Site-Selective Conversion of Azido Groups at Carbonyl α-Positions to Diazo Groups in Diazido and Triazido Compounds

Article abstract of DOI:10.1021/acs.joc.8b02074

This paper reports on the selective conversion of alkyl azido groups at the carbonyl α-position to diazo compounds. Through β-elimination of dinitrogen, followed by hydrazone formation/decomposition, α-azidocarbonyl moieties were transformed into α-diazo carbonyl groups in one step. As these reaction conditions do not involve aryl or general alkyl azides, site-selective conversions of di- and triazides were achieved. Through this method, the successive site-selective conjugation of the triazido molecule with three different components is demonstrated.

Full text of DOI:10.1021/acs.joc.8b02074

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Site-Selective Conversion of Azido Groups at Carbonyl α‑Positions
to Diazo Groups in Diazido and Triazido Compounds
Taiki Yokoi, Hiroki Tanimoto,* Tomomi Ueda, Tsumoru Morimoto, and Kiyomi Kakiuchi
Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST),
8916-5 Takayamacho, Ikoma, Nara 630-0192, Japan
S
* Supporting Information
ABSTRACT: This paper reports on the selective conversion of alkyl
azido groups at the carbonyl α-position to diazo compounds. Through
β-elimination of dinitrogen, followed by hydrazone formation/
decomposition, α-azidocarbonyl moieties were transformed into
α-diazo carbonyl groups in one step. As these reaction conditions
do not involve aryl or general alkyl azides, site-selective conversions of
di- and triazides were achieved. Through this method, the successive
site-selective conjugation of the triazido molecule with three different
components is demonstrated.
unique click conjugation reactivity to chemoselectively promote
[3+2] cycloaddition in the presence of azides and has been
developed for application in chemical biology.17,18 However, the
methods of introducing diazo groups often face substrate limita-
tion problems, such as in diazo transfer methods that usually
require 1,3-dicarbonyl structures.14 Owing to its efficiency in
synthetic organic chemistry, accessibility to the diazo group
should be improved, and the conversion of easily introducible
azido groups1a,b,e into diazo functions is a solution for this.
Recently, the direct transformation of azido into diazo groups
has been developed through the Staudinger reaction-based
strategy.19 The application of this strategy to multiple azido
compounds could, however, involve undesirable azido positions,
such as aryl and nonallylic/benzylic/α-carbonyl alkyl azides,11,12
which would generate unstable diazo species. To overcome
these issues, we herein report a new method that allows the azido
group at the carbonyl α-position to selectively transform into a
“stable” diazo group (Scheme 1b).
INTRODUCTION
■
Organic azides (R-N3) have long been identified as versatile and
valuable compounds for the synthesis of natural products,
pharmaceuticals, and functional heterocycles.1 However, despite
their widespread application as nitrene precursors and masked
amines, recent organic azides have received focus mostly in the
optimization of click chemistry by azide−alkyne [3+2] cyclo-
addition reactions that result in robust conjugations between
two molecules.2 Owing to the synthetic accessibility of the sub-
strates, the azido functional group is still within the main stream
of click chemistry.
Given that one-on-one conjugation is now well-established,
advancement in this field is aimed toward the site- or chemo-
selective conjugation of molecules containing multiple clickable
groups for versatile functionalization. To date, site-selective
conjugation strategies using heterocycles and polyalkyne com-
pounds have been developed.3−5 In contrast, difficulties remain
with compounds containing multiple azido groups (multiple
azido compounds) in site-selective reactions, especially among
alkyl azido moieties (Scheme 1a).6 Since multiple azido com-
pounds are easily accessible,1a,b,e such as by late-stage global SN2
azidation, and have a high reactivity with a sufficient molecular
stability, they offer promising platforms7 toward the develop-
ment of multifunctional element-block materials,8 such as
advanced imaging probes and high-performance polymers, by
the integration of various functional units.2e Hence, the recent
growth of interest in the site-selective manipulations of multiple
azido groups in one molecule, such as conjugation,7,9,10 reduc-
tion,11 protection,12 and desymmetrization reactions,13 demands
further exploration.
RESULTS AND DISCUSSION
■
Among the aryl, alkyl, and carbonyl α-positioned azides, we
anticipated that the azido group at the carbonyl α-position could
be selectively transformed into a diazo group. Through
β-elimination using appropriate basic reagents to produce
α-imino carbonyl structures followed by in situ condensation
with sulfonyl hydrazide to generate the corresponding hydra-
zones, the same basic conditions could promote the decom-
position of sulfonyl hydrazones1,20 to produce a stable α-diazo
carbonyl moiety in one step. Considering the stability of
hydrazones, in situ generated ammonia or ammonium salts
would not promote reverse reactions. Under these conditions,
aryl and alkyl azides without reactive hydrogen atoms should not
In contrast, despite its structural similarity to the azido (N3)
group, the nature of the diazo (N2) group is distinctly charac-
teristic.14 As well as its application as a carbene precursor for
cyclopropanation and C−H insertion in natural products and
polymer synthesis,15,16 the diazo functional group exhibits
Received: August 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b02074
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Scheme 1. Multiple Azido/Diazo Compounds
Table 1. Screening of Site-Selective Conversion Conditions
from Diazido to Azido Diazo Amide
a
b
entry
conditions
yield (%)
d
1
2
3
4
5
6
7
DBU (5.0 equiv), 48 h
0
tBuOK (2.5 equiv), 1 h
TBAF (5.0 equiv), 2 h
56
58
59
71
71
77
TBAF (5.0 equiv), H2O (1 equiv), 2 h
TBAF (5.0 equiv), iPr2NEt (5.0 equiv), 1 h
TBAF (5.0 equiv), piperidine (5.0 equiv), 1 h
TBAF (5.0 equiv), pyrrolidine (5.0 equiv), 1 h
TBAF (3.6 equiv), pyrrolidine (5.0 equiv), 1 h
TBAF (5.0 equiv), K2CO3 (2.0 equiv), 2 h
tBuOK (2.5 equiv), pyrrolidine (2.0 equiv), 1 h
KF (5.0 equiv), 18-crown-6 (5.0 equiv), CH3CN, 2 h
pyrrolidine (5.0 equiv), 6 h
entry 8 in THF, 24 h
entry 8 in toluene, 24 h
entry 7 in ethanol, 24 h
entry 7 in DMF, 6 h
c
d
8
9
84 (90)
66
10
11
12
13
14
15
16
17
18
19
20
48
e
0
e
0
0
0
0
f
f
e
55
0
28
71
0
entry 8 with 2,4,6-triisopropylbenzenesulfonylhydrazide
entry 8 with 2,4,6-trimethylbenzenesulfonylhydrazide
entry 8 with 4-methoxybenzenesulfonylhydrazide
entry 8 with 2-nitrobenzenesulfonylhydrazide
a
b
c
0.1 mmol of 1a, 0.1 M in DMSO. Isolated yield. 0.2 M in
d
e
f
DMSO. 1.0 mmol scale reaction. No reaction. Obtained in trace
amounts.
be damaged. Although elimination of dinitrogen from
unactivated alkyl azides by alkoxides of a strong base to obtain
the corresponding imines has also been reported,21 use of appro-
priate base reagents that can abstract only acidic α-hydrogen of
carbonyl groups to promote β-elimination could retain an
unactivated alkyl azido position. Moreover, carbonyl α-position-
selective transformation is essential to avoid the generation of
undesired unstable diazo moiety such as unfunctionalized alkyl
diazo groups (Scheme 1a). However, the assumed α-imino
carbonyl intermediates, especially those that are unsubstituted,
have been reported to be unstable or highly reactive, triggering
degradation or polymerization that limit their synthetic
applications.22 Thus, rapid formation of sulfonyl hydrazones
before degradation or polymerization should be a key to
success.23 With this background, the polar and aprotic DMSO
was selected as a solvent for the immediate condensation of
unstable imino carbonyl intermediates at an ambient temper-
ature avoiding potential thermal decomposition of the products
(Table 1).
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, entry 1), but only a
trace amount of the product was observed. The use of alkoxides
successfully generated 56% of the desired azido diazo compound
2a (entry 2). For the second step, the reaction should be con-
ducted with weaker bases because alkoxides have been reported
to destroy benzylic azides.21 Among them, TBAF (tetrabuty-
lammonium fluoride) as a base reagent24 was observed to
generate a similar yield to entry 2 (entry 3). Additional water to
examine the possible pathway through aldehydes by hydrolysis
did not improve the result (entry 4). Probably because of the
instability of imino carbonyl intermediates as reported,22 no
hydrolysis product or other isolable side product was obtained.
Although further improvement was not accomplished using a
single base, we found that applying additional weak bases
improved the product yields (entries 5−10). After an extensive
survey of organic and inorganic base additives and their
amounts, we found that pyrrolidine generated the best and
most reproducible yield of 84% and was applicable in large-scale
reactions (entry 8). Combination of pyrrolidine with alkoxide
(entry 10) resulted in a lower yield than that in entry 2. The
fluoride ion from potassium fluoride in the presence of crown
ether did not convert the starting azide (entry 11). Because the
old bottle of TBAF, which may be partially decomposed, gave 2a
with slightly low and irreproducible yields, TBAF itself would
work as a suitable base to extract the α-hydrogen of azidoamides
Our investigations began with diazido compound 1a, which
possesses two different alkyl azido groups. To demonstrate the
advantageous character of the azido group, all multiple azido
substrates we tested were concisely prepared by global azidation
of the appropriate halogenated precursors (reaction 1, see
Experimental Section). The reaction was first attempted with
B
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(see Experimental Section). As pyrrolidine itself had no effect in
the case of amide as it is not basic enough (entry 12), the
efficiency of pyrrolidine or other amines would be at the level of
the decomposition of sulfonyl hydrazones.20e Due to the insta-
bility of α-imino carbonyl intermediates,22 successive addition of
pyrrolidine after consumption of starting materials by TBAF was
not efficient. Amines and inorganic base25 without TBAF
required heating and long reaction times (60−80 °C around
30 h) to eliminate dinitrogen and exhibited with low repro-
ducibility. The use of other solvents such as THF, toluene, or
ethanol did not yield the desired products, and polar DMF
slowly afforded 2a in a moderate yield (entries 13−16). Addi-
tionally, we tested some other sulfonyl hydrazides (entries 17−
20). While p-methoxyphenylsulfonyl hydrazide gave 2a in a
similar yield (71%), other reactive hydrazides, such as reactive
mesityl-, 2-nitrophenyl, or triisopropylphenylsulfonylhydra-
zides, did not generate satisfactory results owing to their prior
decomposition under these conditions before the formation of
hydrazones.20d,f
of the desired diazo products. Considering that the α-hydrogen
of ketones is more acidic than that of amides, we found that
sufficient transformation to generate α-diazo ketones was
achieved enough using only pyrrolidine of a weak base without
TBAF.26 This result indicates that TBAF for amides is required
only to extract α-hydrogen atoms in less acidic compounds.
In the case of ketones that produce more stable enolates than
amides, we observed a dimerized product such as 4i′ in the
absence of aza nucleophiles probably through the [3+2] reaction
as depicted in reaction 2.27 This kind of the side reaction might
After identifying suitable conditions (entry 8 in Table 1), we
then scoped the monoazido compounds for general utility of this
method (Scheme 2). The substituents on amido-nitrogen atoms
also be one of the reasons of moderate yields compared to those
of amides. α-Azido acetophenone 3i, previously converted into
4i in 49% yield,19b and para-substituted compounds 3j−k were
efficiently transformed into 4i−k in 74%, 75%, and 58% yields,
respectively. The secondary alkyl azido group in ketone 3l could
produce a similar yield of 4l (63%). Despite the potential
β-elimination, dialkyl ketone 3m was successfully transformed
into diazo product 4m in 51% yield.
Scheme 2. Scope of Monoazido Substrates
With the successful results from monoazido amides and
ketones, we further expanded the scope of the substrates to
di- and triazido compounds for site-specific conversion into
stable functional diazo groups (Scheme 3). All azido groups in
the substrates as well as 1a were introduced in one step that
demonstrated their easy accessibility. Similar to 1a in Table 1,
diazide 1b, containing azido aryl and α-azido amido moieties,
transformed into azido diazo product 2b in 82% yield. Even in
the presence of potentially reactive benzylic azide,21 2c was
gratifyingly obtained in 89% yield. We then studied selective
diazo formation with substrates possessing two α-azido carbonyl
structures. With the appropriate conditions for ketones, diazide
1d possessing keto- and amido-azido moieties was successfully
converted into 2d. Furthermore, diazo compound 2e was
selectively synthesized from bis(α-azidoamido) material 1e
since the less active secondary alkyl azido amido moiety (less
acidic hydrogen) in 1e remained under the reaction con-
ditions.26 The moderate yield is probably due to the lability of
the α-iminocarbonyl intermediate of this compound since the
side product α-azido propionamide without acetyl moiety was
obtained as an inseparable mixture. However, the possible
inverse azido diazo or bis-diazo products were not observed, and
2e was obtained as a sole azido diazo product. Subsequently, we
submitted triazido substrates, and the azido group at the
α-carbonyl position in 5a with one aryl and two alkyl azido
moieties was successfully manipulated to produce diazo
molecule 6a, which possessed distinguishable aryl and alkyl
azido groups,6,9 as a sole product. Furthermore, with tris(alkyl
azido) compound 5b containing keto- and amido-azido frag-
ments, the established reaction conditions with pyrrolidine
afforded the diazido keto-diazo product 6b. The moderate yield
of 6b is following those of monoazido ketones (Scheme 2), and
the use of a weak base converted the site-selective keto-azido
group in the presence of other two azido groups.
a
b
c
4.4 equiv of TBAF. Without pyrrolidine. 0.1 M in DMSO.
(aryl and alkyl) did not influence the conversion to afford 4a−c
in 75%, 87%, and 79% yields, respectively. As well as protected
compound 4d, the substrates 3e−f bearing hydroxyl and amino
groups were also acceptable to this method. As well as the
purification stage,26 inhibition of condensation with hydrazide
and imine intermediates by reactive hydroxyl or amino groups
might be the reason for their moderate yields. Although the use
of sulfonyl hydrazides under basic conditions possibly reduces
vinyl groups, 4g was successfully obtained in 87% yield.20d The
plausible reaction intermediate sulfonyl hydrazone (Scheme 1b)
was confirmed by 4h (74%) and was stable enough under basic
conditions because of the stability of the hydrazone anion by the
presence of a phenyl group.
Next, we studied the reaction with ketones. However, the
TBAF/pyrrolidine system only produced moderate or low yields
C
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Scheme 3. Site-Selective Conversion to Diazo Groups with
Di- and Triazido Compounds
Scheme 5. Successive Conjugation with Three Different
Components
82% yield. After the second conversion of the azido group on the
amido moiety in 10 to diazo amide 11 in 75% yield, the second
diazo-selective [3+2] cyclization with ethyl acrylate,17 followed
by azide-strained alkyne cyclization,2a,d successfully furnished
12. It should be mentioned that each of the three alkyl azido
groups in 5b, which were previously difficult to differentiate,7
was conjugated with three different dipolarophiles by successive
site-selective conversion into diazo groups.
a
0.1 M in DMSO.
The obtained azido diazo materials are highly versatile,28 and
2a was chemoselectively conjugated, as shown in Scheme 4.
CONCLUSION
■
Scheme 4. Chemoselective Conjugation of Azido Diazo
Compound
In summary, we have achieved the site-selective conversion of
azido groups at carbonyl α-positions to diazo groups in one step.
As this transformation is dependent on a high reactivity at
carbonyl α-positions, aryl and unreactive alkyl azides were not
included. With this method, site-selective diazo transformation
with the di- and triazido molecules was achieved, as well as the
successive integration of various components. This selective
azido-manipulation method will likely expand the efficiency and
availability of diazo groups and will also develop the site-
selective assembly of multiple functional components onto one
molecular platform possessing over three types of azido groups.
Further development of this site-selective conversion strategy to
other clickable groups and application aimed at integration of
multiple functional components will be reported in due course.
EXPERIMENTAL SECTION
■
Caution! Organic azides, especially multiple azido compounds as well
as diazo compounds, are potentially hazardous and explosive. Although
we have never experienced such an explosion with those used in this
study, all manipulations should be carefully conducted behind a safety
shield in a hood. Sodium azide should be handled with a plastic spatula.
At the azidation stage of azido compound preparation, complete
removal of residual halogenated solvent used in the last steps or
extractions should be kept in mind to avoid generation of an explosive
species such as diazidomethane from dichloromethane.30
Staudinger−Bertozzi ligation19b,29 with phosphine 7 produced
azido-selectively conjugated diazo compound 8. On the other
hand, diazo-selective conjugation was conducted by [3+2]
cycloaddition with acrylate to generate pyrazoline azide 9 as a
single isomer.17
Finally, we demonstrated the efficiency of our method by site-
selective conjugation7c of the tris(alkylazido) platform com-
pound 5b with three different components by the way of
successive diazo conversion (Scheme 5). With the generation of
diazido diazo compound 6b from 5b by ketone-selective con-
version (Scheme 3), diazo-selective cycloaddition with naphtho-
quinone and subsequent air oxidation25 occurred to afford 10 in
General Information of Analysis and Reagents. H and 13C
1
NMR spectra were recorded at 500 MHz for 1H NMR, 126 MHz for
13C NMR, and 202 MHz for 31P NMR. Chemical shifts are reported as
δ values in ppm and calibrated with respect to the residual solvent peak
(CDCl3: δ 7.26 for 1H NMR and δ 77.00 for 13C NMR) or
D
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tetramethylsilane (δ 0 for 1H NMR). 31P NMR spectra were calibrated
with an external reference (phosphoric acid in benzene-d6 as δ 0.0). The
abbreviations used are as follows: s (singlet), d (doublet), t (triplet),
q (quartet), br (broad peak), and m (complex multiplet). Mass spectra
were recorded by an EI-magnetic sector (70 eV), CI-magnetic sector,
ESI-TOF, and MALDI-spiral TOF. The materials, which were hard to
be purified by neutral silica gel column chromatography, were purified
by a recycling preparative gel permeation chromatography (GPC;
chloroform as an eluent). Dimethyl sulfoxide (DMSO) was distilled
under reduced pressure after refluxing in the presence of calcium
hydride.
Synthesis of Diazo Compounds. General Procedure. Storage of
TBAF. Tetrabutylammonium fluoride (TBAF) was purchased as a
1 mol/L solution of THF. Because we encountered irreproducible
results when we used old solution, probably due to the decomposition
of TBAF by the reagent itself or contaminated water from moisture,31
the newly purchased bottle of TBAF solution was repacked in small
subsection vial bottles. These were filled with nitrogen gas and were
stored in the refrigerator. With these small batch bottles, we successfully
obtained reproducible results as described in the article. In addition, the
use of commercial solid TBAF hydrate or the removal of THF from the
reagent solution prior to use gave low yields or irreproducible results.
Short path silica gel column chromatography can afford the desired
products in good yields. Exposure to the silica gel column for a long
time reduced the product yields.
From Amides. TBAF (3.6 equiv, 1.0 M in THF, see also General
Information of Analysis and Reagents) was added dropwise to a stirred
solution of α-azido amide (1.0 equiv), p-toluenesulfonyl (tosyl)
hydrazide (5.0 equiv), and pyrrolidine (5.0 equiv) in DMSO (0.2 M
based on an azido substrate unless otherwise noted) at 25 °C (set by a
water bath) under the nitrogen gas atmosphere. After completion of the
reaction checked by TLC, the mixture was diluted with ether and
quenched with water. The solution was extracted three times with ether
and was washed with water and brine. The collected organic layer was
dried over sodium sulfate. Concentration and purification by flash
neutral silica gel column chromatography gave the diazo product.
From Ketones. Pyrrolidine (2.5 equiv) was added dropwise to a
stirred solution of α-azido ketone (1.0 equiv) and p-toluenesulfonyl
hydrazide (5.0 equiv) in DMSO (0.2 M based on an azido substrate
unless otherwise noted) at 25 °C (set by a water bath) under the
nitrogen gas atmosphere. The purification procedure was followed for
amides.
2-Diazo-N-methyl-N-phenylacetamide (4a).32 A total of 13.2 mg
of 4a (75%) was obtained from the reaction with azide 3a (19.0 mg,
0.10 mmol), tosyl hydrazide (93.6 mg, 0.50 mmol, 5.0 equiv),
pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF (0.36 mL,
1.0 M in THF, 0.36 mmol, 3.6 equiv) in DMSO (0.5 mL, 0.2 M) for
1.5 h followed by neutral silica gel chromatography (hexane/ethyl
acetate = 8/1): pale yellow oil; Rf value 0.57 (hexane/ethyl acetate =
1
1/1); IR (NaCl, neat) νmax 2106, 1622, 1591, 1387 cm−1; H NMR
(500 MHz, CDCl3) δ 7.41 (t, 2H, J = 7.5 Hz), 7.33 (t, 1H, J = 7.5 Hz),
7.20 (m, 2H), 4.51 (s, 1H), 3.32 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 165.7, 143.1, 129.8, 127.9, 127.3, 47.3, 37.1; HRMS (CI) calcd for
C9H10N3O [M + H]+ 176.0824, found 176.0826.
N-Benzyl-2-diazo-N-phenylacetamide (4b).32 A total of 21.8 mg of
4b (87%) was obtained from the reaction with azide 3b (26.6 mg,
0.10 mmol), tosyl hydrazide (93.5 mg, 0.50 mmol, 5.0 equiv),
pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF (0.36 mL,
1.0 M in THF, 0.36 mmol, 3.6 equiv) in DMSO (0.5 mL, 0.2 M) for 1 h
followed by neutral silica gel chromatography (hexane/ethyl acetate =
8/1): pale yellow amorphous solid; Rf value 0.63 (hexane/ethyl acetate
= 1/1); IR (NaCl, neat) νmax 3478, 2106, 1624, 1593, 1399 cm−1; 1H
NMR (500 MHz, CDCl3) δ 7.34−7.22 (m, 8H), 7.03−7.01 (m, 2H),
4.93 (s, 2H), 4.45 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 165.8,
141.4, 137.5, 129.6, 128.6, 128.43, 128.36, 128.1, 127.3, 52.9, 47.4;
HRMS (CI) calcd for C15H14N3O [M + H]+ 252.1137, found
252.1143.
N,N-Dibenzyl-2-diazoacetamide (4c). A total of 20.9 mg of 4c
(79%) was obtained from the reaction with azide 3b (28.0 mg,
0.10 mmol), tosyl hydrazide (93.7 mg, 0.50 mmol, 5.0 equiv),
pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF (0.44 mL,
1.0 M in THF, 0.44 mmol, 4.4 equiv) in DMSO (0.5 mL, 0.2 M) for 3 h
followed by neutral silica gel chromatography (hexane/ethyl acetate =
10/1 to 6/1): pale yellow oil; Rf value 0.63 (hexane/ethyl acetate =
1
1/1); IR (NaCl, neat) νmax 2106, 1605, 1428, 1213 cm−1; H NMR
(500 MHz, CDCl3) δ 7.37−7.34 (m, 4H), 7.31−7.28 (m, 2H), 7.23
(br-s, 4H), 4.99 (s, 1H), 4.62−4.29 (br-m, 4H); 13C NMR (126 MHz,
CDCl3) δ 166.5, 136.6 (br), 128.8, 127.6, 126.4 (br), 49.4 (br), 47.0;
HRMS (CI) calcd for C16H16N3O [M + H]+ 266.1293, found
266.1295.
N-(3-Azidopropyl)-2-diazo-N-phenylacetamide (2a). The follow-
ing is a 0.10 mmol scale reaction: 20.5 mg of 2a (84%) was obtained
from the reaction with diazide 1a (25.8 mg, 0.10 mmol), tosyl hydrazide
(93.8 mg, 0.50 mmol, 5.0 equiv), pyrrolidine (42.0 μL, 0.50 mmol,
5.0 equiv), and TBAF (0.36 mL, 1.0 M in THF, 0.36 mmol, 3.6 equiv)
in DMSO (0.5 mL, 0.2 M) for 1 h followed by neutral silica gel column
chromatography (hexane/ethyl acetate = 8/1 to 5/1).
The following is a 1.0 mmol scale reaction: 219.5 mg of 2a (90%) was
obtained from the reaction with diazide 1a (259.1 mg, 1.0 mmol), tosyl
hydrazide (931.9 mg, 5.0 mmol, 5.0 equiv), pyrrolidine (0.42 mL,
5.0 mmol, 5.0 equiv), and TBAF (3.6 mL, 1.0 M in THF, 3.6 mmol,
3.6 equiv) in DMSO (5.0 mL, 0.2 M) for 1 h followed by neutral silica gel
column chromatography (hexane/ethyl acetate = 5/1 to 4/1 to 3/1 to
2/1). Compound 2a: pale yellow oil; Rf value 0.63 (hexane/ethyl acetate =
1/1); IR (NaCl, neat) νmax 2102, 1622, 1592, 1401, 1263 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.43 (dd, 2H, J = 8.0, 7.5 Hz), 7.37 (t, 1H, J =
8.0 Hz), 7.19 (d, 2H, J = 7.5 Hz), 4.42 (s, 1H), 3.84 (t, 2H, J= 7.0Hz), 3.36
(t, 2H, J = 6.5 Hz), 1.83 (tt, 2H, J = 7.0, 6.5 Hz); 13C NMR (126 MHz,
CDCl3) δ 165.9, 141.3, 129.9, 128.3, 128.2, 49.1, 47.4, 46.7, 27.7; HRMS
(CI) calcd for C11H13N6O [M + H]+ 245.1151, found 245.1152.
N-Benzyl-2-diazo-N-(3-((methoxymethoxy)methyl)phenyl)-
acetamide (4d). A total of 28.1 mg of 4d (87%) was obtained from the
reaction with azide 3d (34.0 mg, 0.10 mmol), tosyl hydrazide (93.6 mg,
0.50 mmol, 5.0 equiv), pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and
TBAF (0.36 mL, 0.36 mmol, 3.6 equiv) in DMSO (0.5 mL, 0.2 M) for
1 h followed by neutral silica gel column chromatography (hexane/
ethyl acetate = 10/1 to 6/1 to 4/1): pale yellow oil; Rf value 0.6
(hexane/ethyl acetate = 1/1); IR (NaCl, neat) νmax 2932, 2885, 2107,
1625, 1603, 1587, 1399 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.31−
7.21 (m, 7H), 7.04 (s, 1H), 6.93 (ddd, 1H, J = 6.0, 2.5, 1.5 Hz), 4.92
(s, 2H), 4.66 (s, 2H), 4.53 (s, 2H), 4.46 (s, 1H), 3.37 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 165.8, 141.5, 139.9, 137.4, 129.6, 128.6, 128.3,
127.6, 127.4, 127.32, 127.30, 95.8, 68.3, 55.4, 52.8, 47.4; HRMS
(MALDI-TOF) calcd for C18H19N3NaO3 [M + Na]+ 348.1324, found
348.1314.
E
DOI: 10.1021/acs.joc.8b02074
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The Journal of Organic Chemistry
Article
N-Benzyl-2-diazo-N-(3-(hydroxymethyl)phenyl)acetamide (4e).
A total of 13.0 mg of 4e (46%) was obtained from the reaction with
azide 3e (29.5 mg, 0.10 mmol), tosyl hydrazide (93.2 mg, 0.50 mmol,
5.0 equiv), pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF
(0.36 mL, 1.0 M in THF, 0.36 mmol, 3.6 equiv) in DMSO (0.5 mL,
0.2 M) for 3 h followed by neutral silica gel column chromatography
(hexane/ethyl acetate = 1/1) and GPC for further purification: pale
yellow oil; Rf value 0.5 (hexane/ethyl acetate = 1/2); IR (NaCl, neat)
νmax 3396, 3117, 2106, 1584, 1403 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.32−7.21 (m, 7H), 7.05 (s, 1H), 6.93 (ddd, 1H, J = 5.0, 1.5, 1.5 Hz),
4.92 (s, 2H), 4.66 (d, 2H, J = 5.5 Hz), 4.46 (s, 1H), 1.82−1.78 (m, 1H);
13C NMR (126 MHz, CDCl3) δ 165.9, 142.9, 141.5, 137.4, 129.6,
128.5, 128.4, 127.4, 126.5, 126.4, 64.3, 52.9, 47.5; HRMS (CI) calcd for
C16H16N3O2 [M + H]+ 282.1243, found 282.1236.
by GPC for further purification gave tosyl hydrazone 4h (30.1 mg,
0.0739 mmol, 74%). Recrystallization for X-ray analysis was performed
with hexane/ether by the vapor diffusion method. Compound 4h:
colorless crystal; Rf value 0.27 (hexane/ethyl acetate = 1/1); mp 183−
184 °C; IR (NaCl, neat) νmax 1640, 1594, 1496, 1389, 1348, 1169, 1082,
915 cm−1; 1H NMR (500 MHz, CDCl3, major isomer) δ 8.70 (d, 1H,
J = 5.0 Hz), 7.84 (d, 2H, J = 8.0 Hz), 7.27−7.26 (m, 2H), 7.23−7.18
(m, 3H), 7.14−7.07 (m, 5H), 6.93−6.71 (m, 2H), 3.43 (s, 3H), 2.38
(s, 3H); 13C NMR (126 MHz, CDCl3, major rotamer) δ 163.6, 150.9,
144.1, 140.4, 135.2, 132.5, 129.8, 129.6, 129.2, 128.3, 128.1, 128.0,
126.1, 125.8, 36.4, 21.6; HRMS (ESI) calcd for C22H21N3NaO3S
[M + Na]+ 430.1201, found 430.1197.
α-Diazo Acetophenone (4i)..19b,25a A total of 10.7 mg of 4i (74%)
was obtained from the reaction with azide 3i (16.0 mg, 0.10 mmol),
tosyl hydrazide (93.5 mg, 0.50 mmol, 5.0 equiv), and pyrrolidine
(21.0 μL, 0.25 mmol, 2.5 equiv) in DMSO (0.5 mL, 0.2 M) for 0.5 h
followed by neutral silica gel chromatography (hexane/ethyl acetate =
15/1): pale yellow solid; Rf value 0.37 (hexane/ethyl acetate = 3/1);
mp 45 °C; IR (NaCl, neat) νmax 2106, 1613, 1364, 1227 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.77−7.76 (m, 2H), 7.55 (tt, 1H, J = 7.5, 1.5 Hz),
7.47−7.44 (m, 2H), 5.91 (s, 1H); 13C NMR (126 MHz, CDCl3)
δ 186.3, 136.6, 132.7, 128.6, 126.7, 54.2; HRMS (CI) calcd for C8H7N2O
[M + H]+ 147.0558, found 147.0547.
N-Benzyl-N-(3-(benzylamino)phenyl)-2-diazoacetamide (4f).
A total of 17.2 mg of 4f (48%) was obtained from the reaction with
azide 3f (37.0 mg, 0.10 mmol), tosyl hydrazide (93.2 mg, 0.50 mmol,
5.0 equiv), pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF
(0.50 mL, 1.0 M in THF, 0.50 mmol, 5.0 equiv) in DMSO (0.5 mL,
0.2 M) for 6 h followed by neutral silica gel column chromatography
(hexane/ethyl acetate = 10/1 to 8/1 to 6/1): pale yellow oil; Rf value
0.77 (hexane/ethyl acetate = 1/1); IR (NaCl, neat) νmax 2102, 1597,
1492, 1399, 1346 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.34 (dd, 2H,
J = 7.0, 5.5 Hz), 7.33−7.21 (m, 8H), 7.08 (dd, 1H, J = 8.0, 8.0 Hz), 6.55
(dd, 1H, J = 8.5, 2.0 Hz), 6.35 (dd, 1H, J = 7.5, 1.0 Hz), 6.21 (dd, 1H, J =
2.0, 2.0 Hz), 4.86 (s, 2H), 4.52 (s, 1H), 4.23 (s, 2H), 4.19 (br, 1H); 13C
NMR (126 MHz, CDCl3) δ 165.9, 148.9, 142.5, 138.6, 137.8, 130.1,
128.7, 128.5, 128.3, 127.40, 127.36, 127.2, 116.8, 112.6, 112.2, 52.7,
47.9, 47.3; HRMS (MALDI-TOF) calcd for C22H20N4ONa [M + Na]+
379.1535, found 379.1529.
N-(2-Oxo-2-phenylethyl)benzamide (4i′, CCDC No. 1839204),
Dimeric Compound from 3i. To a stirred solution of azido ketone 3i
(16.2 mg, 0.10 mmol) in DMSO (1.0 mL, 0.1 M) was added TBAF
(0.22 mL, 1.0 M in THF, 0.22 mmol, 2.2 equiv) at 25 °C. After 15 min,
the reaction was quenched with water, and the mixture was extracted
twice with ether. The combined organic layer was washed with brine
and was dried over sodium sulfate. Concentration and purification by
neutral silica gel column chromatography (hexane/ethyl acetate = 10/1
to 5/1) gave 5.0 mg of compound 4i′ (42%). Recrystallization for X-ray
analysis was performed with hexane/ethyl acetate by the vapor diffusion
method. Compound 4i′: yellow crystal; Rf value 0.27 (hexane/ethyl
acetate = 2/1); mp 115−116 °C; IR (NaCl, neat) νmax 3330, 3061, 2924,
1698, 1645, 1537, 1488, 1225 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.03
(dd, 2H, J = 8.5, 1.0 Hz), 7.88 (dd, 2H, J = 8.0, 1.5 Hz), 7.05 (m, 1H),
7.55−7.51 (m, 3H), 7.47 (dd, 2H, J = 8.0, 6.5 Hz), 7.34 (br, 1H), 4.96
(d, 2H, J = 4.0 Hz); 13C NMR (126 MHz, CDCl3) δ 194.2, 167.4, 134.3,
134.2, 133.8, 131.8, 129.0, 128.6, 128.0, 127.1, 46.9; LRMS (EI, M =
C15H13NO2) m/z 239 (20%, M+), 211 (18), 134 (20), 105 (100); HRMS
(EI) calcd for C15H13NO2 (M+) 239.0946, found 239.0952.
N-Benzyl-2-diazo-N-(4-vinylphenyl)acetamide (4g). A total of
23.9 mg of 4g (87%) was obtained from the reaction with azide 3g
(29.1 mg, 0.10 mmol), tosyl hydrazide (93.1 mg, 0.50 mmol, 5.0 equiv),
pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF (0.36 mL,
1.0 M in THF, 0.36 mmol, 3.6 equiv) in DMSO (0.5 mL, 0.2 M) for 1 h
followed by neutral silica gel column chromatography (hexane/ethyl
acetate = 10/1 to 8/1): pale yellow oil; Rf value 0.8 (hexane/ethyl
acetate = 1/1); IR (NaCl, neat) νmax 2106, 1624, 1600, 1509,
1396 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, 2H, J = 8.5 Hz),
7.29−7.22 (m, 5H), 6.97 (d, 2H, J = 8.0 Hz), 6.67 (dd, 1H, J = 17.0,
11.0 Hz), 5.74 (d, 1H, J = 17.0 Hz), 5.29 (d, 1H, J = 11.0 Hz), 4.92
(s, 2H), 4.49 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 165.8, 140.7,
137.4, 137.3, 135.5, 128.6, 128.5, 128.4, 127.4, 127.2, 115.2, 52.8, 47.4;
LRMS (EI, M = C17H15N3O) m/z 277 (M+, 2%), 249 (48), 158 (10),
130 (11), 91 (100); HRMS (EI) calcd for C17H15N3O (M+) 277.1215,
found 277.1208.
2-Diazo-1-(4-methoxyphenyl)ethan-1-one (4j)..19b,25a A total of
13.2 mg of 4j (75%) was obtained from azide 3j (19.1 mg, 0.10 mmol), tosyl
hydrazide (93.9 mg, 0.50 mmol, 5.0 equiv), and pyrrolidine (21.0 μL,
0.25 mmol, 2.5 equiv) in DMSO (0.5 mL, 0.2 M) for 3 h followed by neutral
silica gel chromatography (hexane/ethyl acetate = 10/1 to 6/1): pale yellow
solid; Rf value 0.50 (hexane/ethyl acetate = 1/1); mp 75−76 °C; IR (NaCl,
N-Methyl-N,2-diphenyl-2-(2-tosylhydrazineylidene)acetamide
(4h, CCDC No. 1839202). TBAF (0.36 mL, 1.0 M in THF, 0.36 mmol,
3.6 equiv) was added dropwise to a stirred solution of azide 3h
(26.6 mg, 0.10 mmol) and tosyl hydrazide (93.5 mg, 0.50 mmol,
5.0 equiv) in DMSO (0.5 mL, 0.2 M) at 25 °C under a nitrogen
atmosphere. The reaction mixture was diluted with diethyl ether and
quenched with a saturated aqueous sodium bicarbonate solution after
stirring for 1 h. The mixture was extracted three times with ether and
was washed with water and brine. The collected organic layer was dried
over sodium sulfate. Concentration and purification by neutral silica gel
column chromatography (hexane/ethyl acetate = 5/1 to 2/1) followed
1
neat) νmax 3099, 2115, 1611, 1590, 1567, 1388, 1372 cm−1; H NMR
(500 MHz, CDCl3)δ 7.74 (d, 2H, J= 9.0 Hz), 6.93 (d, 2H, J= 9.0 Hz), 5.85
(s, 1H), 3.87 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 185.2, 163.2, 129.4,
128.7, 113.8, 55.4, 53.5; LRMS (EI, M = C9H8N2O2) m/z 176 (79%, M+),
135 (100), 120 (28), 91 (35), 77 (52); HRMS (EI) calcd for
C9H8N2O2 (M+) 176.0586, found 176.0589.
F
DOI: 10.1021/acs.joc.8b02074
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The Journal of Organic Chemistry
Article
1-(4-Bromophenyl)-2-diazoethan-1-one (4k)..19b,25a A total of
13.0 mg of 4k (58%) was obtained from the reaction with azide 3k
(17.4 mg, 0.10 mmol), tosyl hydrazide (93.1 mg, 0.50 mmol, 5.0 equiv),
and pyrrolidine (21.0 μL, 0.25 mmol, 2.5 equiv) in DMSO (0.5 mL,
0.2 M) for 0.5 h followed by neutral silica gel chromatography (hexane/
ethyl acetate = 10/1): pale yellow solid; Rf value 0.37 (hexane/ethyl
acetate = 3/1); mp 110−111 °C; IR (KBr, disc) νmax 3115, 2118, 1608,
diazide 1c (32.1 mg, 0.10 mmol), tosyl hydrazide (93.8 mg, 0.50 mmol,
5.0 equiv), pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF
(0.36 mL, 0.36 mmol, 3.6 equiv) in DMSO (0.5 mL, 0.2 M) for 1 h
followed by neutral silica gel chromatography (hexane/ethyl acetate =
10/1 to 8/1): pale yellow oil; Rf value 0.23 (hexane/ethyl acetate =
1
3/1); IR (NaCl, neat) νmax 2104, 1623, 1397, 706 cm−1; H NMR
(500 MHz, CDCl3) δ 7.35 (t, 1H, J = 8.0 Hz), 7.29−7.24 (m, 4H),
7.23−7.21 (m, 2H), 7.00−6.98 (m, 2H), 4.93 (s, 2H), 4.44 (s, 1H),
4.29 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 165.7, 141.9, 137.3,
137.1, 130.1, 128.6, 128.5, 128.3, 128.1, 127.9, 127.5, 54.0, 52.9, 47.6;
HRMS (CI) calcd for C16H15N6O [M + H]+ 307.1307, found
307.1304.
1
1590, 1401, 1379, 1070 cm−1; H NMR (500 MHz, CDCl3) δ 7.63
(d, 2H, J = 8.5 Hz), 7.59 (d, 2H, J = 8.5 Hz), 5.88 (s, 1H); 13C NMR
(126 MHz, CDCl3) δ 185.1, 135.3, 131.9, 128.2, 127.6, 54.4; LRMS
(EI, M = C8H5BrN2O) m/z 226 (42%, M+ of 81Br), 224 (42, M+ of
79Br), 185 (55), 183 (56), 89 (100); HRMS (EI) calcd for
C8H579BrN2O (M+) 223.9585, found 223.9589.
2-Diazo-1-phenylpropan-1-one (4l). A total of 10.0 mg of 4l (63%)
was obtained from the reaction with azide 3l (17.4 mg, 0.10 mmol),
tosyl azide (93.1 mg, 0.50 mmol, 5.0 equiv), and pyrrolidine (21.0 μL,
0.25 mmol, 2.5 equiv) in DMSO (1.0 mL, 0.1 M) for 0.5 h followed by
neutral silica gel chromatography (hexane/ethyl acetate = 20/1): pale
yellow oil; Rf value 0.40 (hexane/ethyl acetate = 3/1); IR (NaCl, neat)
2-Azido-N-benzyl-N-(4-(2-diazoacetyl)phenyl)acetamide (2d,
CCDC No.1839203). A total of 21.5 mg of 2d (65%) as a pale yellow
oil was obtained from the reaction with diazide 1d (34.8 mg,
0.10 mmol), tosyl hydrazide (93.5 mg, 0.50 mmol, 5.0 equiv), and
pyrrolidine (21.0 μL, 0.25 mmol, 2.5 equiv) in DMSO (0.5 mL, 0.2 M)
for 0.5 h followed by neutral silica gel column chromatography
(hexane/ethyl acetate = 2/1). Solid 2d was obtained after storage in a
refrigerator. Recrystallization for X-ray analysis was performed with
hexane/ethyl acetate by the vapor diffusion method. Compound 2d:
pale yellow solid; Rf value 0.37 (hexane/ethyl acetate = 1/1); mp 65−
66 °C; IR (NaCl, neat) νmax 2105, 1671, 1602, 1361 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.74 (d, 2H, J = 8.0 Hz), 7.28−7.26 (m, 3H), 7.17
(dd, 2H, J = 4.0, 3.5 Hz), 7.06 (d, 2H, J = 7.5 Hz), 5.87 (s, 1H), 4.91
(s, 2H), 3.60 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 184.7, 166.9,
144.0, 136.6, 136.0, 128.9, 128.6, 128.5, 128.3, 127.9, 54.8, 53.3, 50.9;
LRMS (EI, M = C17H14N6O2) m/z 334 (18%, M+), 250 (21), 222 (27),
187 (28), 174 (62), 118 (71), 91 (100); HRMS (EI) calcd for
C17H14N6O2 (M+) 334.1178, found 334.1177.
1
νmax 2071, 1606, 1344, 1003 cm−1; H NMR (500 MHz, CDCl3)
δ 7.59−7.57 (m, 2H), 7.50−7.47 (m, 1H), 7.44−7.41 (m, 2H), 2.15
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 190.2, 137.6, 131.3, 128.5,
127.1, 29.7, 9.5; LRMS (EI, M = C9H8N2O) m/z 160 (16%, M+), 132
(24), 104 (100), 103 (78), 77 (59), 51 (32); HRMS (EI) calcd for
C9H8N2O (M+) 160.0637, found 160.0631.
4-(Benzyloxy)-1-diazobutan-2-one (4m). A total of 10.3 mg of 4m
(51%) was obtained from the reaction with azide 3m (21.8 mg,
0.10 mmol), tosyl hydrazide (93.5 mg, 0.50 mmol, 5.0 equiv), and
pyrrolidine (21.0 μL, 0.25 mmol, 2.5 equiv) in DMSO (1.0 mL, 0.1 M)
for 4 h followed by neutral silica gel chromatography (hexane/ethyl
acetate = 10/1): pale yellow oil; Rf value 0.60 (hexane/ethyl acetate =
1/1); IR (NaCl, neat) νmax 2866, 2104, 1637, 1369, 1322, 1097 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.36−7.27 (m, 5H), 5.36 (s, 1H), 4.52
(s, 2H), 3.76 (t, 2H, J = 6.5 Hz), 2.59 (br-s, 2H); 13C NMR (126 MHz,
CDCl3) δ 193.0, 137.9, 128.4, 127.68, 127.66, 73.2, 65.8, 55.1, 41.3;
HRMS (CI) calcd for C11H13N2O2 [M + H]+ 205.0977, found
205.0979.
2-Azido-N-benzyl-N-(3-(N-benzyl-2-diazoacetamido)phenyl)-
propanamide (2e). A total of 23.1 mg of 2e (51%) was obtained from
the reaction with diazide 1e (46.9 mg, 0.10 mmol), tosyl hydrazide
(93.5 mg, 0.50 mmol, 5.0 equiv), pyrrolidine (42.0 μL, 0.50 mmol,
5.0 equiv), and TBAF (0.36 mL, 0.36 mmol, 3.6 equiv) in DMSO
(0.5 mL, 0.2 M) for 1 h followed by neutral silica gel column
chromatography (hexane/ethyl acetate = 10/1 to 4/1) and GPC for
further purification: pale yellow oil; Rf value 0.67 (hexane/ethyl acetate
= 1/1); IR (NaCl, neat) νmax 2107, 1665, 1595, 1395, 702 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.36 (t, 1H, J = 7.5 Hz), 7.25−7.22
(m, 6H), 7.10−7.03 (m, 6H), 6.40 (s, 1H), 4.94−4.75 (m, 4H), 3.90
(s, 1H), 3.25 (q, 1H, J = 6.0 Hz), 1.29 (d, 3H, J = 6.0 Hz); 13C NMR
(126 MHz, CDCl3) δ 169.9, 165.3, 142.2, 141.2, 136.7, 136.1, 130.9,
129.4, 129.0, 128.6, 128.5, 128.0, 127.8, 127.7, 127.5, 54.1, 53.0, 52.4,
47.4, 16.3; HRMS (ESI) calcd for C25H23N7NaO2 [M + Na]+ 476.1811,
found 476.1804.
N-(4-Azidophenyl)-N-benzyl-2-diazoacetamide (2b). A total of
23.9 mg of 2b (82%) was obtained from the reaction with diazide 1b
(30.6 mg, 0.10 mmol), tosyl hydrazide (93.6 mg, 0.50 mmol, 5.0 equiv),
pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF (0.36 mL,
1.0 M in THF, 0.36 mmol, 3.6 equiv) in DMSO (0.5 mL, 0.2 M) for 1 h
followed by neutral silica gel chromatography (hexane/ethyl acetate =
15/1 to 10/1): pale yellow oil; Rf value 0.37 (hexane/ethyl acetate =
3/1); IR (NaCl, neat) νmax 2107, 1623, 1505, 1397, 1294, 1280 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.29−7.24 (m, 3H), 7.21−7.19
(m, 2H), 7.00−6.95 (m, 4H), 4.89 (s, 2H), 4.43 (s, 1H); 13C NMR
(126 MHz, CDCl3) δ 165.8, 139.9, 137.8, 137.2, 129.9, 128.6, 128.4,
127.5, 120.0, 52.8, 47.4; LRMS (EI, M = C15H12N6O) m/z 292
(3%, M+), 264 (52), 236 (27), 223 (24), 196 (18), 91 (100), 84 (19);
HRMS (EI) calcd for C15H12N6O (M+) 292.1073, found 292.1071.
N-(4-Azidophenyl)-N-(2-(3-azidopropoxy)benzyl)-2-diazoaceta-
mide (6a). A total of 30.6 mg of 6a (78%) was obtained from triazide 5a
(40.6 mg, 0.10 mmol), tosyl hydrazide (93.7 mg, 0.50 mmol, 5.0 equiv),
pyrrolidine (42.0 μL, 0.50 mmol, 5.0 equiv), and TBAF (0.36 mL,
0.36 mmol, 3.6 equiv) in DMSO (0.5 mL, 0.2 M) for 1 h followed by
neutral silica gel chromatography (hexane/ethyl acetate = 10/1 to 8/1
to 6/1): pale yellow oil; Rf value 0.77 (hexane/ethyl acetate = 1/1); IR
(NaCl, neat) νmax 2103, 1623, 1505, 1396, 1287, 1244 cm−1; 1H NMR
N-(3-(Azidomethyl)phenyl)-N-benzyl-2-diazoacetamide (2c).
A total of 27.1 mg of 2c (89%) was obtained from the reaction with
G
DOI: 10.1021/acs.joc.8b02074
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The Journal of Organic Chemistry
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(500 MHz, CDCl3) δ 7.26−7.25(m, 1H), 7.20 (ddd, 1H, J = 8.0, 8.0,
1.5 Hz), 7.02 (d, 2H, J = 8.5 Hz), 6.94 (d, 2H, J = 8.5 Hz), 6.89 (dd, 1H,
J = 7.5, 7.5 Hz), 6.78 (d, 1H, J = 8.0 Hz), 4.96 (s, 2H), 4.44 (s, 1H), 3.91
(t, 2H, J = 6.0 Hz), 3.38 (t, 2H, J = 7.0 Hz), 1.89 (tt, 2H, J = 7.5, 6.0 Hz);
13C NMR (126 MHz, CDCl3) δ 165.6, 156.3, 139.8, 138.2, 130.4,
129.8, 128.8, 125.2, 120.8, 119.8, 110.9, 64.2, 48.0, 47.4, 47.3, 28.7;
LRMS (EI, M = C18H17N9O2) m/z 391 (9%, M+), 363 (42), 335 (26),
162 (24), 134 (100), 105 (45); HRMS (EI) calcd for C18H17N9O2
(M+) 391.1505, found 391.1503.
Ethyl 5-((3-Azidopropyl)(phenyl)carbamoyl)-4,5-dihydro-1H-pyr-
azole-3-carboxylate (9). To a stirred solution of alkyl azido α-diazo
amido compound 2a (11.2 mg, 0.05 mmol) in acetonitrile/water
(2.5 mL, 0.02 M, 1/1) was added ethyl acrylate (27.5 μL, 0.25 mmol,
5.0 equiv), and the mixture was stirred at room temperature for 24 h.
After removal of solvent in vacuo, the resulting crude material was
purified by neutral silica gel column chromatography (hexane/ethyl
acetate = 3/1 to 2/1 to 1/1), and 13.5 mg of pyrazoline 9 (86%) was
obtained: pale yellow oil; Rf value 0.37 (hexane/ethyl acetate = 1/1); IR
(NaCl, neat) νmax 3323, 2096, 1700, 1660, 1258, 1119 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.49 (dd, 2H, J = 8.0, 7.5 Hz), 7.42 (dd, 1H, J =
7.0, 6.5 Hz), 7.20 (d, 2H, J = 7.5 Hz), 6.43 (s, 1H), 4.41 (dd, 1H, J = 7.5,
7.0 Hz), 4.25 (q, 2H, J = 7.5 Hz), 3.85 (ddd, 1H, J = 14.5, 7.5, 7.0 Hz),
3.74 (ddd, 1H, J = 14.0, 7.5, 7.0 Hz), 3.34 (dd, 2H, J = 7.0, 6.5 Hz), 3.08
(dd, 1H, J = 17.0, 7.5 Hz), 2.77 (dd, 1H, J = 17.0, 7.5 Hz), 1.82 (tt, 1H,
J = 7.5, 7.0 Hz), 1.31 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3)
δ 170.8, 162.1, 142.6, 140.5, 130.4, 128.9, 128.5, 61.3, 60.5, 49.1, 47.8,
36.5, 27.0, 14.2; LRMS (EI, M = C16H20N6O3) m/z 344 (3%, M+), 299
(19), 176 (25), 141 (87), 106 (48), 95 (100); HRMS (EI) calcd for
C16H20N6O3 (M+) 344.1597, found 344.1594.
2-Azido-N-(6-azidohexyl)-N-(3-(2-diazoacetyl)phenyl)acetamide
(6b). A total of 124.5 mg of 6b (51%) was obtained from the reaction
with triazide 5b (253.1 mg, 0.658 mmol), tosyl hydrazide (613.0 mg,
3.29 mmol, 5.0 equiv), and pyrrolidine (137.5 μL, 1.65 mmol,
2.5 equiv) in DMSO (6.6 mL, 0.1 M) for 15 min followed by neutral
silica gel column chromatography (hexane/ethyl acetate = 3/1 to 2/1):
pale yellow oil; Rf value 0.4 (hexane/ethyl acetate = 1/1); IR (NaCl,
neat) νmax 2105, 1670, 1578, 1362 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.72 (d, 1H, J = 7.5 Hz), 7.63 (s, 1H), 7.55 (dd, 1H, J = 7.0, 7.0 Hz),
7.35 (d, 1H, J = 8.0 Hz), 5.92 (s, 1H), 3.73 (t, 2H, J = 7.5 Hz), 3.54
(s, 2H), 3.24 (t, 2H, J = 6.5 Hz), 1.60−1.50 (m, 4H), 1.40−1.31 (m,
4H); 13C NMR (126 MHz, CDCl3) δ 184.5, 166.9, 141.3, 138.6, 132.0,
130.5, 126.7, 126.3, 55.0, 51.2, 50.9, 49.6, 28.7, 27.4, 26.3, 26.2; HRMS
(ESI) calcd for C16H19N9NaO2 [M + Na]+ 392.1559, found 392.1556.
Conjugation Reactions Using Azido Diazo Substrates.
2-Azido-N-(6-azidohexyl)-N-(3-(4,9-dioxo-4,9-dihydro-1H-
benzo[f ]indazole-3-carbonyl)phenyl)acetamide (10). To a stirred
solution of diazido diazo compound 6b (159.9 mg, 0.433 mmol) and
1,4-naphthoquinone (103.7 mg, 0.649 mmol, 1.5 equiv) in DMSO
(8.7 mL, 0.05 M) was added cesium carbonate (282.6 mg, 0.866 mmol,
2.0 equiv) at room temperature under open-air conditions. After 2 h,
the reaction was quenched with water, and the mixture was extracted
three times with dichloromethane. The combined organic layer was
washed three times with water and brine. The collected organic layer
was dried over sodium sulfate. Concentration and purification by silica
gel column chromatography (hexane/ethyl acetate = 2/1 to 1/1 to 1/1
+ 5% methanol) gave 185.4 mg of pyrazole 10 (82%): pale blown
amorphous solid; Rf value 0.2 (dichloromethane/methanol = 20/1); IR
(NaCl, neat) νmax 2934, 2105, 1681, 1582, 1331, 1255, 917 cm−1; 1H
NMR (500 MHz, CDCl3) δ 8.27−8.24 (m, 2H), 8.17 (d, 1H, J = 8.0
Hz), 7.88 (s, 1H), 7.85−7.79 (m, 2H), 7.65 (dd, 1H, J = 8.0, 7.5 Hz),
7.47 (d, 1H, J = 8.5 Hz), 3.76 (t, 2H, J = 7.5 Hz), 3.64 (s, 2H), 3.30
(t, 2H, J = 7.0 Hz), 1.58−1.53 (m, 4H), 1.38−1.34 (m, 4H); 13C NMR
(126 MHz, CDCl3) δ 185.6, 177.8, 176.0, 167.4, 140.5, 138.0, 135.2,
134.5, 133.9, 133.0, 132.4, 130.55, 130.50, 130.3, 127.9, 127.0, 121.2,
51.4, 51.2, 49.6, 28.7, 27.3, 26.4, 26.2; HRMS (ESI) calcd for
C26H23N9NaO4 [M + Na]+ 548.1771, found 548.1778.
N4-Butyl-N1-(3-(2-diazo-N-phenylacetamido)propyl)-2-
(diphenylphosphoryl)terephthalamide (8). To a stirred solution of
alkyl azido α-diazo amido compound 2a (11.2 mg, 0.05 mmol) in
THF/water (1.0 mL, 0.05 M, 10/1) was added phosphine reagent 7
(31.8 mg, 0.075 mmol, 1.5 equiv), and the mixture was stirred at room
temperature for 24 h. The resulting mixture was transferred to another
flask with ethyl acetate and was concentrated in vacuo. The obtained
crude material was purified by neutral silica gel column chromatog-
raphy (hexane/ethyl acetate = 1/1 to dichloromethane/methanol =
15/1) followed by GPC, and 20.0 mg of the ligation product 8 (70%)
was obtained: pale yellow amorphous solid; Rf value 0.17 (dichloro-
methane/methanol = 15/1); IR (NaCl, neat) νmax 3286, 3061, 2931,
1
2106, 1645, 1542, 1407 cm−1; H NMR (500 MHz, CDCl3) δ 8.32
(t, 1H, J = 6.0 Hz), 7.99 (d, 1H, J = 8.5 Hz), 7.87 (dd, 1H, J = 13.5,
1.0 Hz), 7.83 (dd, 1H, J = 8.0, 4.0 Hz), 7.65−7.61 (m, 4H), 7.53−7.50
(m, 2H), 7.44−7.38 (m, 6H), 7.35−7.32 (m, 1H), 7.13 (d, 2H, J =
7.0 Hz), 6.53 (br-s, 1H), 4.37 (s, 1H), 3.69 (t, 2H, J = 7.0 Hz), 3.34
(dd, 2H, J = 12.0, 7.0 Hz), 2.94 (dd, 2H, J = 13.0, 7.0 Hz), 1.50 (ddt, 2H,
J = 7.5, 7.5, 7.5 Hz), 1.42 (ddt, 2H, J = 7.0, 7.0, 7.0 Hz), 1.31 (qdd, 2H,
J = 7.5, 7.5, 7.5 Hz), 0.90 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz,
CDCl3) δ 166.8 (d, J = 3.1 Hz), 166.0, 165.6, 143.0 (d, J = 8.4 Hz),
141.1, 135.9 (d, J = 10.8 Hz), 132.4 (d, J = 10.8 Hz), 132.2 (d, J =
2.4 Hz), 131.9 (d, J = 10.8 Hz), 131.5, 130.8 (d, J = 2.4 Hz), 130.7, 130.4
(d, J = 8.4 Hz), 129.8, 128.55, 128.45, 128.32, 128.26, 47.3, 46.4, 39.8, 36.8,
31.4, 27.0, 20.0, 13.7; 31P NMR (202 MHz, benzene-d6) δ 32.9; HRMS
(ESI) calcd for C35H36N5NaO4P [M + Na]+ 644.2403, found 644.2403.
N-(6-Azidohexyl)-2-diazo-N-(3-(4,9-dioxo-4,9-dihydro-1H-
benzo[f ]indazole-3-carbonyl)phenyl)acetamide (11). To a solution
of diazide 10 (133.9 mg, 0.255 mmol), tosyl hydrazide (237.8 mg,
1.27 mmol, 5.0 equiv), and pyrrolidine (106 μL, 1.27 mmol, 5.0 equiv)
in DMSO (2.55 mL, 0.1 M) was added dropwise TBAF (1.53 mL,
1.0 M in THF, 1.53 mmol, 6.0 equiv) at 25 °C. After 4 h, the reaction
mixture was diluted with dichloromethane and water. The mixture was
extracted three times with dichloromethane, and the organic layer was
washed twice with water. The collected organic layer was dried over
H
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The Journal of Organic Chemistry
Article
sodium sulfate. Concentration and purification by neutral silica gel
column chromatography (dichloromethane to dichloromethane/
methanol = 20/1) followed by GPC gave 97.2 mg of 11 (75%): pale
blown amorphous solid; Rf value 0.47 (dichloromethane/methanol =
20/1); IR (NaCl, neat) νmax 2934, 2860, 2106, 1682, 1578, 1407 cm−1;
1H NMR (500 MHz, CDCl3) δ 8.27−8.25 (m, 1H), 8.22−8.21
(m, 1H), 8.12 (d, 1H, J = 8.0 Hz), 7.86 (s, 1H), 7.84−7.78 (m, 2H),
7.61 (dd, 1H, J = 8.0, 7.5 Hz), 7.49 (d, 1H, J = 8.0 Hz), 4.50−4.48
(m, 1H), 3.78 (t, 2H, J = 7.0 Hz), 3.29−3.26 (m, 2H), 1.57−1.51
(m, 4H), 1.39−1.30 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 185.9,
178.0, 176.0, 166.0, 141.5, 137.8, 135.0, 134.4, 133.9, 133.4, 132.5,
130.8, 130.2, 129.6, 127.7, 127.1, 121.1, 51.4, 49.1, 48.0, 28.7, 27.9,
26.4, 26.2; HRMS (ESI) calcd for C26H22N8NaO4 [M + Na]+ 533.1662,
found 533.1653.
next step without further purification. (Beware of residual dichloro-
methane; see also the caution statement above.)
The following is reaction 2: to a stirred solution of crude bromo-
acetamide in DMSO was added sodium azide at ambient temperature.
After completion of the reaction (reaction time noted in each
compound section), the reaction was quenched with water, and the
mixture was extracted three times with ether. The organic layer was
washed with water and brine, and the combined organic layer was dried
over sodium sulfate. Concentration and purification by silica gel column
chromatography gave α-azido acetamide.
N-(3-Bromopropyl)aniline (1a-1). A stirred solution of aniline
(0.455 mL, 5.0 mmol) and 1,3-dibromopropane (3.05 mL, 30.0 mmol,
6.0 equiv) in acetonitrile (10 mL, 0.5 M) was heated up to reflux for 3 h.
After the mixture cooled to room temperature, the reaction mixture was
diluted with water and was extracted three times with ether. The combined
organic layer was dried over magnesium sulfate. Concentration and
purification by silica gel column chromatography (hexane with 5% ether to
hexane/ethyl acetate = 5/1) gave 1a-1 (386 mg, 1.80 mmol, 36%): colorless
oil; Rf value 0.5 (hexane/ethyl acetate = 5/1); IR (NaCl, neat) νmax 3404,
1603, 1506, 1255 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.20 (m, 2H), 6.73
(tt, 1H, J = 7.5, 1.0 Hz), 6.65 (m, 2H), 3.52 (t, 2H, J = 6.5 Hz), 3.35 (t, 2H,
J = 6.0 Hz), 2.16 (tt, 2H, J = 6.5, 6.0 Hz); 13C NMR (126 MHz, CDCl3)
δ 147.6, 129.3, 117.7, 112.9, 42.0, 31.9, 31.2; LRMS (EI, M = C9H12BrN)
m/z 215 (1.2%, M+ of 81Br), 213 (1.4, M+ of 79Br), 106 (100), 77 (15);
HRMS (EI) calcd for C9H1281BrN (M+) 215.0133, found 215.0123.
Ethyl 5-((6-(8,9-Dihydro-1H-dibenzo[3,4:7,8]cycloocta[1,2-d]-
[1,2,3]triazol-1-yl)hexyl)(3-(4,9-dioxo-4,9-dihydro-1H-benzo[f ]-
indazole-3-carbonyl)phenyl)carbamoyl)-4,5-dihydro-1H-pyrazole-
3-carboxylate (12). To a stirred solution of diazo azide 11 (55.6 mg,
0.109 mmol) in acetonitrile/water (5.5 mL, 1/1, 0.02 M) was added
ethyl acrylate (59.5 μL, 0.545 mmol, 5.0 equiv) at room temperature.
After 26 h, the wet organic solvent was removed under reduced
pressure. Then, the resulting crude material was dissolved in
acetonitrile (2.2 mL, 0.05 M). To a stirred acetonitrile solution was
added dibenzocyclooctyne (5,6-dihydro-11,12-didehydrodibenzo[a,e]-
cyclooctyne, 33.3 mg, 0.163 mmol, 1.5 equiv based on 11)33 at room
temperature. After 24 h, the organic solvent was removed under
reduced pressure to obtain crude material, which was purified by neutral
silica gel column chromatography (hexane/ethyl acetate = 1/1 to
dichloromethane to dichloromethane/methanol = 20/1) followed by
GPC to afford 58.9 mg of 12 (66%): pale yellow amorphous solid; Rf
value 0.23 (dichloromethane/methanol = 20/1); IR (NaCl, neat) νmax
3330, 3065, 2933, 2860, 1682, 1581, 1454, 1434, 1334, 1221 cm−1; 1H
NMR (500 MHz, CDCl3) δ 8.24 (d, 1H, J = 7.5 Hz), 8.19−8.15
(m, 2H), 7.91 (s, 1H), 7.78 (dd, 1H, J = 7.5 Hz), 7.73 (dd, 1H, J =
7.5 Hz), 7.65 (dd, 1H, J = 8.0 Hz), 7.62−7.57 (m, 1H), 7.33−7.30
(m, 2H), 7.23−7.12 (m, 6H), 4.43−4.41 (m, 2H), 4.27−4.24 (m, 1H),
4.19 (q, 2H, J = 7.5 Hz), 3.38−3.35 (m, 1H), 3.26−3.17 (m, 1H), 3.08
(dd, 2H, J = 11.0 Hz), 2.95−2.86 (m, 2H), 1.86 (br-s, 1H), 1.70
(m, 1H), 1.54−1.45 (m, 2H), 1.31−1.18 (m, 9H); 13C NMR
(126 MHz, CDCl3) δ 185.7, 177.9, 175.9, 170.4, 162.1, 146.4, 142.3,
141.5, 140.44, 140.40, 138.6, 137.57, 137.55, 134.8, 134.6, 134.07, and
134.04 (conformers), 133.6, 133.02, 132.99, 132.41, 131.84, 131.80,
130.8, 130.6, 130.2, 129.8, 129.36, 129.31, 128.8, 128.1, 127.8, 126.8,
126.5, 126.1, 121.5, 61.3, 60.8, and 60.7 (conformers), 50.1, 50.0, 48.1,
36.5, 32.8, 29.3, and 29.2 (conformers), 26.99 and 26.96 (conformers),
25.7, 25.61, and 25.55 (conformers), 14.13; HRMS (ESI) calcd for
C47H42N8NaO6 [M + Na]+ 837.3125, found 837.3107.
2-Azido-N-(3-azidopropyl)-N-phenylacetamide (1a). According
to the general procedure, 390 mg of 1a (91% from amine for 2 steps)
was obtained from the reactions with (1) 1a-1 (352 mg, 1.65 mmol,
1.0 equiv), bromoacetyl bromide (0.165 mL, 1.88 mmol, 1.14 equiv),
which dissolved in dichloromethane (6 mL), and dichloromethane
solvent (14 mL, 0.12 M); (2) crude bromoacetamide (574 mg), sodium
azide (375 mg, 5.76 mmol, 3.5 equiv), and DMSO (8.3 mL, 0.2 M) for
1 h followed by silica gel column chromatography (hexane/ethyl acetate =
4/1 to 2/1): pale yellow oil; Rf value 0.5 (hexane/ethyl acetate = 2/1); IR
(NaCl, neat) νmax 2935, 2104, 1670, 1493, 1406, 1261 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.48−7.40 (m, 3H), 7.18−7.16 (m, 2H), 3.81
(t, 2H, J = 7.5 Hz), 3.57 (s, 2H), 3.37 (t, 2H, J = 7.0 Hz), 1.85 (tt, 2H,
J = 7.5, 7.0 Hz); 13C NMR (126 MHz, CDCl3) δ 167.4, 140.4, 130.3,
128.9, 127.8, 50.8, 49.0, 47.3, 27.1; HRMS (CI) calcd for C11H14N7O
[M + H]+ 260.1260, found 260.1264.
2-Azido-N-methyl-N-phenylacetamide (3a). Following the general
procedure, 916 mg of 3a (97% from amine for 2 steps) was obtained from
the reactions with (1) N-methyl aniline (0.54 mL, 5.0 mmol, 1.0 equiv),
bromoacetyl bromide (0.50 mL, 5.7 mmol, 1.14 equiv) dissolved in
dichloromethane (20 mL), and dichloromethane solvent (40 mL, 0.13 M);
(2) crude bromoacetamide (1.230 g), sodium azide (810.3 mg, 12.5 mmol,
2.5 equiv), and DMSO (25 mL, 0.2 M) for 20 min followed by silica gel
column chromatography (hexane/ethyl acetate = 3/1 to 2/1): pale yellow
oil; Rf value 0.67 (hexane/ethyl acetate = 1/1); IR (NaCl, neat) νmax 2924,
Preparation of Substrates. General Procedure of the Synthesis
of Azido Acetamides from Amines. The following is reaction 1: in a
two-neck flask, amine was dissolved in dichloromethane under a
nitrogen atmosphere and the solution was cooled to 0 °C. Then, a solu-
tion of bromoacetyl bromide or 2-bromopropionyl bromide in
dichloromethane was added slowly to the reaction mixture, in which
precipitate was formed immediately. The reaction mixture was warmed
to room temperature and was stirred for 1 h. The reaction was
quenched with a saturated aqueous sodium bicarbonate solution, and
the mixture was washed with saturated aqueous sodium bicarbonate.
The organic layer was dried over sodium sulfate. Concentration in
vacuo gave the crude bromoacetamide product, which was used in the
1
2106, 1668, 1595, 1495, 1390, 1267, 1124 cm−1; H NMR (500 MHz,
CDCl3) δ 7.44 (dd, 2H, J = 7.5, 7.5 Hz), 7.38 (t, 1H, J = 7.5 Hz), 7.19
(d, 2H, J = 7.5 Hz), 3.61 (s, 2H), 3.31 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 167.3, 142.1, 130.2, 128.6, 127.0, 50.6, 37.5; LRMS (EI, M =
C9H10N4O) m/z 190 (1.1%, M+), 162 (29), 134 (100), 105 (83), 77 (64);
HRMS (EI) calcd for C9H10N4O (M+) 190.0855, found 190.0858.
I
DOI: 10.1021/acs.joc.8b02074
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The Journal of Organic Chemistry
Article
2-Azido-N-benzyl-N-phenylacetamide (3b). Following the general
procedure, 1.30 g of 3b (98% from amine for 2 steps) was obtained from
the reactions with (1) N-benzylaniline (916 mg, 5.0 mmol, 1.0 equiv),
bromoacetyl bromide (0.50 mL, 5.7 mmol, 1.14 equiv) dissolved in
dichloromethane (20 mL), and dichloromethane solvent (40 mL,
0.13 M); (2) crude bromoacetamide (1.5380 g), sodium azide
(817.5 mg, 12.6 mmol, 2.5 equiv), and DMSO (25 mL, 0.2 M) for
20 min followed by silica gel column chromatography (hexane/ethyl
acetate = 5/1 to 3/1): pale yellow oil; Rf value 0.2 (hexane/ethyl acetate
= 5/1); IR (NaCl, neat) νmax 2104, 1670, 1496, 1399, 1260 cm−1; 1H
NMR (500 MHz, CDCl3) δ 7.35−7.33 (m, 3H), 7.29−7.26 (m, 3H),
7.20−7.18 (m, 2H), 6.97−6.95 (m, 2H), 4.90 (s, 2H), 3.59 (s, 2H); 13C
NMR (126 MHz, CDCl3) δ 167.2 140.2, 136.5, 129.9, 129.0, 128.8,
128.5, 128.2, 127.7, 53.4, 50.8; LRMS (EI, M = C15H14N4O) m/z 266
(8%, M+), 182 (53), 119 (58), 91 (100), 77 (45); HRMS (EI) calcd for
C15H14N4O (M+) 266.1168, found 266.1162.
(100); HRMS (EI) calcd for C16H1679BrNO2 (M+) 333.0364, found
333.0368.
2-Azido-N-benzyl-N-(3-(hydroxymethyl)phenyl)acetamide (3e).
To a stirred solution of bromide 1c-1 (790.6 mg, 2.4 mmol) in
DMSO (12 mL, 0.2 M) at ambient temperature was added sodium
azide (308 mg, 4.73 mmol, 2.0 equiv). After 0.5 h, the resulting mixture
was poured into water, and the mixture was extracted three times with
ether. The organic layer was washed with water and brine. The
combined organic layer was dried over sodium sulfate. Concentration
and purification by silica gel column chromatography (33% to 50%
ethyl acetate in hexane) gave 700 mg of 3e (99%): colorless oil; Rf value
0.17 (hexane/ethyl acetate = 2/1); IR (NaCl, neat) νmax 2926, 2870,
2104, 1662, 1404, 1265 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.34−
7.32 (m, 2H), 7.30−7.26 (m, 3H), 7.18 (d, 1H, J = 7.5 Hz), 7.18 (d, 1H,
J = 6.5 Hz), 7.01 (s, 1H), 6.85−6.83 (m, 1H), 4.89 (s, 2H), 4.67 (d, 2H,
J = 6.0 Hz), 3.60 (s, 2H), 1.94 (br, 1H); 13C NMR (126 MHz, CDCl3)
δ 167.2, 143.2, 140.4, 136.5, 130.0, 129.0, 128.5, 127.7, 127.2, 127.0,
126.2, 64.2, 53.4, 50.8; LRMS (EI, M = C16H16N4O2) m/z 296 (M+,
1%), 268 (3), 238 (6), 136 (10), 118 (12), 91 (100); HRMS (EI) calcd
for C16H16N4O2 (M+) 296.1273, found 296.1271.
2-Azido-N,N-dibenzylacetamide (3c). Following the general
procedure, 1.38 g of 3c (99% from amine for 2 steps) was obtained
from the reactions with (1) N,N-dibenzyl amine (0.96 mL, 5.0 mmol,
1.0 equiv), bromoacetyl bromide (0.495 mL, 5.7 mmol, 1.14 equiv)
dissolved in dichloromethane (20 mL), and dichloromethane solvent
(40 mL, 0.13 M); (2) crude bromoacetamide (1.666 g), sodium azide
(812 mg, 12.5 mmol, 2.5 equiv), and DMSO (25 mL, 0.2 M) for 20 min
followed by silica gel column chromatography (hexane/ethyl acetate =
5/1 to 2/1): colorless oil; Rf value 0.8 (hexane/ethyl acetate = 1/1); IR
(NaCl, neat) νmax 2104, 1658, 1450, 1213 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.40−7.29 (m, 6H), 7.26−7.24 (m, 2H), 7.34 (d, 2H, J =
7.0 Hz), 4.65 (s, 2H), 4.37 (s, 2H), 3.98 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 167.9, 136.4, 135.4, 129.2, 128.7, 128.5, 128.0, 127.8, 126.2,
50.6, 49.3, 48.9; LRMS (EI, M = C16H16N4O) m/z 280 (1.8%, M+), 196
(51), 91 (100); HRMS (EI) calcd for C16H16N4O (M+) 280.1324,
found 280.1306.
2-Azido-N-benzyl-N-(3-((methoxymethoxy)methyl)phenyl)-
acetamide (3d). To a stirred solution of alcohol 3e (479 mg,
1.61 mmol) and tetrabutyl ammonium iodide (119 mg, 0.323 mmol,
0.2 equiv) in dichloromethane (16 mL, 0.1 M) were added
N,N-diisopropylethylamine (1.13 mL, 6.46 mmol, 4.0 equiv) and
chloromethyl methyl ether (0.365 mL, 4.84 mmol, 3.0 equiv) at 0 °C.
After the mixture stirred at room temperature for 3 h, the resulting
mixture was quenched by a saturated aqueous ammonium chlo-
ride solution. The organic components were extracted twice with
dichloromethane and were washed with water and brine. The combined
organic layer was dried over sodium sulfate. Concentration and
purification by silica gel column chromatography (25% to 33% to 50%
ethyl acetate in hexane) gave 449 mg of 3d (82%): colorless oil; Rf value
0.43 (hexane/ethyl acetate = 2/1); IR (NaCl, neat) νmax 2932, 2886,
2105, 1671, 1046 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.32 (d, 2H, J =
5.0 Hz), 7.29−7.23 (m, 3H), 7.20−7.18 (m, 2H), 6.98 (s, 1H), 6.58
(m, 1H), 4.89 (s, 2H), 4.66 (s, 2H), 4.53 (s, 2H), 3.60 (s, 2H), 3.37
(s, 3H); 13C NMR (126 MHz, CDCl3) δ 167.1, 140.3, 136.5, 129.8,
129.0, 128.4, 127.8, 127.6, 127.3, 127.1, 95.8, 68.1, 55.4, 53.3, 50.8;
LRMS (EI, M = C18H20N4O3) m/z 340 (M+, 0.2%), 312 (2), 250 (15),
91 (100); HRMS (EI) calcd for C18H20N4O3 (M+) 340.1535, found
340.1528.
N-Benzyl-2-bromo-N-(3-(hydroxymethyl)phenyl)acetamide (1c-1).
To a stirred solution of 3-aminobenzyl alcohol (616 mg, 5.0 mmol) in
ethanol (8.3 mL, 0.6 M) was added benzaldehyde (0.61 mL, 5.0 mmol,
1.2 equiv) at room temperature. After 2 h, the mixture was cooled
to 0 °C, and then sodium borohydride (632 mg, 15.0 mmol, 3.0 equiv)
was added carefully. After the mixture stirred at room temperature
for 12 h, the resulting mixture was poured into a saturated aqueous
sodium bicarbonate solution. The organic components were extracted
three times with ethyl acetate and were washed with brine.
The combined organic layer was dried over sodium sulfate. Concen-
tration in vacuo gave (3-(benzylamino)phenyl)methanol (1.14 g) as a
crude material, which was submitted to the next step without
purification.
To a solution of the crude amine (1.14 g) in dichloromethane
(40 mL, 0.13 M) was added bromoacetyl bromide (0.49 mL, 5.7 mmol,
1.14 equiv) dissolved in dichloromethane (20 mL) at 0 °C. After the
mixture stirred at room temperature for 1 h, the reaction was quenched
with a saturated aqueous sodium bicarbonate solution at 0 °C. The
resulting mixture was washed with a saturated aqueous sodium
bicarbonate solution and was dried over sodium sulfate. Concentration
and purification by silica gel column chromatography (hexane/ethyl
acetate = 8/1 to 5/1 to 3/1 to 2/1 to 1/1) gave 522 mg of 1c-1 (31%
from amine for 2 steps): colorless oil; Rf value 0.40 (hexane/ethyl
acetate = 1/1); IR (NaCl, neat) νmax 3410, 1656, 1439, 1401, 700 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.35−7.31 (m, 2H), 7.29−7.24
(m, 3H), 7.19−7.18 (m, 2H), 7.10 (s, 1H), 6.95 (d, 1H, J = 7.0 Hz),
4.88 (s, 2H), 4.67 (s, 2H), 3.67 (s, 2H); 13C NMR (126 MHz, CDCl3)
δ 166.4, 143.0, 141.3, 136.5, 129.8, 128.8, 128.5, 127.6, 127.2, 126.9,
126.2, 64.2, 53.6, 27.4; LRMS (EI, M = C16H16BrNO2) m/z 335 (0.8%,
M+ of 81Br), 333 (0.8, M+ of 79Br), 254 (61), 236 (51), 132 (40), 91
2-Azido-N-benzyl-N-phenylacetamide (1e-1).34 To a stirred
solution of 1,3-phenylenediamine (1.08 g, 10 mmol) in ethanol
(16.7 mL, 0.6 M) was added benzaldehyde (3.1 mL, 30 mmol,
3.0 equiv), and the mixture was stirred at room temperature for 0.5 h
with a covered flask to protect from light. Then, the mixture was cooled
to 0 °C, and sodium borohydride (1.69 g, 40 mmol, 4.0 equiv) was
added carefully. After the mixture stirred at room temperature for 12 h,
the resulting mixture was poured into a saturated aqueous sodium
bicarbonate solution. The organic components were extracted three
times with ethyl acetate and were washed with brine. The combined
organic layer was dried over magnesium sulfate. Concentration and
purification by silica gel column chromatography (hexane/ethyl acetate
= 6/1) gave 2.75 g of N,N′-dibenzylamine 1e-1 (95%). This compound
was soon submitted to the next step without collecting analytical
data.
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138.0, 136.5, 135.4, 129.0, 128.5, 128.3, 127.7, 127.6, 115.6, 53.3, 50.8;
LRMS (EI, M = C17H16N4O) m/z 292 (M+, 4%), 208 (10), 145 (11),
118 (12), 91 (100); HRMS (EI) calcd for C17H16N4O (M+) 292.1324,
found 292.1324.
2-Azido-N-benzyl-N-(3-(benzylamino)phenyl)acetamide (3f).
To a stirred solution of diamine 1e-1 (787 mg, 2.73 mmol) in
dichloromethane (23 mL) was added bromoacetyl bromide (0.28 mL,
2.87 mmol, 1.05 equiv) dissolved in dichloromethane (10 mL) at 0 °C.
After the mixture stirred at room temperature for 1 h, the reaction was
quenched with a saturated aqueous sodium bicarbonate solution and
was dried over sodium sulfate. Concentration in vacuo gave
bromoacetamide (1.09 g) as a crude material, which was submitted
to the next step without purification.
To a stirred solution of the bromide (1.09 g) in DMSO (14 mL,
0.2 M) was added sodium azide (354 mg, 5.46 mmol, 2.0 equiv) at
room temperature. After 1 h, the reaction was quenched with water, and
the organic components were extracted three times with ether. The
organic layer was washed with water and brine. The combined organic
layer was then dried over sodium sulfate. Concentration and
purification by silica gel column chromatography (14% to 20% to
25% to 33% ethyl acetate in hexane) gave 429 mg of 3f (42%): white
solid; Rf value 0.43 (hexane/ethyl acetate = 2/1); mp 73.6−74.3 °C; IR
(NaCl, neat) νmax 3373, 3033, 2103, 1661, 1602, 1494 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.38−7.34 (m, 2H), 7.31−7.28 (m, 3H), 7.27−
7.24 (m, 3H), 7.19 (dd, 2H, J = 7.5, 6.5 Hz), 7.09 (dd, 2H, J = 8.0,
8.0 Hz), 6.58 (dd, 1H, J = 8.0, 2.0 Hz), 6.26 (dd, 1H, J = 7.5, 1.0 Hz),
6.10 (dd, 1H, J = 2.5, 1.5 Hz), 4.82 (s, 2H), 4.22 (s, 3H), 3.57 (s, 2H);
13C NMR (126 MHz, CDCl3) δ 167.3, 149.1, 141.3, 138.4, 136.9,
130.4, 129.0, 128.7, 128.4, 127.53, 127.50, 127.3, 116.5, 113.3, 111.7,
53.2, 50.7, 47.9; LRMS (EI, M = C22H21N5O) m/z 371 (M+, 2%), 343
(88), 252 (37), 91 (100); HRMS (EI) calcd for C22H21N5O (M+)
371.1746, found 371.1751.
N-Methyl-2-oxo-N,2-diphenylacetamide (3h-1).35 To a stirred
solution of benzoylformic acid (750 mg, 5.0 mmol) in dichloromethane
(5 mL, 1 M) were added a catalytic amount of DMF (1 drop) and oxalyl
chloride (0.475 mL, 5.5 mmol, 1.1 equiv) at room temperature. The
reaction mixture was stirred at room temperature until generation of gas
was stopped (1.5 h). Then, the reaction mixture was cooled to 0 °C.
To the cooled mixture were added N-methyl aniline (0.81 mL,
7.5 mmol, 1.5 equiv) and triethylamine (1.75 mL, 12.5 mmol,
2.5 equiv). Then, the mixture was stirred at room temperature for
1 h. The reaction was quenched with water, and the mixture was
extracted three times with ethyl acetate. The combined organic layer
was washed with brine and was dried over magnesium sulfate.
Concentration and purification by silica gel column chromatography
(hexane/ethyl acetate = 3/1 to 1/1) gave 1.195 g of 3h-1 (100%): white
solid; Rf value 0.63 (hexane/ethyl acetate = 1/1); mp 61−62 °C; IR
(NaCl, neat) νmax 1680, 1651, 1595, 1495, 1234 cm−1; 1H NMR
(500 MHz, CDCl3, major rotamer listed as similar to the referred
referred) δ 7.85 (m, 2H), 7.57 (m, 1H), 7.46−7.42 (m, 2H), 7.25−7.20
(m, 3H), 7.14−7.13 (m, 2H), 3.49 (s, 3H); 13C NMR (126 MHz,
CDCl3, major rotamer listed as the referred report) δ 190.8, 167.0,
141.1, 134.2, 133.4, 129.5, 129.4, 128.7, 128.1, 126.7, 36.2; LRMS
(EI, M = C15H13NO2) m/z 239 (26%, M+), 134 (51), 105 (100), 77
(46); HRMS (EI) calcd for C15H13NO2 (M+) 239.0946, found 239.0968.
2-Azido-N-benzyl-N-(4-vinylphenyl)acetamide (3g). To a stirred
solution of 4-vinyl aniline (0.58 mL, 4.95 mmol) in ethanol (8.3 mL,
0.6 M) was added benzaldehyde (0.76 mL, 7.50 mmol, 1.5 equiv), and
the mixture was stirred at room temperature for 1 h. Then, the mixture
was cooled down to 0 °C, and sodium borohydride (631 mg,
15.0 mmol, 3.0 equiv) was added carefully. After the mixture stirred at
room temperature for 12 h, the resulting mixture was poured into a
saturated aqueous sodium bicarbonate solution. The organic
components were extracted twice with ethyl acetate and were washed
with brine. The combined organic layer was dried over magnesium
sulfate. Concentration in vacuo gave benzylamine (1.27 g) as a crude
material, which was submitted to the next step without purification.
To a stirred solution of N-benzyl-4-vinylaniline (1.27 g) in
dichloromethane (40 mL) was added bromoacetyl bromide
(0.49 mL, 5.64 mmol, 1.14 equiv) dissolved in dichloromethane
(20 mL) at 0 °C. After the mixture stirred at room temperature for 1 h,
the reaction was quenched with a saturated aqueous sodium
bicarbonate solution and was dried over sodium sulfate. Concentration
in vacuo gave bromoacetamide (1.66 g) as a crude material, which was
submitted to the next step without purification.
To a stirred solution of the bromide (1.66 g) in DMSO (25 mL,
0.2 M) was added sodium azide (646 mg, 9.90 mmol, 2.0 equiv) at
room temperature. After 1 h, the reaction was quenched with water, and
the organic components were extracted three times with ether. The
organic layer was washed with water and brine. The combined organic
layer was then dried over sodium sulfate. Concentration and
purification by silica gel column chromatography (11% to 14% to
25% ethyl acetate in hexane) gave 551 mg of 3g (38% for 3 steps): pale
yellow oil; Rf value 0.47 (hexane/ethyl acetate = 3/1); IR (NaCl, neat)
νmax 2103, 1669, 1508, 1397 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37
(d, 2H, J = 8.5 Hz), 7.29−7.26 (m, 3H), 7.19 (d, 1H, J = 7.5 Hz), 7.19
(d, 1H, J = 6.0 Hz), 6.91 (d, 2H, J = 8.5 Hz), 6.67 (dd, 1H, J = 18.0,
11.0 Hz), 5.75 (d, 1H, J = 18.0 Hz), 5.32 (d, 1H, J = 11.0 Hz), 4.89
(s, 2H), 3.61 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 167.2, 139.5,
2-Azido-N-methyl-N,2-diphenylacetamide (3h).35 To an ice-
cooled stirred solution of 3h-1 (1.13 g, 4.70 mmol) in ethanol and
dichloromethane (11.5 mL, 2/1, 0.4 M) was added sodium
borohydride (242 mg, 6.39 mmol, 1.36 equiv), and the reaction
mixture was stirred at room temperature. After 1 h, the reaction was
quenched by the careful addition of a saturated aqueous ammonium
chloride solution, and the mixture was extracted three times with ethyl
acetate. The combined organic extract was washed with brine and was
dried over magnesium sulfate. Removal of organic solvents gave the
crude material, which was used for the next step without further
purification.
To an ice-cooled stirred solution of the crude alcohol in
dichloromethane (4.7 mL, 1 M) were added triethylamine (1.94 mL,
13.8 mmol, 2.94 equiv) and methanesulfonyl chloride (0.462 mL,
5.97 mmol, 1.27 equiv, with slow addition), and the reaction mixture
was stirred at the same temperature. After 1 h, the reaction was
quenched with water, and organic materials were extracted three times
with ethyl acetate. The combined organic layer was washed with brine
and was dried over magnesium sulfate. Removal of organic solvents
afforded the crude mesylate compound, which was submitted to the
next step without further purification. (Beware of residual dichloro-
methane; see also the caution statement above.)
To an ice-cooled stirred solution of the crude mesylate material in
DMF (4.7 mL, 1 M) was added sodium azide (657 mg, 7.03 mmol,
1.5 equiv), and the mixture was stirred at room temperature. After 3 h,
the reaction was quenched with water, and the organic components
were extracted three times with ether. The combined extracts were
washed with water and brine. The combined organic layer was dried
over sodium sulfate. Concentration and purification by silica gel column
chromatography (hexane/ethyl acetate = 5/1) gave 1.01 g of 3h (80%
for 3 steps): white solid; Rf value 0.60 (hexane/ethyl acetate = 2/1); mp
81−82 °C; IR (NaCl, neat) νmax 2098, 1666, 1491, 1387, 1236 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.36−7.29 (m, 6H), 7.13−7.11
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(m, 2H), 6.90 (br-s, 2H), 4.61 (s, 1H), 3.30 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 168.8, 142.1, 134.2, 129.7, 129.0, 128.9, 128.5,
128.0, 127.6, 62.8, 37.8; HRMS (CI) calcd for C15H15N4O [M + H]+
267.1246, found 267.1262.
quenched with water, and the organic components were extracted three
times with ether. The combined organic layer was washed with water
and brine and was dried over sodium sulfate. Concentration and
purification by silica gel column chromatography (hexane/ethyl acetate
= 8/1) gave 1.05 g of 3k (87%): pale yellow solid; Rf value 0.40
(hexane/ethyl acetate = 5/1); mp 79 °C; IR (KBr, disc) νmax 2918,
2118, 1694, 1588, 1401, 1224, 1072, 1011, 815 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.78 (d, 2H, J = 9.0 Hz), 7.65 (d, 2H, J = 9.0 Hz),
4.53 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 192.3, 133.0, 132.4,
129.5, 129.4, 54.8; HRMS (CI) calcd for C8H779BrN3O [M + H]+
239.9772, found 239.9767.
Phenacyl Azide (3i). To a stirred solution of phenacyl bromide
(1.50 g, 7.54 mmol) in DMSO (38 mL, 0.2 M) at ambient temperature
was added sodium azide (1.20 g, 18.8 mmol, 2.5 equiv). After 15 min,
the resulting mixture was poured into water with ice and the mixture
was extracted twice with ether. The organic layer was washed with water
and brine. The combined organic layer was dried over sodium sulfate.
Concentration and purification by silica gel column chromatography
(hexane/ethyl acetate = 5/1) gave 1.14 g of 3i (94%): pale yellow oil; Rf
value 0.53 (hexane/ethyl acetate = 3/1); IR (NaCl, neat) νmax 2104,
1697, 1218 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.91 (dd, 2H, J = 8.0,
1.5 Hz), 7.65−7.62 (m, 1H), 7.50 (dd, 2H, J = 8.0, 8.0 Hz), 4.58
(s, 2H); 13C NMR (126 MHz, CDCl3) δ 193.2, 134.2, 134.1, 129.0,
127.9, 54.8; HRMS (CI) calcd for C8H8N3O [M + H]+ 162.0667,
found 162.0675.
2-Azido-1-phenylpropan-1-one (3l). To a stirred solution of
2-bromopropiophenone (0.76 mL, 5.0 mmol) in DMSO (25 mL,
0.2 M) at ambient temperature was added sodium azide (813 mg,
12.5 mmol, 2.5 equiv). After 0.5 h, the reaction was quenched with
water, and the organic components were extracted three times with
ether. The combined organic layer was washed with water and brine and
was dried over sodium sulfate. Concentration and purification by silica
gel column chromatography (hexane/ethyl acetate = 10/1) gave
757 mg of 3l (87%): pale yellow oil; Rf value 0.40 (hexane/ethyl acetate =
5/1); IR (NaCl, neat) νmax 2123, 2094, 1690, 1217, 964 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.96−7.94 (m, 2H), 7.62 (t, 1H, J = 7.5 Hz), 7.51
(dd, 2H, J = 7.5, 7.5 Hz), 4.72 (q, 1H, J = 7.0 Hz), 1.57 (t, 3H, J =
7.0 Hz); 13C NMR (126 MHz, CDCl3) δ 196.7, 134.2, 133.9, 128.9,
128.6, 58.3, 16.5; HRMS (CI) calcd for C9H10N3O [M + H]+ 176.0824,
found 176.0829.
2-Bromo-1-(4-methoxyphenyl)ethan-1-one (3j-1).36 To a stirred
solution of 4′-methoxyacetophenone (750.7 mg, 5.0 mmol) in
1,4-dioxane (8.2 mL, 0.6 M) was added bromine (0.28 mL,
5.45 mmol, 1.09 equiv) dissolved in ether (6.6 mL), and the mixture
was heated up to 40 °C. After 2 h, the resulting mixture was cooled to
room temperature and was washed five times with water. Then, the
organic layer was dried over sodium sulfate. Concentration to obtain
the crude solid material, which was recrystallized from ether, gave
329 mg of 3j-1 (29%): colorless crystal; Rf value 0.50 (hexane/ethyl
acetate = 2/1); mp 70−71 °C; IR (NaCl, neat) νmax 1686, 1600, 1261,
1206, 1170, 1022 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.97 (d, 2H, J =
8.5 Hz), 6.96 (d, 2H, J = 8.5 Hz), 4.40 (s, 2H), 3.89 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 190.0, 164.1, 131.4, 126.9, 114.0, 55.6, 30.7;
LRMS (EI, M = C9H9BrO2) m/z 230 (46%, M+ for 81Br), 228 (46, M+
for 79Br), 135 (100); HRMS (EI) calcd for C9H981BrO2 (M+)
229.9765, found 229.9767.
2-(2-(Benzyloxy)ethyl)oxirane (3m-1). To a stirred solution of
D-aspartic acid (1.33 g, 10.0 mmol) in aqueous sulfuric acid (3.5 mL of
conc sulfuric acid, 66 mmol, 6.6 equiv, diluted with 27 mL of water) at
−5 °C was added potassium bromide (5.4 g, 45 mmol, 4.5 equiv)
followed by the slow addition of an aqueous solution of sodium nitrite
(1.2 g, 18 mmol, 1.8 equiv, dissolved in 2.4 mL of water). After 3 h at
0 °C, the brown mixture was extracted four times with ethyl acetate.
The combined organic layer was dried over magnesium sulfate. Con-
centration in vacuo gave the brominated product (1.70 g) as a white
solid. The compound was used without purification.
To a stirred solution of crude α-bromo carboxylic acid in THF
(23 mL) was slowly added borane−THF complex (0.92 M in THF,
28.1 mL, 25.9 mmol, 3.0 equiv) at 0 °C. The white solution formed was
stirred for 1 h at 0 °C, and then the cooling bath was removed to warm
up to room temperature. After 2 h, the mixture was cooled again to 0 °C,
and potassium carbonate (2.59 g) dissolved in water (10 mL) was
slowly added. The suspension was stirred for 10 min at room tem-
perature, and then the mixture was filtered through Celite; the
precipitate was rinsed twice with diethyl ether. The obtained organic
filtrate was washed with brine and was dried over magnesium sulfate.
Concentration gave the crude bromohydrin product (1.17 g) as a pale
yellow oil. The material was submitted to the next step without further
purification.38
To suspension of sodium hydride (60% in material oil, 500 mg,
20.8 mmol, 3.0 equiv) in THF (10 mL) at −16 °C was added a solution
of crude bromohydrin in THF (10 mL) dropwise. After 30 min, benzyl
bromide (0.91 mL, 7.6 mmol, 1.1 equiv) and tetrabutylammonium
iodide (2.56 g, 6.93 mmol, 1.0 equiv) were successively added to the
reaction mixture at −10 °C, and the mixture was warmed up to room
temperature. After an additional 3 h, water (10 mL) followed by
saturated ammonium chloride aqueous solution (10 mL) was added
carefully to the reaction mixture. After 1 h, the organic materials were
extracted twice with ethyl acetate. The combined organic layer was
dried over magnesium sulfate. Concentration and purification by silica
gel column chromatography (hexane/ethyl acetate = 8/1 to 6/1) gave
692 mg of 3m-1 (39% for 3 steps). Although this is a chiral product,
optical rotation value was not measured because its chirality
2-Azido-1-(4-methoxyphenyl)ethan-1-one (3j). To a stirred
solution of 3j-1 (267 mg, 1.16 mmol) in DMSO (5.8 mL, 0.2 M) at
ambient temperature was added sodium azide (190 mg, 2.91 mmol,
2.5 equiv). After 20 min, the reaction was quenched with water, and the
organic components were extracted three times with ether. The
combined organic layer was washed with water and brine and was dried
over sodium sulfate. Concentration to obtain crude solid material,
which was recrystallized from hexane, gave 159 mg of 3j (71%): pale
yellow crystal; Rf value 0.60 (hexane/ethyl acetate = 1/1); mp 73 °C; IR
(NaCl, neat) νmax 2123, 1683, 1600, 1239, 1180, 1019, 945, 825 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.89 (d, 2H, J = 9.0 Hz), 6.96 (d, 2H, J =
9.0 Hz), 4.51 (s, 2H), 3.89 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 191.6, 164.2, 130.3, 127.3, 114.1, 55.6, 54.5; LRMS (EI, M =
C9H9N3O2) m/z 191 (2%, M+), 135 (100), 92 (34), 77 (35); HRMS
(EI) calcd for C9H9N3O2 (M+) 191.0695, found 191.0692.
2-Azido-1-(4-bromophenyl)ethan-1-one (3k).37 To a stirred
solution of 4-bromo phenacyl bromide (1.39 g, 5.0 mmol) in DMSO
(25 mL, 0.2 M) at ambient temperature was added sodium azide
(814 mg, 12.5 mmol, 2.5 equiv). After 10 min, the reaction was
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disappeared in next step. Compound 3m-1: colorless oil; Rf value 0.60
(hexane/ethyl acetate = 5/1); IR (NaCl, neat) νmax 2860, 2359, 1455,
1362, 1103, 833, 739, 698 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37−
7.33 (m, 4H), 7.32−7.27 (m, 1H), 4.53 (s, 2H), 3.67−3.60 (m, 2H),
3.08 (ddt, 1H, J = 6.0, 4.5, 3.0 Hz), 2.79 (dd, 1H, J = 5.0, 4.5 Hz), 2.53
(dd, 1H, J = 5.0, 3.0 Hz), 1.92 (m, 1H), 1.78 (ddt, 1H, J = 14.0, 6.0,
6.0 Hz); 13C NMR (126 MHz, CDCl3) δ 138.2, 128.4, 127.6, 73.1, 67.0,
50.1, 47.1, 32.9; HRMS (CI) calcd for C11H15O2 [M + H]+ 179.1072,
found 179.1076.
1H NMR (500 MHz, CDCl3) δ 7.68 (d, 2H, J = 8.5 Hz), 7.30−7.26
(m, 3H), 7.18−7.16 (m, 2H), 6.80 (d, 2H, J = 8.5 Hz), 4.86 (s, 2H),
3.65 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 166.2, 140.8, 139.0,
136.2, 130.1, 128.9, 128.6, 127.8, 94.3, 53.5, 26.9; LRMS (EI, M =
C15H13BrINO) m/z 431 (5%, M+ of 81Br), 429 (5, M+ of 79Br), 352 (2),
350 (100), 223 (26), 91 (77); HRMS (EI) calcd for C15H1379BrINO
(M+) 428.9225, found 428.9224.
2-Azido-N-(4-azidophenyl)-N-benzylacetamide (1b). To a stirred
solution of 1b-1 (215 mg, 0.50 mmol) in DMSO/water (3.3 mL, 5/1,
0.15 M) were added sodium azide (98.2 mg, 1.5 mmol, 3.0 equiv),
copper(I) iodide (19.8 mg, 0.1 mmol, 0.2 equiv), sodium L-ascorbate
(9.9 mg, 0.05 mmol, 0.1 equiv), and N,N′-dimethylethylenediamine
(16.1 μL, 0.15 mmol, 0.3 equiv) successively at room temperature. After
12 h, the resulting mixture was poured into water, and the organic
components were extracted three times with ether. The organic layer
was washed with brine followed by drying over sodium sulfate.
Concentration and purification by silica gel column chromatography
(hexane/ethyl acetate = 5/1 to 4/1) gave 138 mg of 1b (90%): pale
yellow oil; Rf value 0.57 (hexane/ethyl acetate = 3/1); IR (NaCl, neat)
νmax 2103, 1672, 1505, 1279, 1256 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.28−7.26 (m, 3H), 7.18−7.16 (m, 2H), 6.99 (d, 2H, J = 8.5 Hz), 6.92
(d, 2H, J = 8.5 Hz), 4.87 (s, 2H), 3.58 (s, 2H); 13C NMR (126 MHz,
CDCl3) δ 167.2, 140.7, 136.7, 136.3, 129.7, 129.1, 128.6, 127.8, 120.3,
53.4, 50.8; LRMS (EI, M = C15H13N7O) m/z 307 (7%, M+), 279 (58),
118 (28), 91 (100); HRMS (EI) calcd for C15H13N7O (M+) 307.1182,
found 307.1174.
1-Azido-4-(benzyloxy)butan-2-one (3m). To a stirred solution of
3m-1 (542 mg, 3.04 mmol) in methanol/water (10.9 mL, 8/1, 0.3 M)
were added ammonium chloride (326 mg, 6.08 mmol, 2.0 equiv) and
sodium azide (1.58 g, 24.3 mmol, 8.0 equiv) successively at room
temperature. Then the reaction mixture was warmed to 40 °C. After
10 h, the resulting mixture was cooled to room temperature and then
was diluted with water. The organic materials were extracted twice with
ether. The combined organic layer was dried over magnesium sulfate.
Concentration in vacuo gave crude azidohydrin (620 mg), which was
submitted to the next step without further purification.
To a solution of oxalyl chloride (0.29 mL, 3.36 mmol, 1.2 equiv) in
dichloromethane (1.7 mL) under a nitrogen atmosphere was added
DMSO (0.40 mL, 5.6 mmol, 2.0 equiv), and the obtained crude
material was dissolved in dichloromethane (7.6 mL, 0.4 M) dropwise at
−78 °C. After 20 min, triethylamine (1.95 mL, 14.0 mmol, 5.0 equiv)
was added slowly to the reaction mixture at the same temperature, and
the mixture was warmed up to room temperature. After 30 min, the
reaction mixture was diluted with dichloromethane and was washed
with saturated aqueous ammonium chloride solution and twice with
brine. The combined organic layer was dried over sodium sulfate.
Concentration and purification by silica gel column chromatography
(hexane/ethyl acetate = 4/1 to 2/1) gave 571 mg of 3m (86% for
2 steps): colorless oil; Rf value 0.33 (hexane/ethyl acetate = 3/1); IR
2-Azido-N-(3-(azidomethyl)phenyl)-N-benzylacetamide (1c).
To a stirred solution of 1c-1 (66.8 mg, 0.2 mmol) were added
4-toluenesulfonyl chloride (45.9 mg, 0.24 mmol, 1.2 equiv),
4-dimethylaminopyridine (3.2 mg, 0.02 mmol, 0.1 equiv) in dichloro-
methane (2.0 mL, 0.1 M), and triethylamine (37 μL, 0.26 mmol,
1.3 equiv) dropwise at 0 °C. After the mixture stirred at room
temperature for 4 h, the reaction was quenched with water at 0 °C. The
organic components were extracted twice with dichloromethane and
then were washed with water and brine. The combined organic layer
was dried over sodium sulfate. Concentration in vacuo gave crude
tosylate (61.8 mg), which was submitted to the next step without
purification. (Beware of residual dichloromethane; see also the caution
statement above.)
To a stirred solution of the crude tosylate (61.8 mg) in DMSO
(0.64 mL, 0.2 M) was added sodium azide (20.9 mg, 0.316 mmol,
2.5 equiv) at room temperature. After 1 h, the reaction was quenched
with water, and the organic components were extracted 3 times with
ether. The combined organic layer was washed with water and brine and
then was dried over sodium sulfate. Concentration and purification by
silica gel column chromatography (hexane/ethyl acetate = 8/1 to 4/1)
gave 41.4 mg of 1c (65% for 2 steps): pale yellow oil; Rf value 0.83
(hexane/ethyl acetate = 1/1); IR (NaCl, neat) νmax 2103, 1670, 1400,
1263, 1217, 707 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.37 (t, 1H, J =
8.0 Hz), 7.31−7.26 (m, 4H), 7.19−7.17 (m, 2H), 6.94−6.92 (m, 2H),
4.90 (s, 2H), 4.30 (s, 2H), 3.59 (s, 2H); 13C NMR (126 MHz, CDCl3)
δ 167.1, 140.8, 137.6, 136.3, 130.5, 129.1, 128.6, 128.5, 128.1, 127.83,
127.78, 53.9, 53.4, 50.9; HRMS (CI) calcd for C16H16N7O [M + H]+
322.1416, found 322.1413.
1
(NaCl, neat) νmax 2869, 2103, 1728, 1281, 1101, 740, 699 cm−1; H
NMR (500 MHz, CDCl3) δ 7.37−7.34 (m, 2H), 7.31−7.29 (m, 3H),
4.51 (s, 2H), 4.00 (s, 2H), 3.76 (t, 2H, J = 6.0 Hz), 2.70 (t, 2H, J =
5.5 Hz); 13C NMR (126 MHz, CDCl3) δ 203.1, 137.6, 128.5, 127.8,
127.7, 73.3, 64.9, 58.1, 40.4; HRMS (CI) calcd for C11H14N3O2
[M + H]+ 220.1086, found 220.1086.
N-Benzyl-2-bromo-N-(4-iodophenyl)acetamide (1b-1). To a
stirred solution of 4-iodoaniline (1.09 g, 5.0 mmol) in methanol
(8.3 mL, 0.6 M) was added benzaldehyde (0.51 mL, 5.0 mmol,
1.0 equiv) at room temperature. After 0.5 h, the mixture was cooled to
0 °C. Sodium borohydride (631 mg, 15.0 mmol, 3.0 equiv) was added
to the mixture carefully, and then the mixture was warmed up to room
temperature. After 12 h, the resulting mixture was poured into a
saturated aqueous sodium bicarbonate solution. The organic
components were extracted three times with ethyl acetate and were
washed with brine. The collected organic layer was dried over sodium
sulfate. Concentration in vacuo gave N-benzyl-4-iodoaniline (1.06 g) as
a crude material, which was submitted to the next step without further
purification.
To a stirred solution of the crude amine (1.06 g) in dichloromethane
(30.0 mL, 0.2 M) was added bromoacetyl bromide (0.34 mL,
3.92 mmol, 1.14 equiv) dissolved in dichloromethane (11.5 mL) at
0 °C. After the mixture stirred at room temperature for 2 h, the reaction
mixture was quenched with a saturated aqueous sodium bicarbonate
solution at 0 °C. The resulting mixture was washed with a saturated
aqueous sodium bicarbonate solution, and the organic layer was dried
over sodium sulfate. Concentration and purification by silica gel column
chromatography (hexane/ethyl acetate = 5/1 with 5% toluene) gave
1.33 g of 1b-1 (62%): white solid; Rf value 0.27 (hexane/ethyl acetate =
5/1); mp 90−91 °C; IR (NaCl, neat) νmax 1663, 1482, 1006 cm−1;
1-(4-(Benzylamino)phenyl)ethan-1-one (1d-1). To a stirred
solution of 4′-aminoacetophenone (4.10 g, 30.3 mmol, 3.0 equiv) in
M
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acetonitrile (20 mL, 1.5 M) were added potassium carbonate (2.09 g,
15.2 mmol, 1.5 equiv) and benzyl bromide (1.20 mL, 10.1 mmol)
successively at room temperature. After 26 h at room temperature, the
insoluble potassium carbonate was removed by filtration through filter
paper and was washed with ethyl acetate. The collected filtrate was
concentrated and was purified by silica gel column chromatography
(hexane/ethyl acetate = 2/1) to obtain 2.00 g of 1d-1 (88% based on
benzyl bromide): orange solid; Rf value 0.60 (hexane/ethyl acetate =
1/1); mp 90.1−91.8 °C; IR (NaCl, neat) νmax 3349, 1650, 1596, 1358,
N-Benzyl-N-(3-(N-benzyl-2-bromoacetamido)phenyl)-2-bromo-
propanamide (1e-2). To a stirred solution of the diamine 1e-1 (2.33 g,
8.08 mmol) in dichloromethane (77.0 mL, 0.083 M) was added
bromoacetyl bromide (0.70 mL, 8.08 mmol, 1.0 equiv) dissolved in
dichloromethane (10.0 mL) dropwise at 0 °C. After the mixture stirred
at room temperature for 1 h, 2-bromopropionyl bromide (0.85 mL,
8.08 mmol, 1.0 equiv) dissolved in dichloromethane (10.0 mL) was
added to the reaction mixture at 0 °C. After the mixture stirred at room
temperature for 1 h, the reaction was quenched with a saturated
aqueous sodium bicarbonate solution at 0 °C. The resulting mixture
was washed with a saturated aqueous sodium bicarbonate solution and
was dried over sodium sulfate. Concentration and purification by silica
gel column chromatography (hexane/ethyl acetate = 5/1 to 3/1 to 2/1)
gave 1.64 g of 1e-2 (37%): colorless viscous oil; Rf value 0.30 (hexane/
ethyl acetate = 3/1); IR (NaCl, neat) νmax 1664, 1596, 1391, 701 cm−1;
1H NMR (500 MHz, CDCl3) δ 7.37 (t, 1H, J = 8.0 Hz), 7.26−7.25
1
1280, 1179 cm−1; H NMR (500 MHz, CDCl3) δ 7.82 (d, 2H, J =
8.5 Hz), 7.38−7.34 (m, 4H), 7.32−7.29 (m, 1H), 6.60 (d, 2H, J =
8.5 Hz), 4.63 (s, 1H), 4.41 (s, 2H), 2.49 (s, 3H); 13C NMR (126 MHz,
CDCl3) δ 196.4, 151.9, 138.2, 130.7, 128.8, 127.5, 127.3, 126.8, 111.5,
47.5, 26.0; LRMS (EI, M = C15H15NO) m/z 225 (M+, 77%), 210 (62),
91 (100); HRMS (EI) calcd for C15H15NO (M+) 225.1154, found
225.1155.
(m, 6H), 7.10−7.09 (m, 6H), 6.60 (br-s, 1H), 5.07−4.56 (m, 4H), 3.93
(br-s, 1H), 3.44 (s, 2H), 1.71 (br-d, 3H, J = 6.5 Hz); 13C NMR
(126 MHz, CDCl3) δ 168.9, 166.0, 141.7, 141.5, 136.1, 135.9, 130.8,
129.4, 128.87, 128.85, 128.75, 128.63, 128.58, 128.4, 127.95, 127.91,
53.33, 53.31, 38.9, 27.0, 21.6; LRMS (EI, M = C25H24Br2N2O2) m/z
546 (1.3%, M+ of 81Br × 2), 544 (3, M+ of 81Br + 79Br), 542 (1.3, M+ of
79Br × 2), 465 (85), 463 (85), 223 (25), 91 (100); HRMS (EI) calcd for
C25H2479Br2N2O2 (M+) 542.0205, found 542.0198.
N-(4-Acetylphenyl)-N-benzyl-2-bromoacetamide (1d-2). To a
stirred biphasic solution of 1d-1 (2.00 g, 8.86 mmol) in dichloro-
methane and water (125 mL, 1/4, 0.07 M) was added potassium
carbonate (368 mg, 2.66 mmol, 0.2 equiv) at 0 °C. Then, bromoacetyl
bromide (1.15 mL, 13.3 mmol, 1.5 equiv) dissolved in dichloromethane
(45 mL) was added dropwise over 40 min at the same temperature.
After 2 h, the mixture was warmed at room temperature. After 12 h, the
reaction mixture was diluted with dichloromethane and was washed
twice with water. The combined organic layer was dried over sodium
sulfate. Concentration and purification by silica gel column
chromatography (hexane/ethyl acetate = 2/1) gave 3.01 g of 1d-2
(98%): white solid; Rf value 0.50 (hexane/ethyl acetate = 1/1); mp 79−
80 °C; IR (NaCl, neat) νmax 1666, 1600, 1265 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.94 (d, 2H, J = 9.0 Hz), 7.27−7.26 (m, 3H),
7.18−7.175 (m, 4H), 4.92 (s, 2H), 3.67 (s, 2H), 2.60 (s, 2H); 13C NMR
(126 MHz, CDCl3) δ 196.8, 166.1, 145.2, 136.9, 136.1, 129.8, 128.8,
128.6, 128.4, 127.8, 53.5, 26.9, 26.7; HRMS (CI) calcd for
C17H1779BrNO2 [M + H]+ 346.0443, found 346.0439.
2-Azido-N-(3-(2-azido-N-benzylacetamido)phenyl)-N-benzylpro-
panamide (1e). To a stirred solution of 1e-1 (157 mg, 0.289 mmol) in
DMSO (1.4 mL, 0.2 M) was added sodium azide (58.0 mg,
0.867 mmol, 2.5 equiv) at room temperature. After 1 h, the reaction
was quenched with water, and the organic components were extracted
three times with ether. The organic layer was washed with water and
brine. The combined organic layer was then dried over sodium sulfate.
Concentration and purification by silica gel column chromatography
(hexane/ethyl acetate = 2/1) gave 129 mg of 1e (95%): white solid; Rf
value 0.30 (hexane/ethyl acetate = 3/1); mp 104−105 °C; IR (NaCl,
1
neat) νmax 2105, 1667, 1397, 1235, 703 cm−1; H NMR (500 MHz,
CDCl3) δ 7.39 (t, 1H, J = 8.0 Hz), 7.28−7.25 (m, 5H), 7.10−7.01
(m, 7H), 6.31 (s, 1H), 4.91−4.71 (br, 4H), 3.22−3.15 (m, 3H), 1.30
(br-d, 3H, J = 6.5 Hz); 13C NMR (126 MHz, CDCl3) δ 169.7, 166.8,
141.6, 141.0, 136.0, 135.8, 131.3, 129.4, 129.0, 128.9, 128.7, 128.6,
128.5, 128.1, 128.0, 54.0, 53.1, 53.0, 50.7, 16.2; HRMS (CI) calcd for
C25H25N8O2 [M + H]+ 469.2100, found 469.2095.
2-Azido-N-(4-(2-azidoacetyl)phenyl)-N-benzylacetamide (1d).
To a stirred solution of N-benzyl-4-aminoacetophenone (175 mg,
0.500 mmol) in THF (6.4 mL) was added trimethylphenylammonium
tribromide (207 mg, 0.550 mmol, 1.1 equiv) at 0 °C. After 12 h, the
resulting precipitate was removed by filtration and was washed with
ethyl acetate. Then the filtrate was washed with water and brine. The
combined organic layer was dried over sodium sulfate. Concentration
and purification by silica gel column chromatography (hexane/ethyl
acetate = 4/1 to 2/1) gave 97.2 mg of dibromide (46%) as a colorless
oil. Because the dibromide product was relatively unstable, this was
soon submitted to the next step without collecting analytical data.
To a stirred solution of the dibromide (273 mg, 0.642 mmol) in
DMSO (6.5 mL, 0.1 M) was added sodium azide (104 mg, 1.60 mmol,
2.5 equiv) at room temperature. After 1.5 h, the reaction was quenched
with water. The organic components were extracted three times with
ether and were washed with brine. The combined organic layer was
dried over sodium sulfate. Concentration and purification by silica gel
column chromatography (hexane/ethyl acetate = 4/1 to 2/1) gave
176 mg of 1d (79%): pale yellow oil; Rf value 0.60 (hexane/EtOAc =
N-(2-(3-Bromopropoxy)benzyl)-4-iodoaniline (5a-1). To a stirred
solution of salicylaldehyde (1.23 g, 10 mmol) and potassium carbonate
(2.77 g, 20 mmol, 2.0 equiv) in DMF (29 mL, 0.34 M) was added
1,3-dibromopropane (4.1 mL, 40 mmol, 4.0 equiv) at 0 °C. After 24 h at
room temperature, the resulting mixture was diluted with ethyl acetate
and was washed with water, 1 N HCl (twice), a saturated aqueous
sodium bicarbonate solution, and brine. The combined organic layer
was dried over sodium sulfate. Concentration and purification by silica
gel column chromatography (hexane elution to hexane with 12% ethyl
acetate) gave 1.86 g of 2(3-bromopropoxy)benzaldehyde (76%). This
product was soon submitted to the next step without collecting
analytical data.
1
1/1); IR (NaCl, neat) νmax 2105, 1672, 1600, 1215 cm−1; H NMR
(500 MHz, CDCl3) δ 7.90 (d, 2H, J = 8.5 Hz), 7.29−7.26 (m, 3H),
7.17−7.13 (m, 4H), 4.93 (s, 2H), 4.52 (s, 2H), 3.62 (s, 2H); 13C NMR
(126 MHz, CDCl3) δ 192.1, 166.8, 145.2, 135.8, 134.0, 129.5, 128.6,
127.9, 54.8, 53.2, 50.8; HRMS (CI) calcd for C17H16N7O2 [M + H]+
350.1365, found 350.1360.
To a stirred solution of 4-iodoaniline (1.36 g, 6.23 mmol) and the
synthesized aldehyde above (1.82 g, 7.48 mmol, 1.2 equiv) in ethanol
(31 mL, 0.2 M) was added acetic acid (0.43 mL, 7.48 mmol, 1.2 equiv)
N
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at room temperature. After 1 h, sodium cyanoborohydride (620 mg,
9.35 mmol, 1.5 equiv) was added to the reaction mixture at 0 °C. After
the mixture stirred at room temperature for 13 h, the resulting mixture
was poured into a saturated aqueous sodium bicarbonate solution. The
organic components were extracted twice with ether and were washed
with brine. The combined organic layer was dried over sodium sulfate.
Concentration and purification by silica gel column chromatography
(hexane/ethyl acetate = 5/1 with 2% trimethylamine) gave 2.71 g of 5a-
1 (97%): white oil; Rf value 0.67 (hexane/ethyl acetate = 2/1); IR
156.6, 140.5, 136.8, 131.2, 129.7, 129.3, 124.2, 120.8, 120.1, 111.1, 64.3,
50.9, 48.0, 47.7, 28.6; LRMS (EI, M = C18H18N10O2) m/z 406
(11%, M+), 162 (81), 134 (100), 105 (83); HRMS (EI) calcd for
C18H18N10O2 (M+) 406.1614, found 406.1617.
1
(NaCl, neat) νmax 3418, 1589, 1434, 1454, 1238, 811, 752 cm−1; H
NMR (500 MHz, CDCl3) δ 7.40−7.39 (m, 2H), 7.28−7.24 (m, 2H),
6.92 (dd, 2H, J = 12.5, 7.5 Hz), 6.43 (d, 2H, J = 9.0 Hz), 4.30 (s, 2H),
4.17 (t, 2H, J = 5.5 Hz), 4.13 (br-s, 1H), 3.58 (t, 2H, J = 6.5 Hz), 2.33
(tt, 2H, J = 6.5, 6.0 Hz); 13C NMR (126 MHz, CDCl3) δ 156.3, 147.5,
137.7, 128.9, 128.6, 126.6, 120.8, 115.3, 111.2, 78.2, 65.1, 43.4, 32.0,
30.1; LRMS (EI, M = C16H17BrINO) m/z 447 (99%, M+ of 81Br), 445
(100, M+ of 79Br), 229 (60), 227 (61) 107 (60), 91 (34); HRMS (EI)
calcd for C16H1779BrINO (M+) 444.9538, found 444.9536.
1-(3-((6-Bromohexyl)amino)phenyl)ethan-1-one (5b-1). To a
stirred solution of 3′-aminoacetophenone (1.35 g, 10.0 mmol) in
acetonitrile (20 mL, 0.5 M) was added 1,6-dibromohexane (9.10 mL,
60.0 mmol, 6.0 equiv), and the mixture was heated to 90 °C. After 3 h,
water (100 mL) was added to the mixture at room temperature for
quenching the reaction. The organic components were extracted three
times with ethyl acetate and was dried over sodium sulfate.
Concentration and purification by silica gel column chromatography
(hexane elution to hexane/ethyl acetate = 5/1) gave 1.19 g of 5b-1
(40%): yellow oil; Rf value 0.65 (hexane/ethyl acetate = 1/1); IR
(NaCl, neat) νmax 3386, 2932, 2856, 1677, 1603 cm−1; 1H NMR
(500 MHz, CDCl3) δ 7.28−7.23 (m, 2H), 7.18 (br, 1H), 6.80 (dd, 1H,
J = 7.0, 2.0, 2.0 Hz), 3.42 (t, 2H, J = 6.5 Hz), 3.16 (t, 2H, J = 7.0 Hz),
2.57 (s, 3H), 1.87 (tt, 2H, J = 7.5, 7.0 Hz), 1.65 (tt, 2H, J = 7.5, 6.5 Hz),
1.52−1.41 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 198.7, 148.3,
138.1, 129.3, 117.8, 117.6, 111.4, 43.8, 33.8, 32.6, 29.1, 27.9, 26.8, 26.2;
LRMS (EI, M = C14H20BrNO) m/z 299 (M+ of 81Br, 12%), 297 (M+ of
79Br, 12), 218 (9), 148 (100); HRMS (EI) calcd for C14H20BrNO (M+)
297.0728, found 297.0726.
2-Bromo-N-(2-(3-bromopropoxy)benzyl)-N-(4-iodophenyl)-
acetamide (5a-2). To a stirred solution of the 5a-1 (2.57 g, 5.76 mmol)
in dichloromethane (49 mL) was added bromoacetyl bromide
(0.57 mL, 6.57 mmol, 1.14 equiv) dissolved in dichloromethane
(20 mL) at 0 °C. After the mixture stirred at room temperature for 1 h,
the reaction was quenched with saturated aqueous sodium bicarbonate
at 0 °C. The resulting mixture was washed with a saturated aqueous
sodium bicarbonate solution. The combined organic layer was dried
over sodium sulfate. Concentration and purification by silica gel column
chromatography (hexane elution to hexane with 14% to 20% to 23%
ethyl acetate) gave 3.28 g of 5a-2 (quant): colorless oil; Rf value 0.33
(hexane/ethyl acetate = 3/1); IR (NaCl, neat) νmax 1664, 1483, 1244,
1
1005, 754 cm−1; H NMR (500 MHz, CDCl3) δ 7.65 (d, 2H, J =
8.5 Hz), 7.22 (dd, 1H, J = 8.5, 8.0 Hz), 7.17 (d, 1H, J = 7.5 Hz), 6.87
(t, 1H, J = 7.5 Hz), 6.82−6.80 (m, 3H), 4.93 (s, 2H), 3.96 (t, 2H, J =
5.5 Hz), 3.63 (s, 2H), 3.47 (t, 2H, J = 6.5 Hz), 2.14 (tt, 2H, J = 6.5,
5.5 Hz); 13C NMR (126 MHz, CDCl3) δ 165.9, 156.6, 140.9, 138.7,
131.1, 130.2, 129.3, 124.1, 120.8, 111.1, 94.1, 65.1, 48.0, 32.0, 30.2,
27.0; LRMS (EI, M = C18H18Br2INO2) m/z 569 (0.4%, M+ of 81Br × 2),
567 (0.8, M+ of 81Br + 79Br), 565 (0.4, M+ of 79Br × 2), 488 (99), 486
(100), 229 (39), 227 (40), 107 (38); HRMS (EI) calcd for
C18H1879Br2INO2 (M+) 564.8749, found 564.8738.
2-Azido-N-(3-(2-azidoacetyl)phenyl)-N-(6-azidohexyl)acetamide
(5b). To stirred solution of 5b-1 (2.13 g, 7.13 mmol) in dichloro-
methane (66 mL, 0.1 M) was added bromoacetyl bromide (0.71 mL,
8.13 mmol, 1.14 equiv) dissolved in dichloromethane (20 mL) at 0 °C.
After the mixture stirred at room temperature for 1 h, the reaction
mixture was quenched with a saturated aqueous sodium bicarbonate
solution at 0 °C. The resulting mixture was washed with a saturated
aqueous sodium bicarbonate solution, and the organic layer was dried
over sodium sulfate. Concentration in vacuo gave crude amide (3.12 g),
which was submitted to the next step without further purification.
To a solution of crude ketone in THF (92 mL, 0.08 M) under a
nitrogen atmosphere was added trimethylphenylammonium bromide
(2.95 g, 7.84 mmol, 1.1 equiv) at 0 °C. After 13 h, the reaction mixture
was filtered through Celite, and then the filtrate was washed with water
and brine. The organic layer was dried over sodium sulfate. Con-
centration in vacuo gave crude tribromide (4.4826 g), which was
submitted to the next step.
2-Azido-N-(4-azidophenyl)-N-(2-(3-azidopropoxy)benzyl)-
acetamide (5a). To a stirred solution of 5a-2 (3.23 g, 5.69 mmol) in
DMSO/water (10/1, 56 mL, 0.1 M) were added sodium azide (1.66 g,
25.6 mmol, 4.5 equiv), copper(I) iodide (217 mg, 1.13 mmol,
0.2 equiv), sodium L-ascorbate (116 mg, 0.569 mmol, 0.1 equiv), and
N,N′-dimethylenediamine (183 μL, 1.71 mmol, 0.3 equiv) successively
at room temperature. After 16 h, the reaction mixture was poured into
water and was extracted three times with ether. The combined organic
layer was washed with brine and then was dried over sodium sulfate.
Concentration and purification by silica gel column chromatography
(hexane/ethyl acetate = 3/1) gave 2.03 g of 5a (88%): colorless oil; Rf
value 0.50 (hexane/ethyl acetate = 2/1); IR (NaCl, neat) νmax 2101,
To a solution of crude tribromide in DMSO (36 mL, 0.2 M) was
added sodium azide (1.85 g, 28.5 mmol, 4.0 equiv) at room tem-
perature. After 1 h, the reaction was quenched with water, and the
organic components were extracted three times with ether. The
combined organic layer was washed with water and brine and then was
dried over sodium sulfate. Concentration and purification by silica gel
column chromatography (13% to 20% to 25% to 35% ethyl acetate in
hexane) gave 1.94 g of 5b (71% for 3 steps): colorless oil; Rf value 0.50
(hexane/EtOAc = 1/1); IR (NaCl, neat) νmax 2935, 2858, 2103, 1670,
1
1671, 1505, 1279, 1246 cm−1; H NMR (500 MHz, CDCl3) δ 7.22
1
1438, 1263 cm−1; H NMR (500 MHz, CDCl3) δ 7.90 (d, 1H, J =
(ddd, 1H, J = 8.0, 7.5, 1.5 Hz), 7.15 (dd, 1H, J = 7.5, 1.5 Hz), 6.97−6.92
(m, 4H), 6.86 (dd, 1H, J = 7.5, 7.5 Hz), 6.79 (d, 1H, J = 8.0 Hz), 4.96
(s, 2H), 3.91 (t, 2H, J = 6.0 Hz), 3.56 (s, 2H), 3.40 (t, 2H, J = 6.5 Hz),
1.89 (tt, 2H, J = 6.5, 6.0 Hz); 13C NMR (126 MHz, CDCl3) δ 166.9,
8.0 Hz), 7.76 (s, 1H), 7.62 (dd, 1H, J = 8.0, 8.0 Hz), 7.44 (d, 1H, J =
8.0 Hz), 4.58 (s, 2H), 3.73 (t, 2H, J = 7.5 Hz), 3.53 (s, 2H), 3.23 (t, 2H,
J = 7.0 Hz), 1.57−1.50 (m, 4H), 1.40−1.30 (m, 4H); 13C NMR
O
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Article
(126 MHz, CDCl3) δ 192.1, 166.7, 141.6, 136.1, 133.5, 130.9, 128.0,
127.3, 55.0, 51.2, 50.8, 49.6, 28.6, 27.3, 26.3, 26.1; HRMS (CI) calcd for
C16H21N10O2 [M + H]+ 385.1849, found 385.1841.
Crystal data for 2d (CCDC no. 1839203) (CIF)
Crystal data for 4i′ (CCDC no. 1839204) (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: tanimoto@ms.naist.jp.
■
ORCID
Methyl 4-(Butylcarbamoyl)-2-(diphenylphosphaneyl)benzoate
(7). To a stirred solution of 1-methyl-2-aminoterephthalate (976 mg,
5.0 mmol) in aq 4 M HCl (26.9 mL) was added NaNO2 (380 mg,
5.5 mmol, 1.1 equiv) dissolved in water (9.8 mL) dropwise at 0 °C.
After 30 min, potassium iodide (4.15 g, 25 mmol, 5.0 equiv) in water
(33 mL, 0.15 M) cooled at −15 °C was slowly added to the reaction
mixture at 0 °C. After the mixture was stirred at room temperature for
4 h, the reaction was quenched with a saturated aqueous sodium
bicarbonate solution. The precipitated solid was collected by filtration
and was washed with iced water. The obtained solid was recrystallized
from methanol/water (1/1) to give 901 mg of 3-iodo-4-
(methoxycarbonyl)benzoic acid (59%) as a yellow solid. Analytical
data were identical to those reported.29a,39
Hiroki Tanimoto: 0000-0002-4121-6807
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by the research grant from the
NAIST foundation (29390001). We thank Ms. Yoshiko
Nishikawa (MS measurements) and Mr. Shohei Katao (X-ray
crystallographic analysis) of NAIST. We also thank Editage
(www.editage.jp) and Professor Leigh McDowell of NAIST for
English language editing.
In a flame-dried flask, obtained 3-iodo-4-(methoxycarbonyl)benzoic
acid (980 mg, 2.91 mmol) was dissolved in methanol (29 mL, 0.1 M).
To the stirred solution were added palladium(II) acetate (76.2 mg,
0.291 mmol, 0.1 equiv), triethylamine (0.82 mL, 5.82 mmol, 2.0 equiv),
and diphenylphosphine (0.56 mL, 2.91 mmol, 1.0 equiv) at room
temperature. The reaction mixture was stirred at reflux for 10 h, and
then the resulting mixture was cooled down to room temperature. The
crude material obtained after concentration in vacuo was dissolved with
dichloromethane and was washed with water and aq 1 M HCl. After
removal of organic solvent, the resulting material was dissolved by
methanol and an equal volume of water was added to the solution. The
solution was cooled to 4 °C for 2 h, and the resulting solid was collected
by filtration to afford 663 mg of methyl 3-(diphenylphosphaneyl)-4-
(methoxycarbonyl)benzoic acid29a,39 as blown powder, which was
submitted to the next step without further purification.
To a stirred solution of 3-(diphenylphosphaneyl)-4-(methoxycarbonyl)-
benzoic acid (657 mg) in dichloromethane (80 mL) were added N-(3-
(dimethylamino)propyl)-N′-ethylcarbodiimide hydrochloride (427 mg,
2.22 mmol, 1.23 equiv), and 4-dimethylaminopyridine (22.1 mg,
0.186 mmol, 0.1 equiv) at room temperature. Then, a solution of
n-butylamine (0.196 mL, 1.98 mmol, 1.1 equiv) in dichloromethane
(10 mL) was added to the mixture. After 18 h, the reaction mixture was
diluted with dichloromethane and was washed with 10% HCl (twice),
saturated aqueous sodium bicarbonate (twice), water, and brine. The
combined organic layer was dried over sodium sulfate. Concentration
and purification by silica gel column chromatography (hexane/ethyl
acetate = 4/1 to 3/1) gave 473 mg of 7 (39% from iodide for 2 steps):
yellow solid; Rf value 0.6 (hexane/ethyl acetate = 1/1); mp 78−79 °C;
IR (NaCl, neat) νmax 3299, 2955, 1720, 1638, 1541, 1434, 1288 cm−1;
1H NMR (500 MHz, CDCl3) δ 8.10 (dd, 1H, J = 8.5, 4.0 Hz), 7.80
REFERENCES
■
̈
(1) (a) Organic Azides: Synthesis and Applications; Brase, S., Banert, K.,
Eds.; John Wiley & Sons: West Sussex, U.K., 2010. For selected reviews
published after this perspective book, see:. (b) Tanimoto, H.; Kakiuchi,
K. Recent Applications and Developments of Organic Azides in Total
Synthesis of Natural Products. Nat. Prod. Commun. 2013, 8, 1021−
1034. (c) Intrieri, D.; Zardi, P.; Caselli, A.; Gallo, E. Organic Azides:
“Energetic Reagents” for the Intermolecular Amination of C−H Bonds.
Chem. Commun. 2014, 50, 11440−11453. (d) Song, X.-R.; Qiu, Y.-F.;
Liu, X.-Y.; Liang, Y.-M. Recent Advances in the Tandem Reaction of
Azides with Alkynes or Alkynols. Org. Biomol. Chem. 2016, 14, 11317−
11331. (e) Wu, K.; Liang, Y.; Jiao, N. Azidation in the
Difunctionalization of Olefins. Molecules 2016, 21, 352. (f) Huang,
G.; Yan, G. Recent Advances in Reactions of Azides. Adv. Synth. Catal.
2017, 359, 1600−1619.
(2) (a) Click Chemistry for Biotechnology and Materials Science;
Lahann, J., Ed.; John Wiley & Sons: West Sussex, U.K., 2009. (b) Kolb,
H. C.; Finn, M. G.; Sharpless, K. B. Click Chemistry: Diverse Chemical
Function from a Few Good Reactions. Angew. Chem., Int. Ed. 2001, 40,
2004−2021. (c) Tornøe, C. W.; Christensen, C.; Meldal, M. Cu-
Catalyzed Azide-Alkyne Cycloaddition. Chem. Rev. 2008, 108, 2952−
3015. (d) Debets, M. F.; van der Doelen, C. W. J.; Rutjes, F. P. J. T.; van
Delft, F. L. Azide: A Unique Dipole for Metal-Free Bioorthogonal
Ligations. ChemBioChem 2010, 11, 1168−1184. (e) Huang, D.; Liu, Y.;
Qin, A.; Tang, B. Z. Recent Advances in Alkyne-based Click
Polymerizations. Polym. Chem. 2018, 9, 2853−2867.
̀
(3) (a) Decuypere, E.; Plougastel, L.; Audisio, D.; Taran, F. Sydnone−
Alkyne Cycloaddition: Applications in Synthesis and Bioconjugation.
Chem. Commun. 2017, 53, 11515−11527. (b) Kozma, E.; Demeter, O.;
Kele, P. Bio-orthogonal Fluorescent Labelling of Biopolymers through
Inverse-Electron-Demand Diels-Alder Reactions. ChemBioChem 2017,
18, 486−501. (c) Carell, T.; Vrabel, M. Bioorthogonal Chemistry
Introduction and Overview. Top. Curr. Chem. 2016, 374, 9. (d) Row, R.
D.; Prescher, J. A. Constructing New Bioorthogonal Reagents and
Reactions. Acc. Chem. Res. 2018, 51, 1073−1081. For other recent
methods, see: (e) Meguro, T.; Yoshida, S.; Hosoya, T. Sequential
Molecular Conjugation Using Thiophene S,S-Dioxides Bearing a
Clickable Functional Group. Chem. Lett. 2017, 46, 1137−1140. (f) An,
P.; Lewandowski, T. M.; Erbay, T. G.; Liu, P.; Lin, Q. Sterically
Shielded, Stabilized Nitrile Imine for Rapid Bioorthogonal Protein
Labeling in Live Cells. J. Am. Chem. Soc. 2018, 140, 4860−4868.
(4) (a) Agard, N. J.; Prescher, J. A.; Bertozzi, C. A. A Strain-Promoted
[3 + 2] Azide−Alkyne Cycloaddition for Covalent Modification of
Biomolecules in Living Systems. J. Am. Chem. Soc. 2004, 126, 15046−
15047. (b) Zhou, F.; Tan, C.; Tang, J.; Zhang, Y.-Y.; Gao, W.-M.; Wu,
H.-H.; Yu, Y.-H.; Zhou, J. Asymmetric Copper(I)-Catalyzed Azide−
Alkyne Cycloaddition to Quaternary Oxindoles. J. Am. Chem. Soc. 2013,
(dd, 1H, J = 8.0, 1.5 Hz), 7.38−7.33 (m, 6H), 7.29−7.26 (m, 4H), 7.12
(dd, 1H, J = 3.5, 1.5 Hz), 5.70 (br-s, 1H), 3.75 (s, 3H), 3.31 (dd, 2H, J =
12.5, 6.5 Hz), 1.47−1.41 (m, 2H), 1.24 (ddt, 2H, J = 15.5, 7.5, 7.5 Hz),
0.90 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 166.5 (d, J =
2.4 Hz), 166.3, 141.5 (d, J = 28.8 Hz), 137.5, 137.2 (d, J = 10.7 Hz),
136.3 (d, J = 18.0 Hz), 133.8 (d, J = 20.4 Hz), 132.0, 131.0 (d, J =
2.4 Hz), 129.0, 128.6 (d, J = 7.2 Hz), 127.1, 52.3, 39.6, 31.2, 19.9, 13.7;
31P NMR (202 MHz, benzene-d6) δ −2.90; HRMS (ESI) calcd for
C25H27NO3P [M + H]+ 420.1729, found 420.1730.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02074.
■
S
1H, 13C, and 1P NMR spectra and crystallographic data for
compounds 4h, 4i′, and 2d (PDF)
Crystal data for 4h (CCDC no. 1839202) (CIF)
P
DOI: 10.1021/acs.joc.8b02074
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135, 10994−10997. (c) Yoshida, S.; Hatakeyama, Y.; Johmoto, K.;
Uekusa, H.; Hosoya, T. Transient Protection of Strained Alkynes from
Click Reaction via Complexation with Copper. J. Am. Chem. Soc. 2014,
136, 13590−13593. (d) Brittain, W. D. G.; Buckley, B. R.; Fossey, J. S.
Asymmetric Copper-Catalyzed Azide−Alkyne Cycloadditions. ACS
Catal. 2016, 6, 3629−3636. (e) Hatit, M. Z. C.; Seath, C. P.; Watson, A.
J. B.; Burley, G. A. Strategy for Conditional Orthogonal Sequential
CuAAC Reactions Using a Protected Aromatic Ynamine. J. Org. Chem.
2017, 82, 5461−5468. (f) Chen, M.-Y.; Xu, Z.; Chen, L.; Song, T.;
Zheng, Z.-J.; Cao, J.; Cui, Y.-M.; Xu, L.-W. Catalytic Asymmetric
Huisgen Alkyne−Azide Cycloaddition of Bisalkynes by Copper(I)
Nanoparticles. ChemCatChem 2018, 10, 280−286. (g) Huxley, M. T.;
Burgun, A.; Ghodrati, H.; Coghlan, C. J.; Lemieux, A.; Champness, N.
R.; Huang, D. M.; Doonan, C. J.; Sumby, C. J. Protecting-Group-Free
Site-Selective Reactions in a Metal−Organic Framework Reaction
Vessel. J. Am. Chem. Soc. 2018, 140, 6416−6425.
(5) (a) Zhang, H.; Tanimoto, H.; Morimoto, T.; Nishiyama, Y.;
Kakiuchi, K. Regioselective Rapid Synthesis of Fully Substituted 1,2,3-
Triazoles Mediated by Propargyl Cations. Org. Lett. 2013, 15, 5222−
5225. (b) Zhang, H.; Tanimoto, H.; Morimoto, T.; Nishiyama, Y.;
Kakiuchi, K. Acid-mediated synthesis of fully substituted 1,2,3-triazoles:
multicomponent coupling reactions, mechanistic study, synthesis of
serine hydrolase inhibitor and its derivatives. Tetrahedron 2014, 70,
9828−9835. (c) Zhang, Y.; Li, J.; Wang, M.; Zhang, H.; Tanimoto, H.;
Morimoto, T.; Kakiuchi, K. Synthesis of Fused 1,2,3-Triazoles through
Carbocation-Mediated Intramolecular [3 + 2] Cycloaddition of Azido-
propargyl Alcohols. Heterocycles 2017, 94, 1775−1782.
Polymers with over a Million Molecular Weight in One-Pot Click
Polymerization. Macromolecules 2016, 49, 760−766.
(11) (a) Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. The
Chemistry of Amine−Azide Interconversion: Catalytic Diazotransfer
and Regioselective Azide Reduction. J. Am. Chem. Soc. 2002, 124,
10773−10778. (b) Sridhar, P. R.; Prabhu, K. R.; Chandrasekaran, S.
Selective Reduction of Anomeric Azides to Amines with Tetrathiomo-
lybdate: Synthesis of β-D-Glycosylamines. J. Org. Chem. 2003, 68,
5261−5264. (c) Li, J.; Chiang, F.-I.; Chen, H.-N.; Chang, C.-W. T.
Investigation of the Regioselectivity for the Staudinger Reaction and Its
Application for the Synthesis of Aminoglycosides with N-1
Modification. J. Org. Chem. 2007, 72, 4055−4066. (d) Udumula, V.;
Nazari, H. S.; Burt, S. R.; Alfindee, M. N.; Michaelis, D. J. Chemo- and
Site-Selective Alkyl and Aryl Azide Reductions with Heterogeneous
Nanoparticle Catalysts. ACS Catal. 2016, 6, 4423−4427. (e) Meguro,
T.; Yoshida, S.; Hosoya, T. Aromatic Azido-Selective Reduction via the
Staudinger Reaction Using Tri-n-butylphosphonium Tetrafluoroborate
with Triethylamine. Chem. Lett. 2017, 46, 473−476. (f) Meguro, T.;
Terashima, N.; Ito, H.; Koike, Y.; Kii, I.; Yoshida, S.; Hosoya, T.
Staudinger Reaction Using 2,6-Dichlorophenyl Azide Derivatives for
Robust Aza-ylide Formation Applicable to Bioconjugation in Living
Cells. Chem. Commun. 2018, 54, 7904−7907.
(12) Meguro, T.; Yoshida, S.; Igawa, K.; Tomooka, K.; Hosoya, T.
Transient Protection of Organic Azides from Click Reactions with
Alkynes by Phosphazide Formation. Org. Lett. 2018, 20, 4126−4130.
(13) (a) Meng, J.-c.; Fokin, V. V.; Finn, M. G. Kinetic Resolution by
Copper-Catalyzed Azide−Alkyne Cycloaddition. Tetrahedron Lett.
2005, 46, 4543−4546. See also ref 4d. (b) Wu, X.-P.; Su, Y.; Gu, P.
Catalytic Enantioselective Desymmetrization of 1,3-Diazido-2-prop-
anol via Intramolecular Interception of Alkyl Azides with Diazo(aryl)-
acetates. Org. Lett. 2014, 16, 5339−5341. (c) Qiao, J.-B.; Zhao, Y.-M.;
Gu, P. Asymmetric Intramolecular Desymmetrization of meso-α,α′-
Diazido Alcohols with Aryldiazoacetates: Assembly of Chiral C3
Fragments with Three Continuous Stereocenters. Org. Lett. 2016, 18,
1984−1987.
(6) For the reactivity comparison of alkyl and aryl azides against
strained alkynes, see: (a) Dommerholt, J.; Rutjes, F. P. J. T.; van Delft,
F. L. Strain-Promoted 1,3-Dipolar Cycloaddition of Cycloalkynes and
Organic Azides. Top. Curr. Chem. 2016, 374, 16. (b) Dommerholt, J.;
van Rooijen, O.; Borrmann, A.; Guerra, C. F.; Bickelhaupt, F. M.; van
Delft, F. M. Highly Accelerated Inverse Electron-Demand Cyclo-
addition of Electron-Deficient Azides with Aliphatic Cyclooctynes. Nat.
Commun. 2014, 5, 5378.
(7) (a) Hosoya, T.; Hiramatsu, T.; Ikemoto, T.; Nakanishi, M.;
Aoyama, H.; Hosoya, A.; Iwata, T.; Maruyama, K.; Endo, M.; Suzuki,
M. Novel Bifunctional Probe for Radioisotope-Free Photoaffinity
Labeling: Compact Structure Comprised of Photospecific Ligand
Ligation and Detectable Tag Anchoring Units. Org. Biomol. Chem.
2004, 2, 637−641. (b) Yoshida, S.; Misawa, Y.; Hosoya, T. Formal C−
H-Azidation−Based Shortcut to Diazido Building Blocks for the
Versatile Preparation of Photoaffinity Labeling Probes. Eur. J. Org.
Chem. 2014, 2014, 3991−3995. (c) Yoshida, S.; Kanno, K.; Kii, I.;
Misawa, Y.; Hagiwara, M.; Hosoya, T. Convergent synthesis of
trifunctional molecules by three sequential azido-type-selective cyclo-
additions. Chem. Commun. 2018, 54, 3705−3708.
(14) (a) Regitz, M.; Maas, G. Diazo Compounds: Properties and
Synthesis; Academic Press: New York, 1986. For recent reviews, see:.
(b) Zhang, Z.; Wang, J. Recent Studies on the Reactions of α-
Diazocarbonyl Compounds. Tetrahedron 2008, 64, 6577−6605.
(c) Maas, G. New Syntheses of Diazo Compounds. Angew. Chem.,
Int. Ed. 2009, 48, 8186−8195. (d) Ford, A.; Miel, H.; Ring, A.; Slattery,
C. N.; Maguire, A. R.; McKervey, M. A. Modern Organic Synthesis with
α-Diazocarbonyl Compounds. Chem. Rev. 2015, 115, 9981−10080.
(e) Burtoloso, A. C. B.; Momo, P. B.; Novais, G. L. Traditional and New
methods for the Preparation of Diazocarbonyl Compounds. An. Acad.
Bras. Cienc. 2018, 90, 859−893. For a very recently reported diazo
transfer reagent and the references of related researches, see: (g) Xie, S.;
Yan, Z.; Li, Y.; Song, Q.; Ma, M. Intrinsically Safe and Shelf-Stable
Diazo-Transfer Reagent for Fast Synthesis of Diazo Compounds. J. Org.
Chem. 2018, DOI: 10.1021/acs.joc.8b01587.
(8) Chujo, Y.; Tanaka, K. New Polymeric Materials Based on
Element-Blocks. Bull. Chem. Soc. Jpn. 2015, 88, 633−643.
(9) For reactivity among aryl azides, see: (a) Yoshida, S.; Shiraishi, A.;
Kanno, K.; Matsushita, T.; Johmoto, K.; Uekusa, H.; Hosoya, T.
Enhanced Clickability of Doubly Sterically-Hindered Aryl Azides. Sci.
(15) (a) Davies, H. M. L.; Denton, J. R. Application of Donor/
Acceptor-Carbenoids to the Synthesis of Natural Products. Chem. Soc.
Rev. 2009, 38, 3061−3071. (b) Candeias, N. R.; Paterna, R.; Gois, P. M.
P. Homologation Reaction of Ketones with Diazo Compounds. Chem.
Rev. 2016, 116, 2937−2981.
̈
Rep. 2011, 1, 82. (b) Xie, S.; Lopez, S. A.; Ramstrom, O.; Yan, M.;
Houk, K. N. 1,3-Dipolar Cycloaddition Reactivities of Perfluorinated
Aryl Azides with Enamines and Strained Dipolarophiles. J. Am. Chem.
Soc. 2015, 137, 2958−2966. For site-selective conjugation of alkyl
(16) (a) Noels, A. F. Carbene Chemistry: Stereoregular Polymers
from Diazo Compounds. Angew. Chem., Int. Ed. 2007, 46, 1208−1210.
(b) Jellema, E.; Jongerius, A. L.; Reek, J. N. H.; de Bruin, B. C1
Polymerisation and Related C−C Bond Forming ‘Carbene Insertion’
Reactions. Chem. Soc. Rev. 2010, 39, 1706−1723. (c) Ihara, E.
Poly(substituted Methylene) Synthesis: Construction of C−C Main
Chain from One Carbon Unit. Adv. Polym. Sci. 2010, 231, 191−231.
(17) (a) McGrath, N. A.; Raines, R. T. Diazo Compounds as Highly
Tunable Reactants in 1,3-Dipolar Cycloaddition Reactions with
Cycloalkynes. Chem. Sci. 2012, 3, 3237−3240. (b) Gold, B.; Aronoff,
M. R.; Raines, R. T. Decreasing Distortion Energies without Strain:
Diazo-Selective 1,3-Dipolar Cycloadditions. J. Org. Chem. 2016, 81,
5998−6006. (c) Aronoff, M. R.; Gold, G.; Raines, R. T. 1,3-Dipolar
Cycloadditions of Diazo Compounds in the Presence of Azides. Org.
azides by steric hindrance, see: (c) Munster, N.; Nikodemiak, P.; Koert,
̈
U. Chemoselective Layer-by-Layer Approach Utilizing Click Reactions
with Ethynylcyclooctynes and Diazides. Org. Lett. 2016, 18, 4296−
4299.
(10) For site-selective conjugations by directing groups, see: (a) Yuan,
Z.; Kuang, G.-C.; Clark, R. J.; Zhu, L. Chemoselective Sequential
“Click” Ligation Using Unsymmetrical Bisazides. Org. Lett. 2012, 14,
2590−2593. (b) Shi, Y.; Graff, R. W.; Cao, X.; Wang, X.; Gao, H.
Chain-Growth Click Polymerization of AB2 Monomers for the
Formation of Hyperbranched Polymers with Low Polydispersities in
a One-Pot Process. Angew. Chem., Int. Ed. 2015, 54, 7631−7635.
(c) Cao, X.; Shi, Y.; Wang, X.; Graff, R. W.; Gao, H. Design a Highly
Reactive Trifunctional Core Molecule To Obtain Hyperbranched
Q
DOI: 10.1021/acs.joc.8b02074
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Lett. 2016, 18, 1538−1541. (d) Aronoff, M. R.; Gold, G.; Raines, R. T.
Rapid Cycloaddition of a Diazo Group with an Unstrained
Dipolarophile. Tetrahedron Lett. 2016, 57, 2347−2350.
(18) Mix, K. A.; Aronoff, M. R.; Raines, R. T. Diazo Compounds:
Versatile Tools for Chemical Biology. ACS Chem. Biol. 2016, 11, 3233−
3244.
Regioselective Multicomponent Reaction. Org. Lett. 2015, 17, 1914−
1917.
(26) The moderate yields mostly resulted from the requirement of
further purification by gel permeation chromatography.
(27) This form of base-mediated transformation to amides with
́
enolates and azides has been reported: (a) Yao, L.; Smith, B. T.; Aube, J.
Base-Promoted Reactions of Bridged Ketones and 1,3- and 1,4-
Haloalkyl Azides: Competitive Alkylation vs Azidation Reactions of
Ketone Enolates. J. Org. Chem. 2004, 69, 1720−1722. (b) Xie, S.;
(19) (a) Feigelson, G. B. On the conversion of azides to diazo
compounds. Tetrahedron Lett. 1998, 39, 1129−1130. (b) Myers, E. L.;
Raines, R. T. A Phosphine-Mediated Conversion of Azides into Diazo
Compounds. Angew. Chem., Int. Ed. 2009, 48, 2359−2363. (c) Chou,
H.-H.; Raines, R. T. Conversion of Azides into Diazo Compounds in
Water. J. Am. Chem. Soc. 2013, 135, 14936−14939.
̈
Ramstrom, O.; Yan, M. N,N-Diethylurea-Catalyzed Amidation
between Electron-Deficient Aryl Azides and Phenylacetaldehydes.
̈
Org. Lett. 2015, 17, 636−639. (c) Xie, S.; Zhang, Y.; Ramstrom, O.;
Yan, M. Base-Catalyzed Synthesis of Aryl Amides from Aryl Azides and
Aldehydes. Chem. Sci. 2016, 7, 713−718. (d) Choi, H.; Shirley, H. J.;
Hume, P. A.; Brimble, M. A.; Furkert, D. P. Unexpected Direct
Synthesis of N-Vinyl Amides through Vinyl Azide−Enolate [3 + 2]
Cycloaddition. Angew. Chem., Int. Ed. 2017, 56, 7420−7424. For
precedent reports of C−C bond cleavage of α-azido ketones to cyano
carboxylic acids, see: (e) Takahashi, T. T.; Satoh, J. Y. Steroids. Part 2.
C−C Bond Cleavage of α-Azido-Steroidal Ketones. J. Chem. Soc., Perkin
Trans. 1 1980, 1916−1919. (f) Chiba, S.; Zhang, L.; Ang, G. Y.; Hui, B.
W.-Q. Generation of Iminyl Copper Species from α-Azido Carbonyl
Compounds and Their Catalytic C−C Bond Cleavage under an
Oxygen Atmosphere. Org. Lett. 2010, 12, 2052−2055.
(20) (a) Fulton, J. R.; Aggarwal, V. K.; de Vicente. The Use of
Tosylhydrazone Salts as a Safe Alternative for Handling Diazo
Compounds and Their Applications in Organic Synthesis. Eur. J. Org.
Chem. 2005, 2005, 1479−1492. (b) Xia, Y.; Wang, J. N-
Tosylhydrazones: Versatile Synthons in the Construction of Cyclic
Compounds. Chem. Soc. Rev. 2017, 46, 2306−2362. (c) Wang, H.;
Deng, Y.-H.; Shao, Z. An Update of N-Tosylhydrazones: Versatile
Reagents for Metal-Catalyzed and Metal-Free Coupling Reactions.
Synthesis 2018, 50, 2281−2306. (d) Cusack, N. J.; Reese, C. B.; Risius,
A. C.; Roozepeikar, B. 2,4,6-Tri-Isopropylbenzenesulphonyl Hydra-
zide: A Convenient Source of Di-imide. Tetrahedron 1976, 32, 2157−
2162. (e) Corey, E. J.; Myers, A. G. Efficient Synthesis and
Intramolecular Cyclopropanation of Unsaturated Diazoacetic Esters.
Tetrahedron Lett. 1984, 25, 3559−3562. (f) Liu, Z.; Li, Q.; Liao, P.; Bi,
X. Silver-Catalyzed [2 + 1] Cyclopropenation of Alkynes with Unstable
Diazoalkanes: N-Nosylhydrazones as Room-Temperature Decompos-
able Diazo Surrogates. Chem. - Eur. J. 2017, 23, 4756−4760.
(21) Pramanik, S.; Reddy, R. R.; Ghorai, P. Transition Metal-Free
Generation of N-Unsubstituted Imines from Benzyl Azides: Synthesis
of N-Unsubstituted Homoallylic Amines. J. Org. Chem. 2015, 80,
3656−3663.
(28) Jeganathan, A.; Richardson, S. K.; Mani, R. S.; Haley, B. E.; Watt,
D. S. Selective Reactions of Azide-Substituted α-Diazo Amides with
Olefins and Alcohols Using Rhodium(II) Catalysts. J. Org. Chem. 1986,
51, 5362−5367.
(29) (a) Saxon, E.; Bertozzi, C. R. Cell Surface Engineering by a
Modified Staudinger Reaction. Science 2000, 287, 2007−2010.
̈
(b) Schilling, C. I.; Jung, N.; Biskup, M.; Schepers, U.; Brase, S.
Bioconjugation via Azide−Staudinger Ligation: An Overview. Chem.
Soc. Rev. 2011, 40, 4840−4871.
(30) Conrow, R. E.; Dean, W. D. Diazidomethane Explosion. Org.
Process Res. Dev. 2008, 12, 1285−1286.
(22) (a) Patonay, T.; Hoffman, R. V. Base-Promoted Reactions of α-
Azido Ketones with Aldehydes and Ketones: A Novel Entry to α-Azido-
β-Hydroxy Ketones and 2,5-Dihydro-5-hydroxyoxazoles. J. Org. Chem.
(31) (a) Sun, H.; DiMagno, S. G. Anhydrous Tetrabutylammonium
Fluoride. J. Am. Chem. Soc. 2005, 127, 2050−2051. (b) Hogrefe, R. I.;
McCaffrey, A. P.; Borozdina, L. U.; McCampbell, E. S.; Vaghefi, M. M.
Effect of excess water on the desilylation of oligoribonucleotides using
tetrabutylammonium fluoride. Nucleic Acids Res. 1993, 21, 4739−4741.
(32) Doyle, M. P.; Shanklin, M. S.; Pho, H. Q.; Mahapatro, S. N.
Rhodium(II) Acetate and Nafion-H Catalyzed Decomposition of N-
Aryldiazoamides. Efficient Synthesis of 2(3H)-Indolinones. J. Org.
Chem. 1988, 53, 1017−1022.
́
1995, 60, 2368−2377. (b) Patel, J.; Clave, G.; Renard, P.-Y.; Franck, X.
Straightforward Access to Protected syn α-Amino-β-hydroxy Acid
Derivatives. Angew. Chem., Int. Ed. 2008, 47, 4224−4227. (c) Kamal, A.;
Reddy, C. N.; Satyaveni, M.; Chandrasekhar, D.; Nanubolu, J. B.;
Singarapu, K. K.; Maurya, R. A. Cu(OAc)2−Et3N Mediated Oxidative
Coupling of α-Azido Ketones with Pyridinium Ylides: Utilizing in situ
Generated Imines for Regioselective Synthesis of Imidazo[1,2-
a]pyridines. Chem. Commun. 2015, 51, 10475−10478. For a review,
(33) (a) Yoshida, S.; Karaki, F.; Uchida, K.; Hosoya, T. Generation of
Cycloheptynes and Cyclooctynes via a Sulfoxide−Magnesium
Exchange Reaction of Readily Synthesized 2-Sulfinylcycloalkenyl
Triflates. Chem. Commun. 2015, 51, 8745−8748. (b) Mckay, C. S.;
Moran, J.; Pezacki, J. P. Nitrones as Dipoles for Rapid Strain-Promoted
1,3-Dipolar Cycloadditions with Cyclooctynes. Chem. Commun. 2010,
46, 931−933. For a recent review, see: (c) Chupakhin, E. G.; Krasavin,
M. Y. Achievements in the synthesis of cyclooctynes for ring strain-
promoted [3 + 2] azide-alkyne cycloaddition. Chem. Heterocycl. Compd.
2018, 54, 483−501.
(34) Dikusar, E. A.; Potkin, V. I.; Kozlov, N. G.; Yuvchenko, A. P.
Synthesis of N,N′-bis-[3-alkoxy-4-(hydroxy, alkoxy, acyloxy)-phenyl-
methylene- and -Phenylmethyl]-1,3-phenylenediamines. Russ. J. Gen.
Chem. 2009, 79, 258−263.
(35) Chiba, S.; Zhang, L.; Lee, J.-Y. Copper-Catalyzed Synthesis of
Azaspirocyclohexadienones from α-Azido-N-arylamides under an
́
́
́
see: (d) Patonay, T.; Konya, K.; Juhasz-Toth, E. Syntheses and
Transformations of α-Azido Ketones and Related Derivatives. Chem.
Soc. Rev. 2011, 40, 2797−2847.
(23) For the nucleophilicity of hydrazines and hydrazides, see: Nigst,
T. A.; Antipova, A.; Mayr, H. Nucleophilic Reactivities of Hydrazines
and Amines: The Futile Search for the α-Effect in Hydrazine
Reactivities. J. Org. Chem. 2012, 77, 8142−8155.
(24) (a) Clark, J. H. Fluoride Ion as a Base in Organic Synthesis. Chem.
Rev. 1980, 80, 429−452. (b) Hanessian, S.; Devasthale, P. V.
Generation of Functional Diversity via Nitroaldol Condensations of
α-Aminoacid Aldehydes  A New and Stereocontrolled Route to
Acyclic 1,3-Diamino-2-Alcohols. Tetrahedron Lett. 1996, 37, 987−990.
(c) Okutani, M.; Mori, Y. Conversion of Bromoalkenes into Alkynes by
Wet Tetra-n-Butylammonium Fluoride. J. Org. Chem. 2009, 74, 442−
444. (d) Sikervar, V.; Fleet, J. C.; Fuchs, P. L. Fluoride-Mediated
Elimination of Allyl Sulfones: Application to the Synthesis of a 2,4-
Dimethyl-A-ring Vitamin D3 Analogue. J. Org. Chem. 2012, 77, 5132−
5138.
(25) (a) Shu, W.-M.; Ma, J.-R.; Zheng, K.-L.; Sun, H.-Y.; Wang, M.;
Yang, Y.; Wu, A.-X. One-Pot Synthesis of Polyfunctional Pyrazoles: An
Easy Access to α-Diazoketones from Arylglyoxal Monohydrates and
Tosylhydrazine. Tetrahedron 2014, 70, 9321−9329. (b) Shu, W.-M.;
Zheng, K.-L.; Ma, J.-R.; Sun, H.-Y.; Wang, M.; Wu, A.-X. Convenient
Access to Polyfunctional Pyrazoles via a Highly Efficient and
Oxygen Atmosphere. J. Am. Chem. Soc. 2010, 132, 7266−7267.
́
́
́
́
(36) Patonay, T.; Juhasz-Toth, E.; Benyei, A. Base-Induced Coupling
of α-Azido Ketones with Aldehydes - An Easy and Efficient Route to
Trifunctionalized Synthons 2-Azido-3-Hydroxy Ketones, 2-Acylazir-
idines, and 2-Acylspiroaziridines. Eur. J. Org. Chem. 2002, 2002, 285−
295.
(37) Prakash, O.; Pannu, K.; Prakash, R.; Batra, A. [Hydroxy-
(tosyloxy)iodo]benzene Mediated α-Azidation of Ketones. Molecules
2006, 11, 523−527.
R
DOI: 10.1021/acs.joc.8b02074
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(38) Zurwerra, D.; Gertsch, J.; Altmann, K. H. Synthesis of
(−)-Dactylolide and 13-Desmethylene-(−)-dactylolide and Their
Effects on Tubulin. Org. Lett. 2010, 12, 2302−2305.
(39) Sallouh, O.; Weberskirch, R. Facile Formation of Hydrogels by
Using Functional Precursor Polymers and the Chemoselective
Staudinger Coupling. Polymer 2016, 86, 189−196.
S
DOI: 10.1021/acs.joc.8b02074
J. Org. Chem. XXXX, XXX, XXX−XXX