Geminal Diazides Derived from 1,3-Dicarbonyls: A Protocol for Synthesis

Article abstract of DOI:10.1021/acs.joc.5b02328

Geminal diazides constitute a rare class of compounds where only a limited number of methods are available for their synthesis. We present the reaction of 1,3-dicarbonyl compounds (as exemplified by malonates, 3-oxoesters, and 1,3-diketones) with molecular iodine and sodium azide in aqueous DMSO providing a general access to geminal diazides. A broad range of geminal diazides with various structural motifs including sterically demanding substituents and ordinary functional groups were synthesized, and it was shown that the diazidation of 1,3-dicarbonyls can be selectively achieved even in the presence of other 1,3-dicarbonyls with substituents at 2-position. Additionally, several diazides were studied regarding their thermal stability.

Full text of DOI:10.1021/acs.joc.5b02328

Article
pubs.acs.org/joc
Geminal Diazides Derived from 1,3-Dicarbonyls: A Protocol for
Synthesis
†
†
†
†
†
Hellmuth Erhardt, Andreas P. Haring, Andreas Kotthaus, Markus Roggel, My Linh Tong,
̈
†
†
‡
,†
Phillip Biallas, Martin Ju
̈
bermann, Fabian Mohr, and Stefan F. Kirsch*
†
Organic Chemistry, Bergische Universitat
̈
Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany
̈
Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany
‡
Inorganic Chemistry, Bergische Universitat
*
S Supporting Information
ABSTRACT: Geminal diazides constitute a rare class of compounds where only a limited
number of methods are available for their synthesis. We present the reaction of 1,3-dicarbonyl
compounds (as exemplified by malonates, 3-oxoesters, and 1,3-diketones) with molecular
iodine and sodium azide in aqueous DMSO providing a general access to geminal diazides.
A broad range of geminal diazides with various structural motifs including sterically
demanding substituents and ordinary functional groups were synthesized, and it was shown
that the diazidation of 1,3-dicarbonyls can be selectively achieved even in the presence of
other 1,3-dicarbonyls with substituents at 2-position. Additionally, several diazides were studied regarding their thermal stability.
INTRODUCTION
diazides were obtained from the simple treatment of 1,3-
■
38−40
1
,2
dicarbonyls with IBX-SO K,
sodium azide, and catalytic
3
While organic azides have evolved into a major field of
contemporary organic synthesis, in particular due to their
amounts of sodium iodide in aqueous DMSO at room
41
3
−7
temperature (Scheme 1A). The mild reaction conditions
tolerated a range of functional groups; yields were typically
high. A variation of this procedure also allowed for the synthesis
of geminal triazides, highly energetic compounds that must
manifold of applications in chemical biology
and materials
8
−10
science,
geminal diazides are a somewhat neglected class
of compounds. In a breathtaking study from 1908, Forster and
co-workers reported the probably first geminal diazide, ethyl
11
42
2
,2-diazidoacetate CH(N ) CO Et; the synthesis of ethyl 2,2-
3 2 2
12,13
be handled with great caution. At the same time, Sudalai and
diazidomalonate (N ) C(CO Et) was described in 1910.
3
2
2
2
Thereafter, members of the compound class made not more
Scheme 1. Recent Diazidation Protocols
14−16
than sporadic appearances in the literature,
and the
majority of the publications that somehow included geminal
diazides had a research focus where the diazides were mostly
17
innocent bystanders.
To our surprise, the number of reports pointing toward
synthetic applications or useful properties of geminal diazides
was shockingly rare; the few reports we found through our
18−20
review of the literature were hardly cited.
As an exception,
a few preliminary studies were performed that described the
2
1−23
reactivity of selected geminal diazides under irradiation
or
2
4−26
heat.
This lack of interest may have partly arisen from their
27
supposedly hazardous character. On the other hand, only a
small number of methods were known to generate molecules
with two azido groups attached to one carbon atom before
2
012, and most of those methods relied on the classical
2
8−30
treatment of geminal dihalides with sodium azide.
Other
less common methods leading to geminal diazides comprise the
3
1−34
35
use of trimethylsilylazide,
iodine azide, polymeric
36
37
ammonium azide, or aryl sulfonazides.
Recently, we initiated a project that would uncover novel
reactivities and synthetic applications of geminal diazides. To
this end, we required a straightforward and experimentally
simple approach toward the title class of compounds. Our
seminal report from 2012 on the oxidative azidation of
enolizable carbonyls included five examples where geminal
Received: October 7, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02328
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co-workers reported how several aryl ketones can be efficiently
3 remained fully untouched, and the corresponding monoazide
5 was not found. This result leads to the conclusion that, likely
for steric reasons, it is possible to perform the selective diazida-
tion of 1,3-dicarbonyls in the presence of other 1,3-dicarbonyls
with substituents at 2-position.
diazidated by the use of sodium periodate and sodium azide in
43
a hot mixture of DMSO and acetic acid (Scheme 1B). In
015, it was shown by Yanada and co-workers that alkynes
reacted with N-iodosuccinimide and trimethylsilyl azide, leading
2
44
to 2,2-diazidoketones (Scheme 1C). While this method is
arguably the most versatile one, it only provides access to a full
spectrum of diazidated aryl ketones; a flexible method for the
synthesis of the diazidated variants of functionalized alkyl
ketones is still desirable.
We again point out that all of the diazides summarized in
Table 1 are also available by using our traditional diazidation
protocol (3 equiv of IBX-SO K, 0.2 equiv of NaI, 3.3 equiv of
3
41
NaN , rt, DMSO/H O). An example with IBX-SO K as
3
2
3
oxidizing agent instead of iodine is shown in eq 1. Due to the
Herein, we present an experimentally simple method for the
diazidation of 1,3-dicarbonyl compounds. Geminal diazides with
various functional groups were directly accessed by employing
molecular iodine and sodium azide in aqueous DMSO at room
temperature. We also show that the diazides are relatively stable,
a promise for future applications.
fact that the use of IBX-SO K requires a three-step synthesis
3
of the reagent, however, we recommend to test our current
conditions with the iodine−sodium azide couple first when
attempting the diazidation of 1,3-dicarbonyls.
RESULTS AND DISCUSSION
Based on our previous diazidation protocol with IBX-SO K,
■
41
3
we began our study with the reaction of malonate 1a in the
presence of sodium azide, the most abundant and cheapest
azide source, and it was found early that aqueous solutions of
DMSO or THF were required to observe diazidated products,
most likely due to the low solubility of sodium azide in purely
organic solvents. Gratifyingly, molecular iodine was identified as
a suitable oxidant and, when using aqueous DMSO, gave the
desired diazide 2a in promising 65% yield. In order to generate
a full range of geminal diazides derived from 1,3-dicarbonyls,
the reaction of 1,3-dicarbonyls 1 with iodine and sodium azide
was typically performed in aqueous DMSO at room temper-
ature: 1, I (2.2 equiv), NaN (6.0 equiv), rt, DMSO/H O (2:1,
We assume that, under our reaction conditions, iodine (or
IN ) is the electrophilic iodine source that leads to the iodination
3
of the easily enolizable 1,3-dicarbonyl system under formation of
A (Scheme 3). Subsequent nucleophilic substitution gives the
monoazide B, which undergoes a second, probably more rapid,
iodination (giving C) followed by the second azide introduction.
However, at this stage of our studies, we cannot rule out a radical
mechanism.
2
3
2
0
1
.1 M). As shown in Table 1, a variety of malonates (e.g.,
a−d) gave the corresponding diazide products (2a−d) under
The structure of diazide 2m was determined using X-ray
45
crystallographic analysis (see Supporting Information). The
structures of all the geminal diazides 2a−ac were ascertained on
the basis of spectroscopic data. The IR spectra typically showed
the reaction conditions. To our delight, the sterically
demanding tert-butyl diazidomalonate 2c was likewise obtained
in acceptable 51% yield (entry 3). The diazidation of several
acyl acetates was also possible and proved quite robust with
−1
a dominant azide stretching frequency around 2110 cm . In
the 13C NMR spectra, the quaternary carbons attached to the
two azide groups had distinguished chemical shifts ranging
1
regard to bulky R groups: Substrates bearing cyclohexyl, tert-
butyl, or, even more impressive, adamantyl groups were reactive
from 80 to 87 ppm (in CDCl ). The diazides 2 in the present
3
1
(
entries 10−12). Besides acyl acetates with R being an alkyl
study were derivatized with either cyclooctyne or phenyl-
acetylene to obtain the corresponding bis-triazoles through
Huisgen cycloaddition; their full characterization by NMR and
IR techniques as well as by high resolution mass spectrometry
provided unequivocal support for the identity of the diazide
title compounds (see Supporting Information). Greatly to our
surprise, however, the direct measurement of the accurate mass
of several geminal diazides (i.e., 2b, 2c, 2d, 2r, 2x, 2z, 2aa) was
rendered possible by standard ESI techniques. We reasoned
that the geminal diazides derived from 1,3-dicarbonyls must be
considered to be relatively stable.
group, a variety of aryl ketones with electron-rich and electron-
poor substituents at the aryl core R were suitable substrates
1
(
entries 13−17). It is worth mentioning that the diazidation
protocol works well in the presence of a multitude of functional
groups including olefins (e.g., 2r and 2s), ethers (e.g., 2t),
esters (e.g., 2u), silyl ethers (e.g., 2v), and azides (e.g., 2w). Of
relevance, tertiary and secondary alcohols were tolerated
without the need for protecting groups (entries 24 and 25).
The 1,3-dicarbonyls 1z and 1aa, derived from enantiomerically
pure Boc-protected amino acids, delivered the desired diazides
2
z and 2aa without racemization. Furthermore, amide 1ab and
With the goal to roughly estimate safety issues when
handling geminal diazides, we decided to briefly investigate
the thermal behavior of a small number of selected compounds,
2c, 2g, 2m, and 2ac. The thermal stabilities were determined
from TGA and DSC measurements in sealed Al pans using
a nitrogen flow of 30 mL/min at a heating rate of 5 K/min. The
decomposition temperatures are given as onset temperatures
(Table 2). In all cases, no defined melting points (or boiling
points) were found. Instead, all the selected diazides show
similar thermal stability with decomposition temperatures
ranging from 118 to 156 °C. Thermolysis products were not
diketone 1ac gave rise to their corresponding diazides, thus
highlighting our impression that we have a method with broad
scope in hand.
In an early competition experiment with a 1:1 mixture of
acetylacetate 1g and the analogous acetylacetate 3 having an
additional methyl group, we observed an outstanding selectivity
for the diazidated product 2g under our azidation conditions
1
(
Scheme 2). According to H NMR of the crude mixture, the
monoazidated compound 4 was not formed; we assume that
azide 4 might be an intermediate that is further azidated with a
markedly increased rate under the reaction conditions to finally
provide 2g. Even more important, the methylated acetylacetate
24−26
identified,
further studied.
and the pathway of decomposition was not
B
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Article
Table 1. Synthesis of Diazides 2 from 1,3-Dicarbonyls 1
C
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Article
Table 1. continued
a
b
c
Isolated yield after chromatography. I (2.0−2.2 equiv), NaN (3.3−10.0 equiv), rt, DMSO/H O (2:1, 0.1 M). I (2.0−2.2 equiv), NaN
2
3
2
2
3
d
e
(4.0−10.0 equiv), NaHCO (4.0 equiv), rt, DMSO/H O (2:1, 0.1 M). Reaction was carried out at 50 °C. 96% ee for 2z, 93% ee for 2aa.
3
2
D
DOI: 10.1021/acs.joc.5b02328
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Article
triplets). IR spectra were recorded using ATR technique. High resolu-
tion mass spectra were obtained using ESI ionization methods on a
TOF analyzer.
Scheme 2. Selectivity of the Diazidation of a 1:1 Mixture of
a
1
,3-Dicarbonyls 1g and 3 with I /NaN
2
3
CAUTION! Geminal diazides should be handled with care. The
heating bath of the rotary evaporator was set to 40 °C.
General Procedure A for the Preparation of Geminal
Diazides 2. The 1,3-dicarbonyl compound 1 was dissolved in a 2:1
mixture of DMSO and water (0.1 M). Sodium azide (3.3−10.0 equiv)
and iodine (2.05−3.00 equiv) were added consecutively. The reaction
mixture was stirred at room temperature until TLC indicated complete
consumption of the starting material. A saturated aqueous solution of
sodium thiosulfate was added, and the mixture was diluted with water
and extracted with ethyl acetate. The combined organic phases were
dried over magnesium sulfate. Evaporation of the solvent in vacuo and
flash chromatography on silica gel afforded the corresponding geminal
diazides 2.
a
1
Product distribution determined via H NMR of the crude mixture.
General Procedure B for the Preparation of Geminal
Diazides 2. The 1,3-dicarbonyl 1 compound was dissolved in a 2:1
mixture of DMSO and water (0.1 M). Sodium azide (4.0 equiv),
sodium bicarbonate (4.0 equiv), and iodine (2.2 equiv) were added
consecutively. The reaction mixture was stirred at room temperature
until TLC indicated complete consumption of the starting material.
A saturated aqueous solution of sodium thiosulfate was added, and
the mixture was diluted with water and extracted with ethyl acetate.
The combined organic phases were dried over magnesium sulfate.
Evaporation of the solvent in vacuo and flash chromatography on silica
gel afforded the corresponding geminal diazides 2.
Scheme 3. Possible Mechanism for the Diazidation of 1,3-
Dicarbonyls by Use of Molecular Iodine and Sodium Azide
General Procedure C for the Cycloaddition Reaction with
Phenyl Acetylene. The geminal diazide 2 was dissolved in a 2:1
mixture of tBuOH and water (0.3 M). Phenyl acetylene (2.2 equiv),
copper(II) sulfate pentahydrate (0.20 equiv), sodium L-ascorbate
Table 2. Decomposition Temperatures of Geminal Diazides
(
(
0.40 equiv), and tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine
TBTA, 0.01 equiv) were added consecutively. The reaction mixture
2
c, 2g, 2m, and 2ac
was stirred at room temperature until TLC indicated complete con-
sumption of the starting material. Water was added, and the mixture
was extracted with ethyl acetate. The combined organic phases were
dried over magnesium sulfate. Evaporation of the solvent in vacuo and
flash chromatography on silica gel afforded the corresponding geminal
bistriazole.
2
c
2g
2m
2ac
Tdec [°C]
155.5
142.7
143.5
118.0
CONCLUSION
■
General Procedure D for the Cycloaddition with Cyclo-
octyne. The geminal diazide 2 was dissolved in dichloromethane
In conclusion, a novel and mild method for the synthesis of
geminal diazides through the direct double azidation of 1,3-
dicarbonyl compounds was presented. Further studies regarding
the direct diazidation of simple ketones and 2-aryl ketones are
currently under investigation. Our protocol now gives access
to a broad range of previously undisclosed diazides, many of
which contain uncommon groups with sensitive functionalities
or exceptional steric bulk. We also provided evidence that the
geminal diazides are relatively stable having decomposition
temperatures higher than 100 °C. This paper aims to encourage
researchers to synthesize and further utilize members of this
promising class of compounds.
(0.1 M), and cyclooctyne (4.0 equiv) was added. The solution was
stirred at room temperature until TLC indicated complete consump-
tion of the starting material. Evaporation of the solvent in vacuo and
flash chromatography on silica gel afforded the corresponding geminal
bistriazole.
Dimethyl 2,2-Diazidomalonate (2a). Following general procedure
A (0.200 g of of 1a, 2 h 50 °C, 13 h rt, 3.3 equiv of NaN , 3.0 equiv of I ),
3 2
dimethyl 2,2-diazidomalonate 2a was obtained as a colorless
liquid (0.207 g, 0.97 mmol, 65%) after chromatography (PE/EtOAc
1
00/0 → 80/20). TLC: R = 0.54 (PE/EtOAc 80/20, [KMnO ]).
f
4
1
13
H NMR (600 MHz, CDCl ): δ [ppm] 3.92 (s, 6H). C NMR
3
(
151 MHz, CDCl ): δ [ppm] 164.1, 80.1, 54.6. IR: 2962, 2115, 1756,
3
CAUTION! We underline that geminal diazides are still
potentially hazardous chemicals that should be handled with
care.
1
4
437, 1295, 1225, 1068, 1046, 1007, 937, 826, 788, 740, 628, 594, 549,
71 [cm ]. For HRMS, 2a was converted to the bistriazole according
−1
to general procedure C (0.030 g of of 2a, 1 h). Dimethyl 2,2-bis(4-
phenyl-1H-1,2,3-triazol-1-yl)malonate was obtained as a white solid
EXPERIMENTAL SECTION
All commercial reagents were used as received. Thin-layer chromatog-
raphy (TLC) was conducted with coated glass backed plates (silica gel
0 F254) and visualized by exposure to UV light (254 nm) or by
staining with ceric ammonium molybdate (CAM), potassium
(
0.057 g, 0.14 mmol, 97%) after chromatography (PE/EtOAc
■
6
1
100/0 → 80/20). TLC: R
NMR (400 MHz, CDCl ): δ [ppm] 8.46 (s, 2H), 7.84−7.79 (m, 4H),
7.45−7.38 (m, 4H), 7.37−7.31 (m, 2H), 4.09 (s, 6H). C NMR
(101 MHz, CDCl ): δ [ppm] 161.2, 148.5, 129.5, 129.0, 128.9, 126.1,
= 0.21 (PE/EtOAc 80/20), [UV]). H
f
3
1
3
3
+
permanganate (KMnO ), or iodine (I ). Flash chromatography was
120.6, 79.7, 55.4. HRMS: (m/z) calculated for [C21H N O Na ]
18 6 4
4
2
performed on silica gel (43−60 μm); the used eluent is reported in
441.1282, found 441.1266.
Diethyl 2,2-Diazidomalonate (2b). Following general procedure A
1
parentheses (PE, petroleum ether; CH, cyclohexane). H NMR
spectra were recorded at 400 or 600 MHz. 13C NMR spectra were
recorded at 101 or 151 MHz. Chemical shifts are reported in ppm.
The spectra were calibrated relative to the solvent signal. Multiplicity
is indicated as follows: s (singlet); d (doublet); t (triplet); q (quartet);
p (pentet); m (multiplet); dd (doublet of doublets); tt (triplet of
(2.100 g of of 1b, 50 °C, overnight, 3.0 equiv of NaN
, 3.0 equiv of I ),
3
2
diethyl 2,2-diazidomalonate 2b was obtained as a colorless liquid
(1.950 g, 8.05 mmol, 61%) after chromatography (PE/Et O 90/10).
2
1
TLC: R = 0.73 (PE/Et O 80/20, [I ]). H NMR (600 MHz,
CDCl ): δ [ppm] 4.42−4.33 (m, 4H), 1.40−1.31 (m, 6H). C NMR
f
2
2
1
3
3
E
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The Journal of Organic Chemistry
Article
(
2
5
151 MHz, CDCl ): δ [ppm] 163.7, 80.0, 64.2, 14.1. IR: 2987, 2942,
IR: 2984, 2937, 2112, 1742, 1476, 1459, 1419, 1397, 1372, 1358, 1281,
1238, 1192, 1145, 1070, 1036, 1013, 966, 942, 831, 772, 749, 668, 644,
582, 557, 544, 468, 436 [cm ]. For HRMS, 2g was converted to the
3
910, 2876, 2118, 1754, 1468, 1447, 1370, 1298, 1216, 1043, 855, 771,
−1
+
−1
49 [cm ]. HRMS: (m/z) calculated for [C H N O Na ] 265.0656,
7
10
6
4
found 265.0652.
bistriazole according to general procedure C (0.030 g of 2g, 0.16 M,
overnight). tert-Butyl 3-oxo-2,2-bis(4-phenyl-1H-1,2,3-triazol-1-yl)-
butanoate was obtained as a white solid (0.037 g, 0.08 mmol, 67%)
Di-tert-butyl 2,2-Diazidomalonate (2c). Following general proce-
dure A (1.892 g of 1c, 50 °C, overnight, 3.3 equiv of NaN3,
3
.0 equiv of I ), di-tert-butyl 2,2-diazidomalonate 2c was obtained
after chromatography (PE/EtOAc 100/0 → 50/50). TLC: R = 0.46
2
f
1
as a colorless liquid (1.320 g, 4.43 mmol, 51%) after chromatography
(PE/EtOAc 70/30, [UV]). H NMR (600 MHz, CDCl ): δ [ppm]
3
1
(
PE/Et O 95/5). TLC: R = 0.91 (PE/Et O 80/20, [I ]). H NMR
8.31 (s, 2H), 7.83−7.79 (m, 4H), 7.43−7.38 (m, 4H), 7.36−7.31 (m,
2
f
2
2
13
13
(
400 MHz, CDCl ): δ [ppm] 1.54 (s, 18H). C NMR (101 MHz,
2H), 2.55 (s, 3H), 1.65 (s, 9H). C NMR (151 MHz, CDCl ): δ
3
3
CDCl ): δ [ppm] 162.6, 86.1, 80.2, 27.9; IR: 2982, 2937, 2119, 1750,
[ppm] 188.8, 159.6, 148.3, 129.6, 129.0, 128.9, 126.0, 120.9, 88.9, 83.7,
3
−1
+
1
477, 1459, 1396, 1371, 1239, 1143, 1031, 834, 723, 549, 466 [cm ].
27.8, 26.7. HRMS: (m/z) calculated for [C H N O Na ] 467.1802,
24
24
6
3
+
HRMS: (m/z) calculated for [C H N O Na ] 321.1282, found
found 467.1794.
11
18
6
4
3
21.1281.
Diallyl 2,2-Diazidomalonate (2d). Following general procedure A
2.270 g of 1d, 50 °C, overnight, 3.3 equiv of NaN , 3.0 equiv of I ),
tert-Butyl 2,2-Diazido-5-methyl-3-oxohexanoate (2h). Following
general procedure A (1.100 g of 1h, 3 h, 10.0 equiv of NaN , 2.2 equiv
3
(
of I ), tert-butyl 2,2-diazido-5-methyl-3-oxohexanoate 2h was obtained
3
2
2
diallyl 2,2-diazidomalonate 2d was obtained as a colorless liquid (0.980 g,
as a colorless liquid (1.260 g, 4.45 mmol, 89%) after chromatography
3
0
5
5
.68 mmol, 30%) after chromatography (PE/Et O 90/10). TLC: R =
(CH/EtOAc 100/0 → 90/10). TLC: R = 0.48 (CH/EtOAc 90/10,
2
f
f
1
1
.71 (PE/Et O 80/20, [I ]). H NMR (400 MHz, CDCl ): δ [ppm]
[KMnO ]). H NMR (400 MHz, CDCl ): δ [ppm] 2.42 (d, J = 6.8 Hz,
2
2
3
4
3
1
3
.91 (ddt, J = 17.1, 10.4, 5.8 Hz, 2H), 5.40 (dd, J = 17.2, 1.4 Hz, 2H),
2H), 2.26−2.14 (m, 1H), 1.53 (s, 9H), 0.93 (d, J = 6.7 Hz, 6H). C
NMR (101 MHz, CDCl ): δ [ppm] 197.8, 163.1, 86.8, 83.5, 46.3, 27.9,
.33 (dd, J = 10.4, 1.2 Hz, 2H), 4.78 (d, J = 5.9 Hz, 4H). 13C NMR
3
(
3
101 MHz, CDCl ): δ [ppm] 163.4, 130.2, 120.5, 80.1, 68.4. IR:
24.1, 22.5. IR: 2962, 2937, 2875, 2114, 1742, 1468, 1397, 1371, 1239,
1144, 1103, 1049, 999, 982, 934, 831, 754, 707, 625, 555, 545, 468,
436 [cm ]. For HRMS, 2h was converted to the bistriazole according
3
092, 3026, 2989, 2958, 2887, 2118, 1755, 1650, 1452, 1424, 1363,
−1
−1
1
218, 991, 936, 788, 548 [cm ]. HRMS: (m/z) calculated for
+
[
C H N O Na ] 289.0656, found 289.0640.
to general procedure D (0.027 g of 2h, 3.5 h, CDCl ). tert-Butyl 2,2-
3
9
10
6
4
Methyl 2,2-Diazido-3-oxobutanoate (2e). Following general pro-
bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d][1,2,3]triazol-1-yl)-5-meth-
cedure A (2.042 g of 1e, overnight, 10.0 equiv of NaN , 2.2 equiv of
I2), methyl 2,2-diazido-3-oxobutanoate 2e was obtained as a colorless
yl-3-oxohexanoate was obtained as a yellow liquid. TLC: R = 0.19
3
f
1
(CH/EtOAc 80/20, [UV]). H NMR (400 MHz, CDCl
): δ [ppm]
3
liquid (3.065 g, 15.47 mmol, 88%) after chromatography (PE/Et O
2.98−2.91 (m, 2H), 2.91−2.84 (m, 4H), 2.44−2.31 (m, 1H), 2.27−
2
1
9
0/10). TLC: R = 0.55 (PE/Et O 90/10, [I ]). H NMR (400 MHz,
CDCl ): δ [ppm] 3.90 (s, 3H), 2.26 (s, 3H). C NMR (101 MHz,
2.13 (m, 4H), 1.78−1.69 (m, 4H), 1.59 (s, 9H), 1.42−1.27 (m, 12H),
f
2
2
13
13
1.06 (d, J = 6.7 Hz, 6H). C NMR (101 MHz, CDCl
): δ [ppm]
3
3
CDCl ): δ [ppm] 195.5, 164.9, 83.3, 54.4, 25.0. IR: 2962, 2110, 1743,
191.8, 160.4, 145.8, 136.6, 87.7, 86.8, 49.4, 27.8, 27.6, 26.1, 25.7, 25.6,
3
+
1
7
436, 1359, 1274, 1225, 1069, 1038, 1014, 983, 943, 916, 807, 765,
45, 697, 668, 648, 582, 556, 543, 460, 428 [cm ]. For HRMS, 2e was
25.1, 24.4, 23.1, 22.0. HRMS (m/z) calculated for [C27H N O ]
43 6 3
−
1
499.3391, found 499.3389.
converted to the bistriazole according to general procedure D (0.100 g
of 2e, overnight). Methyl 2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta-
tert-Butyl 2,2-Diazido-3-oxo-5-phenylpentanoate (2i). Following
general procedure A (1.250 g of 1i, 3 h, 10.0 equiv of NaN , 2.2 equiv
of I ), tert-butyl 2,2-diazido-3-oxo-5-phenylpentanoate 2i was obtained
as a yellowish liquid (0.830 g, 2.51 mmol, 50%) after chromatography
(CH/EtOAc 100/0 → 90/10). TLC: R = 0.46 (CH/EtOAc 90/10,
): δ [ppm] 7.32−7.27 (m,
2H), 7.23−7.17 (m, 3H), 2.98−2.92 (m, 2H), 2.92−2.86 (m, 2H),
1.48 (s, 9H). 13C NMR (151 MHz, CDCl
): δ [ppm] 197.6, 163.0,
3
[d][1,2,3]triazol-1-yl)-3-oxobutanoate was obtained as a white solid
2
(
0.178 g, 0.43 mmol, 85%) after chromatography (PE/EtOAc 70/30).
1
TLC: R = 0.42 (PE/EtOAc 70/30), [UV]). H NMR (600 MHz,
f
f
1
CDCl ): δ [ppm] 4.04 (s, 3H), 2.90−2.85 (m, 4H), 2.59 (s, 3H),
[KMnO ]). H NMR (600 MHz, CDCl
4 3
3
13
2
.24−2.13 (m, 4H), 1.76−1.69 (m, 4H), 1.42−1.29 (m, 12H).
NMR (151 MHz, CDCl ): δ [ppm] 188.8, 162.4, 146.3, 136.6, 86.2,
C
3
3
5
4.7, 28.8, 27.6, 26.2, 25.7, 25.1, 24.4, 21.9. HRMS: (m/z) calculated
140.2, 128.7, 128.5, 126.6, 86.9, 83.4, 39.4, 29.4, 27.9. IR: 3029, 2982,
2934, 2113, 1742, 1455, 1372, 1237, 1149, 1056, 1028, 1007, 830, 746,
698 [cm ]. For HRMS, 2i was converted to the bistriazole according
to general procedure D (0.035 g, 3.5 h), tert-butyl 2,2-bis(4,5,6,7,8,9-
hexahydro-1H-cycloocta[d][1,2,3]triazol-1-yl)-3-oxo-5-phenylpenta-
+
for [C H N O Na ] 437.2272, found 437.2272.
21
30
6
3
−1
Ethyl 2,2-Diazido-3-oxobutanoate (2f). Following general proce-
dure A (4.084 g of 1f, 2 h, 10.0 equiv of NaN , 2.2 equiv of I ), ethyl
3
2
2
2
9
,2-diazido-3-oxobutanoate 2f was obtained as a colorless liquid (5.861 g,
7.62 mmol, 88%) after chromatography (PE/Et O 100/0 →
noate was obtained as a colorless liquid. TLC: R = 0.37 (CH/EtOAc
f
2
1
1
0/10). TLC: R = 0.59 (PE/Et O 90/10, [I ]). H NMR (600 MHz,
80/20, [UV]). H NMR (400 MHz, CDCl ): δ [ppm] 7.30−7.16 (m,
3
f
2
2
CDCl ): δ [ppm] 4.37 (q, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.36 (t, J =
5H), 3.22 (s, 4H), 2.92−2.85 (m, 4H), 2.23−2.16 (m, 4H), 1.77−1.68
3
13
13
7
8
9
.1 Hz, 3H). C NMR (151 MHz, CDCl ): δ [ppm] 195.6, 164.3,
(m, 4H), 1.59 (s, 9H), 1.41−1.34 (m, 12H). C NMR (101 MHz,
3
3.3, 64.3, 25.1, 14.1. IR: 2985, 2112, 1743, 1359, 1222, 1068, 1008,
CDCl ): δ [ppm] 192.0, 160.1, 145.9, 140.4, 136.6, 128.7, 128.4,
3
−1
42, 853, 747, 582, 544 [cm ]. For HRMS, 2f was converted to the
126.5, 87.9, 86.8, 43.5, 31.6, 27.8, 27.6, 26.1, 25.8, 25.0, 24.4, 22.0.
+
bistriazole according to general procedure D (0.100 g of 2f, overnight).
Ethyl 2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d][1,2,3]triazol-1-
yl)-3-oxobutanoate was obtained as a viscous oil (0.129 g, 0.30 mmol,
HRMS (m/z) calculated for [C31H N O ] 547.3391, found
43 6 3
547.3391.
tert-Butyl 2,2-Diazido-3-cyclohexyl-3-oxopropanoate (2j). Fol-
lowing general procedure B (1.000 g of 1j, 3 h), tert-butyl 2,2-diazido-
3-cyclohexyl-3-oxopropanoate 2j was obtained as a colorless liquid
(0.987 g, 3.20 mmol, 72%) after chromatography (CH/EtOAc
64%) after chromatography (PE/EtOAc 70/30). TLC: R = 0.45 (PE/
f
1
EtOAc 70/30, [UV]). H NMR (600 MHz, CDCl ): δ [ppm] 4.56−
3
4
.49 (m, 2H), 2.91−2.84 (m, 4H), 2.63−2.59 (m, 3H), 2.27−2.14 (m,
13
4
H), 1.78−1.69 (m, 4H), 1.44−1.28 (m, 15H). C NMR (151 MHz,
100/0 → 93/7). TLC: R
f
= 0.51 (CH/EtOAc 90/10, [KMnO
H NMR (400 MHz, C D ): δ [ppm] 2.67 (tt, J = 11.4, 3.4 Hz, 1H),
6 6
4
]).
1
CDCl ): δ [ppm] 188.9, 161.7, 146.2, 136.6, 86.3, 64.8, 28.9, 27.6, 26.2,
3
2
5.7, 25.1, 24.4, 21.9, 13.8. HRMS: (m/z) calculated for
1.88−1.79 (m, 2H), 1.58−1.46 (m, 2H), 1.45−1.33 (m, 3H), 1.19 (s,
+
13
[C H N O Na ] 451.2428, found 451.2408.
9H), 1.08−0.96 (m, 3H). C NMR (101 MHz, C D ): δ [ppm]
22
32
6
3
6
6
tert-Butyl 2,2-Diazido-3-oxobutanoate (2g). Following general
201.1, 163.6, 86.2, 83.8, 46.7, 29.5, 27.6, 25.7, 25.6. IR: 2982, 2935,
2857, 2114, 1737, 1451, 1372, 1237, 1144, 1057, 951, 833, 802, 547
procedure A (1.000 g of 1g, 90 min, 10.0 equiv of NaN , 2.2 equiv of
I2), tert-butyl 2,2-diazido-3-oxobutanoate 2g was obtained as a colorless
liquid (1.370 g, 5.70 mmol, 93%) after chromatography (PE/EtOAc
3
−1
[cm ]. For HRMS, 2j was converted to the bistriazole according to
general procedure D (0.025 g of 2j, 3 h). tert-Butyl 3-cyclohexyl-2,2-
bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d][1,2,3]triazol-1-yl)-3-oxo-
propanoate was obtained as a colorless liquid (0.041 g, 0.08 mmol,
98%) after chromatography (CH/EtOAc 90/10 → 80/20).
1
1
00/0 → 80/20). TLC: R = 0.57 (PE/EtOAc 90/10, [KMnO ]). H
f
4
13
NMR (400 MHz, CDCl ): δ [ppm] 2.26 (s, 3H), 1.54 (s, 9H).
C
3
NMR (101 MHz, CDCl ): δ [ppm] 195.8, 163.1, 86.9, 83.6, 28.0, 25.1.
3
F
DOI: 10.1021/acs.joc.5b02328
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
TLC: R = 0.36 (CH/EtOAc 80/20, [UV, KMnO ]). H NMR (600
133.4, 129.6, 129.2, 129.1, 129.0, 128.8, 126.0, 120.8, 88.5, 82.4,
f
4
+
MHz, CDCl ): δ [ppm] 2.90−2.83 (m, 4H), 2.80 (tt, J = 11.3, 2.9 Hz,
27.4. HRMS (m/z) calculated for [C H N O Na ] 529.1959, found
3
29 26
6
3
1
1
H), 2.48−2.37 (m, 2H), 2.20−2.07 (m, 4H), 1.84−1.76 (m, 2H),
529.1959.
13
.75−1.66 (m, 5H), 1.64−1.60 (m, 10H), 1.40−1.21 (m, 16H).
C
tert-Butyl 2,2-Diazido-3-oxo-3-(p-tolyl)propanoate (2n). Follow-
NMR (151 MHz, CDCl ): δ [ppm] 197.1, 160.2, 145.8, 136.6, 88.2,
ing general procedure B (0.500 g of 1n, 2.5 h, 2.5 equiv of I ), tert-
3
2
8
7.3, 50.9, 32.2, 27.9, 27.6, 26.1, 26.0, 25.9, 25.8, 25.1, 24.5, 22.2.
HRMS (m/z) calculated for [C H N O Na ] 547.3367, found
47.3359.
tert-Butyl 2,2-Diazido-4,4-dimethyl-3-oxopentanoate (2k). Fol-
lowing general procedure B (0.600 g of 1h, 3 h), tert-butyl 2,2-diazido-
,4-dimethyl-3-oxopentanoate 2k was obtained as colorless liquid
0.566 g, 2.00 mmol, 67%) after chromatography (CH/EtOAc 98/2).
H NMR (600 MHz, CDCl ): δ [ppm] 1.54 (s, 9H), 1.26 (s, 9H).
NMR (151 MHz, CDCl ): δ [ppm] 202.6, 163.3, 86.8, 83.4, 44.7,
8.0, 27.5. IR: 2980, 2938, 2876, 2112, 1754, 1726, 1481, 1459, 1396,
372, 1235, 1149, 1106, 1058, 920, 832, 547 [cm ]. For HRMS, 2k
was converted to the bistriazole according to general procedure D
0.026 g of 2k, overnight). tert-Butyl 2,2-bis(4,5,6,7,8,9-hexahydro-1H-
cycloocta[d][1,2,3]triazol-1-yl)-4,4-dimethyl-3-oxopentanoate was
obtained as a colorless liquid (0.037 g, 0.07 mmol, 82%) after chroma-
tography (CH/EtOAc 90/10 → 80/20). TLC: R = 0.36 (CH/EtOAc
butyl 2,2-diazido-3-oxo-3-(p-tolyl)propanoate 2n was obtained as a
white solid (0.395 g, 1.25 mmol, 59%) after chromatography (CH/
+
29
44
6
3
5
EtOAc 95/5 → 90/10). TLC: R = 0.40 (CH/EtOAc 90/10, [UV]).
f
1
H NMR (600 MHz, CDCl ): δ [ppm] 7.95−7.87 (m, 2H), 7.29−7.21
m, 2H), 2.42 (s, 3H), 1.38 (s, 9H). C NMR (151 MHz, CDCl ): δ
3
13
(
3
4
[
ppm] 186.4, 163.9, 145.7, 130.0, 129.8, 129.5, 86.6, 83.1, 27.7, 21.9.
(
IR: 2983, 2117, 1745, 1693, 1605, 1459, 1371, 1234, 1145, 996, 901,
1
13
C
−1
3
829, 793, 726, 602, 544, 474 [cm ]. For HRMS, 2n was converted to
3
the bistriazole according to general procedure D (0.020 g of 2n, 1 h).
tert-Butyl 2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d][1,2,3]triazol-
2
1
−1
1
-yl)-3-oxo-3-(p-tolyl)propanoate was obtained as a colorless liquid
(
9
0.033 g, 0.06 mmol, quant.) after chromatography (CH/EtOAc
0/10 → 80/20). TLC: R = 0.32 (CH/EtOAc 80/20, [UV]). H
f
(
1
NMR (600 MHz, CDCl ): δ [ppm] 7.68−7.64 (m, 2H), 7.19−7.15
3
(
m, 2H), 2.95−2.85 (m, 4H), 2.38 (s, 3H), 1.99−1.59 (m, 8H), 1.58−
13
f
1.24 (m, 12H), 1.24 (s, 9H). C NMR (151 MHz, CDCl ): δ [ppm]
1
3
8
6
1
0/20, [UV]). H NMR (400 MHz, d -DMSO): δ [ppm] 2.82 (td, J =
6
1
2
82.6, 160.8, 145.9, 144.4, 137.1, 132.7, 129.9, 129.1, 87.1, 85.8, 27.6,
.8, 2.4 Hz, 4H), 2.21−2.01 (m, 4H), 1.75−1.63 (m, 4H), 1.63 (s, 9H),
7.3, 26.3, 25.8, 25.2, 24.5, 22.2, 21.8. HRMS (m/z) calculated for
13
.37 (s, 9H), 1.37−1.24 (m, 12H). C NMR (101 MHz, d -DMSO): δ
+
6
[
C H N O Na ] 555.3054, found 555.3048.
30
40
6
3
[
2
ppm] 198.6, 159.2, 145.1, 135.8, 88.5, 87.9, 45.8, 28.3, 27.0, 26.7, 25.1,
tert-Butyl 2,2-Diazido-3-(4-chlorophenyl)-3-oxopropanoate (2o).
+
4.7, 24.3, 23.4, 20.9. HRMS (m/z) calculated for [C H N O Na ]
27 42 6 3
Following general procedure B (1.000 g of 1o, 1 h, 2.0 equiv of I2),
tert-butyl 2,2-diazido-3-(4-chlorophenyl)-3-oxopropanoate 2o was
obtained as a white solid (0.990 g, 2.94 mmol, 75%) after chroma-
5
21.3211, found 521.3210.
tert-Butyl 3-(Adamantan-1-yl)-2,2-diazido-3-oxopropanoate (2l).
Following general procedure B (0.515 g of 1l, 7 h), tert-butyl
-(adamantan-1-yl)-2,2-diazido-3-oxopropanoate 2l was obtained as a
colorless liquid (0.335 g, 0.93 mmol, 50%) after chromatography
tography (CH/EtOAc 97/3). TLC: R = 0.51 (CH/EtOAc 90/10,
f
3
1
[
7
[
UV]). H NMR (600 MHz, CDCl ): δ [ppm] 8.00−7.96 (m, 2H),
3
13
.46−7.43 (m, 2H), 1.39 (s, 9H). C NMR (151 MHz, CDCl ): δ
1
3
(
CH/EtOAc 98/2). TLC: R = 0.48 (CH/EtOAc 90/10, [UV]). H
f
ppm] 185.9, 163.6, 141.2, 131.3, 130.7, 129.2, 87.0, 83.1, 27.8. IR:
NMR (400 MHz, CDCl ): δ [ppm] 2.06−2.00 (m, 3H), 2.00−1.96
3
13
3082, 2982, 2416, 2119, 2103, 1747, 1702, 1585, 1486, 1397, 1372,
(
m, 6H), 1.76−1.65 (m, 6H), 1.55 (s, 9H). C NMR (101 MHz,
1
5
295, 1212, 1146, 1091, 1030, 996, 896, 847, 827, 777, 729, 706, 681,
57, 481, 449 [cm ]. For HRMS, 2o was converted to the bistriazole
CDCl ): δ [ppm] 201.5, 163.2, 86.7, 83.4, 47.3, 38.6, 36.5, 28.1, 28.0.
3
−1
IR: 2980, 2908, 2853, 2112, 1752, 1719, 1455, 1371, 1236, 1144, 1066,
80, 919, 833, 802, 744, 613, 547 [cm ]. For HRMS, 2l was con-
verted to the bistriazole according to general procedure D (0.018 g
of 2l, overnight). tert-Butyl 3-(adamantan-1-yl)-2,2-bis(4,5,6,7,8,9-
hexahydro-1H-cycloocta[d][1,2,3]triazol-1-yl)-3-oxopropanoate was
obtained as a colorless liquid (0.027 g, 0.05 mmol, 94%) after chromato-
−1
according to general procedure D (0.027 g of 2o, overnight). tert-Butyl
-(4-chlorophenyl)-2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d]-
1,2,3]triazol-1-yl)-3-oxopropanoate was obtained as a white solid
0.044 g, 0.08 mmol, 99%) after chromatography (CH/EtOAc
9
3
[
(
9
1
0/10 → 80/20). TLC: R = 0.34 (CH/EtOAc 80/20, [UV]). H
f
NMR (400 MHz, CDCl ): δ [ppm] 7.74−7.69 (m, 2H), 7.40−7.34
3
graphy (CH/EtOAc 90/10). TLC: R = 0.38 (CH/EtOAc 80/20,
f
1
(m, 2H), 2.97−2.82 (m, 4H), 2.46−2.16 (m, 2H), 1.89−1.59 (m, 6H),
[
UV]). H NMR (400 MHz, d -DMSO): δ [ppm] 2.84−2.78 (m, 4H),
6
1
3
1
.54−1.29 (m, 12 H), 1.26 (s, 9H). C NMR (101 MHz, CDCl ): δ
2
1
1
2
5
.15−2.01 (m, 13H), 1.74−1.66 (m, 10H), 1.65 (s, 9H), 1.40−1.21 (m,
3
2H). 13C NMR (101 MHz, CDCl ): δ [ppm] 198.9, 160.4, 137.0,
[ppm] 182.0, 160.5, 146.1, 140.0, 137.1, 133.6, 131.1, 128.8, 87.6, 85.7,
7.6, 27.3, 26.2, 25.8, 25.2, 24.5, 22.1. HRMS (m/z) calculated for
[C H N O ClNa ] 575.2508, found 575.2504.
3
2
31.0, 88.3, 87.3, 49.8, 39.8, 36.8, 28.7, 28.1, 27.7, 26.3, 25.9, 25.4, 24.7,
2.2. HRMS (m/z) calculated for [C H N O Na ] 599.3680, found
+
+
29 37 6 3
33
48
6
3
tert-Butyl 2,2-Diazido-3-(4-methoxyphenyl)-3-oxopropanoate
2p). Following general procedure B (1.000 g of 1p, 3 h, 2.0 equiv
99.3680.
tert-Butyl 2,2-Diazido-3-oxo-3-phenylpropanoate (2m). Follow-
ing general procedure A (0.949 g of 1m, 3.5 h, 6.0 equiv of NaN3,
.2 equiv of I ), tert-butyl 2,2-diazido-3-oxo-3-phenylpropanoate 2m
was obtained as a colorless liquid (1.209 g, 4.00 mmol, 93%) after
chromatography (PE/EtOAc 95/5). Single crystals suitable for crystal
structure analysis were obtained by allowing the liquid obtained from
(
of I ), tert-butyl 2,2-diazido-3-(4-methoxyphenyl)-3-oxopropanoate
2,
2
p was obtained as a white solid (1.025 g, 3.08 mmol, 77%) after
2
2
chromatography (CH/EtOAc 95/5 → 80/20). TLC: R = 0.24 (CH/
f
1
EtOAc 90/10, [UV]). H NMR (600 MHz, CDCl ): δ [ppm] 8.05−
3
1
3
8
.00 (m, 2H), 6.96−6.90 (m, 2H), 3.88 (s, 3H), 1.39 (s, 9H).
C
45
NMR (151 MHz, CDCl ): δ [ppm] 185.3, 164.6, 164.0, 132.5, 125.0,
chromatography to slowly crystallize. TLC: R = 0.46 (PE/EtOAc
3
f
1
114.1, 86.6, 83.2, 55.7, 27.8. IR: 3007, 2980, 2939, 2135, 2116, 1741,
9
5/5, [KMnO ]). H NMR (400 MHz, CDCl ): δ [ppm] 8.06−8.00
4
3
1
7
687, 1590, 1512, 1372, 1318, 1270, 1239, 1145, 1027, 905, 844, 827,
96, 736, 697, 599, 546, 438 [cm ]. For HRMS, 2p was converted
(
m, 2H), 7.64−7.58 (m, 1H), 7.50−7.43 (m, 2H), 1.36 (s, 9H).
−1
1
3
C NMR (101 MHz, CDCl ): δ [ppm] 186.9, 163.8, 134.5, 132.4,
3
to the bistriazole according to general procedure D (0.025 g of 2p,
overnight). tert-Butyl 2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d]-
[1,2,3]triazol-1-yl)-3-(4-methoxyphenyl)-3-oxopropanoate was ob-
tained as a white solid (0.032 g, 0.06 mmol, 73%) after chromato-
1
1
1
5
29.9, 128.8, 86.7, 83.1, 27.7. IR: 3065, 2981, 2936, 2118, 1750, 1704,
598, 1581, 1476, 1450, 1396, 1372, 1281, 1228, 1185, 1146, 1105,
050, 1033, 1000, 898, 830, 789, 768, 750, 700, 687, 674, 612, 582, 547,
−1
21, 468, 445 [cm ]. For HRMS, 2m was converted to the bistriazole
according to general procedure C (0.030 g of 2m, 0.17 M, 4 h). tert-
Butyl 3-oxo-3-phenyl-2,2-bis(4-phenyl-1H-1,2,3-triazol-1-yl)-
propanoate was obtained as a white solid (0.035 g, 0.07 mmol,
graphy (CH/EtOAc 90/10 → 70/30). TLC: R
f
= 0.22 (CH/EtOAc
): δ [ppm] 7.76−7.70 (m,
2H), 6.89−6.81 (m, 2H), 3.84 (s, 3H), 2.98−2.82 (m, 4H), 2.57−2.11
1
80/20, [UV]). H NMR (400 MHz, CDCl
3
1
3
7
0
0%) after chromatography (PE/EtOAc 100/0 → 70/30). TLC: R =
.62 (PE/EtOAc 70/30, [UV]). H NMR (400 MHz, CDCl ): δ
(m, 2H), 1.86−1.60 (m, 6H), 1.58−1.30 (m, 12H), 1.26 (s, 9H).
NMR (101 MHz, CDCl ): δ [ppm] 181.6, 163.8, 160.9, 146.0, 137.1,
C
f
1
3
3
[
ppm] 8.49 (s, 2H), 7.87−7.81 (m, 4H), 7.75−7.70 (m, 2H), 7.62−
132.2, 128.0, 113.7, 87.0, 85.9, 55.6, 27.6, 27.4, 26.3, 25.8, 25.2, 24.5,
+
7
.55 (m, 1H), 7.45−7.39 (m, 6H), 7.37−7.30 (m, 2H), 1.37 (s, 9H).
22.2. HRMS (m/z) calculated for [C H N O Na ] 571.3003, found
30
40
6
4
1
3
C NMR (101 MHz, CDCl ): δ [ppm] 182.1, 160.1, 148.4, 134.3,
571.3008.
3
G
DOI: 10.1021/acs.joc.5b02328
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
tert-Butyl 2,2-Diazido-3-(furan-2-yl)-3-oxopropanoate (2q). Fol-
1397, 1372, 1239, 1150, 1103, 1049, 1028, 999, 940, 831, 735, 697,
612, 547, 467, 442 [cm ]. For HRMS, 2t was converted to the
−1
lowing general procedure B (1.000 g of 1q, 3 h, 2.0 equiv of I ), tert-
2
butyl 2,2-diazido-3-(furan-2-yl)-3-oxopropanoate 2q was obtained as a
bistriazole according to general procedure D (CDCl , overnight). tert-
3
white solid (0.889 g, 3.04 mmol, 64%) after chromatography (CH/
Butyl 7-(benzyloxy)-2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d]-
EtOAc 100/0 → 80/20). TLC: R = 0.45 (CH/EtOAc 70/30, [UV]).
[1,2,3]triazol-1-yl)-3-oxoheptanoate was obtained as a colorless liquid.
f
1
1
H NMR (600 MHz, CDCl ): δ [ppm] 7.67 (dd, J = 1.7, 0.7 Hz, 1H),
TLC: R = 0.32 (CH/EtOAc 80/20, [UV]). H NMR (400 MHz,
3
f
7
.45 (dd, J = 3.7, 0.7 Hz), 6.60 (dd, J = 3.7, 1.7 Hz, 1H), 1.44 (s, 9H).
CDCl ): δ [ppm] 7.34−7.28 (m, 4H), 7.28−7.22 (m, 1H), 4.48 (s,
3
1
3
C NMR (151 MHz, CDCl ): δ [ppm] 175.6, 163.1, 148.3, 148.2,
2H), 3.51 (t, J = 6.3 Hz, 2H), 3.01−2.90 (m, 2H), 2.90−2.84 (m, 4H),
2.28−2.07 (m, 4H), 2.04−1.93 (m, 2H), 1.78−1.67 (m, 6H), 1.57 (s,
3
1
1
5
21.9, 113.0, 86.6, 82.4, 27.8. IR: 3140, 2983, 2938, 2115, 1752, 1694,
566, 1460, 1392, 1372, 1232, 1147, 1025, 941, 886, 857, 825, 766,
13
9H), 1.41−1.26 (m, 12H). C NMR (101 MHz, CDCl ): δ [ppm]
3
−1
91, 545, 440 [cm ]. For HRMS, 2q was converted to the bistriazole
192.7, 160.2, 145.9, 138.6, 136.6, 128.4, 127.7, 127.6, 87.7, 86.8, 73.1,
according to general procedure D (0.034 g of 2q, overnight). tert-Butyl
-(furan-2-yl)-2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d][1,2,3]-
triazol-1-yl)-3-oxopropanoate was obtained as a white solid (0.055 g,
.11 mmol, 90%) after chromatography (CH/EtOAc 90/10 → 70/30).
70.1, 41.7, 29.5, 27.7, 27.6, 26.1, 25.7, 25.0, 24.4, 22.7, 22.0. HRMS
+
3
(m/z) calculated for [C34
H
48
N
6
O
4
Na ] 627.3629, found 627.3637.
tert-Butyl 7-acetoxy-2,2-diazido-3-oxoheptanoate (2u). Follow-
ing general procedure B (0.230 g of 1u, 3 h,), tert-butyl 7-acetoxy-
2,2-diazido-3-oxoheptanoate 2u was obtained as a colorless liquid
(0.170 g, 0.50 mmol, 56%) after chromatography (CH/EtOAc
0
1
TLC: R = 0.21 (CH/EtOAc 80/20, [UV]). H NMR (400 MHz,
f
CDCl ): δ [ppm] 7.47 (dd, J = 1.7, 0.8 Hz, 1H), 7.36 (dd, J = 3.5,
3
0
.8 Hz, 1H), 6.56 (dd, J = 3.6, 1.7 Hz, 1H), 2.97−2.80 (m, 4H), 2.46−
90/10 → 80/20). TLC: R
f
= 0.24 (CH/EtOAc 80/20, [UV, KMnO
4
]).
1
2.03 (m, 2H), 1.87−1.58 (m, 6H), 1.55−1.38 (m, 12H), 1.38 (s, 9H).
H NMR (400 MHz, CDCl
J = 6.9 Hz, 2H), 2.03 (s, 3H), 1.74−1.57 (m, 4H), 1.52 (s, 9H). C NMR
(101 MHz, CDCl ): δ [ppm] 198.1, 171.1, 163.1, 86.9, 83.4, 63.9, 37.0,
27.9, 21.0, 20.1. IR: 2981, 2123, 1740, 1459, 1397, 1372, 1238, 1153, 1098,
3
): δ [ppm] 4.05 (t, J = 6.1 Hz, 2H), 2.58 (t,
1
3
13
C NMR (101 MHz, CDCl ): δ [ppm] 172.3, 159.6, 150.9, 146.4,
3
1
2
5
45.8, 136.8, 119.2, 112.8, 86.7, 84.9, 27.6, 27.5, 26.1, 25.8, 25.1, 24.5,
3
+
2.1. HRMS (m/z) calculated for [C H N O Na ] 531.2690, found
27
36
6
4
−1
31.2690.
E)-tert-Butyl 2,2-Diazido-3-oxo-5-phenylpent-4-enoate (2r). Fol-
lowing general procedure A (0.201 g of 1r, 4 h, 6.0 equiv of NaN3,
.1 equiv of I ), (E)-tert-butyl 2,2-diazido-3-oxo-5-phenylpent-4-
1043, 833, 753, 556 [cm ]. For HRMS, 2u was converted to the
bistriazole according to general procedure D (CDCl , overnight). tert-
(
3
Butyl 7-acetoxy-2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d][1,2,3]-
2
triazol-1-yl)-3-oxoheptanoate was obtained as a colorless liquid. TLC:
2
1
enoate 2r was obtained as a yellowish solid (0.206 g, 0.63 mmol,
7%) after chromatography (PE/EtOAc 90/10). TLC: R = 0.74 (PE/
R
f
= 0.19 (CH/EtOAc 80/20, [UV]). H NMR (400 MHz, CDCl
): δ
3
7
[ppm] 4.09 (t, J = 6.4 Hz, 2H), 3.00−2.89 (m, 2H), 2.89−2.82 (m, 4H),
f
1
EtOAc 90/10, [KMnO ]). H NMR (400 MHz, CDCl ): δ [ppm]
2.25−2.07 (m, 4H), 2.02 (s, 3H), 2.00−1.89 (m, 2H), 1.79−1.65 (m,
4
3
13
7
6
.85 (d, J = 15.8 Hz, 1H), 7.63−7.57 (m, 2H), 7.47−7.39 (m, 3H),
6H), 1.59 (s, 9H), 1.39−1.17 (m, 12H). C NMR (101 MHz, CDCl ): δ
3
.94 (d, J = 15.8 Hz, 1H), 1.52 (s, 9H). 13C NMR (101 MHz, CDCl ):
[ppm] 192.5, 171.2, 160.1, 145.9, 136.6, 87.8, 86.7, 64.1, 41.3, 28.3, 27.8,
3
δ [ppm] 186.7, 163.3, 147.7, 134.0, 131.8, 129.3, 129.1, 118.4, 86.7,
27.6, 26.1, 25.7, 25.0, 24.4, 22.3, 22.0, 21.1. HRMS (m/z) calculated for
+
8
1
1
9
4
3
3.5, 28.0. IR: 3088, 3074, 3030, 3002, 2982, 2937, 2875, 2109, 1750,
708, 1607, 1597, 1575, 1497, 1474, 1450, 1474, 1450, 1395, 1370,
336, 1304, 1275, 1239, 1217, 1181, 1151, 1127, 1049, 1029, 1009,
83, 883, 857, 826, 787, 760, 746, 695, 676, 619, 587, 557, 547, 484,
[C29
H
44
N
6
O
5
Na ] 579.3265, found 579.3265.
tert-Butyl 2,2-Diazido-6-((tert-butyldimethylsilyl)oxy)-3-oxohexa-
noate (2v). Following general procedure B (0.730 g of 1v, 3.5 h), tert-
butyl 2,2-diazido-6-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate 2v
was obtained as a colorless liquid (0.660 g, 1.66 mmol, 72%) after
−1
+
65, 438 [cm ]. HRMS (m/z) calculated for [C H N O Na ]
15
16
6
3
51.1176, found 351.1178.
tert-Butyl 2,2-Diazido-3-oxohept-6-enoate (2s). Following general
chromatography (CH/EtOAc 95/5 → 90/10). TLC: R
f
= 0.56 (CH/
3
1
EtOAc 80/20, [KMnO
]). H NMR (400 MHz, CDCl ): δ [ppm]
4
procedure B (0.677 g of 1s, 3 h), tert-butyl 2,2-diazido-3-oxohept-6-
enoate, 2s was obtained as a yellowish oil (0.587 g, 2.09 mmol, 61%)
after chromatography (CH/Et O 100/0 → 90/10). TLC: R = 0.58
3.62 (t, J = 6.0 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 1.87−1.76 (m, 2H),
1.53 (s, 9H), 0.88 (s, 9H), 0.04 (s, 6H). 13C NMR (101 MHz,
CDCl ): δ [ppm] 198.5, 163.2, 86.8, 83.5, 61.8, 34.1, 28.0, 26.8, 26.0,
2
f
3
1
(
(
(
2
1
2
PE/EtOAc 95/5, [I ]). H NMR (400 MHz, CDCl ): δ [ppm] 5.79
18.4, −5.2. IR: 2955, 2931, 2886, 2858, 2116, 1743, 1472, 1462, 1396,
2
3
ddt, J = 16.9, 10.2, 6.5 Hz, 1H), 5.07 (dq, J = 17.1, 1.6 Hz, 1H), 5.02
dq, J = 10.2, 1.4 Hz, 1H), 2.65 (t, J = 7.2 Hz, 2H), 2.41−2.33 (m,
1372, 1421, 1152, 1101, 1044, 1006, 954, 833, 776, 713, 661, 555, 468,
−
1
447 [cm ]. For HRMS, 2v was converted to the bistriazole according
to general procedure D (CDCl , overnight). tert-Butyl 6-((tert-
H), 1.53 (s, 9H). 13C NMR (101 MHz, CDCl ): δ [ppm] 197.7,
3
3
63.1, 136.2, 116.1, 86.9, 83.4, 36.9, 28.0, 27.4. IR: 3081, 2983, 2935,
butyldimethylsilyl)oxy)-2,2-bis(4,5,6,7,8,9-hexahydro-1H-cycloocta[d]-
−1
113, 1742, 1372, 1237, 1149, 995, 917, 831, 752, 554 [cm ]. For
[1,2,3]triazol-1-yl)-3-oxohexanoate was obtained for mass analysis.
1
HRMS, 2s was converted to the bistriazole according to general
procedure C (0.037 g of 2s, 0.15 M, 3 d). tert-Butyl 3-oxo-2,2-bis(4-
phenyl-1H-1,2,3-triazol-1-yl)hept-6-enoate was obtained as a yellowish
TLC: R
CDCl
2.78 (m, 4H), 2.32−2.03 (m, 6H), 1.75−1.68 (m, 4H), 1.60 (s, 9H),
f
= 0.43 (CH/EtOAc 80/20, [UV]). H NMR (400 MHz,
): δ [ppm] 3.71 (t, J = 6.0 Hz, 2H), 3.04−2.94 (m, 2H), 2.94−
3
13
oil (0.029 g, 0.06 mmol, 45%) after chromatography (PE/EtOAc 70/
1.40−1.17 (m, 12H), 0.86 (s, 9H), 0.03 (s, 6H). C NMR (101 MHz,
CDCl ): δ [ppm] 193.1, 160.2, 145.9, 136.6, 87.7, 86.8, 62.3, 38.6,
29.0, 27.8, 27.6, 26.1, 26.1, 25.8, 25.1, 24.5, 22.0, 18.4, −5.2. HRMS
1
3
0). TLC: R = 0.6 (CH/EtOAc 80/20, [UV]). H NMR (400 MHz,
3
f
CDCl ): δ [ppm] 8.33 (s, 2H), 7.83−7.79 (m, 4H), 7.44−7.38 (m,
3
+
4
(
2
H), 7.36−7.30 (m, 2H), 5.86 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.12
dq, J = 17.0, 1.5 Hz, 1H), 5.08−5.03 (m, 1H), 2.89−2.84 (m, 2H),
(m/z) calculated for [C32H N O SiNa ] 637.3868, found 637.3839.
54 6 4
tert-Butyl 2,2,6-Triazido-3-oxohexanoate (2w). Following general
procedure B (0.520 g of 1w, 3 h), tert-butyl 2,2,6-triazido-3-
oxohexanoate 2w was obtained as a colorless liquid (0.741 g,
13
.65−2.57 (m, 2H), 1.64 (s, 9H). C NMR (101 MHz, CDCl ): δ
3
[
ppm] 191.4, 159.6, 148.3, 136.0, 129.6, 129.0, 128.9, 126.0, 121.0,
1
16.4, 88.9, 83.5, 38.7, 28.5, 27.8. HRMS (m/z) calculated for
1.86 mmol, 81%) after chromatography (CH/EtOAc 95/5 → 90/10).
+
1
[
C H N O Na ] 507.2115, found 507.2115.
TLC: R
CDCl
f
= 0.34 (CH/EtOAc 80/20, [KMnO
4
]). H NMR (600 MHz,
27
28
6
3
tert-Butyl 2,2-Diazido-7-(benzyloxy)-3-oxoheptanoate (2t). Fol-
3
): δ [ppm] 3.34 (t, J = 6.5 Hz, 2H), 2.66 (t, J = 6.9 Hz, 2H),
13
lowing general procedure A (1.53 g of 1t, 3.5 h, 10.0 equiv of NaN3,
2
1.94−1.86 (m, 2H), 1.54 (s, 9H). C NMR (151 MHz, CDCl ): δ
[ppm] 197.8, 163.0, 87.1, 83.4, 50.4, 34.4, 27.9, 22.9. IR: 2983, 2932,
2112, 2098, 1742, 1459, 1397, 1372, 1353, 1239, 1151, 1077, 1031,
3
.2 equiv of I ), tert-butyl 2,2-diazido-7-(benzyloxy)-3-oxoheptanoate
2
2
t was obtained as a colorless liquid (1.27 g, 3.27 mmol, 65%). TLC:
1
−1
R = 0.25 (CH/EtOAc 90/10, [UV, KMnO ]). H NMR (400 MHz,
956, 883, 832, 749, 626, 556, 468, 444 [cm ]. For HRMS, 2w was
f
4
CDCl ): δ [ppm] 7.37−7.30 (m, 4H), 7.30−7.25 (m, 1H), 4.49 (s,
converted to the bistriazole according to general procedure D
(overnight). tert-Butyl 2,2,6-tris(4,5,6,7,8,9-hexahydro-1H-cycloocta-
3
2
H), 3.48 (t, J = 6.1 Hz, 2H), 2.59 (t, J = 7.1 Hz, 2H), 1.78−1.69 (m,
1
3
2
H), 1.67−1.58 (m, 2H), 1.52 (s, 9H). C NMR (101 MHz, CDCl ):
[d][1,2,3]triazol-1-yl)-3-oxohexanoate was obtained for mass analysis.
3
1
δ [ppm] 198.3, 163.1, 138.6, 128.5, 127.7, 127.7, 86.8, 83.4, 73.1, 69.9,
7.3, 29.1, 27.9, 20.5. IR: 2981, 2937, 2861, 2114, 1741, 1476, 1455,
TLC: R = 0.02 (CH/EtOAc 80/20, [UV]). H NMR (400 MHz,
f
3
CDCl ): δ [ppm] 4.36 (t, J = 7.0 Hz, 2H), 2.99−2.89 (m, 2H),
3
H
DOI: 10.1021/acs.joc.5b02328
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2
2
1
1
2
.89−2.81 (m, 6H), 2.81−2.72 (m, 2H), 2.49−2.37 (m, 2H), 2.25−
obtained as a colorless liquid (0.162 g, 0.77 mmol, 50%) after
.06 (m, 4H), 1.87−1.76 (m, 2H), 1.76−1.64 (m, 6H), 1.56 (s, 9H),
chromatography (PE/EtOAc 50/50 → 20/80). TLC: R = 0.62 (PE/
f
1
3
1
.51−1.27 (m, 16H). C NMR (101 MHz, CDCl ): δ [ppm] 192.4,
EtOAc 50/50, [KMnO ]). H NMR (400 MHz, CDCl ): δ [ppm]
3.01 (s, 3H), 2.97 (s, 3H), 2.28 (s, 3H). C NMR (101 MHz,
CDCl ): δ [ppm] 196.6, 162.7, 85.7, 37.7, 37.5, 24.9; IR: 2937, 2110,
3
4
3
13
59.8, 146.0, 144.9, 136.6, 133.0, 88.3, 86.5, 46.9, 38.3, 28.4, 27.7, 27.6,
6.6, 26.1, 26.1, 26.0, 25.7, 25.0, 24.9, 24.6, 24.4, 22.0, 21.8. HRMS
3
+
(m/z) calculated for [C H N O ] 634.4188, found 634.4188.
1739, 1722, 1663, 1495, 1459, 1396, 1358, 1212, 1155, 1056, 1003,
34
52
9
3
tert-Butyl 2,2-Diazido-5-hydroxy-5-methyl-3-oxohexanoate (2x).
999, 961, 942, 884, 773, 719, 670, 650, 585, 557, 536, 466, 455, 419
−1
Following general procedure A (0.200 g of 1x, 4 h, 6.0 equiv of
NaN , 2.2 equiv of I ), tert-butyl 2,2-diazido-5-hydroxy-5-methyl-3-
[cm ]. For HRMS, 2ab was converted to the bistriazole according to
general procedure C (0.030 g of 2ab, 24 h). N,N-Dimethyl-3-oxo-2,2-
bis(4-phenyl-1H-1,2,3-triazol-1-yl)butanamide was obtained as a white
3
2
oxohexanoate 2x was obtained as a colorless liquid (0.214 g, 0.72 mmol,
7
0
[
(
2
1
[
8%) after chromatography (PE/EtOAc 90/10 → 70/30). TLC: R =
solid (0.037 g, 0.09 mmol, 63%) after chromatography (PE/EtOAc
f
1
1
.38 (PE/EtOAc 80/20, [KMnO ]). H NMR (400 MHz, CDCl ): δ
ppm] 3.05 (s, 1H), 2.75 (s, 2H), 1.54 (s, 9H), 1.29 (s, 6H). C NMR
101 MHz, CDCl ): δ [ppm] 199.5, 162.8, 87.3, 83.5, 69.9, 48.9,
100/0 → 0/100). TLC: R
NMR (400 MHz, CDCl
7.42−7.37 (m, 4H), 7.35−7.29 (m, 2H), 3.22 (s, 3H), 2.63 (s, 3H),
2.56 (s, 3H). 13C NMR (101 MHz, CDCl
): δ [ppm] 191.4, 159.5,
148.4, 129.5, 129.0, 128.9, 126.0, 121.4, 84.7, 38.4, 37.8, 26.7. HRMS
f
= 0.15 (PE/EtOAc 80/20, [KMnO
4
]). H
4
3
13
): δ [ppm] 8.32 (s, 2H), 7.82−7.79 (m, 4H),
3
3
9.4, 28.0. IR: 3560, 3436, 2980, 2937, 2116, 1741, 1459, 1372, 1238,
3
−1
148, 1053, 831, 749, 545, 467 [cm ]. HRMS (m/z) calculated for
+
+
C H N O Na ] 321.1282, found 321.1282.
(m/z) calculated for [C22
3,3-Diazido-5,5-dimethylhexane-2,4-dione (2ac). Following gen-
eral procedure A (0.500 g of 1ac, 3 h, 10.0 equiv of NaN , 2.5 equiv of
), 3,3-diazido-5,5-dimethylhexane-2,4-dione 2ac was obtained as a
colorless liquid (0.562 g, 2.51 mmol, 73%) after chromatography
H N O Na ] 438.1649, found 438.1636.
21 7 2
11
18
6
4
tert-Butyl 2,2-Diazido-5-hydroxy-6-methyl-3-oxoheptanoate
2y). Following general procedure A (0.200 g of 1y, 4 h, 6.0 equiv
of NaN , 2.2 equiv of I ), tert-butyl 2,2-diazido-5-hydroxy-6-methyl-3-
(
3
I
3
2
2
oxoheptanoate 2y was obtained as a colorless liquid (0.207 g,
.66 mmol, 76%) after chromatography (PE/EtOAc 90/10 → 80/20).
1
0
(PE/EtOAc 95/5). TLC: R
NMR (400 MHz, CDCl ): δ [ppm] 2.28 (s, 3H), 1.26 (s, 9H).
NMR (101 MHz, CDCl ): δ [ppm] 204.6, 197.1, 86.7, 45.0, 27.2, 25.2.
f
= 0.61 (PE/EtOAc 90/10, [KMnO ]). H
4
1
13
TLC: R = 0.61 (PE/EtOAc 80/20, [CAM]). H NMR (400 MHz,
3
C
f
CDCl ): δ [ppm] 3.93−3.83 (m, 1H), 2.75−2.61 (m, 2H), 2.39 (s,
3
3
1
(
1
2
1
2
H), 1.78−1.65 (m, 1H), 1.54 (s, 9H), 0.96 (d, J = 6.8 Hz, 3H), 0.95
IR: 2974, 2937, 2914, 2876, 2114, 1740, 1716, 1696, 1481, 1396, 1360,
1216, 1178, 1095, 1055, 1038, 996, 941, 880, 796, 767, 724, 698, 671,
d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl ): δ [ppm] 199.3,
3
−1
62.9, 87.2, 83.6, 72.0, 42.0, 33.3, 27.9, 18.5, 17.7. IR: 3569, 3467,
645, 606, 577, 540, 460 [cm ]. For HRMS, 2ac was converted to the
bistriazole according to general procedure C (0.030 g of 2ac, 24 h).
5,5-Dimethyl-3,3-bis(4-phenyl-1H-1,2,3-triazol-1-yl)hexane-2,4-dione
was obtained as a white solid (0.041 g, 0.10 mmol, 72%) after
966, 2936, 2911, 2877, 2115, 1741, 1626, 1460, 1396, 1372, 1239,
−1
150, 1051, 994, 960, 831, 750, 705, 546, 468, 435 [cm ]. For HRMS,
y was converted to the bistriazole according to general procedure D
0.033 g of 2y, overnight). tert-Butyl 2,2-bis(4,5,6,7,8,9-hexahydro-1H-
chromatography (PE/EtOAc 100/0 → 70/30). TLC: R = 0.57 (PE/
(
f
1
EtOAc 80/20, [KMnO ]). H NMR (400 MHz, CDCl ): δ [ppm]
cycloocta[d][1,2,3]triazol-1-yl)-5-hydroxy-6-methyl-3-oxoheptanoate
4
3
1
8
2
.39 (s, 2H), 7.84−7.81 (m, 4H), 7.43−7.39 (m, 4H), 7.36−7.31 (m,
was obtained as a colorless liquid. H NMR (400 MHz, CDCl ): δ
3
H), 2.54 (s, 3H), 1.22 (s, 9H). 13C NMR (101 MHz, CDCl ): δ
[
2
1
ppm] 4.23−4.15 (m, 1H), 3.23−3.00 (m, 2H), 2.94−2.81 (m, 4H),
3
[
ppm] 200.5, 191.2, 148.2, 129.5, 129.0, 128.9, 126.0, 121.1, 88.7, 47.6,
.31−2.09 (m, 4H), 1.82−1.67 (m, 5H), 1.61 (s, 9H), 1.58−1.49 (m,
+
2
9.0, 28.4. HRMS (m/z) calculated for [C H N O Na ] 451.1853,
H), 1.41−1.28 (m, 12H), 0.97 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.6
24 24 6 2
13
found 451.1848.
Hz, 3H). C NMR (101 MHz, CDCl ): δ [ppm] 193.8, 159.8, 146.1,
3
Competition Experiment. tert-Butyl-3-oxobutanoate (1g). (0.100 g,
0.61 mmol, 1.0 equiv) and tert-butyl 2-methyl-3-oxobutanoate (3)
1
2
5
36.7, 88.3, 86.7, 73.1, 45.9, 33.6, 27.8, 27.6, 26.1, 25.8, 25.1, 24.5,
+
2.0, 18.5, 17.4. HRMS (m/z) calculated for [C H N O Na ]
28
44
6
4
(
0.106 g, 0.61 mmol, 1.0 equiv) were dissolved in a 2:1 mixture of
DMSO (4 mL) and water (2 mL). Sodium azide (0.080 g, 1.23 mmol,
.0 equiv) and iodine (0.342 g, 1.35 mmol, 2.2 equiv) were added,
51.3316, found 551.3315.
S)-tert-Butyl 2,2-Diazido-4-((tert-butoxycarbonyl)amino)-3-oxo-
(
2
pentanoate (2z). Following general procedure A (0.500 g of 1z, 0.06
M, DMSO/H O 5/1, 5 h, 10.0 equiv of NaN , 2.2 equiv of I ), (S)-
and the reaction mixture was stirred for 5 h at room temperature.
A saturated aqueous solution of sodium thiosulfate was added, and the
mixture was extracted with ethyl acetate. The combined organic phases
were dried over magnesium sulfate and evaporated in vacuo. A sample
2
3
2
tert-butyl 2,2-diazido-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate
z was obtained as a white solid (0.453 g, 1.23 mmol, 70%, 96% ee)
2
after chromatography (PE/EtOAc 90/10). TLC: R = 0.50 (PE/
f
1
1
of the residue was directly submitted to H NMR spectroscopy. The
EtOAc 85/15, [UV]). H NMR (600 MHz, CDCl ): δ [ppm] 5.01−
3
ratio of the obtained products was determined by integration of the
signals of the acetyl groups.
4
.91 (m, 1H), 4.79−4.67 (m, 1H), 1.53 (s, 9H), 1.43 (s, 9H), 1.35 (d,
13
J = 6.9 Hz). C NMR (151 MHz, CDCl ): δ [ppm] 199.4, 162.6,
3
1
2
7
54.7, 87.2, 82.4, 80.4, 52.3, 28.4, 27.9, 18.6. IR: 2981, 2936,
123, 1737, 1710, 1515, 1455, 1370, 1239, 1152, 1044, 951, 833, 784,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02328.
■
−
1
56, 701, 609, 547, 464 [cm ]. HRMS (m/z) calculated for
S
*
+
[
C H N O Na ] 392.1653, found 392.1645.
14 23 7 5
(
S)-tert-Butyl 2,2-Diazido-4-((tert-butoxycarbonyl)amino)-6-
methyl-3-oxoheptanoate (2aa). Following general procedure A
(
0.360 g of 1aa, 0.04 M, DMSO/H O 5/1, 3 h, 10.0 equiv of NaN ,
Crystallographic data (CIF)
2
3
2
.2 equiv of I ), (S)-tert-butyl 2,2-diazido-4-((tert-butoxycarbonyl)-
NMR spectra, TGA−DSC measurements, crystallo-
2
amino)-6-methyl-3-oxoheptanoate 2aa was obtained as a colorless oil
0.354 g, 0.96 mmol, 79%, 93% ee) after chromatography (PE/EtOAc
graphic data, and HPLC traces (PDF)
(
9
1
0/10). TLC: R = 0.50 (PE/EtOAc 85/15, [UV]). H NMR
f
AUTHOR INFORMATION
Corresponding Author
*E-mail: sfkirsch@uni-wuppertal.de.
(
2
6
400 MHz, CDCl ): δ [ppm] 4.84−4.66 (m, 2H), 1.77−1.61 (m,
■
3
H), 1.53 (s, 9H), 1.43 (s, 9H), 1.36−1.26 (m, 1H), 0.98 (d, J =
13
.3 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H). C NMR (101 MHz, CDCl ): δ
3
[
ppm] 199.6, 162.6, 155.2, 87.1, 82.4, 80.3, 55.1, 41.6, 28.4, 27.9, 25.1,
Notes
2
1
3.5, 21.3. IR: 2962, 2935, 2873, 2122, 1745, 1709, 1498, 1393, 1240,
The authors declare no competing financial interest.
−1
151, 1048, 1023, 831, 547 [cm ]. HRMS (m/z) calculated for
+
[
C H N O Na ] 434.2122, found 434.2130.
17 29 7 5
ACKNOWLEDGMENTS
We thank M. Dlugosch (BUW) for supporting works and A.
Helfer (BUW) for measurements.
2
,2-Diazido-N,N-dimethyl-3-oxobutanamide (2ab). Following
general procedure A (0.200 g of 1ab, 3 h, 10.0 equiv of NaN3,
.5 equiv of I ), 2,2-diazido-N,N-dimethyl-3-oxobutanamide 2ab was
■
2
2
I
DOI: 10.1021/acs.joc.5b02328
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
37) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am.
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DOI: 10.1021/acs.joc.5b02328
J. Org. Chem. XXXX, XXX, XXX−XXX