 mmol, 91%) of a
colorless solid was obtained. TLC: Rf = 0.88 (EA:PE 3:7) [UV,
KMnO4]. 1H NMR (600 MHz, CDCl3): δ 7.53−7.48 (m, 4 H),
7.33−7.28 (m, 4 H), 7.25−7.21 (m, 2 H) ppm. 13C{1H} NMR (151
MHz, CDCl3): δ 137.2, 129.2, 127.7, 127.3 ppm. The analytical data
are in agreement with previously reported ones.20
+
C11H20N8O4Na1 351.1500; Found 351.1499.
2-Azido-N1,N3-dibenzyl-2-methoxymalonamide (2a). According
to general procedure C using (150 mg, 0.41 mmol) 2,2-diazido-
N1,N3-dibenzylmalonamide (1a), 2-azido-N1,N3-dibenzyl-2-methoxy-
malonamide (2a) was obtained as a colorless solid after purification
by column chromatography (EA:PE 3:7). Yield: 120 mg, 0.34 mmol,
83%. TLC: Rf = 0.42 (EA:PE 3:7) [CAM]. IR (ATR): 3324, 2923,
2-Azido-N1,N3-bis(4-iodobenzyl)-2-methoxymalonamide (2d).
According to general procedure C using (300 mg, 0.49 mmol) 2,2-
diazido-N1,N3-bis(4-iodobenzyl)malonamide (1d), 2-azido-N1,N3-bis-
(4-iodobenzyl)-2-methoxymalonamide (2d) was obtained as a
colorless solid after purification by column chromatography (EA:PE
4:6 → 6:4). Yield: 241 mg, 0.40 mmol, 82%. TLC: Rf = 0.45 (EA:PE
4:6) [CAM]. IR (ATR): 3319, 2128, 1687, 1512, 1270, 1005 cm−1.
1H NMR (600 MHz, CDCl3): δ 7.69−7.60 (m, 4 H), 7.15 (t, J = 5.1
Hz, 2 H), 7.03−6.97 (m, 4 H), 4.42 (d, J = 6.0 Hz, 4 H), 3.45 (s, 3 H)
ppm. 13C{1H} NMR (151 MHz, CDCl3): δ 164.3, 138.1, 136.9,
129.6, 94.3, 93.4, 53.5, 43.5 ppm. LRMS (ESI) m/z: 606.0 (100) [M
+ H]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H17-
1
2128, 1685, 1517, 694 cm−1. H NMR (400 MHz, CDCl3): δ 7.37−
7.26 (m, 10 H), 7.16 (br. s., 2 H), 4.50 (d, J = 5.8 Hz, 4 H), 3.47 (s, 3
H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 164.2, 137.2, 129.0,
127.9, 127.8, 94.3, 53.4, 44.1 ppm. LRMS (ESI) m/z: 354.0 (100) [M
+ H]+, 377.0 (24) [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+
+
Calcd for C18H19N5O3Na1 376.1380; Found 376.1382.
2-Amino-N1,N3-dibenzylmalonamide (5). Azide 2a (67 mg, 0.19
mmol, 1.0 equiv) was dissolved in 1.26 mL of DCM (0.15 m).
Palladium on activated charcoal (30 mg, 0.03 mmol, 15 mol %) was
added, and the reaction mixture was stirred for 1 h at room
temperature in an autoclave with a hydrogen pressure of 100 psi.
Filtration over Celite with ethyl acetate as eluent and concentration
under reduced pressure furnished the primary amine 5 as a colorless
solid in 90% (51 mg, 0.17 mmol) yield. TLC: Rf = 0.17 (EA:PE 1:1)
+
I2N5O3Na1 627.9313; Found 627.9314.
2-Azido-2-methoxy-N1,N3-dioctylmalonamide (2f). According to
general procedure C using (150 mg, 0.37 mmol) 2,2-diazido-N1,N3-
dioctylmalonamide (1f), 2-azido-2-methoxy-N1,N3-dioctylmalona-
mide (2f) was obtained as a colorless solid after purification by
column chromatography (EA:PE 2:8). Yield: 128 mg, 0.32 mmol,
87%. TLC: Rf = 0.29 (EA:PE 2:8) [CAM]. IR (ATR): 3324, 2954,
1
[Ninhydrin]. H NMR (400 MHz, CDCl3): δ 8.21 (br. s., 2 H),
1
2126, 1681, 1518, 1158 cm−1. H NMR (400 MHz, CDCl3): δ 6.79
7.39−7.20 (m, 10 H), 4.55−4.37 (m, 4 H), 4.11 (s, 1 H), 2.20 (br. s.,
2 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 169.6, 137.9, 128.8,
127.7, 127.6, 57.0, 43.8 ppm. The analytical data are in agreement
with previously reported ones.13
(br. s., 2 H), 3.44 (s, 3 H), 3.33−3.17 (m, 4 H), 1.51 (quin, J = 7.1
Hz, 4 H), 1.32−1.23 (m, 20 H), 0.92−0.78 (m, 6 H) ppm. 13C{1H}
NMR (101 MHz, CDCl3): δ 164.2, 94.3, 53.3, 40.1, 31.9, 29.4, 29.3,
26.9, 22.7, 14.2 ppm. LRMS (ESI) m/z: 398.3 (69) [M + H]+. HRMS
N1,N3-Dibenzyl-2-iminomalonamide (6). Azide 2a (100 mg, 0.28
mmol, 1.0 equiv) was dissolved in 1.77 mL of THF (0.16 m).
Triphenylphosphine (148 mg, 0.57 mmol, 2.0 equiv) and water (25
μL, 25 mg, 1.41 mmol, 5.0 equiv) were added, and the reaction
mixture was stirred for 48 h at room temperature. Concentration
under reduced pressure and column chromatography (EA:PE 3:7)
furnished the imine 6 as a pale yellow solid in 63% (53 mg, 0.18
+
(ESI-TOF) m/z: [M + Na]+ Calcd for C20H39N5O3Na1 420.2945;
Found 420.2946.
2-Azido-N1,N3-bis(3,3-diethoxypropyl)-2-methoxymalonamide
(2g). According to general procedure C using (150 mg, 0.34 mmol)
2,2-diazido-N1,N3-bis(3,3-diethoxypropyl)malonamide (1g), 2-azido-
N1,N3-bis(3,3-diethoxypropyl)-2-methoxymalonamide (2g) was ob-
tained as a colorless solid after purification by column chromatog-
raphy (EA:PE 8:2). Yield: 140 mg, 0.32 mmol, 95%. TLC: Rf = 0.54
(EA:PE 8:2) [CAM]. IR (ATR): 3330, 2972, 2129, 1701, 1519, 1058
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.41 (br. s., 2 H), 4.55 (t, J =
5.2 Hz, 2 H), 3.73−3.61 (m, 4 H), 3.57−3.45 (m, 4 H), 3.42 (s, 3 H),
3.41−3.35 (m, 4 H), 1.88−1.79 (m, 4 H), 1.26−1.18 (m, 12 H) ppm.
13C{1H} NMR (101 MHz, CDCl3): δ 164.0, 102.4, 94.1, 62.2, 62.2,
1
mmol) yield. TLC: Rf = 0.80 (EA:PE 1:1) [Ninhydrin]. H NMR
(600 MHz, CDCl3): δ 12.18 (s, 1 H), 9.91 (br. s., 1 H), 8.11 (br. s., 1
H), 7.38−7.28 (m, 10 H), 4.57 (d, J = 6.0 Hz, 2 H), 4.51 (d, J = 6.0
Hz, 2 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ 163.6, 158.9,
158.0, 137.2, 136.9, 129.0, 129.0, 128.1, 128.0, 127.9, 127.9, 44.3, 43.7
ppm. The analytical data are in agreement with previously reported
ones.13
2-Azido-N1,N3-dibenzyl-2-(phenylthio)malonamide (7). Thiophe-
nol (42 μL, 45 mg, 0.41 mmol, 1.00 equiv) and triethylamine (57 μL,
42 mg, 0.41 mmol, 1.00 equiv) were dissolved in dry tetrahydrofuran
(6 mL). 2,2-Diazido-N1,N3-dibenzylmalonamide (1a) (150 mg, 0.41
mmol, 1.00 equiv) was added, and the mixture was stirred for 24 h at
ambient temperature. The reaction was terminated with 1 M NaOH,
the aqueous phase was extracted with ethyl acetate, and the combined
organic phase was washed with brine, dried over Na2SO4, and
concentrated in vacuo. After purification by flash chromatography
(PE:EA 70:30), 83% (149 mg, 0.35 mmol) of a yellow oil was
obtained. TLC: Rf = 0.68 (EA:PE 3:7) [UV, KMnO4]. IR (ATR):
3394, 2124, 1691, 1507, 1246, 691 cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.67−7.53 (m, 4 H), 7.49−7.40 (m, 1 H), 7.38−7.25 (m, 8
H), 7.17−7.08 (m, 4 H), 4.43−4.24 (m, 4 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ 165.2, 137.0, 136.9, 130.6, 129.4, 128.8, 128.5,
127.8, 127.8, 77.4, 44.4 ppm. HRMS (ESI-TOF) m/z: [M + Na]+
53.2, 36.1, 32.8, 15.4 ppm. LRMS (ESI) m/z: 388.2 (33) [M −
(EtO)−]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
C18H35N5O7Na1 456.2458; Found 456.2430.
N1,N3-Bis(2-(1H-indol-3-yl)ethyl)-2-azido-2-methoxymalona-
mide (2i). According to general procedure C using (100 mg, 0.21
mmol) N1,N3-bis(2-(1H-indol-3-yl)ethyl)-2,2-diazidomalonamide
(1i), N1,N3-bis(2-(1H-indol-3-yl)ethyl)-2-azido-2-methoxymalona-
mide (2i) was obtained as a colorless solid after purification by
column chromatography (EA:PE 6:4). Yield: 80 mg, 0.17 mmol, 82%.
TLC: Rf = 0.61 (EA:PE 6:4) [CAM]. IR (ATR): 3325, 2122, 1671,
1512, 1228, 740 cm−1. 1H NMR (600 MHz, CDCl3): δ 8.11 (br. s., 2
H), 7.61 (d, J = 7.9 Hz, 2 H), 7.35 (d, J = 7.9 Hz, 2 H), 7.21 (dt, J =
1.1, 7.5 Hz, 2 H), 7.16−7.11 (m, 2 H), 7.02 (d, J = 2.3 Hz, 2 H), 6.90
(t, J = 5.8 Hz, 2 H), 3.69−3.55 (m, 4 H), 3.31 (s, 3 H), 2.98 (dt, J =
1.9, 6.8 Hz, 4 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ 164.3,
136.5, 127.3, 122.5, 122.4, 119.6, 118.8, 112.6, 111.4, 94.0, 53.2, 40.3,
25.3 ppm. LRMS (ESI) m/z: 460.2 (100) [M + H]+, 482.2 (12) [M +
Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C24H25-
+
Calcd for C23H21N5O2S1Na1 454.1310; Found 454.1308.
1,2-Diphenyldisulfane (8). Thiophenol (23 μL, 25 mg, 0.23 mmol,
1.10 equiv) was dissolved in dry tetrahydrofuran (1.5 mL). A 2.5 M
solution of n-buthyllithium in hexane (91 μL, 63 mg, 0.23 mmol, 1.10
equiv) was added, and the resulting mixture was stirred for 5 min at
ambient temperature. 2,2-Diazido-N,N′-dibenzylmalonamide (1a)
(75 mg, 0.21 mmol, 1.00 equiv) was added, and the reaction mixture
was stirred for 12 h at ambient temperature. The reaction was
terminated with 1 M NaOH, the aqueous phase was extracted with
ethyl acetate, and the combined organic phase was washed with brine,
+
N7O3Na1 482.1911; Found 482.1909.
2-Azido-2-methoxy-N1,N3-bis((R)-1-(naphthalen-2-yl)ethyl)-
malonamide (2j). According to general procedure C using (150 mg,
0.31 mmol) 2,2-diazido-N1,N3-bis((R)-1-(naphthalen-2-yl)ethyl)-
malonamide (1j), 2-azido-2-methoxy-N1,N3-bis((R)-1-(naphthalen-
2-yl)ethyl)malonamide (2j) was obtained as a colorless solid after
purification by column chromatography (EA:PE 3:7 → 1:1). Yield:
102 mg, 0.21 mmol, 70%. TLC: Rf = 0.40 (EA:PE 3:7) [CAM]. IR
F
DOI: 10.1021/acs.joc.8b02969
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
(ATR): 3379, 2128, 1683, 1504, 745 cm−1. H NMR (600 MHz,
CDCl3) δ [ppm] 7.77−7.70 (m, 6 H), 7.68 (t, J = 9.0 Hz, 2 H), 7.48−
7.39 (m, 4 H), 7.36−7.31 (m, 2 H), 7.14 (dd, J = 7.9, 17.7 Hz, 2 H),
5.25 (quin, J = 7.2 Hz, 2 H), 3.45 (s, 3 H), 1.62 (d, J = 7.2 Hz, 3 H),
1.61 (d, J = 7.2 Hz, 3 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ
163.6, 163.5, 139.8, 139.6, 133.4, 132.9, 132.9, 128.7, 128.7, 128.1,
128.1, 127.7, 126.3, 126.3, 126.1, 124.7, 124.6, 124.5, 124.4, 94.1,
53.4, 49.8, 49.8, 21.8, 21.7 ppm. LRMS (ESI) m/z: 482.2 (84) [M +
H]+, 504.2 (2) [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
procedure C using (150 mg, 0.41 mmol) 2,2-diazido-N1,N3-
dibenzylmalonamide (1a), 2-Azido-N1,N3-dibenzyl-2-(((3aR,4R,6R,-
6aR)-6-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetra-
hydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)malonamide (2ae) was
obtained as a yellow oil after purification by column chromatography
(EA:DCM 8:2). Yield: 91 mg, 0.15 mmol, 36%. TLC: Rf = 0.63
(EA:PE 8:2) [Cl2]. IR (ATR): 3337, 2126, 1674, 1514, 1155, 1068,
697 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.61 (s, 1 H), 7.52 (t, J =
5.8 Hz, 1 H), 7.40 (t, J = 5.8 Hz, 1 H), 7.36−7.30 (m, 6 H), 7.27 (d, J
= 2.0 Hz, 4 H), 7.13 (d, J = 8.1 Hz, 1 H), 5.58 (dd, J = 2.0, 8.1 Hz, 1
H), 5.38 (d, J = 2.0 Hz, 1 H), 5.08 (dd, J = 5.1, 6.3 Hz, 1 H), 4.98
(dd, J = 2.0, 6.6 Hz, 1 H), 4.59 (dd, J = 6.3, 14.9 Hz, 2 H), 4.45−4.35
(m, 2 H), 4.21−4.16 (m, 1 H), 3.96−3.86 (m, 2 H), 1.53 (s, 3 H),
1.33 (s, 3 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 164.3,
162.8, 149.8, 143.1, 137.5, 137.4, 128.9, 128.0, 127.9, 127.9, 127.8,
114.8, 102.7, 95.8, 93.1, 85.1, 83.9, 79.9, 64.9, 44.0, 27.4, 25.5 ppm.
LRMS (ESI) m/z: 606.2 (100) [M + H]+. HRMS (ESI-TOF) m/z:
+
for C28H27N5O3Na1 504.2006; Found 504.2009.
2-Azido-N1,N3-dibenzyl-2-(decyloxy)malonamide (2aa). Accord-
ing to general procedure C using (150 mg, 0.41 mmol) 2,2-diazido-
N1,N3-dibenzylmalonamide (1a), 2-azido-N1,N3-dibenzyl-2-(decyl-
oxy)malonamide (2aa) was obtained as a colorless solid after
purification by column chromatography (EA:DCM 2:8). Yield: 175
mg, 0.37 mmol, 89%. TLC: Rf = 0.85 (EA:PE 2:8) [CAM]. IR
(ATR): 3341, 3032, 2123, 1684, 1514, 1161, 697 cm−1. H NMR
1
+
(400 MHz, CDCl3): δ 7.39−7.24 (m, 10H), 7.15 (t, J = 5.6 Hz, 2H),
4.50 (d, J = 6.0 Hz, 4H), 3.63 (t, J = 6.7 Hz, 2H), 1.71−1.59 (m, 2H),
1.35−1.24 (m, 14H), 0.88 (t, J = 6.9 Hz, 3H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ 164.6, 137.3, 129.0, 127.8, 127.7, 94.0, 66.6,
44.0, 32.0, 29.6, 29.6, 29.4, 29.4, 26.1, 22.8, 14.2 ppm. LRMS (ESI)
m/z: 480.3 (65) [M + H]+. HRMS (ESI-TOF) m/z: [M + Na]+
[M + Na]+ Calcd for C29H31N7O8Na1 628.2126; Found 628.2130.
2-(2-(1H-Indol-3-yl)ethoxy)-2-azido-N1,N3-dibenzylmalonamide
(2af). According to general procedure C using (150 mg, 0.41 mmol)
2,2-diazido-N1,N3-dibenzylmalonamide (1a), 2-(2-(1H-indol-3-yl)-
ethoxy)-2-azido-N1,N3-dibenzylmalonamide (2af) was obtained as
an orange oil after purification by column chromatography (EA:PE
1:1). Yield: 113 mg, 0.23 mmol, 57%. TLC: Rf = 0.64 (EA:PE 1:1)
[CAM]. IR (ATR): 3357, 2123, 1678, 1511, 1230, 731, 697 cm−1. 1H
NMR (400 MHz, CDCl3): δ 7.99 (br. s., 1 H), 7.62−7.55 (m, 1 H),
7.35−7.28 (m, 7 H), 7.23−7.14 (m, 5 H), 7.09−6.98 (m, 4 H), 4.48−
4.33 (m, 4 H), 3.94 (t, J = 6.8 Hz, 2 H), 3.13 (t, J = 6.7 Hz, 2 H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 164.6, 137.3, 136.3,
128.9, 127.8, 127.7, 127.6, 122.29, 122.26, 119.7, 118.6, 112.2, 111.4,
93.5, 66.7, 43.9, 25.6 ppm. LRMS (ESI) m/z: 483.2 (100) [M + H]+.
+
Calcd for C27H37N5O3Na1 502.2789; Found 502.2777.
2-(Allyloxy)-2-azido-N1,N3-dibenzylmalonamide (2ab). Accord-
ing to general procedure C using (150 mg, 0.41 mmol) 2,2-diazido-
N1,N3-dibenzylmalonamide (1a), 2-(allyloxy)-2-azido-N1,N3-dibenzyl-
malonamide (2ab) was obtained as a colorless solid after purification
by column chromatography (EA:PE 2:8). Yield: 96 mg, 0.25 mmol,
61%. TLC: Rf = 0.54 (EA:PE 3:7) [CAM]. IR (ATR): 3333, 2924,
2127, 1685, 1512, 1154, 695 cm−1. H NMR (600 MHz, CDCl3): δ
1
+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C27H26N6O3Na1
7.38−7.32 (m, 4 H), 7.31−7.26 (m, 6 H), 7.16 (br. s., 2 H), 5.99−
5.91 (m, 1 H), 5.33−5.29 (m, 1 H), 5.25−5.22 (m, 1 H), 4.50 (d, J =
6.0 Hz, 4 H), 4.18 (td, J = 1.3, 6.0 Hz, 2 H) ppm. 13C{1H} NMR
(151 MHz, CDCl3): δ 164.4, 137.2, 129.0, 128.9, 127.9, 127.8, 118.8,
94.0, 67.6, 44.1 ppm. LRMS (ESI) m/z: 380.1 (84) [M + H]+, 402.1
(8) [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
505.1959; Found 505.1949.
2-Azido-N1,N3-dibenzyl-2-(((3S,8S,9S,10R,13R,14S,17R)-10,13-di-
methyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,-
16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-
malonamide (2ag). According to general procedure C using (150
mg, 0.41 mmol) 2,2-diazido-N1,N3-dibenzylmalonamide (1a), 2-
azido-N1,N3-dibenzyl-2-(((3S,8S,9S,10R,13R,14S,17R)-10,13-dimeth-
yl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)malonamide
(2ag) was obtained as a colorless solid after purification by column
chromatography (EA:DCM 3:7). Yield: 164 mg, 0.23 mmol, 56%.
TLC: Rf = 0.28 (EA:PE 2:8) [CAM]. IR (ATR): 3329, 3030, 2125,
+
C20H21N5O3Na1 402.1537; Found 402.1534.
2-Azido-N1,N3-dibenzyl-2-(cyclopropylmethoxy)malonamide
(2ac). According to general procedure C using (150 mg, 0.41 mmol)
2,2-diazido-N1,N3-dibenzylmalonamide (1a), 2-azido-N1,N3-dibenzyl-
2-(cyclopropylmethoxy)malonamide (2ac) was obtained as a color-
less solid after purification by column chromatography (EA:PE 3:7).
Yield: 140 mg, 0.36 mmol, 87%. TLC: Rf = 0.50 (EA:PE 3:7) [CAM].
1
1694, 1536, 1161, 698 cm−1. H NMR (400 MHz, CDCl3): δ 7.41−
IR (ATR): 3347, 2129, 1682, 1513, 1160, 700 cm−1. H NMR (600
1
7.23 (m, 10 H), 7.23−7.15 (m, 2 H), 5.41−5.30 (m, 1 H), 4.59−4.43
(m, 4 H), 3.62−3.49 (m, 1 H), 2.45−2.34 (m, 2 H), 2.07−1.90 (m, 3
H), 1.89−1.78 (m, 2 H), 1.61−1.02 (m, 21 H), 1.00 (s, 3 H), 0.92 (d,
J = 6.6 Hz, 3 H), 0.88 (d, J = 1.8 Hz, 3 H), 0.86 (d, J = 1.8 Hz, 3 H),
0.68 (s, 3 H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 164.9,
164.9, 140.1, 137.4, 137.4, 128.9, 127.8, 127.8, 127.7, 122.7, 94.2,
78.4, 56.9, 56.3, 50.3, 44.0, 42.5, 40.1, 39.9, 39.7, 37.3, 36.6, 36.3,
35.9, 32.1, 32.1, 32.0, 29.7, 28.4, 28.2, 24.4, 24.0, 23.0, 22.7, 21.2,
19.4, 18.9, 12.0 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
MHz, CDCl3): δ 7.37−7.25 (m, 10 H), 7.18 (br. s., 2 H), 4.50 (d, J =
6.0 Hz, 4 H), 3.48 (d, J = 7.2 Hz, 2 H), 1.18−1.07 (m, 1 H), 0.63−
0.52 (m, 2 H), 0.32−0.21 (m, 2 H) ppm. 13C{1H} NMR (151 MHz,
CDCl3): δ 164.6, 137.3, 129.0, 127.8, 127.7, 93.8, 71.6, 44.0, 10.6, 3.5
ppm. LRMS (ESI) m/z: 394.1 (100) [M + H]+. HRMS (ESI-TOF)
+
m/z: [M + Na]+ Calcd for C21H23N5O3Na1 416.1704; Found
416.1705.
2-Azido-N1,N3-dibenzyl-2-((6-hydroxyhexyl)oxy)malonamide
(2ad). According to general procedure C using (80 mg, 0.22 mmol)
2,2-diazido-N1,N3-dibenzylmalonamide (1a), 2-azido-N1,N3-dibenzyl-
2-((6-hydroxyhexyl)oxy)malonamide (2ad) was obtained as a
colorless solid after purification by column chromatography (EA:PE
4:6 → 9:1). Yield: 52 mg, 0.12 mmol, 53%. TLC: Rf = 0.50 (EA:PE
8:2) [CAM]. IR (ATR): 3323, 3033, 2126, 1683, 1514, 1158, 698
+
C44H61N5O3Na1 730.4667; Found 730.4666.
2-Azido-N1,N3-dibenzyl-2-isopropoxymalonamide (2ah). Ac-
cording to general procedure C using (150 mg, 0.41 mmol) 2,2-
diazido-N1,N3-dibenzylmalonamide (1a), 2-azido-N1,N3-dibenzyl-2-
isopropoxymalonamide (2ah) was obtained as a colorless solid after
purification by column chromatography (EA:PE 3:7). Yield: 129 mg,
0.34 mmol, 82%. TLC: Rf = 0.53 (EA:PE 2:8) [CAM]. IR (ATR):
3379, 2119, 1689, 1526, 1505, 1267, 1138, 702 cm−1. 1H NMR (400
MHz, CDCl3): δ 7.38−7.26 (m, 10 H), 7.17 (br. s., 2 H), 4.50 (d, J =
5.8 Hz, 4 H), 4.00 (spt, J = 6.1 Hz, 1 H), 1.29 (d, J = 6.1 Hz, 6 H)
ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 164.9, 137.4, 129.0,
127.8, 127.7, 94.5, 71.8, 44.0, 23.8 ppm. LRMS (ESI) m/z: 382.2 (47)
[M + H]+, 404.1 (5) [M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+
1
cm−1. H NMR (400 MHz, CDCl3): δ 7.39−7.34 (m, 4 H), 7.34−
7.27 (m, 6 H), 7.21 (t, J = 5.6 Hz, 2 H), 4.52 (d, J = 6.0 Hz, 4 H),
3.67 (t, J = 6.4 Hz, 2 H), 3.63 (t, J = 6.4 Hz, 2 H), 1.73−1.67 (m, 2
H), 1.63−1.52 (m, 3 H), 1.45−1.38 (m, 4 H) ppm. 13C{1H} NMR
(101 MHz, CDCl3): δ 164.5, 137.3, 129.0, 127.9, 127.7, 94.0, 66.3,
62.8, 44.0, 32.6, 29.4, 25.7, 25.4 ppm. LRMS (ESI) m/z: 440.2 (100)
[M + H]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
C23H29N5O4Na1 462.2112; Found 462.2111.
+
2-Azido-N1,N3-dibenzyl-2-(((3aR,4R,6R,6aR)-6-(2,4-dioxo-3,4-
dihydropyrimidin-1(2H)-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]-
dioxol-4-yl)methoxy)malonamide (2ae). According to general
Calcd for C20H23N5O3Na1 404.1693; Found 404.1687.
2-Azido-N1,N3-dibenzyl-2-(cyclohexyloxy)malonamide (2ai). Ac-
cording to general procedure C using (100 mg, 0.27 mmol) 2,2-
G
DOI: 10.1021/acs.joc.8b02969
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
diazido-N1,N3-dibenzylmalonamide (1a), 2-azido-N1,N3-dibenzyl-2-
(cyclohexyloxy)malonamide (2ai) was obtained as a colorless solid
after purification by column chromatography (EA:DCM 1:9). Yield:
78 mg, 0.19 mmol, 67%. TLC: Rf = 0.57 (EA:PE 2:8) [CAM]. IR
6.0, 1.3 Hz, 2H) ppm. 13C{1H} NMR (101 MHz, CDCl3): δ 163.9,
147.8, 137.0, 132.7, 129.9, 129.0, 128.8, 128.0, 127.8, 126.0, 120.9,
118.8, 90.2, 68.9, 44.3 ppm. LRMS (ESI) m/z: 482.2 (100) [M +
+
H]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C28H27N5O3Na1
1
(ATR): 3340, 2943, 2126, 1682, 1511, 1144, 696 cm−1. H NMR
504.2006; Found 504.2005.
N1,N3-Dibenzyl-2-(((3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-
17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-2-(4-
(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)malonamide (12d). According
to general procedure D (H2O/t-BuOH) using (30 mg, 0.04 mmol) 2-
azido-N1,N3-dibenzyl-2-(((3S,8S,9S,10R,13R,14S,17R)-10,13-dimeth-
yl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-
tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)malonamide
(2ag), N1,N3-dibenzyl-2-(((3S,8S,9S,10R,13R,14S,17R)-10,13-di-
methyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,-
16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)oxy)-2-(4-
(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)malonamide (12d) was ob-
tained as a yellow solid after purification by column chromatography
(EA:DCM 2:8). Yield: 28 mg, 0.03 mmol, 81%. TLC: Rf = 0.71
(EA:PE 2:8) [CAM]. IR (ATR): 3326, 2932, 1703, 1511, 1150, 1078,
1027, 779, 729, 696 cm−1. 1H NMR (600 MHz, CDCl3): δ 7.80 (s, 1
H), 7.75−7.64 (m, 3 H), 7.46−7.27 (m, 12 H), 5.15 (d, J = 4.9 Hz, 1
H), 4.64−4.53 (m, 4 H), 4.01−3.87 (m, 1 H), 2.24−2.12 (m, 1 H),
2.01−1.93 (m, 1 H), 1.92−1.78 (m, 3 H), 1.70−1.62 (m, 1 H), 1.56−
1.50 (m, 2 H), 1.46−1.28 (m, 10 H), 1.17−0.95 (m, 10 H), 0.91−
0.88 (m, 6 H), 0.87 (d, J = 3.0 Hz, 3 H), 0.86 (d, J = 2.6 Hz, 3 H),
0.63 (s, 3 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ 164.5,
164.3, 143.9, 139.8, 137.2, 131.1, 129.0, 127.9, 127.9, 127.8, 126.6,
126.0, 122.8, 122.0, 121.0, 90.4, 79.0, 56.8, 56.3, 50.1, 44.3, 42.4, 39.9,
39.7, 39.7, 37.3, 36.5, 36.3, 35.9, 32.0, 32.0, 29.3, 28.4, 28.2, 24.4,
24.0, 23.0, 22.7, 21.1, 19.4, 18.9, 12.0 ppm. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C50H65N5O3S1Na1+ 838.4700; Found 838.4684.
Methyl 1-(1,3-Bis(benzylamino)-2-isopropoxy-1,3-dioxopropan-
2-yl)-1H-1,2,3-triazole-4-carboxylate (12e). According to general
procedure D (DMF) using (80 mg, 0.21 mmol) 2-azido-N1,N3-
dibenzyl-2-isopropoxymalonamide (2ah), methyl 1-(1,3-bis(benzyl-
amino)-2-isopropoxy-1,3-dioxopropan-2-yl)-1H-1,2,3-triazole-4-car-
boxylate (12e) was obtained as a colorless solid after purification by
column chromatography (EA:PE 1:1). Yield: 79 mg, 0.17 mmol, 81%.
TLC: Rf = 0.67 (EA:PE 1:1) [CAM]. IR (ATR): 3317, 1682, 1535,
1240 cm−1. 1H NMR (600 MHz, CDCl3): δ 8.32 (s, 1 H), 7.47 (t, J =
5.8 Hz, 2 H), 7.39−7.26 (m, 10 H), 4.68−4.47 (m, 3 H), 4.45−4.30
(m, 1 H), 3.96 (s, 3 H), 0.93 (d, J = 6.1 Hz, 6 H) ppm. 13C{1H}
NMR (151 MHz, CDCl3): δ 163.9, 160.7, 139.9, 136.9, 129.7, 129.1,
128.0, 127.7, 90.7, 73.1, 52.5, 44.4, 23.3 ppm. LRMS (ESI) m/z:
466.2 (15) [M + H]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
(600 MHz, CDCl3): δ 7.38−7.32 (m, 4 H), 7.31−7.26 (m, 6 H), 7.20
(t, J = 5.1 Hz, 2 H), 4.59−4.43 (m, 4 H), 3.73−3.58 (m, 1 H), 2.03−
1.91 (m, 2 H), 1.80−1.68 (m, 2 H), 1.57−1.49 (m, 1 H), 1.49−1.39
(m, 2 H), 1.31−1.12 (m, 3 H) ppm. 13C{1H} NMR (151 MHz,
CDCl3): δ 165.0, 137.4, 128.9, 127.8, 127.7, 94.3, 77.3, 44.0, 33.7,
25.4, 24.4 ppm. LRMS (ESI) m/z: 422.3 (75) [M + H]+, 444.2 (20)
[M + Na]+. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
+
C23H27N5O3Na1 444.2006; Found 444.2007.
2-Azido-N1,N3-dibenzyl-2-(tert-butoxy)malonamide (2aj). Ac-
cording to general procedure C using (100 mg, 0.27 mmol) 2,2-
diazido-N1,N3-dibenzylmalonamide (1a), 2-azido-N1,N3-dibenzyl-2-
(tert-butoxy)malonamide (2aj) was obtained as a colorless solid
after purification by column chromatography (EA:PE 2:8). Yield: 59
mg, 0.15 mmol, 54%. TLC: Rf = 0.65 (EA:PE 2:8) [CAM]. IR
1
(ATR): 3358, 2120, 1681, 1531, 1497, 1135, 693 cm−1. H NMR
(400 MHz, CDCl3): δ 7.37−7.26 (m, 10 H), 7.14 (br. s., 2 H), 4.48
(d, J = 6.1 Hz, 4 H), 1.38 (s, 9 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3): δ 166.1, 137.4, 128.9, 127.7, 92.7, 80.5, 44.1, 29.6 ppm.
LRMS (ESI) m/z: 396.2 (15) [M + H]+, 418.2 (13) [M + Na]+.
+
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C21H25N5O3Na1
418.1850; Found 418.1836.
2-Methoxy-N1,N3-dioctyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-
malonamide (12a). According to general procedure D (H2O/t-
BuOH) using (100 mg, 0.25 mmol) 2-azido-2-methoxy-N1,N3-
dioctylmalonamide (2f), 2-methoxy-N1,N3-dioctyl-2-(4-phenyl-1H-
1,2,3-triazol-1-yl)malonamide (12a) was obtained as a colorless
solid after purification by column chromatography (EA:PE 2:8).
Yield: 94 mg, 0.19 mmol, 75%. TLC: Rf = 0.74 (EA:PE 3:7) [CAM].
IR (ATR): 3313, 2924, 2854, 1698, 1538, 1518, 693 cm−1. 1H NMR
(600 MHz, CDCl3): δ 7.96 (s, 1 H), 7.86−7.83 (m, 2 H), 7.46−7.41
(m, 2 H), 7.37−7.31 (m, 3 H), 3.41 (s, 3 H), 3.39−3.34 (m, 4 H),
1.58 (quin, J = 7.2 Hz, 4 H), 1.36−1.25 (m, 20 H), 0.87 (t, J = 7.2 Hz,
6 H) ppm. 13C{1H} NMR (151 MHz, CDCl3): δ 163.8, 147.7, 130.0,
129.0, 128.7, 126.0, 121.0, 90.5, 54.6, 40.5, 31.9, 29.3, 29.3, 27.0, 22.8,
14.2 ppm. LRMS (ESI) m/z: 500.3 (100) [M + H]+. HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C28H45N5O3Na1+ 522.3415; Found
522.3416.
N1,N3-Dibenzyl-2-((6-hydroxyhexyl)oxy)-2-(4-phenyl-1H-1,2,3-tri-
azol-1-yl)malonamide (12b). According to general procedure D
(DMF) using (180 mg, 0.41 mmol) 2-azido-N1,N3-dibenzyl-2-((6-
hydroxyhexyl)oxy)malonamide (2ad), N1,N3-dibenzyl-2-((6-hydroxy-
hexyl)oxy)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)malonamide (12b) was
obtained as a pale yellow resin after purification by column
chromatography (EA:PE 1:1 → 6:4). Yield: 157 mg, 0.29 mmol,
71%. TLC: Rf = 0.23 (EA:PE 1:1) [CAM]. IR (ATR): 3229, 2932,
+
C24H27N5O5Na1 488.1904; Found 488.1910.
1-Benzyl 1-(3-(1-(1,3-bis(benzylamino)-2-methoxy-1,3-dioxopro-
pan-2-yl)-1H-1,2,3-triazol-4-yl)propyl)-3′H-cyclopropa[1,9][5,6]-
fulleren-C60-Ih-1,1-dicarboxylate (12f). According to general proce-
dure D (H2O/DCM) using (19 mg, 0.05 mmol)), 2-azido-N1,N3-
dibenzyl-2-methoxymalonamide (2a), 1-Benzyl 1-(3-(1-(1,3-bis-
(benzylamino)-2-methoxy-1,3-dioxopropan-2-yl)-1H-1,2,3-triazol-4-
yl)propyl)-3′H-cyclopropa[1,9][5,6]fulleren-C60-Ih-1,1-dicarboxylate
(12f) was obtained as a dark purple solid after purification by column
chromatography (EA:DCM 1:9). Yield: 33 mg, 0.03 mmol, 46%.
TLC: Rf = 0.62 (EA:DCM 1:9) [CAM]. IR (ATR): 3307, 2921, 1740,
1699, 695 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.67 (t, J = 5.9 Hz, 2
H), 7.52 (s, 1 H), 7.51−7.48 (m, 2 H), 7.39−7.28 (m, 13 H), 5.52 (s,
2 H), 4.62−4.53 (m, 4 H), 4.53−4.46 (m, 2 H), 3.36 (s, 3 H), 2.83 (t,
J = 7.5 Hz, 2 H), 2.22−2.09 (m, 2 H) ppm. 13C{1H} NMR (101
MHz, CDCl3): δ 163.9, 163.6, 163.6, 146.6, 145.4, 145.3, 145.3,
145.2, 145.1, 144.9, 144.8, 144.8, 144.8, 144.7, 144.0, 144.0, 143.2,
143.2, 143.2, 143.2, 143.1, 142.4, 142.0, 142.0, 141.1, 141.1, 139.3,
139.1, 137.0, 134.7, 129.3, 129.2, 129.0, 128.9, 128.0, 127.8, 122.6,
90.5, 71.6, 69.2, 66.5, 54.6, 44.3, 28.0, 22.1 ppm. HRMS (ESI-TOF)
1
2858, 1699, 1512, 1156, 693 cm−1. H NMR (400 MHz, CDCl3): δ
7.94 (s, 1 H), 7.86−7.78 (m, 2 H), 7.75 (t, J = 5.8 Hz, 2 H), 7.48−
7.39 (m, 2 H), 7.39−7.28 (m, 11 H), 4.65−4.52 (m, 4 H), 3.59 (t, J =
6.6 Hz, 2 H), 3.52 (t, J = 6.4 Hz, 2 H), 1.58−1.50 (m, 3 H), 1.50−
1.41 (m, 2 H), 1.33−1.21 (m, 4 H) ppm. 13C{1H} NMR (101 MHz,
CDCl3): δ 164.1, 147.7, 137.1, 129.8, 129.0, 129.0, 128.7, 127.9,
127.8, 126.0, 121.0, 90.5, 67.4, 62.6, 44.3, 32.5, 29.3, 25.4, 25.2 ppm.
LRMS (ESI) m/z: 542.2 (100) [M + H]+. HRMS (ESI-TOF) m/z:
+
[M + Na]+ Calcd for C31H35N5O4Na1 564.2581; Found 564.2582.
2-(Allyloxy)-N1,N3-dibenzyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-
malonamide (12c). According to general procedure D (DMF) using
(80 mg, 0.21 mmol) 2-(allyloxy)-2-azido-N1,N3-dibenzylmalonamide
(2ab), N1,N3-dibenzyl-2-(cyclopropylmethoxy)-2-(4-phenyl-1H-1,2,3-
triazol-1-yl)malonamide (12c) was obtained as a colorless solid after
purification by column chromatography (EA:DCM 4:6). Yield: 92
mg, 0.19 mmol, 91%. TLC: Rf = 0.69 (EA:PE 4:6) [CAM]. IR
1
(ATR): 3276, 1683, 1520, 1082, 690 cm−1. H NMR (400 MHz,
CDCl3): δ 7.91 (s, 1H), 7.83−7.78 (m, 2H), 7.72 (t, J = 5.9 Hz, 2H),
7.48−7.40 (m, 2H), 7.39−7.29 (m, 11H), 5.77 (ddt, J = 17.1, 10.3,
6.0 Hz, 1H), 5.18−5.07 (m, 2H), 4.65−4.52 (m, 4H), 4.19 (dt, J =
+
m/z: [M + Na]+ Calcd for C93H33N5O7Na1 1355.2311; Found
1355.2312.
H
DOI: 10.1021/acs.joc.8b02969
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Ko, S. W.; Yun, H.; Yoon, H. J.; Kim, M. S.; Lee, W. K. Preparation of
2,3-diaminopropionate from ring opening of aziridine-2-carboxylate.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02969.
■
S
1H and 13C NMR spectra of selected examples (PDF)
(7) (a) Lieber, E.; Minnis, R. L.; Rao, C. N. R. Carbamoyl Azides.
Chem. Rev. 1965, 65, 377. (b) Balci, M. Acyl Azides: Versatile
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AUTHOR INFORMATION
Corresponding Author
*E-mail: sfkirsch@uni-wuppertal.de.
ORCID
Stefan F. Kirsch: 0000-0003-2628-8703
Notes
The authors declare no competing financial interest.
■
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